To date, no prospective randomized study has evaluated hypomethylating agents against intensive chemotherapy. Proponents of hypomethylating agents argue that they have a lower toxicity profile, allowing patients to receive therapy on an outpatient basis, and that the lower complete response rates do not necessarily translate into lower survival rates. This may be particularly relevant for older MDS patients, who are at higher risk of morbidity from intensive chemotherapy. (Scott & Estey, 2008).

#### **9.9 Autologous stem cell transplantation**

Intensive chemotherapy with AML-like schedules followed by autologous stem cell transplantation may provide an alternative option for patients lacking a suitable donor. Intensive chemotherapy results in complete remission rates of 15-65%. The median remission duration without stem cell transplantation is usually short due to a high incidence of early relapses. In view of the high relapse rate after chemotherapy alone transplantation with autologous stem cells after remission induction and consolidation chemotherapy has been applied in various clinical studies.

Autologous SCT has been extremely investigated in MDS. It is limited to patients who have achieved a CR, can be harvested, and are candidates for the procedure. Autologous SCT after successful induction chemotherapy may increase the proportion of long-term survivors, thus improving CR duration in some patients with MDS, particularly in younger patients in remission. Results for older patients are unsatisfactory. The relapse rate is up to 75%, with a 2-year probability of disease-free survival of only 25% for patients 40-60 years of age (Meletis & Terpos, 2009).

Autologous peripheral stem cells (PB) result in faster hematopoietic recovery, but may be associated with a higher risk of relapse than bone marrow stem cells. In a study comparing 336 patients transplanted with either bone marrow (BM) (n=104) or PB (n=232). In the multivariate Cox model, the event-free survival was not different after PB or BM HSCT. The relapse risk after transplantation with stem cells from either source was similar. A significant interaction between age and the source of stem cells indicated a more favorable potential of autologous PB HSCT in young age groups. As autologous PB and BM HSCT result in equivalent outcomes, given the more rapid hematopoietic recovery PB is the preferred source of stem cells (de Witte et al., 2006).

According to the final results of a prospective randomized European Intergroup Trial (EORTC-06961) autologous stem cell transplantation does not provide longer survival than intensive chemotherapy (de Witte et al., 2010). Therefore, there is very limited enthusiasm for the future of autologous SCT in the management of MDS patients.

Patients with therapy-related MDS/AML had a significantly better disease-free survival than did those with the other categories of disease, even after adjustment for confounding factors in the Cox model, including interval between diagnosis and transplantation. The explanation of this unexpected outcome is not straightforward, but the contribution of patients with favorable cytogenetic characteristics might be relevant. We identified eight patients with t(8;21) or inversion 16 in an incomplete and ongoing analysis. The 3-year disease-free survival of these patients was 57% (de Witte et al., 2007).

#### **9.10 Allogeneic stem cell transplantation**

Despite the approval of three novel agents for MDS, allogeneic stem cell transplantation (alloSCT) is the only curative treatment modality for MDS patients. Allogeneic SCT replaces

To date, no prospective randomized study has evaluated hypomethylating agents against intensive chemotherapy. Proponents of hypomethylating agents argue that they have a lower toxicity profile, allowing patients to receive therapy on an outpatient basis, and that the lower complete response rates do not necessarily translate into lower survival rates. This may be particularly relevant for older MDS patients, who are at higher risk of morbidity

Intensive chemotherapy with AML-like schedules followed by autologous stem cell transplantation may provide an alternative option for patients lacking a suitable donor. Intensive chemotherapy results in complete remission rates of 15-65%. The median remission duration without stem cell transplantation is usually short due to a high incidence of early relapses. In view of the high relapse rate after chemotherapy alone transplantation with autologous stem cells after remission induction and consolidation chemotherapy has

Autologous SCT has been extremely investigated in MDS. It is limited to patients who have achieved a CR, can be harvested, and are candidates for the procedure. Autologous SCT after successful induction chemotherapy may increase the proportion of long-term survivors, thus improving CR duration in some patients with MDS, particularly in younger patients in remission. Results for older patients are unsatisfactory. The relapse rate is up to 75%, with a 2-year probability of disease-free survival of only 25% for patients 40-60 years of

Autologous peripheral stem cells (PB) result in faster hematopoietic recovery, but may be associated with a higher risk of relapse than bone marrow stem cells. In a study comparing 336 patients transplanted with either bone marrow (BM) (n=104) or PB (n=232). In the multivariate Cox model, the event-free survival was not different after PB or BM HSCT. The relapse risk after transplantation with stem cells from either source was similar. A significant interaction between age and the source of stem cells indicated a more favorable potential of autologous PB HSCT in young age groups. As autologous PB and BM HSCT result in equivalent outcomes, given the more rapid hematopoietic recovery PB is the

According to the final results of a prospective randomized European Intergroup Trial (EORTC-06961) autologous stem cell transplantation does not provide longer survival than intensive chemotherapy (de Witte et al., 2010). Therefore, there is very limited enthusiasm

Patients with therapy-related MDS/AML had a significantly better disease-free survival than did those with the other categories of disease, even after adjustment for confounding factors in the Cox model, including interval between diagnosis and transplantation. The explanation of this unexpected outcome is not straightforward, but the contribution of patients with favorable cytogenetic characteristics might be relevant. We identified eight patients with t(8;21) or inversion 16 in an incomplete and ongoing analysis. The 3-year

Despite the approval of three novel agents for MDS, allogeneic stem cell transplantation (alloSCT) is the only curative treatment modality for MDS patients. Allogeneic SCT replaces

from intensive chemotherapy. (Scott & Estey, 2008).

preferred source of stem cells (de Witte et al., 2006).

**9.10 Allogeneic stem cell transplantation**

for the future of autologous SCT in the management of MDS patients.

disease-free survival of these patients was 57% (de Witte et al., 2007).

**9.9 Autologous stem cell transplantation**

been applied in various clinical studies.

age (Meletis & Terpos, 2009).

recipient dysplastic hemopoiesis with healthy donor haemopoiesis and immune system with an attendant graft-versus-leukemia (GvL) effect. Its applicability, however, is limited by the age of MDS patients, high rates of transplant-related mortality (TRM) and availability of a suitable HLA-matched donor. MDS is currently the third most common indication for alloSCT. As the disease is most frequent in the older population, the oftener use and acceptance of reduced-intensity conditioning (RIC) made the procedure more increased.

There are several unresolved issues in connection with transplantation. These are the impact of pre-transplant tumor debulking, the optimal timing and the transplantation of older patients and of those with co-morbidities, and also the issue of post-transplant maintaining therapy. The main difficulty is whether can we identify a subset of patients that could benefit from early transplantation and also a subset that are anticipated not going to benefit from alloSCT. Recent efforts to optimize the curative potential of transplant have focused on pretransplant therapy options, the use of predictive models to improve patient selection, and transplant modifications using reduced conditioning intensity.

Dependent upon disease status at the time of transplantation, 30% to 70% of patients can be expected to be cured of their disease and survive long term. However, posttransplant relapse and graft-versus-host disease (GvHD) remain problems (Bartenstein & Deeg, 2010). No prospective randomized controlled trials have directly compared non-transplant therapies with SCT for MDS.

As more than 50% of the patients will fail to benefit from this treatment approach either due to TRM or to relapse after transplantation being mindful of patient selection is a main issue in decision making.

#### **9.10.1 Patient selection and decision making**

However, as the majority of patients with MDS are in the seventh or eighth decade of life careful consideration must be made to determine whether the patient is a candidate for alloSCT. Only approximately 5-10% of higher risk MDS patients are alloSCT candidates.

Features to consider for alloSCT include the patient's age and IPSS score (moreover WPSS), performance status, co-morbid conditions, availability of a suitable donor (Warlick, 2010; Malcovati et al., 2005; Cutler, 2010a, 2010b;).

The proper assessment of co-morbidities becomes more important. A useful tool is hematopoietic cell transplantation co-morbidity index (HCTCI) developed by Sorror et a. (Sorror et al., 2005). It has been shown to have a predictive utility on survival also in MDS, even in case of patients getting only best supportive care (Zipperer et al., 2009). According to a study on 172 MDS patients assessing the impact of co-morbidities on survival and the prognostic utility of co-morbidity scores patients with an HCTCI of 0 had a median survival time of 68 months, those with an HCTCI of 1 or 2 lived for 34 months, and those with an HCTCI of ≥3 survived for 25 months. The HCTCI was able to further subdivide the IPSS intermediate-2 and high-risk groups. For patients in the IPSS intermediate-1 and low-risk groups, the HCTCI provided no additional prognostic information. The presence of pulmonary disease, gastrointestinal tract ulcers, cardiac disorders, and infection were independent prognostic factors for survival. HCTCI yielded prognostic information independent of the IPSS (Zipperer et al., 2009).

It is also important to determine whether the patient's marrow blast count is sufficiently low. Data suggest that patients with 5–20% marrow blasts have only 25-28% 5-year overall

Treatment Options in Myelodysplastic Syndromes 303

According to the retrospective registry study of de Witte *et al*. low risk patients benefited by early transplantation (within one year after diagnosis) versus more than 12 months from diagnosis. Estimated four-year overall survival was 57 % versus 47% (de Witte et al., 2010). Beside the IPSS there are also important clinical events such as a new transfusion requirement, recurrent infection, or recurrent bleeding episodes that could be considered triggers to move on to transplantation. Transfusion requirement is a very strong predictor of the advantage of early transplantation. WPSS incorporates transfusion dependence into the score, and enables a dynamic assessment of prognosis during the time-course of the disease. WPSS appears more useful than IPSS particularly with respect to patients with low-risk disease (Malcovati et al., 2007). Presumably, identification of newer prognostic markers, using cytogenetic, immunophenotypic, and molecular techniques will enable further improvement in terms of risk stratification and help to clarify the optimal timing for

Standard myeloablative conditioning (SMC) results in high treatment-related mortality. While a high proportion of patients can achieve long-term disease control when undergoing transplantation in early phases of the disease using SMC, transplantation-related deaths account for 20% to 30% of treatment failures with such type of conditioning regimens

A combination of busulfan (Bu) and cyclophosphamide (Cy) has been used as a standard myeloablative regimen for alloSCT. Recent studies postulate that fludarabine (Flu) is a less toxic substitute for Cy. Lee *et al.* compared the two regimens (BuCy vs BuFlu) and showed that there was no significant intergroup difference in the time of engraftment, nausea/vomiting, acute/chronic graft-versus-host disease, hepatic veno-occlusive disease, or hemorrhagic cystitis. Moreover, the 2 groups showed no significant difference in the cumulative risk of relapse, event-free survival, or overall survival (Lee et al., 2010; Kindwall-

As the vast majority of MDS patients are over 60, using SMC is rarely an option. Conditioning regimens with less toxicity for alloSCT are being developed and should be

It has been well established that for many malignancies the curative potential of allogeneic transplantation is, in large part, due to the graft versus malignancy (GVM) effect. This has led to the development of less toxic, nonmyeloablative, and reduced intensity transplantation regimens that would provide donor cell engraftment and generation of a GVM effect. This approach has allowed treatment of older and debilitated patients who have been considered ineligible for transplantation using myeloablative regimens (de Lima

Reduced-intensity conditioning regimens (these regimens cannot be safely administered without stem cell support) usually involve a combination of a purine analog (primarily fludarabine) with an alkylating agent (usually melphalan or busulfan). These reducedintensity regimens are generally considered to include less than 16 mg/kg busulfan or less than 10 Gy total body irradiation (Giralt et al., 1999, 2001). They have been usually associated with prompt engraftment of donor cells procured from both HLA-matched related and unrelated donors, while the truly nonablative regimens (NMA; can be given

available for a higher proportion of patients, particularly those who are elderly.

transplantation, particularly for patients with low-risk disease.

**9.10.3 Conditioning regimen**

Keller & Isola, 2009).

et al., 2004; Gale & Champlin, 1984).

(Bearman et al., 1988; de Lima et al., 2004).

survival whereas lower risk patients (based on WPSS risk score) do well with alloSCT, with a 5-year overall survival of 80% (Alessandrino et al., 2008).

Table 3. Two-year NRM, relapse, OS, and RFS incidences among 4 risk groups of nonmyeloablative and myeloablative patients with AML or MDS. Donors were either related (n=301) or unrelated (n=276) (Sorror et al., 2005).

#### **9.10.2 Appropriate timing of alloSCT**

The timing of transplantation has always been the most controversial topic of discussion for both patients and physicians. The lack of prospective data adds to the doubtfulness in this topic. Faced with the uncertainty of transplantation outcomes but the certainty of eventual MDS disease progression, decisions are often made based on patient preference. It is clear that there is inherent bias in these types of analyses, because the patients included are often selected and represent the best transplant candidates.

To address the shortcomings of these and other biased retrospective analyses, a Markov decision model was generated to best understand how treatment decisions would affect overall outcome in large cohorts of patients with newly diagnosed MDS (Cutler et al., 2004). The decision model was designed to determine if transplantation at the time of initial diagnosis, delayed a fixed number of years, or at the time of leukemic transformation was the optimal usage strategy for transplantation. Using data from several large, nonoverlapping databases, it was demonstrated that the optimal treatment strategy for patients with low- and intermediate-1-risk IPSS disease categories was to delay transplantation until the time of leukemic progression. Immediate transplantation was recommended for patients with high- and intermediate-2-risk IPSS scores (Cutler et al., 2004). However, a major limitation of this study is that it excluded patients over the age of 60 and focused solely on myeloablative conditioning.

survival whereas lower risk patients (based on WPSS risk score) do well with alloSCT, with

Myeloablative

Nonmyeloablative

Myeloablative

Nonmyeloablative

Nonmyeloablative

Nonmyeloablative

The timing of transplantation has always been the most controversial topic of discussion for both patients and physicians. The lack of prospective data adds to the doubtfulness in this topic. Faced with the uncertainty of transplantation outcomes but the certainty of eventual MDS disease progression, decisions are often made based on patient preference. It is clear that there is inherent bias in these types of analyses, because the patients included are often

To address the shortcomings of these and other biased retrospective analyses, a Markov decision model was generated to best understand how treatment decisions would affect overall outcome in large cohorts of patients with newly diagnosed MDS (Cutler et al., 2004). The decision model was designed to determine if transplantation at the time of initial diagnosis, delayed a fixed number of years, or at the time of leukemic transformation was the optimal usage strategy for transplantation. Using data from several large, nonoverlapping databases, it was demonstrated that the optimal treatment strategy for patients with low- and intermediate-1-risk IPSS disease categories was to delay transplantation until the time of leukemic progression. Immediate transplantation was recommended for patients with high- and intermediate-2-risk IPSS scores (Cutler et al., 2004). However, a major limitation of this study is that it excluded patients over the age of

Table 3. Two-year NRM, relapse, OS, and RFS incidences among 4 risk groups of nonmyeloablative and myeloablative patients with AML or MDS. Donors were either

related (n=301) or unrelated (n=276) (Sorror et al., 2005).

selected and represent the best transplant candidates.

60 and focused solely on myeloablative conditioning.

**(%)**

(n=138) 11 14 78 75

(n=28) 4 33 70 63

(n=176) 24 34 51 43

(n=34) 3 42 57 56

(n=19) 27 37 41 36

(n=44) 29 49 29 23

Myeloablative (n=52) 32 27 45 41

Myeloablative (n=86) 46 34 24 20

**Relapse (%)**

**OS (%)**  **RFS (%)**

a 5-year overall survival of 80% (Alessandrino et al., 2008).

Group I (HCT-CI scores 0–2 and low-

Group II (HCT-CI scores 0–2 and intermediate and high-risk diseases)

Group III (HCT-CI scores ≥ 3 and

Group IV (HCT-CI scores ≥ 3 and intermediate and high-risk diseases)

**9.10.2 Appropriate timing of alloSCT**

risk diseases)

low-risk diseases)

**Risk groups Patients NRM**

According to the retrospective registry study of de Witte *et al*. low risk patients benefited by early transplantation (within one year after diagnosis) versus more than 12 months from diagnosis. Estimated four-year overall survival was 57 % versus 47% (de Witte et al., 2010). Beside the IPSS there are also important clinical events such as a new transfusion requirement, recurrent infection, or recurrent bleeding episodes that could be considered triggers to move on to transplantation. Transfusion requirement is a very strong predictor of the advantage of early transplantation. WPSS incorporates transfusion dependence into the score, and enables a dynamic assessment of prognosis during the time-course of the disease. WPSS appears more useful than IPSS particularly with respect to patients with low-risk disease (Malcovati et al., 2007). Presumably, identification of newer prognostic markers, using cytogenetic, immunophenotypic, and molecular techniques will enable further improvement in terms of risk stratification and help to clarify the optimal timing for transplantation, particularly for patients with low-risk disease.

#### **9.10.3 Conditioning regimen**

Standard myeloablative conditioning (SMC) results in high treatment-related mortality. While a high proportion of patients can achieve long-term disease control when undergoing transplantation in early phases of the disease using SMC, transplantation-related deaths account for 20% to 30% of treatment failures with such type of conditioning regimens (Bearman et al., 1988; de Lima et al., 2004).

A combination of busulfan (Bu) and cyclophosphamide (Cy) has been used as a standard myeloablative regimen for alloSCT. Recent studies postulate that fludarabine (Flu) is a less toxic substitute for Cy. Lee *et al.* compared the two regimens (BuCy vs BuFlu) and showed that there was no significant intergroup difference in the time of engraftment, nausea/vomiting, acute/chronic graft-versus-host disease, hepatic veno-occlusive disease, or hemorrhagic cystitis. Moreover, the 2 groups showed no significant difference in the cumulative risk of relapse, event-free survival, or overall survival (Lee et al., 2010; Kindwall-Keller & Isola, 2009).

As the vast majority of MDS patients are over 60, using SMC is rarely an option. Conditioning regimens with less toxicity for alloSCT are being developed and should be available for a higher proportion of patients, particularly those who are elderly.

It has been well established that for many malignancies the curative potential of allogeneic transplantation is, in large part, due to the graft versus malignancy (GVM) effect. This has led to the development of less toxic, nonmyeloablative, and reduced intensity transplantation regimens that would provide donor cell engraftment and generation of a GVM effect. This approach has allowed treatment of older and debilitated patients who have been considered ineligible for transplantation using myeloablative regimens (de Lima et al., 2004; Gale & Champlin, 1984).

Reduced-intensity conditioning regimens (these regimens cannot be safely administered without stem cell support) usually involve a combination of a purine analog (primarily fludarabine) with an alkylating agent (usually melphalan or busulfan). These reducedintensity regimens are generally considered to include less than 16 mg/kg busulfan or less than 10 Gy total body irradiation (Giralt et al., 1999, 2001). They have been usually associated with prompt engraftment of donor cells procured from both HLA-matched related and unrelated donors, while the truly nonablative regimens (NMA; can be given

Treatment Options in Myelodysplastic Syndromes 305

conditioning resulted in inferior disease-free survival (DFS) and OS, but there was no difference in DFS and OS between RIC and SMC regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. These data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles

The addition of alemtuzumab to a RIC regimen dramatically reduces the incidence of acute and chronic GVHD in patients with AML and MDS undergoing allogeneic transplantation, while TRM, relapse risk, OS and DFS are not affected (van Besien et al., 2009). In another study using alemtuzumab-based RIC alloSCT the 3-year non-relapse mortality (NRM) was 31%, DFS was 41% and overall survival (OS) was 46%. Comorbidity scoring and performance status have been suggested as strategies to guide dose adjustment and to identify fit 65- to 70-year-old patients who can tolerate myeloablative conditioning while those with comorbidities receive less intense regimens. HCT-CI was found to be an independent variable affecting 3-year NRM, DFS and OS, indicating that the HCT-CI provides an important means of stratifying patients with a high risk of inferior transplant

The median age of diagnosis for patients with MDS is 76 years of age with 86% of patients older than 60 years. The NCCN Practice Guidelines, as well as recent expert reviews, recommend alloSCT for patients with high-risk MDS without making any age restrictions (Greenberg, 2010). However, registry analysis show that few patients older than 65 years are

There are no randomized controlled clinical trials evaluating the role of alloSCT for the treatment of elderly (> 60 years old) patients with intermediate- to high-risk MDS. The

Lim *et al.* recently published the results of their retrospective survey. Transplant outcomes of 1333 patients with MDS older than 50 years were reported to the European Group for Bone Marrow Transplant. The median age was 56 (range, 50 to 74) with 34% of patients being older than 60 years, 52% having advanced disease at the time of transplant and 62% receiving a RIC regimen. Overall survival for the whole group was 31% at 4 years, with 63% of patients dying of nonrelapse causes. The nonrelapse mortality rate was 36% at 4 years with no significant difference demonstrated in patients older or younger than 60 years. Patients receiving a myeloablative conditioning regimen had a higher risk of transplantrelated mortality than those receiving an RIC regimen (44% *v* 32%). Relapse rates were higher in patients receiving RIC regimens than those receiving myeloablative conditioning (41% *v* 33%). In their multivariate analysis, age was not a significant factor for clinical outcomes of relapse or survival. Significant factors associated with nonrelapse mortality included type of conditioning, advanced disease at transplantation, and donor type. The 4 year overall survival estimate was not significantly different between those < 60 years old and those > 60 years old. However, relapse rate was increased in the > 60-year-old cohort (32% vs 41%). Finally, relapse rate and survival were significantly affected by poor-risk

Two studies address the question of age and outcomes after transplantation.

for both regimen intensity and graft vs leukemia in these diseases (Luger et al., 2011).

outcomes (Lim et al., 2010a; Artz et al., 2006).

highest level of evidence is prospective cohort studies.

**9.10.4 AlloSCT for the elderly**

actually undergoing this procedure.

cytogenetics (Lim, et al., 2010b).

routinely without stem cell support, with neutrophil recovery within 28 days) have been associated with a varying degree of mixed chimerism and a higher risk of primary and secondary graft failures (de Lima et al., 2004).

However, there are currently no completed prospective randomized controlled studies comparing outcomes of RIC to myeloablating conditioning. The best insight into differences in outcome comes from large registry-based retrospective studies. These studies demonstrate that the use of RIC is associated with a reduction in transplant-related mortality but an increased risk of disease relapse. (Horwitz, 2011).

Based on recent relevant data regarding RIC for transplantation (Laport et al., 2008; McClune et al., 2010), patient age and disease status generally dictate the type of conditioning to be utilized. For example, those relatively older patients (i.e. >50 or 60 years) with <10% marrow blasts would generally be recommended to receive RIC, whereas younger patients with a higher marrow blast burden would generally be recommended to receive standard conditioning. Regimens assessing novel approaches to RIC for MDS are being evaluated (Pagel et al, 2009).

At MD Anderson Cancer Center a retrospective analysis of transplantation outcomes was performed to determine whether in AML and MDS a reduced-intensity conditioning regimen would result in lower relapse rates than a truly nonablative regimen. Patients were included in this study if they had either AML or high-risk MDS and had undergone an alloSCT from an HLA-compatible donor with either a truly nonablative regimen of fludarabine, cytarabine (araC), and idarubicin (FAI) or with a RIC regimen with fludarabine in combination with melphalan 140 or 180 mg/m2 (FM140 or FM180). FAI was intended to be the treatment of choice for older patients (> 55 years) with early disease, having sibling donors and who were in remission, and with a high risk of relapse. The 2 doses of melphalan were investigated in an attempt to minimize toxicities observed with FM180. The lower age limit for participation in the FM studies was 55 years, but younger patients with organ dysfunction that made them ineligible for high-dose treatment protocols were also eligible. Both related and unrelated donors were allowed. Patients with more advanced disease were preferably treated with FM in order to provide higher dose intensity in the preparative regimen. The 3-year cumulative incidence of non–relapse-related mortality was significantly higher after conditioning with FM than with FAI. Conversely, the 3-year cumulative incidence of relapse-related mortality was higher after FAI than after FM. The analysis suggests that disease recurrence is more frequent in patients receiving the truly nonablative regimen as compared with those receiving the reduced-intensity regimen of fludarabine and melphalan. for AML and MDS both cytoreduction of the preparative regimen as well as GVM contribute to disease control after allografting with reducedintensity or nonablative conditioning regimens. The relative importance of these mechanisms, however, may differ with regimens other than those tested here. Truly nonablative regimens may be effective in minimal disease states or for diseases highly sensitive to GVM effects and may provide a platform for innovative cell therapy approaches that may obviate the need for direct cytoreduction of the malignancy (de Lima et al., 2004; Virchis et al., 2004).

There are studies intented to compare outcomes with different conditioning approaches. The relative efficacy of 3731 SMC transplant were compared with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004 on AML/MDS patients. NMA

routinely without stem cell support, with neutrophil recovery within 28 days) have been associated with a varying degree of mixed chimerism and a higher risk of primary and

However, there are currently no completed prospective randomized controlled studies comparing outcomes of RIC to myeloablating conditioning. The best insight into differences in outcome comes from large registry-based retrospective studies. These studies demonstrate that the use of RIC is associated with a reduction in transplant-related

Based on recent relevant data regarding RIC for transplantation (Laport et al., 2008; McClune et al., 2010), patient age and disease status generally dictate the type of conditioning to be utilized. For example, those relatively older patients (i.e. >50 or 60 years) with <10% marrow blasts would generally be recommended to receive RIC, whereas younger patients with a higher marrow blast burden would generally be recommended to receive standard conditioning. Regimens assessing novel approaches to RIC for MDS are

At MD Anderson Cancer Center a retrospective analysis of transplantation outcomes was performed to determine whether in AML and MDS a reduced-intensity conditioning regimen would result in lower relapse rates than a truly nonablative regimen. Patients were included in this study if they had either AML or high-risk MDS and had undergone an alloSCT from an HLA-compatible donor with either a truly nonablative regimen of fludarabine, cytarabine (araC), and idarubicin (FAI) or with a RIC regimen with fludarabine in combination with melphalan 140 or 180 mg/m2 (FM140 or FM180). FAI was intended to be the treatment of choice for older patients (> 55 years) with early disease, having sibling donors and who were in remission, and with a high risk of relapse. The 2 doses of melphalan were investigated in an attempt to minimize toxicities observed with FM180. The lower age limit for participation in the FM studies was 55 years, but younger patients with organ dysfunction that made them ineligible for high-dose treatment protocols were also eligible. Both related and unrelated donors were allowed. Patients with more advanced disease were preferably treated with FM in order to provide higher dose intensity in the preparative regimen. The 3-year cumulative incidence of non–relapse-related mortality was significantly higher after conditioning with FM than with FAI. Conversely, the 3-year cumulative incidence of relapse-related mortality was higher after FAI than after FM. The analysis suggests that disease recurrence is more frequent in patients receiving the truly nonablative regimen as compared with those receiving the reduced-intensity regimen of fludarabine and melphalan. for AML and MDS both cytoreduction of the preparative regimen as well as GVM contribute to disease control after allografting with reducedintensity or nonablative conditioning regimens. The relative importance of these mechanisms, however, may differ with regimens other than those tested here. Truly nonablative regimens may be effective in minimal disease states or for diseases highly sensitive to GVM effects and may provide a platform for innovative cell therapy approaches that may obviate the need for direct cytoreduction of the malignancy (de Lima et al., 2004;

There are studies intented to compare outcomes with different conditioning approaches. The relative efficacy of 3731 SMC transplant were compared with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004 on AML/MDS patients. NMA

secondary graft failures (de Lima et al., 2004).

being evaluated (Pagel et al, 2009).

Virchis et al., 2004).

mortality but an increased risk of disease relapse. (Horwitz, 2011).

conditioning resulted in inferior disease-free survival (DFS) and OS, but there was no difference in DFS and OS between RIC and SMC regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. These data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases (Luger et al., 2011).

The addition of alemtuzumab to a RIC regimen dramatically reduces the incidence of acute and chronic GVHD in patients with AML and MDS undergoing allogeneic transplantation, while TRM, relapse risk, OS and DFS are not affected (van Besien et al., 2009). In another study using alemtuzumab-based RIC alloSCT the 3-year non-relapse mortality (NRM) was 31%, DFS was 41% and overall survival (OS) was 46%. Comorbidity scoring and performance status have been suggested as strategies to guide dose adjustment and to identify fit 65- to 70-year-old patients who can tolerate myeloablative conditioning while those with comorbidities receive less intense regimens. HCT-CI was found to be an independent variable affecting 3-year NRM, DFS and OS, indicating that the HCT-CI provides an important means of stratifying patients with a high risk of inferior transplant outcomes (Lim et al., 2010a; Artz et al., 2006).

#### **9.10.4 AlloSCT for the elderly**

The median age of diagnosis for patients with MDS is 76 years of age with 86% of patients older than 60 years. The NCCN Practice Guidelines, as well as recent expert reviews, recommend alloSCT for patients with high-risk MDS without making any age restrictions (Greenberg, 2010). However, registry analysis show that few patients older than 65 years are actually undergoing this procedure.

There are no randomized controlled clinical trials evaluating the role of alloSCT for the treatment of elderly (> 60 years old) patients with intermediate- to high-risk MDS. The highest level of evidence is prospective cohort studies.

Two studies address the question of age and outcomes after transplantation.

Lim *et al.* recently published the results of their retrospective survey. Transplant outcomes of 1333 patients with MDS older than 50 years were reported to the European Group for Bone Marrow Transplant. The median age was 56 (range, 50 to 74) with 34% of patients being older than 60 years, 52% having advanced disease at the time of transplant and 62% receiving a RIC regimen. Overall survival for the whole group was 31% at 4 years, with 63% of patients dying of nonrelapse causes. The nonrelapse mortality rate was 36% at 4 years with no significant difference demonstrated in patients older or younger than 60 years. Patients receiving a myeloablative conditioning regimen had a higher risk of transplantrelated mortality than those receiving an RIC regimen (44% *v* 32%). Relapse rates were higher in patients receiving RIC regimens than those receiving myeloablative conditioning (41% *v* 33%). In their multivariate analysis, age was not a significant factor for clinical outcomes of relapse or survival. Significant factors associated with nonrelapse mortality included type of conditioning, advanced disease at transplantation, and donor type. The 4 year overall survival estimate was not significantly different between those < 60 years old and those > 60 years old. However, relapse rate was increased in the > 60-year-old cohort (32% vs 41%). Finally, relapse rate and survival were significantly affected by poor-risk cytogenetics (Lim, et al., 2010b).

Treatment Options in Myelodysplastic Syndromes 307

analysis, patients with high-risk disease (blasts >5% and International Prognostic scoring system (IPSS) intermediate-2 or high in MDS) had significant poorer DFS. In spite of high NRM, these data indicate that UCBT is an acceptable alternative option to treat adults with high-risk MDS or sAML, without a suitable human leukocyte antigen (HLA)-

The rate of related versus unrelated donor is also changing. The percentage of older patients

A study compared allogeneic sibling-matched SCT data in MDS patients ≤60 years old to clinical outcomes of age-matched non-treated comparable stage MDS patients. Markov decision-making statistical analysis indicated that higher risk IPSS patients ≤60 years old should proceed to such human leucocyte antigen (HLA) identical sibling transplants at diagnosis, whereas for those lower risk MDS patients, delaying transplantation for several

According to newer studies minor HLA disparity in unrelated compared to related donors could have a significant impact on transplant outcomes. To assess whether use of unrelated donors (URD) engenders more potent graft versus leukaemia effect in RIC alloSCT compared to matched related donors (MRD), a retrospective study has been performed Dana-Farber Cancer Institute on patients with different haematological malignancies including 66 MDS patients (Ho et al., 2010). Patients received uniformly fludarabine and intravenous busulfan conditioning, and GVHD prophylaxis with tacrolimus/minimethroxate (mini-MTX) or tacrolimus/sirolimus ± mini-MTX. URD was associated with a

The most important factors for TRM are age, co-morbidities, donor selection and intensity of the conditioning regimen. A careful donor selection and an appropriate choice of

On the other hand preferring RIC as preparative regimen, the incidence of relapse will be higher. So effords are made to reduce relapse rate. Either improving of the pretransplant remission status or by using post-transplant strategies, such as maintenance or consolidation

In addition to age, the cytogenetic risk score remained an independent prognostic factor for relapse. Lenalidomide has shown activity in terms of resolution of chromosomal abnormalities, especially in isolated 5q- but also in complex abnormalities involving 5q-. There are also some observations that MDS patients with poor cytogenetic abnormalities

Besides improving pretransplant status of patients with MDS by inducing clinical and cytogenetic remission, further approaches to reduce the risk of relapse after alloSCT involve

Donor lymphocyte infusion (DLI) can induce durable remission in relapsing patients with hematological malignancies after alloSCT. However, the experience of DLI in patients with MDS is limited. and the role of it is unclear. In Fred Hutchinson Cancer Research Center, Washington 16 patients treated with DLI for relapsed MDS after HCT between 1993 and 2004. CR with resolution of cytopenias and prior disease markers occurred in 3 of 14 patients who could be evaluated. Two patients survived without MDS for 68 and 65 months after DLI, respectively, but died with pneumonia. Grades II-IV acute GVHD and chronic

who are receiving unrelated donor transplants is increasing (Karanes et al., 2008).

years and prior to disease progression would be beneficial (Cutler et al., 2004).

matched donor (Robin et al., 2011).

lower risk of relapse (52% versus 65%).

conditioning regimen will significantly reduce TRM.

therapies can play a role in reducing the risk of relapse (Kröger, 2008).

such as monosomy 7 may benefit from hypomethylating agents (Raj et al., 2007).

**9.10.6 Reducing relapse rate**

post-transplant modifications.

McClune *et al.* included 535 MDS patients and 545 AML patients in first complete remission registered with the Center for International Blood and Marrow Transplant Research from 1995 to 2005. All transplants were (RIC or nonmyeloablative (NMA) conditioning, in contrast to the prior study. Thirty-four percent of MDS patients and 36% of AML patients were > 60 years old. In both the MDS and AML cohorts, age did not significantly affect nonrelapse mortality, disease-free survival, or overall survival. Long-term disease control was seen in about one-third of MDS patients independent of age, supporting the curative potential of SCT for patients with MDS over the age of 60 (McClune et al., 2010).

Castagna *et al.* carried out a retrospective study of 63 patients >60 years with hematological malignancies and treated with RIC and alloSCT. Only the occurrence of aGVHD affected the TRM and OS. Acute GVHD is the main cause of TRM and more efforts should be made to reduce its incidence without sacrificing graft vs tumor effect (Castagna et al., 2010).

Umbilical cord blood (UCB) is feasible as an alternative donor source for RIC alloSCT among older patients with MDS who do not have suitable HLA-matched sibling donors (MSD). Majhail *et al*. compared outcomes of allo-SCT, using MSD or UCB among older patients (age over 55 years) with AML or MDS. All patients received a RIC regimen consisting of cyclophosphamid, fludarabine and 200 cGy TBI. Median age at alloSCT was 63 years for MSD and 61 years for UCB recipients. On multivariate analysis, donor source (MSD vs UCB) did not impact risks of OS, leukemia-free survival and relapse or treatmentrelated mortality (Majhail et al., 2011).

By means of the WPSS the impact of regular transfusion requirement (defined as requiring at least one transfusion every 8 weeks in a 4-month period) can be implicated into the risk stratification and those low-risk patients can be identified who can benefit of allo-SCT. Regular transfusion requirement is given the same regression weight as progressing to a higher cytogenetic risk group (Malcovati et al., 2007).

Based on the available evidence, transplantation for MDS in patients aged 60 or older is the only available curative therapy, but its benefit in terms of OS has not been demonstrated in randomized controlled trials. Careful patient selection may improve the results (Giralt et al., 2011; Ria et al,. 2009; Alatrash et al., 2011).

#### **9.10.5 The issue of the stem cell source and donor selection**

The patients with MDS who received peripheral blood stem cells (PBSC) had a faster engraftment and a lower relapse rate, resulting in improved DFS rates, than patients who received bone marrow stem cells (Guardiola et al., 2002). There is a shifting tendency towards to use PBSC rather than bone marrow stem cells.

Umbilical cord blood has increased access to hematopoietic cell transplantation (HCT) for patients without HLA-matched sibling donors (MSD).

A study was carried out through the Eurocord and European Group for Blood and Marrow Transplantation (EBMT) registries by Robin *et al*., aiming to evaluate the outcomes and risk factors in adult patients who underwent single or double unrelated cord blood transplantation (UCBT) for myelodysplastic syndrome (MDS) or secondary acute myeloblastic leukemia (sAML). A total of 180 adults with MDS (n=39) or sAML (n=69) were analyzed. Median age was 43 (18-72) years. In all, 77 patients (71%) received a single UCBT. Myeloablative conditioning regimen (MAC) was given to 57 (53%) patients. A 2-year non-relapse mortality (NRM) was significantly higher after MAC (62 vs 34). A 2 year DFS and overall survival (OS) were 30 and 34%, respectively. In multivariate

McClune *et al.* included 535 MDS patients and 545 AML patients in first complete remission registered with the Center for International Blood and Marrow Transplant Research from 1995 to 2005. All transplants were (RIC or nonmyeloablative (NMA) conditioning, in contrast to the prior study. Thirty-four percent of MDS patients and 36% of AML patients were > 60 years old. In both the MDS and AML cohorts, age did not significantly affect nonrelapse mortality, disease-free survival, or overall survival. Long-term disease control was seen in about one-third of MDS patients independent of age, supporting the curative

Castagna *et al.* carried out a retrospective study of 63 patients >60 years with hematological malignancies and treated with RIC and alloSCT. Only the occurrence of aGVHD affected the TRM and OS. Acute GVHD is the main cause of TRM and more efforts should be made to

Umbilical cord blood (UCB) is feasible as an alternative donor source for RIC alloSCT among older patients with MDS who do not have suitable HLA-matched sibling donors (MSD). Majhail *et al*. compared outcomes of allo-SCT, using MSD or UCB among older patients (age over 55 years) with AML or MDS. All patients received a RIC regimen consisting of cyclophosphamid, fludarabine and 200 cGy TBI. Median age at alloSCT was 63 years for MSD and 61 years for UCB recipients. On multivariate analysis, donor source (MSD vs UCB) did not impact risks of OS, leukemia-free survival and relapse or treatment-

By means of the WPSS the impact of regular transfusion requirement (defined as requiring at least one transfusion every 8 weeks in a 4-month period) can be implicated into the risk stratification and those low-risk patients can be identified who can benefit of allo-SCT. Regular transfusion requirement is given the same regression weight as progressing to a

Based on the available evidence, transplantation for MDS in patients aged 60 or older is the only available curative therapy, but its benefit in terms of OS has not been demonstrated in randomized controlled trials. Careful patient selection may improve the results (Giralt et al.,

The patients with MDS who received peripheral blood stem cells (PBSC) had a faster engraftment and a lower relapse rate, resulting in improved DFS rates, than patients who received bone marrow stem cells (Guardiola et al., 2002). There is a shifting tendency

Umbilical cord blood has increased access to hematopoietic cell transplantation (HCT) for

A study was carried out through the Eurocord and European Group for Blood and Marrow Transplantation (EBMT) registries by Robin *et al*., aiming to evaluate the outcomes and risk factors in adult patients who underwent single or double unrelated cord blood transplantation (UCBT) for myelodysplastic syndrome (MDS) or secondary acute myeloblastic leukemia (sAML). A total of 180 adults with MDS (n=39) or sAML (n=69) were analyzed. Median age was 43 (18-72) years. In all, 77 patients (71%) received a single UCBT. Myeloablative conditioning regimen (MAC) was given to 57 (53%) patients. A 2-year non-relapse mortality (NRM) was significantly higher after MAC (62 vs 34). A 2 year DFS and overall survival (OS) were 30 and 34%, respectively. In multivariate

potential of SCT for patients with MDS over the age of 60 (McClune et al., 2010).

reduce its incidence without sacrificing graft vs tumor effect (Castagna et al., 2010).

related mortality (Majhail et al., 2011).

2011; Ria et al,. 2009; Alatrash et al., 2011).

higher cytogenetic risk group (Malcovati et al., 2007).

**9.10.5 The issue of the stem cell source and donor selection**

towards to use PBSC rather than bone marrow stem cells.

patients without HLA-matched sibling donors (MSD).

analysis, patients with high-risk disease (blasts >5% and International Prognostic scoring system (IPSS) intermediate-2 or high in MDS) had significant poorer DFS. In spite of high NRM, these data indicate that UCBT is an acceptable alternative option to treat adults with high-risk MDS or sAML, without a suitable human leukocyte antigen (HLA) matched donor (Robin et al., 2011).

The rate of related versus unrelated donor is also changing. The percentage of older patients who are receiving unrelated donor transplants is increasing (Karanes et al., 2008).

A study compared allogeneic sibling-matched SCT data in MDS patients ≤60 years old to clinical outcomes of age-matched non-treated comparable stage MDS patients. Markov decision-making statistical analysis indicated that higher risk IPSS patients ≤60 years old should proceed to such human leucocyte antigen (HLA) identical sibling transplants at diagnosis, whereas for those lower risk MDS patients, delaying transplantation for several years and prior to disease progression would be beneficial (Cutler et al., 2004).

According to newer studies minor HLA disparity in unrelated compared to related donors could have a significant impact on transplant outcomes. To assess whether use of unrelated donors (URD) engenders more potent graft versus leukaemia effect in RIC alloSCT compared to matched related donors (MRD), a retrospective study has been performed Dana-Farber Cancer Institute on patients with different haematological malignancies including 66 MDS patients (Ho et al., 2010). Patients received uniformly fludarabine and intravenous busulfan conditioning, and GVHD prophylaxis with tacrolimus/minimethroxate (mini-MTX) or tacrolimus/sirolimus ± mini-MTX. URD was associated with a lower risk of relapse (52% versus 65%).

#### **9.10.6 Reducing relapse rate**

The most important factors for TRM are age, co-morbidities, donor selection and intensity of the conditioning regimen. A careful donor selection and an appropriate choice of conditioning regimen will significantly reduce TRM.

On the other hand preferring RIC as preparative regimen, the incidence of relapse will be higher. So effords are made to reduce relapse rate. Either improving of the pretransplant remission status or by using post-transplant strategies, such as maintenance or consolidation therapies can play a role in reducing the risk of relapse (Kröger, 2008).

In addition to age, the cytogenetic risk score remained an independent prognostic factor for relapse. Lenalidomide has shown activity in terms of resolution of chromosomal abnormalities, especially in isolated 5q- but also in complex abnormalities involving 5q-. There are also some observations that MDS patients with poor cytogenetic abnormalities such as monosomy 7 may benefit from hypomethylating agents (Raj et al., 2007).

Besides improving pretransplant status of patients with MDS by inducing clinical and cytogenetic remission, further approaches to reduce the risk of relapse after alloSCT involve post-transplant modifications.

Donor lymphocyte infusion (DLI) can induce durable remission in relapsing patients with hematological malignancies after alloSCT. However, the experience of DLI in patients with MDS is limited. and the role of it is unclear. In Fred Hutchinson Cancer Research Center, Washington 16 patients treated with DLI for relapsed MDS after HCT between 1993 and 2004. CR with resolution of cytopenias and prior disease markers occurred in 3 of 14 patients who could be evaluated. Two patients survived without MDS for 68 and 65 months after DLI, respectively, but died with pneumonia. Grades II-IV acute GVHD and chronic

Treatment Options in Myelodysplastic Syndromes 309

The nucleoside analog clofarabine, and the alkylating agent cloretazine are now being tested. There are several clinical trials using new agents that act at a number of different levels. There are new agents with new therapeutic targets, for example tyrosine kinase inhibitors (FLT3 inhibitors), farnesyl-transferase inhibitors (Braun & Fenaux, 2008), which are thought to target mutant ras activity, agents with c-jun modificating effect, MAP-kinase

Using combination of drugs with different and new mechanism of action may also be a novel approach. Azacitidine in combination with histone deacetylase inhibitors might offer better efficacy by modulating the methylation and acetylation states of silenced genes.

Single-agent tipifarnib (a farnesyltransferase inhibitor) in high-risk MDS patients achieves responses comparable to those of standard epigenetic therapies, including hypomethylating agents, and for this reason, farnesyltransferase inhibitors deserve further in MDS. (Braun &

**10. Recommendations for treating lower risk (IPSS low, intermediate-1 or**

Patients with del(5q) chromosomal abnormalities and symptomatic anaemia should receive

Other patientswith symptomatic anaemia with EPO level 500 mU/ml, should be treated with recombinant human EPO or darbepoetin with or without granulocyte-colony stimulatin factor (G-CSF). Non-responders should be considered for treatment with

Those anaemic patients with EPO levels 500 mU/ml should be evaluated to determine whether they have a good probability of responding to immunosuppressive therapy. For those with low probability treatment with azacitidine, decitabine or lenalidomide should be

Non-responders and those with severe cytopenias participation in a clinical trial, or allo-SCT

**11. Recommendations for treating higher risk (IPSS Intermediate-2, high-risk**

Treatment recommendations for higher risk patients depend on whether they are candidate for intensive therapy. Decision should be made by considering the patient's age, comorbidities, physiosocial status and also the patient's preference and the availability of a

For eligible patients the first choice regarding the donor source has remained an HLAmatched sibling though results with HLA-matched unrelated donors have improved to a

Patients older than 55-60 years, particularly those with less than 10 % marrow myeloblasts, would be conditioning with RIC. Patients with high blast count pretransplant debulking therapy is generally needed. Younger patients, regardless of marrow blast burden, will

For patients eligible for intensive therapy lacking a suitable donor using an intensive

**WPSS very low, low and Intermediate) MDS patients**

inhibitors, histone deacetylase inhibitors, which cause epigenetic alterations.

Silverman, 2009, Leuk res

Fenaux, 2008; Grant, 2009).

azacitidine, decitabine or lenalidomide.

**or WPSS high, very high) MDS patients**

generally receive high dose conditioning.

induction chemotherapy should be recommended.

lenalidomide.

recommended.

suitable donor.

similar level.

should be an option.

GVHD occurred after DLI in 6 (43%) and 5 (36%) patients, respectively. All three responders developed grades III-IV acute GVHD and extensive chronic GVHD after DLI. This result refers that DLI can result in CR in some patients with relapsed MDS after transplant, but long-term survival is infrequent (Campregher et al., 2007). Azacitidine combined with DLI for relapsed patients may also result remission (Czibere et al., 2010).

Maintenance therapy with azacitidine is another option. Low dose azacitidine (at 32 mg/m2) given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit (de Lima et al., 2010).

#### **9.10.7 Treatment of relapse**

Standard induction chemotherapy may be used for re-induction. The tolerability and potential of low dose azacitidine for treatment of relapsed MDS is supported by a Phase I trial (de Lima et al., 2010).

Immunotherapeutic strategies for example peptide vaccination targeting leukemiaassociated antigens, such as the Wilm's Tumor protein (WT1) (Keilholz et al., 2009) and whole cell leukemia vaccination with CD80 and IL-2 genetically modified leukemic blasts are currently the subjects of Phase I clinical trial (Ingram et al., 2009).

#### **9.10.8 The effect of iron oveload on the post-tranplantation survival**

Pre-transplantation transfusion history and serum ferritin have significant prognostic value in patients with myelodysplastic syndrome undergoing myeloablative allogeneic stem cell transplantation, inducing a significant increase of non-relapse mortality. An elevated serum ferritin (1000 g/L) has been associated with reduced OS and increased risk of infection following HSCT. Given that ferritin is an acute phase reactant, the elevated ferritin serum level alone does not considered to be a satisfactory marker of iron overload. Other biomarkers of body iron load should be taken into account to estimate the effect of iron overload on the post-transplantation survival (Pullarkat, 2010). These results indicate that transfusion history should be considered in transplantation decision-making in patients with myelodysplastic syndrome. Outcome was significantly worse in subjects receiving more than 20 red cell units.

Elevated pre-transplantation liver iron content estimated by magnetic resonance imaging (MRI) is significantly associated with inferior post-transplantation survival. There is a strong correlation between pre-transplantation serum ferritin level and liver iron content which was mostly dependent on prior transfusion history (Armand).

#### **9.11 New agents**

The past several years have brought exciting new treatments strategies for MDS. However, despite the huge progress, no curative therapy does exist exclusive of alloSCT nowadays. Furthermore, *cure* is not necessarily essential in the presence of drug therapy that can effectively control disease symptoms and prevent disease-related mortality (Tefferi, 2008; Rajkumar, 2008). Since the knowledge of molecular genetics in AML and MDS has expanded recently, targeted therapeutics should offer new possibilities for advancement (Bryan et al., 2010).

GVHD occurred after DLI in 6 (43%) and 5 (36%) patients, respectively. All three responders developed grades III-IV acute GVHD and extensive chronic GVHD after DLI. This result refers that DLI can result in CR in some patients with relapsed MDS after transplant, but long-term survival is infrequent (Campregher et al., 2007). Azacitidine combined with DLI

Maintenance therapy with azacitidine is another option. Low dose azacitidine (at 32 mg/m2) given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with

Standard induction chemotherapy may be used for re-induction. The tolerability and potential of low dose azacitidine for treatment of relapsed MDS is supported by a Phase I

Immunotherapeutic strategies for example peptide vaccination targeting leukemiaassociated antigens, such as the Wilm's Tumor protein (WT1) (Keilholz et al., 2009) and whole cell leukemia vaccination with CD80 and IL-2 genetically modified leukemic blasts

Pre-transplantation transfusion history and serum ferritin have significant prognostic value in patients with myelodysplastic syndrome undergoing myeloablative allogeneic stem cell transplantation, inducing a significant increase of non-relapse mortality. An elevated serum ferritin (1000 g/L) has been associated with reduced OS and increased risk of infection following HSCT. Given that ferritin is an acute phase reactant, the elevated ferritin serum level alone does not considered to be a satisfactory marker of iron overload. Other biomarkers of body iron load should be taken into account to estimate the effect of iron overload on the post-transplantation survival (Pullarkat, 2010). These results indicate that transfusion history should be considered in transplantation decision-making in patients with myelodysplastic syndrome. Outcome was significantly worse in subjects receiving

Elevated pre-transplantation liver iron content estimated by magnetic resonance imaging (MRI) is significantly associated with inferior post-transplantation survival. There is a strong correlation between pre-transplantation serum ferritin level and liver iron content which

The past several years have brought exciting new treatments strategies for MDS. However, despite the huge progress, no curative therapy does exist exclusive of alloSCT nowadays. Furthermore, *cure* is not necessarily essential in the presence of drug therapy that can effectively control disease symptoms and prevent disease-related mortality (Tefferi, 2008; Rajkumar, 2008). Since the knowledge of molecular genetics in AML and MDS has expanded recently, targeted therapeutics should offer new possibilities for advancement

for relapsed patients may also result remission (Czibere et al., 2010).

are currently the subjects of Phase I clinical trial (Ingram et al., 2009).

was mostly dependent on prior transfusion history (Armand).

**9.10.8 The effect of iron oveload on the post-tranplantation survival**

greater benefit (de Lima et al., 2010).

**9.10.7 Treatment of relapse**

trial (de Lima et al., 2010).

more than 20 red cell units.

**9.11 New agents**

(Bryan et al., 2010).

The nucleoside analog clofarabine, and the alkylating agent cloretazine are now being tested. There are several clinical trials using new agents that act at a number of different levels. There are new agents with new therapeutic targets, for example tyrosine kinase inhibitors (FLT3 inhibitors), farnesyl-transferase inhibitors (Braun & Fenaux, 2008), which are thought to target mutant ras activity, agents with c-jun modificating effect, MAP-kinase inhibitors, histone deacetylase inhibitors, which cause epigenetic alterations.

Using combination of drugs with different and new mechanism of action may also be a novel approach. Azacitidine in combination with histone deacetylase inhibitors might offer better efficacy by modulating the methylation and acetylation states of silenced genes. Silverman, 2009, Leuk res

Single-agent tipifarnib (a farnesyltransferase inhibitor) in high-risk MDS patients achieves responses comparable to those of standard epigenetic therapies, including hypomethylating agents, and for this reason, farnesyltransferase inhibitors deserve further in MDS. (Braun & Fenaux, 2008; Grant, 2009).

#### **10. Recommendations for treating lower risk (IPSS low, intermediate-1 or WPSS very low, low and Intermediate) MDS patients**

Patients with del(5q) chromosomal abnormalities and symptomatic anaemia should receive lenalidomide.

Other patientswith symptomatic anaemia with EPO level 500 mU/ml, should be treated with recombinant human EPO or darbepoetin with or without granulocyte-colony stimulatin factor (G-CSF). Non-responders should be considered for treatment with azacitidine, decitabine or lenalidomide.

Those anaemic patients with EPO levels 500 mU/ml should be evaluated to determine whether they have a good probability of responding to immunosuppressive therapy. For those with low probability treatment with azacitidine, decitabine or lenalidomide should be recommended.

Non-responders and those with severe cytopenias participation in a clinical trial, or allo-SCT should be an option.

#### **11. Recommendations for treating higher risk (IPSS Intermediate-2, high-risk or WPSS high, very high) MDS patients**

Treatment recommendations for higher risk patients depend on whether they are candidate for intensive therapy. Decision should be made by considering the patient's age, comorbidities, physiosocial status and also the patient's preference and the availability of a suitable donor.

For eligible patients the first choice regarding the donor source has remained an HLAmatched sibling though results with HLA-matched unrelated donors have improved to a similar level.

Patients older than 55-60 years, particularly those with less than 10 % marrow myeloblasts, would be conditioning with RIC. Patients with high blast count pretransplant debulking therapy is generally needed. Younger patients, regardless of marrow blast burden, will generally receive high dose conditioning.

For patients eligible for intensive therapy lacking a suitable donor using an intensive induction chemotherapy should be recommended.

Treatment Options in Myelodysplastic Syndromes 311

Barrett J, Sloand E Young N. 2006. Determining which patients with myelodysplastic

Bartenstein M Deeg HJ. 2010. Hematopoietic stem cell transplantation for MDS. *Hematol*

Barzi A Sekeres MA. 2010. Myelodysplastic syndromes: a practical approach to diagnosis

Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA Thomas ED.

Bello C, Yu D, Komrokji RS, Zhu W, Wetzstein GA, List AF Lancet JE. 2010. Outcomes

van Besien K, Kunavakkam R, Rondon G, De Lima M, Artz A, Oran B Giralt S. 2009.

Blum W. How much? How frequent? How long? 2010. A clinical guide to new therapies in

Boultwood J, Perry J Pellagatti A. 2010. Frequent mutation of the polycomb-associated

Braun T Fenaux P. 2008. Farnesyltransferase inhibitors and their potential role in therapy

Bryan J, Jabbour E, Prescott H, Garcia-Manero G, Issa JP Kantarjian H. 2010. Current and future management options for myelodysplastic syndromes. *Drugs*, 70,11,1381-94, Campregher PV, Gooley T, Scott BL, Moravec C, Sandmaier B, Martin PJ, Deeg HJ, Warren

Castagna L, Fürst S, Marchetti N, El Cheikh J, Faucher C, Mohty M, Bouabdallah R, Vey N,

Chamuleau ME, Westers TM, van Dreunen L, Groenland J, Zevenbergen A, Eeltink CM,

Cutler CS, Lee SJ Greenberg P. 2004. A decision analysis of allogeneic bone marrow

conditioning regimen and alloSCT. *Bone Marrow Transplant,* Oct 4,

*Blood and Marrow Transplant*,12,954–964,

and treatment. *Cleve Clin J, Med*, 77,1,37-44,

transplantation. *J Clin Oncol*,6, 1562-1568,

myelodysplastic syndrome. *Cancer*, Nov. 8,

*Oncol Clin North Am*,24,2,407-22,

*Transplant*,15,5,610-7,

*Leukemia,*524,5,1062–1065,

*Transplant,*40,10,965-71,

syndrome. *Haematologica,*94,4,496-506,

141,5,576-86,

2011. Iron Overload in Patients with Acute Leukemia or MDS Undergoing Myeloablative Stem Cell Transplantation. *Biol Blood Marrow Transplant*,6,852-60, Artz AS, Pollyea D Kocherginsky M. 2006. Performance status and comorbidity predict

transplant related mortality after allogeneic hematopoietic cell transplantation. *Biol*

syndrome will respond to immunosuppressive treatment. *Haematologica*, 91,5,583-4,

1988. Regimen-related toxicity in patients undergoing bone marrow

after induction chemotherapy in patients with acute myeloid leukemia arising from

Fludarabine-melphalan conditioning for AML and MDS: alemtuzumab reduces acute and chronic GVHD without affecting long-term outcomes. *Biol Blood Marrow*

myelodysplastic syndromes. *Hematology Am Soc Hematol Educ Program*,2010,314-21,

gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia.

for myelodysplastic syndromes and acute myeloid leukaemia. *Br J Haematol*,

EH Flowers ME. 2007. Results of donor lymphocyte infusions for relapsed myelodysplastic syndrome after hematopoietic cell transplantation. *Bone Marrow*

Stoppa AM, Esterni B Blaise D. 2010. Retrospective analysis of common scoring systems and outcome in patients older than 60 years treated with reduced-intensity

Ossenkoppele GJ van de Loosdrecht AA. 2009. Immune mediated autologous cytotoxicity against hematopoietic precursor cells in patients with myelodysplastic

transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. *Blood*,104,579–585,

For higher risk patients who are not candidate for intensive therapy the use of azacitidine, decitabine or a participation in a clinical trial should be considered.

Good supportive care should be given to every MDS patients. This may be the only therapy for those with adverse clinical features or disease progression despite antitumor therapy.

#### **12. Conclusion**

Ten years ago, there was little to offer MDS patients other than transfusion support, but since then, the approach to treating patients with MDS has undergone a progress. New therapeutic options have added to the armamentarium of MDS treatments.

Historically, treatment goals have varied based on patient risk category, with modification of disease reserved for patients in the higher-risk population and response rates being a primary endpoint. In the light of recent data the treatment paradigm should be reevaluated to focus on prolonging time to leukemic transformation and extending survival while improving quality of life. Lenalidomide can modify disease activity, the methyltransferase inhibitors have the ability to prolong survival. These are shifting the focus away from response rates alone. Azacitidine has demonstrated a sustained impact on overall survival. In addition, data suggest that treatment with these therapeutics in patients with lower-risk disease may further extend survival by altering the biology of MDS. The new treatment paradigm should aim for prolonging leukemic-free transformation and extending survival while optimizing quality of life and maintaining hematologic and cytogenetic response.

The results of stem cell transplantation for MDS continue to improve together with the outlook of patients afflicted with myelodysplasia.

The incidence of MDS is increasing parallely with the increase of the average age of the population. That gives a particular importance to the development of MDS therapy has taken place in the last decade. In the close future some more possible progress are expected.

#### **13. References**

For higher risk patients who are not candidate for intensive therapy the use of azacitidine,

Good supportive care should be given to every MDS patients. This may be the only therapy for those with adverse clinical features or disease progression despite antitumor therapy.

Ten years ago, there was little to offer MDS patients other than transfusion support, but since then, the approach to treating patients with MDS has undergone a progress. New

Historically, treatment goals have varied based on patient risk category, with modification of disease reserved for patients in the higher-risk population and response rates being a primary endpoint. In the light of recent data the treatment paradigm should be reevaluated to focus on prolonging time to leukemic transformation and extending survival while improving quality of life. Lenalidomide can modify disease activity, the methyltransferase inhibitors have the ability to prolong survival. These are shifting the focus away from response rates alone. Azacitidine has demonstrated a sustained impact on overall survival. In addition, data suggest that treatment with these therapeutics in patients with lower-risk disease may further extend survival by altering the biology of MDS. The new treatment paradigm should aim for prolonging leukemic-free transformation and extending survival while optimizing quality of life and maintaining hematologic and cytogenetic response. The results of stem cell transplantation for MDS continue to improve together with the

The incidence of MDS is increasing parallely with the increase of the average age of the population. That gives a particular importance to the development of MDS therapy has taken place in the last decade. In the close future some more possible progress are expected.

Advisory Committee of the International Bone Marrow Transplant Registry. 1989. Report

Alatrash G, de Lima M, Hamerschlak N, Pelosini M, Wang X, Xiao L, Kerbauy F, Chiattone

Alessandrino EP, Della Porta MG, Bacigalupo A, Van Lint MT, Falda M, Onida F, Bernardi

Armand P, Kim HT, Rhodes J, Sainvil MM, Cutler C, Ho VT, Koreth J, Alyea EP, Hearsey D,

Trapianto di Midollo Osseo (GITMO). *Blood*, 112,3,895-902,

from the International Bone Marrow Transplant Registry. *Bone Marrow*

A, Rondon G, Qazilbash MH, Giralt SA, de Padua Silva L, Hosing C, Kebriaei P, Zhang W, Nieto Y, Saliba RM, Champlin RE Andersson BS. 2011. Myeloablative Reduced-Toxicity i.v. Busulfan-Fludarabine and Allogeneic Hematopoietic Stem Cell Transplant for Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome in the Sixth through Eighth Decades of Life.  WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano

Neufeld EJ, Fleming MD, Steen H, Anderson D, Kwong RY, Soiffer RJ Antin JH.

decitabine or a participation in a clinical trial should be considered.

therapeutic options have added to the armamentarium of MDS treatments.

outlook of patients afflicted with myelodysplasia.

*Transplant*,48, 453-458,

*Transplant*, Febr. 18,

**12. Conclusion**

**13. References**

2011. Iron Overload in Patients with Acute Leukemia or MDS Undergoing Myeloablative Stem Cell Transplantation. *Biol Blood Marrow Transplant*,6,852-60,

Treatment Options in Myelodysplastic Syndromes 313

Greenberg PL. 2010. Current therapeutic approaches for patients with myelodysplastic

Guardiola P, Runde V Bacigalupo A. 2002. Subcommittee for Myelodysplastic Syndromes

Graubert T. 2010. Therapy-related myelodysplastic syndrome: models and genetics. *Biol*

Grövdal M, Karimi M, Khan R, Aggerholm A, Antunovic P, Astermark J, Bernell P,

Ho VT, Kim HT, Aldridge J, Liney D, Kao G, Armand P, Koreth J, Cutler C, Ritz J, Antin JH,

Horwitz ME. 2011. Reduced intensity versus myeloablative allogeneic stem cell

activity: implications for a phase I clinical study. *Br J Haematol*,145,6,749-60, Jädersten M, Malcovati L, Dybedal I, Della Porta MG, Invernizzi R, Montgomery SM,

Jankowska AM, Szpurka H Tiu RV. 2009. Loss of heterozygosity 4q24 and TET2

Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M DiPersio J. 2006. Decitabine

Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S Cortes J. 2007. Results of a

Karanes C, Nelson GO, Chitphakdithai P, Agura E, Ballen KK, Bolan CD, Porter DL, Uberti

syndrome and acute lymphoid leukemia. Curr Opin *Oncol*,23,2,:197-202, Ingram W, Chan L, Guven H, Darling D, Kordasti S, Hardwick N, Barber L, Mufti GJ

Stem Cell Transplantation. *Biol Blood Marrow Transplant*, 12,702,

in myelodysplastic syndrome*. J Clin Oncol,*26,21,3607-13,

randomized study. *Cancer,*106,1794 –1803,

*Blood*,113,6403–6410,

of the Chronic Leukaemia Working Group of the European Blood and Marrow Transplantation Group. Retrospective comparison of bone marrow and granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells for allogeneic stem cell transplantation using HLA identical sibling donors in myelodysplastic

Engström LM, Kjeldsen L, Linder O, Nilsson L, Olsson A, Holm MS, Tangen JM, Wallvik J, Oberg G, Hokland P, Jacobsen SE, Porwit A Hellström-Lindberg E. 2010. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. *Br J Haematol*,150,3,293-302, Hellström-Lindberg E. 2003. Approach to anemia associated with myelodysplastic

Soiffer RJ Alyea EP. 2010. Use of Matched Unrelated Donors Compared with Matched Related Donors Is Associated with Lower Relapse and Superior Progression-Free Survival after Reduced-Intensity Conditioning Hematopoietic

transplantation for the treatment of acute myeloid leukemia, myelodysplastic

Farzaneh F. 2009. Human CD80/IL2 lentivirus-transduced acute myeloid leukaemia (AML) cells promote natural killer (NK) cell activation and cytolytic

Pascutto C, Porwit A, Cazzola M Hellström-Lindberg E. 2008. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival

mutations associated with myelodysplastic/myeloproliferative neoplasms.

improves patient outcomes in myelodysplastic syndromes: results of a phase III

randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. *Blood,*109,52–57,

JP, King RJ Confer DL. 2008. Twenty years of unrelated donor hematopoietic cell

Grant S. 2009. New agents for AML and MDS. *Best Pract Res Clin Haematol*,22,4,501-7,

syndromes. *Br J Haematol*,150,2,131-43,

syndromes. *Blood*,99,4370–4378,

*Blood Marrow Transplant,* 16,1, suppl,S45-S47,

syndromes. *Curr Hematol Rep,*2,2,122-9,

Cutler C. 2010. Patient selection for transplantation in the myelodysplastic syndromes.

Cutler C. 2010. Allogeneic hematopoietic stem-cell transplantation for myelodysplastic

Czibere A, Bruns I, Kröger N, Platzbecker U, Lind J, Zohren F, Fenk R, Germing U, Schröder

Deeg HJ, Jiang PY, Holmberg LA, Scott B, Petersdorf EW Appelbaum FR. 2004.

Ebert BL, Pretz J Bosco J. 2008. Identification of RPS14 as a 5q- syndrome gene by RNA

Edlin R, Connock M, Tubeuf S, Round J, Fry-Smith A, Hyde C Greenheld W. 2010.

Gale RP Champlin RE. 1984. How does bone-marrow transplantation cure leukaemia?

Garcia JS, Jain N Godley LA. 2010. An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes. *Onco Targets Ther*, 3,1-13, Garcia-Manero G. 2010. Prognosis of myelodysplastic syndromes. *Hematology Am Soc*

Gergis U Wissa U. 2010. High-risk myelodysplastic syndromes: chemotherapy,

Giralt SA, Horowitz M, Weisdorf D Cutler C. 2011. Review of stem-cell transplantation for

Giralt S, Khouri I Champlin R. 1999. Non-myeloablative "mini transplants." *Cancer Treat*

Giralt S, Thall P Khouri I. 2001. Purine analogcontaining preparative regimens: reduced-

Goldberg SL, Chen E, Corral M, Guo A, Mody-Patel N, Pecora AL Laouri M. 2010.

Greenberg PL. 1998. Risk factors and their relationship to prognosis in myelodysplastic

Greenberg PL, Sun Z, Miller KB, Bennett JM, Tallman MS, Dewald G, Paietta E, van der Jagt

myelodysplastic syndromes in older patients in the context of the Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome emanating from the Centers for Medicare and Medicaid Services*. J Clin*

intensity conditioning for patients with hematologic malignancies undergoing

Incidence and clinical complications of myelodysplastic syndromes among United

R, Houston J, Thomas ML, Cella D Rowe JM. 2009. Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colonystimulating factor: results of a prospective randomized phase 3 trial by the Eastern

transplantation, and beyond*. Curr Hematol Malig Rep*, 5,1,1-8,

allogeneic progenitor cell transplantation. *Blood*,97, 631-637,

Cooperative Oncology Group (E1996). *Blood*,114,12,2393-400,

States Medicare beneficiaries. *J Clin Oncol*,28,17,2847-52,

syndromes. *Leuk Res,* 22 Suppl 1,S3-6,

T, Gräf T, Haas R Kobbe G. 2010. 5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after alloSCT: a

Hematologic responses of patients with MDS to antithymocyte globulin plus etanercept correlate with improved flow scores of marrow cells. *Leuk Res*, 28,1177-

Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia. *Health Technol Assess,*14

syndrome. *Hematology Am Soc Hematol Educ Program*,2010,325-9,

retrospective analysis. *Bone Marrow Transplant*,45,5,872-6,

*Hematol Oncol Clin North Am*,24,2,469-76,

interference screen. *Nature*,451,335–339,

*Hematol Educ Program,*2010,330-7,

80,

Suppl 1,69-74,

*Lancet*,2, 28-30,

*Oncol,*29,5,566-72,

*Res,*101, 97-108,

Treatment Options in Myelodysplastic Syndromes 315

Litzow MR, Tarima S, Pérez WS, Bolwell BJ, Cairo MS, Camitta BM, Cutler CS, de Lima M,

Luger SM, Ringdén O, Zhang MJ, Pérez WS, Bishop MR, Bornhauser M, Bredeson CN, Cairo

preparative regimens for AML or MDS. *Bone Marrow Transplant,* Mar 28. Ma, X., Does, M., Raza, A., & Mayne, S.T. 2007. Myelodysplastic syndromes: Incidence and

Majhail NS, Brunstein CG, Shanley R, Sandhu K, McClune B, Oran B, Warlick ED, Wagner

Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R,

Malcovati L Nimer SD. 2008. Myelodysplastic syndromes: diagnosis and staging. *Cancer*

McClune BL, Weisdorf DJ Pedersen TL. 2010. Effect of age on outcome of reduced-

McCormack SE Warlick ED. 2010. Epigenetic approaches in the treatment of

Meletis J Terpos E. 2009. Transplantation strategies for the management of patients with

Mufti GJ Chen TL. 2008. Changing the treatment paradigm in myelodysplastic

National Comprehensive Cancer Network (2010) The NCCN 2.2010 Myelodysplastic

Park S , Kelaidi C, Sapena R, Vassilieff D, Beyne-Rauzy O, Coiteux V, Vey N, Ravoet C,

and acute myeloid leukemia. *Blood,*115,9,1850-7,

survival in the United States. *Cancer,* 109, 1536–1542,

decision making. *J Clin Oncol*, 23,30,7594-7603,

myelodysplastic syndromes. *J BUON*,14,4,551-64,

syndromes. *Cancer Control*, 15 Suppl,14-28,

Cancer Network, Fort Washington, PA).

patients. *Leuk Res*, 34,11,1430-6,

*Oncol,*25,23,3503-10,

*Control*, 15 Suppl,4-13,

*Oncol*,28,1878–1887,

65,

Dipersio JF, Gale RP, Keating A, Lazarus HM, Luger S, Marks DI, Maziarz RT, McCarthy PL, Pasquini MC, Phillips GL, Rizzo JD, Sierra J, Tallman MS Weisdorf DJ 2010. Allogeneic transplantation for therapy-related myelodysplastic syndrome

MS, Copelan EA, Gale RP, Giralt SA, Gulbas Z, Gupta V, Hale GA, Lazarus HM, Lewis VA, Lill MC, McCarthy PL, Weisdorf DJ Pulsipher MA. 2011. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant

JE Weisdorf DJ. 2011. Reduced-intensity hematopoietic cell transplantation in older patients with AML/MDS: umbilical cord blood is a feasible option for patients without HLA-matched sibling donors. *Bone Marrow Transplant,* 14,3,282-9, Malcovati L, Della Porta MG Pascutto C. 2005. Prognostic factors and life expectancy in

myelodysplastic syndromes classified according to WHO criteria: a basis for clinical

Giagounidis A, Hildebrandt B, Bernasconi P, Knipp S, Strupp C, Lazzarino M, Aul C Cazzola M. 2007. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. *J Clin*

intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. *J Clin*

myelodysplastic syndromes: clinical utility of azacitidine. *Onco Targets Ther,* 3,157-

Syndromes Clinical Practice Guidelines in Oncology (National Comprehensive

Cheze S, Rose C, Legros L, Stamatoullas A, Escoffre-Barbe M, Guerci A, Chaury MP, Fenaux P Dreyfus F. 2010. Early introduction of ESA in low risk MDS patients may delay the need for RBC transfusion: a retrospective analysis on 112

transplantation for adult recipients facilitated by the National Marrow Donor Program. *Biol Blood Marrow Transplant,*14,9 Suppl,8-15,

Keilholz U, Letsch A, Busse A, Asemissen AM, Bauer S, Blau IW, Hofmann WK, Uharek L,

Kiladjian JJ, Visentin G, Viey E, Chevret S, Eclache V, Stirnemann J, Bourhis JH, Chouaib S,

Kindwall-Keller T Isola LM. 2009. The evolution of hematopoietic SCT in myelodysplastic

Komrokji RS List AF. 2010. Lenalidomide for treatment of myelodysplastic syndromes: current status and future directions. *Hematol Oncol Clin North Am*, 24,2,377-88, Kröger N. 2008. Epigenetic modulation and other options to improve outcome of stem cell transplantation in MDS. *Hematology Am Soc Hematol Educ Program,*60-7, Kurtin SE , Demakos EP. 2010. An update on the treatment of myelodysplastic syndromes.

Laport GG, Sandmaier BM, Storer BE, Scott BL, Stuart MJ, Lange T, Maris MB, Agura ED,

Lee JH, Choi J, Kwon KA, Lee S, Oh SY, Kwon HC, Kim HJ, Han JY Kim SH. 2010.

intravenous busulfan with cyclophosphamide. *Korean J Hematol*, 45,2,102-8, Lim Z, Brand R Martino R. 2010. Allogeneic hematopoietic stem-cell transplantation for

de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, Braun TM, Nguyen

de Lima M, Anagnostopoulos A, Munsell M, Shahjahan M, Ueno N, Ippoliti C, Andersson

List A, Dewald G Bennett J. 2006. Lenalidomide in the myelodysplastic syndrome with

List AF. 2010. Iron overload in myelodysplastic syndromes: diagnosis and management.

Chauncey TR, Wong RM, Forman SJ, Petersen FB, Wade JC, Epner E, Bruno B, Bethge WA, Curtin PT, Maloney DG, Blume KG Storb RF. 2008. Reducedintensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders.

Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or

patients 50 years or older with myelodysplastic syndromes or secondary acute

HQ, Champlin R Garcia-Manero G. 2010. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule

BS, Gajewski J, Couriel D, Cortes J, Donato M, Neumann J, Champlin R Giralt S. 2004. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell

Program. *Biol Blood Marrow Transplant,*14,9 Suppl,8-15,

syndrome. *Bone Marrow Transplant,* 43,8,597-609,

Biol Blood Marrow Transplant, 14,2,246-55.

myeloid leukemia. *J Clin Oncol,*28,405–411,

finding study. *Cancer,*116,23,5420-31,

transplantation. *Blood,*104,3,865-72,

*Cancer Control*, 17 Suppl,2-8,

chromosome 5q deletion. *N Engl J Med*,355,1456–1465,

MDS. *Blood,*113,26,6541-8,

*Haematologica,*93,3,381-9,

*Clin J Oncol Nurs*,14,3,E29-44,

transplantation for adult recipients facilitated by the National Marrow Donor

Thiel E Scheibenbogen C. 2009. A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and

Fenaux P Caignard A. 2008. Activation of cytotoxic T-cell receptor gammadelta T lymphocytes in response to specific stimulation in myelodysplastic syndromes.

Treatment Options in Myelodysplastic Syndromes 317

Silverman LR. 2009. Hypomethylating agents in myelodysplastic syndromes changing the

Sloand EM, Olnes MJ, Shenoy A, Weinstein B, Boss C, Loeliger K, Wu CO, More K, Barrett

Sloand EM, Wu CO, Greenberg P, Young N Barrett J. 2008. Factors affecting response and

Sloand EM, Olnes MJ, Shenoy A, Weinstein B, Boss C, Loeliger K, Wu CO, More K, Barrett

Sorror ML, Maris MB Storb R. 2005. Hematopoietic cell transplantation (HCT)-specific

Steensma DP. 2009. Myelodysplasia paranoia: iron as the new radon. *Leuk Res,*33,9,1158-63, Steensma DP, Baer MR, Slack JL, Buckstein R, Godley LA Garcia-Manero G. 2009.

Tefferi A. 2008. Is "cure" essential in the treatment of cancer [letter]? *Mayo Clin Proc,*83,1413-

Tefferi A. 2010. Myelodysplastic syndromes--many new drugs, little therapeutic progress.

Virchis A, Koh M, Rankin P, Mehta A, Potter M, Hoffbrand AV Prentice HG. 2004.

Vigil CE, Martin-Santos T Garcia-Manero G. 2010. Safety and efficacy of azacitidine in

Warlick ED. 2010. Optimizing stem cell transplantation in myelodysplastic syndromes:

Wei S, Chen X, Rocha K, Epling-Burnette PK, Djeu JY, Liu Q, Byrd J, Sokol L, Lawrence N,

Wijermans P, Suciu S, Baila L, Platzbecker U, Giagounidis A Selleslag D. 2009. Low dose

de Witte T, Brand R, van Biezen A, Delforge M, Biersack H, Or R, Meloni G, Bandini B,

and combination with other agents. *Leuk Res*,33 Suppl 2,S18-21,

and cytogenetic remissions*. J Clin Oncol,*28,35,5166-73,

and cytogenetic remissions*. J Clin Oncol,*28,35,5166-73,

treatment (ADOPT) trial. *J Clin Oncol*,27,3842–3848,

myelodysplastic syndromes. *Drug Des Devel Ther*, 4,221-9,

unresolved questions. *Curr Opin Oncol*,22,2,150-4,

lenalidomide. *Proc Natl Acad Sci U S A*,106(31),12974-9,

*J Clin Oncol,*26,15,2505-11,

*Blood,*106,2912–2919,

*Mayo Clin Proc*, 85,11,1042-5,

[abstract 226]. *Blood*, 114,22,

syndromes. *Br J Haematol*, 124,1,6-32,

1414,

inevitable: the value of azacitidine as maintenance therapy, effects on transfusion

AJ, Scheinberg P Young NS. 2010. Alemtuzumab treatment of intermediate-1 myelodysplasia patients is associated with sustained improvement in blood counts

survival in patients with myelodysplasia treated with immunosuppressive therapy.

AJ, Scheinberg P Young NS. 2010. Alemtuzumab treatment of intermediate-1 myelodysplasia patients is associated with sustained improvement in blood counts

comorbidity index: a new tool for risk assessment before allogeneic HCT.

Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient

Fludarabine, cytosine arabinoside, granulocyte-colony stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic

Pireddu R, Dewald G, Williams A, Maciejewski J List A. 2009. A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by

decitabine versus best supportive care in elderly patients with intermediate or high risk MDS not eligible for intensive chemotherapy: final results of the randomized phase III study (06011) of the EORTC Leukemia and German MDS Study Groups.

Sierra J, Kroger N, Gratwohl A Niederwieser D. 2006. MDS subcommittee of the EBMT Chronic Leukemia Working Party. The role of stem cell source in autologous

Passweg JR, Giagounidis AA, Simcock M, Aul C, Dobbelstein C, Stadler M, Ossenkoppele G,

Pullarkat V. 2010. Iron overload in patients undergoing hematopoietic stem cell

Pullarkat V. 2009. Objectives of iron chelation therapy in myelodysplastic syndromes: more

Raj K, John A Ho A. 2007. CDKN2B methylation status and isolated chromosome 7

Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius

Robin M, Sanz GF, Ionescu I, Rio B, Sirvent A, Renaud M, Carreras E, Milpied N, Mohty M,

Sanada M, Suzuki T Shih LY. 2009. Gain-of-function of mutated C-CBL tumour

San Miguel Amigo L, Franco Osorio R, Mercadal Vilchez S Martínez-Francés A. 2011.

Scott BL Estey E 2008. Management of myelodysplastic syndromes: 2008 update. *Oncology*

Sekeres MA, Maciejewski JP, Giagounidis AA, Wride K, Knight R Raza A. 2008.

Sekeres MA. 2011a. Epidemiology, natural history, and practice patterns of patients with myelodysplastic syndromes in 2010. *J Natl Compr Canc Netw*,9,1,57-63, Sekeres MA, List AF, Paulic K, Afable M, Englehaupt R Maciejewski JP. 2011b.

borrowed.... *Hematology Am Soc Hematol Educ Program,*656-63,

and darbepoetin in adult patients with cancer. *Blood,*116,20,4045-59,

Rajkumar SV. 2008. Treatment of myeloma: cure vs control. *Mayo Clin Proc,*83,1142-1145, Ria R, Moschetta M, Reale A, Mangialardi G, Castrovilli A, Vacca A Dammacco F. 2009.

abnormalities predict responses to treatment with 5-azacytidine. *Leukemia,*;21,1937–

Managing myelodysplastic symptoms in elderly patients. *Clin Interv Aging,* 4,413-

J, Evanchuk D, Goode MJ, Jakubowski AA, Regan DH Somerfield MR. 2010. American Society of Hematology and the American Society of Clinical Oncology Practice Guideline Update Committee, American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin

Beguin Y, Bordigoni P, de Witte T, Picardi A, Purtill D, Gluckman E, Kroger N Rocha V. 2011. Unrelated cord blood transplantation in adults with myelodysplasia or secondary acute myeloblastic leukemia: a survey on behalf of Eurocord and

Azacitidine adverse effects in patients with myelodysplastic syndromes. *Adv Ther*,

Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. *J Clin Oncol*,26, 5943–5949, Sekeres MA. 2009. Treatment of MDS: something old, something new, something

Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. *Am J Hematol*,86,1,102-3.

with best supportive care--SAKK 33/99. *J Clin Oncol,*29,3,303-9,

transplantation. *Adv Hematol,* 2010. pii: 345756,

than meets the eye? *Blood,*114,26,5251-5,

CLWP of EBMT. *Leukemia,*25,1,75-81,

*(Williston Park)*, 22,12,1344-52,

28 Suppl 4,6-11,

suppressor in myeloid neoplasms. *Nature*,460,904–908,

1944,

23,

Hofmann WK, Schilling K, Tichelli A Ganser A. 2011. Immunosuppressive therapy for patients with myelodysplastic syndrome: a prospective randomized multicenter phase III trial comparing antithymocyte globulin plus cyclosporine

**15**

*Turkey*

**Mantle Cell Lymphoma:**

Yener Koc and Taner Demirer

**Decision Making for Transplant**

*Medical Park Hospital, Antalya and Ankara University Medical School, Ankara*

Mantle Cell Lymphoma (MCL) is a relatively rare type of mature B-cell lymphoma that comprises 5% of Non-Hodgkin's Lymphomas(NHL)1-3. MCL was added to the Revised European–American Lymphoma classification in 1994. Having both indolent and incurable features associated with aggressive clinical course, MCL is most frequently seen in 6th decade of life, with male dominance 3 to 4:12. Malignant origin of MCL cells appear to

Chronic lymphocytic leukemia/small lymphocytic lymphoma

Extranodal marginal zone B-cell lymphoma of MALT

**1. Introduction**

**1. B-cell neoplasms**

1. Precursor B-cell 2. Mature B-cell

**1.1 Definition and clinical characteristics**

derive from an antigen-naive pregerminal center cell4, 5.

Lymphoplasmacytic lymphoma Splenic marginal zone lymphoma

Diffuse large B-cell lymphoma

Primary effusion lymphoma Burkitt's lymphoma/leukemia

**2. T-Cell and NK-Cell neoplasms**

Intravascular large B-cell lymphoma

3. B-cell proliferations of uncertain malignant potential

Table 1. World Health Organization Classification of Lymphomas1.

Follicular lymphoma *Mantle cell lymphoma*

Nodal marginal zone B-cell lymphoma

Mediastinal (thymic) large B-cell lymphoma

hematopoietic stem cell transplantation for patients with myelodysplastic syndromes. *Haematologica,*91,6,750-6,

### **Mantle Cell Lymphoma: Decision Making for Transplant**

Yener Koc and Taner Demirer

*Medical Park Hospital, Antalya and Ankara University Medical School, Ankara Turkey*

#### **1. Introduction**

318 New Advances in Stem Cell Transplantation

de Witte T, Suciu S, Brand R, Muus P Kröger N. 2007. Autologous stem cell transplantation in myelodysplastic syndromes. *Semin Hematol,*44,4,274-7, de Witte T, Hagemeijer A, Suciu S, Belhabri A, Delforge M, Kobbe G, Selleslag D, Schouten

Ximeri M, Galanopoulos A, Klaus M, Parcharidou A, Giannikou K, Psyllaki M, Symeonidis

Zipperer E , Pelz D, Nachtkamp K, Kuendgen A, Gattermann N, Haas R Germing U. 2009.

myelodysplastic syndrome and AML. *Bone Marrow Transplant,*45,4,633-9

syndromes. *Haematologica,*91,6,750-6,

Trial. *Haematologica*,95,10,1754-61,

*Trends Pharmacol Sci*, 31,11,536-46,

hematopoietic stem cell transplantation for patients with myelodysplastic

HC, Ferrant A, Biersack H, Amadori S, Muus P, Jansen JH, Hellström-Lindberg E, Kovacsovics T, Wijermans P, Ossenkoppele G, Gratwohl A, Marie JP Willemze R. 2010. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup

A, Pappa V, Kartasis Z, Liapi D, Hatzimichael E, Kokoris S, Korkolopoulou P, Sambani C, Pontikoglou C Papadaki HA. 2010. Hellenic MDS Study Group, Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion. *Haematologica*,95,3,406-14, Yang X, Lay F, Han H Jones PA. 2010. Targeting DNA methylation for epigenetic therapy.

The hematopoietic stem cell transplantation comorbidity index is of prognostic relevance for patients with myelodysplastic syndrome. *Haematologica,*94,5,729-32, Zy Ingram W, Brand R, Ho A, Kenyon M, Devereux S, Marsh J, Mufti GJ Pagliuca. 2010.

A Impact of pretransplant comorbidities on alemtuzumab-based reduced-intensity conditioning allogeneic hematopoietic SCT for patients with high-risk

#### **1.1 Definition and clinical characteristics**

Mantle Cell Lymphoma (MCL) is a relatively rare type of mature B-cell lymphoma that comprises 5% of Non-Hodgkin's Lymphomas(NHL)1-3. MCL was added to the Revised European–American Lymphoma classification in 1994. Having both indolent and incurable features associated with aggressive clinical course, MCL is most frequently seen in 6th decade of life, with male dominance 3 to 4:12. Malignant origin of MCL cells appear to derive from an antigen-naive pregerminal center cell4, 5.

#### **1. B-cell neoplasms**

	- Chronic lymphocytic leukemia/small lymphocytic lymphoma Lymphoplasmacytic lymphoma Splenic marginal zone lymphoma Extranodal marginal zone B-cell lymphoma of MALT Nodal marginal zone B-cell lymphoma Follicular lymphoma *Mantle cell lymphoma* Diffuse large B-cell lymphoma Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Burkitt's lymphoma/leukemia

#### **2. T-Cell and NK-Cell neoplasms**

Table 1. World Health Organization Classification of Lymphomas1.

Mantle Cell Lymphoma: Decision Making for Transplant 321

For each prognostic factor, 0 to 3 points were given to each patient and points were summed up to a maximum of 11. Patients with 0 to 3 points in summary were classified as low risk, patients with 4 to 5 points as intermediate risk, and patients with 6 to 11 points

Fig. 1. Overall survival according to the mantle cell lymphoma international prognostic

an important biologic marker with strong additional prognostic relevance26.

Although Ki-67 has previously been shown to predict prognosis (Figure 2)32-34, analysis of Ki-67 did not substantially change the regression coefficient of the MIPI score and served as

Recently, proliferation gene expression signature has been reported to be the best molecular predictor of survival in patients with MCL21, leading to a prognostic model defined as an optimized survival predictor composed of five genes: RAN, MYC, TNFRSF10B, POLE2, and SLC29A235. Furthermore, this model was validated for application in formalin-fixed paraffin-embedded tissue samples and appeared superior to the immunohistochemical

Table 3. Simplified MIPI26.

as high risk.

index (MIPI).

marker Ki-6735.

At the time of diagnosis, patients tend to have more extranodal disease and low serum albumin6. Although MCL has differential diagnosis with Chronic Lymphocytic Leukemia (CLL) and low-grade NHL, mimicking malignancies with indolent behavior, it follows an aggressive course with 10% to 15% long-term survivors7 despite administration of standard chemotherapy courses commonly used in NHLs8, corresponding to a median survival of 3 to 5 years.

#### **2. Diagnosis**

Diagnosis of MCL can be made by lymph node or bone marrow biopsy, or analysis of malignant cells obtained from peripheral blood, if the disease is in the leukemic phase9, 10. Differential diagnosis with CLL is important since both MCL and CLL cell have coexpression of CD5 and CD19/2011. Malignant cells are negative for CD10, CD23 and BCL6. Although absence of CD23 antigen expression on malignant cell population strongly favor a diagnosis of MCL12, 13, presence of cyclinD1 expression by immunohistochemical staining14 or determination of t(11;14) translocation by molecular analysis15-18 is required to confirm the diagnosis19. Cyclin D1 is overexpressed in MCL as a result of the landmark t(11;14)(q13;q32) translocation20. Cyclin D1 complex with cyclin dependent kinases 4 and 6 (Cdk4 and Cdk6) and cyclin E-Cdk2, leading to phosphorylation of retinoblastoma protein (Rb), irreversibly inducing progression of the cell from G1 to S phase, which is not the only biologic dysregulation on the way to malignant transformation21-24.

FL, follicular lymphoma; MCL, mantle cell lymphoma; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; LPL, Lymphoplasmacytic lymphoma; MALT, marginal zone lymphoma of MALT type; SMZL, splenic marginal zone lymphoma; HCL, hairy cell leukemia; Ig class, most commonly expressed heavy chain classes; c, cytoplasmic Ig; s, surface Ig.

Table 2. Differential Diagnosis of "Small" B-Cell Lymphomas25.

#### **3. Prognostic parameters**

Prognosis can be estimated by using MIPI (mantle cell lymphoma international prognostic index, Figure 1)26 which seems to be more efficient than international prognostic index (IPI)27 or follicular lymphoma international prognostic index (FLIPI)28, 29, which includes leukemic phase10, 30, 31, besides other clinical parameters used in the IPI.

Table 3. Simplified MIPI26.

320 New Advances in Stem Cell Transplantation

At the time of diagnosis, patients tend to have more extranodal disease and low serum albumin6. Although MCL has differential diagnosis with Chronic Lymphocytic Leukemia (CLL) and low-grade NHL, mimicking malignancies with indolent behavior, it follows an aggressive course with 10% to 15% long-term survivors7 despite administration of standard chemotherapy courses commonly used in NHLs8, corresponding to a median survival of 3

Diagnosis of MCL can be made by lymph node or bone marrow biopsy, or analysis of malignant cells obtained from peripheral blood, if the disease is in the leukemic phase9, 10. Differential diagnosis with CLL is important since both MCL and CLL cell have coexpression of CD5 and CD19/2011. Malignant cells are negative for CD10, CD23 and BCL6. Although absence of CD23 antigen expression on malignant cell population strongly favor a diagnosis of MCL12, 13, presence of cyclinD1 expression by immunohistochemical staining14 or determination of t(11;14) translocation by molecular analysis15-18 is required to confirm the diagnosis19. Cyclin D1 is overexpressed in MCL as a result of the landmark t(11;14)(q13;q32) translocation20. Cyclin D1 complex with cyclin dependent kinases 4 and 6 (Cdk4 and Cdk6) and cyclin E-Cdk2, leading to phosphorylation of retinoblastoma protein (Rb), irreversibly inducing progression of the cell from G1 to S phase, which is not the only

Disease **CD5 CD10 CD23 CD43 Cyclin D1 Ig class FL** - + +/- - - IgM, IgG **MCL** + - - + + IgM/IgD **CLL/SLL** + - + + - IgM/IgD **LPL** - - - +/- - IgM (c) **MALT** - - - +/- - IgM (c, s) **SMZL** - - - - - IgM/IgD **HCL** - - - - -/+ IgG

FL, follicular lymphoma; MCL, mantle cell lymphoma; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; LPL, Lymphoplasmacytic lymphoma; MALT, marginal zone lymphoma of MALT type; SMZL, splenic marginal zone lymphoma; HCL, hairy cell leukemia; Ig class, most

Prognosis can be estimated by using MIPI (mantle cell lymphoma international prognostic index, Figure 1)26 which seems to be more efficient than international prognostic index (IPI)27 or follicular lymphoma international prognostic index (FLIPI)28, 29, which includes

biologic dysregulation on the way to malignant transformation21-24.

commonly expressed heavy chain classes; c, cytoplasmic Ig; s, surface Ig. Table 2. Differential Diagnosis of "Small" B-Cell Lymphomas25.

leukemic phase10, 30, 31, besides other clinical parameters used in the IPI.

**3. Prognostic parameters**

to 5 years.

**2. Diagnosis**

For each prognostic factor, 0 to 3 points were given to each patient and points were summed up to a maximum of 11. Patients with 0 to 3 points in summary were classified as low risk, patients with 4 to 5 points as intermediate risk, and patients with 6 to 11 points as high risk.

Fig. 1. Overall survival according to the mantle cell lymphoma international prognostic index (MIPI).

Although Ki-67 has previously been shown to predict prognosis (Figure 2)32-34, analysis of Ki-67 did not substantially change the regression coefficient of the MIPI score and served as an important biologic marker with strong additional prognostic relevance26.

Recently, proliferation gene expression signature has been reported to be the best molecular predictor of survival in patients with MCL21, leading to a prognostic model defined as an optimized survival predictor composed of five genes: RAN, MYC, TNFRSF10B, POLE2, and SLC29A235. Furthermore, this model was validated for application in formalin-fixed paraffin-embedded tissue samples and appeared superior to the immunohistochemical marker Ki-6735.

Mantle Cell Lymphoma: Decision Making for Transplant 323

combination(FC) can induce a higher response rate of 63% in patients recurrent MCL51. Previously untreated patients have response rate up to 100% with a complete response rate

Fig. 3. Progression-free survival after cyclophosphamide, doxorubicin, vincristine, and

In a randomized study testing addition of rituximab to fludarabine, cyclophosphamide and mitoxantrone (FCM), patients in the rituximab arm were found to have significant improvement in disease free and overall survival52-54. Fludarabine combined with cyclophosphamide and rituximab is a highly effective regimen in patients relapsing from previously received CHOP regimen55. Addition of rituximab to the chemotherapy regimens

Although tolerating patients treated with the hyper-CVAD regimen had excellent response and survival rates of greater than 90% at 3 years and 4.6 years of time to treatment failure (TTF at 8yr , 16% if age>65, 46% if age<65) following 10 year observation period7, 38, 57, 58, patients treated with conventional therapies have also reported to have similar 3 year survival rates59, 60. The hyper-CVAD regimen without stem cell transplantation was not associated with a plateau in the survival curves (Figure 4)57. In this study, beta-2 microglobulin levels and IPI/MIPI scores were found to predict survival57. Hyper-CVAD regimen data may suggest high efficacy of the high-dose Ara-C (HIDAC) regimen, which

prednisone (CHOP) and rituximab and CHOP (R-CHOP)44.

does not appear to increase toxicity56.

needs to be tested in further clinical trials.

of 70% and 28 months of progression free survival51.

Fig. 2. Overall survival of patients with MCL according to Ki-67 proliferation index33.

#### **4. Role of chemotherapy**

When it comes to assessment of long term overall survival, MCL has the worst prognosis among all lymphoma types36, a watch-and-wait strategy should be avoided. Retrospective analyses of administration of standard chemotherapy have not shown any improvement in overall survival in patients with MCL6, 37. Most regiments induce around 80% response rates with complete remissions up to 30% of cases6, 8. While more aggressive regimens were used38, reliable cure rates with conventional treatment has not been reported until now36. Compared to historical controls, median survival with conventional chemotherapy CVP and CHOP have not been improved37. In a randomized trial, these two regimens were associated with similar response rates (84% and 89%) and median overall survivals (32 and 37 months)39. Only one third of patients with untreated40 or relapsed41 MCL will respond to rituximab as single agent. Rituximab may also be used for purging tumor cells either with standard chemotherapy42 or prior to high dose therapy regimens with stem cell support43. But in a randomized trial, addition of rituximab to CHOP regimen failed to improve overall survival (Figure 3)44. Maintenance interferon-alfa therapy following induction regimen has not been proven to improve survival either45, 46.

Fludarabine can also be used in patients with lymphoma with or without rituximab combination47. Fludarabine alone in previously treated MCL can induce temporary responses in a third of patients lasting between 4 to 8 months48. In newly diagnosed patients, fludarabine appears to be more active, inducing responses in 60% , half of which is complete response49. Combining fludarabine with idarubicin or cyclophosphamide may improve induction of complete responses50, 51. Fludarabine and cyclophosphamide

Fig. 2. Overall survival of patients with MCL according to Ki-67 proliferation index33.

When it comes to assessment of long term overall survival, MCL has the worst prognosis among all lymphoma types36, a watch-and-wait strategy should be avoided. Retrospective analyses of administration of standard chemotherapy have not shown any improvement in overall survival in patients with MCL6, 37. Most regiments induce around 80% response rates with complete remissions up to 30% of cases6, 8. While more aggressive regimens were used38, reliable cure rates with conventional treatment has not been reported until now36. Compared to historical controls, median survival with conventional chemotherapy CVP and CHOP have not been improved37. In a randomized trial, these two regimens were associated with similar response rates (84% and 89%) and median overall survivals (32 and 37 months)39. Only one third of patients with untreated40 or relapsed41 MCL will respond to rituximab as single agent. Rituximab may also be used for purging tumor cells either with standard chemotherapy42 or prior to high dose therapy regimens with stem cell support43. But in a randomized trial, addition of rituximab to CHOP regimen failed to improve overall survival (Figure 3)44. Maintenance interferon-alfa therapy following induction regimen has

Fludarabine can also be used in patients with lymphoma with or without rituximab combination47. Fludarabine alone in previously treated MCL can induce temporary responses in a third of patients lasting between 4 to 8 months48. In newly diagnosed patients, fludarabine appears to be more active, inducing responses in 60% , half of which is complete response49. Combining fludarabine with idarubicin or cyclophosphamide may improve induction of complete responses50, 51. Fludarabine and cyclophosphamide

**4. Role of chemotherapy**

not been proven to improve survival either45, 46.

combination(FC) can induce a higher response rate of 63% in patients recurrent MCL51. Previously untreated patients have response rate up to 100% with a complete response rate of 70% and 28 months of progression free survival51.

Fig. 3. Progression-free survival after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and rituximab and CHOP (R-CHOP)44.

In a randomized study testing addition of rituximab to fludarabine, cyclophosphamide and mitoxantrone (FCM), patients in the rituximab arm were found to have significant improvement in disease free and overall survival52-54. Fludarabine combined with cyclophosphamide and rituximab is a highly effective regimen in patients relapsing from previously received CHOP regimen55. Addition of rituximab to the chemotherapy regimens does not appear to increase toxicity56.

Although tolerating patients treated with the hyper-CVAD regimen had excellent response and survival rates of greater than 90% at 3 years and 4.6 years of time to treatment failure (TTF at 8yr , 16% if age>65, 46% if age<65) following 10 year observation period7, 38, 57, 58, patients treated with conventional therapies have also reported to have similar 3 year survival rates59, 60. The hyper-CVAD regimen without stem cell transplantation was not associated with a plateau in the survival curves (Figure 4)57. In this study, beta-2 microglobulin levels and IPI/MIPI scores were found to predict survival57. Hyper-CVAD regimen data may suggest high efficacy of the high-dose Ara-C (HIDAC) regimen, which needs to be tested in further clinical trials.

Mantle Cell Lymphoma: Decision Making for Transplant 325

In a randomized trial testing ASCT versus IFN-alfa consolidation following response to CHOP or CHOP like regimens with or without rituximab, consolidation with BEAM/ASCT improved progression free survival (PFS) but has not been shown to improve overall survival (OS)(Figure 5)93. When patients responding to R-CHOP regimen received HIDAC therapy followed with autologous tranplantation with the BEAM regimen, also a plateau

Fig. 5. Progression-free survival after high-dose radiochemotherapy followed by ASCT and

Autologous transplantation with conventional conditioning regimens without in vivo purging induced a median survival of 47 months88. Analysis of this patient group did not

Addition of rituximab to ASCT regimen leads to better event free survival (EFS) curves in patients with first remission, not affecting progression in patients with relapsed/refractory

The R-HDS regimen consisting of high-dose sequential chemotherapy (including intravenous administration of high-dose cyclophosphamide, high-dose cytarabine, highdose melphalan, and high-dose mitoxantrone plus melphalan) and in vivo purging with rituximab resulted in OS and EFS rates at 54 months were 89% and 79%, respectively96. These results compare favorably with the 42% OS rate and the 18% EFS rate observed in 35 age-matched historic controls treated with standard-dose chemotherapy at the participating

IFN-alfa maintenance in MCL93.

disease91.

centers (Figure 6)96.

reveal a plateau in the survival curve88.

was not observed in time to treatment failure (TTF) and OS curves94.

Fig. 4. Overall survival and time to failure in 97 patients treated with R hyper-CVAD alternating with R M/A57.

Due to advanced age at the time of presentation of MCL, there is a concern about intensive therapy regimens being associated with higher toxicity rates requiring patient selection and patients tolerating intensive therapies are being selected for high-dose therapies with stem cell support.

#### **5. New agents**

Recently, bortezomib61-63, lenalidomide64-66, bendamustine67-69, pixantrone70, azaepothilone ixabepilone71 and mTOR inhibitor temsirolimus72-74 has been shown to demonstrate activity alone and in combination with rituximab and mitoxantrone, and may induce complete responses in relapsed or refractory MCL61, 64, 69, 75, 76. Along with rituximab, these biotherapy agents can be used frontline or may also be introduced into post transplant maintenance to prevent or treat relapses61, 68, 77-81. There may be an advantage of combining rituximab with bendamustine compared to combining with the conventional CHOP regimen in terms of disease free survival82. Recently, it was reported that frontline use of cladribine and rituximab can induce an overall response rate of 87%, with 61% of patients achieving complete remission, suggesting use of this combination for the initial treatment of MCL83. Radioimmunotherapy with 90Y-labeled anti-CD20 monoclonal antibody (ibritumomab tiuxetan) or 131I-rituximab is now being tested in phase I-II trials, including stem cell transplant setting84-87.

#### **6. High dose chemotherapy with autologous stem cell support (ASCT)**

Since conventional and dose intense chemotherapy regimens have failed to induce cure or a plateau phase in time to treatment failure curves, high dose therapy with autologous stem cell support have been studied in the relapse setting88 as well as consolidating complete responses following frontline chemotherapy regimens88-94.

Fig. 4. Overall survival and time to failure in 97 patients treated with R hyper-CVAD

Due to advanced age at the time of presentation of MCL, there is a concern about intensive therapy regimens being associated with higher toxicity rates requiring patient selection and patients tolerating intensive therapies are being selected for high-dose therapies with stem

Recently, bortezomib61-63, lenalidomide64-66, bendamustine67-69, pixantrone70, azaepothilone ixabepilone71 and mTOR inhibitor temsirolimus72-74 has been shown to demonstrate activity alone and in combination with rituximab and mitoxantrone, and may induce complete responses in relapsed or refractory MCL61, 64, 69, 75, 76. Along with rituximab, these biotherapy agents can be used frontline or may also be introduced into post transplant maintenance to prevent or treat relapses61, 68, 77-81. There may be an advantage of combining rituximab with bendamustine compared to combining with the conventional CHOP regimen in terms of disease free survival82. Recently, it was reported that frontline use of cladribine and rituximab can induce an overall response rate of 87%, with 61% of patients achieving complete remission, suggesting use of this combination for the initial treatment of MCL83. Radioimmunotherapy with 90Y-labeled anti-CD20 monoclonal antibody (ibritumomab tiuxetan) or 131I-rituximab is now being tested in phase I-II trials, including stem cell

**6. High dose chemotherapy with autologous stem cell support (ASCT)**

responses following frontline chemotherapy regimens88-94.

Since conventional and dose intense chemotherapy regimens have failed to induce cure or a plateau phase in time to treatment failure curves, high dose therapy with autologous stem cell support have been studied in the relapse setting88 as well as consolidating complete

alternating with R M/A57.

cell support.

**5. New agents**

transplant setting84-87.

In a randomized trial testing ASCT versus IFN-alfa consolidation following response to CHOP or CHOP like regimens with or without rituximab, consolidation with BEAM/ASCT improved progression free survival (PFS) but has not been shown to improve overall survival (OS)(Figure 5)93. When patients responding to R-CHOP regimen received HIDAC therapy followed with autologous tranplantation with the BEAM regimen, also a plateau was not observed in time to treatment failure (TTF) and OS curves94.

Fig. 5. Progression-free survival after high-dose radiochemotherapy followed by ASCT and IFN-alfa maintenance in MCL93.

Autologous transplantation with conventional conditioning regimens without in vivo purging induced a median survival of 47 months88. Analysis of this patient group did not reveal a plateau in the survival curve88.

Addition of rituximab to ASCT regimen leads to better event free survival (EFS) curves in patients with first remission, not affecting progression in patients with relapsed/refractory disease91.

The R-HDS regimen consisting of high-dose sequential chemotherapy (including intravenous administration of high-dose cyclophosphamide, high-dose cytarabine, highdose melphalan, and high-dose mitoxantrone plus melphalan) and in vivo purging with rituximab resulted in OS and EFS rates at 54 months were 89% and 79%, respectively96. These results compare favorably with the 42% OS rate and the 18% EFS rate observed in 35 age-matched historic controls treated with standard-dose chemotherapy at the participating centers (Figure 6)96.

Mantle Cell Lymphoma: Decision Making for Transplant 327

Fig. 8. PFS for patients receiving ASCT for relapsed/refractory disease91.

Fig. 9. Overall survival and event-free survival of patients treated with R-HDS versus

high-dose radioimmunotherapy (RIT) coupled with autologous stem cell support97.

Heavily treated patients with multiple recurrences may undergo an effective salvage with

conventional chemotherapy96.

Fig. 6. Overall survival for mantle cell lymphoma patients after autologous transplantation without in vivo purging88.

Fig. 7. EFS following ASCT after myeloablative therapy with (broken line) or without peritransplant rituximab (solid line)95.

Fig. 6. Overall survival for mantle cell lymphoma patients after autologous transplantation

Fig. 7. EFS following ASCT after myeloablative therapy with (broken line) or without

without in vivo purging88.

peritransplant rituximab (solid line)95.

Fig. 8. PFS for patients receiving ASCT for relapsed/refractory disease91.

Fig. 9. Overall survival and event-free survival of patients treated with R-HDS versus conventional chemotherapy96.

Heavily treated patients with multiple recurrences may undergo an effective salvage with high-dose radioimmunotherapy (RIT) coupled with autologous stem cell support97.

Mantle Cell Lymphoma: Decision Making for Transplant 329

transplantation100-102. A healthy comparison of autologous and allogeneic transplants cannot be made at present, due to lack of randomized trials and the different prognostic groups undergoing each transplant type. By using myeloablative regimens for relapsed patients, allogeneic transplants can induce three year event free survivals (EFS)around 50%99, 101-104. However, if performed in first CR or PR, EFS induced by allo transplants at three years can

be as high as 70%103.

Fig. 11. Event-free survival according to type of BMT103.

achieved105, 117, 118.

**8. Reduced intensity allogeneic stem cell transplantation**

In the allogeneic transplant setting, benefit of cure over transplant related mortality can be positively affected by using reduced intensity (RIC) or non-myeloablative (NMA) conditioning regimens105-116. Using donor lymphocyte infusions for GVL effect in patients undergoing allogeneic transplantation with RIC or NMA regimens, low transplant mortality rates (<10%) and higher OS (73 to 85%) and EFS rates (73 to 82%) can be

Fig. 10. OS and PFS obtained in patients with relapsed MCL treated with 131I-tositumomab, etoposide, cyclophosphamide, and ASCT97.

### **7. Allogeneic transplantation for achieving cure**

Myeloablative or non-myeloablative allo-HSCT is generally performed in patients with lymphoma relapsing following auto-HSCT, since patients need tumor-free grafts that can induce a graft-versus-lymphoma (GVL) effect.

Physicians should consider the need for an allogeneic transplant when there is a need for a GVL effect (high risk of relapse) which can be predicted by the presence of;

and;

in patients considered to be eligible following pretransplant screening tests.

Evidence for presence of graft versus lymphoma (GVL) effect has been reported in patients with MCL who underwent allo-HSCT99. CVL effect may be observed as conversion to pcr negativity for t(11;14) or achieving CR in the presence of GVHD99, or observing lower relapse rates in allo-HSCT recipients compared to patients undergoing autologous

Fig. 10. OS and PFS obtained in patients with relapsed MCL treated with 131I-tositumomab,

Myeloablative or non-myeloablative allo-HSCT is generally performed in patients with lymphoma relapsing following auto-HSCT, since patients need tumor-free grafts that can

Physicians should consider the need for an allogeneic transplant when there is a need for a

Aggressive clinical behavior characterized by not achieving a satisfactory response to

Evidence for presence of graft versus lymphoma (GVL) effect has been reported in patients with MCL who underwent allo-HSCT99. CVL effect may be observed as conversion to pcr negativity for t(11;14) or achieving CR in the presence of GVHD99, or observing lower relapse rates in allo-HSCT recipients compared to patients undergoing autologous

GVL effect (high risk of relapse) which can be predicted by the presence of;

in patients considered to be eligible following pretransplant screening tests.

etoposide, cyclophosphamide, and ASCT97.

induce a graft-versus-lymphoma (GVL) effect.

remaining PET positive following ASCT98

 If the patient is young (<55 years) or, Autologous stem cells cannot be mobilized

A high MIPI score

Multiple relapses

and;

chemotherapy regimens

**7. Allogeneic transplantation for achieving cure**

transplantation100-102. A healthy comparison of autologous and allogeneic transplants cannot be made at present, due to lack of randomized trials and the different prognostic groups undergoing each transplant type. By using myeloablative regimens for relapsed patients, allogeneic transplants can induce three year event free survivals (EFS)around 50%99, 101-104. However, if performed in first CR or PR, EFS induced by allo transplants at three years can be as high as 70%103.

#### **8. Reduced intensity allogeneic stem cell transplantation**

In the allogeneic transplant setting, benefit of cure over transplant related mortality can be positively affected by using reduced intensity (RIC) or non-myeloablative (NMA) conditioning regimens105-116. Using donor lymphocyte infusions for GVL effect in patients undergoing allogeneic transplantation with RIC or NMA regimens, low transplant mortality rates (<10%) and higher OS (73 to 85%) and EFS rates (73 to 82%) can be achieved105, 117, 118.

Mantle Cell Lymphoma: Decision Making for Transplant 331

While standard chemotherapy regimens do not offer long term progression free survival, intensive therapy followed by ASCT should be considered for each newly diagnosed

Multiply relapsed patients will not do well after autologous transplants91, 103. Best time to perform an autologous transplant is following CR91, 92, 119, 120 obtained after high-dose therapy with hyperCVAD or HDS regimen, coupled with rituximab91, including in vivo purging prior to stem cell collection81, 92, 96. With this approach, patients eligible for these sequential intensive regimens may enjoy long term disease free survival, although cure

patient92, especially if the MIPI score is translating into poor prognosis.

Fig. 14. Event-free survival according to remission status at BMT103.

the upfront therapy in the management of patients with MCL92.

Newly diagnosed and relatively younger patients less than 60 years of age who are not eligible for ASCT or relapsing after ASCT, or patients with recurrence following chemotherapy, can still be cured by allogeneic SCT following an effective salvage regimen

As the outcome of transplantation is most promising in the newly diagnosed patients without chemorefractory disease, graft contamination and the lack of a survival plateau following autologous transplantation, allogeneic transplantation deserve investigation as

Patients over age 65, and individuals who are not eligible for ASCT with poor prognostic MIPI scores remain as a major challenge for the hematologist. In this group of patients, promising new drugs such as bendamustine, cladribine and bortezomib in combination with synergizing agents such as rituximab, may be offered to patients in the context of clinical trials. One should remember that ASCT with intermediate dose melphalan at doses

**9. Decision making for transplant options**

cannot be achieved121.

inducing CR or near CR121.

Fig. 12. Kaplan-Meier overall survival (OS) and current progression-free survival (CPFS) accounting for salvage post-DLI in with relapsed MCL who received NMA allogeneic transplantation105.

Fig. 13. Favorable overall survival following reduced intensity allogeneneic transplants by disease group117.

Fig. 12. Kaplan-Meier overall survival (OS) and current progression-free survival (CPFS) accounting for salvage post-DLI in with relapsed MCL who received NMA allogeneic

Fig. 13. Favorable overall survival following reduced intensity allogeneneic transplants by

transplantation105.

disease group117.

#### **9. Decision making for transplant options**