**4. CLL therapy**

### **4.1 Early evolution**

In the 1940's, steroids were the first systemic therapy for CLL. The risk of infection, other adverse effects from long term steroid use as well as transient nature of responses, steroids do not have a central role in the treatment of CLL. They can be used along with anti-CD 20 Ab to achieve remission in some patients.

Steroids were followed by the use of alkylating agent chlorambucil in the treatment of CLL, either in combination or as a single agent. These treatments produced objective response rates but mostly resulted on partial responses [22, 23]. This was followed by a long time period before newer drugs were introduced in the treatment of CLL. Fludarabine has been used in various combinations to improve outcomes in CLL. When compared to CAP (cyclophosphamide, doxorubicin and prednisone), fludarabine showed favorable results [24]. Even when it was compared to chlorambucil, fludarabine induced higher response rates but did not offer any survival advantage at the expense of higher toxicities especially from infection and neutropenia [25]. Cladribine in combination with prednisone achieved response rates

**103**

*Chronic Lymphocytic Leukemia: Rapidly Changing Treatment Landscape*

similar to fludarabine when compared to chlorambucil but failed to demonstrate any survival benefit [26, 27]. Cyclophosphamide combined with fludarabine in previously untreated patients showed lower prevalence of residual disease and increased progression free survival (PFS) but again no benefit in overall survival (OS) [28]. When rituximab was combined with fludarabine and cyclophosphamide there was an improvement in PFS as well as OS [29]. This was observed across multiple phase 3 randomized trials [30, 31]. Subset analysis of these trials led to the discovery that patients with mutated IGHV status, FCR led to long term remissions [30, 32].

Indication for treatment of CLL include severe fatigue, weight loss, night sweats, fever without infection, threatened organ function, progressive lymphadenopathy, anemia or thrombocytopenia that is progressive in nature, autoimmune anemia or thrombocytopenia not responsive to steroids [2]. In addition to these factors, patient age, performance status, presence or absence of del(17p) or TP53 mutation, IGHV mutation status should be assessed prior to initiating treatment in patients with indications to treat. Imaging should be considered as well to evaluate

The CLL 8 trial was a pivotal one that established chemoimmunotherapy as the standard of care for patients that can tolerate it. The FCR regimen (fludarabine, cyclophosphamide and rituxan) was compared against FC (fludarabine, cyclophosphamide). Previously untreated CLL patients were randomized to either receive 6 cycles of FCR or FC. The FCR regimen resulted in higher ORR (90% v/s 80%) and CR rates 94% v/s 22%). The median OS was not reached for FCR and was about 86 months for the FC regimen. Subset analysis showed that the maximal benefit was derived by fit patients with CLL, especially those with mutated IGHV [32]. The FCR regimen however has its share of side effects and

The CCL2M trial looked at the feasibility of Bendamustine-Rituxan (BR) in untreated CLL patients and the results were found to be encouraging [33]. This prompted its comparison to other treatment regimens. The MABLE study looked at BR versus Chlorambucil-Rituxan in patients ineligible to receive fludarabine. Complete response rates were higher in the BR arm (24%) as compared to the chlorambucil-rituxan arm. Overall response rate and overall survival were not different among the two arms. However the PFS (40 months v/s 30 months) and Minimal Residual Disease (MRD) negativity (66% v/s 36%) were higher in the BR

CLL10 trial compared BR with FCR. The primary end point was PFS with the objective to assess non inferiority of BR as compared to FCR. The trial confirmed the superiority of FCR therapy (Median PFS 55 vs. 42 months) in fit patients and in patients with IGHV mutated status. However, in patients over 65 years of age the

The CLL11 trial found that chlorambucil-obinutuzumab had better PFS (26.7 months) as compared to rituximab-chlorambucil (16.3 months). The PFS for chlorambucil monotherapy was the shortest (11.1 months). The obinutuzumabchlorambucil arm also had trend towards OS benefit as compared to the other 2 arms. The study population included CLL patients with comorbidities [35]. Based on these 2 trials both BR and chlorambucil- rituxan or obinutuzumab-chlorambucil

are acceptable alternatives in elderly patients or those with comorbidities.

*DOI: http://dx.doi.org/10.5772/intechopen.88070*

*4.2.1 CLL without del(17p) or TP53 mutation*

cannot be given to older patients.

toxicity profile was better with BR.

arm as compared to the Chlorambucil- rituxan arm [34].

**4.2 Upfront treatment**

disease burden.

*Chronic Lymphocytic Leukemia: Rapidly Changing Treatment Landscape DOI: http://dx.doi.org/10.5772/intechopen.88070*

similar to fludarabine when compared to chlorambucil but failed to demonstrate any survival benefit [26, 27]. Cyclophosphamide combined with fludarabine in previously untreated patients showed lower prevalence of residual disease and increased progression free survival (PFS) but again no benefit in overall survival (OS) [28]. When rituximab was combined with fludarabine and cyclophosphamide there was an improvement in PFS as well as OS [29]. This was observed across multiple phase 3 randomized trials [30, 31]. Subset analysis of these trials led to the discovery that patients with mutated IGHV status, FCR led to long term remissions [30, 32].

#### **4.2 Upfront treatment**

*Advances in Hematologic Malignancies*

NOTCH1 mutations have more aggressive course.

the decision of when to initiate therapy.

**4. CLL therapy**

**4.1 Early evolution**

improved with the use of certain treatment regimens (e.g., fludarabine, cyclophosphamide, rituximab) while that of del(17p) or TP53 mutations remains poor despite such treatments. Analysis of CLL8 trial showed worse outcome in patients with SF3B1 and RPS15 gene mutations. Also, patients with complex karyotype and

The lymphocyte doubling time is the number of months it takes the absolute lymphocyte count to double. Doubling time <12 months is associated with a progressive course and a longer doubling time is associated with an indolent course. This factor is somewhat limited in usefulness because it takes time to measure. In patients with early stage disease, the presence of a short doubling time may favor more aggressive therapy. Higher levels of Beta-2 microglobulin (B2M) are associated with poorer outcome. B2M should be interpreted with caution in the context of renal disease, or alternatively GFR-adjusted B2M can be used although lacks validation in prospective studies [19]. Moreover, approximately half of CLL clones will demonstrate unmutated immunoglobulin heavy chain variable regions (IGHV), a finding associated with shorter survival overall and a higher risk of relapse following conventional treatment, including chemoimmunotherapy and hematopoietic cell transplantation [20].

**3.3 International prognostic index for chronic lymphocytic leukemia (CLL-IPI)**

An international group of investigators did a comprehensive analysis [21] to develop a prognostic index for CLL. Using data from 3472 treatment naive patients participating in prospective, randomized clinical trials, five independent prognostic factors were identified: TP53 deletion or mutation, or both, IGHV mutational status, serum B2M concentration, clinical stage, and age. Using weighted grading of the independent factors, a prognostic index was derived that separated patients into four risk groups with significantly different overall survival at 5 years: low (93%), intermediate (79%), high (63%), and very high risk (23%). This chronic lymphocytic leukemia international prognostic index (CLL-IPI) has now been validated by several other groups and is expected to improve patient counseling and the planning of clinical trials. Other risk scores have been proposed, but none of them has been generally accepted. Of note, none of the scores (including the CLL-IPI) affects

In the 1940's, steroids were the first systemic therapy for CLL. The risk of infection, other adverse effects from long term steroid use as well as transient nature of responses, steroids do not have a central role in the treatment of CLL. They can be

Steroids were followed by the use of alkylating agent chlorambucil in the treatment of CLL, either in combination or as a single agent. These treatments produced objective response rates but mostly resulted on partial responses [22, 23]. This was followed by a long time period before newer drugs were introduced in the treatment of CLL. Fludarabine has been used in various combinations to improve outcomes in CLL. When compared to CAP (cyclophosphamide, doxorubicin and prednisone), fludarabine showed favorable results [24]. Even when it was compared to chlorambucil, fludarabine induced higher response rates but did not offer any survival advantage at the expense of higher toxicities especially from infection and neutropenia [25]. Cladribine in combination with prednisone achieved response rates

used along with anti-CD 20 Ab to achieve remission in some patients.

**102**

Indication for treatment of CLL include severe fatigue, weight loss, night sweats, fever without infection, threatened organ function, progressive lymphadenopathy, anemia or thrombocytopenia that is progressive in nature, autoimmune anemia or thrombocytopenia not responsive to steroids [2]. In addition to these factors, patient age, performance status, presence or absence of del(17p) or TP53 mutation, IGHV mutation status should be assessed prior to initiating treatment in patients with indications to treat. Imaging should be considered as well to evaluate disease burden.

#### *4.2.1 CLL without del(17p) or TP53 mutation*

The CLL 8 trial was a pivotal one that established chemoimmunotherapy as the standard of care for patients that can tolerate it. The FCR regimen (fludarabine, cyclophosphamide and rituxan) was compared against FC (fludarabine, cyclophosphamide). Previously untreated CLL patients were randomized to either receive 6 cycles of FCR or FC. The FCR regimen resulted in higher ORR (90% v/s 80%) and CR rates 94% v/s 22%). The median OS was not reached for FCR and was about 86 months for the FC regimen. Subset analysis showed that the maximal benefit was derived by fit patients with CLL, especially those with mutated IGHV [32]. The FCR regimen however has its share of side effects and cannot be given to older patients.

The CCL2M trial looked at the feasibility of Bendamustine-Rituxan (BR) in untreated CLL patients and the results were found to be encouraging [33]. This prompted its comparison to other treatment regimens. The MABLE study looked at BR versus Chlorambucil-Rituxan in patients ineligible to receive fludarabine. Complete response rates were higher in the BR arm (24%) as compared to the chlorambucil-rituxan arm. Overall response rate and overall survival were not different among the two arms. However the PFS (40 months v/s 30 months) and Minimal Residual Disease (MRD) negativity (66% v/s 36%) were higher in the BR arm as compared to the Chlorambucil- rituxan arm [34].

CLL10 trial compared BR with FCR. The primary end point was PFS with the objective to assess non inferiority of BR as compared to FCR. The trial confirmed the superiority of FCR therapy (Median PFS 55 vs. 42 months) in fit patients and in patients with IGHV mutated status. However, in patients over 65 years of age the toxicity profile was better with BR.

The CLL11 trial found that chlorambucil-obinutuzumab had better PFS (26.7 months) as compared to rituximab-chlorambucil (16.3 months). The PFS for chlorambucil monotherapy was the shortest (11.1 months). The obinutuzumabchlorambucil arm also had trend towards OS benefit as compared to the other 2 arms. The study population included CLL patients with comorbidities [35]. Based on these 2 trials both BR and chlorambucil- rituxan or obinutuzumab-chlorambucil are acceptable alternatives in elderly patients or those with comorbidities.

On a similar note, the COMPLEMENT 1 trial showed the combining ofatumumab to chlorambucil in fludarabine ineligible patients showed better PFS (22.4 months) as compared to the monotherapy arm (13.1 months) [36].

However, with the advent of novel agents the landscape of treatment in CLL has significantly changed. The RESONATE-2 study compared single agent chlorambucil to ibrutinib which is a Bruton's Tyrosine Kinase inhibitor. The ORR (92% v/s 36%) as well as PFS at 2 years (89% v/s 34%) in favor of ibrutinib (**Figure 1**). Based on the results of this study ibrutinib was approved for use in the first line setting of CLL. Results from the ECOG ACRIN Cancer research group trial E1912 were recently published. The study compared FCR versus Ibrutinib + Rituxan (IR) in treatment naive patients without deletion 17p. IR was found to be superior to FCR in all subgroups except for the IGHV mutated group. IR group saw significant less neutropenia and infectious complications as well as compared to FCR [38].

The alliance intergroup study showed that in older patients above 65, ibrutinib should be the standard of care as PFS was better in the ibrutinib arms then the BR arms [39]. However this study did not suggest a benefit of adding anti-CD 20 MAB therapy to ibrutinib monotherapy. In the older patient group, where chlorambucil is a treatment option, the iLLUMINATE trial showed that ibrutinib plus obinutuzumab combination resulted in better PFS as compared to chlorambucil plus obinutuzumab, albeit with greater serious adverse events [40]. Between the RESONATE-2 study and ECOG ACRIN study, ibrutinib has been established a first line recommendation in both younger as well as older patients with CLL.

Recently, CLL14 trial studied the combination of fixed-duration venetoclax and obinutuzumab versus obinutuzumab and chlorambucil in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were evenly randomized to receive 12 months of venetoclax alongside 6 months of obinutuzumab or 6 months of obinutuzumab followed by 6 months of chlorambucil. Results from the trial showed the venetoclax combination reduced the risk of disease progression or death by 67% versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions (HR, 0.33; 95% CI, 0.22-0.51; P < .0001). The overall response rate (ORR) was 85% with venetoclax/ obinutuzumab versus 71% in the control arm (P = .0007). The complete response (CR) or CR with incomplete hematologic recovery (CRi) rates were 50% versus 23%, respectively. The rate of minimal residual disease (MRD)-negativity in the bone marrow was 57% in the venetoclax arm compared with 17% in the obinutuzumab/chlorambucil arm. The MRD-negativity rates in the peripheral blood were

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*Chronic Lymphocytic Leukemia: Rapidly Changing Treatment Landscape*

76% versus 35%, respectively. Venetoclax and obinutuzumab combination is the only chemotherapy-free option with fixed duration that proven to provide such a

Ibrutinib provides durable responses and is well tolerated in patients with del(17p). Historically this group of patients generally have poorer outcomes as compared to patients with CLL but without del(17p) [41]. Other treatments in the front-line setting are listed in NCCN for these patients however none of them are very effective. The CAPTIVATE trial is currently on going looking at venetoclax

Is summary, as far as front line therapy is concerned, for fit patients with IGVH mutated status it is reasonable to use chemo-immunotherapy such as FCR or BR. All other patients including young or older patients with high risk disease such as those with unmutated IGHD, 17p del or p53 mutation or 11q deletion it's recommended to treat with a novel agent such as ibrutinib as there has been accumulating evidence

The International Workshop on CLL (iwCLL) defines relapsed disease when it occurs

The choice of treatment at relapse should consider how soon the relapse happens after initial treatment. If it happens sooner than the expected median PFS for the specific regimen is considered "Early relapse", while it is considered "Late relapse" when it happens after the expected median PFS [42]. Prospective trials have reported median PFS for different regimens, as a rule of thumb, progression within 2–3 years of initial treatment with fludarabine, cyclophosphamide, and rituximab (FCR) or within 1 year of other chemoimmunotherapy regimens may be considered

For early relapsing CLL, it's recommended to start a targeted therapy with either ibrutinib, idelalisib plus rituximab, or venetoclax with or without rituximab rather than retreatment with the prior therapy or a trial of another chemoimmunotherapy

in patients who have previously achieved either a complete or partial remission but then develop progressive disease after a period of 6 months or more. Patients who fail to achieve either a partial or complete remission with therapy or those who develop disease progression within 6 months of last therapy are defined to have refractory disease. This distinction is principally made because many patients with progressive disease occurring later after the discontinuation of treatment can be successfully retreated using the same medication, or by switching to other available treatments. In contrast, patients who have refractory disease are unlikely to respond to a trial of the previously used therapy and have a much poorer prognosis [2]. Of note, The iwCLL response criteria were originally developed using data from patients treated with single agents (i.e., fludarabine, chlorambucil). As first-line therapy has evolved, the overall response rate and median progression-free survival have increased. The definitions of relapsed and refractory disease will likely change as therapy improves especially that we depend on expected progression free survival (PFS) in practice more than the 6 months rule to choose the next regimen as

of better efficacy when compared to chemoimmunotherapy alone.

**4.3 Relapsed or refractory chronic lymphocytic leukemia**

*DOI: http://dx.doi.org/10.5772/intechopen.88070*

*4.2.2 CLL with del(17p) or TP53 mutation*

along with ibrutinib in the upfront setting.

durable response.

*4.3.1 Definitions*

illustrated below.

to have early relapse.

*4.3.2 Targeted therapies of relapsing or refractory CLL*

**Figure 1.**

*Progression-free survival of Ibrutinib vs. Chlorambucil [37].*

*Chronic Lymphocytic Leukemia: Rapidly Changing Treatment Landscape DOI: http://dx.doi.org/10.5772/intechopen.88070*

76% versus 35%, respectively. Venetoclax and obinutuzumab combination is the only chemotherapy-free option with fixed duration that proven to provide such a durable response.

#### *4.2.2 CLL with del(17p) or TP53 mutation*

Ibrutinib provides durable responses and is well tolerated in patients with del(17p). Historically this group of patients generally have poorer outcomes as compared to patients with CLL but without del(17p) [41]. Other treatments in the front-line setting are listed in NCCN for these patients however none of them are very effective. The CAPTIVATE trial is currently on going looking at venetoclax along with ibrutinib in the upfront setting.

Is summary, as far as front line therapy is concerned, for fit patients with IGVH mutated status it is reasonable to use chemo-immunotherapy such as FCR or BR. All other patients including young or older patients with high risk disease such as those with unmutated IGHD, 17p del or p53 mutation or 11q deletion it's recommended to treat with a novel agent such as ibrutinib as there has been accumulating evidence of better efficacy when compared to chemoimmunotherapy alone.

#### **4.3 Relapsed or refractory chronic lymphocytic leukemia**

### *4.3.1 Definitions*

*Advances in Hematologic Malignancies*

compared to FCR [38].

patients with CLL.

On a similar note, the COMPLEMENT 1 trial showed the combining ofatumumab to chlorambucil in fludarabine ineligible patients showed better PFS (22.4 months) as compared to the monotherapy arm (13.1 months) [36].

However, with the advent of novel agents the landscape of treatment in CLL has significantly changed. The RESONATE-2 study compared single agent chlorambucil to ibrutinib which is a Bruton's Tyrosine Kinase inhibitor. The ORR (92% v/s 36%) as well as PFS at 2 years (89% v/s 34%) in favor of ibrutinib (**Figure 1**). Based on the results of this study ibrutinib was approved for use in the first line setting of CLL. Results from the ECOG ACRIN Cancer research group trial E1912 were recently published. The study compared FCR versus Ibrutinib + Rituxan (IR) in treatment naive patients without deletion 17p. IR was found to be superior to FCR in all subgroups except for the IGHV mutated group. IR group saw significant less neutropenia and infectious complications as well as

The alliance intergroup study showed that in older patients above 65, ibrutinib should be the standard of care as PFS was better in the ibrutinib arms then the BR arms [39]. However this study did not suggest a benefit of adding anti-CD 20 MAB therapy to ibrutinib monotherapy. In the older patient group, where chlorambucil is a treatment option, the iLLUMINATE trial showed that ibrutinib plus obinutuzumab combination resulted in better PFS as compared to chlorambucil plus obinutuzumab, albeit with greater serious adverse events [40]. Between the RESONATE-2 study and ECOG ACRIN study, ibrutinib has been established a first line recommendation in both younger as well as older

Recently, CLL14 trial studied the combination of fixed-duration venetoclax and obinutuzumab versus obinutuzumab and chlorambucil in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were evenly randomized to receive 12 months of venetoclax alongside 6 months of obinutuzumab or 6 months of obinutuzumab followed by 6 months of chlorambucil. Results from the trial showed the venetoclax combination reduced the risk of disease progression or death by 67% versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions (HR, 0.33; 95% CI, 0.22-0.51; P < .0001). The overall response rate (ORR) was 85% with venetoclax/ obinutuzumab versus 71% in the control arm (P = .0007). The complete response (CR) or CR with incomplete hematologic recovery (CRi) rates were 50% versus 23%, respectively. The rate of minimal residual disease (MRD)-negativity in the bone marrow was 57% in the venetoclax arm compared with 17% in the obinutuzumab/chlorambucil arm. The MRD-negativity rates in the peripheral blood were

**104**

**Figure 1.**

*Progression-free survival of Ibrutinib vs. Chlorambucil [37].*

The International Workshop on CLL (iwCLL) defines relapsed disease when it occurs in patients who have previously achieved either a complete or partial remission but then develop progressive disease after a period of 6 months or more. Patients who fail to achieve either a partial or complete remission with therapy or those who develop disease progression within 6 months of last therapy are defined to have refractory disease. This distinction is principally made because many patients with progressive disease occurring later after the discontinuation of treatment can be successfully retreated using the same medication, or by switching to other available treatments. In contrast, patients who have refractory disease are unlikely to respond to a trial of the previously used therapy and have a much poorer prognosis [2]. Of note, The iwCLL response criteria were originally developed using data from patients treated with single agents (i.e., fludarabine, chlorambucil). As first-line therapy has evolved, the overall response rate and median progression-free survival have increased. The definitions of relapsed and refractory disease will likely change as therapy improves especially that we depend on expected progression free survival (PFS) in practice more than the 6 months rule to choose the next regimen as illustrated below.

The choice of treatment at relapse should consider how soon the relapse happens after initial treatment. If it happens sooner than the expected median PFS for the specific regimen is considered "Early relapse", while it is considered "Late relapse" when it happens after the expected median PFS [42]. Prospective trials have reported median PFS for different regimens, as a rule of thumb, progression within 2–3 years of initial treatment with fludarabine, cyclophosphamide, and rituximab (FCR) or within 1 year of other chemoimmunotherapy regimens may be considered to have early relapse.

#### *4.3.2 Targeted therapies of relapsing or refractory CLL*

For early relapsing CLL, it's recommended to start a targeted therapy with either ibrutinib, idelalisib plus rituximab, or venetoclax with or without rituximab rather than retreatment with the prior therapy or a trial of another chemoimmunotherapy

regimen. One series reported the median survival of 42 patients unresponsive to fludarabine as 48 weeks and only 11% responded to other chemoimmunotherapies [43]. The optimal length of treatment has not been defined but common practice to continue until disease progression or unacceptable toxicity.

Ibrutinib: it is a common treatment of choice for patients with refractory or early relapsing disease. Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor [44]. The RESONATE trial which is a multicenter open label phase III trial showed better overall response rate (ORR), PFS, and overall survival (OS) compared to ofatumumab (an anti-CD20 monoclonal antibody) in patients with refractory/ relapsed CLL, these benefits were found across all subgroups of patients, including those with high-risk features such as del(17p). This late observation was confirmed in the RENONATE-17 trial in 2016 where ORR was 83% at a median follow up of 28 months in 144 patients with relapsed/refractory CLL/SLL with del(17p) [45, 46]. Expected side effects from ibrutinib include diarrhea, fever, and nausea. Higher rates of atrial fibrillation (6–16%) and pneumonitis were noted in the clinical trials [47], atrial fibrillation is usually manageable without discontinuation of the drug. Another important side effect is increased risk of bleeding, ibrutinib should be used with caution if patient is on one anti-platelet medicine and should be avoided if on two anti-platelets or anticoagulants as fatal cases of bleeding happened in those scenarios. Also, Ibrutinib should be discontinued 3–7 days before and after surgery to decrease risk of perioperative bleeding. Patients should be also reminded to avoid NSAIDs [48]. Ibrutinib is associated with a usually "transient" lymphocytosis that peaks after approximately 4–8 weeks and resolves in the majority despite continued drug exposure with a median duration of 14 weeks. The starting dose of ibrutinib is 420 mg orally once daily, except for patients with mild liver impairment (child-pugh class A), the starting dose is reduced to 140 mg daily since it's metabolized in the liver and is contraindicated in moderate to severe liver impairment.

Idelalisib: It is an oral inhibitor of phosphoinositide 3′-kinase (PI3K) delta. It is given in combination with Rituximab. A phase 3 multicenter trial compared Idelalisib and rituximab vs. placebo and rituximab in 220 patients with relapsed CLL showed superior ORR, PFS, and OS (81%, 93%, and 92%, respectively), these benefits were seen in all prespecified subgroups, including those with 17p deletion, TP53 mutation, and IGHV mutations [49]. Possible side effects include: pneumonia and febrile neutropenia most commonly, but also fatigue, nausea, and diarrhea have been reported. Idelalisib can cause severe elevations in AST and ALT, it is reversible on holding the drug and never led to permanent discontinuation in clinical trials. The starting dose is 150 mg twice daily. Other possible combinations are Idelalisib plus Bendamustine plus Rituxan or idelalisib plus ofatumumab, those combinations led to more grade 3 toxicities and treatment related deaths, respectively, so extreme caution should be paid while choosing patients for these combinations [50, 51]. As with ibrutinib, idelalisib can cause transient lymphocytosis that peaks in the second week of treatment and resolves spontaneously by week 12, adding Rituximab decrease its severity and shortens its duration. CMV monitoring and prophylaxis against Pneumocystis pneumonia (PCP) are important with idelalisib use. It carries a boxed warning regarding hepatotoxicity, colitis, and pneumonitis.

Duvelisib: it is an oral inhibitor of PI3K delta and gamma isoforms. The phase 3 DUO trial was the largest trial to study the efficacy of duvelisib, it included 319 patients assigned to duvelisib vs. ofatumumab. Duvelisib had higher ORR and median PFS (74% and 13.3 months, respectively) [52]. Duvelisib is usually reserved for patients with multiply relapsed disease, usually after treatment with ibrutinib and venetoclax, with or without prior chemoimmunotherapy. The starting dose is 25 mg administered orally twice a day over a 28-day treatment cycle. Toxicities

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more frequent [56].

targeted therapy.

*Chronic Lymphocytic Leukemia: Rapidly Changing Treatment Landscape*

include opportunistic infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Hepatic function and blood counts must be monitored for hepatotoxicity and neutropenia. Like idelalisib, it is recommended to use PCP and CMV

Venetoclax: it is an oral inhibitor of BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of CLL cells. Initial phase 2 trials showed ORR more than 65% for venetoclax [53, 54]. The MURANO trial, an international phase 3 trial, compared Venetoclax plus rituximab vs. bendamustine plus rituximab in 389 patients with relapsed/refractory CLL showed higher PFS of 85% and OS of 92% at 2 years for the venetoclax arm, this effect was maintained in high risk patients and older adults. Patients assigned to venetoclax arm were also more likely to achieve undetectable minimal residual disease (uMRD) which is a status predictive of superior PFS [55]. The most common toxicities are pancytopenia, diarrhea, and upper respiratory tract infection. Because venetoclax increases risk of TLS, high risk patients (i.e. any lymph node >10 cm or lymph node >5 cm and ALC >25 x 109/L) should receive the first few doses in the inpatient setting with IV hydration, use of allopurinol or rasburicase, and frequent monitoring of TLS labs. Venetoclax is started at 20 mg daily and increased gradually over 5 weeks to a final daily dose of 400 mg. Rituximab is started after the patient has completed the escalation schedule and received the 400 mg dose for 7 days. It is common practice

Although both options are valid in late relapsed CLL patients, each option has its advantages and disadvantages. Targeted therapy is generally the preferred option because they have better PFS and may improve OS, the best example on that is the MURANO trial mentioned above, patients who relapsed after 24 months of initial treatment with bendamustine and rituximab were included in the study, and still they had better PFS and OS [55]. Targeted therapy also offers the convenience of an oral regimen. On the other hand, retreatment with initial chemoimmunotherapy regimen may be considered for patients who experienced minimal toxicity with the initial treatment, targeted therapy is associated with unique toxicities and is often administered without breaks until the time of progression. In a phase 2 study, patients who were initially treated with FCR and relapsed after 3 years showed median survival of 5 years and estimated five-year survival rate of 70% when they were retreated with FCR, although the toxicities, especially myelosuppression, were

**Fludarabine-based therapy**: Fludarabine, cyclophosphamide, plus rituximab

**Bendamustine-based therapy**: Bendamustine plus rituximab (BR) is an acceptable alternative to fludarabine-based regimens among patients with decreased renal function or other comorbidities. BR is well tolerated, but appears to be slightly less effective than fludarabine-based regimens [57]. The most common toxicities are neutropenia, thrombocytopenia, and anemia [58]. Infusion is associated with a

**Ofatumumab-based therapy**: Single agent ofatumumab has demonstrated partial response rates of approximately 50% in patients with relapsed or refractory CLL, although response duration is usually short [59]. The combination of ofatu-

mumab plus chlorambucil is expected to result in higher response rates.

(FCR) is a preferred treatment option for younger patients (<70 years) with standard-risk CLL. Patients with del(17p) or *TP53* mutations have particularly poor outcomes following fludarabine-based therapy and should be considered for

hypersensitivity reaction in approximately 5% of patients.

*DOI: http://dx.doi.org/10.5772/intechopen.88070*

to use venetoclax after ibrutinib failure.

*4.3.3 Late relapse: Retreatment versus targeted therapy*

prophylaxis.

*Chronic Lymphocytic Leukemia: Rapidly Changing Treatment Landscape DOI: http://dx.doi.org/10.5772/intechopen.88070*

*Advances in Hematologic Malignancies*

regimen. One series reported the median survival of 42 patients unresponsive to fludarabine as 48 weeks and only 11% responded to other chemoimmunotherapies [43]. The optimal length of treatment has not been defined but common practice to

Ibrutinib: it is a common treatment of choice for patients with refractory or early relapsing disease. Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor [44]. The RESONATE trial which is a multicenter open label phase III trial showed better overall response rate (ORR), PFS, and overall survival (OS) compared to ofatumumab (an anti-CD20 monoclonal antibody) in patients with refractory/ relapsed CLL, these benefits were found across all subgroups of patients, including those with high-risk features such as del(17p). This late observation was confirmed in the RENONATE-17 trial in 2016 where ORR was 83% at a median follow up of 28 months in 144 patients with relapsed/refractory CLL/SLL with del(17p) [45, 46]. Expected side effects from ibrutinib include diarrhea, fever, and nausea. Higher rates of atrial fibrillation (6–16%) and pneumonitis were noted in the clinical trials [47], atrial fibrillation is usually manageable without discontinuation of the drug. Another important side effect is increased risk of bleeding, ibrutinib should be used with caution if patient is on one anti-platelet medicine and should be avoided if on two anti-platelets or anticoagulants as fatal cases of bleeding happened in those scenarios. Also, Ibrutinib should be discontinued 3–7 days before and after surgery to decrease risk of perioperative bleeding. Patients should be also reminded to avoid NSAIDs [48]. Ibrutinib is associated with a usually "transient" lymphocytosis that peaks after approximately 4–8 weeks and resolves in the majority despite continued drug exposure with a median duration of 14 weeks. The starting dose of ibrutinib is 420 mg orally once daily, except for patients with mild liver impairment (child-pugh class A), the starting dose is reduced to 140 mg daily since it's metabolized in the liver

continue until disease progression or unacceptable toxicity.

and is contraindicated in moderate to severe liver impairment.

a boxed warning regarding hepatotoxicity, colitis, and pneumonitis.

Duvelisib: it is an oral inhibitor of PI3K delta and gamma isoforms. The phase 3 DUO trial was the largest trial to study the efficacy of duvelisib, it included 319 patients assigned to duvelisib vs. ofatumumab. Duvelisib had higher ORR and median PFS (74% and 13.3 months, respectively) [52]. Duvelisib is usually reserved for patients with multiply relapsed disease, usually after treatment with ibrutinib and venetoclax, with or without prior chemoimmunotherapy. The starting dose is 25 mg administered orally twice a day over a 28-day treatment cycle. Toxicities

Idelalisib: It is an oral inhibitor of phosphoinositide 3′-kinase (PI3K) delta. It is given in combination with Rituximab. A phase 3 multicenter trial compared Idelalisib and rituximab vs. placebo and rituximab in 220 patients with relapsed CLL showed superior ORR, PFS, and OS (81%, 93%, and 92%, respectively), these benefits were seen in all prespecified subgroups, including those with 17p deletion, TP53 mutation, and IGHV mutations [49]. Possible side effects include: pneumonia and febrile neutropenia most commonly, but also fatigue, nausea, and diarrhea have been reported. Idelalisib can cause severe elevations in AST and ALT, it is reversible on holding the drug and never led to permanent discontinuation in clinical trials. The starting dose is 150 mg twice daily. Other possible combinations are Idelalisib plus Bendamustine plus Rituxan or idelalisib plus ofatumumab, those combinations led to more grade 3 toxicities and treatment related deaths, respectively, so extreme caution should be paid while choosing patients for these combinations [50, 51]. As with ibrutinib, idelalisib can cause transient lymphocytosis that peaks in the second week of treatment and resolves spontaneously by week 12, adding Rituximab decrease its severity and shortens its duration. CMV monitoring and prophylaxis against Pneumocystis pneumonia (PCP) are important with idelalisib use. It carries

**106**

include opportunistic infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Hepatic function and blood counts must be monitored for hepatotoxicity and neutropenia. Like idelalisib, it is recommended to use PCP and CMV prophylaxis.

Venetoclax: it is an oral inhibitor of BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of CLL cells. Initial phase 2 trials showed ORR more than 65% for venetoclax [53, 54]. The MURANO trial, an international phase 3 trial, compared Venetoclax plus rituximab vs. bendamustine plus rituximab in 389 patients with relapsed/refractory CLL showed higher PFS of 85% and OS of 92% at 2 years for the venetoclax arm, this effect was maintained in high risk patients and older adults. Patients assigned to venetoclax arm were also more likely to achieve undetectable minimal residual disease (uMRD) which is a status predictive of superior PFS [55]. The most common toxicities are pancytopenia, diarrhea, and upper respiratory tract infection. Because venetoclax increases risk of TLS, high risk patients (i.e. any lymph node >10 cm or lymph node >5 cm and ALC >25 x 109/L) should receive the first few doses in the inpatient setting with IV hydration, use of allopurinol or rasburicase, and frequent monitoring of TLS labs. Venetoclax is started at 20 mg daily and increased gradually over 5 weeks to a final daily dose of 400 mg. Rituximab is started after the patient has completed the escalation schedule and received the 400 mg dose for 7 days. It is common practice to use venetoclax after ibrutinib failure.

#### *4.3.3 Late relapse: Retreatment versus targeted therapy*

Although both options are valid in late relapsed CLL patients, each option has its advantages and disadvantages. Targeted therapy is generally the preferred option because they have better PFS and may improve OS, the best example on that is the MURANO trial mentioned above, patients who relapsed after 24 months of initial treatment with bendamustine and rituximab were included in the study, and still they had better PFS and OS [55]. Targeted therapy also offers the convenience of an oral regimen. On the other hand, retreatment with initial chemoimmunotherapy regimen may be considered for patients who experienced minimal toxicity with the initial treatment, targeted therapy is associated with unique toxicities and is often administered without breaks until the time of progression. In a phase 2 study, patients who were initially treated with FCR and relapsed after 3 years showed median survival of 5 years and estimated five-year survival rate of 70% when they were retreated with FCR, although the toxicities, especially myelosuppression, were more frequent [56].

**Fludarabine-based therapy**: Fludarabine, cyclophosphamide, plus rituximab (FCR) is a preferred treatment option for younger patients (<70 years) with standard-risk CLL. Patients with del(17p) or *TP53* mutations have particularly poor outcomes following fludarabine-based therapy and should be considered for targeted therapy.

**Bendamustine-based therapy**: Bendamustine plus rituximab (BR) is an acceptable alternative to fludarabine-based regimens among patients with decreased renal function or other comorbidities. BR is well tolerated, but appears to be slightly less effective than fludarabine-based regimens [57]. The most common toxicities are neutropenia, thrombocytopenia, and anemia [58]. Infusion is associated with a hypersensitivity reaction in approximately 5% of patients.

**Ofatumumab-based therapy**: Single agent ofatumumab has demonstrated partial response rates of approximately 50% in patients with relapsed or refractory CLL, although response duration is usually short [59]. The combination of ofatumumab plus chlorambucil is expected to result in higher response rates.

Patients with CLL experience serial relapses and many will be treated with each of these agents at some point during their disease course. A preferred order for their use has not been established. A choice is primarily made based on the patient's prior treatment and the regimens' expected toxicities.


*Article* **Effect of Concurrent Resistance Training on Lower Body Strength, Leg Kick Swimming, and Sport-Specific Performance in Competitive Swimmers**

**Sofiene Amara 1,2,\* , Tiago Manuel Barbosa 3,4 , Oussama Gaied Chortane 1,2 , Raouf Hammami 1,5 , Ahmed Attia 1,2, Sabri Gaied Chortane 1,6 and Roland van den Tillaar 7,\***

**Simple Summary:** Resistance training in and out of the water aims to improve swimming performance. Previous studies have shown that dry land resistance training has positive effects on improving strength and therefore this could optimize swimming performance. The present study investigated the effect of 9 weeks of combined resistance training (aquatic and dry land resistance) on maximum lower body strength, leg kick, and swimming performance in competitive swimmers. The results demonstrated that 9 weeks of combined resistance training could improve the maximum lower body strength and leg kick swimming performance. These improvements can be the essential factors that subsequently positively affected swimming start and turn performance.

**Abstract:** The present study investigated the effect of 9 weeks of combined resistance training (aquatic and dry land resistance) on maximum lower body strength, leg kick, and swimming performance in competitive swimmers. Twenty-two male national competitive swimmers were randomly assigned into two groups: experimental group (EG: age = 16.2 ± 0.3 years) or control group (CG: age = 16.3 ± 0.3 years). The EG performed a combined resistance training while the CG group completed their usual training. One repetition maximum (1RM) back squat, 30 m leg kick, and swimming performance (100 m front crawl, start and turn) were evaluated in pre and post test. The findings showed a significant increase in 1RM back squat (d = 1.90; 14.94 ± 1.32%) after 9 weeks of combined resistance training. In addition, ours results revealed a significant improvement in 30 m leg kick swimming (d = 2.11; 5.84 ± 0.16%) and in all swimming, start and turn performances (d = 1.83 to 2.77; 2.69 ± 0.18% to 15.14 ± 1.06%) in EG. All dependent variables remained unchanged in the CG. To sum up, 9 weeks of combined resistance training can improve the maximum lower body strength and leg kick swimming performance. These improvements can be the essential factors that subsequently positively affected swimming, start and turn performances. Combined resistance training is an effective training that can be incorporated by coaches and swimmers into their programs to improve strength, leg kick swimming, and, subsequently, swimming performance in competitive swimmers.

**Keywords:** dry land training; one repetition maximum; back squat; water parachute; aquatic training; swimming performance

**Citation:** Amara, S.; Barbosa, T.M.; Chortane, O.G.; Hammami, R.; Attia, A.; Chortane, S.G.; van den Tillaar, R. Effect of Concurrent Resistance Training on Lower Body Strength, Leg Kick Swimming, and Sport-Specific Performance in Competitive Swimmers. *Biology* **2022**, *11*, 299. https://doi.org/10.3390/ biology11020299

Academic Editor: Johannes Vogel

Received: 3 January 2022 Accepted: 10 February 2022 Published: 12 February 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Over the years, the 100 m race times have been improved probably due to better aquatic and dry land training programs [1,2]. Concurrent resistance training on dry land and in water showed to be an effective approach to improve swimming performance [1,3,4]. Amara et al. [1] noted that nine weeks of concurrent resistance training could improve maximal upper body strength (12.11 ± 1.79%) and sprint performance in front crawl (4.2 ± 0.2% to 7.1 ± 0.2%) in male competitive swimmers (age = 16.5 ± 0.30 years). Moreover, Lopes et al. [3] reported a significant improvement in sprint swimming performance (4.0% to 4.3%) after eight weeks of dry land strength combined with swimming training in university swimmers of national level (age = 20.55 ± 1.76 years). However, most studies focus upon increasing strength in the upper body, while improving the performance of the lower limbs is also an important factor in determining swimming performance [1,5]. Morouço et al. [5] showed that a relative contribution of leg kick was 29.7% for male swimmers and 33.4% for females. In the same context, Bartolomeu et al. [6] revealed that swim velocity with leg kick was 59% compared with full front crawl velocity in competitive swimmers (age = 14.20 ± 1.71 years). Furthermore, the start and turn are among the most important factors in determining swimming performance these days in competition settings. Morais et al. [7] showed that the start and the turn phases combined accounted for 31% to 32% of the final race time in the four swimming strokes. Notwithstanding, lower body strength and power are found to be two very important underlying factors determining the performance of start and turn in competitive swimmers [8,9]. Thus, it is necessary to know more about the effect of combined resistance training on maximum lower body strength, leg kick swimming, and swimming performance.

Lower limbs strength routines (e.g., countermovement jumps (CMJ), squat, and leg extension) are heavily used in several dry land swimming training programs [3,10]. For instance, Lopes et al. [3] showed that eight weeks of dry land training, including full squat and CMJ exercises, could improve CMJ performance (6.77%) in national competitive swimmers. Moreover, Sammoud et al. [10] revealed that 8 weeks of dry land training based on plyometric jump training (CMJ) could optimize the performance of CMJ (24.5%) and the performance of 25 m front crawl swimming (6.33%) in prepubertal female swimmers (age = 10.0 ± 0.6 years). These authors [3,10] showed that lower body dry land training optimized strength and swimming performance, but the information about the transfer of strength gain in water remains insufficient. Hence, it is necessary to understand the effect of dry land training on leg kick swimming performance.

Resistance training in water with aquatic equipment (e.g., water parachute) is also an effective approach to improve the propulsive force [1,11]. Gourgoulis et al. [11] noted that 11 weeks of training with water parachute improved the performance in the 50, 100, and 200 m front crawl (3.2% to 7.3%) in competitive swimmers. Amara et al. [1] reported that the 50 m front crawl performance was improved after 9 weeks of resistance training in water with water parachute (4.22 ± 0.18%) in young competitive swimmers. Amara et al. [1] also showed that an aquatic resistance training program can improve the performance in the 50 m front crawl arm-pull (7.1 ± 0.23%). The question arises here, could resistance training with this aquatic equipment improve leg kick performance? If so, how efficient is the transfer of dry land strength improvement into in-water leg kick performance?

Training in water with additional resistance by the water parachute is shown to be an effective training to improve swimming performance [11]. However, information about the effect of combined resistance training (additional aquatic resistance in and dry land resistance) on leg kick and swimming performance remains insufficient. Therefore, the objective of this study was to investigate the effect of lower body strength and additional aquatic resistance training (using water parachute) on strength, leg kick, and swimming performance in competitive swimmers. We hypothesized that improving lower body strength could improve leg kick performance and subsequently optimize swimming performance.

#### **2. Materials and Methods**

#### *2.1. Experimental Approach to the Problem*

The present study was applied to examine the effect of combined resistance training (aquatic and dry land resistance training) during a nine-week intervention period on maximum lower body strength (1RM back squat) and swimming performance (100 m front crawl, 30 m leg kick swimming, start and turn performance) compared to standard training. All swimmers participated in a week of familiarization for resistance training in dry land and in the water. All dependent variables were measured pre and post test. All dry land training and testing were performed in the weight room, and all swimming training and testing were performed in a 50 m indoor pool with 27.1 and 25.9 ◦C water and air temperatures (respectively) and 64% relative humidity. All swimmers were asked to avoid all other intensive activities and avoid all stimulating nutrients during the entire experimental period.

#### *2.2. Subjects*

Twenty-two male national competitive swimmers were randomly assigned into two groups: experimental group (EG: *n* = 11, age = 16.5 ± 0.3 years; height: 174 ± 9.80 cm; body mass = 72.7 ± 5.30 kg) or control group (CG: *n* = 11, age = 16.1 ± 0.3 years; height: 175 ± 9.70 cm body mass 73.6 ± 5.25 kg). An a priori power analysis (G \* Power <IP_ADDRESS>, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany) yielded a sample size of at least 9 swimmers per group to detect large effects (d = 1.29), assuming a power of 0.8 and alpha of 0.05. All subjects had three years of experience in resistance training and 5 years of experience in resistance aquatic training. The best time of the fastest swimmer in 100 m front crawl was 57.08 s. All swimmers were informed about all research-related risks and potential benefits. All subjects and parents read and signed written informed consent. This study was approved by an institutional review board of Higher Institute of Sport and Physical Education of Ksar Said, University of Manouba, Tunisia (Research Unit of Sports Performance, Health & Society, UR17JS01) and conducted according to the last declaration of Helsinki.

#### *2.3. Procedures*

This study was integrated into the preparatory phase of the winter competition (September to December). All swimmers were conditioned to training and have started the training season at the same time (3 months before the experimental protocol). The study design consisted of a pretest followed-up by 9 weeks of intervention and a one-week pos test (Figure 1).

#### 2.3.1. Aquatic Resistance Training

The swimming training program was composed of six sessions per week with an hourly volume between 90 and 120 min, and swimming distance between 4000 and 6000 m per session. All-out sets of specific resistance training using only a leg kick (4 sessions in a week) were included in both training programs (EG and CG) immediately after the warm-up (800 m of aerobic training (55% to 80% of maximum heart rate). On Monday and Thursday, swimmers completed 3 sets × 6 reps × 15 m with 60 s and 5 min of rest between repetitions and sets, respectively. On Tuesday and Friday, swimmers completed 2 sets × 4 reps × 25 m with 90 s and 5 min of rest between repetitions and sets, respectively [1,11]. To eliminate the effect of arm stroke, specific resistance training was conducted with the aid of a kickboard, which was held by both hands. The experimental group completed the specific aquatic training with additional resistance using a small water parachute (288 cm2 ). The water parachute was attached to the swimmer's back by a 2 m-long rigid rope with a belt that was fasted around the swimmer's waist [1] (Figure 2).

jump box.

Biology 2022, 11, x 4 of 11

Figure 1. Overview of the study design. CMJ: countermovement jump; CMJ box: countermovement **Figure 1.** Overview of the study design. CMJ: countermovement jump; CMJ box: countermovement jump box. cm2). The water parachute was attached to the swimmer's back by a 2 m-long rigid rope with a belt that was fasted around the swimmer's waist [1] (Figure 2).

Figure 2. Set-up of water parachute during aquatic resistance training. **Figure 2.** Set-up of water parachute during aquatic resistance training.

#### 2.3.2. Lower Body Strength Training 2.3.2. Lower Body Strength Training

Figure 2. Set-up of water parachute during aquatic resistance training.

2.3.2. Lower Body Strength Training

Two non-consecutive sessions of lower body strength per week (separated by 48 h) were set up. Two strength and conditioning coaches designed and conducted the dry land training. Each session started with a 20 min standard warm-up featuring aerobic exercises (ergocycle and treadmill) and two sets of 8 to 10 reps of back squat with lower load (20% to 30% 1RM back squat). Subsequently, subjects performed three lower body strength exercises, which were back squat, countermovement jump (CMJ), and CMJ box with moderate contraction velocity and complete motion angle. The back squat exercise

was performed with an intensity between 60% and 80% of 1RM. The sets varied between 2 and 3 and repetitions between 6 and 10. A custom power rack and a standard Olympic weightlifting bar calibrated and certified (20 kg) were used to perform the back squat and to better control the technique of performing the exercise. Moreover, CMJ and CMJ box exercises consisted of 6 to 8 sets with 6 to 10 repetitions. The recovery between sets and exercises was fixed at 2 min (Table 1) [1,12,13]. The CG was invited to follow their usual training based on general body strength (2 sessions per week: 60 to 75 min per session). General body strength consisted of a general warm-up (cardiorespiratory adaptation and muscle stimulation), general strength exercises (pump-action, medicine ball throw, abdominal exercises), and muscle stretching.

**Table 1.** Detailed resistance training conducted by the experimental group.

1RM: one repetition maximum; CMJ: countermovement jump; CMJ box: countermovement jump box.

2.3.3. Maximum Lower Body Strength Test

On the first day of testing (at 10.00 am), subjects visited the weight room to determine the 1RM back squat test. The strength test was performed using a custom power rack and a standard Olympic weight lifting bar calibrated and certified (20 kg). Two strength and conditioning coaches controlled the execution of the exercises and conducted all measurements of the maximum back squat strength test.

All subjects completed a warm-up on an ergocycle for 3 min, followed-up by 5 min of overall static stretching. Thereafter, subjects performed 1 set of 8 reps and 1 set of 3 reps at 50% and 70% of their estimated 1RM back squat, respectively. The load was gradually increased (10% to 20%), 2 to 3 repetitions and 2 to 4 min of rest were performed. Thereafter, a small increase in the load (5%) and 2 to 4 min of rest were carried out to reach

the 1RM squat. The test was finished when the subjects failed to complete the squat, and the last successful attempt presents the 1RM back squat [14,15]. The intraclass correlation coefficient (ICC) for the pretest and posttest reliability was 0.93. Biology 2022, 11, x 7 of 11

#### 2.3.4. Swimming Performance Measurements

Swimming performance measurements were established on the second day of tests also at 10.00 am. The 100 m front crawl performance and the 30 m leg flutter kick swimming were measured by two qualified timekeepers per stopwatch (SEIKO S120-4030, Tokyo, Japan) and noted in seconds. The starting signal was given by the timers, and diving start was performed in the 100 m front crawl test, whereas a push-off start was used in the 30 m leg kick swimming [1]. The pretest and posttest reliability for 100 m front crawl was ICC = 0.91, and for the 30 m leg kick swimming, ICC = 0.93. 30 m leg kick swimming [1]. The pretest and posttest reliability for 100 m front crawl was ICC = 0.91, and for the 30 m leg kick swimming, ICC = 0.93. To determine the start and turn performances, three cameras (SNC VB 603, Sony, Tokyo, Japan; f = 50 Hz, full HD, 1080 p) were set at well-defined points laterally to the swimming pool about 5 m above the water surface and about 10 m away from the swim-

To determine the start and turn performances, three cameras (SNC VB 603, Sony, Tokyo, Japan; *f* = 50 Hz, full HD, 1080 p) were set at well-defined points laterally to the swimming pool about 5 m above the water surface and about 10 m away from the swimming lane to film the 100 m front crawl test (Figure 3) [1]. A video analysis system (Kinovea, version 0.8.15, Joan Charmant & Contrib., Kinovea.org, accessed on 3 January 2022) was used to evaluate: (i) start performances: Block time (the time lag between the starting signal and the instant the swimmer's feet left the block) and the 15 m time (the time lag between the starting signal and the swimmer's head reaching the 15 m mark). (ii) turn performance: the total turn (the time lag between reaching the 45 m mark and the 15 m mark of the following split) [7,16]. The pretest and posttest reliability of start and turn performances were 0.89 ≤ ICC ≤ 0.95. ming lane to film the 100 m front crawl test (Figure 3) [1]. A video analysis system (Kinovea, version 0.8.15, Joan Charmant & Contrib., Kinovea.org, accessed on 3 January 2022) was used to evaluate: (i) start performances: Block time (the time lag between the starting signal and the instant the swimmer's feet left the block) and the 15 m time (the time lag between the starting signal and the swimmer's head reaching the 15 m mark). (ii) turn performance: the total turn (the time lag between reaching the 45 m mark and the 15 m mark of the following split) [7,16]. The pretest and posttest reliability of start and turn performances were 0.89 ICC 0.95.

Figure 3. Set-up to analyze the start and turn performances. **Figure 3.** Set-up to analyze the start and turn performances.

2.4. Statistical Analyses

3. Results

.

large (d ≥ 1) [20]. The level of significance was established at p ≤ 0.05.

presented as mean and SD, mean difference, partial difference in percentage, and 95% confidence interval. The baseline between-group differences were computed through independent sample t-tests. Normality and sphericity of the data were tested and confirmed using Shapiro–Wilk test and Mauchly test, respectively. Pre and post test reliability was assessed using the intraclass correlation coefficient (ICC2,1) [17]. The standard error of measurement (SEM) was determined by SD of the pretest × √(1-ICC) [18]. Minimum detectable change (MDC) of all dependent variables was derived using SEM × √2 × 1.96, and MDC % was defined as ((MDC/mean of pretest) × 100) [18]. Two-way ANOVA was used to determine the change of strength and swimming performance between pre and post test. The effect size (ES) was assessed by converting partial Eta-squared to Cohen's d [19]. ES was classified as trivial (d < 0.25), small (0.25 ≤ d < 0.50), moderate (0.50 ≤ d < 1) and

#### *2.4. Statistical Analyses*

SPSS 26.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. All data are presented as mean and SD, mean difference, partial difference in percentage, and 95% confidence interval. The baseline between-group differences were computed through independent sample *t*-tests. Normality and sphericity of the data were tested and confirmed using Shapiro–Wilk test and Mauchly test, respectively. Pre and post test reliability was assessed using the intraclass correlation coefficient (ICC2,1) [17]. The standard error of measurement (SEM) was determined by SD of the pretest × √ (1-ICC) [18]. Minimum detectable change (MDC) of all dependent variables was derived using SEM × √ 2 × 1.96, and MDC % was defined as ((MDC/mean of pretest) × 100) [18]. Two-way ANOVA was used to determine the change of strength and swimming performance between pre and post test. The effect size (ES) was assessed by converting partial Eta-squared to Cohen's d [19]. ES was classified as trivial (d < 0.25), small (0.25 ≤ d < 0.50), moderate (0.50 ≤ d < 1) and large (d ≥ 1) [20]. The level of significance was established at *p* ≤ 0.05.

#### **3. Results**

No significant difference in the baseline values between both groups in anthropometrics, swimming performance, and maximum strength test were shown (*p* > 0.05). Significant main effects of time, group, and time × group interaction were shown in all dependent variables (*p* < 0.05).

A significant improvement in 1RM back squat (14.94 ± 1.32%, *p* < 0.001, ES = 1.90 (large)) in EG was found while the 1RM back squat weight remained unchanged in CG (*p* > 0.05, Table 2).

**Table 2.** Changes in the maximum lower body strength, swimming, start and turn performances between the pre and post test in the experimental (EG) and control groups.

MDC: minimal detectable change; ∆: delta change (pre test to post test).

In addition, significant improvement was found in 100 m front crawl (4.41 ± 1.39%, *p* = 0.001, ES = 1.83 (large)) and in 30 m leg kick swimming (5.84 ± 0.16%, *p* < 0.001, ES = 2.11 (large)) after 9 weeks of intervention period in the experimental group, but not in the control group (Table 2).

Also a significant improvement in all start performances (15 m time: 2.69 ± 0.18%, *p* < 0.001, ES = 2.77 (large); block time: 15.14 ± 1.06, *p* < 0.001, ES = 2.61 (large)) and in turn performance (total turn: 2.88 ± 0.08, *p* = 0.001, ES = 1.85 (large)) in the experimental group, while no significant changes in any of these parameters were observed in the control group (*p* > 0.05, Table 2).

#### **4. Discussion**

The aim of the present study was to investigate the effect of concurrent resistance training in water (parachute) and dry land on maximum lower body strength, leg kick, and swimming performances in competitive swimmers. The main results showed significant increases in strength and all swimming variables after nine weeks of combined resistance training, while the control groups did not have positive improvements in any of the selected variables.

Combined resistance training for nine weeks increased the 1RM back squat by 14.94 ± 1.32%. This improvement is in accordance with previous studies conducting dry land interventions between 8 and 10 weeks and intensity between 60% and 80% 1RM [2,21,22]. Garrido et al. [21] also showed that eight weeks of resistance dry land training that included leg extension (intensities between 50% and 75% of the 1RM), CMJ and CMJ box exercises with 2 to 3 sets and 5 to 8 repetitions improved the performance of the 6RM leg extension (55.6%) in young competitive swimmers (12.08 ± 0.76 years). Likewise, Kubo et al. [22] showed 11.3 ± 8.6% improvement in the 1RM half squat performance after 10 weeks of lower limb training (full squat and half squat exercises) in healthy male subjects (age = 20.9 years). In addition, Amara et al. [2] reported that nine weeks of different strength training load including leg extension exercise (high load: 5 to 6 sets and 3 to 5 repetitions; moderate load: 4 to 5 sets and 3 to 5 repetitions; low load: 3 to 4 sets and 3 to 5 repetitions) with intensity between 85% and 95% 1RM leg extension improved the 1RM leg extension (9.87% to 19.82%) in male competitive swimmers. Hence, 8–10 weeks of training at 60–80% of 1RM yields improvements in maximum and power strength of lower limb [2,21,22]. As such, the dry land program design for this research is as effective as others reported in the literature.

According to the previous literature, this study is the first investigation that studied the effect of combined resistance training on leg kick swimming performance; for this reason, it is challenging to benchmark these results against previous findings. Only, Konstantaki et al. [23] noted that training during six weeks based on leg kick training (3 sessions per week) could improve the performance of the 200 m leg kick swimming (6 ± 2%) in male competitive swimmers. Furthermore, the concurrent aquatic and lower limb resistance training improved the 30 m leg kick swimming performance (5.84 ± 0.16%), which is probably caused by the improvement in maximum lower body strength as suggested by the increased 1-RM squat results. More specifically, the transfer of force gain from the lower limb to the leg kick swimming was clearly evident in the EG (1.22 s) better than in the CG (0.22 s) with a difference of ≈1 s, and this explains the effective role of resistance lower limb training in improving the performance of the leg kick swimming in the water.

The 100 m front crawl times increased by approximately 2.63 s (4.41 ± 1.39%) after the concurrent resistance training. In fact, the increase in the maximum strength and the leg kick swimming performance in the EG (9.45 kg, 1.22 s, respectively) compared in the CG (1.46 kg, 0.22 s, respectively) could explain that the swimmers of EG make suitable use of the transfer of gain of force to improve the 100 m swimming performance (2.63 s) compared in CG (0.28 s) with a difference of ≈ 2.35 s. This present investigation is a complement to the previous study developed by Amara et al. [1]. Whereas Amara et al. [1] revealed an improvement of 25 m front crawl arm-pull (1.05 s) due to the transfer of force gain after the increase in maximum upper limb performance (5.45 kg), and subsequently, the sprint swimming velocity was optimized (0.16 ms−1 ). On the other hand, periodization and training planning plays an important role in further improving front crawl performance. Whereas, 8 to 9 weeks of concurrent resistance training during the preparatory phase could be sufficient to cope with the new imposed aquatic and in dry land training load and subsequently the improvement sprint swimming performance (4.22% to 6.82%) [1,3].

A start and turn performance improvement (2.96% to 15.14%) was shown after 9 weeks of concurrent resistance training, in which the contribution of the legs is predominant [5]. An increase in the force of pushing by the legs at the starting block level (start) and at the wall level (turn) due to the improvement in the maximum force of the lower limb can

explain these present results [24,25]. More specifically, the neuromuscular adaptations represented by the learning and coordination of the back squat exercise during the 9 weeks of training, the competitive level of the swimmers, which could favor the specificity of the adaptation to the training, and the transfer of gain of strength may be indirect evidence that justifies the results obtained at the start and turn level [26]. In addition, this study does not present any specific technical start and turn training; therefore, there is no change in the start and turn technique in the two groups. This could confirm the important contribution of maximum lower limb strength in the optimization of start and turn performance.

To sum up, 9 weeks of concurrent training included sets of aquatic resistance and dry land training with 1 to 2 sessions per week, 2 to 3 sets, 6 to 10 repetitions, and intensity between 60% and 80% of 1RM could improve the maximum lower limb strength and ultimately the optimization of swimming performance.

This study has some methodological limitations that warrant discussion. Perhaps the combined resistance training is a limitation because we do not know exactly what the partial contribution of each type of training (dry land vs. in water) is to strength improvement. The small sample size could also be a limiting factor in this study. In addition, the present study only includes male swimmers. Future studies must include female counterparts. Added to that, it is required to reproduce the combined resistance training reported here in other swim strokes (breaststroke, butterfly, and backstroke) and competitive levels. The effect of concurrent resistance training on certain physiological variables (cardiorespiratory adaptation to physical exertion) may also be a future field of study.

#### **5. Conclusions**

This study showed that 9 weeks of concurrent resistance training can improve the maximum lower limb strength. In addition, our findings showed that suitable transfer of strength gain to leg kick swimming, start and turn performance after the concurrent resistance training ultimately improved the 100 m front crawl performance. Concurrent resistance training included dry land exercises (back squat, CMJ, and CMJ box) with 1 to 2 sessions per week, 2 to 3 sets, 6 to 10 repetitions, and intensity between 60% and 80% of 1RM and aquatic resistance training with water parachute is an effective strategy that can be incorporated by coaches and swimmers into their training programs to improve sprint swimming performance in competitive swimmers.

**Author Contributions:** Conceptualization, S.A. and R.v.d.T.; formal analysis, S.A. and R.H.; methodology, S.A., A.A., and S.G.C.; writing—original draft, S.A. and R.H. and writing—review and editing, O.G.C., T.M.B., R.v.d.T., and R.H. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the ethical advisory committee of the Research Unit (UR17JS01) Sports Performance, Health and Society, Higher Institute of Sport and Physical Education of Ksar Saîd, Universite de la Manouba, Tunis, 2010, Tunisia.

**Informed Consent Statement:** Informed consent was obtained from all subjects and guardians involved in the study.

**Data Availability Statement:** The data presented in this study are available on reasonable request from the corresponding author.

**Acknowledgments:** The authors thank all the subjects who participated in this study.

**Conflicts of Interest:** The authors declare no conflict of interest.


**7.5 Radio-nuclear imaging**

Radio nuclear scan has been widely used for the detection of ectopic gastric mucosa especially in cases suspected to have Meckel's diverticulum (Kiratli et al., 2009). Technetium-99m pertechnetate scintigraphy can accurately localize the location of HGMP. The role and use of nuclear imaging in detecting HGMP/CIP remains unknown. One study reported its use in five patients with patches of gastric fundal type columnar epithelium in the proximal esophagus at the level of the upper esophageal sphincter diagnosed by upper endoscopy (Chen et al., 1989). In all instances, the patches contained both chief cells and mucus-secreting cells. Two cases of HGMP/CIP were demonstrated by TcO4-. Unfortunately, TcO4 accumulation in the thyroid glands of three patients caused overlapping activity between the thyroid gland and HGMP/CIP. It was concluded that TcO4- scintigraphy is only suitable for patients who have had a total thyroidectomy or are on suppressive thyroid therapy.

Fig. 8. Narrow band imaging showing an ectopic gastric mucosal patch as salmon coloured patch with greenish background

### **7.6 Contrast fluoroscopy/Barium swallows**

One study showed that careful fluoroscopy study can detect subtle abnormalities that may be due to HGMP/CIP (Takeji et al., 1995). This study detected 27 cases of HGMP/CIP confirmed on endoscopy and biopsy in 1,142 patients undergoing annual health check. The most common radiographic finding was a pair of small indentations on the wall of the esophagus (n=18). Other findings included a rim-like shadow (three patches), a pair of large indentations with a shallowly depression (two patches), one indentation (five patches), a small flat elevation (one patch), a serrated irregular outline (five radiologic lesions consisted of 11 patches), other various irregular outlines (two patches), and a polypoid area (one patch). One study using barium contrast swallow showed features similar to those described for esophageal webs and suggested that in fact, esophageal webs maybe due to HGMP/CIP (Ainley, 2011). This study clearly showed that HGMP/CIP produced the same imaging features of esophageal web on barium swallow. Chronic acid injuries lead to inflammations and subsequent healing results in a web or stricture formation. This has been referred to as type AA ring in contrast to the A (muscular ring) and B (Schatzki ring) rings in the distal esophagus.