A 54-year-old male was admitted to hospital in September 2003 with systemic lymphadenopathy, fatigue and night sweating. Computed tomography scans confirmed cervical, axillary, mediastinal, para-aortic, mesenteric and inguinal lymphadenopathies. Laboratory tests showed an elevated soluble interleukin-2 receptor (14,800 U/ml) and elevated WBC (113.3 x 109/l), comprised of 89% of abnormal lymphoid cells. The bone marrow (BM) was also massively invaded by abnormal lymphoid cells. Biopsy of the cervical lymph node disclosed the diagnosis of FL grade 3A. In immunohistochemical examinations, lymphoma cells were positive for CD10, Bcl-2, and CD20, and t(14;18)(q32;q21) translocation was detected by fluorescence in situ hybridization. Eight cycles of R-CHOP consisting of rituximab, cyclophosphamide, adriamycin, vincristine and prednisolone and subsequent maintenance therapy with rituximab for 8 months induced complete remission (CR), but the disease relapsed 8 months after the cessation of rituximab. Salvage chemotherapy consisting of rituximab and fludarabine induced a partial response, but the disease relapsed again after 14 months. For the second salvage therapy, the patient was enrolled in a clinical trial for treatment with everolimus, a new inhibitor of mammalian target of rapamycin. The drug induced CR, which sustained for 23 months, but lymphoma eventually relapsed (fig. 1a). A second biopsy of the cervical lymph node confirmed the diagnosis of relapsed FL without the evidence of transformation into a more aggressive lymphoma. Then, the patient underwent intensified chemotherapy using cyclophosphamide, high-dose Ara-C, dexamethasone, and etoposide (CHASE), radioimmunotherapy with 90Y ibritumomab tiuxetan and myeloablative chemotherapy with melphalan, cyclophosphamide, etoposide, and dexamethasone (LEED) supported by autologous HSCT. The patient achieved CR, which was confirmed by 18F-FDG-PET (PET) examination and BM analysis (no invasion and normal karyotype). However, 7 months after the transplantation, PET examination revealed generalized lymphadenopathy and uptake in the bilateral femoral nerve (suspected to be neurolymphomatosis). BM infiltration with abnormal lymphoid cells was also identified.
At this time, 81 months from the initial diagnosis of FL, we planned allogeneic HSCT using reduced-intensity conditioning (RIC). To reduce the tumor burden prior to RIC-HSCT, we administered three cycles of salvage therapy, comprised of rituximab and bendamustine, after which only minor cervical lymphadenopathy was identifiable by PET examination. However, myelosuppression accompanied by grade 4 neutropenia lasted for several weeks after the last dose of bendamustine, and BM analysis revealed hypocellularity with an increase in myeloblasts (5.2% of all nucleated cells) and multilineage dysplastic changes, which was documented in this case for the first time (fig. 2a). Chromosomal analysis revealed the presence of complex karyotypic abnormalities, including chromosome 7 deletion (fig. 2b). From these results, the diagnosis of t-MDS, refractory anemia with excess blasts-1, was made. Regarding the MDS International Prognostic Scoring System, the patient was classified as intermediate-2 risk category. Furthermore, the patient's condition was complicated by cytomegalovirus retinitis and required antiviral therapy for 4 weeks.
For simultaneous treatment of both chemotherapy-resistant FL and t-MDS, we performed RIC-HSCT with peripheral hematopoietic stem cells from his HLA-matched sibling (sister) 4 weeks after the diagnosis of t-MDS. At this time, the FL remained in partial remission. The conditioning regimen consisted of fludarabine (25 mg/m2 x 5 days), melphalan (80 mg/m2 x 1 day) and 4 Gy of total body irradiation (TBI). Cyclosporine A and short-term methotrexate were utilized as prophylaxis against graft-versus-host disease (GVHD). Neutrophil engraftment was confirmed on day 14 and platelet engraftment on day 22. There was no acute GVHD, and infectious complications, such as febrile neutropenia, Clostridium difficile-associated colitis, and reactivated cytomegalovirus retinitis, were treated successfully with antibiotics and antiviral agents. BM analysis on day 30 showed complete donor chimerism with a normal karyotype and without any myelodysplastic changes. The patient was discharged on day 56 and his condition was later complicated by chronic GVHD of the hepatic type that was alleviated successfully by re-dosing with cyclosporine A. PET examination on day 80 also showed no abnormal uptake (fig. 1b). Since then, CR of both FL and t-MDS has been maintained for 672 days at the timing of writing.