To the best of our knowledge

To the best of our knowledge, only one other group studied low-dose protracted oral clofarabine in MDS patients who failed hypomethylating agents. They studied 5mg (fixed dose) daily for 10 consecutive days of a 28-day cycle. All patients who were treated for 10 days had a greater than 25% drop in their baseline counts with cycle one and received only seven days of treatment in subsequent cycles. The protocol was then modified to administer clofarabine for seven days which did not result in any significant toxicity. That study was prematurely terminated by the company after 19 patients were enrolled. This case demonstrates the potential of using protracted low-dose oral clofarabine in patients who failed hypomethylating agents, a group of patients with extremely poor outcome. We therefore propose that protracted low-dose oral clofarabine be studied in this patient population.
Contributions
Acknowledgments The protocol was partially supported by Genzyme (now Sanofi), by a grant from the National Cancer Institute Grant CA16056 (OAU, JDG, MW) and by the Nancy C. Cully Endowment for Leukemia Research (MW).
Case report In May 2010, a 63-year-old Japanese male was referred to our hospital with skin rash, fever, general fatigue, bilateral pharyngitis, multiple superficial lymphadenopathies, and weight loss of 10kg in 2 months. His white blood cell count was 9.8×109/L, of which 1.5% were atypical lymphoid cells. His hemoglobin level was 9.7g/dL and his platelet count was 79×109/L. His serum albumin, lactate dehydrogenase, and C-reactive protein levels were 24g/L, 363IU/L, and 11.54mg/dL, respectively. The results of other liver and renal function tests were <1.5 times the upper limits of normal. Although his serum immunoglobulin (Ig) G, IgA, and IgM levels were 3359, 246, and 252mg/dL, respectively, there was no evidence of monoclonal gammopathy. The Coombs test was positive, and tests for human immunodeficiency virus and human T-lymphotropic virus type I were negative. Epstein–Barr virus (EBV) antibody to viral (RS)-CPP antigen (EBVVCA) IgM was negative but EBVVCA IgG was positive. EBV antibody to nuclear antigen (EBNA) IgG was also positive. As positron emission tomography (PET)/computed tomography (CT) images revealed multiple superficial, intra-abdominal, and mesenteric lymphadenopathies that were accompanied by hepatosplenomegaly, a pharyngeal biopsy was performed. Microscopically, the biopsied tissue contained atypical, neoplastic CD3-positive T cells admixed with CD20-negative and EBV-encoded small RNA (EBER)-negative B cells (Fig. 1a). Based on these findings, the patient was diagnosed with peripheral T-cell lymphoma, not otherwise specified. Therefore, he was treated with six cycles of chemotherapy consisting of cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP). After chemotherapy, his blood test results had improved and there was no evidence of hepatosplenomegaly or lymphadenopathy on CT images, nor was there any abnormal accumulation of [18F]-fluorodeoxyglucose (18F FDG) on PET scans. The patient achieved complete remission (CR) in November 2010. However, 1 month later, disease recurrence was confirmed. Thereafter, he received low-dose etoposide, prednisolone, and cyclophosphamide, followed by low-dose methotrexate (MTX) and cyclosporine (CsA). Despite this regimen, we found enlargement of his lymph nodes, particularly of his left axillary lymph nodes, as their diameter was >10cm at this time (Fig. 2a). His serum monoclonal IgM level had also increased to 5445mg/dL. The patient\'s Eastern Cooperative Oncology Group performance status (PS) was 4. A repeat biopsy of the left axillary lymph node was performed in August 2011. A large number of non-neoplastic, CD20- and EBER-positive B cells and neoplastic CD3-positive T cells were found in the biopsy specimen (Fig. 1b). Therefore, the patient was finally diagnosed with angioimmunoblastic T-cell lymphoma (AITL). Based on the diagnosis of AITL with proliferation of CD20- and EBER-positive B cells, the patient was treated with rituximab monotherapy. Although the lymph node did not shrink rapidly, his serum IgM level decreased to 4200mg/dL following two cycles of once-weekly rituximab. He was then treated with four cycles of CHOP combined with rituximab (R-CHOP). The enlarged lymph nodes almost disappeared after this treatment, and his serum IgM level decreased to 800mg/dL. Abnormal 18F FDG accumulation was not detected on PET scans, although a small (2cm) lymph node was detected in the left axillary lymph node on a CT scan taken after four cycles of R-CHOP in January 2012 (Fig. 2b). The patient\'s condition improved dramatically, reaching a PS of 0 at this time. He ultimately completed six cycles of R-CHOP, and CR was maintained for 6 months until relapse in June 2012.