A novel regimen incorporating the concomitant administration of fludarabine and alemtuzumab for the treatment of refractory adult acute lymphoblastic leukaemia: a report of three cases

Treatment of refractory acute lymphoblastic leukaemia (ALL) in adults remains a challenge, with allogeneic stem cell transplant (SCT) representing the only potential curative intervention. Alemtuzumab, a humanized IgG1j anti-CD52 antibody, has been approved for fludarabine-resistant B-cell chronic lymphocytic leukaemia and has been evaluated in other lymphoid malignancies, including ALL (Laporte et al, 2004; Piccaluga et al, 2004; Tibes et al, 2006). However, the data for single-agent alemtuzumab in adult relapsed/refractory ALL appears modest. In previous reports involving 10 patients treated with single-agent alemtuzumab, complete remission (CR) was achieved in only one (Laporte et al, 2004; Piccaluga et al, 2004). Interestingly, the combination of alemtuzumab and fludarabine has been shown to be highly cytotoxic to CD52+ ALL cells in vitro (Golay et al, 2006). We report three cases of refractory adult ALL whereby the concomitant administration of alemtuzumab, fludarabine and polyethylene-glycol conjugated asparaginase (PEG-asparaginase) resulted in clearance of leukaemic blasts and enabled the successful use of allogeneic SCT. Case 1 was a 39-year-old female presenting with precursor B-cell ALL. The patient initially achieved CR with the Larson protocol (Larson et al, 1998) but subsequently relapsed 4 years later. Her ALL proved refractory to two salvage chemotherapy regimens, including hyper-fractionated cyclophosphamide, vincristine, adriamycin and dexamethasone (hyper-CVAD; Kantarjian et al, 2000) and methotrexate, vincristine, PEGasparaginase and prednisone (MOAP; Aguayo et al, 1999), with >60% leukaemic blasts persisting on serial bone marrow examinations. The patient then received FCM (fludarabine 25 mg/m days 1–3, cyclophosphamide 600 mg/m day 1, and mitoxantrone 8 mg/m day 1) in combination with PEGasparaginase 2500 U/m once every 2 weeks for two doses and alemtuzumab 30 mg subcutaneously 3 d per week starting on day 5 (11 doses total). A day + 35 bone marrow examination revealed near total bone marrow aplasia without morphological evidence of leukaemic blasts. Her course was complicated by Staphylococcus aureus bacteraemia. The patient required no further chemotherapy and successfully underwent a one antigen-mismatched unrelated donor SCT. She remained in CR for 8 months post-SCT but then suffered disease relapse and expired shortly thereafter. Case 2 involved a 50-year-old male with primary refractory biphenotypic leukaemia who had failed to achieve CR after having received four standard ALL regimens. The patient’s bone marrow examination revealed >75% leukaemic blasts with a peripheral white blood cell count of 10 · 10/l, including 10% leukaemic blasts. He was given FLAG (fludarabine 30 mg/m days 1–5, Ara-C 2000 mg/m days 1–5, and G-CSF 300 lg/d) in combination with PEG-asparaginase 2500 U/m once every 2 weeks for two doses and alemtuzumab 30 mg subcutaneously 3 d per week starting on day 6 (14 doses total). The patient was noted to have progressive clearance of lymphoblasts from his peripheral blood and subsequently developed persistent pancytopenia over the next 28 d, with a day + 42 bone marrow examination revealing bone marrow aplasia with no morphological evidence of leukaemia (Fig 1). The patient’s course was complicated by neutropenic fevers and vancomycin-resistant enterococcal bacteraemia. He subsequently underwent a successful matched-sibling donor allogeneic SCT and remains in CR 2 years later. Case 3 was a 24-year-old male with precursor B-cell ALL who initially achieved CR with induction chemotherapy but subsequently relapsed within 8 months with ALL that proved resistant to hyper-CVAD, intravenous methotrexate and FLAG. Bone marrow examination revealed >40% leukaemic blasts without peripheral blood involvement. FCM in combination with PEG-asparaginase and alemtuzumab (14 doses total) was initiated as described in case 1. The patient’s course was complicated by Listeria bacteraemia. By day + 42 the patient’s pancytopenia began to resolve and subsequent bone marrow examination revealed trilineage hematopoiesis consistent with CR. The patient subsequently underwent a successful matched unrelated donor SCT and remains in a CR 6 months post-SCT. In all cases, patients presented with relapsed leukaemia which had proved refractory to numerous salvage regimens commonly used in ALL. Although bone marrow examinations revealed >30% involvement with leukaemia prior to the initiation of therapy, all cases exhibited a relatively low burden of disease, with only minimal peripheral blood involvement with leukaemia in one case and absence of hepatosplenomegaly or bulky lymphadenopathy. In addition to the three cases described here, we used this precise regimen in one other patient with refractory pre-B cell ALL. However, this patient withdrew from the regimen early in the course of therapy and opted for supportive care, making it impossible to assess the effectiveness of the regimen in this case. Correspondence