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Acute Lymphoblastic Leukaemia High-Dose Melphalan And Bone Marrow Transplantation (2004) 33, 1107–1114 & 2004 Nature Publishing Group All rights reserved 0268-3369/04 $25.00 www.nature.com/bmt Acute lymphoblastic leukaemia High-dose melphalan and autotransplantation followed by post transplant maintenance chemotherapy for acute lymphoblastic leukemia in first remission J Mehta1, R Powles, B Sirohi, J Treleaven, S Kulkarni and S Singhal1 Leukaemia Unit, The Royal Marsden Hospital, Surrey, UK Summary: We have attempted to improve1 the relatively poor results of high-dose therapy and autotransplantation in adult A total of 65 adults with acute lymphoblastic leukemia acute lymphoblastic leukemia (ALL)2–15 by administering (ALL)received 200 mg/m 2 melphalan and an autograft in maintenance chemotherapy with 6-mercaptopurine (6MP), first remission, with a plan to receive 6-mercaptopurine methotrexate (MTX) and vincristine–prednisone (VP) for 2 (6MP), methotrexate (MTX), and vincristine–prednisone years after transplantation. The results, using melphalan (VP)for 2 years afterwards. There was no transplant- with total-body irradiation (TBI) and autologous bone related mortality. In all, 69% of patients received 6MP, marrow initially and high-dose melphalan alone with 54% received MTX, and 49% received VP. The blood-derived stem cells subsequently, have been very cumulative incidence of relapse at 5 years was 52%. encouraging and strongly suggest that post transplant The 5-year probabilities of disease-free (DFS)and overall maintenance chemotherapy is useful.1 (OS)survival were 48 and 55%. Age 430 years, 44 Our previous report on the outcome of this strategy weeks to attain remission, and t(9;22)or t(4;11) included patients conditioned with melphalan-TBI as well karyotypes were adverse prognostic features. Patients as melphalan, and some patients who had received purged with 0 (standard risk), 1 (intermediate risk), and 2–3 (high marrow.1 The current report includes a homogeneously risk)adverse features had 5-year cumulative incidences of treated group of 65 patients conditioned with high-dose relapse of 19, 59, and 100% (Po0.0001), and 5-year melphalan (200 mg/m2) and receiving unpurged blood- probabilities of DFS of 80, 41, and 0% (Po0.0001). The derived stem cells; 42 of whom were included in the 5-year probabilities of DFS for patients receiving 0, 1, 2, previous report. The report provides longer follow-up (just and 3 maintenance therapy agents were 19, 40, 51, and over 10 years) and assesses applicability of this TBI-free 70% (P ¼ 0.0097). Maintenance therapy intensity was an treatment modality in older patients. Also, a significantly independent determinant of outcome in Cox analysis. larger proportion of patients in this group were treated with These data show that a high-dose melphalan-based a more intensive remission-induction and intensification autograft is safe and could be widely applicable in ALL regimen; allowing assessment of the contribution of the in first remission, and that maintenance chemotherapy intensity of the pre-transplant conventional therapy to very likely contributes to improved outcome of auto- outcome. grafted ALL patients. Bone Marrow Transplantation (2004) 33, 1107–1114. Patients and methods doi:10.1038/sj.bmt.1704517 Published online 12 April 2004 All data were gathered prospectively.16 All consecutive Keywords: 6-mercaptopurine; acute lymphoblastic patients over the age of 15 years who were autografted for leukemia; autotransplantation; high-dose melphalan; ALL in first CR between January 1993 and February 2003 methotrexate; prednisone; vincristine at the Leukaemia Unit of the Royal Marsden Hospital were included. Table 1 shows the patient characteristics. Autotransplantation was performed as the procedure of choice irrespective of the availability of matched sibling donors as part of our ‘sequential high-dose therapy’ approach; the idea being to perform a low-morbidity Correspondence: Dr J Mehta, 676 N St Clair Street, Suite 850, Chicago, autograft as the first step – followed by a salvage allograft IL 60611, USA; E-mail: [email protected] in second remission in relapsing patients. Exceptions to the 1Current address: Hematopoietic Stem Cell Transplant Program, sequential high-dose therapy approach included patients Division of Hematology/Oncology, The Feinberg School of Medicine, taking 48 weeks to attain CR, those with CNS disease and The Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. t(9;22) – who were allografted in first CR if an HLA- Received 10 November 2003; accepted 22 February 2004 matched sibling donor was available. Patients with t(9;22) Published online 12 April 2004 were preferentially transplanted from unrelated donors in PBSCT for ALL in CR1 J Mehta et al 1108 Table 1 Patient characteristics (n ¼ 65) chemotherapy protocol or similar combination induction- intensification. In total, 47patients received phase I Female 29 (45%) (weeks 1–4; vincristine 1.4 mg/m2  4, prednisolone 60 mg/ 2 2 Age (years) 32 (16–67) m  28, daunorubicin 60 mg/m  4, L-asparaginase 10000 U  10) and phase II (weeks 5–9; cyclophosphamide Presentation leukocyte count 5.7(0.1–602) 650 mg/m2  3, cytarabine 75 mg/m2  16, 6MP 60 mg/ 2 Karyotype m  28) induction therapy according to the United King- T(9;22)a 3 (5%) dom Medical Research Council’s adult UKALL XII t(4;11) 6 (9%) chemotherapy protocol, which is more intense. Induction Other clonal 28 (43%) chemotherapy was administered either at the Royal Normal 22 (34%) Marsden Hospital (n ¼ 37) or at other regional hospitals Not available 6 (9%) (n ¼ 28) from where the patients were referred for CNS disease at presentation 2 (3%) autografting in first CR. Immunophenotype B 51 (78%) Central nervous system prophylaxis T 8 (12%) Null 5 (8%) Patients received 2400 cGy cranial irradiation in 15 frac- Unknown 1 (2%) tions after hematologic recovery from intensification or phase II induction and before leukapheresis. No patient Induction therapy received testicular irradiation. Patients without CNS MRC UKALL X (or similar) 18 (28%) MRC UKALL XII (or similar) 47(72%) disease received six injections of intrathecal MTX (usually 15 mg) over the treatment period prior to the CR-transplant interval (weeks) 16 (1–90) transplant, and the two with CNS disease received triple intrathecal chemotherapy with MTX (15 mg), cytarabine Adverse prognostic factors Age 430 years 33 (51%) (30 mg), and hydrocortisone (100 mg) until six consecutive t(4;11) or t(9;22) 9 (14%) spinal fluid samples were free of disease. No intrathecal Time to CR 44 weeks 15 (23%) chemotherapy was administered post transplant based upon our observation that isolated CNS recurrence is Risk stratification exceedingly rare after transplantation in first remission Standard (0 adverse factors) 23 (35%) 17 Intermediate (1 adverse factor) 25 (38%) acute leukemia. High (2 adverse factors) 17(26%) Peripheral blood stem cell harvest aSix patients had Ph+ disease detected on conventional cytogenetic studies (G-banding). RT-PCR was not performed routinely. It is therefore possible The first seven patients received G-CSF (filgrastim) at the that the actual proportion of patients with Ph+ disease may be higher. dose of 125 mg/m2 subcutaneously q12 h starting 2 weeks after a back-up bone marrow harvest for a period of 7days. Stem cells were harvested on days 5–8 (4 consecutive days). the absence of a suitable sibling donor – which explains the The next 58 patients received 12–16 mg/kg filgrastim low number of patients with Ph þ disease in this series. subcutaneously q24 h on days 1–4, and stem cells were Patients with lymphoid blast crisis of chronic myeloid harvested on days 4 and 5. Leukapheresis was performed leukemia were not included. Patients with biphenotypic on a Cobe Spectra (Cobe Industries, Lakewood, CO, USA) disease (presence of myeloid markers) and those with continuous-flow cell separator with 150–200% of the Burkitt-type disease (FAB type L3) received different initial patient’s calculated blood volume being processed at each chemotherapy and were excluded. The transplants were session. performed as part of the standard therapy of adult ALL, and were not performed on a clinical protocol evaluating Cryopreservation and infusion the utility of transplantation. All research protocols were approved by the local institutional review board. All Cells were cryopreserved with 10% dimethylsulfoxide using patients gave informed consent for transplantation. a controlled-rate freezer and were stored in the vapor phase of liquid nitrogen. The cells were rapidly thawed in a water 1 Induction chemotherapy bath at 37 C by the bedside and infused within 2 weeks of collection. A total of 18 patients received induction (weeks 1–4; vincristine 1.5 mg/m2  4, prednisolone 40 mg/m2  28, 2 High-dose therapy and transplant daunorubicin 45 mg/m  2, L-asparaginase 6000 U/ m2  9) and early intensification therapy (weeks 5–6; The conditioning regimen comprised a single dose of vincristine 1.5 mg/m2  1, prednisolone 40 mg/m2  7, dau- 200 mg/m2 melphalan with hydration on day À1. All norubicin 45 mg/m2  2, etoposide 100 mg/m2  5, cytara- cryopreserved cells (excluding back-up marrow) were bine 100 mg/m2  10, 6-thioguanine 80 mg/m2  5) infused on day 0; 24 h after the administration of according to the United Kingdom Medical Research melphalan. No growth factors were administered post Council’s adult UKALL X Regimen B combination transplant to accelerate myeloid recovery. Bone Marrow Transplantation PBSCT for ALL in CR1 J Mehta et al 1109 Supportive care Table 2 Outcome by type of adverse feature All patients were treated in protective isolation in rooms Relapse DFS OS with positive-pressure ventilation. Blood products trans- Age fused were not screened for cytomegalovirus (CMV) 430 years 66 (50–85) 34 (17–52) 38 (20–55) antibody in CMV-seropositive patients.
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