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Asparaginase As Consolidation Therapy in Patients Undergoing Bone Marrow Transplantation for Acute Lymphoblastic Leukemia

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Asparaginase As Consolidation Therapy in Patients Undergoing Bone Marrow Transplantation for Acute Lymphoblastic Leukemia Bone Marrow Transplantation, (1998) 21, 879–885 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Toxicity, pharmacology and feasibility of administration of PEG-L- asparaginase as consolidation therapy in patients undergoing bone marrow transplantation for acute lymphoblastic leukemia ML Graham1, BL Asselin2, JE Herndon II3, JR Casey1, S Chaffee1, GH Ciocci1, CW Daeschner4, AR Davis4, S Gold6, EC Halperin7, MJ Laughlin1, PL Martin8, JF Olson1 and J Kurtzberg1,9 Departments of 1Pediatrics, 3Community and Family Medicine, 5Pharmacy, 7Radiation Oncology and 9Pathology, Duke University Medical Center, Durham, NC; 2Department of Pediatrics, University of Rochester, Rochester, NY; 4Department of Pediatrics, Eastern Carolina University School of Medicine, Greenville; 6Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill; 8Department of Pediatrics, Bowman-Gray School of Medicine, Winston-Salem, NC, USA Summary: for bone marrow transplantation have occasionally been successful, but usually at the price of higher morbidity and We attempted to administer PEG-L-asparaginase (PEG- mortality rates, since most preparative regimens employ L-A) following hematologic recovery to 38 patients maximal or near maximal radiation and chemotherapy undergoing autologous or allogeneic marrow transplan- doses.6–8 tation for acute lymphoblastic leukemia (ALL). Twenty- Other strategies for reducing relapse have been explored. four patients (12 of 22 receiving allogeneic and 12 of 16 Since the development of graft-versus-host disease receiving autologous transplants) received between one (GVHD) in some series of allogeneic BMT has been asso- and 12 doses of PEG-L-A, including nine who com- ciated with a diminished relapse rate,9–12 Sullivan et al13 pleted the planned 12 doses of therapy. The toxicities restricted prophylaxis in order to promote an antileukemic encountered were similar to those observed in non- effect, but found a higher rate of severe GVHD and no transplanted patients undergoing therapy with PEG-L- improvement in overall disease-free survival. Recent trials A and included allergic reactions, pancreatitis, weight in autologous marrow transplantation attempting to induce loss, hypoalbuminemia, and low levels of anti-thrombin a graft-versus-leukemia effect have focused on the use of III. Of the 24 who received the drug, eight remain in immune-modulators such as cyclosporin A,14,15 interferon remission. Of 12 patients in second remission at the time alpha-2b,16,17 linomide,18 and interleukin-2.19–21 The value of transplantation who received PEG-L-A, five of seven of these therapies continues to be explored. who received allogeneic and two of five who received Results from the International Bone Marrow Transplant autologous transplants remain in remission, 16+ to 46+ Registry22 suggested that the use of methotrexate as post- months from transplant. While PEG-L-A could be transplant GVHD prophylaxis was associated with a dimin- administered to most of the patients undergoing mar- ished relapse rate, and led some groups to question if post- row transplantation for ALL, most patients either BMT chemotherapy might be useful. Weisdorf et al10 relapsed while receiving the drug or developed toxicities attempted to deliver chemotherapy with 6-mercaptopurine which resulted in abbreviated courses. At this time, we (6-MP) and methotrexate (MTX) to patients undergoing cannot recommend PEG-L-A as single agent, post- allogeneic BMT for ALL following hematopoietic reconsti- BMT chemotherapy. tution. Patients were randomized to receive further therapy Keywords: pediatric; acute lymphoblastic leukemia; with oral 6-mercaptopurine, 50 mg/m2/day and methotrex- transplantation; l-asparaginase; relapse ate 10 mg/m2/week. Patients randomized to post-transplant chemotherapy received an average of only 60% of the intended chemotherapy, and the authors concluded there was no benefit to receiving the additional treatment (seven Relapse is the predominant cause of treatment failure in of 13 relapses after or during chemotherapy as opposed to pediatric patients undergoing allogeneic or autologous bone six of 14 relapses in patients receiving none). Tiley et al23 marrow transplantation for acute lymphoblastic leukemia administered 6-MP and MTX to 26 patients of a group of (ALL) beyond first remission. Relapse rates of 20–50% 38 who had undergone autologous BMT for high-risk ALL have been reported for patients undergoing allogeneic BMT in first remission. Patients tolerated about 50% of the pro- and 50–80% for patients undergoing autologous BMT for jected treatment. The authors noted a 5-year survival of 1–5 advanced ALL. Attempts to reduce the frequency of leu- 49% in this population, similar to that of a group of patients kemic recurrence by intensification of preparative regimens treated with chemotherapy without ABMT, but could not determine the contribution of the maintenance therapy to event-free survival. Correspondence: Dr ML Graham, Department of Pediatrics, Room 3336, University of Arizona Health Sciences Center, PO Box 245073, Tucson, An agent useful for post-transplant chemotherapy would AZ 85724, USA ideally have little myelosuppressive effect (so as not to Received 26 August 1996; accepted 2 December 1997 endanger the marrow graft), would not show cross-resist- PEG-L-asparaginase following BMT for ALL ML Graham et al 880 ance with the agents used for the transplant regimen and Table 1 Characteristics of patients receiving and not receiving PEG- would be one to which most patients’ leukemia would still l-asparaginase be sensitive. l-Asparaginase may be such an agent. Although it is moderately immunosuppressive,24–26 it is Patients receiving Patients not 27 PEG-L-A receiving usually not myelosuppressive; it has a unique mechanism PEG-L-A of action among available agents,28 and no evidence of cross-resistance to other anti-cancer drugs. Although almost Number 24 14 all relapsing ALL patients will have received the drug pre- Male:female 15:9 7:7 viously, l-asparaginase can be used repeatedly as part of Median age (standard deviation) 8.7 (5.2) 12.0 (5.0) successful remission induction,29–31 suggesting that past in years at BMT Remission status exposure does not preclude an antileukemic response. CR1 2 2 Based on this rationale, we undertook a trial of post- CR2 12 9 transplant PEG-l-asparaginase (PEG-L-A) for patients CR3 or CR4 7 1 undergoing allogeneic or autologous BMT for ALL. PEG- Relapse 3 2 L-A was particularly attractive as a post-BMT agent Disease 32–34 Early B-lineage ALL 19 11 because its diminished immunogenicity might result in T cell disease 5 3 a lower allergy rate for patients with reconstituting immune Type of BMT systems and because its sustained activity after adminis- Autologous 12 4 tration might allow for fewer injections than conventional Allogeneic 12 10 35–38 Preparative regimen formulations. Mel/TBI/Cyclo 12 9 We describe below a pilot study which attempted to TBI/Cyclo 7 4 determine, specifically: (1) whether PEG-L-A could be BU/Cyclo 1 1 administered following recovery from allogeneic or auto- BU/Mel 3 0 logous BMT in patients with acute lymphoblastic leukemia; Mel/TBI 1 0 (2) the toxicity of PEG-L-A in this group of patients; and CR = complete remission; Mel = melphalan; TBI = total body irradiation; (3) the asparaginase pharmacokinetics following the first Cyclo = cyclophosphamide; BU = busulfan. dose in this group of patients. USA); eight marrows were further purged with etoposide, Patients and methods and one was purged with antibodies, etoposide, and 4-hyd- roperoxycyclophosphamide. Patients undergoing allogeneic 8 Patients transplantation had no manipulation of the 2–5 × 10 nucleated cells per kg of recipient weight harvested other Between 1 November 1990 and 1 January 1995, 30 pedi- than red blood cell and/or plasma removal for ABO/Rh atric patients with early B-lineage ALL underwent autolog- blood group incompatibility. ous (n = 16) or non-T cell-depleted, family donor-matched allogeneic (n = 14) BMT at the Duke University Medical Center. In addition, eight patients underwent family donor- Preparative regimens matched allogeneic BMT for T cell malignancy, and were Twenty-one patients received intravenous melphalan, 50– included in this trial. Characteristics of this group of 38 90 mg/m2 over 1 h as a single infusion on day −9, total patients are noted in Table 1. body irradiation, 150 cGy twice a day × 9, days −8to−4 Patients were eligible for BMT on this protocol if they and cyclophosphamide 2.4 g/m2/day, days −3 and −2. had: (1) normal cardiac function (normal ECG, ejection Eleven received total body irradiation, 150 cGy twice a day fraction Ͼ45% or shortening fraction Ͼ28% by × 9, days −8to−4, and cyclophosphamide 2.4 g/m2/day, echocardiogram); (2) normal hepatic function (bilirubin days −3 and −2. Three received busulfan, 37.5 mg/m2/dose Ͻ1.5 mg/dl, transaminases Ͻ2 times normal); (3) adequate every 6 h for 16 doses, days −7to−4, and intravenous mel- renal function (creatinine Ͻ1.5 mg/dl); and (4) normal pul- phalan, 180 mg/m2 over 1 h on day −2. Two received busul- Ͼ 2 monary function (FVC and FEV1 75% of predicted or, fan, 40 mg/m /dose every 6 h for 16 doses, days −9to−6 for children unable to comply with testing, a crying vital and cyclophosphamide, 50 mg/kg/day, days −5to−2. One capacity Ͼ75% of predicted). patient received melphalan 140 mg/m2 over 1 h on day −5 and total body irradiation, 150 cGy twice a day × 9 doses, − Marrow procurement and processing days 4 to 0 (the last dose given 6 h prior to marrow infusion). Total body irradiation was delivered by a 4 MV Patients undergoing autologous BMT had bilateral marrow linear accelerator at extended distance to deliver approxi- aspirates to determine that they were in complete remission.
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