sign in sign up
<<
Home , Asparaginase, Toxicity

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, and feasibility of administration of PEG-L- asparaginase as consolidation therapy in patients undergoing bone marrow transplantation for acute lymphoblastic

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 , 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 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 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, , 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 , 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 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- 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 . 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 disease 5 3 a lower 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 of PEG-L-A in this group of patients; and CR = complete remission; Mel = ; TBI = total body irradiation; (3) the asparaginase following the first Cyclo = ; BU = . in this group of patients.

USA); eight marrows were further purged with , Patients and methods and one was purged with , 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. mately 13 cGy per minute. On each of the first 2 days of They then had 3–5 × 108 nucleated marrow cells per kg radiotherapy treatment, males received once daily dosing harvested, except for two patients in whom previous har- of 2 cGy to the testes. In addition, seven patients whose vests precluded successful procedures; these two underwent indication for BMT included a central growth factor-primed peripheral stem cell harvests. Auto- relapse received additional cranial (900–1080 cGy) and spi- logous marrows and stem cells were purged with anti-CD19 nal (260–900 cGy) radiotherapy boosts in the week before and anti-CD20 antibodies (Biosource, Camarilla, CA, the start of preparative therapy. PEG-L-asparaginase following BMT for ALL ML Graham et al 881 Patients were nursed on the Duke University Pediatric Table 2 Reasons PEG-l-asparaginase was not administered Bone Marrow Transplant Unit in hepafiltered rooms. All patients received transfusion, antibiotic, and nutritional sup- Autologous BMT Allogeneic BMT port according to accepted practice. Patients undergoing allogeneic BMT received GVHD prophylaxis with cyclo- Total patient number 16 22 sporin A for 6 months and methotrexate for up to four Patients receiving PEG-L-A 12 12 Patients not receiving PEG-L-A 4 10 doses. Persistent thrombocytopenia 4 4 Rapid relapse 2 — Alloimmunization 1 — Study design GVHD — 3 Recent pancreatitis — 2 Although the ultimate purpose of post-transplant chemo- Refusal to participate — 2 therapy would be to improve disease-free survival, the Early death — 2 number of patients treated in this study was too small to make a statement of antileukemic efficacy. This was a pilot protocol whose purposes were to attempt to study the tox- icity, pharmacokinetics, and likelihood of administration of Pharmacologic studies PEG-L-A in patients following transplantation for ALL. First dose pharmacokinetics and anti-asparaginase titers were measured in 19 and 15 patients, respectively, Eligibility for asparaginase treatment using previously established methods.35,39,40 Pre-dose aspar- aginase and levels were obtained on day 1 of Patients or their parents were required to give informed PEG-L-A administration, followed when possible by levels consent for this treatment protocol, which was approved by on days 2–5, 8–12, 15–19, 22 and 29. Anti-asparaginase the Duke University Medical Center Institutional Review antibody levels were measured on days 1, 15 and 29 of Board. In order to receive PEG-L-A, all patients were PEG-L-A treatment. Half-lives of l-asparaginase were cal- required to have recovered from mucosal toxicity from the culated using previously described methods35 from a mini- preparative regimen, not to have had recent pancreatitis or mum of four time-points. All levels represent the mean of severe veno-occlusive disease, to have absolute neutrophil assays run in triplicate. It was intended that all patients had counts above 200 and platelet counts above 50 000, be in complete blood counts, functions, amylase, lipase, documented marrow remission, and be at least 30 days total , albumin, prothrombin time, partial thrombo- beyond marrow transplantation. The reasons why 14 of the time, fibrinogen, and III levels checked 38 patients did not receive PEG-L-A are listed in Table 2. every 2 weeks while receiving the drug.

Initiation of treatment Statistical methods PEG-L-A was dosed at 2500 IU/m2/dose and given intra- Exact ␹2 tests compared categorical characteristics of muscularly every 14 days for up to 12 doses. It was to be patients receiving and not receiving asparaginase. t-Tests discontinued for relapse, hypersensitivity, or grade IV (life- and the Wilcoxon two-sample tests compared the age distri- threatening) toxicity. Of the 16 patients who underwent bution of patients receiving and not receiving asparaginase, autologous BMT, 12 (75%) were able to begin PEG-L-A as well as the antibody levels of patients with and without a median of 55 days (range 34–70) after transplantation. prior allergy. Of the 22 patients who underwent allogeneic BMT, 12 (55%) were able to begin PEG-L-A a median of 46 days (range 32–75 days) after transplantation. There were no Results statistically significant differences by ␹2 testing for patients receiving or not receiving PEG-L-A with regard to gender Toxicity (P = 0.51), disease status (P = 0.473), disease (B-lineage vs T cell leukemia), or preparative regimen (P = 0.705) (Table The toxicities seen in this trial are listed in Table 3. They 1). There was a trend toward younger age in patients receiv- were similar to those described previously for PEG-L- ing PEG-L-A (mean 8.7 ± 5.2 years for those receiving it, A.31,34 Of the 24 patients treated with the drug, five 12.0 ± 5.0 years for those not), possibly reflecting a higher developed allergic reactions. Two had both wheezing and rate of certain transplant complications among older skin rash, and the drug was discontinued after each had patients. received three doses. One developed urticaria and facial The limiting eligibility criterion for starting PEG-L-A swelling after the fourth dose and therapy was stopped. One was usually the requirement for platelets of 50 000/␮l. Of developed urticaria after the third dose, but went on to com- the six patients (three autologous, three allogeneic) who plete a total of 12 doses with diphenhydramine therapy eventually began treatment but not until after day +60, before and after each subsequent treatment. One developed delays were due to slow platelet recovery (three wheezing and cyanosis just after the 12th dose. Two of autologous), cyclosporin A toxicity resulting in a seizure these five patients had demonstrated previous allergic reac- and thrombocytopenia (one allogeneic), thrombocytopenia tions to E. coli and/or Erwinia asparaginase; of the other accompanying mild GVHD (one allogeneic), and viral 19 patients treated with PEG-L-A, four had had previous cystitis (one allogeneic). allergic reactions to E. coli asparaginase. PEG-L-asparaginase following BMT for ALL ML Graham et al 882 Table 3 Toxicity of PEG-l-asparaginase (P = 0.92 by t-test), median 12.4 vs 8.9 days). asparagine was depleted for more than 14 days in all but Toxicity No. of patients three patients, one of whom had a prior allergic reaction to affected/ E. coli asparaginase; these three patients had the highest No. studied antibody levels during treatment with PEG-L-A detected in our study. Of the three, two developed allergic reactions to Weight loss у10% of post-BMT discharge weight 7/24 Hypersensitivity 5/24 PEG-L-A, and the third relapsed after five doses. Sample Pancreatitis 2/24 curves for two patients, one with short and one with pro- Paresthesias 1/24 longed duration of asparaginase depletion are illustrated in Laboratory abnormalities Figure 1. Hypoalbuminemia р2.5 g/dl 6/24 Five patients who had pharmacokinetic studies per- 2.6–2.9 g/dl 6/24 formed had had previous hypersensitivity reactions to р 100 mg/dl 11/19 native asparaginase. In only one were a short t1/2 (2.3 days) Functional antithrombin III р60% of normal 12/15 and a short period of asparagine depletion (9 days) docu- Transaminase elevations mented. Of the five patients in our study who developed Ͻ2 times normal 5/24 у2 times normal 4/24 hypersensitivity to PEG-L-A, two had pharmacokinetic studies, and both demonstrated short t1/2 (3.7 and 2.3 days), short periods of asparagine depletion (7 and 9 days), and high anti-asparaginase antibody titers. Antibody titers against asparaginase were measured in 15 patients. Five of the 15 patients had positive titers prior Two of the 24 patients developed symptomatic pan- to starting PEG-L-A, and five others developed positive creatic disease. One developed moderate abdominal pain, titers by day 29 of PEG-L-A therapy. vomiting and an amylase more than twice normal following her third dose of PEG-L-A. Her symptoms resolved over 5 days and she was able to resume treatment 3 weeks after Anti-leukemia efficacy the previous dose and complete the course of 12 treatments. Since this was a pilot trial, we could not determine if the A second patient developed hemorrhagic pancreatitis Ͼ Ͼ asparaginase treatment improved the chance of leukemia- (amylase 1000 IU/ml, lipase 300 IU/ml) complicated free survival. Eight patients, two of 12 autologous and six by severe abdominal pain and vomiting, hypotension, and of 12 allogeneic BMT patients treated with PEG-L-A, sur- disseminated intravascular . He recovered com- vive 20+ to 62+ months after BMT, rates of survival com- pletely, but was not rechallenged with the drug. parable to those for patients reported in other BMT series. One patient, who was also receiving cyclosporin A and Ten of the 24 patients developed relapse while receiving proved to be in relapse, developed paresthesias 3 days after the drug, although all but two of the 10 were in third or starting PEG-L-A, which may have been related to the later remission or in relapse at the time of BMT. drug. No patient developed . Although Of patients in second remission at the time of BMT, five coagulation defects were detected in most of the patients of seven who underwent allogeneic and two of five who tested, no thrombotic events were observed. underwent autologous remain in CR. The median first Four patients developed complications which resulted in remission duration of the seven who remain in CR2 was hospitalization, including one with wheezing, one with 29 months (with three patients who had first CR durations anorexia/severe weight loss, and two with pancreatitis. beyond 4 years, vs a median of 21 months and no first CR Of the 24 treated patients, nine completed the 12 doses duration beyond 32 months among the five patients who of therapy, and one each received 11, eight, and seven relapsed after BMT). This suggests that, to some extent, doses. The other 12 received five or fewer doses. The 15 the long-term survival seen in this group of patients may who did not receive the planned 12 doses had treatment have been related to favorable leukemia features. terminated due to relapse (11), allergy (three) or pan- creatitis (one). Discussion Asparaginase, and anti-asparaginase antibody levels The role of antileukemia chemotherapy following BMT Nineteen of the 24 patients treated with post-transplant remains to be defined. As noted above, we were able to asparaginase were enrolled on a study of the pharmacoki- deliver at least some therapy to over 70% of autologous netics of the first dose. Of the 19, two had never been BMT patients and to over half of allogeneic BMT patients. treated with asparaginase, five had prior hypersensitivity Since relapse rates are very high in patients undergoing reactions to native E. coli asparaginase, and 12 had been autologous BMT for ALL, the fact that most of our patients treated with native asparaginase without clinical reactions were able to start treatment was encouraging. Furthermore, in the past. The mean t1/2 of PEG-L-A for the 19 patients three of the 10 allogeneic BMT patients who did not receive was 11.5 days, the median 8.9 days, and the range 1.5–36 PEG-L-A did not because of problems related at least in

days. The mean t1/2 in the five patients with prior allergic part to graft-versus-host disease (GVHD), which in itself reactions to E. coli asparaginase did not differ significantly is associated with a lower incidence of leukemic relapse.9–13 from the remainder of the group (mean 11.2 vs 11.6 days An agent which could provide an antileukemic effect PEG-L-asparaginase following BMT for ALL ML Graham et al 883 Table 4 Patients treated with PEG-l-asparaginase

Patient Diagnosis Type of Disease Age at diagnosis Time from No. PEG- Toxicity from PEG-L-A Outcome No. BMT status at (years/months) diagnosis to L-A doses (months) BMT BMT (months

1 ALL Allo CR2 3/4 24 12 CCR, 62+ 2 ALL Allo CR2 5/11 42 3 Allergy CCR, 35+ 3 ALL Allo CR2 7/10 25 12 Weight Rel, 25 4 ALL Allo CR2 7/10 35 12 Weight CCR, 33+ 5 ALL Allo CR1 0/5 5 12 CCR, 25+ 6 ALL Allo CR2 14/5 70 3 Allergy CCR, 23+ 7 ALL Allo CR2 5/2 16 12 CCR, 20+ 8 T-ALL Allo CR1(IF) 11/2 3 2 Pancreatitis, weight Rel, 10 9 T-ALL Allo Rel 2 6/10 35 3 Rel, 3 10 T-ALL Allo Rel 1 2/11 23 1 Rel, 2 11 T-ALL Allo CR2 12/8 13 12 Weight Rel, 11 12 T-ALL Allo Rel 1 17/6 6 3 Paresthesias Rel, 2 13 ALL Auto CR3 2/1 30 3 Rel, 3 14 ALL Auto CR3 9/7 111 12 Pancreatitis, allergy Rel, 9 15 ALL Auto CR4 9/1 30 11 Rel, 7 16 ALL Auto CR2 4/7 68 12 Weight CCR, 55+ 17 ALL Auto CR3 8/2 26 3 Rel, 2 18 ALL Auto CR3 3/3 40 7 Rel, 5 19 ALL Auto CR2 0/7 7 12 CCR, 49+ 20 ALL Auto CR2 2/4 32 4 Allergy Rel, 15 21 ALL Auto CR3 7/9 32 5 Rel, 4 22 ALL Auto CR2 0/11 3 5 Rel, 4 23 ALL Auto CR3 6/2 35 8 Weight Rel, 8 24 ALL Auto CR2 4/9 40 5 Weight Rel, 4

Patients listed as CCR were in remission as of 1 August 1997. IF = induction failure; Weight = weight loss Ͼ 10%.

1.5 patients were similar to those seen in non-transplanted patients,35–38 and suggest that in our study PEG-l-asparagi- nase retained one of its most useful properties, the need for relatively infrequent injections. The long-term survival of 1 two of five patients undergoing autologous and five of seven patients undergoing allogeneic BMT in second remission is promising but must be tempered by the fact

-asparaginase that the median duration of the first remission for the seven L 0.5 survivors was 29 months, which of itself would suggest that this patient group had a favorable prognosis. concentration (IU/ml) Serum The toxicity of PEG-L-A in this trial was generally toler- able in patients able to receive the drug. Whereas most patients beyond CR2 relapsed while receiving the drug, 0 patients with less advanced disease (CR1 and CR2) often 02468101214could not meet eligibility requirements to receive the drug Days after administration or developed toxicities which severely limited the period Figure 1 Concentration of l-asparaginase plotted against days after of treatment. Only nine of 38 patients (24%) overall and administration of dose 1 in one patient with prolonged (Ͼ14 days) aspara- eight of 25 (32%) in CR1 or CR2 received the entire 12- ginase depletion (------) and one with brief (Ͻ14 days) depletion (———). treatment regimen. Based on these results, we cannot at this time recommend a phase III trial of single agent, post- transplant PEG-L-A therapy, to a large extent because while offering some degree of GVHD suppression would transplant-related complications limited our ability to be ideal for post-transplant therapy. One laboratory study deliver the drug. A number of patients did not receive PEG- suggested that l-asparaginase showed considerable activity L-A due to thrombocytopenia; two others did not receive in a rat model following allogeneic BMT against GVHD.41 the drug because of recent pancreatitis. In retrospect, the Of our 12 patients who received PEG-L-A, only three had fact that platelet counts continued to rise in most patients any acute GVHD (all stage I) and all had complete resol- despite the PEG-L-A treatment suggest that our require- ution by the start of PEG-L-A treatment. Our study was ment for 50 000 platelets prior to the start of PEG-L-A may therefore too small to detect an impact of PEG-L-A on have been too stringent. The advent of platelet-stimulating GVHD. growth factors42,43 may augment recovery so as to allow The pharmacokinetic profiles obtained for this group of more rapid initiation of post-transplant chemotherapy. PEG-L-asparaginase following BMT for ALL ML Graham et al 884 Chemoprotectants such as lisofylline,44 which appear to lings as treatment of acute and chronic leukemia. Blood 1989; reduce complications following allogeneic transplantation, 73: 1720–1728. might limit other organ toxicities which delayed or pre- 12 Horowitz MM, Gale RP, Sondel PM et al. Graft-versus-leuke- vented the start of PEG-L-A. While our data at this time mia reactions after bone marrow transplantation. Blood 1990; cannot support the development of phase III trials of PEG- 75: 555–562. 13 Sullivan KM, Storb R, Buckner CD et al. Graft versus host L-A, other advances in the treatment and prevention of disease as adoptive immunotherapy in patients with advanced post-marrow transplant complications might improve the hematologic neoplasms. New Engl J Med 1986; 320: 828–834. possibility of delivery of PEG-L-A and allow for future 14 Talbot DC, Powles RL, Sloane JP et al. Cyclosporine-induced studies of its efficacy. graft-versus-host disease following autologous bone marrow transplantation in acute myeloid leukemia. Bone Marrow Transplant 1990; 6: 17–20. Acknowledgements 15 Yeager AM, Vogelsang GB, Jones RJ et al. Induction of cutaneous graft-versus-host disease by administration of cyclosporine to patients undergoing autologous bone marrow Data management support and PEG-L-asparaginase were provided transplantation for acute myeloid leukemia. Blood 1991; 79: by Enzon, Inc., Piscataway, NJ, USA. We thank Bernadette 3031–3035. Dyczewski for help in preparing the manuscript. 16 Meyers JD, Flournoy N, Sanders JE et al. Prophylactic use of human leukocyte interferon after allogeneic marrow transplan- tation. Ann Intern Med 1987; 107: 809–816. References 17 Klingemann H-G, Grigg AP, Wilkie-Boyd K et al. Treatment with recombinant interferon alpha-2b early after bone marrow 1 Chao NJ, Forman SJ. Allogeneic bone marrow transplantation transplantation in patients at high risk for relapse. Blood 1991; for acute lymphoblastic leukemia. In: Forman SJ, Blume KG, 78: 3306–3311. Thomas ED (eds). Bone Marrow Transplantation. Blackwell 18 Bengtsson M, Simonsson B, Carlsson K. Stimulation of NK Scientific Publications: Boston, 1994, pp 618–628. cell, T cell and monocyte functions by the novel immunomod- 2 Ritz J, Ramsey NK, Kersey JH. Autologous bone marrow ulator linomide after autologous bone marrow transplantation. transplantation for acute lymphoblastic leukemia. In: Forman A pilot study in patients with acute myeloid leukemia. Trans- SJ, Blume KG, Thomas ED (eds). Bone Marrow Transplan- plantation 1992; 53: 882–888. tation. Blackwell Scientific Publications: Boston, 1994, 19 Soiffer RJ, Murray C, Cockran K. Clinical and immunologic pp 731–742. effects of prolonged infusion of low-dose recombinant 3 Weisdorf DJ. Autologous bone marrow transplantation for interleukin-2 after autologous and T-cell-depleted allogeneic acute lymphoblastic leukemia. In: Atkinson K (ed). Clinical bone marrow transplantation. Blood 1992; 79: 517–526. Bone Marrow Transplantation. Cambridge University Press: 20 Higuchi CM, Thompson JA, Petersen FB et al. Toxicity and Cambridge, 1994, pp 117–123. immunomodulatory effects of interleukin-2 after autologous 4 Gale RP, Butturini A, Horowitz M. HLA-identical sibling bone marrow transplantation for hematologic malignancies. bone marrow transplantation for acute lymphoblastic leuke- Blood 1991; 77: 2561–2568. mia. In: Atkinson K (ed). Clinical Bone Marrow Transplan- 21 Hamon MD, Prentice HG, Gottlieb DJ et al. Immunotherapy tation. Cambridge University Press: Cambridge, 1994, with interleukin-2 after ABMT in AML. Bone Marrow Trans- pp 191–196. 1993; 11: 399–401. 5 Barrett AJ, Horowitz MM, Gale RP et al. Marrow transplan- 22 Horowitz MM, Gale RP, Barrett AJ et al. Effect of methotrex- tation for acute lymphoblastic leukemia: factors affecting ate on relapse after bone marrow transplantation for acute relapse and survival. Blood 1989; 74: 862–871. lymphoblastic leukemia. Lancet 1989; 1: 535–537. 6 Clift RA, Buckner CD, Applebaum FR et al. Allogeneic mar- 23 Tiley C, Powles R, Treleaven J et al. Feasibility and efficacy row transplantation in patients with acute myeloid leukemia in of maintenance chemotherapy following autologous bone mar- first remission: a randomized trial of two irradiation regimens. row transplantation for first remission acute lymphoblastic leu- Blood 1990; 76: 1867–1871. kemia. Bone Marrow Transplant 1992; 12: 449–455. 7 Phillips GL, Shepherd JD, Barnett MJ et al. Busulfan, cyclo- 24 Hersh EM. Immunosuppression by l-asparaginase and related phosphamide and melphalan conditioning for autologous bone : a review. Transplantation 1971; 12: 368–376. marrow transplantation in hematologic malignancy. J Clin 25 Weksler ME, Weksler BB. Studies of the immunosuppressive Oncol 1991; 9: 1880–1888. properties of asparaginase. 1971; 21: 137–150. 8 Helenglass G, Powles RL, McElwain TJ et al. Melphalan and 26 Durden DL, Distasio JA. Comparison of the immunosuppres- total body irradiation (TBI) versus cyclophosphamide and TBI sive effects of asparaginases from and Vibrio as conditioning for allogeneic matched sibling bone marrow succinogenes. Cancer Res 1980; 40: 1125–1129. transplants for acute myeloblastic leukemia in first remission. 27 Land VJ, Sutow WW, Fernbach DJ et al. Toxicity of l-aspara- Bone Marrow Transplant 1989; 3: 21–29. ginase in children with advanced leukemia. Cancer 1972; 30: 9 Weiden PL, Sullivan KM, Flournoy N et al. Antileukemic 339–347. effect of chronic graft versus host disease: contribution to 28 Chabner BA. therapy: l-asparaginase. In: Chabner improved survival after allogeneic marrow transplantation. BA, Collins JM (eds). Chemotherapy Principles and Practice. New Engl J Med 1981; 304: 1529–1533. JB Lippincott: Philadelphia, 1990, pp 110–153. 10 Weisdorf DJ, Nesbit ME, Ramsey NRC et al. Allogeneic bone 29 Lobel JS, O’Brien RT, McIntosh S et al. Methotrexate and marrow transplantation for acute lymphoblastic leukemia in asparaginase combination chemotherapy in refractory acute remission: prolonged survival associated with graft-versus- leukemia of childhood. Cancer 1979; 43: 1089–1094. host disease. J Clin Oncol 1987; 4: 1348–1355. 30 Reaman GH, Ladisch S, Echelberger C, Poplack DG. 11 Sullivan KM, Weiden PL, Storb R et al. Influence of acute Improved treatment results in the management of single and and chronic graft-versus-host disease on relapse and survival multiple relapses of acute lymphoblastic leukemia. Cancer after bone marrow transplantation from HLA-identical sib- 1980; 45: 3090–3094. PEG-L-asparaginase following BMT for ALL ML Graham et al 885 31 Ettinger LJ, Kurtzberg J, Voute PA et al. An open-label, Escherichia coli l-asparaginase polyethylene glycol adduct. multicenter study of polyethylene glycol-l-asparaginase for Anticancer Res 1981; 1: 373–376. the treatment of acute lymphoblastic leukemia. Cancer 1995; 39 Asselin BL, Lorenson MY, Whitin JC et al. Measurement of 75: 1176–1181. serum l-asparaginase in the presence of l-asparaginase 32 Kamisaki Y, Wada H, Yagura T et al. Reduction in immuno- requires the presence of an l-asparaginase inhibitor. Cancer genicity and rate of Escherichia coli l-asparaginase 1991; 51: 6568–6573. by modification with monomethoxypolyethylene glycol. J 40 Fabry U, Korholz D, Jurgens H et al. to l-aspara- Pharmacol Exp Ther 1981; 216: 410–414. ginase during treatment for acute lymphoblastic leukemia in 33 Abuchowski A, Van Es T, Palczuk NC et al. Treatment of L children – evidence of a complement-mediated mechanism. 5178Y tumor-bearing BDF1 mice with a nonimmunogeneic Pediatric Res 1985; 19: 400–408. l--l-asparaginase. Cancer Treat Rep 1979; 63: 41 Hobik HP. Immunosuppressive wirkung von l-asparaginase 1127–1132. inder graft-versus-host reaktion. Naturwissenschaften 1969; 34 Kurtzberg J, Friedman H, Asselin B. The use of polyethylene 56: 217. glycol-conjugated l-asparaginase (PEG-ASP) in pediatric 42 Basser RL, Rasko JE, Clarke K et al. Thrombopoietic effects patients with prior hypersensitivity to native l-asparaginase. of pegylated recombinant human megakaryocyte growth and Proc Am Soc Clin Oncol 1990; 9: 219 (Abstr.). development factor (PEG-rHu MGDF) in patients with 35 Asselin BL, Whitin JC, Coppola DJ et al. Comparative pharm- advanced cancer. Lancet 1996; 348: 1279–1281. acokinetic studies of three asparaginase preparations. J Clin 43 Fanucchi M, Glaspy J, Crawford J et al. Effects of polyethyl- Oncol 1993; 11: 1780–1786. ene glycol-conjugated recombinant human megakaryocyte 36 Kurtzberg J, Asselin B, Berg S et al. Pharmacokinetics of PEG-l-asparaginase in pediatric patients with known hyper- growth and development factor platelet counts after chemo- sensitivity to native l-asparaginase. Proc Am Assoc Cancer therapy for cancer. New Engl J Med 1997; 336: 404–409. Res 1992; 33: 210 (Abstr. 1257). 44 List A, Maziarz R, Stiff P et al. Lisofylline (LSF) reduces 37 Ho DH, Brown NS, Yen A et al. of rate and improves survival in patients undergoing polyethylene glycol-l-asparaginase. Drug Metab Dispos Biol allogeneic bone marrow transplantation (BMT): results of a Fate Chem 1986; 14: 349–352. randomized, placebo controlled trial. Blood 1996; 88 (Suppl. 38 Park YK, Abuchowski A, Davis S, Davis F. Pharmacology of 1): 459a.