1203

Combination Therapy with , , Polyethylene-Glycol Conjugated-Asparaginase, and Prednisone in the Treatment of Patients with Refractory or Recurrent Acute Lymphoblastic

Alvaro Aguayo, M.D. BACKGROUND. L-asparaginase in combination with methotrexate has synergistic Jorge Cortes, M.D. antileukemic activity in a schedule-dependent fashion. A new preparation of Deborah Thomas, M.D. L-asparaginase, polyethylene-glycol conjugated (PEG)-asparaginase, is a pharma- Sherry Pierce, R.N. cologically different formulation of L-asparaginase with distinct properties includ- Michael Keating, M.B., B.S. ing a longer half-life and less immunogenic properties. Hagop Kantarjian, M.D. METHODS. Patients with refractory or recurrent acute lymphoblastic leukemia (ALL) were treated with a combination of methotrexate (MTX), vincristine, PEG- The Department of Leukemia, The University of asparaginase, and prednisone (MOAP). The treatment was comprised of MTX, 100 Texas, M. D. Anderson Cancer Center, Houston, mg/m2 intravenously (i.v.), over 15 minutes on Days 1 and 14; PEG-asparaginase, Texas. 2500 IU/m2, with a maximum dose of 3750 IU i.v. approximately 4-6 hours after MTX on Days 1 and 14; vincristine, 1.4 mg/m2 (maximum dose, 2 mg) i.v., over 15 minutes on Days 1, 7, and 14; and prednisone, 200 mg daily orally, on Days 1–5 and 14–19. RESULTS. Thirty-two patients with a median age of 34 years (range, 20–74 years) were treated. Eight patients (25%) had ALL that was refractory to prior therapy and 24 patients (75%) had recurrent disease. Seven patients (22%) achieved a complete remission (CR). Five patients (16%) died early due to infections. Features associ- ated with a poor response were high pretreatment lactate dehydrogenase levels and Philadelphia chromosome positive disease. The median duration of CR was 16 weeks and the overall median survival after MOAP therapy was 12 weeks. Anaphy- lactic reactions were not observed during MOAP combination therapy. CONCLUSIONS. MOAP is an active regimen in patients with refractory or recurrent ALL. This regimen is well tolerated and is not associated with allergic reactions. However, further studies regarding the pharmacologic interaction of MTX with PEG-asparaginase are needed to optimize this regimen. Cancer 1999;86:1203–9. © 1999 American Cancer Society.

Presented in abstract form at the 38th Annual KEYWORDS: recurrent, refractory, acute lymphoblastic leukemia, polyethylene-gly- Meeting of the American Society of Hematology, col conjugated (PEG)-asparaginase, L-asparaginase. San Diego, California, December 5–9, 1997.

Address for reprints: Jorge Cortes, M.D., The De- pproximately 90–98% of children with acute lymphoblastic leu- partment of Leukemia, Box 61, The University of Akemia (ALL) achieve a complete remission (CR) and have a cure Texas, M.D., Anderon Cancer Center, 1515 Hol- rate of 70–75%.1,2 However, only 75–85% of adults achieve a CR and combe Blvd., Houston, TX 77030. only 30–40% ultimately are cured with standard front-line chemo- 1,3 Received November 3, 1998; revision received therapy protocols. Patients with recurrent or refractory disease have June 21, 1999; accepted June 21, 1999. a poor prognosis with CR rates of 70–80% for children4 and 20–50%

© 1999 American Cancer Society 1204 CANCER October 1, 1999 / Volume 86 / Number 7 in adults3; in the majority of cases the duration of CR formed in every patient for documentation of ALL and is brief. A recent study from the M. D. Anderson Can- review of the initial and recurrent bone marrow spec- cer Center (MDACC) using different salvage protocols imens was performed in the referred patients when for adult patients with ALL showed a CR rate of 31% available. The diagnosis of ALL was based on morpho- with a projected survival at 5 years of 3%.5 Favorable logic,10,11 cytochemical, immunophenotypic, and cy- predictors for longer survival in the multivariate anal- togenetic criteria.12,13 Informed consent was obtained ysis were age Ͻ40 years, absence of circulating blasts from all patients as required by the institutional re- at the time of disease recurrence, and duration of first view board. CR Ͼ1 year.5 Autologous and allogeneic stem cell transplant MOAP Regimen (SCT) offer an alternative for patients in this setting. The treatment was comprised of MTX, 100 mg/m2 However, issues such as availability of a donor, trans- intravenously (i.v.), over 15 minutes on Days 1 and 14; plant-related morbidity and mortality, limited evi- PEG-L-asparaginase, 2500 IU/m2, with a maximum dence of a graft versus leukemia effect in ALL, and a dose of 3750 IU i.v. given 4–6 hours after the MTX, on high recurrence rate after autologous bone marrow Days 1 and 14; vincristine, 1.4 mg/m2 (maximum dose transplantation (BMT) limit the use of these proce- 2 mg) i.v., over 15 minutes on Days 1, 7, and 14; and 6 dures. Therefore, new salvage strategies are needed prednisone, 200 mg orally daily, on Days 1–5 and in patients who ultimately fail front-line therapy. 14–19. L-asparaginase is an active agent against ALL with Courses were repeated every 28–35 days provided a unique mechanism of action and little cross-resis- there was blood count recovery and a lack of disease tance with other antileukemia agents. The combina- progression or major toxicity. Patients could receive a tion of L-asparaginase with methotrexate (MTX) has maximum of six courses of MOAP. Patients were fol- significant schedule-dependent synergistic activity lowed in the leukemia clinic at least twice a week with 7-9 against ALL by increasing polyglutamation of MTX. a physical examination, CBC, liver and renal function However, L-asparaginase has side effects such as ana- tests, and studies. phylactic reactions, , hepatotoxicity, , , and neurotoxicity that limit its use in adult patients.9 Recently, a polyethyl- Response Criteria and Definitions Ͼ ene-glycol conjugated L-asparaginase (PEG-l-aspara- A CR was defined as a cellular ( 10%) bone marrow Յ ginase) has become available. This preparation has a with 5% blasts, and normal counts with an absolute Ͼ ϫ 9 longer half-life and is less immunogenic than the con- neutrophil count of 1.0 10 /L and a platelet Ͼ ϫ 9 ventional and Erwinia preparations of count 100 10 /L. A partial response was defined L-asparaginase.9 the same as a CR except with 6–25% blasts. Resistant In the current study we report our experience with disease was defined as persistence of the leukemia a combination of MTX, vincristine, PEG-l-asparagi- and induction death was defined as death before re- nase, and prednisone (MOAP) in patients with recur- covery of blood counts. rent or refractory ALL treated at MDACC. Survival was measured from the date of initiation of therapy until death from any cause. CR duration PATIENTS AND METHODS was defined from the date of achievement of CR until Study Group disease recurrence. Performance status (PS) was eval- 14 Patients age Ն16 years with a diagnosis of refractory or uated according on the Zubrod scale. Toxicity was recurrent ALL after at least 1 complete course of in- graded and recorded according to the National Cancer duction were eligible to receive MOAP. Institute Common Toxicity Criteria. Patients were required to have adequate renal ( creatinine Ͻ 2 mg/dL) and hepatic function (total Statistical Analysis serum bilirubin Ͻ 2 mg/dL). Workup at the time of The outcomes evaluated in this study were CR rate, CR disease recurrence included complete history and duration, disease free survival, and overall survival. physical examination, complete blood count (CBC) Survival and remission duration were calculated ac- with platelet count and differential, liver and renal cording to the Kaplan and Meier method.15 The asso- function tests, and coagulation studies including pro- ciation of response with prognostic features for recur- thrombin time, partial thromboplastin time, fibrino- rent or refractory ALL was investigated.5 Differences gen, and fibrin split products. within clinical subgroups were calculated by the chi- A bone marrow aspiration and biopsy were per- square test or Fisher exact test as indicated. Salvage Therapy with MOAP/Aguayo et al. 1205

TABLE 1 Response Rate by Pretreatment Characteristics

CR

Parameter Value No. No. % P value

Age (yrs) Ͻ 40 21 5 24 Ն 40 11 2 18 1.0 PS 0–1 22 6 27 2–3 10 1 10 0.38 Salvage attempt Ͻ 212433 Ն 2 20 3 15 0.37 HCVAD induction therapy Yes 16 5 29 No 16 2 13 0.39 First CR duration Ͻ 1yr 24 5 21 Ն 1yr82251.0 Leukocyte count (ϫ 109/L) Ͻ 10 15 5 33 Ն 10 17 2 13 0.20 Platelet count (ϫ 109/L) Ͻ 100 22 3 14 Ն 100 10 4 40 0.16 Circulating blasts Yes 22 3 14 No 10 4 40 0.16 LDH (IU/mL) Ͻ 600 8 4 50 Ն 600 24 3 13 0.04 Cytogenetics Ph (ϩ)600 Ph (Ϫ) 26 7 27 0.29

CR: complete remission; PS: performance status; HCVAD: , vincristine, , and dexamethasone; LDH: lactate dehydrogenase; Ph: Philadelphia chromosome; (ϩ): positive; (Ϫ): negative.

RESULTS courses. Seven patients (22%) achieved a CR: 6 of 24 Patients Characteristics patients (25%) with recurrent disease and 1 of 8 Between September 1994 and August 1996, 32 patients patients (13%) with primary refractory disease (this were treated with the MOAP regimen. Twenty-one patient also had failed BMT for salvage). Twelve patients (66%) had received prior induction and sal- patients were considered to have resistant disease vage therapies at MDACC, whereas 11 patients (34%) after one course of MOAP, six patients after two initially were treated in other institutions and referred courses, and one patient after six courses. The CR to MDACC after disease recurrence. The median age rate was compared among patients with clinical was 34 years (range, 20–74 years), with 11 patients characteristics recently reported to have prognostic (34%) age Ͼ40 years. Nineteen patients (59%) were significance in refractory or recurrent ALL (Table males and the PS was Ͼ2 in 10 patients (31%). Eight 1).5 CR rates were significantly lower in patients patients (25%) had disease that was refractory to in- with a lactate dehydrogenase (LDH) level Ͼ600 duction therapy and 24 patients (75%) had developed U/mL at the time of the initiation of therapy (13%) recurrent disease after an initial CR. Twenty-four pa- compared with patients with a lower LDH level tients (75%) had never achieved a CR or had a first CR (50%) (P ϭ 0.04). In addition, none of the six pa- duration that lasted Ͻ1 year. Thirteen patients (41%) tients with the Ph chromosome achieved a CR (P ϭ received MOAP as their first salvage attempt, 14 pa- 0.29). One patient with acquired immunodeficiency tients (44%) had failed 1 prior salvage attempt, and 5 syndrome-associated Burkitt ALL achieved a second patients (16%) had failed Ն2 salvage attempts prior to CR with MOAP. Other features such as older age MOAP therapy. Six patients (19%) had Philadelphia (Ͼ40 years), PS Ͼ2, failure with Ͼ1 prior salvage (Ph) chromosome positive disease and 1 patient had attempt, a short (Ͻ1 year) first CR duration, a high human immunodeficiency virus type 1 infection. leukocyte count ( Ͼ 10 ϫ 109/L), and a low platelet count (Ͻ 100 ϫ 109/L) showed only an unfavorable, Response to Therapy nonstatistically significant trend. However, these Twenty-one patients received 1 course of MOAP, 10 differences did not achieve statistical significance, patients received 2 courses, and 1 patient received 6 most likely due to the small number of patients 1206 CANCER October 1, 1999 / Volume 86 / Number 7

TABLE 2 twice the higher normal value (Grade 3-4 toxicity), but Side Effects Associated with MOAP clinical evidence of pancreatitis was not documented in any patient. No. (%) patients with toxicity by grade All 15 patients who were tested for se- rum levels as part of their follow-up had transient Organ toxicity 1–2 3–4 elevations. Five patients (33%) were found to have ammonia serum levels between 35–100 ␮mol/L and 10 Nausea/emesis 7 (22) 1 (3) patients (67%) were found to have ammonia serum Diarrhea 4 (13) 0 Ͼ ␮ Mucositis 4 (13) 3 (9) levels of 100 mol/L. One patient developed pro- Hyperbilirubinemia 10 (31) 20 (63) gressive encephalopathy with somnolence that evolve Hyperglycemia 13 (41) 13 (41) to coma and death although this patient had a signif- Increased amylase levels 5 (16) 2 (6) icant history of alcoholism and was septic at the time Pancreatitis 0 0 of salvage therapy with MOAP. Three other patients Neurologic 3 (9) 1 (3) Cardiac 2 (6) 0 had transient somnolence. No anaphylactic or allergic Coagulopathy 6 (19) 1 (3) reactions were observed during treatment with MOAP. Six patients (19%) died during treatment due to MOAP: methotrexate, vincristine, polyethylene-glycol conjugated-asparaginase, and prednisone. infection. One patient had a fever with a clinical pic- ture compatible with sepsis together with encephalop- athy (mentioned earlier). However, there was no de- (Table 1). The median CR duration was 16 weeks finitive documentation of an infection in the brain or and the median survival was 12 weeks. cerebrospinal fluid and all other cultures were nega- Five patients (16%) died early due to sepsis and 1 tive. Five other patients died early due to infectious patient died 13 days after the second course of MOAP. complications: one patient developed cytomegalovi- Twenty-four patients died due to disease progression rus pneumonia and Candida sepsis, one patient had and 1 patient was alive at last follow-up with recurrent staphylococcus aureus and Torulopsis sepsis, one pa- disease. One of the patients achieving a CR underwent tients died due to Candida species pneumonia, and an allogeneic SCT during the second CR. This patient two patients developed fatal septic shock and fungal developed disease recurrence and died with disease pneumonia. progression 5 months after SCT. DISCUSSION Toxicity Patients with refractory or recurrent ALL have a poor Toxicities observed during treatment with MOAP are prognosis. Although salvage therapy can induce a CR shown in Table 2. Thirty-two patients received a total in 20–50% of patients, remissions usually are short. In of 47 courses of MOAP. Grade 3-4 hyperglycemia the current study we report on a regimen, MOAP, (Ͼ250 mg/dL) was observed during 14 courses of which has moderate activity in ALL. MOAP among 13 patients (41%). In 6 courses (among L-asparaginase has been used for the treatment of 6 patients; 19%) fibrinogen levels decreased to Ͻ 100 ALL for several decades. Its mechanism of action is to mg/dL, and disseminated intravascular coagulation deprive the neoplastic cells of . Because (DIC) occurred in 1 patient (no other cause of DIC was asparagine is an essential for leukemic evident in this patient). No patients developed clinical cells, this depletion inhibits , RNA, and DNA evidence of thrombosis or . Creatinine lev- synthesis.9,16 When used as a single agent, L-aspara- els Ͼ 3 mg/dL (Ͼ Grade 3 toxicity) were observed in 1 ginase can induce a CR in 25–60% of children with patient (3%) during or shortly after therapy. The tran- recurrent ALL.9 L-asparaginase is part of the majority sient elevation of total bilirubin was common. Nine of induction regimens in childhood ALL and also is patients (28%) had an increase of their total bilirubin used frequently during induction for adult ALL. How- to Grade 3-4 (i.e., Ͼ 3 mg/dL) after the first course and ever, its use may be associated with adverse reactions 2 of 10 patients (20%) developed an increase after the including anaphylactic reactions, pancreatitis, and co- second course. Grade 3 elevation of the serum glu- agulopathy, which have limited its use in adults. L-as- tamic pyruvic transaminase (Ͼ 285 IU/L) was ob- paraginase derived from Erwinia chrysanthemi has served in 6 patients (19%) after the first course and in been used for patients who develop hypersensitivity to 1 of 10 patients (10%) after the second course. the E. coli . In a group of 9 patients with newly Five patients (16%) had mild elevation of serum diagnosed ALL randomly treated with E. coli or Er- amylase. Two patients (6%) had amylase levels Ͼ winia L-asparaginase, Asselin et al.17 observed that Salvage Therapy with MOAP/Aguayo et al. 1207 asparagine depletion occurred by Day 7 after the first in the 2 studies were different, including a median age dose of 25,000 IU/m2 of L-asparaginase in both of 30 years (range, 15–52 years) in the study by Ester- groups. Asparagine was measurable by Day 9 in four of hay et al.23 compared with a median age of 34 years the five patients receiving Erwinia-L-asparaginase. (range, 20–74 years) in the current study. Other char- Levels of asparagine remained undetectable for E. co- acteristics (e.g., prior salvage regimens, previous re- li-derived enzyme after 14–15 days.17 In contrast, 1 sponse to therapy, cytogenetics) are not described dose of PEG-l-asparaginase (2000 U/m2), capped at clearly in the original article by Esterhay et al., making 3750 U and repeated at 15-day intervals for 2 consol- further comparisons difficult. Due to the small sample idation courses, depleted asparagine in 67% of pa- size of both studies, the confidence intervals for the tients for 2 weeks through the 3 courses.18 These data response rates in both studies actually overlap. How- suggest that the degree and duration of the asparagine ever this observation could be analyzed in the context depletion depend on the asparaginase preparation. of the interaction between asparaginase and MTX The combination of L-asparaginase with MTX was mentioned earlier. In our study we used PEG-l-aspar- reported to have synergistic antileukemia activity in a aginase instead of L-asparaginase as used by Esterhay schedule-dependent fashion.7-9 MTX and its polyglu- et al.23 L-asparaginase has a significantly shorter half- tamate forms are competitive inhibitors of the dihy- life (8 hours) than PEG-l-asparaginase (14 days). With drofolate reductase. In addition, MTX polyglutamates the longer half-life of PEG-l-asparaginase, the phar- inhibit thymidylate synthetase among other macologic interactions with MTX need to be reevalu- in the purine synthetic pathway that require folate ated. It is conceivable that, with a more prolonged coenzymes. The end result of this inhibition is the inhibition of protein synthesis after PEG-l-asparagi- impairment of both purine and thymidine synthesis, nase, administering MTX 14 days after asparaginase as inhibition of the DNA synthesis, and cell death.19 used in this trial might cause antagonism and a longer Capizzi et al. showed that within 24 hours of exposure interval between the two drugs may be required. Other to L-asparaginase the rate of DNA synthesis in lym- mechanisms of drug resistance including the emer- phoblasts is suppressed and remains at this level for gence of MTX resistance by leukemic cells also may 9–10 days.20,21 During this time the antiproliferative have played a significant role19 and the possibility of effect of MTX is diminished as has been shown by PEG-l-asparaginase being less efficacious than L-as- studies with incorporation of titrated deoxyuridine in paraginase cannot be excluded. cell DNA. This antagonistic effect is due to the inhibi- The toxicity profile of PEG-l-asparaginase might tion of DNA synthesis by L-asparaginase through in- be superior to L-asparaginase, most significantly due hibition of protein synthesis.7 The inhibition of pro- to a lower incidence of allergic reactions.9 In a recent tein synthesis also is accompanied by inhibition of series in 141 adult patients with de novo (therefore, MTX polyglutamation.7 However, on recovery from asparaginase-naive) ALL, 20% of patients experienced the exposure to L-asparaginase, cells are increasingly hypersensitivity reactions, 70% of which were severe.24 sensitive to MTX. The optimal interval between L-as- The incidence of allergic reactions with PEG-l-aspar- paraginase and the subsequent dose of MTX appears aginase has been reported to be approximately 5–10%. to be approximately 10 days for potentially synergistic Frankel et al. reported 2 allergic reactions in 26 pa- cytotoxicity.8 In the clinical setting, results with this tients (8%) treated with PEG-l-asparaginase.18 In this combination in an adult population have been en- trial with PEG-l-asparaginase we found no allergic re- couraging with CR rates of 33–79%, although the actions, although these patients received minimum median CR duration is short (range, 3.3–7.5 exposure to asparaginase, which could explain in part months).8,22,23 this lack of toxicity. Chemically evident DIC was ob- Esterhay et al.23 first studied the combination of served in only one of our patients, but bleeding or MTX, vincristine, L-asparaginase, and dexamethasone thrombosis was not observed in any patient. Larson in 38 adult patients, 14 of whom (37%) had been et al.24 reported 8 thrombotic events among 141 pa- treated previously. Eleven of the 14 previously treated tients treated (6%). In addition, we observed no epi- patients (79%) patients achieved a CR, with a median sodes of clinical pancreatitis, whereas it was reported CR duration of 7.5 months (range, 1.9–55.3 months). to occur in 11% of patients in the study by Larson et They observed an allergic reaction to the E. coli-de- al.24 Other toxicities such as hyperbilirubinemia and rived L-asparaginase in 71% of their patients. In this hyperglycemia were common but had no clinical con- series we observed a lower CR rate (22%) compared sequences. Similar low toxicity using PEG-l-asparagi- with that reported by Esterhay et al. (79%) with a nase was reported by Douer et al.25 levels similar regimen.23 The characteristics of the patients of Ͻ 100 mg/dL were observed in 11 adults with newly 1208 CANCER October 1, 1999 / Volume 86 / Number 7 diagnosed ALL (73%), but allergic reactions, pancre- recurrent acute lymphoblastic leukemia in adults. Haema- atitis, or bleeding were not observed.25 The only sig- tologica 1996;81:20–36. nificant toxic event possibly associated with this reg- 4. Testi AM, Moleti ML, Giona F, Iori AP, Meloni G, Miniero R, et al. Treatment of primary refractory or relapsed acute imen was encephalopathy. L-asparaginase has been lymphoblastic leukemia (ALL) in children. Ann Oncol 1992; shown to cause encephalopathy in 3–5% of patients, 3(9):765–7. although it has been reported to occur in as many as 5. Thomas D, Kantarjian H, Keating MJ, O’Brien S, Pierce S, 25% of patients,26 most likely due to low concentra- Beran M, et al. Adult acute lymphocytic leukemia (ALL) in tions of either L-asparagine or L- in the first relapse: characteristics, outcome, and prognosis with brain and increased levels of ammonia.26,27 High am- salvage therapy [abstract 294]. Blood 1996;88(Suppl 1):76a. 6. Weisdorf DJ, Billet AL, Hannan P, Ritz J, Sallan SE, Steinbuch monia levels were measured in all 15 patients in whom M, et al. Autologous versus unrelated donor allogeneic mar- it was investigated. However, only one patient had row transplantation for acute lymphoblastic leukemia. clinically significant encephalopathy. The contribu- Blood 1997;90(8):2962–8. tion of PEG-L-asparaginase cannot be determined be- 7. Sur P, Fernandes DJ, Kute TE, Capizzi RL. L-Asparaginase- cause this patient had history of alcoholism and was induced modulation of methotrexate polyglutamylation in febrile and sepsis may have contributed to the murine leukemia L5178Y. Cancer Res 1987;47:1313–8. changes in mental status. However, patients should be 8. 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Appraisal of meth- MOAP, although they did not reach statistical signifi- ods for the study of chemotherapy of cancer in man: com- cance, possibly due to the small sample size. In this parative therapeutic trial of and triethyl- group, the factors associated most strongly with a ene thiophosphoramide. J Chron Dis 1960;11:7–33. 15. Kaplan EL, Meier P. Nonparametric estimation from incom- good response were a normal LDH and the absence of plete observations. J Am Stat Assoc 1958;53:457–81. the Ph chromosome. 16. Asselin BL, Within JC, Coppola DJ, Rupp IP, Sallan SE, MOAP is well tolerated and has moderate activity Cohen HC. Comparative pharmacokinetic studies of three for recurrent or refractory ALL. New pharmacokinetic asparaginase preparations. J Clin Oncol 1993;11(9): and pharmacodynamic studies using PEG-l-asparagi- 1780–6. nase and MTX are needed to maximize the potential 17. Asselin BL, N’Dive S, Welle S, Sallan SE. 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