A Phase I Trial of a Single High Dose of Idarubicin Combined With

Home , Idarubicin

Leukemia (1998) 12, 865–868  1998 Stockton Press All rights reserved 0887-6924/98 $12.00 http://www.stockton-press.co.uk/leu A phase I trial of a single high dose of idarubicin combined with high-dose cytarabine as induction therapy in relapsed or refractory adult patients with acute lymphoblastic leukemia MA Weiss, P Drullinsky, P Maslak, D Scheinberg and DW Golde

Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, NY, USA

Relapsed or refractory adult acute lymphoblastic leukemia single large dose based on the long half-life of its active (ALL) carries a grave prognosis. The most promising strategy metabolite idarubicinol. We therefore conducted a phase I for curing these patients is through re-induction chemotherapy followed by successful allogeneic transplant. We studied a new dose escalation study of a single dose of idarubicin combined high-dose induction regimen inorder to improve the outcome with high-dose cytarabine to determine the MTD of idarubicin for these patients. Eighteen adult patients with relapsed/ when given in this regimen. refractory ALL were treated on a phase I study of high-dose cytarabine combined with a single escalating dose of idarubicin. Five patients had primary refractory disease and 13 were Materials and methods .treated in refractory relapse. Nine patients (50%) had Ph؉ ALL The induction regimen was cytarabine 3 g/m2/day intravenously days 1–5 and idarubicin as a single intravenous dose on day Trial design 3. G-CSF 5 ␮g/kg subcutaneously every 12 h was started on day 7. The initial idarubicin dose was 20 mg/m2 with dose escal- Between January 1994 and August 1996, 18 previously ations of 10 mg m2. Cohorts of three patients were treated at treated adult patients with the diagnoses of ALL (17 patients) each idarubicin dose level. Unacceptable toxicity was encoun- or lymphoblastic lymphoma (one patient) were entered on this tered at 50 mg/m2 with one death from infection and one death from cardiotoxicity in a patient with significant prior anthracyc- study. Patients were between 18 and 60 years of age with a line exposure. There were no instances of grade 4 non-hematol- diagnosis of relapsed or refractory ALL or lymphoblastic lym- ogic toxicity encountered at idarubicin doses of 20 mg/m2, phoma. The induction regimen consisted of cytarabine (Ara- 30 mg/m2, or 40 mg/m2. The data suggest a dose–response C) 3.0 g/m2/day intravenously over 3 h on days 1–5. Idarub- relationship for increasing doses of idarubicin with 0/3 com- icin was administered as a single dose on day 3. Three 2 2 plete responses (CR) at 20 mg/m , 1/3 CR at 30 mg/m , and 7/12 patients were accrued to each dose level. If there was one (58%) CR at idarubicin doses у40 mg/m2. We conclude that concomitant administration of cytarabine 3 g/m2/day × 5 and occurrence of grade 4 non-hematologic toxicity at a particular high-dose idarubicin at 40 mg/m2 as a single dose on day 3 can dose level, three additional patients were accrued at that dose be administered safely to patients with refractory and level. Two patients experiencing grade 4 non-hematologic relapsed ALL. toxicity closed accrual to that dose level and defined the pre- Keywords: relapsed refractory adult ALL; cytarabine; idarubicin ceding dose as the phase II dose. Patients were treated at idarubicin dose levels of 20 mg/m2, 30 mg/m2, 40 mg/m2, and 50 mg/m2. Patients achieving a CR received consolidation Introduction therapy with methotrexate 1000 mg/m2 intravenously by 3 h infusion and mercaptopurine 250 mg/m2 orally every 6 h for Curent chemotherapy induction regimens result in complete four doses (total dose 1000 mg/m2) and leucovorin 15 mg/m2 remission for 65–85% of adult patients with acute lympho- every 6 h for nine doses starting 24 h after methotrexate was blastic leukemia (ALL).1–11 There is a significant relapse rate, administered. Consolidation therapy was administered 7–14 however, and only 20–30% of all patients will be cured of days after the patient was discharged from the hospital follow- their disease.1–11 Therefore the majority of adults with ALL will ing induction therapy and was repeated again 14 days later. require therapy for relapsed or refractory disease. Patients with suitable HLA-identical donors were rec- Traditionally, salvage regimens have relied on combi- ommended for allogeneic transplant. Other patients, upon nations of vincristine, prednisone and additional agents which completion of consolidation who continued in CR, proceeded reiterate initial induction strategies.12,13 More recently, ther- to an autologous transplant. The protocol and consent form apy for relapsed and refractory patients has focused on high- were approved by the Institutional Review Board of Memorial dose cytarabine containing regimens. High-dose cytarabine as Hospital. Written informed consent was obtained from all a single agent can produce responses in approximately 30% patients. of relapsed/refractory patients.14 In combination with L-asparaginase,15–17 doxorubicin,18 idarubicin,19,20 or mitoxantrone,21–23 complete responses in as many as 59% of patients Evaluation criteria have been reported. Experience at our institution and else- where with cytarabine and a single high dose of mitoxantrone The diagnosis of ALL (or lymphoblastic lymphoma) was based indicates that the combination is quite active in adult ALL.1,24 on morphologic evaluation of the bone marrow aspirate (or Idarubicin is a particularly interesting drug to administer as a lymph node biopsy). In addition, histochemical, immuno- phenotypic and cytogenetic analyses were performed as adjunctive studies. Chromosome preparations were obtained Correspondence: M Weiss, Memorial Sloan-Kettering Cancer Center, according to conventional methods following short-term cul- 1275 York Avenue, New York, NY 10021, USA; Fax: 212 772 8441 ture. Metaphase preparations were stained to reveal Giemsa Received 12 September 1997; accepted 25 November 1997 and/or quinacrine banding patterns. Cytarabine and high-dose idarubicin in adult ALL MA Weiss et al 866 Table 1 Patient characteristics toxicity. There were no instances of grade 4 non-hematologic toxicity encountered at idarubicin dose levels of 20 mg/m2, Male:Female 13:5 30 mg/m2, or 40 mg/m2. At 50 mg/m2 two of the four patients Median age (range) 32 (20–56) treated died from complications of therapy. One patient who Median duration of prior therapy in had previously received substantial prior anthracycline months (range) 12 (5–36) 2 Prior therapy with cytarabine 18 (doxorubicin 120 mg/m ) and anthracenedione (mitoxantrone Ph+ ALL 9 80 mg/m2) therapy died of congestive heart failure 66 days after receiving high-dose idarubicin. This patient had achieved a CR to this regimen prior to the cardiac death. The second patient to die at the 50 mg/m2 dose level developed progres- Patients were classified as relapsed, primary refractory, or sive pneumonia while pancytopenic and died of uncontrolled refractory relapse, based on their response to prior therapy. Patients who relapsed while not on active therapy were classi- infection on day 31 of therapy. This patient died with a hypo- fied as ‘relapsed’. Patients who never achieved a CR despite cellular bone marrow without evidence of leukemia. These at least one standard course of induction therapy were con- two patients experiencing grade 4 non-hematologic toxicity closed accrual to this dose level and defined 40 mg/m2 as the sidered to be ‘primary refractory’. Patients who relapsed while MTD for this trial. receiving chemotherapy or those who relapsed and did not achieve a second CR to a standard re-induction regimen were classified as in ‘refractory relapse’. A complete response was defined as the disappearance of Response all clinical evidence of leukemia for a minimum of 4 weeks. Eight patients (44%) achieved a complete response. There The patient had to have a neutrophil count greater than 2 1000/␮l, a platelet count greater than 100 000/␮l, no circulat- were no complete reponses seen at the idarubicin 20 mg/m dose level, one CR in three patients treated at idarubicin ing blasts, and a normal bone marrow differential (less than 2 5% blasts) in a qualitatively normal or hypercellular bone 30 mg/m , five CRs in eight patients treated at idarubicin 40 mg/m2, and two of four patients treated at 50 mg/m2 achie- marrow. ved a CR. Patients treated below the MTD had a complete Patients not achieving a CR were considered failures and removed from study. The survival of patients was measured response rate of 17% compared with 58% for patients treated from the initiation of the protocol therapy. Duration of com- at the MTD or higher. Median duration of response was brief plete response was measured from the initial CR until docu- at 2 months (range 1–4 months) with duration of CR ‘censor- ed’ at the time of transplant. Five of these patients ultimately mentation of relapse. Toxicity was graded according to the underwent an allogeneic or autologous transplant. Two National Cancer Institute common toxicity criteria.25 patients who achieved a CR had early relapse and were unable to undergo planned transplant. One patient offered an Results autologous transplant refused this procedure and relapsed 4 months later. Four patients underwent allogeneic bone mar- Patient characteristics row transplant. Three expired from transplant-related complications while in complete remission and one patient remains A total of 18 patients were treated on this protocol (Table 1). alive and in remission 13 months post transplant. One patient There were 13 men and five women. The median age was 32 underwent autologous transplant in CR but relapsed 2 months with a range of 20–56 years. Seventeen patients had ALL and post transplant and subsequently died of disease. one patient had lymphoblastic lymphoma without bone marrow involvement. Nine patients (50%) had Ph+ ALL. There were four cohorts of patients treated (Table 2) at idarubicin Discussion dose levels of 20 mg/m2 (three patients), 30 mg/m2 (three patients), 40 mg/m2 (eight patients) and at 50 mg/m2 (four The majority of adult patients with ALL will relapse from their initial CR or will never achieve a first CR.26 Therefore, most patients). At the time of enrollment on study one patient had adult patients with ALL will be treated in a relapsed or refrac- relapsed disease, one patient had primary refractory ALL, and 16 patients were in refractory relapse. tory setting at some point in their disease course. Current strategies for this frequently encountered entity are inadequate as relapsed patients are only infrequently cured. The best chance Toxicity for curing these patients appears to be induction of second CR followed by an allogeneic transplant. In order to optimize Toxicities are presented in Table 3. As expected with this the likelihood of achieving a CR prior to transplant we investi- high-dose regimen all patients developed grade 4 hematologic gated a high-dose induction regimen which combines cytarabine with a single high dose of idarubicin. Idarubicin is a synthetic antineoplastic anthracycline. Table 2 Response and dose limiting toxicity by dose level Although the precise mechanism of action is unknown, it has Dose level Idarubicin dose Patients CR Dose limiting an inhibitory effect on nucleic acid synthesis possibly via toxicity intercalation and unwinding of the DNA chain as well as through interactions with topoisomerase 2. The absence of a 1 20 mg/m2 30 0 methoxy group at position 4 of the anthracycline structure 2 30 mg/m2 31 0 gives idarubicin a high lipophilicity which results in an 3 40 mg/m2 85 0 increased rate of cellular uptake compared to other anthracy- 4 50 mg/m2 42 2 lines. Moreover, in contrast to other anthracyclines, idarubicinol, the active metabolite of idarubicin is also an active cyto- Cytarabine and high-dose idarubicin in adult ALL MA Weiss et al 867 Table 3 Toxicity

Idarubicin dose 20 mg/m2 30 mg/m2 40 mg/m2 50 mg/m2 patients 3384 NCI GRADE 1234123412341234

Hematologic 0003000300080004 Hemorrhage 2000200020002010 Infection 0210012004400301 Vomiting 0000200032000110 Diarrhea 0000120031002000 Stomatitis 1100200011102010 Cardiac 0000000000000001 Hepatic 0000010011102010 Renal 1000030032000200 Neurologic 0000100010000100 toxic anthracycline. The long half-life of idarubicinol (Ͼ41 h) dose mitoxantrone induces rapid complete remissions in adult makes idarubicin an attractive drug to administer as a single acute lymphoblastic leukemia (ALL) without the use of vincristine large dose. We postulated that a single large dose of idarub- or prednisone. J Clin Oncol 1996; 14: 2480–2485. 2 Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, icin would achieve both high-peak plasma levels as well as Duggan D, Davey F, Sobol R, Frankel S, Hooberman A, Westbrook prolonged cytotoxic levels of anthracycline. In this way we C, Arthur D, Geotge S, Bloomfield C, Schiffer C. A five-drug planned to achieve a higher fractional cell kill by eliminating remission induction regimen with intensive consolidation for cells sensitive to only high-peak levels as well as those requir- adults with acute lymphoblastic leukemia: Cancer and Leukemia ing prolonged exposure to cytotoxic levels. The present study group B study 8811. Blood 1995; 85: 2025–2037. was designed to identify the MTD of idarubicin given in com- 3 Kantarjian HM, Walters RS, Keating MJ, Smith TL, O‘Brien S, Estey EH, Huh Y, Spinola J, Dicke K, Barlogie B, Mcredie K, Freiriech bination with high-dose cytarabine and to assess the toxicity E. Results of the vincristine, doxorubicin, and dexamethasone regi- of this combination when administered to adult patients with men in adults with standard- and high-risk acute lymphocytic leu- relapsed or refractory ALL. kemia. J Clin Oncol 1990; 8: 994–1004. 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