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Bortezomib Added to Daunorubicin and Cytarabine During Induction VOLUME 31 ⅐ NUMBER 7 ⅐ MARCH 1 2013 JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT Bortezomib Added to Daunorubicin and Cytarabine During Induction Therapy and to Intermediate-Dose Cytarabine for Consolidation in Patients With Previously Untreated Acute Myeloid Leukemia Age 60 to 75 Years: CALGB (Alliance) Study 10502 Eyal C. Attar, Jeffrey L. Johnson, Philip C. Amrein, Gerard Lozanski, Martha Wadleigh, Daniel J. DeAngelo, Jonathan E. Kolitz, Bayard L. Powell, Peter Voorhees, Eunice S. Wang, William Blum, Richard M. Stone, Guido Marcucci, Clara D. Bloomfield, Barry Moser, and Richard A. Larson Listen to the podcast by Dr Liesveld at www.jco.org/podcasts Author affiliations appear at the end of this article. ABSTRACT Published online ahead of print at Purpose www.jco.org on November 5, 2012. The purpose of this study was to determine remission induction frequency when bortezomib was Written on behalf of the Alliance for combined with daunorubicin and cytarabine in previously untreated older adults with acute Clinical Trials in Oncology. myeloid leukemia (AML) and safety of bortezomib in combination with consolidation chemother- Supported by Grants No. CA32291 (E.C.A., apy consisting of intermediate-dose cytarabine (Int-DAC). P.C.A.); CA32291 (M.W., D.J.D., R.M.S.); CA33601 (J.L.J., B.K.M.); CA03927 (B.L.P.); Patients and Methods CA47559 (P.M.V.); CA77658, CA101140, Ninety-five adults (age 60 to 75 years; median, 67 years) with previously untreated AML (including 2 CA140148, and CA16058 (G.L., W.B., therapy-related and previous myelodysplastic syndrome) received bortezomib 1.3 mg/m intrave- 2 G.M., C.D.B.); CA35279 (J.E.K.); CA59518 nously (IV) on days 1, 4, 8, and 11 with daunorubicin 60 mg/m on days 1 through 3 and cytarabine (E.S.W.); CA41287 (R.A.L.); CA31946 to 100 mg/m2 by continuous IV infusion on days 1 through 7. Patients who achieved complete the Alliance for Clinical Trials in Oncology; remission (CR) received up to two courses of consolidation chemotherapy with cytarabine 2 and CA33601 to the Alliance Statistical gm/m2 on days 1 through 5 with bortezomib. Three cohorts with escalating dose levels of Center from the National Cancer Institute; 2 by the Leukemia Clinical Research Founda- bortezomib were tested (0.7, 1.0, and 1.3 mg/m ). Dose-limiting toxicities were assessed during tion (G.L., W.B., G.M., C.D.B.); and in part the first cycle of consolidation. The relationship between cell surface expression of CD74 and by Grant No. NIH-5K23CA118419-05 clinical outcome was assessed. (E.C.A.) from the National Institutes of Health. Results Frequency of CR was 65% (62 of 95), and 4% of patients (four of 95) achieved CR with incomplete Presented in part at the 52nd Annual Meet- platelet recovery (CRp). Eleven patients developed grade 3 sensory neuropathy. Bortezomib plus ing of the American Society of Hematol- Int-DAC proved tolerable at the highest dose tested. Lower CD74 expression was associated with ogy, Orlando, FL, December 4-7, 2010, and ϭ 48th Annual Meeting of the American Soci- CR/CRp (P .04) but not with disease-free or overall survival. ety of Clinical Oncology, Chicago, IL, June Conclusion 1-5, 2012. The addition of bortezomib to standard 3 ϩ 7 daunorubicin and cytarabine induction chemotherapy The content of this article is solely the for AML resulted in an encouraging remission rate. The maximum tested dose of bortezomib responsibility of the authors and does not administered in combination with Int-DAC for remission consolidation was 1.3 mg/m2 and proved necessarily represent the official views of tolerable. Further testing of this regimen is planned. the National Cancer Institute. Authors’ disclosures of potential conflicts J Clin Oncol 31:923-929. © 2012 by American Society of Clinical Oncology of interest and author contributions are found at the end of this article. Clinical trial information: NCT00742625. none have provided a clear advantage to induction INTRODUCTION 1-3 Corresponding author: Eyal C. Attar, MD, therapy with cytarabine and an anthracycline. Massachusetts General Hospital Cancer Remission induction chemotherapy with cytarabine Therefore, agents capable of improving on existing Center, 100 Blossom St, Boston, MA and an anthracycline has been a standard treatment regimens with minimal added toxicity are clearly 02114; e-mail: [email protected]. for newly diagnosed acute myeloid leukemia (AML) needed for this age group. © 2012 by American Society of Clinical Bortezomib is a potent, reversible, and spe- Oncology for more than 30 years. The complete remission (CR) rate for patients with AML age Ͼ 60 years is cific inhibitor of the proteasome, a target for 0732-183X/13/3107-923/$20.00 40% to 60%, and several strategies have been em- antineoplastic agents.4 By inhibiting the protea- DOI: 10.1200/JCO.2012.45.2177 ployed to intensify the induction regimen in the some, bortezomib has been demonstrated to in- hope of improving the remission rate; however, hibit the master transcription factor nuclear © 2012 by American Society of Clinical Oncology 923 Attar et al factor-kappa B (NF-␬B), which is increased in the active form in days 1, 4, 8, and 11 and was the first drug to be administered on day 1. AML cells5-7 and leukemia stem cells (LSCs).5,8 Beginning 1 hour after bortezomib on day 1, cytarabine 2 g/m2 by IV infusion We previously demonstrated that bortezomib can be safely over 3 hours once daily was administered on days 1 through 5. Before the cytarabine infusion, corticosteroid ophthalmic solution two drops to each eye added to induction chemotherapy in patients with relapsed or ϫ 9 4 daily was initiated and continued for at least 24 hours after the final dose refractory AML, resulting in an encouraging remission rate. We of cytarabine. also previously demonstrated that expression of CD74, the major Patients were enrolled in one of three consecutive bortezomib dose histocompatibility complex class II chaperone molecule and recep- cohorts, each consisting of three to six patients. The three dose cohorts of tor for macrophage migration inhibitory factor (MIF), which sig- bortezomib assessed were: 0.7, 1.0, and 1.3 mg/m2. Enrollment in a cohort nals via NF-␬B and other molecules,10 was associated with clinical ceased until all three patients in a cohort could be fully assessed for outcome in patients with AML treated with bortezomib, idarubi- treatment-related toxicities. If a cohort already contained three patients 9,11 currently undergoing evaluation for dose-limiting toxicity (DLT), subse- cin, and cytarabine. quent patients were treated at the previous cohort dose of bortezomib The goal of this study was to determine the CR rate in older already tested. If no DLTs were experienced by the first three patients, the patients with AML treated with bortezomib plus daunorubicin and dose was escalated to the next level. If one DLT was experienced among the cytarabine and the maximum-tolerated dose (MTD) of bortezomib first three patients, an additional three patients were enrolled at the same when added to intermediate-dose cytarabine (Int-DAC). We also dose level. If Ͻ two DLTs were experienced among these six patients, dose Ն sought to determine the disease-free (DFS) and overall survival (OS) escalation was permitted. If two DLTs were experienced among three to six patients at a given dose level, the previous lower dose was declared the of patients in this study and the relationship between CD74 expression MTD. Once the maximally tolerated, or maximally tested, dose of bort- and clinical outcome. ezomib was identified, at least 10 additional patients were to be treated with Int-DAC in combination with bortezomib at this dose. The maximum planned dose of bortezomib was 1.3 mg/m2. PATIENTS AND METHODS Patients who experienced bortezomib-related neuropathic pain and/or peripheral sensory neuropathy were managed according to dose-reduction Eligibility for the study was restricted to patients age 60 to 75 years with and discontinuation guidelines set forth in the protocol. DLTs were considered previously untreated AML. An unequivocal histologic diagnosis of AML based only during the first cycle of consolidation therapy and included grade 3 or 4 on WHO criteria (Ն 20% blasts in bone marrow) was required. Acute promy- sensory or autonomic neuropathy, persistent grade 4 thrombocytopenia or elocytic leukemia was excluded. Patients with therapy-related AML and pre- neutropenia at day 42 in the absence of AML, any grade 4 or 5 nonhematologic vious myelodysplastic syndrome (MDS) and myeloproliferative neoplasm toxicity, and any grade 3 nonhematologic toxicity (excluding neuropathy and (MPN) were eligible. Additional eligibility information is provided in the toxicities secondary to neutropenia and sepsis) that did not resolve to grade 2 Appendix (online only). by day 42 unless attributable to persistent or recurrent AML. Grade 4 anorexia (requiring total parenteral nutrition) and grade 4 fatigue (requiring bed rest) Treatment are commonly observed in older patients during AML treatment and were not 2 For remission induction, bortezomib 1.3 mg/m was administered by considered DLTs. rapid intravenous (IV) bolus (3 to 5 seconds) on days 1, 4, 8, and 11. Bort- For patients who completed the first consolidation cycle without DLT ezomib was the first drug to be administered on day 1, 1 hour before dauno- and without development of new grade Ն 3 nonhematologic or infectious rubicin. It was recommended that bortezomib be administered at the same toxicities, a second cycle of consolidation chemotherapy was administered time on days 4, 8, and 11 as on day 1 Ϯ approximately 2 hours. Daunorubicin using the same dose of bortezomib used in the first cycle. Some patients 60 mg/m2/d was administered by IV injection or short IV infusion on days 1 discontinued protocol treatment to pursue allogeneic hematopoietic cell through 3 at approximately the same time daily.
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