Clinical Study of 9-Cis Retinoic Acid
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Leukemia (1998) 12, 1518–1521 1998 Stockton Press All rights reserved 0887-6924/98 $12.00 http://www.stockton-press.co.uk/leu Clinical study of 9-cis retinoic acid (LGD1057) in acute promyelocytic leukemia SL Soignet1, F Benedetti1, A Fleischauer1, BA Parker2, JA Truglia2, M Ra Crisp2 and RP Warrell Jr1 1Developmental Chemotherapy and Leukemia Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center, and the Cornell University Medical College, New York, NY; and 2Ligand Pharmaceuticals Inc. San Diego, CA, USA The use of all-trans retinoic acid (RA) for remission induction some proliferation-associated proteins.14–17 Whereas all-trans markedly increases survival of patients with acute promyelo- RA binds only RARs, 9-cis RA binds and activates both RARs cytic leukemia (APL) compared to patients treated solely with 18–20 cytotoxic chemotherapy. However, clinical resistance to this and RXRs. Preclinical studies also showed that 9-cis agent develops rapidly, which has been associated with a pro- RA was more potent than all-trans RA in inducing myeloid gressive decline in plasma drug concentrations. Previous stud- differentiation in HL60 cells.21,22 ies suggested that 9-cis RA, a retinoid receptor ‘pan agonist’ In a preliminary report, we found that 9-cis RA could did not induce its own catabolism to the same extent as all- induce complete remission in APL, but the drug did not trans RA. Therefore, we conducted a dose-ranging study of this appear capable of reversing clinically acquired retinoid resist- compound in patients with both relapsed and newly diagnosed 23 APL. We treated 18 patients with morphologically diagnosed ance. In this final report, we show non-comparative data APL (13 relapsed, five newly diagnosed). The daily dose of 9- that suggests 9-cis RA can induce remission in both previously cis RA ranged from 30 to 230 mg/m2/day given as a single oral treated and newly diagnosed patients at a level that appears dose. Four of 12 (33%) relapsed patients (three of whom were at least equivalent to that of all-trans RA. previously treated with all-trans RA) and four of five (80%) newly diagnosed patients achieved complete remission. The sole failure in the newly diagnosed group died early from an intracranial hemorrhage. One other patient with t(9;12) translo- Materials and methods cation had substantial hematologic improvement. The drug was generally well tolerated; headache and dry skin were the most common adverse reactions. Three patients were treated with Study design corticosteroids for signs of incipient ‘RA syndrome.’ These pre- liminary data suggest that 9-cis RA is an effective agent for Both newly diagnosed and relapsed patients with APL were remission induction and deserves further investigation in patients with retinoid-sensitive APL. eligible for entry into this dose-ranging study. 9-cis RA Keywords: 9-cis retinoic acid; acute promyelocytic leukemia; differ- (supplied as ALRT1057; LGD1057: Panretin) was supplied in entiation soft gelatin capsules containing either 10 or 25 mg of drug (Ligand Pharmaceuticals, San Diego, CA, USA). The lowest daily dose was 30 mg/m2, which was given as a single daily Introduction oral dose until clinical response, or failure (eg rising blast count in peripheral blood or bone marrow, etc) was determ- Acute promyelocytic leukemia (APL) is characterized by ined. In patients who achieved complete remission (CR), ther- reciprocal translocations between chromosomes 15 and 17 apy was continued for approximately 30 days after the date that fuse genes encoding PML and a nuclear retinoic acid of CR. Dose escalation in the same patient was not performed. receptor (RAR-␣).1,2 The resulting fusion gene, PML/RAR-␣, This study was conducted in parallel with a phase 1 study in 24 encodes a chimeric protein that blocks normal myeloid differ- patients with non-hematological neoplasms, which in part entiation.3 The use of all-trans RA for remission induction of determined the dose that could be concurrently used in APL APL, followed by consolidation with several cycles of cyto- patients. Once a relatively high effective dose for remission 2 toxic chemotherapy, has increased survival almost three-fold induction was identified (230 mg/m ), doses in subsequent compared to patients treated with chemotherapy alone.4–9 A relapsed patients were progressively de-escalated in an effort major limitation of all-trans RA therapy is the development of to establish the lowest effective dose. Newly diagnosed retinoid resistance,5,10 which is manifested clinically by a lim- patients were enrolled at doses that had been determined ited duration of remission in patients treated with all-trans RA effective for remission induction in relapsed patients. alone, who are then clinically unresponsive to further retinoid Newly diagnosed patients who achieved CR received exposure. Patients on continuous all-trans RA therapy manifest additional therapy as consolidation, which generally consisted a progressive decline in plasma drug levels,10,11 and this of three cycles of idarubicin and cytosine arabinoside. The observation has engendered speculation that acquired retinoid first cycle was equivalent to a full-dose induction course (ie 2 resistance was related to autoinduced catabolism of the idarubicin 12 mg/m /day for 3 days, plus cytosine arabinoside 2 drug.10–13 200 mg/m /day for 5 days). The subsequent two courses used 2 In 1990, the family of retinoid ‘X’ receptors (RXRs) was idarubicin 12 mg/m /day for 2 days and cytosine arabinoside 2 described, which were shown to act as cofactors for RARs as 100 mg/m /day for 5 days after recovery from the preceding well as receptors for vitamin D, thyroid hormone and peroxi- cycle. Selected patients also received therapy with a recombi- nant humanized monoclonal antibody directed against CD33 (rHuM195).25 Patients who were treated after relapsing from prior therapy and who achieved CR with 9-cis RA received a Correspondence: RP Warrell Jr, Memorial Sloan-Kettering Cancer variety of post-remission therapies. Center, 1275 York Avenue, New York, NY 10021, USA; Fax: 212 During the study, patients were monitored with periodic 717-321 Presented in part at the International Society of Haematology in Stock- determinations of complete blood counts, serum biochemical holm, Sweden, September 1, 1997 analyses, and bone marrow aspirates and/or biopsies. The Received 17 March 1998; accepted 15 June 1998 clinical protocol was reviewed and approved in advance by 9-cis retinoic acid in acute promyelocytic leukemia SL Soignet et al 1519 this center’s Institutional Review Board. Signed informed con- complete remission with arsenic trioxide. One child (18 sent was obtained from all patients. month old female) with a 9;12 translocation was previously resistant to three cycles of chemotherapy and an abbreviated 17 day course of all-trans RA. Shortly after beginning 9-cis RA Results (140 mg/m2/day), she developed progressive leukocytosis and respiratory distress that ultimately required endotracheal intu- Patient characteristics bation, mechanical ventilation and cessation of therapy. Her clinical condition was consistent with both ‘retinoid acid syn- Between February 1994 and July 1996, 18 patients were drome’ and Pneumocystis pneumonia, and she was treated enrolled. Twelve patients with molecularly confirmed APL with corticosteroids and trimethoprim/sulfamethoxazole. had been previously treated with chemotherapy and 11 of Upon recovery, she had attained marked improvement in both these 12 patients had received prior all-trans RA. One of these her total granulocyte and platelet counts (see Figure 1); how- patients had relapsed from an allogeneic T cell-depleted bone ever, further therapy was declined by her parents and marrow transplant, and one patient had previously received a she expired approximately 2 months later from progressive monoclonal antibody in addition to all-trans RA and cytotoxic leukemia. chemotherapy. Five patients were treated at the time of their initial diagnosis. Relevant characteristics of this patient group are presented in Table 1. The diagnosis of APL was confirmed Adverse effects in 17 of 18 patients by cytogenetics or RT-PCR for PML/RAR- ␣. Despite morphological characteristics that were typical of 9-cis RA was generally well tolerated (Table 3). The most APL, one patient had a variant (9;12) translocation (see common adverse reactions were headache (76%) and dry skin below). (59%). Three patients were treated with high-dose cortico- steroids for signs suggestive of incipient ‘RA syndrome’ (eg weight gain, hectic fever, etc). Four patients experienced bone Clinical efficacy pain that required narcotic analgesics. One patient developed hypercalcemia. Minor adverse effects included liver function Four of the 12 (33%) previously treated confirmed APL abnormalities (ie increases in serum alkaline phosphatase and patients (three of the four CR patients had previously received aspartate aminotransferase activity). all-trans RA) and four of the five (80%) newly diagnosed patients achieved complete remission. The median time to CR was 51 days (range, 23–61 days). Doses that were effective in Discussion inducing complete remission ranged from 50 to 230 mg/m2 (Table 2). Seven of the eight patients who achieved CR were The use of all-trans RA during remission induction has been positive for PML/RAR-␣ by RT-PCR at the time of CR, whereas a major advance in the treatment of APL. Since the introduc- only one was negative. Seven of these patients received con- tion of all-trans RA in the early 1990s, several international solidation with a recombinant humanized anti-CD33 mono- groups have reported a marked increase in both disease-free clonal antibody (rHuM195); the assay converted to negative and overall survival.4–9,26 We recently reported a 5-year in three of the seven patients after antibody therapy alone. update of our experience, which showed approximately 2.5- Three of the newly diagnosed patients who achieved CR fold increase in the proportion of patients alive 5 years from remain alive in first remission for durations ranging from 17+ diagnosis compared with patients who were solely treated to 27+ months.