Oral 9-Cis Retinoic Acid

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Leukemia (2000) 14, 1583–1588  2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Oral 9-cis retinoic acid (Alitretinoin) in the treatment of myelodysplastic syndromes: results from a pilot study WK Hofmann1, WJ Kell2, P Fenaux3, S Castaigne4, A Ganser5, C Chomienne6, R Burnett7, C Kowal8, D Hoelzer1 and AK Burnett2

1Department of Hematology/Oncology, University of Frankfurt/Main, Germany; 2Department of Haematology, University of Wales College of Medicine, Cardiff, UK; 3Department of Hematology, Service des Maladies du Sang, Lille, France; 4Department of Hematology, Hospital Mignot, Le Chesnay, France; 5Department of Hematology/Oncology, Hannover Medical School, Germany; 6Department of Hematology, Hospital Saint Louis, Paris, France; 7Allergan-Ligand Retinoid Therapeutics, High Wycombe, Bucks, UK; and 8Ligand Pharmaceuticals, San Diego, CA, USA

A multicenter phase II study was initiated to investigate the that increase the DNA-binding affinity of RAR and other efficacy, toxicity and tolerability of an oral regimen of 9-cis reti- nuclear receptors.11 noic acid (9CRA) as a differentiation-inducing agent stimulating both retinoic acid receptor (RAR) and retinoic X receptor (RXR). Myelodysplastic syndromes (MDS) are clonal disorders Thirty patients with myelodysplastic syndromes (MDS) were characterized initially by ineffective hematopoiesis and the enrolled into the study. The MDS subtypes were distributed as frequent development of acute leukemia.12–14 The underlying follows: 14 refractory anaemia (RA), four refractory anaemia mechanisms of ineffective hematopoiesis in primary MDS with ringed sideroblasts (RARS), and 12 refractory anaemia have not yet been established, but may involve suppression with excess blasts (RAEB). The age ranged from 40 to 81 years by inhibitory cytokines,15 enhanced spontaneous (median 70). None of these had previously received treatment apoptosis,12,16 and defective responses to growth factors due for MDS other than supportive therapy. 9CRA (Alitretinoin 17 capsules, kindly provided by Allergan-Ligand Retinoid to aberrations of growth factor receptors or post-receptor sig- Therapeutics) was given daily at 60 mg/m2 p.o. for 1 week, fol- nal transduction pathways.18 In addition, there is a block in lowed by an intra-patient escalation to 100 mg/m2 during the cell differentiation of all three hematopoietic lineages.19–21 second week, up to a maximum of 140 mg/m2. The planned The clinical effects of some retinoic acid compounds in treatment duration was 48 weeks. Twenty-five were available MDS patients are known from studies with 13-cis retinoic acid for assessment. One patient (4%) with RA achieved complete 22 hematological remission. Four (16%), two with RA, two with (13CRA) and ATRA (as reviewed by Morosetti and Koeffler). RAEB, had minor responses resulting in decreased transfusion In several studies 10% to 25% of the patients showed requirements or increased neutrophils. Thus, the overall response to treatment with retinoids as single agent. To response rate was 20% in evaluable patients with MDS and 17% improve and extend the treatment results, a number of studies in the study group on an intention-to-treat basis. The most fre- using 13CRA and ATRA in combination with hematopoietic quent side-effects included headache (77%), dry skin (57%), growth factors, or other differentiation inducing agents, such arthralgias (30%), and rash (23%). In conclusion, although mod- as vitamin D3 and cytoreductive agents, such as low-dose est responses were noted in this study, the treatment toler- 23–27 ability was suboptimal. It is conceivable that a lower dosage cytarabine, were initiated, and the results have shown schedule may be efficacious and better tolerated so enabling response rates varying from 15 to 45%. The experiences using prolonged exposure which may be required to induce a differ- combination treatment have been reviewed by Ganser and entiation effect. Leukemia (2000) 14, 1583–1588. Karthaus28 and Santini and Ferrini.29 Keywords: 9-cis retinoic acid; differentiation therapy; myelo- In 1992, 9-cis retinoic acid (9CRA) was identified as being dysplastic syndrome the natural ligand of RXR.30,31 Unlike ATRA, which only binds RAR, 9CRA binds and activates both RAR and RXR.32,33 Pre- clinical studies have suggested that 9CRA may have a greater Introduction potency than ATRA in its ability to induce differentiation and to inhibit proliferation of leukemic cells.34,35 Retinoic acids are non-specific differentiation inducing agents Recently, two clinical phase I studies investigated the opti- which have profound effects on normal and leukemic cells in mal dose scheduling of 9CRA in patients with advanced can- 1–4 vitro. Retinoic acid enhances the cytokine-induced colony cer.36,37 Based on the analysis of toxicity and side-effects of formation of both granulocyte–macrophage and erythroid pro- 9CRA, doses from 140 to 230 mg/m2/day were recommended genitor cells. Furthermore, in vitro studies showed that retino- for single agent trials. In patients with APL, 9CRA, used as ids inhibit clonal growth of human leukemic cells and induce single agent therapy at dosages from 30 to 230 mg/m2/day, 5,6 their differentiation. The retinoid response is mediated by was able to induce complete remissions (CR) in four of 12 nuclear receptors, the retinoic acid receptor (RAR) and the relapsed patients.38 5 retinoic X receptor (RXR). RAR was originally described as On the basis of these in vitro and in vivo findings, the main 7 α the receptor for all-trans retinoic acid (ATRA), and RAR is goal of the present study was to assess 9CRA as a potential one of the genes disrupted by the t(15;17) translocation in component of treatment of MDS patients, with particular 8,9 acute promyelocytic leukemia (APL). In 1990, a new recep- respect to hematopoiesis, transfusion requirements and 10 tor, RXR, was described. This receptor forms heterodimers toxicity.

Patients and methods Correspondence: W-K Hofmann, Department of Hematology and Oncology, Johann Wolfgang Goethe University Hospital, 60590 Patients Frankfurt/Main, Germany; Fax: 49 69 6301 7463 The first two authors contributed equally to the paper. Thirty patients with MDS from six centers (15 men, 15 Received 20 April 2000; accepted 2 May 2000 women) with a median age of 70 years (range 40–81) were 9-cis retinoic acid in myelodysplastic syndromes WK Hofmann et al 1584 enrolled into the study. According to the French–American– weeks or more and were assessable for hematological British cooperative group (FAB) criteria for myelodysplastic response. Four patients received the study medication for the syndromes,39 14 patients had refractory anaemia (RA), four planned time of 48 weeks. The therapy was stopped early in patients RA with ringed sideroblasts (RARS), and 12 patients three patients (one RA, one RARS, one RAEB) following trans- RA with excess blasts (RAEB). One patient had secondary RA formation of MDS to acute myeloid leukemia (AML). The to previous radiation. The patients with RAEB were not candi- median time to transformation to AML from start of the study dates for bone marrow transplantation due to advanced age. medication was 21 weeks. Two patients died during the study Patients were also classified according to the International treatment period, one due to myocardial infarction, and the Prognostic Scoring System (IPSS).40 Five patients had low risk other from intestinal obstruction (Table 1). disease, 17 were in the intermediate-1 group and eight in the intermediate-2 group. There were no high risk group patients. Eligibility criteria included a performance status of more than Treatment response 50% on the Karnofsky scale, life expectancy of more than 3 months, normal hepatic, renal, cardiac function, normal Complete remissions: One patient with RA (UIN304, IPSS coagulation function, and the absence of clinically apparent Int-1), who was transfusion dependent with a frequency of 2 systemic illness. No women of child-bearing potential were units of RBC per week, achieved complete remission with nor- included in the trial. None of the patients had previously malization of peripheral blood cells counts. After 4 weeks of received any treatment other than supportive therapy. Details treatment no transfusions were necessary, and after 12 weeks of patient characteristics are given in Table 1. The study was the hemoglobin was 12.1 g/dl without blood product support. approved by the local ethics committees, and informed writ- The platelet count increased from 79 × 109/l to 200 × 109/l ten consent was obtained from the patients prior to treatment after a treatment period of 12 weeks. The bone marrow with 9CRA. appearance before any treatment with study medication was characteristic for RA with hypercellularity, dysplastic erythro- Study design poiesis and micromegakaryocytes, whereas the results after 44 weeks of treatment with 9CRA showed a normal cellularity, 9-Cis retinoic acid (Alitretinoin) was provided by Allergan- with only minor dysplastic changes. The CR was ongoing for Ligand Retinoid Therapeutics (Bucks, UK) and was supplied the duration of 32 weeks. Unfortunately, in week 44 of treat- as 25 mg or 60 mg soft gelatine capsules. The capsules were ment with 9CRA and during the phase of continuous hemato- given daily at a dose of 60 mg/m2 p.o. for 1 week, followed logical complete remission the patient developed acute by an intra-patient escalation to 100 mg/m2 during the second pancreatitis and died. week if tolerability permitted, up to a maximum of 140 mg/m2. Patients who did not tolerate the initial protocol dose of 60 mg/m2/day despite prophylaxis for headache had a dose Minor responses: Four patients (two RA, two RAEB) had reduction to their individual maximum tolerated dose. The minor responses. Two patients with RA (UIN401, IPSS Low planned treatment duration was 48 weeks. During the study, and UIN504, IPSS Int-1) had an increase in hemoglobin from patients were monitored weekly for the first 4 weeks and 4- 7.2 g/dl to 9.2 g/dl and 8.5 g/dl to 9.7 g/dl, respectively. In weekly thereafter. Each visit included a complete medical his- patient 401 RBC substitution could be stopped whereas in tory, physical examination, and laboratory tests, including a patient 504 this was associated with a significant reduction in complete blood count, differential count, a chemistry profile, transfusion requirement from 3 units of RBC monthly before coagulation profile, and urinalysis. An electrocardiogram and the trial to a mean of 1 unit monthly from week 8 of trial chest X-ray were performed before the study. Bone marrow medication. One patient with RAEB (UIN509, Int-1) showed aspirate and trephine biopsy were obtained before, after 6 a significant increase in the absolute neutrophil count (ANC), months of therapy, and at the end of treatment. The bone mar- from 1 × 109/l prestudy to 4 × 109/l after 8 weeks treatment. row was evaluated morphologically and cytogenetically. One further patient with RAEB (UIN201, Int-2) had a In patients who received treatment with 9CRA at least for reduction in the number of blasts in the peripheral blood asso- 6 weeks the response was assessed on the basis of peripheral ciated with an increase in the platelet count from 108 × 109/l blood parameters. In addition, examination of bone marrow prestudy to 172 × 109/l after 8 weeks of 9CRA (Table 3). The was performed at the end of treatment. Dose limiting toxicity response to 9CRA was not associated with particular clinical was defined as a toxicity of grade 3 or higher by National or laboratory findings in any of these patients. Cancer Institute (NCI) criteria (Table 2). Red blood cell (RBC) concentrates were administered when the hemoglobin level dropped below 8 g/dl or if anemia-related symptoms Toxicity occurred. Platelet transfusions were only given in cases of bleeding. Antibiotics and antipyretics were prescribed when Headache (NCI grade 1–3) was the main side-effect and the body temperature rose to more than 38°C. Emollients were occurred in 23 out of the 30 MDS patients treated with 9CRA prescribed if patients complained of dry skin, and the patients (Table 2). This was the primary reason that treatment was were instructed to drink more than 2 liters water a day. stopped early in four patients. Sixteen patients developed NCI grade 1–2 dermatoses, mainly dryness of the skin. One patient Results suffered from severe dry skin syndrome NCI grade 3. Arthral- gia (NCI grade 1–3) was reported by nine patients and seven Treatment compliance patients reported rash. The serum triglyceride levels were elevated in four patients. In two patients the treatment was The median duration of treatment in this study was 13 weeks stopped early due to symptomatic hypercalcaemia which was (range 1–48). Twenty-five patients (83%) received 9CRA for 6 associated with acute psychotic syndrome in one patient.

Leukemia 9-cis retinoic acid in myelodysplastic syndromes WK Hofmann et al 1585 ale; n.a., not available; Dosage, retinoic acid cis Int-1 50 20 AML PD Int-1 100Int-1 4 40Int-2 Coxitis dexter 38 40 Patient’s request 32Int-2Int-2 Dry skinInt-2 40 70 15 17 13 NA Dry skin, 32 nausea Joint pain Loss of NC follow-up NC NC NC MR (WBC) 19 Int-1 100 48 — NC − + a b 5 Int-1 258 27 Headache, asthenia, Int-2 patient’s request 30 NC 48 — NC 7 Int-2 140 4 Headache NA 5 Int-1 60 9 Oedema, patient’s request NC 5 Int-1 60 1 Rash NA 5 Int-1 40 13 Abdominal pain, patient’s request MR (red. transf.) 8 Int-1 100 6 Dry throat, patient’s request NC 7 Int-1 100 15 Loss of follow-up NC 5 Int-1 100 13 Intestinal obstruction, died NC 5 Int-1 60 4 Patient’s request NA − + − − − − + − − − 14, c c c c − 5, − 18. − 17, −

l) / 9

10 retinoic, clinical responses and side-effects during treatment with 9-

× cis

/l) (

× 5, der(9q), del(12)(q11;q23);

(g/dl) ( − 18. + 15, + 7, + 5, + 4, + 1, + Y, Patient characteristics prior to treatment with 9- + 43XX, del(1)(q41), del(5)(q12;q23), 46-52XY, IPSS score of 0.5 assigned to failed or unavailable cytogenetic results. 306 F 74 RA 9.9 4.1 376 43XX, 304305 F F308 58401 71402 M501 M RA502 M RARS 75 M 56 M 58 9.7 8.6 RA 73 RA 75 RA 17.9 RA 1.0 RAEB509 8.4601 7.2602 8.3 F 9.1 79 9.6 F 19 5.2 F 5.4 65 8.4 64 2.6 4.4 250 74 RAEB 46XX, 303 15p RAEB 46XX 385 RAEB 157 8.4 11 8.6 8.6 46XY 46XY Int-1 2.1 46XY 45XY, 5.9 complex 1.6 30 157 Low 18 Low 55 Low 100 44 140 Pancreatitis 140 n.a. complex 47XX, 6 48 Hypercalcaemia 8 — Headache, dry skin CR NC NC MR (Hb) 307 F 53 RA 7.6 3.2 10 n.a. Table 1 101 M 55 RAEB 10.1 0.5 12 45XY, UIN, patient number; FAB, FABa diagnosis; Hb, hemoglobin;b WBC, white bloodc cell count; IPSS, International Prognostic Scoring System; M, male; F, fem maximum dose tolerated; NC, no changes; NA, not assessable; PD, progressive disease; MR, minor response; CR, complete remission. 503 F 74 RA603604 10.4 F M 67 5.0 81 RARS RAEB 90 9.0 12.6 3.2 45XX, 2.4 179 150 46XX 46XY Low Int-1 30 15 48 16 — Myocardial infarction, died NC NC 102103 F F 65 68 RA RAEB 10.5 9.3 6.5 3.9 526 32 45XX, 46XX Int-1 140 26 Non-compliance NC 504 M 70 RA 9.4 3.1 156 45XY, 104105106 M M M 47 73 73 RA RAEB RAEB 11.9 8.3 12.0 2.7 4.7 3.5 295 55 61 46XY, t(1;7)(p11;p11) Int-1 46XY 47XY, 100 Int-2 20 AML 100 8 AML PD PD 505 F 76 RARS 9.7 13.5 332 45XX, 201301302 F303 M M 61 M 50 40 RAEB 69 RARS RA 9.2 RA 9.4 7.7 4.8 10.1 3.8 3.4 108 6.8 123 74 51 46XX 46XY 46XY n.a. Int-2 Low 140 Int-1 100 60 8 11 Dry skin, Hypercalcaemia depression 1 Headache, nausea, patient’s request NA MR (platelets) NC 506 M 71 RA 12.7 1.2 85 45XY, 507 F 76 RAEB 7.7 3.7 313 45XX, UIN Sex Age FAB Hb WBC Platelets Karyotype IPSS Dosage Weeks508 Reason for withdrawal F 75 RAEB Response 8.4 2.2 120 n.a.

Leukemia 9-cis retinoic acid in myelodysplastic syndromes WK Hofmann et al 1586 Table 2 Adverse events observed with 9-cis retinoic acid in with dose-dependent side-effects. In studies of patients with MDS patients RA and RARS the response to retinoids was enhanced when combined with other differentiation agents or hematopoietic Adverse event Patients (%) NCI grade growth factors23,24,26,27,45 to an overall response rate of about 30%. Headache 23 (77) 1–3 Preclinical studies have suggested that 9CRA, which stimu- Dry skin 17 (57) 1–3 Arthralgia 9 (30) 1–3 lates both retinoic acid receptor and retinoic X receptor, has Rash 7 (23) 1–2 greater potency than ATRA in its ability to induce differen- Fever 6 (20) 1–2 tiation of normal hematopoietic cells and clonal cells from Nausea 6 (20) 1–2 AML cell lines and from patients with AML.35,46 Treatment Oedema 5 (17) 1 with 9CRA was associated with a number of adverse reactions Alopecia 5 (17) 1–2 such as headache and dry skin syndrome which was reflected Hypertriglyceridaemia 4 (13) 1–2 a in previous studies using 9CRA at doses ranging from 5 to 230 Fatigue 4 (13) 1–2 2 36 Facial flushing 4 (13) 1–2 mg/m /day which also showed that hypercalcemia was an Diarrhoea 4 (13) 1–2 important limitation to dose escalation beyond 140 mg/m2. Hearing loss/Tinnitus 4 (13) 1–2 For these reasons our study initiated treatment at a dosage of Epistaxisa 4 (13) 1–2 60 mg/m2/day followed by dose escalation to 100 mg/m2/day Myalgia 4 (13) 1–2 to a maximum of 140 mg/m2/day. Pain 4 (13) 1–2 Infectiona 3 (10) 1–3 Only four patients received the study drug for the planned Dermatitis 3 (10) 1–2 period of 48 weeks, two of whom received reduced dosages Pruritis 3 (10) 1–2 of 15 mg/m2/day or 30 mg/m2/day. The highest dose level of Cough 3 (10) 1–2 140 mg/m2/day was reached only in five patients for a median Hypercalcaemia 2 (7) 1 treatment period of 8 weeks. In 11 patients the dosage was Psychotic syndrome 1 (3) 2 reduced to a level below the starting dose of 60 mg/m2/day to allow continuous treatment for a median duration of 28 a Probably disease related. weeks. These results demonstrate that the proposed dose NCI, National Cancer Institute. escalation was associated with a high rate of adverse events, which resulted in a decrease in the number of patients who Table 3 Responses to 9-cis retinoic acid in MDS patients finished the length of treatment planned in the study. The present study reports an overall response rate of 20% UIN Week Hb WBC Platelets Clinical observations which is in keeping with previously published studies of reti- (g/dl) (×109/l) (×109/l) noids in MDS.22 One patient achieved complete remission while receiving a dose of 9CRA lower than originally CR intended. In addition one patient classified as a minor 304 0 8.6 17.9 79 Two units red cells responder during the 48 weeks study period achieved CR after weekly treatment with 9CRA for 30 months at the dose level of 140 4 10.8 11.4 183 Transfusion independent 2 12 12.1 12.2 212 mg/m . Minor responses were also seen at low doses of trial drug while other patients failed to respond even to high doses. MR It appears that there is no clear relationship between drug 201 0 9.2 4.8 108 8 9.6 4.5 172 dose and response to treatment. The physiological mechanisms of cell differentiation and 401a 0 7.2 5.4 303 One unit red cells weekly 12 9.2 5.6 171 Transfusion independent the results from a number of clinical studies suggest that differentiation induced by retinoic acid may occur after a long lat- 504 0 8.5 3.1 156 Three units red cells 27,47 monthly ency period of up to 6 months in vivo. We assume that 8 9.7 3.9 148 One unit red cells the assessment of efficacy of 9CRA in MDS in this study does monthly not reflect the potential of this agent to stimulate cell differen- 509 0 8.4 2.1 157 tiation. It remains an open question whether 9CRA is an effec- 8 9.5 5.0 173 tive treatment that improves hematopoiesis in MDS patients. As demonstrated in our pilot study, it is possible to induce UIN, patient number; Hb, hemoglobin; WBC, white blood cell count; complete remission in one patient with RA using 9CRA at a CR, complete remission; MR, minor response. dose tolerable for these individuals. Furthermore, minor aThe treatment of this patient with 9CRA at a dosage level of responses were observed. All of these patients received the 2 140 mg/m is continued (compassionate use). The patient achieved treatment for more than 12 weeks although one patient with complete remission after 30 months of 9CRA treatment (Hb 13.1 g/dl) which is still ongoing (last follow-up 07/99: Hb 13.5 g/dl). RAEB showed benefit after only 8 weeks of treatment suggest- ing that a continuous exposure to 9CRA for several weeks is necessary for clinical relevant improvement of hematopoiesis. Discussion A treatment schedule using tolerable doses for a longer treatment period (more than 12 weeks) may be of more benefit The aim of the present pilot study was to determine the tox- than poorly tolerated schedules using higher dosages for a icity, safety and efficacy of the recently available retinoic short duration. Tolerability may be improved with the combi- receptor agonist 9-cis retinoic acid in patients with myelo- nation of retinoid with alpha-tocopherol42 allowing higher dysplastic syndromes. A number of clinical studies using reti- dosing schedules. Further trials are required to answer these noids such as 13-cis retinoic acid41,42 and all-trans retinoic questions. acid43,44 in patients with MDS have shown only a limited In conclusion, although modest responses were noted in efficacy of about 10–25% and the treatment was associated this study, the treatment tolerability was suboptimal. It is con-

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