Results of a Phase II Trial Testing Interferon-Alpha 2b and Cytarabine in Children and Adolescents With Chronic Myelogenous Leukemia

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1 Pediatr Blood Cancer 2006;47: Results of a Phase II Trial Testing Interferon-Alpha 2b and Cytarabine in Children and Adolescents With Chronic Myelogenous Leukemia Frédéric Millot, MD, 1 * Joelle Guilhot, BS, 1 Brigitte Nelken, MD, 2 Thierry Leblanc, MD, 3 Guy Leverger, MD, 4 Frédéric Bernard, MD, 5 Virginie Gandemer, MD, 6 Catherine Béhard, MD, 7 Claire Berger, MD, 8 Guy Cornu, MD, 9 Sylvain Duchène, MD, 1 and François Guilhot, MD 1 Background. Chronic myelogenous leukemia (CML) is a rare disease in children and only few data are available concerning the results of interferon based therapy in this age group. Before the imatinib mesylate era, a prospective phase II trial was conducted to assess the efficacy and tolerance of a combination of interferonalpha 2b (IFN) and cytarabine in children with CML in first chronic phase without a suitable HLA-identical donor. Procedure. Fourteen consecutive children were recruited from 12 pediatric centers. Children received daily IFN (5 million U/m 2 ) and subcutaneous cytarabine (20 mg/m 2 ) for 10 days every month. Results. The median duration of follow-up is 13 months (range 2 32 months). Seven children achieved a complete hematologic response after a median time of treatment of 3 months (range 1 week 4 months). Three children were not evaluable for the cytogenetic response. A major cytogenetic response was achieved in seven patients (including complete cytogenetic response in two patient) within 12 months. The median time to major cytogenetic response was 7 months (range 3 12 months). Thirteen patients discontinued the treatment protocol after a median time of 11 months. Probability of progression free survival at 11 months was 83% (95% CI, 61% 100%). Grade 3 and 4 toxicity was observed in eight patients. The most frequently reported drug-related events were fever, mucositis, neutropenia, and thrombocytopenia. Conclusions. The combination of IFN and cytarabine provides hematologic and cytogenetic responses in children and adolescents with CML. In the imatinib mesylate era, the role of this combination as second line therapy in children with CML remains to be determined. Pediatr Blood Cancer 2006;47: ß 2005 Wiley-Liss, Inc. Key words: children; chronic myelogenous leukemia; clinical trials; cytarabine; interferon INTRODUCTION Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative treatment of chronic myelogenous leukemia (CML). Because HSCT is available to a minority of patients, alternative therapies were developed to suppress Philadelphia (Ph) chromosome-positive metaphases in bone marrow of patients with CML. Before the imatinib mesylate era, the combination of interferon-alpha and cytarabine provided complete cytogenetic responses in 15% 31% of patients with CML in chronic phase [1 4]. Because CML is a rare disease in children, only few data concerning the combination of interferon-alpha and cytarabine were available in this age group [5]. For this reason, we initiated a prospective phase 2 trial in 2000 in order to assess the efficacy and the tolerance of a combination of interferonalpha 2b (IFN) and cytarabine in children and adolescents with CML in first chronic phase. PATIENTS AND METHODS The study was designed as an open trial to test the efficacy and tolerance of IFN in combination with low-dose cytarabine in children and adolescents with early-phase CML. Eligible patients were less than 18 years of age with a recent diagnosis (less than 2 months) of Ph chromosomepositive CML in chronic phase. Patients with a human leukocyte antigen-identical sibling were considered candidates for HSCT and were not included in the study. Pretreatment with hydroxyurea (50 mg/kg of body weight or less, depending on the patient s white blood cell count) was permitted. Hydroxyurea was stopped when study ß 2005 Wiley-Liss, Inc. DOI /pbc treatment was started. IFN and cytarabine were administered as an outpatient basis. IFN was administered subcutaneously on a continuous daily basis at a dose of 5 million U/m 2 in combination with subcutaneous cytarabine (single daily dose of 20 mg/m 2 ) for monthly course of 10 days. Dose adjustments during treatment were as follows: the IFN dose was reduced by 50% in patients with neutrophil counts between 0.5 and /L and platelet counts between 50 and /L; IFN was interrupted in patients with less than /L neutrophils and /L platelets. Monthly cycles of cytarabine were started in patients with neutrophil counts above /L and platelet count above /L. Cytarabine was discontinued if the neutrophil counts dropped below /L or the platelet count dropped below /L. For patients who were receiving the maximal dose of IFN, the dose of cytarabine 1 Oncology Hematology, University Hospital, Poitiers, France; 2 Pediatrics, University Hospital, Lille, France; 3 Pediatrics, St Louis Hospital, Paris, France; 4 Pediatrics, Trousseau Hospital, Paris, France; 5 Pediatrics, University Hospital, Montpellier, France; 6 Pediatrics, University Hospital, Rennes, France; 7 Pediatrics, University Hospital, Reims, France; 8 Pediatrics, University Hospital, Saint Etienne, France; 9 Pediatrics, St. Luc Hospital, Brussels, Belgium Results were presented at the 46th annual meeting of the American Society of Hematology, San Diego, California, December 3 7, *Correspondence to: Frédéric Millot, Service d oncologie hématologique et de therapie cellulaire et Centre de recherche clinique, CHU de Poitiers, 2 rue de la Miletrie Poitiers France. f.millot@chu-poitiers.fr Received 24 May 2005; Accepted 18 July 2005

2 556 Millot et al. could be increased up to 40 mg (total dose) per day for 15 days each month if a good clinical and biological tolerance was observed. In patients who temporarily interrupted the treatment for toxicity, blood analyzes were performed weekly before resuming therapy. Follow-up studies included the following: physical examination, complete blood count, and serum chemistry analyzes weekly until hematologic remission, then every 4 weeks; bone marrow analysis including chromosomal studies every 3 months within the first year of treatment, and every 4 months thereafter. Toxicity criteria were in accordance with guidelines of the National Cancer Institute [6]. Patients were evaluated for time to hematologic and cytogenetic remission, rate of hematologic response at 3 months, rate of cytogenetic response at 12 months, toxicity and progression free survival. Complete hematological response (CHR) required disappearance of disease related symptoms and splenomegaly, a white blood cell count less than /L with a normal differential count or the presence of less than 5% immature granulocytes and a platelet count less than /L. Partial hematologic response was based on the same criteria used for CHR but allowed persistent palpable splenomegaly (although spleen size had to have been reduced by at least 50%) and or platelet count exceeding /L. In children who achieved CHR, cytogenetic responses were determined according to the percentage of Ph chromosome-positive cells in metaphases: a complete cytogenetic response was defined by the absence of Ph chromosome-positive cells, partial and minor cytogenetic responses were defined as decreases to levels from 1% to 34% positive metaphases and from 35% to 95% metaphases, respectively. Major response included complete and partial cytogenetic responses. A minimum of 20 metaphases were required for cytogenetic analysis and the karyotypes were analyzed by members of the Groupe Français de Cytogénétique Hématologique. Children in complete hematologic remission after 3 months of therapy continued to receive the study treatment. Other patients who were not in hematologic remission were given alternative therapy. After 12 months of treatment with IFN in combination with cytarabine, children with at least a partial cytogenetic response (<35% Philadelphia chromosome-positive cells in bone marrow) continued to receive the treatment. However, cytarabine was discontinued in these patients if karyotyping revealed a complete cytogenetic response on two consecutive occasions. Information concerning the patients was prospectively collected and recorded on the case report form. Analyzes were not centralized. For each patient, the mean dose of IFN administered between the start and the discontinuation of IFN (including periods of temporary interruption) was calculated and the median dose of the means of the entire cohort of patients was reported. The dose of cytarabine administered was calculated in a similar way but on the base of periods of 10 days. The trial was approved by the local ethic review board of each institution and conducted in accordance with the Declaration of Helsinky. Informed consent was obtained according to institutional guidelines and good clinical practices of the European Community. Probabilities of survival without progression and duration of hematological and cytogenetic responses were estimated using the Kaplan Meier product limit method. Time to events was calculated from the first day of the study treatment. Response duration in hematological responders was referred to as the time interval from the CHR until loss of complete response. Duration of complete cytogenetic response was defined as the period from the first cytogenetic response until relapse (reappearance of more than 34% of Ph chromosome-positive metaphases or progression of the disease). The current analysis is based on data collected up to March 1, Data were censored at the onset of alternative therapy or HSCT. RESULTS From September 2000 to November 2002, 14 consecutive children were recruited from 12 centers in France and Belgium. Main characteristics of the patients are summarized in Table I. There were 10 boys and 4 girls (ratio 2.5:1) with a median age of 12 years (range ). The median performance status score according to Lansky was 100 (range ). The spleen was enlarged in 9 (64%) children with a median size of 15 cm (range 1 25) below the costal margin. The median white blood cell count was /L (range ). The median observation period for the 14 patients was 13 months (range 2 32). Twelve children were pretreated with hydroxyurea before the start of the combination of IFN cytarabine with a median duration of 23 days (range 18 38). Twelve children were assessable for hematological response (one patient discontinued the treatment early because of toxicity, and another patient was enrolled in complete hematologic response after 1 month of therapy with hydroxyurea). Among these patients, 7 (58%) achieved a CHR after a median time of treatment of 3 months (range, 1 week 4 months). Median duration of CHR was 11 months (range 6 22). Loss of CHR without criteria of blastic or accelerated phase was observed in one child, 7 months after CHR was achieved. One patient who achieved CHR progressed 9 months later. Three children (21%) achieved a partial hematological response (persistence of palpable splenomegaly 3 months after the start of IFN cytarabine). One of these three patients progressed 10 months after the start of study treatment. Three children were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of CHR within 3 months of treatment, progression of the disease). The best cytogenetic response by 12 months was: major response in seven children (50%) including complete cytogenetic response in two children (14%), minor response in three children, and failure in one. The median time to

3 IFN Cytarabine in Children With CML 557 TABLE I. Characteristics of the Patients and Response to Treatment Patient no. Age/sex (years) Spleen size (cm under costal margin) Leukocyte count a (10 9 /L) Time to CHR b Time to best CR (mo)/% Ph þ mitosis Evolution g (months after the start of treatment) 1 16/M weeks 12 mo/26% Loss of MCR d (17 mo) 2 13/M weeks 12 mo/100% No MCR at 12 mo 3 8/F week 6 mo/70% No MCR at 12 mo 4 14/M weeks 9 mo/13% Loss of MCR (14 mo) 5 2/M Failure Absence of CHR (6 mo) 6 13/M weeks 7 mo/94% Loss of CHR (7 mo) 7 14/F PHR c 6 mo/7% Progression (10 mo) 8 14/M PHR 3 mo/0% Off study while CCR e (32 mo) 9 10/M weeks 9 mo/16% Progression (12 mo) 10 9/F PHR 3 mo/27% SCT f (8 mo) in PHR 11 12/M Failure Progression (1 mo) 12 11/F 0 15 Failure Off study at 1 mo (toxicity) 13 12/M weeks 7 mo/0% CCR persistent (16 mo) 14 8/M mo/50% Off study at 6 mo a Leucocyte count at initial diagnosis. b CHR, complete hematological response. c PHR, partial hematological response 3 months after the start of interferon-alpha 2b (IFN) cytarabine. d MCR, major cytogenetic response. e CCR, complete cytogenetic response. f SCT, allogeneic bone marrow transplantation. g Evolution refers to the outcome on this treatment. major cytogenetic response was 7 months (range 3 12). Median duration of major cytogenetic response was 6 months (range 3 32). Loss of major cytogenetic response was observed in two children, 5 months after major cytogenetic response was achieved. Two patients who achieved a major cytogenetic response 6 and 8 months after the start of the study protocol, progressed 10 and 12 months later. Interestingly, among the three children with partial hematological response, a major cytogenetic response was achieved in two of them and a complete cytogenetic response in the other one, 3, 6, and 12 months after the start of treatment, respectively. None of the children died during the median observation period of 13 months. Probability of progression free survival (absence of occurrence of accelerated phase of blastic crisis) at 11 and 13 months was 83% (95% CI, 61% 100%) and 71% (95% CI, 42% 99%), respectively (Fig. 1). Thirteen children discontinued treatment with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (two patients), loss of hematological response (one patient), absence of major cytogenetic response at 12 months (two patients ), loss of major cytogenetic response (two patients), progression (three patients), adverse event (one patient), other (two patients). These children who discontinued combination treatment, were treated with imatinib mesylate (11 patients) or underwent HSCT with matched unrelated donor (2 patients). No treatment-related death occurred. The most frequently reported drug-related events were influenza-like symptoms, mucositis, neutropenia, and thrombocytopenia (Table II). Fever and arthralgias were attributed to IFN whereas mucositis was related to cytarabine. Grade 3/4 non hematologic toxicity (mainly, fever, mucositis, or arthralgias) was TABLE II. Main Side Effects Observed During Treatment Protocol in the 14 Children* Side effect All grades (N ¼ 14) Grade 3 and 4(N¼ 14) Fig. 1. Estimated progression free survival curve. Non hematologic Fever 3 2 Mucositis 2 2 Joint pain 2 2 Cytolytic hepatitis 1 1 Hematologic Anemia 8 3 Neutropenia 8 5 Thrombocytopenia 8 2 *Some patients experienced more than one side effect.

4 558 Millot et al. observed in four patients and grade 3/4 hematologic toxicity (anemia, neutropenia, and thrombocytopenia) in six patients. Occurrence of grade 3 mucositis led to the discontinuation of the treatment in one child. Among the 12 children who received more than 1 month of treatment, 11 episodes of transient interruption of therapy for toxicity occurred in 5 (42%) of them with a median duration of 7 days (range 1 39). The median dose of IFN and cytarabine administered was 3.7 million U/m 2 /day (range ) and 20 mg/m 2 /day (range 11 23), respectively. The median duration of IFN therapy was 11 months (range 1 32). Patients received a median of 7 cycles of cytarabine (range 1 34); 2 patients received at least more than 18 cycles. At last follow-up date only one patient remained on IFN cytarabine therapy. DISCUSSION In children with CML, IFN therapy has been shown to induce a significant decrease of Ph chromosome-positive cells in the bone marrow of some patients with better survival where there is sustained decrease to less than 35% [1,7 10]. Our study was designed because an additive effect of lowdose cytarabine and IFN was reported in adults resulting in higher hematologic and cytogenetic responses than IFN alone although the effect of this combination therapy on survival remains controversial [1,3,4,11,12]. Our prospective phase 2 study showed a complete hematologic response rate of 58% and major cytogenetic response rate of 50% including 14% with a complete cytogenetic response. These results are consistent with those reported in adults treated in first chronic phase [1 4,12]. However, we observed a high rate of discontinuation of the treatment protocol. This was mainly explained by a failure of the treatment due to the absence or loss of hematological or cytogenetic response. The combination of IFN and cytarabine was generally well tolerated in our patients. Transient interruptions of treatment for toxicity occurred in 42% of our patients but were of short duration. In our trial, discontinuation of the treatment resulting from intolerance was rare (one child had to discontinue treatment because of severe mucositis). Gastro-intestinal disorders including mucositis represented one of the more frequent side effects that led to the discontinuation of treatment in adults receiving with IFN and cytarabine for CML [1]. Although it is not easy to distinguish between toxicity induced by either IFN or cytarabine, such side effects are attributable to cytarabine. Two of our patients were treated more than 18 months with combination therapy indicating that cycles of low-dose cytarabine can be administered for a long period of time with safety. When the present study was designed, the combination of IFN and cytarabine was thought to be the best treatment in patients without a suitable stem cell donor. A recent prospective trial conducted in adults demonstrated higher rates of hematological and cytogenetic response and higher rate of freedom from progression in adults receiving imatinib mesylate compared with IFN plus low dose cytarabine [13]. We and others reported 48% 83% of complete cytogenetic response with limited side effects in previously heavily pretreated children receiving imatinib mesylate [14,15]. However, the ability of imatinib mesylate to cure CML remains to be determined and allogeneic bone marrow transplantation remains the only known curative therapy with a leukemia-free survival of 56% at 3 years in children transplanted with a matched unrelated donor and a 5-year event-free survival rate of 73% in those transplanted with a matched sibling donor [16,17]. In the imatinib mesylate era, there is limited interest in the combination of IFN and cytarabine as first line therapy in children. This association may be considered in children without HLA-identical related or unrelated donors who failed on imatinib mesylate therapy. However, the present work reported the response and the toxicity profile of IFN and cytarabine in newly diagnosed children with CML and the use of this combination as a second line therapy remains to be determined. APPENDIX In addition to the authors, the following physicians participated in this study: Jean-Pierre Lamagnère, Pediatrics, University Hospital, Tours, France; Anne Notz, Pediatrics, University Hospital, Bordeaux, France; Dominique Plantaz, Pediatrics, University Hospital, Grenoble, France; Françoise Mazingue, Pediatrics, University Hospital, Lille, France; Karima Yacouben, Pediatrics, Robert Debre Hospital, Paris, France; Antoine Thyss, Oncology, Lacassagne Center, France; Pierre Bordigoni University Hospital, Nancy, France. REFERENCES 1. Guilhot F, Chastang C, Michallet M, et al. Interferon alpha-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 1997;337: Kantarjian HM, O Brien S, Smith TL, et al. Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukaemia with daily doses of interferon alpha and low-dose cytarabine. J Clin Oncol 1999;17: Thaler J, Hilbe W, Apfelbeck U, et al. Interferon-alpha-2C and LD ARA-C for the treatment of patients with CML: Results of the austrian multicenter phase II study. Leukemia Res 1997;21: Arthur CK, Ma DDF. Combined interferon alpha-2a and cytosine arabinoside as first line treatment for chronic myeloid leukaemia. Acta Hematol 1993;89: Millot F, Brice P, Philippe N, et al. Alpha-interferon in combination with cytarabine in children with Philadelphia chromosomepositive chronic myeloid leukaemia. J Ped Hematol Oncol 2002;24: National Cancer Institute Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1988.

5 IFN Cytarabine in Children With CML Dow LW, Raimondi SC, Culbert SJ, et al. Response to alphainterferon in children with Philadelphia chromosome positive chronique myelocytic leukaemia. Cancer 1991;68: Talpaz M, Kantarjian HM, Kurzrock R, et al. Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukaemia. Ann Inter Med 1991;114: The Italian Cooperative Group on chronic myeloid leukemia. Long term follow-up of the Italian trial of interferon-a versus conventional chemotherapy in chronic myeloid leukemia. Blood 1998;92: Allan NC, Richards SM, Shepherd PCA. UK medical research council randomised, multicentre trial of interferon-a for chonic myeloid leukemia: Improved survival irrespective of cytogenetic response. Lancet 1995;345: Kantarjian HM, Keating MJ, Estey EH, et al. Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-a and low doses cytarabine. J Clin Oncol 1992;10: Baccarani M, Rosti G, De Vivo A, et al. A randomized study of interferon-alpha versus interferon-alpha and low dose arabinosyl cytosine in chronic myeloid leukemia. Blood 2002;9: O Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic phase chronic myeloid leukaemia. N Engl J Med 2003;348: Millot F, Guilhot J, Nelken B, et al. Results of the Glivec (STI571)- CML-Ped phase II trial testing imatinib mesylate (Gleevec TM )in children with chronic myelogenous leukemia in advanced phase, resistant or intolerant to interferon or in relapse after stem cell transplantation (abstract). Blood 2003;102: Champagne MA, Capdeville R, Krailo M, et al. Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosomepositive leukemia: Results from a Children s Oncology Group phase 1 study. Blood 2004;104: Cwynarski K, Roberts IA, Iacobelli S, et al. Stem cell transplantation for chronic myeloid leukaemia in children. Blood 2003;102: Millot F, Esperou H, Bordigini P, et al. Allogeneic bone marrow transplantation for chronic myeloid leukemia in childhood: A report from the Société Française de Greffe de moelle et de Thérapie Cellulaire (SFGM-TC). Bone Marrow Transplant 2003;32: