Phase II study of low-dose interleukin-11 in patients with MDS

ORIGINAL ARTICLE:CLINICALPhase II study of low-dose interleukin-11in patients with myelodysplastic syndromeALBERTO J.MONTERO1,ZEEV ESTROV2,EMIL J.FREIREICH2,ISSA F.KHOURI2, CHARLES A.KOLLER2,&RAZELLE KURZROCK31Hematology-Oncology Division,Hollings Cancer Center,Medical University of South Carolina,Charleston,South Carolina,USA,2Department of Leukemia,M.D.Anderson Cancer Center,Houston,Texas,USA,and3Division of Cancer Medicine–Phase I Program,M.D.Anderson Cancer Center,Houston,Texas,USA(Accepted11April2006)AbstractSevere thrombocytopenia places patients with myelodysplastic syndrome(MDS)at risk of serious hemorrhage.Currently, therapeutic options are limited to platelet transfusions.The only commercially available growth factor that increases platelet counts is interleukin-11(IL-11).We report the results of a phase II trial to more accurately assess the clinical response and toxicity data for low-dose IL-11(10m g/kg/day)in patients with MDS.In this study,nine of32assessable patients(28%) demonstrated increases in their platelet counts after treatment.Of these,five were considered major platelet responses (15%),as defined by World Health Organization criteria.Four patients had minor platelet responses(13%).The median duration of platelet response was9months.Low-dose IL-11was well tolerated,with no observed grade4toxicities.Our study provides additional clinical evidence that chronic administration of IL-11,at low doses,can raise platelet counts and reduce platelet transfusion requirements in a subset of patients with MDS.Keywords:MDS,thrombocytopenia,IL-11,oprelvekin,NeumegaIntroductionMany patients with myelodysplastic syndrome (MDS)suffer from and succumb to morbidities associated with pancytopenia,even before transfor-mation to acute leukemia occurs[1].For instance, severe thrombocytopenia places patients with MDS at significant risk of serious hemorrhage[1,2]. Currently,therapeutic options are limited to platelet transfusion support.Platelets are short lived,and the benefit of transfusing platelets is transient,generally lasting3days or less.Transfusing platelets also comes with a risk of bacterial and viral infections,as well as platelet alloimmunization leading to increased immune-mediated platelet destruction[3,4]. Recombinant human interleukin-11(IL-11)or oprelvekin is a novel thrombopoietic growth factor that directly stimulates the proliferation and matura-tion of megakaryocyte progenitor cells,as well as hematopoietic stem cells[5,6],and is approved by the Food and Drug Administration(FDA)for the prevention of severe thrombocytopenia following myelosuppressive chemotherapy in patients with non-myeloid malignancies[7].Data from two published, randomized,placebo-controlled studies suggest that subcutaneous injections of IL-11(50m g/kg/day)in patients with solid tumors,for5–7days post-cytotoxic chemotherapy,can reduce the need for platelet transfusions by approximately30%[8,9].At this dose level,used for a short period of time,the most frequent toxicities are mild anemia,edema,fatigue,and atrial arrhythmias.Severe toxicities are rare.IL-11in the treatment of severe thrombocytopenia in MDS has not been well studied.Our initial experience indicated that treating patients with bone marrow failure states with IL-11at the doses (25–50m g/kg/day)approved for the prevention of chemotherapy-induced thrombocytopenia resultedCorrespondence:Razelle Kurzrock,Division of Cancer Medicine–Phase I Program,M.D.Anderson Cancer Center,Houston,TX77030,USA. E-mail:rkurzroc@Leukemia&Lymphoma,October2006;47(10):2049–2054ISSN1042-8194print/ISSN1029-2403onlineÓ2006Informa UK Ltd.DOI:10.1080/10428190600758058in significant peripheral and pulmonary edema (R.Kurzrock,unpubl.data).Based on these observations,a pilot study of IL-11at lower doses (10m g/kg/day)was begun.Our initial results in a small and heterogeneous group of patients suggested that IL-11was much better tolerated at these lower doses,with a significant reduction in edema and other severe toxicities,and increased platelet counts in thrombocytopenic patients with bone marrow failure(MDS,aplastic anemia,graft failure and other bone marrow failure states)[10,11].We therefore initiated a phase II study to obtain further clinical response and toxicity data with low-dose IL-11in the treatment of severe thrombocytopenia in a larger and more uniform group of patients with MDS. Materials and methodsPatients with thrombocytopenia due to MDS docu-mented by a bone marrow examination were eligible for the protocol.The diagnosis was made on the basis of a review of a bone marrow aspirate and trephine biopsy and karotype analysis performed at the M.D. Anderson Cancer Center.Patients must have not received any chemotherapy or experimental therapy for at least4weeks.Other eligibility criteria included a platelet count5506109/l.Patients with active or a prior history of congestive heart failure,known allergies to Escherichia coli,or documented myeloid leukemia were ineligible to participate in this study. All patients signed an informed consent in accor-dance with internal review board policies. Treatment planPatients were to receive at least two courses of therapy.For thefirst2months of the study (induction period)the patients received daily sub-cutaneous IL-11(10m g/kg/day)for2weeks followed by a2week rest period.The dose was reduced by 50%for grade3toxicity and was discontinued for any grade4toxicity.After thefirst course,the dose of IL-11could be raised up to15m g/kg/day increments/ month up to25m g/kg/day(within the FDA-approved dose range)in subsequent courses if only grade1or less toxicity was observed.After thefirst two courses, patients who demonstrated evidence of a response to IL-11could continue receiving maintenance therapy(the same dose of IL-11as during the induction phase)on either a daily or alternate day schedule according to tolerance,with or without a rest period,in order to maintain platelet counts between150and4506109/l.Patients with a hemoglobin510g/dl and serum erythropoietin (EPO)levels5500IU,were permitted to receive either erythropoietin or darbepoietin.The use of granulocyte colony-stimulating factor(G-CSF)dur-ing the trial was not excluded.The baseline evaluation included a complete blood cell count with differential and reticulocyte counts,an electrocardiogram,and liver and kidney function tests.A bone marrow aspirate and biopsy with cytogenetic analysis was performed within1month before therapy,and repeated at4–8week intervals as appropriate.During therapy,patients were moni-tored with a complete blood cell count and differential and reticulocyte counts,two to three times per week,for thefirst6weeks,and then at least weekly.Liver and kidney function tests were repeated every2weeks.Response criteriaPublished guidelines from the World Health Organi-zation(WHO)International Working Group for response criteria in MDS were utilized[12].A major platelet response in patients with a pre-treatment platelet count of51006109/l was an absolute increase of306109/l or more.For platelet transfu-sion-dependent patients,the stabilization of platelet counts and transfusion independence for8weeks or more were required.A minor platelet response in patients with a baseline platelet count of51006109/l was a50%or more increase in platelet count with a net increase4106109/l and5306109/l.Baseline platelet,hemoglobin,and neutrophil counts were the median of three untransfused counts available 2weeks prior to starting therapy.Transfused platelet counts were not considered in the evaluation of the response.Patients did not receive platelet transfusions for counts4106109/l in the absence of overt clinical bleeding.Platelet responses had to last at least8weeks while on therapy.A minor neutrophil response in patients with a baseline absolute neutrophil count 51500/mm3was at least a100%increase,with an absolute neutrophil count increase of5500/mm3. ResultsIn total,35patients were registered on the trial. None of these patients overlapped with the patients published previously by us,who were treated on our pilot trials[10,11].Of these,32were assessable for response.One patient was registered but never enrolled.A second was lost to follow-up and the third opted to leave the study early to receive alternative therapy.Patient characteristicsApproximately half of the patients had unclassified MDS(n¼15).Other diagnoses included the full2050 A.J.Montero et al.spectrum of MDS(Table I).The median Interna-tional Prognostic Scoring System(IPSS)score was 1.Fifteen patients had bicytopenias,and16were pancytopenic at the time of enrollment.Seventeen women and18men were enrolled,with a median age of66years(range24–80years)(Table I). Seventeen patients had diploid cytogenetics.The other patients had a variety of chromosomal aberra-tions(Table I).The median baseline platelet count was16.56109/l(37616109/l).Twenty-two patients received growth factor(G-CSF or EPO)support, either prior to enrollment or during participation in this study.The majority of patients had received prior therapy for MDS;only four patients had not received any prior therapy,including growth factors (Table II).During maintenance therapy with IL-11, most enrolled patients received10m g/kg either daily or on alternate days without a rest period. (Registration on this trial pre-dated approval of azacitidine for MDS.)ResponsesNine of32assessable patients(28%)had increases in their platelet counts with low-dose IL-11.Of these,five were considered major platelet responses(15%), as defined by WHO criteria,in that patients were no longer transfusion dependent while on therapy or had an absolute increase in the platelet count of 30,000/mm3or more(Table III).Four patients hadTable I.Baseline characteristics of the patients.PatientBaseline median countsID Sex IPSS Age(years)Diagnosis Cytogenetics Cytopenias Blasts(%)Platelets WBC Hemoglobin 1M0.551CMML Diploid238.515.913.82F 1.564MDS772016 1.610.33F 1.565MDS del(7);inv(1)222213.39.94M264MDS t(2;5);77,þ212638 4.78.95F167RARS del(13)2014 3.510.66M158MDSþ8,inv(9)2214 3.410.67F138MDS del(7);del(20);7610299.112.18M0.566MDS Diploid3222 3.599F271RAEB-2Diploid31139 3.811.110M155MDS Diploid24816.59.911*M71MDSþ812F179RAEB-2Diploid3961 2.510.513F0.551MDS Diploid207 6.711.214F0.578CMML Diploid2318 4.710.615M0.580RARS Diploid2214 4.79.516M0.580MDS Diploid218 4.410.817M376RAEB-2add(1);add(3);75,77,þ8;del(13)2104 5.49.918F0.578RA Diploid3118 2.911.419M263CMML Diploid211646.310.620M 1.561MDSþ1;del(1;7)3410 2.3 6.821F124MDSþ83011 1.3 6.322M0.573MDS Diploid3117 1.97.723F162RAEB-1i17q25311.411.824F 1.566RARS77256110.711.125M269RAEB-2del(5);t(15;18);add(20)31018 1.3926M 1.563MDS(del5q)5q31;del(1;7)309.97.727F0.540Aplastic anemia Diploid306 2.67.628M276RAEB-2del7q7,þ83718 1.79.429F272RAEB-2Diploid31311 2.18.730F137RAEB-175,77,713,718,þ1214377.514.231M370RAEB-27731520.5 3.89.732M167RAEB-2Diploid3632 1.79.333F0.558MDS Diploid308 3.47.934F 1.550MDS773420 2.48.435F0.567MDS Diploid3018 3.29.1 IPSS,International Prognostic Scoring System;WBC,white blood cell count;CMML,Chronic Myelomonocytic Leukemia;MDS, myelodysplastic syndrome;RARS,Refractory Anemia with Ringed Sideroblasts;RAEB,Refractory Anemia with Excess Blasts;RA, Refractory Anemia.*Registered but never enrolled.Phase II study of low-dose IL-11in MDS2051minor platelet responses(13%),with a net absolute increase in platelet counts410,000and 530,0006109/l.One patient who was not receiving G-CSF had a minor neutrophil response while receiving IL-11.The median duration of the platelet response was9months(range2–32months). Approximately half of the platelet responders had diploid cytogenetics(Table I).ToxicityLow-dose IL-11was well tolerated,with no observed grade4toxicities.Approximately60%of enrolled patients reported no adverse effects associated with the administration of low-dose IL-11.Overall,the incidence of grade3toxicities was18%(Table IV).Of these,one patient discontinued the study due to grade 3fatigue.A second patient with multiple co-morbid-ities was taken off the study due to the onset of grade3peripheral edema and ascites,which did not improve despite holding IL-11.Two other patients reported grade3dyspnea and one patient reported grade3 chest pain(without evidence of myocardial infarct), all of which were reversible upon discontinuation of IL-11.Other reported toxicities were mild(grade1–2) and included:rash(n¼1),peripheral edema(n¼3), excessive tearing(n¼1)and a hematoma at the injection site(n¼1)(Table IV).DiscussionMDS is a clonal hematological disorder character-ized by ineffective hematopoiesis and usually a hypercellular bone marrow[2].As such,the inability of affected lineages to normally undergo differentia-tion results clinically in peripheral blood cytopenias. Although MDS is considered a pre-leukemic disease, many patients do not progress to acute myeloid leukemia[1].Indeed,significant morbidity and mortality associated with MDS is a consequence of cytopenias.Both anemia and neutropenia seen in MDS can be improved in a proportion of patients by treatment with hematopoietic growth factors.Both G-CSF and granulocyte-macrophage colony-stimu-lating factor(GM-CSF)are effective in increasing absolute neutrophil counts(80–90%),although randomized trials have not demonstrated prolonged survival[6,13–20].The efficacy of EPO in alleviat-ing anemia in MDS is comparatively low(20–25%) and is generally limited to a subset of patients with serum erythropoietin levels5500U/L[17,21,22]. Platelet responses to EPO,GM-CSF or G-CSF are rare.IL-11is a thrombopoietic cytokine that promotes hematopoietic stem cell growth as well as megakar-yocyte differentiation,resulting in increased plateletTable II.Prior therapies.Prior therapyNumber of patientsErythropoietin22G-CSF15Cyclosporine3Anti-thymocytic globuline3Intravenous immunoglobulin2Allo BMT1Thalidomide1Tipifarnib1Arsenic trioxide1GM-CSF1None4G-CSF,granulocyte colony-stimulating factor;Allo BMT,allogeneic bone marrow transplant;GM-CSF,granulocyte-macro-phage colony-stimulating factor.Table III.Responses to low-dose interleukin-11.Platelet transfusion Platelet responseDuration of Mean baseline Mean treatmentPatient ID dependent Major Minor response(months)platelet number platelet number 1No Yes 2.18.5202Yes Yes{ 6.1316223No Yes13.322487No Yes1429618Yes Yes{10223612*No No No32615713Yes Yes Unavailable72418No Yes 4.6186523Yes Yes833035Yes Yes{Unavailable1826*Patient was not receiving granulocyte colony-stimulating factor(G-CSF)or granulocyte-macrophage colony-stimulating factor(GM-CSF). Absolute increase in neutrophil count4500/mm3(from baseline of675to1970),therefore meeting criteria for a major neutrophil response. {Previously platelet transfusion dependent,with stabilization of platelet counts and platelet transfusion independence for more than2months on interleukin-11.2052 A.J.Montero et al.counts in animal models of compromised hemato-poiesis[23].Several studies have shown that IL-11 can attenuate chemotherapy-induced thrombocyto-penia[8,9].Our initial pilot studies with low-dose IL-11in patients with diverse bone marrow failure states(secondary to MDS,graft failure,chemother-apy or aplastic anemia)suggested platelet response rates of about30%,and included two multilineage responders[10,11].In the present study exclusively involving patients with MDS,the platelet response rate was28%,with no multilineage responses. However,interestingly,one patient who did not have any significant improvement in platelet count had a major white blood cell response and was not on G-CSF.The purpose of this phase II study was to provide additional efficacy and toxicity data on the use of low-dose subcutaneous IL-11in patients with MDS;no overlap exists between these results and our pilot studies[10,11].Consequently,these data provide more definitive response data and confirm that low-dose IL-11can be given for prolonged periods of time and can modestly increase platelet counts and reduce transfusion requirements in a subset of patients with MDS.Other recently identified thrombopoietic mole-cules may play an important role in the treatment of thrombocytopenia in MDS[24].Among these are recombinant human thrombopoietin[5,25]and human megakaryocyte growth and development factor [26–29].In addition to problems with antibody production,the efficacy of these molecules in the clinic has been questionable[27].To our knowledge, there are no published phase II data on the use of thrombopoietin in MDS.This molecule,however, had minimal efficacy in the graft failure setting[25]. The lack of efficacy in the latter setting might be attributable to the small number of doses given per protocol design(one tofive doses per month). Other growth factors also have some thrombo-poietic activity in bone marrow failure states[5].IL-3 has also shown modest thrombopoietic activity in aplastic anemia and MDS[30];IL-3and GM-CSF have shown more substantial responses,albeit still in a minority of patients[31];stem cell factor has also been shown to produce multilineage responses in a subset of patients with aplastic anemia[32].Finally, IL-6has also been shown to have thrombopoietic activity in MDS,but with significant toxicities[33]. 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