Recombinant Human Erythropoietin (rhuepo) for Treatment of Myelodysplastic Syndrome

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1 Recombinant Human Erythropoietin (rhuepo) for Treatment of Myelodysplastic Syndrome Zella R. Zeigler ", Douglas Jonesb, Craig S. Rosenfeld a, Richard K. Shadduck a *West Penn Hospital, Western Pennsylvania Cancer Institute, Pittsburgh, Pennsylvania, USA; bmontefiore Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA Key Words. Myelodysplasia * Refractory anemia Erythropoietin Abstract. Sixteen patients (ages 53 to 85) with myelodysplastic syndrome s) were treated with mombinant human erythropoietin (rhuepo) to observe its effects on hematopoiesis. All were transfusion dependent and had Hb levels less than 9. g/dl and less than 1% marrow blasts. Eight patients had refractory anemia (RA), one had refractory anemia with excess blasts (RAEB), and seven had refractory anemia with ringed sideroblasts (RAW). A response was defined as an increase in Hb by greater than 2 g/dl and/or a decrease in transfusion requirement by greater than 5%. Patients were considered to be evaluable if on study greater than two months. Three of thirteen evaluable patients had a response. One patient with RA had a sustained trilineage hematologic response with no evidence of disease progression. None of the patients had trouble with hypertension or with thrombotic events. This suggests than an occasional patient with MDS will respond to rhuepo. In some patients, this may be beneficial clinically. Introduction Myelodysplastic syndrome (MDS) consists of a group of stem cell disorders that have altered hematopoiesis and varying degrees of cytopenias [l, 21. Any of the three hematopoietic cell lines may be affected; however, a bothersome anemia is often the major clinical problem. Although some patients with myelodysplasia develop leukemia, others have bleeding and/or infections due to the associated thrombocytopenia and/or neutropenia. Correspondence: Dr. Zella R. Zeigler, Western Pennsylvania Cancer Institute, Western Pennsylvania Hospital, 48 Friendship Avenue, Pittsburgh, PA 15224, USA. Received August 12, 1992; provisionally accepted September 13, 1992; accepted for publication November 2, OAlphaMed Press /$5./ Because there is a lack of effective therapy [3] and transfusion support remains the mainstay of therapy, we evaluated whether pharmacologic doses of recombinant human erythropoietin (rhuepo) could improve hematopoiesis in a series of patients with MDS. Materials and Methods Between December 1989 and June 1991, 16 patients with MDS were administered rhu- EPO (provided by the R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ) for six months of study. Eligibility criteria included MDS with a performance score of -2 and anemia with a hemoglobin <9 g/dl. The bone marrow had to contain at least 2+ iron stores and <lo% bone marrow blasts. All patients had failed to respond to vitamins B,, B,, and folic acid. Patients were ineligible if they had clinically significant pulmonary or cardiac disease when transfused to an adequate Hb level. Individuals with hypertension (diastolic of >loo), a history of seizures or recent thrombotic disorders (within one year of study) were excluded from participation in this clinical trial. Patients were also ineligible if they had received hematopoietic growth factors within one month. All patients gave written informed consent; the consent was approved by the Institutional Review Boards of Montefiore University Hospital and West Penn Hospital, Pittsburgh, PA. Baseline evaluation included a history and physical examination, electrocardiogram, chest radiograph, CBC and differential, platelet and reticulocyte counts, urinalysis, electrolytes, liver chemistry tests, blood urea nitrogen, creatinine, STEM CELLS 1993;11:49-55

2 5 Erythropoietin and MDS glucose, calcium, phosphorous, total protein, cholesterol, uric acid, serum iron, iron binding capacity and femtin. Serum EPO levels were measured by an enzyme immunoassay (R&D Systems, Minneapolis, MN). In addition, a bone marrow aspirate and biopsy were obtained for morphology and cytogenetic analysis. During the study, physical examination and complete blood counts including reticulocytes were monitored weekly, and serum chemistry tests were monitored at 6, 12 and 24 weeks. Bone marrow studies were repeated at three and six months of therapy. MDS: Classification All patients in this study underwent entry bone marrow aspirates and biopsies. A SO cell differential was performed on all bone marrow aspirates. In addition, percentage of ringed sideroblasts was measured on iron stains. All patients were then categorized as having refractory anemia (RA), RA with excess blasts (RAEB) or RA with ringed sideroblasts (RARS) according to standard French-American-British (FAB) criteria [4]. Definition of Response All 16 patients were transfusion dependent. For data analysis, the baseline Hb level was taken as the lowest value prior to the last transfusion before study entry. A response was defined either as an increase in Hb by >2 g/dl or a SO% decrease in transfusion requirement. The baseline transfusion requirement was the average of the transfusions in the three months prior to study entry. Drug Administration rhuepo (R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ) was administered at 5 Ukg i.v. thrice weekly for the initial three months. If there was no Hb response, the dose was escalated to 75 Ukg i.v. thrice weekly for an additional three months. Doses were tapered based upon weekly Hb levels if 4 weeks or greater post-transfusion as follows: Hb gldl twice weekly; g/dl once weekly; and held if >12. g/dl. Results The median age of patients in this study was 71. years with a range of The median hemoglobin level was 8.2 gidl (range = g/dl). Four patients had splenomegaly (ranging from cm); none of these had a response to rhuepo. Eight patients had RA, one had RAEB, and the remainder had RARS. Half of the patients had chromosome abnormalities. There was a wide range in bone marrow cellularity and percentage of erythroblasts. The median serum erythropoietin level was 238. mu/ml (range = ). There was no correlation between the serum erythropoietin level and the hemoglobin level measured on the same day in these patients, (r =.93, NS). Therefore, these patients do not appear to have had an appropriate response to their anemia. Red cell transfusion requirements were variable and ranged from 4 17 to mymonth (median = 737). Four patients had previous growth factor therapy, three had granulocyte-macrophage colony stimulating factor (GM-CSF), and one had low dose erythropoietin. The clinical characteristics of the patients and their responses are summarized in Table I. None of these patients experienced seizures, thrombosis or hypertension. Common mild side effects consisted of skin rash (12%), fever and chills (12%), abdominal discomfort (19%) and cellulitis at the site of injection (19%). These were minor toxicities of grade 1-2 using the World Health Organization (WHO) scale. Of 16 patients that entered the study, 13 completed at least two months of therapy and were considered evaluable. Three patients withdrew early. Patient #8 was withdrawn because of severe pneumonia (week 4); patient #15 was withdrawn because of disease progression from RARS to RAEB (week 2); and patient #16 withdrew for. personal reasons (week 6). An additional two patients were withdrawn by the investigators because of serious adverse experiences. Patient #5 was withdrawn (week 16) because of splenic pain related to the rhuepo injections, and patient #13 was removed from study because of line sepsis at week 23. In patient #5, exacerbation of splenic pain occurred reproducibly immediately following the drug injections and abated prior to the next injection. Although line sepsis was not a direct result of erythropoietin therapy, the insertion of a central line was necessitated in patient #13 because of a lack of venous access. Therefore, the sepsis was a complication of the route of drug administration. Three of thirteen (23%) of the evaluable patients had a response to rhuepo therapy.

3 able I. rhuepo in myelodysplasia, clinical characteristics and response 2 a 2 Prior Rx Bone Marrow EPO Level RBC TX =r W t # (FAB) Non-vitamin Karyotype Cellularity Erythroblasts mulml &month Spleen Outcome a R Sustained response, wk 2 F? 1. RA GM-CSF 5% 59% RA 5q- 4% 11% 1, RA 54-35% 8% ,5 4. RA 5q- 6% 34% RA 85% 42% 53. 1, RA rhuepo* * 5q-, 1% 6% 27% RA 8. RA 6% 7% 6% 26% , 9. RAEB GM-CSF 5q- 3% 8% ,56 1. RARS 7q- 4% 36% RARS 8% 24% RARS GM-CSF 9q- 8% 41% RARS 9% 79% RARS 15. RARS 16. RARS 2q- ND 9% 9% 9% 52% 85% 89% ,95 *Trilineage **6 U 3xlwk sq TX = transfusion; NE = nonevaluable; = no response 12. CM 12.5 CM 6. CM 5. CM Transient TX response ; off study, wk 16; splenic pain NE; off study, wk 4; pneumonia Transient TX response ; off study, wk 23; line sepsis NE; off study, wk 6; personal reasons NE; off study, wk 2; disease progression!? $ 8 3

4 52 Erythropoietin and MDS 8 7 Absolute 6 retics 5 191~ 4 () 1 I Time (months) 5 4 Plateletslul 3 x13lul Fig. Trilineage response to rhuepo in MDS (RA). rhuepo administration is represented by the..., d bar. Blood transfusions (2 U) are indicated by arrows. Hb is represented by filled circles and absolute retics by open circles. Absolute neutrophil count (ANC) is depicted by x and platelets by closed squares. Time is shown as months in relationship to rhuepo. The times to a doubling ofanc, retics and platelets were 2, 3 and 5 months, respec ti vel y. 2 1 (m) However, only one patient became transfusion independent. The other two had only a transient decrease in their transfusion requirement. Absolute reticulocytes showed a median 3.6-fold increase above baseline in the three responders (range = ). By contrast, the median increase was lower at.9-fold (range x baseline) in the 1 evaluable nonresponders, p =.4. Nine of ten nonresponders had absolute reticulocytes'that ranged from x their baseline values. One of the nonresponders had an increase in absolute reticulocytes to 3.8 less than baseline. Therefore, a modest increase in reticulocytes was seen in 4/13 evaluable patients. Of these, 314 had evidence of a clinical response, albeit in two of them the response was only a transient decrease in transfusion requirement. The patient who became transfusion independent had RA and had a granulocyte and platelet response as well (Fig. 1). Moreover, this patient's trilineage response has persisted in spite of discontinuing rhuepo injections over two years ago, and there has been no evidence of disease progression. The time course of his cell lineage responses were 2, 3 and 5 months for neutrophils, reticulocyte count and platelet count, respectively. This patient had normal cytogenetics, so it was not possible to determine if rhuepo may have stimulated the normal or abnormal clone. The serum erythropoietin levels (Table I) in the three responders were 399.6, and mu/ml, respectively, and did not differentiate them from the nonresponders. Discussion This report describes a Phase I1 open label high dose erythropoietin (rhuepo) study in a series of 16 patients with MDS. The drug was well tolerated in most patients; none had problems with hypertension or thrombosis. One out

5 ~~ ~~ - ZeiglerlJones/Rosenfeld/Shadduck 53 Table 11. Responses to rhuepo in clinical trials in MDS (response criterion Hb increase by 22 gm% or Hct increase by >6% and/or RBC transfusion independence) rhuepo RA RARS Author Dose Range Responsepatients Responsepatients Bessho Stebler 12, U iv. 3xlweek 5 Ukg sq 3dweek I13 - Schouten 8 Ulkg sq 3xlweek 18 Stein 8-1,6 Ukg i.v. 2xlweek 218 Gazzola 15 Ulkg sq %/week 112 Present Series 75 Ulkg i.v. 3xlweek Total: 5129 (17%) 12 (%) of the 16 patients had disease progression from RARS to RAEB two weeks following initiation of rhuepo therapy. It seems unlikely that this short course of therapy was responsible for disease progression; however, it seemed to be prudent to discontinue treatment. One patient with RA and normal chromosomes had a dramatic trilineage response which persisted without requiring further treatment. Two other patients had a transient decrease in transfusion needs. The patients in this series were primarily limited to the FAB subtypes RA and RARS [4]. Although there were two responses in RA and one in RARS, the dramatic clinical response was seen in a patient with RA. The present study utilized a high dose (5-75 Ukg) of rhuepo that was administered intravenously. The drug concentrations that were available for study did not permit administration of these doses subcutaneously because of volume. However, it is possible that S.C. administration of the drug may give a longer half-life and more consistent and/or improved responses. Nevertheless, the results in this series are consistent with previously reported trials [5-151 of rhuepo in MDS (Table 11). Data from previous studies and the present study have been reorganized in Table I1 to include responses that are clinically dramatic, e.g. an increase in Hb >2 g/dl and/or an increase in Hct by > 6%. Using these criteria, the combined data show a 17% response in 29 patients with RA and a % response in 2 patients with RARS. The doses of rhuepo associated with clinical response range from 12, units i.v. thrice weekly to a high of 1,6 Ukg i.v. ( -112, units) thrice weekly. In the present study, the three responses were observed at a dose of 5 Ukg i.v. thrice weekly. The current data suggest that a subset of patients with MDS, especially those with RA, may benefit from treatment with rhuepo. Baseline serum EPO levels did not, in our study, identify potential responders. Therefore, we suggest that a trial of high-dose rhu- EPO is warranted in patients with MDS of the subtype RA. One patient with RA had a tnlineage response to rhuepo. The bone marrow in this patient showed resolution of erythroid hyperplasia with a decrease in dysplastic red cells. Moreover, the hematologic response was maintained after discontinuation of the rhuepo, and the patient has received no further blood transfusion. This pattern of response is in contrast to that observed in other MDS patients responding to rhuepo [ Most responses have been erythroid and transient or required continued administration of this agent. At least one other transient trilineage response has been reported in a patient with RAEB by Shouten et al. [7]. Although these studies show there is some activity of rhuepo in MDS, the response rate appears to be low and is therefore disappointing. The EPO responsive colony forming uniterythroid (CFU-e) are cells that occur late in the continuum of development from burst forming unit-erythroid (BFU-e) cells [ 16-17]. BFU-e require erythropoietin plus other growth factors such as interleukin (IL-3) or GM-CSF to develop in vitro; perhaps similar combinations of growth factors will be required for in vivo cell proliferation [ Since erythropoietin was well tolerated in these patients and there was some degree of hematopoietic activity, it would make sense to explore the role of combinations of growth factors such as EPO plus GM-CSF or IL-3 in this

6 54 Erythropoietin and MDS group of patients. Perhaps this might enhance the effect of erythropoietin by generation of erythropoietin-sensitive cells from earlier red cell progenitors. This might be especially attractive since trials of GM-CSF [ and of IL-3 [3, 271 in myelodysplasia have been disappointing because of the general lack of an erythroid response. Acknowledgments The authors thank Carolyn Elwood for preparing the manuscript and Laura Getfy, RN, for collecting the data. References Hoelzer D, Ganser A, Heimpel H. Atypical leukemias: preleukemia, smoldering leukemia and hypoplastic leukemia. Recent Results Cancer Res 1984;93: Mufti GJ, Galton DAG. Myelodysplastic syndromes: natural history and features of prognostic importance. Baillieres Clin Haematol 1986; Greenberg PL. Treatment of rnyelodysplastic syndromes. Blood Rev 1991;5:42-5. Bennett JM, Catovasky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51: Bessho M, Jinnai I, Matsuda A, Saito M, Hirashima K. Improvement of anemia by recombinant erythropoietin in patients with rnyelodysplastic syndromes and aplastic anemia. Int J Cell Cloning 199;8: Stebler C, Tichelli A, Dazzi H, Gratwohl A, Nissen C, Speck B. High-dose recombinant human erythropoietin for treatment of anemia in myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria: a pilot study. Exp Hematol 199; 18: Schouten HC, Vellenga E, van Rhenen DJ, de Wolf JTM, Coppens PJW, Blijham GH. Recombinant human erythropoietin in patients with myelodysplastic syndromes. Leukemia 1991;5: Stein RS, Abels RI, Krantz SB. Pharmacologic doses of recombinant human erythropoietin in the treatment of myelodysplastic syndromes. Blood 1991 ;78: Cazzola M, Ponchio L, Beguin Y, et al. Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase 1/11 clinical trial. Blood 1992;79: Bowen D, Culligan D, Jacobs A. The treatment of anaemia in the myelodysplastic syndromes with recombinant human erythropoietin. Br J Haematol 199 1;77: van Kamp H, Prinsze-Postema TC, Kluin PM, et al. Effect of subcutaneously administered human recombinant erythropoietin on erythropoiesis in patients with myelodysplasia. Br J Haematol 1991;78: Hellstrom E, Birgegard G, Lockner D, Helmers C, 6st A, Wide L. Treatment of myelodysplastic syndromes with recombinant human erythropoietin. Eur J Haematol 1991;47: Kurzrock R, Talpaz M, Estey E, O Brien S, Estrov Z, Gutterman JU. Erythropoetin treatment in patients with myelodysplastic syndrome and anemia. Leukemia 1991;5: Shepherd JD, Currie CJ, Sparling TG, Krystal G, Eaves AC. Erythropoietin therapy of myelodysplastic syndromes. Blood 1992;79: Verhoef GEG, Zachte P, Ferrant A, et al. Recombinant human erythropoetin for the treatment of anemia in the myelodysplastic syndromes: a clinical and erythmkinetic assessment. Ann Hemato1 1992;64: Krantz SB. Erythropoietin. Blood 1991;77: Gregory CJ, Eaves AC. Human marrow cells capable of erythropoietic differentiation in vitro: definition of three erythroid colony responses. Blood 1977;49: Emerson SG, Yang YC, Clark SC, Long MW. Human recombinant granulocyte-macrophage colony stimulating factor and interleukin-3 have overlapping but distinct hematopoietic activities. J Clin Invest 1988;82: Emerson SG, Sieff CA, Wang EA, Wong GG, Clark SC, Nathan DG. Purification of fetal hematopoietic progenitors and characterization of recombinant rnultipotential colony-stimulating activity. J Clin Invest 1985;76: Migliaccio G, Migliaccio AR, Visser JWM. Synergism between erythropoietin and interleukin-3 in the induction of hematopoietic stem cell proliferation and erythroid burst colony formation. Blood 1988;72: Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulccyte-macrophage colony-stimulating factor in patients with myelodysplastic activities. N Engl J Med 1987; 317:

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