Document GKwvg3jpBwn6MX6QOLEQ2Jeg7

High-Dose Melphalan and Granulocyte-Macrophage Colony-Stimulating Factor for Refractory Multiple Myeloma By Bart Barlogie, Sundar Jagannath, Dennis 0. Dixon, Bruce Cheson, Leslie Smallwood, Allison Hendrickson, Joseph D. Purvis, Eric Bonnem, and Raymond Alexanian High-dose melphalan has induced remissions in about 40% of patients with refractory myeloma, but the mortality has been high, at about 20%. due to complicationsof prolonged granulocytopenia. In an attempt to stimulate earlier granulocyte recovery, recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered subcutaneously t o 23 patients with refractory myeloma who had been treated with melphalan at a high dose of 100mg/m2. Thirty-nine percent of patients achieved marked tumor cytoreduction by at least 75%. 2 died within 2 months from infectious complications during severe neutropenia; and median durations of relapse-free and overall survival were 7 and 10+ months, respectively. The nine patients presenting with both advanced age over 50 years and a long history of prior therapy of over 1 year required significantly longer median times of 31 days for granulocytes and of 63 days for platelets to reach safe levels of at least 5OO/pL and 5O,OOO/pL, respectively, than the 14 remaining patients who had none or only one of these adverse features (21 and 26 days, respectively). In a historic control of 43 patients treated previously with high-dose melphalan but without GM-CSF, hematologic recovery t o the aforementioned levels of granulocytes and platelets proceededover almost 5 weeks, regardlessof age and prior treatment exposure. Thus GM-CSF seems t o hasten marrow recovery, especially in patients with adequate normal marrow stem-cell reserve as defined by younger age or less prior therapy. While not shortening the duration of neutropenia, GM-CSF dose increments (from 0.25 to 0.5 to 0.75 mg/m2) increased the incidence of severe toxicity from 0% to almost 40%. especially among older patients. These results support the usefulness of low-dose GM-CSF (0.25 mg/m2) in stimulating marrow recovery in selected patients with adequate marrow reserve treated with high-dose melphalan for refractory multiple myeloma. 0 1990by The American Society ofHematology. MELPHALAN AND prednisone in standard doses have been the mainstay of therapy for multiple myeloma for over 20 years, inducing remissions in about one half of patients and providing a median survival of about 3 years.' When resistance to melphalan-prednisone develops, a regimen combining continuous infusions of vincristine and adriamycin with high doses of dexamethasone (VAD) reestablished disease control in approximately 40% of patients2 In case of additional resistance to VAD, high-dose melphaIan (HDM) was effective in about 40% of patients, but prolonged marrow-aplasia led to fatal infections in about 20%.3To induce earlier granulocyte recovery after HDM, a clinical trial was designed to evaluate the role of granulocytemacrophage colony-stimulating factor (GM-CSF), a recombinant hematopoietin with major proliferative and differentiating effects on granulocytic and monocytic lineages4*'In comparison with a group of 43 patients who had previously received H D M alone, added GM-CSF hastened hematologic recovery, especially of granulocytes but primarily in younger patients with limited prior drug exposure. MATERIALS AND METHODS Twenty-three patients with refractory myeloma were enrolled in a trial to examine whether daily subcutaneous administration of GM-CSF would speed up hematologic recovery after intravenous (IV) HDM at a dose of 100 mg/m2.Eligibility criteria included good performance (Zubrod score less than 3) and no major renal function impairment (creatinine less than 3 mg%), which had been established as favorable features for survival in a previous trial of 43 patients receiving HDM without GM-CSF.3 Tables 1 and 2 summarize the characteristics of patients treated with HDM with GM-CSF. Approximately one half was older than 50 years, had extensive marrow plasmacytosis greater than 30%,and had been treated for over 1 year. The median number of prior treatment regimens was two; about 80%were refractory to alkylating agents and to VAD; three had even received high-dose therapy requiring autologous hematopoietic stem cell support (marrow, one patient; blood stem cells, two patients). Radiotherapy to marrow- containing bones such as spine and pelvis had been given to almost 40%. Myeloma staging (serum beta-2-microglobulin, B2M)6 and assessment of disease aggressiveness (serum lactic dehydrogenase, LDH)' indicated unfavorable features for survival in no more than one quarter of patients3 Adverse features for responsiveness to therapy (low DNA and RNA content) were present in 30%.* After a written informed consent was obtained in accordance with institutional policy, a single IV infusion of HDM (100 mg/m2) was given in 100 mL of dextrose and water over 30 minutes, after premedication with 100mg of dexamethasone as well as metoclopramide (40 mg) and diphenhydraminehydrochloride (25 mg).Melphalan was provided by Burroughs-Wellcome (Research Triangle Park, NC). GM-CSF, provided by Schering-Plough (Kenilworth, NJ), was given subcutaneously starting 3 days after melphalan at an initial dose of 0.25 mg/m2,with weekly escalation by 0.25 mg/m2 to a maximum of 0.75 mg/mz if neutropenia less than 500/pL persisted. Eleven patients were started at the lowest dose level of 0.25 mg/m2, and 12 received 0.5 mg/m2 as their initial dose. GM-CSF was discontinued whenever granulocyte counts exceeded 2,OOO/pL From the Division of Hematology-Oncology, University ofArkansas for Medical Sciences, Little Rock. AR; the Division of Cancer Treatment, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda. MD; the Division of Cancer Therapy, Burroughs Wellcome. Research Triangle Park, NC; Schering-Plough Research, Kenilworth. NJ; and the University of Texas M.D. Anderson Cancer Center, Houston, TX. Submitted December I !, 1989; accepted April 25, 1990. Supported in part by Grants No. CA 37161 and CA 16672 from the National Cancer Institute, Bethesda. MD. Address reprint requests to Bart Barlogie, MD, Arkansas Cancer Research Center, 4301 W Markham, Slot 508. Little Rock, A R 72205. Thepublication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.section I734 solely to indicate thisfact. 0 I990 by The American Society of Hematology. 0006-4971/90/7604-0021S3.00/0 B l ~ dV,OI 7 6 , N O 4 (August 15). 1990: pp 677-680 677 6 7 8 BARLOGIE ET AL Table 1. Patient and Disease Characteristics Parameter N Total Male Age >50 years Zubrod performance >1 Serum creatinine r 1.4 mg% Serum beta-2-microglobulin 6 mg/L Serum lactic dehydrogenase > 3 0 0 u/L Marrow plasma cells > 3 0 % Plasma cells hypodiploidor with low RNA index I4 23 19 11 3 4 6 4 12 7 on 3 successive days. Antibiotic prophylaxis consisted of trimethoprim-sulfamethoxazole (160 mg/800 mg; given twice a day, every other day) or, in case of drug allergy, of ciprofloxacin (750 mg given twice a day, every other day). When overt infection developed, IV broad-spectrum antibiotics were instituted. Serial assessments of myeloma protein and bone marrow plasmacytosis were conducted to define remission. Clinical response was defined by 75% or greater reduction of myeloma protein synthesis9; complete remission required the disappearance of myeloma protein on immunofixation studies. Responding patients were followed on no treatment until relapse. Relapse-free survival and overall survival times were calculated by life-table analysis from the onset of treatment. Statistical methods included xz tests for comparison of rates"; Kaplan-Meier estimates" of relapse-free survivaland survivalcurves; and generalized Wilcoxon tests12for comparison of curves. To relate the results of GM-CSF-supported HDM to those observed in 43 previous patients with advanced and refractory myeloma receiving HDM without GM-CSF,3 their hematologic recovery patterns were examined in relationship to age and duration of prior therapy, the two features noted to affect the durations of granulocytopenia and thrombocytopenia after HDM with added GM-CSF. RESULTS Nine of 23 patients (39%) treated with HDM and GMCSF achieved a calculated tumor regression of a t least 75%, two of whom have relapsed 3 and 4 months after HDM; and six patients have died (Table 3). The median durations of relapse-free and overall survival were 7 and 10+ months, respectively. Two patients died on days 18 and 24 after Table 3. Clinical Outcome Parametei Early death within 2 months Responding Surviving Median months relapsefree Median months surviving N 2 9 17 7 1o-t HDM from systemic aspergillosis when granulocyte levels were still under lOO/pL; both patients had serum creatinine elevations above 2.5 mg% before HDM, and one was 78-years-old. The four remaining deaths occurred between 3 and 6 months after HDM and were due to disease progression. Granulocytes recovered to greater than 5OO/pL after a median of 25 days, and the median time to a platelet count exceeding 50,OOO/pL was 32 days (Fig 1). One third of patients had a total white blood cell (WBC) count of less than 200/pL for more than 5 days. Pneumonia and/or sepsis were documented in 15 of 23 patients. The median duration of hospitalization was 4 weeks. Of six patients receiving H D M in the outpatient clinic, only one required hospital admission upon onset of neutropenic fever for intravenous (IV) antibiotics. Multiple pretreatment variables that might affect the speed of hematologic recovery were examined. Recovery of platelets (greater than 5O,OOO/pL) and, less markedly, of granulocytes (greater than 5OO/pL) proceeded faster in patients 550 years and in those treated within 12 months of their primary therapy (Table 4). Similarly, milder degree of anemia (hemoglobin greater than 10 g%) was associated with significantly earlier platelet recovery within 3 weeks as opposed to over 8 weeks in the more severely anemic patients. None of the other pretreatment variables, including those associated with tumor mass, extent of marrow plasmacytosis, type and number of prior treatment regimens, and renal function were associated with the duration of cytopenia after HDM; similarly, the GM-CSF starting dose did not influence the speed of hematologic recovery. 1 Table 2. Prior Treatment History Parameter N Total 2 2 prior regimens MP or VMCP-VBAP VAD High-dose therapy with autologous stem-cell support Radiotherapyto spine or pelvis >12 monthsfrom first treatment Never responded 23 15 18 19 3 9 12 6 Abbreviations:MP, melphalan.prednisone: VMCP, vincristine, melphaIan, cyclophosphamide,prednisone; VBAP, vincristine, BCNU. Adriamycin. prednisone. II I I III 0 10 20 30 40 50 60 70 DAYS AFTER MELPHALAN Fig 1. Median days with 95% confidence intervals t o granulocyte levels greater than W / p L (0)and to platelets greater than 5O,OOO/pL (A)after administration of melphalan 100 mg/m2 with GM-CSF for refractory myeloma (n = 23). HDM/GM-CSF FOR REFRACTORY MULTIPLE MYELOMA +Table 4. Hematologic Recovery After High-Dose Melphalan GM-CSF Parameter Median Days to Granulocytes N >5001pL P Platelets>50,OOO/pl Age (yrs) 550 >50 Months from 1st Treatment 512 2 12 Hemoglobin Is%) 110 >lo 12 21 .07 1 1 29 10 21 13 31 .01 13 29 10 21 .2 25 47 22 59 59 23 Age >50 and >12 mos from first treatment Other 9 14 31 21 .03 63 26 679 P .02 ,0001 .0004 ,009 Among the 23 patients receiving HDM with GM-CSF, the concurrence of advanced age (greater than 50 years) and extensive prior therapy (greater than 1 year) identified a poor risk group of nine patients in whom granulocyte and platelet recoveries were markedly delayed compared with those lacking both adverse features (Table 4 and Fig 2). The median times to granulocyte counts exceeding 500/rL and to platelet counts exceeding 50,OOO/~Lamong 43 patients treated previously without GM-CSF were 35 and 32 days, respectively, independent of age and duration of prior treat- lr 10.8 A' 10 20 30 40 50 Ell DAYSAFTER MELPHALAN 70 EgL? 04 CL 0 6 : c0.2 dt- B o 10 20 30 40 50 Ell 70 DAYS AFTER MELPHALAN Fig 2. Faster granulocyte (AI and platelet recoveries (6) in patients 1 5 0 years andlor with 1 1 2 months of prior therapy in = 14; 0 ) compared with those presenting with both adverse features (n = 9: AI.A, P = .03;B, P = .W9. ment exposure. Among comparable patients up to age 50 years and/or with prior therapy not exceeding 12 months (applying to 24 of the previous trial without GM-CSF and to 14 of the current trial), GM-CSF shortened median granulo- cyte recovery from 35 to 21 days (P= .0001) and platelet recovery from 3 1 to 26 days (P = .2). HDM produced mild nausea and only occasional vomiting when antiemetic prophylaxis was given. Toxicity attributed to GM-CSF included rash (three patients), diarrhea (eight patients), nausea and vomiting (eight patients), bone pain (five patients), temperature elevation to r39.5OC (10 patients), and capillary leak syndrome with pericardial effusion (one patient, 78-years-old, with serum creatinine greater than 2.5 mg% and death from pulmonary aspergillosis on day 18). The incidence of toxicity was dose related, so that none of the 11 patients receiving the lowest dose of 0.25 mg/m2 had grade 3 or 4 extramedullary toxicity, compared with 18% of those receiving 0.5 mg/m2 and 38%of those receiving 0.75 mg/m2 (P= .01). Thus GM-CSF dose reduction or interruption was required in 4 of 22 patients who received 0.5 mg/m2 and in 9 of 18 patients who received 0.75 mg/m2 (P= .07). Except for those treated at the lowest dose of 0.25 mg/m2, more patients over age 50 years experienced grade 3 and 4 GM-CSF-related toxicity (64%) than younger patients (25%,P = .1). DISCUSSION IV-administered HDM is emerging as a useful therapy for both refractory and newly diagnosed myeloma.'*'' The present study was designed to assess the role of GM-CSF in patients who are most likely to benefit from HDM (ie, those with good performance and relatively normal renal function); such patients had a median survival of about 1 year in the earlier trial of 43 not receiving GM-CSF.3About 40%of patients in the current study have responded for a median duration of 7 months; and early mortality was about 10%. In the absence of two unfavorable features (ie, age greater than 50 years and extensive prior therapy for more than 12 months), recovery of granulocytes and platelets to safe levels exceeding SOO/pL and 50,00O/pL, respectively, occurred within 21 and 26 days after HDM. Appreciating the obvious limitations inherent in comparisons with historic controls, 24 680 BARLOGIE ET AL similar patients (among a larger group of 43) treated previously without GM-CSF required 2 additional weeks for granulocyte and 5 more days for platelet recovery to compa- rable levels. Thus GM-CSF seems to be useful mainly in hastening neutrophil recovery in younger individuals with adequate hematopoietic stem-cell reserve. In the absence of therapeutic benefit and with increased toxicity from higher doses, especially among older patients, the generally well- tolerated low GM-CSF dose of 0.25 mg/m2 is recommended for use in conjunction with HDM. The question arises where, in the overall management of myeloma, HDM and GM-CSF should be used. Since GM- C S F affords shortening of potentially fatal marrow aplasia mainly in younger patients with shorter prior treatment history, this approach should be considered as salvage therapy early on when it is clear that VAD is ineffective in newly diagnosed or refractory myeloma. H D M is especially attractive because its efficacy extends to the presence of hypodiploidy and low plasma-cell R N A content, both of which are frequently associated with primary drug resistance.8 While superior to melphalan doses of 100 mg/m2, marrow- ablative treatment with even higher doses of up to 200 mg/m2 or combined with total body irradiation does not result in a high frequency of durable complete remissions even when applied as consolidation treatment after VAD or similar induction In the absence of an apparent adverse effect on remission and survival times of up to 30% plasma cells in autografts, advances can be expected from more marked tumor cytoreduction prior to marrow-supported high-dose therapy, employing truly non-crossresistant regimens such as VAD, HDM with GM-CSF, and a recently reported regimen combining etoposide, dexamethasone, Ara-C, and cis-platinum (EDAP).l6 Compared with other cytotoxic agents, melphalan seems to exert damage toward early hematopoietic progenitor cells, where a benefit from GM-CSF was perhaps not expected because of its presumed effect on more mature progeny." A recent experimental trial with marrow-ablative total body irradiation in monkeys, however, demonstrated complete hematologic recovery with G-CSF without hematopoietic stem-cell support, suggesting therefore a stimulatory effect of G-CSF (and perhaps of GM-CSF) on an early progenitor compartment.I8 While recently identified as a potential myeloma growth factor in vitro together with interleukin-6 (IL-6),I9 GM-CSF administered after HDM did not increase, even transiently, marrow plasmacytosis or myeloma protein concentrations monitored at weekly intervals. As the toxicities of other hematopoietic growth factors, such as interleukin-3 or interleukin-1 are being defined, combinations of such growth factors may complement and eventually perhaps replace hematopoietic stem cells as a means of supporting marrow-ablative cytotoxic therapy. REFERENCES 1. Barlogie B, Epstein J, Selvanayagam P, Alexanian R: Plasma cell myeloma-new biological insights and advances in therapy. Blood 73365, 1989 2. Barlogie B, Smith L, Alexanian R Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310:1353,1984 3. Barlogie B, Alexanian R, Smallwood L, Cheson B, Dixon D, Dicke K, Cabanillas F Prognostic factors with high-dose melphalan for refractory multiple myeloma. Blood 72:2015, 1988 4. Weisbart RH, Golde DW: Physiology of granulocyte and macrophage colony-stimulating factors in host defense, in Golde DW (ed): Hematology/Oncology Clinics of North America: Hematopoietic Growth Factors, Vol 3. Philadelphia, Pa, Saunders, 1989, p401 5 . Vadhan-Raj S, Keating M, LeMaistre A, Hittleman WN, McCredie K, Trujillo JM, Broxmeyer HE, Henney C, Gutterman JU: Effects of recombinant human granulocyte-macrophage-colonystimulating factor in patients with myelodysplastic syndrome. N Engl J Med 317:1545,1987 6. Alexanian R, Barlogie B, Fritsche H: Beta-2-microglobulin in multiple myeloma. Am J Hematol20:345,1985 7. Barlogie B, Smallwood L, Smith T, Alexanian R: High serum levels of lactic dehydrogenase identify a high-grade lymphoma-like myeloma. Ann Intern Med 110:521, 1989 8. Barlogie B, Alexanian R, Smith L, Dixon D, Smallwood L, Delasalle K Prognostic implications of tumor cell DNA and RNA content in multiple myeloma. Blood 66:338, 1985 9. McLaughlin P, Alexanian R: Myeloma protein kinetics following chemotherapy. Blood 60351.1982 10. Colton T: Statistics in Medicine. Boston, Mass, Little, Brown, 1974 11. Kaplan EL, Meier P Nonparametric estimation from incomplete observations. J Am Statist Assoc 53:457, 1958 12. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censoredsamples. Biometrika 52:203, 1965 13. Selby PF, McElwain TJ, Nanci AC, Perren TJ, Powles RL, Tillyer CR, Osborne RJ, Slevin ML, Malpas JS: Multiple myeloma treated with high dose intravenous melphalan. BR J Haematol 6655, 1987 14. Barlogie B, Alexanian R, Dicke K, Zagars G, Spitzer G, Jagannath S, Horowitz L: High dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma. Blood 70:869, 1987 15. Gore ME, Viner C, Meldrum M, Bell J, Milan S, Zuiable A, Slevin M, Selby PJ, Clark PI, Millar B, Maitland JA, Judson IR, Tillyer C, Malpas JS, McElwain TJ: Intensive treatment of multiple myeloma and criteria for complete remission. Lancet 2:879, 1989 16. Barlogie B, Alexanian R, CabanillasF Etoposide,dexamethasone, cytosine-arabinoside and cis-platinum (EDAP) in VADrefractory myeloma. J Clin Oncol7: 1514, 1989 17. Demetri GD, Griffin JD: Hemopoietins and leukemia, in Golde, DW (ed):Hematology/Oncology Clinics of North America: Hematopoietic Growth Factors, Vol 3. Philadelphia, Pa, Saunders 1989, p 534 18. Schuening FG, Storb R, Goehle S, Graham TC, Applebaum FR, Hackman R, Souza LM: Effect of recombinant human granulocyte colony-stimulating factor on hematopoiesis of normal dogs and on hematopoietic recovery after otherwise lethal total body irradiation. Blood 74:1308, 1989 19. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe 0,Tanaka H, Kuramoto A, Kishimoto T: Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332:83, 1988