Document OEaXzYVepB53Jz8OLq5qo4BG1

Myeloma Bone Marrow Transplantation (2002) 30, 367373 2002 Nature Publishing Group All rights reserved 02683369/02 $25.00 www.nature.com/bmt Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma S Giralt1, A Aleman1, A Anagnostopoulos1, D Weber2, I Khouri1, P Anderlini1, J Molldrem1, NT Ueno1, M Donato1, M Korbling1, J Gajewski1, R Alexanian2 and R Champlin1 1Department of Blood and Bone Marrow Transplantation, University of Texas MD Anderson Cancer Center, Houston, TX, USA; and 2Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA Summary: The purpose of the study was to determine the feasibility and efficacy of a reduced intensity conditioning regimen of fludarabine and melphalan for allogeneic transplantation in patients with multiple myeloma. From August 1996 to December 2000, 22 patients received a reduced intensity conditioning regimen with fludarabine and melphalan. Median age was 51 years (range, 4564), median time from initial therapy to transplant was 36 months (range, 3135 months). Disease phase prior to transplant was primary refractory in two patients, refractory relapse in 11 patients, sensitive relapse in eight patients and initial remission consolidation in one patient. The median number of prior therapies was five (range, 17), and median beta 2 microglobulin prior to transplant was 3.0 mg/l (range, 1.07.3). All patients received unmanipulated grafts from either HLA matched sibling donors (n = 13) or matched unrelated donors (n = 9). Eighteen patients received fludarabine 30 mg/m2 for 4 days with melphalan 140 mg/m2 as a single dose and four patients received fludarabine 25 mg/m2 for 5 days with melphalan 90 mg/m2 daily for 2 days. All 21 patients evaluable for engraftment achieved a neutrophil count of 0.5 109/l after a median of 12 days (range, 924), 18 patients achieved platelet transfusion independence after a median of 14 days (range, 847). All engrafting patients had 100% donor cell engraftment. Seven patients achieved a complete remission. Six patients are currently alive with a median follow-up of 15 months (range, 1047 months). The actuarial survival and progression-free survival is 30 11% and 19 9% at 2 years. Non-relapse mortality at 100 days was 19 10% and 40 10% at 1 year. Fludarabine/melphalan combinations are feasible and allow consistent engraftment of allogeneic progenitor cells from both related and unrelated donors in patients with multiple Correspondence:Dr S Giralt, Department of Blood and Bone Marrow Transplantation, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Houston Texas, 77030, USA Received 12 February 2002; accepted 3 May 2002 myeloma and should be explored in patients with less advanced disease. Bone Marrow Transplantation (2002) 30, 367373. doi:10.1038/sj.bmt.1700652 Keywords: fludarabine/melphalan; myeloma; allografts Multiple myeloma is a neoplastic proliferation of plasma cells. Traditional approaches to therapy for myeloma have included systemic chemotherapy and radiation to affected sites.1 Approximately 50% of patients will respond to initial therapy with alkylator-steroid combinations. Complete remissions occur in approximately 10% of patients and recurrence of disease is usually inevitable with emergence of resistant clones. Therefore, less than 15% of patients with myeloma will survive more than 10 years when treated with conventional chemotherapy alone.13 The use of high-dose chemo-radiotherapy with or without stem cell support was pioneered by McElwain and Barlogie.46 High-dose chemotherapy resulted in a higher incidence of complete remission, and improved survival and progression-free survival when compared to conventional chemotherapy in both randomized and non-randomized trials.712 However, recurrence of disease usually develops, and only a minority of patients remain progression-free 10 years after transplant.1315 High-dose chemotherapy with allogeneic transplantation has the potential of adding a graft-versus-myeloma effect in addition to a stem cell product free of tumor cell contamination.16,17 However, despite high complete remission rates of 3050%, disease-free survival at 5 years after allografting is only 25%, due primarily to the high treatmentrelated mortality of 40 to 50%.1822 Purine analog containing non-myeloablative chemotherapy can allow engraftment of allogeneic hematopoietic progenitor cells with acceptable toxicity in patients considered ineligible for standard myeloablative therapy and allogeneic transplantation either because of age or medical condition.2326 Therefore use of less intensive preparative regimens might provide an avenue for exploiting the graftversus-myeloma effect without the toxicities seen with myeloablative therapies. We report the long-term results of our intial experience with a reduced intensity conditioning Fludarabine/melphalan conditioning for patients with MM S Giralt et al 368 regimen of fludarabine and melphalan for patients with five times weekly until day 100. Patients with CMV anti- multiple myeloma undergoing allogeneic progenitor cell genemia or with positive shell vial cultures were treated transplantion.26 with ganciclovir 5 mg/kg intravenously twice daily for 14 days, then daily for 8 weeks. All patients received G-CSF 5 g/kg subcutaneously Patients and methods daily from day +7 until achievement of an absolute neutrophil count (ANC) of 1.5 109/l for 3 days in a row. Eligibility criteria Patients were eligible for this program if they had multiple myeloma and were considered poor candidates for autologous transplantation either because of disease status or inability to collect autologous stem cells. Patients up to the age of 65 years with a related HLA-compatible donor or fully matched unrelated donor were considered eligible if their Zubrod performance status was 2, left ventricular ejection fraction was 40%, serum creatinine was 2.0 mg/dl, bilirubin 3 times upper limit of normal and transaminases 4 times upper limit of normal. Both patient and donor signed written informed consent and were treated on protocols approved by the Institutional Review Board of the University of Texas MD Anderson Cancer Center. Packed red blood cells were transfused to maintain hemoglobin levels 8 gm/dl, and platelets were transfused to keep the platelet count 20 109/l. All blood products were filtered and irradiated to 1500 cGy. Patients with neutropenic fever were treated with broad spectrum antibiotics according to institutional protocols. Patients developing grade 2 or greater acute GVHD received methylprednisolone at least 0.5 mg/kg every 6 h and could be enrolled on any existing protocol for the treatment of GVHD. Bone marrow aspiration along with serum and urine protein electrophoresis were carried out routinely 34 weeks after infusion and 3 and 12 months later and bone marrow underwent morphologic evaluation, FISH, cytogenetics and chimerism evaluation. Unrelated donors were procured and consented through the National Marrow Donor Program according to currently accepted standards and procedures. Statistical endpoints Treatment plan From August 1996 to July 2000, all recipients of sibling donor transplants received fludarabine 30 mg/m2 intravenously daily over 30 min on days 4, 3, 2, 1 and melphalan 140 mg/m2 intravenously on day 1. Recipients of unrelated donor bone marrow were prepared with fludarabine 25 mg/m2 intravenously daily for 5 days and with melphalan 90 mg/m2 intravenously daily for 2 days until December 1998, after which they were conditioned with the same preparative regimens used for the sibling transplants. Donor-derived, filgrastim-stimulated peripheral blood stem cells or steady state bone marrow was infused on day 0. Drugs were dosed according to adjusted body weight in patients whose actual weight was 20% over ideal body weight. Graft-versus-host disease (GVHD) prophylaxis consisted primarily of tacrolimus (FK506, Prograf, Fujisawa, Japan) given from day 2 until at least 3 to 6 months after transplant, in combination with methotrexate 5 mg/m2 on days 1, 3, 6 and 11. Whole blood tacrolimus levels were monitored three times a week until day 90 post transplant, and weekly thereafter. Tacrolimus dose was modified to keep whole blood tacrolimus levels between 4 and 10 ng/ml. Antibacterial, antifungal and antiviral prophylaxis followed institutional protocols. This included trimethoprim/sulfamethaxozole for Pneumocystis carinii prophylaxis, acyclovir for herpes simplex virus prophylaxis, fluconazole for fungal prophylaxis, and penicillin and norfloxacillin or ciprofloxacillin for bacterial prophylaxis. CMV prophylaxis consisted of biweekly surveillance blood and urine cultures for CMV using shell vial and rapid antigen techniques. Recipients of unrelated or mismatched related donor transplants or patients on high-dose steroids received prophylactic ganciclovir 5 mg/kg intravenously Major endpoints included: neutrophil recovery defined as an ANC of 0.5 109/l for 3 days in a row, and platelet recovery as a platelet count of 20.0 109/l independent of platelet transfusions. Complete remission was determined by the European Bone Marrow Transplant Registry (EBMT)/International Bone Marrow Transplant Registry (IBMTR). Their criteria require the absence of a monoclonal protein on two consecutive immune fixation tests on blood and urine with a normal bone marrow examination in patients who had serum or urine monoclonal peaks. The criteria for complete remission are less stringent in patients with non-secretory myeloma who require only normal bone marrow examination with disappearance of extramedullary plasmacytomas.27 Acute and chronic GVHD were scored according to published guidelines.28,29 Chimerism was determined on bone marrow samples by cytogenetics or restriction fragment length polymorphisms using established techniques.30,31 Toxicity was graded according to Bearman criteria.32 Survival and disease-free survival calculations were analyzed as of 1 March 2001, using the techniques described by Kaplan and Meier.33 Univariate analysis was done using the logrank technique as determined by a commercially available statistical package (Statistica 2000, StatSoft Inc, Tulsa, OK, USA). Patient characteristics Patient characteristics are summarized in Table 1. The median age was 51 years (range, 4664) and 11 patients had advanced refractory myeloma and nine had failed prior autologous transplant. The median number of prior therapies was five, and the median time to transplant from diagnosis was 36 months (range, 3135 months). Bone Marrow Transplantation Table 1 Characteristics of patients with multiple myeloma undergoing allogeneic transplants with a reduced intensity conditioning regimen of fludarabine melphalan at MDACC n n = 22 Age Median time to transplant (months) No. prior therapies Auto-transplant failures Disease status at transplant First remission Primary refractory Sensitive relapse Refractory relapse Immuneglobulin type Ig-G Ig-A Ig-D Light chain only Non-secretory Pre-transplant -2-microglobulin Conditioning regimen FM140 mg/m2 FM180 mg/m2 Donor type 6/6 Sibling 6/6 MUD 5/6 Sibling 51 (4564) 36 (3135) 5 (29) 9 1 2 8 11 12 5 1 3 1 3.0 (1.07.3) 18 4 12 9 1 n = number; FM = fludarabine/melphalan; MUD = matched-unrelated donor. Results Toxicity The preparative regimen was well tolerated with only one instance of grade 4 toxicity in a patient who died with multiorgan failure and tumor lysis. Bearman toxicities grade 2 are summarized in Table 2. Four patients died before day 100, one from multiorgan failure and tumor lysis, and three from acute GVHD and infections. The 100day non-relapse mortality rate was 19 10%. Five additional patients died between day 100 and day 360 from non-relapse causes (GVHD with infections); thus, the 1 year non-relapse mortality rate was 40 10%. Univariate analysis of pretransplant and transplant variables predicting for 100 day and 1 year non-relapse mortality is presented in Table 3. There was a trend for patients transplanted within 3 years of diagnosis to have a lower risk of nonrelapse mortality at 1 year post transplant as compared to patients undergoing allografts greater than 3 years from diagnosis (23% vs 55%) Table 2 Toxicities grade 2 according to bearman scale Mucositis Liver Heart Kidney Lung Diarrhea Grade 2 Grade 3 Grade 4 0 2140 6 0 0000 0 0 1111 0 Fludarabine/melphalan conditioning for patients with MM S Giralt et al Table 3 Univariate analysis of risk factors predicting for day 100 and day 360 NRM Variable %NRM at day P (Cox's 100/day 360 F test) Age 50 (n = 9) 50 (n = 13) Patient sex M (n = 11) F (n = 11) Donor sex M (n = 16) F (n = 6) Time Dx to transplant 3 years (n = 11) 3 years (n = 11) Disease stage Refractory relapse (n = 11) Other (n = 11) Donor type Sibling (n = 12) Mismatched or unrelated (n = 10) 22/44 16/38 9/34 27/45 17/50 19/38 9/23 27/55 27/46 9/36 17/42 20/40 NS NS NS 0.11 NS NS Engraftment and chimerism Twenty-one patients achieved neutrophil recovery at a median of 12 days post transplant (range, 924). Eighteen patients achieved platelet transfusion independence at a median of 14 days post transplant (range, 847). Seventeen patients had chimerism analysis on day 30 of unsorted bone marrow cells with all patients having greater than 90% donor cell engraftment. No instances of secondary autologous reconstitution were observed, and at 1 year all six patients tested had 100% donor cells in unsorted bone marrow as determined by cytogenetics or molecular techniques. Response: Sixteen patients (72%) responded according to the EBMT/IBMTR criteria. Seven patients (32%) achieved a complete remission, and nine achieved a partial remission (40%). Three patients who achieved CR progressed at 8, 17 and 19 months post transplant. Individual responses as well as subsequent responses to donor lymphocyte infusion are summarized in Table 4. Graft-versus-host disease: Ten patients developed acute GVHD grade 2 for an actuarial rate of 46% 10%. Six patients developed acute GVHD grade 3, for an actuarial risk of 27% 9%. No significant differences were observed among recipients of unrelated or mismatched transplants with regard to the risk of acute GVHD when compared to recipients of matched related donor transplants. Six patients developed chronic GVHD, all of these patients had extensive chronic GVHD. Survival and progression-free survival: The overall survival for all patients is 30 11% at 2 years with six patients currently alive at a median follow-up of 15 months (range, 947 months); the median survival for all patients was approximately 10 months. The progression-free survival for all patients was 19 10% at 2 years with two 369 Bone Marrow Transplantation Fludarabine/melphalan conditioning for patients with MM S Giralt et al 370 Table 4 Response to therapy and to donor lymphocyte infusions UPN Sex/Age Ig Months to Disease status at Donor Response DLI Survival subtype transplant transplant type (months) Outcome 930104 000093 950300 970013 M/49 M/45 M/47 F/54 970039 F/50 970071 930286 960379 970217 F/53 M/46 F/49 F/50 980070 M/51 980103 F/49 980390 F/48 980408 980015 990260 980194 F/50 M/51 M/60 F/53 980397 000221 970143 970204 950192 M/64 F/57 M/55 M/49 M/48 910097 F/49 IgA 81.5 BJP 49.6 IgG 58.5 IgG 36.0 IgA 30.5 IgG 16.9 IgG 52.7 IgG 14.4 IgA 53.3 IgG 33.8 IgD 3.3 IgA 5.9 IgA 16.5 IgA 19.8 BJP 36.8 IgG 33.9 IgG 53.6 BJP 109.4 IgG 13.3 IgG 41.8 NS 135.2 IgG 96.4 Refractory Sensitive Refractory Sensitive Sensitive Primary Refractory Refractory Sensitive Sensitive First rem Refractory Sensitive Refractory Refractory Refractory Refractory Refractory Refractory Sensitive Refractory Sensitive MUD Sibling Sibling Sibling Sibling Sibling Sibling Sibling Sibling 1 Ag MM Sibling Sibling Sibling Sibling MUD Sibling MUD MUD MUD MUD MUD MUD MUD PR PR SD PR CR PR CR ED SD CR CR NR PR CR PR PR PR NR NR CR CR PR No Yes No Yes with Chemo Yes with Chemo Yes No No No No No Yes with Chemo No No Yes Yes No No Yes Yes Yes No 4.5 Died in PR with chronic GVHD 10.3 Alive in PR, 8 weeks post DLI no GVHD 1.9 Died with GVHD 25.6 Died from disease. No response to DLI 3. 29.4 Relapsed from CR. Responded to chemo and DLI. Relapsed and died from disease. 47.2 Alive in PR, no definite response to DLI 5.8 Died chronic GVHD 0.16 Died multiorgan failure 2.4 Died acute GVHD 3.7 Died chronic GVHD and infection 35.0 Alive in CR 16.9 Died disease progression. No response to DLI 4.4 Died chronic GVHD 20.3 Alive in CR 8.4 Died disease progression no response to DLI 9.6 Died disease progression and lung cancer. PR to DLI and chemotherapy 10.2 Alive in PR 2.2 Died acute GVHD 10.4 Died disease progression. Transient PR to DLI 9.7 Died disease progression. No response to DLI 24.4 Died accident, 2 weeks post DLI for disease progression 5.1 Died chronic GVHD and infection patients alive in continuing complete remission at 20+ and 35+ months, two patients with unmaintained partial remissions at 10 months, and one patient alive without progression after donor lymphocyte infusions, chemotherapy and thalidomide at 47 months. Univariate analysis on factors predicting for survival and progression-free survival have been summarized in Table 5. Table 5 Univariate analysis on prognostic factors for progression free survival and overall survival in patients undergoing allografting after a fludarabine/melphalan conditioning regimen Variable %OS @ P %PFS @ P 2 years 2 years Age 50 (n = 9) 28 NS 17 NS 50 (n = 13) 44 20 Patient sex M (n = 11) 31 NS 12 NS F (n = 11) 44 18 Donor sex M (n = 16) 28 NS 19 NS F (n = 6) 50 17 Time Dx to transplant 3 years (n = 11) 41 0.13 27 NS 3 year (n = 11) 33 0 Disease stage Refractory relapse (n = 11) 32 NS 9 NS Other (n = 11) 43 24 Donor type Sibling (n = 12) 39 NS 22 NS Mismatched or unrelated (n = 10) 36 10 Discussion The existence of a graft-versus-myeloma effect has been directly demonstrated by the responses seen to donor lymphocyte infusion in patients relapsing after conventional allogeneic stem cell transplantation.16,17,34,35 Notwithstanding, it has not been possible to effectively exploit the graftversus-myeloma effect of allogeneic transplantation due to the high rates of treatment-related deaths that have been observed in this patient population with this procedure. In previous comparative analyses, overall survival and progression-free survival were inferior in allografted recipients when compared to autografted patients despite a significantly lower relapse rate.20 Various investigators have postulated that by using reduced intensity conditioning regimens it would be possible to transplant older and debilitated patients, with less toxicity. The rationale for this approach is that less tissue destruction may result in a lower release of inflammatory cytokines and therefore a lower incidence of GVHD and other causes of non-relapse deaths.2325,36,37 The reasons for exploring the combination of fludarabine and melphalan as a conditioning regimen for allogeneic transplantation in myeloma are derived from the following observations. First, melphalan is the most commonly used alkylating agent in myeloma, it has well documented activity against resistant myeloma at high doses and is well tolerated with little extramedullary toxicity even in older and debilitated patients.38,39 Second, fludarabine is a potent immunosuppressive agent that can inhibit the mixed lymphocyte reaction in vitro and facilitate engraftment.39 Third, Bone Marrow Transplantation purine analogs can inhibit the mechanisms of DNA repair that come into effect after alkylator-induced damage, thus potentially enhancing the antimyeloma effect of melphalan.39,40 Fludarabine-melphalan combinations used as described here resulted in universal donor cell engraftment with no instances of primary or secondary autologous reconstitution. Lower doses of melphalan (100 mg/m2) without fludarabine, have been showed by Badros et al41 to result in high rates of engraftment, except for one instance of secondary autologous reconstitution and three instances of mixed chimerism. These results contrast with the results of this study in which no instances of mixed chimerism or autologous reconstitution were seen. That difference suggests a role for fludarabine in facilitating engraftment of allogeneic stem cells, and that doses of melphalan below 100 mg/m2 might be associated with higher rates of graft failure. The immediate toxicity of the regimen was mild, but the 40% incidence of non-relapse deaths at 1 year remains excessive. The data in this report suggest that better patient selection could reduce non-relapse deaths, since patients transplanted within 3 years of diagnosis had a 1-year nonrelapse mortality rate of 23%. GVHD was the second most common cause of death aside from disease progression. Future strategies to prevent GVHD in the setting of nonablative transplantation include addition of a monoclonal antibody against CD52 (CAMPATH 1-H) and addition of mycophenolate-mofetil.42,43 Peggs et al42 recently reported that the use of pretransplant CAMPATH 1H was associated with a lower incidence of moderate and severe acute GVHD; however, it is unknown whether the reduction in rates of GVHD may translate into a higher relapse rate, and inferior outcomes because of disease progression.42 The primary cause of treatment failure was disease recurrence which caused the death of eight patients. Thus, despite achieving donor cell engraftment, the graft-versusmyeloma effect did not result in long-term disease control. In this report, 10 patients received DLIs either because of relapse or failure to achieve complete remission after withdrawal of immunosuppression. Only three of these patients responded to DLI or withdrawal of immunosuppression. Of interest, most patients in this study were treated for chemorefractory relapses; in a recent update by Lokhorst et al17 chemosensitivity was an important predictor for response to donor lymphocyte infusions in myeloma. Therefore, to optimize the results of non-ablative and reduced intensity conditioning in myeloma it will be necessary to treat patients earlier in the course of their disease when the disease is more sensitive to therapeutic maneuvers. This initial experience with reduced intensity conditioning for multiple myeloma demonstrates that durable donor cell engraftment can be achieved, and a small fraction of patients with advanced resistant disease can achieve longterm disease control. This and other reports seem to confirm that non-relapse mortality rates are lower than with conventional ablative therapy. Among patients transplanted less than 3 years from diagnosis, the non-relapse mortality rate at 100 days was 9%, and at 1 year 23%. Similarly, the EBMTR reported a non-relapse mortality rate at 1 year of 10% in patients with myeloma who were allografted early Fludarabine/melphalan conditioning for patients with MM S Giralt et al during the course of their disease.44 These observations underscore the fact that optimal use of allogeneic transplantation depends on appropriate timing of the procedure.20 The optimal non-ablative transplant strategy is unknown. Molina et al43 reported that a regimen of low-dose total body irradiation (200 cGy) was associated with a high risk of graft failure in patients with myeloma who had never received intensive therapy. However, when this preparative regimen is given within 39 months of high-dose melphalan, the use of low-dose TBI was associated with universal donor cell engraftment, a high response rate and a low non-relapse mortality. The advantages of different reduced intensity strategies will need to be determined by carefully designed trials. This analysis was not intended to define the importance of the stem cell product in determining transplant outcomes. All recipients of unrelated donor progenitor cells received bone marrow, while all other patients received filgrastim stimulated bone marrow. Most peripheral blood stem cell recipients received within 45 106 CD34+ cells/kg. Therefore with the small number of patients and the homogeneity of stem cell dose, meaningful differences would be difficult to detect and the analysis was not performed. However, further study of non-ablative transplantation in a more homogeneous group of newly diagnosed myeloma patients or as first salvage therapy will need to look at cell doses and cell source as important variables for outcome. Non-ablative and reduced intensity conditioned allografts as frontline therapy for multiple myeloma should still be confined to clinical trials. With the current results of autografting and thalidomide, autologous transplantation should still be considered the frontline treatment of choice for most patients with multiple myeloma. However, patients with chromosome 13 abnormalities, and those with high tumor masses refractory to induction therapy could be considered for frontline allografting if an HLA-compatible donor is available, since results of autologous transplantation in these settings have been poor.11,45,46 Notwithstanding the limited experience to date, it is possible to say that further exploration of allogeneic transplantation for myeloma should only be undertaken in the context of non-ablative and reduced intensity conditioning regimens, with little if any role for conventional myeloablative therapies. References 1 Kyle R. Multiple myeloma: review of 869 cases. Mayo Clin Proc 1975; 50: 2940. 2 Alexanian R, Bonnet J, Gehan E et al. Combination chemotherapy for multiple myeloma. 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