Comparison of Reduced-Intensity and Conventional Myeloablative Regimens for Allogeneic Transplantation in Non-Hodgkin s Lymphoma

Biology of Blood and Marrow Transplantation 12:1326-1334 (2006) 2006 American Society for Blood and Marrow Transplantation 1083-8791/06/1212-0001$32.00/0 doi:10.1016/j.bbmt.2006.08.035 Comparison of Reduced-Intensity and Conventional Myeloablative Regimens for Allogeneic Transplantation in Non-Hodgkin s Lymphoma Roberto Rodriguez, 1 Auayporn Nademanee, 1 Nora Ruel, 1 Eileen Smith, 1 Amrita Krishnan, 1 Leslie Popplewell, 1 Jasmine Zain, 1 Kathy Patane, 1 Neil Kogut, 2 Ryotaro Nakamura, 1 Clarence Sarkodee-Adoo, 3 Stephen J. Forman 1 1 Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California; 2 Southern California Permanente Bone Marrow Transplant Program, Duarte, California; and 3 City of Hope Good Samaritan Transplant Program, Phoenix, Arizona Correspondence and reprint requests: Roberto Rodriguez, MD, Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, 1500 E Duarte Road, MOB 3001, Duarte, CA 91001 (e-mail: robertorodgriguez@coh.org). Received December 5, 2005; accepted August 20, 2006 ABSTRACT Reduced-intensity regimens (RIRs) are being used with increasing frequency in patients with non-hodgkin s lymphoma (NHL) undergoing allogeneic transplantation. The impact of dose reduction on relapse and survival has not been extensively studied. We performed a retrospective analysis of 88 patients conditioned with conventional myeloablative regimens (CMRs) (n 48) and an RIR (n 40) of fludarabine 125 mg/m 2 and melphalan 140 mg/m 2. Compared with the patients receiving CMR, those receiving RIR were older, had more often failed autologous transplantation, and had more frequently received peripheral blood and unrelated donor transplants. Graft-versus-host disease prophylaxis was provided with cyclosporine methotrexate prednisone for the CMR and with cyclosporine mycophenolate methotrexate for the RIR. The relapse rate was significantly lower in the patients receiving CMR than in those receiving RIR (13% vs 28%; P.05). The 1-year transplantation-related mortality rate was 33% for CMR and 28% for RIR (P.40). Kaplan-Meier 2-year overall survival and progression-free survival were 52% and 46% for CMR versus 53% and 40% for RIR (P not significant). Using cumulative incidence functions based on competing risks, univariate analysis, and treatment-related prognostic factors, we found that higher treatment intensity (P.03; relative risk [RR] 35%) and absence of previous autologous transplantation (P.0007; RR 20%) were associated with a lower relapse rate. Using a Cox univariate proportional hazards model, we found that chemosensitive disease at transplantation (P.05; RR 57%) and absence of previous autologous transplantation (P.002; RR 37%) were associated with improved survival. Our observation of similar survival in the patients receiving CMR and those receiving RIR confirms that RIRs are feasible alternatives for high-risk patients with NHL; however, the data suggest that reduced treatment intensity and previous autologous transplantation are associated with increased relapse. 2006 American Society for Blood and Marrow Transplantation KEY WORDS Reduced-intensity conditioning regimen Allogeneic stem cell transplantation Non-Hodgkin s lymphoma Reduced-intensity regimens (RIRs) carry reduced regimen-related toxicity and mortality after allogeneic hematopoietic cell transplantation (HCT) for various hematologic malignancies, allowing older and sicker patients to undergo this procedure. By decreasing the cytoreductive properties of therapy, RIRs shift the burden of therapy toward the immunologic power of the graft (graft-versus-malignancy effect [GVM]). Thus, relapse may be more common in patients with malignancies less sensitive to the GVM effect, potentially offsetting any survival benefit. Few long-term reports have studied the outcome for non-hodgkin s lymphoma (NHL) after RIRs. Allogeneic HCT for NHL is usually recommended for patients with high-risk disease who are poor candidates for high-dose chemotherapy with au- 1326

Reduced-Intensity and Conventional Myeloablative Regimens 1327 tologous HCT or have relapsed after this procedure. Conventional myeloablative regimens (CMRs) are associated with prohibitive transplantation-related mortality (TRM) for patients failing autologous transplantation [1,2], and RIRs have reopened the possibility of exploring allogeneic transplantation in this setting. Early TRM for such patients has been acceptable [3,4], but the long-term benefit of this approach has not been well studied. At our institution, all patients with NHL undergoing allogeneic transplantation since the year 2000 were conditioned with an RIR. To determine whether this strategy had an impact on relapse and survival, we compared the cohort of patients receiving the RIR of fludarabine and melphalan (flu/mel) with our experience using CMR during the previous decade. Herein we report the results of this analysis on 88 consecutive patients who underwent transplantation since 1991. METHODS The City of Hope Lymphoma database was used to identify all patients with NHL undergoing allogeneic transplantation at our institution. Two cohorts of patients were retrospectively analyzed and compared for survival outcomes and risk of relapse. The first cohort included all patients who underwent allogeneic transplantation between 1991 and 2000, when fractionated total body irradiation (FTBI) was uniformly incorporated into our conditioning regimens; during this period, all patients were conditioned with a CMR. The second cohort included all patients conditioned with an RIR of flu/mel between 2000 and December 2003. The patients were further analyzed according to 4 diagnostic categories: intermediate grade B-cell (diffuse large B-cell, including transformed disease and follicular grade 3), low-grade B-cell (follicular grade 1 and 2, and chronic lymphocytic leukemia/small lymphocytic lymphoma), mantle cell, and T-cell. Patients with high-grade histologies according to the Working Formulation [5] were excluded because of the small number of these patients. This analysis was reviewed and approved by the City of Hope s institutional review board. Treatment Patients in the CMR group received an FTBIbased regimen (n 41) or busulfan and cyclophosphamide (n 7) if there were contraindications for FTBI. The dose of FTBI was 1320 cgy in 11 fractions. Cyclophosphamide was given after FTBI, at a dose of 60 mg/kg of ideal body weight. The flu/mel RIR comprised fludarabine 25 mg/m 2 daily for 5 days, followed by melphalan 140 mg/m 2 intravenously. Graft-versus-host disease (GVHD) prophylaxis in CMR comprised cyclosporine and methotrexate, with or without methylprednisolone. In contrast, GVHD prophylaxis in RIR comprised cyclosporine and mycophenolate mofetil for patients receiving matched sibling donor HCT, with the addition of methotrexate for those receiving unrelated donor HCT. Supportive Care Antimicrobial prophylaxis, blood product transfusions, growth factor support, and treatment of GVHD were given in accordance with institutional guidelines or protocols available at the time of transplantation. The stem cell source was determined by the treating physician or donor availability. Peripheral blood and bone marrow were procured from sibling donors or unrelated donors through the National Marrow Donor Program according to guidelines available at the time of collection. Assessment of Outcome Response and relapse were defined according to standard criteria for lymphoma [6]. Patients still alive at the time of analysis were censored at the last follow-up date. Overall survival (OS) was measured from the time of transplantation until death or the last follow-up. Progression-free survival (PFS) was measured from transplantation until progression or death from any cause. TRM was measured from the date of transplantation to the date of death from complications of transplantation. Statistical Methods Demographic and disease characteristics were summarized for all patients using descriptive statistics. The probabilities of OS and PFS were estimated using Table 1. Patient characteristics CMR RIR P Value N 48 40 Low-grade B-cell 18 16 NS Intermediate-grade B-cell 16 12 NS Mantle-cell 10 5 NS T-cell 4 7 NS Age (years, median, range) 44 (18-54) 51 (20-67).0002 Previous regimens (median) 3 2.02 Previous autologous transplantation 5 16.002 Chemosensitivity at transplantation 24 31.007 FTBI regimen 41 0 <.0001 MUD 8 17.009 PBSCs 16 36.0001 Median follow-up (months, range) 69 (33-97) 20 (6-42) NS indicates not significant; MUD, matched unrelated donor; PBSCs, peripheral blood stem cells.

1328 R. Rodriguez et al. Table 2. Histological diagnoses Histology CMR (n 48) RIR (n 40) Intermediate-grade B cell 16 12 DLCL 9 7 t-dlcl* 7 3 Follicular grade 3 2 Low-grade B cell 18 16 Follicular grade 1/2 10 8 SLL/CLL 8 8 Mantle cell 10 5 T cell 4 7 CTCL 4 4 AILD 1 PLL 1 ALCL 1 DLCL indicates diffuse large-cell lymphoma; SLL, small lymphocytic lymphoma; CLL, chronic lymphocytic leukemia; CTCL, cutaneous T-cell lymphoma; AILD, angioimmunoblastic lymphadenopathy with dysproteinemia; PLL, prolymphocytic leukemia; ALCL, anaplastic large-cell lymphoma. *Transformed. the Kaplan-Meier method. Two-tailed tests of significance were used, with variables defined as significant if P values were at least.05. Survival estimates were calculated based on the product-limit method, and 95% confidence intervals were calculated using the logit transformation with Greenwood s variance estimate. TRM and relapse rates were analyzed using cumulative incidence functions based on competing risks. Cumulative incidence and P values were estimated using the cmprsk package of Gray [7] written in R version 2.2.1 [8]. Unless otherwise indicated, Kaplan-Meier log-rank P values are reported for PFS and OS. Competing risk regression P values were estimated using cmprsk and the proportional hazards subdistribution model of Fine and Gray [9], whereas factors possibly associated with OS and PFS were examined by univariate Cox regression analysis [10]. The variables tested included age, treatment intensity, disease grade, remission status, number of previous regimens, sibling versus unrelated transplantation, chemosensitivity, and previous autologous transplantation. The risk ratio was calculated for each variable. The 2-sided Fisher s exact test was used to compare proportions. The assumption of proportionality of the hazard ratio was tested for each variable between the 2 groups [11]. The 2-sample t test was used to compare sample means and continuous variables. GVHD was reported using crude incidence rates. RESULTS Patient Characteristics A total of 88 patients with low-grade (n 34), intermediate grade (n 28), mantle cell (n 15), and T-cell (n 11) NHL underwent allogeneic HCT with CMR (n 48) or flu/mel RIR (n 40) (Table 1). Specific histologies are given in Table 2. Since the year 2000, patients were considered eligible for the flu/mel RIR if they had a diagnosis of NHL regardless of age, with creatinine clearance 40 ml/min, carbon monoxide diffusion capacity (DLCO) of 40% of predicted, and cardiac ejection fraction (EF) of 45%. High-risk features for TRM for this cohort included previous autologous transplan- Figure 1. Probability of relapse at 2 years for all patients based on conditioning treatment intensity: 28% for RIR and 13% for CMR (P.05).

Reduced-Intensity and Conventional Myeloablative Regimens 1329 Figure 2. OS and PFS based on conditioning treatment intensity. tation (n 15), age 50 years (n 23), DLCO 50 (n 1), and EF 50% (n 1). Significant differences were observed between the 2 groups. Compared with the patients receiving RIR, those receiving CMR were more likely to be younger, to have been more heavily pretreated, and to have more often received a matched sibling transplant and bone marrow as the transplant source. Conversely, the patients receiving RIR were more likely to have previously received an autologous transplant. As expected, follow-up was longer for the patients receiving CMR. Relapse, PFS, and OS Overall, 20 patients relapsed, 12 after RIR and 8 after CMR, for 2-year relapse rates of 28% and 13%, respectively (P.05), (Figure 1). When analyzed by diagnostic category, patients with intermediate-grade B-cell lymphoma had a statistically significant higher Figure 3. TRM based on conditioning treatment intensity.

1330 R. Rodriguez et al. 2-year relapse rate after RIR (44%) compared with CMR (12%) (P.02). The 2-year relapse rates for patients with low-grade disease were 19% after RIR and 12% after CMR (P.56), and those for patients with mantle cell disease were 60% after RIR and 20% after CMR (P.05). No relapses were observed in patients with T-cell disease in either cohort. OS and PFS were not statistically different between the patients receiving RIR and those receiving CMR. The 2-year OS was 53% for RIR and 52% for CMR (P.99), and the 2-year PFS was 40% for RIR and 46% for CMR (P.46) (Figure 2). Similarly, by diagnostic category, there were no statistically significant differences in OS or PFS. The 2-year OSs by diagnostic category after RIR and CMR, respectively, were 36% and 50% (P.32) for intermediate grade B-cell disease, 68% and 56% (P.56) for low-grade B-cell disease, 30% and 50% (P.6) for mantle cell disease, and 57% and 50% for T-cell disease. The 2-year PFSs after RIR and CMR, respectively, were 31% and 44% (P.18) for intermediate grade B-cell disease, 49% and 50% (P.83) for low grade B-cell disease, 20% and 40% (P.36) for mantle cell disease, and 57% and 50% for T-cell disease. TRM and Cause of Death The risk of 2-year TRM was 28% for RIR and 38% for CMR (P.4) (Figure 3). Analysis of risk factors for nonrelapse mortality, including age ( 50 years), donor type (related vs unrelated), diagnosis, chemosensitivity at time of transplantation, stem cell source, previous autologous transplantation, and type of conditioning regimen, showed a trend for previous autologous transplantation predicting for TRM (P.07). Among the patients receiving RIR, 18 patients have died, due to relapse (n 7), GVHD (n 8), infection without GVHD (n 2), or interstitial pneumonia (n 1). Of the patients conditioned with CMR, 27 have died; causes of death included relapse (n 6), GVHD (n 4), infection without GVHD (n 8), veno-occlusive disease of the liver (n 2), interstitial pneumonitis/diffuse alveolar hemorrhage (n 2), graft failure (n 1), encephalitis (n 1), renal failure (n 1), and unknown (n 2). GVHD Incidence of grade II IV acute GVHD was 45% after CMR and 65% after RIR. Incidence of chronic GVHD was 72% (37% extensive) and 76% (50% extensive) of evaluable patients after CMR and RIR, respectively. Univariate Analysis Univariate analysis identified the following variables as significantly associated with improved OS: chemosensitive disease at time of transplantation (P.05; relative risk [RR] 57%) and absence of previous autologous transplantation (P.002; RR 37%). Similarly, PFS was higher for patients with chemosensitive disease (P.04; RR 57%) (Table 3). Significant predictors of relapse included treatment intensity and previous autologous HCT. Both CMR (P.05; RR 35%) and absence of previous autologous HCT (P.0007; RR 20%) significantly reduced the incidence of relapse. The data at hand suggest that previous autologous transplantation had a dominant effect on relapse and survival. The relative contributions of previous autologous transplantation and dose intensity on relapse and survival by multivariate analysis cannot be reliably estimated because of limited observations in these strata, with only 5 CMR patients receiving previous autologous transplantation. Within the RIR cohort Table 3. Results of Univariate Analysis OS PFS Relapse Rate P Value P Value P Value Conditioning treatment intensity RIR Default Default Default CMR.99.46.003 RR 35% Diagnosis/histology Low-grade.12.34.30 Intermediate-grade.19.53.36 Mantle-cell lymphoma.58.29.07 Age (continuous).96.53.03 Remission status (disease status at transplantation) Not in remission Default Default Default In remission.99.99.99 Number of previous regimens 1 or 2 regimens.51.80.40 3 or more regimens Default Default Default FTBI No Default Default Default Yes.74.87.10 Donor type Matched unrelated donor Default Default Default Sibling.93.91.82 Chemosensitivity Resistant relapse Default Default Default Sensitive relapse.05.04.47 rr 57% rr 57% Previous autologous transplantation Yes Default Default Default No.002.0002.0007 rr 37% rr 32% rr 20% OS and PFS univariate proportional hazards P values are based on Cox models; relapse rates are based on competing-risks regression.

Reduced-Intensity and Conventional Myeloablative Regimens 1331 Figure 4. OS and PFS for patients receiving RIR, based on previous autologous transplantation. alone, patients who failed a previous autologous transplantation (n 15) were at higher risk of relapse (P.03) and had significantly worse PFS (P.02) and OS (P.06) (Figures 4 and 5). DISCUSSION The premise behind RIRs to reduce TRM while preserving the antitumor effect of the graft is one of the major recent advances in HCT [12]. Although this less toxic approach is likely to improve survival for patients with malignancies sensitive to the GVM effect, others may suffer higher relapse rates, ultimately defeating the curative purpose of the transplantation. Studies have found that reducing the intensity of the conditioning regimen is associated with increased relapse for chronic myeloid leukemia and acute myeloid leukemia in the settings of CMR [13,14] and RIR [15]. This retrospective comparison of the 2 conditioning treatments for NHL showed no significant differ- Figure 5. Probability of relapse for patients receiving RIR based on previous autologous transplantation.

1332 R. Rodriguez et al. ence in survival despite a lower relapse with CMR. Given that TRM was similar in the 2 cohorts, we speculate that longer follow-up of the RIR cohort likely will lead to a survival difference favoring CMR. These observations must be interpreted within the context of different patient characteristics between cohorts, such that the RIR group was at higher risk of TRM because of greater age, previous autologous transplantation, and unrelated donor source. Thus, RIR allowed older and sicker patients to receive potentially curative transplants without significantly increasing TRM. Severe GVHD rates were higher in the RIR group. This paradoxical observation may be explained by a higher proportion of older patients and unrelated donor transplants in this cohort; in addition, prophylaxis with cyclosporine and mycophenolate mofetil, which has been associated with acceptable rates of acute GVHD in the nonmyeloablative setting [16], may not be adequate with the flu/mel RIR [17]. Recently, 2 studies using RIR for NHL suggested high relapse rates after RIR for aggressive histology and refractory disease [18,19] with results similar to ours. In the first series, 88 patients with relapsed and refractory NHL (33 diffuse large-cell lymphoma [DLCL] or transformed disease, 41 low-grade lymphoma, and 10 mantle-cell lymphoma) conditioned with an RIR of alemtuzumab, fludarabine 150 mg/m 2, and melphalan 140 mg/m 2, had actuarial 3-year OS, PFS, and relapse rates of 34%, 34%, and 52%, respectively, in the aggressive lymphomas; 60%, 50%, and 50% in mantle-cell lymphoma; and 73%, 65%, and 44% in low-grade NHL [18]. The second report of 188 patients with NHL reported to the European Group for Blood and Marrow Transplantation (62 aggressive histology; 52 low-grade and 22 mantle cell) treated with various RIRs, showed 1-year PFS and probability of relapse of 32% and 47%, respectively, for aggressive histology; 61% and 21% for low-grade disease; and 31% and 48% for mantle-cell disease [19]. These findings support a role for intensifying the regimen for intermediate-grade B-cell and mantle-cell NHL. A recent study by the Seattle Consortium (including City of Hope), using a nonmyeloablative regimen of fludarabine and 2 Gy total body irradiation (TBI) for aggressive NHL, found that among 40 patients with aggressive NHL (31 with DLCL), the 1 year OS, PFS, and relapse rates were 63%, 49%, and 36%, respectively [20]. Chemosensitive disease was present in 28 patients at time of transplantation and appeared to be predictive of outcome. These favorable results may reflect differences in patient characteristics, such as proportion of transformed and chemosensitive disease at time of transplantation. Interestingly, we found that absence of previous autologous transplantation strongly predicted for improved OS (P.02, hazard ratio [HR] 0.37) and decreased relapse (P.0007; HR 0.2), with a trend toward lower TRM (P.07). Thus, RIR offers the possibility of allogeneic transplantation for these patients, but outcome is offset by higher relapse and TRM. These results suggest that high-dose chemotherapy may lead to greater chemoresistance and organ toxicity, potentially offsetting any graft-versus- Figure 6. OS based on chemosensitivity (SR, sensitive relapse; RR, refractory relapse).

Reduced-Intensity and Conventional Myeloablative Regimens 1333 leukemia (GVL) effect. Because previous autologous transplantation co-segregated closely with reduced treatment intensity in this study, we could not determine the strength of each variable as a prognostic factor; within the RIR cohort, failing a previous autologous transplantation had a significant negative impact on relapse and survival (Figures 4 and 5). As with other series, our experience shows that chemosensitivity at the time of transplantation is associated with better survival (Figure 6) [18,21]. Our results should be interpreted with caution given the retrospective nature of the analysis, the different patient characteristics between cohorts, and the small number of patients within each category of lymphoma. We grouped patients into diagnostic categories reflecting clinical behavior and cell of origin; considering the biologic heterogeneity of lymphomas, however, the sensitivity to the GVL effect may vary within those relatively homogenous categories (eg, de novo DLCL vs transformed lymphoma, follicular lymphoma vs chronic lymphocytic leukemia, and cutaneous T-cell lymphoma vs other T-cell lymphomas). Moreover, genetic differences within specific histologies [22] likely will influence responses to allografting, and such testing may enhance the understanding of the immune processes involved in the GVL effect and yield useful predictive information before transplantation. In our patient population, survival was similar between the patients receiving CMR and those receiving RIR, confirming that RIR is safe for older and sicker patients. 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