Volume 15, Issue 5 , Pages 547-553, May 2009
Allogeneic Stem Cell Transplantation for Patients with Relapsed Chemorefractory Aggressive Non-Hodgkin Lymphomas
Article Outline
Abstract
Patients with chemorefractory aggressive non-Hodgkin's lymphomas (NHL) generally have poor clinical outcomes with available therapies. Allogeneic transplantation may be curative, but few studies are available to guide transplant decision making in this setting. We examined allogeneic transplantation outcomes for 46 patients with chemorefractory, aggressive NHL patients who had either stable disease (SD; n = 32) or progressive disease (PD; n = 14), respectively, following last salvage treatment. The median age was 46 years (range: 22-63 years). Thirty-nine patients received matched sibling allografts, whereas 7 underwent unrelated donor transplantation. Diagnoses included diffuse large B-cell lymphoma (n = 18), Burkitt's lymphoma (n = 3), transformed B cell lymphoma (n = 5), mantle cell lymphoma (n = 11), and peripheral T cell lymphoma (n = 9). The median number of prior therapies was 3 (range: 2-8). Median follow-up of surviving patients is 5 years. Five-year overall survival (OS), progression-free survival (PFS), and relapse rate for the whole cohort (n = 46) were 38%, 34%, and 35%, respectively. The rate of grade II-IV acute graft-versus-host disease (aGVHD) was 43%. Of the 33 evaluable patients 75% developed chronic GVHD (cGVHD). Overall nonrelapse mortality (NRM) rate was 34%. The 5-year OS and PFS rates for patients with SD and PD were 46% versus 21% (P = .01; log-rank test), and 46% veruss 7% (P = .0002; log-rank test), respectively. This study confirms that allogeneic transplant is curative for a subset of chemorefractory patients with SD. However, patients with PD had uniformly poor outcomes following allografting with conventional conditioning approaches. Given the outcomes seen here in the setting of PD, such patients should proceed with transplant only in the setting of investigational therapy.
Key Words: Aggressive non-Hodgkin lymphoma, Allogeneic stem cell transplantation, Refractory, Relapsed, Graft-versus-host disease
Introduction
High-dose therapy and autologous hematopoietic stem cell transplantation (HSCT) is standard therapy for patients with relapsed chemosensitive diffuse large B cell lymphoma (DLBCL), and appears to be curative for 40% to 45% of the patients 1, 2, 3. Relapsed non-Hodgkin lymphoma (NHL) patients with other aggressive histologies including peripheral T cell lymphoma (PTCL), transformed B cell lymphoma, mantle cell lymphoma (MCL), and Burkitt lymphoma (BL), generally do not achieve sustained remissions following autologous transplantation 4, 5, 6, 7, 8. Results of autologous HSCT in the high-risk group of relapsed aggressive NHL patients who are refractory to salvage chemotherapy have been uniformly disappointing. Allogeneic HSCT is a potentially curative modality for a number of hematologic malignancies, including indolent and aggressive lymphomas 9, 10, 11. The advantages of an allogeneic graft include a tumor-free graft, and a potential immune-mediated graft-versus-lymphoma (GVL) effect.
Despite the inherent risk of increased transplant-related morbidity and mortality (TRM) associated with allogeneic HSCT, select relapsed aggressive NHL patients, especially the subgroup with chemosensitive disease, can achieve long-term remissions following allografting 11, 12, 13, 14, 15, 16. Aggressive NHL patients who are refractory to salvage chemotherapy have poor prognosis. There are only limited data available about the outcomes following allogeneic HSCT for this extremely poor-risk group. We describe here the outcomes of chemorefractory aggressive NHL patients with mature follow-up undergoing allogeneic transplantation at our institution.
Patients and Methods
Patient Population
Patients with a history of histologically confirmed aggressive NHL undergoing allogeneic HSCT were identified from a prospectively maintained database of all patients undergoing HSCT at Ohio State University. Acceptable histologies included DLBCL, BL, transformed B cell lymphoma, PTCL, and MCL 17, 18, 19. Patients with a diagnosis of indolent lymphoma and those with lymphoblastic lymphoma were not included in this study. Patients undergoing allogeneic transplantation with an untreated relapse (i.e., patients not receiving salvage chemotherapy before transplant) were also excluded. For aggressive NHL patients receiving salvage chemotherapy before transplantation, response to salvage therapy was assessed according to standard criteria [20]. Patients achieving partial response (PR) or complete response (CR) to salvage chemotherapy were considered to have chemosensitive disease and were excluded from this analysis. Those patients with an available normal gallium or PET (positron emission tomography)-scan before transplantation (regardless of the presence or absence of residual radiographic abnormalities on CT scans) were also excluded. Aggressive NHL patients who had chemorefractory disease (i.e., patients with stable disease [SD] or progressive disease [PD]) as specified by Cheson et al.'s [20] criteria following salvage chemotherapy, constitute the subject of this study.
Transplantation Procedure and Supportive Care
All patients were treated in HEPA-filtered inpatient bone marrow transplantation unit, and received fungal, herpes zoster, bacterial, and Pneumocystis jiroveci prophylaxis. Patients and their donors were tested for HLA-A, HLA-B, and HLA-C by at least standard serologic typing and for HLA-DRB1 by high-resolution techniques. Unmanipulated hematopoietic stem cells (HSCs; mobilized from peripheral blood or harvested from nonstimulated marrow) were infused through a central venous catheter on day zero. Allogeneic HSCT recipients were monitored weekly for cytomegalovirus (CMV) reactivation with hybrid capture assay. Ganciclovir or foscarnet were used at the discretion of treating physician for patients with evidence of CMV reactivation. All patients received irradiated and leukoreduced blood products. CMV negative products were used for CMV seronegative patients. Neutrophil engraftment was defined as first of 3 successive days with ANC ≥0.5 × 109/L after posttransplantation nadir. Platelet engraftment was considered to have occurred on the first of 3 consecutive days with a platelet count of 20 × 109/L or higher, in the absence of platelet transfusion. Graft-versus-host disease (GVHD) was graded using standard criteria [21]. Patients achieving neutrophil engraftment were evaluable for acute GVHD (aGVHD), whereas patients surviving at least 100 days posttransplantation were evaluable for chronic GVHD (cGVHD).
Post-HSCT Monitoring
Patients underwent restaging bone marrow aspiration and biopsy (if abnormal before transplantation) and computed tomography of the chest, abdomen, and pelvis on day +60 (or earlier if clinically indicated) after HSCT. Imaging studies were repeated at 3 monthly intervals for first 3 years and annually thereafter through 5 years after HSCT. All posttransplant radiographic studies were retrospectively reviewed and responses assessed according to standard criteria [20]. In the ambulatory setting (postallografting), patients were followed at least weekly until day +90, then every 4 to 6 weeks up to day +180, followed by outpatient visits at least every 12 weeks until 3 years posttransplantation. Relapse or disease progression was histologically confirmed (when possible). Donor lymphocyte infusions (DLIs) were not routinely performed in patients with persistent disease or relapse posttransplantation.
Data Collection and Statistical Analysis
Data were collected using retrospective chart and database review. All available pathologic, radiologic, and autopsy reports were reviewed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. OS was defined as the time from transplant to death from any cause, and surviving patients were censored at last follow-up. PFS from transplantation was calculated using death and disease progression and/or relapse as events. Nonrelapse mortality (NRM) was defined as death from any cause other than disease progression or relapse. Cumulative incidence was estimated for NRM and relapse risk, with relapse as a competing risk for the former and death in remission for the latter. Gary's test was used to assess the difference between various subgroups for NRM and relapse rate. All calculations were performed using the SPSS 13.0 statistical package (SPSS Inc, Chicago, IL), except competing risk analysis for the cumulative incidence of NRM and relapse risk, which was performed by using R-Project (version 2.8.0; http://www.r-project.org/). All P-values are 2 sided.
Results
Patient Characteristics
One hundred eight patients with aggressive NHL underwent allogeneic HSCT between 1988 and 2007 at our institution. Forty-six patients with chemorefractory disease following salvage chemotherapy, undergoing allogeneic transplantation between 1994 and 2007, met the inclusion criteria of this study. The median age was 46 years (range: 22-63 years). Median Karnofsky performance status at the time of transplantation was 90 (range: 60-100). Thirty-nine patients received matched sibling allografts, whereas 7 underwent unrelated donor SCT. All except 3 patients received myeloablative conditioning. Histologic diagnosis (confirmed by review at Ohio State University) included DLBCL (n = 18), BL (n = 3), transformed B cell lymphoma (n = 5), MCL (n = 11), and PTCL (n = 9). The median number of prior therapies was 3 (range: 2-8). No patient previously underwent autologous HSCT. At the time of transplantation 41 (89%) patients had advanced stage (Ann Arbor stage III/IV) disease, 23 (50%) patients had elevated lactate dehydrogenase (LDH), 36 (78%) had extranodal involvement, whereas 14 (30%) patients had bulky disease (lymph nodes >5 cm). Among the patients with bulky disease 8 had SD, whereas 6 had PD (P = .22) before allografting. Four patients (9%) had central nervous system (leptomeningeal), and 29 (63%) had bone marrow involvement at the time of transplantation. None of the patients were positive for human immunodeficiency virus (HIV) or human T cell-lymphotropic virus.
Response to Salvage Therapy
At the time of allogeneic HSCT, of the 46 patients with chemorefractory disease following salvage chemotherapy, 32 patients had SD, whereas 14 patients had PD according to standard criteria [20]. Table 1 compares the baseline characteristics of chemorefractory patients with SD or PD at the time of transplantation. Five patients had PD following salvage chemotherapy because of development of (histology confirmed) new lesions. Patients in the SD or PD groups were comparable in terms of patient age, disease stage, histologies, stem cell source, CD34 dose, T cell dose, and GVHD prophylaxis regimen. Patients with SD were more heavily pretreated (median number of therapies 4) compared to PD patients (median number of therapies 2), whereas a higher proportion of patients in PD had elevated LDH. Thirty-one percent (n = 10) of B cell lymphoma patients in the SD group and 21% (n = 3) in the PD group had not previously received rituximab with salvage chemotherapy (P = .49). All patients with SD received myeloablative conditioning, whereas 3 patients with PD had reduced-intensity conditioning (RIC).
Table 1. Patient Characteristics at the Time of Allogeneic Transplantation
| Stable Disease Group | Progressive Disease Group | ||
|---|---|---|---|
| N = 32 (%) | N = 14 (%) | P-Value | |
| Median age, years (range) | 47 (22-59) | 44 (29-63) | >.05 |
| Sex (male/female) | 24/8 | 10/4 | >.05 |
| Stage | |||
 I-II | 2 (60) | 3 (22) | >.05 |
| III-IV | 30 (93) | 11 (78) | |
| B symptoms | 17 (53) | 10 (71) | >.05 |
| LDH | |||
| Normal | 19 (59) | 4 (29) | .05 |
| High | 13 (41) | 10 (71) | |
| Age adjusted International Prognostic Index | |||
| Low or low/intermediate | 13 (41) | 4 (29) | >.05 |
| High or high/intermediate | 19 (59) | 10 (71) | |
| Donor source | |||
| HLA-matched sibling | 27 (84) | 10 (71) | >.05 |
| HLA-matched unrelated | 4 (13) | 3 (22) | |
| HLA-mismatched related | 1 (3) | 1 (7) | |
| Diagnosis | |||
| Diffuse large B cell lymphoma | 11 (34) | 7 (50) | >.05 |
| Mantle cell lymphoma | 10 (31) | 1 (7) | |
| Peripheral T cell lymphoma | 4 (13) | 5 (35) | |
| Transformed B cell lymphoma | 4 (13) | 1 (7) | |
| Burkitt lymphoma | 3 (9) | – | |
| Median number of therapies before HSCT (range) | 4 (3-6) | 2 (2-8) | .02 |
| Median CD34+ cell dose (106 cells/kg recipient wt) | 5.44 | 4.82 | >.05 |
| Median CD3+ cell dose (108 cells/kg recipient wt) | 2.76 | 2.66 | >.05 |
| Myeloablative conditioning | |||
| Yes | 32 (100) | 11 (78) | .02 |
| No | – | 3 (22) | |
| Conditioning regimen | |||
| Bu/Cy based | 27 (84) | 11 (78) | >.05 |
| Flu/Bu based | – | – | |
| Others | 5 (16) | 3 (22) | |
| Stem cell source | |||
| Bone marrow | 18 (56) | 10 (71) | >.05 |
| Peripheral blood | 14 (44) | 04 (29) | |
| Graft-versus-host disease prophylaxis | |||
| Methotrexate/Cyclosporine | 23 (71) | 11 (78) | >.05 |
| Methotrexate/Tacrolimus | 9 (29) | 3 (22) |
Transplantation Outcomes
Median follow-up of surviving patients following allogeneic HSCT is 5 years. Median time to neutrophil and platelet engraftment was 14 days and 22 days, respectively. Rate of grade II-IV aGVHD was 43% (n = 20) overall, and 35% (n = 5) and 46% (n = 15) in the PD group and the SD group (P = .48), respectively (Table 2). Among the 33 evaluable patients, rate of cGVHD was 75% overall. In patients with PD and SD, rates of cGVHD were 52% (7 evaluable patients), and 80% (26 evaluable patients), respectively (P = .19). The cumulative incidence of NRM at 5 years in the SD group and PD group was 29% (n = 10), and 43% (n = 6) (P = 0.24; Gray's test), respectively. The corresponding day 100 NRM rates were 9% and 43%, respectively. In the PD group, causes of death included disease progression (n = 5), pulmonary failure (n = 2), aGVHD (n = 1), pulmonary aspergillosis with aGVHD (n = 1), sepsis (n = 1), and veno-occlusive disease (VOD) (n = 1). Causes of death among the SD group were disease progression (n = 8), sepsis with (n = 2) and without GVHD (n = 3), pulmonary failure (n = 1), GVHD (n = 2), and VOD (n = 2).
Table 2. Transplant Outcomes of Chemorefractory Patients undergoing Allogeneic Transplantation
| Stable Disease Group | Progressive Disease Group | P-Value | |
|---|---|---|---|
| N = 32 (%) | N = 14 (%) | ||
| Acute GVHD | 15 (46%) | 5 (35%) | .48 |
| Chronic GVHD | 21 (80%) | 4 (57%) | .19 |
| Relapse rate | 25% | 50% | .08† |
| Nonrelapse mortality | 29% | 43% | .24† |
| Progression-free survival (5 year) | 46% | 7% | .0002 |
| Overall survival (5 year) | 46% | 21% | .01 |
| Response rates | |||
| Overall response rate | 26 (81%) | 4 (28) | .0005∗ |
| Complete remission | 21 (65%) | 3 (21%) | |
| Partial remission | 5 (16%) | 1 (7%) | |
| Stable disease | 4 (13%) | 5 (36%) | |
| Progressive disease | 2 (6%) | 5 (36%) |
∗P-value is for the difference of overall response rate (complete remission + partial remission) between the 2 groups. |
†P-values calculated by Gray's test. |
Response Rates and Survival
Following HSCT the rates of CR, PR, SD, and PD in patients with PD at the time of transplantation were 21% (n = 3), 7% (n = 1), 36% (n = 5), and 36% (n = 5), respectively (Table 2). The response rates in the SD group in similar order were 65% (n = 23), 16% (n = 3), 13% (n = 4), and 6% (n = 2). Overall response rate (CR + PR) was markedly superior in SD group compared to the PD group (81% versus 28%, respectively; P = .0005). Immunosuppressive medications were withdrawn in 2 PD group patients at the time of disease progression. In the first patient with anaplastic large cell lymphoma (who initially entered CR after HSCT), tapering immunosuppression at the time of histologically proven relapse on day +310, produced a second CR lasting 7 months. In the second patient with angioimmunoblastic lymphoma, discontinuation of immunosuppressive at the time of disease progression (day +120) did not induce any GVL effect. Another patient in the PD group received DLI at the time of disease relapse, which produced a CR lasting +11 months. DLI was given to 2 patients in the SD group. The first patient received DLI because of secondary graft failure, and remains disease free at last follow-up. The second patient was given DLI because of persistent disease after transplantation, which produced a CR lasting 4 months.
At last follow-up, 3 patients in PD group are alive. Two patients are currently in remission (with no active cGVHD), whereas the third patient (on immunosuppression for extensive cGVHD) is currently undergoing chemotherapy after disease relapse. Interestingly all 3 surviving patients in the PD group received RIC at the time of transplantation. None of the patients undergoing myeloablative conditioning survived beyond 6 months post-HSCT. Fourteen SD group patients are currently alive and all have no evidence of disease. Four patients are currently on immunosuppressive medications for extensive cGVHD. Among the 4 patients with active leptomeningeal involvement before myeloablative transplantation, 1 patient is alive and in remission 9 years posttransplantation, 2 patients died at 5 and 6 months posttransplant because of disease progression, whereas the fourth patient died at 3 months postallografting, while in remission secondary to pulmonary aspergillosis. The 5-year actuarial OS, PFS, and relapse rate for the whole cohort (n = 46) were 38%, 34%, and 35%, respectively. Cumulative incidence of disease relapse was higher in patients with PD compared to patients with SD (50% versus 25%; P = .08). The 5-year OS and PFS rates for patients with SD and PD were 46% versus 21% (P = .01; log-rank test) (Figure 1), and 46% versus 7% (P = .0002; log-rank test) (Figure 2), respectively. Fve-year OS for patients with DLBCL, PTCL, MCL, BL, and transformed B cell lymphoma was 38%, 33%, 18%, 33%, and 100%, respectively. Five-year PFS in similar order was 38%, 22%, 18%, 33%, and 80%. The rate of NRM for patients with DLBCL, PTCL, MCL, BL, and transformed B cell lymphoma was 38%, 33%, 55%, 0%, and 0%, respectively. Relapse rates for these patients in identical order were 24%, 44%, 27%, 66%, and 20%. Development of cGVHD was not associated with OS (P = .7), PFS (P = .5), or lower relapse rates (P = .6).
Figure 1
Kaplan-Meier estimates of OS following allogeneic transplantation (solid curve = stable disease group; interrupted curve = progressive disease group).
Figure 2
Kaplan-Meier estimates of PFS following allogeneic transplantation (solid curve = stable disease group; interrupted curve = progressive disease group).
To address the patient selection bias inherently associated with evolving transplantation practices over time, and the general advances in supportive care, outcomes of patients transplanted between 1994 and 2000 (group O; n = 20) were compared with those transplanted between 2001 and 2007 (group N; n = 26). The 5-year OS for patients in group O and group N was 40% and 38% (P = .99), respectively. Five-year PFS in similar order was 40% and 30% (P = .70), respectively. On multivariate logistic regression analysis, PD at the time of transplantation was the only variable predictive for inferior PFS (P = .03), but not inferior OS (P = .19).
Discussion
Allogeneic HSCT remains the sole curative modality for high-risk relapsed aggressive NHL patients 11, 12, 13, 14, 15, 16. Studies focusing solely on the outcomes of patients with chemorefractory disease at the time of transplantation have not been previously reported. We report here 5-year OS and PFS rates of 38% and 34%, respectively, for patients with chemorefractory aggressive lymphomas.
This study highlights the heterogeneity in transplant outcomes for chemorefractory aggressive NHL patients. The group of patients with SD following salvage chemotherapy in our study had encouraging 5-year OS and PFS rates of 46% each. These results are quite encouraging, especially in the context of the dismal outcomes of these high-risk patients with standard chemotherapy or autologous HSCT. Caution, however, needs to be exercised while interpreting these results, as patient selection certainly is partly responsible for these favorable outcomes, because even these poor prognosis chemorefractory patients with SD were judged young and healthy enough to undergo myeloablative allogeneic HSCT. Nonetheless, survival rates of SD group in this study are comparable to previous studies reporting allogeneic transplantation outcomes of relapsed aggressive NHL (with similar inherent selection biases) 12, 13, 14, 15. Doocey et al. [13] reported 5-year OS of 48% in a cohort of 44 aggressive NHL patients (including 9 with chemorefractory disease). Similarly, French [14] and Japanese [12] registry data have reported OS rates of 41% and 42%, respectively, with allografting in aggressive NHL. Although these studies included patients with refractory disease, their outcomes were not reported separately. Interestingly in Doocey et al. [13], the relapse rate in patients with refractory disease was not significantly different from patients with chemosensitive disease. Inferior OS for chemorefractory patients was seen in Italian registry data, but that study included a substantial proportion of patients with indolent histologies and Hodgkin disease (HD) [9]. The majority of the patients in previously reported studies of allogeneic transplantation for aggressive NHL received total body irradiation (TBI)-based conditioning regimens. In contrast, none of the patients in this study received TBI, which suggests that non-TBI based conditioning regimens at least produces outcomes comparable to TBI conditioning in aggressive NHL following allogeneic HSCT.
Importantly, this study identifies a cohort of chemorefractory patients with PD following salvage chemotherapy, who, despite receiving mostly myeloablative transplantation, had dismal 5-year OS and PFS of 21% and 7%, respectively. Patients exhibiting disease progression despite combination salvage chemotherapy clearly represent a group with extremely poor prognosis, who are unlikely to benefit from allografting and should be spared the toxicities of donor transplantation. At the same time, chemorefractory patients with SD perhaps have a less aggressive disease biology, and, if transplant eligible, they appear to have at least a reasonable chance of long-term survival with allogeneic transplantation. This is noteworthy, because these SD patients have a uniformly poor outcome if they undergo high-dose therapy and autologous transplantation. Such divergent outcomes indicate that the encouraging results of chemorefractory patients in our study are likely a result of immune-mediated lymphoma eradication, and are not simply because of the intensity of conditioning chemotherapy administered. Because functional imaging (positron-emission tomography [PET]-scanning) or biopsies to confirm active lymphoma were not routinely performed in all the patients with SD in this study, it is possible that these favorable outcomes are because of a chance inclusion of large proportion of patients with residual radiographic abnormalities merely representing “nonviable lymphoma.” However, survival outcomes of 14 patients in the SD group who had either a positive PET scan or histology-confirmed viable lymphoma at the time of transplantation were comparable to entire group overall (5-year OS of 45%, compared to 46% in patients without such evidence).
The overall NRM rate of 34% in this study for high-risk patients predominantly undergoing myeloablative allogeneic is comparable to previous studies of myeloablative allogeneic transplantation in aggressive NHL, where NRM rates have ranged from 20% to 45% 12, 13, 15, 22. In the modern era of transplantation NRM rates over 30% even following ablative conditioning are unacceptably high. Reduced-intensity conditioning (RIC) transplantation is an attractive modality that has shown impressively low NRM rates without compromising efficacy in the indolent lymphomas 10, 23. However, for patients with relapsed aggressive lymphomas, NRM rates with RIC allogeneic transplantation, with a few exceptions 9, 24 have been surprisingly high (range: 25%-38%) 25, 26, 27. For patients with chemosensitive disease, OS rates have been encouraging (45%-80%) 24, 27, 28. Information about outcomes of chemorefractory patients following RIC is limited, but at least 2 studies suggest significantly inferior outcomes of such patients compared to those with chemosensitive relapse 25, 28. Prospective trials comparing myeloablative conditioning with RIC in the setting of chemorefractory aggressive NHL are unlikely to be performed, and the choice of conditioning regimen will continue to largely depend on patient age, performance status, disease bulk, and physician preference.
In conclusion, a subgroup of chemorefractory patients with SD by standard radiographic criteria following salvage chemotherapy can experience favorable outcomes following allogeneic transplantation and and should not be excluded solely based on the lack of evidence of chemosensitive disease. Patients with PD have a dismal prognosis despite allogeneic transplantation, and should not be considered for allogeneic transplantation except in the setting of a clinical trial.
Acknowledgments
Financial disclosure: The authors have nothing to disclose.
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Financial disclosure: See Acknowledgments on page 552.
PII: S1083-8791(09)00056-1
doi:10.1016/j.bbmt.2009.01.010
© 2009 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 15, Issue 5 , Pages 547-553, May 2009
