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Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin Lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% CI 10-21%) and 33% (95% CI 25-41%) respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and KPS < 90 were significant risk factors for TRM, PFS and OS, whereas chemosensitivity at transplantation was not. Dose intensity of the conditioning regimen (RIC vs NST) did not impact outcomes. Unrelated donor HCT with RIC/NST can salvage some patients with relapsed/refractory HL, but relapse remains a common reason for treatment failure. Clinical studies should be aimed at reducing the incidence of acute Graft-versus-Host Disease and relapse.
Although most patients with Hodgkin lymphoma (HL) can expect long-term survival with standard chemotherapy and/or radiation therapy, the prognosis is less favorable for patients with relapsed and/or refractory disease.1 Most patients with relapsed disease are treated with high-dose chemotherapy and autologous stem cell rescue, based on the results of studies showing durable responses in 40-50% of patients with relapsed HL and in 25-40% of patients with refractory HL.2-5 Therapeutic options for patients relapsing after high-dose chemotherapy are limited and generally non-curative.
Myeloablative allogeneic hematopoietic cell transplantation (HCT) derives its benefit from both the pre-transplant conditioning regimen and a post-transplant immune-mediated graft-versus-malignancy effect. Although earlier studies suggested the existence of a graft-versus-HL effect, the high transplant-related mortality (TRM) associated with the use of myeloablative conditioning offset any potential benefit on survival.6-9 Reduced intensity conditioning regimens have been developed in an attempt to decrease the mortality caused by traditional high-dose chemotherapy and radiation conditioning regimens.10 A variety of conditioning regimens, ranging in intensity from immune suppressive and truly non-myeloablative to reduced intensity have been introduced into practice. Such regimens have allowed allogeneic HCT in persons who are traditionally not considered for myeloablative transplant regimens because of age or comorbidities.11-13 In addition, reduced intensity allogeneic HCT is increasingly used as a salvage strategy for patients who relapse after previous high-dose chemotherapy with autologous stem cell rescue.14
Data on the use of reduced intensity (RIC) and nonmyeloablative stem cell transplantation (NST) for patients with relapsed and refractory HD are starting to emerge. Several small single institution retrospective trials have reported low early transplant related mortality (TRM) and encouraging progression-free survival data, although with limited follow-up.15,16 Data from three prospective trials have been reported recently.17-19 All three studies reported on the outcomes of patients with relapsed and/or refractory HL (in many cases after previous high-dose chemotherapy) undergoing allogeneic HCT with a conditioning regimen of fludarabine and melphalan. These studies confirmed a low day 100 TRM (ranging from 4% to 12.5%) with a projected progression-free survival (PFS) of 32% - 39% at 2-4 years. Disease relapse/progression continued to be the major reason for treatment failure in all three publications. A retrospective analysis by the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation (EBMT) comparing reduced intensity conditioning outcomes with outcomes after standard myeloablative conditioning also showed a reduction in day 100 TRM (15% with RIC versus 28% with myeloablative conditioning, p=0.003) and a projected 3-year PFS of 19% after RIC HCT.20
Only a minority of patients in the previously cited studies underwent transplantation with an unrelated donor graft. Recent studies support the notion that the results of unrelated donor HCT are comparable to sibling grafts, if HLA matching at the allele level is employed for unrelated donor selection.21,22 We therefore analyzed the clinical outcomes of 143 patients undergoing unrelated donor HCT with a RIC/NST conditioning regimen for relapsed and refractory HL.
The CIBMTR is a research affiliation of the International Bone Marrow Transplant Registry (IBMTR), Autologous Blood and Marrow Transplant Registry (ABMTR) and the National Marrow Donor Program (NMDP) that comprises a voluntary working group of more than 450 transplant centers worldwide that contribute detailed data on consecutive allogeneic and autologous transplants to a Statistical Center at the Health Policy Institute of the Medical College of Wisconsin in Milwaukee or the NMDP Coordinating Center in Minneapolis. Participating centers are required to report all consecutive transplants; compliance is monitored by on-site audits. Subjects are followed longitudinally, with yearly follow-up. Computerized checks for errors, physicians’ review of submitted data and on-site audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are done with a waiver of informed consent and in compliance with HIPAA regulations as determined by the Institutional Review Board and the Privacy Officer of the Medical College of Wisconsin.
The CIBMTR collects data at two levels: registration and research. Registration data include disease type, age, sex, pretransplant disease stage and chemotherapy-responsiveness, date of diagnosis, graft type (bone marrow- and/or blood-derived stem cells), high-dose conditioning regimen, post-transplant disease progression and survival, development of a new malignancy and cause of death. Requests for data on progression or death for registered patients are at six-month intervals. All CIBMTR teams contribute Registration data. Research data are collected on a subset of registered patients selected using a weighted randomization scheme and include detailed disease, and pre- and post-transplant clinical information.
Conditioning regimens were categorized as reduced intensity or non myeloablative using consensus criteria proposed by the Regimen Related Toxicity Working Committee of the CIBMTR. Regimens employing TBI < 500 cGy, busulfan doses ≥ 9 mg/kg or melphalan doses < 150 mg/m2 were categorized as reduced intensity. Regimens using fludarabine without busulfan and/or melphalan and regimens using TBI doses of 200 cGy (with or without fludarabine) were categorized as nonmyeloablative. Regimens that did not fit these criteria were assigned by the authors based on recommendations of the Regimen Related Toxicity Working Committee. This consensus definition reflects the practice of a large segment of the transplant community and has also been proposed and used by others.23,24
There were 143 patients undergoing an unrelated donor HCT between 1999 and 2004 with RIC/NST conditioning for relapsed or refractory HL identified from the CIBMTR database. Patients undergoing a cord blood transplant (n=4), those undergoing planned tandem (autologous followed by RIC/NST allogeneic) HCT (n=3), and those who received a RIC/NST allogeneic HCT for a different second malignancy were excluded from analysis. HLA compatibility of donors and recipients was documented at low resolution (antigen level) for HLA A and B antigens and at high resolution (allele level) for the HLA-DRB1 allele. Chemosensitive disease was defined as a 50% reduction in the sum of the bidimensional diameter of all disease sites with no new sites of disease.
Outcomes analyzed included transplant-related mortality (TRM), progression, progression-free survival (PFS) and overall survival (OS). TRM was defined as death within 28 days post-transplant or death without lymphoma-progression. Subjects with lymphoma-progression were censored at the time of progression and a cumulative incidence estimate was derived with progression or relapse as the competing risk. Progression was defined as progressive lymphoma post transplant (≥28 d) or lymphoma-recurrence. It could follow a period of “stable” disease post transplant, or a partial or complete remission. Progression represents new or larger areas of lymphoma (≥25% increase in largest diameter) compared to the best post transplant lymphoma state. Progression was summarized by the cumulative incidence estimate with TRM as the competing risk. For PFS, subjects were considered treatment-failures at the time of lymphoma-progression or death from any cause. Subjects alive without evidence of lymphoma-progression were censored at last follow-up and the PFS event was summarized by a survival curve. The OS interval variable was defined as time from the date of transplant to the date of death or last contact and summarized by a survival curve.
Univariate probabilities of developing TRM and lymphoma relapse/progression were calculated using cumulative incidence curves to accommodate corresponding competing risks25. Probabilities of 100-day, overall and progression-free survival were calculated using Kaplan-Meier estimator26. Confidence intervals (CI) were calculated with a log-transformation.
Cox proportional hazards model was used to identify risk factors associated with outcomes. A stepwise forward selection multivariate model was built to identify covariates which influenced outcomes. Any covariate with a p-value ≤0.05 was considered significant. The proportionality assumption for Cox-regression was tested by adding a time-dependent covariate for each risk factor and each outcome. Tests indicated that all variables met the proportional-hazards assumption. Results were expressed as relative risks (RR) or the relative rate of occurrence of the event. The following variables were considered in multivariate analyses: age at transplant, Karnofsky Performance Status (KPS) at transplant, disease status and chemosensitivity at transplant, extranodal involvement prior to transplant, serum LDH concentration at transplant, time from autologous HCT to allogeneic HCT, donor type (HLA matched versus HLA mismatched), donor-recipient gender match (female donor into male recipient versus all other combinations) and donor-recipient CMV status (both donor and recipient CMV seronegative versus all other combinations) (Table 1). Analyses were performed using SAS software, version 8.2 (SAS Institute).
Patient, disease and transplant characteristics are described in Table 2. Ninety four patients (66%) received RIC regimens where as 49 (34%) patients received non myeloablative conditioning regimen (Table 3). As expected, this was a group of heavily pretreated patients. Ninety six percent of patients had been treated with at least three previous chemotherapy regimens and the majority of patients (89%) had received a prior autologous HCT. In addition, 47% had disease characterized as chemoresistant at the time of allogeneic HCT, 50% had extranodal involvement prior to transplant and 32% had a Karnofsky performance status <90 pre-allogeneic transplant. Twenty three percent received a graft from an HLA mismatched unrelated donor, however we do not have the results of high-resolution HLA typing for class I HLA antigens, and thus the number of patients receiving an allele mismatched product might be substantially higher. Most patients (73%) received a peripheral blood stem cell graft and were transplanted after 2000. The median follow-up for survivors was 25 months.
Cumulative incidences for TRM, progression/relapse, acute and chronic GVHD and Kaplan Meier curves for PFS and OS are shown in Figure 1. Cumulative incidence of TRM following unrelated donor RIC/NST for relapsed or refractory HD was 15% at 100 days (95% CI 10-21%), 30% (95% CI 22-37%) at one year and 33% (95% CI 25-41%) at two years (Figure 1a). In multivariate analysis lower KPS at transplantation (RR 3.05 for KPS <90, p<0.001) and the presence of extranodal disease at transplantation (RR 2.36, p=0.007) were associated with an increased risk of TRM (Table 4).
The cumulative incidence of progression/relapse in the RIC/NST group was 40% at one year (95% CI 32-49%) and 47% at two years (95% CI 39-56%) (Figure 1a). No variables were associated with a higher risk of relapse/progression (Table 4). The probability of PFS at one year was 30% (95% CI 23-38%) and at two years 20% (95% CI 13-27%). In multivariate analysis factors with a significant effect on PFS were a lower KPS (RR 2.19 for KPS <90, p<0.001) and extranodal involvement at transplantation (RR 1.73, p=0.006) (Table 4).
The probability of survival after RIC/NST was 56% (95% CI 48-64%) at one year and 37% (95% CI 29-46%) at two years (Figure 1b). In multivariate analysis factors significantly affecting survival were a lower KPS (RR 2.33 for KPS <90, p<0.001), presence of extranodal disease at diagnosis (RR 2.11, p=0.001), and abnormal serum LDH concentration (RR 1.86, p=0.008) (Table 4).
In order to separate the effects of differing intensity of conditioning regimens, we analyzed the effects of reduced intensity conditioning and nonmyeloablative conditioning separately in a multivariate analysis. There were no significant differences between RIC and NST on the primary outcomes for TRM, progression/relapse, PFS and OS. The two groups were combined for the final analysis to increase the overall power of the study.
RIC/NST conditioning regimens were associated with a high incidence of acute and chronic GVHD. The probability of grade 2-4 acute GVHD by day 100 was 60% (95% CI 51-69%) (Figure 1c), and the probability of chronic GVHD was 66% at one year (95% CI 58-74%) and 68% at two years (95% CI 60-76%) (Figure 1d).
In our multivariate analysis sensitivity to chemotherapy immediately prior to transplant was not identified as a characteristic with a significant effect on PFS or OS. Since prior studies have identified chemosensitivity as an important predictor for survival we performed an additional analysis for the effect of chemosensitivity on PFS and OS. The Kaplan Meier curves for PFS and OS for chemosensitive and chemoresistant patients are shown in Figure 2.
Causes of death are listed in Table 5. Relapse/progression was the main cause of death after RIC/NST transplantation. Infection was the second most common cause of death, whereas organ failure and interstitial pneumonitis were rare after RIC/NST.
Treatment options for patients with relapsed or refractory HL, in particular patients who relapse after previous high-dose chemotherapy treatment, remain limited. The use of allogeneic HCT with a RIC/NST conditioning regimen has theoretical appeal for those patients, but reported outcome data are sparse and mostly limited to patients receiving matched sibling grafts. Our study represents the largest group of unrelated donor HCT recipients with RIC/NST for relapsed/refractory HL analyzed to date, and almost all patients in our analysis underwent RIC/NST HCT as a salvage strategy after previously failed high-dose chemotherapy with autologous stem cell rescue. This study confirms the feasibility of RIC/NST unrelated donor allogeneic HCT and shows that approximately 20% of patients with multiply relapsed or refractory HL may experience prolonged PFS with a projected 2-year OS of 37%. Not unexpectedly relapse/progression remains a significant problem in this group of heavily pretreated patients.
Our survival results are comparable with previously published data. The recently published EBMT experience reports a 3-year PFS of 19% (95% CI 11%-28%), with a 3-year OS of 35% (95% CI 24%-45%).20 Slightly better survival results have been reported in the three prospective studies. Peggs et al. reported a 4-year actuarial PFS of 22.6% and OS of 45% for recipients of an unrelated donor graft in their prospective study.17 Progression-free survival at 2 years was 32% ± 10% in the Spanish prospective trial, but only 2 of 40 patients in this study received an unrelated donor graft.18 In the MD Anderson study 2-year PFS was 32% (95% CI 20%-45%), and no difference was noted between recipients of related (n=25) and unrelated (n=33) donor grafts.19 The apparent survival difference between the prospective trials and the registry data is not unexpected and probably explained by the carefully controlled eligibility criteria and therapeutic conditions that apply to prospective trials.
Reduced intensity conditioning regimens are designed to limit TRM, and several studies have reported low transplant related mortality after reduced intensity HCT. The day-100 TRM of 15% (95% CI 10-21%) and TRM of 30% (95% CI 22%-37%) at 1 year and 33% (95% CI 25%-41%) at 2 years seem therefore somewhat disappointing. In the EBMT study cumulative TRM was 15% at 3 months (95% CI 9%-24%), 23% at 1 year (95% CI 15%-34%) and 24% at 3 years (95% CI 16%-35%)20. This study however included predominantly matched sibling donors (86.5%), and fewer patients had failed a previous autologous HCT (61.8%). Much lower cumulative incidences of TRM were reported in the UK study (4.1% at 100 days and 16.3% at 2 years) and the Spanish study (12.5% at 100 days and 25% at 3 years).17,18 However, in the UK study TRM at 2 years was significantly higher with unrelated donor HCT than when a matched sibling donor was used (34.1% [16.5-70.3] vs. 7.2% [1.9-27.5], p=0.02). The most favorable TRM data come from the MD Anderson patient cohort, where day 100 TRM was 7% (95% CI 2%-12%) and 2-year TRM was 15% (95% CI 8%-28%), with no significant difference noted between related and unrelated graft recipients.19 A comparison of TRM between studies is difficult without adjustment for some of the known risk factors for TRM after allogeneic HCT; of note is that the patients in our study represented a poor-risk group, including KPS < 90 for one third of all RIC/NST recipients.
A high incidence of acute GVHD was noted in our study, with a 60% probability of grade 2-4 acute GVHD at 100 days (95% CI 51%-69). For comparison, the incidence of grade 2-4 acute GVHD in the MD Anderson unrelated donor cohort was 39% (95% CI 26%-60%).19 The UK study does not allow for a meaningful comparison of acute GVHD incidence, as in-vivo T cell depletion with alemtuzumab was an integral part of the conditioning regimen on that protocol. Any discussion of the differences in TRM and acute GVHD incidence between our study and some of the referenced trials remains necessarily speculative. The extent of HLA matching at the allele level was not available for most of the patients in our database, precluding an analysis of the effect of allele matching on outcomes, in particular incidence of GVHD. The presence of a significant number of HLA mismatched donor-recipient pairs (23%), even at this low level of HLA matching, could explain the relatively high incidence of acute GVHD in this study.
The primary causes of death of non relapse mortality in our study were infectious in 22% and GVHD in 9% of all deaths. One could hypothesize that the high incidence of acute GVHD in this study can at least partially explain the significant TRM, as infectious complications and occurrence of GVHD are often related. This would suggest that attempts to reduce the incidence of acute GVHD could result in more favorable TRM. In support of this hypothesis are the findings by Peggs et al. that the use of alemtuzumab in the conditioning regimen resulted in lower incidences of non-relapse mortality and acute and chronic GVHD without affecting the incidence of relapse/progression after matched sibling RIC HCT.27
We were not able to show a significant effect of the intensity of the conditioning regimen (nonmyeloablative versus reduced intensity) on TRM or survival. Our study had only very limited power to detect differences between these two transplant approaches, and great care should therefore be used in interpreting these results. Anderlini et al, have suggested a benefit of reduced intensity conditioning with fludarabine and melphalan over nonmyeloablative conditioning with fludarabine and cyclophosphamide16. Since the current study included a wide variety of nonmyeloablative and reduced intensity conditioning regimens it is not very suitable for a direct comparison between the various regimens. In addition, retrospective studies can not control for potential bias resulting in the selection of one conditioning regimen over another for any particular patient.
Our study did not show an effect of pre-transplant chemosensitivity on survival in the multivariate analysis. The reasons for this discrepancy between our findings and previously reported effects of chemosensitivity remain speculative. Selection bias might have played a role; the reason for administration of a RIC/NST conditioning is not collected by the CIBMTR and patients with highly refractory disease might therefore preferentially have been treated with more intense conditioning regimens or might have been denied RIC/NST procedures altogether. The relatively recent introduction of PET scanning might have resulted in more accurate but altered definitions of remission status at the time of transplantation and precludes comparison between studies. Finally, prognostic differences between the patients in our study and in other studies may explain the lack of effect attributable to chemosensitivity.
In summary, our study shows that some patients with highly refractory/relapsed HL can be salvaged with the use of unrelated donor RIC/NST HCT. The results of our and other recently published analyses establish the feasibility of this procedure for patients with relapsed or refractory HL. However, both in our and in other studies relapse/progression continues to be the most common cause of treatment failure, and long-term prognosis continues to be largely determined by patient related (KPS) and disease related (extranodal disease) factors rather than by the choice of conditioning approach. These data support the notion that careful patient selection remains the single most important factor to improve outcomes from RIC/NST unrelated donor HCT for this indication. In addition, approaches to further reduce the incidence of GVHD and TRM after RIC/NST HCT should result in more favorable outcomes. This should foremost include HLA matching at the allele level and could also include the addition of alemtuzumab to the conditioning regimen, the use of umbilical cord blood grafts, or the use of a tandem approach (high-dose chemotherapy with autologous stem cell rescue followed by an allogeneic HCT with nonmyeloablative conditioning) in high-risk patients.27-29 Development of multi-institutional clinical trials to examine these options is highly desirable.
Supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Association of Medical Microbiology and Infectious Disease Canada; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech, an Invitrogen Company; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gambro BCT, Inc.; Gamida Cell, Ltd.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; Merck & Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka Pharmaceutical Development & Commercialization, Inc.; Pall Life Sciences; PDL BioPharma, Inc; Pfizer Inc; Pharmion Corporation; Saladax Biomedical, Inc.; Schering Plough Corporation; Society for Healthcare Epidemiology of America; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex; Teva Pharmaceutical Industries; The Marrow Foundation; THERAKOS, Inc.; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government.
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