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Originally published as JCO Early Release 10.1200/JCO.2006.06.9914 on August 8 2006 © 2006 American Society of Clinical Oncology. Factors Associated With Outcomes in Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning After Failed Myeloablative Hematopoietic Cell Transplantation
From the Fred Hutchinson Cancer Research Center; University of Washington School of Medicine; Veterans Affairs Puget Sound Health Care System, Seattle, WA; Stanford University, Stanford; City of Hope Comprehensive Cancer Center, Duarte, CA; Rocky Mountain Cancer Center, Denver, CO; Oregon Health and Science University, Portland, OR; University of Utah, Salt Lake City, UT; Baylor University, Dallas, TX; Medical College of Wisconsin, Milwaukee, WI; University of Liège, Liège, Belgium; University of Leipzig, Leipzig, Germany; and the University of Torino, Torino, Italy Address reprint requests to Brenda M. Sandmaier, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D1-100, PO Box 19024, Seattle, WA 98109-1024; e-mail: bsandmai{at}fhcrc.org
Purpose: Several studies have investigated the feasibility of allogeneic hematopoietic cell transplantations (HCTs) after reduced-intensity conditioning in patients who experienced relapse after myeloablative HCT. Although most studies showed relatively low nonrelapse mortality (NRM) rates and encouraging short-term results, it has yet to be defined which patients would benefit most from these approaches. Patients and Methods: We analyzed data from 147 patients with hematologic malignancies who experienced treatment failure with conventional autologous (n = 135), allogeneic (n = 10), or syngeneic (n = 2) HCT and were treated with HLA-matched related (n = 62) or unrelated (n = 85) grafts after conditioning with 2 Gy of total-body irradiation with or without fludarabine. Results: Three-year probabilities of NRM, relapse, and overall survival were 32%, 48%, and 27%, respectively, for related recipients, and 28%, 44%, and 44%, respectively, for unrelated recipients. The best outcomes were observed in patients with non-Hodgkin's lymphoma, whereas patients with multiple myeloma and Hodgkin's disease had worse outcomes as a result of high incidences of relapse and progression. Being in partial remission (PR) or complete remission (CR) at HCT (P = .002) and developing chronic graft-versus-host disease (GVHD; P = .03) resulted in lower risks of relapse and progression. Factors associated with better overall survival were PR or CR (P = .01) and lack of comorbidity (P = .03) at HCT and absence of acute GVHD after HCT (P = .06). Conclusion: Encouraging outcomes were seen with allogeneic HCT after nonmyeloablative conditioning in selected patients who had experienced relapse after a high-dose HCT, particularly in patients with non-Hodgkin's lymphoma. Results with unrelated grafts were comparable with results with related grafts.
Autologous hematopoietic cell transplantation (HCT) has been a widely used treatment for patients with certain hematologic malignancies.1 Although improvements in supportive care and the use of peripheral blood instead of marrow as stem cell source have improved the safety of HCT, relapses and secondary myelodysplastic syndromes have remained major challenges.1,2 The outcomes for patients with relapse or secondary malignancies after autologous HCT have been generally poor.1 Although conventional chemotherapy might induce complete remission (CR) or partial remission (PR) in a number of patients, responses are rarely durable. Alternatively, a second high-dose HCT from allogeneic donors has been a potentially curative option but has been characterized by treatment-related mortality rates of 50% to 80%.3-5 Similarly, treatment options for patients who experience relapse after conventional allogeneic HCT have been limited. Donor lymphocyte infusion (DLI) can induce durable remissions in patients with relapsed chronic myeloid leukemia,6-8 but responses are by far less frequent and durable in patients with other hematologic malignancies.6-9 Several studies have investigated the feasibility of allogeneic HCT after nonmyeloablative or reduced-intensity conditioning in patients who experienced treatment failure with myeloablative HCT.10-16 These approaches have focused on eradicating malignancies through immune-mediated graft-versus-tumor effects17 rather than with high-dose radiotherapy or chemotherapy.18-22 Although most studies showed relatively low nonrelapse mortality (NRM) rates and encouraging short-term results,10-16,23 which patients would benefit most from these approaches has remained undefined. Here, we analyze data from 147 patients who experienced treatment failure with conventional autologous (n = 135), allogeneic (n = 10), or syngeneic (n = 2) HCT and underwent HLA-matched related (n = 62) or unrelated (n = 85) grafts, after conditioning with 2 Gy of total-body irradiation with or without 90 mg/m2 of fludarabine, with the aim of determining factors predicting HCT outcomes.
Patients Table 1 lists the patient characteristics. The 147 patients underwent allogeneic HCT after nonmyeloablative conditioning on prospective multi-institutional research protocols between January 13, 1999 and December 12, 2004. Results were analyzed as of January 11, 2006. The median patient age was 46 years (range, 9 to 73 years). Sixty-two patients received grafts from related donors, and 85 received grafts from unrelated donors. Stem-cell sources were peripheral blood in 141 patients and marrow in six patients; the latter were unrelated grafts. Patients had previously experienced treatment failure with autologous (n = 135), allogeneic (n = 10), or syngeneic (n = 2) HCT after high-dose conditioning. The diagnoses of patients who experienced failure with allogeneic HCT included acute lymphoblastic leukemia (n = 4), acute myeloid leukemia (n = 3), and chronic myeloid leukemia (n = 3). The second allogeneic HCT was performed with a different donor in nine patients and with the same donor in one patient. Median time between the two allogeneic transplantations was 25 months (range, 5 to 90 months), and no patients had acute or chronic graft-versus-host disease (GVHD) at the time of the second HCT. Fourteen patients had experienced failure with more than one HCT. Data on the first 55 patients have been previously reported.16 Their results are updated here with 46 additional months of follow-up and combined with results from 92 additional patients.
Compatibility between patients and donors for HLA-A, HLA-B, and HLA-C antigens was assessed by intermediate-resolution DNA typing to a level at least as sensitive as serology and for HLA-DRB1 and HLA-DQB1 by high-resolution techniques.25 One hundred twenty-eight patients received grafts from HLA-matched donors, and 19 patients received grafts from HLA-mismatched donors. Pretransplantation comorbidities were determined from the patients' transplantation evaluation notes and scored using an HCT-specific comorbidity index (HCT-CI), as previously reported.26 Patients with underlying diseases in CR or PR at the time of HCT were defined as having chemotherapy-sensitive disease, whereas all other patients were classified as having chemotherapy-insensitive disease. Patients were treated at 12 academic centers, with the Fred Hutchinson Cancer Research Center acting as the coordinating center. Protocols were approved by the institutional review boards of the Fred Hutchinson Cancer Research Center and the collaborating sites. All patients signed consent forms approved by the local institutional review boards.
Conditioning Regimen and Postgrafting Immunosuppression
GVHD Grading and Therapy and Supportive Care Standard prophylaxis against infections was used.32 Patients with chronic GVHD requiring systemic immunosuppressive therapy continued prophylaxis against Pneumocystis carinii and pneumococcal infections.
Follow-Up
Treatment of Persistent/Progressive or Relapsed Diseases and Prevention of Graft Rejection
Statistical Methods
Engraftment All patients had transient hematopoietic toxicity after HCT. The median neutrophil nadir was 203/µL (range, 0 to 2,340/µL). The median number of days with neutrophils less than 500/µL was 6 days (range, 0 to 62 days), with 16% of patients maintaining neutrophils more than 500/µL after HCT. The median platelet nadir was 30,000/µL (range, 2,000 to 406,000/µL). The median number of days with platelets less than 20,000/µL was 0 days (range, 0 to 29 days), with 50% of patients maintaining platelets more than 20,000/µL after HCT. Median numbers of platelet and RBC transfusions were zero (range, zero to 84 transfusions) and four (range, zero to 70 transfusions), respectively. Median donor T-cell chimerism levels on days 28, 56, 84, 180, and 365 after HCT were 95%, 97%, 97%, 99%, and 100%, respectively. Sustained engraftment was achieved in 141 patients, whereas six patients (five unrelated recipients, including one of six marrow recipients; and one related recipient) experienced rejection of their grafts 13 to 1,123 days after HCT. Diagnoses of patients with graft rejection included myelodysplastic syndromes (n = 2), lymphoma (n = 2), acute myeloid leukemia (n = 1), and multiple myeloma (n = 1). Graft rejections were seen in five of 137 patients who experienced failure with an autologous or syngeneic HCT and in one of 10 patients who experienced failure with an allogeneic HCT. Confirming previous observations,33,36 day 28 donor T-cell chimerism levels predicted graft rejection, with four of nine patients with day 28 levels less than 50%, two of 18 patients with day 28 levels between 50% and 75%, and none of 108 patients with levels more than 75% experiencing graft rejections (P < .001).
GVHD and NRM One hundred–day and 3-year probabilities of NRM were 18% and 32%, respectively, in related recipients, and 6% and 28%, respectively, in unrelated recipients (Fig 1). Having experienced failure with autologous/syngeneic HCT versus allogeneic HCT (P = .01) was associated with increased risk of NRM (Table 2), although the low number of patients (n = 10) in the allogeneic group limited the validity of this observation. There was a slightly higher risk of NRM in patients with comorbidities at HCT as assessed by the HCT-CI (P = .29).
Relapse/Progression Three-year probabilities of relapse/progression were 48% in related recipients and 44% in unrelated recipients. As shown in Figure 2A and in Table 3, relapses were more frequent in patients with multiple myeloma, Hodgkin's disease, and myeloid malignancies than in patients with non-Hodgkin's lymphoma (P < .0001). Increasing patient age (P = .02) and being in PR or CR at HCT (P = .002; Fig 2B) were each associated with a lower risk of relapse in univariate analysis. In multivariate analysis, diagnosis group (P = .0001) and being in PR or CR at HCT (P = .001) remained significantly associated with lower relapse risk (Table 2).
Survival Median follow-up time for surviving patients was 813 days (range, 84 to 1,925 days) and was greater than 3 and 4 years in 39% and 20% of surviving patients, respectively. Eighty-eight patients died 7 to 1,902 days (median, 194 days) after HCT (Fig 3A). Causes of death were relapse/progression (n = 47), GVHD with or without infection (n = 24), respiratory failure (n = 5), multiple organ failure (n = 3), suicide (n = 2), infection without GVHD (n = 2), secondary acute myeloid leukemia (n = 1), tumor lysis syndrome (n = 1), chronic heart failure (n = 1), myocardial infarction (n = 1), and brain lesions of unknown etiology (n = 1). Three-year probabilities of overall survival were 27% in related recipients and 44% in unrelated recipients. Factors associated with better overall survival in univariate analyses were being in PR or CR at HCT (P = .01) and absence of comorbidity (HCT-CI score = 0; P = .03). Only being in PR or CR at HCT remained significantly associated with better overall survival in multivariate analysis (P = .01; Table 2). Interestingly, the risk of overall mortality was similar in patients who experienced failure with an allogeneic HCT and in patients who experienced failure with an autologous/syngeneic HCT (HR = 0.80; P = .62). Figure 3B and Table 3 show overall survival according to diagnosis.
Three-year probabilities of progression-free survival were 20% in related recipients and 28% in unrelated recipients (P = .05; Fig 3C). Other factors associated with better progression-free survival in univariate analysis were being in PR or CR at HCT (P = .0009; Fig 2C) and diagnosis group (P = .07). Specifically, 3-year probabilities of progression-free survival were 57% in patients with mantle cell lymphoma, 56% in patients with indolent non-Hodgkin's lymphoma, 30% in patients with acute lymphoblastic leukemia, 29% in patients with myeloid malignancies, 10% in patients with multiple myeloma, and 8% in patients with Hodgkin's disease (Table 3). In multivariate analyses, better progression-free survival was associated with diagnosis group (P = .04) and being in PR or CR at HCT (P = .0004; Table 2).
Impact of Acute and Chronic GVHD on HCT Outcomes
All the patients in this study had exhausted high-dose chemoradiotherapy options as a result of cumulative organ toxicities. Allogeneic HCT was used as treatment of last resort. To minimize toxicities and mortality, the conditioning regimen was of minimal intensity, and the task of eradicating the patients' hematologic malignancies and producing cures was placed almost entirely on allogeneic graft-versus-tumor effects. Overall, the expectations of tumor-cell kill by grafted immune cells were met in a slight majority of patients, and approximately 55% of the patients remained in remission at 3 years, whereas 45% experienced relapse or progression. Results were better in patients who received transplantation in CR or PR (approximately 65% remission rate) than in patients not in CR or PR (approximately 45% remission rate). Graft-versus-tumor effects were most impressive in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma (0% to 10% 3-year relapse rate), intermediate in patients with aggressive non-Hodgkin's lymphoma and various myeloid malignancies (30% to 45% 3-year relapse rate), and least impressive in patients with advanced multiple myeloma and Hodgkin's disease (60% to 70% 3-year relapse rate). The exact reasons for the variable graft-versus-tumor effects are unclear but might include variation in tumor burden, which is consistent with better outcomes in patients who proceeded to HCT in CR or PR; variability in kinetics of tumor cell growth; presentation and density of minor histocompatibility (and perhaps tumor-specific) target antigens on tumor cells; susceptibility of tumor cells to cytotoxic cell kill; access of tumor to donor lymphocytes; and other factors. Whether any of these variables can be manipulated to enhance the speed and effectiveness of graft-versus-tumor effects in this setting remains to be determined. In the meantime, efforts have been focused on reducing tumor burden through preceding cytoreductive autologous HCT in the case of multiple myeloma,37 the addition of radiolabeled monoclonal antibodies against CD20 or CD45 in the case of advanced non-Hodgkin's lymphoma38 or myeloid malignancies,39 or increases in the intensity of the conditioning regimen in the case of advanced Hodgkin's lymphoma.40 The allogeneic graft-versus-tumor effects came at a price, GVHD. The overall 3-year NRM rate, both for recipients of related and unrelated grafts, was approximately 30%; of this rate, 11% was from regimen-related toxicity that might or might not have been favored by pre-existing comorbid conditions (eg, heart disease), 1.5% was from infections without GVHD, 1.5% was from suicide, and 16% was from complications related to acute (8%) or chronic (8%) GVHD. A previous analysis had shown that, although acute GVHD increased the risk of mortality, it was not statistically significantly associated with beneficial graft-versus-tumor effects.20 Indeed, grade 2 to 4 acute GVHD was associated with worse survival in the current study. Thus, future efforts should focus on preventing this complication. In contrast, as confirmed among present patients and by other groups of investigators,41-44 chronic GVHD conveyed significant graft-versus-tumor effects. Thus, although complicated by the need for more prolonged immunosuppressive therapy, chronic GVHD has been associated with improved progression-free survival after nonmyeloablative conditioning. 41 In the current study, the association between chronic GVHD and better progression-free survival did not reach statistical significance, possibly because of the number of patients included. In conclusion, allogeneic graft-versus-tumor effects can be used with some success as therapy of last resort in patients with hematologic malignancies who have exhausted other treatment options including high-dose therapy with stem-cell rescue. Outcomes with related and unrelated grafts have been comparable.
The authors indicated no potential conflicts of interest.
We thank data coordinators Heather Hildebrant, Debbie Bassuk, and Chris Davis; study nurses Mary Hinds, John Sedgwick, and Michelle Bouvier; Helen Crawford, Bonnie Larson, and Sue Carbonneau for manuscript preparation; and the physicians, nurses, and patients involved in this study.
published online ahead of print at www.jco.org on August 7, 2006 Supported in part by Grants No. HL36444, CA78902, CA92058, CA18029, CA49605, and CA15704 from the National Institutes of Health, Department of Health and Human Services, Bethesda, MD. F.B. is a research associate of the National Fund for Scientific Research Belgium and is supported in part by postdoctoral grants from the Fulbright Commission and from the Centre Anticancéreux près l'Université de Liège. Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Bethge WA, Hegenbart U, Stuart MJ, et al: Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood 103:790-795, 2004 35. Gooley TA, Leisenring W, Crowley J, et al: Estimation of failure probabilities in the presence of competing risks: New representations of old estimators. Stat Med 18:695-706, 1999[CrossRef][Medline] 36. Baron F, Baker JE, Storb R, et al: Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 104:2254-2262, 2004 37. Maloney DG, Molina AJ, Sahebi F, et al: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102:3447-3454, 2003 38. Pagel JM, Hedin N, Subbiah K, et al: Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas. Blood 101:2340-2348, 2003 39. Pagel JM, Appelbaum FR, Sandmaier BM, et al: 131I-anti-CD45 antibody plus fludarabine, low-dose total body irradiation and peripheral blood stem cell infusion for elderly patients with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Blood 106:119a, 2005 (abstr 397) 40. Peggs KS, Hunter A, Chopra R, et al: Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet 365:1934-1941, 2005[CrossRef][Medline] 41. Perez-Simon JA, Diez-Campelo M, Martino R, et al: Impact of CD34+ cell dose on the outcome of patients undergoing reduced-intensity-conditioning allogeneic peripheral blood stem cell transplantation. Blood 102:1108-1113, 2003 42. Crawley C, Lalancette M, Szydlo R, et al: Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: An analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 105:4532-4539, 2005 43. Cao TM, Shizuru JA, Wong RM, et al: Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose. Blood 105:2300-2306, 2005 44. Michallet AS, Furst S, Le QH, et al: Impact of chimaerism analysis and kinetics on allogeneic haematopoietic stem cell transplantation outcome after conventional and reduced-intensity conditioning regimens. Br J Haematol 128:676-689, 2005[CrossRef][Medline] Submitted April 11, 2006; accepted June 29, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
