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Originally published as JCO Early Release 10.1200/JCO.2005.04.569 on April 4 2005 © 2005 American Society of Clinical Oncology. Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning for Advanced Chronic Lymphocytic LeukemiaFrom the Fred Hutchinson Cancer Research Center; University of Washington; VA Puget Sound Health Care System; Hematologics Inc, Seattle, WA; Stanford University, Stanford, CA; University of Leipzig, Leipzig, Germany; Baylor University, Dallas, TX; Oregon Health & Science University, Portland, OR; University of Utah, Salt Lake City, UT; University of Colorado, Denver, CO; Medical College of Wisconsin, Milwaukee, WI; University of Torino, Torino, Italy; and Emory University, Atlanta, GA Address reprint requests to David Maloney, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D1-100, PO Box 19024, Seattle, WA 98109-1024; e-mail: dmaloney{at}fhcrc.org
PURPOSE: Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. The aim of this study was to analyze the outcome of patients with advanced CLL when treated with nonmyeloablative conditioning and hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: Sixty-four patients diagnosed with advanced CLL were treated with nonmyeloablative conditioning (2 Gy total-body irradiation with [n = 53] or without [n = 11] fludarabine) and HCT from related (n = 44) or unrelated (n = 20) donors. An adapted form of the Charlson comorbidity index was used to assess pretransplantation comorbidities. RESULTS: Sixty-one of 64 patients had sustained engraftment, whereas three patients rejected their grafts. The incidences of grades 2, 3, and 4 acute and chronic graft-versus-host disease were 39%, 14%, 2%, and 50%, respectively. Three patients who underwent transplantation in complete remission (CR) remained in CR. The overall response rate among 61 patients with measurable disease was 67% (50% CR), whereas 5% had stable disease. All patients with morphologic CR who were tested by polymerase chain reaction (n = 11) achieved negative molecular results, and one of these patients subsequently experienced disease relapse. The 2-year incidence of relapse/progression was 26%, whereas the 2-year relapse and nonrelapse mortalities were 18% and 22%, respectively. Two-year rates of overall and disease-free survivals were 60% and 52%, respectively. Unrelated HCT resulted in higher CR and lower relapse rates than related HCT, suggesting more effective graft-versus-leukemia activity. CONCLUSION: CLL is susceptible to graft-versus-leukemia effects, and allogeneic HCT after nonmyeloablative conditioning might prolong median survival for patients with advanced CLL.
Chronic lymphocytic leukemia (CLL), a low-grade lymphoproliferative disorder, is the most common adult hematologic malignancy in Western countries.1 Median age of CLL patients at diagnosis is 72 years,2 and only 10% to 15% are younger than 50 years.3 Fludarabine is the typical first-line therapy for CLL. It has shown better response rates than single alkylating agents or combination chemotherapy, but with no survival benefit.4–6 Twenty percent of CLL patients are refractory to first-line fludarabine therapy, and their median survival is only 12 months,7 whereas all other patients eventually experience disease relapse after response to fludarabine, with a median survival of 21 months.8 The use of alemtuzumab, the drug approved by the US Food and Drug Administration for treatment of patients with fludarabine-refractory CLL, has extended survival to 16 months, with a 2-year survival rate of 40%.9 Treatment with other nucleoside analogs, combination chemotherapy with or without fludarabine, or new biologic agents such as rituximab has not demonstrably extended survival of fludarabine-refractory CLL patients over that achieved with alemtuzumab.7,9–16 In previously treated CLL, some improvement of survival was noted after a combination of fludarabine/cyclophosphamide/rituximab.17 Autologous high-dose hematopoietic cell transplantation (HCT) has been offered to a selected group of young and chemotherapy-sensitive CLL patients with minimal tumor burden and successful collection of hematopoietic progenitor cells. Although nonrelapse mortality (NRM) was less than 10%,18 autologous HCT was associated with relapse rates of 41% to 58%, with no survival plateau.18,19 Fludarabine-refractory CLL has usually been a reason for ineligibility for autologous HCT.20 Myeloablative allogeneic HCT has the advantage of graft-versus-leukemia (GVL) effects, which result in a low risk of relapse (13% to 25%) in younger recipients of unrelated or related grafts.18,19,21 However, myeloablative allogeneic HCT is associated with 35% to 60% NRM.19,21–24 Despite the high NRM, 3-year survival rates among patients with fludarabine-responsive or -naïve CLL who underwent myeloablative allogeneic HCT have ranged from 41% to 56%, with a suggestion of a plateau in disease-free survival (DFS).18,19,21 Survival rates for patients with fludarabine-refractory CLL were 36% at 2 years25 and 32% at 5 years.23 On the basis of preclinical canine studies,26 we have developed a nonmyeloablative regimen for allogeneic HCT in patients with hematologic malignancies consisting of conditioning with 2 Gy total-body irradiation (TBI) with or without three doses of fludarabine, and post-transplantation immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP).27–29 Here we describe the outcomes of 64 patients with chemotherapy-refractory CLL who underwent related or unrelated HCT using this regimen.
Eligibility Criteria This analysis includes data from 64 patients diagnosed with CLL who underwent allogeneic HCT after nonmyeloablative conditioning on Fred Hutchinson Cancer Research Center (FHCRC; Seattle, WA) multi-institutional protocols for patients with hematologic malignancies between December 16, 1997, and December 11, 2003. The primary differences between protocols were the use of HLA-matched related or unrelated grafts, variations in the duration and intensity of CSP and MMF, and the addition of fludarabine to 2 Gy TBI. These changes were made over time to reduce both the risks of graft-versus-host disease (GVHD) and graft rejection.
Patients were treated at 12 centers with the FHCRC acting as the coordinating center. Protocols were approved by the institutional review boards of the FHCRC and the collaborating sites. All patients signed consent forms approved by the local institutional review boards. Inclusion criteria included diagnoses of CLL,30 small lymphocytic lymphoma, or CLL/prolymphocytic leukemia; age In this study, chemotherapy (and fludarabine) -refractory CLL was defined as either inability to meet National Cancer Institute (NCI) Working Group Criteria for partial remission (PR) or complete remission (CR),30 or relapse/progression within 6 months of completion of chemotherapy. Pretransplantation comorbidities were scored using an adapted form of Charlson Comorbidity Index (CCI),31,32 whereas post-transplantation toxicities were graded using the NCI Common Toxicity Criteria.
HLA Typing and Matching
Conditioning Regimen and Post-Transplantation Immunosuppression
Collection of Hematopoietic Cells and Supportive Care
Analyses of Donor Chimerism, Disease Responses, and Risk Factors Beta2-microglobulin was assessed using an immunoglobulin assay Abbott test kit (Abbott Park, IL). The upper limit of the reference range was 2.5 µg/mL, which was the value detected in the 95th percentile of the population at the University of Washington Medical Center (Seattle, WA). Cytogenetics were assessed in most patients (n = 51) using conventional karyotype G banding in addition to interphase cytogenetics with florescence in situ hybridization. Ten patients were tested only by conventional cytogenetic methods, and three patients were not evaluated for cytogenetic abnormalities before HCT.
Monitoring Minimal Residual Disease
Statistical Methods
Patient Characteristics Forty-four patients received related grafts and 20 patients received unrelated grafts (Table 1). Patients had multiple risk factors: median age was 56 years; median interval between diagnosis and HCT was 4.4 years; CCI scores of  1 for pretransplantation comorbidities were present in 48% of patients (20 patients had a score of 1, seven patients had a score of 2, and four patients had a score of 3; Table 2); chemotherapy resistance to pretransplantation salvage treatment was present in 53% of patients and untreated relapse occurred in 11% of patients; there was a median of four prior treatment regimens; and disease refractoriness to at least one regimen was present in all but two patients (97%). Thirty patients (47%) were refractory to one regimen, 23 patients (36%) were refractory to two regimens, and nine patients (14%) were refractory to three regimens. Eighty-eight percent of patients were refractory to fludarabine, 25% of patients were refractory to rituximab, 30% of patients were refractory to alkylating agents, and 22% of patients were refractory to other miscellaneous regimens. Among fludarabine-refractory patients, 47 patients did not respond or experienced disease progression, whereas nine patients experienced disease relapse within 6 months after a fludarabine-containing regimen. In addition, patients had multiple adverse disease burden characteristics40,41: bulky lymphadenopathy (lymph node diameter 5 cm, 28%), splenomegaly (47%), CD5/CD9 coexpression of CD38 more than 30% (58%), beta2-microglobulin more than 2.5 µg/mL (53%), 50% marrow infiltration with CLL cells (52%), and unfavorable cytogenetics42 (39%). No significant differences in adverse disease burden characteristics were present between related and unrelated recipients.
Favorable cytogenetics included either a normal karyotype or a single abnormality of del(13q), whereas unfavorable cytogenetics included del(11q), del(17p), trisomy 12, other rare abnormalities [t(11:17), t(11:13), t(14:18), t(5:17), and monosomy 7], and complex karyotypic abnormalities (> two abnormalities).
Engraftment Kinetics and Donor Chimerism
GVHD and Toxicities Grade 4 toxicities were infrequent and most commonly included hematologic toxicity (32%; Fig 1), in part explained by the fact that 25% of patients had neutropenia (< 500 cells/µL) and/or thrombocytopenia (< 20 x 103 cells/µL) before HCT.
Disease Responses and Clearance of Molecular Disease Three patients without measurable disease at HCT have remained in CR. Among 61 patients with measurable disease at HCT, the 2-year cumulative probabilities for achieving CR and PR were 50% and 17%, respectively. Related recipients had lower CR rates (42%) than unrelated recipients (78%; P = .005). This difference remained significant after adjusting for pretransplantation disease burden characteristics (P = .03). Of 54 patients with CD5/CD19-coexpressing CLL cells detected by flow cytometry pre-HCT, 36 cleared their disease post-HCT, whereas 21 of 33 patients cleared previously identified cytogenetic abnormalities (Fig 2A) . All three patients with del(11q) before HCT achieved post-transplantation CR; one of these patients died as a result of NRM, and two are alive at 6 and 49 months, respectively, after HCT. Among the five patients with del(17p) before HCT, two died early as a result of progression, one died as a result of NRM in CR, and two are alive in CR and PR at 12 and 7 months post-transplantation, respectively. Seven patients had complete cytogenetic and flow cytometric responses while clinically they were in PR. Among patients who achieved CR, two experienced disease relapse at 2 and 3 years after HCT, respectively; among patients with PR, two experienced disease progression. IgH VDJ detection before and after HCT was performed in 11 FHCRC patients who were in CR (Fig 2B). Clone-specific IgH VDJ rearrangements in all 11 patients cleared within 3 to 30 months after HCT. Ten of the 11 patients had fludarabine-refractory CLL. Nine of the 11 patients are alive and eight have sustained molecular remissions at a median of 38 months (range, 28 to 63 months), whereas one patient experienced disease relapse 39 months after HCT.
The estimated 2-year rate of relapse/progression was 26%. Rates of relapse/progression were 34% for related and 5% for unrelated recipients (hazard ratio [HR], 0.3; P = .08) at 2 years (Fig 3), and after adjusting for pretransplantation disease burden characteristics, the HR remained 0.3 (P = 0.1). The estimated 2-year rate of relapse-related mortality (Fig 4) was 18% (22% for related and 5% for unrelated recipients; P = 0.16). At a median follow-up of 24 months (range, 3 to 63 months; 31 months [range 3 to 63 months] for related and 12 months [range, 3 to 39 months] for unrelated recipients), 39 patients were living: 25 in CR, five in PR, two with stable disease, and seven with relapse/progressive disease.
Timing of GVHD and GVL Effects The median times for onset of acute and chronic GVHD were 1.4 and 4.5 months, respectively (Table 3). In comparison, the median times for resolution of cytogenetic abnormalities, disappearance of CD5/CD19-coexpressing CLL cells, disappearance of lymphadenopathy, and achievement of molecular remissions were 3.0, 5.7, 8.6, and 12 months, respectively. Of note, the respective onsets for each of the landmarks occurred earlier among unrelated than related recipients. Two patients experienced disease relapse at 28.2 and 37.9 months, respectively, after achieving initial remissions, whereas 16 patients experienced disease progression after a median of 3.3 months with stable disease. Overall, 15 related recipients and one unrelated recipient experienced disease progression.
DLI Eight patients received DLI for treatment of disease progression/relapse (n = 6) or graft rejection (n = 1) among related recipients, and for Epstein-Barr virus-associated lymphoproliferative disease (n = 1) arising from unrelated donor cells (the patient's CLL was in CR). Five patients received DLI after chemotherapy (Table 4). Six patients failed to respond to DLI. One patient achieved PR associated with GVHD followed by multiorgan failure and death. One patient experienced CR of his lymphoproliferative disease and is alive 9.3 months after HCT.
NRM and Survival Rates of day 100 and 2-year NRM were 11% and 22%, respectively, with no significant differences between related and unrelated recipients (Fig 4). The nonrelapse deaths included infections with acute (n = 4) or chronic (n = 6) GVHD, cardiac arrest (n = 2), pulmonary hemorrhage after rejection (n = 1), cerebrovascular stroke (n = 1), and de novo metastatic lung cancer (n = 1). Kaplan-Meier probabilities of DFS and OS at 2-years were 52% and 60%, respectively. Median DFS was 28 months, whereas median OS has not yet been reached (4-year OS, 54%). Two-year OS and DFS of related compared with unrelated recipients were 56% v 75% (P = .33) and 44% v 75% (P = .15), respectively (Fig 4).
Risk Factors Predicting Outcome After HCT
Patients with CLL who are unresponsive to or have early relapse after treatment with fludarabine have median survivals of 12 and 20 months, respectively.7,8 Better treatments are needed. Current treatments include the use of the anti-CD52 monoclonal antibody alemtuzumab,9 and the combination of fludarabine, cyclophosphamide, and rituximab,11 which result in CR rates of 3% and 7%, respectively. Alemtuzumab extended median survival from 12 to 16 months, with a 2-year survival of 40% when compared with historical controls. Myeloablative allogeneic HCT might result in long-term DFS. However, even in younger patients with fludarabine-sensitive/naïve CLL, conventional HCT had high early NRM,19,24 and OS rates ranged from 32% to 36%.23,25 Here, we report on the use of a nonmyeloablative conditioning regimen for allogeneic HCT for older patients with chemotherapy-refractory CLL, and show CR and PR rates of 50% and 17%, respectively, with 2-year survival of 60%. Encouragingly, progression/relapse rates have been low, especially for unrelated recipients (2-year relapse rates were 5% and 34%, respectively). Longer follow-up is required. Eighty-eight percent of the current patients had fludarabine-refractory CLL, and 64% had active or chemotherapy-resistant disease at the time of HCT.
Given the minimal-intensity conditioning, the achievement of CR and PR must be attributed to powerful GVL effects. Although 16 of 64 patients had progressive CLL early after HCT at a median of 3.3 months, only two of 64 patients had late relapses 28 to 38 months after HCT. These relapse/progression rates do not seem to be significantly different from the rates of 13% to 25% at 3 years reported after myeloablative HCT in younger patients with less advanced disease.19,21 Not surprisingly, greater disease burden before HCT, such as bulky lymphadenopathy, predicted the highest relapse/progression rates. Such patients might benefit from earlier referral to nonablative HCT trials after failed treatment with fludarabine; those patients had received a median of five preceding regimens, and 50% of them were refractory to
Current unrelated recipients experienced greater CR rates and less relapse/progression than related recipients. This difference might be due in part to higher disease burdens before HCT among related recipients. In part, it might be due to greater GVL effects owing to greater genetic disparities with their donors for minor histocompatibility antigens on malignant and nonmalignant hematopoietic cells.44–46 This assumption is also supported by more rapid disease responses among unrelated recipients. Clearly, longer follow-up is needed to verify these early observations. The observed improved outcome among patients age We also evaluated the effects of known poor prognostic factors on outcome after nonmyeloablative HCT. In contrast to other studies, we found unfavorable cytogenetics47–50 or CD38+ expression51,52 were not associated with worse outcome.53 Although this might be due to small patient numbers, it was possible that GVL effects outweighed adverse effects of these prognostic factors, or perhaps that these factors had less prognostic significance for chemotherapy-refractory CLL than for early-stage or untreated patients receiving standard chemotherapy.54–56 Ongoing studies are examining the effects of adverse prognostic factors including zeta-chain-associated protein 7057 and unmutated immunoglobulin gene54 in larger numbers of patients. Although our results in patients with advanced CLL have been encouraging, there is room for improvement, given that 22% of patients have died as a result of NRM and 18% have died as a result of relapsed/progressive CLL. Pretransplantation comorbidities, as assessed by increased CCI scores, were an independent strong predictor for NRM, consistent with previous observations in patients with various hematologic malignancies.32,36 Unfortunately, comorbidities remain a problem of this population, given the advanced age of most patients with CLL. One major cause of NRM has been GVHD and associated infections; in particular, invasive mold infections.58,59 Our data suggested that there were more deaths from acute GVHD among patients with CCI scores of more than 0 compared with those with a score of 0 (13% v 0%; P = .1). Studies are under way to reduce the incidence of severe GVHD by lengthening the duration of immunosuppression or adding a third agent such as rapamycin. Other studies have focused on better early diagnosis and prevention of fungal infections.59–64 To address the issue of relapse/disease progression, we examined the effects of DLI in a small number of patients (n = 8). Surprisingly, we found that patients who experienced disease progression generally did not respond to DLI. This may be due to the use of a suboptimal dose of DLI for inducing strong GVL effects. Alternatively, some patients with bulky advanced disease may have tumor cell clones that are resistant to the GVL-mediated killing. Future approaches using more specific targeting of malignant CLL cells by isolation, expansion, and injection of specific cytotoxic donor T lymphocytes may improve tumor control. Other groups have reported the use of reduced-intensity conditioning regimens followed by HCT for treatment of CLL. Dreger et al65 retrospectively summarized data from 77 patients with CLL who underwent transplantation in 29 European centers, mainly from related donors (82%), using several different reduced-intensity regimens; Schetelig et al66 reported data from 30 patients administered fludarabine, busulfan, and antithymocyteglobulin conditioning and undergoing transplantation from related (50%) or unrelated donors (50%); and Khouri et al43 reported data on 17 patients undergoing transplantation from related donors using fludarabine and cyclophosphamide conditioning. Patients enrolled onto these studies had shown OS of 72%, 72%, and 80% and DFS of 56%, 67%, and 60% at 2 years, respectively. In a comparison of risk factors, 88% of our patients had fludarabine-refractory CLL compared with 82% fludarabine exposure in the study by Dreger et al,65 33% fludarabine-refractoriness in the study by Schetelig et al,66 and 100% refractoriness or relapse after fludarabine in the study by Khouri et al.43 In addition, patients in our study were older (median age, 56 v 50 to 54 years), had received more prior regimens (median, four v three), and had more or comparable chemotherapy-resistant disease at the time of HCT (53% v 35% to 53%, respectively). The two studies that included unrelated grafts reported worse survivals (HR, 2.3)65 and higher rates of NRM (28% v 0%, respectively)66 among unrelated compared with related recipients. In contrast, in our study we discovered better survival (75% v 56%), lower relapse (5% v 34%), and similar NRM (20% v 22%) rates for unrelated compared with related recipients, respectively. Longer follow-up is required, both to assess risk of disease relapse and toxicity due to GVHD and infections. Reduced-intensity conditioning regimens containing alemtuzumab have been used to decrease the risk of GVHD after allogeneic HCT. Mackinnon et al67 reported the use of this approach in low-grade lymphoma (including nine patients with CLL) followed by preemptive DLI to control disease progression, relapse, or refractoriness. They reported 3-year rates of OS and DFS of 73% and 65%, respectively, for the entire group of patients with low-grade lymphoma. We have demonstrated the feasibility of and early outcome results with a nonmyeloablative conditioning regimen to prepare patients with fludarabine-refractory CLL for HLA-matched related or unrelated allogeneic HCT. This approach has a significant NRM (22% at 2 years) but is associated with CR and PR rates of 50% and 17%, respectively, including molecular remissions in all 11 patients tested. Only one of those 11 patients eventually experienced disease relapse. No other treatment option offers this level of disease response in this patient population. Comparisons of nonmyeloablative HCT results with those after conventional therapies including alemtuzumab or the combination of fludarabine, cyclophosphamide, and rituximab are difficult to make because of differences in patient characteristics. However, current 2-year OS and DFS of 60% and 52%, respectively, compared favorably with previously reported results.9 Results support the need for prospective phase III studies comparing the different treatment modalities for patients with fludarabine-refractory CLL.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Monic J. Stuart, Genentech; Michael R. Loken, HematoLogics. Leadership Position: Michael R. Loken, HematoLogics. Consultant/Advisory Role: Michael R. Loken, HematoLogics. Stock Ownership: Monic J. Stuart, Genentech; Michael R. Loken, HematoLogics. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
We thank the data coordinators Chris Davis and Heather Hildebrant; the study nurses Steve Minor, Mary Hinds, and John Sedgwick; Bonnie Larson and Helen Crawford for manuscript preparation; Paula Ladne for PCR analysis; and all of the transplantation teams at the participating institutions.
Supported by grant Nos. CA78902, CA92058, CA18029, CA49605, and CA15704 from the National Institutes of Health, Department of Health and Human Services, Bethesda, MD, and Leukemia and Lymphoma Society Specialized Center of Research grant 7040. M.S. was supported in part by a grant from the Oncology Research Faculty Development Program of the Office of International Affairs of the National Cancer Institute. B.B. was supported by a grant from Ministero dell'Istruzione, dell'Università, della Ricerca, Italy. Presented in part at the Tandem Bone Marrow Transplantation meeting, February 13-17, 2004, Orlando, FL (for part of the patient population). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) negative VDJ. HCT, hematopoietic cell transplantation.
