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Originally published as JCO Early Release 10.1200/JCO.2005.03.962 on July 25 2005

Journal of Clinical Oncology, Vol 23, No 24 (August 20), 2005: pp. 5788-5794
© 2005 American Society of Clinical Oncology.
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Unrelated Donor Marrow Transplantation for B-Cell Chronic Lymphocytic Leukemia After Using Myeloablative Conditioning: Results From the Center for International Blood and Marrow Transplant Research

Steven Z. Pavletic, Issa F. Khouri, Michael Haagenson, Roberta J. King, Philip J. Bierman, Michael R. Bishop, Michael Carston, Sergio Giralt, Arturo Molina, Edward A. Copelan, Olle Ringdén, Vivek Roy, Karen Ballen, Douglas R. Adkins, Philip McCarthy, Daniel Weisdorf, Emili Montserrat, Claudio Anasetti

From the National Cancer Institute, Bethesda, MD; M.D. Anderson Cancer Center, Houston, TX; Center for International Blood and Marrow Transplant Research; National Marrow Donor Program; University of Minnesota, Minneapolis, MN; University of Nebraska Medical Center, Omaha, NE; City of Hope National Cancer Center, Duarte, CA; Ohio State University, Columbus, OH; Karolinska University Hospital, Huddinge, Sweden; Mayo Clinic, Jacksonville; Massachusetts General Hospital, Boston, MA; Washington University School of Medicine, St Louis, MO; Roswell Park Cancer Institute, Buffalo, NY; and Hospital Clinic, IDIBAPS, University of Barcelona, Spain; H. Lee Moffitt Cancer Center, Tampa, FL

Address reprint requests to Steven Pavletic, MD, Graft-versus-Host and Autoimmunity Unit, Experimental Transplantation and Immunology Branch, National Cancer Institute, 9000 Rockville Pike, Building 10, Room CRC 3-3330, Bethesda, MD 20892-1907; e-mail: pavletis{at}mail.nih.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL).

PATIENTS AND METHODS: A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients.

RESULTS: Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively.

CONCLUSION: These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
B-cell chronic lymphocytic leukemia (CLL) is an incurable disease for which better treatments are needed, especially for patients with aggressive subtypes.1-4 The recent introduction of new drugs, antibodies, and their combinations has increased the rate and quality of remissions and may be prolonging survival in some patients with CLL, but none of these strategies has curative potential.3,4 Although CLL is often a disease with an indolent and prolonged clinical course, more than 90% of younger patients die as a result of causes directly related to CLL.5 Prognosis is especially poor for chemotherapy-refractory patients or those who received more than three prior treatment regimens.6,7

Autologous hematopoietic stem-cell transplantation was tested as a strategy to improve survival in patients with advanced CLL; however, results showed a constant rate of post-transplantation relapse (50% to 60% at 3 years) without suggestion of cure.8-10 In contrast, allogeneic HSCT (alloHSCT) from HLA-matched related donors yields a relapse rate of only 10% to 20% in advanced CLL patients whose disease has progressed after multiple regimens or whose disease was chemotherapy refractory.10-17 Lower relapse rates after alloHSCT for CLL are presumably due to potent allogeneic graft-versus-leukemia (GVL) effects and because stem cells are free from leukemic cell contamination.11,18-22 The allogeneic GVL effect can overcome resistance toward high-dose therapy and eradicate minimal residual disease in poor-risk CLL patients.22 Unfortunately, only a minority of patients have a sibling donor.

Transplantations of stem cells from unrelated donors (URDs) have been used for a variety of hematologic malignancies23-26 but rarely have been considered for CLL because of concerns about toxicity and the advanced age of patients.27,28 Recently, an increasing number of CLL patients have been successfully treated with URD stem-cell transplantation after reduced-intensity or nonmyeloablative conditioning.29-31 These transplantations have been associated with decreased early transplantation-related mortality and good antileukemic effects; however, duration of follow-up is too short to adequately assess this benefit. We analyzed long-term outcomes in 38 URD bone marrow transplantation patients who received high-dose myeloablative conditioning and were reported to the National Marrow Donor Program (NMDP).


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Data Sources
Unrelated donors were identified through the NMDP (based in Minneapolis, MN). Marrow procurement procedures were performed through NMDP-approved donor and collection centers. Transplantations were performed at 18 centers affiliated with the NMDP. Donor identification, marrow harvesting and transport, transplantation, baseline donor and recipient data gathering, follow-up data gathering, data storage and analysis, and patient and donor safety monitoring were coordinated and overseen by the NMDP.32 In addition to baseline information, follow-up reporting forms were submitted at 100 days, 6 months, 1 year, and then annually post-transplantation. The CLL disease-specific forms were designed at the time of study planning using the International Bone Marrow Transplant Registry forms as a template.15 Disease-specific forms contained information on 164 items including information on CLL status at the time of diagnosis, previous treatments, disease parameters at the time of the transplantation, responses to transplantation, and post-transplantation follow-up information.

Patient Eligibility
Patients who underwent transplantation between 1993 and 1999 were eligible for the study. Ninety-one donor searches were conducted for CLL patients during the same time period and 60 eventually received transplants. Twenty-two patients who received URD transplants for CLL were excluded from this analysis for the following reasons: nine transplants were from donors from cooperative registries or were performed by international centers that do not provide data to the NMDP, nine patients received a nonmyeloablative preparative regimen, in three patients B-cell immunophenotype could not be verified, and one patient lacked follow-up data.

All URD donors were adults who signed written statements of informed consent before donation. All recipients signed informed consents for transplantation and for submission of the data to the NMDP. Informed consents were approved by the local transplantation center institutional review board.

Study End Points
Primary end points in this analysis were overall survival (OS) and failure-free survival (FFS). Secondary end points included engraftment, complete response (CR), disease progression, and acute and chronic graft-versus-host disease (GVHD). Disease responses were recorded at the time of the best response post-transplantation, and were defined as achievement of complete or partial response after transplantation by using published National Cancer Institute criteria.33 According to these criteria, CR was defined as lymphocyte count less than 4,000/µL, neutrophil count more than 1,500/µL, hemoglobin more than 11.0 g/dL, platelet count more than 100,000/µL, absence of organomegaly, and less than 30% lymphocytes in the bone marrow aspirate. FFS was defined as survival without clinical evidence of progressive leukemia. The definition of post-transplantation progression included patients who had primary progressive disease after transplantation, those who failed to achieve CR or partial response, and those who experienced CLL progression after initial complete or partial response. Immunophenotyping or cytogenetic or molecular criteria was not used for remission or relapse assessment because this information was inconsistently reported. Engraftment was defined as the first of 3 consecutive days when the absolute neutrophil count (ANC) exceeded 0.5 x 109/L. Secondary graft failure was defined by initial neutrophil recovery followed by a decline in ANC to below 0.5 x 109/L for at least 3 consecutive days. Progressive disease was considered as a primary cause of death in all patients who have died for any reason after CLL progression. Acute and chronic GVHD were diagnosed and graded according to consensus criteria.34

Statistical Analysis
OS and FFS curves were calculated using the method of Kaplan and Meier.35 Twenty-one patient- or donor-related parameters were included in the univariate analyses if P ≤ .10 for either primary outcome. The log-rank statistic was used to test differences in the primary outcomes among various groups. Because of the low number of events, a 95% log-transformed CI was determined for each outcome.36 SAS software (SAS Institute, Cary, NC) was used for the univariate analyses; PROC LIFETEST (SAS Institute) was used to determine the Kaplan-Meier rates.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Transplant Recipients
Clinical characteristics of 38 CLL patients who underwent transplantation are presented in Table 1. All patients had typical CLL morphology and immunophenotype as required by National Cancer Institute criteria.33 No patients had Richter syndrome or other transformation. There were insufficient data to use the following characteristics in the analysis: bone marrow involvement pattern (diffuse v other), beta2-microglobulin levels, post-transplantation bone marrow immunophenotyping and immunoglobulin rearrangement studies, and size of the largest nodal mass.


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  		Table 1. Patient and Donor Characteristics Prior to Starting the Conditioning Regimen

 
Transplantation Regimens
Thirty-five (92%) patients received a high-dose conditioning regimen that included cyclophosphamide and total-body irradiation alone (n = 29) or in combination with other agents (n = 6) such as etoposide, thiotepa, or antithymocyte globulin (Table 2). Most patients received GVHD prophylaxis with the combination of cyclosporine and methotrexate (61%), or tacrolimus and methotrexate (21%). Two patients received marrow grafts that were depleted of T lymphocytes. Two patients received post-transplantation donor leukocyte infusions for the treatment of persistent or recurrent CLL.


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  		Table 2. Transplantation Characteristics

 
Engraftment
The median time to an ANC of 0.5 x 109/L was 20 days (range, 8 to 73 days). Four patients had primary graft failure and died; two of them had progressive disease. The cumulative incidence of engraftment at 100 days post-transplantation is 89% (95% CI, 74% to 96%). Of the 34 patients who engrafted, five patients experienced transient neutropenia and three patients experienced irreversible secondary graft failure, of whom two died (one with progressive disease). Because of the small number of patients, it was difficult to identify any trends in characteristics of patients who lost their grafts. All three patients with secondary graft failure were HLA mismatched but only one of four patients with primary graft failure was HLA mismatched. Of interest, the majority of patients with primary or secondary graft failure (six of seven) received three or fewer prior chemotherapy regimens; none received T-cell depletion.

Response and Disease Progression
Thirty-six of 38 patients had available information on best response post-transplantation. Twenty-one (58%) patients achieved CR, six (17%) achieved partial response, four (11%) had stable disease, two (6%) had progressive disease, and three (8%) were reported as not assessable for restaging. The median time to achieve CR was 3 months (range, 1 to 48 months). Delayed CR occurred late in three patients at 35, 40, and 48 months, respectively, and was not due to secondary interventions for CLL (Fig 1). Five-year cumulative incidence of CLL progression was 32% (95% CI, 18% to 47%). Four patients who achieved CR ultimately experienced disease progression at 10, 12, 21, and 48 months post-transplantation, respectively (Fig 2). In univariate analysis, only recipient age younger than 45 years (P = .02) and recipient cytomegalovirus serology-positive status (P = .06) were suggestive of predicting a higher rate of disease progression. None of the variables, including chemotherapy-refractory disease (P = .19), was significantly predictive for attaining CR or for the disease progression (data not shown).



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  		Fig 1. Cumulative incidence of complete response after unrelated donor bone marrow transplantation for chronic lymphocytic leukemia. Disease responses were defined at the time of best response after transplantation by using National Cancer Institute criteria.33

 


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  		Fig 2. Overall survival, failure-free survival, and the cumulative incidence of disease progression after unrelated donor bone marrow transplantation for chronic lymphocytic leukemia.

 
Survival
Eleven (29%) patients are alive and disease free at the median follow-up of 6.0 years (range, 3.0 to 9.0 years). The estimated 100-day survival is 71% (95% CI, 54% to 83%). Estimated OS at 5 years is 33% (95% CI, 19% to 48%; Fig 2). The treatment-related mortality (TRM) at 5 years is 38% (95% CI, 22% to 53%). TRM occurred within 3 years post-transplantation in 11 patients and after 3 years in four patients, at 38, 47, 51, and 62 months, respectively. Of 27 patients who have died, the primary causes of death were transplantation-related toxicity in three, GVHD in seven (acute in two, chronic in five), infection in four, status epilepticus in one, and progressive disease in 12 patients. Estimated FFS at 5 years is 30% (95% CI, 17% to 46%; Fig 2). Parameters suggestive of better FFS and OS in the univariate analysis are shown in Table 3. The number of prior chemotherapy regimens did not affect OS or FFS. Chemotherapy-sensitive versus -refractory disease and lower lymphocyte count at transplantation were disease factors significantly associated with better survival in univariate analyses (Table 3). Because of small sample size and multiple comparisons, these P values should still be interpreted with caution and considered exploratory.


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  		Table 3. Results of the Univariate Analyses at 5 Years

 
Four patients developed new malignancies post-transplantation; these included two skin carcinomas, one lymphoma, and one nonspecified solid tumor. The patient who developed post-transplantation lymphoma subsequently experienced disease relapse with CLL and died. One patient with skin carcinoma died without recurrent CLL. The other two patients with second malignancies are alive and without recurrent CLL.

GVHD
The cumulative incidence of grades 2 to 4 acute GVHD at 100 days was 45% (95% CI, 29% to 60%) and the cumulative incidence of grades 3 to 4 acute GVHD was 29% (95% CI, 16% to 44%). The 5-year cumulative incidence of chronic GVHD in assessable patients surviving 100 days was 85% (95% CI, 60% to 95%).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
This study demonstrates that URD transplantation can result in lasting remissions in patients with advanced CLL. The delayed time period of several months to achieve CR post-transplantation is consistent with the gradual eradication of chemotherapy-refractory CLL cells by an allogeneic GVL effect rather than the high-dose therapy.18-22 The vast majority of studies of alloHSCT for CLL have reported patients observed for a median time of less than 5 years, and none of them was focused on URD.8-16 Michalett et al17 recently reported a 10-year follow-up of 54 allogeneic sibling marrow transplantations who received myeloablative conditioning for advanced CLL. The 10-year OS and DFS were 41% and 36% respectively, demonstrating durable leukemia control, although three patients died as a result of disease progression between 7 and 16 years post-transplantation. In this current series, all but one of the disease progressions occurred within 2 years of transplantation. The 5-year incidence of disease progression of 32% in the current study is higher than the usual 10% to 20% reported in matched sibling transplantation studies in CLL,10-17 but this also may be a consequence of possible different physician practices that tend to select patients with more advanced disease for URD transplantation.

Khouri et al37 reported 5-year follow-up in 28 patients with relapsed or refractory CLL who received myeloablative conditioning; seven patients received cells from an unrelated donor. In patients who were chemotherapy sensitive at the time of transplantation, the 5-year survival was 78% compared with 31% for those who were refractory to conventional chemotherapy. Our report also suggested a potential survival difference in patients with chemotherapy-refractory versus chemotherapy-sensitive disease.

Transplantation-related mortality of 30% to 40% has been observed in most original matched sibling studies using myeloablative conditioning.10 In this series TRM was 38%, indicating the possible overriding effects of TRM over leukemic causes of death and possibly negating some of the GVL effects. The survival results presented here should also be interpreted in light of poor long-term prognosis for similar patients when treated with conventional therapies.6,7 A recent comparison study demonstrated that in advanced CLL, conventional therapies are inferior in providing long-term disease control and have inferior survival compared with sibling donor alloHSCT at 5 year follow-up.38

Chronic GVHD represents a serious impediment to quality of life and survival. In a survey of patients after nonmyeloablative alloHSCT for CLL, chronic GVHD was significantly associated with CRs and with the probability of staying in remission.31 Additional studies are needed to better understand and separate harmful effects of chronic GVHD from beneficial anti-CLL mechanisms.

Whether using a peripheral-blood stem-cell (PBSC) source instead of bone marrow would result with improved survival after myeloablative URD transplantation for CLL is not known. Matched sibling phase III trials suggested that patients with advanced hematologic malignancy, such as CLL patients reported here, may benefit from the stem-cell source when compared with bone marrow, largely because of lower TRM.39,40 However, there were not enough CLL patients in those trials to make a statement about the role of PBSC for CLL. A randomized phase III trial of PBSC versus marrow from unrelated donors is currently ongoing and may help to answer some of these questions.

Nonmyeloablative stem-cell transplantation using PBSC and reduced-intensity conditioning is less toxic and has the advantage of permitting application of allogeneic transplantation in older patient populations where CLL is more prevalent.21,29,30 The German cooperative group conducted a prospective study and reported encouraging outcomes in CLL patients who received matched sibling donor or URD alloHSCT after nonmyeloablative conditioning. There was no nonrelapse mortality after matched sibling donor transplantation, but the nonrelapse mortality rate after URD transplantation was 28%.29 Results of the German study show the promise of nonmyeloablative strategies but also emphasize the challenges intrinsic to the URD transplantation procedure. Another recent comparison study showed no significant difference in nonrelapse mortality between HLA-matched related and unrelated transplant recipients (22% at 2 years) but URD transplantations had significantly lower relapse rates.30

In addition to HLA match, female donor to male or female recipients was the main potentially modifiable transplantation-related factor predicting better OS and FFS. In matched sibling transplantation studies, female donor to male recipient conveys lower risk of relapse and higher risk of acute and chronic GVHD; in contrast, the female donor to female recipient combination is associated with less GVHD.41 In URD transplantation the beneficial effect of female donor on survival was observed in hematologic malignancy patients receiving nonmyeloablative conditioning, possibly due to higher importance of the allograft antitumor effects in the setting with reduced intensity conditioning.42 It is likely that in the present study, the beneficial effects of female donor are due partly to the improved GVL effect in the context of a transplantation conditioning that is insufficiently effective.

This report demonstrates that URD alloHSCT can induce lasting remissions in patients with advanced CLL. In view of the strong allogeneic GVL effect, the chemotherapy-refractory nature of advanced CLL, and high TRM, the use of nonmyeloablative regimens should be explored for this disease. Given that graft failure and GVHD are major contributors to TRM, use of HLA-mismatched donors should be avoided. Late TRM observed in this study demonstrates the necessity of reporting long-term follow-up results to assess fully the outcome in allogeneic transplantation trials.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
Although all authors completed the disclosure declaration, the following author or immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other
Daniel Weisdorf National Marrow Donor Program

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) ≥ $100,000 (N/R) Not Required


   Acknowledgment
 
We thank NMDP patients, donors, transplantation and collection centers, physicians, staff, and data managers who made this work possible.


   NOTES
 
Supported by funding from the National Marrow Donor Program, the Health Resources and Services Administration grant No. 240-97-0036 and the Office of Naval Research grant No. N00014-93-0658 to the National Marrow Donor Program.

Presented in part as an oral presentation at the 36th Annual Meeting of the American Society of Oncology Meeting, May 20 to 23, 2000, New Orleans, LA (abstr 8).

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
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38. Bredeson CN, Sobocinski KA, Giralt S, et al: Salvage therapy for CLL: HLA-identical sibling transplantation vs. non-transplant therapies—An International Bone Marrow Transplant Registry and MD Anderson Cancer Center (MDACC) Study. Blood 98:482a, 2001 (abstr 2011)

39. Bensinger WI, Martin PJ, Storer B, et al: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344:175-181, 2001[Abstract/Free Full Text]

40. Couban S, Simpson DR, Barnett MJ, et al: A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 100:1525-1531, 2002[Abstract/Free Full Text]

41. Randolph SS, Gooley TA, Warren EH, et al: Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 103:347-352, 2004[Abstract/Free Full Text]

42. Maris MB, Niederwieser D, Sandmeier BM, et al: HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102:2021-2030, 2003[Abstract/Free Full Text]

Submitted November 5, 2004; accepted May 9, 2005.


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