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Journal of Clinical Oncology, Vol 19, Issue 4 (February), 2001: 1152-1159
© 2001 American Society for Clinical Oncology

CD6+ Donor Marrow T-Cell Depletion as the Sole Form of Graft-Versus-Host Disease Prophylaxis in Patients Undergoing Allogeneic Bone Marrow Transplant From Unrelated Donors

By Robert J. Soiffer, Edie Weller, Edwin P. Alyea, Peter Mauch, Iain L. Webb, David C. Fisher, Arnold S. Freedman, Robert L. Schlossman, John Gribben, Stephanie Lee, Kenneth C. Anderson, Karen Marcus, Richard M. Stone, Joseph H. Antin, Jerome Ritz

From the Departments of Adult Oncology, Radiation Oncology, and Biostatistics, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA.

Address reprint requests Robert J. Soiffer, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email: robert_soiffer@ dfci.harvard.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: The role of donor marrow T-cell depletion (TCD) in preventing graft-versus-host disease (GVHD) after transplantation of unrelated allogeneic marrow remains undefined. Because different TCD methodologies differ in the degree and specificity with which T cells are removed, it is likely that transplant outcomes would depend on which technique is used. Herein, we report results in the first 48 recipients of unrelated marrow using CD6+ TCD as the sole form of GVHD prophylaxis.

PATIENTS AND METHODS: Median age of patients was 46 years (20 to 58 years). Donors were matched at A/B HLA loci. Ablation consisted of cyclophosphamide and fractionated total-body irradiation (TBI; 14 Gy). To facilitate engraftment, patients also received 7.5 Gy (22 points) or 4.5 Gy (26 points) of total lymphoid irradiation (TLI) before admission. No additional immune suppressive prophylaxis was administered. Granulocyte colony-stimulating factor was administered daily from day +1 to engraftment.

RESULTS: All 48 patients demonstrated neutrophil engraftment. An absolute neutrophil count of 500 x 106/L was achieved at a median of 12 days (range, 9 to 23 days). There were no cases of late graft failure. The number of CD34+ cells infused/kg was associated with speed of platelet and neutrophil recovery. The dose of TLI did not influence engraftment. Grades 2-4 acute GVHD occurred in 42% of patients (95% confidence interval [CI], 0.28 to 0.57). Mortality at day 100 was 19%. There have been only five relapses. Estimated 2-year survival was 44% (95% CI, 0.28 to 0.59) for the entire group, 58% for patients less than 50 years of age. In multivariable analysis, age less than 50 years (P = .002), cytomegalovirus seronegative status (P = .04), and early disease status at bone marrow transplant (P = .05) were associated with superior survival.

CONCLUSION: CD6+ TCD does not impede engraftment of unrelated bone marrow after low-dose TLI, cyclophosphamide, and TBI. CD6+ TCD as the sole form of GVHD prophylaxis results in an incidence of GVHD that compares favorably with many adult studies of unrelated transplantation using unmanipulated marrow and immune-suppressive medications, especially in light of the median age of our patients (46 years). Although event-free survival in patients less than 50 years of age is very encouraging, older patients experience frequent transplantation-related complications despite TCD.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
DURING THE PAST decade, allogeneic bone marrow transplantation (BMT) from unrelated volunteers has emerged as a therapeutic option for patients in whom transplantation is indicated but for whom a suitably HLA-matched family member cannot be identified.1-6 Graft-versus-host disease (GVHD) is the major complication of BMT from unrelated donors and contributes to the high morbidity and mortality associated with this treatment approach.1-6 Intensifying the degree of immune suppression during and after transplantation of unrelated marrow has led to a decrease in the incidence of severe GVHD. However, nonrelapse mortality remains high, often as a consequence of the development of infectious complications in these severely immune compromised hosts.

Donor marrow T-cell depletion (TCD) has been demonstrated to decrease the incidence and severity of GVHD after transplantation of matched sibling grafts.6-12 It has been suggested that TCD might be particularly beneficial in patients receiving unrelated marrow given the high likelihood of developing severe GVHD in this setting. However, concern regarding the development of graft rejection, lymphoproliferative disease, and disease relapse (all of which have been associated with some TCD techniques) raises doubts about the potential success of this approach to GVHD prophylaxis in patients transplanted with unrelated marrow.1,13-16

Since TCD methods differ in the intensity and specificity with which they remove T cells, it is likely that transplant outcome would be dependent on which technique is employed. The antibody we have employed for TCD, T12, is an immunoglobulin M monoclonal antibody that recognizes CD6+ T cells but does not react with thymocytes, natural killer (NK) cells, B cells, monocytes, or hematopoietic precursors.17 Incubation with T12 and rabbit complement depletes approximately 1.5 to 2.0 logs of mature T cells from bone marrow.18 In patients receiving CD6+ depleted HLA-identical sibling marrow after cyclophosphamide (Cy)/total-body irradiation (TBI) conditioning, the incidence of grades 2-4 acute GVHD has been approximately 18% in the absence of immune suppressive medication for GVHD prophylaxis.12,19,20 Hematopoietic engraftment has occurred in 99% of patients. In contrast, in our initial experience transplanting CD6-depleted HLA-mismatched related marrow, however, the incidence of graft failure was high. In these patients, graft rejection was mediated by recipient-derived alloreactive T cells capable of destroying donor hematopoietic elements.21 Presumably, residual host T cells had been able to survive the ablative regimen and could proliferate in response to the strong allogeneic stimulus of HLA-nonidentical donor marrow.22 We then added total lymphoid irradiation (TLI) before conditioning to target these host cells in that patient population.23 Engraftment has occurred in 93% of such patients receiving one to two antigen-mismatched CD6-depleted related marrow after TLI/Cy/TBI.24 Our favorable experience with donor marrow CD6+ TCD in patients undergoing BMT from HLA-mismatched related donors led us to explore this approach to GVHD prophylaxis in patients undergoing unrelated BMT.

Herein, we report our initial results in the first 48 adult patients receiving CD6+ T-cell–depleted allogeneic BMT from HLA-matched unrelated donors after preparation with TLI/Cy/TBI. CD6+ TCD was the sole form of GVHD prophylaxis used in these patients. Thus, patients were not routinely exposed to the immune suppressive effects of medications such as cyclosporine, methotrexate, or corticosteroids. Patients were observed for hematopoietic engraftment, the development of acute and chronic GVHD, transplantation-related complications, and disease relapse.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
Between January 1996 and December 1999, 48 patients with hematologic malignancy underwent allogeneic BMT from an unrelated donor on two consecutive studies. Eligibility requirements included age >= 18 years and <= 60 years, Eastern Cooperative Oncology Group performance status 0-2, absence of active infection at the time of study entry, and absence of an available HLA-identical or one antigen–mismatched related donor. Treatment protocols were approved by the Human Subjects Protection Committee of Dana-Farber Cancer Institute (DFCI). Written informed consent was obtained in all cases.

Donor Population
Donors were identified through the National Marrow Donor Program (NMDP, Minneapolis, MN). All donors were required to match recipients at HLA-A and HLA-B loci through serologic means, although most were also matched at a molecular level. HLA-C matching was not a criterion for donor selection in this cohort of patients. Class II typing was performed with sequence-specific oligonucleotide probes. All donors and recipients were matched at HLA-DR loci by molecular analysis. Identity at HLA-DQ typing was not mandatory. HLA typing of donors and patients were confirmed at the histocompatibility labs at DFCI or Brigham and Women’s Hospital. Marrow was obtained at an NMDP or affiliated collection site and transported to our institution by arrangements made through the NMDP.

Preparative Regimen
All 48 patients registered to these studies received Cy 60 mg/kg intravenous x 2 (days -5, -4) on 2 consecutive days, followed by TBI as ablation. TBI was administered at a dose of 14 Gy in equal 2.0 Gy fractions given twice daily, on days -3, -2, and -1 and once on day 0. All patients were treated on a dedicated facility using opposing anterior-posterior/posterior-anterior fields at a dose rate of .10 Gy/min. TLI was administered before ablation to reduce the risk of rejection of the CD6+-depleted marrow. During the week before admission (days -10 to -6), the first 22 patients received 7.5 Gy TLI delivered through five daily 1.5 Gy fractions to complementary mantle (morning) and inverted-Y (afternoon) ports, as previously described.25 When it became evident that all patients receiving 7.5 Gy TLI engrafted, a subsequent group of 26 patients received 4.5 Gy TLI in 3 fractions. A back-up source of autologous stem cells, either marrow or peripheral-blood, was obtained from recipients when feasible before beginning conditioning.

Marrow Processing
Donor bone marrow was harvested on the last day of TBI administration and transported to the Cell Manipulation Laboratory at DFCI where it was processed. Marrow processing was initiated immediately on receipt of the marrow. Mononuclear cells were isolated from marrow by Ficoll-Hypaque centrifugal sedimentation. This product was then depleted of CD6+ T cells by complement mediated antibody lysis using anti-T12 monoclonal antibody, as previously described.12 Immunophenotypic analysis of the marrow product was performed before and after antibody-mediated purging. Monoclonal antibodies to CD3, CD4, CD6, CD8, CD20 (B cells), and CD56 (NK cells) were employed as previously described. After purging, marrow-derived mononuclear cells were suspended in 50-mL media and infused into the patient through an indwelling central venous catheter within 24 hours of harvesting in most cases. In one case, a marrow transported from abroad was infused 30 hours after harvest. No patients received prophylactic immune suppressive therapy to prevent development of GVHD, including corticosteroids, methotrexate, or cyclosporine.

Supportive Care
All patients were treated in HEPA-filtered rooms using standard reverse isolation procedures. Oral trimethoprim-sulfamethoxazole was administered to all patients from admission until the development of a fever requiring intravenous anti-bacterial antibiotics. Trimethoprim-sulfamethoxazole (or an alternative) was resumed after discharge to prevent Pneumocystis carinii infection. Acyclovir was administered for herpes simplex and herpes zoster prophylaxis. Patients who were themselves seropositive or had donors seropositive for cytomegalovirus received higher doses of acyclovir until day +120 after BMT. Screening for cytomegalovirus antigenemia was performed weekly when possible until day +120. Patients with evidence of CMV antigenemia in their blood received ganciclovir for 4 weeks, during which time acyclovir was discontinued. All patients received granulocyte colony-stimulating factor (G-CSF, 5 µg/kg) beginning at day +1 and continuing until the absolute neutrophil count exceeded 1.0 x 109 cells/L. All patients received prestorage leukoreduced RBCs and single-donor apheresis platelets leukoreduced at the time of collection. All blood components were irradiated to prevent transfusion-related GVHD. Patients were cared for at the inpatient unit at DFCI (until February 1997) or the DFCI Oncology Unit at Brigham and Women’s Hospital (March 1997 to August 1999).

Patient Evaluation
Data was evaluated as of June 15, 2000. Median follow-up among survivors was 18 months. Neutrophil engraftment was defined as the first of 2 consecutive days in which the absolute neutrophil count exceeded 0.5 x 109 cells/L. Platelet engraftment was defined as the first of 7 consecutive days in which the platelet count has been greater than 20 x 109 cells/L independent of transfusion. Acute GVHD was graded according to established criteria.26 Remission status was assessed by physical exams, radiographs, computed tomography, bone marrow evaluation, and cytogenetic/polymerase chain reaction studies when appropriate at approximately 6 and 12 months after BMT and then yearly thereafter or as clinically indicated.

Statistical Considerations
Event-free survival (EFS) was measured from the date of bone marrow infusion to the date of relapse, progression, or date of death in remission; patients were censored at the date on which they were last seen and reported without disease. Overall survival (OS) was measured from the date of bone marrow infusion to the date of death or date last known alive. Engraftment, EFS, and OS are calculated by the Kaplan-Meier method.27 EFS and OS were compared according to patient characteristics using the log-rank test.28 Fisher’s exact test and the Wilcoxon rank sum test were applied to correlate presence of engraftment and grades 2-4 acute GVHD with discrete and continuous clinical variables.29 Multivariate analyses included fitting a logistic regression model for the bivariate outcomes and the Cox proportional hazards regression model for the time to event outcomes.30


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient and Donor Characteristics
Forty-eight patients underwent CD6-depleted allogeneic transplantation from unrelated donors on two consecutive protocols between January 1996 and December 1999. Patient characteristics are listed in Table 1. There were 29 men and 19 women. Median age was 46 years (range, 20 to 58 years). Fourteen patients (29%) were over 50 years of age. The median age of donors was 35 years (range, 22 to 54 years). There were 30 males and 18 females. Ten male recipients had female donors. Seventeen patients (35%) were CMV seronegative and received CMV seronegative marrow. Diagnoses included acute myelogenous leukemia (n = 14), acute lymphoblastic leukemia (n = 13), chronic myelogenous leukemia (CML; n = 11), myelodysplasia (n = 6), and advanced non-Hodgkin’s lymphoma (n = 4). Twenty patients (42%) were transplanted for CML in stable phase or acute leukemia in first remission (adverse cytogenetics). These patients were considered to have early disease. Those patients with a history of relapsed leukemia, lymphoma, or myelodysplasia (n = 28, 58%) were considered to have advanced disease at the time of transplantation. All donors were HLA-A and HLA-B identical to recipients by serologic testing, and for the last 33 patients, molecular testing. In 11 patient/donor pairs, serologic testing detected differences at one HLA-C locus. All donors and patients were identical at HLA-DR and 46 of 48 at HLA-DQ after evaluation with sequence specific oligonucleotide probes.


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  		Table 1. Patient/Donor Characteristics
 
Marrow Treatment
After washing and isolation of mononuclear cells from donor marrow by Ficoll-Hypaque density centrifugation and CD6+ TCD, a median of 5.6 x 107 cells/kg (range, 2.5 to 13.4 x 107 cells/kg) were infused. After complement mediated antibody lysis, a median of 5.0 x 105 CD3+ cells/kg (95.7% reduction) and 5.5 x 105 CD6+ cells/kg (95.0% reduction) were infused into recipients ( Table 2). The median number of CD34+ cells infused from the marrow was 1.4 x 106 cells/kg (range, 0.7 to 3.9 CD34+ cells/kg). Marrow processing resulted in less than 1 log depletion of CD56+ NK cells and CD20+ B cells.


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  		Table 2. Marrow Depletion
 
Engraftment
All 48 patients engrafted neutrophils. The median day to achieve 500 x 106 neutrophils/L was day +12 (range, 9 to 23 days) ( Fig 1). No patients manifested late graft failure. Patients achieved a platelet count in excess of 20,000 x 106/L, independent of transfusion at a median of 24 days after marrow infusion (range, 13 to 61 days). Six patients died before full platelet engraftment. The median duration of inpatient hospitalization, including Cy/TBI ablation, was only 27 days (median), with a range of 19 to 68 days.



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  		Fig 1. Neutrophil and platelet engraftment. The proportion of patients achieving an absolute neutrophil count of 500 x 106 cells/L and a platelet count of 20,000 x 106 cells/L independent of transfusion is plotted against time after infusion of CD6+ T-cell–depleted marrow.

 
A multivariable analysis assessing the relationship between speed of engraftment and pretreatment variables was performed. Speed of neutrophil engraftment did not correlate with age, sex, disease, or CMV status. There was a correlation, however, between the number of CD34+ cells infused and neutrophil recovery (P = .02). Both the number of CD34+ (P = .02) and CD3+ (P = .004) cells infused were associated with the speed of platelet engraftment. In addition, male patients with female donors seemed to recover platelet counts more rapidly (P = .04).

GVHD
Estimated risk of acute grades 2-4 GVHD was 42% (95% confidence interval [CI, 0.28 to 0.57) in the absence of any prophylactic immune suppressive medication. The incidence of grades 3-4 GVHD was 16%. Fourteen patients have developed chronic GVHD (four extensive and 10 limited). Clinical variables including patient/donor age, patient/donor sex, CMV serostatus, disease status at transplantation, dose of TLI administered, HLA-C disparity, and the number of cellular subsets infused were examined to determine their influence on the development of GVHD. Only patient age seemed to be associated with grades 2-4 GVHD. Patients over age 50 had a GVHD incidence of 64% compared with 32% under age 50 (P = .06). The total number of mononuclear cells, CD34+, CD3+ T cells, or CD6+ T cells infused did not correlate with the development of GVHD in univariate analysis.

Patient Outcome
Mortality at 100 days was 19%. Kaplan-Meier estimated survival at 2 years was 44% (95% CI, 28% to 59%). Five patients have relapsed, three with acute lymphoblastic leukemia and two with acute myeloid leukemia, all within 6 months of transplantation. Estimated relapse-free survival was 43% at 2 years ( Fig 2). No patients with CML have relapsed, and all surviving CML patients are negative for bcr·abl by PCR. Younger patient age (P = .01) and CMV serostatus (P = .05) were associated with improved survival in univariate analysis ( Table 3). Multivariable analysis, accounting for all covariates, suggested that age (P = .002), stage of disease at BMT (P = .05), and CMV serostatus (P = .04) were associated with superior survival. The number of CD34+ or CD3+ cells did not seem to influence survival.



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  		Fig 2. Outcome after CD6+ TCD BMT from unrelated donors. Estimated (A) OS and (B) relapse-free survival after TCD BMT is displayed.

 

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  		Table 3. Correlation of Covariates With Outcome
 
Estimated survival for patients under age 50 at the time of BMT was 58% at 2 years, whereas survival has been disappointing in the 14 patients older than 50 years ( Fig 3). Among patients less than 50 years of age at the time of BMT, estimated 2-year EFS and OS was 76% for patients transplanted for acute leukemia in first remission or stable-phase CML compared with 42% for patients transplanted for more advanced disease ( Fig 4). Causes of death in the entire cohort were idiopathic pneumonitis (n = 6), leukemia relapse (n = 5), GVHD,4 Epstein-Barr virus–related lymphoproliferative disease (n = 3), hepatic veno-occlusive disease (n = 1), and infection caused by fungus (n = 2), bacteria (n = 1), CMV (n = 1), and atypical mycobacteria (n = 1).



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  		Fig 3. Influence of age on patient outcome. Kaplan-Meier estimated probability of OS for patients less than and older than 50 years at BMT.

 


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  		Fig 4. Influence of disease status on transplantation outcome. Kaplan-Meier estimated probability of survival in patients less than 50 years of age stratified by disease status. Patients transplanted for acute leukemia in first remission (adverse cytogenetics) and stable-phase CML are classified as having early leukemia and are compared with patients transplanted for advanced leukemia/lymphoma.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although TCD decreases the incidence and severity of GVHD after allogeneic BMT from HLA-matched sibling donors, it has not supplanted cyclosporine and methotrexate as the preferred method of GVHD prophylaxis for these patients in most transplant centers. The reasons for the reluctance to adopt TCD for GVHD prevention include reports of higher rates of graft failure, EBV lymphoproliferative disease, and disease relapse among patients receiving depleted marrow as well as the relative efficacy of combinations of immune suppressive medications in preventing GVHD. In clinical settings in which the innate risk of GVHD is particularly high, however, such as transplantion of matched unrelated or mismatched related marrow, TCD strategies may hold particular advantages compared with traditional forms of GVHD prophylaxis, especially if it can obviate the use of additional immune suppressive medications in the majority of patients.

Our results suggest that CD6+ TCD of unrelated donor marrow allows transplantation to be performed from unrelated donors without the routine use of prophylactic immune suppressive medications. Medications such as cyclosporine/FK506 and methotrexate can lead to increased renal, hepatic, and pulmonary damage, which may compromise survival. The incidence of GVHD in our series was equivalent to or lower than all series in which T-cell replete marrow was employed along with chemoprophylaxis for GVHD prevention.1-6 This is notable because the median age of our patient population was 46 years and no children were included in our study. The relatively low incidence of organ toxicity and severe GVHD combined with rapid engraftment aided, in part, by the use of G-CSF led to shorter overall hospital stays than previously reported. Such results, if confirmed, could lead to a substantial decrease in total transplantation costs.31

In our series, engraftment did not seem to be impeded by CD6 depletion. There were no cases of early or late graft failure despite the fact that 11 of 48 patients were mismatched serologically at an HLA-C locus.32 This may be attributable to the additional immunosuppression administered to patients in the form of TLI immediately before admission for transplantation. The total radiation dose delivered to lymphoid areas may be sufficient to disable, either directly or indirectly, allospecific host T cells capable of rejecting donor hematopoietic elements.23,33,34 Our prior experience with HLA-mismatched related marrow has suggested that such additional treatment is necessary to reliably achieve engraftment in that setting.21,22 However, it is not certain that TLI is required to attain engraftment in recipients of HLA-matched unrelated marrow. Indeed, TLI aggravates esophagitis and may potentiate other complications, particularly pneumonitis. When we reduced the dose of TLI from 7.5 Gy to 4.5 Gy, no compromise in engraftment was detected. The role of TLI in facilitating engraftment in this setting is not clear, and we are now exploring whether it is necessary at all in recipients of CD6+-depleted unrelated grafts. The relationship between the number of CD34+ cells infused and rapidity of engraftment suggests that, at least when T-cell–depleted transplantation is contemplated, attention should be paid to the number of stem cells obtained from donors.

There have been only five relapses thus far among the 48 patients transplanted. No patients with CML have relapsed. Several other series of TCD of unrelated donor marrow have also observed a relatively low incidence of posttransplant relapse.35,36 It has been suggested that increased intensity of GVHD/leukemia reactions mediated by allospecific effector cells in unrelated marrow compared with related marrow may compensate for the relative loss of graft-versus-leukemia activity associated with TCD. Indeed, the incidence of GVHD we observed with CD6 depletion of unrelated marrow is higher than what we have documented after transplantation of CD6-depleted related marrow.12,19,20 In turn, the relapse rate after CD6 depletion of unrelated marrow seems lower than that noted with transplantation of CD6-depleted related marrow. This reduction in recurrence rates may be attributable to higher rates of GVHD and presumed increased graft-versus-leukemia activity after unrelated BMT.

Judging the overall efficacy of TCD strategies for unrelated donor transplantation is difficult, in part because there are many different TCD techniques which have varying effects on the ultimate composition of infused marrow.7-11,37-39 The number of T cells remaining in the marrow product along with the distribution of other marrow cellular elements may influence the incidence of GVHD, quality of engraftment, and graft-versus-leukemia activity produced by the unrelated graft. Definitive conclusions comparing a specific TCD strategy with conventional chemoprophylaxis cannot be generalized to include all the disparate TCD techniques. For instance, CD6+ TCD with T12 antibody used in this report does not provide an exhaustive removal of T cells. The median number of CD3+ cells infused was 5.0 x 105 CD3+ cells/kg. As such, it is to be expected that results from our purging technique may differ from approaches in which the degree and specificity of TCD varies and additional prophylaxis for GVHD is administered. Although the addition of immune suppressive medication might be effective in reducing the incidence of GVHD further, whatever advantage might be gained from such a maneuver must be weighed against the influence such additional treatment might have on organ toxicity and infectious complications.

The outcomes we have observed in patients less than 50 years of age are extremely encouraging. Patients transplanted for acute leukemia in first remission (adverse cytogenetics) or CML seem to do extremely well with survival comparable with similar patients transplanted with related CD6-depleted marrow. Results in patients with more advanced disease were also encouraging. Unfortunately, initial results in the small number of patients older than 50 years of age were disappointing because of high transplant-related mortality despite TCD. A careful comparison of the outcome of unrelated transplantation and alternative therapies needs to be performed to guide treatment of such older individuals.

A recent retrospective analysis from the NMDP suggests that patients who received T-cell–depleted unrelated marrows fared as well as those receiving immune suppressive therapy for GVHD prophylaxis.40 If the encouraging results we have observed can be validated, a prospective randomized trial comparing CD6 depletion with chemoprophylaxis will be warranted to determine if CD6 depletion, which only removes a modest number of T cells, yet avoids routine immune suppressive prophylaxis, can improve on results obtained with unpurged marrow. Recent refinements in HLA typing as well as newer approaches toward chemoprophylaxis make historical comparisons to older published series of questionable value.41-43 Clearly, continued efforts to limit the intensity of GVHD must be pursued because the morbidity and mortality associated with unrelated BMT remains unacceptably high. All patients should be encouraged to participate in investigational protocols the aim of which is to make unrelated transplantation safer.


   ACKNOWLEDGMENTS
 
Supported by National Institutes of Health grant no. AI 29530.

We acknowledge the National Marrow Donor Program for identifying and delivering bone marrow for our patients. In addition, we express our appreciation to the nurses, house officers, social workers, pharmacists, and nutrition staff of Dana-Farber Cancer Institute and Brigham and Women’s Hospital for the outstanding care they delivered to our patients. We also thank Deborah Liney and Sarah Windawi for their outstanding work as unrelated donor search coordinators. Len Martyr provided invaluable assistance in data management. Lastly, we appreciate the dilligence and dedication of the technicians in the Cell Manipulation Laboratory for their willingness to process marrows at any time day or night.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Kernan NA, Bartsch G, Ash RC, et al: Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 328: 593-602, 1993[Abstract/Free Full Text]

2. Hansen JA, Gooley TA, Martin PJ, et al: Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338: 962-968, 1998[Abstract/Free Full Text]

3. Lamparelli T, Van Lint MT, Gualandi F, et al: Bone marrow transplantation for chronic myeloid leukemia (CML) from unrelated and sibling donors: single center experience. Bone Marrow Transplant 20: 1057-1062, 1997[Medline]

4. Geller RB, Devine SM, O’Toole K, et al: Allogeneic bone marrow transplantation with matched unrelated donors for patients with hematologic malignancies using a preparative regimen of high-dose cyclophosphamide and fractionated TBI. Bone Marrow Transplant 20: 219-225, 1997[Medline]

5. Sierra J, Radich J, Hansen JA, et al: Marrow recipients from unrelated donors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 90: 1410-1414, 1997[Abstract/Free Full Text]

6. Ringden O, Remberger M, Mattsson J, et al: Transplantation with unrelated bone marrow in leukaemic patients above 40 years of age. Bone Marrow Transplant 21: 43-49, 1998[Medline]

7. Wagner JE, Donnenberg AD, Noga SJ, et al: Lymphocyte depletion of donor bone marrow by counterflow centrifugal elutriation: Results of a phase I clinical trial. Blood 72: 1168-1176, 1988[Abstract/Free Full Text]

8. Hale G, Cobbold S, Waldmann H: T cell depletion with CAMPATH-1 in allogeneic bone marrow transplantation. Transplantation 45: 753-759, 1988[Medline]

9. Filipovich AH, Vallera D, McGlave P, et al: T cell depletion with anti-CD5 immunotoxin in histocompatible bone marrow transplantation: The correlation between residual CD5 negative T cells and subsequent graft-versus-host disease. Transplantation 50: 410-415, 1990[Medline]

10. Bunjes D, Hertenstein B, Weisneth M, et al: In vivo/ex vivo T cell depletion reduces the morbidity of allogeneic bone marrow transplantation in patients with acute leukaemias in first remission without increasing the risk of treatment failure: Comparison with cyclosporin/methotrexate. Bone Marrow Transplant 15: 563-568, 1995[Medline]

11. Papadopoulos EB, Carabasi MH, Castro-Malaspina H, et al: T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: Freedom from relapse in the absence of graft-versus-host disease. Blood 91: 1083-1090, 1998[Abstract/Free Full Text]

12. Soiffer RJ, Murray C, Mauch P, et al: Prevention of graft-versus-host-disease by selective depletion of CD6 positive T lymphocytes from donor bone marrow. J Clin Oncol 10: 1191-1200, 1992[Abstract]

13. Marmont AM, Horowitz MM, Gale RP, et al: T-cell depletion of HLA-identical transplants in leukemia. Blood 78: 2120-2130, 1991[Abstract/Free Full Text]

14. Goldman JM, Gale RP, Horowitz MM, et al: Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: Increased risk for relapse associated with T-cell depletion. Ann Intern Med 108: 806-814, 1988

15. Mitsuyasu RT, Champlin RE, Gale RP, et al: Treatment of donor bone marrow with monoclonal anti-T-cell antibody and complement for the prevention of graft-versus-host disease: A prospective, randomized, double-blind trial. Ann Intern Med 105: 20-26, 1986

16. Zutter MM, Martin PJ, Sale GE, et al: Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood 72: 520-529, 1988[Abstract/Free Full Text]

17. Reinherz EL, Geha R, Rappaport JM, et al: Reconstitution after transplantation with T-lymphocyte-depleted HLA haplotype-mismatched bone marrow for severe combined immunodeficiency. Proc Natl Acad Sci USA 79: 6047-6051, 1982[Abstract/Free Full Text]

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Submitted February 25, 2000; accepted October 25, 2000.


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