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© 1999 American Society for Clinical Oncology Comparative Outcomes of T-Cell–Depleted and Non–T-Cell–Depleted Allogeneic Bone Marrow Transplantation for Chronic Myelogenous Leukemia: Impact of Donor Lymphocyte InfusionFrom the Divisions of Hematologic Malignancies and Biostatistics, Dana-Farber Cancer Institute; and Division of Hematology-Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Address reprint requests to Dr. Robert J. Soiffer, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email robert_soiffer{at}dfci.harvard.edu
PURPOSE: Donor lymphocyte infusion (DLI) can restore complete remission in patients with chronic myelogenous leukemia (CML) who have relapsed after T-cell–depleted (TCD) allogeneic bone marrow transplantation (BMT). The existence of salvage treatment for patients with DLI after TCD allogeneic BMT prompted an evaluation of overall outcome after CD6+-TCD allogeneic BMT for patients treated during the time when DLI has been available. PATIENTS AND METHODS: We performed a retrospective analysis of outcomes of 46 patients who underwent TCD allogeneic BMT for stable-phase CML and compared these outcomes with those of 40 patients who underwent non-TCD allogeneic BMT. All subjects were patients at one of two neighboring institutions during a period when DLI was available. All patients received marrow from HLA-identical sibling donors, underwent similar myeloablative regimens, and had similar pretreatment characteristics. RESULTS: After BMT, the TCD group had a lower incidence of grade 2 to 4 acute (15% v 37%, P = .026) and chronic graft-versus-host disease (GVHD) (18% v 42%, P = .024) than did the non-TCD group. The 1-year treatment-related mortality rates for the TCD group and the non-TCD group were 13% and 29%, respectively (P = .07). The estimated 3-year probability of relapse (cytogenetic or hematologic) was higher for patients in the TCD group than for patients in the non-TCD group (62% v 24%, P = .0003). Twenty-three patients (20 in the TCD group and three in the non-TCD group) received and were assessable for response to DLI. After DLI, 17 of 20 patients in the TCD group and two of three patients in the non-TCD group achieved complete remission. Donor lymphocyte infusion induced GVHD in nine of 23 patients. Thirty (65%) of 46 patients in the TCD group and 27 (69%) of 39 assessable patients in the non-TCD group remained alive without evidence of disease. The estimated 3-year overall survival rates were similar for the TCD group and the non-TCD group (72% v 68%, respectively; P = .38). At last follow-up, there was no difference in the overall prevalence of GVHD or the proportion of patients requiring immunosuppressive agents between groups. CONCLUSION: These results suggest that the combination of T-cell depletion and post-BMT DLI is a viable treatment option for patients undergoing allogeneic BMT for CML and should be prospectively compared with traditional forms of GVHD prophylaxis.
T-CELL DEPLETION of donor marrow decreases the incidence of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT).1-6 However, this reduction in GVHD incidence has been associated with a loss of graft-versus-leukemia (GVL) activity, particularly in patients undergoing BMT for chronic myelogenous leukemia (CML).7,8 The resultant increase in relapse rates has led most centers to reject T-cell depletion as a GVHD prophylaxis for the majority of patients with CML. Strategies to restore GVL activity after T-cell–depleted (TCD) allogeneic BMT are required to make T-cell depletion a viable option for GVHD prophylaxis for these patients. Donor lymphocyte infusion (DLI) has emerged as a promising therapy for patients with CML who have relapsed after allogeneic BMT. Donor lymphocyte infusion can induce complete remission in more than 75% of patients with cytogenetic or hematologic relapse, without the need for additional chemotherapy.9-11 Although DLI has been associated with GVHD induction in many series, recent efforts to limit the incidence and severity of GVHD by engineering the number of infused T cells and their composition have met with apparent partial success without compromise of efficacy.12-15 The availability of DLI to patients who have undergone TCD allogeneic BMT may lead to a reassessment of the role of T-cell depletion as GVHD prophylaxis for CML patients. To assess the overall outcome of CML patients undergoing TCD allogeneic BMT in the era of DLI, we retrospectively evaluated the cases of 46 patients who underwent CD6+-TCD allogeneic BMT at Dana-Farber Cancer Institute (DFCI) and compared their outcomes with those of 40 patients who underwent non-TCD allogeneic BMT with traditional forms of pharmacologic prophylaxis for GVHD at neighboring Brigham and Women's Hospital (BWH) during the same period. All patients included in this analysis received marrow from an HLA-identical sibling donor and underwent similar myeloablative regimens. Incidence of acute and chronic GVHD, transplant-related mortality, relapse rates, and disease-free survival (DFS) after BMT alone were assessed. In addition, the prevalence of GVHD, use of immunosuppressive agents, percentage of patients remaining disease-free, and overall survival were examined after salvage therapy with DLI. Our preliminary results confirm that DLI can restore the GVL activity lost after TCD allogeneic BMT and suggest that the combination of T-cell depletion and post-BMT DLI should be formally compared with pharmacologic methods of GVHD prophylaxis in patients undergoing BMT for CML.
Patient Characteristics Included in this retrospective study were 86 patients who underwent HLA-identical sibling donor allogeneic BMT between January 1990 and October 1996 at two Harvard tertiary care institutions (DFCI and BWH) for the treatment of stable-phase CML. All patients underwent comparable conditioning regimens of cyclophosphamide therapy and total-body irradiation (TBI). Patients treated at DFCI received CD6+-TCD marrow (n = 46), whereas patients treated at BWH received unmanipulated marrow (non-TCD group; n = 40). Patients were treated in accordance with protocols approved by the Human Protection Committees at each institution. These groups of patients represent all consecutive patients with stable-phase CML who presented during this period and were treated with similar ablative regimens. Patients treated with higher doses of TBI or busulfan as part of conditioning were not included in this analysis. All patients received marrow from HLA-A, -B, or -DR identical siblings. Patients receiving marrow from matched unrelated donors or mismatched donors (related or unrelated) were not included in our analysis.
Clinical characteristics of the 86 patients are listed in Table 1. The overall median age at the time of BMT was 41 years (range, 24 to 59), 55% of patients were male, and serologies in 48% of patients were positive for cytomegalovirus. The median time from diagnosis of CML to BMT was 1 year (range, 1 to 9 years). Eleven patients in the TCD group and four patients in the non-TCD group received interferon alfa (IFN
BMT Regimen and GVHD Prophylaxis Donor marrow was collected using standard techniques. Patients at BWH received non-TCD marrow and GVHD prophylaxis with either methotrexate (MTX) and cyclosporine (CsA) (n = 38) or MTX and FK-506 (n = 2). At DFCI, donor marrow was selectively T-cell depleted in vitro with anti-T12 (CD6) monoclonal antibody and rabbit complement, as previously described.16 Patients in the TCD group received no immunosuppressive therapy for GVHD prophylaxis. Clinical grading of acute and chronic GVHD was based on previously published criteria.17 Patients were considered to have hematologic relapse if there was evidence of hypercellularity on bone marrow histologic analysis, along with the presence of the Philadelphia chromosome on karyotypic analysis. Patients were considered to have cytogenetic relapse when they had normocellular marrow and white blood cell counts in the normal range and the Philadelphia chromosome was present on karyotypic analysis. Rearrangement of the bcr-abl gene as detected by polymerase chain reaction was not used as a criterion to define relapse after BMT.
DLI
Statistical Analysis
Outcome After BMT Median length of follow-up after BMT for patients in the TCD group was 44 months (range, 5 to 78 months) and for patients in the non-TCD group was 32 months (range, 3 to 62 months). Ninety-seven percent of all patients were followed up for more than 1 year after BMT. Patients in the TCD group had a lower incidence of grade 2 to 4 acute GVHD than did patients in the non-TCD group (15% v 37%, P = .026, Fig 1). Similarly, patients in the TCD group had a lower incidence of chronic GVHD, compared with patients in the non-TCD group (18% v 42%, P = .024). There was one early death (within 100 days of BMT) in the TCD group (2%), secondary to graft failure. There were six early deaths in the non-TCD group (15%), five due to pulmonary toxicity and one to acute GVHD and progressive multiorgan failure. The 1-year treatment-related mortality rates for patients in the TCD group and those in the non-TCD group were 13% and 29%, respectively (P = .07).
As expected, the risk of relapse (hematologic or cytogenetic) after BMT was notably higher in the TCD group (Fig 2). Twenty-six patients relapsed after TCD allogeneic BMT (hematologic relapse in 14 and cytogenetic relapse in 12), whereas four relapsed after non-TCD allogeneic BMT (hematologic relapse in one and cytogenetic relapse in three). The estimated 3-year probability of relapse was 62% in the TCD group and 24% in the non-TCD group (P = .0003). The Kaplan-Meier DFS after BMT seemed lower for patients in the TCD group than for patients in the non-TCD group, although this difference was not statistically significant (Fig 3).
Outcome After DLI
After DLI, 17 of 20 patients in the TCD group and two of three assessable patients in the non-TCD group achieved complete hematologic and cytogenetic response. All responders to DLI remained in remission, with a median length of follow-up after DLI of 15 months (range, 3 to 34 months) for patients in the TCD group and 26 months (range, 11 to 41 months) for patients in the non-TCD group. Two patients who failed to achieve remission after DLI (one from each group) underwent a second allogeneic BMT, but only one (from the non-TCD group) remained alive and in remission at the time of analysis. After DLI, nine of 20 patients in the TCD group developed GVHD requiring treatment with immunosuppressive agents, whereas none of the patients in the non-TCD group developed GVHD. Of the nine patients who developed GVHD after DLI, one developed gastrointestinal symptoms suggesting acute GVHD, whereas eight developed cutaneous and hepatic involvement clinically compatible with chronic disease. There was one death related to GVHD after DLI. The percentage of patients developing GVHD (acute and/or chronic) at any time during the treatment course (either after BMT or after DLI) was lower for the TCD group than for the non-TCD group (33% v 70%, P = .002). However, at long-term follow-up there was no difference in the prevalence of GVHD between the TCD and non-TCD groups (27% v 25%, P = .99; Fig 4). In addition, there was no difference in the proportion of patients requiring immunosuppressive agents at last follow-up between the TCD and non-TCD groups (15% v 25%, P = .35).
At final analysis, 30 (65%) of 46 patients in the TCD group and 27 (69%) of 39 assessable patients in the non-TCD group remained alive without evidence of disease (Fig 4). To assess the effect of DLI on DFS, we determined the current DFS, based on disease status at last follow-up (Fig 5).20 In this analysis, we assumed that patients who reentered and remained in remission after DLI were disease-free. There was no difference in estimated 3-year current DFS rates between the TCD and non-TCD groups (65% v 67%, P = .72). Similarly, there was no difference in overall survival between the two groups (Fig 6). The estimated 3-year overall survival rate was 72% for patients in the TCD group, compared with 68% for patients in the non-TCD group (P = .38).
Considerable laboratory and clinical evidence has established that donor-derived immune effector cells are critical to the success of allogeneic BMT for CML. Although the precise roles of the various cellular components have not been entirely elucidated, it is clear that donor T lymphocytes are crucial for establishing hematopoietic engraftment, providing immunity against virally transformed cells (eg, Epstein-Barr virus cells) and, particularly in CML, destroying residual occult leukemia cells not eliminated by the ablative regimen.21,22 However, when donor T cells are infused into recipients as part of the marrow inocula, GVHD and its attendant complications often result, despite pharmacologic prophylaxis with immunosuppressive agents such as CsA and MTX. T-cell depletion of donor marrow to reduce the incidence of GVHD—although promising when used for diseases less dependent on GVL activity, such as acute leukemias and lymphomas–has in general been associated with a dramatic increase in disease recurrence in patients who undergo BMT for CML.7,8 The pivotal question in transplantation for CML is not whether T cells are important in curing this disease (they are) but rather how and when those T cells should be delivered to the recipient. Performing a moderate rather than exhaustive depletion of T cells might limit the incidence and severity of GVHD without compromising overall antileukemic activity. Strategies that limit the number of T cells eliminated by marrow-purging techniques have improved rates of engraftment and decreased the incidence of Epstein-Barr virus–related lymphoproliferative disease after BMT but have thus far not had a dramatic impact on relapse of CML.5,6 Laboratory investigators have tried to determine the threshold number of donor marrow T cells below which GVHD will not occur without compromising antileukemic activity. Although some data are available for certain strain combinations in murine studies, findings in humans are less clear.23-26 The determining factor regulating the development of GVHD and antitumor activity may be not the precise number of T cells but rather the cytotoxic and helper T-cell precursor frequencies in donor-recipient combinations.27,28 Selective removal of specific T-cell subsets from donor marrow has been tried in an attempt to eliminate cells that predominantly mediate GVHD without destroying all cell subsets with GVL activity. Although a strategy involving donor marrow CD8+-cell depletion was successful in limiting GVHD without increasing rates of CML relapse, overall outcome was not improved, because of a high incidence of nonrelapse mortality.29 For T-cell depletion strategies to offer any advantage over traditional pharmacologic prophylaxis, they must decrease not only GVHD incidence but fatal transplant-related complications as well. The method of T-cell depletion used in this study (CD6+-cell depletion) has been associated with a comparatively low transplant-related mortality, due in part to a reduction in GVHD but also due to elimination of the need for routine immunosuppressive medications such as MTX and CsA that contribute to organ toxicity and infection after BMT.5,6,30,31 The present study confirms results from previously published series, namely that TCD allogeneic BMT for CML can result in a lower incidence of acute morbidity and mortality compared with non-TCD allogeneic BMT, but this advantage is offset by a higher rate of relapse. However, our study demonstrates that a large fraction of patients who relapse after TCD allogeneic BMT can be successfully treated with administration of donor lymphocytes in the post-BMT period. In this retrospective study, overall results of TCD allogeneic BMT plus DLI at a later date seem comparable to those of T cell–replete (unmanipulated) transplantation. Although further follow-up is needed to ascertain the endurance of these remissions, the results are nonetheless provocative and raise the question of whether a two-step approach to allogeneic BMT should be considered for CML.32 There is considerable evidence to suggest that cytokines released from tissues in the recipient immediately after myeloablative chemotherapy stimulate alloreactive donor T cells to set up a cytokine cascade, leading to manifestations of acute GVHD.33-35 Delivering just enough T cells to promote engraftment but not enough to cause GVHD at the time of marrow infusion allows the establishment of mixed donor-recipient hematopoietic chimerism. Donor T cells can then be added at a later date, before relapse, long after ablation (to avoid toxicity), when cytokine stimulation will not be a factor.36 It would be hoped that these T cells would have antileukemic efficacy without producing GVHD severe enough to result in fatal complications. Both murine and human studies have addressed the issue of timing of DLI after allogeneic BMT. When infusion of donor-derived T cells was delayed by 21 days after TCD allogeneic BMT in mice, antileukemic activity was maintained in the absence of GVHD.37,38 In humans, when donor buffy coat was administered at the time of unmanipulated marrow infusion, there was a marked increase in incidence of GVHD and mortality in patients with advanced leukemia.39 However, studies in which donor lymphocytes have been infused at different times after TCD allogeneic BMT found that the risk of acute GVHD decreases as the time from BMT increases.40 The dose as well as the timing of T-cell infusion has been demonstrated to be a crucial factor in the development of GVHD after DLI.12,14,41,42 The methods used to deliver alloreactive T cells to patients with CML need to be explored in future prospective studies. If the responses to DLI are long-lasting, it may be possible to devise a safer transplantation strategy using T-cell depletion to establish hematopoietic engraftment and tolerance to the donor first, which will allow for the later infusion of alloreactive donor T cells with antileukemic efficacy (either at a predetermined time or at the time of relapse).40,43,44 Early detection of persistent disease by polymerase chain reaction analysis, or demonstration of donor-recipient chimerism by restriction-fragment-length-polymorphism analysis, may allow for the administration of lower doses of DLI, which may minimize toxicity and result in improved efficacy.43,45,46 However, as these approaches are further developed, there may also be new agents (such as interleukin-1 receptor antagonist and interleukin 4) that through their effects on cytokine release after ablation may reduce some of the manifestations of GVHD after T cell–replete BMT without compromising GVL activity.47,48 Further clinical studies should prospectively compare T-cell depletion and post-BMT DLI with traditional forms of GVHD prophylaxis to gain an accurate understanding of the advantages and disadvantages of both approaches in terms of treatment-related mortality, leukemia-free survival, and long-term disability due to GVHD and its complications.
Supported by National Institutes of Health grant no. AI29530. R.J.S. is a recipient of the Baruj Benacerraf Clinical Investigator Award at Dana-Farber Cancer Institute.
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McCarthy PL, Abhyankar S, Neben S, et al: Inhibition of interleukin-1 by an interleukin-1 receptor antagonist prevents graft-versus-host disease. Blood 78:1915-1918, 1991 Submitted July 2, 1998; accepted October 27, 1998. This article has been cited by other articles:
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TOP
ABSTRACT
INTRODUCTION
) at some point before BMT. There was no difference in age, sex, cytomegalovirus status, timing of BMT, and prior IFN
