Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT.

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P=0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with <15% BM blasts survived long term as compared with none with more advanced disease (P=0.03). HaploSCT with this fludarabine, melphalan and thiotepa and ATG RIC is an effective, well-tolerated conditioning regimen for patients with AML/MDS with low disease burden at the time of transplant and allowed a high rate of engraftment in patients without DSA. Patients with overt relapse fared poorly and require novel treatment strategies.

Phase II study of unrelated cord blood transplantation for adults with high-risk hematologic malignancies.

Cell dose is a critical determinant of outcomes in unrelated cord blood (CB) transplantation. We investigated a strategy in which CB units should contain at least 2 x 10(7) total nucleated cells/kg of recipient weight, otherwise a second unit had to be added. We report the results of a study that was prematurely closed owing to toxicity. Patients with advanced hematologic malignancies without a human leukocyte antigen-matched sibling or unrelated donor were eligible. Conditioning regimen consisted of fludarabine and 12 Gy of total body irradiation (n=11), or melphalan (n=4), with antithymocyte globulin. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Fifteen patients with acute leukemia (n=9), chronic myelogenous leukemia (n=2), multiple myeloma (n=2) and lymphoma (n=2) were treated; 60% had relapsed disease at transplantation. Three patients received double CB transplants. The 100-day and 1-year treatment-related mortality rates were 40 and 53%, respectively. Median time to neutrophil and platelet engraftment was 22 days (n=10) and 37 days (n=10), respectively. One patient had secondary graft failure and five patients failed to engraft. Two patients are alive and disease free; 4-year actuarial survival is 33 versus 0% for patients transplanted in remission versus in relapse. We concluded that disease status was the main determinant of treatment failure in this study.

Umbilical cord blood-derived cells for tissue repair.

Hematopoietic tissue-derived cells, including stem cells, have been shown to generate solid organ tissue-specific cells. Besides bone marrow and peripheral blood, umbilical cord blood (UCB) has the advantage of being an easily accessible stem cell source provided as a banked cell product. Using the xenogeneic human into NOD/SCID mouse stem cell transplant model preliminary data suggest UCB-derived tissue-specific cells generated in liver, pancreas, CNS and endothelium. In a clinical sex-mismatched UCB transplant setting Y-positive, UCB-derived gastrointestinal epithelial cells and CNS-specific cells have been identified in female patients. The potential therapeutic use of UCB cells for tissue repair is, however, limited by a low total stem cell number available and by HLA-disparity.

Circulating stem cells and tissue repair.

Stem cells are defined as cells that have clonogenic, self-renewing capacities and the capability to differentiate into multiple cell lineages. Whereas embryonic stem cells are derived from mammalian embryos in the blastocyst stage and can generate terminally differentiated cells of all 3 embryonic germ layers, adult human stem cells are capable of maintaining, generating, and replacing terminally differentiated cells within their own specific tissue as a consequence of physiologic cell turnover or tissue injury. The traditional idea of organ-restricted stem-cell differentiation is now being challenged by the suggestion that adult stem cells retain developmental plasticity. Preclinical and clinical studies described in this review provide evidence that within the blood circulate not only progenitor cells that differentiate into hematopoietic cells, but also stem/progenitor cells which can participate in the homeostasis, repair and replacement of solid organ tissues. In addition to the occurrence of cell fusion, there are 4 suggested mechanisms of adult stem cell differentiation into solid organ cells. Preclinical data support these models particularly that of transdifferentiation as the most likely model, allowing stem/progenitor cells to differentiate across lineage, tissue, and germ layer boundaries. There is increasing evidence that we can manipulate in vivo circulating adult stem cells to repair or regenerate solid organ tissue, which offers potential clinical benefit in the treatment of many hereditary and acquired diseases.

A mathematical model of haemopoiesis as exemplified by CD34 cell mobilization into the peripheral blood.

A mathematical model for the kinetics of haemopoietic cells, including CD34+cells, is proposed. This minimal model reflects the known kinetics of haemopoietic progenitor cells, including peripheral blood CD34+ cells, white blood cells and platelets, in the presence of granulocyte colony-stimulating factor. Reproducing known perturbations within this system, subjected to granulocyte colony-stimulating factor treatment and apheresis of peripheral blood progenitor cells (CD34+ cells) in healthy individuals allows validation of the model. Predictions are made with this model for reducing the length of time with neutropenia after high-dose chemotherapy. Results based on this model indicate that myelosuppressive treatment together with infusion of CD34+ peripheral blood progenitor cells favours a faster recovery of the haemopoietic system than with granulocyte colony-stimulating factor alone. Additionally, it predicts that infusion of white blood cells and platelets can relieve the symptoms of neutropenia and thrombocytopenia, respectively, without drastically hindering the haemopoietic recovery period after high dose chemotherapy.

Adult stem cells and tissue repair.

Recently, adult stem cells originating from bone marrow or peripheral blood have been suggested to contribute to repair and genesis of cells specific for liver, cardiac and skeletal muscle, gut, and brain tissue. The mechanism involved has been termed transdifferentiation, although other explanations including cell fusion have been postulated. Using adult stem cells to generate or repair solid organ tissue obviates the immunologic, ethical, and teratogenic issues that accompany embryonic stem cells.

Extracorporeal photopheresis therapy in the management of steroid-refractory or steroid-dependent cutaneous chronic graft-versus-host disease after allogeneic stem cell transplantation: feasibility and results.

We conducted a retrospective analysis of all allogeneic stem cell transplantation (ASCT) patients started on extracorporeal photopheresis (ECP) for the management of steroid-dependent (SD) or steroid-refractory (SR) cutaneous chronic graft-versus-host disease (cGVHD) following ASCT during a 36-month period (9/98-8/01). Only SD or SR patients who were treated by ECP after day 100 and who received at least 4 weeks of ECP were considered evaluable for this analysis. Out of 64 ASCT patients reviewed, 32 patients met the inclusion criteria. All 32 patients had been previously treated with systemic corticosteroids with 11 (34%) being SR and 21 (66%) SD. Cutaneous cGVHD was extensive in 28 patients (88%) and was accompanied by visceral (hepatic, gastrointestinal) cGVHD in 23 patients (72%). The 32 evaluated patients had received a median of three prior therapies before ECP, most commonly systemic corticosteroids, tacrolimus, and mycophenolate mofetil. Patients received a median of 36 ECP sessions (range 12-98) over a median of 5.3 months (range 1-28), with a median of six sessions per month. The complete response (CR) rate was 22% (n=7) and the partial response rate was 34% (n=11). In all, 28 patients were on systemic corticosteroid therapy at ECP initiation and 18 patients achieved 50% dose reduction while on ECP, yielding a 64% steroid-sparing response rate. Of seven CRs, five are ongoing. A total of 11 (34%) patients have died after ECP, with all cases due to visceral cGVHD or cGVHD-related infectious complications. All 21 surviving patients remain on at least some immunosuppressive cGVHD therapy (including ECP in eight). Overall, ECP displays a substantial response rate and, in particular, steroid-sparing activity in SR/SD extensive cutaneous cGVHD. However, most patients continue to require at least some chronic therapy and cGVHD-related morbidity and mortality remain high.

Long-term follow-up of normal peripheral blood progenitor cell donors treated with filgrastim: no evidence of increased risk of leukemia development.

Data on the long-term safety of filgrastim administration in peripheral blood progenitor cell (PBPC) donors are scarce. The main theoretical risk is believed to be the possible development of leukemia. We conducted a survey of filgrastim-treated related donors to determine the incidence of leukemia after PBPC donation. Of the 343 PBPC donors eligible for inclusion in the survey, 281 (82%) were interviewed by telephone between December 1998 and February 2000. The mean age at donation was 44 years. The median time elapsed after PBPC donation was 39 months, and in 278 (99%) of the interviewed donors it was at least 1 year. At the time of the interview none of the donors had been diagnosed with acute or chronic leukemia. Although the sample size is small and the follow-up duration is limited, these data suggest that exposure to filgrastim is not associated with any notable risk of leukemia development in PBPC donors.

Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma.

The purpose of the study was to determine the feasibility and efficacy of a reduced intensity conditioning regimen of fludarabine and melphalan for allogeneic transplantation in patients with multiple myeloma. From August 1996 to December 2000, 22 patients received a reduced intensity conditioning regimen with fludarabine and melphalan. Median age was 51 years (range, 45-64), median time from initial therapy to transplant was 36 months (range, 3-135 months). Disease phase prior to transplant was primary refractory in two patients, refractory relapse in 11 patients, sensitive relapse in eight patients and initial remission consolidation in one patient. The median number of prior therapies was five (range, 1-7), and median beta 2 microglobulin prior to transplant was 3.0 mg/l (range, 1.0-7.3). All patients received unmanipulated grafts from either HLA matched sibling donors (n = 13) or matched unrelated donors (n = 9). Eighteen patients received fludarabine 30 mg/m(2) for 4 days with melphalan 140 mg/m(2) as a single dose and four patients received fludarabine 25 mg/m(2) for 5 days with melphalan 90 mg/m(2) daily for 2 days. All 21 patients evaluable for engraftment achieved a neutrophil count of >0.5 x 10(9)/l after a median of 12 days (range, 9-24), 18 patients achieved platelet transfusion independence after a median of 14 days (range, 8-47). All engrafting patients had 100% donor cell engraftment. Seven patients achieved a complete remission. Six patients are currently alive with a median follow-up of 15 months (range, 10-47 months). The actuarial survival and progression-free survival is 30 +/- 11% and 19 +/- 9% at 2 years. Non-relapse mortality at 100 days was 19 +/- 10% and 40 +/- 10% at 1 year. Fludarabine/melphalan combinations are feasible and allow consistent engraftment of allogeneic progenitor cells from both related and unrelated donors in patients with multiple myeloma and should be explored in patients with less advanced disease.

Long-term outcome in acute myelogenous leukemia autografted with mafosfamide-purged marrow in a single institution: adverse events and incidence of secondary myelodysplasia.

We have analyzed the long-term outcome and toxicities in 98 patients with high-risk acute myelogenous leukemia (AML) who were treated with autologous bone marrow transplantation (ABMT) and monitored for a median observation period of 11.67 years. Between 1983 and 1994, 98 patients in our institution in first or second and higher complete remission (CR) underwent total body irradiation and high-dose cyclophosphamide prior to ABMT purged with mafosfamide. Twenty-seven out of the 90 evaluable patients (30%) were alive and in continuous CR for a median of 11.67 years (range, 6.39-15.53) after ABMT and could be considered as 'cured'. Among the 90 patients, 39 were transplanted at first CR and had a significantly higher survival rate than those transplanted at > or = 2 CR. Younger patients (<40 years) had a better prognosis and patients with FAB M1-4 had a more favorable outcome than those with M5. Long-term complications included four patients with cardiac complications, two with renal insufficiency. Five developed HCV infections, four myelodysplastic syndrome. The incidence of cataract among the long-term survivors was 44.4%. Therefore, a significant number of adult patients with AML in first CR derived long-term benefit from ABMT, despite the risks of a few long-term complications and of MDS (4.4%).

Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin's lymphoma.

BACKGROUND: Several recent reports have suggested that patients with non-Hodgkin's lymphomas (NHL) who undergo autologous stem cell transplantation (ASCT) are at increased risk of developing therapy-related myelodysplastic syndrome (tMDS) and acute myelogenous leukemia (tAML). PATIENTS AND METHODS: We analyzed 493 patients with NHL who underwent ASCT at The University of Texas M.D. Anderson Cancer Center between January 1990 and August 1999. RESULTS: With a median follow-up time of 21 months after HDT, 22 patients developed persistent cytopenia in at least one cell line with morphologic or cytogenetic evidence of tMDS or tAML. Univariate analysis identified prior fludarabine therapy, bone marrow involvement with lymphoma, and total body irradiation (TBI) as significant risk factors for the development of tMDS/tAML (P <0.05). Multiple logistic regression analysis showed that TBI was independently associated with an increased risk of developing tMDS/tAML (P <0.01). Further analysis of the patients who received TBI revealed that patients receiving TBI in combination with cyclophosphamide and etoposide were more likely to develop tMDS/tAML than those who received TBI with cyclophosphamide or thiotepa (P <0.01). The median survival of patients developing tMDS/tAML was 7.5 months (range 0-32 months). CONCLUSIONS: TBI, especially when used in combination with cyclophosphamide and etoposide as the pretransplant conditioning regimen, is a significant risk factor for the development of tMDS/tAML.

Donor lymphocyte apheresis for adoptive immunotherapy compared with blood stem cell apheresis.

Donor lymphocyte transfusion has gained considerable interest as adoptive cellular immunotherapy for prevention or treatment of relapse after allogeneic stem cell transplantation. This study was designed to compare the yield of CD3(+), CD3(+)4(+), CD3(+)8(+), CD19(+), CD3(-)56(+)16(+), and CD34(+) cells contained in apheresis products from 61 consecutive non-cytokine treated, human leukocyte antigen (HLA)-matched donors for lymphocyte collection with the corresponding apheresis-derived cell yield from 112 consecutive, HLA-matched donors for blood stem cell collection who received recombinant human granulocyte colony stimulating factor (rhG-CSF, filgrastim) 6 microg/kg every 12 hours until cell collection was completed. Apheresis was started on day 4 or 5 of rhG-CSF treatment. The yield of lymphoid subsets was significantly different in the two sample groups, rhG-CSF treated product yields exceeding untreated product yields by a median of 2.1-fold (range: 1.3-2.6). However, the CD34(+) cell yield in rhG-CSF-treated apheresis products exceeded untreated products by 26-fold. A single untreated apheresis procedure was usually sufficient to collect a target dose of 1 x 10(8)/kg CD3(+) cells. Untreated apheresis products contained a median of 0.2 x 10(6)/kg CD34(+) cells. A potential engraftment dose of > or =0.5 x 10(6) CD34(+) cells per kg of recipient body weight was contained in 16% of 57 untreated apheresis products. One single apheresis performed in a normal, untreated donor provides a sufficient amount of CD3(+) cells for adoptive immunotherapy. Compared with that of an rhG-CSF stimulated apheresis product, the CD34(+) cell count is usually, but not always, below the engraftment dose range. RhG-CSF treatment has little effect on the yield of lymphoid subsets collected by apheresis but is highly selective of the release of CD34(+) cells. This report provides baseline data for studies that will show whether other cytokines such as granulocyte macrophage colony stimulating factor (GM-CSF) and/or Flt-3 Ligand can immunomodulate allotransfusates in vivo to improve the graft-vs.-leukemia (GVL) effect after allogeneic stem cell transplantation, while lowering the incidence and severity of graft-vs.-host disease (GVHD).

Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality.

This study investigated the use of a nonablative conditioning regimen to decrease toxicity and achieve engraftment of an allogeneic blood stem cell transplant, allowing a graft-versus-malignancy effect to occur. All patients had follicular or small cell lymphocytic lymphoma after relapse from a prior response to conventional chemotherapy. Patients received a preparative regimen of fludarabine (25 mg/m(2) given daily for 5 days or 30 mg/m(2) daily for 3 days) and intravenous cyclophosphamide (1 g/m(2) given daily for 2 days or 750 mg/m(2) daily for 3 days). Nine patients received rituximab in addition to the chemotherapy. Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Twenty patients were studied; their median age was 51 years. Twelve were in complete remission (CR) at transplantation. All patients achieved engraftment of donor cells. The median number of days with severe neutropenia was 6. Only 2 patients required more than one platelet transfusion. The cumulative incidence of acute grade II to IV GVHD was 20%. Only one patient developed acute GVHD of greater than grade II. All patients achieved CR. None have had a relapse of disease, with a median follow-up period of 21 months. The actuarial probability of being alive and in remission at 2 years was 84% (95% confidence interval, 57%-94%). Nonablative chemotherapy with fludarabine/cyclophosphamide followed by allogeneic stem cell transplantation is a promising therapy for indolent lymphoma with minimal toxicity and myelosuppression. Further studies are warranted to compare nonablative allogeneic hematopoietic transplantation with alternative treatment strategies.

Leukapheresis reduces early mortality in patients with acute myeloid leukemia with high white cell counts but does not improve long- term survival.

PURPOSE: Current published data on therapeutic leukapheresis in hyperleucocytic AML does not define the impact on survival from this procedure. Between 1992 and 1999 we saw 146 patients with newly-diagnosed AML (APL excluded) and an initial WBC count > 50 x 10(9)/L of whom 71 underwent leukapheresis at the discretion of their treating doctors. We compared outcome (early mortality, CR, and overall survival) rates in the patients who were and were not pheresed. After accounting for covariates relevant to these outcomes, including age, performance status, and cytogenetics, there was evidence (p = .006) that pheresis reduced 2-week mortality rate and a suggestion (p = .06) that this resulted in a higher CR rate. However there was no evidence that pheresis lengthened longer-term or overall survival; if anything the suggestion was the converse (p = .06). These data may reflect the fact that the patients chosen to have pheresis were prognostically unfavorable as defined by variables that were not captured in our data set, since the alternative explanation i.e. that pheresis per se shortens overall survival seems less likely. Whether the above justifies the use of pheresis in the absence of evidence from a randomized trial is doubtful, but it seems likely that any long-term benefit to be derived from this procedure must await further advances in anti-leukemia therapy.

Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter?

Hematopoietic stem cells from 4 different sources have been or are being used for the reconstitution of lymphohematopoietic function after myeloablative, near-myeloablative, or nonmyeloablative treatment. Bone marrow (BM)-derived stem cells, introduced by E. D. Thomas in 1963, are considered the classical stem cell source. Fetal liver stem cell transplantation has been performed on a limited number of patients with aplastic anemia or acute leukemia, but only transient engraftment has been demonstrated. Peripheral blood as a stem cell source was introduced in 1981, and cord blood was introduced as a source in 1988. The various stem cell sources differ in their reconstitutive and immunogenic characteristics, which are based on the proportion of early pluripotent and self-renewing stem cells to lineage-committed late progenitor cells and on the number and characteristics of accompanying "accessory cells" contained in stem cell allografts.

Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study.

Relapse after allogeneic progenitor cell transplant is associated with a poor prognosis for patients with advanced leukemia, with few curative options available. Use of novel chemotherapeutic agents with limited toxicity is warranted. We investigated the role of decitabine, a pyrimidine analogue with significant anti-leukemic effect and limited toxicity, in this setting. Fourteen patients with advanced acute leukemia or transformed chronic myelogenous leukemia (CML) who had failed previous allogeneic transplant were treated. Decitabine at doses of 100 mg/m2 to 150 mg/m2 given every 12 h for 5 days was followed by infusion of stem cells from the original donor 2 to 5 days after the completion of chemotherapy. Dose of decitabine was escalated in cohorts of three patients based on the modified Fibonacci scheme. The primary study end-point was assessment of the toxicity of the regimen with secondary endpoints of response and survival. Eight patients responded with either a complete remission or partial hematological remission (absence of blasts in peripheral blood and bone marrow but with platelet count <100 x 10(9)/l). Toxicity was limited with no grade 3 or 4 toxicity directly attributable to the treatment. The median survival for all patients was 190 days (range 11 to 1215+ days). Decitabine at doses of 100 mg/m2 to 150 mg/m2 given every 12 h for 5 days, followed by stem cell infusion from the original donor was well tolerated, and was associated with acceptable myelosuppression. Current response data should encourage further study of this drug, either alone or in combination with other agents, for treatment of relapsed acute leukemia after an allogeneic transplant.

Thiotepa, busulfan, cyclophosphamide (TBC) and autologous hematopoietic transplantation: an intensive regimen for the treatment of multiple myeloma.

The study was designed to evaluate the efficacy and safety of an intensive, tri-alkylator conditioning regimen, consisting of thiotepa, busulfan and cyclophosphamide (TBC), prior to autologous hematopoietic cell transplantation in patients with multiple myeloma (MM) and to analyze factors associated with outcome. One hundred and twenty patients with MM received high-dose chemotherapy with TBC followed by autologous bone marrow (n = 24) or peripheral blood stem cell (PBSC) transplantation (n = 96). Fifty-four patients had chemosensitive disease and 66 had refractory disease at the time of transplantation. The overall response rate was 81% and the complete remission (CR) rate was 26%. Patients with chemosensitive disease had a CR rate of 52% vs 5% for patients with refractory disease. Multivariable analysis determined disease status at transplant as the factor most likely associated with long survival. Estimated median survival was 48, 35 and 9 months for patients with chemosensitive, primary refractory or disease in refractory relapse, respectively. Short interval from diagnosis to transplant among patients with primary refractory disease and younger age were also favorable prognostic factors for survival. Patients with refractory disease pre-transplant who achieved remission criteria rapidly after treatment had a worse outcome than the slow responders. Treatment-related mortality with the introduction of PBSC and better supportive care was 4.8%. In conclusion, TBC is an effective and relatively well-tolerated intensive conditioning regimen in patients with MM. A more favorable outcome was observed in patients with chemosensitive disease and with early treatment for primary refractory disease. TBC merits further study in these subgroups and comparison with alternative regimens in prospective studies is warranted.

Controlled trial of filgrastim for acceleration of neutrophil recovery after allogeneic blood stem cell transplantation from human leukocyte antigen-matched related donors.

The rapid recovery of hematopoiesis after allogeneic blood stem cell transplantation has been attributed to the quality and quantity of hematopoietic progenitors in the blood stem cell grafts from filgrastim-stimulated donors. To determine whether further stimulation with filgrastim after transplantation would affect hematopoietic recovery, a prospective, randomized, controlled study was performed. Forty-two adult recipients of allogeneic blood stem cells from human leukocyte antigen-matched related donors were randomized to receive 10 microg/kg per day filgrastim subcutaneously from day 1 through neutrophil recovery or no growth factor support after transplantation. There was no significant difference between the 2 groups in the number of CD34(+) cells infused (median, 4.8 vs 4.3 x 10(6)/kg). Graft-versus-host (GVHD) disease prophylaxis consisted of tacrolimus and steroids for 9 patients and tacrolimus and minimethotrexate for 33 patients. The group receiving filgrastim had a shorter time to neutrophil levels greater than 0.5 x 10(9)/L (day 12 vs day 15, P =.002) and to neutrophil levels greater than 1.0 x 10(9)/L (day 12 vs day 16, P =.01). The filgrastim group also had a trend for earlier discharge (day 16 vs 20, P =.05). There was no significant difference between the groups in time to platelet recovery, number of transfusions, regimen-related toxicity, infection, incidence of GVHD, relapse, survival, or hospital charges. It can be concluded that the administration of filgrastim after allogeneic blood stem cell transplantation shortens the time to neutrophil recovery. (Blood. 2001;97:3405-3410)

Continuous complete remission in adult patients with acute lymphocytic leukaemia at a median observation of 12 years after autologous bone marrow transplantation.

We report our long-term experience with autologous bone marrow transplantation (ABMT) for 32 adult patients with acute lymphocytic leukaemia (ALL) in second or later remission (CR), or in first CR but with high-risk. Bone marrow was purged with mafosfamide (n = 25) or with immunomagnetic beads and monoclonal antibodies (n = 7). Retrospective analysis showed that 12 out of 32 patients were in continuous complete remission (CCR) at a median of 143 months (range 66-181 months). A plateau was reached at 50 months and the disease-free and overall survival rates were both 37.5%. It was notable that durable CCR could be achieved for patients in second (three out of nine) or third (one out of six) CR. ABMT could produce durable CCR and the long-term outcome compared favourably with those reported for allogeneic transplantation.

Long-Term follow-up of recipients of CD8-depleted donor lymphocyte infusions for the treatment of chronic myelogenous leukemia relapsing after allogeneic progenitor cell transplantation.

Donor lymphocyte infusions (DLIs) are an effective treatment for relapsed Chronic myeloid leukemia (CML) after allogeneic transplantation but are limited by the occurrence of GVHD. CD8+ T lymphocytes are involved in the pathogenesis of GVHD but may not be essential for the graft-versus-leukemia (GVL) effect in CML. We have treated 26 CML patients with posttransplantation relapse with CD8-depleted DLI. Thirteen of 15 patients (87%) who relapsed in early-phase CML achieved complete cytogenetic response, but only 1 of 11 who relapsed in advanced-phase disease achieved complete response. Acute GVHD occurred in 2 patients (8%), and extensive chronic GVHD occurred in 2 patients (11%). Treatment-related mortality was 11.5%. Responses were durable; with a median follow-up of 4.2 years (1-7.5 years), only 1 responding patient relapsed (7%). CD8-depleted DLI was equally effective and safe after unrelated donor transplants and sibling transplants. Cytogenetic clonal evolution at the time of DLI was not predictive of treatment failure unless associated with hematologic criteria for disease acceleration. CD8 depletion is an effective method to separate GVL from GVHD for posttransplantation relapsed CML. This strategy is associated with durable complete remissions and a low rate of complications and therefore merits further investigation in larger-scale comparative trials.