Successful remission rates and survival after lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies postallogeneic hematopoietic cell transplantation

Few therapeutic strategies exist for hematologic malignancies relapsing post allogeneic hematopoietic cell transplantation. We present outcomes on 35 patients with nonchronic myelogenous leukemia (CML) hematologic malignancies, the majority having acute myelogenous leukemia (AML) or myelodysplastic syndromes/myeloproliferative disorders (MDS/MPD) (n = 22) receiving lymphodepleting chemotherapy followed by donor lymphocyte infusion (DLI) at 2 T cell dose levels (0.5 and 1.0 × 10(8) CD3/kg). Forty-nine percent of patients achieved complete remission (CR), with a median duration of remission of 6 months (range: 2-71+). CR rates were similar between the 2 groups. The incidence of acute graft-versus-host disease (aGVHD) of any grade was 49%. We saw a higher incidence of grade II-IV aGVHD, with a rate of 66% using the higher-dose DLI (grade III, 33% and grade 4, 20%) versus only 25% (10% grade III-IV) with the lower-dose DLI (P?= .06). Overall survival at 1 and 2 years was 30% (95% confidence interval [CI], 16%-45%) and 19% (95% CI, 8%-34%); however, for those achieving CR, 1- and 2-year survival was improved at 44% (95% CI, 20%-66%) and 28% (95% CI, 8%-52%) (P = .03), respectively. These results demonstrate that DLI after lymphodepleting chemotherapy for relapsed hematologic malignancies results in frequent CRs. The lower DLI dose regimen improved the tolerability of this therapeutic approach, with modest rates of severe aGVHD.     

Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation.

The use of myeloablative preparative therapy and allogeneic stem cell transplantation (alloSCT) as salvage therapy for adult patients with relapsed hematologic malignancy after autologous stem cell transplantation (autoSCT) is generally unsuccessful due to very high treatment-related mortality rates. We evaluated the outcome of HLA-matched related donor alloSCT following nonmyeloablative preparative therapy in 13 patients (median age, 38 years) with relapsed hematologic malignancies (Hodgkin's disease, n = 4; Hodgkin's disease and advanced myelodysplastic syndrome, n = 1; non-Hodgkin's lymphoma, n = 6; multiple myeloma, n = 2) after initial autoSCT. Median time from autoSCT to alloSCT was 12 months (range, 3-24 months); 6 patients had chemotherapy-refractory disease following autoSCT, 6 were in untreated relapse, and 1 had a partial response from salvage chemotherapy. Preparative therapy consisted of cyclophosphamide, 150-200 mg/kg; peritransplantation anti-thymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal irradiation); and a very short course of cyclosporine as GVHD prophylaxis. All patients achieved initial mixed chimerism as defined by greater than 1% donor peripheral white blood cells. Seven patients, who had no evidence of GVHD, received prophylactic DLI beginning 5 to 6 weeks after transplantation for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-tumor effect. Six patients showed conversion to full donor chimerism and 1 lost the graft. Grade II or greater acute GVHD occurred in 9 patients. Seven patients achieved a complete response; 6 had no response. The median survival time of the 13 patients is currently 10 months (range, 3-39 months), with an overall survival probability at 2 years of 45% (95% confidence interval [CI], 19%-73%) and a disease-free survival probability at 2 years of 37.5% (95% CI, 12%-65%). Thus, this novel nonmyeloablative alloSCT strategy followed by prophylactic DLI was well tolerated and can result in durable disease-free survival among patients with advanced hematologic malignancies after a failed autoSCT. Further follow-up and evaluation of additional patients are required to conclusively establish the role of this strategy in the treatment of hematologic malignancies after an autologous transplantation.     

Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation.

We retrospectively analyzed outcomes among 307 consecutive patients who had recurrent or persistent acute leukemia (n = 244), chronic myelogenous leukemia in blast phase (CML; n = 28), or advanced myelodysplastic syndromes (MDS; n = 35) after allogeneic hematopoietic cell transplantation and who received at least 1 relapse-directed intervention: withdrawal of immunosuppression, chemotherapy, or donor lymphocyte infusion (DLI). Transplants were performed at a single institution between 1995 and 2004, and outcomes were analyzed according to time intervals from transplantation to detection of malignancy: "early," <100 days (n = 111); "intermediate," 100-200 days (n = 73); and "late," >200 days (n = 123). The overall remission rate was 30%. Compared to early recurrence, intermediate recurrence and late recurrence were associated with increasing probabilities of remission (hazard ratios, 1.89 and 2.16; P = .05 and .02) and decreasing risks of overall mortality (hazard ratios, 0.73 and 0.33; P = .05 and <.0001). The 2-year overall survival (OS) estimates for patients with early, intermediate, and late recurrence were 3%, 9%, and 19%, respectively. Remission was associated with a median survival prolongation of 9.5 months. Individual types or combinations of these nonrandomly assigned relapse-directed interventions were not associated with higher or lower probabilities of remission or survival. More effective intervention strategies are needed for treatment of recurrent high-risk hematologic malignancies after hematopoietic cell transplantation. In the absence of innovative clinical trials, patients with early recurrence might wish to forego further interventions in favor of palliative care.     

Clearance of Hematologic Malignancies by Allogeneic Cytokine-Induced Killer Cell or Donor Lymphocyte Infusions

Well-established donor lymphocyte infusion (DLI) and novel cytokine-induced killer (CIK) cell therapy for the treatment of relapsing hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) were compared with respect to feasibility, safety, and efficacy. Altogether, a total of 221 infusions were given to 91 patients (DLI, n = 55; CIK, n = 36). T cell recovery was significantly improved after CIK cell therapy (P < .0001). Although patients with CIK cell treatment showed a significantly worse prognosis at the time of HSCT (risk score, 1.7 versus 2.1; P < .0001), DLI and CIK cell therapy induced complete remission (CR) in 29% and 53% patients, respectively, whereas relapse occurred in 71% and 47%. In both groups, all patients with overt hematologic relapse at the time of immunotherapy (DLI, n = 11; CIK, n = 8) succumbed to their disease, while 36% and 68% patients with DLI or CIK cell therapy applied due to molecular relapse or active disease at the time of transplantation achieved CR. The 6-month overall survival rate in the latter patients was 57% and 77%, respectively, with a median follow-up of 27.9 months (range, .9 to 149.2 months). The 6-month cumulative incidence of relapse was 55% and 22% in patients who received DLI and CIK cell therapy, respectively (P = .012). Acute graft-versus-host disease developed in 35% of the patients who received DLI and in 25% of those who received CIK. No transfusion-related deaths occurred. These data, while underscoring the therapeutic value of conventional DLI, suggest the improved safety and to a certain extent efficacy of CIK cell therapy for patients at high risk for post-transplantation relapse of various hematologic malignancies.     

Graft-versus-host reactions and the effectiveness of donor lymphocyte infusions.

We retrospectively analyzed 83 consecutive recipients of donor lymphocyte infusions (DLI) after allogeneic transplantation for factors associated with disease response and graft-versus-host disease (GVHD). DLI was highly effective in relapsed chronic phase chronic myeloid leukemia (CML), with 71% of patients achieving durable complete remissions (CR). In relapsed acute myeloid leukemia, DLI led to durable CRs in 31% of patients; the rate was <20% in all other diseases. Achieving full donor chimerism and GVHD were predictive of CR. Grade II or higher acute or chronic GVHD occurred in 36 (43%) patients and contributed to death in 13 (16%). Even more patients, 33 (40%), died of their underlying malignancy, including 10 who developed active GVHD. In relapsed CML, most durable CRs occurred without clinically apparent GVHD, yet all responders achieved full donor chimerism, including 6 with coincident normal host hematopoiesis at the time of DLI. Thus, in CML, potent lymphohematopoietic graft-versus-host reactions occurred even in the absence of clinically apparent GVHD; this confirms the ability to dissociate these processes and argues against a leukemia-specific immunologic effect. DLI clearly has efficacy in the treatment of relapsed disease after allogeneic transplantation. However, with the exception of CML, most patients die of their underlying disease because of insufficient antitumor activity even with active GVHD.     

Lymphohematopoietic graft-vs.-host reactions can be induced without graft-vs.-host disease in murine mixed chimeras established with a cyclophosphamide-based nonmyeloablative conditioning regimen.

Mixed hematopoietic chimerism can be induced in mice receiving allogeneic bone marrow transplantation (BMT) after nonmyeloablative host conditioning with depletion T cells with of anti-T cell monoclonal antibodies (mAbs), low-dose (3 Gy) total-body irradiation (TBI), and local thymic irradiation (7 Gy). These mice are specifically tolerant to donor and host antigens. When nontolerant donor T cells are given to chimeras several months after BMT, full donor-type chimerism develops, but graft-vs.-host disease (GVHD) does not occur. The induction of such lymphohematopoietic GVH reactions without GVHD could provide an approach to separating graft-vs.-leukemia (GVL) from GVHD in patients with hematologic malignancies. To make the nonmyeloablative conditioning regimen described above more cytoreductive for such malignancies, we have now modified it by replacing TBI with cyclophosphamide (CP). Treatment with anti-CD4 and anti-CD8 mAbs on day -5, 200 mg/kg CP on day -1, and 7 Gy thymic irradiation on day 0 was only slightly myelosuppressive and allowed fully major histocompatibility complex (MHC)-mismatched (with or without multiple minor antigen disparities) allogeneic bone marrow to engraft and establish long-term mixed chimerism in 40 to 82% of recipients in three different strain combinations. The administration of nontolerant donor spleen cells at 5 weeks or at 5, 8, and 11 weeks posttransplant was capable of eliminating host hematopoietic cells, leading to full or nearly full donor chimerism in six of six and two of four chimeric animals in two different strain combinations. No clinical evidence of GVHD was observed in any recipients of these donor leukocyte infusions (DLI). These studies demonstrate that induction of mixed chimerism with nonmyeloablative conditioning followed at appropriate times by DLI might allow lymphohematopoietic GVH reactions, and hence GVL effects, to eliminate chronic hematologic malignancies without causing clinically significant GVHD.     

The Impact of Chimerism Patterns and Predonor Leukocyte Infusion Lymphopenia on Survival following T Cell-Depleted Reduced Intensity Conditioned Transplants

Donor leukocyte infusions (DLI) are frequently required following reduced intensity conditioned (RIC) allografts to convert mixed chimerism (MC) to full donor chimerism (FDC). The rationale is to break tolerance and maximize the graft-versus-leukemia responses. We analyzed the impact of chimerism in 125 recipients of RIC (Alemtuzumab containing) transplants. Four patterns of chimerism were seen: (1) always 100% donor chimerism (54%), (2) persisting MC (22%), (3) MC with subsequent development of FDC (18%), (4) lost donor chimerism (6%). Forty-five (36%) patients received DLI. Chimerism patterns and pre-DLI lymphocyte counts (pDLI[Ly]) were significantly associated with DLI responsiveness. Complete disease responses were seen in 6 of 17 (35%) group A patients, 9 of 10 (90%) group C patients, and 0 of 6 group B patients (P = .027), supporting reports that chimerism response is a surrogate marker for disease response. In those with MC, pDLI(Ly) were significantly lower in DLI responsive than nonresponsive patients (P = .044). At 2 years, group C patients had a significant survival advantage (P = .009) compared to all other groups. In conclusion, the chimerism pattern was the best indicator of improved survival in this cohort (ie, MC later converting to FDC). In those with MC, response to DLI therapy was associated with a low lymphocyte count pre-DLI.     

The role of disease stage in the response to donor lymphocyte infusions as treatment for leukemic relapse.

Between 1991 and 1999, 44 leukemic patients received donor lymphocyte infusions (DLIs) at our center (22 patients with chronic myelogenous leukemia [CML]; 10 with acute myelogenous leukemia; 11 with acute lymphatic leukemia; and 1 with myelodysplastic syndrome). Seventeen patients received graft-versus-host disease (GVHD) prophylaxis with methotrexate (MTX) at the time of DLI. In CML patients, 15 of 22 (68%) re-entered complete remission after DLI. At 3 years post-DLI, patients with cytogenetic (n = 10) or molecular (n = 3) relapse had a current leukemia-free survival (cLFS) rate of 85% compared with 0% for patients with hematologic relapse (P < .001). Among 15 CML patients who initially responded to DLI, 4 patients relapsed within the first 2 years. Four of 16 patients (25%) with acute leukemia had an initial response with complete remission after DLI. Two of them subsequently relapsed within 1 year. Patients with acute leukemia who relapsed within 1 year of hematopoietic stem cell transplantation (n = 9) had 0% cLFS at 18 months; patients with later relapse had 29% cLFS (P = .015). The overall probability of cLFS at 3 years for CML patients was 46%. For other diseases, cLFS was 13% at 18 months after DLI. Patients who developed chronic GVHD secondary to DLI showed a 3-year cLFS of 51% compared with 18% for patients without chronic GVHD (P = .022). This study emphasizes the importance of early disease stage and presence of chronic GVHD for effective DLI.     

Adoptive immunotherapy to increase the level of donor hematopoietic chimerism after nonmyeloablative marrow transplantation for severe canine hereditary hemolytic anemia.

Severe hemolytic anemia in Basenji dogs secondary to pyruvate kinase deficiency can be corrected by allogeneic hematopoietic cell transplantation (HCT) from littermates with normal hematopoiesis after conventional myeloablative or nonmyeloablative conditioning regimens. If the levels of donor chimerism were low (<20%) after nonmyeloablative HCT, there was only partial correction of the hemolytic anemia. We next addressed whether allogeneic cell therapy after nonmyeloablative HCT would convert mixed to full hematopoietic chimerism, achieve sustained remission from hemolysis, and prevent progression of marrow fibrosis and liver cirrhosis. Three pyruvate kinase-deficient dogs were given HCT from their respective dog leukocyte antigen-identical littermates after nonmyeloablative conditioning with 200 cGy of total body irradiation. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. All 3 dogs engrafted and had mixed hematopoietic chimerism with donor levels ranging from 12% to 55% in bone marrow. In 2 of the 3 dogs, there were decreases in the levels of donor chimerism so that at 25 weeks after nonmyeloablative HCT, hemolysis recurred that was associated with increased reticulocyte counts. All 3 dogs then had 2 serial infusions of donor lymphocytes (DLI) from their respective donors at least 20 weeks apart to convert from mixed to full donor chimerism. Both dogs with recurrence of hemolytic anemia after nonmyeloablative HCT achieved higher levels of donor chimerism, with donor contributions ranging from 47% to 62% in the bone marrow and 50% to 69% and 16% to 25% in the granulocyte and mononuclear cell fractions of the peripheral blood, respectively, and with remission of the hemolytic anemia. One dog responded after the first DLI, and 5 weeks after the second DLI, the other dog converted to full donor chimerism. At last follow-up, all these dogs showed clinical improvement, as determined by increasing hematocrits and normal reticulocyte counts. Analysis of the marrow 3 years after HCT showed normal cellularity, a normal myeloid-erythroid ratio, and no or minimal marrow fibrosis. Liver biopsies demonstrated normal histologies with no or minimal fibrosis. We conclude that DLI after nonmyeloablative HCT can increase the levels of donor cells contributing to hematopoiesis in recipients, inducing remissions of the hemolytic process and preventing complications associated with iron overload.     

Alpha-interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease.

Donor lymphocyte infusion (DLI) results in complete cytogenetic remission (CCR) of relapsed chronic-phase chronic myeloid leukemia (CML-CP) after allogeneic stem cell transplantation (SCT) in up to 80% of patients. The main complication of DLI is graft-versus-host disease (GVHD). Decreasing the dose of DLI is associated with less GVHD but also with a longer interval between treatment and CCR. We postulated that combining alpha-interferon (alpha-IFN) with DLI would enable us to decrease the dose of DLI, thereby limiting GVHD, and at the same time to decrease the interval between DLI and CCR for patients with either a hematologic or cytogenetic relapse. For molecular relapses, we hypothesized that because of a lower tumor load, very low doses of DLI without alpha-IFN could be an effective treatment. Two groups of CML-CP patients treated with DLI at a very low dose of 0.5 to 1.0 x 10(7) mononuclear cells per kilogram, containing 2 to 6 x 10(6) CD3+ T cells per kilogram, were analyzed: 13 patients with a cytogenetic or a hematologic relapse after allogeneic SCT (group A) were treated with additional alpha-IFN therapy at a dose of 3 x 10(6) U 5 d/wk, and 8 patients with a molecular relapse were treated without alpha-IFN (group B). Twelve patients from group A reached a CCR. The median interval between DLI and CCR was 7 weeks (range, 5-18 weeks) for group A. All patients with a CCR reached complete donor chimerism at a median of 10 weeks after DLI (range, 6-121 weeks). Eleven patients reached molecular remission at a median of 15 weeks after DLI (range, 8-34 weeks). In group B, all patients reached a molecular remission at a median of 14 weeks (range, 12-29 weeks). Five patients from group A developed acute GVHD grade II to IV and extensive chronic GVHD. In group B, 1 patient developed acute GVHD grade II to IV and subsequently developed extensive chronic GVHD. With a median follow-up of 62 months, 10 patients in group A are alive and in continuous CCR. One patient had a molecular relapse, for which she successfully received additional DLI; another patient reached molecular remission only after 5 doses of DLI. Two patients from group A died of a gram-negative sepsis, and 1 died of an acute myocardial infection. In group B, all patients are alive and in molecular remission with a median follow-up of 20 months. One patient's disease progressed but was successfully treated with DLI plus alpha-IFN. In conclusion, very-low-dose DLI in combination with alpha-IFN as treatment for cytogenetic or hematologic relapses of CML-CP after allogeneic SCT reduced the interval to obtain a CCR with acceptable GVHD when compared with the literature. Patients with a CCR also reached complete donor chimerism and complete molecular remissions. For patients with a molecular relapse, very-low-dose DLI alone is sufficient to induce molecular remissions in most patients and is associated with limited GVHD.     

Incidence and Outcome of Late Relapse after Allogeneic Stem Cell Transplantation for Myelofibrosis

In this cross-sectional study, we retrospectively evaluated the files of 227 patients with myelofibrosis who underwent transplantation between 1994 and 2015 for relapse later than 5 years after allogeneic stem cell transplantation (SCT). A total of 94 patients who were alive and in remission at 5 years were identified with follow-up of at least 5 years (median, 9.15 years) after SCT. Thirteen patients (14%) experienced late molecular (n = 6) or hematologic (n = 7) relapse at a median of 7.1 years while 81 patients did not experience relapse. Relapse patients received either donor lymphocyte infusion (DLI) (n = 7) and/or second transplantation (n = 4). Of those, 72.7% achieved again full donor cell chimerism and molecular remission, and after a median follow-up of 45 months, the 3-year overall survival rates for patients with or without relapse were 90.9% (95% confidence interval [CI], 77% to 100%) and 98.8% (95% CI, 96% to 100%), respectively (P = .13). We conclude that late relapse occurs in about 14% of the patients and the majority can be successfully salvaged with DLI and/or second allograft. All patients with molecular relapse are alive and support the long-time molecular monitoring in myelofibrosis patients after allogeneic SCT.     

Reversal of Low Donor Chimerism after Hematopoietic Cell Transplantation Using Pentostatin and Donor Lymphocyte Infusion: A Prospective Phase II Multicenter Trial

In a multicenter, prospective, phase II study we evaluated the safety and efficacy of pentostatin followed by donor lymphocyte infusion (DLI) in patients with low donor Tcell chimerism after allogeneic hematopoietic cell transplantation (HCT). Thirty-six patients with low donor blood CD3 chimerism were enrolled in this study. Thirty-five patients received a total of 41 DLIs after a dose of pentostatin, and 1 patient received pentostatin only. Median donor CD3 chimerism prompting the initiation of pentostatin and DLI was 28% (range, 5% to 47%). Responses (defined by increases in donor CD3 chimerism ≥10% maintained to day 56 post-DLI) were seen in 16 patients (44.4%) with a median rise in CD3 donor chimerism to 64% (range, 48% to 100%). There was a trend for better responses among 21 patients who received first treatment within 100 days after transplant (57% response rate) compared with15 patients who received first treatment more than 100 days after HCT (27% response rate, P?=?.07). Fourteen patients (39%) developed grades II to IV acute graft-versus-host disease (GVHD) at a median of 10 days (range, 0 to 83) after DLI. Ten patients (28%) developed extensive chronic GVHD. Seventeen patients (47%) developed new grade 4 cytopenias after DLI. There was no difference in relapse between nonresponders and responders. Twenty-eight patients (78%) died, most (n?=?21) because of relapse. Five of 16 responders (31%) are alive, all disease-free, at a median of 60 months (range, 21 to 132) after DLI. Six of 20 nonresponders (30%) are alive at a median of 47 months (range, 16 to 100) after DLI, 3 in complete remission. Pentostatin and DLI had acceptable toxicity and appeared to increase low donor CD3 chimerism after HCT but had no impact on mortality.     

Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma.

Donor lymphocyte infusions (DLIs) have been demonstrated to induce clinical responses in patients with relapsed multiple myeloma after allogeneic bone marrow transplantation, but the immunologic mechanisms involved have not been well characterized. In patients with chronic myelocytic leukemia (CML), remissions following DLI are invariably associated with conversion to complete donor hematopoiesis, suggesting that the target antigens of this response are expressed on both normal and CML-derived hematopoietic stem cells. In the present study, we examined hematopoietic chimerism and the complexity of the T-cell receptor (TCR) repertoire in 4 patients with relapsed multiple myeloma who received infusions of donor CD4+ lymphocytes. Three of 4 patients had a clinical response that began 1 to 2 months after DLI. All 3 responding patients developed lymphocytosis at the initiation of response that was due to a 2- to 4.5-fold increase in the number of CD3+ T cells. In 1 patient, this was due primarily to increases in CD3+ and CD8+ cells; in 2 patients, to increased numbers of CD3+ and CD8+ and CD3+ and CD4+ T cells. In all responding patients, conversion to complete donor hematopoiesis occurred in the first 2 months after DLI. The single nonresponding patient remained it 100% recipient hematopoiesis. The TCR repertoire complexity was examined by polymerase chain reaction amplification of complementary-determining region 3 (CDR3) derived from 24 Vbeta gene subfamilies. In 2 patients, the initiation of myeloma response and conversion to complete donor hematopoiesis was associated with normalization of TCR complexity. Complete donor chimerism and normal TCR complexity remained stable in all patients and did not change with subsequent relapse or development of graft-versus-host disease (GVHD). Thus, conversion to full donor chimerism was temporally associated with the antimyeloma effect of DLI but not with the development of GVHD. Nevertheless, the maintenance of stable donor hematopoiesis did not prevent disease relapse and was not associated with prolonged remission. The selective relapse of myeloma cells without concomitant return of mixed hematopoietic chimerism suggests that myeloma tumor cells in some patients develop resistance to immune destruction.     

Reduced-intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusions for chemotherapy-sensitive myeloma: limited efficacy of graft-versus-tumor activity.

Reduced-intensity conditioning regimens allow application of allogeneic stem cell transplantation to greater numbers of patients with myeloma by reducing transplantation-related mortality. We prospectively evaluated the role of an approach incorporating in vivo T-cell depletion and subsequent adjuvant donor lymphocyte infusions (DLIs) as part of front-line therapy for chemotherapy-sensitive multiple myeloma. Twenty patients with HLA-matched related (n = 12) or unrelated (n = 8) donors entered the study. None had previously undergone autologous transplantation. Acute graft-versus-host disease (GVHD) following transplantation was minimal (3 grade II and no grade III or IV). Nonrelapse mortality rate was relatively low (15%) compared with conventional myeloablative allogeneic transplantation series, although it remained significantly higher than in the autologous setting. Disease responses by 6 months posttransplantation were modest (2 in complete remission, 4 in partial remission, 2 were minimally responsive, 6 had no change, 3 had progressive disease, and 3 were not evaluable). Fourteen patients received escalating-dose DLI for residual/progressive disease. Three developed acute GVHD and 2 developed limited chronic GVHD. Seven demonstrated further disease responses, which appeared to be more common in those developing GVHD (5 of 5 versus 2 of 9; P =.02). All responses were associated with conversion from mixed to full donor T-cell chimerism. Response durations were disappointing (5 <12 months) and progression often occurred despite persisting full donor chimerism. Two-year estimated overall survival and current progression-free survival rates (intention to treat with DLI from 6 months) were 71% and 30%, respectively. The current approach incorporating T-cell depletion appears excessively immunosuppressive despite attempts to restore immune function with DLI. Dose escalation failed to allow convincing dissociation of graft-versus-myeloma from GVHD. Attempts to hasten immune reconstitution and to focus and amplify appropriate components of allogeneic T-cell responses will be required to increase complete remission rates and response durations.     

Photochemical treatment of donor lymphocytes inhibited their ability to facilitate donor engraftment or increase donor chimerism after nonmyeloablative conditioning or establishment of mixed chimerism.

Donor T-cells can provide a graft-versus-leukemia effect and help to promote donor engraftment after allogeneic BMT; however, these benefits can be outweighed by the ability of the cells to induce life-threatening GVHD. Photochemical treatment (PCT) of T-cells with S-59 psoralen and long-wavelength UV-A light can inhibit their proliferative capacity and significantly decrease their ability to induce acute GVHD after allogeneic BMT. PCT donor T-cells have been shown to facilitate donor engraftment in a myeloablative BMT model. In this study, we examined whether donor T-cells subjected to PCT ex vivo could retain the ability to facilitate engraftment or increase donor chimerism after nonmyeloablative BMT or after establishment of mixed hematopoietic chimerism. In a transplantation model in which mice were conditioned for BMT with sublethal (600 cGy) TBI, an infusion of PCT donor T-cells was unable to facilitate engraftment of donor BM. A BMT model was used in which a mixture of allogeneic and syngeneic marrow cells was infused into lethally irradiated recipients for establishment of mixed hematopoietic chimerism. The goal was to determine whether PCT donor splenocytes could increase levels of donor chimerism. Recipients of splenocytes treated with UV-A light only (no S-59 psoralen) and given at the time of BMT or in a donor lymphocyte infusion (DLI) had significantly higher levels of donor chimerism than did recipients of BM only. Although PCT donor splenocytes given at the time of BMT modestly increased donor chimerism, PCT donor splenocytes given in a DLI did not increase donor chimerism. A nonmyeloablative BMT model was employed for determining whether DLI given relatively late after BMT could increase donor chimerism. Recipient mice were conditioned for BMT with a combination of low-dose TBI (50 or 100 cGy) and anti-CD154 (anti-CD40L) monoclonal antibody for achievement of low levels of mixed chimerism. When control mixed chimeras were given a DLI 71 days after BMT, donor chimerism was significantly increased. In contrast, PCT of the donor cells eliminated the ability of the cells to increase donor chimerism after infusion. Together results from these 3 distinct BMT models indicate that PCT of donor T-cells significantly inhibited the ability of the cells to facilitate donor engraftment after nonmyeloablative BMT or to increase donor chimerism in mixed hematopoietic chimeras when the cells were administered in a DLI.     

Allogeneic cell therapy for patients who relapse after autologous stem cell transplantation.

Allogeneic donor leukocytes can be used after nonmyeloablative conditioning to exploit their graft-versus-tumor (GVT) activity in the setting of reduced conditioning-regimen toxicity. This approach may be particularly useful for patients who relapse after autologous stem cell transplantation (SCT). However, GVT activity, toxicity, and ability to establish mixed chimerism may differ in patients who were heavily pretreated prior to SCT compared with patients treated earlier in the course of their disease. We have performed a series of studies of nonmyeloablative allogeneic transplantation and present data on the subset of 14 patients treated for relapse after autologous SCT: 4 patients received no conditioning and unstimulated donor leukocyte infusions (DLI), 10 patients received conditioning with fludarabine and cyclophosphamide followed by unstimulated or granulocyte-colony-stimulating factor (G-CSF)-stimulated allogeneic peripheral blood stem cells (PBSCs), 4 patients received no graft-versus-host disease (GVHD) prophylaxis, and 10 patients received cyclosporine GVHD prophylaxis. All but 1 patient had sustained donor chimerism at least 30 days after allogeneic cell therapy (ACT), and 8 patients had more than 80% donor chimerism after ACT. Acute GVHD developed in 11 patients (grade III-IV, n = 6). Aplasia was more frequent in the patients receiving unstimulated PBSCs, despite the development of mixed chimerism. There were 6 complete responses and 4 partial responses; response was independent of conditioning and growth-factor stimulation of the donor graft. Five patients died of treatment-related causes and 4 patients died from progressive disease. Four patients remained alive 27 to 194 weeks (median, 66 weeks) after ACT. Prior autologous SCT may define a subset of patients at particularly high risk for GVHD and other toxicity after ACT. However, these data show that ACT with either DLI or G-CSF-stimulated blood cells results in direct GVT activity in some patients with Hodgkin's disease, myeloma, and non-Hodgkin's lymphoma, even after relapse from autologous SCT. Most patients developed donor chimerism with minimal conditioning. Alternative prophylactic regimens that control GVHD while maintaining GVT are needed to improve outcomes in these heavily pretreated patients.     

HLA单倍体与全相合异基因造血干细胞移植治疗恶性血液病

背景：异基因造血干细胞移植是治疗恶性血液病的一种非常有效的方法。单倍体相合的造血干细胞移植扩大了移植的应用范围,是无HLA相合供者患者的一种重要选择。 目的：比较HLA单倍体相合与全相合异基因造血干细胞移植治疗恶性血液病的临床疗效。 方法：回顾性分析接受异基因造血干细胞移植79例恶性血液病患者的临床资料,其中HLA单倍体相合组26例、全相合组53例,对比两组受者移植物抗宿主病的发生率、复发率、2年生存率等。 结果与结论：78例受者获得完全、持久供者干细胞植入;1例受者在移植后28 d尚未植入,后因感染死亡。两组慢性移植物抗宿主病发生率、复发率和2年无病生存率差异无显著性意义(P > 0.05)。单倍体相合组急性移植物抗宿主病发生率高于全相合组(P < 0.05);2年总生存率低于全相合组(P < 0.05)。提示血缘HLA单倍体相合移植治疗恶性血液病的安全性及疗效接近于全相合移植,在缺乏HLA相合供者的情况下,行HLA单倍体相合造血干细胞移植治疗恶性血液病是切实可行的选择。     

Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed.

Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m(2)) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.     

Host Lymphocyte Depletion as a Strategy to Facilitate Early Full Donor Chimerism after Reduced-Intensity Allogeneic Stem Cell Transplantation

Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (RIC-alloHSCT) is associated with lower toxicity but higher rates of prolonged mixed chimerism than myeloablative conditioning. Decreased pretransplantation host T cell numbers are associated with less graft rejection and early full donor chimerism. To compensate for variability in pretransplantation host lymphocyte numbers and facilitate the achievement of rapid full donor chimerism, we tested a strategy of targeted lymphocyte depletion (TLD) using chemotherapy at conventional doses to provide cytoreduction and lymphocyte depletion before RIC-alloHSCT. In our study, 111 patients with advanced hematologic malignancies received 1 to 3 cycles of conventional-dose chemotherapy to reduce circulating lymphocytes to a predetermined level. Patients then underwent RIC-alloHSCT from HLA-matched siblings. Patients received a median of 2 cycles of TLD chemotherapy, resulting in a median 71% decline in CD4⁺ count. All patients engrafted; there were no late graft failures. By day +14, median CD3⁺ chimerism was 99% donor and was significantly associated with lower post-TLD CD4⁺ counts (P = .012). One- and 5-year treatment-related mortality were 15% and 21%, respectively. At 1-year follow-up, 66% of patients had achieved complete remission (CR) of which 92% were not in CR at the time of transplantation. Overall survival at 1 and 5 years post transplantation were 66% and 47%, respectively.     

Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions.

Donor leukocyte infusions (DLI) can induce a direct graft-vs-leukemia (GVL) reaction and restore complete remission for patients who relapse after allogeneic bone marrow transplantation (BMT). A critical and unanswered concern is the long-term safety and durability of DLI. To determine remission duration, long-term toxicity, and survival after DLI-induced remissions, we identified 73 patients who achieved complete remission after DLI. Follow-up information was obtained for 66 of the 73 patients, including 39 patients with chronic myelogenous leukemia (CML) and 27 patients with other diseases. Median follow-up for all patients was 32 months; the probability of survival at 1, 2, and 3 years was 83% (95% confidence interval [CI] 74-92), 71% (60-83), and 61% (49-74), respectively. For CML, survival probability at 1, 2, and 3 years was 87% (76-98), 76% (62-90), and 73% (58-88). For other diseases, survival probability at 1 and 2 years is 77% (61-93) and 65% (46-84). Five of 39 patients with CML relapsed, and 11 of 27 patients with other diseases relapsed. Treatment-related toxicity accounted for 10 deaths. Extended follow-up shows that DLI-induced remissions are durable, especially for patients with CML. Late relapses still occur, however, and toxicity remains significant. Continued follow-up will best define the long-term GVL effects of DLI, especially for diseases other than CML.