Effect of induced GVHD in leukemia patients relapsing after allogeneic bone marrow transplantation: single-center experience of 33 adult patients.

In a retrospective single center study, we examined the outcome of induced GVHD in leukemia patients relapsing after allogeneic BMT. Thirty-three adult patients with leukemia (15 AML, 3 ALL, and 15 CML) persisting or relapsing 1-36 months (median, 6) after allogeneic BMT underwent various immune manipulations and consequently developed acute and/or chronic GVHD at our center. Immunotherapies to elicit GVHD comprised chemotherapy followed by PBSC (n = 18), non-myeloablative transplant (n = 2), PBL followed by IFN-alpha (n = 5), PBL alone (n = 3), abrupt cessation of CsA (n = 3), and CsA withdrawal combined with IFN-alpha (n = 2). Twenty-four (72.7%) patients obtained a remission including complete hematological or cytogenetic remission, respectively, for acute leukemias or CML. Overall survival of patients, estimated at 3 years using the Kaplan-Meier method, was 33.9% (95% CI, 20-52%). Twelve patients including two patients with ALL remain in complete hematological (n = 5) or cytogenetic remission (n = 7) 3-93 months (median 12) after achieving remission. Twelve (63.2%) of 19 dead patients died due to treatment-related toxicities; five patients from acute GVHD, three from GVHD followed by infections and four from infections. By multivariate Cox analysis, only chronic GVHD resulted in a higher probability of disease-free survival (P = 0.026). Eight patients who had both acute GVHD < or = grade I and chronic GVHD are all alive without leukemia. We conclude that acute GVHD is associated with considerable toxicity while chronic GVHD plays a role in retaining remission in leukemia relapsing after allogeneic BMT.     

Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia [published erratum appears in Blood 1989 Aug 15;74(3):1180]

To assess the influence of graft-versus-host disease (GVHD) on recurrent leukemia and survival after allogeneic marrow transplantation, we studied 1,202 patients with acute nonlymphocytic leukemia (ANL), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML) given unmodified marrow grafts from HLA- identical siblings. Proportional hazards regression models using acute GVHD and chronic GVHD as time-dependent covariates demonstrated a significant association of GVHD with a decreased relative risk (RR, 0.33 to 0.42) of relapse in patients with ANL, ALL, and CML transplanted in advanced disease. Among patients developing either acute or chronic GVHD, treatment failure (that is, mortality or relapse) was decreased in patients with ALL transplanted in relapse (RR = 0.70, P less than .033) and CML in blast crisis (RR = 0.37, P less than .009). This effect was independent of age, sex, preparative regimen, GVHD prophylaxis, or length of follow-up. Five-year actuarial estimates were derived for the subset of 657 patients who survived in remission 150 days after transplant and were at risk for development of chronic GVHD. Among patients with ANL in first remission or CML in chronic phase, GVHD had an adverse effect on survival and no apparent influence on relapse. Among patients with ANL and ALL transplanted in relapse, the probability of relapse after day 150 was 74% without [corrected] GVHD, 45% with acute and chronic GVHD, 35% with [corrected] only acute GVHD, and 34% with only chronic GVHD (P less than .001). Actuarial survival in these four GVHD groups was 25%, 34%, 59%, and 62%, respectively (P less than .009). Among patients with CML in acceleration or blast crisis, the probability of relapse after day 150 was 65% without GVHD and 36% with acute and/or chronic GVHD (P less than .017). We conclude that acute and chronic GVHD were associated with a durable antileukemic effect and improved survival in patients transplanted in advanced stages of ALL and CML.     

Graft-versus-leukemia reactions after bone marrow transplantation

To determine whether graft-versus-leukemia (GVL) reactions are important in preventing leukemia recurrence after bone marrow transplantation, we studied 2,254 persons receiving HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission, acute lymphoblastic leukemia (ALL) in first remission, and chronic myelogenous leukemia (CML) in first chronic phase. Four groups were investigated in detail: recipients of non--T-cell depleted allografts without graft-versus-host disease (GVHD), recipients of non-- T-cell depleted allografts with GVHD, recipients of T-cell depleted allografts, and recipients of genetically identical twin transplants. Decreased relapse was observed in recipients of non--T-cell depleted allografts with acute (relative risk 0.68, P = .03), chronic (relative risk 0.43, P = .01), and both acute and chronic GVDH (relative risk 0.33, P = .0001) as compared with recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect of GVHD. AML patients who received identical twin transplants had an increased probability of relapse (relative risk 2.58, P = .008) compared with allograft recipients without GVHD. These data support an antileukemia effect of allogeneic grafts independent of GVHD. CML patients who received T-cell depleted transplants with or without GVHD had higher probabilities of relapse (relative risks 4.45 and 6.91, respectively, P = .0001) than recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect independent of GVHD that is altered by T-cell depletion. These results explain the efficacy of allogeneic bone marrow transplantation in eradicating leukemia, provide evidence for a role of the immune system in controlling human cancers, and suggest future directions to improve leukemia therapy.     

异基因造血干细胞移植治疗白血病76例临床观察

目的观察不同来源的异基因造血干细胞移植治疗白血病的疗效并探讨主要并发症的处理方案。方法对2001年9月至2007年3月第四军医大学西京医院血液科76例白血病患者行异基因造血干细胞移植治疗,其中慢性粒细胞白血病34例,急性髓性白血病24例,急性淋巴细胞白血病15例,T细胞淋巴瘤/白血病3例。人类白细胞抗原(HLA)全相合的同胞供者57例,1个HLA位点不合同胞供者3例,HLA单倍型半相合同胞供者7例,非血缘供者9例。预处理方案采用改良的马利兰联合环磷酰胺(BUCY)或改良的环磷酰胺联合全身放疗及阿糖胞苷或鬼臼乙叉甙(CyTBI Ara-c/VP-16)方案。采用标准的环孢素A(CsA)联合短期甲氨蝶呤(MTX)方案预防移植物抗宿主病(GVHD);无关供者移植加用抗人胸腺细胞球蛋白,单倍型半相合移植同时加用CD25单克隆抗体。结果96.1%(73/76)获得植入。24.7%(18/73)出现急性GVHD,32.9%(24/73)出现慢性GVHD;合并重症肝静脉闭塞病2例;并发纯红细胞性再生障碍性贫血5例。随访3~72个月,现存活56.6%(43/76),43.4%(33/76)在移植后1~36个月时死亡,19例死于白血病复发,14例死于移植相关并发症。结论多种来源的异基因造血干细胞移植是治疗白血病的有效方法,于慢性粒细胞白血病慢性期、急性白血病缓解期移植效果较好,移植前处于高危难治状态的病例复发率仍较高。     

Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia

Allogeneic bone marrow transplantation is the treatment of choice for many childhood leukemias. The donor of choice-an HLA matched sibling-is only available about 30% of the time. Unrelated donors are an alternative choice. In this report, we describe the results of unrelated donor bone marrow transplants (BMT) in 50 children with leukemia (25 acute lymphoblastic leukemia [ALL], 3 acute myeloid leukemia [AML], 3 juvenile chronic myelogenous leukemia [JCML], 10 chronic myeloid leukemia [CML]) or myelodysplastic syndrome (MDS; 9). The median age of the 31 male and 19 female patients was 9 years (range 2 to 18). Only 13 patients were serologically matched at HLA-A, B, DR, and DQ with their donors; 6 of these were reactive in mixed lymphocyte culture. The other 37 patients were mismatched for one (36 patients) or more (1 patient) HLA antigens. Pretransplant conditioning included cytosine arabinoside, cyclophosphamide, fractionated total body irradiation (TBI) (with lung, liver, and more recently, kidney shielding), and methylprednisolone. High-risk patients also received busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of T- cell depletion with IgM monoclonal antibody T10B9 plus complement and posttransplant cyclosporine-A. Forty-nine patients (98%) engrafted. Median times to greater than 500 polymorphonuclear leukocytes (PMN)/microL and greater than 25,000 platelets/microL were 18 and 20 days, respectively. Acute GVHD > or = grade II occurred in 16 patients (33%); 13 (81%) of these died. Chronic GVHD developed in 30 of 40 patients at risk, but was extensive in only 5. Event-free survival (EFS) for all patients was 44% +/- 7% (median follow-up was 49 months), and overall survival was 50 +/- 7%. Patients with low-risk disease (ALL or AML in first or second remission and CML in chronic phase) had a better EFS than children with high-risk disease (60% v 34%, P = .07). There was no significant difference in EFS between patients who were serologically matched with their donors (46%) and those who were partially mismatched (43%) (P = .97). These data compare favorably with published reports for children transplanted with HLA-matched sibling donors and should encourage earlier consideration of unrelated donor BMT in children with leukemia or myelodysplasia.     

Clinical impact of graft-versus-host disease against leukemias not in remission at the time of allogeneic hematopoietic stem cell transplantation from related donors. The Japan Society for Hematopoietic Cell Transplantation Working Party

Acute graft-versus-host disease (GVHD) increases post-transplant mortality and morbidity, but exerts a potent graft-versus-leukemia (GVL) effect. To clarify the impact of GVHD on outcome after transplant in aggressive diseases, patients with acute myeloid or lymphoblastic leukemia (AML, n = 366 or ALL, n = 255) in nonremission states, or chronic myelogenous leukemia (CML, n = 180) in accelerated phase (AP) or blastic crisis (BC), who received allogeneic hematopoietic stem cell transplantation (HSCT) from a related donor between 1991 and 2000, were analyzed. Significant improvement in overall and disease-free survival (DFS) was detected with grade I acute GVHD in AML (P = 0.0002 for overall survival and 0.0009 for DFS, respectively) and in CML (P = 0.0256 and 0.0366, respectively), while the trend towards improved survival was observed in ALL. Relapse rate was lower in grade I acute GVHD than in grade II in all three diseases, suggesting that treatment for grade II GVHD may compromise the GVL effect associated with GVHD. Chronic GVHD was found to suppress relapse in CML and ALL, but not in AML, although no improvement in survival was observed in any disease category. Our results suggest that treatment for grade II acute GVHD may need to be attenuated in transplant for refractory leukemias.     

HIGH INCIDENCE OF EARLY LEUKEMIC RELAPSE IN PATIENTS GIVEN CYCLOSPORIN AND T CELL DEPLETED HLA-IDENTICAL SIBLING MARROW TRANSPLANTS FOR ACUTE LEUKEMIA IN FIRST REMISSION*

:Twelve patients with acute nonlymphoblastic leukemia (ANL, n = 6) or acute lymphoblastic leukemia (ALL, n = 6) in first complete remission received cyclophosphamide 120 mg/kg and total body irradiation (TBI) 12 Gy followed by HLA-identical sibling marrow that had been depleted of T cells by incubation with anti-CD2 (with or without anti-CD8) monoclonal antibody and rabbit complement. These 12 patients were compared historically to 25 patients with ANL (n = 15) or ALL (n = 10) in first remission given cyclophosphamide 120 mg/kg and TBI 12 Gy followed by non-T cell depleted HLA-identical sibling marrow for parameters of relapse and survival. Thirty-six of the 37 patients received cyclosporin as post transplant prophylaxis for graft-versus-host disease (GVHD). All surviving patients have been followed for a minimum of one year from transplant. The actuarial rate of leukemic relapse in the T-depleted group was 62% compared to 37% in the non-depleted group (p< 0.02). Additionally, relapse occurred significantly earlier post transplant in the T-depleted recipients (p = 0.012). Actuarial survival at two years post transplant was 24% for the T-depleted recipients and 41 % at six years post transplant for the non-depleted recipients (not significant, p = 0.37). We have previously shown that GVHD is less severe in patients given T cell depleted transplants. Taken together, these findings suggest that (under the protocol conditions used) a graft-versus-leukemia effect is not separable from a GVHD effect in man. More effective anti-leukemia therapy must be devised before the benefit of T cell depletion can be applied to patients with ANL or ALL receiving HLA-identical sibling marrow transplants in first remission. (Aust NZ J Med 1988; 18: 587–593).     

Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia

The role of transplantation in infants with acute lymphoblastic leukemia (ALL) is not defined. We analyzed results of 40 infants diagnosed before age 12 months who received a hematopoietic cell transplant (HCT) between July 1982 and February 2003 in first complete remission (CR1; n = 17), CR2/3 (n = 7), or relapse (n = 16). Patients were conditioned with cyclophosphamide with total body irradiation (n = 39) or busulfan (n = 1). Donors were matched related (n = 8), mismatched related (n = 16), or unrelated (n = 16). Graft-versus-host disease (GVHD) prophylaxis was methotrexate or cyclosporine (n = 7) or methotrexate plus cyclosporine (n = 33). Thirty-nine patients engrafted, 20 developed acute GVHD, and 7 developed chronic GVHD. Sixteen patients relapsed and 7 died of other causes. Patients in CR1 had disease-free survival (DFS) of 76% compared with 45% for CR2/CR3 and 8% for relapse (P < .001). Of 33 patients with cytogenetic data, 26 (79%) had MLL gene rearrangement. Fourteen of these 26 were in CR1 and 11 survive in remission. Outcome was associated with phase of disease, but having the MLL gene was not a factor predictive of outcome. Late effects included growth and other hormone deficiencies. These data demonstrate that infants with ALL and MLL gene have excellent DFS when they received transplants in CR1, and consideration for transplantation in CR1 is warranted.     

Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia?

Optimal prophylaxis of graft-versus-host disease (GVHD) is controversial. We compared efficacy of three posttransplant immune suppressive regimens in 2,286 recipients of HLA-identical sibling bone marrow transplants for acute lymphoblastic leukemia (ALL) in first remission, acute myelogenous leukemia (AML) in first remission, or chronic myelogenous leukemia (CML) in first chronic phase. Six hundred forty received methotrexate, 977 received cyclosporine, and 669 received combined cyclosporine and methotrexate. In children, the three regimens resulted in similar outcomes. In adults, cyclosporine and methotrexate had comparable risks of acute and chronic GVHD. Compared with methotrexate, cyclosporine was associated with less interstitial pneumonia (relative risk [RR] = 0.6; P < .001), less treatment-related mortality (RR = 0.6; P < .001), more relapses (RR = 1.6; P < .05), and less treatment failure (relapse or death from any cause; RR = 0.7; P < .001). Different effects were observed in different leukemias. In ALL, the rate of leukemia relapse was increased with cyclosporine versus methotrexate, with no effect on other outcomes. In AML and CML, interstitial pneumonia, treatment-related mortality, and treatment failures were decreased with cyclosporine, with no increase in relapse. Similar analyses comparing cyclosporine plus methotrexate with cyclosporine alone showed that adults receiving the combination had less acute GVHD (RR = 0.5; P < .001), less chronic GVHD (RR = 0.7; P < .01), and less interstitial pneumonia (RR = 0.7; P < .001). Treatment failure (RR = 0.8; P < .05) was marginally reduced. Separate analyses in ALL and AML showed less acute GVHD with combined therapy, but no significant effect on other outcomes. In CML, acute GVHD, interstitial pneumonia, treatment-related mortality, and treatment failure were decreased with combined therapy.     

Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children

Acute lymphoblastic leukemia (ALL) is the most common indication for transplantation of marrow from unrelated donors in children. We analyzed results of this procedure in children with ALL treated according to a standard protocol to determine risk factors for outcome. From January 1987 to 1999, 88 consecutively seen patients with ALL who were younger than 18 years received a marrow transplant from an HLA-matched (n = 56) or partly matched (n = 32) unrelated donor during first complete remission (CR1; n = 10), second remission (CR2; n = 34), third remission (CR3; n = 10), or relapse (n = 34). Patients received cyclophosphamide and fractionated total-body irradiation as conditioning treatment and were given methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Three-year rates of leukemia-free survival (LFS) according to phase of disease were 70% for CR1, 46% for CR2, 20% for CR3, and 9% for relapse (P <.0001). Three-year cumulative relapse rates were 10%, 33%, 20%, and 50%, respectively, and 3-year cumulative rates of death not due to relapse were 20%, 22%, 60%, and 41%, respectively, for patients with CR1, CR2, CR3, and relapse. Grades III to IV acute GVHD occurred in 43% of patients given HLA-matched transplants and in 59% given partly matched transplants (P =.10); clinical extensive chronic GVHD occurred in 32% and 38%, respectively (P =.23). LFS rates were lower in patients with advanced disease (P <.0001), age 10 years or older (P =.002), or short duration of CR1 (P =.007). Thus, in addition to phase of disease, age and duration of CR1 were predictors of outcome after unrelated-donor transplantation for treatment of ALL in children. Outcome was particularly favorable in younger patients with early phases of the disease.     

非血缘关系异基因骨髓移植19例临床分析

目的 探讨非血缘关系异基因骨髓移植（URD－BMT）的疗效和相关合并症。方法 我所1998年8月－2001年2月行19例URD－BMT。预处理方案：2例以全身照射（TBI）为主的方案,其余均用化疗方案。移植物抗宿主症（GVHD）的预防：所有患者均接受环孢素A和短程甲氨蝶呤方案。其中7例用霉酚酸酯（MMF）,1例用CD3＋CD25,9例用抗胸腺细胞球蛋白（ATG）,其中1例骨髓经免疫毒素体外去除T淋巴细胞。骨髓回输：18例经股动脉插管输入。结果 19例中2例因观察期尚短不能评价,其余17例均植活。超急性GVHD发生7例;急性GVHDⅡ-Ⅳ度为9／17例,累积发生率为53.0%。采用单因素分析表明,HLA配型不合、未用ATG、MMF、输入细胞数枵植活时间,对Ⅱ-Ⅳ度急性GVHD的发生率均无显著影响。感染情况：移植后5周内发热的患者为11／17例。在随访期内,10例发生巨细胞病毒感染。存活情况：19例中死亡6例。18个月无病存活58.3%。结论 URD－BMT作为治疗恶性血液病的方法,因移植相关病死率较高,尚不能大规模开展。当高危急性白血病、慢性髓细胞白血病的患者没有合适的亲缘供者时,URD－BMT不失为治疗的措施之一。     

Transplantation of highly purified CD34+ progenitor cells from unrelated donors in pediatric leukemia

Unrelated donors are commonly used for hematopoietic stem cell transplants, but graft-versus-host disease (GVHD) is a major problem. We investigated whether transplantation of purified mobilized peripheral-blood CD34(+) stem cells from unrelated donors would prevent acute and chronic GVHD in pediatric patients with leukemia and avert the need for pharmacologic immunosuppression. Thirty-one pediatric patients with acute lymphoblastic leukemia (ALL, n = 16), acute myeloid (n = 7), chronic myeloid (n = 6), or juvenile myelomonocytic leukemia (n = 2) underwent transplantation. The median purity of CD34(+) cells after positive magnet-activated cell sorting was 98.5%. Patients received a median of 8.0 x 10(6) CD34(+) cells and 6 x 10(3) CD3(+) T lymphocytes per kilogram, with no posttransplantation pharmacologic immunosuppression. Primary acute GVHD > or = grade II was seen in only 10% of patients (n = 3) and occurred only after human herpesvirus 6 (HHV 6) infection. Two patients had limited chronic GVHD. Engraftment occurred in all patients (primary engraftment, n = 26; engraftment after reconditioning, n = 5). The 2-year survival estimate was 38% for all patients and 63% for patients with ALL in complete remission. Patients with myeloid malignancies had a poor outcome. In comparison to a historical control group who received unmanipulated bone marrow, our patients had a lower incidence of GVHD (P <.001). No difference was observed in the probability of relapse or survival. Study patients with ALL in remission showed a trend toward better survival (P =.07). Transplantation of purified peripheral-blood CD34(+) cells from unrelated donors effectively minimizes GVHD and may be a good therapeutic option for patients with relapsed ALL.     

Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions

The efficacy and toxicity of donor leukocyte infusions (DLI) after unrelated donor bone marrow transplantation (BMT) is largely unknown. We identified 58 recipients of unrelated DLI (UDLI) for the treatment of relapsed disease from the National Marrow Donor Program database. A retrospective analysis was performed to determine response, toxicity, and survival after UDLI and to identify factors associated with successful therapy. UDLI was administered for relapsed chronic myelogenous leukemia (CML) (n = 25), acute myelogenous leukemia (AML) (n = 23), acute lymphoblastic leukemia (ALL) (n = 7), and other diseases (n = 3). Eight patients were in complete remission (CR) before UDLI, and 50 were evaluable for response. Forty-two percent (95% confidence interval [CI], 28%-56%) achieved CR, including 11 of 24 (46%; 95% CI, 26%-66%) with CML, 8 of 19 (42%; 95% CI, 20%-64%) with AML, and 2 of 4 (50%; 95% CI, 1%-99%) with ALL. The estimated probability of disease-free survival (DFS) at 1 year after CR was 65% (95% CI, 50%-79%) for CML, 23% (95% CI, 9%-38%) for AML, and 30% (95% CI, 6%-54%) for ALL. Acute graft-versus-host disease (GVHD) complicated UDLI in 37% of patients (grade II-IV, 25%). A total of 13 of 32 evaluable patients (41%) developed chronic GVHD. There was no association between cell dose administered and either response or toxicity. In a multivariable analysis, only a longer interval from BMT to relapse and BMT to UDLI was associated with improved survival and DFS, respectively. UDLI is an acceptable alternative to other treatment options for relapse after unrelated donor BMT. (Blood. 2000;95:1214-1221)     

Anti-thymocyte globulin overcomes the negative impact of HLA mismatching in transplantation from unrelated donors

OBJECTIVE: About one third of patients requiring allogeneic hematopoetic stem cell transplantation (HSCT) would not find a matched sibling or alternative donor. Allogeneic HSCT from matched unrelated and mismatched donors carries an increased risk of graft-vs-host disease (GVHD) and transplant-related mortality (TRM). MATERIALS AND METHODS: We used anti-thymocyte globulin (ATG-Fresenius) at a median dose of 90 mg/kg body weight as part of a total body irradiation or busulfan-based conditioning regimen for prevention of serious GVHD. All patients received cyclosporine A and short-course methotrexate. We compared outcomes of 65 recipients of human leukocyte antigen (HLA)-mismatched unrelated grafts and 194 recipients of HLA-matched unrelated grafts. Mismatches involved one or two loci. Both groups were comparable in age, graft source, diagnosis, stage of disease, and conditioning regimen, and differed only in dose of ATG administered. RESULTS: For matched and mismatched transplants, respectively, there was no significant difference in graft failure (0.5% vs 3%; p = 0.16), in the cumulative incidence of grade II to IV acute GVHD (45% vs 35%; p = 0.14) and no difference in overall chronic GVHD (42% vs 40%; p = 0.68). Estimated overall survival (OS) and disease-free survival (DFS) at 5 years were 55% vs 50% (p = 0.99) and 47% vs 47% (p = 1.0), respectively. The cumulative incidence of relapse and TRM at 5 years were 24% vs 25% (p = 0.63), and 29% vs 27% (p = 0.59), respectively. CONCLUSION: Inclusion of ATG-Fresenius in the conditioning regimen permits HSCT from mismatched unrelated donors without excess TRM and GVHD, resulting in identical OS and DFS of recipients of HLA-matched and HLA-mismatched grafts.     

Donor leukocyte infusions in acute lymphocytic leukemia

Donor leukocyte infusion (DLI) has well-documented activity in CML but the role of DLI in other diseases is less well defined. To evaluate the strategy in acute lymphocytic leukemia (ALL) we evaluated 44 ALL patients from 27 centers who were treated with DLI. Patients with persistent or recurrent disease received DLI from the original marrow donor (30 matched related, four mismatched family, and 10 matched unrelated). Chemotherapy was given before DLI to 28 patients. Of 15 patients who received no pre-DLI chemotherapy, two achieved complete remissions, lasting 1112 and 764+ days. In four patients who received DLI as consolidation of remission induced by chemotherapy or immunosuppression-withdrawal, duration of remission post DLI was 65, 99, 195 and 672+ days. Of 25 patients who received DLI in the nadir after chemotherapy, 13 survived > or =30 days post DLI but did not achieve remission, seven died within less than 30 days post DLI, and five entered remissions that lasted 42, 68, 83, 90, 193 days. Seven patients who did not respond to the initial DLI received a second DLI; none of these patients attained durable remission. Eighteen of 37 evaluable patients developed acute GVHD and five of 20 evaluable patients developed chronic GVHD. Overall actuarial survival is 13% at 3 years. In conclusion, DLI has limited benefit in ALL. New approaches are needed in this group of patients.     

Unrelated donor or autologous marrow transplantation for treatment of acute leukemia

High-dose chemoradiotherapy followed by marrow transplantation from an HLA-matched sibling donor is curative for patients with acute leukemia. Autologous marrow transplantation has been used with success for some patients without such a sibling. Alternatively, the option of performing a transplant from an HLA-matched unrelated donor has been made possible by the recent development of large registries of HLA- typed volunteers. The purpose of this study was to compare the outcomes for patients with advanced leukemia treated by unrelated or autologous marrow transplantation. Forty-three patients with acute myeloid or lymphoid leukemia were transplanted from a closely HLA-matched unrelated donor. Results were compared with those of a disease-, disease-stage-, and age-matched cohort of 77 patients treated with autologous marrow transplantation at the same institution during the same period. Myeloid reconstitution with peripheral granulocyte counts greater than 10(9)/L was achieved in 93% of unrelated recipients and 70% of autologous recipients at a median of 24 and 36 days after transplantation, respectively (P = .0001). The cumulative proportions of patients discharged alive (79% v 77%) and times from transplant to first hospital discharge (35 v 34 days) were not different between unrelated and autologous recipients (P = .65). For patients transplanted in complete remission, relapse occurred after transplantation in 27% of the unrelated and in 55% of the autologous recipients (P = .08). For patients transplanted in relapse, the corresponding posttransplant relapse rates were 48% and 63%, respectively (P = .72). Forty percent of unrelated recipients and 28% of autologous recipients died in remission. Leukemia-free survivals were 33% for unrelated and 25% for autologous recipients transplanted in remission (P = .45), and 12% for unrelated and 5% for autologous recipients transplanted in relapse (P = .75). Unrelated donor transplants appear no less effective than autologous transplants to achieve long-term survival and may be more effective in eradicating leukemia in patients who have failed conventional chemotherapy. Further studies are warranted to assess the relative effectiveness of unrelated and autologous transplantation performed earlier in the course of the disease.     

Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients

Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5-37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.     

Outcomes of unrelated cord blood transplants and allogeneic-related hematopoietic stem cell transplants in children with high-risk acute lymphocytic leukemia

Acute lymphocytic leukemia (ALL) is a common indication for hematopoietic stem cell transplantation (HSCT) in children. Use of unrelated cord blood (UCB) has become increasingly popular as a stem cell source, given the rapid availability and decreased GVHD potential. Publications describing outcomes of children with leukemia who underwent UCB transplants have compared them to those having received unrelated donor marrow transplants. Results are similar. We compared our outcomes using UCB vs allogeneic-related hematopoietic stem cells in pediatric ALL patients since 1992. A total of 49 patients were analyzed. All patients were either in CR1 with high-risk features (n=21) or in CR2 (n=28) with initial remission less than 36 months. Patients received myeloablation with fractionated total body irradiation, cyclophosphamide, and etoposide and GVHD prophylaxis with cyclosporine and methotrexate. Antithymocyte globulin was added for UCB recipients to address the HLA differences. In all, 23 patients underwent allogeneic -related HSCT and 26 underwent UCB transplantation. Other than increased time to engraftment for UCB recipients, results are equivalent. The 3-year overall survival is 64% and 3-year event-free survival is 60% for both groups. Rates of GVHD and transplant-related mortality are also equivalent. UCB is a reasonable option for children with ALL who are referred for HSCT.     

Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant

We report 27 patients with relapsed acute or chronic leukemia who underwent a second hematopoietic stem cell transplant (HSCT) from a related or unrelated donor. Seventeen patients were diagnosed with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL) and four with chronic myeloid leukemia (CML). Ages ranged from 22 to 49 years (median 37); 13 patients were female and 14 male. Relapse was diagnosed between 1 and 45 months after the first HSCT. Sixteen patients who relapsed had received an autologous transplant initially and 11 an allogeneic transplant. Ten patients relapsed within 6 months and 17 patients later than 6 months. Chemotherapy was used as reinduction for relapse after HSCT in 16 patients who had received an autologous transplant and in three who had received an allogeneic transplant, since the latter did not respond to reduction of immunosuppression to induce a graft-versus-leukemia (GVL) reaction. Five of these 19 patients (26%) achieved complete remission (CR), seven patients did not respond to chemotherapy and seven achieved a partial remission (PR). The stem cell source for the second HSCT included bone marrow (n = 12) and PBSC (n = 4) from genotypically identical unrelated donors, PBSC (n = 7) and bone marrow (n = 3) from related donors. Currently eight of the 27 patients are alive and disease-free after the second HSCT. One patient is alive and disease-free after two allogeneic transplants (day +1538), eight patients, who relapsed after an autologous transplant followed by an allogeneic transplant (days +248 to +1140), acute myeloid leukaemia (n = 6) and chronic myeloid leukemia (n = 2) are alive and disease-free. The overall disease-free survival is 30% (8/27). The overall disease-free survival of autologous transplant patients subsequently undergoing an allogeneic transplant is 43% (P = 0.049). It is suggested that a second HSCT is possible for patients with leukemia relapse following the first autologous transplant. A second transplant might also be offered to patients relapsing after the first allogeneic HSCT. Bone Marrow Transplantation (2000) 25, 41-45.