Allogeneic bone marrow transplantation from partially mismatched related donors as therapy for primary induction failure acute myeloid leukemia

The outcome of acute myeloid leukemia patients with primary refractoriness to conventional chemotherapy is extremely poor. Allogeneic bone marrow transplants with matched sibling or matched unrelated donors provide 10-20% disease-free survival in this setting. We analyzed our transplant experience using readily available partially mismatched related donor (PMRD) in patients with primary induction failure (PIF) AML. Between March 1994 and December 1998, 13 patients with PIF AML were transplanted from 0-3 HLA antigen mismatched donors. All 12 evaluable patients engrafted at a median of day +16. Ten (77%) patients survived at least 100 days after transplant. Acute GVHD (grade II) was observed in one of 12 patients. Chronic GVHD was seen in one of 10 patients surviving beyond day 100. The major cause of failure was relapse of disease in six occurring 3-12 months after PMRD BMT. Three patients are alive without disease 14, 36 and 45 months post BMT with Karnofsky scores of 100%. The actuarial 3-year probabilities of relapse and disease-free survival were 0.54 and 0.19, respectively. We concluded that a PMRD graft is a viable option, comparable to the use of matched related or unrelated donors, in patients with PIF AML in whom time is of the essence.     

Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients

Between February 1993 and December 1999, 201 patients (1-59 years old, median 23) with acute leukemia (67% not in remission) underwent ex vivo T-cell-depleted (TCD) bone marrow transplants (BMT) from partially mismatched related donors (PMRD; 92% mismatched for 2-3 HLA A, B, DR antigens). Conditioning comprised total body irradiation, cyclophosphamide, cytarabine, etoposide, anti-thymocyte globulin (ATG), and methylprednisolone. Graft-versus-host disease (GVHD) prophylaxis comprised partial TCD with OKT3 (n=143) or T10B9 (n=58), steroids, ATG, and cyclosporine. The engraftment rate was 98%. The cumulative incidences of grades II-IV acute GVHD and chronic GVHD were 13 and 15%, respectively. The 5-year cumulative incidences of relapse and transplant-related mortality (TRM) were 31 and 51%, respectively. The actuarial 5-year overall survival (OS) and disease-free survival (DFS) probabilities were 19 and 18%, respectively. Patient age >15 years, active disease at transplant, donor age >25 years, and 3-antigen donor mismatch (host-versus-graft) affected the outcome adversely. The actuarial 5-year OS of four groups of patients identified based upon these risk factors was 39, 20, 13, and 0%, respectively (P<0.0001). We conclude that PMRD BMT is a potential treatment option for patients with high-risk acute leukemia who require an alternative donor transplant and fall into a group with a reasonable expected outcome.     

Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings,partially HLA-mismatched related donors,and HLA-matched unrelated donors

Allogeneic hematopoietic stem cell transplantation (HSCT) is a proven curative therapy for many hematologic malignancies. HSCT from HLA-identical sibling donors (ISDs) is still the golden standard. For the remaining 70% of the patients lacking an ISD, alternative (partially) HLA-matched family donors (MFDs) and HLA-matched unrelated donors (MUDs) are now widely accepted. However, it is presently unclear whether outcome after HSCT from an MFD or an MUD is superior. Thus, the classical clinical end points after HSCT from an ISD (n = 138), MFD (n = 86), and MUD (n = 101) were compared by means of univariate and multivariate statistical analyses. MFD transplantations with HLA class II (DRB1 +/- DQB1) mismatches in graft-versus-host (GVH) direction showed an increased risk of grades II to IV graft-versus-host disease, and MFD transplantations with more than a single HLA class I (A +/- B +/- C) mismatch in host-versus-graft (HVG) direction were associated with a higher risk of graft failure. However, no significant difference in overall survival was detectable among the 3 study groups after adjustment for the main predictors of transplantation outcome. Thus, for patients lacking an ISD, an already identified MFD with an HLA-DRB1 +/- DQB1 mismatch in GVH or a combined HLA-A +/- B +/- C mismatch in HVG direction should be accepted only in clinically urgent settings that leave no time to identify an MUD.     

T cell non-depleted bone marrow transplantation for primary refractory erythroleukemia using a partially HLA-mismatched related donor]

We performed an HLA-mismatched T cell non-depleted bone marrow transplant on a 53-year-old man with acute erythroleukemia that was highly resistant to conventional remission-induction chemotherapy. After conditioning that included total body irradiation, the patient received a two-HLA-antigen-mismatched bone marrow graft harvested from his sister using tacrolimus and methotrexate for graft-versus-host disease (GVHD) prophylaxis. He successfully established rapid engraftment accompanied by steroid-responsive GVHD localized to the skin. Although bone marrow samples on day 31 and day 66 disclosed a complete remission with full donor chimerism, the patient relapsed and died of pulmonary infection on day 154. There is evidence that tacrolimus is effective in alleviating GVHD. Selected patients who have partially mismatched related donors with less HLA disparity may benefit from tacrolimus-based T cell non-depleted bone marrow transplants because of the more potent graft-versus-leukemia effect that can be expected compared to transplants using T cell depleted inoculum.     

Allogeneic hematopoietic cell transplantation with reduced-intensity conditioning following FLAMSA for primary refractory or relapsed acute myeloid leukemia

Patients with primary refractory or relapsed acute myeloid leukemia (AML) have a dismal prognosis. We report a retrospective single center analysis of aplasia-inducing chemotherapy using fludarabine, cytarabine, and amsacrine (FLAMSA) followed by reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (HCT) in 62 consecutive primary refractory or relapsed AML patients. Two-year event-free survival and overall survival (OS) were 26 and 39 %, respectively. Risk stratification according to cytogenetic and molecular genetic markers showed superior survival in patients in the intermediate-1 risk group (2-year OS 70 %) compared to the intermediate-2 risk (2-year OS 34 %, p?=?0.03) and adverse risk (2-year OS 38 %, p?=?0.06) group. The use of HLA-matched versus HLA-mismatched donors had no significant influence on survival (p?=?0.98). Two-year OS in the elderly subgroup defined by age ≥60 years was 31 % compared to 46 % in the group of younger patients <60 years (p?=?0.19). Cumulative incidence of non-relapse mortality at 2 years adjusted for relapse as competing risk was 20 % for patients <60 years and 26 % for older patients (p?=?0.55). Chronic graft-versus-host disease was associated with a statistically significant superior survival (p?<?0.01). FLAMSA-RIC followed by allogeneic HCT enables long-term disease-free survival in primary refractory or relapsed AML even in the elderly patient population.     

Hematopoietic SCT from partially HLA-mismatched (HLA-haploidentical) related donors

Hematopoietic SCT from a partially HLA-mismatched (HLA-haploidentical) first-degree relative offers the benefits of rapid and near universal donor availability but also the risks that result from traversing the HLA barrier; namely, graft failure, severe GVHD and prolonged immunodeficiency. Improvements over the last 10 years in conditioning regimens, graft engineering and pharmacological immunoprophylaxis of GVHD have substantially reduced the morbidity and mortality of HLA-haploidentical SCT. Highly immunosuppressive but nonmyeloablative conditioning extends the availability of HLA-haploidentical SCT to elderly hematologic malignancy patients lacking HLA-matched donors and permits recovery of autologous hematopoiesis in the event of graft failure. Current regimens for HLA-haploidentical SCT are associated with a 2-year non-relapse mortality of 20+/-5%, relapse of 35+/-15% and overall survival of 50+/-20%. Major developmental areas include harnessing natural killer cell alloreactivity to reduce the risk of disease relapse and improving immune reconstitution by delayed infusions of lymphocytes selectively depleted of alloreactive cells. Hematologic malignancy patients who lack suitably matched related or unrelated donors can now be treated with HLA-haploidentical related donor or unrelated umbilical cord blood SCT. Future clinical trials will assess the relative risks and benefits of these two graft sources.     

Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease

To reduce the morbidity and mortality associated with unrelated donor bone marrow (BM) transplantation and potentially extend the pool of suitable donors, cryopreserved unrelated donor umbilical cord blood was considered as an alternate source of hematopoietic stem cells for transplantation. Patients with leukemia, BM failure syndrome, or inborn error of metabolism were eligible for a phase I clinical trial designed to estimate the risk of graft failure and severe acute graft-versus- host disease after transplantation of umbilical cord blood from unrelated donors. As of December 21, 1995, unrelated donor umbilical cord blood was used to reconstitute hematopoiesis in eighteen patients aged 0.1 to 21.3 years weighing 3.3 to 78.8 kg with acquired or congenital lympho-hematopoietic disorders or metabolic disease. Patients received either HLA-matched (n = 7) or HLA-1 to 3 antigen disparate (n = 11) grafts collected and evaluated by the New York Blood Center (New York, NY). The probability of engraftment after unrelated donor umbilical cord blood transplantation was 100% with no patient having late graft failure to date. The probability of grade III-IV acute graft-versus-host disease at 100 days was 11%. With a median follow-up of 6 months (range, 1.6 to 17 months); the probability of survival at 6 months is 65% in this high risk patient population. We conclude that cryopreserved umbilical cord blood from HLA-matched and mismatched unrelated donors is a sufficient source of transplantable hematopoietic stem cells with high probability of donor derived engraftment and low risk of refractory severe acute graft-versus-host disease. Limitations with regard to recipient size and degree of donor HLA disparity remain to be determined.     

Allogeneic transplantation for advanced acute leukemia

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Phase I trial of interleukin-2 after unmodified HLA-matched sibling bone marrow transplantation for children with acute leukemia

Allogeneic bone marrow transplantation (BMT) for advanced acute leukemia is associated with a high risk of relapse. It is postulated that interleukin-2 (IL-2) administered after BMT might induce or amplify a graft-versus-leukemia effect and thereby reduce the relapse rate. To identify an IL-2 regimen for testing this hypothesis, a phase I trial of IL-2 (Roche) was performed in children in complete remission (CR) without active graft-versus-host disease (GVHD) off immunosuppressive agents after unmodified allogeneic matched-sibling BMT for acute leukemia beyond first remission. Beginning a median of 68 days after BMT, 17 patients received escalating doses of induction IL-2 (0.9, 3.0, or 6.0 x 10(6) IU/m2/d representing levels I, II, and III) for 5 days by continuous intravenous infusion (CIV). After 6 days of rest, they received maintenance IL-2 (0.9 x 10(6) IU/m2/d) for 10 days by CIV infusion. Levels I and II were well-tolerated, but, of 6 patients at level III, 1 developed pulmonary infiltrates, 1 developed hypotension (both resolved), and 1 died of bacterial sepsis and acute respiratory distress syndrome. Grade II acute GVHD developed in 1 patient at level I and 1 at level III. The maximum tolerated dose of induction IL-2 was level II. IL-2 induced lymphocytosis, with an increase in CD56+ and CD8+ cells. Ten patients remain in CR at 5+ to 67+ months. Thus, a regimen of IL-2 has been identified that did not induce a high incidence of acute GVHD when administered to children after unmodified allogeneic BMT. Its clinical activity will be assessed in a phase II trial.     

Allogeneic bone marrow transplantation for infants with acute leukemia or myelodysplastic syndrome

The objective of this study is to investigate the outcome of children 24 months of age or younger (infants) at the time of allogeneic bone marrow transplantation (BMT) for acute leukemia or myelodysplasia. We analyzed the survival rate, prognostic factors, incidences of late sequelae, and immune reconstitution in 22 infants who underwent allogeneic BMT. The 5-year event-free survival estimate was 45.5% (95% confidence interval (CI), 24.4% to 63.3%). Six patients died of transplant-related complications and six died of disease relapse. Remission status at the time of BMT was the most important prognostic factor (P = 0.005): no patient who received a transplant while their disease was not in remission survived, whereas the 5-year survival estimate for infants who underwent BMT during remission was 56% (95% CI, 31% to 75%). Long-term outcomes in the 10 infant survivors were compared with those of 10 older controls matched for diagnosis, disease status at the time of BMT, calendar year at the time of BMT, and source of stem cells. Immune function 1 year after transplantation and the incidences and spectra of late sequelae were similar for both groups during a median of 3.5 years (range, 1.5 to 7.2 years) of follow-up.     

Allogeneic bone marrow transplantation using partially-matched related donors

Six patients with advanced leukemia and one with severe combined immunodeficiency syndrome received allogeneic bone marrow transplantation (BMT) from HLA haploidentical donors who were compatible for one or two loci on the non-shared chromosome. Methotrexate was used for prophylaxis against acute graft-versus-host disease (GVHD). All patients engrafted but developed moderate to severe acute GVHD, and three patients died. Two leukemic patients relapsed but two others survived and were free of disease 403 and 936 days post-transplant. BMT using related partially matched donors may result in durable engraftment and long-term survivors. The implications of using such donors in expanding the application of BMT are discussed.     

异基因造血干细胞移植治疗MDS临床研究

目的探讨HLA配型相合异基因造血干细胞移植（allo—HSCT）治疗骨髓增生异常综合征（MDS）的可行治疗方案和疗效。方法以HLA配型相合的骨髓移植治疗MDS患者6例,预处理方案为非清髓性预处理方案1例,清髓性预处理方案5例;以霉酚酸酯、环孢菌素A加短疗程的甲氨喋呤预防移植物抗宿主病（GVHD）。结果6例患者均造血重建。5例清髓性预处理方案仍然无病存活,非清髓性预处理方案1例移植后出现MDS,于移植后17个月死亡。移植后最长无病存活时间已达8a。移植期间发生Ⅰ、Ⅱ°急性移植物抗宿主病（aGVHD）4例。结论allo-HSCT治疗MDS可行、有效,清髓性预处理方案可能对于长期稳定植入有利。     

Allogeneic stem-cell transplantation in patients with refractory acute leukemia: a long-term follow-up

We examined retrospectively 44 patients with refractory acute leukemia (acute myeloid leukemia (AML)/acute lymphoblastic leukemia=25/19) who underwent allogeneic transplantation at our center between 11/1990 and 04/2004. The median leukemic blasts was 25% and age 28 years (range, 3-56). Twenty-one patients had untreated relapse, 13 failed reinduction, eight in partial remission and two aplastic. Conditioning was myeloablative using cyclophosphamide, busulfan, total-body irradiation and etoposide (Bu/Cy/VP, n=22; TBI/Cy/VP, n=17; others, n=5) followed by marrow or peripheral blood transplant (n=23/21) from unrelated or related donors (n=28/16). All patients had graft-versus-host disease (GVHD) prophylaxis with cyclosporin and methotrexate. One patient experienced late graft failure. Severe acute-GVHD and chronic-GVHD appeared in eight and 14 patients, respectively. Thirteen patients (30%) remain alive after a median of 25.3 months (range, 2.4-134.1); with 31 deaths, mostly from relapse (n=15) and infections (n=12). Overall survival (OS) and progression-free survival (PFS) at 5 years was 28 and 26%, respectively. OS and PFS were significantly better with blasts < or =20% and time to transplant < or =1 year while transplant-related mortality was less with the use of TBI. We conclude that patients with refractory leukemia can benefit from allogeneic BMT, especially with < or =20% marrow blast.     

Allogeneic or autologous bone marrow transplantation for acute non-lymphocytic leukemia in first remission

One hundred and seven consecutive patients with acute non-lymphocytic leukemia (ANL) aged less than 56 years were allocated to receive either allogeneic (allo-BMT) or autologous bone marrow transplantation (auto-BMT) when first complete remission (CR1) was achieved. CR was obtained in 96 patients. Twenty-four patients had an HLA-identical sibling donor and 20 of these (83%) had an allograft in CR1. Thirty-three patients (44% of the CR1 patients without donor) had an autograft in CR1. The reasons for not transplanting patients in CR1 were early relapse (nine patients), refusal (11 patients) or medical problems (23 patients). The 4-year leukemia-free survival (LFS) probability for all the CR1 patients was 25%. For the allo-BMT patients, the 4-year LFS was 71%, and for the auto-BMT patients 31% (log-rank p = 0.028). The relapse probabilities were 33% and 48% respectively (p = 0.40). If the results are analysed according to the intent of the protocol, patients with a donor had an LFS of 53%, and patients without a donor an LFS of 16% (p = 0.003). This study confirms the value of allo-BMT for consolidation of ANL in CR1. The attempt to autograft all CR1 patients without a compatible donor has not resulted in any marked improvement of LFS.     

Allogeneic transplantation for the elderly patient with acute myelogenous leukemia or myelodysplastic syndrome

Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) are diseases of the elderly. Allogeneic hematopoietic stem cell transplantation (HSCT) offers the possibility of cure for these malignancies, but until recently its use was restricted to younger patients due to prohibitive treatment-related mortality. Improvements in supportive care and development of reduced-intensity preparative regimens have allowed patients in the sixth, seventh, and to a lesser extent, eighth decade of life to be treated with allogeneic transplantation. Major obstacles to extending this form of treatment to older patients are lack of promptly available donors, graft-versus-host disease (GVHD), delayed immune recovery, and the high prevalence of refractory and relapsed disease intrinsic to the natural history of these myeloid malignancies. Here we review current results of allogeneic blood and marrow transplantation for AML and MDS in the elderly.     

Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors

Background

Transplantation from an HLA-matched sibling is the treatment of choice for young patients with acquired severe aplastic anemia. For older patients, the acceptable upper age limit for transplantation as first-line treatment varies. The current analysis, therefore, sought to identify age or ages at transplantation at which survival differed.

Design and Methods

We studied the effect of patients’ age, adjusting for other significant factors affecting outcomes, in 1307 patients with severe aplastic anemia after HLA-matched sibling transplantation using logistic and Cox regression analysis. Age categories (<20 years, 20–40 years, >40 years) were determined using Martingale residual plots for overall survival and categories based on differences in survival.

Results

Patients aged over 40 years old were more likely to have had immunosuppressive therapy, a poor performance score and a longer interval between diagnosis and transplantation. Neutrophil recovery was similar in all age groups but patients aged over 40 years had a lower likelihood of platelet recovery compared to patients aged less than 20 years (OR 0.45, P=0.01) but not compared to those aged 20–40 years (OR 0.60, P=0.10). Compared to the risk of mortality in patients aged less than 20 years, mortality risks were higher in patients over 40 years old (RR 2.70, P<0.0001) and in those aged 20–40 years (RR 1.69, P<0.0001). The mortality risk was also higher in patients aged over 40 years than in those 20–40 years old (RR 1.60, P=0.008).

Conclusions

Mortality risks increased with age. Risks were also higher in patients with a poor performance score and when the interval between diagnosis and transplantation was longer than 3 months, implying earlier referral would be appropriate when this treatment option is being considered.