Maintenance therapy after allogeneic hematopoietic cell transplantation for acute myeloid leukemia

With improvements in the safety of allogeneic hematopoietic cell transplantation, disease recurrence following the procedure is now the most frequent reason for treatment failure. Administration of maintenance therapy after transplantation is one way to try and prevent recurrence. This paper provides a brief review of the topic.     

Monosomy 7 associated with pediatric acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS): successful management by allogeneic hematopoietic stem cell transplant (HSCT)

Pediatric acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with monosomy 7 is associated with poor disease-free survival when treated by conventional chemotherapy, immunosuppression or supportive measures. Hematopoietic stem cell transplant (HSCT) may improve outcomes; however, data to support this are limited. To better understand the curative potential of HSCT in these patients, all cases of AML and MDS with monosomy 7 treated by two transplant programs (1992 to present) were reviewed. A total of 16 patients were treated, all by allogeneic HSCT. Primary diagnoses were MDS (N = 5), therapy-related MDS (N = 3), AML (N = 5) and therapy-related AML (N = 3). In all, 11 patients (69%) survive event-free at 2 years with median follow-up of 986 days (range 330-2011 days). Toxicity caused deaths of the five nonsurviving patients, four of whom were transplanted with active leukemia. Allogeneic HSCT is effective therapy for childhood AML and MDS associated with monosomy 7, particularly for patients with AML in complete remission and MDS.     

Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS

This study investigated the feasibility of allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) as postconsolidation therapy for patients with myelodysplastic syndromes (MDSs) or acute myeloid leukemia after MDS. Patients with a histocompatible sibling were candidates for alloSCT and the remaining patients for ASCT. Remission-induction therapy consisted of 1 or 2 courses with idarubicin, cytarabine, and etoposide, followed by one intensive consolidation course with cytarabine and mitoxantrone. Initially, bone marrow cells were used for ASCT. Subsequently, mobilized blood stem cells were used in an attempt to shorten posttransplantation hypoplasia. With a median follow-up of 3.6 years the 184 evaluable patients showed a 4-year survival rate of 26% and a median survival of 13 months. The remission-induction chemotherapy induced complete remission (CR) in 100 patients (54%). The 4-year disease-free survival (DFS) rate was 29% and the median DFS was 12 months. Twenty-eight of 39 patients (72%) with a donor were allografted in CR-1, including 2 patients who underwent transplantation in CR-1 without a consolidation course. Thirty-six of 59 patients (61%) without a donor received ASCT in CR-1. The 4-year DFS rates in the group of patients with or without a donor were 31% and 27%, respectively. The 4-year survival rates from CR were 36% and 33%, respectively. This large prospective study shows the feasibility of both alloSCT and ASCT. This treatment approach leads to a relatively high remission rate, and the majority of patients in remission received the SCT in CR-1. The ongoing study investigates whether this approach is better than treatment with chemotherapy only.     

Donor cell-derived acute myeloid leukemia developed shortly after allogeneic bone marrow transplantation for MDS overt leukemia

We report a patient with myelodysplastic syndrome (MDS) overt leukemia who developed an acute myeloid leukemia (AML) in donor cells shortly after bone marrow transplantation (BMT) from his HLA-matched sibling. Molecular analysis using microsatellite repeats by polymerase chain reaction proved the new leukemia to be of donor cell origin. The patient received chemotherapy with idarubicin and ara-C, but he died due to mucormycosis.     

Autologous stem cell transplantation for therapy-related acute myeloid leukemia and myelodysplastic syndrome

We report the results of 65 patients with treatment-related myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) who were transplanted from an autograft and reported to the EBMT. The median age was 39 years (range, 3-69), and stem cell source was bone marrow (n = 31), or peripheral blood progenitor cells (n = 30), or the combination of both (n = 4). The primary disease was solid tumors (n = 37), Hodgkin's disease (n = 13), non-Hodgkin's lymphoma (n = 10), acute lymphoblastic leukemia (n = 2) or myeloproliferative syndromes (n = 3). The types of MDS were as follows: RAEB (n = 1; 2%), RAEB-t (n = 3; 5%), or AML (n = 56; 87%). The median time between diagnosis and transplantation was 5 months (range, 3-86). The Kaplan-Meier estimates of the probability of 3-year overall and disease-free survival were 35% (95% CI: 21-49%) and 32% (95% CI: 18-45%), respectively. The median leukocyte engraftment was faster after transplantation with peripheral blood stem cells than with bone marrow: 12 (range, 9-26) vs 29 (range, 11-67) days (P<0.001). The cumulative incidence of relapse was 58% (95% CI: 44-72%) and of treatment-related mortality 12% (95% CI: 6-38%). Lower relapse rate was seen in patients transplanted in first complete remission (CR1 vs non-CR1: 3 years: 48 vs 89%; P = 0.05). Furthermore, age beyond 40 years resulted in a higher treatment-related mortality (47 vs 7%; P = 0.01). In a multivariate analysis, transplantation in CR1 age as well as their interaction influenced overall survival significantly. Autologous transplantation may cure a substantial number of patients with treatment-related MDS/AML, especially if they are in CR1 and of younger age.     

Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS)

We investigated a dose-reduced conditioning regimen consisting of treosulfan and fludarabine followed by allogeneic stem cell transplantation (SCT) in 26 patients with secondary AML or MDS. Twenty patients were transplanted from matched or mismatched unrelated donors and six from HLA-identical sibling donors. The median age of the patients was 60 years (range, 44-70). None of the patients was eligible for a standard myeloablative preparative regimen. No graft-failure was observed, and leukocyte and platelet engraftment were observed after a median of 16 and 17 days, respectively. Acute graft-versus-host disease (GvHD) grade II-IV was seen in 23% and severe grade III GvHD in 12% of the patients. No patients experienced grade IV acute GvHD. Chronic GvHD was noted in 36% of the patients, which was extensive disease in 18%. The 2-year cumulative incidence of relapse was 21%. The relapse rate was higher in patients beyond CR1 or with intermediate two or high risk MDS (P = 0.02). The treatment-related mortality at day 100 was 28%. The 2-year estimated overall and disease-free survival was 36-34%, respectively. No difference in survival was seen between unrelated and related SCT.     

Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS

Clonal cytogenetic abnormalities are a major risk factor for relapse after hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS). We determined the impact of the recently established 5-group cytogenetic classification of MDS on outcome after HCT. Results were compared with the impact of the International Prognostic Scoring System (IPSS) 3 cytogenetic risk groups, and the additional effect of a monosomal karyotype was assessed. The study included data on 1007 patients, 1-75 years old (median 45 years), transplanted from related (n = 547) or unrelated (n = 460) donors. Various conditioning regimens were used, and marrow, peripheral blood, or cord blood served as stem cell source. Both IPSS and 5-group cytogenetic risk classifications were significantly associated with post-HCT relapse and mortality, but the 5-group classification discriminated more clearly among the lowest- and highest-risk patients. A monosomal karyotype tended to further increase the rates of relapse and mortality, even after considering the IPSS or 5-group classifications. In addition, the pathologic disease category correlated with both relapse and mortality. Mortality was also impacted by patient age, donor type, conditioning regimen, platelet count, and etiology of MDS. Although mortality declined significantly in recent years, novel strategies are needed to overcome the barrier of high-risk cytogenetics.     

Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning

Reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) has improved the accessibility of transplantation in patients previously ineligible. We report the results of allografting following conditioning with fludarabine, busulphan, and alemtuzumab in 62 patients with myelodysplastic syndromes (MDSs) (matched sibling donors [24] or volunteer unrelated donors [VUDs, 38]). The median age for sibling recipients was 56 years (range, 41-70 years) and for VUD recipients, 52 years (range, 22-65 years), with a median follow-up (survivors) of 524 days (range, 93-1392 days) and 420 days (range, 53-1495 days), respectively. The nonrelapse mortality (NRM) at days 100, 200, and 360 was 0%, 5%, and 5%, respectively, for siblings and 11%, 17%, and 21%, respectively, for VUD. The overall survival at one year was 73% for siblings and 71% for VUDs, with a disease-free survival (DFS) of 61% and 59%, respectively. The prognostic significance of the International Prognostic Scoring System (IPSS) was preserved. Of recipients, 86% achieved full-donor chimerism. The cumulative incidence at day 100 of grades III to IV graft-versus-host disease (GVHD) for VUD recipients was 9% and for sibling recipients, 0%. There were 26 patients (16 sibling and 10 VUD) who received donor lymphocyte infusion (DLI) at a median of 273 days (range, 126-1323 days). RIC allogeneic HSCT using this protocol appears to be safe and permits durable donor engraftment. Longer follow-up is required to confirm any potential survival advantage.     

Effectiveness of allogeneic hematopoietic cell transplantation for older patients with acute myeloid leukemia

Outcomes with conventional chemotherapy for older patients with acute myeloid leukemia (AML) remain disappointing, with few cures. For younger patients with AML, allogeneic hematopoietic cell transplantation (HCT) offers the best chance for cure, but this strategy is seldomly used for older patients. With recently improved methodologies, transplantation has become increasingly safe, suggesting that its use in older patients be reconsidered. This report will address four issues: the current frequency of transplantation for AML according to patient age; the impact of patient age on transplant outcomes; the comparative outcomes of transplantation versus chemotherapy for older patients with AML; and possible methods to improve the outcome of allogeneic HCT in older patients with AML.     

Pre-engraftment graft-versus-host disease after allogeneic hematopoietic cell transplantation for acute leukemia

Objectives: Acute graft‐versus‐host disease (GVHD) usually occurs with neutrophil engraftment following allogeneic hematopoietic cell transplantation (HCT), but it can also occur before engraftment. We intended to analyze the effects of timing of acute GVHD on leukemia relapse and mortality. Methods: The outcomes of pre‐ and postengraftment GVHD were investigated in 384 patients who underwent allogeneic HCT for acute leukemia. Results: Acute GVHD occurred in 100 patients, pre‐engraftment in 22 and postengraftment in 78. Compared with postengraftment GVHD, pre‐engraftment GVHD was more severe, as assessed by overall grade, with more frequent and more severe skin involvement and higher incidences of non‐infectious fever, diarrhea, hepatic dysfunction, renal insufficiency, and weight gain. Compared with patients without acute GVHD, those with postengraftment GVHD had lower cumulative incidence of relapse [CIR; hazard ratio (HR), 0.470; P = 0.006] and higher cumulative incidence of non‐relapse mortality (CINRM; HR, 2.568; P < 0.001), while those with pre‐engraftment GVHD had similar CIR (HR, 0.815; P = 0.059) and higher CINRM (HR, 2.872; P = 0.036). Overall survival of patients with pre‐engraftment GVHD was lower than that of those without acute GVHD (HR, 1.976; P = 0.017), which was similar to that of those with postengraftment GVHD (HR, 0.969; P = 0.878). Separate analyses of the effects of timing of acute GVHD on post‐transplant outcomes in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) showed similar trends. Conclusion: Pre‐engraftment GVHD might be a ‘cytokine storm’ type syndrome rather than ‘real’ GVHD, indicating the need for separate analyses of pre‐ and postengraftment GVHD in future trials.     

Survival following relapse after allogeneic hematopoietic cell transplantation for acute leukemia and myelodysplastic syndromes in the contemporary era

Objective/BackgroundRelapse is the most common cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). No standard of care exists, and a wide range of treatments are used for post-alloHCT relapse. In the recent era, several novel therapies including targeted agents are available for acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).MethodsWe reviewed outcomes after alloHCT relapse, with or without use of these newer agents for ALL, AML, and MDS. In total, 115 adults with relapsed or refractory ALL (n = 17), AML (n = 67), and MDS (n = 31) at median 5 (range, 1–64) months after their first alloHCT in 2010–2018 were included.ResultsMedian follow-up was 19 (range, 6–80) months after relapse from alloHCT. Targeted agents were given to 29 (25%) patients. In multivariable analysis, use of targeted agent at any time point after relapse was not associated with survival. Matched unrelated (vs. matched sibling; hazard ratio [HR] 1.70; p = .027) or haploidentical donor grafts (vs. matched sibling; HR 2.69; p = .003), presence of grade II–IV acute graft-versus-host disease before relapse (HR 2.46; p < .001), and less than 12 months from HCT to relapse (<6 vs. > 12 months; HR 6.34; p < .001; 6–12 vs. > 12 months; HR 3.16; p = .005) were adverse prognostic factors for post-relapse survival.ConclusionOutcomes after alloHCT relapse remain poor regardless of the novel agent use. Innovative treatment strategies are needed to improve outcomes after relapse post-alloHCT.     

Role of allogeneic and autologous hematopoietic stem cell transplantation in acute myeloid leukemia

Most younger patients with acute myeloid leukemia will enter remission of disease. Prevention of relapse is now the central therapeutic issue. A number of factors predict the risk of relapse, the most powerful of which is cytogenetics. Both allogeneic and autologous transplantation have been extensively used as remission consolidation, but intensive chemotherapy has also provided improved results such that the choice of consolidation treatment is not clear. Recent prospective trials of allogeneic and autologous transplantation with careful analysis have not always shown a survival benefit, although both approaches have significantly reduced relapse risk. In analysis where relapse risk is taken into account based on cytogenetics, there is little evidence of the benefit of transplantation in good-risk patients, partly because patients in this group who relapse can then undergo successful salvage therapy. The results are still uncertain in standard-risk patients, so transplantation should continue to be used in the context of a trial. Poor-risk patients have a higher failure rate after transplantation, and for these patients novel approaches are required.     

Comparative effectiveness of busulfan/cyclophosphamide versus busulfan/fludarabine myeloablative conditioning for allogeneic hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome

Objective/BackgroundBusulfan/cyclophosphamide (Bu/Cy) and busulfan/fludarabine (Bu/Flu) are both standard myeloablative conditioning (MAC) regimens for allogeneic hematopoietic cell transplantation (alloHCT). We compared the effectiveness of these regimens with a focus on quality of life (QOL).MethodsThis was a single center, retrospective analysis of adult acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients who underwent a first T-cell replete HLA-8/8 matched related or unrelated donor alloHCT. Patients received a myeloablative regimen of either parenteral Bu/Cy or Bu/Flu. Outcomes assessed included infections, graft-versus-host-disease (GVHD), relapse, relapse mortality (RM), relapse-free survival (RFS), nonrelapse mortality (NRM), overall survival (OS), and QOL.ResultsFrom 2008 to 2017, 126 AML and 84 MDS adult patients age ≥18 years were identified meeting inclusion criteria. In terms of QOL, there were no significant differences between Bu/Cy and Bu/Flu cohorts in the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) scores or mucositis severity for either AML or MDS patients. Amongst AML patients, those receiving Bu/Flu had more rapid neutrophil and platelet recovery and a shorter length of hospital stay (LOS); there were no differences in the other posttransplant outcomes. Similarly, amongst MDS patients, those receiving Bu/Flu had more rapid platelet recovery and a shorter LOS as well as more CMV infections, but less NRM and no differences in other outcomes.ConclusionWe confirmed that myeloablative Bu/Flu conditioning has comparable clinical and QOL outcomes to Bu/Cy.     

Allogeneic transplantation for myelodysplastic syndrome (MDS)

Haematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). Developing conditioning regimens with low toxicity, at the same time as preserving an effective graft versus tumour response, is pivotal to expanding the scope for allogeneic transplantation in older patients with MDS. With the introduction of reduced intensity conditioned regimens, transplant centres worldwide are able to offer allogeneic HSCT to a much larger cohort of patients. Graft versus host disease (GvHD) remains a significant cause of morbidity and mortality, however with the use of T-cell depletion, centres have been able to utilise volunteer unrelated donors with an increasing degree of HLA disparity. The graft versus dysplasia effect resulting from allogeneic HSCT and the infusion of donor leukocytes has led to a greater understanding of the immunological mechanisms that govern outcome following transplantation in MDS.     

Low-dose cytosine-arabinoside in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)

Summary Ten AML- and two MDS-patients in whom conventional chemotherapy was contraindicated or ineffective were treated with low dose ARA-C, 10 mg/m² per 12^hs.c. for 2–4 weeks. Seven patients obtained a complete and two a partial remission. Our findings suggest that low dose ARA-C may act both by induction of differentiation and/or inhibition of proliferation.Supported by the Hamburger Krebsgesellschaft