Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial.

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.

Activating killer immunoglobulin-like receptor incompatibilities enhance graft-versus-host disease and affect survival after allogeneic hematopoietic stem cell transplantation.

OBJECTIVES: Killer immunoglobulin-like receptors (KIRs) regulate function of natural killer (NK) cells and a subset of T cells. In this study, we prospectively evaluated the impact of donor and recipient activating KIR genes on outcome of allogeneic hematopoietic stem cell transplantation (alloHSCT) for patients with hematological malignancies. METHODS: One-hundred consecutive recipients of myeloablative transplantation and their donors were tested for KIR genotype as well as for immune reconstitution, including activating KIR expression on NK cells and T cells. RESULTS: In a multivariate analysis, mismatches of particular activating KIRs such that the patient was negative and the donor was positive (P-D+) resulted in increased risk of acute (KIR2DS1) and chronic (KIR2DS3) graft-versus-host disease (GVHD) as well as relapse (KIR2DS5). KIR2DS1 incompatibility in the same direction in the presence of HLA-C-group 2 ligand in recipient was associated with reduced overall (risk ratio, RR = 3.01; P = 0.01) and disease-free survival (RR = 2.92, P = 0.03). Activating mismatches in P-D+ direction resulted in decreased CD4+ : CD8+ T-cell ratio up to 1 yr after alloHSCT, as a consequence of decreased CD3+CD4+ number within the first 100 d and increased CD3+CD8+ number in later time-points. Among six evaluated patients, expression of activating KIRs on NK cells and T cells was particularly prominent for those developing intestinal GVHD. CONCLUSION: Our findings indicate that the presence of particular activating KIRs in donor with their absence in recipient enhances GVHD, which is not accompanied by graft-versus-leukemia effect. Evaluation of activating KIR genotype may allow optimization of both donor selection and transplantation procedure in order to avoid GVHD.

Treosulfan and fludarabine low-toxicity conditioning for allogeneic haematopoietic stem cell transplantation in chronic myeloid leukaemia.

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is the only treatment of proven long-term efficacy in chronic myeloid leukaemia (CML), although high non-relapse mortality (NRM) observed after conventional myeloablative conditioning limits its applicability. This phase II trial evaluated the efficacy and toxicity of a new preparative regimen consisting of treosulfan 3 x 14 g/m(2) and fludarabine 5 x 30 mg/m(2), in patients with CML in chronic phase. Among the 40 patients included, 18 received alloHSCT from a sibling and 22 from an unrelated donor. All patients engrafted with 92.5% of cases achieving complete donor chimaerism by day +100. All but one patient had achieved complete cytogenetic remission on day +100. Grade III or IV non-haematological toxicities included: neutropenic fever (10%), nausea/vomiting (10%), elevated liver enzymes (5%) and infection (2.5%). The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 22.5% and extensive chronic GVHD, 14%. The 2-year probability of overall survival, leukaemia-free survival and NRM was 85%, 82.5% and 15% respectively. At 1 year post-transplant, 85% of survivors had a Karnofsky index of 100%. We concluded that treosulfan and fludarabine conditioning is a low-toxicity regimen with high anti-leukaemic potential that seems feasible in CML patients referred for alloHSCT.

The incidence and risk factors for chronic graft-versus-host-disease.

OBJECTIVES: Chronic graft-versus-host-disease (cGVHD) deteriorates survival and quality of life after allogeneic hematopoietic cell transplantation (alloHCT). We evaluated the incidence and risk factors for this complication based on a single-center experience. METHODS: 255 consecutive patients, aged 29 (10-56) years, who survived without disease progression after alloHCT performed between 1992-2003 were included in the analysis. The preparative regimen was myeloablative, donors were either related (n=177) or unrelated volunteers (URD-HCT) (n=78). RESULTS: Cumulative incidence of the overall and extensive cGVHD equaled 48% and 22%, respectively. In a multivariate analysis the following factors were associated with increased risk of cGVHD: preceding grade II-IV acute GVHD, recipient age > or =40 years, URD-HCT, the diagnosis of chronic myeloid leukemia (CML) or myelodysplastic syndrome, and CD3 cell dose 50 x 10(6)/kg. Similar factors, excluding recipient age contributed to increased risk of extensive cGVHD, however, the cut-point for CD3 cell dose was 100 x l0(6)/kg and the use of steroids for acute GVHD prophylaxis was found an additional risk factor. In a CML subgroup the risk of cGVHD was increased for patients previously treated with interferon. CONCLUSIONS: Various recipient-, donor-, and procedure-related factors are related to the risk of cGVHD. Individualized treatment and modification of risk factors may contribute to improved outcome.

Treosulfan, cyclophosphamide and antithymocyte globulin for allogeneic hematopoietic cell transplantation in acquired severe aplastic anemia.

To reduce the risk of graft rejection after allogeneic hematopoietic cell transplantation (alloHCT) for patients with acquired severe aplastic anemia (SAA), we introduced an intensified preparative regimen consisting of treosulfan 10 g/m2/d on days -7, -6, cyclophosphamide 40 mg/kg/d on days -5, -4, -3, -2 and anti-thymocyte globulin 2 mg/kg/d on days -3, -2, -1. Six patients with the history of multiple transfusions were treated with alloHCT from either HLA-identical sibling (n=3) or an unrelated volunteer (n=3). Each, bone marrow and peripheral blood was used as a source of stem cells in three cases. All patients engrafted and achieved complete donor chimerism. None of the patients experienced severe organ toxicity. No severe acute graft-versus-host-disease (GVHD) was observed; two patients experienced extensive chronic GVHD. At the median follow-up of 14.5 (13-27) months all patients remained alive and disease-free. Our observation indicates that treosulfan + cyclophosphamide + antithymocyte globulin conditioning is well-tolerated and allows stable engraftment in acquired SAA.

Treatment of elderly patients with acute myeloid leukemia adjusted for performance status and presence of comorbidities: a Polish Adult Leukemia Group study.

This prospective study estimated outcomes in 509 elderly patients with acute myeloid leukemia (AML) with different treatment approaches depending on Eastern Cooperative Oncology Group (ECOG) performance status and Charlson Comorbidity Index (CCI). Patients were stratified into fit (ECOG 0-2 and CCI 0-2) or frail (ECOG>2 and/or CCI>2) groups. Fit patients with CCI 0 received intensive chemotherapy whilst reduced-intensive chemotherapy (R-IC) was given to those with CCI 1-2. Frail patients received best supportive therapy. Fit patients presented a longer overall survival (OS) than frail subjects, but 8-week mortality rates were similar. The complete response (CR) rate between fit CCI 0 and CCI 1-2 subgroups was significantly different. Both of the fit subgroups showed similar 8-week mortality rates and OS probabilities. Allocating fit patients with CCI 1-2 to R-IC enabled an increase in the group of elderly patients who could be treated with the intention of inducing remission.

[Impact of chronic graft-versus-host disease on long-term outcome after allogeneic hematopoietic cell transplantation in adult acute lymphoblastic leukemia]. / Wplyw przewleklej choroby przeszczep-przeciw-gospodarzowi na odlegle wyniki allogenicznej transplantacji komórek krwiotwórczych u doroslych chorych na ostra bialaczke limfoblastyczna.

Chronic graft-versus-host-disease (cGVHD) is a major cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT). However, it may be accompanied by graft-versus-leukemia (GVL) reaction contributing to decreased risk of relapse. The aim of this study was to evaluate the influence of cGVHD on outcome of adult acute lymphoblastic leukemia (ALL) patients treated with alloHCT. Fifty-five ALL patients, aged 24 (18-54) years, who survived without progression at least 100 days after alloHCT from HLA-identical sibling (n = 40, 73%) or an unrelated volunteer (n = 15, 27%) were included in the analysis. 24 patients 44% were given alloHCT in first complete remission, whereas the remaining 31 patients (44%) were in more advanced disease. The probability of overall survival (OS) and disease-free survival (DFS) equaled 57% and 48% at 8 years, respectively. Cumulative incidence of relapse and non-relapse mortality (NRM) was 39% and 13%, respectively. OS rate equaled 51% for patients without cGVHD, 94% for patients with limited cGVHD, and 38% for those with extensive cGVHD. In the respective subgroups relapse incidence was 60%, 9% and 0%, whereas the incidence of NRM equaled 3%, 6% and 62%. In multivariate analysis the lack of cGVHD was the most important factor associated with increased risk of relapse and deteriorated DFS. Extensive, but not limited cGVHD was associated with increased risk of NMR. Our findings confirm that in adults with ALL, cGVHD is accompanied by a strong GVL reaction. Induction of limited cGVHD may constitute the most effective prophylaxis of relapse in this group of patients.