Novel Strategies to Treat Acute Myeloid Leukemia Gediga, Miriam Helena Eva; Middeke, Jan Moritz; Ruhnke, Leo
Deutsche medizinische Wochenschrift (1946),
04/2023, Letnik:
148, Številka:
8
Journal Article
While the "7+3" regimen of cytarabine + anthracycline has been the backbone of acute myeloid leukemia (AML) treatment for four decades, several novel drugs have been approved in the past five years. ...Despite these promising novel therapeutic options, treatment of AML remains challenging, given the biologically heterogenous character of the disease.
This review provides an update on novel treatment strategies for AML.
This article is based on the current European LeukemiaNet (ELN) recommendations and the DGHO «Onkopedia» guideline on AML treatment.
The treatment algorithm is based on patient-related and disease-specific factors, such as patient age and fitness as well as AML molecular profile. Younger patients considered fit for intensive chemotherapy receive 1-2 courses of induction therapy ("7+3" regimen, eg. cytarabine/daunorubicin, or CPX-351 for patients with myelodysplasia-related AML or therapy-related AML). For CD33+ patients or those with evidence of an
mutation "7+3" in combination with Gemtuzumab-Ozogamicin (GO) or Midostaurin is recommended, respectively. For consolidation, patients receive either high-dose chemotherapy (± GO/± Midostaurin) or undergo allogeneic hematopoietic cell transplantation (HCT), based on ELN risk stratification. In some cases, maintenance therapy with oral azacytidine or
inhibitor is indicated. Patients experiencing relapse should receive chemotherapy-based re-induction therapy or, in case of an
mutation, Gilteritinib and subsequently undergo allogeneic HCT. For older patients or those considered unfit for intensive therapy, azacytidine in combination with Venetoclax is a promising novel treatment strategy. Although not yet approved by the European Medical Agency (EMA), for patients with
IDH1 or
mutations treatment with the IDH1 and IDH2 inhibitors Ivosidenib and Enasidenib should be considered.
Highlights • This is a study of serial donor chimerism analysis (>2300 samples) in 155 recipients of allografts for multiple myeloma. • A chimerism drop without relapse was rare. • The predictive ...value of serial chimerism analysis for heralding relapse was limited because of the high frequency of extramedullary relapses after allo-SCT. • In multivariable analysis, the most relevant variable for OS was progressive disease before allo-SCT. • Adverse cytogenetics such as del17p, t(4,14) or amp(1q21) were not associated with shorter survival after allo-SCT in our series.
Abstract 2748
Prediction of treatment outcome in the context of specific therapies is a major goal of clinical research. Monosomal karyotype has been established as an independent prognostic marker ...in patients with AML treated with chemotherapy. Our goal was to investigate the prognostic value of a monosomal karyotype (MK) in patients with acute myeloid leukemia (AML) treated with allogeneic hematopoietic cell transplantation (HCT).
We performed a retrospective cohort analysis in patients with high risk AML who received a first allogeneic HCT from an HLA-compatible donor in one out of six major German transplant centers between 01/2005 and 12/2008. Chromosomal aberrations were classified according to ELN criteria. Monosomal karyotype was defined as two or more distinct autosomal monosomies or one single autosomal monosomy in the presence of structural abnormalities. Survival endpoints were analysed in a complete case analysis with Cox regression modelling. Age, Karnofsky performance status, HCT comorbidity index, remission status at HCT, donor type, sex and CMV match were selected as potential confounders a priori for the model while stepwise backward selection was applied to a set of additional covariates including karyotype information. Model selection was based on the likelihood ratio test. We checked the proportional hazard assumption by generating a time-dependent covariate and testing the interaction term with the predictors of the model.
Data from 236 patients with complete karyotype information were analysed. The median age at HCT was 55 years (range, 21 to 77 years). The HCT-comorbidity index was low, intermediate and high in 22%, 27% and 49% of patients. According to ELN criteria chromosomal aberration were classified as intermediate risk in 33% and as high risk in 67% of the patients. The karyotype of 26% of patients met the criteria for a monosomal karyotype. At HCT 60% of patients had less than 5% marrow blasts, 18% had 5 to 20% marrow blasts and 21% had more than 20% marrow blasts. The median interval from diagnosis to HCT was 107 days. Donors were matched siblings in 27%, matched unrelated donors in 49% and partially matched unrelated donors with one to two mismatches in 25% of the patients. Only 16% of the patients were treated with myeloablative conditioning regimens while the remaining patients received reduced intensity conditioning. At the time of analysis, 110 patients were alive with a median follow up of 28 months (range, 8 months to 61 months). Overall survival at 3 years was 51% (95% CI, 42% to 60%) for MK-negative patients and 16% (95% CI, 5% to 27%) for MK-positive patients (log rank test, p<0.0001) (see overall survival by MK-karyotype in high risk patients only in Figure 1). Cox regression modelling was performed as a complete case analysis with data from 221 patients. The cytogenetic classification according to ELN (HR 1.8, p=0.014) and MK karyotype (HR 2.1, p=0.001) together improved the predictive power of the Cox regression model. When MK karyotype was removed from the final model including cytogenetic risk according to ELN the model significantly lost predictive power (likelihood ratio test, p=0.001).
The presence of a monosomal karyotyp is an independent prognostic factor in patients being treated with allogeneic stem cell transplantation and predicts for inferior survival.
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Bug:Celgene: Honoraria.
•A clofarabine-based salvage therapy combined with early allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory acute myeloid leukemia provides good long-term ...results•Comorbidity evaluation based on the hematopoietic cell transplantation–specific comorbidity index and Eastern Cooperative Oncology Group score provided prognostic information on overall survival and thus show the feasibility and clinical relevance of comorbidity evaluation at the time of diagnosis of relapsed or refractory acute myeloid leukemia
In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be the only treatment providing long-term disease control. The BRIDGE trial studied the safety and efficacy of a clofarabine-based salvage therapy before HSCT in patients with r/r AML. Here, we report the long-term follow-up of this phase II multicenter trial and exploratory analyses on the impact of comorbidity on outcome. Eighty-four patients with a median age of 61 years (range, 40 to 75) were enrolled. Patients were scheduled for at least 1 cycle of salvage therapy with CLARA (clofarabine 30 mg/m2; cytarabine 1 g/m2, days 1 to 5). Chemo-responsive patients with a donor received HSCT after first CLARA. The conditioning regimen consisted of clofarabine 30 mg/m2, day −6 to −3, and melphalan 140 mg/m2 day −2. The Eastern Cooperative Oncology Group (ECOG) score, the hematopoietic cell transplantation–specific comorbidity index (HCT-CI), and the Cumulative Illness Rating Scale were obtained at study enrollment as well as before HSCT. Sixty-seven percent of the patients received HSCT within the trial. After a median follow up of 40 months, the estimated 3-year overall survival (OS) for all enrolled patients and those with HSCT within the trial was 40% and 55%, respectively. Relapse-free survival for patients who underwent transplantation with a complete remission afterwards (n = 50) was 48%, calculated from the day of transplantation. In multivariate analysis, both the HCT-CI and ECOG score had a statistically significant impact on OS with a hazard ratio of 1.22 (P = .025)and 1.72 (P = .001), respectively. Using a clofarabine-based salvage therapy combined with early allogeneic HSCT, we were able to achieve good long-term results for patients with r/r AML. In this cohort, both the HCT-CI and the ECOG scores gave prognostic information on OS, showing the feasibility and clinical relevance of comorbidity evaluation at the time of diagnosis of r/r AML patients.
Highlights • A clofarabine-based salvage therapy combined with early allogeneic HSCT in patients with relapsed or refractory AML provides good long-term results. • Comorbidity evaluation based on the ...HCT-CI and ECOG score provided prognostic information on OS and thus showing the feasibility and clinical relevance of comorbidity evaluation at the time of diagnosis of relapsed or refractory AML.
Abstract Interleukin 17A (IL-17)-producing CD4+ T helper type 17 (Th17) cells have recently drawn attention as possible effector cells of acute graft-versus-host disease (GVHD) after allogeneic ...hematopoietic cell transplantation (HCT) in murine models. Their role after allogeneic HCT in humans is unknown. In this prospective study, Th17, Th1/17, and Th1 cells were quantified in the peripheral blood of 80 patients within the first 3 months after allogeneic HCT using intracellular cytokine staining and flow cytometry. Within the observation period, Th1, Th1/17, and Th17 cells did not reconstitute to levels of healthy control subjects. In contrast to Th1 cells, no further expansion of Th1/17 and Th17 cells was observed during the first month after HCT. Antithymocyte globulin during conditioning significantly reduced the frequency of Th1/17 and Th17 cells but not of Th1 cells. Acute GVHD was not associated with significant changes in the size of the Th1, Th1/17, or Th17 cell subsets. Cytomegalovirus reactivation triggered the expansion of all T helper subsets, and Th1 cells showed the strongest increase. In contrast, no significant changes were found in the T helper cell compartment of patients with bacterial infections compared with time-matched control subjects. In conclusion, quantitative reconstitution of Th1, Th1/17, and Th17 cells is impaired within the first 3 months after HCT, especially when antithymocyte globulin is administered during conditioning. Cytomegalovirus reactivation, but not acute GVHD or bacterial infection, triggered the absolute expansion of these T cell subsets.
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