Characteristics and outcome of patients with acute myeloid leukemia and trisomy 4.

We retrospectively studied 125 patients with acute myeloid leukemia and trisomy 4 (median age at diagnosis, 58 years; range, 16-77 years) treated between 2000 and 2019 within a multicenter study. Trisomy 4 was the sole abnormality in 28 (22%) patients and additional abnormalities were present in 97 (78%) patients. Twenty-two (22%) and 15 (15%) of 101 tested patients harbored NPM1 and FLT3-ITD mutations. Two (3%) of 72 tested patients had double CEBPA mutations. Data on response to intensive anthracycline-based induction therapy were available for 119 patients. Complete remission was achieved in 67% (n=80) and the early death rate was 5% (n=6). Notably, patients with trisomy 4 as sole abnormality had a complete remission rate of 89%. Allogeneic hematopoietic cell transplantation was performed in 40 (34%) patients, of whom 19 were transplanted in first complete remission. The median follow-up of the intensively treated cohort was 5.76 years (95% confidence interval [95% CI]: 2.99-7.61 years). The 5-year overall survival and relapse-free survival rates were 30% (95% CI: 22-41%) and 27% (95% CI: 18-41%), respectively. An Andersen-Gill regression model on overall survival revealed that favorable-risk according to the European LeukemiaNet classification (hazard ratio [HR]=0.34; P=0.006) and trisomy 4 as sole abnormality (HR=0.41; P=0.01) were favorable factors, whereas age with a difference of 10 years (HR=1.15; P=0.11), female gender (HR=0.74; P=0.20) and allogeneic hematopoietic cell transplantation (HR=0.64; P=0.14) did not have an significant impact. In our cohort, patients with trisomy 4 as their sole abnormality had a high complete remission rate and favorable clinical outcome. Allogeneic hematopoietic cell transplantation did not seem to improve overall survival.

Efficacy of chemotherapy protocols for hematological malignancies: H-CVAD versus GELA/BURKIMAB/PETHEMA LAL.

The hyper-CVAD/methotrexate-cytarabine (H-CVAD/ MTX-AraC) chemotherapy protocol has been one of the standard treatments for hematological malignancies, such as mantle cell lymphoma (MCL), Burkitt lymphoma (BL), and B-cell and T-cell acute lymphoblastic leukemia. Because results of this therapy are poor, it has been progressively replaced with new specific regimens with better efficacy profiles (GELA protocol for MCL, BURKIMAB for BL, and PETHEMA for B-cell and T-cell acute lymphoblastic leukemia [ALL]). The objective of this study was to analyze the response rates and survival of these therapeutic regimens. This retrospective and descriptive observational study of 81 patients compared 42 patients treated with hyper-CVAD/methotrexate-cytarabine (group A) with 39 patients treated with GELA/BURKIMAB/PETHEMA (group B). More patients in group B than in group A completed the treatment (89.7% vs. 47.6%, p < 0.001). In group A, 14.3% did not complete treatment because of death compared with 7.7% in group B, and 29% in group A had cycle delays versus 6.7% in group B (p < 0.001). In group A, 78.6% of group A achieved a complete response (CR) compared with 94.9% of group B (p = 0.050). Disease-free survival (DFS) and overall survival (OS) were significantly higher in group B (p < 0.001 in both cases). Data for current therapeutic protocols have indicated superior efficacy, with higher complete response rates, as well as better disease-free survival and overall survival results. This article provides the best results in terms of the efficacy of treatment of four hematological malignancies (MCL, BL, B-cell ALL, and T-cell ALL) with the most current specific therapeutic regimens (GELA for MCL, BURKIMAB for BL, and PETHEMA for B-cell ALL and T-cell ALL) with respect to a classic general protocol (H-CVAD/MTX-AraC for all four). These results may represent a great advance in the treatment of these blood cancers, achieving an important long-term benefit for these hematological patients.

Outcomes and prognostic factors of adults with refractory or relapsed T-cell acute lymphoblastic leukemia included in measurable residual disease-oriented trials.

Despite high complete remission (CR) rates with frontline therapy, relapses are frequent in adults with T-cell acute lymphoblastic leukemia (T-ALL) with limited salvage options. We analyzed the outcomes and prognostic factors for CR to salvage therapy and overall survival (OS) of patients with R/R T-ALL included in two prospective measurable residual disease-oriented trials. Seventy-five patients (70 relapsed, 5 refractory) were identified. Relapses occurred in bone marrow, isolated or combined in 50 patients, and in the central nervous system (CNS; isolated or combined) in 20. Second CR was attained in 30/75 patients (40%). Treatment with FLAG-Ida and isolated CNS relapse were independently associated with a higher CR rate after first salvage therapy. The median OS was 6.2 (95% confidence interval [CI], 3.9-8.6) months, with a 4-year OS probability of 18% (95% CI, 9%-27%). No differences in survival were observed according to the treatment with hematopoietic stem cell transplantation in patients in CR after first salvage therapy. Multivariable analysis showed a ≥12-month interval between first CR and relapse, CR after first salvage therapy and isolated CNS relapse as favorable prognostic factors for OS with hazard ratios (HR) (95% CI) of 1.931 (1.109-3.362), 2.958 (1.640-5.334), and 2.976 (1.157-7.655), respectively. This study confirms the poor outcomes of adults with R/R T-ALL among whom FLAG-Ida was the best of the rescue therapies evaluated. Late relapse, CR after first rescue therapy and isolated CNS relapse showed prognostic impact on survival. More effective rescue therapies are needed in adults with R/R T-ALL.

Characteristics, clinical outcomes, and risk factors of SARS-COV-2 infection in adult acute myeloid leukemia patients: experience of the PETHEMA group.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces higher morbidity and mortality in hematological malignancies, but evidence in acute myeloid leukemia (AML) is scarce. A multicenter observational study was conducted to determine the clinical outcomes and assess the impact of therapeutic approaches in adult AML patients with SARS-CoV-2 infection in the first wave (March-May 2020). Overall, 108 patients were included: 51.9% with active leukemia and 70.4% under therapeutic schedules for AML. Signs and symptoms of SARS-CoV-2 were present in 96.3% of patients and 82.4% received specific treatment for SARS-CoV-2. The mortality rate was 43.5% and was correlated with age, gender, active leukemia, dyspnea, severe SARS-CoV-2, intensive care measures, neutrophil count, and D-dimer levels. A protective effect was found with azithromycin, lopinavir/ritonavir, and normal liver enzyme levels. During the SARS-CoV-2 first wave, our findings suggested an increased mortality in AML in a short period. SARS-CoV-2 management could be guided by risk factors in AML patients.

The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial.

We sought to predict treatment responses and outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) from our FLUGAZA phase III clinical trial (PETHEMA group) based on mutational status, comparing azacytidine (AZA) with fludarabine plus low-dose cytarabine (FLUGA). Mutational profiling using a custom 43-gene next-generation sequencing panel revealed differences in profiles between older and younger patients, and several prognostic markers that were useful in young patients were ineffective in older patients. We examined the associations between variables and overall responses at the end of the third cycle. Patients with mutated DNMT3A or EZH2 were shown to benefit from azacytidine in the treatment-adjusted subgroup analysis. An analysis of the associations with tumor burden using variant allele frequency (VAF) quantification showed that a higher overall response was associated with an increase in TET2 VAF (odds ratio (OR), 1.014; p = 0.030) and lower TP53 VAF (OR, 0.981; p = 0.003). In the treatment-adjusted multivariate survival analyses, only the NRAS (hazard ratio (HR), 1.9, p = 0.005) and TP53 (HR, 2.6, p = 9.8 × 10-7) variants were associated with shorter overall survival (OS), whereas only mutated BCOR (HR, 3.6, p = 0.0003) was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low-intermediate cytogenetic risk (HR, 1.51, p = 0.045) and mutated NRAS (HR, 3.66, p = 0.047) benefited from azacytidine therapy. In the subgroup analyses, patients with mutated TP53 (HR, 4.71, p = 0.009) showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. The study is registered at ClinicalTrials.gov as NCT02319135.

Comparison in safety of chemotherapy protocols for blood cancers: toxicity of H-CVAD versus GELA/BURKIMAB/PETHEMA LAL.

BACKGROUND AND OBJECTIVE: The Hyper-CVAD/Methotrexate-Cytarabine (H-CVAD/MTX-AraC) chemotherapy protocol has been one of the standard treatments for blood cancers, such as Mantle cell lymphoma (MCL), Burkitt's lymphoma (BL) and B-cell and T-cell acute lymphoblastic leukaemia (ALL). Due to high toxicity, it has been progressively replaced with new specific regimens with a better safety profile (GELA protocol for MCL, BURKIMAB for BL and PETHEMA for B-cell and T-cell ALL). The objective of this study is to analyse the toxicity and infectious complications of these therapeutic regimens, as well as the event free survival (EFS). PATIENTS AND METHODS: This is a retrospective and descriptive observational study of 81 patients, comparing 42 patients treated with H-CVAD/MTX-AraC (group A) versus 39 patients treated with GELA/BURKIMAB/PETHEMA (group B). RESULTS: All patients in group A developed pancytopenia, but in group B 74.4% neutropenia, 51.3% thrombocytopenia and 69.2% anaemia. The total number of infections in group A was higher than in group B: 154 versus 48, 3.67 versus 1.23 per patient and 0.59 versus 0.25 per cycle. Likewise, febrile neutropenia happened: 106 versus 21 cases, 2.52 versus 0.52 per patient and 0.41 versus 0.11 per cycle. EVS is higher in group B: 33% versus 79% (2-year), and 24% versus 69% (5-year). CONCLUSIONS: Current therapeutic protocols have shown higher EFS due to better safety profile, with less haematological, neurological and haemorrhagic toxicity, as well as lower rates of infectious complications.