Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia.

BACKGROUND: The combination of ivosidenib - an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) - and azacitidine showed encouraging clinical activity in a phase 1b trial involving patients with newly diagnosed IDH1-mutated acute myeloid leukemia. METHODS: In this phase 3 trial, we randomly assigned patients with newly diagnosed IDH1-mutated acute myeloid leukemia who were ineligible for intensive induction chemotherapy to receive oral ivosidenib (500 mg once daily) and subcutaneous or intravenous azacitidine (75 mg per square meter of body-surface area for 7 days in 28-day cycles) or to receive matched placebo and azacitidine. The primary end point was event-free survival, defined as the time from randomization until treatment failure (i.e., the patient did not have complete remission by week 24), relapse from remission, or death from any cause, whichever occurred first. RESULTS: The intention-to-treat population included 146 patients: 72 in the ivosidenib-and-azacitidine group and 74 in the placebo-and-azacitidine group. At a median follow-up of 12.4 months, event-free survival was significantly longer in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group (hazard ratio for treatment failure, relapse from remission, or death, 0.33; 95% confidence interval [CI], 0.16 to 0.69; P = 0.002). The estimated probability that a patient would remain event-free at 12 months was 37% in the ivosidenib-and-azacitidine group and 12% in the placebo-and-azacitidine group. The median overall survival was 24.0 months with ivosidenib and azacitidine and 7.9 months with placebo and azacitidine (hazard ratio for death, 0.44; 95% CI, 0.27 to 0.73; P = 0.001). Common adverse events of grade 3 or higher included febrile neutropenia (28% with ivosidenib and azacitidine and 34% with placebo and azacitidine) and neutropenia (27% and 16%, respectively); the incidence of bleeding events of any grade was 41% and 29%, respectively. The incidence of infection of any grade was 28% with ivosidenib and azacitidine and 49% with placebo and azacitidine. Differentiation syndrome of any grade occurred in 14% of the patients receiving ivosidenib and azacitidine and 8% of those receiving placebo and azacitidine. CONCLUSIONS: Ivosidenib and azacitidine showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population. Febrile neutropenia and infections were less frequent in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group, whereas neutropenia and bleeding were more frequent in the ivosidenib-and-azacitidine group. (Funded by Agios Pharmaceuticals and Servier Pharmaceuticals; AGILE ClinicalTrials.gov number, NCT03173248.).

Ageing-resembling phenotype of long-term allogeneic hematopoietic cells recipients compared to their donors.

BACKGROUND: Ageing is a complex phenomenon that leads to decreased proliferative activity, loss of function of the cells, and cellular senescence. Senescence of the immune system exacerbates individual's immune response, both humoral and cellular but increases the frequency of infections. We hypothesized that physiological ageing of adaptive immune system occurs in recipients of allogeneic hematopoietic cells transplant (allo-HCT) at faster rate when compared to their respective donors since the small number of donor cells undergo immense proliferative stress restoring recipients hematopoiesis. We compared molecular characterizations of ageing between recipients and donors of allo-HCT: telomeric length and immunophenotypic changes in main lymphocyte subsets - CD4+, CD8+, CD19+, CD56+. RESULTS: Median telomeric length (TL) of CD8+ lymphocytes was significantly longer in donors compared to recipients (on average 2,1 kb and 1,7 kb respectively, p = 0,02). Similar trends were observed for CD4+ and CD19+ although the results did not reach statistical significance. We have also found trends in the immunophenotype between recipients and donors in the subpopulations of CD4+ (naïve and effector memory), CD8+ Eomes+ and B-lymphocytes (B1 and B2). Lower infection risk recipients had also a significantly greater percentage of NK cells (22,3%) than high-risk patients (9,3%) p = 0,04. CONCLUSION: Our data do not support the initial hypothesis of accelerated aging in the long term all-HCT recipients with the exception of the recipients lymphocytes (mainly CD8+) which present some molecular features, characteristic for physiological ageing (telomeric shortening, immunophenotype) when compared to their respective donors. However, a history of lower infection numbers in HCT recipients seems to be associated with increased percentage of NK cells. The history of GVHD seems not to affect the rate of ageing. Therefore, it is safe to conclude that the observed subtle differences between recipients' and donors' cells result mainly from the proliferative stress in the early period after allo-HCT and the difference between hosts' and recipients' microenvironments.

Immune escape of B-cell lymphoblastic leukemic cells through a lineage switch to acute myeloid leukemia.

Acute leukemia (AL) with a lineage switch (LS) is associated with poor prognosis. The predisposing factors of LS are unknown, apart from KMT2A rearrangements that have been reported to be associated with LS. Herein, we present two cases and review all 104 published cases to identify risk factors for LS. Most of the patients (75.5%) experienced a switch from the lymphoid phenotype to the myeloid phenotype. Eighteen patients (17.0%) experienced a transformation from acute myelogenous leukemia (AML) to acute lymphoblastic leukemia (ALL). Forty-nine (46.2%) patients carried a KMT2A rearrangement. Most of the cases involved LS from B-cell ALL (B-ALL) to AML (59.4%), and 49 patients (46.2%) carried KMT2A-rearrangements. Forty patients (37.7%) received lineage-specific immunotherapy. Our findings suggest that the prevalence of KMT2A rearrangements together with the lineage-specific immunotherapy may trigger LS, which supports the thesis of the existence of leukemia stem cells that are capable of lymphoid or myeloid differentiation.

A hybrid protocol CLAG-M, a possible player for the first-line therapy of patients with mixed phenotype acute leukemia. A Polish Adult Leukemia Group experience.

Introduction: Mixed-phenotype acute leukemia (MPAL) is a rare disease with poor prognosis. So far, no standard approach has been established as the "know-how" of MPAL is based only on retrospective analyses performed on small groups of patients. Materials and methods: In this study, a retrospective analysis of the outcomes of adult MPAL patients included in the PALG registry between 2005 and 2024 who received the CLAG-M hybrid protocol as induction or salvage therapy was performed. Results: Sixteen of 98 MPAL patients received CLAG-M: eight as first-line and eight as salvage therapy. In the first line, two patients achieved partial response (PR), and six achieved complete remission (CR), of whom four successfully underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Two patients who did not undergo alloHSCT promptly relapsed. Within the whole group, the overall response rate (ORR) was 75% (n = 12/16). With the median follow-up of 13 months, six out of eight patients remain in CR, however, two of them died due to acute graft versus host disease. Out of eight patients who received CLAG-M in the second line, four patients (50%) obtained CR. AlloHSCT was conducted in seven cases, six of which were in CR. Only two patients remained in CR at the time of the last follow-up. Tolerance to treatment was good. The median times for severe neutropenia and thrombocytopenia were 22 days (range, 16-24) and 17 days (range, 12-24), respectively. Overall, grade 3-4 infections were observed in 12 cases, and all infections presented successful outcomes. Conclusions: CLAG-M is an effective first-line salvage regimen for MPAL with an acceptable safety profile. Early achievement of CR with prompt alloHSCT allows for satisfactory disease control.

Isolated Progression of Multiple Myeloma into the Extramedullary Plasmacytoma of Dura Mater: A Case Report and Review of the Literature.

Multiple myeloma (MM) is a disease caused by the uncontrolled proliferation of clonal plasma cells in bone marrow. Extramedullary plasma cell infiltrations may occur at the time of diagnosis but usually arise during systemic disease progression. Central nervous system (CNS) plasmacytomas are extremely rare (less than 1% of patients with MM) and usually occur as a result of systemic disease progression. The frequency of extramedullary progression to CNS without simultaneous systemic progression is not known. Here, we present a challenging case in which local disease progression to CNS occurred without any signs of systemic progression. The extramedullary plasmacytoma originated from the dura mater of the brain mimicking a brain tumor. We review and discuss further treatment options that are available in such rare clinical scenarios in relation to the treatment already undertaken.

The role of daratumumab in relapsed/refractory CD38 positive acute leukemias-case report on three cases with a literature review.

Primary refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) and mixed phenotype myeloid/T-cell acute leukemia have dismal prognoses. New treatment approaches, preferably targeting specific leukemic aberrations to overcome resistance, are urgently needed. The bright expression of the CD38 antigen found in several cases of T-ALL led to an investigation into the role of anti-CD38 antibodies in the treatment of T-ALL. Here, we present three cases of resistant and relapsed T-ALL and myeloid/T-cell treated with daratumumab-based therapy, including venetoclax and bortezomib (Dara-Ven-Bor). All patients achieved complete remission, with minimal residual disease negativity within four weeks of treatment, allowing them to proceed to allogeneic hematopoietic cell transplantation. The toxicity of the triple schema was acceptable. Our patients and other cases reviewed here suggest that daratumumab combined with venetoclax and bortezomib may be a very effective and relatively safe salvage treatment, even in primary resistant T-ALL.

Outcome of a Real-Life Population of Patients With Acute Promyelocytic Leukemia Treated According to the PETHEMA Guidelines: The Polish Adult Leukemia Group (PALG) Experience.

BACKGROUND: Acute promyelocytic leukemia (APL) has a favorable prognosis. However, results of randomized studies do not necessarily reflect the outcomes of a real-life population. PATIENTS AND METHODS: We analyzed 283 unselected APL patients treated in 20 Polish hospitals between 2005 and 2017. All patients were intended to be treated with PETHEMA (Programa Español para el Tratamiento de las Hemopatías Malignas) protocols based on all-trans retinoic acid plus chemotherapy. RESULTS: The probability of overall survival at 4 years was 67%, while event-free survival was 64%. The early death (ED) rate was 20.1% (n = 57), while 3.5% (n = 10) patients died before induction therapy was started. The main causes of ED included hemorrhage (45.6%), infections (17.5%), and differentiation syndrome (14.5%). Of 273 treated patients, 214 (78.4%) experienced hematologic morphologic remission, 2 (0.7%) were found to have resistant disease, 47 (17.2%) could not be evaluated for response because of ED, and in 6 (3.7%) no data concerning the response were available. Multivariate analyses showed that predictors of ED and overall survival were Eastern Cooperative Oncology Group performance status > 2, age > 60 years, and all types of bleeding episodes that occurred before starting therapy, while an additional predictor of event-free survival was high white blood cell count (> 10 109/L). CONCLUSION: ED remains a major problem in APL patients, especially in a real-life population. Shortening of the time between the initial contact with a health care professional, and all-trans retinoic acid administration and the use of appropriate supportive care could improve the outcome of unselected APL population, mainly by reducing the ED rate.

Horse phenotyping based on video image analysis of jumping performance for conservation breeding.

BACKGROUND: Many horse breeds in the world are reserved as genetic resources; however, their characteristics seem to be insufficiently clarified, especially in terms of horse performance. Two jumping ability evaluation methods have been used to compare different types of performance breeds and on this basis their applicability for precision phenotyping has been determined. METHODS: Jumping data of 186 young Polish Warmblood stallions (27 with an endangered status) bred for sport and multipurpose use was collected during their performance tests organised under identical environmental conditions following the same guidelines. Jumping data consisted of objective measurements of free jumping parameters and the marks for jumping. Video recordings of 514 jumps (73 records for 27 stallions with an endangered status) were collected using a digital Panasonic AG-EZ 35 camera (25 fr/sec). Filming was recorded during a free jumping test in the line on a doublebarre obstacle (100-120 cm × 100 cm). Spatial and temporal variables of the jump were measured. The analysis of variance was performed (SAS, General Linear Model and Mixed procedures) using the statistical model, which included the random effect of the horse and fixed effects of the year of test, breeding status, height of jump and the successive number of the jump for objective kinematic data. The fixed effects of the year of test and breeding status were included in the model for subjective performance test data. RESULTS: Performance marks for free jumping were lower in the endangered group of stallions in the trainers' opinion (p ≤ 0.05), while no statistically significant differences were found in the judges' opinions. Statistically significant differences in jumping variables were measured for the bascule points-the elevations of the withers and croup were higher in the endangered group (p ≤ 0.001) and the take-off time was prolonged (p ≤ 0.05), which explained the subjective evaluation. DISCUSSION: The use of objective evaluation methods provides important information for practice, as phenotypic differences between horses may be unclear in the subjective evaluation. The objective evaluation should be used to characterise the performance potential of different breeds, because the information from the evaluators might not be consistent. Such characteristics should be recorded at least for every new population.