Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

A real-life overview of a hematopoietic cell transplant program throughout a four-year period, including prospective registry, exclusion causes and final donor selection.

Traceability of patients who are candidates for Hematopoietic cell transplant (HCT) is crucial to ensure HCT program quality. Continuous knowledge of both a detailed registry from a HCT program and final exclusion causes can contribute to promoting a real-life vision and optimizing patient and donor selection. We analyzed epidemiological data reported in a 4 year-monocentric prospective registry, which included all patients presented as candidates for autologous (Auto) and/or allogeneic (Allo) HCT. A total of 543 patients were considered for HCT: 252 (42.4%) for Allo and 291 (57.6%) for Auto. A total of 98 (38.9%) patients were excluded from AlloHCT due to basal disease progression more commonly (18.2%). Seventy-six (30.2%) patients had an HLA identical sibling, whereas 147 (58.3%) patients had only Haplo. UD research was performed in 106 (42%) cases, significantly more often in myeloid than lymphoid malignancies (57% vs 28.7%, p < 0.001) but 61.3% were finally canceled, due to donor or disease causes in 72.4%. With respect to Auto candidates, a total of 60 (20.6%) patients were finally excluded; progression was the most common cause (12%). Currently, Haplo is the most frequent donor type. The high cancellation rate of UD research should be revised to optimize further donor algorithms.

miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk.

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.

[Effectiveness and safety of lenalidomide in myelofibrosis patients: a case series from the Spanish compassionate use program]. / Efectividad y seguridad de lenalidomida en pacientes con mielofibrosis: serie de casos del programa de uso compasivo español.

OBJECTIVE: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (CMPN) characterized by clonal proliferation of the pluripotent hematopoietic germinal cell, fibrosis, and bone marrow angiogenesis, and with extra medullary hematopoiesis. Lenalidomide is an immunomodulatory and antiangiogenic agent that has shown clinical benefit in MF patients in several phase II clinical trials. In this work, we present the results of the retrospective assessment of a series of 32 patients diagnosed with MF that received treatment with lenalidomide within the Spanish program of hospital compassionate use. METHOD: Multicenter, retrospective study of a case series of MF patients receiving compassionate treatment with lenalidomide. RESULTS: We gathered information on 32 MF patients that were treated with lenalidomide at 17 Spanish hospitals. The mean age was 68 years (range, 50-83), 72% males. Twenty-six (81%) patients had intermediate-high risk according to Dupriez prognostic score. In 16 patients, the daily dose scheduled was 10 mg/day for 21 days in 28-day cycles; the remaining patients received lower doses or other regimes. In 29 out of 32 patients, response assessment was available. Two patients had complete clinical and hematologic response and 14 had partial response. The most common adverse events observed were neutropenia (56%), thrombocytopenia (50%), and anemia (40%). CONCLUSIONS: Continuous treatment with lenalidomide is active in MF patients pretreated heavily. Lenalidomide-induced myelosuppression and other associated toxicities are manageable with dose adjustments.

Objetivo: La mielofibrosis (MF) es una neoplasia mieloproliferativa crónica (NMPc) caracterizada por la proliferación clonal de la célula germinal hematopoyética multipotente, fibrosis y angiogénesis de la médula ósea, y con hematopoyesis extramedular. Lenalidomida es un agente inmunomodulador y antiangiogénico, que ha mostrado beneficio clínico en pacientes con MF en diversos ensayos clínicos de fase II. En el presente trabajo presentamos los resultados de la evaluación retrospectiva de una serie de 32 pacientes diagnosticados de MF que recibieron tratamiento con lenalidomida dentro de un programa de uso compasivo en hospitales españoles. Método: Estudio multicéntrico, retrospectivo de una serie de casos de MF en tratamiento compasivo con lenalidomida. Resultados: Se recogió información de 32 pacientes con MF que habían sido tratados con lenalidomida en 17 hospitales españoles. La mediana de edad fue de 68 años (extremos, 50-83), el 72% eran varones. Veintiséis (81%) pacientes presentaban un riesgo intermedio-alto según la puntuación pronóstica de Dupriez. La dosis de lenalidomida programada fue en 16 pacientes de 10 mg/día durante 21 días en ciclos de 28 días; el resto de los pacientes recibió dosis inferiores u otros esquemas. Se dispuso de la evaluación de respuesta en 29 de los 32 pacientes. Dos pacientes presentaron respuesta clínico-hematológica completa y 14 presentaron respuesta parcial. Los acontecimientos adversos más frecuentemente observados fueron neutropenia (56%), trombocitopenia (50%), y anemia (40%). Conclusiones: El tratamiento continuado con lenalidomida es activo en pacientes con MF fuertemente pretratados. La mielosupresión que provoca la lenalidomida y otras toxicidades asociadas son manejables con ajustes de dosis.

Relapse of chronic myeloid leukemia after allogeneic stem cell transplantation: outcome and prognostic factors: the Chronic Myeloid Leukemia Subcommittee of the GETH (Grupo Español de Trasplante Hemopoyético).

In order to analyze the outcome of patients with chronic myeloid leukemia (CML) who relapse after allogeneic stem cell transplantation (SCT), we investigated data from 107 patients reported to the Spanish Registry, GETH. In all, 93 (87%) patients were treated after relapse; 36 out of 49 that failed to achieve a response received a second relapse-treatment, and seven a third one. At the last follow-up, the number of patients in molecular or cytogenetic remission was 29 and 13, respectively. Overall survival and progression-free survival after relapse were 53.6% (95% CI: 42.9--64.2) and 52% (95% CI: 41-63) at 5 years, respectively. In multivariate analysis, survival was significantly related to CML phase at relapse (cytogenetic or chronic phase vs advanced phases) and time from transplant to relapse (<1 vs >or=1 year). Patients with no adverse factors had a better survival compared with patients with one or two adverse features (65 vs 35 vs 0%, respectively). We conclude that a significant proportion of CML patients that relapse after transplantation can regain complete and long-lasting remissions with one or more salvage therapies. Disease stage at relapse and time from transplant to relapse should be taken into account when comparing results of different salvage treatments.

Central and extrapontine myelinolysis following allogeneic peripheral haematopoietic progenitor cell transplantation. Favourable outcome in a patient with chronic myeloid leukaemia.

A 48-year-old-man in the first chronic phase of chronic myeloid leukaemia developed a central nervous system complication on day +57 after HLA-identical peripheral blood progenitor cell (PBPC) transplantation. The clinical picture evolved to a reversible pseudobulbar palsy requiring mechanical ventilation. MRI examination disclosed lesions typical of central and extrapontine myelinolysis (CEPM), which disappeared on a repeat examination 20 days later. The patient had received cyclosporine A (CsA) as GVHD prophylaxis and severe hyponatremia was detected 7 days after the first neurological sign. CEPM has been described in alcohol-induced liver disease, following rapidly corrected hyponatremia and associated with CsA in orthotopic liver transplantation. This is the first reported case of CEPM in PBPC transplantation, and CsA seems to have played a role in the development of this very serious complication.

Unrelated donor bone marrow transplantation as treatment for chronic myeloid leukemia: the Spanish experience. The Chronic Myeloid Leukemia Subcommittee of the GETH. Grupo Español de Trasplante Hemopoyético.

BACKGROUND AND OBJECTIVE: To analyze the results of unrelated bone marrow transplantation (UDBMT) as treatment for chronic myeloid leukemia (CML) in Spain. DESIGN AND METHODS: Eighty-seven consecutive UDBMT performed in 9 centers between October 1989 and February 1998 were evaluated. This represents more than 95% of UDBMT for CML performed in adult transplant centers in Spain during this period. The patients' median age was 31.5 years (range, 12-49). The median interval from CML diagnosis to UDBMT was 30 months (range, 3-160). Seventy-nine percent of transplants were performed during the first chronic phase (1CP). RESULTS: Actuarial probability of survival and disease-free survival at 4 years for the whole series was 24% (95% confidence interval [CI]: 14%-34%) and 20% (CI: 10%-30%), respectively. The cumulative incidence of relapse and transplant-related mortality (TRM) was 7% (CI: 4%-10%) and 71% (CI: 60%-82%), respectively. The main causes of death were graft failure (n=7), infection (n=23), and graft-versus-host disease (GvHD) (n=25). The actuarial probability of acute GvHD grade II-IV and grade III-IV was 56% (CI:46%-66%) and 36% (CI: 26%-36%), respectively. The cumulative incidence of extensive chronic GvHD was 18% (CI: 9%-27%). Univariate analyses showed that the pre-transplant factor with the highest influence on survival was disease status at transplant (30% in 1CP vs. 0% in advanced phases; p=0.0001). Other pre-transplant factors influencing survival among patients in 1CP were: patient's age (older than 30 years 11% vs. 48%), interval diagnosis-transplantation (longer than 2 years 17% vs. 55%), donor type (HLA, B, DRB1 identical 32% vs. 25%), CMV serologic status (donor and recipient negative 63% vs. 24%), year of transplantation (before 1995 19% vs. 40%), and conditioning regimen (cyclophosphamide plus total body radiation 40% vs. 16%). The main risk factors had a cumulative effect on survival. Thus, probability of survival ranged from 66% (CI: 39%-93%) in patients in 1CP, under 40 years of age, transplanted from an HLA, A, B, DRB1 identical donor during the first two years after diagnosis, to 0% in those with three or more risk factors. INTERPRETATION AND CONCLUSIONS: This experience shows that UDBMT used to have a high TRM that has progressively decreased along the years. At the present time, the results are encouraging, particularly when UDBMT is performed under favorable conditions.