Adoptive immunotherapy via Donor lymphocyte infusions following allogeneic haematopoietic stem cell transplantation for Myelofibrosis: A real world, retrospective multi-centre study

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option for Myelofibrosis (MF). Relapse however remains a significant problem in up to 20-30% of cases. Donor Lymphocyte Infusions (DLI) represent a potentially effective strategy for relapse prevention and management, but optimal timing based on measurable residual disease (MRD)/chimerism analyses and regimen choice remain undetermined. We performed a retrospective ‘real world’ analysis of a multicentre cohort of MF allo-HCT patients from 8 European transplant centres who received DLI between 2005-2022. Response was assessed using IWG-MRT defined response criteria, and survival endpoints were estimated using the Kaplan-Meier estimator and log-rank test. The study included 28 patients with a median age of 58 years and a Karnofsky performance status of >80. The majority of patients had DIPPS-plus Intermediate-2 or high-risk disease at the time of allo-HCT. In vivo T cell depletion was utilised in 20 (71.2%) cases, with 19/20 patients receiving anti-thymocyte globulin (ATG). Indication for DLI was either ‘pre-emptive’ (n=15), due to a decrease in recipient chimerism (n=13) or molecular relapse (n=2), or ‘therapeutic’ (n=13) for clinician-defined haematological/ clinical relapse. No patient received DLI prophylactically. Median time to DLI administration was 23.4 months post allo-HCT. Of the 16 patients receiving >1 dose of DLI, 12 were part of a planned escalating dose regimen. Median follow-up from time of 1st DLI administration was 55.4 months. Response rates to DLI were CR (n=9), PR (n=1), and clinical improvement (n=6). Chimerism levels improved in 16 patients, and stable disease was reported in 5 patients. No response or progression was reported in 7 patients. DLI-induced aGVHD was reported in 11 (39%) cases, grade 3/4 (n=7;25%). Median overall survival from time of 1st DLI was 62.6 months, and the cumulative incidence of relapse/progression after 1st DLI was 30.8% at 6 months. This study highlights that good response rates can be achieved with DLI even after frank relapse in some patients within a cohort where other treatment options are very limited. More prospective studies are warranted to identify the optimal DLI regimen and timing to improve patient outcomes

Safety and efficacy of ponatinib in real world clinical practice. Results from the Spanish Compassionate Use Program. A GELMC study

Aims: The purpose of this study is to provide safety and efficacy information from patients treated with ponatinib in real world clinical practice.N

CNL and aCML should be considered as single entity based on molecular profiles and outcomes

Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences of these disorders we undertook a multi-center international study of one of the largest case series (CNL, n=24; aCML, n=37 cases, respectively), focusing on the clinical and mutational profiles (n=53 with molecular data) of these diseases. We found no differences in clinical presentation or outcomes between both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms (MDS/MPN). We identified four high-risk mutated genes, specifically CEBPA (β=2.26, HR=9.54, p=0.003), EZH2 (β=1.12, HR=3.062, p=0.009), NRAS (β=1.29, HR=3.63, p=0.048) and U2AF1 (β=1.75, HR=5.74, p=0.013) by multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases

Phase I study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias

Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial.Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days.Patients had AML (n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression.Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed