FLT3-ITD and NPM1 mutations are key to defining the genetic risk profile of acute myeloid leukemia (AML). We aimed to assess the prognostic features of the FLT3-ITD and NPM1 mutations in old and/or unfit individuals with AML treated with non-intensive therapies in the era before azacitidine-venetoclax approbation. The results of various non-intensive regimens were also compared. We conducted a retrospective analysis that included patients treated with different non-intensive regimens, between 2007 and 2020 from PETHEMA AML registry. We compiled 707 patients with a median age of 74 years and median follow-up time of 37.7 months. FLT3-ITD patients (N = 98) showed a non-significant difference in overall survival (OS) compared to FLT3-ITD negative-patients (N = 608) (P = 0.17, median OS was 5 vs 7.3 months respectively). NPM1-mutated patients (N = 144) also showed a non-significant difference with NPM1 wild type (N = 519) patients (P = 0.25, median OS 7.2 vs 6.8 respectively). In the Cox regression analysis neither NPM1 nor FLT3-ITD nor age were significant prognostic variables for OS prediction. Abnormal karyotype and a high leukocyte count showed a statistically significant deleterious effect. Azacitidine also showed better survival compared to FLUGA (low dose cytarabine plus fludarabine). NPM1 and FLT3-ITD seem to lack prognostic value in older/unfit AML patients treated with non-intensive regimens other than azacitidine-venetoclax combination.

CNS relapse in patients with Diffuse Large B Cell Lymphoma (DLBCL) is usually an early complication and with poor prognosis. R-CHOP, the standard treatment for DLBCL plays a minimal role preventing leptomeningeal and/or brain parenchyma relapse. Risk factors have been previously identified for this complication and high dose intravenous methotrexate (HDMTX) has been suggested as an effective strategy to prevent CNS lymphoma relapse (GELTAMO guidelines Haematologica 2017 and British guidelines BJAEM 2020). Unfortunately the administration of HDMTX is related with risk of renal, hepatic and haematological adverse events. Methods: This is an open-label, interventional, non-randomized, phase 2, pilot, multicenter study in Diffuse large B-cell lymphoma (DLBCL) patients at high risk of CNS relapse to assess of prophylactic effect of 2,000 unit of Glucarpidase in MTX related-toxicity administered after 12 hours of HDMTX. This study will be performed in the context of in-patients setting for receiving the three HDMTX courses. Criteria for CNS involvement are concordant with those of the last approved version of the GELTAMO guideline for the diagnostic, prevention, and therapeutical management of Central Nervous System involvement in patients with diffuse large cell B Lymphoma (revised 2017) [1]. Inclusion criteria: Age 18 year and above, diagnosis with diffuse large B-cell lymphoma at high risk of CNS involvement and adequate haematological, renal and hepatic function. Criteria to consider risk of CNS involvement were: >=2 extranodal site involved plus an elevated LDH and/or lymphoma involvement of the testis, breast, adrenal gland or kidney In order to include patients without CNS involvement, patients will be included in the study with a negative result of the CSF cytometry flow test, which will be performed according to normal clinical practice. Primary objective is: To describe the reduction of MTX levels after systematic administration of reduced Glucarpidase doses (2,000 units) 12 hours following start of HDMTX infusion in DLBCL patients at high risk for CNS involvement, receiving multiple cycles of HDMTX. Secondary objectives are: To analyze the prophylactic effect of Glucarpidase administered after 12 hour of high-dose MTX (HDMTX) on the incidence and severity and duration of MTX related-toxicity (renal toxicity, mucositis, liver toxicity, neutropaenia, thrombocytopaenia). To assess the incidence of CNS relapse during one year To assess the length of hospital stay (LOS) during HDMTX therapy To analyze the appearance of antibodies against Glucarpidase To analyze the appearance of neutralizing antibodies against Glucarpidase The study is currently enrolling. NCT05022797. CRIS Fundation. BTG.

Background: CNS relapse in patients with Diffuse Large B Cell Lymphoma (DLBCL) is usually an early complication and with poor prognosis. R-CHOP, the standard treatment for DLBCL plays a minimal role preventing leptomeningeal and/or brain parenchyma relapse. Risk factors have been previously identified for this complication and high dose intravenous methotrexate (HDMTX) has been suggested as an effective strategy to prevent CNS lymphoma relapse (GELTAMO guidelines Haematologica 2017 and British guidelines BJAEM 2020). Unfortunately the administration of HDMTX is related with risk of renal, hepatic and haematological adverse events. Aims: Primary objective is: To describe the reduction of MTX levels after systematic administration of reduced Glucarpidase doses (2,000 units) 12 hours following start of HDMTX infusion in DLBCL patients at high risk for CNS involvement, receiving multiple cycles of HDMTX. Secondary objectives are: To analyze the prophylactic effect of Glucarpidase administered after 12 hour of high-dose MTX (HDMTX) on the incidence and severity and duration of MTX related-toxicity (renal toxicity, mucositis, liver toxicity, neutropaenia, thrombocytopaenia). To assess the incidence of CNS relapse during one year To assess the length of hospital stay (LOS) during HDMTX therapy To analyze the appearance of antibodies against Glucarpidase To analyze the appearance of neutralizing antibodies against Glucarpidase The study is currently enrolling. ClinicalTrials.gov Identifier: NCT05022797 Methods: This is an open-label, interventional, non-randomized, phase 2, pilot, multicenter study in Diffuse large B-cell lymphoma (DLBCL) patients at high risk of CNS relapse to assess of prophylactic effect of 2,000 unit of Glucarpidase in MTX related-toxicity administered after 12 hours of HDMTX. This study will be performed in the context of in-patients setting for receiving the three HDMTX courses. Criteria for CNS involvement are concordant with those of the last approved version of the GELTAMO guideline for the diagnostic, prevention, and therapeutical management of Central Nervous System involvement in patients with diffuse large cell B Lymphoma (revised 2017) [1]. Inclusion criteria: Age 18 year and above, diagnosis with diffuse large B-cell lymphoma at high risk of CNS involvement and adequate haematological, renal and hepatic function. Criteria to consider risk of CNS involvement were: >=2 extranodal site involved plus an elevated LDH and/or lymphoma involvement of the testis, breast, adrenal gland or kidney In order to include patients without CNS involvement, patients will be included in the study with a negative result of the CSF cytometry flow test, which will be performed according to normal clinical practice. Results: Trial ongoing Image:Summary/Conclusion: Trial ongoing

For patients with AML, the best alternative donor remains to be defined. We analyze outcomes of patients who underwent myeloablative umbilical cord blood or haploidentical hemopoietic stem cell transplantation (HSCT) in Spain. Fifty-one patients underwent single umbilical cord blood transplantation supported by a third party donor (Haplo-Cord) between 1999 and 2012, and 36 patients received an haploidentical HSCT with post-transplant cyclophosphamide (PTCY-haplo) between 2012 and 2014 in GETH centers. The Haplo-Cord cohort included a higher proportion of patients with high disease risk index and use of TBI in the conditioning regimen, and hematopoietic cell transplantation-age Comorbidity Age Index was higher in PTCY-haplo patients. Cumulative incidence of neutrophil engraftment was 97% in the Haplo-Cord and 100% in the PTCY-haplo group, achieved in a median of 12 and 17 days, respectively (P=0.01). Grade II-IV acute GvHD rate was significantly higher in the PTCY-haplo group (9.8% vs 29%, P=0.02) as well as chronic GvHD rates (20% vs 38%, P=0.03). With a median follow-up of 61 months for the Haplo-Cord group and 26 months for the PTCY-haplo cohort, overall survival at 2 years was 55% and 59% (P=0.66), event-free survival was 45% vs 56% (P=0.46), relapse rate was 27% vs 21% (P=0.79), and non-relapse mortality was 17% vs 23% (P=0.54), respectively. In this multicenter experience, Haplo-Cord and PTCY-haplo HSCT offer valid alternatives for patients with AML. Neutrophil engraftment was faster in the Haplo-Cord cohort, with similar survival rates, with higher GvHD rates after haploidentical HSCT.

Relapsed or refractory Hodgkin lymphoma (advanced HL) still remains a therapeutic challenge. Recently, unmanipulated haploidentical related donor transplant with reduced conditioning regimen (HAPLO-RIC) and post-transplant cyclophosphamide (PT-Cy) as GvHD prophylaxis has became a promising rescue strategy potentially available to almost every patient. This paper reports our multicenter experience using an IV busulfan-based HAPLO-RIC regimen and PT-Cy in the treatment of 43 patients with advanced HL. Engraftment occurred in 42 patients (97.5%), with a median time to neutrophil and platelet recovery of 18 and 26 days. Cumulative incidences of grades II–IV acute GvHD and chronic GvHD were 39% and 19%, respectively. With a median follow-up of 25.5 months for survivors, 27 patients are alive, with 22 of them disease free. Cumulative incidences of 1-year non-relapse mortality and relapse at 2 years were 21% and 24%, respectively. The estimated 2-year event-free survival (EFS) and overall survival (OS) were 48% and 58%, respectively. CR prior to HAPLO-RIC correlated with better EFS (78.5% vs 33.5%; P=0.015) and OS (86% vs 46%; P=0.044). Our findings further confirm prior reports using HAPLO-RIC in advanced HL in a multicenter approach employing an IV busulfan-based conditioning regimen.

Allogeneic transplantation is the only curative option for patients with high risk hematologic malignancies. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that's why HAPLO-HSCT offers a therapeutic option to most of these patients with the advantages of quick availability, easy programation and logistics, and a committed donor. Bone marrow (BM) or peripheral blood stem cells (PBSC) could be used as graft source but it's not established if any of them offer significant advantages.

Allogeneic transplantation is the only curative option for patients with high risk leukemias or MDS. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor; that's why haploidentical stem cell transplantation (HAPLO-HSCT) offers a therapeutic option to most of these patients. Myeloablative conditioning (MAC) used to obtain better disease control than reduced intensity conditioning regimens (RIC), but with higher toxicity, rendering long term similar results.