Venetoclax-based low intensity therapy in molecular failure of NPM1-mutated AML.

ABSTRACT: Molecular failure in NPM1-mutated acute myeloid leukemia (AML) inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low-dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here, we report on an international multicenter cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66 patients (84%) and MRD negativity in 56 (71%). Eighteen of 79 patients (23%) required hospitalization, and no deaths were reported during treatment. Forty-one patients were bridged to allogeneic transplant with no further therapy, and 25 of 41 were MRD negative assessed by reverse transcription quantitative polymerase chain reaction before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45%, and in responding patients, there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs 91%; P < .01), worse OS (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06-5.86; P = .036), and EFS (HR, 1.87; 95% CI, 1.06-3.28; P = .03). Eighteen of 35 patients who did not undergo transplant became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax-based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1-mutated AML, either as a bridge to transplant or as definitive therapy.

At-Home Foscarnet Administration in Patients with Cytomegalovirus Infection Post-Allogeneic Stem Cell Transplantation: A Unicentric, Safe, and Feasible Program.

Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our hospital designed an at-home FCN administration model to avoid the hospitalization of patients requiring FCN treatment. This study analyzes whether the at-home administration of FCN is as safe and effective as its hospital administration. We collected and compared demographic, clinical, analytical, and economic data of patients with CMV infection post-allo-HCT who received FCN in the hospital (n = 16, 17 episodes) vs. at-home (n = 67, 88 episodes). The proportions of patients with cured CMV infections were comparable between the two groups (65.9% vs. 76.5%, p = 0.395). The median duration of FCN treatment was 15 (interquartile range [IQR] 9-23) and 14 (IQR 11-19) days in the HCU and inpatient cohorts, respectively (p = 0.692). There were no significant differences in the FCN toxicities between groups except for hypocalcemia (26.1% vs. 58.8%, p = 0.007), which was more prevalent in the inpatient cohort. A significant cost-effectiveness was found in the HCU cohort, with a median savings per episode of EUR 5270. It may be concluded that home administration of FCN is a safe, effective, and cost-efficient therapeutic option for patients with CMV infection and disease.

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome.

Germ line predisposition in acute myeloid leukemia (AML) has gained attention in recent years because of a nonnegligible frequency and an impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germ line variants (GVs) in 288 genes related to cancer predisposition in 47 patients with available paired, tumor-normal material, namely bone marrow stroma cells (n = 29), postremission bone marrow (n = 17), and saliva (n = 1). These patients correspond to 2 broad AML categories with heterogeneous genetic background (AML myelodysplasia related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia, or strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, 6 affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41, and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21, and CSF3R). We did not find differences in clinical characteristics nor outcome between carriers of GVs vs noncarriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.

Real-World Data on Chronic Myelomonocytic Leukemia: Clinical and Molecular Characteristics, Treatment, Emerging Drugs, and Patient Outcomes.

Despite emerging molecular information on chronic myelomonocytic leukemia (CMML), patient outcome remains unsatisfactory and little is known about the transformation to acute myeloid leukemia (AML). In a single-center cohort of 219 CMML patients, we explored the potential correlation between clinical features, gene mutations, and treatment regimens with overall survival (OS) and clonal evolution into AML. The most commonly detected mutations were TET2, SRSF2, ASXL1, and RUNX1. Median OS was 34 months and varied according to age, cytogenetic risk, FAB, CPSS and CPSS-Mol categories, and number of gene mutations. Hypomethylating agents were administered to 37 patients, 18 of whom responded. Allogeneic stem cell transplantation (alloSCT) was performed in 22 patients. Two-year OS after alloSCT was 60.6%. Six patients received targeted therapy with IDH or FLT3 inhibitors, three of whom attained a long-lasting response. AML transformation occurred in 53 patients and the analysis of paired samples showed changes in gene mutation status. Our real-world data emphasize that the outcome of CMML patients is still unsatisfactory and alloSCT remains the only potentially curative treatment. However, targeted therapies show promise in patients with specific gene mutations. Complete molecular characterization can help to improve risk stratification, understand transformation, and personalize therapy.

Results of ARI-0001 CART19 cell therapy in patients with relapsed/refractory CD19-positive acute lymphoblastic leukemia with isolated extramedullary disease.

We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with the CD19-directed CAR T cells ARI-0001 in two centers (adult and pediatric), including patients treated in the CART19-BE-01 trial and the consecutive compassionate use program. iEMD was detected by PET-CT in 78% (14/18), and/or by cerebrospinal fluid analysis in 28% (5/18). Patients received cyclophosphamide and fludarabine followed by 1 × 106 ARI-0001 cells/kg, initially as a single dose (first patient) and later split into three fractions (10%, 30%, and 60%). Cytokine release syndrome (CRS) occurred in 50% (9/18) of patients, with no cases of grade ≥3 CRS, and 1 case (6%) of grade 1 neurotoxicity. Tocilizumab was used in 6% of patients (1/18). Procedure-related mortality was 0% at 2 years. Objective responses were seen in 94% (95% confidence interval [CI]: 73%-99%) of patients, with complete responses (CR) seen in 78% (95% CI: 52%-94%) of them. Progression-free and overall survival were 49% (95% CI: 30%-79%) and 61% (95% CI: 40%-92%) at 2 years. In conclusion, the use of ARI-0001 cells in patients with R/R ALL and iEMD was associated with a safety and efficacy profile that is comparable with what is observed in patients with marrow involvement and in line with other CART19 products.

Results of ARI-0001 CART19 Cells in Patients With Chronic Lymphocytic Leukemia and Richter's Transformation.

CART19 cells are emerging as an alternative therapy for patients with chronic lymphocytic leukemia (CLL). Here we report the outcome of nine consecutive patients with CLL treated with ARI-0001 CART19 cells, six of them with Richter's transformation (RT). One patient with RT never received therapy. The cytokine release syndrome rate was 87.5% (12.5% grade ≥3). Neurotoxicity was not observed in any patient. All patients experienced absolute B-cell aplasia, and seven (87.5%) responded to therapy. With a median follow-up of 5.6 months, two patients with RT experienced a CD19-negative relapse. In conclusion, ARI-0001 cell therapy was feasible, safe, and effective in patients with high-risk CLL or RT.

Risk Factors for Mortality in Hematopoietic Stem Cell Transplantation Recipients with Bloodstream Infection: Points To Be Addressed by Future Guidelines.

In recent years, important epidemiologic changes have been described in hematopoietic stem cell transplantation (HSCT) recipients with bloodstream infection (BSI), with increases in gram-negative bacilli and multidrug resistant (MDR) gram-negative bacilli. These changes have been linked to a worrisome increase in mortality. We aimed to define the risk factors for mortality of HSCT patients experiencing BSI. All episodes of BSI in patients with HSCT between 2008 and 2017 were prospectively collected. Multivariate analyses were performed. A total of 402 BSI episodes were documented in 293 patients who had undergone HSCT (75.4% allogenic, 32.3% autologous, 19.3% second HSCT). The median time from HSCT to BSI was 62 days (interquartile range, 9 to 182 days). Gram-positive cocci accounted for 56.7% of the episodes; gram-negative bacilli, for 42%. The most common microorganisms were coagulase-negative staphylococci (30.6%) and Pseudomonas aeruginosa (15.9%). MDR gram-negative bacilli caused 11.9% of all episodes. Clinical characteristics, source of BSI, etiology, and outcomes changed depending on time since HSCT. Globally, 26.6% of episodes were treated with inappropriate empiric antibiotic therapy, more frequently in BSI episodes caused by P. aeruginosa, MDR P. aeruginosa, and MDR gram-negative bacilli. The 30-day mortality was 19.2%. Independent risk factors for mortality were BSI occurring ≥30 days after HSCT (odds ratio [OR], 11.21; 95% confidence interval [CI], 4.63 to 27.19), shock (OR, 7.10; 95% CI, 2.98 to 16.94), BSI caused by MDR P. aeruginosa (OR, 4.45; 95% CI, 1.12 to 17.72), and inappropriate empiric antibiotic therapy for gram-negative bacilli or Candida spp. (OR, 3.73; 95% CI, 1.27 to 10.89). HSCT recipients experiencing BSI have high mortality related to host and procedure factors, causative microorganism, and empiric antibiotic therapy. Strategies to identify HSCT recipients at risk of MDR P. aeruginosa and reducing inappropriate empiric antibiotic therapy are paramount to reduce mortality.

Complement as the enabler of carfilzomib-induced thrombotic microangiopathy.

Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.

The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever.

BACKGROUND: Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. METHODS: Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. RESULTS: The incidence of NF among the groups was reduced (64%, 44%, and 24%; P<0.001), with a non-significant decrease in hospital readmissions as well (12%, 6%, and 2%; P = 0.07). The most important variables identified for NF were: HCT-CI >2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age ≥60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05). CONCLUSIONS: G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial.

Impact of intensifying primary antibiotic prophylaxis in at-home autologous stem cell transplantation program for lymphoma patients.

Despite the use of fluoroquinolone (FQ) prophylaxis, neutropenic fever (NF) is the most frequent cause of hospital readmission in ambulatory care programs for patients treated with autologous stem cell transplantation (ASCT). We analyzed the impact of intensifying primary prophylaxis with the addition of piperacillin/tazobactam (PT) to FQ. Between January 2002 and August 2018, 154 lymphoma patients conditioned with BEAM were included (40% received ceftriaxone (Ct) plus FQ and 60% PT plus FQ). NF and hospital readmission were required in 84 vs. 41% (p < .0001) and 12 vs. 1% (p = .007) of patients within the Ct and PT groups, respectively. The multivariate analysis showed that PT plus FQ retained its independent protective factor for NF (odds ratio (OR): 0.13; p < .001) and for hospital readmission (OR: 0.07; p = .01). The use of PT and FQ prophylaxis may effectively prevent episodes of NF and hospitalizations in lymphoma patients managed in our at-home ASCT care model.

A reproducible and safe at-home allogeneic haematopoietic cell transplant program: first experience in Central and Southern Europe.

In 2015, we implemented an at-home allogeneic haematopoietic cell transplant (allo-HCT) program. Between 2015 and 2018, 252 patients underwent allo-HCT; 41 patients underwent allo-HCT in the at-home program (46% myeloablative; 63% unrelated donor; 32% posttransplant cyclophosphamide), and these patients were compared with 39 in-patients; safety, capacity to release beds for other programs, and economic efficiency cost were evaluated. We observed a lower incidence of febrile neutropenia in the at-home group compared with that in the in-patient group (32% versus 90%; p < 0.0001), whereas the incidence of aspergillosis was similar among groups (at-home 1% versus in-patient 3%; p = 0.5). The at-home patients showed a lower incidence of 1-year severe graft-versus-host disease (GVHD; 10% versus 29%; p = 0.03). There were no differences in 1-year transplant-related mortality, relapse, or overall survival among groups. The re-admission rate in the at-home group was 7%. The at-home setting was less expensive (9087 €/transplant), and its implementation increased capacity by 10.5 allo-HCTs/year. Moreover, a chimeric antigen receptor T-cell program could be established without increasing beds. Thus, our at-home allo-HCT program may be a safe modality to reduce febrile neutropenia and acute GVHD, resulting in lower re-admission rates.