Spleen tyrosine kinase/FMS-like tyrosine kinase-3 inhibition in relapsed/refractory B-cell lymphoma, including diffuse large B-cell lymphoma: updated data with mivavotinib (TAK-659/CB-659).

We report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report). Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60-120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity. A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) and 38% (26/69), respectively. Median duration of response was 28.1 months overall and not reached in DLBCL responders. In subgroups with DLBCL of germinal center B-cell (GCB) and non-GCB origin, ORR was 28% (11/40) and 58% (7/12), respectively. Median progression free survival was 2.0 and 1.6 months in the lymphoma and DLBCL cohorts, respectively. Grade ≥3 treatment-emergent adverse events occurred in 96% of all lymphoma patients, many of which were limited to asymptomatic laboratory abnormalities; the most common were increased amylase (29%), neutropenia (27%), and hypophosphatemia (26%). These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL. Trial registration: ClinicalTrials.gov number: NCT02000934.

Genomic mutation profile in progressive chronic lymphocytic leukemia patients prior to first-line chemoimmunotherapy with FCR and rituximab maintenance (REM).

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment.

A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia.

BACKGROUNDPassive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID-19. Evidence from controlled clinical trials is inconclusive.METHODSWe conducted a randomized, open-label, controlled clinical trial at 27 hospitals in Spain. Patients had to be admitted for COVID-19 pneumonia within 7 days from symptom onset and not on mechanical ventilation or high-flow oxygen devices. Patients were randomized 1:1 to treatment with CP in addition to standard of care (SOC) or to the control arm receiving only SOC. The primary endpoint was the proportion of patients in categories 5 (noninvasive ventilation or high-flow oxygen), 6 (invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), or 7 (death) at 14 days. Primary analysis was performed in the intention-to-treat population.RESULTSBetween April 4, 2020, and February 5, 2021, 350 patients were randomly assigned to either CP (n = 179) or SOC (n = 171). At 14 days, proportion of patients in categories 5, 6, or 7 was 11.7% in the CP group versus 16.4% in the control group (P = 0.205). The difference was greater at 28 days, with 8.4% of patients in categories 5-7 in the CP group versus 17.0% in the control group (P = 0.021). The difference in overall survival did not reach statistical significance (HR 0.46, 95% CI 0.19-1.14, log-rank P = 0.087).CONCLUSIONCP showed a significant benefit in preventing progression to noninvasive ventilation or high-flow oxygen, invasive mechanical ventilation or ECMO, or death at 28 days. The effect on the predefined primary endpoint at 14 days and the effect on overall survival were not statistically significant.TRIAL REGISTRATIONClinicaltrials.gov, NCT04345523.FUNDINGGovernment of Spain, Instituto de Salud Carlos III.

Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

Efficacy and safety of pixantrone for the treatment of multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas.

BACKGROUND AND OBJECTIVE: Few treatment options exist for patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who fail first- and second-line therapies. Pixantrone is a novel aza-anthracenedione agent with reduced potential for cardiotoxicity but maintained anti-tumour activity relative to anthracyclines. The current retrospective, observational, real-life study was undertaken in 79 patients who received pixantrone monotherapy for multiply R/R aggressive B-cell NHL in Spain and Italy. RESULTS: Before pixantrone, patients had received a median of 3 prior therapies and 84.6% of them were refractory to the last regimen. Median progression-free survival (mPFS) was 2.8 months (95% confidence interval [CI] 2.1-3.6) and median overall survival (mOS) was 4.0 months (95%CI 5.6-7.9), with an objective response rate (ORR) of 29% (complete remission [CR]: 13.2%, partial remission [PR]: 15.2%). Patients receiving ≥2 cycles of pixantrone showed mPFS and mOS of 3.1 and 6.0 months, respectively, and an ORR of 36.8% (CR: 17.5%, PR: 19.3%). Overall, 63.3% of patients reported ≥1 adverse event (AE), most commonly haematological AEs. One patient developed grade 2 sinus tachycardia. CONCLUSION: Pixantrone was effective and well tolerated in a real-world population of multiply R/R patients with aggressive B-cell NHL, many of whom had very poor prognostic factors.

Differences in ex-vivo Chemosensitivity to Anthracyclines in First Line Acute Myeloid Leukemia.

BACKGROUND: Induction schedules in acute myeloid leukemia (AML) are based on combinations of cytarabine and anthracyclines. The choice of the anthracycline employed has been widely studied in multiple clinical trials showing similar complete remission rates. MATERIALS AND METHODS: Using an ex vivo test we have analyzed if a subset of AML patients may respond differently to cytarabine combined with idarubicin, daunorubicin or mitoxantrone. Bone marrow (BM) samples of 198 AML patients were incubated for 48 hours in 96 well plates, each well containing different drugs or drug combinations at different concentrations. Ex vivo drug sensitivity analysis was made using the PharmaFlow platform maintaining the BM microenvironment. Drug response was evaluated as depletion of AML blast cells in each well after incubation. Annexin V-FITC was used to quantify the ability of the drugs to induce apoptosis, and pharmacological responses were calculated using pharmacokinetic population models. RESULTS: Similar dose-respond graphs were generated for the three anthracyclines, with a slight decrease in EC50 with idarubicin (p=1.462E-06), whereas the interpatient variability of either drug was large. To identify those cases of selective sensitivity to anthracyclines, potency was compared, in terms of area under the curve. Differences in anthracycline monotherapy potency greater than 30% from 3 pairwise comparisons were identified in 28.3% of samples. Furthermore, different sensitivity was detected in 8.2% of patients comparing combinations of cytarabine and anthracyclines. DISCUSSION: A third of the patients could benefit from the use of this test in the first line induction therapy selection, although it should be confirmed in a clinical trial specifically designed.

Correction: Early myeloma-related death in elderly patients: development of a clinical prognostic score and evaluation of response sustainability role.

Following the publication of this article, the author notes that the following information was missed from the acknowledgments section.

Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature.

Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) ≥ 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb ≥ 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years.

High prognostic value of measurable residual disease detection by flow cytometry in chronic lymphocytic leukemia patients treated with front-line fludarabine, cyclophosphamide, and rituximab, followed by three years of rituximab maintenance.

It has been postulated that monitoring measurable residual disease (MRD) could be used as a surrogate marker of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients after treatment with immunochemotherapy regimens. In this study, we analyzed the outcome of 84 patients at 3 years of follow-up after first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) induction followed by 36 months of rituximab maintenance thearpy. MRD was assessed by a quantitative four-color flow cytometry panel with a sensitivity level of 10-4 Eighty out of 84 evaluable patients (95.2%) achieved at least a partial response or better at the end of induction. After clinical evaluation, 74 patients went into rituximab maintenance and the primary endpoint was assessed in the final analysis at 3 years of follow-up. Bone marrow (BM) MRD analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36 months of maintenance therapy. Thirty-seven patients (44%) did not have detectable residual disease in the BM prior to maintenance therapy. Interestingly, 29 patients with detectable residual disease in the BM after induction no longer had detectable disease in the BM following maintenance therapy. After a median followup of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either undetectable or detectable residual disease in the BM, who had achieved a complete response at the time of starting maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated vs unmutated OS: 85.7% alive at 7.2 years vs 79.6% alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic controls, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early undetectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strategies. This trial is registered with EudraCT n. 2007-002733-36 and ClinicalTrials.gov Identifier: NCT00545714.

Early myeloma-related death in elderly patients: development of a clinical prognostic score and evaluation of response sustainability role.

Although survival of elderly myeloma patients has significantly improved there is still a subset of patients who, despite being fit and achieving optimal responses, will die within 2 years of diagnosis due to myeloma progression. The objective of this study was to define a scoring prognostic index to identify this group of patients. We have evaluated the outcome of 490 newly diagnosed elderly myeloma patients included in two Spanish trials (GEM2005-GEM2010). Sixty-eight patients (13.8%) died within 2 years of diagnosis (early deaths) due to myeloma progression. Our study shows that the use of simple scoring model based on 4 widely available markers (elevated LDH, ISS 3, high risk CA or >75 years) can contribute to identify up-front these patients. Moreover, unsustained response (<6 months duration) emerged as one important predictor of early myeloma-related mortality associated with a significant increase in the risk of death related to myeloma progression. The identification of these patients at high risk of early death is relevant for innovative trials aiming to maintain the depth of first response, since many of them will not receive subsequent lines of therapy.

Pharmacological profiles of acute myeloid leukemia treatments in patient samples by automated flow cytometry: a bridge to individualized medicine.

BACKGROUND: We have evaluated the ex vivo pharmacology of single drugs and drug combinations in malignant cells of bone marrow samples from 125 patients with acute myeloid leukemia using a novel automated flow cytometry-based platform (ExviTech). We have improved previous ex vivo drug testing with 4 innovations: identifying individual leukemic cells, using intact whole blood during the incubation, using an automated platform that escalates reliably data, and performing analyses pharmacodynamic population models. PATIENTS AND METHODS: Samples were sent from 24 hospitals to a central laboratory and incubated for 48 hours in whole blood, after which drug activity was measured in terms of depletion of leukemic cells. RESULTS: The sensitivity of single drugs is assessed for standard efficacy (EMAX) and potency (EC50) variables, ranked as percentiles within the population. The sensitivity of drug-combination treatments is assessed for the synergism achieved in each patient sample. We found a large variability among patient samples in the dose-response curves to a single drug or combination treatment. CONCLUSION: We hypothesize that the use of the individual patient ex vivo pharmacological profiles may help to guide a personalized treatment selection.

Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial.

BACKGROUND: Imatinib, given concurrently or alternating with chemotherapy, has improved the response and survival of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) but relapses are still frequent. The aim of this study was to evaluate the feasibility and results of giving imatinib concurrently with intensive chemotherapy, stem cell transplantation and post-transplant imatinib maintenance therapy in patients with newly diagnosed Ph(+) ALL. DESIGN AND METHODS: This was a phase II study of patients with newly diagnosed Ph(+) ALL given standard chemotherapy, together with imatinib (400 mg/day) until stem cell transplantation, followed by imatinib maintenance therapy for all patients regardless of the molecular status of the disease. RESULTS: Of the 30 patients included, 27 (90%) achieved complete remission, one was resistant to treatment and two died during induction therapy. The percentages of major and complete molecular responses were 86% and 21% after induction, and 81% and 65% after consolidation, respectively. Similar results were observed assessing minimal residual disease by flow cytometry. Of the 27 patients who achieved complete remission, 21 underwent stem cell transplantation (16 allogeneic, 5 autologous). Imatinib (400 mg/day) could be administered after transplantation for a median of 3.9 months in 12 patients, although it was interrupted in 10 patients (in 2 cases because of side effects of the drug). Nine patients relapsed, four before and five after stem cell transplantation and eight patients died of transplant-related causes. With a median follow-up of 4.1 years, the probabilities (95% CI) of disease-free and overall survival were 30% (15% to 45%) and 30% (16% to 45%), respectively. CONCLUSIONS: These results confirm that imatinib is an effective first-line treatment for adult Ph(+) ALL when given concurrently with chemotherapy, making stem cell transplantation feasible in a high proportion of patients. However, post-transplantation imatinib administration was limited, mainly because of transplantation-derived complications rather than drug-specific toxicity.

Hla-DPB1 mismatch in HLA-A-B-DRB1 identical sibling donor stem cell transplantation and acute graft-versus-host disease.

BACKGROUND: The role of human leukocyte antigen (HLA)-DPB1 as a transplantation antigen is controversial. A higher incidence of acute graft-versus-host disease (aGVHD) has been described after unrelated donor bone marrow transplant when both HLA-DPB1 alleles were mismatched. METHODS: We investigated the impact of a single HLA-DPB1 mismatch after HLA-A-B-DRB1 identical sibling donor transplantation on aGVHD. We analyzed 627 adult patient-donor pairs and identified 30 pairs without HLA-DPB1 identity (4.78%). In 17 cases, the patient had an allele that was not shared by the donor. RESULTS: The cumulative incidence of grades II-IV aGVHD was higher in the HLA-DPB1 mismatched group (66.7% vs. 35.7%, p=0.012). The HLA-DPB1 mismatch was identified by multivariate analysis as an independent risk factor for aGVHD (p=0.020, RR=2.68, 95% CI: 1.73-3.62). CONCLUSIONS: HLA-DPB1 can mediate alloreactive responses. A single HLA-DPB1 mismatch increases the risk of aGVHD after sibling donor stem cell transplantation.

Cyclophosphamide, pegylated liposomal doxorubicin (Caelyx), vincristine and prednisone (CCOP) in elderly patients with diffuse large B-cell lymphoma: results from a prospective phase II study.

BACKGROUND AND OBJECTIVES: Anthracycline-based combination chemotherapy regimens are the standard therapy for patients with diffuse large B-cell lymphoma (DLBCL), but such regimens may be poorly tolerated in elderly patients. DESIGN AND METHODS: In a prospective phase II study we analyzed the feasibility of a regimen (CCOP) that includes pegylated liposomal doxorubicin (Caelyx ) plus vincristine, cyclophosphamide and prednisone in patients with DLBCL above the age of 60 years. RESULTS: Thirty-three patients, with a median age of 74 years, were enrolled in the study. The overall response rate was 64% (49% complete remissions and 15% partial remissions). The estimated one-year overall and event-free survivals were 55% (95% CI, 38-72) and 45% (95%CI, 28-62), respectively. The only relevant toxicity was neutropenia, which reached grades 3-4 in 21 cases (64%). INTERPRETATION AND CONCLUSIONS: These results suggest that CCOP appears to be an acceptable alternative for elderly patients with DLBCL, and randomized trials against a conventional doxorubicin-containing regimen are justified.