Clinical Lymphoma, Myeloma & Leukemia最新文献

Chemoimmunotherapy (CIT) is the standard frontline treatment for advanced indolent non-Hodgkin lymphomas (iNHL). While lenalidomide-based immunotherapy remains the standard of care for relapsed iNHL, its frontline use is limited, due to nonsuperiority as compared to CIT. Agents that engage T-cells, polarize macrophage phenotype to a more antitumoral phenotype, and/or to target epigenetic pathways could enhance immunotherapy. We summarize in this review safety plus efficacy data from published and/or ongoing clinical trials investigating the combination of lenalidomide-based immunotherapy with T-cell engagers (including anti-CD3/CD20 bispecific antibodies), macrophage-targeting agents (including BTK inhibitors and anti-CD47 antibodies), and epigenetic modifiers (including EZH2 inhibitors). We also summarize the activity in iNHL of agents targeting antigens other than CD20 (including CD19 and CD79b), and novel immunotherapies and cellular therapies (including NK-cell based treatments). The therapeutic landscape of iNHL is soon to significantly change.

Background: LOXO-338 is a novel, orally bioavailable small-molecule inhibitor of Bcl-2, designed to achieve selectivity for Bcl-2 over Bcl-xL, thus avoiding dose-limiting thrombocytopenia associated with Bcl-xL inhibition. This first-in-human, open-label, Phase 1 study investigated LOXO-338 in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or B-cell non-Hodgkin lymphoma (NHL) (NCT05024045).

Patients and methods: Patients with histologically confirmed advanced B-cell malignancies who had received ≥ 2 prior therapies were enrolled in Phase 1 dose escalation (interval 3 + 3 design). LOXO-338 was administered orally as 50 to 300 mg once-daily dose until discontinuation due to progressive disease or unacceptable toxicity. The primary objective was to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose of LOXO-338. Secondary objectives included safety, tolerability, pharmacokinetics, and preliminary antitumor activity.

Results: In total, 27 patients with CLL/SLL (n = 10) or NHL (n = 17) were treated. No dose-limiting toxicities occurred and the MTD was not reached. Treatment-emergent adverse events occurred in 23 patients (85%); anemia (22%) and fatigue (22%) were the most prevalent. Treatment-related adverse events (TRAEs) occurred in 15% and were mostly grade 1 (11%) or 2 (4%); grade ≥ 3 or serious TRAEs were not reported. Tumor lysis syndrome was not observed. The overall response rate was 19% (95% CI: 6.3, 38.1) and disease control rate was 67% (95% CI: 46, 83.5). LOXO-338 was orally bioavailable with dose-dependent increases in exposure.

Conclusion: LOXO-338 was well tolerated with a favorable safety profile in previously treated patients with advanced hematologic malignancies. Preliminary efficacy was observed in this heavily pretreated population supporting further investigation.

Background: Isatuximab-based combinations are widely used to treat patients with relapsed or refractory multiple myeloma, and will soon become part of the standard first-line therapies in transplant-eligible and transplant-ineligible newly diagnosed patients. Isatuximab is currently approved for intravenous fixed volume (250ml) administration, with a maximum infusion rate of 200 ml/h and at least 75 minutes required for 1 administration. A recent clinical trial suggested the safety of a faster, 30-minute administration of isatuximab. Other trials are ongoing. Based on this early data as well as previous experience with monoclonal antibody therapies, the rapid, 30-minutes intravenous isatuximab administration was adopted at our institution as standard of care.

Methodology: We here report the early real-world data on this new standard.

Purpose: Recent studies describe inferior outcomes in newly diagnosed multiple myeloma (NDMM) patients with t(11;14) treated with novel agents.

Materials and methods: We analyzed 240 NDMM transplant eligible (TE) patients who received triplet induction regimen in the GEM05MENOS65 (bortezomib, thalidomide and dexamethasone - VTD) and GEM2012 (bortezomib, lenalidomide and dexamethasone - VRD) clinical trials.

Results: t(11;14) and standard risk (SR) non-t(11;14) were prevalent in 51 (21%) and 189 (79%) patients, respectively. Patients with t(11;14) treated with VTD had a lower overall response rate (ORR) (84% vs. 97%, P = .044) and lower negative minimal residual disease (MRD) (7.7% vs 35.1%, P = .049) after induction, as compared to SR non-t(11;14), while there were no differences in ORR (87% vs. 89%) or negative MRD (13.2% vs. 24.4%, P = .2) for these 2 subgroups in patients treated with VRD. The presence of t(11;14) impacted negatively on PFS in patients with VTD (hazard ratio 2.70; P = .005), while no differences were observed in those treated with VRD.

Conclusion: TE NDMM patients harboring t(11;14) had an inferior outcome compared with SR patients when receiving induction therapy with VTD while no differences were observed when receiving a lenalidomide containing regimen.

Background: Acute myeloid leukemia (AML) arising from myelodysplastic syndromes (MDS) is a unique subtype of secondary AML (sAML) with poor prognosis. We defined its epidemiologic profile in older adults.

Methods: Using the SEER-Medicare database, we identified MDS cases that progressed to AML between 2007 and 2017, during the era of hypomethylating agents (HMA). Established algorithms determined demographics, MDS histology, MDS risk by Simplified Myelodysplastic Syndrome Risk Score (SMMRS), comorbidity, transfusion burden, and HMA therapy. We defined overall survival (OS) after sAML, and examined factors associated with AML and mortality, including the impact of prior HMA therapy.

Results: Of 15,227 MDS patients, 12.3% developed AML. Incidence varied by MDS histology and SMMRS. Time to AML was shorter with higher SMMRS. Older age and higher comorbidity were associated with lower odds of AML. Higher SMMRS (OR = 2.5, 95CI: 2.0-3.0), transfusion dependence (OR = 2.6, 95CI: 2.1-3.2), and HMA use (OR = 4.9, 95CI: 4.4-5.5) were associated with increased transformation risk. Median OS after AML diagnosis was 3 months. OS rates at 1 and 2 years were 25% and 12%. Survival varied by antecedent MDS histology, being longest in those with ringed sideroblasts (P < .001). Older age (HR = 1.4, 95CI: 1.1-1.9) and higher SMMRS (HR = 1.8, 95CI: 1.5-2.2) were associated with risk of death. Antecedent HMA exposure was associated with longer OS (4 vs. 2 months, P < .01), with 4 or more HMA cycles associated with decreased risk of death (HR = 0.53, 95CI: 0.47-0.60).

Conclusion: Risk of sAML is significant even in lower-risk MDS histologies. Survival is poor and varies by antecedent MDS characteristics. HMA exposure association with longer survival warrants further analysis.

Familial multiple myeloma (MM) is a relatively rare entity. Data on epidemiology, underlying germline genetic predisposition, and clinical features of familial MM continue to expand, especially in recent years. The risk of MM has been reported to be increased by 2 to 4 times among first-degree relatives of MM patients along with monoclonal gammopathy of undetermined significance (MGUS), other hematological malignancies, and several solid tumors by multiple groups. The association between MM risk and having a first-degree relative with a history of MM is stronger among African Americans/Blacks (OR = 5.52, 95% CI: 1.87-16.28) than European Americans/Whites (OR = 1.26, 95% CI: 0.75-2.10). Although data on clinical features and prognosis of familial cases are limited, preliminary data suggest a better prognosis among familial cases. Sequencing studies in familial cases have discovered rare disease-causing variants among which CDKN2A, USP45, MYH14, EPOR, HERC1, KLHL18, and KLHDC3 are shared by independent groups. Some of these candidate genes possess functions related to myelomagenesis such as B-cell development, immunoglobulin gene regulation, immune pathways, DNA damage/repair, ubiquitination, and cell adhesion mechanisms. Our group has recently completed an analysis among our Turkish MM families to confirm the findings of the International Consortium. The odds ratio (OR) for single nucleotide polymorphism rs28199 in nonfamilial MM cases compared to healthy control was 1.18, with an OR of 2.86 in familial MM cases compared to nonfamilial cases. Despite the accumulation of data, most questions remain to be answered. Future studies may elucidate underlying biological mechanisms, and develop polygenic risk scores, leading advancements in prognostic evaluation and clinical management.

Measurable/minimal residual disease (MRD) is 1 of the most powerful prognostic factors for progression-free survival and overall survival in multiple myeloma (MM) and may guide therapeutic approaches. Here, we provide an overview of the current state of MRD testing in MM in Canada, highlighting its current use, approaches, and barriers. Furthermore, we discuss the available MRD assays and address questions on their appropriateness for routine practice and clinical trials. We also provide insights into timepoints for MRD testing and the relevance of achieving durable MRD negativity. The consensus recommendations herein were agreed upon by Canadian hematologists practicing at academic cancer centers and community cancer centers, clinical trial investigators, laboratory personnel, MM patients, and took into consideration the Canadian therapeutic landscape and the impact of anticipated regulatory approvals.

Background: Early continuous lenalidomide use for multiple myeloma (MM) treatment has led to more patients with lenalidomide-refractory disease at earlier lines of therapy (LOTs). Real-world treatment practices and outcomes in elderly patients with comorbidities are not well characterized.

Materials and methods: Using the Surveillance, Epidemiology, and End Results-Medicare database, we analyzed data from patients who were diagnosed with MM between 2014 and 2019, had 1 to 3 prior LOTs, including a proteasome inhibitor and an immunomodulatory drug, and were lenalidomide refractory. Patients were followed from index (initiation of first subsequent LOT after meeting eligibility criteria and after January 1, 2016) until death, end of continuous Medicare enrollment, or December 31, 2020.

Results: This analysis included 1297 patients (median age, 75 years). The mean National Cancer Institute Comorbidity Index score was 0.87 and 81% had at least 1 comorbidity. Singlet, doublet, and triplet therapies each accounted for ∼30% of index regimens. The most common regimens, ± corticosteroid, were daratumumab-pomalidomide (15%), pomalidomide (13%), and daratumumab (12%). Median overall survival and time to next treatment (TTNT) were 29.3 and 8.5 months, respectively. TTNT decreased with successive LOTs (1 prior LOT, 11.0 months; 3 prior LOTs, 6.1 months).

Conclusion: Elderly patients with comorbidities and lenalidomide-refractory disease after 1 to 3 LOTs receive suboptimal regimens, have poor outcomes, and move rapidly through treatments, highlighting the need for new effective treatments for this difficult-to-treat population.