Clinical Lymphoma, Myeloma & Leukemia最新文献

Background: Daratumumab, bortezomib, thalidomide, and dexamethasone (Dara-VTd) is the current standard of care in Europe based on the CASSIOPEIA study, which demonstrated improved depth of response and progression-free survival when daratumumab is added to VTd.

Patients and methods: We conducted a retrospective analysis of patients treated with VTd or Dara-VTd at the Royal Marsden Hospital (RMH). Post-transplant response was assessed by biochemical response and minimal residual disease (MRD) using flow cytometry (sensitivity 10⁻⁵), with additional stratification by cytogenetic risk.

Results: A total of 173 patients (103 Dara-VTd, 70 VTd) with balanced baseline characteristics were included; 150 patients (87%) had a full cytogenetic panel. Median follow-up was 18.6 months. Post-transplant overall response rate was higher with Dara-VTd than VTd (97.1% vs. 87.1%), as was MRD negativity (78.6% vs. 55.7%). While Dara-VTd consistently outperformed VTd, the benefit decreased in patients with multiple high-risk cytogenetic abnormalities. Twenty-four-month progression-free survival was 97.3%, 94.1%, and 63.9% for patients with 0, 1, and ≥ 2 abnormalities treated with Dara-VTd, compared with 82.6%, 61.9%, and 55.6% for VTd, respectively.

Conclusion: Adding daratumumab to VTd improves post-transplant response and MRD negativity in real-world practice. The magnitude of benefit diminishes with increasing numbers of high-risk cytogenetic abnormalities, supporting the value of risk-adapted strategies and real-world MRD assessment in treatment evaluation.

Glyphosate-based formulations (GBFs), such as Roundup, are the most heavily used herbicides in the world. In 2015, the International Agency for Research on Cancer (IARC) concluded that glyphosate and GBFs are probably carcinogenic to humans (group 2A), mainly for non-Hodgkin lymphoma (NHL). However, this finding has been controversial and most pesticide regulatory agencies have not followed their lead. The purpose of this review is to update the scientific literature linking exposure to glyphosate and GBFs to the development of NHL, with emphasis on new findings over the last 5 years. The recent epidemiologic studies provide new evidence for an association between exposure to GBFs and an increased risk of NHL. A new animal study has also shown that glyphosate and GBFs are carcinogenic in rats and also cause acute leukemia. Mechanistic studies have continued to demonstrate that glyphosate and GBFs are genotoxic to human lymphocytes and other cells. Genotoxic and other biological effects have also been shown in human studies and in various animal and cell models with these agents even at low doses. A novel mechanism of chelation and sequestration of glyphosate in bone with slow release over days to weeks resulting in prolonged bone marrow and blood exposure may lead to the development of acute leukemia and other hematologic malignancies. These new findings continue to provide consistent, coherent and compelling evidence that glyphosate and GBFs are a cause of NHL in humans exposed to these agents, and should prompt new reviews by pesticide regulatory agencies around the world.

Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in multiple myeloma (MM) patients over 65 years remains unclear due to their underrepresentation in clinical trials. This study evaluates the safety and efficacy of auto-HCT in this population using real-world data from the TriNetX network.

Methods: A retrospective cohort study was conducted on MM patients treated at Hospital 12 de Octubre (2013-2023). Three cohorts were analyzed: patients > 65 years undergoing auto-HCT (n = 60), ≤ 65 years with auto-HCT (n = 235), and > 65 years without auto-HCT (n = 59). A validation cohort from TriNetX included 5087 patients > 65 and 10,667 ≤ 65 years receiving auto-HCT, along with 54,757 > 65 years without auto-HCT. Primary outcomes included progression-free survival (PFS), time to next treatment (TNT), overall survival (OS), and non-relapse mortality (NRM).

Conclusion: Auto-HCT improved PFS and OS in selected elderly patients. The 6-year PFS was 45.0% (> 65) versus 55.0% (≤ 65) (HR 1.25; P = .365), and the 6-year OS was 57.8% (> 65) versus 81.1% (≤ 65) (HR 2.11; P = .025). TNT rates were similar (64.4% vs. 63.6%; HR 0.93; P < .01). Toxicity and mortality were comparable. These findings support auto-HCT as a valuable consolidation therapy in selected elderly MM patients, emphasizing the need for personalized strategies to optimize outcomes.

Blinatumomab, a CD3×CD19 bispecific T-cell engager, has demonstrated efficacy in relapsed/refractory (R/R) and measurable residual disease-positive (MRD+) B-cell acute lymphoblastic leukemia (B-ALL), as well as in frontline consolidation following the ECOG-ACRIN E1910 trial that established its regulatory approval in this setting. However, its optimal timing during induction and across combined treatment phases in newly diagnosed Philadelphia chromosome-negative (Ph-) B-ALL remains under investigation. We performed a systematic review and proportional meta-analysis following PRISMA guidelines to evaluate clinical outcomes of blinatumomab-based frontline regimens in adolescents and adults with Ph- B-ALL. Studies were stratified by treatment phase (induction, consolidation, or both). Primary endpoints were complete remission (CR) and MRD negativity; secondary endpoints included 3-year overall survival (OS) and safety. Thirteen studies (n = 827) met inclusion criteria. The pooled CR rate among studies using blinatumomab during induction was 77% (95% CI 70-83%). The overall pooled MRD negativity rate across all phases was 88% (95% CI 82-92%), with comparable results across subgroups. The pooled 3-year OS was 67% (95% CI 55-78%), though survival differed by patient fitness and chemotherapy backbone. Grade ≥3 cytokinerelease syndrome and neurotoxicity occurred in <10% of patients. Frontline blinatumomab regimens achieve high complete remission (77%) and deep MRD negativity (88%) with manageable toxicity in Ph- B-ALL. Variations in OS appear driven by patient heterogeneity and concurrent chemotherapy intensity rather than blinatumomab timing. Future studies should refine its integration within targeted and genomically defined strategies, particularly for high-risk subsets such as Ph-like and KMT2A-rearranged B-ALL.

The transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, termed Richter transformation (RT), continues to be the unmet need for patients with chronic lymphocytic leukemia (CLL). There remains no standard of care treatment for RT, where survival after the diagnosis is short. However, there have been recent developments in the study of RT, where incidence may be decreasing, prognostic factors of survival are being redefined, and novel treatments have been developed. These studies may have moved the needle on outcomes for patients with RT, providing hope to physicians and patients alike. In this review article, we discuss these recent findings related to RT in the modern era of therapy, highlighting our approach to treatment and interesting RT designated trials that are ongoing.

Background: In multiple myeloma, t(11;14) confers a unique biology including a lymphoplasmacytic phenotype and an association with plasma cell leukemia. Some studies report a favourable while others a worse prognosis, compared to non-t(11;14) cases. Dependence of t(11;14) cells on the BCL2 pathway offers a potential therapeutic target.

Methods: We performed a matched comparison of real-world outcomes in patients with and without t(11;14) as a benchmark for future therapy targeting BCL2. A retrospective observational study was conducted using the Canadian Myeloma Research Group database between 2004-2022. FISH and karyotype studies were used to identify which patients carried the t(11;14) versus those who did not. Those found to harbour the t(11;14) were matched one-to-one with a non-t(11;14) cohort based on age at line 1 of therapy, gender, year of diagnosis and history of autologous stem cell transplant.

Results: Compared with non-t(11;14), those with t(11;14) had similar PFS during line 1 (44 (95%CI: 32-51) months vs. 44 (95%CI: 36-65) months), but shorter PFS in line 2 (18 (95% CI: 11-22) months vs. 32 (95%CI: 23-49) months) resulting in a shorter PFS2 (55 (95%CI: 45-87 months vs. 83 (95%CI: 74-115) months).

Conclusions: Although not yet translating into a worse OS, this merits longer follow up. This suggests the need for optimal treatment choice and sequencing at relapse within this unique cytogenetic group. Our large, matched comparison in real-world t(11;14) myeloma serves as an important benchmark for studies looking at targeted BCL2 inhibitors in these patients.

Background: Frontline therapy fails to cure ∼ 25% of patients with large B-cell lymphoma (LBCL), underscoring the need for clinical trials to improve outcomes. However, enrollment remains limited by logistical and structural barriers. Investigator-initiated trials (IITs) at our center enroll patients 5 to 10 times faster than industry-sponsored trials, yet the influence of geography and socioeconomic status on participation remains poorly understood.

Methods: We retrospectively reviewed adults with newly diagnosed large B-cell lymphoma (LBCL) referred to Fred Hutchinson Cancer Center (FHCC) between October 2022 and June 2024. Patients were prescreened by a clinical research nurse and investigators for frontline IIT eligibility. Demographic, geographic, and socioeconomic data were collected, including sex, race, ethnicity, distance from FHCC, area deprivation index, insurance, and interpreter need. Logistic and elastic net regression were used to evaluate predictors of trial enrollment. Trial-ineligible patients were analyzed descriptively.

Results: Of 153 patients, 68 (44%) were trial-eligible; 24 (35%) enrolled. Enrolled patients lived closer to FHCC (median 15 vs. 50 miles; P = .00015) and had lower ADI scores (median 8 vs. 21; P = .006) than non-enrolled eligible patients. In univariate analysis, both distance and ADI were associated with enrollment; in multivariable stepwise regression, only distance remained significant. Elastic net regression identified both distance and ADI as frequently selected predictors. Among 85 trial-ineligible patients, 61% had already initiated treatment; these patients also lived farther away and in more deprived areas.

Conclusion: Geographic distance and neighborhood deprivation significantly influenced trial enrollment, even in investigator-initiated trials (IITs). Decentralized trial models, telemedicine triage, and system-level interventions are needed to reduce these inequities.

Methods: The outcomes of all newly diagnosed acute myeloid leukemia (AML) patients treated with intensive chemotherapy (IC) at a single center between 2018 and 2024 were evaluated.

Results: The complete remission (CR) rates were not significantly different between ELN2022 favorable (fav) versus intermediate (int) risk patients. Of patients achieving CR, 81% of int risk and 85% of adverse (adv) risk patients intended for allogeneic stem cell transplant (HSCT) underwent HSCT in CR1. The overall survival (OS) and relapse-free survival (RFS) were not significantly different between ELN fav versus int risk patients. In contrast, OS was significantly worse in ELN adv risk patients, including those who underwent HSCT, due to both lower CR and higher relapse rates. Within the ELN adv group, patients with RUNX1 mutations had a superior OS compared with other myelodysplasia-related (MR) mutations or adv risk cytogenetics without RUNX1. TP53 mutated patients had the worst outcome. Based on these results, a transplant-adjusted prognostic scoring system was devised, incorporating HSCT into an integrated postremission strategy. In this model, ELN fav and int risk patients were considered good risk, RUNX1mut and KMT2Ar patients intermediate risk, other ELN adv non-TP53 mutated patients poor risk, and TP53 mutated patients very poor risk. The 5-year OS in these groups was 78%, 54%, 22% and 0%, respectively (P < .001).

Conclusions: This revised classification provides a better discrimination of prognostic groups as compared with ELN2022, likely due to the high rate of HSCT now achievable for ELN int risk patients. However, results in ELN adv risk patients remain suboptimal.

Background: Philadelphia-negative B-cell acute lymphoblastic leukemia (Ph- B-ALL) remains a therapeutic challenge in adults. Cytogenetic abnormalities and measurable residual disease (MRD) are key prognostic markers, but their integration with allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined.

Materials and methods: This single-center retrospective study analyzed 368 adult Ph- B-ALL patients, classifying them into 9 cytogenetic subgroups. We evaluated the prognostic effect of high-risk cytogenetics (KMT2A-rearranged, 14q32/IGH, t(1;19)) and MRD status on outcomes, with particular focus on HSCT's modifying role.

Results: Without HSCT, patients with high-risk cytogenetics had significantly inferior 3-year survival compared with cytogenetically normal patients (overall survival (OS): 24.3% vs. 56.5%, P < .001; disease-free survival (DFS): 8.3% vs. 41.4%, P < .001). HSCT eliminated these disparities, yielding comparable outcomes between high-risk and normal subgroups (post-HSCT OS 76.9% vs. 70.8%, P = .603). MRD positivity after consolidation independently predicted relapse in nontransplant patients (HR 3.29, 95% CI, 1.31-8.27, P = .012) but not after HSCT. Reduced-intensity conditioning was associated with worse DFS compared with myeloablative regimens (HR 2.51, 95% CI, 1.24-5.10, P = .011).

Conclusion: Our results support a dual approach: HSCT for patients with high-risk cytogenetics or MRD positivity, and MRD-guided therapy for those not eligible for transplant. These findings reinforce risk-adapted strategies and lay the groundwork for future trials combining genetic and MRD-guided management in Ph- B-ALL.

Background: Multiple myeloma (MM) is a hematologic malignancy defined by clonal proliferation of plasma cells in the bone marrow. The introduction of bortezomib, a proteasome inhibitor, has significantly improved outcomes in MM, becoming a cornerstone of therapy since its approvals for relapsed/refractory MM in 2003 and newly diagnosed MM (NDMM) in 2008. Bortezomib induces apoptosis in malignant plasma cells by disrupting protein degradation pathways.

Rationale: Triplet regimens combining bortezomib with immunomodulatory drugs, alkylating agents, and corticosteroids have shown high efficacy, especially in NDMM patients ineligible for autologous stem cell transplant (ASCT). However, clinical trials often underrepresent real-world populations, with 40% to 50% of MM patients not meeting eligibility criteria.

Methods: To address this evidence gap, we performed a retrospective analysis of national real-world data from the Czech Republic, assessing 17 years of experience with bortezomib-based triplet regimens in transplant-ineligible NDMM patients.

Conclusions: This study provides critical insights into the long-term effectiveness and applicability of bortezomib-based therapies outside of controlled trial settings, offering a more comprehensive understanding of treatment outcomes in routine clinical practice.