Clinical Lymphoma, Myeloma & Leukemia最新文献

Background: Discontinuation of TKI therapy and treatment-free remission (TFR) have become new goals for chronic-phase chronic myeloid leukemia (CP-CML). The aim of this study was to estimate the TFR post discontinuation of TKI therapy at 3 tertiary-care centers.

Patients and methods: CP-CML patients aged ≥16 years who had an attempt to discontinue TKI therapy till June 2022, were eligible. The collected data included patients' demographics, prognostic score, type and duration of TKI therapy, response dates, relapse dates, response to re-initiation of TKI therapy, and risk factors for relapse.

Results: Fifty-five patients (35, 63.6% females) with a median age of 40 (range 16-74) years at diagnosis discontinued therapy. Forty-eight (87.3%) patients received imatinib as first line therapy. Twenty-nine (52.7%) patients were receiving imatinib at the time of TKI-discontinuation. Median time from diagnosis to TKI discontinuation was 86 months (IQR 60;132) and median duration of TKI therapy after achieving DMR was 66 months (IQR 47;114). After a median follow up of 34 (IQR 12;68) months, 15 (27.3%) patients relapsed. Median time to relapse was 5 months (range 2-38). Most of the relapses occurred during the first 6 months except 3 (20%) patients. All the relapsed patients achieved MMR after a median of 3 (range 2-6) months after restarting TKI therapy. None of the patients progressed to advanced-phase.

Conclusion: Our experience confirms that discontinuation of TKI therapy in CP-CML patients is feasible and safe in routine clinical practice, and can achieve TFR in more than two-third of carefully selected patients.

Background: In the last decade, TKIs improved the overall survival (OS) of chronic myeloid leukemia (CML) patients who achieved a deep and sustained molecular response (DMR, defined as stable MR4 and MR4.5). Those patients may attempt therapy discontinuation. In our analysis, we report the differences in eligibility criteria due to time of response and different TKI used as frontline treatment analyzed in a large cohort of CP-CML patients.

Methods: Data were exported by LabNet CML, a network founded by GIMEMA in 2014. The network standardized and harmonized the molecular methodology among 51 laboratories distributed all over Italy for the diagnosis and molecular residual disease (MRD) monitoring.

Results: Out of 1777 patients analyzed, 774 had all evaluable timepoints (3, 6, and 12 months). At 3 months, 40 patients obtained ≥MR4: of them 14 (3.6%) with imatinib, 8 (5.8%) with dasatinib, and 18 (7.4%) with nilotinib (P = .093); at 6 months, 146 patients were in MR4: 42 (11%) with imatinib, 38 (28%) with dasatinib, and 66 (27%) with nilotinib (P < .001). At 12 months, 231 patients achieved a DMR: 85 (22%) with imatinib, 55 (40%) with dasatinib and 91 (38%) with nilotinib (P < .001). Achieving at least ≥MR2 at 3 months, was predictive of a DMR at any timepoint of observation: with imatinib 67% versus 30% of patients with 2 years was significant for patients who at 3 months had ≥MR2 (18% vs. 9.9% of pts with

Conclusion: In conclusion, reaching ≥MR2 and a MR3 at 3 months it seems predictive of a DMR at any time point. Considering the prerequisite for a discontinuation with a sustained DMR only a minority of patients can be eligible for the discontinuation, regardless the frontline treatment received.

Systemic mastocytosis (SM) is a heterogeneous myeloid neoplasm, characterized by clonal proliferation of mast cells (MCs) in ≥ 1 extracutaneous organs, including the bone marrow (BM) and gastrointestinal tract. Aberrant MC proliferation is driven by mutation KIT D816V in ≈90-95% of SM patients. Indolent SM (ISM) is the most common SM subtype with various symptoms that can be severe. Advanced SM (AdvSM) has markedly poor prognosis. The advent of KIT inhibitors, targeting mutant KIT and neoplastic MCs, led to a paradigm shift in SM management and markedly improved outcomes. Midostaurin inaugurated the era of KIT inhibitors and was approved for AdvSM in 2017. Avapritinib is the first highly potent and selective inhibitor of KIT D816V that was approved to treat AdvSM and symptomatic ISM (platelets ≥ 50 × 10⁹/L), in the US, in 2021 and 2023, respectively. Pooled analysis of the EXPLORER and PATHFINDER studies, assessing avapritinib in AdvSM, demonstrated rapid and profound reductions (≥ 50%) in markers of MC burden, high response rates (71-75%), and prolonged survival. In the PIONEER study, avapritinib significantly and rapidly improved symptoms/quality of life, and reduced markers of MC burden in ISM patients. The investigational agents bezuclastinib and elenestinib are highly potent and selective inhibitors of KIT D816V with minimal blood-brain barrier penetration. Bezuclastinib reduced markers of MC burden by ≥ 50% in ≈50% of AdvSM patients and ≈90-100% of nonAdvSM patients and reduced symptoms (≥ 50%) in the APEX and SUMMIT studies, respectively. Elenestinib demonstrated dose-dependent efficacy in reducing MC burden markers and improved symptoms in ISM patients in the HARBOR study.

Background: Recent approvals of chimeric antigen receptor T-cells (CAR T) and bispecific antibody therapies offer new hope for relapsed refractory multiple myeloma (RRMM) patients, with superior efficacy over standard regimens observed in clinical trials. However, relapse after BCMA-directed therapy is common and requires further investigation.

Patients and methods: We conducted a retrospective cohort study on 57 RRMM patients treated with BCMA-directed CAR T. Only the patients who had an initial response and lost BCMA-expressing identified PC following CAR T infusion at Day 30 were included in the analysis. Multicolor flow cytometry (MFC) to detect BCMA + plasma cell (PC) re-emergence was performed on bone marrow samples at defined intervals and clinical responses were assessed using International Myeloma Working Group criteria.

Results: The majority of patients achieved undetectable BCMA on MFC postinfusion, with subsequent BCMA+ PC re-emergence observed in 55% of cases. Notably, 91% of patients experiencing clinical relapse showed BCMA+ PC re-emergence, often preceding relapse. Early relapse (<6 months) was associated with earlier BCMA re-emergence.

Conclusion: Early BCMA+ PC re-emergence may serve as a prognostic marker for clinical relapse post-BCMA CAR T therapy. Monitoring BCMA+ PC levels via MFC offers potential for early relapse detection and informed treatment decisions. Further studies, including novel BCMA-directed minimal residual disease (MRD) detection technologies, are warranted to validate these findings and refine RRMM management strategies.

Philadelphia-like (Ph-like) or BCR::ABL1-like acute lymphoblastic leukemia (ALL) is a common high-risk subtype of B-cell precursor ALL (B-ALL) characterized by a diverse range of genetic alterations that challenge diagnose and converge on distinct kinase and cytokine receptor-activated gene expression profiles, resembling those from BCR::ABL1-positive ALL from which its nomenclature. The presence of kinase-activating genetic drivers has prompted the investigation in preclinical models and clinical settings of the efficacy of tyrosine kinase inhibitor (TKI)-based treatments. This was further supported by an inadequate response to conventional chemotherapy, high rates of induction failure and persistent measurable residual disease (MRD) positivity, which translate in lower survival rates compared to other B-ALL subtypes. Therefore, innovative approaches are underway, including the integration of TKIs with frontline regimens and the early introduction of immunotherapy strategies (monoclonal antibodies, T-cell engagers, drug-conjugates, and CAR-T cells). Allogeneic hematopoietic cell transplantation (HSCT) is currently recommended for adult BCR::ABL1-like ALL patients in first complete remission. However, the incorporation of novel therapies, a more accurate diagnosis and a more sensitive MRD assessment may modify the risk stratification and the indication for transplant in these patients.

Background: The efficacy of elotuzumab, an anti-SLAMF7 monoclonal antibody, in treating relapsed/refractory multiple myeloma (RRMM) and newly-diagnosed multiple myeloma (NDMM) has varied in randomized controlled trials (RCTs). Moreover, there is limited data on its real-world application.

Patients and methods: We conducted a systematic review and meta-analysis of RCTs investigating the addition of elotuzumab to backbone antimyeloma regimens. The primary outcome of interest was progression-free survival (PFS). Secondary efficacy outcomes included overall survival (OS), overall response rate (ORR), and rates of very good partial response or better (VGPR). Key toxicities were also evaluated.

Results: Three RRMM trials (n = 915) and 5 NDMM trials (n = 1790) were included, with 50% of the 2705 patients receiving elotuzumab-containing triplets or quadruplets. In RRMM settings, elotuzumab use significantly improved PFS (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.60-0.82; P < .001; I² = 0%). This benefit was consistent among patients with high-risk cytogenetics (HR, 0.62; 95% CI, 0.43-0.90; P = .01; I² = 0%) and was particularly evident in those previously treated with proteasome inhibitors (PIs) or immunomodulatory drugs (IMiDs). The RRMM cohort also demonstrated better OS, ORR, and ≥VGPR rate. However, the NDMM cohort showed no significant improvements in any efficacy outcomes. Despite an increase in severe (grade ≥3) infections, elotuzumab use did not adversely affect rates of severe cytopenias, severe cardiac disorders, or second primary malignancies.

Conclusion: Our results suggest that elotuzumab-containing regimens represent valuable therapeutic options for PI/IMiD-exposed patients with RRMM. In contrast, elotuzumab's role in frontline settings remains limited.

Background: Multiple myeloma (MM) clinical management is challenging owing to its relapse and refractoriness to treatment. Understanding the treatment patterns and refractory dynamics is crucial for optimizing patient care. This study aimed to estimate the evolution of MM according to the treatment line and refractoriness status in Italy.

Materials and methods: A new epidemiological model was developed using epidemiological and clinical data from literature. Prevalent MM patients were characterized by calibrating the model inputs. Incident patients were included starting in 2021, when antiCD38-containing regimens were reimbursed as first-line treatments in Italy. The model employed a 1-year cycle Markov structure to simulate patient flow through the treatment lines, accounting for the development of lenalidomide and anti-CD38 monoclonal antibody (mAb) refractoriness.

Results: In 2020, Italy had an estimated 33,734 prevalent MM patients. By 2027, treated patients were projected to increase from 28,499 to 35,074. The introduction of lenalidomide and mAb therapies in earlier lines has resulted in a higher accumulation of patients in the early lines, with a corresponding decrease in the proportion of patients requiring subsequent lines of therapy. Furthermore, the proportion of patients refractory to both lenalidomide and mAbs in the second to fourth lines of treatment is estimated to increase from 1.6% in 2021 to 29.7% by 2027.

Conclusion: Our model revealed a rising prevalence of patients receiving first-line treatment owing to more effective treatments. The marked increase in the number of refractory patients in subsequent lines underscores the urgent need for innovative therapies to address treatment resistance.

Background: 'Standard of care' therapies for adult acute myeloid leukemia (AML) have yielded 5-year overall survival (OS) rates of 30%-45 %. Risk stratification and novel targeted therapies have improved 5-year OS rates to >75 % for certain groups in specialized centers.

Patients and methods: This is a retrospective cohort analysis of outcomes in patients ≥18 years with newly diagnosed AML treated between 2005 and 2019 in the Harris Health County, Safety-Net Hospital System in Houston, TX.

Results: 192 patients were identified. Median age was 52 years, 52 % were male and 57 % identified as Hispanic. Most patients were uninsured or indigent, receiving care under the county's financial assistance programs (62 %). Of the 184 response-assessable patients, 139 achieved composite complete remission (CRc) (76 %). 182 patients had indications for HCT and only 25 patients received HCT (14 %), with main reasons including noncitizenship status and financial/insurance constraints. The 5-year OS rate in the entire cohort was 30 % (35 % in patients <60 years and 16 % if ≥60 years), with 92 % of deaths attributed to AML-related complications. Early death (<4 weeks) rate was 2 %. Secondary, adverse-risk AML, and uninsured status all portended significantly worse OS rates, per multivariate analysis. Patients with indications for HCT who received this modality fared significantly better than those who did not receive it (5-year OS 54 % vs. 21 %).

Conclusions: Optimizing AML remission induction regimens, reducing medication costs, ensuring timely administration of AML directed therapies, enhancing equity and diversity in clinical trials, and addressing socioeconomic factors may improve leukemia care for underserved patients.

Background: Thiotepa-based autologous stem cell transplantation (ASCT) improves survival in primary central nervous system lymphoma (PCNSL), but > 30% of patients are unable to undergo ASCT following commonly used intensive induction regimens.

Methods: This retrospective population-based study included consecutive patients ≥ 18 years old with PCNSL who were intended for ASCT in Alberta, Canada between 2011 and 2022. A reduced-intensity induction protocol was further abbreviated in 2018 to decrease toxicity and expediate ASCT by incorporating rituximab, procarbazine, and only 2 doses of high-dose methotrexate and 1 cycle of high-dose cytarabine before consolidation with thiotepa-busulfan conditioning. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method.

Results: Among 71 patients with median age 58 years (range 26-72), ASCT was completed in 56 (79%), with the transplantation rate among patients > 60 years old increasing by 30% following the abbreviation of induction therapy. With median follow-up time 3.9 years, 4-year PFS and OS were 69% (95% CI 56%-79%) and 80% (95% CI 67%-88%) for all patients and 75% (95% CI 57%-86%) and 85% (95% CI 68%-93%) for ASCT recipients, respectively. There was 1 death due to treatment-related mortality during induction and none after ASCT, including among 17 transplanted patients > 60 years old.

Conclusion: An abbreviated induction regimen followed by thiotepa-busulfan-based ASCT achieves high transplantation rates with low risks of relapse and treatment-related mortality, thereby providing an effective treatment strategy for PCNSL.