Clinical Lymphoma, Myeloma & Leukemia最新文献

Introduction: Uptake of BCMA-directed antibody drug conjugates (ADCs) in multiple myeloma has been hindered by ocular side-effects. Belantamab mafodotin (BelMaf) and MEDI2228 are BCMA-directed monoclonal-antibodies conjugated to the microtubule inhibitor, monomethyl auristatin F and the alkylator, pyrrolobenzodiazepine, respectively. Differences in ADC payload, antibody specificity and linker stability influence ocular toxicity.

Aim/methods: We investigated the tolerability and ocular toxicity profiles of BCMA-directed ADC therapy. Retrospective study of 111 patients treated with BCMA-directed ADCs between 2019 and 2022.

Results: Eighty-seven percent of patients were triple-class refractory, 50% penta-class refractory, 14% had prior BCMA-directed therapy and 24% extraosseous disease. Treatments included BelMaf monotherapy (n = 56), BelMaf combination therapy (n = 12) and MEDI2228 monotherapy (n = 43). The overall response rate was 30% for BelMaf and 44% for MEDI2228. Photophobia was more common with MEDI2228 (any-grade: 12% vs. 49%, P < .001), whereas keratopathy was more common with BelMaf (any-grade: 59% vs. 9%, P = .002). Four MEDI2228 recipients developed keratopathy, all grade 1 and associated with dry eyes and/or photophobia. Dose delay for ocular toxicity was comparable for BelMaf and MEDI2228 (28% vs. 19%, P = 0.2), as was the rate of dose reduction (18% vs. 12%, P = .4). The most common reasons for treatment discontinuation were progression/death (BelMaf = 71%, MEDI2228 = 44%) and ocular toxicity (BelMaf = 18%, MEDI2228 = 30%).

Conclusions: Treatment interruptions, dose reductions and drug discontinuation are common with BCMA-directed ADC therapy. Research to optimize the administration schedule of these agents is warranted. BelMaf and MEDI2228 produce distinct patterns of ocular side-effects, namely keratopathy and reduced visual-acuity with the former, and photophobia and dry eyes with the latter.

Over the last 2 decades, progress in research, treatment approaches, and market dynamics have influenced our treatment of chronic myeloid leukemia in chronic phase (CML-CP). The choice of frontline therapy depends on the treatment goal (normalizing survival only or achieving a treatment-free remission [TFR]), the toxicity profile of each BCR::ABL1 tyrosine kinase inhibitor (TKI), the patient's comorbidities, and the cost and affordability of the treatment. When overall survival is the aim of therapy, generics of imatinib and of second-generation BCR::ABL1 TKIs offer an excellent treatment value. For patients with high-risk CML-CP or those aiming for TFR, second-generation TKIs might be the optimal frontline strategy. Challenges persist in ensuring universal access to therapy, particularly for patients in poorer conditions or geographies. With cost-effective generics now accessible, all patients with CML-CP should have the opportunity to receive imatinib (price < $1000/year worldwide), and most can have access to safe and effective second-generation TKIs. This still may not be possible in the United States and in other nations where second-generation TKIs, even generics, are still too expensive and of poor "treatment value." Strategies such as dose optimization can enhance the TKI affordability without compromising efficacy, particularly for elderly or low-risk patients. For a novel TKI to become established frontline therapy, it should improve the durable deep molecular response rate (BCR::ABL1 transcripts on the International Scale < 0.01% for ≥ 2 years), demonstrate a favorable safety profile, and provide a good treatment value (cost versus efficacy and safety benefits).

Multiple myeloma increasingly presents with multi-class drug resistance after frontline treatment. Although chimeric antigen receptor (CAR) T-cells have emerged as a highly effective treatment modality available at first relapse, their widespread adoption has been hindered by high costs and complicated logistics. We collected evidence from randomized phase III clinical trials, subgroup analyses, and recent guidelines to form an evidence-based, non CAR-T treatment framework. The main determinant of second-line therapy selection includes refractoriness, particularly to lenalidomide and anti-CD38 monoclonal antibodies, followed by cytogenetic risk, relapse aggressiveness, frailty, and patient preferences. In lenalidomide-sensitive or naive patients, regimens that combine an anti-CD38 monoclonal antibody with an immunomodulatory drug (IMiD) or a proteasome inhibitor provide the most consistent benefit. In lenalidomide-refractory patients, non-lenalidomide containing combinations are preferred. Moreover, anti-CD38 antibody refractory relapse excludes further anti-CD38 antibody use in second-line combinations. Due to anti-CD38 antibody incorporation in frontline regimens, refractoriness to this drug class is becoming increasingly prevalent, necessitating the use of novel approaches. Combinations based on belantamab mafadotin, an antibody drug conjugate targeting B cell maturation antigen (BCMA), are currently the leading non CAR-T options in this setting, while exportin-1 inhibitors, such as selinexor, and next-generation proteasome inhibitors offer additional options. Ongoing trials assessing T-cell redirecting bispecific antibodies targeting B cell maturation antigen or GPRC5D may further improve outcomes at first relapse as access and safety profiles evolve. In conclusion, early-relapse multiple myeloma care should be individualized in order to optimize patient outcomes and achieve long-term remissions with acceptable toxicity profile.

Background: Multiple myeloma (MM) is a bone marrow plasma cells malignancy. Despite impressive advancements of treatments, MM remains incurable due to complex clonality. Here, we present a novel 14-color flow cytometry (FACS) protocol for robust detection and visualization of MM clonality.

Method: We developed a single-tube 14-color FACS protocol to analyze fresh bone marrow samples, tested on 8 MM patients. A premixed, stable antibody cocktail was used to enhance reproducibility and streamline workflow. Dimensionality reduction technique (t-SNE) was applied to visualize plasma cell clonality.

Results: Our panel shown CD38⁺ CD138⁺ plasma cells, and their clonality. As expected, MM patients had unique clonal patterns with significant heterogeneity at primary diagnosis. Advanced t-SNE analysis provides a convenient visualization of multi-parameter heterogeneity in a unified 2-D plot. Importantly, our data presents some similarities among patients, and further differences between primary analysis and secondary relapse.

Conclusions: Taken together, our protocol provides a robust and efficient method for improving MM diagnosis using commercially available antibodies and a standard FACS machine. Concise visualization of multi-parameter FACS will help therapeutic decisions and advance the personalized treatment strategies with emerging antigen-specific drugs.

Objective: The CARTITUDE-1 Trial (C-1) led to the approval of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, for patients with relapsed or refractory multiple myeloma (RRMM) after ≥ 3 lines of therapy. However, the inclusion criteria may not fully represent patients in the real-world (RW).

Methods: Leveraging a national multicenter cohort of patients with RRMM, we conducted a retrospective analysis comparing 73 patients who received cilta-cel in the RW to 97 patients treated in C-1 by evaluating clinical characteristics, depth of response, survival outcomes, and toxicity.

Results: Results showed that the RW baseline demographics such as age, proportion of racial minorities, gender, prior therapies, and disease characteristics, including high-risk cytogenetics, were broadly similar to the C-1 population. In the RW group, fewer patients had Eastern Cooperative Oncology Group 0 (16% vs. 40%, P < .001), more patients had extramedullary disease (29% vs. 13%, P = .02), and fewer were refractory to bortezomib (47% vs. 68%, P = .007) and anti-CD38 monoclonal antibody (88% vs. 97%, P = .03). Forty-five percent of RW patients did not meet the inclusion criteria for C-1. The overall response rate was lower in the RW group (88% vs. 97%, P = .015). The survival outcomes at 24-months including the progression-free survival (58% in RW vs. 62% in C1, P = .98) and overall survival (72% vs. 74%, P = .9) were similar. The safety profile of RW patients was better with fewer treatment-related adverse events.

Conclusion: Our study demonstrates the comparable efficacy of cilta-cel in patients with RRMM treated in a RW setting.

Introduction: To evaluate the impact of long-term peripherally inserted central catheters (PICC) on symptomatic venous thrombosis (s-VT), we reviewed clinical charts of patients suffering from chronic hematological diseases with in-situ PICC placement for at least 90 days after catheterization at the Hematology Unit of the Federico II University Medical School of Naples (Italy). The period of observation was between January 2014 and December 2023.

Methods: A total of 1150 PICCs were inserted into 1150 patients at the hematologic diagnosis. Underlying chronic diseases were the following: non-Hodgkin lymphoma (n = 760, 66.1%), Hodgkin lymphoma (n = 200, 17.4%), multiple myeloma (n = 100, 8.7%), chronic lymphocytic leukemia (n = 50, 4.3%), severe aplastic anemia (n = 15, 1.3%), sickle cell disease (n = 10, 0.9%), thalassemia (n = 10, 0.9%), and hemophilia (n = 5, 0.4%). PICCs were successfully inserted in all cases. The median duration of in-situ PICC placement was 300 days (range, 120-400 days).

Results: A s-VT occurred in 30 cases (2.6%), with a rate of 0.13 (95% CI, 0.04-0.30) per 1000 implantation days. The median period time between PICC insertion and thrombotic episode was 30 days (range, 4-95 days). No serious complication was associated with these events. Hodgkin lymphoma (compared to the other diseases) resulted in a numerically higher incidence of PICC-related s-VT.

Conclusion: PICCs represent a useful and safe frontline central vascular approach for patients with chronic hematologic diseases, with a thrombotic risk profile comparable to that reported with centrally inserted totally implantable venous access devices (TIVADs).

Background: CD19 CAR T-cell therapy is a significant advance in B-NHL and ALL. This study describes the incidence, onset, and factors of dermatologic adverse events (dAE) post-therapy.

Methods: A retrospective analysis at Memorial Sloan Kettering Cancer Center (4/2013-8/2020) identified 193 patients undergoing CD19 CAR T-cell therapy. We aimed to characterize dAEs post CAR T-cell therapy including the 100-day cumulative incidence, time to dAE onset, and associations with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

Results: Eighty-two patients experienced 94 dAEs within the first 100 days (incidence: 0.42 (95% CI: 0.36-0.51) post CAR T-cell therapy. Common dAEs were rash (30.9%, n = 29) including maculopapular rash, inflammatory papules, and local erythema; infection (23.4%, n = 22) including cellulitis and folliculitis; and xerosis (16.0%, n = 15). Specific early onset dAEs included rash and chemotherapy-related events, eg, alopecia, mucositis (median 12- and 17-days postinfusion, respectively). Thrombocytopenic purpura and xerosis presented later (median 22-and 25-days). CRS and dAEs occurred in 33.5% of patients, with CRS preceding dAEs in 86% of cases. Among 15% with ICANS and dAEs, ICANS was antecedent in 67%.

Conclusion: dAEs following CAR T-cell therapy are common but mostly low-grade and often manifest within the initial month postinfusion.

Background: Classic follicular lymphoma is generally considered incurable. Standard management includes a "watch and wait" strategy for patients with low tumor burden, while those with high tumor burden typically receive chemotherapy.

Objectives: We aimed to evaluate the potential for curability in a cohort of patients managed with systemic therapy, without the use of a watch-and-wait approach.

Methods: This study is a retrospective, real-world analysis of patients treated in routine clinical practice. We analyzed 183 previously untreated patients with low-grade follicular lymphoma (LGFL) treated at Auxilio Mutuo Cancer Center in Puerto Rico between June 2002 and July 2023. All patients began therapy shortly after diagnosis, without observation. We stratified treatment based on the presence or absence of "clinically discordant indolent histology" (CDIH), defined by aggressive clinical features such as B symptoms, high lactic dehydrogenase (LDH), SUV >14 on PET, Ki-67 > 30%, or involvement of atypical sites including lung, pleura, soft-tissue, CNS and bones. Patients with CDIH typically received R-CHOP x6 followed by FND (fludarabine, Novantrone [mitoxantrone] and dexamethasone). Non-CDIH patients mostly received FND-R. All patients received 2 years of rituximab maintenance. The primary endpoint was failure-free survival (FFS).

Results: Among 183 patients, the median follow-up for censored cases was 8.5 years (range: 6 to 261 months). At 10 years, the FFS was 80%; at 15 years, 75%. Of 61 patients followed for more than 10 years, 57 (93%) remain relapse-free, suggesting a potential for cure in those who remain failure-free beyond a decade.

Conclusion: Our findings support the hypothesis that early initiation of chemotherapy may potentially result in cure for patients with classic follicular NHL. These results warrant confirmation in future prospective studies.