BCMA AND CD19 CAR T CELL THERAPY

The FDA is investigating reports of T-cell malignancies,including CAR-positive lymphoma, in patients treated with BCMA- or CD19-directed CAR T cell therapies. TheFDA is assessing the risk of T-cell malignancy, and evaluating the need for regulatory action. Approved therapies include Abecma, Breyanzi, Carvykti, Kymriah,Tecartus, and Yescarta, with a labeled class warning for potential secondary malignancies.

At ASH 2023 BMS's Abecma, a CAR-T therapy for multiple myeloma demonstrated no advantage in extending patient lives compared to standard treatments after prior therapies. Although it delayed disease progression, overall survival rates didn't show a substantial advantage, partly due to patients passingaway before receiving Abecma and fewer receiving effective interim treatments. While experts findpromise in Abecma's progression-free survival, the FDA emphasizes overall survival in evaluating cancer drugs,complicating its approval, especially amidst the ongoing investigations into CAR T therapy risks.

MYELOFIBROSIS / THROMBOCYTOPENIA

An AI-powered machine learning algorithm showcased at the 2023 ASH Annual Meeting accuratelydistinguished between prefibrotic primary myelofibrosis(pre-PMF) and essential thrombocythemia (ET) in diagnostic bone marrow biopsies, achieving a notable92.3% accuracy. Trained on a dataset of 32,226 patient derived whole-slide images (WSI), the algorithm demonstrated 66.6% sensitivity and 100% specificity ina validation cohort. Lead author Dr. AndrewSrisuwananukorn emphasized the algorithm's role as a clinical decision support tool for physicians, aiding in screening and diagnosis. The algorithm, trained using WSI from the University of Florence and validated at the Moffitt Cancer Center, was developed using the open source AI framework Slideflow. Utilizing Aperio AT2slide scanners, the algorithm can produce predictionson a standard laptop within 6 seconds. Achieving an area under the receiver operator curve (AUROC) of 0.90,the model's accuracy was maintained at 92.3%following optimization thresholding. This approachmarks a crucial step in the integration of AI algorithms into clinical practice.

CHRONIC LYMPHOCYTIC LEUKEMIA

In the Phase 3 FLAIR trial presented at the 2023 ASH Annual Meeting,ibrutinib and venetoclax demonstrated improved survival over fludarabine,cyclophosphamide, and rituximab (FCR) in treatment-naive chronic lymphocyticleukemia (CLL) patients. Notably, theduration of therapy with ibrutinib/venetoclax wasdetermined by the patient's minimal residual disease(MRD) response. At a median follow-up of 43.7 months,97.2% of patients on ibrutinib/venetoclax remainedprogression-free, showcasing the efficacy of an MRD guided approach. The trial is the first to demonstrate that an MRD-guided strategy with continued treatment beyond MRD negativity provides a significant advantage over chemotherapy in terms of progression-free survival and overall survival.

MULTIPLE MYELOMA

The Phase 3 PERSEUS trial presented at the 2023 ASHAnnual Meeting demonstrated a significant improvement in progression-free survival compared to the current standard-of-care regimen of VRd followed by ASCT, VRdconsolidation, and lenalidomide maintenance in newly diagnosed, transplant-eligible multiple myeloma patients.At a median follow-up of 47.5 months, the 4-year PFS rate with D-VRd was 84.3% compared to 67.7% with VRd,resulting in a 58% reduction in the risk of disease progression or death.

MYELOFIBROSIS

The phase 3 TRANSFORM-1 study presented at the2023 ASH Annual Meeting showed that combiningnavitoclax with Jakafi significantly reduced spleen volume by 35% or more in myelofibrosis patients,outperforming Jakafi alone. Although symptomscores didn't vary significantly, the combo'seffectiveness in targeting the BCL-XL pathway demonstrated promise against JAK resistance and high molecular risk mutations,despite an increase in manageable side effects. Navitoclax's efficacy againstmyeloproliferative neoplasms (MPN) is promising, particularly in overriding JAK resistance when combined with Jakafi. The study also highlighted the importanceof high molecular risk mutations in myelofibrosis. AbbVie has stated it aims fornavitoclax's FDA submission in 2023 pending pivotal study results.