Nocardial infections have been rare after allogeneic hematopoietic stem cell transplantation (HSCT). We report 10 recent cases of late-onset nocardiosis (median time of onset of 508 days after transplantation) primarily in patients on high doses of corticosteroids for graft-versus-host disease. All 10 patients had pulmonary infection caused by Nocardia species susceptible to trimethoprim-sulfamethoxazole (TMP-SMX). At time of diagnosis 8 of 10 patients were not receiving TMP-SMX for prophylaxis of Pneumocystis jiroveci pneumonia (PJP; 7 on atovaquone, 1 on i.v. pentamidine). After the initiation of atovaquone prophylaxis for PJP in place of TMP-SMX for many UCLA allogeneic HSCT patients in 2012, 9 cases of nocardiosis occurred in 411 patients (2.2%) over the next 6 years (2012 to 2017) compared with only 1 case in 575 patients (0.17%) during the previous 12 years (2000 to 2011). Although there were no deaths directly related to nocardial infection treated primarily with TMP-SMX, overall mortality in this group of patients was 40%. Based on this experience, the use of atovaquone for PJP prophylaxis in place of TMP-SMX may be associated with an increased risk for previously rare nocardial infections after allogeneic HSCT.
T-cell redirection therapy with chimeric antigen receptor (CAR)-T cells and bispecific antibodies (BiAbs) has shown promising efficacy in heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients, leading to the approval of two CAR-T cell products and numerous BiAb trials. Data regarding outcomes after relapse following BiAbs are urgently needed to develop strategies for sequencing salvage therapies. We identified fifty-eight patients progressing after a BiAb trial at the Mount Sinai Hospital. Progression-free survival (PFS) to first- (PFS1) and second salvage therapy (PFS2), and overall survival (OS) were estimated using the Kaplan-Meier method. Patients had a median age of 67 years and 78% had high-risk cytogenetics. They had a median of 6 prior therapy lines, 89% were triple-class refractory and 44% were penta-drug refractory. After the BiAb trial, patients were followed for a median of 30.5 months and received a median of two additional salvage therapies (range: 1-9). The most common first salvage was T-cell redirection in nineteen patients (ten BiAb and nine CAR-T). Ten patients received T-cell redirection as second salvage. T-cell redirection therapy as first or second salvage was feasible and associated with a median PFS1 of 28.9 months and PFS2 of 30.9 months and an OS of 62% at 2 years. Sequential use of different T-cell redirection therapies is possible and can lead to deep and durable responses following relapse after BiAb therapy in RRMM.
Multiple myeloma remains an incurable disease despite numerous novel agents being approved in the last decade. Furthermore, disease behavior and susceptibility to current treatments often vary drastically from patient to patient. To date there are no approved therapies in myeloma that are targeted to specific patient populations based on genomic or immunologic findings. Precision medicine, using biomarkers descriptive of a specific tumor’s biology and predictive of response to appropriate agents, may continue to push the field forward by expanding our treatment arsenal while refining our ability to expose patients to only those treatments likely to be efficacious. Extensive research efforts have been carried out in this endeavor including the use of agents targeting Bcl2 and the RAS/MAPK and PI3K/AKT/mTOR pathways. Thus far, clinical trials have yielded occasional successes intermixed with disappointments, reflecting significant hurdles which still remain including the complex crosstalk between oncogenic pathways and the nonlinear genetic development of myeloma, prone to cultivating sub-clones with distinctive mutations. In this review, we explore the landscape of precision therapeutics in multiple myeloma and underscore the degree to which research efforts have produced tangible clinical results.
Background: Novel treatment approaches including chimeric antigen receptor (CAR) T therapy and bispecific antibodies (Abs) have shown remarkable efficacy in highly pretreated multiple myeloma (MM) patients. With recent approval of BCMA-targeted CAR T in MM, and other agents in development, CAR T is poised to become more widely used in relapsed/refractory disease (RRMM). However, the prognosis, clinical outcome, and treatment approach to RRMM patients presenting with relapsed disease after CAR T are unknown. Methods: Demographics, disease characteristics and post-study outcomes were collected retrospectively in patients who relapsed after BCMA-targeted CAR T therapy at a single academic institution (Mount Sinai Hospital, NY). We identified 74 patients who previously enrolled on 1 of 6 clinical trials. At the data cutoff (July 2021), 4 patients died on trial and were not evaluable, whereas 31 patients had left the trial due to disease progression (PD) and were included. Five patients had received CAR T reinfusion after initial PD, in which case date of PD after reinfusion was considered the start of post-CAR T evaluation. This retrospective study was approved by the institutional review board (GCO#:11-1433). Survival analyses and follow-up duration were calculated by (reverse) Kaplan-Meier analysis. Results: At time of PD after CAR T, the 31 patients had a median age of 61 years (range 35-75) and 19 (61%) were male. Median time from diagnosis was 74 months (range 22-282). Of these 26 patients (84%) had high-risk cytogenetics on FISH [t(4;14), t(14;16), t(14;20), loss of TP53 or 1q21 gain]. Patients were highly pretreated with a median of 5 prior lines (range 1-18). 28 patients (90%) had received prior autologous stem cell transplant. Patients were refractory to various treatments: thalidomide (6% refractory), lenalidomide (74%), pomalidomide (84%), bortezomib (61%), carfilzomib (87%), ixazomib (23%), CD38-mAb (97%), alkylating agents (54%), venetoclax (19%) and selinexor (19%). Most (84%) were triple-class refractory. Fifteen patients (48%) had received DCEP and 4 (13%) had received prior treatment with non-BCMA-targeted bispecific Ab. Upon CAR T relapse, 12 patients (39%) progressed with new/increased extramedullary disease. Information on additional MM treatment was available for 28 patients (90%); 1 patient was treated with cytarabine for MDS, 1 received no treatment, and 1 was lost to follow-up. Median time from relapse to first subsequent treatment was 30 days (range 0-201). Patients received a median of 2 additional treatment lines (range 0-8). The most common initial treatment after CAR T relapse was chemotherapy with (V)DCEP or VD-PACE (10/28, 36%). Stem cell boost with prior chemotherapy was part of the initial approach in 5 patients (18%) and was performed in 12 patients at any time after CAR T relapse (43%). Five patients (18%) were treated with bispecific Ab immediately after CAR T and 12 (43%) received bispecific Ab therapy at any point after CAR T. Selinexor-based regimens were used in 3 (11%) patients immediately after and in 10 (36%) at any point after CAR T relapse. Best response to initial treatment varied widely with 46% ORR (7 CR, 5 VGPR, 1 PR, 7 SD, 8). Median time to progression was 105 days (95% CI: 78-204) for the initial treatment after CAR T. Across various treatment lines after relapse, 33 occurrences of durable response (>120 days, range 128-555) were noted, of which 8 involving stem cell transplant, 8 involving bispecific Abs (alone or in combination with approved anti-MM agents), 5 involving selinexor-based treatments, 3 with venetoclax and 3 involving a MEK inhibitor. Median PFS of patients transitioning to bispecific Ab therapy immediately after CAR T was not yet reached. At time of analysis, 16 patients (52%) were alive and median overall survival after relapse on CAR T was 15.0 months (455 days, 95% CI: 422-NE) with a median follow-up of 501 days. Conclusion: RRMM patients relapsing after T cell engager therapy are a challenging population. Studying the prognosis of these patients including response to subsequent therapy will provide important clinical insights, especially as CAR T moves to an earlier treatment setting. Even though, due to selection, our cohort might be biased towards subjects with early CAR T failure, we show that novel agents, including bispecific Abs can cause durable responses in post-CAR T relapse. Updated results will be presented at the meeting. Figure 1 Figure 1. Disclosures Richard: Karyopharm, Janssen: Honoraria. Richter: Oncopeptides: Consultancy; X4 Pharmaceuticals: Consultancy; Sanofi: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Adaptive Biotechnologies: Consultancy; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Chari: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.
Acute myeloid leukemia (AML) is a highly heterogeneous disease arising from acquired genetic and epigenetic aberrations which stifle normal development and differentiation of hematopoietic precursors. Despite the complex and varied biological underpinnings, induction therapy for AML has remained fairly uniform over 4 decades and outcomes remain poor for most patients. Recently, enhanced understanding of the leukemic epigenome has resulted in the translational investigation of a number of epigenetic modifying agents currently in various stages of clinical development. These novel therapies are based on mechanistic rationale and offer the potential to improve AML patient outcomes. In light of many recent advances in this field, we provide an updated, clinically oriented review of the evolving landscape of epigenetic modifying agents for the treatment of AML.
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