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<jats:title>Abstract</jats:title><jats:p>It is well-established that most patients with systemic light chain (AL) amyloidosis have multi-organ involvement and are often diagnosed after a lag period of increasing symptoms. We leverage electronic health record (EHR) data from the TriNetX research network to describe the incidence, timing, and co-occurrence of precursor conditions of interests in a cohort of AL amyloidosis patients identified between October 2015-December 2020. Nineteen precursor diagnoses of interest representing features of AL amyloidosis were identified using ICD codes up to 36 months prior to AL amyloidosis diagnosis. Among 1,401 patients with at least 36 months of EHR data prior to AL amyloidosis diagnosis, 46% were females, 16% were non-Hispanic Black, and 6% were Hispanic. The median age was 71 (range, 21–91) years. The median number of precursor diagnoses was 5 with dyspnea and fatigue being the most prevalent. The time from the first occurrence of a precursor to AL diagnosis ranged from 3.2 to 21.4 months. Analyses of pairwise co-occurrence of specific diagnoses indicated a high association (Cole’s coefficient &gt;0.6) among the examined precursor diagnoses. These findings provide novel information about the timing and co-occurrence of key precursor conditions and could be used to develop algorithms for early identification of AL amyloidosis.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017–March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank <jats:italic>p</jats:italic> = 0.35) or between TCZ and non-TCZ groups (log-rank <jats:italic>p</jats:italic> = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36–1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Multiple myeloma (MM) therapeutics have evolved tremendously in recent years, with significant improvement in patient outcomes. As newer treatment options are developed, stem cell transplant (SCT) remains an important modality that provides excellent disease control and delays the progression of disease. Over the years, SCT use has increased overall in the U.S., but two distinct gaps remain, including suboptimal use overall and racial-ethnic disparities. We evaluated the National Cancer Database (NCDB) to study what sociodemographic factors might play a role within a given racial-ethnic group leading to disparate SCT utilization, such that targeted approaches can be developed to optimize SCT use for all. In nearly 112,000 cases belonging to mutually exclusive categories of non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), Hispanics, non-Hispanic Asians (NHA), and others, we found certain factors including age, comorbidity index, payor type, facility type (academic vs. community) and facility volume to be uniformly associated with SCT use for all the racial-ethnic groups, while gender was not significant for any of the groups. There were several other factors that had a differential impact on SCT utilization among the various race-ethnicity groups studied, including year of diagnosis (significant for NHW, NHB, and Hispanics), income level (significant for NHW and Hispanics), literacy level (significant for NHW and NHB), and geographic location of the treatment facility (significant for NHW and NHA). The suboptimal SCT utilization overall in the U.S. suggests that there may be room for improvement for all, even including the majority NHW, while we continue to work on factors that lead to disparities for the traditionally underserved populations. This study helps identify sociodemographic factors that may play a role specifically in each group and paves the way to devise targeted solutions such that resource utilization and impact can be maximized.</jats:p>

<jats:title>Abstract</jats:title><jats:p>We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) without autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM) irrespective of ASCT eligibility in a single-arm, phase II study. The primary endpoint was the rate of stringent complete response (sCR) and/or measurable residual disease (MRD) &lt; 10<jats:sup>−5</jats:sup> by next-generation sequencing (NGS) at the end of cycle 8 (C8). MRD was also assessed on peripheral blood samples using both the EXENT<jats:sup>®</jats:sup> system and liquid chromatography–mass spectrometry (LC–MS). Forty-two patients entered the treatment phase; forty were evaluable for the primary endpoint. The rate of sCR and/or MRD &lt; 10<jats:sup>−5</jats:sup> following C8 was 30/40 (75%), meeting the statistical threshold for efficacy. The 10<jats:sup>−6</jats:sup> MRD negative rate improved with treatment beyond C8. Agreement between EXENT<jats:sup>®</jats:sup> and NGS was high and increased over time; agreement between LC-MS and NGS was lower. The estimated 3-year progression-free survival progression-free survival was 85%, and 3-year overall survival was 95%. Upper respiratory infections occurred in 67% (7% grade 3–4). There were no treatment-related deaths. Extended frontline Dara-KRd induced a high rate of sCR and/or MRD negativity; the rate and depth of MRD negativity improved beyond C8.</jats:p>

<jats:title>Abstract</jats:title><jats:p>The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, <jats:italic>p</jats:italic> &lt; 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; <jats:italic>p</jats:italic> &lt; 0.0001), and overall survival (OS) (12.2 vs 27.5 months; <jats:italic>p</jats:italic> = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, <jats:italic>n</jats:italic> = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, <jats:italic>n</jats:italic> = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, <jats:italic>p</jats:italic> = 0.3798) and OS (not reached [NR] vs 27.5 months, <jats:italic>p</jats:italic> = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, <jats:italic>p</jats:italic> &lt; 0.0001) and OS (12.2 vs 27.5, <jats:italic>p</jats:italic> = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma with sparse tumor B-cells and a favorable prognosis. Variant growth patterns of NLPHL, however, often show advanced stage, progression to T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and a worse prognosis. We studied the tumor microenvironment (TME) of NLPHL and THRLBCL using highplex imaging and spatial profiling at the single cell level. Our findings show distinct differences in TME composition and spatial configuration that differ among typical and variant NLPHL and THRLBCL. Typical NLPHL show abundant helper T-cell subsets, while THRLBCL show abundant cytotoxic T-cells and macrophages. Tumor B-cell size and content is lowest in typical NLPHL, followed by variant NLPHL, and highest in THRLBCL, whereas an opposite trend characterized TME B-cells. CD4/CD8 double-positive T-cells are seen in all NLPHL but not in the majority of THRLBCL and are spatially distant from LP-cells and TFH-rosettes. The differences in macrophage/monocyte content in distinguishing NLPHL pattern E from THRLBCL is further corroborated in independent cohorts of cases. Our results validate the current approach to classification and in addition provide novel insights that could be leveraged to refine clinical management for patients with this spectrum of lymphomas.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/<jats:italic>BCR::ABL1</jats:italic>, a distinct entity within the group of AML with defining genetic abnormalities, belong to the adverse-risk group of the 2022 ELN classification. However, there is little data on outcome since the era of tyrosine kinase inhibitors. Among 5819 AML cases included in the DATAML registry, 20 patients with de novo <jats:italic>BCR::ABL1</jats:italic><jats:sup>+</jats:sup>AML (0.3%) were identified. Eighteen patients treated with standard induction chemotherapy were analyzed in this study. Imatinib was added to chemotherapy in 16 patients. The female-to-male ratio was 1.25 and median age was 54 years. The t(9;22) translocation was the sole chromosomal abnormality in 12 patients. Main gene mutations detected by NGS were <jats:italic>ASXL1</jats:italic>, <jats:italic>RUNX1</jats:italic> and <jats:italic>NPM1</jats:italic>. Compared with patients with myeloid blast phase of chronic myeloid leukemia (CML-BP), de novo <jats:italic>BCR::ABL1</jats:italic><jats:sup>+</jats:sup>AML had higher WBC, fewer additional chromosomal abnormalities, lower CD36 or CD7 expression and no <jats:italic>ABL1</jats:italic> mutations. Seventeen patients (94.4%) achieved complete remission (CR) or CR with incomplete hematologic recovery. Twelve patients were allografted in first remission. With a median follow-up of 6.3 years, the median OS was not reached and 2-year OS was 77% (95% CI: 50–91). Four out of five patients who were not transplanted did not relapse. Comparison of <jats:italic>BCR::ABL1</jats:italic><jats:sup>+</jats:sup>AML, CML-BP, 2017 ELN intermediate (<jats:italic>n</jats:italic> = 643) and adverse-risk patients (<jats:italic>n</jats:italic> = 863) showed that patients with <jats:italic>BCR::ABL1</jats:italic><jats:sup>+</jats:sup>AML had a significant better outcome than intermediate and adverse-risk patients. <jats:italic>BCR::ABL1</jats:italic><jats:sup>+</jats:sup>AML patients treated with imatinib and intensive chemotherapy should not be included in the adverse-risk group of current AML classifications.</jats:p>

<jats:title>Abstract</jats:title><jats:p>B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25−0.76, <jats:italic>P</jats:italic> = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31−3.98, <jats:italic>P</jats:italic> = 0.004) and time to severe infection (HR 2.04, 1.05–3.96, <jats:italic>P</jats:italic> = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21−0.93, <jats:italic>P</jats:italic> = 0.032) and incidence rate (IRR:0.32, 95% 0.17–0.59, <jats:italic>P</jats:italic> &lt; 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.</jats:p>