Venetoclax and hypomethylating (VEN-HMA) agents in octogenarians and nonagenarians with acute myeloid leukemia (AML). 

Highlight(s): very elderly patients with AML can be treated successfully with VEN-HMA, and a subset of patients (23%) have prolonged survival. Reduced dosing duration may be appropriate in this population, adjusted on a patient-by-patient basis to minimize myelosuppression.

Data from a recent multicenter retrospective study of 154 patients with AML with a median age of 82 years (range, 80-92) who received VEN-HMA (83% with azacitidine and 17% with decitabine) were analyzed  . Most patients (53%) had European LeukemiaNet 2017 adverse risk AML, 33% had intermediate, 8% had favorable, and 6% were unknown. With a median follow-up of 7.7 months, 36 patients (23%) remained in remission, with 31 (20%) still on VEN-HMA. The 30-day and 60-day mortality rates were 8.5% and 17%, respectively. The composite complete remission (CRc) rate for patients with newly diagnosed AML without prior myelodysplastic syndrome (MDS) was 73% (48 of 66). Median overall survival (OS) was 8.1 months, and in patients who achieved a CRc, median OS was 13.2 months. Patients receiving VEN   for 14 to 21 days had similar response outcomes compared with those receiving it for 28 days. Favorable risk AML, NPM1, and FLT3 mutations were associated with improved response rates, whereas patients with relapsed and refractory AML, prior MDS, prior HMA, TP53 mutations, and complex karyotype had lower response rates. 31% of patients on this study received prior HMA (excluded from VIALE-A); and these patients had inferior outcomes. Treatment-emergent grade 3-4 anemia occurred in 50%, thrombocytopenia in 48%, neutropenia in 53%, and neutropenic fever in 46%. Cause of death was attributed to progression/relapse (60%), sepsis (8%), and non-AML causes (8%), with the rest of causes unknown.

Efficacy and safety of bendamustine‐containing bridging therapy (BT) in relapsed/refractory (R/R) large B‐cell lymphoma (LBCL) patients receiving CD19 chimeric antigen receptor (CAR) T-cells.

Highlight(s): BT with bendamustine containing regimens is safe for patients requiring disease control during CAR T‐cell manufacturing.

R/R LBCL patients who received systemic BT after leukapheresis were divided into two BT groups, with and without bendamustine. Patients who only received steroids or had pre‐apheresis bendamustine exposure were excluded. Separate safety and efficacy analyses were carried out for Axi‐cel and Tisa‐cel. Of 243 patients who received BT, bendamustine was included in 62 (26%). There was a higher rate of BT progressors in the non‐bendamustine group (62% vs. 45%, p= 0.02). Concerning efficacy of CAR T-cell therapies, complete responses were comparable for bendamustine versus non‐bendamustine BT cohorts with Axi‐cel (70% vs. 53%, p= 0.12) and Tisa‐cel (44% vs. 36%, p= 0.70). 12‐month progression‐free, and overall survival were not significantly different between BT groups with Axi‐cel (56% vs. 43% and 71% vs. 63%) and Tisa‐cel (25% vs. 26% and 52% vs. 48%); there were no differences when BT response was considered. CAR T‐cell expansion for each construct was similar between BT groups. Regarding safety, cytokine release syndrome grade ≥3 (6% vs. 6%, p= 0.79), neurotoxicity grade ≥3 (15% vs. 17%, p= 0.68), severe infections, and neutropenia post‐infusion were comparable among BT regimens. This same group (Iacoboni et al.) previously published   the use of bendamustine pre-apheresis and its negative impact on results in R/R LBCL receiving CD19 CAR T‐cells.

Molecular diagnosis of primary CNS lymphoma (PCNSL) in 2024 using MYD88Leu²⁶⁵Pro and IL-10.

Highlight(s): In this viewpoint, evidence supporting the routine use of MYD88Leu²⁶⁵Pro and IL-10 in diagnosing PCNSL is considered, and some examples of the frequent difficulties found in the diagnosis of PCNSL are provided. 

Histopathological assessment of tumor tissue collected by stereotactic brain biopsy is the gold standard for PCNSL diagnosis, reducing the risk of unnecessary and irreversible sequelae related to more extensive surgical approaches. This strategy has a high success rate but obtaining an adequate tumor specimen from  deep areas of the CNS, or in unfit or frail patients, can result sometimes in an unacceptably high risk of morbidity or mortality. In some patients, lymphoma diagnosis can be achieved by conventional cytology or flow cytometry analysis of cerebrospinal fluid (CSF) or vitreous humor. The assessment of clonality of lymphoid populations by detection of clonal immunoglobulin rearrangements is a well-established method recommended to improve diagnostic sensitivity in difficult cases; however, the small number of tumor cells in these CNS compartments often hampers definitive diagnosis.  Prolonged corticosteroid exposure before biopsy, often prescribed to manage symptoms, is another source of diagnostic delay because it causes tumor regression (the so-called vanishing tumor), resulting in misleading findings for radiologists and pathologists.  

The MYD88Leu²⁶⁵Pro hotspot mutation has been identified in up to 92% of CSF samples and up to 83% of ocular fluid samples collected from patients with PCNSL. High IL-10 concentrations have been detected in both CSF and intraocular fluids and have been statistically significantly higher in patients with PCNSL than in non-neoplastic control participants. 

Several independent studies have shown that MYD88Leu²⁶⁵Pro and IL-10 concentrations can distinguish PCNSL with high sensitivity (94%) and specificity (98%) from other neurological (neoplastic and non-neoplastic) disorders (see Table of original article). Combined detection of these biomarkers on CSF samples aids in early diagnosis, might act as a surrogate diagnostic approach whenever brain biopsy cannot be performed, and are reliable tools for distinguishing intraocular lymphoma. Conversely, although effective chemoimmunotherapy is followed by a normalization of MYD88 and IL-10 in CSF samples in some patients, more investigation is warranted to establish the role of these biomarkers in defining therapeutic response and monitoring disease during follow-up.

Response and resistance to menin inhibitor in upstream binding transcription factor (UBTF-TD) acute myeloid leukemia (AML).

Highlight(s): The clinical response to revumenib and subsequent potential on-target resistance mechanism observed in a clinical case provide a strong rationale for the further investigation of menin inhibitors, including as part of combination therapeutic strategies, to overcome drug resistance in this high-risk AML subtype that needs new treatment approaches.

A UBTF-TD has recently been detected in a new subtype of AML that is observed predominantly in younger patients and is associated with a high risk of relapse and inferior survival outcomes. UBTF-TD AML shares a transcriptional profile  with AML due to mutated NPM1 (nucleophosmin 1) and AML due to rearranged KMT2A (lysine methyltransferase 2A), both of which can be targeted by menin inhibitors. A report of the case of a man 20 years of age with relapsed AML 21 months after allogeneic hematopoietic cell transplantation was recently published in the New England Journal of Medicine  . Diagnostic samples were assessed retrospectively, and an in-frame UBTF-TD was detected on NGS (next-generation sequencing) panel. After obtaining approval for the compassionate use of revumenib, oral treatment at a dose of 163 mg twice   daily with concurrent posaconazole therapy was initiated. Morphologic remission with hematologic improvement occurred in all three blood-cell lineages without clinical signs of differentiation syndrome. The patient had disease relapse with 10% bone marrow blasts 5 months after the initiation of revumenib. Results of longitudinal molecular testing showed the emergence of variants in CBL (Cbl protooncogene) and PTPN11 (protein tyrosine phosphatase nonreceptor type 11) during week 4 and week 9 of treatment, respectively; and two previously described somatic variants (Thr344Met and Met322Ile, shown in different NGS reads) in menin 1 (MEN1) at the time of relapse.

Pembrolizumab and low-dose, single-fraction radiotherapy (RT) for patients with relapsed or refractory  multiple myeloma (RRMM).

Highlight(s): Hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) RT and pembrolizumab (anti-PD1) used to treat people with RRMM was safe. Activity was observed in patients who had previous CAR T-cell therapy and, to a lesser extent, patients who had no previous CAR T-cell therapy. 

Currently, the use of RT alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. For the combination of RT with anti-PD1 for people with RRMM, clinical data are lacking. A recent prospective, single-group, open-label, phase 2 pilot trial in the USA, enrolled 25 patients with RRMM. On day 1, patients received hypofractionated 8 Gy/1 fx RT to either symptomatic or progressing extra-osseous or osseous myeloma sites (for RT candidacy, patients were required to have a minimum of one osseous or extra-osseous lesion that could be irradiated). Patients also received pembrolizumab (200 mg/kg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Toxicity, as the primary outcome, was deemed to be acceptable if no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 heavily pretreated patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response) and median overall survival was 23.3 months. There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths.