Risk Stratification in Older Intensively Treated Patients With AML

Highlight(s): The new acute myeloid leukemia (AML) classification (AML60+) provides prognostic information for intensively treated patients 60 years and older with AML and high-risk myelodysplastic syndrome (HR-MDS) and identifies patients who benefit from intensive chemotherapy and allogeneic hematopoietic cell transplantation (allo-HCT).

Intensively treated patients older than 60 years with AML and HR-MDS from two cohorts (NCRI-AML18 and HOVON-SAKK) were included (n=1,910). The median patient age was 67 years. Using a random survival forest approach, clinical, molecular, and cytogenetic variables were evaluated in an AML development cohort (n= 1,204) for association with overall survival (OS). Relative weights of selected variables determined the prognostic model, which was validated in AML (n= 491) and HR-MDS cohorts (n= 215). The complete cohort had a high frequency of poor-risk features, including 2022 European LeukemiaNet adverse-risk (57.3%), mutated TP53 (14.4%), and myelodysplasia-related genetic features (65.1%). Nine variables were used to construct four groups with highly distinct 4-year OS in the (1) AML development, (2) AML validation, and (3) HR-MDS test cohorts ([1] favorable: 54% ±4%, intermediate: 38% ± 2%, poor: 21% ± 2%, very poor: 4% ± 1%; [2] 54% ± 9%, 43% ± 4%, 27% ± 4%, 4% ± 3%; and [3] 54% ± 10%, 33% ± 6%, 14% ± 5%, 0% ± 3%, respectively). Importantly, patients within the AML60+ intermediate- and very poor-risk group significantly benefited from allo-HCT (p= 0.01 and 0.03, respectively). In contrast, the poor-risk patients showed an indication, albeit nonsignificant (p= 0.07), for improved outcome after allo-HCT (see Fig 5. in the original publication). Sixteen percent of the patients with AML had FLT3-ITD, but but only 10% of those patients received an FLT3 inhibitor in the development cohort, These analyses did not include an assessment of measurable residual disease, either after intensive therapy, pre- or post-allo-HCT.

Prognostic impact of cytogenetic abnormalities by FISH in AL amyloidosis with daratumumab-based frontline therapy

Highlight(s): In patients with AL amyloidosis in the context of Dara-V(C)d therapy, gain/amp(1q) [+1q] is associated with worse outcomes. On the other hand, t(11;14) does not appear to be an adverse prognostic factor.

An international retrospective cohort study that included 283 patients with AL amyloidosis treated with frontline daratumumab-bortezomib-cyclophosphamide-dexamethasone (Dara-VCD) or Dara-VD (n= 283) were performed to investigate the prognostic impact of cytogenetic abnormalities by FISH (fluorescence in situ hybridization). The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) [hereafter, +1q], hyperdiploidy, del(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The endpoints of interest were rate of hematologic complete response (heme-CR), very good partial response or better (≥VGPR), and hematologic event-free survival (heme-EFS). The incidence of abnormalities was as follows: t(11;14) 53.4%; del (13q) 28.9%; +1q 22.3%; hyperdiploidy 19.4%; HR translocations 6.6%; and del(17p) 4.5%. The heme-CR rate by cytogenetic subgroup was: t(11;14) vs. no t(11;14) 45.2% vs. 41.8% (p=0.597); del(13q) vs. no del(13q) 46.8% vs. 42.8% (p=0.594); +1q vs. no +1q 30.2% vs. 47.9% (p=0.022); hyperdiploidy vs. no hyperdiploidy 39.5% vs. 44.9% (p=0.541); HR translocations vs. none: 45.5% vs. 43.1% (p=0.877); and del(17p) vs. no del(17p) 50.0% vs. 42.9% (p=0.658), respectively. Similarly, +1q was the only subgroup with a significantly lower ≥VGPR rate (64.2% vs. 79.0%; p=0.033). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months (95% confidence interval [CI], 24.7-not reached), and the 2-year OS was 80.98% (95% CI, 75.6-85.4). The presence of +1q was significantly associated with worse heme-EFS on multivariate analysis (hazard ratio 2.06, 95% CI, 1.14-3.71; p=0.017). Notably, there was no adverse prognostic impact of t(11;14) on heme-EFS or on OS.

Mass spectrometry–based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma

Highlight(s): Peripheral blood (PB) mass spectrometry (MS) provides significant prognostic information in the maintenance setting and complements bone marrow (BM) measurable residual disease (MRD) in newly diagnosed multiple myeloma (NDMM).  MS’s prognostic performance is most significant 18 months after transplant.

This study evaluated the significance of PB MS MRD-negativity during posttransplant therapy in patients with NDMM. Serum samples from 138 patients treated in the phase 3 ATLAS trial (NCT02659293) of posttransplant maintenance with either carfilzomib, lenalidomide, and dexamethasone, or with lenalidomide alone, were analyzed using EXENT MS methodology (The Binding Site, part of Thermo Fisher Scientific; which uses matrix assisted laser desorption ionization - time of flight [MALDI-TOF]). There was high agreement between MRD by MS in the PB and paired BM MRD results at the 10^–5 threshold, assessed by either next-generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS-negativity was associated with improved progression-free survival (PFS), which, in landmark analysis, reached statistical significance after 18 cycles after transplant. Combined PB/BM MRD- negativity (“double MRD-negativity”) by MFC or NGS was associated with superior PFS compared with MRD-negativity by only 1 modality. Sustained MS-negativity carried similar prognostic performance to sustained BM MRD-negativity at the 
10^–5 threshold. Another similar study by Ortiz de Landazuri et al., “Serum mass spectrometry for treatment monitoring in patients with multiple myeloma receiving ARI0002h CAR T-cells” was discussed in a previous IACH news of the week (June 30, 2024; https://onlinelibrary.wiley.com/doi/10.1111/bjh.19589).

Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations

This iteration of the 2024 European LeukemiaNet (ELN) Less-Intensive acute myeloid leukemia (AML) classification was based on currently available genetic data from less-intensively treated patients, which remain limited. These recommendations were recently published in Blood journal, given that the 2022 ELN genetic risk classifications (https://doi.org/10.1182/blood.2022016867) were based on young patients receiving intensive treatment.

The 2024 ELN Less-Intensive genetic risk classification applies to patients receiving either hypomethylating agent (HMA) monotherapy, HMA/venetoclax (VEN), or azacitidine / ivosidenib (AZA / IVO) for IDH1mut AML. For patients with favorable-risk disease, median overall survival (OS) times have been reported to be greater than 24 months; for adverse-risk patients, OS ranges between 5 to 8 months, whereas the remaining patients are categorized as intermediate-risk. Table 1 of the original publication outlines a proposed ELN genetic risk classification framework:

Favorable:

Mutated NPM1 (FLT3-ITD^neg, NRAS^wt, KRAS^wt, TP53^wt)

Mutated IDH2 (FLT3-ITD^neg, NRAS^wt, KRAS^wt, TP53^wt)

Mutated IDH1 (TP53^wt)

Mutated DDX41

Other cytogenetic and/or molecular abnormalities (FLT3-ITD^neg, NRAS^wt, KRAS^wt, TP53^wt)

Intermediate:

Other cytogenetic and molecular abnormalities (FLT3-ITD^pos and/or NRAS^mut and/or KRAS^mut; TP53^wt)

Adverse:

Mutated TP53

Although patients with NPM1mut or IDH2mut AML appear sensitive to VEN treatment, favorable clinical outcomes appear limited to cases lacking activated signaling gene co-mutations. DDX41mut (two-thirds of germline origin) has increasingly been linked to favorable outcomes in AML, after both HMA monotherapy or VEN-based combination therapies. Finally, all patients with IDH1mut have favorable outcomes after AZO/IVO. TP53mut is universally associated with adverse clinical risk, with poor outcomes for HMA therapy alone or in combination with VEN. Complex karyotype is present in the majority (80-90%) of TP53mut cases. Although the median OS for cytogenetic adverse-risk AML without concurrent TP53mut treated with AZA/VEN is 23.4 months, additional confirmatory studies in the setting of less-intensive therapies are needed . A recent study indicates that patients with AML and myelodysplasia-related mutations are particularly responsive to HMA/VEN; consistent with other reports linking splicing factor variants or ASXL1 mutations to improved outcomes after HMA/VEN. However, even within this category, the co-presence of signaling gene mutations is associated with inferior prognosis. For AML sub-groups with specific gene rearrangements (e.g., translocations, inversions), characterization of their impact on prognosis was not possible, owing to their rarity in older age patients resulting in a paucity of available data.

Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies

Highlight(s): patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM), that includes prior anti-B‑cell maturation antigen (BCMA) therapy, responded to treatment with teclistamab, with over 50% of patients achieving a response. Responses occurred early, deepened over time, and were durable. 

In the ongoing phase 1/2 MajesTEC-1 study (NCT03145181; NCT04557098), a cohort of patients who had prior BCMA-targeted therapy (antibody-drug conjugate [ADC] or chimeric antigen receptor [CAR]-T cell therapy) were enrolled to explore teclistamab (CD3 x BCMA-directed bispecific antibody) in patients previously exposed to anti-BCMA treatment. At median follow-up of 28.0 months (range, 0.7–31.1), 40 patients with prior BCMA-targeted therapy had received subcutaneous 1.5 mg/kg weekly teclistamab. Median prior lines of treatment were 6 (range, 3-14). Prior anti-BCMA therapy included ADC (n = 29), CAR-T cells (n = 15), or both (n = 4). Overall response rate was 52.5%; 47.5% of patients achieved very good partial response or better and 30.0% achieved complete response or better. Median duration of response was 14.8 months, median progression-free survival was 4.5 months, and median overall survival was 15.5 months. The most common treatment-emergent adverse events (TEAEs) were neutropenia, infections, cytokine release syndrome, and anemia; cytopenias and infections were the most common grade ≥3 TEAEs. Infections occurred in 28 (70.0%) patients (n = 13 [32.5%] maximum grade 3/4; n = 4 [10%] grade 5). Prior to starting teclistamab, baseline BCMA expression and immune characteristics were unaffected by prior anti-BCMA treatment.