E1910 trial: Blinatumomab for measurable residual disease (MRD)-negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults.

Highlight(s): In this randomized trial, adding blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival (at 3 years: 85% vs. 68%).

In the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN)-led E1910 trial (NCT02003222), which was an international, randomized, phase 3 clinical trial, the authors studied the effect of the addition of blinatumomab (a bispecific T-cell engager [BiTE] antibody construct that transiently links CD19-positive B cells to CD3-positive T cells) to standard consolidation chemotherapy in patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy.  Patients were randomly assigned to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or four cycles of consolidation chemotherapy alone. Blinatumomab was administered at a dose of 28 μg per day for 4 weeks, with a 2-week interval between cycles, followed by 4 cycles of chemotherapy and 2 additional cycles of blinatumomab, or 4 cycles of consolidation chemotherapy only (see Figure 1. Treatment schema from original article). Stratification occurred based on patient age, CD20 status, rituximab use, and whether transplantation was intended. The primary endpoint was overall survival (OS), the secondary endpoint was relapse-free survival (RFS).

Complete remission with or without full count recovery was observed in 395 of 488 (81%) enrolled patients. Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to OS (at 3 years: 85% vs. 68%; hazard ratio [HR] for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P= 0.002), and the 3-year RFS was 80% with blinatumomab and 64% with chemotherapy alone (HR for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events (grade 3 or higher, e.g., dysphasia, dysarthria, tremor, confusion; see Appendix 2 of Supplementary material) was reported in the blinatumomab group (23% of the 111 patients) compared with the chemotherapy-only group (5% of the 112 patients) (P<0.001).

Low dose lenalidomide versus placebo in non-transfusion dependent patients with low risk, del(5q) myelodysplastic syndromes (SintraREV): a randomised, double-blind, phase 3 trial.

Highlight (s): low doses of lenalidomide over two years delays the time to transfusion dependency and improves the rate and quality of the responses, with a manageable safety profile in patients who are non-transfusion dependent (NTD) with del(5q) low-risk myelodysplastic syndromes (LR-MDS) (NCT01243476).

Eligible patients aged 18 years or older diagnosed with LR or intermediate-1-risk del(5q) MDS with NTD anemia (according to the IPSS), and were erythropoietin-stimulating agent naive.  61 patients were randomly assigned (2:1) to receive lenalidomide (n=40; two did not receive treatment) 5 mg daily in 28-day cycles versus placebo (n=21) for 2 years. The primary endpoint was time to transfusion dependency. The median age was 72 (interquartile range [IQR] 65.4–81.9) years, and 50 (82%) patients were female. The median follow-up time was 60.6 (IQR 32.1–73.9) months. Regarding the primary endpoint, the median time to transfusion dependency was not reached (95% confidence interval [CI] not applicable) in the lenalidomide group versus 11.6 months (95% CI 0.0–30.1) in the placebo group (p=0·0027). Lenalidomide significantly reduced the risk of transfusion dependency by 69.8% (hazard ratio 0.30, 95% CI 0.13–0.69; p=0·0046). Among 61 patients, only those treated with lenalidomide achieved erythroid or cytogenetic responses. The most frequent treatment-related adverse event was neutropenia, occurring in 24 (63%) of 38 patients in the lenalidomide group (grade 3 and 4 in 17 [45%] patients and one [3%], respectively) and four (19%) of 21 patients in the placebo group (grade 3 in one [5%] patient). Thrombocytopenia was detected in seven (18%) of 38 patients receiving lenalidomide (grade 3 in two [5%] patients). Regarding the non-hematological toxicity, skin disorders (rash in nine [23%] of 38 patients) were the most frequently described toxicities among patients receiving lenalidomide, being grade 3 in one (3%) of 38 patients. 19 serious adverse events were reported in 13 patients, 18 in the lenalidomide group and one in the placebo group, five of which were potentially related to the study drug. No treatment-related deaths were identified.

Optimizing the Post-CAR T Monitoring Period for Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel.

Highlight (s): New-onset cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are rare after 2 weeks for Axicabtagene Ciloleucel (Axi-cel), Tisagenlecleucel (Tisa-cel), and Lisocabtagene Maraleucel (Liso-cel). Non-relapse mortality (NRM) beyond day 28 is largely driven by infection.

This retrospective study across 9 centers involving 475 patients infused with Axi-cel, Tisa-cel, and Liso-cel from 2018 to 2023, aimed to assess CRS and ICANS onset and duration, as well as causes of NRM in real-world CAR T-cell recipients. While differences were noted in the incidence and duration of CRS and ICANS between CAR T-cell products, new-onset CRS and ICANS are exceedingly rare after two weeks following infusion (0% and 0.7% of patients, respectively). No new cases of CRS occurred after two weeks and a single case of new-onset ICANS occurred in the third week following infusion. NRM is driven by ICANS in the early follow-up period (1.1% until day 28), then by infection through three months post-infusion (1.2%). With limited detail in the data provided regarding infectious agents, the Supplementary Table shows COVID-19 and bacteremia events (Acinetobacter baumannii, Enterococcus faecium, Streptococcus mitis).

Clinical Outcomes After Idecabtagene Vicleucel in Older Multiple Myeloma Patients: A Multicenter Real-world Experience.  

Highlight(s):  Frailty and geriatric characteristics such as polypharmacy, comorbidities, and organ dysfunction in older patients with multiple myeloma (MM) did not confer an inferior overall outcome.

Less than 3% of older adults with MM are reportedly involved in clinical trials. In this multicenter retrospective study, clinical outcomes along with frailty and geriatric characteristics such as comorbidities, polypharmacy, falls, neuropathy, organ dysfunction, and performance status were evaluated in younger (<65 years) versus older (≥65 years) patients who received commercial Idecabtagene vicleucel (Ide-cel). At data cut-off, a total of 156 patients (n=75, ≥65 years) were infused with Ide-cel. In older patients (median age: 69 years, range: 65-83 years;  66.7% frail; 77.3% did not meet KarMMa eligibility criteria), with a median follow-up duration of 14.2 months, the best overall response rate (ORR) was 86.7%, which was comparable to pivotal KarMMa study results (ORR: 73%). Median progression-free survival (PFS) and overall survival (OS) in older patients were 9.1 months and 26.5 months, respectively. Grade 3 or higher cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed in 1% and 4% of older patients, respectively. Compared to younger patients, the older patients had a significantly higher prevalence of frailty, and geriatric characteristics such as polypharmacy (5+ drugs; 97%), 4+ comorbidities (69%), and organ dysfunction (35%) (p<0.05). The number of previous lines of therapy received by both age groups and the duration between MM diagnosis and chimeric antigen receptor T-cell infusion were evaluated, but no discernible differences were observed. The safety and efficacy of Ide-cel therapy were similar in younger and older patients.

How I (Diagnose and) Treat Myeloid / Lymphoid Neoplasms (MLN) with Tyrosine Kinase (TK) Gene Fusions.

The fifth edition of the World Health Organization (WHO) classification and the International Consensus Classification (ICC) both include a category "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions" (WHO, MLN-TK; ICC, M/LN-eo-TK). This rare group comprises phenotypically and prognostically heterogeneous disorders that present a significant diagnostic challenge.  Key phenotypic characteristics include the concurrent presence of eosinophilia and a bone marrow (BM) phenotype typical of a chronic myeloid neoplasm with or without a blast phase (BP) of lymphoid, myeloid, or mixed phenotype in the BM (BP-BM) or lymph nodes or other tissues (extramedullary disease, EMD).

Fusion genes, including more than 70 different TK fusion genes with recurrent involvement of PDGFRA, PDGFRB, FGFR1, JAK2, ABL1, and FLT3, have been identified in clinically and morphologically distinct MLN with or without eosinophilia.  FIP1L1::PDGFRA accounts for approximately 50-60% of MLN-TK. It is formed by a small, cytogenetically cryptic deletion at chromosome 4q12. It can be detected, usually on peripheral blood (PB) samples, by reverse transcriptase-polymerase chain reaction (RT-PCR) or inferred by fluorescence in situ hybridization (FISH) analysis (CHIC2 deletion).  Of note, the expression of FIP1L1::PDGFRA in many cases is low, and therefore nested or other sensitive RT-PCR is required which comes with a risk of false positive results. FISH analysis may yield false negative results due to small clone size.  In FIP1L1::PDGFRA negative cases, FISH analyses on PB samples with break-apart probes are typically used to identify rearrangements of PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, ABL1, and ETV6, the latter because it is a recurrent partner gene of all TKs.

Increasingly, MLN-TK is diagnosed following the finding of a TK fusion mRNA by RNA sequencing (RNAseq; targeted or whole transcriptome) or a TK rearrangement by whole genome sequencing (WGS). Although, these genomic technologies will play an increasingly important role in the diagnosis of hematological malignancies in the coming years, they are not available routinely in many centers.  In the absence of a specific TK fusion gene, however, somatic mutations prove clonality, which may enable a diagnosis of chronic eosinophilic leukemia (CEL)/CEL- not specified. Such mutations typically activate TK signaling pathways, e.g. KIT (usually D816V), JAK1/JAK2 (including JAK2 V617F), STAT5A/STAT5B, or other processes, e.g. ASXL1, CBL, EZH2, RUNX1, SRSF2.

Response assessment is challenging for many reasons: a) the heterogeneous phenotypes (chronic phase vs. BP, lineage involvement of BP, EMD) may necessitate computed tomography (CT) or increasingly, positron emission tomography (PET-CT) for EMD in addition to standard hematologic assessments, b) the need for repeated BM biopsies for cytogenetic analysis as the gold-standard for a cytogenetic response, c) the variability of cut-offs, potential differences between BM and PB and lack of standardized definition of response by FISH (“cytogenetic FISH response”), d) the lack of standardized quantitative RT-PCR assays due to the heterogeneity and rarity of individual fusion genes and e) the potentially discrepant response between PB, BM, and EMD. FISH analysis in PB remains the most used assessment methodology with cytogenetic analysis and qualitative/quantitative RT-PCR assays providing complementary results based on availability.

TK inhibitors (TKIs) with variable efficacy are available for all fusion genes (see Table 4 from original article), but a long-term favorable clinical course under TKI monotherapy is currently only observed in MLN-PDGFRA/PDGFRB fusion genes with imatinib. The combination of durable responses, low rates of resistance, and potential discontinuation on low-dose imatinib in MLN-PDGFRA/PDGFRB is in stark contrast to the markedly more aggressive phenotypes associated with other MLN-TK subtypes. Depending on the fusion gene, disease phase, and response, (early) allogeneic hematopoietic cell transplantation (alloHCT) should be considered in eligible patients. Since primary/secondary BP-BM/EMD occur more frequently in MLN-FGFR1/ JAK2/FLT3/ETV6::ABL1, a sequential combination of selective TKIs with or without prior intensive chemotherapy, rarely local radiation radiotherapy and/or subsequent alloHCT should be considered.

Except for a subset of cases that achieve a durable response in chronic phase, e.g. on pemigatinib in MLN-FGFR1 or nilotinib/dasatinib in MLN-ETV6::ABL1, early alloHCT remains the primary treatment option in eligible patients with MLN-FGFR1/ JAK2/FLT3/ETV6::ABL1, usually following bridging with a specific TKI. The specific TKIs could also be considered post-alloHCT.