Daratumumab in pediatric relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma: the DELPHINUS study [Phase 2 clinical trial]. 

Highlight(s): Daratumumab plus chemotherapy may effectively bridge children and young adults with relapsed/ refractory T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) to allogeneic hematopoietic stem cell transplant (HSCT).

This phase 2, open-label DELPHINUS study (NCT03384654) evaluated daratumumab (16 mg/kg IV weekly on days 1, 8, 15, and 22 of cycles 1 and 2, then every 2 weeks for 8 doses, followed by every 4 weeks after that) plus backbone chemotherapy in children with relapsed/refractory B-cell ALL (n=7) after ≥2 relapses, and children and young adults with T-cell ALL (children, n=24; young adults, n=5) or LL (n=10) after first relapse. The primary endpoint was complete response (CR) in the B-cell ALL (end of cycle 2) and T-cell ALL (end of cycle 1) cohorts, after which patients could proceed off study to HSCT. Seven patients with advanced B-cell ALL received daratumumab with no CRs achieved; this cohort was closed because of futility. For the childhood T-cell ALL, young adult T-cell ALL, and T-cell LL cohorts, the CR (end of cycle 1) rates were 41.7%, 60.0%, and 30.0%, respectively; overall response rates (any time point) were 83.3% (CR + CR with incomplete count recovery [CRi]), 80.0% (CR + CRi), and 50.0% (CR + partial response), respectively; minimal residual disease negativity (<0.01%) rates were 45.8%, 20.0%, and 50.0%, respectively; observed 24-month event-free survival rates were 36.1%, 20.0%, and 20.0%, respectively; observed 24-month overall survival rates were 41.3%, 25.0%, and 20.0%, respectively; and allogeneic HSCT rates were 75.0%, 60.0%, and 30.0%, respectively. No new safety concerns with daratumumab were observed. Although CD38 expression on blasts declined over time with daratumumab, inferences regarding CD38 expression and its potential impact on efficacy cannot be made because of the small sample size of this cohort.

Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia [Phase 1b–2 clinical trial]. 

Highlight(s): In the FELIX study, obecabtagene autoleucel (obe-cel) resulted in a high incidence of response among adults with relapsed or refractory B-cell acute lymphoblastic leukemia  (ALL), with toxic effects mostly limited to patients with a high bone marrow burden.

Obe-cel is an autologous 41BB-ζ anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that uses an intermediate-affinity CAR to reduce toxic effects and improve persistence. The authors conducted a phase 1b–2 multicenter study  [FELIX clinical trial; NCT04404660] of obe-cel in adults (≥18 years of age) with relapsed or refractory B-cell ALL. The FELIX study was conducted at 34 sites in Spain, the United Kingdom, and the United States. The main cohort, cohort 2A, included patients with morphologic disease; patients in cohort 2B had measurable residual disease. The primary endpoint was overall remission (complete remission [CR] or CR with incomplete hematologic recovery) in cohort 2A.  Of the 153 enrolled patients, 127 (83.0%) received at least one infusion of obe-cel and were evaluable. In cohort 2A (94 patients; median follow-up, 20.3 months), overall remission occurred in 77% (95% confidence interval [CI], 67 to 85), with CR in 55% (95% CI, 45 to 66) and CR with incomplete hematologic recovery in 21% (95% CI, 14 to 31). The prespecified null hypotheses of overall remission (≤40%) and CR (≤20%) were rejected (p<0.001). In the 127 patients who received at least one obe-cel infusion (median follow-up, 21.5 months), the median event-free survival was 11.9 months (95% CI, 8.0 to 22.1); estimated 6- and 12-month event-free survival was 65.4% and 49.5%, respectively. The median overall survival was 15.6 months (95% CI, 12.9 to not evaluable); estimated 6- and 12-month overall survival was 80.3% and 61.1%, respectively. Grade 3 or higher cytokine release syndrome developed in 2.4% of the patients, and grade 3 or higher immune effector cell–associated neurotoxicity syndrome developed in 7.1% of the patients.

Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial [Phase 3 clinical trial].

Highlight(s): In the era of targeted therapies, watch-and-wait remains the standard of care, irrespective of risk factors for early-stage chronic lymphocytic leukemia (CLL).

The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression, to receive ibrutinib (n=182) at a daily dose of 420 mg, or placebo (n=181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments. Ibrutinib significantly delayed progression to symptomatic disease (p < 0.001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases (p=0.562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch-and-wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group.

Acute Leukemias of Ambiguous Lineage With MDS-Associated Mutations Show Similar Prognosis Compared to Acute Myeloid Leukemia With MDS-Associated Mutations: A Study From the Bone Marrow Pathology Group [Retrospective study].  

Highlight(s): Acute leukemia of ambiguous lineage (ALAL) showed remarkably similar myelodysplastic syndrome (MDS)-associated gene mutation characteristics to acute myeloid leukemia (AML), including similar average number of mutations per case, similar proportions of cases with mutation in each MDS-associated gene, and RUNX1 the most commonly mutated in both. The presence of more than one MDS-associated mutation does not worsen prognosis compared with only one.

Cases of newly diagnosed, by WHO 5th edition and International Consensus Classification (ICC) criteria, de novo AML and ALAL, including acute undifferentiated leukemia (AUL) and mixed phenotype acute leukemias (MPAL), with MDS-associated mutations were collected, defined as having one or more mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, STAG2, and/or RUNX1.   The authors collected 23 cases of ALAL (12 MPAL and 11 AUL) and 167 cases of AML with MDS-associated mutations that met inclusion criteria. The year of initial diagnosis ranged from 2013 to 2023, with a median of 2017. Follow-up duration from initial diagnosis ranged from 1.1 to 68.8 months, with a mean of 15.1 months. Mean age at diagnosis was 61.6 and 65.9 years for AML and ALAL, respectively.  ALAL more often had an abnormal karyotype (47.8%). However, an abnormal karyotype did not affect overall survival (OS) or relapse-free survival (RFS; p=0.40). No significant differences in these factors were found when comparing AUL to MPAL.  There were no differences in mutation rates for each MDS-associated gene between ALAL and AML. ALALs with multiple MDS-associated mutations showed no difference in survival compared with one (p=0.23). Median OS and RFS in ALAL and AML with MDS-associated mutations were similar. Comparing ALALs and AMLs treated with AML-directed chemotherapy regimens showed no differences in OS or RFS. Thirteen ALALs (57%) underwent allogeneic hematopoietic stem cell transplant (AHSCT), which trended toward improved OS and RFS, but these were not statistically significant. However, these conclusions are limited by the small number of ALAL cases (only 23 cases), the heterogeneity among chemotherapy regimens, and the use of AHSCT Univariate Cox regression analysis showed no significant differences in risk when comparing age, diagnosis (AUL vs. MPAL), marrow blast %, marrow cellularity, white blood count WBC count, presence of RUNX1 mutation, karyotype (normal vs. abnormal), AHSCT status (transplant vs. no transplant), or chemotherapy regimen (ALL vs. AML vs. combination regimens

Indeterminate DC histiocytosis is distinct from LCH and often associated with other hematopoietic neoplasms [Retrospective study].

Highlight(s): Indeterminate dendritic cell histiocytosis (IDCH) is often associated with other hematopoietic neoplasms, and such cases are associated with an inferior prognosis.

IDCH is a rare and poorly understood entity characterized by the accumulation of CD1a⁺/S100⁺ histiocytes (as Langerhans cell histiocytosis [LCH]) but with a reduced-absent expression of Langerin/CD207. Of 51 cases evaluated, 43 cases of IDCH (defined by CD1a⁺/CD207^<20% immunophenotypic profile) were eligible for inclusion. The clinical, pathologic, and molecular landscape was examined. Median age at presentation was 70 years (interquartile range, 44-80) with cutaneous (31/43; 72%) and nodal (11/43; 26%) involvement predominating. Eighteen (42%) individuals had an associated nonhistiocytic hematopoietic neoplasm (“secondary” IDCH), whereas 7 (16%) had a concurrent or prior histiocytosis with non-IDCH histology (“mixed” histiocytosis). Most cases exhibited morphology indistinguishable from LCH but with a CD1c⁺/CSF1R/CD115⁻ phenotype, mirroring the signature of normal indeterminate cells and type-2 conventional dendritic cells. Mutational analysis revealed frequent KRAS (13/32; 41%) and BRAF p.V600E (11/36, 31%) mutations that were nearly mutually exclusive. RNA-sequencing analysis uncovered ETV3::NCOA2 fusion in 6 other patients presenting as a sole genetic alteration without any other concurrent histiocytic or hematopoietic neoplasm. BRAF and MAP2K1 alterations were significantly associated with partial/retained (1-20%) Langerin expression (p=0.005) and mixed histiocytosis (p=0.002). Remarkably, myeloid alterations (DNMT3A, TET2, and SRSF2) co-occurred in IDCH tissues of several individuals. Paired sequencing of IDCH and concurrent non-IDCH hematopoietic neoplasm in 4 individuals revealed shared mutations. Age at diagnosis and any nodal involvement at diagnosis predicted inferior overall survival, but BRAF/RAS pathway alterations did not affect the outcome

Delaying pegaspargase during induction in adults with acute lymphoblastic leukaemia is associated with lower risk of high-grade hepatotoxicity without adversely impacting outcomes [Retrospective study].

Highlight(s): Delaying pegaspargase administration from day 4 to day 15 during the induction cycle in adults with acute lymphoblastic leukemia (ALL) might reduce the risk of high-grade hepatotoxicity without adversely impacting clinical efficacy outcomes.

Pegaspargase-associated hepatotoxicity is most common during induction, and its incidence increases with age and body mass index (BMI). The authors retrospectively reviewed 141 adult patients with newly diagnosed ALL who received pegaspargase during induction from November 2013 to February 2024. There were 78 (55.3%) patients who received early pegaspargase (EP) on day 4 and 63 (44.7%) patients who received delayed pegaspargase (DP) on day 15. High-grade hepatotoxicity (grade ≥ 3 “transaminitis” and/or hyperbilirubinemia) occurred more frequently in the EP group (p=0.06). Rates of complete remission and negative minimal residual disease post-induction were not different between cohorts. Univariate logistic regression analysis showed that BMI and age significantly predicted an increased risk of high-grade hepatotoxicity, while DP was associated with a lower risk (odds ratio=0.44; p=0.04). Overall survival and event-free survival were not significantly different between cohorts. When the authors focused solely on patients who received CALGB (Cancer and Leukemia Group B) 10403 chemotherapy, some patients received EP and some patients received DP, administration of the latter was not associated with less hepatotoxicity (p=0.70). The mBFM (modified Berlin–Frankfurt–Münster) regimen includes daunorubicin on days 1–3 and pegaspargase on day 15, while the CALGB 10403 includes daunorubicin on days 1, 8, 15, and 22 and pegaspargase on day 4. Thus, mBFM separates the administration of daunorubicin and asparaginase, while in CALGB 10403, both early and late pegaspargase are concurrent with daunorubicin. Since daunorubicin can be hepatotoxic, it is possible that close administration of the two agents (which occurs in CALGB with both EP and DP, and not mBFM which is always associated with DP) increases the risk of hepatotoxicity rather than EP administration per se.

Development of hyperdiploidy starts at an early age and takes a decade to complete [Basic research].  

Highlight(s):  In patients with multiple myeloma (MM), the first hyperdiploidy event occurred within the first three decades of life and took a decade to complete.

Here, the authors used 72 whole genome sequencing samples from patients with MM with hyperploidy (HMM) and identified pre and post HMM mutation to define the chronology of development of hyperdiploidy. An MM cell accumulated on a median 0.56 mutations per mb pre-HMM and for every clonal pre-HMM mutation, 1.21 mutations accumulated post-HMM. This analysis using mutations before and after hyperdiploidy shows that hyperdiploidy happens after somatic hypermutation, pre-hyperdiploidy mutations are activation-induced deaminase and age/Clock-like signature driven. In contrast, post-hyperdiploidy mutations are from DNA damage and apolipoprotein B mRNA editing enzyme, catalytic polypeptide. Interestingly, the first hyperdiploidy event occurred within the first 3 decades of life and took a decade to complete. Copy number changes affecting chromosomes 15 and 19 occurred first. Finally, mutations in pre-initiating events affect chromosomes at different rates, while post-initiating event mutational processes affect each chromosome equally.