Dexamethasone dose intensity does not impact outcomes in newly diagnosed multiple myeloma: a secondary SWOG analysis [Retrospective study]

Highlight(s): this post hoc analysis suggests that dexamethasone dose reductions (below 40-60 milligrams weekly) are common in newly diagnosed multiple myeloma (NDMM), even within clinical trials. Dexamethasone dose reductions did not impact progression-free survival (PFS) or overall survival (OS). Dexamethasone can be lowered or discontinued during NDMM after the initial few cycles or as soon as any level of response is achieved. 

This is a secondary pooled analysis of the S0777 (NCT00644228) and S1211 SWOG (NCT01668719)  studies of NDMM, which employed lenalidomide-dexamethasone (Rd) alone with or without bortezomib (VRd) and with or without elotuzumab (Elo-VRd). The planned dexamethasone intensity was 40-60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for Grade 3+ toxicities per both study protocols). Of 541 evaluated patients, the LD-DEX group comprised 373 (69%). There was no difference in PFS or OS between the FD-DEX or LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in multivariate models were treatment arm, age ≥70, and thrombocytopenia; FD-DEX did not significantly improve either outcome. Neither study included patients who received planned upfront autologous stem cell transplant or upfront CD38-targeted monoclonal antibodies. The largest limitation of this post hoc analysis is the lack of specific reasons for dexamethasone dose reduction in most cases. 

Intrathecal chemotherapy as treatment for chimeric antigen receptor T cell (CAR T) therapy associated neurotoxicity [Retrospective study]

Highlight(s): The use of early intrathecal chemotherapy (ITC) for the management of immune effector cell-associated neurotoxicity syndrome (ICANS) showed promising results in this cohort of non-Hodgkin lymphoma (NHL) patients who received CAR T cell therapy. 

This is a retrospective analysis of the outcomes of 12 consecutive NHL patients who received ITC to treat ICANS. Seventy-nine   patients received immune effector cell (IEC) therapy during the study, 33 (42%) of which developed ICANS. Twelve of these patients received ITC with the first lumbar puncture. Median age was 65 (range 47-79) years. Three of these patients had received tisa-cel, 2 had received liso-cel, and 7 had received axi-cel. Ten of the 12 patients had developed cytokine release syndrome (CRS) before their ICANS diagnosis, with a median time from IEC to CRS of 2.5 (0-5) days. ICANS was grade 1 (n=4), grade 2 (n=2) and grade 3 (n=6). The median time to development of ICANS was 5 (2-13) days. The median time from the development of ICANS to receiving ITC was 3 (1-23) days with 5 patients receiving ITC in the first 24 hours of symptoms. Ten patients in this cohort received methotrexate and 3 received cytarabine (one received methotrexate and cytarabine). Ten patients received a single dose of ITC. All patients received systemic corticosteroids before ITC and 6 patients (50%) received Anakinra as part of ICANS management. Median time from initiation of steroid therapy to ITC was 3 (1-24) days. Eleven of the 12 patients had resolution of their ICANS with median time from ITC to ICANS resolution of 2 (1-24 days).  Five patients had complete resolution of ICANS within 24 hours of ITC. Five patients whose ICANS showed no response to corticosteroids had resolution of ICANS symptoms after ITC. Early administration of ITC is feasible and highly effective in the management of ICANS. Since multiple therapies were administered, the relative contribution of each therapeutic measure cannot be dissected. 

PHF6 mutations in chronic myelomonocytic leukemia identify a unique subset of patients with distinct phenotype and superior prognosis [Retrospective study]

Highlight(s): Plant homeodomain finger protein 6 (PHF6) mutation (PHF6^MUT) identifies a unique subset of patients with chronic myelomonocytic leukemia (CMML) characterized by thrombocytopenia, higher prevalence of loss of Y chromosome (LoY) and superior prognosis.

This retrospective study was inspired by observations from exploratory analyses of an institutional cohort with CMML (N = 398) that revealed no instances of blast transformation in the seven patients with PHF6^MUT. A subsequent Mayo Clinic enterprise-wide database search identified 28 more cases with PHF6^MUT. Compared with their wild-type PHF6 counterparts (PHF6^WT; N = 391), PHF6^MUT cases (N = 35) were more likely to co-express TET2 (89% vs. 45%; p < 0.01), RUNX1 (29% vs. 14%; p = 0.03), CBL (14% vs. 2%; p < 0.01), and U2AF1 (17% vs. 6%; p =0.04) and less likely SRSF2 (23% vs. 45%; p < 0.01) mutation. They were also more likely to display LoY (21% vs. 2%; p <0.01) and platelets <100x10⁹/L (83% vs. 51%; p < 0.01). Multivariable analysis identified PHF6^MUT (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.15–0.50) and DNMT3A^MUT (HR 5.8, 95% CI 3.3–10.5) as the strongest molecular predictors of overall survival. The same was true for blast transformation-free survival with a corresponding HR (95% CI) of 0.08 (0.01–0.6) and 9.5 (3.8–23.5). At a median of 20 months follow-up, blast transformation was documented in none of the 33 patients with PHF6^MUT/DNMT3A^WT but in 6 (32%) of 19 with DNMT3AMUT and 74 (20%) of 374 with PHF6^WT/DNMT3A^WT (p < 0.01). The specific molecular signatures sustained their significant predictive performance in the context of the CMML-specific molecular prognostic model (CPSS-mol).

Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial [Clinical trial]

Highlight(s): Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukemia (AML).

KOMET-001 (NCT04067336) is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib (an oral selective menin inhibitor with known preclinical activity in menin-dependent AML models) in adults with relapsed or refractory AML. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. For phase 1a, patients (all molecular subtypes) received ziftomenib (50–1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b.

From September 12, 2019, to August 19, 2022, 83 patients received 50–1000 mg ziftomenib. Median follow-up was 22.3 months (interquartile range [IQR] 15.4–30.2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anemia (24%), febrile neutropenia (22%), pneumonia (19%), differentiation syndrome (15%), thrombocytopenia (13%), and sepsis (12%). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial hematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing.

Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B

Highlight(s): Fidanacogene elaparvovec was superior to prophylaxis for the treatment of participants with hemophilia B, leading to reduced bleeding and stable factor IX expression.

This is an phase 3 open-label clinical trial (BENEGENE-2; NCT03861273) of fidanacogene elaparvovec (an adeno-associated virus [AAV] gene-therapy vector for hemophilia B containing a high-activity human factor IX variant) at a dose of 5x1011 vector genome copies per kilogram of body weight. Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were eligible for screening if they had received at least 6 months of therapy with prophylactic factor IX concentrate. The primary end point, tested for noninferiority, was the annualized bleeding rate (treated and untreated bleeding episodes) from week 12 to month 15 after treatment with fidanacogene elaparvovec as compared with the prophylaxis lead-in period. Superiority, additional efficacy end points, and safety were also assessed.

Of 316 men who underwent screening for the lead-in study, 204 (64.6%) were not eligible; 188 (59.5%) of those were ineligible owing to the presence of anti-AAV neutralizing antibodies. Of the 45 participants who received fidanacogene elaparvovec, 44 completed at least 15 months of follow-up. The annualized rate of bleeding for all bleeding episodes decreased by 71%, from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after gene therapy, a treatment difference of −3.15 episodes (95% CI, −5.46 to −0.83; p = 0.008). This result shows the noninferiority and superiority of fidanacogene elaparvovec to prophylaxis. At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0). A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, development of factor IX inhibitors, or malignant conditions were observed.