Chronic graft-vs-host disease (cGVHD)

Based on 3-year follow-up data from the phase 2 ROCKstar study (NCT03640481), belumosudil  (an oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 [ROCK2],  which regulates multiple profibrotic processes) approved for patients with cGVHD who failed two lines (2-5 prior lines of systemic therapy), produced maintained the response and there were no safety alerts, according to information presented by Corey S. Cutler, M.D. (Dana Farber Cancer Institute, Boston, USA), at the 50th Annual EMBT Meeting. At a median follow-up of 30 months, including 20 previously unreported participants who were enrolled in a subsequent biomarker study, overall response rates (ORRs; primary endpoint) in the populations of patients who received belumosudil at 200 mg once daily (n = 77) and twice daily (n = 75) were 74% (95% CI, 63%-83%; P <0.0001) and 76% (95% CI, 65%-85%; P <0.0001), respectively. 23.4% and 25.3% respectively, successfully stopped all immunosuppressants. Belumosudil was shown to be well tolerated as in the first data report (in 2020), and the incidence rates for each safety event remained stable, and no new treatment-related adverse events occurred.
-Reference: Belumosudil for chronic graft-versus-host disease after ≥2 prior lines of systemic therapy: 3-year follow-up of the ROCKstar study. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract OS13-01.

Immune effector cell therapy-associated cytokine release syndrome.  

At the 50th Annual EMBT Meeting, Richard Maziarz, M.D. (Oregon Health & Science University, Portland, USA), presented the results from the phase 2 placebo-controlled randomized cohort (NCT0471366) that enrolled adults planning to receive axicabtagene ciloleucel (axi-cel; Yescarta) for relapsed/refractory large B-cell lymphoma (RR-LBCL [n=47]). Prophylactic administration of itacitinib (a potent, oral, selective JAK1 inhibitor [n=23]) 200 mgs twice daily (BID) from 3 days before infusion through day 26, versus placebo (n=24). Primary endpoint was day 14 cytokine release syndrome (CRS) grade >1 incidence. Itacitinib was well tolerated and decreased the incidence and severity of CRS  vs. placebo (17.4% vs. 56.5% experienced grade 2 CRS, p=0.003; 95% CI: 0.14-0.65) and immune effector cell–associated neurotoxicity syndrome (ICANS [13% vs. 34.8%, respectively]). No grade 3/4 CRS occurred. Median time to ICANS was 5 and 6.5 days, respectively; median duration was 2 and 3.5 days, respectively. Lymphoma best overall response to axi-cel showed no differences between treatment arms. However, persistent grade 3/4 thrombocytopenia (38.1%; [grade 4: n=4] vs. 18.2%; [grade 4: n=0]) and 3/4 neutropenia at day 28 (33.3% [grade 4: n=3] vs. 13.6%; [grade 4: n=0]) was more frequent in the itacitinib arm, with comparable severe infection rates.  Further investigation of itacitinib on chimeric antigen receptor T (CAR T)-cell expansion and function are ongoing.  
-Reference: Itacitinib for the prevention of immune effector cell therapy-associated cytokine release syndrome: results from the phase 2 INCB 39110-211 placebo-controlled randomized cohort. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract OS6-04.

Multiple myeloma (MM) and chimeric antigen receptor T (CAR T) cell therapy.

CAR T cell therapy has become a key option for patients with relapsed and refractory MM (RRMM). Due to a variety of logistical issues, patients may warrant “bridging” therapy (BT) between T-cell leukapheresis and lymphodepleting chemotherapy. This bridge may serve multiple roles: provide disease control during the manufacturing process, potentially reduce CAR T-cell therapy related toxicities, and/or potentially improve remission durability as a result. A retrospective multicenter study observed RRMM patients receiving idecabtagene vicleucel (ide-cel) treatment, were included.  Of 214 ide-cel patients, 170 (79%) underwent BT, comprising 12% selinexor, 45% alkylator, 15% proteasome inhibitor (PI) combinations, 18%  immunomodulatory (IMiD) +/- monoclonal antibody (mAb) combinations, and 11% other therapies (e.g., belantamab mafodotin, focal radiation). Forty-four patients (21%) did not receive BT (no-BT). The median BT duration was 1 month (range, 1-7). At 3 months post-CAR T, response didn’t differ between BT and no-BT with p= 0.802 for overall response rate (≥ partial response [PR]); p = 0.208 for complete response (CR), consistent across BT subgroups.  Median follow-up: 9.7 months (range: 0.2–19.5). Median progression-free survival (PFS): 8.16 months (95% CI: 6.61–9.31), overall survival (OS): not reached (NR). 1-year PFS and OS rates: 36% and 63%, respectively. BT patients showed inferior PFS (6.68 vs. 11.48 months in no-BT, p=0.007) and OS (13.85 vs. NR months in no-BT, p=0.002).  Patients with no-BT before ide-cel showed prolonged PFS and OS, possibly indicating less aggressive disease. Conversely, alkylator-based BT resulted in inferior PFS and OS compared to other BT types or no-BT approaches. This trend might relate more to refractory myeloma than directly to alkylators, proposing the potential benefit of early CAR T-cell therapy before standard treatment resistance. Tailoring BT based on patient history, toxicity risks, and disease traits is crucial.  

Non-Hodgkin lymphoma (NHL) and bispecific antibodies (BsAb).

While less is known about infection rates after BsAb treatment for lymphoma, concerns regarding an increased risk of infection have been raised by BsAb use in myeloma. A systematic review and meta-analysis of 27 studies that included 2100 patients with lymphoma treated with CD20-directed BsAb, was performed. Median follow-up was 12 months; 17% of patients had received prior cellular therapies. The pooled prevalence of infections of any-grade was 44% (95% CI: 37-50%), with a prevalence of grade >2 infections of 20% (95% CI: 15-21%) and 3% of patients experiencing fatal infections (95% CI: 2-5%). Infection rates did not differ between patients with aggressive or indolent lymphomas, or between BsAb monotherapy and combination therapy. Viral infections constituted a significant proportion (41%) of fatal infections; highlighting the importance of prophylaxis, vaccination, and investigation for viral reactivation. 

Diffuse large B-cell lymphoma (DLBCL).  

Recently, according to a press release from Roche, positive results were achieved in the randomized (2:1), phase 3 clinical trial (STARGLO; NCT04408638) assessing second line therapy with glofitamab (Columvi; off-the-shelf CD20xCD3 T-cell engaging bispecific antibody of fixed-duration) plus gemcitabine and oxaliplatin versus rituximab and oxaliplatin for 270 patients with relapsed/refractory DLBCL who cannot receive autologous stem cell transplant (ASCT). Positive results were shown in overall survival (primary endpoint): “Columvi, in combination with chemotherapy, demonstrated a statistically significant improvement in overall survival for people with relapsed or refractory DLBCL. Data from the STARGLO study will be submitted to health authorities and presented at an upcoming medical meeting”. Safety data with this study combination were consistent with the known safety profiles of these individual agents.