Outcome of large B-cell lymphoma patients treated with tafasitamab plus lenalidomide either before or after CAR-T-cells.

Tafasitamab plus lenalidomide (TAFA-LEN) treatment relevance pre- or post-anti-CD19 CAR T-cell is currently debated. We analyzed large B-cell lymphoma patients in the DESCAR-T registry treated with axi-cel or tisa-cel in ≥3rd line (L3+) and TAFA-LEN before (n=15, 'TL-pre-CAR-T' set) or directly after (n=52, 'TL-post-CAR-T' set) CAR T-cell. We compared TAFA-LEN v. other treatments using inverse probability weighting in the TL-post-CAR-T set. In the TL-post-CAR-T' set, the median follow-up duration (mFUD) was 7 months, and the median progression-free survival, overall survival and duration of response since the 1st treatment for progression (mPFS2/mOS2/mDOR2) were 3, 4.7 and 8.1 months, respectively. The best overall response rate (bORR) and best complete response rate (bCRR) after TAFA-LEN were 13.5% and 7.7%, respectively. Outcomes were better for patients who relapsed >6 months after CAR T-cell (mPFS2: 5.6 vs. 2 months, p=0.0138; mOS2: not reached vs. 3.8 months, p=0.0034). bORR and bCRR between TAFA-LEN and other treatments were 20.6% vs. 24.9% and 11.6% vs. 15.6%, respectively. Outcomes were similar between TAFA-LEN and other treatments (mPFS2: 2.9 [2-2.6] vs. 2.4 [1.5-4.2] months, p=0.91; mOS2: 3.3 [1.8-6.4] vs. 5.5 [4.4-6.3] months, p=0.06). In an exploratory analysis of the TL-pre-CAR-T set (mFUD since CAR T-cell: 2.8 months), the median TAFA-LEN treatment duration prior to CAR-T was 3.7 months and no patients were reported to become CD19 negative. The bORR, bCRR, 6-month PFS and OS rates after CAR T-cell infusion were 45.5%, 36.4%, 20.1% and 58.2%, respectively. Neither TAFA-LEN nor comparative salvage treatments improved outcomes of patients who relapsed after CAR T-cell.

Brexucabtagene autoleucel in relapsed or refractory mantle cell lymphoma, intention-to-treat use in the DESCAR-T registry.

Not available.

Efficacy of ruxolitinib in the treatment of relapsed/refractory large granular lymphocytic leukaemia.

Large granular lymphocytic (LGL) leukaemia is a rare chronic lymphoproliferative disorder characterized by an expansion of cytotoxic T or NK cells. Despite a usually indolent evolution, most patients will require a treatment over the course of the disease because of cytopenia or symptomatic associated autoimmune disorders. First-line treatment is based on immunosuppressive agents, namely cyclophosphamide, methotrexate and ciclosporin. However, relapses are frequent, and there is no consensus on the management of relapsed/refractory patients. The implication of the JAK/STAT pathway in the pathogenesis of this disease has prompted our group to propose treatment with ruxolitinib. A series of 21 patients who received this regimen is reported here. Ten patients (47.6%) were refractory to the three main immunosuppressive drugs at the time of ruxolitinib initiation. Ruxolitinib yielded an overall response rate of 86% (n = 18/21), including 3 complete responses and 15 partial responses. With a median follow-up of 9 months, the median response duration was 4 months. One-year event-free survival and 1-year overall survival were 57% and 83% respectively. Mild side effects were observed. Biological parameters, notably neutropenia and anaemia, improved significantly, and complete molecular responses were evidenced. This study supports ruxolitinib as a valid option for the treatment of relapsed/refractory LGL leukaemia.

Long-term results of Waldenström macroglobulinaemia treatment by bendamustine and rituximab: A study on behalf of the French Innovative Leukemia Organization (FILO).

The bendamustine-rituximab (BR) schedule is an efficient first-line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression-free (PFS) and overall survival (OS). With a median follow-up of 76.1 months (95% confidence interval [CI] 69.9-80.6), 5-year outcome is still excellent at 66.63% (95% CI 56.09-79.17) for PFS and 80.01% (95% CI 70.82-90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99-27.64) at 66 months. Relapsed patients who received ibrutinib as second-line clearly benefited from this schedule. This confirms current recommendations suggesting BR long-term efficacy as first-line option in WM.

Combined inhibition of Wee1 and Chk1 as a therapeutic strategy in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents that have significantly improved clinical outcome, most patients relapse and develop drug resistance. MM is characterized by genomic instability and a high level of replicative stress. In response to replicative and DNA damage stress, MM cells activate various DNA damage signaling pathways. In this study, we reported that high CHK1 and WEE1 expression is associated with poor outcome in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Combined targeting of Chk1 and Wee1 demonstrates synergistic toxicities on MM cells and was associated with higher DNA double-strand break induction, as evidenced by an increased percentage of γH2AX positive cells subsequently leading to apoptosis. The therapeutic interest of Chk1/Wee1 inhibitors' combination was validated on primary MM cells of patients. The toxicity was specific of MM cells since normal bone marrow cells were not significantly affected. Using deconvolution approach, MM patients with high CHK1 expression exhibited a significant lower percentage of NK cells whereas patients with high WEE1 expression displayed a significant higher percentage of regulatory T cells in the bone marrow. These data emphasize that MM cell adaptation to replicative stress through Wee1 and Chk1 upregulation may decrease the activation of the cell-intrinsic innate immune response. Our study suggests that association of Chk1 and Wee1 inhibitors may represent a promising therapeutic approach in high-risk MM patients characterized by high CHK1 and WEE1 expression.