BCMA-directed CAR T-cell therapy in patients with multiple myeloma and CNS involvement [Retrospective study]

Highlight: 

B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory multiple myeloma (MM) and central nervous system (CNS) involvement is feasible without excess neurotoxicity. Screening for CNS involvement before CAR-T therapy could be warranted in high-risk patients.

Ten patients received either idecabtagene vicleucel (n = 6) or ciltacabtagene autoleucel (n = 4), where brain/cranial nerve and/or spinal cord involvement/leptomeningeal disease were evident on either magnetic resonance imaging (100%) and/or cerebrospinal fluid (40%). Eight patients had their CNS diagnosis before CAR T-cell therapy, and two were diagnosed within 14 days post-infusion. Seven received CNS-directed therapy during bridging before CAR T-cell therapy (2 patients received radiotherapy [RT] alone, 3 received RT plus intrathecal  (IT) chemotherapy, 1 received IT chemotherapy only, and 1 received surgery plus RT). There were no excess toxicities: no cytokine release syndrome grade ≥3; 10% immune effector cell-associated neurotoxicity syndrome (ICANS) grade 3; and no ICANS grade 4. The best overall response rate was 80% (≥70% very good partial response) and a 100% CNS response.

Impact of treatment for adolescent and young adults with essential thrombocythemia and polycythemia vera [Retrospective study] 

Highlights: 

●      Essential thrombocythemia (ET) and polycythemia vera (PV) in adolescent and young adults (AYA), are similar conditions to those in older patients and are linked with thrombotic complications and the potential progression to secondary myelofibrosis (sMF).

●      Unlike adults, AYA patients naturally face a lower age-related risk and have a different range of cardiovascular risk factors. Although thrombosis rates are similar, the benefits of antiplatelet therapy are not as well established in AYA patients.

●      Notably, no progression was observed in AYA patients treated with interferon, strongly supporting its potential as a first-line treatment for this younger group, who are expected to live with their myeloproliferative neoplasm for many years.

Among 348 patients (278 ET, 70 PV) with a median age of 20 years, the risk of a thrombotic event was 1.9 per 100 patient-years. Risk factors for thrombosis included elevated white blood cell count (>11x 10⁹/L) with a hazard ratio [HR]: 2.73, p=0.012) and absence of splenomegaly at diagnosis (HR: 5.66, p=0.026), while cytoreductive drugs did not reduce this risk. The incidence of sMF was 0.7 per 100 patient-years. CALR mutation (HR: 6.00, p<0.001) and any history of thrombosis (HR: 3.84, p=0.015) were associated with sMF risk. Interferon as a first-line treatment significantly improved myelofibrosis-free survival compared to other treatments or the absence of cytoreduction (p=0.046).

Efficacy of Combined CD38 and PD1 Inhibition with Isatuximab and Cemiplimab in Relapsed/Refractory NK/T-Cell Lymphoma [Phase II trial] 

Highlights: 

●      This study aimed to assess the efficacy and safety of combining cemiplimab, an anti-PD1 antibody, with isatuximab, an anti-CD38 antibody, in relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (R/R ENKTL).

●      The hypothesis was that CD38 blockade could enhance the antitumor activity of PD1 inhibitors.

●      The combination of isatuximab and cemiplimab demonstrated sustained antitumor activity and a manageable safety profile in R/R ENKTL.

Eligible patients received cemiplimab (250 mg on days 1 and 15) and isatuximab (10 mg/kg on days 2 and 16) intravenously every four weeks for six cycles. Responders then received cemiplimab (350 mg) and isatuximab (10 mg/kg) every three weeks for up to 24 months. Out of 37 patients enrolled, the CR rate was 51% (19/37), exceeding the primary endpoint (complete response [CR] rate) of 40%, and the objective response rate was 65% (24/37). After a median follow-up of 30.2 months (95% confidence interval [CI]: 25.6–34.8 months), the median progression-free survival was 9.5 months (95% CI: 1.4–17.6 months), while the median overall survival had not yet been reached. Most adverse events were mild (grade 1-2), with grade ≥3 events (32%) and no treatment-related deaths. This phase II trial is registered here

Consensus recommendations from the 2024 Lymphoma Research Foundation workshop on treatment selection and sequencing in CLL or SLL

Recommendations: 

1. When initial treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) is advised, the authors advise against the use of traditional chemotherapy agents such as fludarabine, cyclophosphamide, bendamustine, and chlorambucil.

2. When initial treatment of CLL/SLL is advised, they recommend targeted agents such as venetoclax-obinutuzumab (Ven-O), acalabrutinib with or without obinutuzumab, or zanubrutinib.

3. When to use a covalent Bruton tyrosine kinase inhibitors (cBTKi) vs. Ven-O in CLL/SLL (see Figure 1 in the original article):

●      Patient preference is often the most important factor.

●      Key features of acalabrutinib or zanubrutinib:

        A.    Therapy until progression or intolerance

        B.    Only oral therapy

        C.    Limited visits/laboratory monitoring.

●      Key features of venetoclax and obinutuzumab:

        A.    Time-limited therapy

        B.    Includes intravenous therapy (obinutuzumab)

        C.    Frequent visits/labs over the first 8 weeks

●      Strongly recommend against acalabrutinib or zanubrutinib if:

        A.    Concomitant dual antiplatelet therapy (DAPT) (check with                                cardiologist if DAPT is necessary).

        B.    Concomitant warfarin (check if non-warfarin anticoagulation is                        acceptable).

        C.    History of major bleeding with ongoing risk.

        D.    History of ventricular arrhythmia with ongoing risk.

●      Influences toward acalabrutinib or zanubrutinib.

        A.    Presence of a 17p deletion by fluorescence in situ hybridization or                 a TP53 mutation by next-generation sequencing (NGS).

●      Influences toward venetoclax and obinutuzumab:

        A.    Concomitant single antiplatelet therapy.

        B.    Concomitant anticoagulation (non-warfarin).

        C.    History of atrial fibrillation or flutter.

4. For patients who require second-line treatment after frontline cBTKi, when use of an alternative cBTKi is not appropriate or preferred, they recommend Ven with an anti-CD20 monoclonal antibody (mAb). Although rituximab with Ven is approved for patients with relapsed/refractory CLL/SLL, the majority of the panel recommends obinutuzumab with Ven in this setting (see Figure 2 in the original paper).

5. For patients who discontinue a cBTKi because of intolerance and require further CLL/SLL treatment, an alternative second-generation cBTKi (acalabrutinib or zanubrutinib) can be considered unless the reason for intolerance was a life- or organ-threatening condition.

6. For patients with CLL/SLL and ≥2 prior therapies, including a cBTKi and Ven, when retreatment with Ven w/wo an anti-CD20 mAb or transitioning to an alternate cBTKi is not preferred, the authors recommend pirtobrutinib in most cases. In patients who are deemed good candidates, lisocabtagene maraleucel should also be considered for this line or subsequent lines of therapy.

7. If participation in a clinical trial is not feasible or preferable, the following options include: a phosphoinositide 3-kinaseδ (PI3Kδ) inhibitor and allogeneic stem cell transplantation (in patients with CLL/SLL who are refractory to at least two prior therapies, including Ven and a cBTKi, and who have achieved remission with subsequent therapy).