Severe ICANS after CAR T-cell therapy and assessment of prevention with levetiracetam for seizure prophylaxis following CAR T-cell for DLBCL & PMBCL in Europe: a survey on behalf of the Cellular Therapy & Immunobiology Working Party (CTIWP) of the EBMT [Descriptive study]

Highlight(s): There was heterogeneity in immune-effector cell-associated neurotoxicity syndrome (ICANS) prophylaxis practices among EBMT-affiliated centers, opening the way for future studies to assess the impact of standardized strategies in preventing neurologic toxicities.

To evaluate the incidence of severe ICANS and identify potential risk factors, the authors surveyed to delve into real-world practices for ICANS prophylaxis and assess the criteria guiding centers in adopting prophylactic strategies. In March 2024, they sent a questionnaire to 200 EBMT-affiliated centers who had reported at least one chimeric antigen receptor (CAR) T-cell treatment to the registry. The SurveyMonkey tool was deployed to facilitate efficient data collection across centers.

Six centers (10%) reported using prophylactic treatment prior to severe ICANS, including corticosteroids and anakinra. Forty-two centers (68%) confirmed using levetiracetam as seizure prophylaxis after CAR T-cell infusion at some point since

their cellular therapy program was initiated. Nine centers (14%) start the anti-epileptic drug upon lymphodepletion, 10 (16%) after CAR T-cell infusion, seven centers (11%) start levetiracetam at the onset of cytokine release syndrome, twenty (32%) upon the development of any neurologic abnormality. One center reported clobazam prophylaxis, while the remaining centers used anti-epileptic drugs for secondary prophylaxis or as treatment of clinical/electroencephalographic abnormalities. Notably, three centers reported recently abandoning seizure prophylaxis.

Comparison of EasyM, a clonotypic mass spectrometry assay, and EuroFlow minimal residual disease assessment in multiple myeloma [Retrospective study]

Highlight(s): The peripheral blood (PB) clonotypic mass spectrometry (MS) assay appears to be more sensitive in detecting residual disease in multiple myeloma (MM) than the validated and widely accepted bone marrow (BM) EuroFlow next-generation flow (NGF) cytometry minimal residual disease (MRD) approach with a sensitivity of 10^-5. Concordance between MS and NGF was poor, with 53% of complete response (CR) samples showing detectable M-protein by EasyM MS despite EuroFlow NGF MRD negativity.

BM MRD assessment with next-generation sequencing (NGS) or NGF cytometry can achieve a minimum sensitivity of 10^-5. However, it requires an invasive procedure. Additionally, specimen quality and failure to capture MM’s spatial heterogeneity may limit this single-site BM biopsy approach. PB-based MS can sequentially quantify unique amino acid sequences and molecular masses of monoclonal proteins (M-proteins), offering the potential for highly sensitive, non-invasive sequential MRD assessment. Two MS methods, the clonotypic peptide, and intact immunoglobulin light chain, have been employed. The former approach has lower throughput but is personalized and highly sensitive, able to detect residual M-proteins at 0.001g/L.

The authors retrospectively evaluated the PB clonotypic MS EasyM assay in MM patients (n=62) undergoing sequential EuroFlow NGF MRD. MM patients enrolled in the Australasian Leukaemia and Lymphoma Group MM19 and MM21  trials with measurable M-protein ≥2g/L by serum protein electrophoresis and/or free light chains (FLC) ≥100mg/L at baseline were identified. EuroFlow NGF MRD status was determined from BM samples at pre-autologous stem cell transplant(ASCT), post-ASCT, and end-of-consolidation timepoints in MM19 and MM21 and post cycle 2 of consolidation in MM21. Matched serum samples and additionally unmatched samples post cycle 7 of consolidation in MM19 were evaluated with EasyM.

MS analysis was successful in 57/62 (92%) patients.  Sequential MS samples revealed rising M-protein levels in 6 patients, coinciding with relapse in 2 patients and preceding relapse in 4 patients by 3, 15, 25, and 38 months. Matched BM NGF results were available for 5 patients at the time of rising M-protein levels, and of note, 1 patient was NGF MRD negative (NGF-), while 4 patients were NGF MRD positive (NGF+).  A total of 136 serum samples for MS with matched BM for NGF were available. Forty-five samples (33%) were NGF- compared to 7 (5%) MS- samples from 3 patients.  Ninety-eight (72%) samples were concordant. As patients progressed through treatment, the discordances between detectable M-protein by MS analysis and NGF- (MS+/NGF-) increased, accounting for 4%, 19%, 30%, and 54% of samples at the four time points.  The association between MS and NGF was not significant at any time point. MS- was not significantly associated with progression-free survival in this small cohort.

Proteasome inhibitors related thrombotic microangiopathy: a systematic and comprehensive review [Systematic review]

This systematic review includes 44 studies with 115 cases of proteasome inhibitor (PI)-induced thrombotic microangiopathy (TMA), where carfilzomib was implicated in 101 cases. There is an approximate 14.9% rate of adverse outcomes in PI-TMA, though this figure may underestimate the true prevalence, as some cases likely go undiagnosed or unrecognized. Treatment approaches varied: 28 patients received supportive care, 43 underwent therapeutic plasma exchange (TPE), nine were treated exclusively with eculizumab (ECU), and 13 received both TPE and ECU. ECU significantly improved outcomes for patients unresponsive to initial TPE, achieving complete remission in seven cases. The need for dialysis emerged as a significant predictor of outcomes, often indicating a poor prognosis. For patients suspected of having PI-TMA, it is advisable to discontinue the offending medication promptly, even without definitive laboratory confirmation. Practical approaches could include using peripheral blood smears to identify schistocytes and performing complement function tests. Testing for sC5b-9 terminal complement complex  may also help diagnose suspected cases of PI-TMA. In cases where the diagnosis is challenging, a kidney biopsy may assist if conditions permit. A comprehensive evaluation of the complement system, including genetic mutations, function, and associated complement inhibitory factor antibodies, should be included in the assessment of PI-TMA. Early administration of eculizumab may be beneficial in cases of suspected complement abnormalities or suboptimal response to initial treatments. See Figure 2, “Comprehensive management of PI-TMA,” in the original publication.

Ruxolitinib-based regimen in children with autoimmune or autoinflammatory disease-related haemophagocytic lymphohistiocytosis [Retrospective study]

Highlight(s): This study showed that a subset of patients with hemophagocytic lymphohistiocytosis (HLH) can be treated with JAK inhibition without cytotoxic chemotherapy. Responses were impressive, rapid, and were well tolerated.

The authors conducted a retrospective, single-center study examining a ruxolitinib (RUX)-based regimen in children with autoinflammatory disease- or autoimmune disease-related HLH. Patients were first treated with RUX monotherapy, and additional treatments including methylprednisolone and etoposide were added sequentially when the disease could not be controlled. The study included 26 patients with a median follow-up of 23.9 months, of whom 15 had prior treatments. The overall response rate at week 8 with the RUX-based regimen was 96.2%, with 92.3% attaining complete response (CR) and 3.9% attaining partial response. The 2-year overall survival rate was 96.2% (95% CI, 80.4% to 99.9%). During RUX monotherapy, 46.1% of patients achieved CR as the best response, with a median first response time to RUX of 2 days. Additionally, 53.8% of patients required additional glucocorticoids and 23.1% required etoposide chemotherapy. All observed adverse events were manageable and acceptable.

Johnson & Johnson submits applications in the U.S. and EU seeking approval of DARZALEX FASPRO® / DARZALEX® as subcutaneous monotherapy for high-risk smoldering multiple myeloma [News drug-regulation]

The applications are supported by data from the ongoing phase 3 AQUILA study (NCT03301220) of DARZALEX FASPRO® as monotherapy for the treatment of adult patients with high-risk smoldering multiple myeloma. A total of 390 patients were randomized 1:1 to daratumumab (DARA) monotherapy (1800 mg plus 2000 U/mL of recombinant human hyaluronidase) or active monitoring. Treatment continued for up to cycle 39, 36 months, or until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was progression-free survival (PFS). Eligible patients had a clonal bone marrow plasma cell (BMPC) level of at least 10% and at least 1 of the following risk factors: a serum M-protein level of at least 30 g/L; immunoglobulin (Ig)A SMM; immunoparesis with reduction of 2 uninvolved Ig isotypes; serum involved:uninvolved free light chain ratio of at least eight and <100; and/or clonal BMPCs >50% to <60% with measurable disease. Initial findings from the study will be presented at the 2024 ASH Annual Meeting in December. PFS was significantly improved with DARA vs. active monitoring (hazard ratio [HR]  0.49; 95% confidence interval [CI], 0.36-0.67; p <0.0001), and there was a positive “trend” in favor of DARA for the secondary endpoint of PFS on first-line MM treatment (HR, 0.58; 95% CI, 0.35-0.96).

FDA-approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia [News drug regulation]

On November 8, 2024, the Food and Drug Administration approved obecabtagene autoleucel (Aucatzyl, Autolus Inc.), a genetically modified autologous CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy, for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Efficacy was evaluated in FELIX (NCT04404660), an open-label, multicenter, single-arm phase 1b/2 trial that enrolled adults with relapsed or refractory CD19-positive B-cell ALL. Enrolled patients were required to have relapsed following a remission lasting 12 months or less, relapsed or refractory ALL following two or more prior lines of systemic therapy, or disease that was relapsed or refractory 3 or more months after allogeneic stem cell transplantation. The primary efficacy outcome measures were the rate and duration of complete remission (CR) achieved within 3 months after infusion. Of the 65 patients evaluable for efficacy, 27 (42%; 95% confidence interval [CI]: 29%, 54%) achieved CR within 3 months. The median duration of CR achieved within 3 months was 14.1 months (95% CI: 6.1, not reached).