Nivolumab + AVD in Advanced-Stage Classic Hodgkin’s Lymphoma [Phase 3 clinical trial]

Highlight(s): Nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD) resulted in more prolonged progression-free survival (PFS) than brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) in adolescents and adults with stage III or IV advanced-stage classic Hodgkin’s lymphoma (HL) and had a better side-effect profile.

This is a phase 3, multicenter, open-label, randomized trial  (S1826 trial; NCT03907488) involving patients of at least 12 years of age with stage III or IV newly diagnosed HL. Patients were randomly assigned to receive BV+AVD or N+AVD. The primary endpoint was PFS, the time from randomization to the first observation of progressive disease or death from any cause.

Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved PFS as compared with BV+AVD (hazard ratio [HR] for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided p= 0.001). Owing to the short follow-up time, the authors repeated the analysis with a more extended follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year PFS  was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (HR for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, seven patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation. Unfit and frail older patients were not included in this trial. However, the 2-year PFS in patients older than 60 years was 88% with N+AVD, compared with 65% with BV+AVD (HR for disease progression or death, 0.30).

Outcomes After Brexucabtagene Autoleucel Administered as a Standard Therapy for Adults With Relapsed/Refractory B-Cell ALL [Retrospective study]

Highlight(s): Similar to ZUMA-3, high rates of measurable residual disease (MRD)-negative complete remission (CR) were observed after brexu-cel treatment for relapsed/refractory (R/R) B-cell ALL (B-ALL). Hematopoietic stem cell transplantation (HCT) as consolidation after brexu-cel resulted in improved progression-free survival (PFS).

The authors developed a collaboration across 31 United States centers to study adults with B-ALL who received brexu-cel (CD19-directed chimeric antigen receptor [CAR] T-cell therapy) outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. At data lock, 204 patients had undergone apheresis, and 189 were infused. The median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were MRD negative remissions. Median PFS was 9.5 months, and median overall survival was not reached. Grade 3-4 cytokine release syndrome (median time to onset was 5 days) and immune effector cell–associated neurotoxicity syndrome (median time to onset was 7 days) occurred in 11% and 31%, respectively. Tocilizumab, steroids, and/or anakinra were administered to 129 (68%), 121 (64%), and 44 (23%), respectively, to treat CAR-related toxicity. Infections were implicated in several early and later non-relapse deaths; infectious deaths were most commonly attributed to fungal infection (n=56). In multivariable analysis, patients receiving consolidative HCT (hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared to those without consolidation or maintenance therapy.

Rapid high-dose cyclophosphamide as bridging treatment for advanced therapies in multiple myeloma [Retrospective study]

Highlight(s): The study shows the efficacy and safety of rapid, peripheral, high-dose cyclophosphamide in 15 patients intending to proceed with chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsAbs), or long-term regimens.

This was a single-center retrospective review of 15 patients with relapsed/refractory multiple myeloma who received rapid high-dose cyclophosphamide (TurboCy) as bridging therapy for CAR T-cell therapy (n=10), BsAbs (n=3), autologous stem cell transplant (n=1), or “conventional agents” (n=1). The primary outcomes of interest were overall response rate (ORR), clinical benefit rate (defined as stable disease or better), and success rate in proceeding with the intended line of therapy. All patients were admitted for TurboCy, which was administered intravenously over 60 minutes at a target dose of 1500 mg/m² every 12 hours for two doses (3000 mg/m² total). Intravenous (IV) mesna was co-administered at the same dose as TurboCy along with continuous IV hydration at 83 cc/hour unless there were concerns for volume overload). All patients received peg-filgrastim 6 mg on-body injector after discharge from the hospital and then were followed twice weekly in the outpatient clinic until count recovery. During the neutropenia period, patients were prescribed levofloxacin and fluconazole until neutrophil recovery, along with standard acyclovir prophylaxis. Of the 15 patients included in this analysis, the median age was 55 (range 37–73) years. High-risk cytogenetic abnormalities were identified in eight (53%) patients, with four (26%) harboring 2+ high-risk abnormalities. Extramedullary disease was present in 10 (67%) patients. A total of eight (53%) patients received more than one cycle of TurboCy. The ORR was 80% (12/15), and the clinical benefit rate was 100% in a heavily pretreated high-risk cohort. Two of the three patients with less than a partial response had prior cyclophosphamide exposure. With a median follow-up of 7.3 months from the first TurboCy administration, the median OS was not reached (95% confidence interval 6.1 months–not estimable). Cytopenias were common, but no deaths occurred during bridging. All patients proceeded to their following line of intended therapy.

Efficacy of intravenous high-dose methotrexate in preventing relapse to the central nervous system in R-CHOP(-like)-treated, high-risk, diffuse large B-cell lymphoma patients and its effect on mortality [Systematic review and meta-analysis]

Highlight(s): These data indicate that high-dose methotrexate (HD-MTX) does not prevent or, at best, only slightly reduces the incidence of later central nervous system (CNS) relapse. An impact of HD-MTX on survival could also not be demonstrated. The overall risk of bias was adjudged as “serious,” and the quality of the evidence was rated as “low.”

This study aimed to evaluate: (i) whether the addition of prophylactic intravenous HD-MTX reduces the risk of CNS relapse in high-risk diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP or similar and (ii) whether HD-MTX prophylaxis confers an overall survival benefit, irrespective of CNS relapse. They performed a systematic search of MEDLINE/PubMed and EMBASE for data on DLBCL patients at high risk of CNS relapse treated with R-CHOP or similar who received HD-MTX as an intervention and a comparator arm of patients who did not receive prophylaxis and/or intrathecal prophylaxis. A risk of bias was estimated using the ROBINS-I tool, and the GRADE approach assessed the quality of the evidence. Finally, a meta-analysis based on the systematic review was conducted. A total of 1,812 studies were screened. No randomized controlled trials were identified. Seven observational studies comprising 1,661 patients met the inclusion criteria. We found a statistically non-significant relative risk of 0.54 (95% confidence interval [CI]: 0.27-1.07) of CNS relapse for patients receiving HD-MTX versus controls. The meta-analysis investigating mortality demonstrated a relative risk of death of 0.70 (95% CI: 0.44-1.11) for patients treated with HD-MTX versus controls. The calculated statistical heterogeneity was 55% after sensitivity analysis. The overall risk of bias was adjudged as “serious,” and the quality of the evidence was rated as “low.”

How I Treat Older Patients with Relapsed/ Refractory Diffuse Large B Cell Lymphoma [Review article]

Diffuse large B-cell lymphoma is an aggressive, yet curable malignancy. However, older patients are at higher risk of relapsed disease as they may not be eligible for full-intensity frontline chemoimmunotherapy or have comorbidities that limit standard treatments.

Here are some key messages:

• Formal fitness determinations including geriatric assessments remain critical (but there needs to be more guidance on utilizing this tool in the relapsed setting).

• Since age is not considered a delineating factor for chimeric antigen receptor (CAR) T-cell therapy eligibility, disease status, physical and social factors help determine which patients can safely receive CAR T-cell therapy.

• The authors prefer liso-cel (especially for those ≥80 years), since it has lower rates of immune-effector cell-associated neurotoxicity syndrome than either axi-cel or tisa-cel across multiple studies, including some matched comparisons.

• Bridging therapy:

-  Priority should be given to clinical trials, radiotherapy if relapsed disease occurs in limited areas, or polatuzumab-based regimens if not used in the first-line setting.

-  Avoid bendamustine prior to apheresis.

-  For patients with multifocal relapse who have already received polatuzumab-based treatment, the authors prefer a salvage chemotherapy regimen with rituximab in combination with gemcitabine and oxaliplatin (GemOx).

-  Although not yet approved in the second line, the addition of glofitamab to GemOx is also being considered in the STARGLO trial.

• If relapse occurs despite CAR T-cell therapy or alternative therapies being preferred, many novel therapeutic options and combinations exist with some potential modifications for older adults, such as: 

-  Bispecific antibodies.

-  Tafasitamab and lenalidomide.

-  Polatuzumab containing regimens.

-  Loncastuximab tesirine.

See the algorithm of Figure 1 and the Visual abstract in the original article.