Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO): a multicentre, single-arm, phase 2 trial [Clinical trial]

Highlight(s): The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with the diffuse large B-cell lymphoma variant of Richter transformation (DLBCL-RT).

This was a prospective, open-label, multicentre, single-arm, investigator-initiated, phase 2 study (NCT04082897). Eligible patients had a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma with biopsy-proven transformation to DLBCL; had not previously received treatment for DLBCL-RT, although they could have received CLL therapies. 

Patients (n=28) received 35 cycles of 21 days of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and day 15 of cycle 1; 1000 mg on day 1 of cycles 2–8) and intravenous atezolizumab (a PD-L1 checkpoint inhibitor  [1200 mg on day 2 of cycle 1 and 1200 mg on day 1 of cycles 2–18]), and continuous oral venetoclax (ramp-up from 20 mg/day on day 15 of cycle 1 according to CLL schedule, then 400 mg/day from day 1 of cycle 3 to day 21 of cycle 35). 

The primary endpoint was the overall response rate at day 21 of cycle 6 in the intent-to-treat population. Median follow-up was 16·8 months (interquartile range 7.8–32.0). At cycle 6, 19 of 28 patients responded, yielding an overall response rate of 67.9% (95% confidence interval [CI] 47.6–84.1). 

Treatment-emergent adverse events that were grade 3 or worse were reported in 17 (61%; 95% CI 40.6–78.5) of 28 patients, with neutropenia being the most frequent (11 [39%; 21.5–59.4] of 28 patients). Serious treatment-emergent adverse events were reported in eight (29%; 14.2–48.7) patients, which were most commonly infections (five [18%; 6.1–36.9] of 28 patients). There were two (7%) deaths attributable to adverse events during the study: one from sepsis and one from fungal pneumonia, which were not considered directly treatment-related by the investigators. Six (21.4%) patients had immune-related adverse events, none of which led to discontinuation. No tumor lysis syndrome was observed. In the MOLTO study, among four patients with clonally unrelated Richter transformation, three patients did not show a response and required salvage treatment, and one patient did show a partial response at cycle 6 but subsequently discontinued treatment due to myelodysplasia development. 

TP53 Mutated Acute Myeloid Leukemia: How Can We Improve Outcomes? [Review article]

Despite advances in the treatment paradigm of patients with acute myeloid leukemia (AML), TP53-mutated AML represents a molecular subgroup that has failed to improve, with an overall survival (OS) of around 6 months that is independent of age and fitness. The authors propose a treatment algorithm (see Figure 2 in the original publication).       

They prioritize participation in clinical trials whenever feasible and for patients eligible for an allogeneic hematopoietic stem cell transplantation (allo-HSCT), they prefer a hypomethylating agent (HMA)  + venetoclax. For patients who do not qualify for allo-HSCT, they prefer single-agent HMA therapy. While HMA + venetoclax might induce a higher response rate compared to HMA alone, it has not been demonstrated to improve OS in TP53-mutated AML. The authors do consider the addition of venetoclax if no response occurs on HMA over 4-6 cycles in patients not eligible for allo-HSCT. In general, they avoid intensive chemotherapy in TP53 mutated AML as survival outcomes with intensive chemotherapy are similar compared to less intensive approaches but side effects are usually higher. However, potential consideration of intensive chemotherapy with CPX-351 or high-dose cytarabine regimens could be considered for patients with TP53 mutations as a subclone or as a salvage therapy, although with only supportive data in patients with > 20% blasts.

Advanced imaging for earlier diagnosis and morbidity prevention in multiple myeloma: A British Society of Haematology and UK Myeloma Society Good Practice Paper [Guideline]

The British Society of Haematology  (BSH) produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base, but for which a degree of consensus or uniformity is likely to be beneficial to patient care. 

Recommendations: 

-    All multiple myeloma (MM) patients should have access to advanced imaging by whole-body (WB) magnetic resonance imaging with diffusion weighting (WB-MRI) or F18-fluorodeoxyglucose positron emission tomography integrated with computed tomography (FDG-PET/CT) at diagnosis and relapse, whenever presence of active disease is suspected by diagnostic test results or clinical symptoms.
-    Non-functional imaging by low-dose WB-CT or X-ray skeletal survey is not an adequate substitute for WB-MRI or FDG-PET/CT imaging; X-ray skeletal survey is not recommended for any standard MM assessment.
-    There should be an ambition to implement access to the most sensitive and appropriate imaging for all patients; WB-MRI has highest sensitivity by prospective comparison; however, FDG-PET/ CT is the alternative modality of choice.
-    Advanced imaging at best response should be considered to provide a baseline for comparative imaging and adequate decision-making at relapse. Matching imaging modality pre- and post-therapy facilitates clinical decision-making at relapse.
-    For patients with oligo-or non-secretory MM, and some types of extramedullary disease, regular advanced WB imaging should generally be accessible on a 3–4 monthly basis, as in solid cancer monitoring; if deemed clinically appropriate, clinical teams may opt for larger scanning intervals at an individual patient level. Cumulative radiation exposure should be considered regarding the choice of imaging modality (see Table 1 in the original paper).
-    For assessment of disease response to treatment in clinical trials, currently FDG-PET/ CT is the most evidence-based modality. In standard clinical care, WB-MRI can equally be used for response assessment.
-    Scan results should, where clinically indicated, be presented and reviewed in a specialist hematology/myeloma multidisciplinary team meeting with radiologists experienced in advanced myeloma imaging interpretation.

Outcomes of patients with primary central nervous system lymphoma following CD19-targeted chimeric antigen receptor T-cell therapy [registry study]

Highlight(s): chimeric antigen receptor (CAR)  T-cell therapy in patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL), had anti-tumor efficacy and not higher toxicity to that observed. Despite most patients experiencing an objective response to CAR T-cell therapy, most responses were not durable.

The study population included patients with a diagnosis of R/R PCNSL who received commercially available CAR T-cell therapy (i.e. axi-cel or tisa-cel).  The primary endpoint was overall survival (OS) defined as the time from CAR T-cell infusion to death from any cause.  

Twenty-four patients meeting the eligibility criteria were analyzed. The median number of prior therapies was 4 (range, 1-10), including 12 patients (50%) who had undergone a prior autologous stem cell transplantation. Bridging therapy was utilized in 5 patients (20%), and twenty-one patients (88%) had active disease before CAR T-cell infusion while 3 patients (12%) were in complete response (CR). Tisa-cel and axi-cel were infused in 21 (88%) and 3 (12%) patients, respectively. Among 23 patients evaluable for response, the overall response rate was 61% (N=14) by day 100, including 3 patients (13%) with partial response and 11 patients (48%) with CR. The median follow-up from CAR T-cell infusion was 26 months (range, 3-38). The 1- and 2-year OS rates were 55% (95% confidence interval [CI], 35%-75%) and 50% (95% CI, 29%-71%), and the 1- and 2-year progression free survival rates were 48% (95% CI, 28%-69%) and 28% (95% CI, 9%-51%), respectively.