Chimeric antigen receptor (CAR) T-cells, bispecific antibodies (BsAbs), and relapsed and refractory large B-cell lymphoma (R/R LBCL).  

 Due to their comparatively similar mechanisms of action, BsAbs and CAR T-cell therapies have led to concerns about immune-killing resistance that may develop after switching to BsAbs as well as T-cell exhaustion that may have an impact on the results of subsequent CAR T-cell therapies. In this study, CAR T-cells appear to be effective in patients who progress after exposure to BsAbs, highlighting that both sequencing modalities seem effective. 
This study had two parts; the first part was a retrospective analysis of 47 patients with R/R LBCL treated with CD19-targeted CAR T-cells after prior BsAb exposure (CD19/CD3 BsAbs, were excluded). The best overall (ORR) and complete response rate (CRR) achieved with prior BsAb treatment was 46% and 19%, respectively. The median progression-free survival (PFS) was 3.1 months (95% CI 2.7- 4.4 months) and the 6-month PFS was 21% (95% CI 11%-34%).  In 26 (55%) patients, BsAb therapy was the last regimen before CAR T-cells. The best overall response rate (ORR) to CAR T-cells was 85% (CRR 43%), without significant differences between patients who had previously responded [partial response or CR] or not (stable disease or progressive disease) to BsAb treatment [86% vs. 84%, p=1.0]. At a median follow-up of 10.5 months, the median PFS was 6.6 months (95% CI 2.6-not reached [NR]), and the median OS was NR (95% CI 9.0-NR). The estimated 1-year PFS and overall survival (OS) were 42% (95% CI 25.9- 57.7) and 55% (95% CI 37.5-70.6), respectively.  
In the second part of the study, the outcomes of a BsAb-naïve control group with 42 patients treated with CAR T-cell therapy among 980 patients from the DESCAR-T registry,  were compared with outcomes of those of the BsAb-exposed group. The latter group achieved a higher ORR compared with the control group (86% vs. 55%, p=0.02) but CRR, 1-year PFS, and 1-year OS were not statistically different between BsAb-exposed and naïve patients (43% vs. 38%; p=0.5, 43% vs. 29%; p=0.1, and 55% vs. 37%; p=0.08). Concerning the safety profile, comparable rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome  (ICANS) were observed in both groups.

Chimeric antigen receptor (CAR) T-cells and Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL).  

Histological transformation (HT) of WM/LPL represents a rare but severe event occurring in less than 5% of the cases with a median overall survival (OS) of 1.5 to 2.7 years. Regarding such patients with transformed WM/LPL, little is known regarding the effectiveness of CAR T-cell therapy. A retrospective collaborative study to evaluate the efficacy and safety of CAR T-cells in 23 patients with HT-WM was published.  Overall, CAR T-cell therapy is associated with high efficacy in HT-WM, especially given the poor outcome of these patients with standard treatments. Furthermore, CAR T-cell therapy seems to be well tolerated in these patients, with no unexpected toxicity. 
The median time from WM to HT diagnosis was 4.5 years (interquartile range (IQR), 0.3-6.7), including five cases (22%) with concurrent diagnosis of WM and large B-cell lymphoma (LBCL). Patients received a median of 1 line of treatment (range, 0-4) for WM and 2 lines (range, 1-4) for HT before CAR T-cell infusion, and eight patients (35%) had undergone prior autologous stem cell transplantation (SCT) (two as part of WM treatment and six for HT) and one allogeneic SCT after HT. Seventeen patients (74%) received a bridging therapy of whom only six (35%) responded (complete response [CR] or partial response). The best overall response rate was 96% (95% CI, 78-100), including 87% CR (95% CI, 66-97).  At 6 months, 73% of the patients remained in CR. After a median follow-up of 28 months (range, 3-57), the estimated progression-free survival rates at 1 and 2 years were 73.4% (95% CI, 50.2-87.1) and 67.5% (95% CI, 42.9-83.2), respectively. The estimated OS rates at 1 and 2 years were 80.5% (95% CI, 50.6-89.2) and 69.5% (95% CI, 44.6-85.3), respectively. Eight patients experienced relapse/progression during follow-up. Among these, six occurred within the first 6 months following CAR T cell infusion and were related to LBCL relapse.

Myelodysplastic syndromes (MDS).

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, a systemic autoinflammatory disease, is linked to mutations in the UBA1 gene, which encodes the major E1-activating enzyme required for ubiquitylation. While mutations at the p.M41 hotspot were the first to be associated with VEXAS, additional variants in UBA1 have since been characterized as pathogenic. UBA1 mutations typically co-occur with common myeloid driver gene mutations including DNMT3A, TET2, and SF3B1 in VEXAS, clonal hematopoiesis, and MDS. The prevalence of MDS in VEXAS patients is also high (25-55%). Molecular and clinical presentations of UBA1-mutated MDS were published recently. Droplet digital polymerase chain reaction profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established World Health Organization disease classification (no identified driver mutations or mutations only in DNMT3A, TET2, or ASXL1 genes), identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n=2027) they identified an additional 27 variants in 26 (1%) patients. Inflammatory clinical presentation and vacuoles were observed in 83% and 71%, respectively, of patients with pathogenic UBA1 mutations. Vacuoles were identified in all 13 patients with UBA1 p.M41 VAF >2% and in 71% (15/21) of patients with available slides. Retrospective clinical review where possible showed that 83% (28/34) of UBA1-mutant cases had VEXAS-associated diagnoses or inflammatory clinical presentation. 

Acute myeloid leukemia (AML).  

FLT3-ITD mutation and adverse karyotype are currently used for risk stratification due to inconsistent results and uncertainty around how other factors might  influence treatment, particularly given the strong prognostic impact of post-induction measurable residual disease (MRD). NPM1 mutations (NPM1mut) are found in approximately 30% of adults with AML, with a prognosis that is generally favorable. In a recent study with NPM1mut AML patients (n=1357), MRD negativity detected in peripheral blood after two treatment courses is the major determinant of outcome, independent of other factors and transplantation in first complete remission (CR1).  FLT3-ITD (hazard ratio [HR] 1.28, 95%CI 1.01-1.63), DNMT3A (HR 1.65, 95%CI 1.32-2.05), WT1 (HR 1.74, 95%CI 1272-2.38) and non-ABD NPM1 mutations (HR 1.64, 95%CI 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients achieving MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse and poorer OS. Intensified chemotherapy with the FLAG-Ida regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the highest-risk molecular subgroups.

Monoclonal B-cell lymphocytosis (MBL).

MBL progresses to chronic lymphocytic leukemia (CLL) requiring therapy at 1% to 5% per year. Patients with CLL separate into 3 distinct epigenetic subtypes (epitypes) that reflect progressive DNA methylation changes that occur during B-cell development. These epitype signatures (low-programmed, intermediate-programmed [IP], and high-programmed) predict clinical outcomes irrespective of disease stage and treatment. Recently the IP epitype has been shown to be enriched for high-risk immunoglobulin lambda variable (IGLV) 3-21 rearrangements, impacting outcomes for these patients. This combined approach was used in a recent study to identify 219 MBL patients by producing an epigenetic and light chain immunoglobulin (ELCLV3-21) signature. The ELCLV3-21 high-risk signature distinguished MBL individuals with a high probability of progression (39.9% and 71.1% at 5 and 10 years, respectively). ELCLV3-21 improved the accuracy of predicting time to therapy for individuals with MBL compared with other established prognostic indicators, including the CLL international prognostic index (c-statistic, 0.767 vs. 0.668, respectively). Comparing ELCLV3-21 risk groups in MBL vs. a cohort of 226 patients with CLL revealed that ELCLV3-21 high-risk individuals with MBL had a significantly shorter time to therapy (P= 0.003) and reduced overall survival (P= 0.03) compared with ELCLV3-21 low-risk individuals with CLL. Although this new prognostic signature is promising, further validation in independent data sets is crucial, especially considering the relatively low number of ELCLV3-21 high-risk IP individuals included. Assessing the impact of the ELCLV3-21 signature in more homogeneously treated cohorts is essential.