Tuning Responses to Polatuzumab Vedotin in B-cell Lymphoma.

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79B, is the first new drug approved for first-line therapy of diffuse large B-cell lymphoma in more than two decades, although factors determining treatment responses to polatuzumab vedotin remain unknown. Two new studies identified central mechanisms of lower sensitivity, namely reduced accessibility of the CD79B epitope through N-linked glycosylation of CD79B and lower CD79B surface expression levels due to the activity of the KLHL6 E3 ligase. See related article by Corcoran et al., p. 1653 (6) See related article by Meriranta et al. (7).

High-Grade B-Cell Lymphoma, Not Otherwise Specified: CNS Involvement and Outcomes in a Multi-Institutional Series.

Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL, NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL, NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal=6, parenchymal=4, and both=1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR=3.5) and testicular (in men) or female pelvic (in women) involvement (OR=8.1). There was no significant difference in survival outcomes between HGBL, NOS patients with (median PFS=4 years) or without (median PFS=2.4 years) baseline CNS involvement (p=0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% versus 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-GCB subtype, and DEL phenotype, however, high CNS-IPI was not. The prognosis of relapsed HGBL, NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and CAR T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease. These patients represent an unmet need and should be prioritized for experimental approaches.

Evaluation of prognostic factors for high-risk classical Hodgkin lymphoma undergoing autologous transplantation.

There are limited data assessing the risk scores for primary treatment failure (PTF) classical Hodgkin lymphoma (cHL, PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE is a multicenter retrospective cohort of patients with PTF- cHL (15 years or older) diagnosed on or after Jan 1, 2005, at 15 US medical centers. PTF was defined as one of the following patterns of failure: [1] progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); [2] partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); [3] progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR, early relapse [ER]). A total of 478 patients were included in the analysis. Among these, 217 (45%) were PP, 86 (18%) were PR/SD, and 175 (37%) were ER. The 6-month and 1-year cumulative incidence of non-relapse mortality following auto-HCT was 0.9% and 1.1%, respectively. The median PFS and OS following auto-HCT were 4.33 years and 10.09 years, respectively. While those not in CR at the time of auto-HCT was associated with inferior PFS and OS, advanced age and those diagnosed before 2011 were associated with inferior OS. This study showcases the safety and long-term efficacy of auto-HCT, even in patients with high risk disease who are traditionally considered chemo-refractory and will serve as a benchmark for the ongoing transplant vs no transplant trials.

Impact of Memory T Cells on SARS-COV-2 Vaccine Response in Hematopoietic Stem Cell Transplant.

During the COVID-19 pandemic, hematopoietic stem cell transplant (HSCT) recipients faced an elevated mortality rate from SARS-CoV-2 infection, ranging between 10-40%. The SARS-CoV-2 mRNA vaccines are important tools in preventing severe disease, yet their efficacy in the post-transplant setting remains unclear, especially in patients subjected to myeloablative chemotherapy and immunosuppression. We evaluated the humoral and adaptive immune responses to the SARS-CoV-2 mRNA vaccination series in 42 HSCT recipients and 5 healthy controls. Peripheral blood mononuclear nuclear cells and serum were prospectively collected before and after each dose of the SARS-CoV-2 vaccine. Post-vaccination responses were assessed by measuring anti-spike IgG and nucleocapsid titers, and antigen specific T cell activity, before and after vaccination. In order to examine mechanisms behind a lack of response, pre-and post-vaccine samples were selected based on humoral and cellular responses for single-cell RNA sequencing with TCR and BCR sequencing. Our observations revealed that while all participants eventually mounted a humoral response, transplant recipients had defects in memory T cell populations that were associated with an absence of T cell response, some of which could be detected pre-vaccination.

Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

Microfluidic Immuno-Serolomic Assay Reveals Systems Level Association with COVID-19 Pathology and Vaccine Protection.

How to develop highly informative serology assays to evaluate the quality of immune protection against coronavirus disease-19 (COVID-19) has been a global pursuit over the past years. Here, a microfluidic high-plex immuno-serolomic assay is developed to simultaneously measure50 plasma or serum samples for50 soluble markers including 35proteins, 11 anti-spike/receptor binding domian (RBD) IgG antibodies spanningmajor variants, and controls. This assay demonstrates the quintuplicate test in a single run with high throughput, low sample volume, high reproducibilityand accuracy. It is applied to the measurement of 1012 blood samples including in-depth analysis of sera from 127 patients and 21 healthy donors over multiple time points, either with acute COVID infection or vaccination. The protein analysis reveals distinct immune mediator modules that exhibit a reduced degree of diversity in protein-protein cooperation in patients with hematologic malignancies or receiving B cell depletion therapy. Serological analysis identifies that COVID-infected patients with hematologic malignancies display impaired anti-RBD antibody response despite high level of anti-spike IgG, which can be associated with limited clonotype diversity and functional deficiency in B cells. These findings underscore the importance to individualize immunization strategies for these high-risk patients and provide an informative tool to monitor their responses at the systems level.

High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study.

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Targeted engagement of ß-catenin-Ikaros complexes in refractory B-cell malignancies.

In most cell types, nuclear ß-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of ß-catenin but critically depended on GSK3ß for effective ß-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that ß-catenin formed repressive complexes with lymphoid-specific Ikaros factors at the expense of TCF7. Instead of MYC-activation, ß-catenin was essential to enable Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC. To leverage this previously unrecognized vulnerability of B-cell-specific repressive ß-catenin-Ikaros-complexes in refractory B-cell malignancies, we examined GSK3ß small molecule inhibitors to subvert ß-catenin degradation. Clinically approved GSK3ß-inhibitors that achieved favorable safety prof les at micromolar concentrations in clinical trials for neurological disorders and solid tumors were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of ß-catenin, repression of MYC and acute cell death. Preclinical in vivo treatment experiments in patient-derived xenografts validated small molecule GSK3ß-inhibitors for targeted engagement of lymphoid-specific ß-catenin-Ikaros complexes as a novel strategy to overcome conventional mechanisms of drug-resistance in refractory malignancies. HIGHLIGHTS: Unlike other cell lineages, B-cells express nuclear ß-catenin protein at low baseline levels and depend on GSK3ß for its degradation.In B-cells, ß-catenin forms unique complexes with lymphoid-specific Ikaros factors and is required for Ikaros-mediated tumor suppression and assembly of repressive NuRD complexes. CRISPR-based knockin mutation of a single Ikaros-binding motif in a lymphoid MYC superenhancer region reversed ß-catenin-dependent Myc repression and induction of cell death. The discovery of GSK3ß-dependent degradation of ß-catenin as unique B-lymphoid vulnerability provides a rationale to repurpose clinically approved GSK3ß-inhibitors for the treatment of refractory B-cell malignancies. GRAPHICAL ABSTRACT: Abundant nuclear ß-cateninß-catenin pairs with TCF7 factors for transcriptional activation of MYCB-cells rely on efficient degradation of ß-catenin by GSK3ßB-cell-specific expression of Ikaros factors Unique vulnerability in B-cell tumors: GSK3ß-inhibitors induce nuclear accumulation of ß-catenin.ß-catenin pairs with B-cell-specific Ikaros factors for transcriptional repression of MYC.

Optimization of Radium-223 Treatment of Castration-resistant Prostate Cancer Based on the Burden of Skeletal Metastasis and Clinical Parameters.

BACKGROUND: Radium-223 dichloride (Ra-223) is now frequently used to treat prostate cancer that has metastasized to bone, although patient selection continues to be suboptimal for determining who will benefit most from this novel treatment modality. MATERIALS AND METHODS: Seventy-nine patients with metastatic castration-resistant prostate cancer (mCRPC) were treated with Ra-223 from 2012 to 2016. The burden of skeletal metastasis was determined for each using the Bone Scan Index (BSI) as a ratio of diseased to normal bone. Clinical, laboratory, and survival data were collected and examined for associations with BSI, and treatment tolerability was assessed. RESULTS: Chemotherapy-naïve patients were significantly more likely to complete the full course of treatment. Median follow-up was 31 months (range 0.7-38.8 months) and median overall survival was 15.4 months (range 9.5-20.6 months). Overall survival was significantly associated with findings on bone scans (P < .05). Patients with higher BSI tended toward poorer outcomes. Nearly half the patients with low baseline BSI survived 3 years or more following Ra-223 treatment. By contrast, only 20% of the patients with high baseline BSI lived for 1 year, and none lived for an additional 3. Baseline BSI was significantly associated with decreased hemoglobin, higher serum PSA and alkaline phosphatase levels, and treatment-associated reductions in platelet and absolute neutrophil counts. CONCLUSION: Our results suggest better outcomes to Ra-223 therapy for patients who are chemotherapy-naïve and who undergo treatment earlier in the course of their disease as reflected by low BSI and concordant laboratory parameters.

Genetic Modeling of B-cell State Transitions for Rational Design of Lymphoma Therapies.

The use of genomic data to analyze primary endpoints for clinical trials in diffuse large B-cell lymphomas (DLBCL) significantly improved the development of rational drug combinations for genetically defined patient subsets. Recent genetic mouse models and their ability to recapitulate transitions between germinal center exit and memory B-cell characteristics in DLBCL will accelerate the development of rationale-based clinical trials. See related article by Flümann et al., p. 78 (3). See related article by Venturutti et al., (5).

Microfluidic immuno-serology assay revealed a limited diversity of protection against COVID-19 in patients with altered immunity.

The immune response to SARS-CoV-2 for patients with altered immunity such as hematologic malignancies and autoimmune disease may differ substantially from that in general population. These patients remain at high risk despite wide-spread adoption of vaccination. It is critical to examine the differences at the systems level between the general population and the patients with altered immunity in terms of immunologic and serological responses to COVID-19 infection and vaccination. Here, we developed a novel microfluidic chip for high-plex immuno-serological assay to simultaneously measure up to 50 plasma or serum samples for up to 50 soluble markers including 35 plasma proteins, 11 anti-spike/RBD IgG antibodies spanning all major variants, and controls. Our assay demonstrated the quintuplicate test in a single run with high throughput, low sample volume input, high reproducibility and high accuracy. It was applied to the measurement of 1,012 blood samples including in-depth analysis of sera from 127 patients and 21 healthy donors over multiple time points, either with acute COVID infection or vaccination. The protein association matrix analysis revealed distinct immune mediator protein modules that exhibited a reduced degree of diversity in protein-protein cooperation in patients with hematologic malignancies and patients with autoimmune disorders receiving B cell depletion therapy. Serological analysis identified that COVID infected patients with hematologic malignancies display impaired anti-RBD antibody response despite high level of anti-spike IgG, which could be associated with limited clonotype diversity and functional deficiency in B cells and was further confirmed by single-cell BCR and transcriptome sequencing. These findings underscore the importance to individualize immunization strategy for these high-risk patients and provide an informative tool to monitor their responses at the systems level.

Predictive factors and outcomes for ibrutinib in relapsed/refractory marginal zone lymphoma: a multicenter cohort study.

Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: "ibrutinib responders"-patients who achieved complete or partial response (CR/PR) to ibrutinib; "stable disease (SD)"; and "primary progressors (PP)"-patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23-7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03-8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17-37.62, p < 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15-12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.

Comprehensive Clinicopathologic and Molecular Analysis of Mast Cell Leukemia With Associated Hematologic Neoplasm: A Report and In-Depth Study of 5 Cases.

Mast cell leukemia with associated hematologic neoplasm (MCL-AHN) is a rare and highly aggressive entity that remains understudied due to the paucity of cases. We present a case of a 45-year-old man who was concurrently diagnosed with mast cell leukemia and acute myeloid leukemia. We identified four additional patients who had MCL-AHN in our institution and performed whole-exome sequencing of all available tumors. Our series revealed a novel and identical NR2F6 variant shared among two of the patients. This case series and sequencing results demonstrate the importance of fully characterizing rare tumors that are resistant to treatment.

Pevonedistat, a NEDD8-Activating Enzyme Inhibitor, Induces Apoptosis and Augments Efficacy of Chemotherapy and Small Molecule Inhibitors in Pre-clinical Models of Diffuse Large B-cell Lymphoma.

We studied the biological activity of pevonedistat, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, in combination with various cytotoxic chemotherapy agents and small molecule inhibitors in lymphoma pre-clinical models. Pevonedistat induced cell death in activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cell lines and to a lesser degree in germinal center B-cell (GCB) DLBCL cell lines. In pevonedistat sensitive cells, we observed inhibition of NFκB activity by p65 co-localization studies, decreased expression of BCL-2/BCL-XL and upregulation of BAK levels. Pevonedistat enhanced the activity of cytarabine, cisplatin, doxorubicin and etoposide in ABC-, but not in the GCB-DLBCL cell lines. It also exhibited synergy with ibrutinib, selinexor, venetoclax and A-1331852 (a novel BCL-XL inhibitor). In vivo, the combination of pevonedistat and ibrutinib or pevonedistat and cytarabine prolonged survival in SCID mice xenograft models when compared with monotherapy controls. Our data suggest that targeting the neddylation pathway in DLBCL is a viable therapeutic strategy and support further clinical studies of pevonedistat as a single agent or in combination with chemotherapy or novel targeted agents.

Cost-effectiveness of polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma.

A recent phase II trial showed that use of polatuzumab vedotin in combination with bendamustine plus rituximab (Pola-BR) in transplant-ineligible patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) resulted in longer progression-free survival and overall survival compared to bendamustine plus rituximab (BR) alone. In this study, we constructed a Markov model to assess the cost-effectiveness of Pola-BR versus BR in transplant-ineligible R/R DLBCL. We calculated the incremental cost-effectiveness ratio (ICER) of each treatment strategy from a US payer perspective, using a lifetime horizon and a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). Use of Pola-BR was associated with an incremental cost of $92,641 compared to BR alone ($200,905 vs $108,265, respectively), an incremental effectiveness of 1.76 QALYs (2.35 vs 0.59 QALYs, respectively), and an ICER of $52,519/QALY. These data suggest that use of Pola-BR for R/R DLBCL is likely to be cost-effective compared to BR alone.

Cost-effectiveness of first-line vs third-line ibrutinib in patients with untreated chronic lymphocytic leukemia.

The ALLIANCE A041202 trial found that continuously administered ibrutinib in the first-line setting significantly prolonged progression-free survival compared with a fixed-duration treatment of rituximab and bendamustine in older adults with chronic lymphocytic leukemia (CLL). In this study, we created a Markov model to assess the cost-effectiveness of ibrutinib in the first-line setting, compared with a strategy of using ibrutinib in the third-line after failure of time-limited bendamustine and venetoclax-based regimens. We estimated transition probabilities from randomized trials using parametric survival modeling. Lifetime direct health care costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated from a US payer perspective. First-line ibrutinib was associated with an improvement of 0.26 QALYs and 0.40 life-years compared with using ibrutinib in the third-line setting. However, using ibrutinib in the first-line led to significantly higher health care costs (incremental cost of $612 700), resulting in an ICER of $2 350 041 per QALY. The monthly cost of ibrutinib would need to be decreased by 72% for first-line ibrutinib therapy to be cost-effective at a willingness-to-pay threshold of $150 000 per QALY. In a scenario analysis where ibrutinib was used in the second-line in the delayed ibrutinib arm, first-line ibrutinib had an incremental cost of $478 823, an incremental effectiveness of 0.05 QALYs, and an ICER of $9 810 360 per QALY when compared with second-line use. These data suggest that first-line ibrutinib for unselected older adults with CLL is unlikely to be cost-effective under current pricing. Delaying ibrutinib for most patients with CLL until later lines of therapy may be a reasonable strategy to limit health care costs without compromising clinical outcomes.