High-dose IV ascorbic acid therapy in CCUS patients with TET2 mutations.

This was a phase II trial, evaluating the safety/efficacy of high-dose IV-ascorbic acid in patients with TET2 mutant CCUS. Eight of 10 patients enrolled were eligible for response assessment. At week 20, there were no responses by IWG MDS criteria. NCT03418038.

Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL.

ABSTRACT: Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.

CREBBP histone acetyltransferase domain mutations predict response to mTOR inhibition in relapsed/refractory follicular lymphoma.

Despite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker-directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2-mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi-responders, and describe distinct transcriptional characteristics and co-occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL.

Low magnesium levels and prognosis in newly diagnosed diffuse large B-cell lymphoma.

Magnesium (Mg) is an essential element involved in cellular metabolism. We demonstrated that in patients with diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (SCT), those with a serum Mg < 2.0 mg/dL at the time of transplant had worse outcomes. In this study, we aimed to learn the prognostic value of low serum Mg in patients with untreated DLBCL. We analyzed serum from 408 patients and tested 2 Mg cutpoints-low (<1.7 mg/dL) and low normal (<2.0 mg/dL), a range we found associated with lower survival in the SCT group. We found 3% of patients with low levels and 23% with low normal levels. Low normal serum Mg levels were associated with a higher stage at diagnosis, more extranodal involvement, higher international prognostic index score, lower overall survival (OS), and event-free survival. These data warrant testing Mg replacement to a target of >2.0 mg/dL to learn if survival can be improved.

CODOX-M/IVAC-R versus DA-EPOCH-R in double hit/triple hit lymphoma patients aged 60 years or under.

Intensified chemoimmunotherapy regimens are often used in young patients with double hit and triple hit lymphoma (DHL/THL) despite no survival benefit compared to R-CHOP. Favorable retrospective reports on the application of CODOX-M/IVAC-R are subject to selection bias as only young fit patients can tolerate this treatment. We conducted a retrospective analysis to investigate outcome differences between CODOX-M/IVAC-R and DA-EPOCH-R in DHL/THL patients aged 60 years or younger. 113 patients were identified; CODOX-M/IVAC-R (N=49) and DA-EPOCH-R (N=64). 80% (39/49) achieved complete (CR) after completing CODOX-M/IVAC-R compared to 58% (37/64) with DA-EPOCH-R. The median follow-up was 5.3 years and 3.3 years for the CODOX-M/IVAC-R and DA-EPOCH-R group respectively. CODOX-M/IVAC-R demonstrated superior EFS on univariate (HR=0.54, 95%CI=0.31-0.97) and multivariable analysis adjusted for age, BCL translocation (BCL2 vs BCL6 vs both), IPI score and receipt of ASCT (aHR=0.52, 95%CI=0.29-0.93); however there was no significant influence on OS (aHR=0.92, 95%CI=0.46-1.84). The 1, 2 and 5 years EFS in the CODOX-M/IVAC-R group was 68.3%, 64.1% and 61.5% respectively compared to 52.4%, 48.9% and 39.5% respectively in the DA-EPOCH-R group. Primary refractory disease or relapse occurred in 33% (16/49) of CODOX-M/IVAC-R and 54% (35/64) of DA-EPOCH-R recipients, and produced median OS of 10.3 months and 33.7 months, respectively, indicating poor outcomes in the CODOX-M/IVAC-R subgroup with R/R disease. More patients were able to receive subsequent salvage therapies in the DA-EPOCH-R group. No patients died of regimen toxicity and the rates of CNS relapse and therapy related hematologic neoplasms were similar in both groups.

Prognostic relevance of clonal hematopoiesis in myeloid neoplastic transformation in patients with follicular lymphoma treated with radioimmunotherapy.

While novel radioisotope therapies continue to advance cancer care, reports of therapy-related myeloid neoplasms (t-MN) have generated concern. The prevalence and role of clonal hematopoiesis (CH) in this process remain to be defined. We hypothesized that: (i) CH is prevalent in relapsed follicular lymphoma and is associated with t-MN transformation, and (ii) radiation in the form of radioimmunotherapy (RIT) plays a role in clonal progression. In this retrospective cohort study, we evaluated the prevalence and prognostic impact of CH on clinical outcomes in 58 heavily pre-treated follicular lymphoma patients who received RIT. Patients had been given a median of four lines of therapy before RIT. The prevalence of CH prior to RIT was 46%, while it was 67% (P=0.15) during the course of RIT and subsequent therapies in the paired samples. Fourteen (24%) patients developed t-MN. Patients with t-MN had a higher variant allele fraction (38% vs. 15%; P=0.02) and clonal complexity (P=0.03) than those without. The spectrum of CH differed from that in age-related CH, with a high prevalence of DNA damage repair and response pathway mutations, absence of spliceosome mutations, and a paucity of signaling mutations. While there were no clear clinical associations between RIT and t-MN, or overall survival, patients with t-MN had a higher mutant clonal burden, along with extensive chromosomal abnormalities (median survival, afer t-MN diagnosis, 0.9 months). The baseline prevalence of CH was high, with an increase in prevalence on exposure to RIT and subsequent therapies. The high rates of t-MN with marked clonal complexities and extensive chromosomal damage underscore the importance of better identifying and studying genotoxic stressors accentuated by therapeutic modalities.

Monocyte response to SARS-CoV-2 protein ORF8 is associated with severe COVID-19 infection in patients with chronic lymphocytic leukemia.

The open reading frame 8 (ORF8) protein, encoded by the SARS-CoV-2 virus after infection, stimulates monocytes/macrophages to produce pro-inflammatory cytokines. We hypothesized that a positive ex vivo monocyte response to ORF8 protein pre-COVID-19 would be associated with subsequent severe Coronavirus disease 2019 (COVID-19). We tested ORF8 ex vivo on peripheral blood mononuclear cells from 26 anonymous healthy blood donors and measured intracellular cytokine/ chemokine levels in monocytes by flow cytometry. The percentage of positive monocyte staining in the sample and change in mean fluorescence intensity (ΔMFI) after ORF8 were used to calculate the adjusted MFI for each cytokine. We then tested pre-COVID-19 peripheral blood mononuclear cell samples from 60 chronic lymphocytic leukemia (CLL) patients who subsequently developed COVID-19 infection. Severe COVID-19 was defined as hospitalization due to COVID-19. In the 26 normal donor samples, the adjusted MFI for interleukin (IL)-1ß, IL-6, IL-8, and CCL-2 were significantly different with ORF8 stimulation versus controls. We next analyzed monocytes from pre-COVID-19 PBMC samples from 60 CLL patients. The adjusted MFI to ORF8 stimulation of monocyte intracellular IL-1ß was associated with severe COVID-19 and a reactive ORF8 monocyte response was defined as an IL-1ß adjusted MFI ≥0.18 (sensitivity 67%, specificity 75%). The median time to hospitalization after infection in CLL patients with a reactive ORF8 response was 12 days versus not reached for patients with a non-reactive ORF8 response with a hazard ratio of 7.7 (95% confidence interval: 2.4-132; P=0.005). These results provide new insight on the monocyte inflammatory response to virus with implications in a broad range of disorders involving monocytes.

Dependence of peripheral T-cell lymphoma on constitutively activated JAK3: Implication for JAK3 inhibition as a therapeutic approach.

Peripheral T-cell lymphoma (PTCL) is a clinically heterogeneous group that represents 10%-15% of all lymphomas. Despite improved genetic and molecular understanding, treatment outcomes for PTCL have not shown significant improvement. Although Janus kinase-2 (JAK2) plays an important role in myeloproliferative neoplasms, the critical role of JAK isoforms in mediating prosurvival signaling in PTCL cells is not well defined. Immunohistochemical analysis of PTCL tumors (n = 96) revealed high levels of constitutively active JAK3 (pJAK3) that significantly (p < 0.04) correlated with the activation state of its canonical substrate STAT3. Furthermore, constitutive activation of JAK3 and STAT3 positively correlated, at least in part, with an oncogenic tyrosine phosphatase PTPN11. Pharmacological inhibition of JAK3 but not JAK1/JAK2 significantly (p < 0.001) decreased PTCL proliferation, survival and STAT3 activation. A sharp contrast was observed in the pJAK3 positivity between ALK+ (85.7%) versus ALK-negative (10.0%) in human PTCL tumors and PTCL cell lines. Moreover, JAK3 and ALK reciprocally interacted in PTCL cells, forming a complex to possibly regulate STAT3 signaling. Finally, combined inhibition of JAK3 (by WHI-P154) and ALK (by crizotinib or alectinib) significantly (p < 0.01) decreased the survival of PTCL cells as compared to either agent alone by inhibiting STAT3 downstream signaling. Collectively, our findings establish that JAK3 is a therapeutic target for a subset of PTCL, and provide rationale for the clinical evaluation of JAK3 inhibitors combined with ALK-targeted therapy in PTCL.

Characteristics and outcomes of incidentally diagnosed diffuse large B-cell lymphoma and implications for cancer screening.

Differences in characteristics and outcomes between incidental and symptomatic presentations of Large B-Cell Lymphoma.

The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair.

Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Cell of origin is not associated with outcomes of relapsed or refractory diffuse large B cell lymphoma.

Activated B cell (ABC) type diffuse large B cell lymphoma (DLBCL), double hit lymphoma (DHL) and double expressor lymphoma (DEL) have poor outcomes to frontline R-CHOP but impact of these molecular features on outcomes of relapsed/refractory (R/R) disease is not well-characterized. We evaluated the association of diagnostic cell of origin (COO), double hit and double expressor status with overall survival after first relapse in DLBCL patients who were enrolled into the Molecular Epidemiology Resource (MER) cohort. COO was available from immunohistochemistry (IHC) using Hans criteria or gene expression profiling (GEP) (Nanostring) on the diagnostic FFPE biopsy. Of 373 pts with R/R DLBCL, 278 had COO by IHC: 152 were GCB, 107 were non-GCB. One hundred and fourty had COO by GEP: 44 were ABC, 65 were GCB and 13 were unclassifiable. Nineteen out of 163 (12%) were DHL; 30 out of 135 (22%) had DEL. COO, either by IHC (2 years OS GCB: 45% [CI95 : 38-54] vs. non-GCB: 44% [CI95 :36-55], p > 0.05) or GEP (2 years OS ABC: 42% [CI95 : 29-59] vs. GCB: 40% [CI95 : 30-54], p > 0.05), was not associated with difference in OS. DHL (2 years OS 16 [CI95 :6-45] vs. 45% [CI95 : 34-59], p < 0.01) and DEL (2 years OS 33% [CI95 : 20-56], vs. 50% [CI95 : 41-60], p < 0.05) had lower OS than non-DHL and non-DEL/non-DHL counterparts, respectively. COO by IHC or GEP was not associated with OS in R/R DLBCL while DHL and DEL were adverse prognostic markers in DLBCL at first relapse.

Survival trends in young patients with Waldenström macroglobulinemia: Over five decades of experience.

Waldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10-year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960-1977, n = 12), Group 2 (1978-1995, n = 48), and Group 3 (1996-2013, n = 74). Among young patients, there was no disease-specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5-23), 16 years (95% CI 14-22), and 15 years (95% CI 10-NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years-of-life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age- and sex-matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

Clinical characteristics, prognostic indicators, and survival outcomes in intravascular lymphoma: Mayo Clinic experience (2003-2018).

Intravascular lymphoma (IVL) is a rare extranodal non-Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003-2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS-IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non-CNS-IVL patients with abnormal FDG-PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS-IVL and 63.5% (35/55) had non-CNS-IVL. CNS-IVL group consists of clinically isolated CNS involvement (CNS-only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M-IVL) (14.5%; 8/55). Non-CNS-IVL group consists of clinically isolated skin involvement (skin-only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P-IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B-cell IVL. Rituximab + high-dose methotrexate-based regimen were used in 75% (12/16) of CNS-IVL patients and RCHOP in 60% (17/28) of non-CNS-IVL patients. Estimated 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin-only IVL was associated with excellent survival. Platelet count <150x109 /L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.

Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a histiocytic neoplasm that predominantly harbors mitogen-activated protein kinase (MAPK) pathway variants. MAPK inhibitors typically are effective treatments, but mutations outside the MAPK pathway, such as CSF1R variants, may cause refractory ECD. We describe a patient with a novel somatic mutation in CSF1R (CSF1RR549_E554delinsQ ) that resulted in refractory ECD affecting the central nervous system. Cell model studies, RNA sequencing analysis, and in silico protein modeling suggested that she had a gain-of-function mutation occurring in a region critical for autoinhibition. The patient was treated with pexidartinib, a CSF1R inhibitor, and has had a complete clinical and metabolic response lasting more than 1.5 years to date. To our knowledge, this is the first report to describe successful treatment of a patient with ECD by using an agent that specifically targets CSF1R. This case also highlights the critical role of individualized molecular profiling to identify novel therapeutic targets in ECD.

Multicentric Castleman disease: A single center experience of treatment with a focus on autologous stem cell transplantation.

Castleman disease (CD) is a rare lymphoproliferative disease characterized by diverse clinical and pathologic features. Due to its rarity, there are limited studies comparing currently available therapies. The role of autologous stem cell transplantation (ASCT) in CD has not yet been established. In this paper, we describe the clinical characteristics, treatment choices, and outcomes in 34 Mayo Clinic patients diagnosed with multicentric CD from July 1, 2003 to April 30, 2018. Eighteen patients (53%) also met the criteria for POEMS, including 14 with the osteosclerotic variant. The first-line treatments included: steroid monotherapy (4), cytotoxic chemotherapy (6), rituximab alone (8) or with chemotherapy (2), anti-IL6 treatment (3), and ASCT (10). The median follow-up was 4.8 (range: 0.1-15.2) years. The 5- and 10-year overall survival rates were 84% and 71%, respectively. Sixteen patients received high-dose chemotherapy followed by ASCT during their disease course. Among those, 14 had multicentric CD associated with POEMS. There were no transplant-related deaths. All patients had at least a partial response to ASCT, most of whom achieved a complete response. The favorable outcomes seen with ASCT in this cohort suggest that transplantation may have a role in multicentric CD, particularly for patients with multicentric CD associated with POEMS.

Disease outcomes and biomarkers of progression in smouldering Waldenström macroglobulinaemia.

Patients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and ß2 -microglobulin (ß2 M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and ß2 M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.

Ibritumomab Tiuxetan Radioimmunotherapy for Primary Gastrointestinal Follicular Lymphoma.

Primary gastrointestinal follicular lymphoma (PGIFL) is characterized by localized involvement of the gastrointestinal (GI) tract. PGIFL usually runs an indolent course. External beam radiation therapy is curative in a substantial proportion of localized follicular lymphomas, but GI toxicities may discourage its use in PGIFL. Ibritumomab tiuxetan radioimmunotherapy (RIT) is a radioimmunoconjugate of anti-CD20 monoclonal antibody linked to chelator tiuxetan and radioisotope. RIT delivers confined high-intensity radiation with short path length specifically targeting lymphoma cells and sparing normal tissue. In this case series report, we included six cases of PGIFL treated with RIT. All patients had low-risk, localized, and nonbulky disease. All patients responded completely and were relapse-free for the duration of follow-up. Hematologic toxicities were seen, but none were serious. RIT is a potentially curative treatment option in PGIFL with a tolerable toxicity profile.

Acalabrutinib for mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a unique type of non-Hodgkin lymphoma characterized by the overexpression of cyclin D1. MCL patients typically live for years but experience multiple relapses. Acalabrutinib is a novel second-generation oral Bruton tyrosine kinase inhibitor approved by the US Food and Drug Administration for relapsed MCL based on a clinical trial demonstrating an overall response rate of 81%. It provides a valuable new treatment option for MCL patients and is now being tested upfront.

Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma.

Targeting the B-cell receptor and phosphatidylinositol 3-kinase/mTOR signaling pathways has shown meaningful, but incomplete, antitumor activity in lymphoma. Glycogen synthase kinase 3 (GSK3) α and ß are 2 homologous and functionally overlapping serine/threonine kinases that phosphorylate multiple protein substrates in several key signaling pathways. To date, no agent targeting GSK3 has been approved for lymphoma therapy. We show that lymphoma cells abundantly express GSK3α and GSK3ß compared with normal B and T lymphocytes at the messenger RNA and protein levels. Utilizing a new GSK3 inhibitor 9-ING-41 and by genetic deletion of GSK3α and GSK3ß genes using CRISPR/CAS9 knockout, GSK3 was demonstrated to be functionally important to lymphoma cell growth and proliferation. GSK3ß binds to centrosomes and microtubules, and lymphoma cells treated with 9-ING-41 become arrested in mitotic prophase, supporting the notion that GSK3ß is necessary for the progression of mitosis. By analyzing recently published RNA sequencing data on 234 diffuse large B-cell lymphoma patients, we found that higher expression of GSK3α or GSK3ß correlates well with shorter overall survival. These data provide rationale for testing GSK3 inhibitors in lymphoma patient trials.