Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy.

Antibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy.

Beyond surgery: the proper role and delivery of radiation therapy in the local-regional management of BIA-ALCL.

For localized breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), surgical resection is crucial; however, radiation therapy (RT) can be utilized as local-regional therapy if surgery is incomplete or not recommended. We present the case of a woman with BIA-ALCL who received systemic therapy and consolidation RT.

Cytomegaloviral Infections in Recipients of Chimeric Antigen Receptor T-Cell Therapy: An Observational Study With Focus on Oncologic Outcomes.

Background: Patients with B-cell lymphoma and acute lymphoblastic leukemia (ALL) who receive chimeric antigen receptor T-cell (CAR-T) therapy may experience clinically significant cytomegalovirus infection (CS-CMVi). However, risk factors for CS-CMVi are not well defined. The aims of our study were to identify risk factors for CS-CMVi and the association between CS-CMVi and nonrelapse mortality (NRM) in lymphoma and ALL patients after CAR-T therapy. Methods: We performed a retrospective single-center cohort analysis of CAR-T recipients between January 2018 and February 2021 for treatment of lymphoma and ALL. We collected data on demographics, oncologic history, CAR-T therapy-related complications, and infectious complications within 1 year of therapy. Results: Of 230 patients identified, 22 (10%) had CS-CMVi. At 1 year following CAR-T therapy, 75 patients (33%) developed relapsed disease and 95 (41%) died; NRM at 1 year was 37%. On Cox regression analysis, Asian or Middle Eastern race (adjusted hazard ratio [aHR], 13.71 [95% confidence interval {CI}, 5.41-34.74]), treatment of cytokine release syndrome/immune effector cell-associated neurotoxicity syndrome with steroids (aHR, 6.25 [95% CI, 1.82-21.47]), lactate dehydrogenase at time of CAR-T therapy (aHR, 1.09 [95% CI, 1.02-1.16]), and CMV surveillance (aHR, 6.91 [95% CI, 2.77-17.25]) were independently associated with CS-CMVi. CS-CMVi was independently associated with NRM at 1 year after CAR-T therapy (odds ratio, 2.49 [95% CI, 1.29-4.82]). Conclusions: Further studies of immunologic correlatives and clinical trials to determine the efficacy of prophylactic strategies are needed to understand the role of CS-CMVi and post-CAR-T mortality.

Radiotherapy in the treatment of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder.

BACKGROUND: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-LPD) is an increasingly recognized entity with heterogeneous management strategies that may include radiotherapy. OBJECTIVE: Our aim was to characterize treatment options for PCSM-LPD, with a focus on the role of radiotherapy. METHODS: This is a retrospective review of 46 patients seen in the Cutaneous Lymphoma Program at the University of Texas MD Anderson Cancer Center, with a clinicopathologic review consistent with PCSM-LPD. All patients were biopsied and underwent observation, topical/intralesional steroids, and/or radiotherapy. Patients were confirmed to have residual disease prior to radiotherapy. RESULTS: All patients achieved a complete response (CR). Sixteen patients (35%) received focal radiotherapy, with a CR in 15 (94%). The CR rate following ultra-low-dose radiotherapy (4 Gy in 1-2 fractions) was 92%. There was no grade 3 toxicity after radiotherapy. Thirty patients were managed without radiotherapy, with excision and observation or steroids. CONCLUSION: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder has excellent outcomes, and management strategies may include observation following biopsy, steroids, or radiation. Ultra-low-dose radiotherapy results in excellent outcomes with limited toxicity and is effective for persistent lesions after steroidal therapy.

Brentuximab vedotin plus cyclophosphamide, doxorubicin, etoposide, and prednisone followed by brentuximab vedotin consolidation in CD30-positive peripheral T-cell lymphomas: a multicentre, single-arm, phase 2 study.

BACKGROUND: CD30 expression is universal in anaplastic large-cell lymphoma and is expressed in some other peripheral T-cell lymphoma subtypes. Incorporation of brentuximab vedotin into initial therapy for people with CD30-positive peripheral T-cell lymphomas prolonged progression-free survival, but there is room for improvement, especially for people with non-anaplastic large-cell lymphoma subtypes. METHODS: We conducted a multicentre, international, single-arm, phase 2 trial to evaluate the safety and activity of CHEP-BV (cyclophosphamide, doxorubicin, prednisone, brentuximab vedotin, and etoposide) followed by brentuximab vedotin consolidation in patients with CD30-expressing peripheral T-cell lymphomas across five academic centres in the USA and Canada. Adults aged 18 years or older with newly diagnosed, untreated CD30-positive peripheral T-cell lymphomas, Eastern Cooperative Oncology Group score of 0-2, and adequate organ function were eligible to receive six planned cycles of CHEP-BV (ie, 1·8 mg/kg brentuximab vedotin intravenously on day 1, cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, etoposide 100 mg/m2 daily intravenously on days 1-3, and prednisone 100 mg daily orally on days 1-5) with prophylactic G-CSF. Patients who responded to the treatment could receive brentuximab vedotin consolidation for up to ten additional cycles either after autologous haematopoietic stem-cell transplantation (HSCT) or directly after CHEP-BV. The primary endpoints were unacceptable toxicity during a 3-plus-3 safety lead-in in participants who received study treatment and completed the safety evaluation period (to confirm the recommended phase 2 dose of brentuximab vedotin in CHEP-BV) and the complete response rate after CHEP-BV induction therapy in participants who received study treatment and had response evaluation. The study was registered at ClinicalTrials.gov (NCT03113500), and this cohort completed the trial. The trial is ongoing with the enrolment of a new cohort. FINDINGS: 54 patients were screened for eligibility and 48 were eligible for the study. The participants (18 [38%] women and 30 [63%] men; 34 [71%] White, four [8%] Black, five [10%] Asian, ten [21%] Hispanic, and 37 [77%] non-Hispanic people) were recruited and enrolled between Dec 4, 2017, and June 14, 2021, and followed up until Aug 25, 2023, when the database was locked for analysis. 48 participants were evaluable for toxicity, and 47 were evaluable for response (one participant died from COVID-19 before response assessment). During the safety lead-in, one of six participants had an unacceptable toxicity (ie, platelet count <10 000 per mm3 in a participant with extensive bone marrow involvement), and the proposed phase 2 dose of 1·8 mg/kg brentuximab vedotin in CHEP-BV was confirmed. At completion of CHEP-BV, 37 of 47 participants had complete response, yielding a complete response rate of 79% (95% CI 64-89). The most common CHEP-BV-related toxicities of grade 3 or higher were neutropenia (14 [29%] of 48), leukopenia (11 [23%]), anaemia (ten [21%]), febrile neutropenia (ten [21%]), lymphopenia (nine [19%]), and thrombocytopenia (nine [19%]). There were no treatment-related deaths. INTERPRETATION: In patients with mostly CD30-expressing peripheral T-cell lymphomas other than non-anaplastic large-cell lymphoma, CHEP-BV (with or without autologous HSCT) followed by brentuximab vedotin consolidation was safe and active. FUNDING: SeaGen, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and the National Cancer Institute of the National Institutes of Health.

Response-adapted ultra-low-dose 4 Gy radiation as definitive therapy of gastric MALT lymphoma: a single-centre, pilot trial.

BACKGROUND: Given the favourable prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, treatment-related toxicity should be minimised. We aimed to evaluate the efficacy of 4 Gy radiotherapy given in a response-adapted approach. METHODS: We conducted a single-centre, single-arm, prospective trial at MD Anderson Cancer Center (Houston, TX, USA) of response-adapted ultra-low-dose radiotherapy. Eligible patients were 18 years or older and had newly diagnosed or relapsed Helicobacter pylori-negative gastric MALT lymphoma, with stage I-IV disease. Given the expected low toxicity profile of treatment, performance status was not an exclusion criterion. Patients received external beam photon-based radiotherapy for a total dose of 4 Gy in two fractions. Patients with a complete response to 4 Gy via endoscopy and imaging at 3-4 months were observed; patients with a partial response were re-evaluated in 6-9 months. Residual disease at 9-13 months or stable or progressive disease at any time required additional treatment with 20 Gy. The primary endpoint was gastric complete response at 1 year (second evaluation timepoint) after 4 Gy treatment. All analyses were performed as intention to treat. This trial is registered at ClinicalTrials.gov (NCT03680586) and is complete and closed to enrolment. FINDINGS: Between March 27, 2019, and Oct 12, 2021, we enrolled 24 eligible patients. The median age of participants was 67 years (IQR 58-74; range 40-85); 15 (63%) were female and nine (37%) male; 18 (75%) were White, four (17%) Asian, and two (8%) Hispanic; 20 (83%) had stage I disease, one (4%) stage II, and three (13%) stage IV. Median follow-up time was 36 months (IQR 26-42). 20 patients (83%) had a complete response to 4 Gy (16 at 3-4 months, four at 9-13 months); two patients received 20 Gy for symptomatic stable disease at 3-4 months and two for residual disease at 9-13 months; all had a complete response. The 3-year local control rate was 96% (95% CI 88-100), with one local relapse at 14 months after 4 Gy radiotherapy salvaged successfully with 20 Gy. One patient with stage IV disease had a distant relapse. The most common adverse events were grade 1 nausea (nine [38%] of 24 patients who received 4 Gy and two [50%] of four patients who received 20 Gy) and grade 1 abdominal pain (five [21%] of 24 and zero of four, respectively). No grade 3 or worse adverse events were noted, including no treatment-related deaths. INTERPRETATION: Most patients had a complete response after 4 Gy radiotherapy; all who required an additional 20 Gy had a complete response within 12 months. This response-adapted strategy could be used to select patients who would benefit from additional radiotherapy and spare others potential associated toxicity. FUNDING: National Cancer Institute.

The CNS relapse in T-cell lymphoma index predicts CNS relapse in patients with T- and NK-cell lymphomas.

ABSTRACT: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

Optical genomic mapping is a helpful tool for detecting CCND1 rearrangements in CD5-negative small B-cell lymphoma: Two cases of leukemic non-nodal mantle cell lymphoma.

Optical genome mapping (OGM) is a new DNA-based technology which provides comprehensive examination of the entire genome. We report two patients who presented with splenomegaly and leukocytosis with lymphocytosis including villous lymphocytes. Neither patient had lymphadenopathy. Bone marrow evaluation showed involvement by small B-cell lymphoma in a sinusoidal and interstitial distribution, and immunophenotypic analysis showed that the neoplastic cells were positive for B-cell markers and cyclin D1 but were negative for SOX11 and CD5. Initially, the clinicopathologic features in both patients were thought to be suspicious for hairy cell leukemia variant or splenic marginal zone lymphoma. However, OGM detected CCND1 rearrangement: t(2;11)/IGK::CCND1 in one case and t(11;14)/IGH::CCND1 in the other case. These cases illustrate the valuable role OGM can play in establishing the diagnosis of MCL. Case 1 also contributes to the paucity of literature on the rare occurrence of IGK::CCND1 in MCL.

Safety and efficacy of tenalisib in combination with romidepsin in patients with relapsed/refractory T-cell lymphoma: results from a phase I/II open-label multicenter study.

Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma (TCL). In vitro studies suggest a synergistic anti-tumor potential for the combination of tenalisib with the histone-deacetylase inhibitor, romidepsin. This multicenter, open-label, phase I/II study was designed to characterize the safety, efficacy and pharmacokinetics of oral tenalisib twice-daily and intravenous romidepsin administered on days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL. Phase I/dose escalation determined the maximum tolerated dose (MTD)/optimal doses of tenalisib and romidepsin. The phase II/dose expansion assessed the safety and anti-tumor activity of the combination at MTD/optimal dose. Overall, 33 patients were enrolled. In dose escalation, no dose-limiting toxicity was identified. Hence, the recommended doses for dose expansion were tenalisib 800 mg twice daily orally, and romidepsin 14 mg/m2 intravenous. Overall treatment-emergent adverse events of any grade reported in >15% of patients were nausea, thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. Twenty-three patients (69.7%) had related grade ≥3 treatment-emergent adverse events. The overall objective response rate in evaluable patients was 63.0% (peripheral TCL: 75% and cutaneous TCL: 53.3%), with a complete response and partial response of 25.9% and 37.0% respectively. The median duration of response was 5.03 months. Co-administration of tenalisib and romidepsin did not significantly alter the pharmacokinetics of romidepsin. Overall, tenalisib and romidepsin combination demonstrated a favorable safety and efficacy profile supporting its further development for relapsed/refractory TCL (clinicaltrials gov. Identifier: NCT03770000).

Pralatrexate injection combined with CHOP for treatment of PTCL: results from the Fol-CHOP dose-finding phase 1 trial.

ABSTRACT: Pralatrexate is a folate antagonist that selectively enters cells expressing reduced folate carrier type 1 and competitively inhibits dihydrofolate reductase, leading to interruption of RNA synthesis, DNA replication, and apoptosis. This phase 1 study was conducted to evaluate the maximum tolerated dose (MTD) of pralatrexate in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen (part 1) and the response and pharmacokinetics of 6 cycles of this combination (CHOP + Folotyn 30 mg/m2 [Fol-CHOP]) in patients with newly diagnosed peripheral T-cell lymphoma (PTCL). In part 1, on days 1 and 8 of each cycle, patients were treated with 10, 15, 20, 25, or 30 mg/m2 of pralatrexate in combination with CHOP, per dose escalation, in 5 sequential cohorts. No patients experienced DLTs in cohorts 1, 2, 3, 4, and 5. The pralatrexate dose of 30 mg/m2 was selected to be combined with CHOP for part 2 and administered to 33 additional patients in the expansion cohort. At the MTD, the Fol-CHOP regimen was generally well tolerated in patients with PTCL, with an overall response rate (ORR) of 83.9% (20 complete response and 6 partial response), as assessed by treating investigators. Thirty-five patients (67.3%) experienced grade 3/4 treatment-emergent adverse events, the most common of which were anemia (21.2%), neutropenia (19.2%), febrile neutropenia (11.5%), fatigue, mucosal inflammation, nausea, and vomiting (7.7% each). In conclusion, Fol-CHOP was found to be a safe and effective treatment for newly diagnosed PTCL and deemed worthy of further investigation. This trial was registered at www.ClinicalTrials.gov as #NCT02594267.

Prolonged cytopenia following CD19 CAR T cell therapy is linked with bone marrow infiltration of clonally expanded IFNγ-expressing CD8 T cells.

Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine signaling gene sets, associated with prolonged cytopenia. In line with this, we found that hematopoietic stem cells from these patients expressed IFN-γ response signatures. IFN-γ deregulates hematopoietic stem cell self-renewal and differentiation and can be targeted with thrombopoietin agonists or IFN-γ-neutralizing antibodies, highlighting a potential mechanism-based approach for the treatment of CAR T-associated prolonged cytopenia.

Safety of Concurrent Radiation Therapy With Brentuximab Vedotin in the Treatment of Lymphoma.

Purpose: Purpose: Radiation therapy (RT) and the antibody-drug conjugate brentuximab vedotin (BV) are standard-of-care treatment options for patients with certain B and T-cell lymphomas; however, there are limited data exploring the safety of concurrent BV and RT (BVRT). Methods and Materials: We performed a single institutional retrospective review of 44 patients who received BVRT. Results: Twenty percent of patients (9/44) developed new grade 2 or higher (G2+) hematologic toxicity (HT) after BVRT, which was associated with radiation dose (median dose of 35 Gy in those with new G2+ HT compared with 15 Gy in those without; P < .001). Acute G2+ elevation in aspartate transaminase or alanine transaminase level was associated with administration of concurrent chemotherapy with BVRT (57% vs 21%; P = .047) but was not associated with any RT factors. Local control (LC) was achieved in 24 of 42 patients (57%) with available follow-up. Ten patients (23%) proceeded to stem cell transplant or cellular therapy after BVRT at a median of 48 days (interquartile range, 27-188 days). At last follow-up, 10 patients (23%) remained without evidence of disease. Conclusions: Our analysis demonstrates that the combination of BV and RT is well tolerated, though care should be taken during RT planning to reduce the risk of HT. This combination can be considered for patients in need of both local and systemic disease control.

Clinical relevance of MYC/BCL2 expression and cell of origin in patients with diffuse large b-cell lymphoma treated with autologous transplant.

Dual expression of MYC and BCL2 proteins (double-expressor lymphoma [DEL]) as well as cell of origin (COO) are important prognostic factors in patients with diffuse large B-cell lymphoma (DLBCL) after conventional chemotherapy. We studied the prognostic impact of DEL and COO in patients with relapsed DLBCL treated with autologous stem cell transplant (ASCT). Three-hundred and three patients with stored tissue samples were identified. Classification was successful in 267 patients: 161 (60%) were DEL/non-double hit (DHL), 98 (37%) were non-DEL/non-DHL, and 8 (3%) were DEL/DHL. Compared to non-DEL/non-DHL, DEL/DHL had worse overall survival while DEL/non-DHL did not significantly differ in overall survival. On multivariable analysis, DEL/DHL, age >60 years, and >2 prior therapies, but not COO, were important prognostic factors for overall survival. When we explored the interaction of COO and BCL2 expression, patients with germinal center B-cell (GCB)/BCL2 (+) had inferior progression-free survival (PFS) compared to GCB/BCL2 (-) patients (HR, 4.97; P = 0.027). We conclude that the DEL/non-DHL and non-DEL/non-DHL subtypes of DLBCL have similar survival after ASCT. The negative impact of GCB/BCL2 (+) on PFS warrants future trials targeting BCL2 after ASCT. The inferior outcomes in DEL/DHL need to be verified in a larger number of patients.

Complete Response to tenalisib and romidepsin with long-term maintenance using tenalisib monotherapy in a patient with relapsed and refractory sézary syndrome.

Mycosis fungoides (MF) and Sézary Syndrome (SS) are the most common subtypes of cutaneous T cell lymphomas (CTCL). Advanced-stage MF/SS have poor prognoses and may be refractory to multiple systemic treatments. These cases can be difficult to achieve and maintain complete response and there is a need for novel therapeutics. Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway by Tenalisib presents one such emerging drug. We report a relapsed/refractory SS patient achieving complete remission using the combination of Tenalisib and Romidepsin and subsequently maintaining long-duration CR with Tenalisib monotherapy.

A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy.

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy.

Spleen tyrosine kinase/FMS-like tyrosine kinase-3 inhibition in relapsed/refractory B-cell lymphoma, including diffuse large B-cell lymphoma: updated data with mivavotinib (TAK-659/CB-659).

We report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report). Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60-120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity. A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) and 38% (26/69), respectively. Median duration of response was 28.1 months overall and not reached in DLBCL responders. In subgroups with DLBCL of germinal center B-cell (GCB) and non-GCB origin, ORR was 28% (11/40) and 58% (7/12), respectively. Median progression free survival was 2.0 and 1.6 months in the lymphoma and DLBCL cohorts, respectively. Grade ≥3 treatment-emergent adverse events occurred in 96% of all lymphoma patients, many of which were limited to asymptomatic laboratory abnormalities; the most common were increased amylase (29%), neutropenia (27%), and hypophosphatemia (26%). These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL. Trial registration: ClinicalTrials.gov number: NCT02000934.