scholarly journals Dose Finding Study of Ibrutinib and Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma

2021 ◽  
Author(s):  
Craig A Portell ◽  
Nolan A Wages ◽  
Brad S. Kahl ◽  
Lihua E Budde ◽  
Robert W Chen ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Kinase Inhibitors ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Assessment Method ◽  
Dose Finding ◽  
Optimal Dosing ◽  
Mantle Cell ◽  
Starting Dose ◽  
Finding Study

Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton's Tyrosine Kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib(IBR) has shown synergy in pre-clinical MCL models. Prior MCL studies of the combination report promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual re-assessment method of 6 combinations of IBR (280mg, 420 mg, and 560mg PO daily) and VEN (max dose of 200mg and 400mg PO daily). Eligible participants were not previously exposed to BTKi's and not high risk for Tumor Lysis Syndrome (TLS). VEN, initiated first at 100mg, then at 20mg PO daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level. Combination treatment continued for six 28 day cycles. 35 participants were enrolled and treated. One TLS event occurred with starting dose of 100mg VEN; no TLS was seen with 20mg. The optimal dosing combination was considered to be VEN 200mg and IBR 420mg with an ORR of 93.8% (95% CI: 73.6-99.7%) and DLT incidence of 6.2% (95% CI: 0.3-26.4%). Overall response for all arms was 82.3% (28/34; 95% CI: 65.5-93.2%) with a CR rate of 42.4% (14/33; 95% CI: 25.5-60.8%). A participant was not allocated to IBR 560mg and VEN 400mg. ORR benefit was not seen with higher dosing combinations and toxicity was higer; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560.

scholarly journals Spontaneous Tumor Lysis Syndrome in Blastoid-Variant Mantle Cell Lymphoma: Considerations for the General Internist

2020 ◽  
Vol 8 ◽  
pp. 232470962094470 ◽  
Author(s):  
Vishal Patel ◽  
Robert Case
Keyword(s):  
Uric Acid ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
General Internist ◽  
Tumor Lysis ◽  
Spontaneous Tumor ◽  
Mantle Cell ◽  
Spontaneous Tumor Lysis Syndrome

Spontaneous tumor lysis syndrome (SPTLS) is a rare phenomenon that can manifest in rapidly proliferating hematological malignancies and solid tumors prior to initiating cytotoxic therapy. We encountered a patient who originally presented with diffuse lymphadenopathy, abdominal distention, and dyspnea, who had laboratory abnormalities suggestive of SPTLS. His peripheral flow cytometry and lymph node biopsy revealed blastoid-variant mantle cell lymphoma. Prior to initiating chemotherapy, acute kidney injury (AKI) and uric acid had improved with intravenous fluids and the initiation of allopurinol. However, after beginning chemotherapy, the patient developed a second AKI concerning for tumor lysis syndrome (TLS). He went on to have renal recovery and did not require renal replacement therapy. With the exception of case reports, there is limited evidence to guide general medicine clinicians who encounter cases of SPTLS. Expert-based guidelines are available to guide use of rasburicase, an uricase enzyme, before initiation of chemotherapy for certain malignancies when risk for TLS is considered high. Despite these guidelines, the role of rasburicase in preventing AKI remains controversial after inconclusive results in a meta-analysis. The causative relationship between uric acid and AKI in TLS is based on a mechanism of tubular obstruction. There are also mechanisms by which uric acid may cause AKI without tubular obstruction related to acute hyperuricemic nephropathy. Further characterization of the role of uric acid in causing AKI in patients without tubular obstruction may identify new mechanisms of injury and offer insight into new treatment strategies.

Revised Dose Ramp-Up to Mitigate the Risk of Tumor Lysis Syndrome When Initiating Venetoclax in Patients With Mantle Cell Lymphoma

2018 ◽  
Vol 36 (35) ◽  
pp. 3525-3527 ◽  
Author(s):  
Matthew S. Davids ◽  
Gottfried von Keudell ◽  
Craig A. Portell ◽  
Jonathon B. Cohen ◽  
David C. Fisher ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Tumor Lysis ◽  
Mantle Cell

scholarly journals Venetoclax as a single agent and in combination with PI3K‐MTOR1/2 kinase inhibitors against ibrutinib sensitive and resistant mantle cell lymphoma

2018 ◽  
Vol 184 (2) ◽  
pp. 298-302 ◽  
Author(s):  
Huijuan Jiang ◽  
Tint Lwin ◽  
Xiaohong Zhao ◽  
Yuan Ren ◽  
Grace Li ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Kinase Inhibitors ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Mantle Cell

scholarly journals Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Michael Wang ◽  
Radhakrishnan Ramchandren ◽  
Robert Chen ◽  
Lionel Karlin ◽  
Geoffrey Chong ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Complete Response ◽  
Clinical Activity ◽  
Phase 3 ◽  
Increased Risk ◽  
Mantle Cell ◽  
Data Informed

AbstractIbrutinib plus venetoclax, given with an ibrutinib lead-in, has shown encouraging clinical activity in early phase studies in mantle cell lymphoma (MCL). The ongoing phase 3 SYMPATICO study evaluates the safety and efficacy of concurrently administered, once-daily, all-oral ibrutinib plus venetoclax in patients with relapsed/refractory MCL. A safety run-in (SRI) cohort was conducted to inform whether an ibrutinib lead-in should be implemented for the randomized portion. Patients received concurrent ibrutinib 560 mg continuously plus venetoclax in a 5-week ramp-up to venetoclax 400 mg for up to 2 years. The primary endpoint was occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs). The SRI cohort enrolled 21 patients; six and 15 were in low- or increased-risk categories for TLS, respectively. During the 5-week venetoclax ramp-up, three patients had DLTs, and one patient at increased risk for TLS had a laboratory TLS; no additional TLS events occurred during follow-up. With a median follow-up of 31 months, the overall response rate was 81% (17/21); 62% (13/21) of patients had a complete response. SRI data informed that the randomized portion should proceed with concurrent ibrutinib plus venetoclax, with no ibrutinib lead-in. Ibrutinib plus venetoclax demonstrated promising efficacy; no new safety signals were observed.Trial registration: ClinicalTrials.gov, NCT03112174. Registered 13 April 2017, https://clinicaltrials.gov/ct2/show/NCT03112174.

The role of Bruton’s tyrosine kinase inhibitors in the management of mantle cell lymphoma

2020 ◽  
Vol 26 (5) ◽  
pp. 1190-1199
Author(s):  
Kirollos S Hanna ◽  
Maren Campbell ◽  
Alex Husak ◽  
Sabrina Sturm
Keyword(s):  
Tyrosine Kinase ◽  
Mantle Cell Lymphoma ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Cell Lymphoma ◽  
Bruton’S Tyrosine Kinase ◽  
Front Line ◽  
Bruton's Tyrosine Kinase ◽  
Mantle Cell

Mantle cell lymphoma is a rare subtype of B-cell non-Hodgkin’s lymphomas that is generally classified as an aggressive lymphoma requiring front-line chemo-immunotherapy with stem cell rescue. Despite effective treatment, many patients relapse or are refractory to front-line therapy. In addition, these patients may also develop drug resistance requiring novel modalities for subsequent lines. Bruton’s tyrosine kinase inhibitors have demonstrated a well-tolerated safety and efficacy profile across several B-cell malignancies. Ibrutinib, acalabrutinib, and zanubrutinib are FDA-approved as treatment options for patients with Mantle cell lymphoma following one prior line of therapy. Various factors should be considered which include the adverse event profile of these agents and ability to adhere to therapy. In this article, we review the role of Bruton’s tyrosine kinase inhibitors for the management of Mantle cell lymphoma and review the clinical pharmacology, pharmacokinetics, safety and efficacy, and future directions.

Ibrutinib-associated tumor lysis syndrome in chronic lymphocytic leukemia/small lymphocytic lymphoma and mantle cell lymphoma: A case series and review of the literature

2017 ◽  
Vol 24 (7) ◽  
pp. 544-549 ◽  
Author(s):  
Krystal S Titus-Rains ◽  
Jamie N Brown ◽  
Julia M Hammond
Keyword(s):  
Adverse Drug Reaction ◽  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Case Series ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
Tumor Lysis ◽  
Mantle Cell

Background Tumor lysis syndrome results when intracellular contents are released during cell lysis. Ibrutinib, a Bruton tyrosine kinase inhibitor, is used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström’s macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Tumor lysis syndrome caused by ibrutinib therapy is potentially life threatening, but is rare and not often reported in clinical trials. Objective The purpose of this case series is to describe the occurrence of tumor lysis syndrome in two patients initiated on ibrutinib, and to highlight the importance of close monitoring during therapy. Discussion One patient with chronic lymphocytic leukemia/small lymphocytic lymphoma and one patient with mantle cell lymphoma developed laboratory and clinical tumor lysis syndrome following initiation of ibrutinib therapy. Assessment with the Naranjo Adverse Drug Reaction Probability Scale indicated one probable relationship and one possible relationship between ibrutinib therapy and tumor lysis syndrome. There were additional factors that may have confounded the laboratory and clinical factors observed, including baseline laboratory values and concurrent medications. Both patients were managed with supportive therapies. A literature review identified five additional reported cases of tumor lysis syndrome following ibrutinib therapy. Conclusion This case series identifies one patient with a probable relationship and one patient with a possible relationship between the development of tumor lysis syndrome and treatment with ibrutinib. Although uncommon, proper attention should be given to monitoring for this adverse drug reaction and appropriate follow-up should occur despite ibrutinib’s ease of administration.

Ibrutinib-associated tumor lysis syndrome in a patient with mantle cell lymphoma: A case report

2016 ◽  
Vol 23 (3) ◽  
pp. 235-239 ◽  
Author(s):  
Varinder Kaur ◽  
Arjun Swami
Keyword(s):  
Mantle Cell Lymphoma ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Rare Complication ◽  
Tumor Lysis Syndrome ◽  
B Cell Lymphoma ◽  
Tumor Lysis ◽  
Mantle Cell ◽  
Hodgkin's Lymphomas

Mantle cell lymphoma accounts for 5–7% of all non-Hodgkin’s lymphomas. Under the current WHO classification, it is categorized as an indolent B cell lymphoma, but has an aggressive clinical course. New insights into leukemogenic molecular pathways of mantle cell lymphoma have uncovered unique therapeutic targets. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is the newest drug in the arsenal that has shown promising efficacy in relapsed mantle cell lymphoma. Long-term studies have shown that grade 3 or 4 adverse events are infrequent. Asymptomatic lymphocytosis is frequently seen with ibrutinib use in mantle cell lymphoma; however, tumor lysis syndrome is an extremely rare complication. To date, only two patients with ibrutinib-associated tumor lysis syndrome in mantle cell lymphoma have been described in a long-term follow-up study. Both patients met laboratory criteria for tumor lysis syndrome, however, but did not develop clinical tumor lysis syndrome. We, here describe a patient with relapsed mantle cell lymphoma who developed clinical tumor lysis syndrome with ibrutinib monotherapy.

Evaluation of Novel Cell Cycle Inhibitors in Mantle Cell Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4748-4748
Author(s):  
In-Woo Park ◽  
M.V. Ramana Reddy ◽  
E. Premkumar Reddy ◽  
Jerome E. Groopman
Keyword(s):  
Cell Cycle ◽  
Mantle Cell Lymphoma ◽  
Kinase Inhibitors ◽  
Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Apoptotic Pathway ◽  
Mantle Cell ◽  
Cell Cycle Inhibitors ◽  
Related Compounds ◽  
Cell Cycle Status

Abstract Signature abnormalities in the cell cycle and apoptotic pathway have been identified in mantle cell lymphoma (MCL), affording the opportunity to develop targeted therapies. Here, we report on a novel class of kinase inhibitors, styryl sulfones, that differ from prior cell cycle inhibitors in that they are not related to purines or pyrimidines. We observed that two closely related compounds, ON013100 and ON01370, altered the growth and cell cycle status of MCL lines and potently inhibited the expression of several important molecules, including CDK4, p53, MDM2, cyclin D, and cyclin B. Using both TUNEL and PARP assays, we found that these compounds caused apoptosis in MCL cells. In addition, using molecular analyses, we observed the modulation of caspase-3 activity but not the expression of Bcl family molecules in these cells. Next, we investigated the cytotoxicity of the MCL lines upon treatment with styryl sulfone compounds in combination with other currently used chemotherapeutic agents, such as doxorubicin (DOX) or vincristine (VCR). We found that the combination of DOX plus styryl sulfone or VCR plus styryl sulfone increased cytotoxicity by one log scale, compared with the single styryl sulfone compound. Thus styryl sulfones alone, or in combination with chemotherapeutic agents, present attractive opportunities for new drug development in MCL.

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