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 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.

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.

PP-014 HYPERACUTE TUMOR LYSIS SYNDROME INDUCED BY RITUXIMAB IN MANTLE CELL LYMPHOMA

2014 ◽  
Vol 38 ◽  
pp. S32 ◽  
Author(s):  
P. Patir ◽  
A. Ersoy ◽  
M. Karateke ◽  
A. Donmez ◽  
M. Tombuloglu
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Tumor Lysis ◽  
Mantle Cell

Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms - Update of the “Bolus” Infusion Schedule of Alvocidib.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2959-2959
Author(s):  
Beata Holkova ◽  
Edward B. Perkins ◽  
Prithviraj Bose ◽  
Daniel M Sullivan ◽  
Rachid Baz ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Research Funding ◽  
Phase I Trial ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Tumor Lysis ◽  
Mantle Cell ◽  
Infusion Schedule ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 2959 Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell cycle and survival signaling pathways. We have previously reported that the cyclin-dependent kinase inhibitor alvocidib interacts with bortezomib, a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene 22:7108, 2003; Dai et al, Blood 104:509, 2004). These actions were associated with inhibition of NF-κB DNA binding, increased expression of pJNK, and down-regulation of XIAP and Mcl-1. Based on these findings, a phase I trial was initiated in which bortezomib was administered in conjunction with alvocidib on the same days, according to 2 separate schedules: a “hybrid” infusion schedule (half the dose over 30 minutes and half over a 4-hour infusion); and a bolus infusion schedule in which alvocidib was administered over 1 hour. Results of the hybrid infusion schedule have recently been reported (Holkova et al, Clin Cancer Res 17:3388, 2011). The primary objective was to identify the maximum tolerated doses (MTDs) for the combination in the treatment of recurrent or refractory indolent B-cell neoplasms. Eligible patients included those with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL), with recurrent or refractory disease following at least 1 prior systemic therapy. To date, 43 patients have been treated at 9 dose levels. Patients with the following disease types have been treated: MM n=25 (Waldenstrom's macroglobulinemia n=2), NHL n=18 (mantle cell lymphoma n=5). The male:female ratio was n = 31 (72%):12 (28%); the median age was 65 (range: 40–79) years; ECOG performance scores ranged from 0–1; and the median number of prior therapies was 3 (range: 1–10). The schedule of administration was bortezomib via intravenous push over 3–5 seconds followed by alvocidib via intravenous 1-hour infusion on days 1, 4, 8, and 11; on a 21-day cycle, with indefinite continuation for responding patients and those with stable disease. Adverse events (AEs) were evaluated using CTCAE version 4. Dose limiting toxicities (DLTs) observed to date are shown in Table 1. Grade 3 and 4 AEs possibly, probably, or definitely related to study treatment tht occurred in ≥ 5% of patients were dehydration (7%), diarrhea (19%), fatigue (16%), febrile neutropenia (5%), leukopenia (37%), lymphopenia (28%), neutropenia (58%), peripheral neuropathy (12%), and thrombocytopenia (44%). No grade 5 events were observed. One patient developed tumor lysis syndrome and required hospitalization for 48 hours with complete recovery. Common grade 2 AEs possibly, probably or definitely related to treatment were anemia (30%), anorexia (28%), diarrhea (47%), fatigue (60%), leukopenia (47%), lymphopenia (28%), and thrombocytopenia (56%). Of the 43 patients treated, 38 have been evaluable for response. Patient responses are shown in Table 2. Correlative studies examining expression of pJNK, Mcl-1, XIAP, PARP, and NFκB are being collected for processing at the end of the study. Collectively, these findings indicate that the combination of bortezomib and alvocidib, the latter administered as a 1-hour infusion, is tolerable. The regimen appears active in patients with relapsed and/or refractory MM or NHL, justifying phase II studies to determine the activity of this regimen more definitively. The MTD has not yet been reached. Table 1. Dose levels and DLTs Dose Level Bortezomib (mg/m2) Alvocidib (mg/m2) Patients treated/# DLTs DLT 1 1.0 15 3/0 2 1.3 15 5/0 3 1.3 22 3/0 4 1.3 30 3/0 5 1.3 40 7/1 Grade 3 back pain 6* 1.3 50 5/1 Grade 3 fatigue 7** 1.3 60 8/2 Grade 3 febrile neutropenia Grade 3 tumor lysis syndrome 8** 1.3 75 6/2 Grade 3 diarrhea Grade 3 esophagitis/oral mucositis 9** 1.3 90 3/2 Grade 3 febrile neutropenia Grade 4 absolute neutrophil count decrease * Study is currently enrolling to dose level 6 ** Exceeded MTD Table 2. Response by diagnosis NHL MM Total (n = 15) (n = 23) (n = 38) Complete Remission 2b,c 1a 3 Partial Remission 3 7d,e 10 Complete + Partial Remission N(%) 5 (33) 8 (35) 13 (34) a Includes 1 patient with prior bortezomib b Includes 1 patient with prior autologous SCT c Includes 1 patient with mantle cell lymphoma d Includes 1 patient with Waldenstrom's macroglobulinemia e Includes 1 patient still under active treatment Disclosures: Baz: Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding.

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.

Safety, Tolerability and Activity of Ofatumumab, Bendamustine and Dexamethasone Combination As First-Line Treatment of Mantle-Cell Lymphoma in the Elderly: A Multicenter Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1647-1647 ◽  
Author(s):  
Michele Magni ◽  
Massimo Di Nicola ◽  
Carmelo Carlo-Stella ◽  
Liliana Devizzi ◽  
Anna Guidetti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Human Monoclonal Antibody ◽  
Tumor Lysis Syndrome ◽  
Molecular Probe ◽  
First Line ◽  
Term Survival ◽  
Mantle Cell

Abstract Abstract 1647 Background and Aims: Mantle cell lymphoma (MCL) is the aggressive subtype of non Hodgkin's lymphoma with the poorest long-term survival probability. There is no consensus for its treatment: in most cases, R-CHOP immuno-chemotherapy, with its 34% complete remission (CR) rate, is still considered the standard of care. Very encouraging results have been reported using more aggressive induction treatments as first-line therapy but these have a role only in the initial management of clinically fit patients less than 60–65 years of age. Since the median age at diagnosis is 63 years and intensive treatment tend to be poorly tolerated by elderly patients, a frontline therapy that can be administered to this category of patients is needed. The main objective of the present study was to design a well tolerated regimen, applicable to the vast majority of patients over 60 years with MCL, while improving the limited efficacy of R-CHOP immunochemotherapy. To achieve this goal, we have used two novel drugs, i.e. ofatumumab and bendamustine. Ofatumumab is a fully human monoclonal antibody targeting a unique epitope on the CD20 molecule: its superior complement-dependent cytotoxicity compared to rituximab may translate into longer duration of treatment response. Bendamustine is a unique agent with both nitrogen mustard group and a benzimidazole ring: when given to relapsed or refractory MCL patients in combination with rituximab, it has shown a very favourable toxicity profile, as well as considerable activity. Methods: Previously untreated patients with MCL, any stage (patients with disease limited only to the bone marrow were excluded), aged ≥ 60 years, were enrolled into a therapeutic protocol consisting of six cycles of immunochemotherapy as follows: ofatumumab 1000 mg i.v. on day 1 (300 mg only for the first cycle); bendamustine 120 mg/sm i.v. on day 2 and 3; dexamethasone 40 mg i.v. on day 1 to 4. Each cycle of therapy was administered every 21 days. Hematopoietic growth factors were used in case of neutropenia. Results: As of July 31, 2011, 36 of the 50 planned patients have been enrolled and 19 have received the whole treatment. Cyclin D1 immunohistochemistry was positive in 18 patients (95%), thus confirming the diagnosis, while in the patient found negative at cyclin D1 analysis, Sox11 was used to confirm MCL; 1 patient (5%) had blastoid histology. Median age was 69 years (range 60–81), stage at diagnosis was IV in 95% of patients; MIPI score was low in 8 (42%), intermediate in 8 (42%) and high in 3 patients (16%); there were 15 male (79%) and 4 female patients (21%). Bone marrow (BM) involvement was detected by immunohistochemistry in 15 (79%) patients and by polymerase chain reaction (PCR) in all patients. Involvement of peripheral blood was detected by flow-cytometry in 12 cases (63%), by PCR in 18 cases (94%), while no data were available in the remaining case. A molecular probe was available for all patients: bcl1/IGH rearrangement was detected by PCR in 11 patients (58%), and an IGH allele-specific oriented primer was designed for the remaining 8 patients (42%). Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥ 3 treatment-related AE were neutropenia (10.5%), febrile neutropenia (10.5%), anemia (5.2%) and thrombocytopenia (5.2%). Two patients (10.5%) experienced tumor lysis syndrome: one was complicated by acute renal failure and the other by disseminated intravascular coagulation; both recovered with adequate therapy. Infectious complications consisted of one episode of pneumonia and one herpes zoster reactivation: both cases were resolved with antibiotic and antiviral therapy, respectively. Of note, 10 patients (52%) experienced cytomegalovirus reactivation, detected as pp65 antigen immunofluorescence, without evidence of infection: all these patients received anti-CMV therapy with negativization of the assay. Among the 19 patients evaluable for response, overall response rate was 94%, with CR in 17 patients, partial remission in one patient and progressive disease after the second cycle in one patient; 15 out of 15 patients evaluable for minimal residual disease in the BM showed molecular remission. Conclusions: Chemotherapy with bendamustine and ofatumumab appears generally safe and well tolerated to date in MCL patients aged ≥ 65 years requiring treatment. Preliminary data about efficacy are encouraging: accrual is ongoing for further evaluation. Disclosures: Off Label Use: ofatumumab, in label for CLL.

scholarly journals Bendamustine, Obinutuzumab and Venetoclax As Induction Therapy for Untreated Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Irl Brian Greenwell ◽  
Jeffrey M. Switchenko ◽  
Kami J. Maddocks ◽  
Brad S. Kahl ◽  
Alexander F. M. Craig ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Advisory Committees ◽  
Tumor Lysis ◽  
Phase 2 Study ◽  
Mantle Cell ◽  
Grade 3 ◽  
Stage 1

Bendamustine-rituximab (BR) is a standard of care for patients with mantle cell lymphoma (MCL) with median progression free survival (PFS) of approximately 3 years. Venetoclax has proven activity both as a single agent and in combination with other targeted therapies in relapsed MCL. We developed a phase 2 study of bendamustine, obinutuzumab, and venetoclax (BOV) for untreated patients with MCL to determine the efficacy and toxicity of this combination (NCT03872180). Patients ≥ 18 years old with untreated MCL received up to six 28-day cycles of BOV, consisting of bendamustine (90mg/m2 on D1-2) and obinutuzumab (1000mg, C1: D 1,8,15 and C2-6: D1) with a venetoclax ramp up from 20mg to 200mg during the first cycle and then 400mg on days 1-10 of cycles 2-6. Post-induction therapy is determined by the treating physician and is not dictated by the study. The primary endpoint was CR rate at the end of induction, per Lugano criteria. We assumed a historical CR rate of 60% with BR, with a goal CR rate of 85% with the BOV regimen and plan to accrue 23 total patients to assess for this difference. This was a two-stage design that included 9 patients in stage 1 with a requirement of 7 CR's in the first 9 patients to justify continued accrual. Secondary and correlative endpoints include PFS/overall survival, toxicity (including frequency and severity of tumor lysis syndrome), and MRD negativity using both commercial IgHTS assays as well as CAPP-Seq. Supportive care included G-CSF, antimicrobial prophylaxis, and prescribed monitoring for and management of tumor lysis syndrome. 11 patients have initiated therapy. Median age is 70 years (45-80), with 7 males and 4 females. All 11 patients had marrow involvement. Five patients had Ki67 index ≥30%, and TP53/17p abnormalities were found in 2 patients. Eight patients have completed 6 cycles, one patient discontinued study therapy after 5 cycles due to thrombocytopenia and 2 patients remain on therapy after 5 cycles of treatment. Of 9 patients who have completed end of treatment restaging, the ORR was 100%, including 8 CR's (89%) and 1 PR. The two patients currently completing study therapy have completed their interim PET/CT's and both have achieved CR. Three patients experienced grade 3+ obinutuzumab infusion reactions on cycle 1 day 1, with both patients requiring admission but subsequently fully recovering. One of these patients chose to forgo additional obinutuzumab while a second patient safely completed 6 cycles of treatment. The third patient initiated treatment in the hospital and experienced atrial fibrillation requiring ICU transfer, as well as grade 2 hyperkalemia while receiving day 1 treatment. Cardiology did not feel AFib was a result of TLS. She was ultimately able to safely complete 6 cycles of obinutuzumab. Although this event was not clear clinical TLS, the protocol was subsequently amended to incorporate venetoclax administration beginning on day 8 of cycle 1 to prevent overlapping infusional and TLS toxicities from venetoclax and obinutuzumab on day 1. No other patients have had TLS to date. Grade 3/4 hematologic toxicities include neutropenia (n=4), anemia (n=1), thrombocytopenia (n=4) leukopenia (n=3), and lymphopenia (n=10). Grade 3/4 non-hematologic toxicities included rash (n=2), hypophosphatemia (n=2). One patient has experienced prolonged leukopenia 2 months after finishing 6 cycles of therapy and was unable to collect stem cells after cycle 4 for a planned post-induction autologous transplant. To date, 2 patients have relapsed at 7 and 8 months after completing therapy, and one patient died suddenly while in remission of unknown causes at 6 months post-treatment. Of the two relapses, one patient chose not to receive any obinutuzumab during treatment due to a grade 3 reaction during cycle 1, and both patients initially presented with aggressive leukemic phase disease with Ki67 > 30%. Here we report the pre-planned stage 1 of this phase 2 study, the BOV regimen has resulted in CRs in 8 of the first 9 patients, and accrual continues to stage 2. Expected hematologic and infusional toxicities have been manageable. One patient has discontinued therapy due to toxicity, and the prescribed venetoclax ramp-up has successfully avoided clinically significant tumor lysis syndrome. Accrual continues, and additional follow-up of currently treated patients will provide insights into response duration, OS, and rate of MRD negativity with this regimen. Disclosures Greenwell: Acrotech Biopharma LLC, Kyowa Kirin: Consultancy; Lymphoma Research Foundation: Research Funding. Maddocks:Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Kahl:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Research Funding. Alizadeh:Janssen: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy; Pfizer: Research Funding. Allen:Curio Sciences: Honoraria; Bayer: Consultancy, Other; Clinical Care Options: Speakers Bureau; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy.

The efficacy of ibrutinib-based combination therapy for mantle cell lymphoma: A systematic review.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19043-e19043
Author(s):  
Prem Thirunagari ◽  
Aida Siyahian ◽  
Ahmad Iftikhar ◽  
Ahsan Wahab ◽  
Afia Ashraf ◽  
...  
Keyword(s):  
Systematic Review ◽  
Combination Therapy ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Newly Diagnosed ◽  
Phase Ii Studies ◽  
Mantle Cell ◽  
Drug Regimens ◽  
Treatment Table

e19043 Background: Mantle Cell Lymphoma (MCL) is generally treated with rituximab (R) in combination with other drugs. However, treatment for relapsed or refractory (RR) MCL is challenging. For Ibrutinib (Ibr), we aim to determine the efficacy in combination therapy for newly diagnosed (ND) and RR MCL. Methods: Per PRISMA guidelines, a systematic review was performed using four databases. Results: Eleven studies with 363 patients were identified, most commonly studied regimens were ibrutinib in combination with R in 2 phase II studies and 2 studies on Ibr in combination with venetoclax. Ibr was also studied as part of the three-drug regimens in combination with bendamustine & R, lenalidomide & R, and obinutuzumab & venetoclax. Ibr was studied in combination with other drugs such as palbociclib, ublituximab, and bortezomib as part of the two-drug regimens. Results summarized in Table. Adverse events included cytopenia, atrial fibrillation, septic shock, tumor lysis syndrome, and GI toxicities. Conclusions: Ibr in combination with R demonstrated the highest overall ORR and CR in treatment of ND MCL, whereas combination with venetoclax and obinutuzumab demonstrated highest overall ORR and CR in treatment of RR MCL. Additional studies are needed to further assess and confirm its role in treatment. [Table: see text]

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.

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