High Incidence of Autoimmune Complications during Combined Fludarabine and Rituximab Therapy in CLL: Rapid Clearance of Rituximab as a Contributing Factor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4208-4208
Author(s):  
Ndegwa Njuguna ◽  
Paul V Beum ◽  
Berengere Vire ◽  
Gerald E Marti ◽  
Therese White ◽  
...  
Keyword(s):  
Half Life ◽  
Single Agent ◽  
Serum Levels ◽  
Pure Red Cell Aplasia ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Phagocytic Cells ◽  
High Incidence ◽  
Anti Cd20 ◽  
Combination Regimens

Abstract Autoimmune cytopenias (AIC), particularly autoimmune hemolytic anemia (AIHA), pure red cell aplasia (PRCA) and immune-thromobcytopenic purpura (ITP) are important complications of fludarabine (F) treatment of chronic lymphocytic leukemia (CLL). Rituximab (R), a chimeric anti-CD20 monoclonal antibody, is an effective treatment for these autoimmune complications. The introduction of rituximab into fludarabine containing combination regimens has been expected to decrease the incidence of AIC. The experience in some studies (CALBG 9712, 2% incidence of AIC with FR; Byrd, 2003) but not others (6.5% incidence in 300 patients treated with FCR; Borthakur, 2007) supported this view. We compared the incidence of AIC during treatment in 2 CLL cohorts, one treated with F (1998–2004, n=21), the other with FR (2005–2008, n=17, rituximab 375mg/m2 q4 weeks). Five of 21 patients (24%) in the F group developed AIC (3 ITP, 1 PRCA, 2 AIHA), while 3 of 17 patients (18%) in the FR group developed AIC (2 AIHA, 1 autoimmune neutropenia). Two patients with ITP in the first cohort and all three patients in the second were successfully treated for their AIC with 4 infusions of rituximab over 2–4 weeks. Interestingly, although rituximab did not prevent the occurrence of AIC it remained effective in treating the complication, indicating that serum levels of rituximab could be too low to prevent the onset of AIC. We therefore measured rituximab serum levels in 7 patients (average ALC 134 K/mL, range 10–423) at 6, 24 and 120 hours from the start of the infusion. The average peak serum level at 6 hours, typically shortly after the end of the infusion, was 93μg/mL (32–155). By 24 hours, the average level declined to 66μg/mL (39–90), and by 120 hours to 11μg/mL (0–30, undetectable in 2). Based on these measurements, we estimate the half life of rituximab during this first cycle at 1–2 days. This extremely short half life is consistent with enhanced clearance of cell bound rituximab either during phagocytosis proper or during a form of abortive phagocytosis, also called trogocytosis, during which rituximab/CD20 complexes are pulled off the CLL cell surface and ingested by phagocytic cells (Beum, 2006). Consistent with the expected correlation of high tumor burden with rituximab clearance, we found higher rituximab serum levels in subsequent cycles: in cycle 2, 3 of 4 patients had an average increase in serum concentration of 27% at 24 hours, and in cycle 3 one patient had a 72% higher level than in the first cycle. Thus, at least in the first cycles, rituximab is cleared within a week, giving rise to a prolonged period of essentially single agent fludarabine effects. This could contribute to the persistently high incidence of AIC despite the use of rituximab in fludarabine combination regimens. These data indicate that, at least in the first cycles, additional infusions of rituximab may be necessary to prevent the onset of AIC in CLL patients treated with fludarabine-containing regimens.

Rapid Clearance of Rituximab Contributes to the Continued High Incidence of Autoimmune Complications of Chemoimmunotherapy for Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4628-4628
Author(s):  
Clifton C. Mo ◽  
Mohammed Z.H. Farooqui ◽  
Paul V. Beum ◽  
Ndegwa Njuguna ◽  
Gerald E Marti ◽  
...  
Keyword(s):  
At Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Half Life ◽  
Trough Level ◽  
Standard Dose ◽  
Serum Levels ◽  
Tumor Burden ◽  
Lymphocytic Leukemia

Abstract Abstract 4628 Introduction: Autoimmune cytopenias (AIC) are frequently seen in patients with chronic lymphocytic leukemia (CLL). Autoimmune hemolytic anemia (AIHA) is most common, although immune thrombocytopenia (ITP) and pure red cell aplasia (PRCA) can also occur. Fludarabine (F), the most active agent used to treat CLL, has been associated with the development of AIC. Although rituximab (R) is an effective treatment for F-associated AIC, its incorporation into F-based CLL regimens has failed to consistently prevent the occurrence of AIC (incidence of 6.5% in patients treated with F, R, and cyclophosphamide (FCR) (Borthakur et al, Br J Haematol. 2007)). We hypothesized that differences in R pharmacokinetics can explain the apparent paradox of efficacy in treating but failure in preventing AIC. Patients and Methods: To determine whether the addition of R to F decreased the incidence of autoimmune complications, we compared the incidence of AIC in 2 CLL cohorts - one treated with standard dose F (25 mg/m2/d ×5 q4 wk, 1998–2004, n=21) and the other with standard dose FR (R: 375 mg/m2 q4 wk, 2005–2010, n=29). F-associated AIHA was diagnosed if the patient experienced a hemoglobin drop of ≥ 2 g/dL and had either a positive DAT or at least two of the following: absolute reticulocyte count >50K/μ L, elevated LDH, total bilirubin >1.0 mg/dL, haptoglobin <30 mg/dL. Patients with hemoglobin levels of ≥10 g/dL and either a positive DAT or at least two of the aforementioned criteria prior to the start of therapy were deemed “at-risk” of developing AIHA. We measured R serum levels during FR treatment in order to examine the CLL-specific pharmacokinetic profile of R and its potential relevance to the development of AIC. Rituximab serum levels were determined by flow cytometry, based on the binding of mAb HB43 (anti-human IgG, Fc specific) to Raji cells reacted with standards and serum samples (Beum et al, J Immunol Methods. 2004). Cycle-specific parameters of peak level, trough level, and half-life were analyzed across time. Results: Six of 21 patients (29%) in the F cohort developed AIC during therapy (2 AIHA, 3 ITP, 1 PRCA), compared to 6 of 29 patients (21%) in the FR cohort (4 AIHA, 1 autoimmune neutropenia, 1 amegakaryocytic thrombocytopenia). Four patients in the FR cohort were identified as “at-risk” for AIHA prior to therapy; 2 of these patients developed AIHA during/immediately after therapy and were treated with steroids and R, while 2 were preemptively given an additional dose of R in each of the first 2 cycles and subsequently did not develop AIHA. Within the FR cohort, median serum peak R levels of 90, 111, 135, and 173 μ g/mL were achieved in cycles 1, 2, 3, and 4, respectively. Trough R levels were undetectable in all 14 patients treated with standard dose FR at the end of cycle 1, and increased progressively over time (25%, 50%, and 71% of patients had detectable levels at the end of cycles 2, 3, and 4, respectively). By contrast, 1 of the 2 “at-risk” patients given additional R had a detectable trough level at the end of cycle 1. The serum R half-life was surprisingly short especially in cycle 1 with a median of 26 hours (range 11–73) and increased progressively in subsequent cycles (81, 133, and 194 hours in cycles 2, 3, and 4, respectively). During cycle 1, patients with heavy tumor burden (bulky lymph nodes and/or ALC>100K/μ L, n=7 patients) had a substantially shorter mean R half-life compared to those without (21 hours vs 61 hours, P=.004). Conclusion: Surprisingly, R did not significantly change the incidence of AIC in the FR cohort compared to F alone, despite its efficacy in treating this complication. Here we show that in previously untreated CLL patients, R is rapidly cleared with a half-life of only a few days in the first cycles. This effectively limits the effect of R during the initial cycles and may explain why AIC are common even with R-based chemoimmunotherapy. Furthermore, we find that the serum half-life of R is highly dependent upon tumor burden, suggesting that fixed standard dosing of R is inadequate. In patients at risk for AIC, additional doses of rituximab in the first two cycles may be able to prevent the onset of such complications. Alternatively, such patients might benefit from a non-fludarabine-containing regimen. Disclosures: Off Label Use: Rituximab was used for treatment/prevention of autoimmune hemolytic anemia.

scholarly journals Retreatment with obinutuzumab: An addition to the therapeutic landscape of chronic lymphocytic leukemia

2019 ◽  
Vol 7 ◽  
pp. 2050313X1882391 ◽  
Author(s):  
Sharad Khurana ◽  
Salman Ahmed ◽  
Victoria R Alegria ◽  
Sonikpreet Aulakh ◽  
Meghna Ailawadhi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Remission ◽  
Single Agent ◽  
Chronic Lymphocytic Leukemia Patient ◽  
Lymphocytic Leukemia ◽  
Viable Option ◽  
Leukemia Patient ◽  
Therapeutic Landscape ◽  
Response Status ◽  
Anti Cd20

Obinutuzumab is used for the treatment of chronic lymphocytic leukemia. So far there are no data of using this for retreatment in patients who have received it previously. We introduced obinutuzumab for the retreatment in a chronic lymphocytic leukemia patient, who had first achieved partial remission with it and eventually relapsed over a course of 2.5 years. After retreatment with single-agent obinutuzumab, the patient achieved a partial remission again within one cycle and continues to maintain the response status. This case is a platform for considering obinutuzumab as a viable option for retreatment of chronic lymphocytic leukemia patients who have received it before, similar to the pattern of use for other anti-CD20 monoclonal antibodies in this disease, including rituximab.

Anti-CD20 monoclonal antibody rituximab for the treatment of B-cell chronic lymphocytic leukemia-associated pure red cell aplasia

2004 ◽  
Vol 5 (6) ◽  
pp. 546-547 ◽  
Author(s):  
Despina Pantelidou ◽  
Costas Tsatalas ◽  
Dimitris Margaritis ◽  
Vasiliki Kaloutsi ◽  
Emmanuel Spanoudakis ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Pure Red Cell Aplasia ◽  
Lymphocytic Leukemia ◽  
Red Cell ◽  
Red Cell Aplasia ◽  
Anti Cd20 ◽  
Cell Chronic Lymphocytic Leukemia

scholarly journals Potential of 2018 ASH CLL Data to Alter Standard of Care for Initial CLL Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5816-5816
Author(s):  
Bruce A Feinberg ◽  
Richard Sweat ◽  
Yolaine Jeune-Smith ◽  
Ajeet Gajra
Keyword(s):  
Market Research ◽  
Randomized Study ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Primary Specialty ◽  
Anti Cd20

Introduction In the past 5 years, four drugs have received approval for the treatment of Chronic lymphocytic leukemia (CLL), with most of the data supporting their approvals presented at an ASH meeting. How treating hematologists and oncologists (H/O) incorporate these agents into their practice has implications for all stakeholders. We conducted market research with H/O to understand how CLL data presented at ASH 2018 might alter their treatment preferences. Methods A live meeting in February 2019 convened H/O. The participants were shown data from selected oral and/or poster presentations from the 2018 ASH Annual Meeting and responded to questions regarding their perceptions on the data and its potential impact on current practice. The presentations used included the following: 1) Alliance A041202: a phase III, randomized study in older patients with untreated CLL comparing ibrutinib ± rituximab with bendamustine + rituximab (BR) (Woyach JA, et al. Blood. 2018;132[Suppl 1]:6); and 2) E1912: a phase III, randomized study in younger patients with untreated CLL comparing ibrutinib + rituximab with fludarabine + cyclophosphamide + rituximab (FCR) (Shanafelt TD, et al. Blood. 2018;132[Suppl 1]:LBA-4). Participants submitted their demographic responses via a web-based survey and data impression responses via an audience response system at the live meeting. Results 59 H/O participated in this live market research on February 22-23, 2019 and identified their primary specialty as 61% hematologist/oncologist and 34% medical oncologist. The participants were mostly community-based physicians, 50% in private community and 45% in community practices owned by a hospital or academic center. Over one-third have been in practice >20 years and see an average of 20+ patients per day. In the prior 3 months, 31%, 27%, and 18% of the participants initiated first-line treatment on 1, 2, or 3 CLL patients, respectively. The most commonly preferred first-line treatments for CLL patients ≥65 years without del(17p) were: BR (38%), ibrutinib (34%), anti-CD20 monotherapy (17%), and FCR (7%). Based on the results of the Alliance A041202 trial, 88% are likely to use single-agent ibrutinib as their preferred first-line therapy for older CLL patients, 45% very likely and 43% moderately likely. The most commonly preferred first-line treatments for CLL patients <65 years without del(17p) were: FCR (37%), BR (30%), ibrutinib (18%), and ibrutinib + anti-CD20 monotherapy (13%). Based on the results of the E1912 trial, the participants are likely to adopt ibrutinib + CD20 monoclonal antibody (51%), single-agent ibrutinib (20%), FCR (16%), or BR (13%) as their preferred first-line therapy for younger CLL patients. Conclusion Studies of newer mechanism of action drugs like Bruton's tyrosine kinase (BTK) inhibitors are perceived as compelling by treating oncologists and appear likely to replace more traditional chemotherapy-based regimens. The clinical, financial, and patient-centric outcomes of such rapid changes to standard of practice warrant further research. Disclosures Feinberg: Cardinal Health: Employment. Sweat:Cardinal Health: Employment. Jeune-Smith:Cardinal Health: Employment. Gajra:Cardinal Health: Employment.

Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies.

1991 ◽  
Vol 9 (1) ◽  
pp. 175-188 ◽  
Author(s):  
H G Chun ◽  
B Leyland-Jones ◽  
B D Cheson
Keyword(s):  
Clinical Trials ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Action ◽  
Low Grade ◽  
Significant Activity ◽  
Prolymphocytic Leukemia ◽  
Lymphoid Malignancies ◽  
Fludarabine Phosphate ◽  
Combination Regimens

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.

scholarly journals Where to start? Upfront therapy for follicular lymphoma in 2018

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 185-188 ◽  
Author(s):  
John P. Leonard ◽  
Loretta J. Nastoupil ◽  
Christopher R. Flowers
Keyword(s):  
Follicular Lymphoma ◽  
Treatment Options ◽  
Single Agent ◽  
Chronic Health Condition ◽  
Health Condition ◽  
Tumor Burden ◽  
Laboratory Findings ◽  
Routine Surveillance ◽  
Wide Range ◽  
Anti Cd20

Abstract The initial approach to the management of follicular lymphoma (FL) is challenging for patients and physicians. Most FL patients present with minimal symptoms; given the lack of a survival benefit to early treatment in this population, a period of observation without therapy is often appropriate. Once there is disease progression beyond low-tumor-burden criteria or symptoms prompting intervention, patients may be considered for an array of potential treatment options. These range from single-agent rituximab (anti-CD20) to various forms of chemoimmunotherapy, including rituximab or the newer anti-CD20 monoclonal antibody obinutuzumab. Unfortunately, prognostic and other clinical factors are of limited value in guiding optimal selection of therapy. Once patients complete initial treatment and achieve a complete or a partial remission, the next decision relates to the pros and cons of maintenance anti-CD20 therapy. Maintenance antibody administration can improve progression-free, but not overall, survival; hence, patient preferences typically drive this decision. Monitoring after remission is achieved should generally be guided by symptoms, physical examination, and laboratory findings, with routine surveillance imaging discouraged in the absence of new clinical issues. Given the wide range of options available and the importance of optimizing quality of life in this chronic health condition, education and shared decision making are pillars in the upfront management of FL to help patients achieve the best possible outcomes.

scholarly journals Follicular Lymphoma Microenvironment Signatures Define Patients Subsets Obtaining Long Term Clinical Benefit after Single-Agent First-Line Anti-CD20 Immunotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3500-3500
Author(s):  
Enrico Derenzini ◽  
Marcello Del Corvo ◽  
Maria Chiara Quattrocchi ◽  
Marta Castelli ◽  
Maria Rosaria Sapienza ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Single Agent ◽  
Tumor Burden ◽  
Advisory Board ◽  
First Line ◽  
Immune Signature ◽  
Anti Cd20 ◽  
Term Benefit

Abstract The role of first-line single agent Rituximab immunotherapy in follicular lymphoma (FL) is still a matter of debate. Although a subset of patients (pts) may obtain long term benefit with upfront immunotherapy, first-line therapy with standard chemoimmunotherapy offers better results in terms of progression free survival (PFS) compared to single agent Rituximab. On the other hand, there is no clear demonstration of sizeable long term benefit with first-line Rituximab compared to an initial wait and see approach, as most FL pts will ultimately be exposed to chemotherapy at some point in their disease course. Here we show that the efficacy of front line anti CD20 immunotherapy in FL could be dependent on microenvironmental factors, and that specific immune signatures could define FL pts subsets obtaining maximal benefit from upfront anti CD20 immunotherapy. First, we retrospectively analyzed the outcome of our single center cohort of 81 FL pts treated with first-line single agent Rituximab therapy with (n=53) or without (n=28) maintenance. The vast majority of pts considered in this analysis were treated in the context of several clinical trials exploring the efficacy of upfront single agent originator (SAKK 35/98, 35/03, 35/10: n= 68) or biosimilar (JASMINE and REFLECTIONS B328/06 n= 9) Rituximab, which were ran at our center from 2000 to 2018. Four patients received off-label single agent Rituximab. Median age was 55 years (y), 52% (42) of patients were female, 72% (58) stage III-IV, 76% (62) were Follicular international prognostic index (FLIPI) score 0-2, 26% (21) were bulky, 52% (42) were high tumor burden according to the GELF criteria. After a median follow-up of 9.5 y, the overall survival (OS) and PFS rates were 82% and 35% respectively. With a long follow-up, these data are in line with previous findings indicating that a sizeable fraction of FL pts derive long term benefit from upfront single agent Rituximab maintaining a continuous complete remission. Paraffin embedded tissue from initial diagnosis was available in 39 pts. In order to dissect determinants of Rituximab immunotherapy efficacy in this homogeneous chemo-naive population, we analyzed FL diagnostic biopsies (n=39 FL + 5 healthy controls) with targeted gene expression profiling (T-GEP) on the NanoString platform, using the PanCancer Immune Profiling panel, which includes 730 genes belonging to the most relevant immunologic checkpoints and pathways. A 20-gene signature including genes involved in chemokine-cytokine signaling, T-regulatory cells, natural-killer cell activity and interleukin-17 signaling was significantly associated with the achievement of a complete response after induction +/- maintenance treatment. A simple 6-gene immune signature (hereafter ImSig) was found to be significantly associated with PFS, with IL22RA2, CCL22, TNFRSF4, IL17RB, CCL19 overexpression and CD209 downregulation being associated with worse outcome. By applying the maxstat package 10-y PFS was 65% for ImSig low pts vs 6% for ImSig high pts (p&lt;0.0001). In multivariate analysis only the 6-gene ImSig and Rituximab maintenance retained independent prognostic value (p&lt;0.001 and 0.002 respectively). As opposite, GELF criteria (present/absent = 27/12) and FLIPI score (0-2/3-5 = 23/16) were not associated with PFS. The 6-gene immune signature was validated in silico in 2 independent publicly available cohorts of FL pts treated with upfront chemoimmunotherapy: a cohort of 137 pts (Silva et al 2019, Affimetryx platform) and a cohort of 50 pts (Bararia et al. 2020), the latter analyzed on the NanoString Platform with the same T-GEP panel (PanCancer Immune Profiling) used in our discovery cohort. The 6-gene signature was confirmed to be a powerful outcome predictor in these 2 chemoimmunotherapy-treated cohorts, and notably the 10-y PFS rates of ImSig low vs high patients mirrored the results observed with single agent immunotherapy in the discovery cohort. The results here reported indicate that pts with a favorable immune signature could derive maximal benefit from a first-line chemo-free treatment approach with single agent Rituximab, achieving and maintaining complete remission in the long term, irrespective of the tumor burden and other clinical variables. Thus, profiling of FL microenvironment with T-GEP could provide a useful tool for selecting patients who may be suitable for a chemo-free upfront treatment with anti CD20 immunotherapy. Disclosures Derenzini: TG-THERAPEUTICS: Research Funding; ASTRA-ZENECA: Consultancy, Other: ADVISORY-BOARD; ADC-THERAPEUTICS: Research Funding; TAKEDA: Research Funding; BEIGENE: Other: ADVISORY BOARD. Pileri: CELGENE: Other: ADVISORY BOARD; NANOSTRING: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY-BOARD. Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD. OffLabel Disclosure: First line single agent Rituximab in Follicular Lymphoma

scholarly journals Frontline treatment in CLL: the case for time-limited treatment

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 59-67
Author(s):  
Vincent Lévy ◽  
Alain Delmer ◽  
Florence Cymbalista
Keyword(s):  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
High Rate ◽  
Continuous Treatment ◽  
Fixed Duration ◽  
Mutational Status ◽  
Therapeutic Decisions ◽  
Pharmacological Interactions ◽  
Anti Cd20

Abstract Over the last decade, the advent of Bruton tyrosine kinase inhibitors (BTKi) has profoundly modified the therapeutic strategy in chronic lymphocytic leukemia (CLL), introducing the concept of treatment until progression. Initially, the bcl-2 inhibitor venetoclax (VEN) was used as a single agent and then was rapidly combined in VEN-based regimens associated with either anti-CD20 or with BTKi. These regimens yielded a high rate of complete remission, leading to their use as a fixed duration treatment. The decision between continuous treatment with BTKi and VEN-based combinations relies mostly on comorbidities, comedications, and patient/physician preferences. Notably, with BTKi, cardiovascular comorbidities, hypertension, and potential pharmacological interactions should be carefully evaluated. On the other hand, the risk of tumor lysis syndrome with VEN should be monitored at treatment initiation. TP53 alteration and IGHV mutational status should also be assessed, as they remain important for therapeutic decisions. Fit patients with a TP53 wild type and IGHV-mutated CLL may still benefit from fludarabine-cyclophosphamide-rituximab chemoimmunotherapy (CIT), as it may result in a very long remission duration. VEN-based treatments are well tolerated, and no additional toxicity has been observed when combined with anti-CD20 or BTKi. The 1-year fixed-duration association of VEN plus obinutuzumab was evaluated in frontline for older adult patients. Nonetheless, considering the favorable outcome, an extension of indication for fit younger patients is expected. The association of VEN and BTKi is promising, even if the follow-up is still short. It is currently being tested against CIT, BTKi continuous treatment, and VEN plus anti-CD20.

scholarly journals Phase 1 Study of TG-1701, a Selective Irreversible Inhibitor of Bruton's Tyrosine Kinase (BTK), in Patients with Relapsed/Refractory B-Cell Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4001-4001
Author(s):  
Chan Y. Cheah ◽  
Nicholas Wickham ◽  
Costas K. Yannakou ◽  
Katharine L Lewis ◽  
Chi-Hung Hui ◽  
...  
Keyword(s):  
B Cell ◽  
Phase 1 ◽  
Single Agent ◽  
Employment Equity ◽  
Once Daily ◽  
Btk Inhibitor ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
Combination Regimens ◽  
Dose Levels

Introduction Agents targeting BTK have demonstrated activity in a variety of B-cell malignancies, however not all patients respond to therapy, and amongst those that do respond, complete remissions are rare. BTK-based combination regimens have the potential to increase depth of response and permit time-limited therapy, however innovative approaches to accelerate the development of combination regimens are needed. TG-1701 is a novel, orally available and covalently-bound BTK inhibitor that exhibits superior selectivity for BTK compared with ibrutinib in in vitro whole kinome screening (Abstr 3973, EHA 2018). Herein we report the first results of a unique Phase 1 parallel dose-escalation study of TG-1701 monotherapy and TG-1701 in combination with umbralisib, a novel PI3K-δ and casein kinase-1ε inhibitor, and ublituximab, a glycoengineered anti-CD20 mAb (1701 + U2). Methods The primary objectives of the study are to characterize the safety profile and to determine the recommended Phase 2 dose of TG-1701 as a single agent and in combination with U2. Other objectives include assessment of pharmacokinetics (PK), preliminary antitumor activity, and pharmacodynamics (PD [BTK occupancy]). Eligible patients must have B-cell malignancy relapsed or refractory (R/R) to one or more prior standard therapy. Treatment consists of escalating doses of oral TG-1701 once daily (QD), continuously administered in 28-day (D) cycles (C). Patients in the 1701 + U2 combination arm receive escalating TG-1701 oral QD + umbralisib 800 mg oral QD + ublituximab 900 mg IV on D1, 8, 15 of C1, and D1 of C2-6. All patients are treated until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw study consent. Results As of July 15, 2019, 19 patients (WM = 6, CLL = 4, FL = 4, MZL = 2, DLBCL = 2, MCL = 1) have been treated with TG-1701: 3 patients at 100 mg QD, 9 patients at 200 mg QD (expansion before opening combination), 3 patients at 300 mg QD single agent arm, and 4 patients at 100 mg QD combination arm. Patients had a median of 2 prior systemic therapies (range, 1 - 5), and all of them received previous anti-CD20 therapy. Four patients were refractory to their last prior therapy, 8 had extranodal disease, and 8 had bulky disease. To date, patients have received a median of 4 (range, 2 - 10) cycles of TG-1701. No dose-limiting toxicity (DLT) have been observed to date. The most common treatment-related adverse events (TRAE) are: neutropenia (21%), diarrhea (16%), nausea (16%), bruising (16%), infection (16%), ALT/AST elevation (11%), rash (11%), abdominal pain (11%), and fatigue (11%). Grade 3 TRAE are: asymptomatic and isolated lipase elevation (N=1), nausea (N=1), rash (N=1), and acute respiratory tract infection (N=1). There have been no grade 4 TRAE nor treatment discontinuations due to adverse events. Linear kinetics are apparent, evidenced by approximately dose proportional increase in AUC on C1D1 and C1D8. High systemic clearance (CL) has been observed with a mean CL/F of 55.4 L/hr and half-life of 2.24 hours. Tmax is observed between 1 to 4 hours post dose. PK-PD (BTK occupancy) relationship at 200 mg on C1D1 is presented in Figure 1. Decrease from baseline in tumor burden is presented in Figure 2. Two patients at the lowest dose (100 mg QD) have achieved a partial response (PR): MCL = ↓78% and WM = ↓88%. All 3 evaluable patients treated with 100 mg 1701 + U2 have achieved a response at the first response assessment: 1 CR (FL) and 2 PR (FL ↓88%, and MZL ↓65%). All patients remain on study treatment, except for both patients with DLBCL that discontinued due to disease progression. All patients with CLL have shown lymphocytosis during the first 2 cycles of therapy. Near complete BTK occupancy has been achieved in all patients at all dose levels (Figure 1). Conclusions TG-1701, a once daily BTK inhibitor has an encouraging preliminary safety profile, with clinical and pharmacodynamic activity at all dose levels evaluated. This study (NCT03671590) continues enrollment in TG-1701 single-agent and 1701 + U2 combination arms. Disclosures Cheah: Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Roche, Abbvie: Research Funding; Roche: Other: Travel expenses. Wickham:Roche: Honoraria; Celgene: Other: Travel/Meeting Expenses . Turpuseema:TG Therapeutics Inc.: Employment, Equity Ownership. Miskin:TG therapeutics Inc.: Employment, Equity Ownership. Tang:TG Therapeutics Inc., Roche, Alexion: Equity Ownership; TG Therapeutics Inc.: Employment. Normant:TG Therapeutics Inc.: Employment, Equity Ownership. Ricart:TG Therapeutics, Pfizer, Merck: Equity Ownership; TG therapeutics Inc.: Employment. Tam:Abbvie, Janssen, Beigene, Roche, Novartis: Honoraria; Abbvie, Janssen: Research Funding.

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