Incidence of Infectious Complications Associated with Bendamustine and Anti-CD20 Monoclonal Antibody Combination at Memorial Sloan Kettering Cancer Center (MSKCC)

Abstract Introduction: The combination of bendamustine (B) and rituximab (R) is an effective and relatively well tolerated treatment for B-cell malignancies. However, there is increased concern regarding infectious complications since FDA approval, in particular due to reports of prolonged and profound lymphopenia associated with BR. [Saito, Blood Cancer J 2015; Garcia-Munoz, Ann Hematol 2014] There have been numerous case reports of opportunistic infection (OI) with BR, such as viral reactivation (HBV, VZV, HSV, CMV, EBV) and Pneumocystis jiroveci. [Abkur, Clinical Case Reports 2015;Carter, Leuk Res 2011; Tsutsumi, Int J Hematol 2012; Lim, Ann Hematol 2011] A retrospective analysis conducted in Israel showed that B ± R therapy was associated with 47% incidence of infectious complications (ICs) with 2 out of 183 pts received antimicrobial prophylaxis (ppx) and 65% G-CSF use.[Gafter-Gvili, Blood 2014, abs 3077]Another study concluded that a prolonged period of VZV ppx may be advisable with BR.[Allen, Blood 2015, abs 4167] Brugger et al published a practice guide for B-based therapy with a section devoted to discussing potential ICs and considerations for antimicrobial ppx.[Brugger, Oncologist 2013] In prospective trials (StiL and Bright), Rummel et al reported a 37% incidence of unspecified infectious episodes and Flinn et al reported 55% incidence of all infections with 10% OI despite 30% G-CSF use.[Rummel, Lancet 2013, Flinn, Blood 2014] Antimicrobial ppx and G-CSF use were not mandated in those trials. With these reports and OI episodes in a few of our patients, we performed a retrospective analysis at MSKCC to evaluate the incidence of ICs and potential risk factors in patients treated with B and anti-CD20 antibody ± R maintenance. Methods: Pts ≥18 year old with CD20+ NHL and received ≥2 cycles of B and anti-CD20 antibody (rituximab or ofatumumab) ± R maintenance from 2008 through 2015 were included. Pts were excluded if they received B monotherapy, switched treatment before completion of planned course, or underwent stem cell transplantation right after completion of bendamustine combination. Infection data were collected for up to 1 yr post B-based treatment with a cutoff date of 5/1/2016. Adverse drug events (ADEs) including neutropenia, neutropenic fever (NF), lymphopenia, time to lymphocyte recovery, and liver function abnormalities were graded according to CTCAE v4.0. Univariate analysis with Fisher's exact test was used to evaluate the potential risk factors (degree of lymphopenia and neutropenia, R maintenance, and line of therapy) for ICs. Results: 416 pts were included in this retrospective analysis (Table 1). Initial bendamustine dose ranged from 50mg/m2 to 120mg/m2, with 11.5% of pts requiring dose attenuation. 55.8% received B and anti CD-20 antibody as ≥ 2nd line therapy. The incidence of ICs was 20% (n = 83; 95% CI: 16 to 24%) and 6% (n = 25; 95% CI 3.7-8.5%) of which was OI in this cohort (Table 2). The 25 OI cases consisted of viral (n = 19), fungal (n = 1), and PJP (n = 5). Nine cases occurred during B-based treatment and 16 cases occurred up to a year post (one was on R maintenance). All 25 cases were associated with either no ppx (n = 21), early ppx cessation (≤ 1 month post) (n = 2), or non-compliance (n = 2). One pt died of disseminated histoplasmosis 1.5 years after completed rituximab maintenance without additional treatment. Antimicrobial ppx, mainly anti-viral and anti-PJP, was employed in 36.1% of pts and primary or secondary G-CSF ppx in 64.7%. ICs were not associated with SLL/CLL histology (p = 0.471), R maintenance (p = 0.843), line of therapy (p = 0.804), and grade of lymphopenia (p = 0.554) or grade of neutropenia (p = 0.839) (Table 2). However, OI was associated with lack of antimicrobial ppx (p = 0.048). Other ADEs included grade 3/4 neutropenia (65.8%), NF (2.9%), grade 3/4 lymphopenia (76%), and elevated liver function tests (91.5% grade 1). The median absolute lymphocyte counts nadired after cycle 3 and persisted for at least 6 months following completion of bendamustine combination (Figure 1). Conclusions: The 20% incidence of infectious complication and 6% of opportunistic infection with bendamustine and anti-CD20 antibody combination at MSKCC are somewhat lower than that reported in prospective trials and retrospective analysis by Gafter-Gvili et al, possibly due to antimicrobial ppx and G-CSF use. We have implemented a prophylaxis guideline at MSKCC. Disclosures Hamlin: Celgene: Membership on an entity's Board of Directors or advisory committees; Xencor: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; Seattle Genetics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Novartis: Research Funding. Kumar:Celgene: Honoraria, Other: Scientific Advisory Board; Celgene: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding. Moskowitz:Seattle Genetics: Honoraria, Research Funding; Merck: Honoraria; Bristol Myers Squibb: Honoraria. Moskowitz:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Noy:Pharmacyclics, LLC, an AbbVie Company: Other: travel, accommodations, expenses, Research Funding. Zelenetz:Gilead Sciences: Research Funding.

Download Full-text

Toxicities and Outcomes of Ibrutinib-Treated Patients in the United States: Large Retrospective Analysis of 621 Real World Patients

Blood ◽

10.1182/blood.v128.22.3222.3222 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3222-3222 ◽

Cited By ~ 12

Author(s):

Anthony R. Mato ◽

Nicole Lamanna ◽

Chaitra S. Ujjani ◽

Danielle M. Brander ◽

Brian T. Hill ◽

...

Keyword(s):

Atrial Fibrillation ◽

Clinical Trials ◽

Retrospective Analysis ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Common Reason ◽

Discontinuation Rate ◽

Advisory Committees ◽

Line Of Therapy

Abstract Introduction: Ibrutinib (Ibr) is a kinase inhibitor (KI) indicated for treating CLL. Clinical trials that led to its approval showed that its unique side effects differ from traditional chemotherapy toxicities. We previously reported (Mato et al, ASH 2015) that intolerance was the most common reason for discontinuation of Ibr in 123 patients treated in a real world setting. Whether reasons for discontinuation reported in clinical trials mirror those encountered in the real world is unknown and has not been studied. Therefore, we conducted a retrospective analysis of 621 CLL patients treated with Ibr either on clinical studies or commercially. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. Patients and Methods: This multicenter, retrospective analysis included Ibr-treated CLL patients at 9 US cancer centers or the Connect® CLL Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death or last f/u) as determined by the Kaplan Meier method. Comparisons of outcomes data were made using the log rank (LR) test. All other comparisons were descriptive. Results: 621 patients treated with Ibr were identified. Table 1 includes available baseline characteristics stratified by line of therapy. A total of 546 (88%) patients were treated with commercial drug. Clinical trial patients were younger (median age 57 vs. 61 years), had a longer time from diagnosis to Ibr (median 85 vs. 72 months) and were more consistently initiated at 420 mg daily (100% vs. 89%). With a median f/u of 14.5 months, the Ibr discontinuation rate was estimated to be 42% (median time to Ibr discontinuation was 7 months). Reasons for discontinuation are listed in table 2. Notably, Ibr toxicity was the most common reason for discontinuation in all settings. Ibr starting dose (420 mg daily vs. < 420 mg daily) did not impact the proportion of patients who discontinued Ibr due to toxicity (51% vs. 50%). In relapsed CLL, the 5 most common Ibr-related toxicities as a reason for discontinuation included: atrial fibrillation (12.3%), infection (10.7%), pneumonitis (9.9%), bleeding (9%), and diarrhea (6.6%). In front line CLL, the 3 most common Ibr-related toxicities as a reason for discontinuation included arthralgia (41.6%), atrial fibrillation (25%), and rash (16.7%). Median times to discontinuation by toxicity were as follows: bleeding (8 months), diarrhea (7.5 months), atrial fibrillation (7 months), infection (6 months), arthralgia (5 months), pneumonitis (4.5 months), and rash (3.5 months). Median PFS and OS for the entire cohort were 35 months and not reached (median f/u 17 months) respectively. Figure 1 describes PFS for Ibr treated patients stratified by line of therapy (A), reason for discontinuation (B), clinical trial participation (C) and depth of response (D). In a multivariable model, complex karyotype was validated as an independent predictor of PFS (HR 1.6, CI 1.1-2.5 p=.04) but not OS (HR 1.6, CI .9-3.1 p=.1). Conclusions: In the largest reported series on Ibr-treated CLL patients, we show that 40% of patients have discontinued Ibr during this observation period. Intolerance as opposed to CLL progression or transformation was the most common reason for discontinuation. As compared to previous reports from clinical trials, the discontinuation rate appears to be higher suggesting (1) a learning curve in terms of toxicity management, (2) a higher incidence of toxicity in clinical practice, (3) or a lower threshold for discontinuation given alternative choices. Outcomes remain excellent and were not impacted by line of therapy and whether patients were treated on studies or commercially. These data strongly argue to find strategies to minimize Ibr intolerance so that efficacy can be further maximized. Figure 1 Figure 1. Disclosures Mato: Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Lamanna:Acerta: Research Funding; TGR Therapeutics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Ujjani:Gilead: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy. Brander:TG Therapeutics: Research Funding; Gilead: Honoraria. Howlett:Sandoz: Honoraria; Teva: Speakers Bureau; Amgen: Honoraria; Pfizer: Honoraria; Eisai: Honoraria. Skarbnik:Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Cheson:Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Nasta:Millennium Pharmaceuticals: Research Funding. Schuster:Janssen Research & Development: Research Funding; Hoffman-LaRoche: Research Funding; Gilead: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Nabhan:Seattle Genetics: Research Funding; Cardinal Health: Consultancy; Infinity: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Astellas: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.

Download Full-text

Prolonged Lymphopenia and Infection Risk Is Mitigated By Antimicrobial Prophylaxis in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) Treated with Bendamustine +/- Anti-CD20 Antibody: The Australasian Lymphoma Alliance Experience

Blood ◽

10.1182/blood-2020-138642 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 47-49

Author(s):

Kate Manos ◽

Masa Lasica ◽

Andrew Grigg ◽

Pietro R Di Ciaccio ◽

Jonathan Wong ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Antimicrobial Prophylaxis ◽

Advisory Committees ◽

Cd20 Antibody ◽

Grade 3 ◽

Anti Cd20 ◽

The Relationship

Background: Bendamustine +/- anti-CD20 antibody is a highly effective regimen for iNHL. Though initially favoured for its toxicity profile, subsequent analyses demonstrate profound and prolonged lymphopenia and the landmark phase III GALLIUM study showed a grade 3-5 infection rate of 20-26% in the bendamustine arms (Hiddemann JCO 2018). The relationship between severity and duration of lymphopenia and infection, and the role of antimicrobial prophylaxis (ppx), are not fully characterised. We performed a multicentre, retrospective analysis of bendamustine-treated iNHL patients (pts) to define the type and onset of infections, identify concomitant risk factors and evaluate the role of ppx. Methods: iNHL pts aged ≥18 yrs, treated with bendamustine +/- anti-CD20 in 1st-3rd line from 2011-2019, were identified from 9 Australian centres. HIV, prior transplant and long-term immunosuppression were excluded. Demographics, treatment, lymphocyte counts, infections and ppx were collected from baseline to 24 months post end of bendamustine treatment (EOT) or subsequent lymphoma therapy. Association between potential risk factors and infection was evaluated by logistic regression (odds ratio, OR) and negative binomial regression (incidence rate ratio, IRR) with Stata 16.1. Results: 302 pts were eligible. Baseline and treatment characteristics are summarised in Table 1. 252 infection episodes occurred across 134 pts (44%), equally divided between during therapy and after EOT (Figure 1A, Table 2). Infections on treatment occurred in 30% of pts (n=92) with 18% hospitalised (n = 54; n = 20 with febrile neutropenia (FN)) and dose delay /modification/ discontinuation in 11%. Late infections post EOT occurred in 23% of pts (n=70) with 11% hospitalised (n = 32; n = 12 with FN); infection post EOT was more common in pts on maintenance anti-CD20 (infection rate 49% v 16%, OR 5.1 p<0.001). Opportunistic infections (OI) occurred in 21 pts: VZV (n=9; 4 on treatment, 5 post EOT, 1 on ppx); HSV (n=5, all on treatment without ppx); PJP (n=1, on treatment without ppx); nocardiosis (n=1, on treatment); other fungal infections (n=3, all on treatment); PML (n=1, 1-yr post EOT); CMV (n=1, at EOT). Lymphopenia was near universal and prolonged; 98% of pts became lymphopenic (53% grade 3, 9% grade 4) with a median nadir of 0.4x109/L (range 0-2.3). Median time to recovery (>1x109/L) was 10 months post EOT; 39% of pts remained lymphopenic (4% grade 3/4) at 2 yrs (Figure 1B). However, neither lymphopenia nadir nor duration correlated with infection post EOT (OR 0.53 p=0.26 and 0.97 p=0.29 respectively) and the relationship between lymphocyte nadir and OI was not significant (OR 0.09 p=0.053). VZV/HSV and PJP ppx were prescribed to 42% and 54% respectively during treatment and continued for a median of 3 months post EOT (range 0-27, cessation date unknown in 60%). PJP ppx (sulfamethoxazole/trimethoprim) was associated with fewer bacterial infections (OR 0.44 p=0.003) but did not reduce the incidence of FN (OR 0.83 p=0.63). Antiviral ppx (aciclovir/valaciclovir) was associated with fewer VZV/HSV infections (OR 0.10 p=0.026). More ppx was prescribed in 2018-2019 (post GALLIUM) than 2011-2017 (PCP ppx - OR 5.19 p<0.001; VZV ppx - OR 3.76 p<0.001; Figure 2) with an associated fall in the number of infections per pt (IRR 0.55, p=0.011). Factors independently associated with an increased number of infections (during and post EOT) were obinutuzumab vs rituximab (IRR 2.76, p<0.001), maintenance anti-CD20 (IRR 3.43 p<0.001), and stage III/IV disease (IRR 2.55, p=0.002). Factors specifically associated with infection post EOT were maintenance (OR 5.10 p<0.001) and obinutuzumab (OR 3.51 p=0.001). ECOG, hypogammaglobulinaemia, comorbidity index, treatment line and disease subtype were not associated with infections during or post treatment. Conclusion: iNHL pts receiving bendamustine are at high risk of prolonged lymphopenia and infectious complications extending beyond treatment completion, with half of infections occurring post treatment cessation. Lymphopenia duration and nadir did not correlate with infection. PJP and antiviral ppx reduced risk of bacterial and VZV/HSV infections respectively, though rates of PJP and VZV/HSV were low. Prolonged ppx to mitigate the risk of late infections should be considered, particularly in pts with additional risk factors such as concomitant obinutuzumab and anti-CD20 maintenance. Disclosures Manos: Bristol-Myers Squibb: Other: Travel. Di Ciaccio:Jansen: Honoraria, Other: travel and accomodation grant. Hamad:Abbvie: Honoraria; Novartis: Honoraria. Gregory:Janssen: Consultancy; F. Hoffmann-La Roche, Genentech, Inc., MSD, AbbVie, BeiGene, AstraZeneca, Celgene, BMS: Research Funding; F. Hoffmann-La Roche, Novartis, Sandoz, Gilead, AbbVie, MSD: Honoraria; F. Hoffmann-La Roche, Novartis, AbbVie: Speakers Bureau; F. Hoffmann-La Roche, Novartis, Sandoz, Gilead: Membership on an entity's Board of Directors or advisory committees. Gangatharan:Roche: Other: Travel grant. Hawkes:Merck Sharpe &Dohme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding, Speakers Bureau; BMS celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; takeda: Speakers Bureau.

Download Full-text

A Retrospective Analysis of Pneumocystis Jirovecii Pneumonia Infection in Patients Receiving Idelalisib in Clinical Trials

Blood ◽

10.1182/blood.v128.22.3705.3705 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3705-3705 ◽

Cited By ~ 17

Author(s):

Laurie H Sehn ◽

Michael Hallek ◽

Wojciech Jurczak ◽

Jennifer R. Brown ◽

Paul M. Barr ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pneumocystis Jirovecii Pneumonia ◽

Employment Equity ◽

Advisory Committees ◽

Increased Risk ◽

Equity Ownership ◽

Cd20 Antibody ◽

Anti Cd20 ◽

Support Research

Abstract Introduction: Opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) occur commonly in immunocompromised hosts such as patients (pts) with cancer (especially hematological malignancies such as chronic lymphocytic leukemia [CLL] and indolent non-Hodgkin lymphoma [iNHL]) or those receiving immunosuppressive therapies (such as steroids, chemotherapy). Recently, an increased risk of PJP infection was identified in 3 ongoing phase 3 studies evaluating idelalisib, administered in combination with the standard regimens rituximab (R) or bendamustine and rituximab (BR), in front-line CLL and early-line iNHL. Subsequently, a comprehensive analysis evaluating PJP infection across the clinical development program was performed to identify possible risk factors for developing PJP infection, including age, concomitant therapy (co-therapy) administered, geographic distribution of PJP infection, and regional use of prophylaxis. Methods: A retrospective analysis of 2198 pts receiving study treatment with idelalisib alone or in combination with co-therapy (anti-CD20 antibody or BR) and pts receiving only co-therapy (anti-CD20 ± bendamustine) (n = 1391 and 807, respectively) across 8 studies (frontline/relapsed CLL and relapsed iNHL) between 2010 and 2016 was performed. PJP infection was defined based on MedDRA high-level term of pneumocystis infections. In this analysis, other parameters were included for evaluation of risk of developing PJP infection-prophylaxis for PJP, geographic region, age, and CD4 count. Results: The overall incidence of PJP infection was 2.5% in pts on idelalisib ± co-therapy vs 0.2% in pts receiving only anti-CD20 antibody alone or BR alone (relative risk = 12.5). The median time to PJP event was 141 days since initiation of IDELA or co-therapy. The incidence of PJP infection was similar, irrespective of pt age. In the pt population receiving IDELA ± co-therapy - prophylaxis for PJP reduced the incidence of infection to 1.3% (from 3.4% in pts not receiving prophylaxis). Additionally, analysis by type of co-therapy received - the incidence of PJP infection was 2.2% vs 3.1% with IDELA + BR and IDELA + anti-CD20 alone respectively. A correlation between CD4 count (<200 cells/mcL) and an increased risk of PJP infection was not observed. Additional data are provided in Table 1. Conclusion: There is a small but increased risk of PJP infection during treatment with idelalisib within the clinical trial program. These data suggest that prophylaxis for PJP may reduce the risk of infection by as much as 60%. Administration of PJP prophylaxis is now recommended in all pts receiving treatment with idelalisib. Disclosures Sehn: roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Hallek:Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Jurczak:Gilead Sciences: Research Funding; Celltrion, Inc: Research Funding; Janssen: Research Funding; Bayer: Research Funding; Acerta: Research Funding. Brown:Infinity: Consultancy; Gilead Sciences: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Sun BioPharma: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy; Abbvie: Consultancy. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Catalano:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Coutre:Gilead Sciences: Consultancy, Research Funding. Furman:Gilead Sciences: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy; Abbvie: Consultancy, Honoraria. Lamanna:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zelenetz:Gilead Sciences: Research Funding. Sharman:Gilead Sciences, Inc.: Honoraria, Research Funding. Adewoye:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Salles:Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Download Full-text

Risk Factors Associated with the Development of Infusion-Related Reactions in Patients with Chronic Lymphocytic Leukaemia Treated with Anti-CD20 Monoclonal Antibodies: Analysis of the CLL11 Study Dataset

Blood ◽

10.1182/blood.v124.21.3339.3339 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3339-3339 ◽

Cited By ~ 4

Author(s):

Ciara Louise Freeman ◽

Mark Dixon ◽

Richard Houghton ◽

Kathryn Humphrey ◽

Gunter Fingerle-Rowson ◽

...

Keyword(s):

Risk Factors ◽

Monoclonal Antibodies ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukaemia ◽

Signs And Symptoms ◽

Leukemic Cells ◽

Tumour Burden ◽

Advisory Committees ◽

Anti Cd20

Abstract Background: The administration of anti-CD20 monoclonal antibodies (mAb) in patients with B-cell lympho-proliferative disorders is frequently accompanied by a constellation of signs and symptoms that have been labelled as infusion-related reactions (IRR). The pathophysiology of IRR remains poorly understood as do predictors of risk, which may relate to the mechanism of action of the anti-CD20, disease-related factors such as tumour burden or host factors such as polymorphisms of Fc gamma receptor 3A (FcγRIIIA). In the CLL11 trial (NCT01010061), patients with previously untreated chronic lymphocytic leukaemia and comorbidities were randomised to receive either rituximab (type I anti-CD20 mAb) or obinutuzumab (type II and glycoengineered anti-CD20 mAb) in combination with chlorambucil for six cycles. Obinutuzumab led to faster depletion of B cells and achieved an improvement in outcome parameters such as response and progression-free survival compared with the rituximab arm, but was also associated with a higher rate and increased severity of IRR. To better understand the profile of risk for IRR in patients with CLL, we performed an exploratory analysis on data obtained from patients treated with either one of the two antibodies given in combination with chlorambucil. Methods: Patients from the prospective, randomized Phase III CLL11 study who received a first infusion of obinutuzumab (N=331) or rituximab (N=326) were included. Baseline pre-treatment risk factors thought to play a possible role in the development of IRR were identified a priori and included patient demographics, concurrent conditions and premedications, parameters of disease burden, prognostic factors, laboratory variables and FcγR genotype. Baseline values for mean fluorescence intensity (MFI) of CD20, gated on the circulating CLL clone, and MFI of CD16, gated on the natural killer (NK) cell population (CD56+16+) in peripheral blood were also available for N=510 patients. The primary outcome, development of an IRR with the first infusion, was defined as the occurrence of related signs and symptoms during or within 24 hours of administration of antibody. Due to the short-term nature of the initial IRR a multivariate logistical regression analysis was performed rather than a time to event analysis. Internal validation of this model, derived from a single dataset, was conducted using the established resampling technique of bootstrapping. This assessed the proportion of times each variable retained significance at α=0.10 when the model was fitted to bootstrapped samples of the dataset. Results: Patients that appeared to be at greater risk of developing any grade of IRR with the first infusion of rituximab or obinutuzumab were those treated with obinutuzumab, those with higher surface expression CD20 on CLL cells (MFI CD20) and greater FcγRIIIA (MFI CD16) on NK cells in peripheral blood, those with higher affinity FcγRIIIA genotype (VV), more pronounced neutropenia and splenomegaly at baseline (Table 1). Higher baseline absolute lymphocyte count and the presence of respiratory comorbidity also appeared to increase risk. All variables significant for inclusion in the model are shown in Table 1. Looking at those patients treated with obinutuzumab only, the most important determinant of risk was MFI CD20 (OR 3.6 95% CI 1.6-7.9). The impact of glucocorticoid premedication in reducing risk in obinutuzumab treated patients was not sufficient to reach significance, however, patients were not randomised to this intervention. Conclusion: This work identifies novel disease- and patient-specific biological variables that appear to play a role in the development of IRR in patients with CLL treated with anti-CD20 mAb, although the treatment received (obinutuzumab >rituximab) confers greatest risk. In addition to parameters of tumour burden, target antigen expression and gene polymorphisms of FcγR also appear to contribute to the risk of developing an IRR. Our results support the hypothesis that higher rates of IRR seen with the administration of obinutuzumab may result from stronger activation upon binding to CD20 on leukemic cells and subsequent enhanced cross-linking between CD20 expressing leukemic cells and FcγRIIIA bearing effector cells. Further studies involving obinutuzumab in this patient population will be needed to externally validate the results of this exploratory analysis. Disclosures Freeman: Roche Pharmaceuticals: clinical research fellowship supported by Roche Pharmaceuticals (secondment from Bart's) Other. Dixon:Roche Pharmaceuticals: Employment. Houghton:Roche Pharmaceuticals: Employment. Humphrey:Roche: Employment. Fingerle-Rowson:Roche Pharmaceuticals: Employment. Kreuzer:Roche Pharmaceuticals: Research Funding. Engelke:Roche: Travel grants Other. Hallek:Roche Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Goede:Bristol Myers Squibb: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

Download Full-text

Alkaline Phosphatase (ALP) Variation During Carfilzomib Treatment Is Associated to Best Response in Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.2865.2865 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2865-2865 ◽

Cited By ~ 2

Author(s):

Maurizio Zangari ◽

Latha Polavaram ◽

Fenghuang Zhan ◽

Guido J. Tricot ◽

Ravi Vij ◽

...

Keyword(s):

Retrospective Analysis ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Proteasome Inhibitors ◽

Phase 2 ◽

Two Phase ◽

Advisory Committees ◽

Best Response ◽

Ortho Biotech

Abstract Abstract 2865 Poster Board II-841 BACKGROUND: The ubiquitin-proteasome pathway, which has been shown to be an essential cellular degradative system in myeloma cells, can also regulate bone formation through its effects on osteoblast differentiation. Retrospective analysis of variation of ALP during treatment with bortezomib indicates a close correlation between myeloma response and serum ALP levels which multiple studies have shown to be of bone origin. To determine if this effect is a class effect of proteasome inhibitors (PIs), this retrospective study analyzed variation of ALP in relationship to myeloma response during treatment with carfilzomib, the first in a new class of selective epoxyketone PIs that has demonstrated encouraging safety and efficacy in two phase 2 studies of relapsed or refractory myeloma patients. METHODS: Retrospective analysis of serum ALP was performed on relapsed or refractory myeloma patients enrolled on two phase 2 studies (PX-171-003 and PX- 171-004) evaluating the safety and efficacy of single agent carfilzomib. We analyzed data from 38 patients in the first cohort of the PX-171-003 study, a relapsed and refractory myeloma trial for patients who have received ≥ 3 prior therapies including bortezomib and an IMiD and 29 patients in PX-171-004, a relapsed or refractory myeloma trial that included bortezomib naïve patients. All patients received 20 mg/m2 of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. RESULTS: Seventy-seven patients were enrolled. The median age was 63 years with a median time since diagnosis of 4.6 years, 52% were male, 84.% had relapsed after autologous transplants, 82.% were previously exposed to bortezomib, and 92% were previously exposed to an IMiD. Sixty seven patients with ALP data were evaluable for response. In PX-171-003 the ORR (≥PR) was 18% and the clinical benefit response (CBR; ≥MR) was 26%, while in PX-171-004 the ORR was 35.5% overall and 57% in bortezomib naive patients. ALP increment from baseline, which was most evident during the second cycle of treatment, was statistically different in patients who achieved ≥VGPR compared to all others on Days 1 (P=0.0049) and 8 (P=0.006) of Cycle 2. In all patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline An ALP increase over the same period of time was seen in 26 %, 13%, and 11% of patients achieving PR, MR, and SD, respectively. None of the patients with progressive disease exhibited a similar increase. Our study indicates that response first assessed on Day 15 of Cycle 1 parallels the ALP elevation which returned to baseline levels at the end of Cycle 3. CONCLUSIONS: This retrospective analysis on a subset of patients in these ongoing phase 2 studies of single agent carfilzomib in relapsed or refractory multiple myeloma suggests that elevation in ALP may be associated with best response. Taken with previous publications describing bortezomib treatment, these results suggest that this specific anabolic bone phenomenon could be a class effect of proteasome inhibitors. These phase 2 studies are ongoing with a higher dose of carfilzomib (27 mg/m2) being evaluated. The data from this small subset analysis suggests that further exploration of this relationship is warranted. Disclosures: Zangari: Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Vij:Proteolix: Consultancy, Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stewart:Millennium: Consultancy, Research Funding; Proteolix: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria. Wang:Proteolix: Honoraria, Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau.

Download Full-text

A Randomized Study of Low Dose Oral Clofarabine 10 Mg Versus 20 Mg (flat dose) Daily × 5 for Patients with Higher-Risk Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v120.21.3851.3851 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3851-3851

Author(s):

Stefan Faderl ◽

Guillermo Garcia-Manero ◽

Farhad Ravandi ◽

Jorge E. Cortes ◽

Zeev Estrov ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Randomized Study ◽

Patient Characteristics ◽

Median Number ◽

Infectious Complications ◽

Advisory Committees ◽

Platelet Recovery ◽

Flat Dose ◽

Secondary Mds

Abstract Abstract 3851 Clofarabine (CLO) is a nucleoside analog with activity in myeloid malignancies. We have previously reported an overall response rate (ORR) of 43% (CR rate 25%) in patients (pts) with higher-risk MDS treated with oral CLO at doses between 20 mg/m2 and 40 mg/m2 daily × 5 (S Faderl et al. J Clin Oncol 2010, 28: 2755). However, myelosuppression and infectious complications were frequent. We therefore developed a trial based on a Bayesian randomization design of CLO 10 mg vs 20 mg (flat dose) orally daily × 5 days with the objective to maintain reasonable efficacy and minimize toxicities. Cycles were repeated every 4 to 8 weeks for up to a total of 12. Pts were eligible if they had MDS with ≥ 5% blasts (including RAEB-t by FAB) or IPSS intermediate-2 and high-risk, and CMML. Hematopoietic growth factor support prior to and during the study was permitted. Thirty-two pts (19 RAEB [59%], 7 RAEB-t [22%], 2 MDS/MPN [6%], 4 CMML [13%]) were randomized. Patient characteristics were similar between the groups and are summarized in Table 1. Table 1: Patient Characteristics Characteristic 10 mg 20 mg N 16 16 Median age, yrs (range) 67.5 (43–87) 72.5 (54–84) Median WBC, ×109/L (range) 4 (1.2–121.3) 4.8 (0.4–47) Median blood blasts, % (range) 0.5 (0–25) 3.5 (0–32) Median marrow blasts, % (range) 12 (4–28) 12 (2–24) Secondary MDS, N (%) 9 (56) 4 (25) Median N prior therapies (range) 1 (0–3) 1 (0–4) Prior hypomethylator therapy, N 14 (88%) 13 (81%) Cytogenetics 5 (31) 6 (38) Diploid, N (%) 4 (25) 4 (25) -5/5q- and/or -7/7q- 4 (25) 2 (13) IM/not done Seven pts (22%) responded: 3 CR and 4 CR without platelet recovery (CRp). Four pts (25%) in the 10 mg group and 3 pts (19%) in the 20 mg group responded (differences not significant). Median remission duration was 6.5 months for all pts (6.5 months [10 mg]; 4.4 months [20 mg], p=.942). The median number of cycles was 2 in each treatment group with a range of 1–4 (10 mg) and 1–12 treatment cycles (20 mg), respectively. One pt in each group died. Median survival for the whole group was 8.5 months (8.2 months [10 mg]; 8.5 months [20 mg], p=.9). Clofarabine at both 10 mg and 20 mg orally daily × 5 has a comparable CR/CRp rate as do higher doses. Myelosuppression does still occur but prolonged myelosuppression has been rare. Even lower doses including at different schedules may still warrant further study. Disclosures: Faderl: Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Clofarabine in MDS. O'Brien:Avila: Research Funding; Bayer: Consultancy; Bristol-Myers Squibb: Research Funding; Gilead Sciences: Consultancy, Research Funding; Celgene: Consultancy; Cephalon: Consultancy; CII Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Research Funding; Genzyme: Consultancy; GlaxoSmithKline: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Seattle Genetics, Inc.: Consultancy; Sigma Tau Pharmaceuticals: Consultancy; Talon: Research Funding; The Medal Group: Speakers Bureau. Kantarjian:Genzyme: Research Funding.

Download Full-text

Hypercholesterolemia In Imatinib Intolerant/Resistant CML-CP Patients Treated With Nilotinib: A Retrospective Analysis

Blood ◽

10.1182/blood.v122.21.1503.1503 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1503-1503 ◽

Cited By ~ 9

Author(s):

Devendra K. Hiwase ◽

David T Yeung ◽

Lisa Carne ◽

David Ross ◽

Andrew Grigg ◽

...

Keyword(s):

Risk Factors ◽

Lipid Profile ◽

Retrospective Analysis ◽

Board Of Directors ◽

Research Funding ◽

Lipid Profiles ◽

Cvd Risk Factors ◽

Cvd Risk ◽

Advisory Committees ◽

Before And After

Abstract Background CML patients (pts) enjoy prolonged leukaemia-free survival with tyrosine kinase inhibitor (TKI) treatment. Addressing common non-CML causes of morbidity and mortality such as cardiovascular disease (CVD) and its associated risk factors is therefore increasingly important. Anecdotal evidence suggests a possible association between nilotinib (NIL) therapy and vascular events though there is little good quality evidence in this regard. The incidence of hyperlipidaemia and hyperglycaemia is higher in NIL-treated pts compared to imatinib- (IM) treated pts; conversely IM treatment may retard development of dyslipidaemia and hyperglycaemia. This retrospective analysis assessed the lipid profile of CML-CP pts before and after changing from IM to NIL therapy. Method Plasma lipid profile (total cholesterol, LDL, HDL and triglycerides), TKI exposure, and CVD risk factors before and after switchover to NIL of chronic phase CML pts were analysed. Baseline measurements were done during IM treatment or within 2 weeks of changing from IM to NIL. Follow-up results were obtained at least 1 month after starting NIL. Results Thirty-one CML pts were switched to NIL (median dose 400mg bd) after a median of 27 (1-96) months of IM therapy, predominantly for intolerance (16/31, 52%) or for failure to achieve deep molecular responses (13/31, 42%). Median age at NIL start was 51 (17-80) years (Table I). After switching to NIL, three pts had new onset PVD/IHD and one patient had multiple recurrences of PVD. Antihypertensive and hypoglycaemic medications were started in one additional patient each after switching over to NIL. Three pts were excluded from further analysis because of lack of data (n=2) or pre-existing dyslipidemia (n=1). The remaining pts had 90 TC assays, 72 of which were full lipid profiles whilst on NIL. Observations were censored at the time of statin commencement. Median time to 1st lipid measurement on NIL was 108 days (28-633) after switching. Median TC on IM was 4.7mM (2.1-6.4), compared to 6.1mM on NIL (3.1-8.5). Median peak TC on NIL was 6.8mM. Full fasting lipid profiles available for 11 pts before and after switching showed significantly increased LDL to be the major contributor to the increase in TC (Fig. 2). Thirteen pts had a fasting TC >5.5 mM (210 mg/dL) whilst on NIL, peaking at 312 days (medians). Eight of 13 pts started statins treatment for dyslipidemia whilst on NIL; (all retrospectively confirmed to be appropriate according to Australian National Heart Foundation guidelines, using a composite measure of CVD risk); whilst the other 5 were offered lifestyle modifications only. Of note, 2 pts had dyslipidaemia prior to starting IM treatment, discontinued statins whilst on IM, and had recurrence of dyslipidaemia after switching to NIL necessitating resumption of statin treatment. In addition, the 2 pts with PVD were also offered statins (total starting statin n=10) Discussion This retrospective analysis showed a high incidence of dyslipidemia in a cohort of CML pts treated with second-line NIL after IM therapy; 10/31 pts required lipid lowering agent. While the epidemiological association between nilotinib and CVD remains controversial, the increase in TC may have a contributing effect. Monitoring lipid levels in NIL-treated pts is prudent, along with screening for and minimisation of concomitant CVD risk factors, especially in pts previous treated with IM which may mask underlying metabolic syndromes. # DKH DTY and LC contributed equally to this work. Disclosures: Hiwase: Novartis Pharmaceuticals: Research Funding. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria. Hughes:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Download Full-text

Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination with Ibrutinib Is Highly Active in Patients with Relapsed and/or Refractory CLL and MCL; Results of a Phase II Trial

Blood ◽

10.1182/blood.v124.21.4679.4679 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4679-4679 ◽

Cited By ~ 5

Author(s):

Jeff P. Sharman ◽

Charles M. Farber ◽

Daruka Mahadevan ◽

Marshall T. Schreeder ◽

Heather D. Brooks ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Alkylating Agent ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Highly Active ◽

Efficacy Assessment ◽

Equity Ownership ◽

Anti Cd20

Abstract Introduction: Ublituximab (UTX) is a novel, chimeric monoclonal antibody (mAb) which targets a unique epitope on the CD20 antigen and has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab and ofatumumab, particularly against cells that express low CD20 levels. Two Phase I trials of single agent UTX in relapsed/refractory CLL reported significant response rates with rapid and sustained lymphocyte depletion and a manageable safety profile. Ibrutinib, a novel oral BTK inhibitor approved for patients with previously treated CLL and MCL, displays high single agent activity and has reported increased activity in combination with non-glycoengineered anti-CD20 mAbs. Herein we report safety and efficacy data on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, from an ongoing Phase 2 trial. Methods: Eligible patients have relapsed or refractory CLL/SLL or MCL with an ECOG PS ≤ 2. The study was designed to assess safety, tolerability, and early overall response rate, with an initial safety run-in period consisting of 6 patients followed by open enrollment. UTX (Cohorts of 600 and 900 mg for CLL and at 900 mg for MCL patients) is administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib is started on Day 1 and continues daily at 420 mg and 560 mg for CLL and MCL patients respectively. Following Cycle 6, patients come off study but remain on ibrutinib. Primary endpoint for safety: Adverse Events and Dose Limiting Toxicities (DLT) during safety run-in. Phase II primary efficacy endpoint: ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only. Results: 40 patients (33 CLL/ 7 MCL) have been enrolled to date with enrollment continuing. 23 M/17 F, median age 72 yr (range 52-86), ECOG 0/1/2: 20/19/1, median prior Tx = 2 (range 1-6), 38% with ≥ 2 prior anti-CD20 therapies; prior purine analog = 43%; prior alkylating agent = 68%; and prior purine and alkylating agent = 43%. No DLTs were observed during the safety run-in. Gr 3/4 AE’s occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia, thrombocytopenia, diarrhea, rash, leukocytosis, and infusion related reaction. There were no Grade 3/4 adverse events reported in ≥ 10% of patients. Ibrutinib was dose reduced due to an AE in 2 patients (1 diarrhea, 1 rash) and discontinued in 2 patients due to ibrutinib related AE’s (diarrhea and rash). IRR’s were managed with infusion interruptions with no patient requiring an ublituximab dose reduction. As of July 2014, 24/40 patients are evaluable for response. Best response to treatment is as follows: TableTypePts (n)CR (n)PR (n)SD (n)ORR (%)CLL non 17p/11q10-9190%17p/11q817-100%Total CLL18116194%MCL632183% The one CLL patient who achieved stable disease had a 46% nodal reduction. UTX appears to control ibrutinib related lymphocytosis with more than half of the patients within normal range for ALC by first efficacy assessment. Conclusions: Data suggests ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in patients with relapsed or refractory CLL and MCL. ORR was 94% in patients with CLL (100% in patients with high risk CLL: 17p, 11q del with 1 CR), with responses attained rapidly (median TTR: 8 weeks). In MCL, 83% of patients achieved a response at first efficacy assessment, with 50% of patients achieving a CR by week 20. For most patients, responses improved by the second efficacy assessment. The addition of ublituximab appears to mitigate ibrutinib related lymphocytosis producing earlier clinical responses than historically seen with ibrutinib monotherapy. Efficacy and safety will be updated on all enrolled patients. Disclosures Sharman: TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding. Farber:Leukemia Lymphoma Society NJ Chapter: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Stock ownership Other. Schreeder:TG Therapeutics, Inc.: Research Funding. Kolibaba:TG Therapeutics: Research Funding; Gilead: Research Funding; Glaxo Smithkline: Research Funding. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Greenwald:TG Therapeutics: Research Funding.

Download Full-text

Phase IIa Study of Single-Agent MOR208 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v126.23.1528.1528 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1528-1528 ◽

Cited By ~ 4

Author(s):

Wojciech Jurczak ◽

Pier Luigi Zinzani ◽

Gianluca Gaidano ◽

Andre Goy ◽

Mariano Provencio ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Hodgkin's Lymphoma ◽

Clinical Activity ◽

Advisory Committees ◽

Cd20 Antibody ◽

Grade 3

Abstract Introduction: There remains a high unmet medical need for new therapies for patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is a B-lymphocyte, lineage-specific surface antigen that is highly expressed by most B-cell NHLs. CD19 expression is maintained on lymphoma cells which have CD20 expression downregulated following treatment with the CD20 antibody, rituximab. Consequently, MOR208 (XmAb5574; MOR00208), an Fc-engineered, humanized, monoclonal antibody that targets CD19, may have clinical utility as a new therapeutic approach to R-R NHL. A phase I study showed MOR208 to be safe and well-tolerated with encouraging single-agent activity in patients with chronic lymphocytic leukemia (CLL); an intravenous dose of 12 mg/kg was recommended for phase II studies. Methods: This is a non-randomized, open-label, multicenter, two-stage, phase IIa study of MOR208 in adult patients with R-R NHL whose disease had progressed after at least one prior therapy containing the CD20 antibody, rituximab. In stage 1, 10 patients were to be enrolled into each of four NHL subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent NHL (iNHL) and mantle cell lymphoma (MCL). Patients were to receive single-agent MOR208, 12 mg/kg intravenously, weekly, for 8 weeks (2 cycles). Those with at least stable disease by the 2007 International Response Criteria could continue MOR208 treatment for an additional 4 weeks (total of 12 weeks of therapy). Patients with a complete or partial response (CR or PR) after 12 weeks could then receive MOR208 as maintenance therapy, every 2 or 4 weeks depending on the investigator's decision, until progression. In stage 2, cohorts with ≥2 responses (CR or PR) were to be expanded by at least 20 additional patients. The primary endpoint was the overall response rate (ORR). Key secondary endpoints included duration of response, safety, immunogenicity of MOR208, pharmacokinetics and pharmacodynamics. Results: The DLBCL and FL cohorts were expanded (to N=35 and N=34 patients, respectively), leading to a total enrollment of 92 patients: 56 (61%) were male; median age was 66.5 (range 35-90) years; 80 (87%) had stage III-IV disease; 41 (45%) had received ≥3 prior lines of therapy and 10 (11%) had received a prior stem-cell transplant. The investigator-assessed ORR across all NHL subtypes was 23% (21/92 patients; 16 not evaluable at cutoff) with clinical activity seen in the DLBCL (26% [9/35]; 2 CR, 7 PR); FL (26% [9/34]; 3 CR, 6 PR) and iNHL (27% [3/11]; 2 CR, 1 PR) cohorts (MCL, 0/12 responses). The iNHL cohort was not expanded as the response pattern in this subgroup was heterogeneous according to lymphoma subtype. The longest durations of response recorded to date are 15.4 months for FL and 14.2 months for DLBCL (both ongoing). Grade ≥3 non-hematologic and hematologic treatment-emergent adverse events (TEAEs) were recorded in 24 (26%) and 14 (15%) of 92 patients, respectively. The most commonly reported grade ≥3 hematologic TEAEs were neutropenia (7 [8%] of 92 patients, anemia (4 [4%]), and thrombocytopenia (4 [4%]); such TEAEs were seen most frequently in the DLBCL cohort (10 [29%] of 35 patients overall; neutropenia, 5 [14%], anemia, 4 [11%], thrombocytopenia, 2 [6%]). Dyspnea was the most commonly reported grade ≥3 non-hematologic TEAE (4 [4%] of 92 patients). Infusion-related reactions were seen in 9 (10%) of 92 patients; all were grade 1-2, except for one case of dyspnea, grade 4. There were no treatment-related deaths. Clinical activity in patients with R-R DLBCL appeared to be dependent on attaining a defined cumulative exposure (AUC0-t) over 8 weeks of around 11,000 day*µg/mL; i.e., at the data cutoff date, all 8 patients with a PR after 2 cycles showed an exposure above this potential threshold level. Conclusions: MOR208 demonstrated encouraging single-agent activity with CRs observed in patients with R-R DLBCL, FL, and iNHL. MOR208 was well tolerated without significant infusional toxicity. These data support further development of MOR208 in combination with other agents (including lenalidomide and bendamustine), and protocols for studies in patients with R-R DLBCL are now being developed. Disclosures Jurczak: CELLTRION, Inc,: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gaidano:Celgene: Research Funding; MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards. Goy:Celgene: Consultancy, Research Funding, Speakers Bureau; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Research Funding. Buske:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy. Korolkiewicz:MorphoSys AG: Employment. Striebel:MorphoSys AG: Employment. Blum:Morphosys: Research Funding; Gilead: Research Funding; Millenium: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene: Research Funding.

Download Full-text

Impact of the COVID-19 Pandemic on in-Person Visit Rates Among Patients with Hematologic Malignancies in the United States

Blood ◽

10.1182/blood-2021-153625 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1930-1930

Author(s):

Gaurav Goyal ◽

Krystal W. Lau ◽

Xiaoliang Wang ◽

Amy J. Davidoff ◽

Scott F. Huntington ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hematologic Malignancies ◽

Publicly Traded ◽

Advisory Committees ◽

Visit Rate ◽

Line Of Therapy ◽

Monthly Visit ◽

All Diseases ◽

Privately Held

Abstract Background/objectives: The COVID-19 pandemic led to a dramatic reduction of in-person medical care in the general population; however, impacts have not been well-characterized for patients with hematologic malignancies. This study assessed the impact of COVID-19 on healthcare delivery for patients with hematologic malignancies with documented active treatment. Methods: Patients from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database with confirmed diagnosis of AML, DLBCL, FL, MCL, CLL or MM, and age ≥ 18 years at initial diagnosis were included. To be included in the study, documented receipt of at least one systemic, non-maintenance line of therapy between March 1, 2016 - February 28, 2021 was required. Patients were categorized into treatment types within lines of therapy: Oral therapy (OralTx); outpatient infusions (OutPtTx); and inpatient infusions, including hematopoietic transplants and CAR-T cell therapy (InPtTx). Monthly visit rates were calculated as the number of visits (telemedicine or in-person [in-clinic treatment administration, vitals, and/or labs]) per active patient per 30-day standardized month. Only visits occurring within a line of therapy were included (i.e. during active therapy, excluding surveillance). Telemedicine was only available for abstraction during the pandemic period. We used time-series forecasting methods on pre-pandemic monthly visit rate data (March 2016 - February 2020) to estimate projected counterfactual visit rates between March 2020 - February 2021 (expected in-person visit rates if the pandemic had not occurred) for all diseases combined, each disease, and each treatment type. Differences between projected and actual monthly visit rates during the pandemic period were considered statistically significant and related to the pandemic if the actual visit rate was outside of the 95% prediction interval (PI) surrounding the projected estimate. Results: A total of 22,559 patients were included in this analysis (6,241 OralTx, 14,501 OutPtTx, 7,675 InPtTx): 4,069 AML, 3,641 DLBCL, 2,004 FL, 1,899 MCL, 4,574 CLL and 6,701 MM. There was a gradual downward trend in in-person visit rates across all diseases over the study period (March 2016 - February 2021, Figure) and general visit frequencies were lower for OralTx and higher for OutPtTx and InPtTx overall. For all diseases combined, early pandemic months (March - May 2020) saw an 18% (95% PI 8.9% - 25%) reduction in in-person visit rates averaged across OralTx and OutPtTx, with the projected rate being 1.5 (95% PI 1.3 - 1.6) visits per patient per month, compared to an actual rate of 1.2. Reductions in the in-person visit rates were significant for all 3 treatment types for MM, for OralTx for CLL, and for OutPtTx for MCL and CLL. Telemedicine visit rates were greatest for patients who received OralTx, followed by OutPtTx, then InPtTx, with greater use in the early pandemic months and subsequent decrease in later months. All in-person visit rates increased close to predicted rates in the later half of the pandemic period. Conclusions: In treatment of hematologic malignancies, overall documented in-person visit rates for patients on OralTx and OutPtTx significantly decreased during early pandemic months, but returned close to the projected rates later in the pandemic. There were no significant reductions in the overall in-person visit rate for patients on InPtTx. Variability in these trends by disease type was observed, with significant reductions in in-person visits impacting MM, CLL, and MCL. Figure. Visit rates over time according to treatment category Figure 1 Figure 1. Disclosures Lau: Roche: Current equity holder in publicly-traded company; Flatiron Health Inc: Current Employment. Wang: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Davidoff: AbbVie: Other: Family member consultancy; Amgen: Consultancy. Huntington: Bayer: Honoraria; Thyme Inc: Consultancy; Novartis: Consultancy; Flatiron Health Inc.: Consultancy; Genentech: Consultancy; SeaGen: Consultancy; Servier: Consultancy; AstraZeneca: Consultancy, Honoraria; TG Therapeutics: Research Funding; DTRM Biopharm: Research Funding; AbbVie: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Calip: Pfizer: Research Funding; Roche: Current equity holder in publicly-traded company; Flatiron Health Inc: Current Employment. Shah: AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Epizyme: Research Funding. Stephens: CSL Behring: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Celgene: Consultancy; JUNO: Research Funding; Mingsight: Research Funding; Abbvie: Consultancy; Arqule: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Epizyme: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Miksad: Flatiron Health Inc: Current Employment, Current holder of individual stocks in a privately-held company; Roche: Current equity holder in publicly-traded company. Parikh: GNS Healthcare: Current holder of individual stocks in a privately-held company; Onc.AI: Current holder of individual stocks in a privately-held company; Humana: Honoraria, Research Funding; Nanology: Honoraria; Thyme Care: Honoraria; Flatiron Health Inc: Honoraria. Takvorian: Pfizer: Research Funding; Genentech: Consultancy. Neparidze: GlaxoSmithKline: Research Funding; Janssen: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees. Seymour: Flatiron Health Inc: Current Employment; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Current equity holder in publicly-traded company; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

Download Full-text