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 3077Another 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.
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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.
Introduction: B-cell malignancies may depend on the histone methyl transferase EZH2 to perpetuate a less differentiated state, with activating mutations of EZH2 being potential oncogenic drivers. ...Tazemetostat, a potent, selective EZH2 inhibitor, is in Phase 2 clinical development in relapsed or refractory (RR) Non-Hodgkin Lymphoma (NHL). Objective responses were observed in patients with EZH2 mutant or wild type (WT) tumors in the Phase 1 part of the Phase 1/2 study. The ongoing Phase 2 study enrolls patients with mutant or WT EZH2 havingRR Diffuse Large B-Cell Lymphoma (DLBCL) or Follicular Lymphoma (FL) to determine efficacy and safety. The primary endpoint is overall response rate. Here we report results of a molecular analysis of circulating tumor DNA (ctDNA) collected from patient's plasma and associations with preliminary response data, including the discovery of novel candidate molecular predictors of tazemetostat response.
Methods: Archived tumor and/or plasma-derived ctDNA samples were obtained during screening in the Phase 2 trial of tazemetostat in NHL (NCT01897571).Prospectively, archived tumor was analyzed for EZH2 hot spot mutations Y646X, A682G and A692V using the cobas® EZH2 Mutation Test (Roche Molecular Systems, in development). Retrospectively, next generation sequencing (NGS) was performed on archived tumor DNA (target coverage of 1,500X) and ctDNA (20,000X for somatic mutations and 5,000X for structural alterations) to identify somatic mutations, amplifications, and translocations in a panel of 62 genes commonly altered in NHL. Best objective overall response (Cheson 2007) on June 01, 2017 was used to generate three groups: responders (CR + PR; n = 43), progressive disease (PD; n = 66), and patients with either stable disease (SD) or unknown (UK) clinical response (n=76). Genetic alterations identified in ctDNA collected pre-dose, at variant allele frequencies greater than 0.5%, and associated with either the responder or PD groups (discovery case set, n=109) were identified using Fischer's exact test (two-tailed).
Results: Regardless of sample type or technology the concordance rate for detection of EZH2 status was > 95%. NGS and the cobas Test of archived tumor samples was > 99% concordant (n = 128) with 19 EZH2 mutant cases detected by the cobas Test. Concordance of EZH2 status between archived tumor detected by the cobasTestor NGS and ctDNA by NGS was 95% (n = 185). Consistent with published literature KMT2D (65% somatic sequence mutations) and BCL2 (55% of cases including amplification, translocations, somatic sequence mutations) were the most frequently altered genes in our patient population, with somatic sequence mutations in other chromatin modifying proteins CREBBP, HIST1H1E, EZH2, and EP300 occurring in 36, 23, 14 and 11% of patients respectively. With the exception of PIM1 (30% DLBCL and 6% FL) and TNFRSF14 (10% DLBCL and 29% FL) the top 5 genes identified had similar mutation frequencies between DLBCL (n=122) and FL (n=63) cases. Analysis of 109 discovery cases, including both DLBCL and FL patients revealed STAT6 mutations as the variant demonstrating the most significant association (P <0.13) with clinical response (CR + PR) to tazemetostat. Further refinement of the analysis by disease cohort identified CREBBP (P <0.10) and EZH2 (P <0.07) associated with clinical response in DLBCL (n=76) and FL (n=33) respectively. In contrast mutations in ten genes including PIM1 , BCL6 , TP53 and HIST1H1E were affiliated (all P <0.06) with PD (i.e. lack of response to tazemetostat) across both the FL and DLBCL cohorts, with only BCL2 variants demonstrating significance through multiple test correction (adjusted P value = 0.04).
Conclusions: The molecular predictors identified in this ctDNA analysis contain genes previously described as potential predictors of tazemetostat response in archived tumor analysis such as STAT6 , EZH2 , TP53 and HIST1H1E . In addition to these genes, we were able to uncover variants in CREBBP , BCL2 , BCL6 and PIM1 that may offer new insights into potential mechanisms of response, or lack of response to tazemetostat. Moreover to identification of molecular predictors of response, plasma based ctDNA screening has been demonstrated to be a viable method to identify NHL patients with mutant EZH2 in the absence of tumor samples or with lesions in anatomical sites of high risk.
Daigle:Epizyme, Inc: Employment, Equity Ownership. McDonald:Epizyme, Inc: Employment, Equity Ownership, Research Funding. Morschhauser:Roche: Consultancy, Honoraria; Servier: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Salles:Roche/Genentech: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria; Janssen, Celgene, Novartis, and Amgen: Consultancy, Honoraria. Ribrag:Roche: Honoraria, Other: travel, accommodation, expenses; Epizyme: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Esai: Honoraria, Research Funding; Pharmamar: Consultancy; BMS: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; ArgenX: Research Funding; MSD: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Tilly:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunogen: Honoraria. Gerecitano:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Johnson:Epizyme, Inc: Consultancy, Honoraria, Research Funding. Radford:GlaxoSmithKline: Equity Ownership; Novartis: Speakers Bureau; AztraZeneca: Equity Ownership; Seattle Genetics: Speakers Bureau; ADC Therapeutics: Research Funding; Takeda: Research Funding, Speakers Bureau. Dickinson:GlaxoSmithKline: Honoraria, Research Funding. Opat:Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Beigene: Research Funding; Mundipharma: Consultancy; Amgen: Research Funding. Jurczak:Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jagiellonian University: Employment; Gilead: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Celtrion: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding. Cartron:Celgene: Consultancy, Employment; Sanofi, BMS, Jansen, celgene, Roche, Gilead: Equity Ownership; Roche: Consultancy, Equity Ownership, Honoraria, Research Funding. Lamy:Roche: Consultancy, Honoraria. Zinzani:Celgene, Janssen, Gilead, Roche, Takeda, BMS, MSD, Sandoz, Servier, Mundipharma: Speakers Bureau; Merck: Consultancy, Other: Advisory board; Celgene, Roche, Janssen, Gilead, Takeda, BMS, MSD, Servier, Sandoz, Mundipharma: Honoraria. Assouline:Janssen: Honoraria; Paladin: Speakers Bureau; Bristol Myer Squibb: Speakers Bureau; Novartis Canada Inc.: Honoraria; Pfizer: Speakers Bureau. Morin:Epizyme, Inc: Consultancy. Wu:Roche: Employment, Equity Ownership. Sausen:Personal Genome Diagnostics: Employment. Clawson:Epizyme, Inc: Employment, Equity Ownership. Ho:Epizyme, Inc: Employment, Equity Ownership. Miao:Epizyme, Inc: Employment, Equity Ownership. Blakemore:Epizyme Inc.: Employment, Equity Ownership.
Introduction
Venetoclax (V), an orally administered, highly selective, potent BCL-2 inhibitor, induces high ORR when given as monotherapy to pts with relapsed/refractory (R/R) CLL, including ...high-risk populations, e.g. del(17p). V is also well tolerated when combined with rituximab (R) and achieves improved CR rates and minimal residual disease negativity (MRD-). Here, we provide first released data from the primary analysis of MURANO (NCT02005471), the first Phase 3 study of V in pts with R/R CLL, which assessed efficacy/safety of VR vs standard chemoimmunotherapy, bendamustine (B) + rituximab (BR).
Methods
Eligibility for this open-label, randomized, Phase 3 study included R/R CLL requiring treatment (iwCLL guidelines), 1-3 prior lines of therapy (including ≥1 chemo-containing) and ECOG PS ≤1. Prior B was allowed provided response duration was ≥24 mo. Pts were randomized (1:1) to VR or BR. Stratification factors were del(17p), responsiveness to prior therapy and geographic region.
In the VR arm, a 4- or 5-wk graduated dose ramp-up of V from 20-400 mg daily was used to mitigate potential tumor lysis syndrome (TLS) risk. Beginning at Wk 6, R was then given monthly for six 28-day cycles (IV 375 mg/m2 first dose, then 500 mg/m2) in combination with V daily. Pts continued with V 400 mg for a maximum of 2 yr or until disease progression (whichever first). In the BR arm, pts were given B (IV 70 mg/m2) on Days 1 and 2 of each of six 28-day cycles in combination with R using same R dosing schedule. MRD was centrally assessed by ASO-PCR and/or flow cytometry in peripheral blood at screening, Mo. 4 and 9, and 3-monthly follow-up visits.
The primary endpoint was investigator (INV)-assessed PFS. An interim analysis was preplanned at ~140 INV-assessed PFS events. On data review, an Independent Data Monitoring Committee recommended study arms to be unblinded to the sponsor as pre-specified statistical boundaries for early stopping were crossed for PFS in favor of VR.
Results
389 pts were enrolled in VR (n=194) and BR (n=195) arms, which were well balanced: median (range) age, 64.5 (28-83) vs 66.0 (22-85) yr; 1 prior therapy, 57.2% vs 60.0%; fludarabine refractory, 14.1% vs 15.5%; del(17p), 26.6% vs 27.2%. At data cut-off (8 May 2017; median follow-up, 23.8 mo. range 0.0-37.4), INV-assessed PFS was superior for VR vs BR with HR 0.17, 95% CI 0.11-0.25, P<0.0001; median not reached vs 17.0 mo. (Fig 1). 24-mo. PFS estimates were 84.9% vs 36.3%, respectively. Consistent treatment effects on PFS were observed in all subgroups assessed (Fig 2). With HR 0.19, 95% CI 0.13-0.28, P<0.0001, Independent Review Committee-assessed PFS showed a similar magnitude of benefit. Key secondary efficacy endpoints showed consistent improvements for VR vs BR including a notable improvement in OS (HR 0.48, 95% CI 0.25-0.90). INV-assessed ORR was 93.3% with VR vs 67.7% with BR (Δ=25.6%, 95% CI 17.9-33.3%); CR/CRi was achieved in 26.8% vs 8.2% of pts, respectively (Table 1). Higher peripheral blood MRD- rates attained at any time were seen with VR vs BR (83.5% vs 23.1%; Δ=60.4%, 95% CI 52.3-68.6%) by ITT analysis. MRD negativity was more durable in the VR arm.
Consistent with known safety profiles of the regimens, Grade 3-4 neutropenia was higher in VR arm but there was no increase in febrile neutropenia or Grade 3-4 infection (Table 2). There were 6 (3.1 %) and 2 (1.1%) Grade ≥3 AEs of TLS reported for VR and BR, respectively; one clinical TLS event in each arm (a Grade 4 acute renal failure in BR, transient increase in creatinine in VR; VR event occurred on an earlier 4-week ramp-up schedule). Richter transformation was confirmed in 6 pts and 5 pts for VR vs BR, respectively. AEs leading to death were seen in 5.2% vs 5.9% of pts. Median relative V dose intensity was 97% of protocol-specified drug exposure.
Conclusion
The primary analysis of MURANO, the first Phase 3 study of V in R/R CLL, shows a profound improvement in PFS vs standard BR chemoimmunotherapy, with consistent effects in all-risk subsets. Key secondary endpoints, including OS, ORR and CR rate, also showed consistent improvements with remarkable rates of peripheral blood MRD- that exceed those previously attained in treatment of R/R CLL. This enhanced disease control was achieved in a multinational setting with an acceptable safety profile, without significant TLS, demonstrating that treatment with VR resulted in outcomes superior to that of BR for pts with R/R CLL.
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Seymour:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps:Celgene: Consultancy; Oncternal: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Eichhorst:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Hillmen:Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. D'Rozario:Roche: Consultancy. Assouline:Lundbeck: Other: Advisory Board; Paladin: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myer Squibb: Speakers Bureau; Roche Canada: Consultancy. Owen:AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Merck: Honoraria. Gerecitano:Merck: Consultancy; Mass Medical International: Consultancy; Incyte: Consultancy; Arcus Medica: Consultancy; Aratana: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Samus Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Orexo: Consultancy. Robak:AbbVie: Honoraria, Research Funding; Akari Therapeutics Plc: Honoraria, Research Funding; Roche: Honoraria, Research Funding. De la Serna:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jaeger:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria; AOP Orphan: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; GSK: Honoraria; Infinity: Honoraria; Millennium: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding. Cartron:Gilead: Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Montillo:Novartis: Honoraria; Roche: Research Funding; Abbvie: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Humerickhouse:AbbVie: Employment, Equity Ownership. Punnoose:Genentech: Employment. Li:Genentech: Employment. Boyer:Roche: Employment. Humphrey:F-Hoffmann-La Roche: Employment, Equity Ownership. Mobasher:Roche: Equity Ownership; Genentech: Employment. Kater:Roche: Consultancy; Acerta/Astra Zeneca: Consultancy, Research Funding; Roche/Genentech: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Research Funding; Sandoz: Consultancy.
Introduction
Early relapse after frontline therapy of follicular lymphoma (FL) has been previously shown to correlate with a shorter survival. However, earlier studies were analyzed based on standard ...CT scan imaging. In this study, we examined the impact of early relapse on FL survival using 18FDG PET (PET) imaging.
Patients and Methods
We identified 1,120 patients (≥ 18 years) with follicular lymphoma (FL) diagnosed between 1998 and 2009 excluding those with ≤2 visits, divergent histology at initial diagnosis, and presence of concurrent malignancy. OS was defined as time of diagnosis to last follow up or death. Patients were excluded from event free survival analysis if they were never treated, or died before or during frontline treatment. Achieving event free survival at 24 mo (EFS24) was defined as being alive and event free 24 months from start of treatment. Not achieving EFS24 was defined as being alive but having an event by 24 months from start of treatment. An event was progression or change of treatment. Subsequent OS was defined as time from 24 months after start of treatment to last follow up or death and was compared between patients who achieved or did not achieve EFS24 by Kaplan-Meier method and log-rank test.
Results
Stage at diagnosis for 1,110 patients was I, N=196; II, N=143; III-IV, N=745. Median age of diagnosis was 57 years with 51% males. With a median follow up of 8.2 years (range 0.2-17.5 years), median overall survival was not reached. At diagnosis, 676 patients were imaged with PET while 408 patients were imaged with CT. Stage I and II patients imaged with a PET at diagnosis had a significantly better OS than those imaged with a CT scan (log-rank p=0.003 and 0.041, respectively) (Figure 1A-B). In advanced stage patients (III/IV), PET versus CT imaging did not affect OS (Figure 1C). For stage I patients the 10-year OS was 82% using CT imaging and 94% using PET imaging. For stage II patients 10 year OS was 68% by CT imaging and 90% by PET imaging. We subsequently analyzed the predictive value of EFS24 using PET imaging using a subset of 303 stage II-IV FL patients treated with RCHOP as frontline therapy evaluable for EFS24 (Figure 2A). CT imaged patients demonstrated a better OS benefit for patients achieving EFS24 (Figure 2B). In contrast, the impact of EFS24 on OS was insignificant for PET imaged patients (Figure 2C). The 10 year OS for CT imaged patients was 83% (95% CI 74-93%) for those achieving EFS24, and 41% (95% CI 20-84%) for those not achieving EFS24. For patients imaged with PET prior to first treatment, 10 year OS was 80% (95% CI 69-93%) for those achieving EFS24, and 75% (95% CI 61-92%) for those not achieving EFS24.
Conclusion
Use of PET imaging is an increasingly common practice in management of lymphoma. Analyzing the overall survival of PET imaging versus CT imaged patients, PET imaging at diagnosis more accurately predicts overall survival for stage I and II patients. EFS24 as examined using CT based imaging has been proposed to inform OS in FL. In this single center subset, the predictive value of EFS24 is not observed in patients imaged with PET at the time of treatment. Therefore, EFS24 as a clinical marker for poor outcome may need to be re-examined using modern PET imaging. In conclusion, PET imaging is an important component of the management of FL for appropriate staging and assessment of prognosis.
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Moskowitz:Genentech BioOncology: Consultancy; Merck: Consultancy, Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding. Horwitz:Kyowa-Hakka-Kirin: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Aileron Therapeutics: Research Funding; BMS: Consultancy; HUYA: Consultancy. Zelenetz:Celgene: Consultancy; Amgen: Consultancy. Moskowitz:Seattle Genetics: Honoraria, Research Funding; ADC Therapeutics: Research Funding; Incyte: Research Funding; Takeda: Honoraria; Bristol Myers-Squibb: Consultancy, Research Funding. Gerecitano:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamlin:Seattle Geneitcs: Other: research support; Novartis: Other: research support; Incyte: Other: research support; Gilead: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support; Celgene: Consultancy, Honoraria. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Noy:Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau. Straus:Received consulting fee from Seattle Genetics for involvement in the research: Consultancy. Drullinsky:Seattle Genetics: Honoraria, Other: Ad Board. Younes:Sanofi: Honoraria; Bayer: Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Curis: Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria; Novartis: Research Funding; Takeda Millenium: Honoraria; Johnson & Johnson: Research Funding; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria.
INTRODUCTION
Next-generation sequencing of diffuse large B cell lymphoma (DLBCL) has revealed a vast landscape of genetic alterations. Unfortunately, very few of these carry a significant prognostic ...power or confer a different response to therapy. Unique, in this respect, are mutations in TP53, which have been implicated in over a third of the refractory cases to frontline regimes. This study aimed to evaluate the association between clinical phenotype, disease course and specific genomic alterations of TP53mut DLBCL, comparing de novo to relapsed or refractory disease (R/R), and chemo-sensitive to chemo-resistant cases.
METHODS
We performed a retrospective analysis of patients with DLBCL, treated at Memorial Sloan Kettering Cancer Center, harboring a TP53mut. Formalin fixed, paraffin embedded samples were sequenced using a custom DNA capture panel. Germline variants were filtered against the 1000 Genomes Project. Significant non-synonymous variants were identified by mapping to the COSMIC database, as well as clear inactivating mutations in established tumor suppressor genes. Analysis for TP53 mutations was performed per their affected p53 protein domains, including DNA binding motifs (Loop-L2, Loop-L3, Loop-Sheet-Helix), evolutionary conserved regions, non-conserved and truncating non-missense mutations.1Sequencing was performed at various time-point in the course of the disease. We evaluated TP53mut allele frequency (AF), overall number of TP53mut /patient, and concurrent alterations in other genes. Disease characteristics and clinical course were extracted for first line treatment of DLBCL, as well as from R/R cases. Cell of origin (COO) determination and MYC, BCL2 and BCL6 rearrangements at the time of sequencing were recorded. We evaluated response to treatment and survival in the subset of patients sequenced at diagnosis. Transformed indolent lymphoma (t-DLBCL) cases were evaluated in respects to the time of transformation, but considered R/R if previously treated with chemotherapy.
RESULTS
Of 360 sequenced DLBCL cases, 84 were found to carry a TP53 mutation (35 de novo ; 49 R/R). Of these, 61% had a stage IV disease at presentation, involving extra-nodal sites (mostly musculoskeletal, lung, gastrointestinal and hepatic). Central nervous system involvement was rare throughout the course of the disease (2%). t-DLBCL represented a considerable part of the TP53mut population, more so in R/R disease (59% vs. 29%, p=0.01), where it originated more commonly from follicular lymphoma (76% vs. 50%, p=0.2). R/R was also enriched for Double-Hit disease (41% vs. 20%, p=0.06) and for MYC copy number alterations (59% vs. 20%, p=0.02), though the number of evaluable cases was small.
We identified 105 TP53 mutations, with most patients (86%) harboring only one. Overall, 49% of patients had a mutation involving a DNA binding motif, 26% a non-missense truncating mutations, and 35% a mutation affecting non- DNA binding motif regions (figure 1). R/R disease was associated with a higher AF (0.52 vs. 0.35, p=0.01), but not with a higher overall number of TP53mut or the affected p53 domain. Patients had a median of 4 concurrent mutations in other genes without a clear association with R/R .
Among the R/R patients, 65% were refractory to their first-line chemotherapy, with a median of 4 therapy lines overall. Further, of the 23 patients receiving autologous stem cell transplantation, 52% were refractory. Taken together, these observations suggest that TP53mut may be an early event conferring a high rate of multi-drug resistance. Refractoriness to frontline therapy was also observed in 49% of the de novo case. However, with a median follow-up of 30 months, 2y PFS was nearly 50%, demonstrating a subset of TP53mut patients who fare well (figure 2). There was no association between PFS and the site of TP53mut, total number of TP53 mutations or number and type of concurrent mutations.
CONCLUSIONS
TP53mut is associated with multi-drug resistance and a worse prognosis. However, nearly 50% of newly diagnosed patients can be expected to respond to frontline regimens, many of whom achieving long term remissions. We could not find a clear genomic feature to differentiate Responsive from Refractory patients. Future research should focus on prospectively examining the role of TP53mut in predicting treatment outcomes.
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Zelenetz:Amgen: Consultancy; Celgene: Consultancy. Moskowitz:Celgene: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Genentech BioOncology: Consultancy. Palomba:Merck: Consultancy. Noy:Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau. Straus:Received consulting fee from Seattle Genetics for involvement in the research: Consultancy. Gerecitano:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees. Horwitz:Kyowa Hakko Kirin: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Mundipharma: Consultancy; HUYA: Consultancy; BMS: Consultancy; Seattle Genetics: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Aileron Therapeutics: Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Seattle Genetics: Honoraria, Research Funding; Incyte: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Takeda: Honoraria. Hamlin:Seattle Geneitcs: Other: research support; Celgene: Consultancy, Honoraria; Novartis: Other: research support; Portola: Consultancy, Honoraria, Other: research support; Gilead: Consultancy, Honoraria; Incyte: Other: research support. Kumar:Seattle Genetics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. He:Foundation Medicine, Inc: Employment, Other: Stock. Miller:Foundation Medicine: Employment, Other: Stock. Dogan:Peer Review Institute: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Consultancy. Younes:Bayer: Honoraria; Merck: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Millenium: Honoraria; Johnson & Johnson: Research Funding; Seattle Genetics: Honoraria; Novartis: Research Funding; Curis: Research Funding; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.
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Background
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare disease. In the absence of consensus guidelines, treatment is controversial. Here, we describe the characteristics and ...outcomes of consecutive NLPHL patients diagnosed at Memorial Sloan Kettering Cancer Center (MSKCC) with a focus on active surveillance (AS) as a first-line management strategy.
Methods
We included consecutive patients aged 16 years (y) or older who were diagnosed and followed at MSKCC between 1974 and 2016. All cases were confirmed by a MSKCC hematopathologist as NLPHL without evidence of transformation. We excluded composite lymphomas and patients with any prior hematological malignancy or concomitant active cancer. We compared outcomes between patients followed expectantly (AS) and those treated actively (AT), which included radiotherapy (RT) only, chemotherapy (+/- Rituximab) (CT), combined modality (+/- Rituximab) (CMT), and rituximab monotherapy (R). Progression-free survival (PFS) was defined as time from diagnosis to a biopsy-proven disease progression or relapse, initiation of further treatment or death. PFS2 was defined as time from diagnosis to second biopsy-proven disease progression or relapse, initiation of 3rd-line treatment or death. AS was considered a 1st-line treatment. We used univariable and multivariable survival analyses stratifying patients by disease stage.
Results
In total, 163 patients were included. The median follow-up was 5.7y (Min-Max: 0.3 - 42.7) with 24.5% (n=40) of patients followed for 10y or more. Patient characteristics for all, AS and AT patients are shown in Table 1. Patients were treated with RT only (n=75, 46.0%), AS (n=37, 22.7%), CT (n=26, 15.9%), CMT (n=19, 11.7%) or R alone (n=6, 3.7%).
Overall, outcome of patients was excellent, with 10-year PFS, PFS2 and overall survival (OS) estimates of 71.2% 95%-CI: 59.3-80.1, 92.5% 95%-CI: 83.7-96.6 and 96.6% 95%-CI: 87.6-99.1, respectively. Seven patients died, 3 deaths were likely treatment related and only one lymphoma related death occurred after progression. Twelve transformations to aggressive lymphomas occurred after a median of 7.0y (Min-Max: 0.4 - 15.6). The transformation rate was 0.99% per patient year. Twelve secondary cancers occurred after a median of 7.8y (Min-Max: 1.1 - 24.8).
Only bulky disease ≥ 5 cm (n=21, HR: 3.1 95%-CI: 1.3-7.2, p=0.008) and extranodal disease (n=11, HR: 7.7 95%-CI: 2.1-28.5, p=0.002 were risk factors for a shorter PFS in the final multivariate model after correcting for received treatment.
In pairwise comparison, PFS with CMT (p=0.038) and RT (p=0.032) was superior to AS, but CT was not (p>0.999). PFS2 and OS were not significantly different between groups.
Patients, who received AT (n=126) overall tended to have superior PFS than those in the AS group (n=37) (5-year PFS 97.2% 95%-CI: 79.2-92.2 vs. 76.5% 95%-CI: 55.7-88.5, p=0.068), though this benefit was mainly seen in early stage disease (Ann Arbor I/II) (5-year PFS 94.2% 95%-CI: 86.7-97.6 vs. 65.1% 95%-CI: 43.5-80.2, p<0.001). This did not translate into better PFS2 (p=0.568) or OS (p=0.303) (Figure 1) and was confirmed in a multivariate model controlling for potential confounders that influenced the initial treatment decision. Comparing results in the AS and AT group, death occurred in 0 vs. 7 (0.0% vs. 5.6%), transformation in 2 vs. 10 (5.4% vs. 7.9%) and secondary cancers in 2 vs. 10 (5.4% vs. 7.9%) patients. Only 24.3% (n=9) of the 37 AS patients required treatment after a median of 5.1y (Min-Max: 0.3 - 23.2). Treatments after initial AS were localized radiation (n=4), R-CHOP (n=4) and R monotherapy (n=1) given for local symptoms (n=3), transformation (n=2), progressing nodes (n=2), systemic symptoms (n=1), adrenal insufficiency due to adrenal mass (n=1) and change of management strategy in stable disease (n=1).
Conclusion
NLPHL has an excellent prognosis. Bulky and extranodal disease were identified as potential risk factors for progression. With the limitations of a retrospective analysis, it can be concluded that AS is a viable management strategy in NLHPL. The majority of AS patients require no treatment after multiple years of observation and those that do, can be adequately managed with established treatments. Additionally, no evidence was found for an increased rate of transformation or worse PFS2 or OS in AS patients. Treatment related deaths exceeded deaths from lymphoma.
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Moskowitz:Celgene: Consultancy; Genentech BioOncology: Consultancy; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Merck: Consultancy, Research Funding; Pharmacyclics: Research Funding. Zelenetz:Genentech/Roche, GSK, Gilead, Celgene, Janssen, Hospira, Amgen, Takeda Pharma, Novartis, Nanostring Technologies, Portola Pharmaceuticals, Adaptive Biotechnology: Consultancy; GSK, Janssen, Roche, Gilead, Bristol Myers: Research Funding; Boehringer Ingelheim: Other: DMC Membership. Kumar:Seattle Genetics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Incyte: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding.
Background: Epigenetic manipulation and immunomodulation are therapeutic strategies in hematologic malignancies. In our previous study, the combination of romidepsin and lenalidomide showed a 51% ...overall response rate (ORR), 23% complete response (CR) rate in patients with relapsed/ refractory B-cell (BCL) and T-cell (TCL) lymphoma. Given the potential synergy of proteasome inhibitors with histone deacetylase inhibitors and lenalidomide, we conducted a phase Ib/IIa study evaluating the safety and toxicity of romidepsin and lenalidomide with carfilzomib in patients with relapsed/refractory lymphoma. Here we report the completed phase II results.
Methods: Romidepsin and carfilzomib were given IV on days 1, 8 and lenalidomide was given orally on days 1-14 of a 21-day cycle. A standard 3+3 dose escalation was followed: The starting dose was romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2. Tumor response was based on disease-specific criteria.Patients could be treated until progression, intolerance, or response adequate to allow allogeneic transplantation.
Results: 24 of the 27 patients treated as part of the study were evaluable for determination of the maximum tolerated dose. Additionally, one was evaluable for efficacy and 2 were evaluable for toxicity only. 16 patients were treated for TCL: PTCL-NOS-7, AITL-5, MF-2, transformed MF-1, extra-nodal NK/T-cell lymphoma-1. 11 patients were treated for BCL: DLBCL (7) mantle cell lymphoma (MCL) (2), follicular lymphoma (FL) (2). Of note, one of the aforementioned AITL patients had concurrent DLBCL and was evaluated for efficacy in both B-cell and T-cell cohorts.
Dose level 2 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 45mg/m2) exceeded the MTD with 2/6 DLTs: 1 grade 3 thrombocytopenia resulting in treatment delay and 1 grade 4 thrombocytopenia. There were no DLTs among 6 patients treated in dose level 1 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2) and dose level 1 was deemed the MTD.
Overall, grade 3-4 toxicities in >10% patients included neutropenia and thrombocytopenia. 16 treatment related serious adverse events were seen in 9 patients and included: anemia-1, vomiting/diarrhea-1, dyspenea-1, edema-1, febrile neutropenia-1, fever-2, generalized weakness-1, heart failure-1, hypotension-1, infection-2, gastrointestinal bleed-1, and DVT-1.
Of the 11 TCL evaluable for response at the MTD, ORR was 45.5% (5/11, 95% CI: 23.4 to 83.3%). The complete response (CR) rate was 36.4% (4/11, 95% CI: 10.9 to 69.2%) and the partial response (PR) rate was 9% (1/11, 95% CI: 2.3 to 51.8%). The median event free survival (EFS) for patients with TCL was 13.6 w (95% CI: 5.7-74.6). Among all patients with TCL (N=16), the ORR was 50% (8/16). CRs were seen in 4/5 AITL and 1/7 PTCL-NOS; PRs were seen in PTCL-NOS-1, AITL-1, and transformed MF-1.
Of the 8 BCL evaluable for response at MTD, the ORR was 50% (4/8, 95% CI: 0-41%) with 3 PRs and 1 CR. The median EFS for patients with BCL was 19.8 w (95% CI: 5.4-NR). Among all patients with BCL evaluable for response (n=10), PRs were seen in 4 patients with DLBCL and 1 patient with MCL. One patient with concurrent DLBCL and AITL achieved a CR.
The median EFS for all patients treated at the MTD was 14.5 w (95% CI: 5.7 to NR). The median time to best response was 5.7 w. The median duration of response was 38.7 w (95% CI: 9.7 to NR). 3 patients with TCL and 1 with MCL underwent allogeneic transplantation following response to this therapy and were censored at time of transplant. Sustained complete responses were seen in 2 additional patients with TCL: one remained in CR for 11.7 months and another remains on treatment at 17 months. The median duration of follow up was 56.0 w (range 2.4 to 102.1 w).
Conclusions: The MTD dose for phase 2 study was identified as romidepsin 8mg/m2, lenalidomide 15mg and carfilzomib 36mg/m2. No unexpected toxicities have emerged. At this dose, the overall response rate for BCL and TCL was 50%. Responses were seen across various BCL and TCL histologies. In particular, in AITL, the regimen has shown responses in all 5 patients. Given the promising overall and complete response rates, the regimen warrants further study.
Mehta-Shah:Celgene: Research Funding; Verastem: Research Funding; Bristol Myers-Squibb: Research Funding. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding; Incyte: Research Funding. Lunning:Onyx: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy; Juno: Consultancy; Genentech: Consultancy; Gilead: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Epizyme: Consultancy. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Gerecitano:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zelenetz:Amgen: Consultancy; Celgene: Consultancy. Hamlin:Gilead: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support; Incyte: Other: research support; Celgene: Consultancy, Honoraria; Seattle Geneitcs: Other: research support; Novartis: Other: research support. Noy:Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau. Younes:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Johnson & Johnson: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Curis: Research Funding; Takeda Millenium: Honoraria; Seattle Genetics: Honoraria; Sanofi: Honoraria; Merck: Honoraria; Janssen: Honoraria. Dogan:Roche Pharmaceuticals: Consultancy; Peer Review Institute: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:Mundipharma: Consultancy; Aileron Therapeutics: Research Funding; BMS: Consultancy; HUYA: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Consultancy, Research Funding.
Introduction:The combination of brentuximab vedotin (BV) with AVD chemotherapy followed by 30Gy involved-site radiotherapy (ISRT) for the treatment of early stage, unfavorable risk Hodgkin lymphoma ...(HL) has demonstrated promising efficacy and an acceptable safety profile in the first cohort of this pilot study (Kumar et al, Blood, 2016). In cohort 2, we tested whether the ISRT dose could be reduced to 20Gy to minimize RT-related toxicity while maintaining efficacy.
Methods: Patients received 4 cycles of BV 1.2 mg/kg with AVD chemotherapy every 2 weeks, followed by 30 Gy ISRT in cohort 1 and 20Gy ISRT in cohort 2. Eligible patients were untreated stage I/II, classical HL with any of the following unfavorable risk factors: bulky disease (maximal transverse or coronal diameter >7 cm on CT), elevated ESR, extranodal involvement, >2 lymph node sites, or infradiaphragmatic disease. Patients with stage IIB disease with disease bulk or extranodal involvement were eligible. PET/CT after 2 and 4 cycles and after ISRT were interpreted with the 5-point Deauville scale (negative=1-3). The primary endpoint of cohort 2 was to evaluate preliminary efficacy with the rate of complete responses (CRs).
Results: In cohort 2, 29 patients were enrolled with median age of 33 (range 19-55), 100% stage II, 69% with disease bulk (>7cm), 41% elevated ESR, 38% B-symptoms, 21% extranodal involvement, 72% >2 involved lymph node sites, and 3% infradiaphragmatic disease. Twenty patients (69%) had bulky anterior mediastinal masses, ranging from 7 to 17.3cm. Nine patients (31%) had advanced stage disease by the GHSG criteria: IIBX (n=7) and IIBXE (n=2) disease.
In cohort 2, 90% and 93% of patients achieved a negative PET scan after 2 and 4 cycles of therapy, respectively (Figure 1). Of the 2 patients with positive PET-4 scans, one underwent a biopsy that was negative for HL and the other was not biopsied due to the inaccessible location of residual FDG-uptake. Both patients received ISRT. The 28 patients who have completed combined modality therapy (CMT) all have achieved CRs. One additional patient chose to forego ISRT, received 2 additional cycles of ABVD off study, and achieved a CR. To date, the median duration of remission is 8.5 months, with a range of less than 1 month to 17 months. No relapses have occurred. The efficacy is similar across cohorts 1 and 2 with interim PET negative rates of ≥90% and all patients who completed CMT have achieved a CR (Figure 1). In cohort 1, two patients had biopsy-proven primary refractory HL after 4 cycles of chemotherapy and in cohort 2, there have been no treatment failures.
Conclusion: BV+AVD x 4 cycles followed by 20Gy ISRT is an effective treatment program for early stage, unfavorable risk HL, including a high proportion of patients with bulky disease. As with 4 cycles of escalated BEACOPP tested in the GHSG HD11 clinical trial, 20Gy ISRT appears to be adequate consolidation after BV+AVD x 4 cycles. A third cohort of this pilot study is currently accruing in which patients receive BV+AVD x 4 cycles followed by 30Gy consolidation volume radiation. There is also a planned 4th cohort with no radiotherapy for PET-negative patients after 4 cycles of BV+AVD. After completion of the 4 cohorts, we plan to recommend the therapeutic strategy with the greatest efficacy and least toxicity to be further studied in a larger, randomized prospective study for early stage, bulky HL. Updated response data for all patients will be presented at the meeting.
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Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Casulo:Gilead: Honoraria, Other: travel support; Celgene: Research Funding; Infinity: Consultancy. Advani:Sutro: Consultancy; Nanostring: Consultancy; Celgene: Research Funding; Agensys: Research Funding; Spectrum: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Juno Therapeutics: Consultancy; Gilead: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Merck: Research Funding; Infinity: Research Funding; Kura: Research Funding; Cell Medica: Research Funding; Pharmacyclics: Consultancy. Barr:Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Infinity: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Research Funding. Chen:Affimed: Research Funding; Pfizer: Consultancy; Merck: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Drullinsky:Seattle Genetics: Honoraria, Other: Ad Board. Friedberg:Bayer HealthCare Pharmaceuticals.: Other: Data and Safety Monitoring Board: Bayer HealthCare Pharmaceuticals.. Gerecitano:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamlin:Gilead: Consultancy, Honoraria; Seattle Geneitcs: Other: research support; Incyte: Other: research support; Novartis: Other: research support; Celgene: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support. Horwitz:Kyowa Hakko Kirin: Consultancy, Research Funding; BMS: Consultancy; Mundipharma: Consultancy; Aileron Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; HUYA: Consultancy; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Spectrum Pharmaceuticals: Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Honoraria; Seattle Genetics: Honoraria, Research Funding. Noy:Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau. Palomba:Merck: Consultancy. Straus:Received consulting fee from Seattle Genetics for involvement in the research: Consultancy. Younes:Takeda Millenium: Honoraria; Johnson & Johnson: Research Funding; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Curis: Research Funding; Seattle Genetics: Honoraria; Sanofi: Honoraria; Merck: Honoraria; Janssen: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Bayer: Honoraria; Novartis: Research Funding. Zelenetz:Celgene: Consultancy; Amgen: Consultancy. Moskowitz:Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Celgene: Consultancy.
DLBCL, the most common lymphoid malignancy in adults, is an aggressive form of non-Hodgkin lymphoma (NHL) with significant heterogeneity in terms of gene expression, prognosis and response to ...treatment. Certain histone modifications and HDAC expression patterns have been implicated in the pathobiology of DLBCL and other cancers. Aberrant PTEN/PI3K/AKT signaling is also frequently observed in a variety of human cancers including DLBCL, where loss of PTEN activity and/or activating mutations in PI3K and AKT have been shown to reduce apoptosis and promote cell proliferation. Synergistic anti-tumor effects achieved with HDAC and PI3K inhibitor combinations in various DLBCL xenograft models have provided a strong rationale for testing a highly potent dual HDAC and PI3K inhibitor, CUDC-907. Significant anti-tumor effects have been observed across a wide range of DLBCL models exposed to CUDC-907, including the U2932 ABC DLBCL model that harbors BCL2 translocation and over-expresses cMYC and BCL6, and the WSU-DLCL-2 GCB DLBCL model that harbors EZH2 mutation. These disease mechanisms and preclinical data have led to testing of CUDC-907 in an ongoing Phase 1 trial in patients (pts) with various hematologic cancers.
Sixty-three heavily pre-treated pts with lymphoma or multiple myeloma have received CUDC-907 in 21-day cycles according to once daily (QD), intermittent (BIW or TIW), or five days on/two days off (5/2) dosing schedules. CUDC-907 was escalated in 30 mg increments such that pts received 30-60 mg QD, 60-150 mg intermittently, or 60 mg 5/2. A dose expansion using the 60 mg 5/2 dose and schedule is ongoing. Thus far, CUDC-907 has demonstrated a manageable side effect profile and sustained clinical efficacy, particularly in the subset of pts with RR DLBCL.
The most common treatment-related adverse events (AEs) were diarrhea (54%; 5% Grade ≥3), fatigue (37%; 3% Grade ≥3), nausea (22%) and thrombocytopenia (18%; 14% Grade ≥3), with dose limiting toxicities of hyperglycemia (QD and BIW schedules) and diarrhea (QD and TIW schedules). Side effects were reversible and manageable. Among 11/18 subjects with RR DLBCL who were evaluable for disease response, 6/11 (55%) achieved objective responses (2 CRs and 4 PRs); lasting a median of 119 days (range: 48 - 354+). Of 7 pts with sufficient tissue, 3 response-evaluable pts were found to over-express MYC and BCL2 by IHC, meeting criteria applied to "double-expressor" (DE) DLBCL. On CUDC-907 monotherapy, 2/3 confirmed pts with DE DLBCL have attained objective responses: 1 ongoing CR (followed by autologous stem cell transplant) and 1PR (lasting 132 days). The third response-evaluable pt with DE DLBCL has experienced lengthy stabilization of disease (171+ days).
Signals emerging from preclinical and clinical studies suggest that pts with DLBCL, including those with particularly aggressive disease, may derive benefit from treatment with CUDC-907. Enrollment of pts with RR DLBCL is ongoing into the expansion phase of the Phase 1 trial that is testing CUDC-907 on the 60 mg 5/2 RP2D as monotherapy and in combination with rituximab. Tissue obtained from pts with RR DLBCL treated with CUDC-907 will be assessed for MYC, BCL2, and other genetic aberrations that will be correlated with clinical outcomes observed in the trial. A Phase 2 trial of CUDC-907 in RR NHL is currently being planned, with emphasis on MYC aberrations.
Younes:Celgene: Honoraria; Incyte: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Bayer: Honoraria; Bristol Meyer Squibb: Honoraria; Novartis: Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding; Curis: Research Funding; Takeda Millenium: Honoraria. Berdeja:Acetylon: Research Funding; Onyx: Research Funding; Abbvie: Research Funding; Curis: Research Funding; Celgene: Research Funding; Takeda: Research Funding; MEI: Research Funding; Novartis: Research Funding; Janssen: Research Funding; BMS: Research Funding; Array: Research Funding. Flinn:Celgene Corporation: Research Funding. Clancy:Curis: Employment, Equity Ownership. Ma:Curis: Employment, Equity Ownership. Sun:Curis: Employment, Equity Ownership. Tian:Curis: Employment, Equity Ownership. Wang:Curis: Employment, Equity Ownership. Viner:Curis: Employment, Equity Ownership.
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