Post ASH speaker abstracts 2018

Low Grade Lymphoma

Abstracts to support presentations from Steve Robinson, Tim Illidge and Will Townsend

Follicular Lymphoma

Discovery and Validation of a Simplified Scoring System (the PRIMA-Prognostic Index) in De Novo Follicular Lymphoma Treated Initially with Immunochemotherapy

Result Type: Paper
Number: 413
Presenter: Emmanuel Bachy
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Indolent Lymphomas, Novel Therapies, and Diagnostics

Emmanuel Bachy1*, Matthew J Maurer, MS2, Thomas M Habermann, MD3, Benedicte Gelas Dore4*, Delphine Maucort-Boulch5*, Jane Estell6*, E. Van Den Este7*, Reda Bouabdallah, MD8*, Andrew L Feldman, MD9, Joan Bargay, MD, PhD10*, Alain Jacques Delmer, MD11, Susan L Slager, PhD12, Maria Gomes Silva13*, Olivier Fitoussi, MD14*, David Belada, MD, PhD15*, Herve Maisonneuve, MD16, Tanin Intragumtornchai, MD17*, Stephen M. Ansell, MD, PhD3, Thierry Lamy, Pr, MD, PhD18, Peggy Dartigues-Cuillères, MD19*, Brian K Link, MD20, John F Seymour, MBBS, PhD21, James R. Cerhan, MD, PhD12 and Gilles Andre Salles, MD, PhD22

1CHU Lyon Sud, Pierre-béNite, France
2Division of Biostatistics, Mayo Clinic, Rochester, MN
3Division of Hematology, Mayo Clinic, Rochester, MN
4Lysarc, Lyon, France
5Université Claude Bernard Lyon 1, Lyon, France
6Haematology Department, Concord Cancer Centre, Concord Hospital, Concord, NSW, Australia
7UCL, Brussel, BEL
8Institut Paoli-Calmettes, Marseille, FRA
9Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
10Hospital Sont LLatzer, Palma de Mallorca, Spain
11Hematology department, Hopital Robert Debre CHU de Reims, Reims, FRA
12Department of Health Sciences Research, Mayo Clinic, Rochester, MN
13Inst. Portuges de Oncologia, Lisbon, PRT
14Polyclinique Bordeaux Nord-Aquitaine, Bordeaux, France
154th Department of Internal Medicine – Hematology, University Hospital and Charles University Faculty of Medicine in Hradec Kralove, Czech Republic, Hradec Kralove, CZE
16Centre Hospitalier Departemental, La Roche-sur-Yon, FRA
17King Chulalongkorn Memorial Hospital, Bangkok, THA
18INSERM U917, CHU Pontchaillou, Rennes, France
19Institue Gustave Roussy, Villefjuif, France
20University of Iowa Hospitals and Clinics, Iowa City, IA
21Peter MacCallum Centre & Royal Melbourne Hospital, Melbourne, Australia
22Hematology Department, Centre Hospitalier Lyon-Sud, Pierre-Benite, France

 

Introduction: In follicular lymphoma (FL), no prognostic index has been built based on a cohort of patients treated only with initial immunochemotherapy. Given the emergence of new biomolecular and metabolic prognostic factors in FL, an easy-to-compute and reliable scoring system utilizing such variables could aid in trial stratification and routine clinical evaluation.

Methods: The primary endpoint for model building was progression-free survival (PFS). For discovery, we used the large prospective PRIMA trial cohort of 1,135 patients treated with initial R-chemotherapy +/- R-maintenance. Variables considered for model building included age, sex, performance status, B symptoms, stage, number of nodal and extranodal sites involved, LDH, hemoglobin, longest diameter of the largest lymph node, presence of effusion and compression syndrome, circulating lymphoma cells, platelet count, serum albumin, bone marrow involvement, and ß2m. For validation, we combined 175 patients with high tumor burden FL from the R-CHVP+interferon arm of treatment from the FL2000 trial and 304 patients prospectively enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) who were treated upfront with immunochemotherapy. Event-free survival (EFS) was the endpoint available in the validation cohort.

For model building, we used a two-step approach based on resample Cox regression and conditional inference trees analyses to identify 3 patient groups of approximately equal size and experiencing differential outcome in terms of PFS. For comparison with the FLIPI, model’s discrimination was computed using the Concordance Probability Estimates (CPE) based upon Harrell’s c-index. All statistical tests were 2-sided. A P value <.05 was considered statistically significant. Results: The final simplified score based on the discovery set was called the PRIMA-PI (PRIMA-prognostic index) and comprised 3 risk categories: high (ß2m > 3 mg/L), low (ß2m ≤ 3 mg/L without bone marrow involvement) and intermediate (≤ 3 mg/L with bone marrow involvement).

In the discovery cohort, the PRIMA-PI was highly discriminatory with 5-year PFS of 69% (95%CI: 64-73%), 55% (49-60%) and 37% (32-42%) in the low-, intermediate- and high-risk groups respectively (P<0.0001, Figure 1a). The PRIMA-PI outperformed the FLIPI by concordance probability (CPE 0.577 for the FLIPI and 0.604 for the PRIMA-PI). The PRIMA-PI was superior to the FLIPI both in the observation and the maintenance arm. The PRIMA-PI and the FLIPI similarly predicted OS with a 5-yr OS of 93% in the low/intermediate-risk category versus 84% in the high-risk category for the FLIPI and 93% and 81% for the PRIMA-PI respectively (P<0.0001 for each). However, the PRIMA-PI displayed better predictive performance than the FLIPI for cause-specific death. The PFS at 24 months (PFS24) was a strong post-treatment prognostic parameter for subsequent OS in the discovery cohort and the PRIMA-PI was a better predictor of PFS24 than the FLIPI. For patients without disease progression before 24 months, 5-year OS from the 24-month landmark or the risk-defining event was 92% (95% CI, 80-94%), compared to 63% (95% CI, 57-70%) for patients who progressed in the first 24 months (P<0.0001). In the validation cohort, the PRIMA-PI remained highly discriminatory: 5-year EFS was 77% (69-83%), 57% (48-66%) and 44% (35-52%) in the low-, intermediate- and high-risk groups respectively (P<0.0001, Figure 1b). Finally, the PRIMA-PI was at least as discriminant as the FLIPI in terms of statistical performances in the validation cohort (CPE 0.605 for the FLIPI and 0.606 for the PRIMA-PI). Conclusion: We developed and validated a new prognostic tool comprising only 2 parameters (bone marrow involvement and ß2m) which are easily measured clinically. The PRIMA-PI is a new and easy-to-compute prognostic index for patients treated upfront with immunochemotherapy. This could serve as a basis for building more sophisticated and integrated biomolecular scores.

Long Term Follow-up of the PRIMA Study: Half of Patients Receiving Rituximab Maintenance Remain Progression Free at 10 Years

Result Type: Paper
Number: 486
Presenter: Gilles Andre Salles
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Follicular Lymphoma, First Line

Gilles Andre Salles, MD, PhD1, John Francis Seymour, MBBS2, Pierre Feugier, MD3*, Fritz Offner, MDPhD4, Armando Lopez-Guillermo5, David Belada, MD, PhD6*, Luc Xerri, MD, PhD7*, Reda Bouabdallah, MD8*, John Catalano9, Pauline Brice, MD10, Corinne Haioun, MD11, Alejandro Martín, MD, PhD12*, Lars Moller Pedersen13*, Alain Jacques Delmer, MD14, David Simpson, MBChB15, Sirpa Leppa, MD16, Pierre Soubeyran, MD, PhD17*, Rene-Olivier Casasnovas, MD18*, Tanin Intragumtornchai, MD19*, Vincent Ribrag20, Maria Gomes Silva21*, Emmanuelle Nicolas-Virelizier, MD22*, Thomas Lister, MD23, Jane Estell24*, Gustavo Milone, MD 25, Anne Sonet, MD26*, Julie Assemat27*, Harald Zeuner28*, Bertrand Coiffier, MD, PhD29 and Herve Tilly30

1Hematology, Hospices Civils de Lyon – Université de Lyon, Pierre-Bénite, France
2Peter MacCullum Cancer Center, Melbourne, Australia
3Hematology Department, CHU Nancy, Vandoeuvre Les Nancy Cedex, France
4Hematology, University Hospital Ghent, Gent, Belgium
5Hematology, Hospital Clinic, Barcelona, Spain
64th Department of Internal Medicine – Hematology, University Hospital and Charles University Faculty of Medicine in Hradec Kralove, Czech Republic, Hradec Kralove, CZE
7Bio-Pathology Department, Institut Paoli-Calmettes and Aix-Marseille Universite, Marseille, France
8Institut Paoli Calmettes, Department of Hematology, Marseille, France
9Frankston Hospital, Frankston, Victoria, Australia
10Hematology Department, AP-HP Hopital Saint-Louis, Paris, France
11Lymphoid malignancies unit, University Hospital Henri Mondor, Creteil, France
12Department of Hematology, Hospital Universitario de Salamanca / IBSAL, Salamanca, ESP
13Roskilde Hospital, Roskilde, Denmark
14Hematology department, Hopital Robert Debre CHU de Reims, Reims, FRA
15North Shore Hospital, Auckland, New Zealand
16Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
17Institut Bergonie, Bordeaux, FRA
18CHU Dijon, Dijon, FRA
19King Chulalongkorn Memorial Hospital, Bangkok, THA
20Gustave Roussy Cancer Campus, Villejuif, France
21Inst. Portuges de Oncologia, Lisbon, PRT
22Centre Léon Bérard, Lyon, France
23Barts Cancer Institute, London, United Kingdom
24Haematology Department, Concord Cancer Centre, Concord Hospital, Concord, NSW, Australia
25FUNDALEU, Buenos Aires, Argentina
26Hematology Department, CHU Montgodinne, montgodinne, Belgium
27LYSARC, Pierre Benite, France
28F. Hoffmann-La Roche Ltd, Basel, Switzerland
29Department of Hematology, Hospices Civils de Lyon, Lyon, France
30Hematology Department, Centre Henri Becquerel, Rouen, France

 

In patients with follicular lymphoma and a high tumor burden, the intergroup PRIMA phase III study was designed to evaluate the potential benefit of 2 years of rituximab (R) maintenance after response to first line R-chemotherapy induction regimens (patients registered from 12/2004 until 4/2007). At a median follow up of 3 years (Lancet 2011) and 6 years (Blood 2013 122:509), a significant sustained improvement in progression free survival (PFS) was demonstrated in patients receiving R-maintenance; hazard ratios (HR) of 0.55 and 0.58, respectively. We report here the long term results of this study with 4 additional years of follow-up.

Patients initially randomized between observation (n=513) and R-maintenance (n=505) were all followed for 7 years after randomization and thereafter until the 31/12/16 after having given an informed consent for this extended follow-up period consisting of a yearly physician visit (imaging procedures were according to local center practices after year 7). At data-base lock, the median follow-up of the entire patient cohort was 9 years (9.7 years for the 607 patients agreeing to extended follow-up).

Median PFS for patients in the observation arm was reached at 4.06 years as compared to 10.49 years in the R-maintenance arm (Log-Rank, P<.0001; HR=0.61, 95% confidence interval (95%CI) 0.52-0.73). At 10 years, 51% of the patients in the R-maintenance arm (versus 35% in the observation arm) were estimated to be free of disease progression. The benefit of R-maintenance for PFS was significant in all predefined patient strata: age (cutpoint=60 years), gender, the 3 FLIPI categories, quality of response to induction immunochemotherapy (CR/CRu and PR) and in patients having received R-CHOP (HR=0.57; 95%CI 0.47-0.70), while only a trend was observed for those having received R-CVP (HR=0.75; 95%CI 0.53-1.07). In a Cox regression model, R-maintenance remained an independent covariate from the above characteristics (HR=0.60; 95%CI 0.50-0.71). The median time to new anti-lymphoma treatment was 6.1 years in the observation arm but has not yet been reached in the R-maintenance arm (P<.0001; HR=0.66; 95%CI 0.55-0.78), with a 10-year estimate of 53% of the patients in this arm not having received a new treatment (versus 41% in the observation arm). At data base lock, 84 and 88 patients have died in the observation and R-maintenance arm, respectively. Main causes of death in the observation and R-maintenance arms were respectively: lymphoma progression in 38 and 39 patients, malignancies for 24 and 6 patients (with respectively 7 and 2 myeloid disorders; no other specific distribution pattern) infections in 6 and 11 patients (1 PML in each arm), and cardiovascular disorders in 4 and 8 patients. No new safety signals were identified with the additional 4 years of follow-up. Overall survival estimates (Kaplan-Meier) at 10 years were identical (80%) in each arm. Age >= 60 years, male sex and high FLIPI category, but not randomization arm, were all associated with a higher risk of death in a Cox regression model.

In summary, PRIMA study long term follow-up demonstrates that R-maintenance after induction immunochemotherapy provides a significant long term PFS benefit over observation. Despite the lack of OS benefit, it is noteworthy that more than half of the patients in the R arm remain free of disease progression and have not required new anti-lymphoma treatment beyond 10 years. With the prolonged life-expectancy of patients with follicular lymphoma, it is important to consider long term treatment-related toxicities and the risk of secondary malignancies related to repeated therapeutic interventions. Obtaining truly durable response with 1st line induction followed by R-maintenance remains an appealing treatment strategy for these patients.

Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab and Bendamustine in Patients with Previously Untreated Follicular Lymphoma: An Interim Analysis

Result Type: Paper
Number: 481
Presenter: Anas Younes
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Follicular Lymphoma, First Line

Anas Younes, MD1, Burke M. John2*, Catherine S Diefenbach3, Silvia Ferrari4*, Cyrus Kahn5*, Jeffrey P. Sharman, MD6, Monica Tani7*, Chaitra S. Ujjani, MD8, Umberto Vitolo, MD9, Sam Yuen10*, Paul Woodard, MD11, Kirsten Mundt, PhD12*, Günter Fingerle-Rowson13, Surya Chitra11*, Gila Sellam12*, Rodica Morariu-Zamfir12* and Michael Gilbertson14*

1Memorial Sloan Kettering Cancer Center, New York, NY
2US Oncology Research, The Woodlands, TX
3NYU Langone Medical Center, New York, NY
4Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
5Allegheny Health Network Cancer Institute, Pittsburgh, PA
6Willamette Valley Cancer Institute, Eugene, OR
7Ospedale Santa Maria delle Croci, Ravenna, Italy
8Georgetown University Hospital Lombardi Comprehensive Cancer Center, Washington, DC
9Dipartimento di Oncologia e Ematologia, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
10Calvary Mater Newcastle Hospital, Newcastle, Australia
11Genentech, Inc., South San Francisco, CA
12F. Hoffmann-La Roche Ltd, Basel, Switzerland
13F. Hoffmann-La Roche Ltd., Basel, Switzerland
14Monash Health, Melbourne, Australia

 

Introduction: The Phase III Gallium study has shown that induction with the anti-CD20 monoclonal antibody obinutuzumab (GA101; G) plus chemotherapy followed by maintenance with G alone significantly prolongs PFS relative to the corresponding rituximab-containing regimen in previously untreated pts with follicular lymphoma (FL). However, FL remains incurable, and most pts eventually relapse. Atezolizumab (atezo), which targets programmed death-ligand 1 (PD-L1), has a complementary mechanism of action to G and has the potential to improve outcomes when added to G-chemotherapy in FL. We report interim data from a single FL cohort from our Phase Ib/II study (NCT02596971) of the safety and efficacy of induction with G-bendamustine (benda)-atezo followed by maintenance with G-atezo.

Methods: Pts (≥18 yrs old, ECOG PS 0–2) with FL (previously untreated grade 1, 2 or 3a disease requiring therapy or relapsed/refractory [R/R]) received induction with infusions of G 1000 mg on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2–6, benda 90 mg/m2 on days 1 and 2 of cycles 1–6, and atezo 840 mg on days 1 and 15 of cycles 2–6 (28-day cycles). Maintenance in pts with CR or PR consisted of G 1000 mg on day 1 of every other month and atezo 840 mg on days 1 and 2 of each month for ≤24 months. Enrollment included an initial safety run-in phase with intensive safety monitoring in 6 pts before the main enrolment (expansion phase) began; R/R pts were permitted in the safety run-in phase only. The primary endpoint was CR (PET-CT) rate at end of induction (EOI) determined by independent review committee (IRC) using modified Lugano 2014 criteria. Secondary endpoints included CR rate at EOI assessed by investigator (INV) using modified Lugano 2014, CR rate at EOI by IRC and INV using modified Cheson 2007, ORR at EOI by IRC and INV using modified Lugano 2014 and modified Cheson 2007, DoR, and PFS and EFS by INV. MRD as an exploratory endpoint was centrally assessed by next generation sequencing of the B-cell receptor VDJ region in peripheral blood mononuclear cells. Safety and tolerability were also assessed. This interim analysis was performed after the first 15 pts with previously untreated FL had completed induction or discontinued beforehand (interim analysis efficacy population). The data cut-off for the analysis was March 7, 2017.

Results: In total, 42 pts (including 40 with previously untreated FL) were enrolled and treated. At the time of data cut-off, 22 were still in induction, 3 had discontinued because of AEs, 17 had completed induction, and 15 were receiving maintenance. Pt demographics and disease characteristics are shown in Table 1. CR rates (IRC and INV) were 67% (n=10/15) by modified Lugano 2014 and Cheson 2007 criteria (Table 2). Most pts received >95% of the planned doses of G, benda and atezo during induction. The median dose intensity for all three drugs was 100%, with means of 95.1% to 99.2%. All pts had ≥1 AE, 20 (48%) had a grade 3–4 AE, and 1 had a grade 5 (fatal) AE (unrelated sudden death). A second grade 5 AE (atezo-related cardiac arrest) was reported after the data cut-off in a pt with grade 4 myocarditis and bronchiolitis obliterans (likely immune-mediated AEs) in whom the cardiac arrest was preceded by a dyspnea event. Nine pts (21%) had SAEs. AEs led to dose reduction (benda only) in 4 (10%) pts (grade 4 neutropenia, grade 2 diarrhea, two grade 3 transaminase increases) and to withdrawal of at least one treatment in 4 (10%) pts (grade 4 myocarditis in the pt with cardiac arrest after data cut-off, grade 3 lipase increase, grade 3 cough, grade 3 pneumonia); 22 (52%) pts had AEs requiring interruption of any treatment. The most common hematologic toxicity was neutropenia; other frequent toxicities were infusion-related reactions (IRRs), fatigue and gastrointestinal events (Table 3). The most common treatment-related grade 3–4 toxicities were neutropenia (6 pts [14%], 3 of whom received G-CSF prophylaxis) and thrombocytopenia (2, 5%). The most frequent treatment-related SAE was IRR (2 [5%], both atezo-related).

Conclusions: In this interim analysis of the G-benda-atezo combination, one treatment-related death occurred. Toxicity was otherwise manageable. Preliminary efficacy data show encouraging first-line activity in FL. Results from the final analysis based on 40 pts, including DoR, PFS and EFS, will be presented at the meeting.

A 3-Arm Randomized Phase II Trial with Bendamustine/Rituximab Therapy in Untreated High Risk (HR) Follicular Lymphoma (FL): Bortezomib Induction or Novel IMiD® Continuation (BIONIC) Study from the ECOG-ACRIN Cancer Research Group

Result Type: Paper
Number: 482
Presenter: Andrew Evens
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Follicular Lymphoma, First Line

Andrew M. Evens, DO, MSc1, Fangxin Hong, PhD2*, Thomas M Habermann, MD3, Ranjana H. Advani, MD4, Randy D. Gascoyne, MD5*, Thomas E Witzig, MD3, Andrew Quon, MD6*, Erik A. Ranheim, MD, PhD7, Puneet Cheema, MD8*, Philip Dy, MD9*, Timothy E. O’Brien, MD10, Jane N. Winter, MD11, Terrence Paul Cescon12*, Julie Chang, MD13 and Brad S. Kahl, MD14

1Division of Hematology/Oncology, Chief, Tufts University School of Medicine and Cancer Center, Boston, MA
2ECOG-ACRIN Biostatistics Center, Dana Farber Cancer Institute, Boston, MA
3Division of Hematology, Mayo Clinic, Rochester, MN
4Stanford University, Stanford, CA
5BC Cancer Research Center, Vancouver, BC, Canada
6Department of Radiology, Stanford University, Stanford, CA
7University of Wisconsin School of Medicine, Madison, WI
8HealthEast Cancer Center, Maplewood, MN
9Cancer Care Specialists, Effingham, IL
10MetroHealth Medical Center, Cleveland, OH
11Department of Medicine-Hematology/Oncology, Robert H. Lurie Comp. Cancer Center, Chicago, IL
12Berks Hematology, West Reading, PA
13University of Wisconsin Hospitals and Clinics, Madison, WI
14Washington University School of Medicine, Saint Louis, MO

 

Background: The BIONIC study tested whether bortezomib (V) improved the complete remission (CR) rate when added to standard bendamustine/rituximab (BR) induction in untreated high risk (HR) FL and whether lenalidomide (Len) integrated as “continuation” treatment (Tx) given concurrently with maintenance rituximab (MR) enhanced remission duration vs MR alone.

Methods: Study eligibility included: ages ≥18 years; untreated; HR disease; and grade I/II or IIIa FL with the latter determined by central pathologic review (NCT01685008). HR disease was defined as high tumor burden by GELF and/or FLIPI score 3-5. Pts were randomized to 1 of 3 arms in a 1:2:2 ratio (stratified by FLIPI & GELF): a) BR induction x 6 followed by MR q 2 months x 2 years (BR-R) vs b) BVR induction x 6 (V: 1.3 mg/m2 IV/SQ days 1, 4, 8, 11) followed by MR q 2 months x 2 years (BVR-R) vs c) BR x 6 followed by q 2 months MR x 2 years + Len 20 mg/day (21/28 days) continuation x 1 year (BR-LR). Initial plans were to enroll 250 pts; due to a high non-enrollment rate to the continuation/maintenance phase of Tx (ie, 10% BR-R arm, 22% of BVR-R, and 26% BR-LR arm), an additional 36 pts were randomized to the BR+R vs BR+LR arms to preserve study power. In these study arms, 54, 66, and 83 FL pts, respectively, received post-induction Tx. Response was assessed by 2007 IWG criteria with PET/CT. The 1st primary objective was previously presented (ie, CR rate BVR 74% vs 59% two BR induction arms combined, P=0.008, Evens et al ASCO 2016). We report here on all study endpoints, including the 2nd primary objective of 1-year disease-free survival (DFS) with Len continuation Tx (ie, BR-LR vs standard BR-R) as well as progression-free survival (PFS), overall survival (OS), and safety/tolerability across all Tx arms & phases of Tx.

Results: The study enrolled from 1/2011 to 5/2015 with a final accrual of 289 pts. 30 pts were excluded for never starting study Tx (n=9), ineligibility (n=5), and central pathology review (n=16), yielding 257 evaluable pts (ie, BR-R n=60; BVR-R n=85; BR-LR n=112). Among all pts, median age was 61 years (24-89); GELF was high in 91%; FLIPI 3-5 in 57%; ECOG PS: 0=56%, 1=42%, and 2=2%; B symptoms present 28%; marrow involvement 59%; >1 extranodal site 27%; and stages IIB 7%, III 27% and IV 66%. For induction Tx received, 88%, 87%, and 78%, respectively, of pts randomized to the BR-R vs BVR-R vs BR-LR arms received all 6 planned cycles. CR rates for induction Tx by were 71%, 74%, and 55%, respectively. Collectively, the 1-year DFS results suggested no added benefit from lenalidomide (details to be presented at meeting). With a median follow-up of 3.95 years, the median PFS has not been reached in any arm. Among the first 250 pts enrolled, 3-year PFS rates for BR-R vs BVR-R vs BR-LR Tx arms were 76% vs 81% vs 74%, respectively, P=0.49 (see Figure 1A); the 3-year PFS rates including the additional 36 enrolled pts were nearly identical. The most common grade 3/4 AEs among pts randomized to Len-R continuation vs MR were: neutropenia 66% vs 20% (P<0.0001); febrile neutropenia 10% vs 2% (P=0.05); anemia 6% vs 0 (P=0.08); fatigue 6% vs 2% (P=0.40); and pneumonia 6% vs 2% (P=0.40). Of patients assigned to Len-R, 59% had dose reductions of Len, most due to an adverse event (AE). When comparing Len-R continuation vs MR, 17% vs 6% of pts (P=0.06), respectively, came off continuation/maintenance Tx due to AE/toxicity. By study arm, rates of all 2nd cancers (including skin) were 6%, 9%, and 8% for BR-R, BVR-R and BR-LR, respectively (P=0.45); non-melanoma skin cancer rates were 2% on each arm. Overall, there were 34 deaths on study, including 7 grade 5 lethal events (2.7%). Of the latter, 4 (1.4%) were possibly related to Tx with 1 occurring during induction, 2 during maintenance, and 1 post-maintenance off study. The corresponding 3-year OS rates for all pts treated in the BR-R vs BVR-R vs BR-LR arms were 87% vs 90% vs 84%, respectively, P=0.37 (see Figure 1B).

Conclusions: The BIONIC study showed that Tx with standard BR induction followed by MR was safe in HR FL. The addition of V to BR induction enhanced the CR rate, but did not translate into improved PFS. Additionally, Len continuation Tx as prescribed in this study was associated with increased toxicity vs MR, while yielding similar PFS and OS vs BR-R treated pts. Based upon these results, neither V added to BR induction nor Len added to MR following BR induction can be recommended in FL. Quality of life analyses as well as detailed imaging and correlative biomarker studies are underway.

Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101)

Result Type: Paper
Number: 410
Presenter: Andres Forero-Torres
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Indolent Lymphomas, Novel Therapies, and Diagnostics

Andres Forero-Torres, MD1*, Rod Ramchandren, MD2, Abdulraheem Yacoub, MD3*, Michael S. Wertheim, MD4*, William J. Edenfield, MD5*, Paolo Caimi, MD6, Martin Gutierrez, MD7*, Luke Paul Akard, MD8, Carolina Escobar, MD9*, Justin Call, MD10*, Daniel Persky, MD11, Swami P. Iyer, MD12, Douglas J. DeMarini, PhD13*, Li Zhou, PhD13*, Swamy Yeleswaram, PhD13* and Tycel J. Phillips, MD14

1University of Alabama Birmingham, Birmingham, AL
2Karmanos Cancer Institute, Detroit, MI
3University of Kansas Cancer Center, Westwood, KS
4Hematology/Oncology Associates of Treasure Coast, Port St Lucie, FL
5Greenville Health System Cancer Institute, Greenville, SC
6Department of Medicine-Gastroenterology, Cleveland, OH
7Hackensack University Medical Center, Hackensack, NJ
8Indiana Blood & Marrow Transplantation, LLC, Indianapolis, IN
9Texas Oncology-Baylor Charles A. Sammons Cancer Center Blood and Marrow Transplant, Dallas, TX
10Utah Cancer Specialists-Network, Salt Lake City, UT
11Division of Hematology/Oncology, University of Arizona Cancer Center, Tucson, AZ
12Houston Methodist Cancer Center, Houston, TX
13Incyte Corporation, Wilmington, DE
14University of Michigan, Ann Arbor, MI

 

Introduction: Constitutive activation of the PI3Kδ pathway is associated with increased malignant B-cell proliferation and survival. INCB050465 is a highly selective and highly potent next-generation PI3Kδ inhibitor (≥19,000-fold more selective for PI3Kδ versus other isoforms), designed to eliminate hepatotoxicity associated with first-generation PI3Kδ inhibitors. Here we report safety and efficacy results from a phase 1/2 study of patients with relapsed or refractory B-cell malignancies treated with INCB050465 monotherapy (NCT02018861).

Methods: Adult patients were eligible for study participation if they had relapsed or refractory lymphoid B-cell malignancies (excluding Burkitt lymphoma and precursor B-cell lymphoblastic leukemia/lymphoma), Eastern Cooperative Oncology Group performance status score ≤2 (≤1 during dose escalation), normal hepatic and renal function, ≥1 prior treatment regimen, and no autologous hematopoietic stem-cell transplant (HSCT) within 3 months or allogeneic HSCT within 6 months of screening. The protocol was initiated with a single-patient cohort, treated with oral INCB050465 5 mg once daily (QD). Subsequent cohorts used a 3+3 design and evaluated doses of 10–45 mg QD. Based on pharmacokinetics/pharmacodynamics, the 20 and 30 mg QD cohorts were expanded. In November 2016, the treatment schedule was modified to introduce once-weekly (QW) dosing after week 9, based on emerging PK, safety, and efficacy data. Treatment responses were assessed every 9 weeks by the Lugano Classification, International Working Group on Chronic Lymphocytic Leukemia (CLL) criteria, or the 6th International Workshop on Waldenstrom Macroglobulinemia (WM) criteria as appropriate. Mandatory Pneumocystis jiroveciipneumonia (PJP) prophylaxis was implemented in May 2017.

Results: As of the data cutoff (May 20, 2017), 72 patients were treated (median age, 66 [range, 30–89] years). Baseline tumor subtypes treated included NHL (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), Hodgkin lymphoma, CLL, and WM (Table 1). Sixty percent of patients received ≥3 prior systemic regimens. Median duration of exposure was 16.4 (range, 1–85.7) weeks; no dose-limiting toxicities occurred. Overall, 76% of patients discontinued therapy, most commonly due to disease progression (40%) and treatment-emergent adverse events (TEAEs; 18%). Dose interruption occurred in 39% of patients and dose reduction in 6% of patients due to TEAEs.

Most common nonhematologic TEAEs (all grade [Gr]; Gr ≥3) were nausea (36%; 0%), diarrhea (33%; 6%), fatigue (29%; 0%), vomiting (24%; 0%), and cough (22%; 0%). Gr ≥3 hematologic TEAEs were neutropenia (19%), lymphopenia (18%), thrombocytopenia (10%), leukopenia (8%), and anemia (6%). Serious TEAEs were reported in 38% of patients, most frequently diarrhea (n=5), pyrexia (n=5), hypotension (n=3), and colitis (n=3). One patient had grade 3 pneumonitis; none had PJP or grade >1 elevated transaminase while on study treatment.

Of note, among 16 patients with NHL who received QW dosing, none discontinued treatment because of a TEAE while on the QW schedule (median treatment duration on the QW schedule, 16.2 [range, 0.7–28.7] weeks).

Of 72 patients treated, 69 (96%) were evaluable for response (Table 1); objective responses occurred at all doses, except 5 mg QD. Among patients with NHL, 93% (26/28) of the objective responses were observed at 9 weeks. All 16 patients receiving QW dosing had a response/stable disease during QD dosing; 9 patients remained on the QW schedule at the data cutoff date.

Conclusion: In patients with relapsed or refractory B-cell malignancies, INCB050465 demonstrated manageable toxicities with no clinically meaningful transaminitis or PJP. Objective response rates were generally high and 93% of patients with NHL who responded did so at the first assessment. The QW schedule appears to improve tolerability and prolong time on study treatment in NHL subtypes. Phase 1 and 2 studies are underway to investigate this and other dosing regimens in patients with NHL. Updated data will be presented.

Mantle Cell Lymphoma

 

Initial Treatment with Lenalidomide Plus Rituximab for Mantle Cell Lymphoma: 5-Year Follow-up and Correlative Analysis from a Multi-Center Phase II Study

Result Type: Paper
Number: 154
Presenter: Jia Ruan
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Mantle Cell Lymphoma, New Therapies

Jia Ruan, MD, PhD1, Peter Martin, FRCPC, MD, MS2, Paul J Christos, Dr.P.H., M.S.3*, Leandro Cerchietti, MD1, Bijal D. Shah, MD4, Stephen J. Schuster, MD5, Wayne Tam, MD, PhD1, Amelyn Rodriguez, BSN, RN, OCN1*, David Hyman1*, Maria Nieves Calvo Vidal, PhD2*, Lidia Roman Gonzalez1*, Sonali M. Smith, MD6, Jakub Svoboda, MD5, Richard R. Furman, MD1, Morton Coleman, MD7* and John P. Leonard, MD2

1Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY
2Department of Medicine, Weill Cornell Medicine, New York, NY
3Department of Healthcare Policy & Research, Weill Cornell Medicine, New York, NY
4Malignant Hematology, Moffit Cancer Center, Tampa, FL
5Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
6Section of Hematology/Oncology, University of Chicago, Chicago, IL
7Division of Hematology and Oncology, Weill Cornell Medicine /New York Presbyterian Hospital, New York, NY

 

Background: We previously reported early results of a multicenter phase 2 study of lenalidomide plus rituximab as initial treatment for MCL (NEJM 2015:373:1835), which was highly effective (ORR 92%, CR 64%) and well tolerated. Here we present outcomes with 5-year follow-up, as well as exploratory analysis of immunologic biomarkers and minimal residual disease measurement.

Methods: The study includes both induction and maintenance. Lenalidomide was administered at 20 mg daily on days 1-21 of a 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during maintenance. Standard dose rituximab was administered weekly x 4 during cycle 1, then once every other cycle. Treatment was continuous until progression, with option to stop therapy after 3 years. Plasma samples were obtained at baseline, C2D1 and C4D1 to measure cytokines (IFNγ, IL10, IL12p70, IL12, IL1β, IL2, IL4, IL6, IL8, TNFα) and chemokines (MCP1, MCP4, Eotaxin, IP10, MDC, Eotaxin3, TARC, MIP1α, MIP1β, IL8), using MesoScale Discovery V-plex assays. The cytokine/chemokine levels over time, and their associations with responses and treatment-emergent rash were analyzed with Wilcoxon signed-rank and rank-sum tests. MRD was assessed using ClonoSEQTM(Adaptive Biotechnologies, Seattle WA) on subjects with available paired pre-treatment tissue and post-induction PB samples.

Results: 38 subjects requiring therapy were enrolled at 4 centers from 7/2011 to 4/2014. The median age was 65 and MIPI scores evenly distributed between low-, intermediate-, and high-risk. Median follow-up was 58 months with range of 36-70 months. Two patients were inevaluable – one withdrew consent, other was intolerant of tumor flare. Twenty-two (61%) of the evaluable 36 patients remain in remission, including 13 (36%) beyond 5 years. Nineteen patients remain on treatment and 3 opted to stop therapy after 3 years. Eleven patients had progression – 3 with primary refractory disease and 8 following initial responses (4 CRs with PFS of 18, 38, 39 and 49 months, 4 PRs with PFS at 14, 25, 28 and 43 months). Six evaluable patients died, 3 from progression, 3 from unrelated comorbidities. Median PFS and DOR have not been reached. The 3-yr and 4-yr PFS rates were estimated at 80.3% (95% CI = 63.0%, 90.1%) and 69.7% (95% CI = 50.6%, 82.6%), with 3-yr and 4-yr OS rates at 91.9% (95% CI = 76.9%, 97.3%) and 82.6% (95% CI = 65.3%, 91.9%). TEAEs during maintenance included asymptomatic grade 3-4 cytopenias (42% neutropenia, 5% thrombocytopenia, 3% anemia), and grade 1-2 infections (45% URI, 16% UTI, 13% sinusitis and 8% cellulitis), all managed in outpatient settings. Five patients required brief hospitalization for IV antibiotics: 1 (3%) developed neutropenic fever in setting of cholecystitis, 3 (8%) had pneumonia and 1 (3%) had recurrent UTI. Secondary malignancies included squamous-cell carcinoma in 2 subjects, basal-cell carcinoma in 1 subject, and melanoma in situ in 2 subjects. Merkel-cell carcinoma developed in an 86-year-old subject after 18 months of therapy, and pancreatic cancer was diagnosed in a 68-year-old patient after 12 months of therapy.

Compared to baseline, cytokine levels at C2D1 and C4D1 showed Th1/Th2 modulation, with significant increase in IFNγ (p=0.004 and p=0.007) and IL4 (p=0.004 and p=0.017), as well as significant decrease in IL2 (p=0.046 and p=0.032), IL10 (p=0.004 and p=0.007) and TNFα (p<0.0001 and p<0.0001). Chemokine levels showed uniform reduction in MCP1 (p<0.0001 and p=0.001), MDC (p<0.0001 and p<0.0001), MIP1α (p=0.007 and p=0.001) and MIP1β (p<0.0001 and p<0.0001), suggesting Th2 to Th1 switch. Responses at month 3 correlated with C4D1 higher levels of IL10 (p=0.04) and IL2 (p=0.05), both anti-tumor cytokines, and lower levels of MDC (p=0.04). TEAE of rash was significantly associated with increased IL2 levels at C2D1 (p=0.03) and C4D1 (p=0.01). One time MRD assay in 7 CR subjects with available samples who have completed at least 3-year study treatment showed MRD negativity in 6 out of 7 (86%) patients. Concusions: Lenalidomide and rituximab as initial treatment for MCL can achieve high rate of complete responses and MRD negativity with durable remissions beyond 4 years. The nature of toxicity was not significantly affected by continuous treatment, particularly in the context of close follow-up. Further evaluation of this active regimen in larger, randomized frontline trials is warranted (ClinicalTrials.gov – NCT01472562).

Validation of POD24 As a Robust Early Clinical Endpoint of Poor Survival in Follicular Lymphoma: Results from the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) Investigation Using Individual Data from 5,453 Patients on 13 Clinical Trials

Result Type: Paper
Number: 412
Presenter: Carla Casulo
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Indolent Lymphomas, Novel Therapies, and Diagnostics

Carla Casulo, MD1, Jennifer Le-Rademacher, PhD2*, Jesse Dixon, Stat2*, Gilles Andre Salles, MD, PhD3, Eva Hoster4*, Michael Herold, MD5, Wolfgang Hiddemann4*, Catherine Sebban, MD6*, Robert Marcus7*, Eva Kimby, MD, PhD8, Howard Hochster, MD9*, Umberto Vitolo, MD10, Emmanuel Gyan, MD-PhD11, Fang-Shu Ou, PhD12*, Tina Nielsen13*, Kenneth A. Foon, MD14, Shi Qiuan, PhD2* and Christopher Flowers, MD, MS15

1Division of Hematology/Oncology, James P. Wilmot Cancer Center, Rochester, NY
2Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
3Centre Hospitalier Lyon-Sud, Pierre-Benite, France
4Department of Medicine III, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
5HELIOS Klinikum Erfurt, Erfurt, DEU
6Department of Hematology, Centre Leon Berard, Lyon, France
7Department of Haematology, Addenbrookes Hospital, Cambridge, United Kingdom
8Department of Internal Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
9Yale Cancer Center, New Haven, CT
10Dipartimento di Oncologia e Ematologia, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
11Department of Hematology and Cell Therapy, University Hospital, Tours, France
12Division of Biomedical Statistics and Informatics,Mayo Clinic, Rochester, MN
13F. Hoffmann-La Roche Ltd, Basel, Switzerland
14CELGENE CORPORATION – GLOBAL, Summit, NJ
15Winship Cancer Institute Bone Marrow & Stem Cell Transplantation, Atlanta, GA

 

Introduction: Follicular lymphoma (FL) is the most common indolent lymphoma with a median survival approaching 20 years. However, there is significant clinical heterogeneity with a subset of patients experiencing transformation, early recurrence or refractory disease. Data from the National LymphoCare Study and others identified that progression of disease within 24 months of diagnosis in patients treated with chemoimmunotherapy (POD24) is associated with poor subsequent overall survival (OS). Using the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) data, we sought to i) evaluate the association between FL international prognostic index (FLIPI) and other baseline factors on progression-free survival within 24 months of trial enrollment (PFS24) and ii) to validate POD24 as an early clinical endpoint in FL.

Methods: We performed a pooled analysis of 13 randomized clinical trials of patients in both the pre and post rituximab era (total sample size of 5,453, Table). Logistic regression model was used to evaluate the association between FLIPI, gender, and performance status (PS) with PFS24. Cox regression with POD24 as a time-dependent covariate was used to evaluate the association between POD24 and subsequent OS. An additional landmark analysis was conducted to evaluate the association of POD24 on OS for the subset of patients who were alive at 24 months post trial registration. Baseline Beta 2 Microglobulin (B2M) data were available for 9 of the 13 studies (total sample size of 4,361). Additional analyses including B2M along with other baseline factors were conducted on this subset of patients.

Results: 29% of patients progressed and 2.5% died without progressive disease within 24 months from trial registration. Patients alive without progression at 24 months were younger and more commonly had favorable PS, limited stage, low FLIPI risk score, normal baseline hemoglobin, and normal baseline B2M. A multivariable logistic regression model indicated that being male (odds ratio (OR) = 1.35; 95%CI = (1.19 – 1.52); p < .01), having PS >= 2 (OR = 1.85; (1.47 – 2.38); p < .01) and high FLIPI risk score (3 – 5) (OR = 2.94; (2.38 – 3.57); p < .01 compared to low risk (0 or 1) were associated with increased risk of progression or death before 24 months. Elevated baseline B2M (>= 3mg/L) (OR = 1.47; (1.25 – 1.75); p < .01) was also associated with increased risk of progression or death before 24 months.

Results of the time-dependent Cox model, adjusted for gender and stratified by PS and FLIPI, indicate that POD24 was associated with poor subsequent OS (hazard ratio (HR) = 5.24; (4.63 – 5.93); p < .01). Results of the landmark analysis confirm the association between POD24 and OS in patients who were alive 24 months after trial registration (Figure). Similar results were observed in the subset of patients with baseline B2M after adjusting for its effect along with other covariates.

Conclusions: This pooled analysis of >5,000 patients with FL included in 13 prospective clinical trials is the largest cohort to date validating early progression as a robust indicator of poor FL survival. We identified male gender, poor PS, high FLIPI score, and elevated baseline B2M as predictors of early death and progression. These provide well-defined clinical factors for building comprehensive prognostic models in the future that incorporate clinical and molecular predictors of POD24. Results on maintenance and response to therapy as factors impacting POD24 will be updated in the presentation. Our results confirm POD24 as an early clinical endpoint of poor survival in FL that should be utilized to identify patients for prospective clinical trials.

Analysis of a Naturally Occurring PAR4 Variant By Hydrogen/Deuterium Exchange Reveals Its Structural Rearrangement upon Activation By Thrombin and the Molecular Basis for Altered Reactivity

Result Type: Paper
Number: 453
Presenter: Xu Han
Program: Oral and Poster Abstracts
Session: 301. Vascular Wall Biology, Endothelial Progenitor Cells, and Platelet Adhesion, Activation, and Biochemistry: Platelet Adhesion, Activation, and Biochemistry

Xu Han, BS, MS, Lukas Hofmann, PhD*, Maria de la Fuente, BS*, Tivadar Orban, PhD*, Nathan Alexander, PhD*, Krzysztof Palczewski, PhD* and Marvin T Nieman, PhD

Pharmacology, Case Western Reserve University, Cleveland, OH

 

Protease activated receptors 1 and 4 (PAR1 and PAR4) are GPCRs that mediate thrombin signaling on human platelets. In this dual receptor system, PAR4 is responsible for sustained signaling required for stable platelet aggregation. In addition, common PAR4 polymorphisms affect its reactivity, which contributes to the variability in platelet response among individuals. The threonine residue 120 leads to a variant that is hyper-reactive to agonists and resistant to some antagonist compared to an alanine at this site. The molecular mechanisms by which this substitution influences PAR4 activation are not known. Further, the structural basis for PAR activation in general is also unknown. PARs are activated by enzymatic cleavage of the N-terminus exposing a tethered ligand that interacts with a binding pocket on the receptor’s extracellular side. Since the ligand is attached to the receptor, there are likely substantial conformational changes that occur during PAR activation. The goal of this study was to determine the structural rearrangement of PAR4 upon activation by thrombin to test the hypothesis that polymorphisms at position 120 directly contribute to the ligand binding site and the subsequent PAR4 signaling cascades. Here, we used hydrogen-deuterium exchange mass spectrometry to map the conformational rearrangement of the hyper-reactive PAR4 variant (PAR4-120T). Full length human PAR4-120T was expressed in and purified from SF9 insect cells without additional stabilizing modifications. Our initial peptide mapping studies generated 93.5% (344/368) amino acid sequence coverage with multiple overlapping peptides. In the uncleaved (apo) state, the seven transmembrane domains of PAR4 show limited deuterium uptake as a result of being buried in detergent micelles. TM4 and TM5 displayed lower deuterium uptake than the other helices which potentially indicate the formation of dimerization interface, which is in agreement with our previous biochemical studies. Helix 8, a short α-helix between TM7 and C-terminus, showed reduced deuterium uptake. Together with other studies, this may indicate helix 8 plays a role in anchoring the receptor on lipid rafts. In comparison, the N- and C-termini displayed higher solvent accessibility based on the high deuterium uptake. Surprisingly, the tethered ligand sequence of PAR4 (GYPGQV) at the N-terminus has significantly lower solvent accessibility than neighboring regions in the apo state. This suggests it is less flexible and may be localized near the binding pocket even before thrombin cleavage. Comparison of deuterium uptake between apo and thrombin cleaved (active) states of PAR4-120T revealed reduced solvent accessibility at amino acids Cys149-Leu156 at TM3 and Ser329-Ser333 at TM7. This identifies the potential tethered ligand binding region of PAR4, which has not been previously described yet. Interestingly, in our molecular models Thr120 was located near this region spatially, which potentially explains the impact of this residue on PAR4 reactivity. We further observed an increase in deuterium uptake indicating a potential role for extracellular loop III and the connected regions of TM6 and TM7 in the receptor activation mechanism. In summary, our study on PAR4 is the first to elucidate the structural dynamics and molecular rearrangement of a protease activated receptor upon activation. Our results provide the overall molecular architecture of PAR4, uncovers the tethered ligand binding region, and further reveals the molecular basis for the inter-individual platelet reactivity based on the genotype of this key platelet receptor. Altogether, our studies may have significant clinical impact towards explaining the diversity of individual responses to existing and forthcoming therapies.

Four Versus Two Years of Rituximab Maintenance (R-maintenance) Following Bendamustine Plus Rituximab (B-R): Initial Results of a Prospective, Randomized Multicenter Phase 3 Study in First-Line Follicular Lymphoma (the StiL NHL7-2008 MAINTAIN study)

Result Type: Paper
Number: 483
Presenter: Mathias Rummel
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Follicular Lymphoma, First Line

Mathias J Rummel, MD, PhD1*, Christian Buske, MD2, Bernd Hertenstein, MD3*, Christian Lerchenmüller, MD4*, Michael Koenigsmann, MD5, Elisabeth Lange, MD6*, Manfred Reeb, MD7*, Ulrich Kaiser, MD8*, Christina Balser, MD9*, Dirk Behringer, MD10*, Jan Dürig, MD11*, Tobias Gaska, MD12, Georg Maschmeyer, MD13, Georg Schliesser, MD14*, Alexander Christoph Burchardt, MD15*, Juergen Barth15*, Frank Kauff15*, Axel Hinke, PhD16* and Richard Greil, MD17

1Universitätsklinikum Giessen, Giessen, Germany
2Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany
3I. Medizinische Klinik, Klinikum Bremen-Mitte, Bremen, Germany
4Hematology and Oncology, Outpatient Clinic, Münster, Germany
5Outpatient Oncology Center, Hannover Medical School, Hannover, Germany
6Evangelisches Krankenhaus Hamm, Hamm, Germany
7IDGGQ GbR, Kaiserslautern, Germany
8St. Bernward Hospital, Hildesheim, Germany
9Oncology, Practice for Oncology, Marburg, Germany
10Department of Haematology, Oncology and Palliative Care, Augusta-Kranken-Anstalt gGmbH Bochum, Bochum, Germany
11Department of Hematology, University Hospital Essen, Essen, Germany
12Hematology und Oncology, Brüderkrankenhaus St. Josef, Paderborn, Germany
13Klinikum Ernst von Bergmann, Potsdam, Germany
14Practice for Oncology, Giessen, Germany
15Med. Clinic IV, Hematology, University Hospital Giessen, Giessen, Germany
16CCRC Cancer Clinical Research Consulting, Düsseldorf, Germany
17Paracelsus Medical University Salzburg, Salzburg, Austria

 

Background: R-maintenance for 2 years is part of a standard treatment approach for previously untreated follicular lymphoma. In this study we compared the efficacy and safety of 4 versus 2 years of R-maintenance following first-line treatment with B-R.

Methods: Patients included in the study were required to have stage II (bulky disease >7 cm), III, or IV disease. Patients were treated with up to 6 cycles of B-R plus 2 additional cycles of Rituximab. All responding patients received 2 years R-maintenance (375 mg/m2 every 2 months). Patients who tolerated treatment for the entire 2 years and who were still in remission hereafter were subsequently randomized to 2 more years of R-maintenance or observation. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rates, overall survival (OS), and toxicity.

Results: A total of 612 patients with follicular lymphoma were enrolled in the study. Of enrolled patients, 555 were evaluable for response and 497 (90%) responded to B-R induction, with 181 patients (33%) achieving a complete remission. A total of 261 patients discontinued treatment during induction or the first 2 years of R-maintenance. The most frequent reasons for discontinuation included progression in 85 of 261 pts (33%), patient’s or doctor’s choice in 55 pts (21%), toxicity or infections in 29 pts (11%), Rituximab intolerance in 14 pts (5%), or death in 11 pts (4%) with a median age of 70 years and 5 pts who died from infections. Of 351 patients randomized to 2-years or 4-years of R-maintenance, 350 were evaluable (n = 172 and n = 178, respectively). The median age was 60 years and patient characteristics were comparable between groups. The median observation time was 36 months following randomization. Median PFS and OS have not yet been reached in either arm. PFS appears superior with 4 years versus 2 years of R-maintenance with a hazard ratio (HR) of 0.63 (95% CI 0.36-1.11; fig. 1). There was no difference in OS between groups. One patient died from a progressive multifocal leukoencephalopathy (PML, randomized to 4 years of Rituximab). A historical comparison for PFS between responding patients given 2 years of R-maintenance in this MAINTAIN trial and subjects from the former StiL NHL1 study (B-R versus CHOP-R) who received B-R only appears to favor R-maintenance with a HR of 0.78 (95% CI 0.54-1.04). Data analysis is ongoing and updated results will be presented at the ASH meeting.

Conclusions: Results at the time of this analysis appear to favor 4-years over 2-years of R-maintenance and 2-years over observation compared to a historical control. Further analysis including the updated dataset will be presented at the ASH meeting and should provide more definitive evidence regarding the benefit of prolonged R-maintenance.

Long Term Follow-up of the PRIMA Study: Half of Patients Receiving Rituximab Maintenance Remain Progression Free at 10 Years

Result Type: Paper
Number: 486
Presenter: Gilles Andre Salles
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Follicular Lymphoma, First Line

Gilles Andre Salles, MD, PhD1, John Francis Seymour, MBBS2, Pierre Feugier, MD3*, Fritz Offner, MDPhD4, Armando Lopez-Guillermo5, David Belada, MD, PhD6*, Luc Xerri, MD, PhD7*, Reda Bouabdallah, MD8*, John Catalano9, Pauline Brice, MD10, Corinne Haioun, MD11, Alejandro Martín, MD, PhD12*, Lars Moller Pedersen13*, Alain Jacques Delmer, MD14, David Simpson, MBChB15, Sirpa Leppa, MD16, Pierre Soubeyran, MD, PhD17*, Rene-Olivier Casasnovas, MD18*, Tanin Intragumtornchai, MD19*, Vincent Ribrag20, Maria Gomes Silva21*, Emmanuelle Nicolas-Virelizier, MD22*, Thomas Lister, MD23, Jane Estell24*, Gustavo Milone, MD 25, Anne Sonet, MD26*, Julie Assemat27*, Harald Zeuner28*, Bertrand Coiffier, MD, PhD29 and Herve Tilly30

1Hematology, Hospices Civils de Lyon – Université de Lyon, Pierre-Bénite, France
2Peter MacCullum Cancer Center, Melbourne, Australia
3Hematology Department, CHU Nancy, Vandoeuvre Les Nancy Cedex, France
4Hematology, University Hospital Ghent, Gent, Belgium
5Hematology, Hospital Clinic, Barcelona, Spain
64th Department of Internal Medicine – Hematology, University Hospital and Charles University Faculty of Medicine in Hradec Kralove, Czech Republic, Hradec Kralove, CZE
7Bio-Pathology Department, Institut Paoli-Calmettes and Aix-Marseille Universite, Marseille, France
8Institut Paoli Calmettes, Department of Hematology, Marseille, France
9Frankston Hospital, Frankston, Victoria, Australia
10Hematology Department, AP-HP Hopital Saint-Louis, Paris, France
11Lymphoid malignancies unit, University Hospital Henri Mondor, Creteil, France
12Department of Hematology, Hospital Universitario de Salamanca / IBSAL, Salamanca, ESP
13Roskilde Hospital, Roskilde, Denmark
14Hematology department, Hopital Robert Debre CHU de Reims, Reims, FRA
15North Shore Hospital, Auckland, New Zealand
16Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
17Institut Bergonie, Bordeaux, FRA
18CHU Dijon, Dijon, FRA
19King Chulalongkorn Memorial Hospital, Bangkok, THA
20Gustave Roussy Cancer Campus, Villejuif, France
21Inst. Portuges de Oncologia, Lisbon, PRT
22Centre Léon Bérard, Lyon, France
23Barts Cancer Institute, London, United Kingdom
24Haematology Department, Concord Cancer Centre, Concord Hospital, Concord, NSW, Australia
25FUNDALEU, Buenos Aires, Argentina
26Hematology Department, CHU Montgodinne, montgodinne, Belgium
27LYSARC, Pierre Benite, France
28F. Hoffmann-La Roche Ltd, Basel, Switzerland
29Department of Hematology, Hospices Civils de Lyon, Lyon, France
30Hematology Department, Centre Henri Becquerel, Rouen, France

 

In patients with follicular lymphoma and a high tumor burden, the intergroup PRIMA phase III study was designed to evaluate the potential benefit of 2 years of rituximab (R) maintenance after response to first line R-chemotherapy induction regimens (patients registered from 12/2004 until 4/2007). At a median follow up of 3 years (Lancet 2011) and 6 years (Blood 2013 122:509), a significant sustained improvement in progression free survival (PFS) was demonstrated in patients receiving R-maintenance; hazard ratios (HR) of 0.55 and 0.58, respectively. We report here the long term results of this study with 4 additional years of follow-up.

Patients initially randomized between observation (n=513) and R-maintenance (n=505) were all followed for 7 years after randomization and thereafter until the 31/12/16 after having given an informed consent for this extended follow-up period consisting of a yearly physician visit (imaging procedures were according to local center practices after year 7). At data-base lock, the median follow-up of the entire patient cohort was 9 years (9.7 years for the 607 patients agreeing to extended follow-up).

Median PFS for patients in the observation arm was reached at 4.06 years as compared to 10.49 years in the R-maintenance arm (Log-Rank, P<.0001; HR=0.61, 95% confidence interval (95%CI) 0.52-0.73). At 10 years, 51% of the patients in the R-maintenance arm (versus 35% in the observation arm) were estimated to be free of disease progression. The benefit of R-maintenance for PFS was significant in all predefined patient strata: age (cutpoint=60 years), gender, the 3 FLIPI categories, quality of response to induction immunochemotherapy (CR/CRu and PR) and in patients having received R-CHOP (HR=0.57; 95%CI 0.47-0.70), while only a trend was observed for those having received R-CVP (HR=0.75; 95%CI 0.53-1.07). In a Cox regression model, R-maintenance remained an independent covariate from the above characteristics (HR=0.60; 95%CI 0.50-0.71). The median time to new anti-lymphoma treatment was 6.1 years in the observation arm but has not yet been reached in the R-maintenance arm (P<.0001; HR=0.66; 95%CI 0.55-0.78), with a 10-year estimate of 53% of the patients in this arm not having received a new treatment (versus 41% in the observation arm). At data base lock, 84 and 88 patients have died in the observation and R-maintenance arm, respectively. Main causes of death in the observation and R-maintenance arms were respectively: lymphoma progression in 38 and 39 patients, malignancies for 24 and 6 patients (with respectively 7 and 2 myeloid disorders; no other specific distribution pattern) infections in 6 and 11 patients (1 PML in each arm), and cardiovascular disorders in 4 and 8 patients. No new safety signals were identified with the additional 4 years of follow-up. Overall survival estimates (Kaplan-Meier) at 10 years were identical (80%) in each arm. Age >= 60 years, male sex and high FLIPI category, but not randomization arm, were all associated with a higher risk of death in a Cox regression model.

In summary, PRIMA study long term follow-up demonstrates that R-maintenance after induction immunochemotherapy provides a significant long term PFS benefit over observation. Despite the lack of OS benefit, it is noteworthy that more than half of the patients in the R arm remain free of disease progression and have not required new anti-lymphoma treatment beyond 10 years. With the prolonged life-expectancy of patients with follicular lymphoma, it is important to consider long term treatment-related toxicities and the risk of secondary malignancies related to repeated therapeutic interventions. Obtaining truly durable response with 1st line induction followed by R-maintenance remains an appealing treatment strategy for these patients.

High Complete Response Rates with Pembrolizumab in Combination with Rituximab in Patients with Relapsed Follicular Lymphoma: Results of an Open-Label, Phase II Study

Result Type: Paper
Number: 414
Presenter: Loretta Nastoupil
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Indolent Lymphomas, Novel Therapies, and Diagnostics

Loretta Nastoupil, MD1, Jason R. Westin, MD2, Nathan H. Fowler, MD3*, Michelle A. Fanale, MD4, Felipe Samaniego, MD5, Yasuhiro Oki, MD6,7, Ly Dsouza, PA-C8*, Chizobam Obi, RN9*, JingJing Cao8*, Xiaoyun Cheng10*, Man Chun John MA, PhD8*, Wang Zhiqiang9*, Lei Feng, MS11*, Shouhao Zhou12*, R. Eric Davis, MD1* and Sattva S. Neelapu, MD13

1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Lymphoma and Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston
3Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX
4University of Texas MD Anderson Cancer Center, Houston, TX
5M.D. Anderson Cancer Center, Houston, TX
6Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston
7Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX
8Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
9The University of Texas MD Anderson Cancer Center, Houston, TX
10MD.Anderson Cancer Center, Houston, TX
11Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX
12Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
13Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX

 

Background: Follicular lymphoma (FL) tumors are infiltrated with antitumor T cells, however, their function is impaired by immune checkpoints such as PD-1/PD-ligand pathway. Blocking PD-1 enhances the function of antitumor T cells in FL [Nattamai D & Neelapu SS, Blood, 2007]. In addition, blocking PD-1 on NK cells has been shown to enhance the ADCC effect of NK cells [Gorgun et al, Clin Cancer Res, 2015]. We reasoned that the combination of pembrolizumab, an anti-PD-1 antibody, and rituximab (R), an anti-CD20 antibody that induces ADCC, is likely to be synergistic through activation of both the innate and adaptive immune systems and result in enhanced clinical activity in FL.

Methods: We evaluated pembrolizumab and R in an open-label, non-randomized, single institution, phase II trial (N=30). Key inclusion criteria included adult patients (age ≥ 18 years), with FL grade 1-3a, ECOG performance status (PS) 0-1, in relapse after ≥1 prior therapy and R sensitive disease, defined as a complete (CR) or partial response (PR) lasting at least 6 months after the most recent R-containing therapy. Patients received R (375 mg/m2IV) on days 1, 8, 15, and 22 of cycle 1 and pembrolizumab (200mg IV) q 3 weeks for up to 16 cycles starting on day 2 of cycle 1. Primary endpoint was overall response rate (ORR). Response assessment was performed as per the Lugano Classification (Cheson et al, J Clin Oncol, 2014).

Results: As of February 2, 2017, 30 patients have initiated therapy and 10 are still in therapy. All 30 patients are evaluable for safety. Twenty-five patients have had at least 8 infusions of pembrolizumab or stopped therapy due to progression or toxicity and are evaluable for efficacy. Median age was 64 years (range 43-84), 57% were male, 73% had an ECOG PS of 0, 73% had intermediate or high risk FLIPI, and 50% had high tumor burden as defined by GELF criteria. Median prior therapy = 1 (range 1-4). Adverse events (AE) regardless of causality were mild, most were grade 1-2. Grade 3 AE’s included nausea (N=2), infusion reaction (N=2), hypertension (N=1), aseptic meningitis (N=1), and pneumonia (N=1). Immune-related (IR) AEs included diarrhea (grade 1 N=6, grade 2 N=4), rash (grade 1 N=2, grade 2 N=2), transaminitis (grade 1 N=4), pneumonitis (grade 2 N=1), pancreatitis (grade 2 N=1), and hypothyroidism (grade 1 N=1). Five discontinued therapy as a result of recurrent grade 2 IR AEs (diarrhea N=3, rash N=1, pneumonitis N=1). Among evaluable patients, ORR is 64% (CR N=12; PR N=4), CR rate is 48%. With a median follow up of 11 months (range 3.7-21), 15 (60%) patients are still in ongoing remission. No deaths have been observed. PD-L1 expression was tested in 8 baseline tumor samples using PD-L1 22C3 IHC pharmDx and was detected in histiocytes in all 8 tumors, but was present in only 1-8% of tumor cells in 5 tumors and was not associated with response. Immune cell gene signature analysis in baseline tumors by Nansotring in 12 patients showed an association between presence of high levels of CD8+ T-effector score and induction of a CR. Additional biomarker analyses from baseline tumors and serial peripheral blood mononuclear cell samples are ongoing and will be presented along with updated clinical data.

Conclusions: Promising efficacy was observed with pembrolizumab and R in relapsed FL with meaningful overall and CR rates. The combination also appears to be well tolerated. Analysis of immune cell gene signatures in baseline tumors may identify a potential predictive biomarker. Further investigation is warranted.

Maintenance Rituximab or Observation after Frontline Treatment with Bendamustine-Rituximab (BR) for Follicular Lymphoma: A Real World Analysis Across 13 US Cancer Centers

Result Type: Paper
Number: 2779
Presenter: Brian Hill
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster II

Brian T. Hill, MD, PhD1, Loretta Nastoupil, MD2, Allison M. Winter, MD3, Melody R Becnel, MD2, James R. Cerhan, MD, PhD4, Thomas M Habermann, MD5, Brian K Link, MD6, Matthew J Maurer, MS7, Bita Fakhri, MD, MPH8, Prathima Reddy, MD9*, Stephen D. Smith, MD10, Dhruvika Mukhija, MD1*, Deepa Jagadeesh, MD, MPH1, Amrita Desai, MD11*, Juan Pablo Alderuccio, MD11, Izidore S Lossos, MD12, Pooja Mehra, MD13*, Craig A. Portell, MD14, Max L. Goldman, BA15, Oscar Calzada, BS16*, Jonathon B Cohen, MD, MS17, Mohammad Junaid Hussain, MD18, Nilanjan Ghosh, MD, PhD18, Paolo Caimi, MD19, Timothy Tiutan, MD20*, Peter Martin, FRCPC, MD, MS20, Abhigna Kodali, MD21*, Andrew M. Evens, DO, MSc21 and Brad S. Kahl, MD22

1Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
2The University of Texas MD Anderson Cancer Center, Houston, TX
3Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
4Department of Health Sciences Research, Mayo Clinic, Rochester, MN
5Division of Hematology, Mayo Clinic, Rochester, MN
6University of Iowa Hospitals and Clinics, Iowa City, IA
7Division of Biostatistics, Mayo Clinic, Rochester, MN
8Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO
9Internal Medicine, CHI Franciscan Hospital, Federal Way, WA
10University of Washington, Seattle, WA
11University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL
12University of Miami School of Medicine, Miami, FL
13University of Virginia, Charlottesville, VA
14Division of Hematology and Oncology, University of Virginia, Charlottesville, VA
15School of Medicine, Emory University, Atlanta, GA
16Emory University School of Medicine, Atlanta, GA
17Emory University, Atlanta, GA
18Levine Cancer Institute, Charlotte, NC
19University Hospitals of Cleveland, Cleveland, OH
20Weill Cornell Medical College-New York Presbyterian Hospital, New York, NY
21Tufts University School of Medicine and Cancer Center, Boston, MA
22Washington University School of Medicine, Saint Louis, MO

 

Introduction: For follicular lymphoma (FL) patients (Pts) in need of therapy, frontline treatment with bendamustine-rituximab (BR) has become a standard treatment option. The prospective randomized PRIMA trial demonstrated that rituximab maintenance (RM) after response to treatment with R-CHOP is safe and improves progression-free survival (PFS) vs observation (Obs). However, there remains lack of consensus regarding the application of RM after front-line BR; there are no randomized clinical trials demonstrating its safety/efficacy. Recently-presented data from the GALLIUM study comparing outcomes of FL Pts treated with either BR or B in combination with obinutuzumab (G) followed by RM or G maintenance showed a fatal adverse event (AE) rate of 4.7% and 5.9%, respectively with a median follow-up of 41 months (Hiddemann, EHA 2017). The aim of this study was to assess the efficacy and safety of RM vs. Obs after frontline BR for FL.

Methods: We conducted a comprehensive multi-institutional retrospective analysis of outcomes of FL Pts (grade I/II & IIIA) initiated on therapy with BR between 2011-2016 followed by either RM or Obs. The decision to apply RM was based on preferences of individual treating physician and/or patient. Individual patient records were queried for baseline demographic, disease characteristics, and treatment history. Outcomes included adverse events during or after BR induction, response rates, PFS, overall survival (OS) and cause of death (COD).

Results: We collected data on 640 Pts across 13 US academic medical centers. Median age was 60 years (range 21-88). 52% were male and 87% were Caucasian (N = 397 with available data). FLIPI was low (20%), intermediate (38%) and high risk (41%) (N=545), 21% had B symptoms (N = 422) and 23%, had bulky disease (N=408). 91% had grade I/II FL and 9% had grade IIIA (N=632). The median time from diagnosis to treatment was 1 month (range 0 – 135 months). With a median follow-up of 36 months, 63 Pts died (9.8%): COD was lymphoma (n=26), infection or multi-organ system failure (MOSF) (n=12), unknown (n=12) solid tumor (n=10), MDS (N=1) cardiovascular (n=1) and progressive multifocal leukoencephalopathy (n=1), representing a fatal AE rate of 2.3% or 4.1% if cases of unknown COD are excluded or included in determining fatal AE rate, respectively. Median time to death was 22 months (range 2-74 months). Among the 584 Pts who received ≥4 cycles of BR, responses to induction therapy were available in 394 cases. RM was more commonly applied in responding Pts than Obs: in the 260 Pts selected for RM, the complete and partial remission (CR, PR) rates were 71% and 28%, respectively and in the 134 Pts selected for Obs, the CR and PR rates were 58% and 30%, respectively, (P<0.001). Median number of cycles was 6 and median B dose was 90 mg/m2 and did not differ between RM and Obs Pts (P=0.14 for cycle, P=0.40 for dose). RM was administered q2 months (66%), q3 months (30%) or 4 doses q6 months (4%) for a mean of 18 months (range 3-24). The 3-year PFS for PR Pts was 80% and 44% for RM vs Obs, respectively (P=0.002). The 3-year PFS for CR Pts was 86% and 80% for RM vs. Obs, respectively (P=0.54). For Pts in PR/CR, multivariable analysis suggested that high FLIPI vs. low/intermediate was associated with worse PFS [hazard ratio (HR) 2.47, 95% confidence interval (95% C.I.) 1.43–4.28), P=0.001] and OS [HR 5.47 (95% CI 1.81-16.53), P=0.003]. RM was associated with improvement in PFS for Pts in PR [HR 0.36 (95% CI 0.18-0.71), P=0.003] but no benefit for Pts in CR [HR 0.80 (95% CI 0.38–1.66), P=0.55]. There was no association between use of RM and OS. Kaplan Meier estimates of PFS and OS (Figure) are depicted based on response (CR or PR) to BR induction.

Conclusions: In this large outcomes analysis of FL Pts treated with BR followed by RM, the fatal AE rate was comparable to that reported in GALLIUM when accounting for the real world nature of this unselected Pt cohort. RM was associated with a significant improvement in PFS vs. Obs in Pts who achieved PR after induction but no observed benefit for Pts in CR. In addition, we identified that the FLIPI was strongly prognostic for Pt survival for responding patients. Within the limitations inherent to retrospective analysis, these data suggest that FL Pts with partial response to BR induction therapy experience prolongation of PFS with RM, but consistent with the findings in the PRIMA study, there was no obvious impact on OS.

Median 3.5-Year Follow-up of Ibrutinib Treatment in Patients with Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis

Result Type: Paper
Number: 151
Presenter: Simon Rule
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Mantle Cell Lymphoma, New Therapies

Simon Rule, MD1*, Martin Dreyling, MD, PhD2, Andre Goy, MD3, Georg Hess4*, Rebecca Auer, MD, PhD5*, Brad S Kahl, MD6, Jose Angel Hernandez-Rivas7*, Anil Londhe, PhD8*, Fong Clow, ScD9, Sanjay Deshpande8*, Lori Parisi8*, Michael Wang, BS10 and Natalie Dennis11*

1Plymouth University Medical School, Plymouth, United Kingdom
2Department of Medicine III, Klinikum der Universität München, Munich, Germany
3John Theurer Cancer Center, Hackensack Meridian Health, New York, NY
4Department of Hematology, Medical Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
5Barts Cancer Institute, London, United Kingdom
6Department of Medicine, Washington University School of Medicine in St. Louis, Saint Louis, MO
7Department of Hematology, Hospital Infanta Leonor, Madrid, Spain
8Janssen Research & Development, Raritan, NJ
9Pharmacyclics, Sunnyvale, CA
10Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX
11Parexel, Worthing, GBR

 

Introduction: Ibrutinib is a first-in-class oral inhibitor of Bruton’s tyrosine kinase approved for relapsed/refractory mantle cell lymphoma (R/R MCL). We previously reported results of a pooled analysis of 370 patients with R/R MCL treated with ibrutinib in the SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391) studies (median follow-up 24 months; Rule S et al, Br J Haematol [in press]). Here, we present median 3.5 year follow-up in these patients, including additional exposure and follow-up of 87 patients across the 3 studies who enrolled in the long-term access study CAN3001 (NCT01804686).

Methods: Patients enrolled in SPARK, RAY, and PCYC-1104 received ibrutinib 560 mg orally once daily until progressive disease or unacceptable toxicity. Study inclusion and exclusion criteria were similar except patients in SPARK were required to have received both rituximab and bortezomib, and in RAY, prior rituximab. Patients who continued to benefit from ibrutinib therapy at end of study were eligible to enroll in CAN3001, a phase 3b open-label study providing continued access to ibrutinib. Safety reporting in CAN3001 was limited to grade 3/4 adverse events (AEs) and serious adverse events (SAEs). This pooled analysis was limited to patients on ibrutinib therapy, excluding crossover patients. Investigator-assessed tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated. PFS and OS were analyzed by number of prior lines of therapy (LOT) and best tumor response. Patients in CAN3001 were censored from OS analysis upon treatment or study discontinuation. Treatment-emergent adverse events (TEAEs) of ≥ grade 3 were summarized.

Results: Of a total 370 patients, 111 were enrolled in PCYC-1104, 120 in SPARK, and 139 in RAY; 87 of 370 patients subsequently enrolled in CAN3001. The median duration of follow-up in the pooled data set was 41.1 months (95% confidence interval [CI], 37.3-42.5); median treatment exposure was 11.1 months (range: 0.03-72.1). Eighty-three and 40 patients had ibrutinib exposure ≥ 3 and ≥ 4 years, respectively. Fifty-four of 87 (62.1%) patients enrolled in CAN3001 remain on ibrutinib. Patients had a median of 2 (range: 1-9) prior LOT before receiving ibrutinib.

The proportion of patients achieving complete response (CR) increased to 26.5% with 41 months of follow-up. At 2 and 3 years, respectively, 36% (95% CI, 0.31-0.42) and 26% (0.20-0.32) of patients were progression free, and the median PFS was 13.0 months (Table). Median PFS in patients with 1 prior LOT was 33.6 (19.4-42.1) months (Figure) and in patients achieving CR was 46.2 (42.1-not estimable) months (Table). Patients with favorable baseline disease characteristics were more likely to remain on ibrutinib > 3 years.

Overall, 53% (95% CI, 0.47-0.58), 45% (0.39-0.50), and 37% (0.25-0.49) of patients were alive at 2, 3, and 5 years, respectively. Median OS was 26.7 months (Table).

Grade ≥ 3 TEAEs occurred in 295 (79.7%) patients, with the new onset events decreasing after Year 1 (67.8%, 47.8%, 34.8%, 36.1%, and 20.0% for Years 1, 2, 3, 4, and > 4, respectively). Cumulative incidence of any major hemorrhage was 7.3%, and new onset events decreased after Year 1 (4.9%, 2.2%, 2.6%, 2.4%, and 0% for Years 1, 2, 3, 4, and > 4, respectively). The most common (incidence ≥ 5%) grade ≥ 3 TEAEs were neutropenia (17.0%), thrombocytopenia (12.2%), pneumonia (11.9%), anemia (9.5%), atrial fibrillation (5.9%), and hypertension (5.1%). Most of these AEs were more common during the first year of ibrutinib treatment. Treatment-emergent SAEs occurred in 229 (61.9%) patients and new onset SAEs decreased over time (incidence: 47.3%, 33.9%, 29.6%, 25.3%, and 12.5% for Years 1, 2, 3, 4, and > 4, respectively).

Conclusion: In this pooled analysis of ibrutinib-treated R/R MCL patients with median 3.5 years of follow-up, more than a quarter of patients remained progression free and nearly half were alive at 3 years. Clinical outcomes were best for patients who achieved CR and those who were treated with ibrutinib at first relapse/progression. New onset grade ≥ 3 AEs/SAEs decreased over time. This project was sponsored by Janssen. Writing assistance was provided by Natalie Dennis of PAREXEL and was funded by Janssen Global Services, LLC.

Rituximab Maintenance after First-Line Immunochemotherapy in Mantle Cell Lymphoma: Long-Term Follow-up of the Randomized European MCL Elderly Trial

Result Type: Paper
Number: 153
Presenter: Eva Hoster
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Mantle Cell Lymphoma, New Therapies

Eva Hoster1,2*, Hanneke Kluin-Nelemans, MD, PhD3*, Olivier Hermine, MD, PhD4*, Jan Walewski, MD, PhD5, Marek Trneny, MD6, Christian H. Geisler, MD, PhD7, Stephan Stilgenbauer, MD, PhD8, Catherine Thieblemont, MD, PhD9*, Ursula Vehling-Kaiser, MD10*, Jeanette K. Doorduijn, MD, PhD11, Lionel Karlin, MD12*, Roswitha Forstpointner, MD1*, Herve Tilly13, Michal Szymczyk, MD5*, Vincent Ribrag, MD14, Marc Andre, MD15*, Wolfram Klapper, MD16*, Wolfgang Hiddemann1*, Michael Unterhalt, MD, PhD1* and Martin Dreyling, MD, PhD1

1Department of Medicine III, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
2University Hospital Munich, Munich, Germany
3Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
4Hematology Department, AP-HP Hôpital Necker, University Paris Descartes, Paris, France
5Department of Lymphoid Malignancy, Maria Skłodowska-Curie Institute – Oncology Center, Warsaw, Poland
6First Department of Medicine – Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic
7Department of Hematology, Rigshospitalet, Copenhagen, Denmark
8Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany
9Hematology Department, Hospital Saint-Louis, Paris, France
10Hematology Oncology, Dayclinic Landshut, Landshut, Germany
11Erasmus MC Cancer Institute, Rotterdam, Netherlands
12Ch Lyon Sud, Pierre Bénite, France
13Henri Becquerel Centre, Université de Rouen, Rouen, France
14Institut Gustave-Roussy, Villejuif, France
15Service d’Hématologie CHU Godinne, Yvoir, Belgium
16Department of Pathology, Hematopathology Section and Lymph Node Registry, University of Kiel, Kiel, Germany

 

Background: Mantle cell lymphoma (MCL) is characterized by a poor prognosis. Starting in 2004, the European MCL Network has performed the double randomized MCL Elderly trial for first-line treatment of patients with MCL, Ann-Arbor stage II-IV, aged 60 years or older and not suitable for autologous stem cell transplantation (Kluin-Nelemans et al., NEJM 2012). Median age of the 560 patients included was 70 years (range, 60-87). The first randomization compared 8xR-CHOP with 6xR-FC induction, the second randomization compared rituximab (R) maintenance with interferon-alpha (IFN) maintenance, both given in remission until progression. The primary evaluation of the induction part showed that R-FC could not improve complete remission rates compared with R-CHOP, while overall survival (OS) with R-FC was substantially shortened compared to R-CHOP. The primary evaluation of the maintenance part showed a prolonged progression-free survival (PFS) in remission with R compared to IFN. After R-CHOP induction, PFS and OS were substantially prolonged by R vs. IFN. We report here the long-term follow-up of the time-to-event endpoints with robust 5-year estimates after a median follow-up of 6.7 years.

Methods: While the primary maintenance question was evaluated per protocol adjusting for interim analyses, the other analyses were according to the intention to treat without adjustment. 95% confidence intervals for Kaplan-Meier estimates were calculated by using Greenwood’s variance and the log-log transformation. Using competing risk methods, we additionally estimated cumulative incidences of treatment failure (stable or progressive disease) and of death without treatment failure.

Results: Failure-free survival after start of R-FC or R-CHOP induction was overlapping with 5-year probabilities of 31% (95% CI 25%-37%) in both groups. While R-FC showed lower 5-year cumulative incidence of treatment failure compared with R-CHOP (51% vs. 60%, p=0.083), the cumulative incidence of death without treatment failure was higher with R-FC (19% vs. 9% with R-CHOP, p=0.0032). OS was substantially shorter after R-FC with 5-year probabilities of 42% (36%-49%) compared with 58% (51%-64%) after R-CHOP (p=0.0012). This observation was related to the higher cumulative incidence of death without treatment failure after R-FC and a shorter OS after first treatment failure (R-FC: median 1.0 vs. R-CHOP: 2.3 years).

The efficacy of R maintenance was confirmed with a significantly prolonged PFS from end of induction (primary evaluation, p=0.0109, hazard ratio 0.48, 5-year PFS, R: 53%, 44%-61% vs. IFN: 23%, 15%-31%); OS was also prolonged (p=0.008). After response to R-CHOP, the 5-year PFS with R vs. IFN was 51% (40%-62%) vs. 22% (14%-32%, Figure 1A, p<0.0001) in comparison to 52% (39%-63%) vs. 32% (20%-45%) after R-FC (p=0.032, interaction p=0.19). With R-maintenance after R-FC, the 5-year cumulative incidence of death without progression was as high as the cumulative incidence of progression (24% and 23%, respectively). After R-CHOP, OS was prolonged by R vs. IFN with 5-year OS of 79% (67%-86%) vs. 59% (48%-69%, p=0.0026, Figure 1B), in contrast to R-FC with 5-year OS of 57% (44%-68%) vs. 54% (39%-66%, p=0.60, interaction p=0.096). Conclusions: After long-term follow-up we confirm the substantially prolonged PFS and OS with R-maintenance after R-CHOP induction in first-line treatment of older MCL patients who are no candidates for autologous stem cell transplantation. Despite indications for anti-lymphoma activity, induction with six cycles of R-FC was associated with severe treatment complications leading to a higher cumulative incidence of death without treatment failure and shorter survival compared with 8 cycles of R-CHOP.[/et_pb_text][et_pb_image src="http://www.post-ash.co.uk/wp-content/uploads/2018/01/153.jpg" _builder_version="3.0.92"][/et_pb_image][et_pb_text _builder_version="3.0.92"]

Efficacy and Safety of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma in the Phase 2 ACE-LY-004 Study

Result Type: Paper
Number: 155
Presenter: Michael Wang
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Mantle Cell Lymphoma, New Therapies

Michael Wang, BS1, Simon Rule, MD2*, Pier Luigi Zinzani, MD, PhD3, Andre Goy, MD4, Rene-Olivier Casasnovas, MD5*, Stephen D. Smith, MD6, Gandhi Damaj, MD7, Jeanette K. Doorduijn, MD, PhD8, Thierry Lamy, Pr, MD, PhD9, Franck Morschhauser, MD, PhD10*, Carlos Panizo, MD, PhD11*, Bijal Shah, MD12, Andrew Davies, PhD13*, Richard Eek, MBCHB14*, Jehan Dupuis, MD15*, Eric Jacobsen, MD16, Arnon P. Kater, MD, PhD17, Steven Le Gouill, MD PhD18*, Lucie Oberic, MD19*, Tadeusz Robak, MD, PhD20, Todd Covey, PhD21*, Richa Dua, PharmD21*, Ahmed Hamdy, MD21, Xin Huang21*, Raquel Izumi, PhD21, Priti Patel, MD21*, J. Greg Slatter, PhD21* and Wojciech Jurczak, PhD, MD22

1Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Plymouth University Medical School, Plymouth, United Kingdom
3Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy
4John Theurer Cancer Center, Hackensack Meridian Health, New York, NY
5Hopital d’Enfants, CHU Dijon, Dijon, France
6Fred Hutchinson Cancer Research Center, Seattle, WA
7Institut d’Hematologie de Basse-Normandie, Caen, France
8Erasmus MC, Lunenburg Lymphoma Phase I/II Consortium, Rotterdam, Netherlands
9CHU Rennes, Rennes, France
10CHRU Lille – Hôpital Claude Huriez, Lille, France
11Clínica Universidad de Navarra, Pamplona, Spain
12Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL
13Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
14Border Medical Oncology, Wodonga, Australia
15Unité Hémopathies Lymphoïdes, AP-HP Hôpital Henri Mondor, Créteil, France
16Dana-Farber Cancer Institute, Boston, MA
17Academic Medical Center, Lunenburg Lymphoma Phase I/II Consortium, Amsterdam, Netherlands
18CHU de Nantes – Hotel Dieu, Nantes, France
19Institut Universaitaire de Cancer-Oncopole (IUCT-O), Toulouse, France
20Copernicus Memorial Hospital, Medical University of Lodz, Lodz, Poland
21Acerta Pharma, Redwood City, CA
22Department of Haematology, Jagiellonian University, Krakow, Poland

 

Background: MCL is an aggressive B-cell non-Hodgkin lymphoma with poor prognosis. Pts with R/R MCL typically experience low overall response rates (ORRs) and short remissions. Bruton tyrosine kinase (BTK) is a clinically validated target in MCL. Acalabrutinib (ACP-196) is a highly selective, potent, covalent inhibitor of BTK with minimal off-target activity. The Phase 2 ACE-LY-004 study assessed acalabrutinib monotherapy in R/R MCL pts.

Methods: Eligible pts were aged ≥18 y with confirmed MCL, ECOG PS ≤2, and had relapsed after or were refractory to 1-5 prior therapies. Exclusion criteria included prior BTK or BCL-2 inhibitor exposure and concomitant warfarin or equivalent vitamin K antagonists. Acalabrutinib was administered orally at 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. The primary endpoint was ORR (complete response [CR] + partial response) by investigator assessment based on the Lugano Classification (Cheson, et al. 2014). Secondary endpoints included ORR by Independent Review Committee (IRC) assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, pharmacokinetics (PK) and pharmacodynamics. Time to response (TTR) was an exploratory endpoint.

Results: 124 pts from 9 countries were treated. Median age was 68 y (range 42-90) with 65% aged ≥65 y. Baseline characteristics included ECOG PS ≤1 (93%), bulky lymph nodes ≥10 cm (8%), extranodal involvement (73%) and intermediate/high risk simplified MCL International Prognostic Index scores (44%/17%). Median number of prior therapies was 2 (range 1-5); 24% were refractory to the most recent prior treatment. Acalabrutinib PK parameters indicated rapid absorption and elimination. Median BTK target occupancy at steady state was 99% 4 h after dosing and 95% at trough (12 h after dosing). As of Feb 28, 2017, median time on study was 15.2 mo (range 0.3-23.7). Investigator-assessed ORR was 81% (95% CI, 73%-87%), with 40% (95% CI, 31%-49%) achieving CR (Table). High concordance (91% and 94%) was observed between investigator- and IRC-assessed ORR and CR, respectively. ORR and CR rates were consistent across prespecified subgroups of age, tumor bulk (≥10 cm) and number/type of prior treatment. Median TTR was 1.9 mo (range 1.5-4.4). Median DOR was not reached (NR); the 12-mo DOR was 72% (95% CI, 62%-80%). DOR by best response is shown in the figure. Median PFS and OS were NR. The 12-mo PFS and OS rates were 67% (95% CI, 58%-75%) and 87% (95% CI, 79%-92%), respectively. The most frequent adverse events (AEs; ≥20%) were primarily Grade 1/2 and included headache (38%), diarrhea (31%), fatigue (27%) and myalgia (21%). Grade 3/4 AEs (≥5%) included neutropenia (10%), anemia (9%) and pneumonia (5%). There were no cases of atrial fibrillation and 1 case of Grade 3 hypertension (1%), The most common bleeding events were contusion (13%) and petechiae (9%); all bleeding events were Grade 1/2 except one event of Grade 3 gastrointestinal (GI) hemorrhage occurring in 1 pt (1%) with a history of a GI ulcer. Tumor lysis syndrome (Grade ≥3) was reported in 3 pts (2%) and all cases occurred after treatment discontinuation due to disease progression. Second primary malignancies occurred in 8 pts (6%), 4 of which were skin neoplasms. One Grade 5 AE was reported in a pt with a history of aortic stenosis who died of worsening aortic stenosis not considered related to study treatment. Median relative dose intensity (ratio of actual to planned cumulative dose during drug exposure period) was 99% (range 27%-100%). Treatment discontinuation was primarily due to PD (31%) and AE (6%). AEs leading to discontinuation occurred in only one pt each and were aortic stenosis, B-cell lymphoma (DLBCL), blood blister and petechiae (both in 1 pt with Grade 3 acute coronary syndrome which was treated with Plavix, resulting in blood blister/petechiae formation [considered related]), dyspnea and leukostasis syndrome (in the same pt), noncardiac chest pain, pulmonary fibrosis and thrombocytopenia. At cutoff, 56% of pts remain on treatment.

ConclusionsIn R/R MCL pts, treatment with single-agent acalabrutinib resulted in high ORR and CR rates, with durable and clinically meaningful responses. A favorable safety profile was also demonstrated, with a low frequency and severity of AEs and few discontinuations due to AEs. Given this favorable benefit-risk profile, acalabrutinib represents a promising treatment option for R/R MCL.