Post ASH speaker abstracts 2018

CLL

Abstracts to support presentations from Piers Patten

Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia – Results from Pre-Planned Interim Analysis of the Randomized Phase 3 Murano Study

Result Type: Paper
Number: LBA-2
Presenter: John Seymour
Program: General Sessions
Session: Late-Breaking Abstracts Session

John F Seymour, MBBS, PhD1, Thomas J. Kipps, MD2, Barbara F. Eichhorst, MD3*, Peter Hillmen, MBChB, FRCP, FRCPath, PhD 4, James M. D’Rozario, MBBS FRACP FRCPA5, Sarit Assouline, MD6, Carolyn Jane Owen, MD, FRCPC7, John Gerecitano, MD, PhD8, Tadeusz Robak, MD, PhD9, Javier De la Serna, MD10*, Ulrich Jaeger, MD11*, Guillaume Cartron, MD, PhD12*, Marco Montillo, MD13, Rod Humerickhouse, MD, PhD14*, Elizabeth Punnoose, PhD15*, Yan Li, PhD16*, Michelle Boyer, PhD17*, Kathryn Humphrey, BSc18*, Mehrdad Mobasher, MD, MPH15 and Arnon P. Kater, MD19

1Peter MacCallum Centre & Royal Melbourne Hospital, Melbourne, Australia
2University of California School of Medicine, San Diego, CA
3University Hospital Cologne, Cologne, Germany
4St. James’s University Hospital, Leeds, United Kingdom
5The John Curtin School of Medical Research, Australian National University, Canberra, Australia
6Segal Cancer Center, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada
7Departments of Medicine and Oncology, University of Calgary, Calgary, AB, Canada
8Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
9Department of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland
10Hospital Universitario 12 de Octubre, Madrid, Spain
11Dept. of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
12Department of Hematology, CHU Montpellier, Montpellier, France
13Department of Onco-Hematology, Division of Hematology, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy
14AbbVie Inc., North Chicago, IL
15Genentech, Inc., South San Francisco, CA
16Genentech Inc., South San Francisco, CA
17F. Hoffmann-La Roche, Ltd., Welwyn Garden City, United Kingdom
18F-Hoffmann-La Roche Ltd., Welwyn Garden City, United Kingdom
19Academic Medical Center, Amsterdam, and HOVON CLL-WG, Amsterdam, Netherlands

 

 

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/m2first 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 VR resulted in outcomes superior to that of BR for pts with R/R CLL.

Randomized Trial of Ibrutinib Versus Ibrutinib Plus Rituximab (Ib+R) in Patients with Chronic Lymphocytic Leukemia (CLL)

Result Type: Paper
Number: 427
Presenter: Jan Burger
Program: Oral and Poster Abstracts
Session: 642. CLL: Therapy, excluding Transplantation: Targeting MRD Negative CLL Through Combinations of Novel Agents and Antibody

Jan A. Burger, MD, PhD 1, Mariela Sivina, PhD2*, Alessandra Ferrajoli, MD3, Nitin Jain, MD1, Ekaterina Kim, PhD2*, Tapan Kadia, MD3, Zeev Estrov, MD4, Graciela Nogueras González5*, Xuelin Huang, PhD6*, Maro Ohanian, DO3*, Michael Andreeff, MD, PhD3, Mathew Thomas2*, Lynette Alexander-Williams2*, Hagop M. Kantarjian, MD3, Susan M. O’Brien, MD7, William G Wierda, MD, PhD3 and Michael J. Keating, MD3*

1Department of Leukemia, MD Anderson Cancer Center, Houston, TX
2The University of Texas, MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4University of Texas M.D. Anderson Cancer Center, Houston, TX
5The University of Texas, MD Anderson, HOUSTON, TX
6The University of Texas, MD Anderson, Houston, TX
7Chao Family Comprehensive Cancer Center at UC Irvine Medical Center, Orange, CA

Background: Single agent ibrutinib is currently approved as monotherapy for the treatment of CLL, both in treatment-naïve and relapsed patients; it induces high response rates, which are durable in most patients. Results from a Phase II study combining ibrutinib with rituximab in high-risk patients with CLL demonstrated encouraging high overall response rates (ORR 95%, Burger JA, Lancet Oncology 14: 1090, 2014). To determine whether rituximab provides added benefit to ibrutinib therapy, we conducted an open label randomized single center trial of ibrutinib versus ibrutinib plus rituximab in 206 patients with CLL (NCT02007044).

Methods: Patients were randomized to receive ibrutinib (Ib, n= 102) or ibrutinib plus rituximab (Ib+R, n= 104). Patients with relapsed CLL and treatment naïve patients with high-risk disease (del17p or TP53 mutation, n=27), who were evenly distributed among the treatment arms, were eligible. Patients were treated with ibrutinib 420 mg PO daily, until adverse events, disease progression, or death precluded further therapy. Patients randomized to Ib+R received rituximab during the first 6 months of treatment (375 mg/m2 weekly during the first 4 weeks [cycle 1], then monthly for cycles 2-6), in addition to ibrutinib. The primary end point was progression free survival (PFS); secondary end points included ORR per revised iwCLL criteria, safety, and tolerability.

Results: The median age was 65 years, 70% were male, 37% had del17p or TP53 mutation, 20% del11q, 72% unmutated IgHV, and 38% advanced stage disease (Rai stage 3-4). The median baseline absolute lymphocytic count (ALC) and β2 microglobulin at start of therapy were 30x109/L (0.5 – 350.9x109/L) and 3.7 mg/L (1.3 – 13.1 mg/L), respectively. After a median observation time of 25.2 and 22.7 months, 79 (77%) or 71 (68%) of patients continue ibrutinib treatment on the Ib or Ib+R arm, respectively. 188 patients were evaluable for response assessment. 20 patients (21%) on the Ib arm and 26 patients (28%) on the Ib+R arm achieved a complete remission (CR), p=0.309; partial remissions (PR) were achieved in 72 (77%) and 68 (72%) of patients receiving Ib or Ib+R, respectively, accounting for an ORR of 98% for Ib-, and 100% for Ib+R-treated patients. Bone marrow flow cytometry assessments for minimal residual disease (MRD) at time of last follow up showed significantly lower level of residual CLL cells in Ib+R treated patients (median: 4.9% CLL cells) when compared to Ib treated patients (17.1%, p=0.002). CR with MRD-negativity was observed in 5 patients treated with Ib+R and in 1 patient treated with Ib. The median time to normalization of the absolute lymphocyte count (ALC, ≤4.0 K/uL) was significantly shorter in Ib+R- compared to Ib-treated patients (3.0 vs. 8.9 months, p<0.001) (Figure 1A). The median time to achieve CR was also significantly shorter in Ib+R treated patients (11.5 months, versus 21.1 months in the Ib treated patients; p=0.032); however, there was not a significant difference in PFS between the patients treated with Ib and Ib+R during the observation period of time (91.2% vs. 90.4%, p=0.788, Figure 1B). Among the 56 patients that came off study (23 from Ib, and 33 from Ib+R), side effects and/or toxicities were the most common cause for therapy discontinuation (n=28); death was reported in 5 patients. Causes of death were renal failure, cerebral hemorrhage, bowel perforation with colon hematoma, pneumonia, and respiratory failure. 8 patients had disease progression (5 on Ib and 3 on the Ib+R arm); disease transformation was reported in 3 patients, occurring between 11 to 16 months on treatment. Discontinuation due to second malignancies was reported in 6 patients with colorectal cancer, liposarcoma, melanoma, pleomorphic sarcomatoid tumor, and 2 cases of new-onset CML. The most frequently reported related adverse events (AE) were similarly distributed in both arms, including arterial hypertension, neutropenia, diarrhea, and atrial fibrillation.

Conclusion: The addition of rituximab to ibrutinib in relapsed and high-risk CLL patients did not improve the PFS. However, patients treated with Ib+R reached their remissions significantly faster and achieved lower MRD levels. Given these results, single-agent ibrutinib should remain standard-of-care therapy in CLL, but the addition of rituximab can be considered in patients in whom a faster response is desirable.

Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy

Result Type: Paper
Number: 428
Presenter: Peter Hillmen
Program: Oral and Poster Abstracts
Session: 642. CLL: Therapy, excluding Transplantation: Targeting MRD Negative CLL Through Combinations of Novel Agents and Antibody

Peter Hillmen, MBChB, FRCP, FRCPath, PhD 1,2, Talha Munir2*, Andy Rawstron, PhD2*, Kristian Brock, MSc, BSc3*, Samuel Munoz Vicente, MSc3*, Francesca Yates, PhD3*, Rebecca Bishop, BSc3*, Christopher Fegan, MD4*, Donald Macdonald5*, Alison McCaig, PhD6*, Anna Schuh, MD7, Andrew Pettitt, FRCPath, PhD8*, John G. Gribben, MD DSc FMedSci9, Stephen Devereux, FRCP, FRCPath, PhD10, Adrian Bloor11*, Christopher P Fox, MBChB PhD12* and Francesco Forconi13*

1University of Leeds, Leeds Institute of Cancer and Pathology, Leeds, United Kingdom
2St. James’s Institute of Oncology, Leeds, United Kingdom
3Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom
4Cardiff and Vale University Health board, Cardiff, GBR
5Imperial College Healthcare NHS Trust, London, GBR
6Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
7Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
8Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom
9Barts Health NHS Trust, London, United Kingdom

10Kings College Hospital, London, United Kingdom
11The Christie NHS Foundation Trust, Manchester, United Kingdom
12Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
13University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom

 

Background: A major aim of treatment in Chronic Lymphocytic Leukemia (CLL) is to eradicate detectable minimal residual disease (MRD) which is associated with improved outcome regardless of the therapy used to achieve it. Antigen-mediated proliferation & Bcl-2 mediated survival are key to CLL pathogenesis. Ibrutinib (IBR) is an oral BTK inhibitor affecting antigen-induced proliferation & cell adhesion/migration whilst venetoclax (VEN) is a potent, highly selective, orally bioavailable Bcl-2 inhibitor affecting CLL cell survival. Both IBR & VEN are approved as single agents for CLL. IBR leads to a rapid nodal response with re-distribution of CLL into the peripheral blood, whereas VEN leads to depletion of CLL cells to levels where they cannot be detected in some patients. IBR leads to reduction of anti-apoptotic molecules such as MCL1, hence theoretically potentiating the effect of VEN. Therefore we tested the hypothesis that combining IBR & VEN would improve the efficacy of either on its own. The CLARITY trial (ISCRTN13751862) is a feasibility study to investigate the safety & efficacy of IBR combined with VEN in patients with relapsed/refractory CLL.

Methods: A total of 50 patients with CLL requiring therapy who had either relapsed within 3 years of FCR or BR or had 17p deletion & had failed at least one line of therapy were to be recruited. After 8 weeks of IBR monotherapy (420mg/day), VEN was added first at a dose of 10mg/day with weekly escalations to 20mg, 50mg, 100mg, 200mg to a final dose of 400mg/day. No tumour lysis syndrome (TLS) was seen for the first 3 patients starting at 10mg/day of VEN so all subsequent patients began VEN at 20mg/day.

The primary end-point is MRD eradication (defined as <1 CLL cell in 10assessed by 8-color flow) in the marrow after 12 months of IBR+VEN. Key secondary end-points are MRD eradication from the marrow after 6 & 24 months of IBR+VEN as well as safety. Critical safety events were the incidence of laboratory & clinical TLS. All patients were given prophylactic uric acid reducing agents beginning at least 72 hours prior to starting VEN. Over the first 3 months of combined therapy the level of CLL in the peripheral blood was monitored weekly during VEN escalation & monthly thereafter. Here we report the first key secondary end-point of response after 6 months IBR+VEN.

Results: 50 patients were recruited from May 2016 to July 2017. The median number of prior therapies was 2 (range: 1-6) including FCR or BR in 44/47(94%). 9/45 (20%) 17p deleted, 12/45 (27%) 11q deleted, & 36/47 (77%) have unmutated VH genes. To date 41 patients have completed the dose escalation of VEN combined with IBR. Two biochemical TLS events were reported – one with an increase in creatinine & phosphate, & the other an isolated phosphate increase (which does not meet the definition of TLS). Dosing of VEN was interrupted until the biochemical abnormalities resolved & the patients subsequently escalated to 400mg/day of VEN with no further TLS. As yet there have been no SUSARs, 22 SAEs, & 43 grade 3 or 4 AEs reported. Notably there were five grade 3 or 4 infections & 19 episodes of grade 3 or 4 neutropenia. All SAEs resolved with appropriate management & all patients remain on therapy following resolution. No AEs have been fatal. 25 patients have reached their 8 month (6 months of IBR+VEN) marrow & CT-scan assessments. All 25 patients have responded (25/25 [100%] overall response rate) & 15/25 (60%) have achieved a CR or CRi with all of the remaining PR’s due to small volume lymphadenopathy at the site of larger nodes at baseline. After 6 months of IBR+VEN 21/25 (84%) have no morphological evidence of CLL in the marrow biopsy, 19/25 (76%) have less than 1% CLL cells in the marrow & 7/25 (28%) have achieved an MRD negative remission (<10-4). Patients will continue IBR+VEN for the same duration of time as it took them to achieve MRD negativity (i.e. patients who are MRD negative after 6 months IBR+VEN will stop both drugs after 12 months of IBR+VEN). Therefore all patients will continue on IBR+VEN until at least the 14 month assessment (after 12 months of IBR+VEN).

Conclusion: The combination of IBR with VEN is well tolerated in relapsed, refractory CLL with only two of 41 patients experiencing biochemical TLS to date. All 25 patients reaching the initial response assessment after 6 months of IBR+VEN have responded, 60% are in CR & 28% have achieved an MRD negative remission in the marrow. These early results suggest a potent synergy between ibrutinib & venetoclax.

A Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

Result Type: Paper
Number: 496
Presenter: Matthew Davids
Program: Oral and Poster Abstracts
Session: 642. CLL: Therapy, excluding Transplantation: Targeting MRD Negative CLL with Combinations of Novel Agents and Chemoimmunotherapy Regimens, New Treatments

Matthew S. Davids, MD1, Haesook T Kim, PhD1, Danielle M. Brander, MD2, Jad Bsat, BA1*, Alexandra Savell, BS3*, Karen Francoeur, RN1*, Caron Jacobson, MD1*, Samuel Y. Ng, MD, PhD1, Ann S. LaCasce, MD, MSc1, Ephraim P. Hochberg, MD4*, Ronald W. Takvorian, MD4*, Jeremy S. Abramson, MD, MMSc4, David C. Fisher, MD, PhD5* and Jennifer R. Brown, MD, PhD1

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Department of Medicine, Duke University Medical Center, Durham, NC
3Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
4Massachusetts General Hospital Cancer Center, Boston, MA
5Dana-Farber Cancer Institute, Boston, MA

 

Introduction: FCR provides prolonged disease free survival for many CLL patients (pts) with mutated IGHV; however, pts with unmutated IGHV typically have less durable responses. Furthermore, complete response (CR) with bone marrow minimal residual disease negativity (BM MRD-neg) is only achieved in about 20% of pts. Given the excellent efficacy and tolerability of frontline ibrutinib across CLL risk types, we are conducting an ongoing investigator-initiated, multicenter phase II study of ibrutinib plus FCR (iFCR) as frontline treatment for young, fit CLL pts (NCT02251548).

Methods: The primary endpoint is the rate of CR with BM MRD-neg 2 mo. after FCR. Secondary endpoints include response rates, PFS, and safety/tolerability. Ibrutinib 420 mg daily monotherapy is given for 7 days, followed by combination with FCR for up to 6 cycles. Responders continue on ibrutinib maintenance for at least 2 years. A recent study amendment allows accrual of 50 additional pts who discontinue ibrutinib if BM MRD-neg. after 2 years of maintenance and can restart ibrutinib if they recur. Antimicrobial prophylaxis and growth factor support are mandatory. To be eligible, pts must be ≤ 65 yrs old, meet IW-CLL criteria for initial therapy, have adequate organ function, and ECOG PS ≤1. IW-CLL 2008 and CTCAE v4 criteria are used to evaluate efficacy and toxicity, with responses requiring radiographic confirmation, and evaluations after 3 cycles, 2 mo. after final FCR, and q6 mo. thereafter. MRD is assessed by 4-color flow cytometry (10-4 sensitivity) and by ClonoSEQ (Adaptive).

Results: As of the data cutoff of July 1, 2017, 49 pts have been accrued, including 35 pts in the original cohort and 14 pts in the new expansion cohort, in whom safety and efficacy data are not yet available. Pt characteristics for all 49 pts include: median age at enrollment 55 yrs (range 38-65), del(11q) in 12/47 tested (26%), del(17p) in 4/47 tested (9%), unmutated IGHV in 26/46 tested (57%), ZAP-70 positivity in 27/46 tested (59%), TP53 mutation without del(17p) in 3 pts (6%), and NOTCH1 mutation in 2/33 tested (6%). Baseline blood counts were as follows: WBC median 87.2, (range 2.6-776), Hgb median 12.2 (range 7.8-15.9), Plts median 134 (range 43-366). Median baseline β2M was 4.2 mg/dL (range 2.9-12.6).

In the 35 pts evaluable for toxicity, gr 3/4 hematologic toxicity included: neutropenia 29% (23% gr3, 6% gr4), thrombocytopenia 26% (all gr3), and anemia 6% (all gr 3). All grade non-hematologic toxicities occurring in >15% of pts included nausea (71%), bruising (43%), rash (43%, including 34% gr1, 9% gr 2, and 1 gr 3), fatigue (37%), and gr 1 diarrhea (26%). Bleeding events included gr1 epistaxis (n=2), gr1 rectal bleeding and gr2 menorrhagia (n=1 each). SAEs included gr3 pneumonia (n=2), gr 3 febrile neutropenia, gr 3 atrial fibrillation, gr 3 transaminitis, gr 3 pneumatosis intestinalis, gr 3 Anaplasmosis infection, and gr 3 appendicitis (n=1 each). 6/35 (17%) of pts experienced ≥gr 3 infection. Number of FCR cycles administered was: 6 (n=31), 5 (n=2), 4 (n=1), 3 (n=1). One pt with febrile neutropenia had ibrutinib dose reduction, and 18% of pts had at least 1 dose reduction of chemotherapy.

In the 35 pts evaluable for efficacy, the ORR is 100%, including 63% (22/35) with best response of CR/CRi. All 13 PR pts have residual lymph nodes ≤ 2.5 cm in long axis by CT imaging. The rate of CR with BM MRD-neg 2 mo. post FCR (primary endpoint) is 37% (13/35), with a best rate that increased with post-FCR ibrutinib maintenance to 57% (20/35). Best rate of BM MRD-negativity by flow irrespective of IW-CLL response is 83% (29/35), including 10/13 (77%) of pts in PR. With a median follow-up of 20 mo. (range 13-33), all pts are alive, and 86% (30/35) remain on treatment, with 2 BM MRD-neg pts electing to discontinue ibrutinib, 2 pts who discontinued ibrutinib due to toxicity (gr3 pneumatosis intestinalis and gr 3 transaminitis), and 1 pt with del(17p) who achieved MRD-pos PR and elected to pursue allogeneic stem cell transplant.

Conclusions: iFCR induced deep responses in a relatively high risk group of previously untreated young CLL pts, with 57% achieving CR with BM-MRD-neg and 83% achieving BM MRD-neg, significantly higher than the 20% rate seen historically with FCR alone. Low rates of hematologic and infectious toxicities may be due to mandatory growth factor and antimicrobial prophylaxis. Updated results on the ibrutinib discontinuation cohort will be presented.

Phase II, Multicenter Trial, Exploring “Chemo-Sparing” Strategy Associating Obinutuzumab+Ibrutinib Followed By a MRD Driven Strategy, in Previously Untreated Symptomatic Medically Fit Chronic Lymphocytic Leukemia Patients (CLL): Preliminary Results of the Induction Phase of the Icll-07 Filo Study

Result Type: Paper
Number: 497
Presenter: Pierre Feugier
Program: Oral and Poster Abstracts
Session: 642. CLL: Therapy, excluding Transplantation: Targeting MRD Negative CLL with Combinations of Novel Agents and Chemoimmunotherapy Regimens, New Treatments

Anne-Sophie Michallet, MD, PhD1*, Marie-Sarah Dilhuydy, MD2*, Fabien Subtil3*, Valérie Rouille4*, Beatrice Mahe, MD5*, Kamel Laribi6*, Bruno Villemagne7*, Gilles Andre Salles, MD, PhD8, Olivier Tournilhac, MD, PhD9*, Alain Jacques Delmer, MD10, Christelle Portois11*, Brigitte Pegourie, MD12*, Veronique Leblond13,14, Cecile Tomowiak, MD15*, Sophie de Guibert16*, Frederique Orsini17*, Anne Banos, MD18*, Philippe Carassou19*, Guillaume Cartron, MD, PhD20*, Luc Mathieu Fornecker21*, Loic Ysebaert, MD, PhD22*, Caroline Dartigeas23*, Margot Truchan24*, Thérèse Aurran, MD25*, Florence Cymbalista26, Stéphane Leprêtre, MD27*, Vincent Levy, MD, PhD28*, Florence Nguyen Khac29*, Magali Le Garff-Tavernier30*, Carmen Aanaei31*, Michel Ticchioni32*, Remi Letestu33* and Pierre Feugier, MD34*

1Centre Léon Bérard, LYON, FRA
2CHU Hopitaux de Bordeaux, Pessac, France
3Department of biostatistics, Hospices Civils de Lyon, LYON, France
4CHU, Montpellier, France
5Clinical Hematology, Nantes University Hospital, Nantes, France
6Department of Hematogy, Centre Hospitalier Le Mans, Le Mans, France
7CH La Roche sur Yon, La Roche Sur Yon, FRA
8Hematology, Hospices Civils de Lyon – Université de Lyon, Pierre-Bénite, France
9Service d’Hematologie Clinique et de Therapie Cellulaire, CHU, Universite Clermont Auvergne, EA7453 CHELTER, CIC501, Clermont Ferrand, France
10Hematology department, Hopital Robert Debre CHU de Reims, Reims, FRA
11hematology, CHU Saint Etienne, Saint Etienne, France
12Hôpital A.Michallon, CHU Grenoble, Grenoble, France
13Département d’ Hématologie, Hôpital Pitié-Salpêtrière APHP, UPMC Université Paris, Paris, France
14Department of Clinical Hematology, AP-HP Hôpital Pitié-Salpêtrière, Paris, France
15Department of Oncology-Haematology and Cell Therapy, CHU, Poitiers, INSERM, Inserm CIC 1402, Poitiers, France, Poitiers, France
16Centre Hospitalier Pontchaillou, Rennes, FRA
17CH Annecy, ANNECY, France
18Clinical Hematology, Centre Hospitalier de la Cote Basque, Bayonne, France
19CH Metz, Metz, FRA
20Department of Clinical Hematology, University Hospital of Montpellier, Montpellier, France
21Haematology, University Hospital, Strasbourg, France
22Departement d’Hematologie, IUCT-Oncopole, Toulouse, France
23Hôpital Bretonneau CHU de Tours, Tours, France
24CHU angers, ANGERS, France
25Institut Paoli Calmette, Marseille, France
26Laboratoire d’hématologie, Hôpital Avicenne, Bobigny Cedex, France
27Department of clinical Hematology, Centre Henri Becquerel, Rouen, France
28URC/CRC, Hopital Avicenne, AP-HP, Bobigny, France
29APHP Hôpital de La pitié Salpétriere, Paris Cedex 13, FRA
30APHP Hôpital de la Pitié Salpétrière, PARIS, France
31CHU Saint Etienne, Saint Etienne, France
32CHU NICE, NICE, France
33Laboratoire d’Hématologie, APHP Hôpital Avicenne, Bobigny, FRA
34Hematology Department, CHU Nancy, Vandoeuvre Les Nancy Cedex, France

 

Achievement of CR with undetectable residual disease (uMRD) may be associated with a longer survival in CLL. New therapeutic agents have recently emerged, including new anti-CD20 antibodies and agents targeting BCR signaling. We conducted a multicenter phase II trial aimed to explore the efficacy of an induction treatment associating obinutuzumab and ibrutinib, followed by immunochemotherapy only in case of PR or detectable MRD. FIT treatment-naïve patients with active Binet stage A to C CLL and no TP53 mutation/deletion were eligible if CIRS score was < 7 and ECOG 0 or 1. Induction treatment consisted of 6 courses of obinutuzumab (1000 mg D1, D8, D15 for cycle 1 and D1 for cycles 2 to 6) along with ibrutinib 420 mg daily for 9 months. A first assessment of response was performed at month 9, including CT-scan, bone marrow (BM) biopsy and peripheral blood (PB) and BM MRD testing. Patients in CR with uMRD (<10-4, by 8-color cytometry) received ibrutinib alone for 6 additional months whereas the others received 4 courses of fludarabine + cyclophosphamide and obinutuzumab while continuing ibrutinib. Patients with stable or progressive disease were taken off study. Final evaluation of response was performed at Day 1 Month 16. The primary objective of this study was to obtain 30% of CR (according to IWCLL 2008 guidelines) with uMRD in BM at month 16. We report the preliminary results of the induction phase of this trial, including toxicities and response rates.

Between November 2015 and May 2017, 135 planned patients were enrolled (Table 1) including 89 males and 46 females; 8.2% were Binet stage A, 67.2% stage B and 24.6% stage C. The median age was 62.5 years (range, 35-80 years). Patients with del11q, del13q and trisomy 12 were 20.8% (25/120), 52% (51/98) and 21.6% (21/97) respectively; 9% (10/109) 12.5 % had a complex karyotype (>3 abnormalities). The median concentration of Beta 2 microglobulin was 3.6 mg/L (1.5-7). The median of creatinine clearance (Cockroft) was 81 ml/min (42-155).

A total of 37 serious AEs were observed with 24 related to the treatment, including 3 tumor lysis syndrome (grade 3), 5 cardiac events (1 hypertension (grade 3) and 2 atrial flutter (grade 2 and 3) and 2 atrial fibrillation (grade 3)), 1 diabetes mellitus (grade 2), 3 febrile neutropenia (grade 4), 2 neutropenia (grade 3), 1 pneumonia (grade 4), 1 hepatocellular injury (grade 3), 1 severe pain (grade 3), 1 hemoptysis (grade 3), 1 infection of listeria meningitidis complicated with disseminated intravascular coagulation (grade 3), 1 thrombocytopenia (grade 4), 1 hemorragic renal cyst (grade 3), 1 brain hemorrhage (grade 4), 1 diarrhea ( grade 3) and 1 vomiting (grade 3). Two patients died during the study at the cut-off date, one of unknown cause and one of brain hemorrhage due to fall on the stairs not reliable to therapy.

Among the other AE, Infusion Related Reaction (IRR) only occurred during cycle 1 at day 1 for 69,5% of the patients (34.8% grade 1, 57.6% grade 2 and 7.6% grade 3), 14.5% at day 2 (only grade 1 and 2) and none at day 8 and 15, respectively. Grade 3-4 neutropenia were observed in 24.3%, 7.7%, 10.2%, 12.2%, 11.8%, 11,1%, 13.6%, 16.7% and 2.7% of cases during cycles 1 to 9, respectively. Grade 3-4 thrombocytopenia and anemia were mainly observed during cycle 1 (30.8% and 6%, respectively). Other significant toxicity was digestive (nausea, vomiting and diarrhea) occurring in 33,6% of the patients (grade 1 and 2) but only during cycle 1.

At Month 9, 92% of the patients had received the 8 planned infusions of obinutuzumab; Ibrutinib dosage was reduced for 5 patients (5/77; 6,8%) and definitively stopped in 3 out of them (3,9%) due to AE (atrial fibrillation, atrial flutter and neutropenia).

Seventy-three patients are evaluable so far for the response at M9. The ORR was 100% with 37% in CR (IWCLL criteria) and 63% in PR. Among the 63 (86%) patients with positive BM MRD, 22 were in CR and 41 in PR; 8 patients had uMRD in PB and BM including 4 patients in CR.

These preliminary results indicated that this 9 month « chemo-free » induction is associated with a high CR rate (37%) without excess of toxicity. However, the majority of the patients required subsequent immuno-chemotherapy because of detectable BM MRD.

Incidence and Type of Opportunistic Infections during Ibrutinib Treatment at a Single Academic Center

Result Type: Paper
Number: 830
Presenter: Kerry Rogers
Program: Oral and Poster Abstracts
Session: 642. CLL: Therapy, excluding Transplantation: New Agents, Infections, and PET/CT

Kerry A. Rogers, MD 1, Mousa Luay, MD2*, Qiuhong Zhao, MS3*, Tracy Wiczer, PharmD4*, Lauren Levine, PharmD4*, El Boghdadly Zeinab, MBBCh5*, James S. Blachly, MD2, John C. Byrd, MD3, Tomas Guerrero, MD6*, Jeffrey A. Jones, MD, MPH, MBA2, Shindiapina Polina, MD, PhD2*, Audrey Sigmund, MD6*, Matthew Sullivan, MD6*, Farrukh T. Awan, MD, MS2 and Jennifer A. Woyach, MD2

1Division of Hematology, Ohio State University Hospital, Columbus, OH
2Division of Hematology, The Ohio State University, Columbus, OH
3Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
4Department of Pharmacy, The Ohio State University, Columbus, OH
5Division of Infectious Disease, The Ohio State University, Columbus, OH
6Department of Internal Medicine, The Ohio State University, Columbus, OH

 

Background: Ibrutinib is an irreversible inhibitor of Burton’s tyrosine kinase (BTK) in the B-cell receptor (BCR) signaling cascade and is a practice changing treatment for chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Ibrutinib also inhibits Interleukin-2 Inducible Kinase (ITK) in T-cells and has demonstrated immunomodulatory effects. Recently, cases of opportunistic infections (OI) have been reported during ibrutinib treatment including pneumocystis jirovecii pneumonia (PJP), cryptococcus, and fusarium. To date there are no reports on OI in large unselected cohorts of patients taking ibrutinib. We conducted a single-institution retrospective study to determine the incidence and type of OI during ibrutinib treatment as well as outcomes and characteristics associated with risk.

Methods: We reviewed medical records of all patients treated with ibrutinib at the Ohio State University between June 1st 2010 and March 31st 2016. Patients who received ibrutinib for graft versus host disease were excluded. All charts were initially reviewed by one of the investigators and patients with OI were independently reviewed by a second investigator. Baseline patient and disease characteristics were captured at time of starting ibrutinib. All OI occurring after the first dose of ibrutinib were recorded. Onset of OI was considered as the time of first presentation for a complaint related to OI. Time to OI was calculated from the date of starting ibrutinib until the onset of OI or censored at the last assessment date, discontinuation of ibrutinib, or death prior to OI as competing risks. The cumulative incidence of OI was estimated and the Fine and Gray regression models were used to examine the association between patient characteristics and risk of OI. Covariates with significance level of p<0.20 from univariable analyses were further evaluated in a multivariable analysis using a stepwise selection procedure, retaining those with p<0.05 in the final model. Results: The cohort included 566 patients. Median age was 65 (range 23-89) and 70.1% (397/566) were men. The majority of patients had CLL (73.7%, 417/566). Other diagnoses included mantle cell lymphoma (9.9%, 56/566), indolent B-cell malignancies (8.1%, 46/566; 11 Waldenström’s Macroglobulinemia, 13 Hairy Cell Leukemia, 15 Follicular Lymphoma, 6 Marginal Zone Lymphoma, and 1 Prolymphocytic Leukemia), and aggressive lymphoma (8.3%, 47/566; 35 diffuse large B-cell or transformed lymphoma and 12 Richter’s syndrome). Median number of prior treatments was 3 (range 0-18) and 6.5% (37/566) of patients were treatment naïve. Ibrutinib was prescribed on clinical trial for 80.9% (458/566) of patients with the rest receiving it as standard of care. A second agent was given with ibrutinib in 30.9% (175/566) of cases and was most often a monoclonal antibody (81.7%, 143/175). Use of antiviral prophylaxis was common (78.6%, 445/566) with fewer patients receiving PJP (44.9%, 254/566) or fungal (11.5%, 65/566) prophylaxis. The most utilized prophylactic antifungal agent was fluconazole (70.8%, 46/65). Total ibrutinib exposure for the cohort was 1,225 person-years with a median exposure of 1.98 (range 0.008-6.40) years. Median duration of follow-up was 2.69 (range 0.03-6.40) years. Twenty-three of 566 (4.1%) patients developed an OI at a median of 0.39 (range 0.03-4.33) years after starting ibrutinib. The cumulative incidence of OI was 2.3% (95% CI: 1.3-3.8%) at 0.5 years and increased to 4.7% (95% CI: 3.0-7.0-%) at 5 years. Types of OI and outcomes are detailed in Table 1. Median survival of the entire cohort was not reached. Among 23 OI patients, the median survival after infection was 1.39 years. Univariable analysis revealed ≥3 prior treatments (HR 2.61), diabetes (HR 3.03), pulmonary disease (HR 2.81), chronic kidney disease (HR 2.56), and liver disease (HR 6.42) were associated with an increased risk for OI (p<0.05). In a multivariable analysis ≥3 prior treatments (HR 2.87, 95% CI: 1.12-7.35; p=0.028), diabetes (HR 3.63, 95% CI: 1.50-8.77; p=0.004), and liver disease (HR 7.53, 95% CI: 2.14-26.49; p=0.002) retained independent association with OI development. Conclusions: The cumulative incidence of OI during ibrutinib treatment was low (4.7% at 5 years) and the most common type was invasive fungal (61%) with no PJP cases. Three or greater prior treatments, diabetes, and liver disease were independently associated with risk for OI.

Analysis of PET-CT to Identify Richter’s Transformation in 167 Patients with Disease Progression Following Kinase Inhibitor Therapy

Result Type: Paper
Number: 834
Presenter: Anthony Mato
Program: Oral and Poster Abstracts
Session: 642. CLL: Therapy, excluding Transplantation: New Agents, Infections, and PET/CT

Anthony R. Mato, MD1, William G Wierda, MD, PhD2, Matthew S. Davids, MD3, Bruce D. Cheson, MD4, Steven Coutre, MD5, Michael Choi, MD6, Richard R. Furman7*, Leonard Heffner, MD8*, Paul M. Barr, MD9, Herbert Eradat10*, Lang Zhou11*, Maria Verdugo, MD12*, Jalaja Potluri11 and Jeffrey Jones, MD13*

1Center for Chronic Lymphocytic Leukemia, University of Pennsylvania, Philadelphia, PA
2University of Texas MD Anderson Cancer Center, Houston, TX
3Dana-Farber Cancer Institute, Boston, MA
4Georgetown University Medical Center, Washington, DC
5Stanford Cancer Center, Stanford University School of Medicine, Stanford
6UCSD Moores Cancer Center, San Diego
7Weill Cornell Medicine, New York
8Department of Hematology and Medical Oncology, Emory University School of Medicine, Emory
9Wilmot Cancer Institute, University of Rochester Cancer Center, Rochester, NY
10University of California Los Angeles, Los Angeles
11AbbVie Inc., North Chicago, IL
12AbbVie Inc, North Chicago, IL
13Ohio State University Comprehensive Cancer Center, Columbus, OH

 

Introduction: Positron emission tomography–computed tomography (PET-CT) has been utilized in CLL to help identify patients (pts) with Richter’s transformation (RT). Data from kinase inhibitor (KI)-naïve pts suggest that maximum standardized uptake value (SUVmax) of ≥10 on PET can distinguish RT from CLL with 91% sensitivity, 95% specificity (Michallet, 2014). Additionally, in the setting of CLL progression, SUVmax ≥10 identified pts with inferior survival, independent of RT diagnosis (Falchi, 2014). Whether PET can accurately identify and risk-stratify pts failing KI therapy with RT vs. CLL is unknown. In a phase 2 trial (NCT021412820), treatment with the BCL-2 inhibitor venetoclax (VEN) was evaluated in pts in whom prior ibrutinib or idelalisib had failed. All consented pts were required to undergo PET imaging to identify and exclude RT. Therefore, this represents the largest, uniform dataset of KI-treated pts who have undergone PET imaging and were subsequently uniformly treated.

Methods: Pts were evaluated at screening by PET and excluded from the study if RT was confirmed on core biopsy of the most suspicious node. Biopsy of the suspicious area was mandatory if PET SUVmax was ≥10 or for pts with CD38+, ZAP 70+, TP53 mutated and IGHV unmutated CLL with an SUVmax 4–10 with ≥1 of the following: B symptoms, nodes >5 cm, and/or LDH elevation. We used descriptive methods, logistic regression, and receiver operator characteristic (ROC) analysis to define post-KI PET test characteristics.

Results: 167 pts were screened, of whom 84 (50%) had PET SUV ≥5 and 25 (15%) had SUV ≥10. 57 pts met protocol criteria for biopsy at screening to evaluate for RT (SUV ≥10, n=18; SUV <10 with other factors, n=17): 35 underwent biopsy and 22 did not meet enrollment criteria for other reasons so no biopsy was performed. Of these 35 pts, 8 had RT (failed screening due to confirmed RT [all with large B-cell lymphoma]), 2 had other malignancies (metastatic anal cancer and neuroendocrine tumor), and 25 had biopsy demonstrating CLL. Based on a logistic regression analysis of 35 pts who underwent biopsy (Table 1), PET SUVmax ≥10 did not adequately distinguish RT post-KI therapy vs. CLL (OR, 1.79 [95% CI: 0.4–9]; p=.5) with 26% sensitivity, 82% specificity, 63% positive predictive value, and 50% negative predictive value. ROC area for SUVmax ≥10 was 56%.

For pts who failed screening, median number of FDG-avid nodes with an SUV >3 was 4 (range: 1–11) and median SUVmax was 8 (range: 2–28), with 12 (39%) who had SUV ≥10 (Table 2). For 127 enrolled pts, median number of FDG-avid nodes was 5 (range: 1–13) and median SUVmax was 5 (range: 0–73), with 13 (10%) who had SUV ≥10. There was a statistical trend for higher SUVmax for pts who did not meet screening criteria vs enrolled (p=.0607). The objective response rate to VEN was similar for pts when stratified by screening PET SUV ≥10 (62%, 8/13) vs <10 (56%, 53/94). Median PFS was also similar for pts when stratified by screening PET SUV ≥10 (19.2 months [95% CI: 0.4, -]) vs <10 (21.9 months [95% CI: 15.9, -]). Fifty-six (44%) pts discontinued VEN, with 28 (22%) due to CLL progression and 6 (5%) due to biopsy-confirmed RT following both imaging and clinical changes. Median time to CLL progression was 8.4 months (range: .1–22.8) and to RT was 11.5 months (range: 4.4–19.7). For pts who discontinued VEN due to RT, median number of FDG-avid nodes at screening (pre-VEN) was 3 (range: 1–6) and SUVmax was 5.5 (range: 2–15). PET SUV ≥10 at screening did not predict development of subsequent RT when on VEN (OR, 1.483 [95% CI: .2–13.8]; p=.7289). Compared with 127 enrolled pts, pts who developed RT while on VEN were older, had a higher median number of prior therapies, and the majority had at least 1 poor-risk prognostic feature at study enrollment (Table 2).

Conclusions: In the largest series of PET-CTs prospectively performed in pts following KI discontinuation, we conclude that PET SUV ≥10 alone lacks both sensitivity and specificity to distinguish CLL progression vs RT. CLL progression following KI exposure appears more metabolically active than previously reported following R-chemotherapy failure. RT was confirmed for 14% (8/57) of pts suspected of CLL progression with BCRi therapy, which suggests that screening for RT may be important upon BCRi failure. In addition, PET SUV ≥10 did not identify VEN-treated patients with an inferior ORR or PFS. Analysis to identify clinical factors distinguishing KI-treated pts with likely RT is ongoing.