Population Based Observational Study Demonstrates Significant Increase in Watch-and-Wait for Newly Diagnosed Mantle Cell Lymphoma

Abstract Background: Mantle cell lymphoma (MCL) is associated with a poor prognosis relative to other indolent B-cell lymphomas where clinicians have traditionally been reluctant to adopt watch-and-wait (W+W) strategies. US registry data from 2004 to 2011 demonstrated 6% of new diagnoses were observed beyond 3 months from diagnosis (Cancer 2016; 122: 2356-63), although other studies have demonstrated higher rates of W+W with no detriment to patient survival. Currently no consensus exists on how to determine suitability for W+W. The MCL Biobank Observational Study was set up to capture clinical behaviour across the United Kingdom and to characterise patients enrolled to W+W compared to those who receive upfront systemic therapy. The study remains open to recruitment. Method: From January 2015 to April 2017 222 patients from 49 centres in the United Kingdom enrolled to the study. All new MCL diagnoses compatible with WHO diagnostic criteria were eligible, with no specific exclusion criteria. Baseline data was recorded at entry including investigator decision to start systemic therapy or enter W+W. Clinical updates were provided at 6 month intervals. In contrast to previous studies W+W was defined as a period lasting at least 1 year from date of diagnosis. Results: All patients were followed-up for a minimum of 1 year. The median age was 70 (range 32-90), 69.4% were male and 47.1% were MIPI high risk. At 1 year follow-up 60 patients (27.0%) were on W+W, 141 (63.5%) received systemic therapy, 16 (7.2%) received isolated radiotherapy and 5 (2.3%) received palliative care. At 2 year follow-up 16 of 85 patients (18.9%) remained on W+W. There were no deaths recorded in patients on W+W. Estimated 2-year survival of the whole population was 80.6%. Univariate analysis comparing baseline characteristics of patients on W+W with those receiving systemic therapy showed no significant difference in age (median age 71.7 vs 69.0; p=0.48), baseline WCC (median 8.0 x 109/L vs 8.9 x 109/L; p=0.09) or performance status (ECOG >1 OR 0.7; p=0.51) meaning the MIPI was not predictive of suitability for W+W (MIPI high risk OR 1.18; p=0.61). Positive predictors for W+W included measures of low disease proliferation: LDH ratio <1.0 (p=<0.001), Beta-2-microglobulin < 3.5 mcg/ml (p=0.011) and Ki67 <30% (p=0.001). In addition, female sex (p=0.010) predicted for indolent behaviour. Measures of high disease burden were generally negative predictors including presence of B symptoms (p=0.001), haemoglobin <100 g/L (p=0.014) and stage IV disease (p=<0.001). The absence of measurable disease on CT was predictive of W+W (p=0.009), although measurable disease was identified in the majority of cases (70.2%) illustrating most patients on W+W were not the leukaemic, non-nodal subtype. Conclusion: This study demonstrates that adoption of W+W in the United Kingdom significantly exceeds use in previous observational studies and highlights a fundamental shift in clinical approach. The results show that conservative management can be reasonably adopted in a significant proportion of patients. Patients with low disease burden appear best candidates and markers of cell turnover may aid clinical judgement. The MIPI does not have a role in this setting. Longer follow-up will establish if W+W confers survival benefit. Disclosures Pettitt: Celgene: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Gilead: Research Funding; Napp: Research Funding; GSK/Novartis: Research Funding; Chugai: Research Funding. Rule:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees.

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Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽

10.1182/blood-2019-124192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5263-5263

Author(s):

Karin Hohloch ◽

Christine Windemuth-Kieselbach ◽

Pier Luigi Zinzani ◽

Roberto E. Cacchione ◽

Wojciech Jurczak ◽

...

Keyword(s):

Follicular Lymphoma ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Therapy ◽

First Line ◽

Advisory Committees ◽

Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

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Non-Bcl2 Mutations Are Predominant in Patients (pts) with Venetoclax Resistant Mantle Cell Lymphoma (MCL) - Response and Clinical Outcomes in Ultra-Refractory MCL

Blood ◽

10.1182/blood-2019-126175 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2815-2815 ◽

Cited By ~ 1

Author(s):

Preetesh Jain ◽

Shuangtao Zhao ◽

Rashmi Kanagal-Shamanna ◽

Lucy Navsaria ◽

Holly Hill ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Advisory Board ◽

Advisory Committees ◽

Ki 67 ◽

Mantle Cell ◽

Btk Inhibitors

Introduction: Mantle cell lymphoma (MCL) patients (pts) who progress after ibrutinib and other lines of treatment "ultra-refractory MCL" have poor outcomes and exhibit BTK mutations infrequently (Jain P et al BJH 2018, Martin P et al Blood 2016). Venetoclax has shown promising efficacy in Phase I trial in NHL (Davids M et al JCO 2017) and is now under trials in MCL. Venetoclax response in pts with MCL after progression on ibrutinib was reported (Eyre T et al Haematologica 2018), however, genomic alterations associated with venetoclax resistance are not described. We present our experience in 24 pts with MCL treated with venetoclax and report their mutation profiles associated with progression on venetoclax. Methods: We collected data from 24 pts with MCL who were treated with venetoclax (off clinical trial) as a salvage measure after failing multiple lines of prior therapies. Pt characteristics were collected from the time of initiating venetoclax. Progression free survival (PFS) was calculated from the time of initiating venetoclax to the date of progression or to last follow up date/date of death while overall survival (OS) was calculated from the time of initiating venetoclax to the date of last follow up date/date of death. Post venetoclax survival was calculated from the date of discontinuing venetoclax to the date of last follow up/death. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed from evaluable biopsy samples from 7 pts (5 pts at/before starting venetoclax and 6 pts after progression of venetoclax), this included 5 pts who have pairs available for analysis (pre and post venetoclax). Results: Twenty four pts were treated with venetoclax (12 started as single agent and 8 started with combination with obinutuzumab and 3 with BTK inhibitors with/without obinutuzumab). Four pts had initial single agent venetoclax and later were rechallenged with combinations. Initial dose of venetoclax was dose escalation from 20 mg, then 50 mg then 100 mg PO daily up to 400 mg daily in 18/24 pts while in 3 pts it was 100 mg daily and in another 3 it was 400 mg daily. Median age at venetoclax start was 69 years (58-82). Median number of prior lines of therapy was 5 (range 1-11; including 17 pts who progressed on ibrutinib or other BTK inhibitors, 5 had exposure to ibrutinib and discontinued for intolerance, 4 had prior SCT and 2 had prior anti CD19 cellular therapy). At the baseline (pre/at-venetoclax start), 13 pts (54%) had blastoid/pleomorphic histology and 11 (46%) had classic variant morphology, the median Ki-67% was 60% (5-90%) and pts with Ki-67% ≥ 50 were 11 (55%), 4 pts did not have available Ki-67% values. Overall response rate (ORR) was 65% (13/20) - complete remission 25% (5/20) and partial remission 40% (8/20). Stable disease was observed in 10% (2/10), primary refractory were 25% (5/20). Four pts were not evaluable for response assessment. The median follow up after starting venetoclax was 17.5 months (1-27). The median PFS was 7.7 months (2 year 20%) and the median OS was 13.5 months (2 year 30%) Figure-1A-B. Pts in CR had a PFS of 15 months vs no CR 10 months (p=0.29). At the last follow up, 11 pts remained on venetoclax therapy (4 alive and 7 dead). Overall, 15 pts progressed and 14 pts were alive. The median post venetoclax survival was 6 months. Among 20 pts who discontinued venetoclax, 1 achieved CR and 3 PR on subsequent therapies. Among the 20 pts who discontinued venetoclax, 6 discontinued due to intolerance. In addition, we evaluated the somatic mutation profile in pts who progressed on venetoclax using WES. Figure-1C shows mutation spectrum. In our cohort, pts with MCL who progressed on venetoclax exhibited infrequent Bcl2 mutations (one pt at progression; 14 %; p.H3D) while the mutation frequency of other genes such as TP53 (71% vs. 40%), ATM (43% vs. 20%), KMT2D (57% vs. 20%), CELSR3 (57% vs. 20%), and KMT2C (43% vs. 20%) increased by > 2-fold at progression (compared to pretreatment samples, p=N.S due to small cohort size). The mutation of CARD11 (14%) and SMARCA4 (14%) was only observed at progression. Further details on copy number abnormalities will be presented. Conclusions: Venetoclax has promising results in refractory pts with MCL. Combination clinical trials with obinutuzumab, acalabrutinib are ongoing in MCL. We have characterized mutations and aneuploidy abnormalities in venetoclax resistant MCL pts and shown that unlike CLL, Bcl2 mutations are infrequent in venetoclax resistant MCL. Disclosures Nastoupil: Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Fowler:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Aviara: Research Funding; Dava Oncology: Honoraria; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; BioInvent: Consultancy, Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; VelosBio: Research Funding.

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Outcomes, Causes of Discontinuation and Mutation Profile of Patients with Mantle Cell Lymphoma Who Progressed on Acalabrutinib

Blood ◽

10.1182/blood-2018-99-115179 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4151-4151 ◽

Cited By ~ 3

Author(s):

Preetesh Jain ◽

Rashmi Kanagal-Shamanna ◽

Shaojun Zhang ◽

Chi Young Ok ◽

Makhdum Ahmed ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Copy Number ◽

Research Funding ◽

Cell Lymphoma ◽

Median Number ◽

Copy Number Alterations ◽

Advisory Committees ◽

Mantle Cell

Abstract Introduction: Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved for treatment of relapsed patients (pts) with mantle cell lymphoma. We have reported previously that ibrutinib refractory MCL pts have poor survival. However, outcomes, causes of discontinuation, management and the genomic landscape of MCL in pts who discontinued acalabrutinib are rarely reported. Method: We reviewed charts from all MCL pts treated with single agent acalabrutinib (n=28) in the relapsed setting and identified 15 pts who discontinued acalabrutinib and who are described in this analysis. Outcome after discontinuing acalabrutinib is reported. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed on 10 tumor specimens and 5 matched germline samples collected from 9 pts whose MCL progressed on acalabrutinib; among these pts 4 tumors were collected at baseline and 6 were collected after disease progression. One patient had sufficient DNAs available for both time points (baseline and progression). Results: The median duration on treatment with acalabrutinib was 6.5 months (1 to 29 months) and the median number of cycles of acalabrutinib treatment was 6 (range, 1-30). Seven pts had complete remission (CR) as their best response on acalabrutinib, 5 were primary refractory and 3 achieved partial remission. In 12 pts (80%) acalabrutinib was discontinued due to disease progression (2 pts transformed from classic to blastoid and pleomorphic type at progression) and 3 pts were discontinued due to intolerance (one for fatigue and idiopathic encephalopathy, one due to unrelated severe aortic stenosis and another for cytopenias secondary to therapy related myelodysplasia; all three pts were in CR). Nine pts had classic and 3 pts each had blastoid or pleomorphic features before starting acalabrutinib. Overall, median Ki-67 expression was 50% (range, 5-100) and all pts had high a MIPI score. The median number of prior treatments was 1 (range, 1-3); all chemo-immunotherapy (10 pts were previously treated with rituximab-hyper-CVAD) and none with ibrutinib. Two pts who transformed on acalabrutinib received acalabrutinib for a median duration of 12 months (range, 8-16.5). Median follow up after discontinuation was 27 months and the median survival was 25 months (26 months for progression and 1.5 months for intolerance; p <0.001, Figure-1A). Patients who discontinued due to intolerance did not get subsequent treatment for MCL. Among the 12 pts who progressed on acalabrutinib, 11 pts received systemic therapy for MCL [seven received ibrutinib based therapies (2 non responders, 3 achieved CR and 2 were PR and all pts progressed subsequently), 3 got chemo-immunotherapy and progressed and one pt did not receive any treatment and was lost to follow up and died. Six patients received a clinical trial with CAR-T cells (results will be reported separately). Overall, at the time of last follow up, 8 pts were alive and 7 were in CR. Recurrently mutated genes in these tumors included ATM (6/10; 60%), TP53 (4/10; 40%), KMT2C (3/10), MYCN (2/10), NOTCH1 (2/10), NOTCH3 (2/10), and MEF2B (2/10) (Fig. 1B). We did not detect any mutation or copy number alterations in BTK, PLCG2, TRAF2/3 and MYD88 that have been reported previously to be associated with ibrutinib resistance. Compared to tumors at baseline, ATM was mutated at a higher frequency in samples at progression (67% vs. 50%; p=NS). To investigate the mutation evolution on acalabrutinib treatment, mutation profiles, particularly the mutation variant allelic fractions (VAFs), were compared between the baseline and progression samples from pt-1 (Fig. 1C). Mutation of MYCN, MEF2B, ATM, and NOTCH1 were identified in both tumors at similar VAFs, whereas mutation of CARD11 (two mutations), NLRC5 and B2M were detected only at progression. In pt-1, both the NLRC5 and β2M mutations acquired at disease progression were truncating, suggesting loss-of-function alterations. Copy number analysis reveals frequent whole-genome doubling and intensive copy number alterations in all tumors, including recurrent losses of chromosome 9p, 17p, and chromosome 13, indicating chromosomal instability as a driver of disease progression. Conclusion: Patients who progress on acalabrutinib have a poor outcome, and newer therapies are required for their treatment. In this small cohort, we observed non-BTK mutations associated with acalabrutinib resistance and disease progression. Disclosures Nastoupil: Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Merck: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Honoraria, Research Funding; Karus: Research Funding; Novartis: Honoraria; Juno: Honoraria. Neelapu:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Wang:Acerta Pharma: Honoraria, Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Research Funding; Kite Pharma: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

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Rituximab Plus Bendamustine and Cytarabine (R-BAC) in Elderly Patients with Newly Diagnosed Mantle Cell Lymphoma: Long Term Follow-up and Mrd Results of a Phase 2 Study from the Fondazione Italiana Linfomi

Blood ◽

10.1182/blood-2021-153364 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 384-384

Author(s):

Maria Chiara Tisi ◽

Luca Nassi ◽

Caterina Patti ◽

Michele Spina ◽

Simone Ferrero ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees ◽

Mantle Cell

Abstract The activity of the combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) was evaluated in a phase 2 multicentre trial from the Fondazione Italiana Linfomi (FIL RBAC500) in previously untreated patients with mantle cell lymphoma (MCL) who were not eligible to stem cell transplant. Maintenance treatment was not planned after induction therapy, and no patient in the study received rituximab maintenance. Fifty-seven patients (median age 71 years, range 61-79) were recruited and treated with 4 to 6 cycles between 2012 and 2014. Despite some concern in terms of hematological toxicity, the R-BAC regimen was associated with high complete remission (CR) rate (91%), 2-years overall survival (OS) of 86% (74-93), and 2-years progression free survival (PFS) of 81% (68-89). Here, we present long-term survival outcomes. After 7 years of median follow-up (86 months, range 57-107), the median OS and PFS for all patients were not reached (Figure 1A and 1B). The 7-years PFS and OS rates were 56% (95%CI 41-67) and 63% (95%CI 46-72), respectively. Patients who achieved CR (n=53) had a 7 years PFS of 59% (95% CI 44-71), with the curve that appears to plateau after 6 years. Adverse predictive factors affecting PFS were blastoid morphology (p<0.05), elevated Ki67 > 30% (p<0.05), and failure to achieve CR after 2 cycles (p=0.03). Early-progression of disease (<24 months from start of R-BAC) was associated with impaired overall survival (p<0.05). Eight patients (14%) developed a secondary neoplasia: 1 parotid heteroplasia, 1 parotid nodular hyperplasia, 1 prostate cancer, 1 bladder cancer, 1 larynx, 1 thyroid cancer, 1 lung cancer and 1 secondary acute myeloid leukemia. Among the 25 relapsed patients, 8 did not receive any other treatment. Six had Ibrutinib monotherapy as second line, of whom 4 responded (3 are still in CR), 4 had CHOP or CHOP-like regimens with only partial responses. As per protocol, 31 patients with molecular marker at diagnosis and available samples were followed-up for minimal residual disease (MRD) with ASO-droplet digital polymerase chain reaction (D-PCR). Patients with MRD persistence at the end of induction, either in peripheral blood or bone marrow, had significantly worse 7 years-PFS (p<0.05 for them both). In conclusion, in elderly patients with newly diagnosed MCL, R-BAC showed sustained efficacy over time, which compared favorably with any other reported immuno-chemotherapy regimen (with or without maintenance) in similar populations. With a median OS exceeding 60% after 7-years this regimen has significantly impacted on the life-expectancy of elderly patients with MCL. Figure 1 Figure 1. Disclosures Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nassi: Takeda: Consultancy; Incyte: Consultancy; Kyowa Kirin: Consultancy; Roche: Consultancy. Ferrero: Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Roche, Italfarmaco: Consultancy, Honoraria; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Merli: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; EUSA Pharma: Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses.

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CD5 Negative Mantle Cell Lymphoma: Clinicopathologic Correlations and Outcome in 58 Cases

Blood ◽

10.1182/blood.v128.22.2964.2964 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2964-2964

Author(s):

Annapurna Saksena ◽

Yuan Miao ◽

Pei Lin ◽

Michael Wang ◽

C. Cameron Yin ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

P Value ◽

Clinicopathologic Features ◽

Advisory Committees ◽

Mantle Cell

Abstract Introduction: Mantle cell lymphoma (MCL) is a B-cell neoplasm that has a characteristic immunophenotype of being positive for CD5, B-cell antigens and cyclin D1. A small subset of cases of MCL can be negative for CD5, approximately 5% in the literature. The clinicopathologic features and prognosis of patients with CD5-negative MCL are poorly characterized. Here, we study a group of patients with CD5- MCL and compare them with a group patients with CD5+ MCL. Methods: From a total of 270 cases of MCL accessioned from 2004-2015, 58 CD5- cases (study group) and 212 CD5+ cases (control group) were identified. All cases of MCL were positive for cyclin D1 by immunohistochemistry and, in most patients, CCND1-IGH was shown FISH. Cases negative for CD5 were assessed by flow cytometry and/or immunohistochemistry. Fisher exact test was utilized to analyze differences between the CD5- and CD5+ groups. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazards model analyses for OS and PFS were performed (SPSS 22 software). A P-value of less than 0.05 was considered statistically significant. Results: The CD5- group included 39 men and 19 women with a median age of 66 years (range, 36- 88 years) at time of diagnosis. The CD5- and CD5+ groups shared overlapping clinicopathological features, but CD5- cases showed a lower percentage of men (P=0.006) than CD5+ cases. Treatment information was available for 50 patients. Twenty-nine (58%) patients were treated initially with R-Hyper CVAD therapy (rituximab, fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and cytarabine). Seventeen (34%) patients were treated initially with less aggressive therapy: 7 with R-CHOP; 8 had other rituximab-based chemotherapy regimens; 2 received rituximab as a single agent. Four patients (8%) were observed without therapy. After induction, 34 patients achieved complete remission (CR), 5 patients achieved partial remission (PR), 6 patients showed no response (NR) or progressive disease (PD), and 5 patients lost follow-up. Ten patients also underwent stem cell transplantation (SCT): 5 patients received allogeneic SCT, the other 5 autologous SCT. With a median follow-up of 45.7 months (range, 2.0-174.3 months), 13 of 56 (23.2%) patients died, 43 of 56 (76.8%) patients were alive at last follow-up, and the rest of 2 patients lost follow up. The induction chemotherapy regimens and CR and PR rate were not significantly different between the CD5- and CD5+ groups (p>0.05). Survival analysis showed patients with CD5- MCL had a tendency for longer OS (Figure 1A, P=0.078). Further analysis showed that lack of CD5 expression predicted a superior OS in a few subsets of MCL patients defined with 1) normal WBC count (p=0.049); 2) Stage I/II disease (p=0.046); 3) Low/intermediate MIPI (p=0.041) and 4) Ki67≥30% (at a borderline p value of 0.05). Patients with CD5- MCL also showed a significantly longer progression-free survival (PFS) (Figure 1B, P=0.01). Absence of CD5 expression was associated with a better PFS in MCL patients with advanced disease (stage III-IV) (P=0.035), a normal leukocyte count (P=0.018), a normal serum lactate dehydrogenase level (P=0.046), classical morphology (P=0.029), and low/intermediate MIPI (p=0.0004). Multivariate Cox regression analysis revealed that MIPI was the only independent prognostic factor for both OS and PFS (P=0.026 and P=0.001 respectively) and CR/PR also predict a better OS (P=0.004) in CD5- MCL patients. Conclusion: The clinicopathologic features were similar between patients with CD5- MCL and those with CD5+ MCL, except that less men in the CD5- MCL group. Lack of CD5 expression was associated with a favorable PFS in MCL patients. Recognizing this subgroup of CD5- MCL has not only a diagnostic significance, but also a prognostic significance. Figure Figure. Disclosures Wang: Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Onyx: Research Funding.

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Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Increases Overall Survival When Compared to 6 Courses of CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT in Mantle Cell Lymphoma: Final Analysis of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)

Blood ◽

10.1182/blood.v120.21.151.151 ◽

2012 ◽

Vol 120 (21) ◽

pp. 151-151 ◽

Cited By ~ 38

Author(s):

Olivier Hermine ◽

Eva Hoster ◽

Jan Walewski ◽

Vincent Ribrag ◽

Nicole Brousse ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Final Analysis ◽

High Dose ◽

Advisory Committees ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 151 Background MCL outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggest that the addition of rituximab and/or high dose ARA-C may significantly improve outcome. A phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an ORR of 95% with a CR rate of 61%, a median EFS of 83m and a 75% survival rate at 5 years (Delarue et al Blood 20012). Two years ago we presented preliminary results of the the MCL randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B) and have shown that after a follow up (FU) median of 27m patients of Arm B experienced a significantly better time to treatment failure (TTF) (49m vs NR; p=0.0384, HR 0.68), but no overall survival difference. Here, we present final results after a longer FU. Methods Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point TTF was monitored continuously by a sequential procedure based on a one sided triangular test. Stable diseases after induction, progression or death from any causes were considered as treatment failure. Sample size was calculated to detect a relative risk of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 455 patients evaluable for the primary analysis (19 no MCL, 13 not yet documented, 7 lost of follow up, 2 stage 1, and 1 R bendamustine chemotherapy) displayed the following characteristics (A vs B): median age 54 vs 56 year, male 79% vs 79%, stage IV 82% vs 81%, B symptoms 43% vs 31%, ECOG >2 4% vs 4%, elevated LDH 39% vs 35%, and MIPI low/int/high risk 60%/25%/15% vs 64%/23%/13%, respectively. After induction overall response (OR) was similar in both arms (90% vs 95%; p=0.19) but CR and CR/CRu rates were significantly higher in arm B (25% vs 36%; p=0.012 and 40% vs 54%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%). After transplantation OR and CR rates were comparable in both arms (98% vs 97% and 63% vs 61%). After a median FU of 51 months, TTF was longer in Arm B (46m vs 88m; p=0.0382, HR 0.68) mainly due to a lower number of relapses after CR/CRu/PR (n= 81 vs 40). The rate of ASCT-related death in remission was similar in both arms (4% vs 4%). Although CR rate after ASCT was similar in both arms, remission duration (RD) after ASCT was superior in Arm B (49m vs 84m; p=0.0001). At the time of final analysis, OS was superior in Arm B (NR vs 82m, p=0.045). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 9% vs 30%, WBC 50% vs 75%, platelets 10% vs 74%), renal toxicity (creatinine grade 1/2: 10% vs 44%, grade 3/4: none vs 1%), and grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar. Conclusions With a longer FU, we confirmed that high dose ARA-C in addition to R-CHOP increases significantly complete response rates, TTF and in addition overall survival without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients <65 y. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding. Gisselbrecht:roche: Consultancy, Research Funding; baxter: Research Funding.

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Phase II Multicenter Study of the Safety and Efficacy of Single-Agent Lenalidomide in Subjects with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Follow-up Analysis of the NHL-003 Study.

Blood ◽

10.1182/blood.v120.21.2738.2738 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2738-2738

Author(s):

Pier Luigi Zinzani ◽

Julie M Vose ◽

Myron S. Czuczman ◽

Craig Reeder ◽

Corinne Haioun ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Advisory Committees ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 2738 Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin's lymphoma (NHL) with poor prognosis that necessitates the development of new treatments. Lenalidomide is a unique immunomodulatory agent with antiproliferative and tumoricidal effects on MCL cells. NHL-003 was a phase II, open-label, multicenter trial for subjects with relapsed aggressive NHL that tested single-agent lenalidomide 25 mg PO days 1–21 every 28 days. The primary endpoint was overall response rate (ORR); secondary endpoints included complete response (CR) rate, duration of response (DOR), survival, and safety. At the time of the initial publication (Witzig et al. Ann Oncol.2011;22:1622–1627), MCL subgroup analysis showed an ORR of 42%; the median DOR had not been reached. The purpose of this report is to provide long-term efficacy and safety results for the MCL subgroup from NHL-003. Results: Subjects with MCL (N=57) had a median age of 68 y (range, 33–82), were predominantly male (77%) with good ECOG performance status (89% PS 0–1) and advanced-stage disease (88% stage III/IV). Subjects had received a median of 3 (range, 1–13) prior systemic therapies. According to the current central review at a median follow-up of 12.4 mo, subjects achieved an ORR of 35% (CR/CRu 12%) following lenalidomide, including a median DOR of 16.3 mo (Table 1). The ORR to single-agent lenalidomide was 44% (CR/CRu 21%) by independent assessment, with a median DOR not yet reached. Median PFS was 8.8 mo by central review and 5.7 mo according to investigators. Subjects responded quickly, with a median time to first response of 1.9 mo (central and investigator). Median DOR for subjects in CR and overall survival for all subjects have not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), fatigue (9%), and diarrhea (5%). Other AEs included one subject with grade 1 to 2 tumor flare reaction, one subject with grade 3 deep vein thrombosis, and two subjects with second primary malignancies suspected of being related to treatment (one grade 3 squamous cell carcinoma of the skin that resolved and one grade 4 AML in a heavily pretreated individual with 5 prior cancer therapies). Conclusions: This subset analysis from a phase II study further confirms the efficacy of lenalidomide in subjects with relapsed MCL. Responders have a long DOR with manageable side effects. These results support continued investigation of lenalidomide alone or in combination for the treatment of MCL. Disclosures: Zinzani: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Czuczman:Celgene: Consultancy, Consultant Celgene Advisory Board Other. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding. Haioun:Celgene: Celgene Advisory Board Consultant Other, Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pietronigro:Celgene: Employment. Ervin-Haynes:Celgene: Employment. Li:Celgene: Employment. Witzig:Celgene: Research Funding.

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Bruton's Tyrosine Kinase Inhibition Is Associated with Manageable Cardiac Toxicity

Blood ◽

10.1182/blood.v126.23.4529.4529 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4529-4529 ◽

Cited By ~ 2

Author(s):

Alison Romisher ◽

Joseph Carver ◽

Stephen J. Schuster ◽

Jakub Svoboda ◽

Alexandra Vandegrift ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cardiac Toxicity ◽

Cell Lymphoma ◽

Advisory Committees ◽

Co Morbidity ◽

Mantle Cell ◽

Bcr Signaling ◽

History Of

Abstract Introduction: Ibrutinib (Ibr) is a small molecule that effectively targets B cell malignancies by inhibiting Bruton's tyrosine kinase activity (BTK). Clinical studies have shown a consistent increase in OS, PFS and response rate for relapsed-refractory CLL and mantle cell lymphoma (MCL) with variable cardiac toxicity (CT) (Table 1). Methods: Retrospective analysis of pts treated at The Abramson Cancer Center at the University of Pennsylvania to identify the incidence and characteristics of Ibr related CT. Results: We identified 32 pts treated with Ibr (87.6% CLL, 6.2 MCL, 6.2% other). The median age was 65 yrs (47-83). 53% of patients had a prior history of cardiovascular (CV) comorbidities: 16% hypertension (HTN), 3 % arrhythmia, 9% CAD, 0% with heart failure. During the course of therapy, we identified 11 pts (mean age 69.6 yrs; range 51-83) with presumed Ibr-induced CT: 5 with AF (16%), 4 patients with aggravation of pre-existing HTN (13%), 1 with sinus bradycardia (3%), and 1 with unexplained syncope (3%). 88% were male and all had at least one cardiac co-morbidity. The median time to onset of AF was 197 days (63-358) and acceleration of HTN 42 days (27-57). All of the HTN patients had pre-existing HTN and of the 5 pts with AF, 2 had a history of HTN, 2 PAF, and 3 CAD. All patients were co-managed by the treating oncologist and cardiologist. Successful management of CT did not require Ibr discontinuation in all pts. We observed no arrhythmia or treatment related embolic/bleeding events; AF pts were all anticoagulated (3% warfarin, 87% novel antithrombotic drug). In 2/5 AF pts, Ibr dose was reduced. BTK inhibition may induce unique CT by affecting the regulation of off target kinases with BTK selectivity (Table 2). Table 3 provides recommendations for management of Ibr related CT for the practicing oncologist. Conclusions: We identified a 34% incidence of Ibr related CT. These results are unique in that we provide long-term follow up of such events and demonstrate that in practice, Ibr related CT can successfully be managed by the medical oncologist / cardio-oncology team. No pts discontinued Ibr in this series due to CT events. Pre-existing CV disease is a major risk factor for Ibr-related AF and HTN. The absence of cardiac co-morbidity may have negative predictive value. In conclusion, there is a potential for CT in elderly patients with pre-existing cardiac disease and HTN treated with Ibr. This suggests the need for proactive co-management of these patients with cardiologists trained in cardio-oncology. Table 1. Reported CT among CLL/ mantle cell lymphoma pts Cardiac Event CLL (Byrd, 2013) MCL (Wang, 2014) RESONATE (Byrd, 2014) Follow-up analysis (Byrd, 2015) AF 3 (4%) 5 (4.5%) 6 (3%) 8 (6%) Peripheral edema 18 (21%) 3 (2.7%) 22 (11%) NA Hypertension 5 (11%) NA NA 27 (20%) Dyspnea NA 30 (27%) 23 (12%) NA Supraventricular tachycardia 1 (1%) NA NA NA Table 2. Possible mechanisms of Ibr-related CT Protein Relation to BCR signaling Proposed mechanism Clinical CT Phosphatidylinositol 3-kinase (PI3K) Upstream activator and downstream substrate of BTK Alter gene expression in ventricular tissue;Compromised regulation of autonomic calcium oscillations in cardiac cells to alter automaticity AF, Hemodynamic compromise, Bradycardia Heat shock protein 70 Decreased HSP 70 levels in response to attenuated PI3K activity Compromised role in cardiac remodeling under pressure overload or stress AF, hypertension Phospholipase C gamma 2 (PLCγ-2) Downstream protein activated by BTK in BCR signaling Attenuated activation of PLCγ-2 compromises calcium signaling AF, cardiac arrhythmia Table 3. Penn recommendations for management of Ibr treated patients with CT AF Exclude hyperthyroidismConsider Ibr dose reductionRate control beta or calcium channel blocker. Start at low dose, uptitrate to HR < 100. If limited by hypotension, consider digoxinCVA Prevention with anticoagulation based on CHA2DS2-VASC score HTN ACE inhibitors and/or calcium channel blockers as first line Bradycardia Differentiate whether pt is symptomaticIf asymptomatic and HR increases appropriately with exertion, no further evaluation or treatment necessary Avoid negative chronotropic medications Disclosures Schuster: Novartis: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees. Svoboda:Seattle Genetics: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Celldex: Research Funding. Rago:Gilead Sciences: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees. Mato:Genentech: Consultancy; Gilead: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pronai Pharmaceuticals: Research Funding; Pharmacyclics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

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Predictive Power of Early, Sequential MRD Monitoring in Peripheral Blood and Bone Marrow in Patients with Mantle Cell Lymphoma Following Autologous Stem Cell Transplantation with or without Rituximab Maintenance; Interim Results from the LyMa-MRD Project, Conducted on Behalf of the Lysa Group

Blood ◽

10.1182/blood.v126.23.338.338 ◽

2015 ◽

Vol 126 (23) ◽

pp. 338-338 ◽

Cited By ~ 11

Author(s):

Mary B Callanan ◽

Marie-Hélène Delfau ◽

Elizabeth Macintyre ◽

Catherine Thieblemont ◽

Lucie Oberic ◽

...

Keyword(s):

Patient Outcome ◽

Bone Marrow ◽

Clinical Outcome ◽

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Cell Lymphoma ◽

Advisory Committees ◽

Mantle Cell

Abstract INTRODUCTION : Minimal residual disease (MRD) is emerging as an important predictor of clinical outcome in patients with mantle cell lymphoma (MCL). However, its utility in everyday clinical practice remains uncertain since standardized MRD monitoring strategies and response criteria are not yet formally established. To address this question, we conducted the LyMa-MRD project as an ancillary biology study in a prospective phase III trial in MCL (NCI NCT00921414; LyMa Trial). METHODS : The present MRD analysis was performed in a subgroup of randomized patients (n=178) of the 299 MCL patients (<66yrs) enrolled in the LyMa trial (Sept 2008 to Aug 2012). Briefly, all patients were previously untreated and received 4 courses of R-DHAP followed by ASCT using an R-BEAM conditioning regimen (n=257). After ASCT, patients were randomized between observation (obs) (n=120) versus Rituximab maintenance (RM) (n=119). The first planned interim-analysis, with a median follow-up of 40.6 months was presented at ASH 2014 and indicated superior PFS in the RM versus Obs arms (Le Gouill et al. ASH 2014). Sequential MRD monitoring was a predefined secondary objective and was performed throughout. At interim analysis the aim was to determine if peripheral blood (PB) and/or bone marrow (BM) MRD status, pre- and post ASCT, can predict patient outcome in terms of PFS according to RM or Obs. MRD was quantitatively assessed in PB and / or BM after induction, after ASCT by using gold standard EURO-MRD RQ-PCR assays and interpretation guidelines, targeted to clonal immunoglobulin gene rearrangements, in national reference laboratories. MRD data for survival analysis was generated from assays with a minimal sensitivity of at least 10-4. MRD status was assigned according to EURO-MRD interpretation guidelines. MRD negativity at a given time point was defined as absence of RQ-PCR amplification product in a given follow-up sample (minimal assay sensitivity of 10-4). RESULTS: Among the 299 patients enrolled in the LyMa trial, MRD data in PB and / or BM was successfully generated pre- and/or post-ASCT phases, for a total of 178 randomized patients. Of the 61 out of 239 randomized patients without MRD data, 9 are ongoing and other reasons were no MRD target or MRD assay failure. Pre-ASCT MRD in BM and PB was negative in 66% (n=98) and 80% (n=120), of samples, respectively. Post-ASCT, MRD in BM and PB was found negative in 82% (n=122) and 95% (n=162), respectively. MRD status pre-ASCT in either BM or PB was predictive of longer PFS (respectively; p= 0.0451, p= 0.0016). In contrast, PB MRD status, post-ASCT failed to predict PFS while there was a trend for a better PFS for patients achieving MRD negativity in the BM (median PFS: NR vs 43.4 months ; p= 0.07 ). We next investigated patient outcome according to MRD status pre-ASCT and randomization arms. In BM and PB, respectively, 72% and 79% of patients in the obs arm were MRD negative compared to 59% and 80% in the RM arm, respectively. The estimated 3y-PFS for MRD pos/obs, neg/obs, pos/RM, neg/RM patients, according to BM and PB MRD status were: 61,6% (IC95%, 35.4-79.8) vs 83.9% (IC95%, 70.1-91.7) vs 86.2% (IC95%, 67.3-94.6) vs 91.8% (IC95%, 76.3-97.3) (p=0.0110) and 51.8% (IC95%, 24.4-73.6) vs 86.5% (IC95%, 73.5-93.4) vs 80% (IC95%, 50-93.1) vs 92.8% (IC95%, 81.6-97.3) ( p=0.0027), respectively. CONCLUSION : Pre-ASCT MRD status in both BM and PB is an early predictor of PFS in younger MCL patients receiving ASCT. RM provides longer PFS regardless of MRD status pre-ASCT. Early sequential MRD monitoring at the pre-ASCT treatment phase thus offers strong potential for early clinical outcome prediction and MRD-guided, risk-adapted treatment in future MCL trials. Our preliminary results also suggest continued, clinically relevant, direct or indirect Rituximab-mediated anti-tumor activity, in rare residual circulating or 'tissue-resident' MCL cells. Disclosures Thieblemont: St. Louis Hospital, Paris, France: Employment. Casasnovas:Roche: Consultancy, Research Funding; Takeda: Consultancy; Gilead: Consultancy. Ribrag:Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽

10.1182/blood-2019-122393 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2898-2898

Author(s):

Vania Phuoc ◽

Leidy Isenalumhe ◽

Hayder Saeed ◽

Celeste Bello ◽

Bijal Shah ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Fdg Pet ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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