Estimates and Timing of Therapy Initiation during the First Decade for Patients with Follicular Lymphoma Who Were Observed at Diagnosis

Background: Observation or "wait and watch" (W/W) strategy remains a viable option in the rituximab era for asymptomatic, stage II-IV, low-tumor burden patients with FL grade 1-2, 3A. Studies to date both in pre and post rituximab era have not shown an overall survival benefit from immediate treatment in such low-risk patients.To improve our understanding and to better counsel FL patients on W/W strategy, we sought to estimate the incidence of treatment initiation at landmark time points in our prospectively observed cohort from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). We further evaluate the association between the presence of GELF criteria (MER treatment criteria) at diagnosis and initiation of treatment patterns, transformation rates and cause of death in FL patients managed by W/W. Methods: FL patients on W/W strategy were identified from MER of the University of Iowa/Mayo Clinic Lymphoma SPORE. From 2002-2015, consecutive patients with newly diagnosed FL were offered enrollment. Patients were managed per treating physician and followed prospectively. Baseline clinical and pathological data were abstracted using a standard protocol. Cumulative incidence estimates of treatment initiation for follicular lymphoma were calculated using transformation to large cell lymphoma (as the first event) and death due to any cause as competing risks. Transformation was defined based on biopsy-proven disease. Patients were retrospectively considered to meet treatment criteria at diagnosis if they had the presence of any GELF criteria components per available abstracted data in the MER database. Not all GELF criteria were prospectively assessed and captured for all patients, and thus the MER treatment criteria utilized here will be conservative for formal GELF assessment. Results: A total of 401 FL patients were identified in MER on W/W strategy. Baseline characteristics for W/W patients showed a favorable profile such as normal LDH (89%), low and intermediate FLIPI score in 48% and 35% respectively, no B symptoms (97%), low tumor burden (<4 nodal groups) in 72%, and GELF positive vs. negative in 36% and 64% respectively. At a median follow up of 8 years (IQR 5.9-12), 64% initiated treatment for FL only. Cumulative incidence estimates of treatment initiation at sequential time points were calculated from the initiation of observation (Table1&2). At diagnosis, the likelihood of treatment initiation was 15%, 26%, and 42% in the next 1, 2, and 5 years. The incidence of treatment initiation decreased over time as patients remained treatment-free after diagnosis (Figure 1A [blue curve]). Patients that met MER treatment criteria had increased rates of therapy initiation (33.2% vs. 21.9%) in the next two years and untreated transformation to large cell lymphoma [red curve] (8.7% vs. 4.5%) during the next 5 years (Figure 1B). Despite this, the rate of lymphoma related death at 10 years was similar between groups (met treatment criteria = 6.2% vs. 7.1%) (Figure 1C, [green curve]). Discussion: The longer duration of W/W strategy suggests a decreasing need for treatment over time. We provide time point estimates, which would be helpful for counseling patients. Of note, long-term continuous oncologic assessment and follow-up is necessary since approximately 66% of patients in this mature cohort initiated treatment by 8 years median follow up. MER treatment criteria at diagnosis identified patients with higher rates of transformation and therapy initiation in the first two years but did not identify those with worse lymphoma specific survival. Identification of biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients. Disclosures Ansell: Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Wang:Incyte: Research Funding; Innocare: Research Funding; Novartis: Research Funding. Witzig:MorphSys: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Maurer:Morphosys: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding. Nowakowski:NanoString: Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy; Kymera: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Patterns of therapy initiation during the first decade for patients with follicular lymphoma who were observed at diagnosis in the rituximab era

Blood Cancer Journal ◽

10.1038/s41408-021-00525-0 ◽

2021 ◽

Vol 11 (7) ◽

Author(s):

Arushi Khurana ◽

Raphael Mwangi ◽

Stephen M. Ansell ◽

Thomas M. Habermann ◽

James R. Cerhan ◽

...

Keyword(s):

Follicular Lymphoma ◽

Treatment Initiation ◽

Tumor Burden ◽

Watch And Wait ◽

University Of Iowa ◽

Therapy Initiation ◽

Overall Survival Benefit ◽

The University ◽

Biological Differences

AbstractImmediate treatment for asymptomatic, low-tumor burden follicular lymphoma (FL) has not shown an overall survival benefit over “watch and wait” (W/W) strategy. We estimated incidence of treatment initiation at specific time points and assessed its association with the presence of any criteria such as GELF, BNLI, GITMO at diagnosis. FL patients managed by W/W strategy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE between 2002 and 2015. Cumulative incidence estimates of treatment initiation were calculated using transformation (as the first event) and death as competing risks. 401 FL patients were identified on W/W strategy. At a median follow-up of 8 years, 256 (64%) initiated treatment. For patients on the W/W strategy for 5 years, the likelihood of treatment initiation in the next 5 years was 12% compared to 43% at diagnosis unlike transformation rates which remained steady. Patients with any of popular treatment criteria at diagnosis did not have increased therapy initiation rates (44% vs. 42%) during the first 5 years or lymphoma-related death rates at 10 years (6% vs. 7%). Identifying biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients.

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LONG-TERM RESULTS of the GIMEMA VTD Consolidation TRIAL In Autografted MULTIPLE Myeloma PATIENTS (VEL-03-096): IMPACT of Minimal RESIDUAL DISEASE Detection by REAL Time Quantitative PCR On LATE Recurrences and Overall SURVIVAL

Blood ◽

10.1182/blood.v118.21.827.827 ◽

2011 ◽

Vol 118 (21) ◽

pp. 827-827 ◽

Cited By ~ 5

Author(s):

Marco Ladetto ◽

Simone Ferrero ◽

Daniela Drandi ◽

Federica Cavallo ◽

Luigia Monitillo ◽

...

Keyword(s):

Clin Oncol ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Tumor Burden ◽

Long Term Results ◽

Clinical Relapse ◽

Advisory Committees ◽

Tumor Load

Abstract Abstract 827 Background and aims: We have recently shown that a consolidation therapy with bortezomib/thalidomide/dexamethasone (VTD) in multiple myeloma (MM) patients responding to autologous transplantation (ASCT) induces major tumor shrinking assessed by real time-quantitative (RQ)-PCR. Moreover we found that low levels of minimal residual disease (MRD) associated to a better progression-free survival (PFS) [GIMEMA VEL-03-096 trial, EudraCT Number 2004-000531-28: Ladetto et al, J Clin Oncol 2010]. We here present the updated results of this study at a median follow-up of 65 months. In the present analysis the following additional issues have been addressed: a) impact of MRD on PFS over time, with special interest to the role of MRD kinetics on outcome; b) impact of MRD on overall survival (OS). Patients and methods: Inclusion criteria and treatment schedule for this study have been already reported [Ladetto et al., J Clin Oncol 2010] and included: 1) a documented complete or very good partial remission following ASCT delivered as first line treatment; 2) no previous therapy with thalidomide or bortezomib; 3) presence of a molecular marker based on the immunoglobulin heavy chain rearrangement (IGH). MRD was assessed on bone marrow samples at diagnosis, study entry, after two VTD courses, at the end of treatment and then at six months intervals, up to clinical relapse. Patients underwent MRD detection using either qualitative nested PCR and RQ-PCR, employing IGH-derived patient specific primers as already described [Voena et al., Leukemia 1997; Ladetto et al., Biol Bone Marrow Transpl 2000]. For outcome analysis patients were grouped according to following definitions: a) MRD negativity on two consecutive samples by the most sensitive PCR method (nested PCR): full molecular remission (FMR); b) MRD negativity on two consecutive samples by RQ-PCR (less sensitive but currently better standardized, according to European Study Group on MRD detection guidelines [van der Vendel et al., Leukemia 2007]): standard molecular remission (SMR); c) post-treatment tumor load above the median by RQ-PCR: high tumor burden (HTB); d) post-treatment tumor load below the median by RQ-PCR: low tumor burden (LTB); e) recurrence of detectable MRD after FMR/SMR: molecular relapse (M-rel); f) increase of MRD levels of at least one log: active disease (AD). Results: Feasibility, toxicity and clinical outcome of the trial have been already reported [Ladetto et al., J Clin Oncol 2010]. Thirty-nine patients were enrolled and median clinical follow-up from start of first line treatment is 65 months. 270 of the planned samples for MRD monitoring (86%) were actually received by the centralized lab. So far 17 relapses and six deaths have been reported. Following VTD consolidation, 7/38 evaluable patients achieved FMR (18%) and 15/38 achieved SMR (39%). Three M-rel were observed, two of them followed by clinical relapse within six months. Achievement of SMR proved highly predictive for PFS (5-years (y) PFS 82% vs 44%, p=0.009, figure 1A), as well as the presence of HTB and AD (5-y PFS 35% vs 87%, p<0.001, figure 2). Interestingly, patients with LTB and no evidence of M-rel or AD had an excellent outcome with a 5-y PFS of 87%, (even considering that molecular follow-up was incomplete due to lack of samples in the two events observed in the low risk group, figure 2). Most notably, none of the patients achieving FMR or SMR has so far died and both SMR and AD proved to be significant predictors for OS (respectively, 5y-OS 100% vs 74%, p=0.012, figure 1B, and 5y-OS 86% vs 100%, p=0.037, data not shown). Conclusions: Our long-term results indicate that: 1) the achievement of SMR following VTD consolidation in MM patients is associated with a better outcome in terms of PFS and OS; 2) a dynamic increase in molecular tumor burden (AD), detectable by RQ-PCR, predicts late disease relapses several months before clinical recurrence. Taken together these results suggest the importance of developing tailored treatment for patients with high residual burden or showing increasing levels of MRD during follow-up, as already pursued for example in mantle cell lymphoma [Andersen et al., J Clin Oncol 2009]. Disclosures: Ladetto: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Bayer: Honoraria; Mundipharma: Honoraria; Janssen-Cilag: Research Funding; Italfarmaco: Research Funding. Cavallo:celgene: Honoraria. Guglielmelli:celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Merck: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

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Reduced-Intensity Induction with Dasatinib Vs. Hypercvad + 2nd Generation TKIs with MRD-Guided Follow-up Therapy Leads to Comparable Rates of MRD-Negative Remission While Reducing Transfusions and Neutropenia in Ph+ ALL

Blood ◽

10.1182/blood-2020-141264 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-44

Author(s):

Jonathan Webster ◽

Hua-Ling Tsai ◽

Eric Gehrie ◽

Tania Jain ◽

Christopher S. Hourigan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Initiation ◽

Advisory Board ◽

High Dose ◽

Allogeneic Bone ◽

Advisory Committees ◽

2Nd Generation ◽

Reduced Intensity

Background: Reduced-intensity induction (RII) with imatinib yields comparable outcomes to HyperCVAD with imatinib with fewer induction deaths and an improved CR rate in Ph+ ALL (Chalandon. Blood. 2015). Dasatinib with steroids also produces excellent responses with little toxicity (Foa. Blood. 2011). Allogeneic bone marrow transplant (AlloBMT) remains the goal of therapy in Ph+ ALL based on contemporary trials with TKIs demonstrating improved survival in patients transplanted in CR1, and we have shown that transplant following induction with dasatinib yields better outcomes than with imatinib. Thus we implemented RII with dasatinib for the treatment of Ph+ ALL and compared to patients who received HyperCVAD with a 2nd generation TKI. Methods: Patients with newly diagnosed Ph+ ALL admitted to Johns Hopkins Hospital from September 2017-June 2020 underwent a 4-week RII with: vincristine 2 mg/d weekly, dexamethasone 40 mg PO weekly on days 1 and 2, and dasatinib 100 mg PO daily. CNS prophylaxis with IT MTX was given on day 8. Dexamethasone and vincristine were reduced by 50% for patients over age 70. Filgrastim was started on day 15 for patients without ANC recovery. Patients who received HyperCVAD with dose adjustments for age (Rausch et al. Cancer. 2020) from July 2011-June 2020 were included for comparison. Dasatinib 100 mg PO daily or nilotinib 400 mg PO BID were given with HyperCVAD at the discretion of the treating physician. Rituximab 375 mg/m^2 on days 1 and 8 was given based on CD20 status. Subsequent therapy after induction was not specifically mandated. Results: 21 patients received RII and 24 received HyperCVAD. The cohorts were comparable in terms of gender (38.1% female vs. 50%, p=0.55), age (median 49.8 vs. 50.3, p=0.33), age >60 (33.3% vs. 29.2%, p>0.99), median WBC at diagnosis (19 vs. 23.5, p=0.56), and the presence of decompensated DIC (fibrinogen <150) prior to treatment initiation (4.8% vs. 8.3%, p>0.99). Among the patients treated with HyperCVAD, 15 received dasatinib (62.5%) and 9 received nilotinib (37.5%). Rituximab use was balanced between the cohorts (61.9% vs. 58.3%, p>0.99). Table 1 compares the time to ANC recovery >500, transfusion requirements within 30 days of chemotherapy initiation, rates of decompensated DIC following treatment initiation, and the duration of inpatient hospitalization for induction. While the rates of decompensated DIC were similar in each cohort, patients treated with RII required fewer platelet and pRBC transfusions. ANC recovery was faster following RII, and only 5 patients (23.8%) received growth factor support. All patients achieved a hematologic response. There was one induction death with HyperCVAD (4.2%). Most patients received a subsequent cycle of high-dose (HD) MTX and Ara-C with TKI (76.2% following RII and 91.7% following HyperCVAD). The remaining patients treated with RII subsequently received HD MTX (14.2%) or blinatumomab (9.5%) with TKI due to co-morbidities. Among those patients treated with HD MTX and Ara-C, blinatumomab was given with TKI to 6 patients (37.5%) who initially received RII and 1 patient (4.5%) after HyperCVAD (p=0.03) due to persistent MRD. As shown in Figure 1, the incidence of MRD-negativity by multi-color flow cytometry (MFC) with a sensitivity of 10-4 at day 120 after treatment initiation was similar for RII (85.4%, 95% CI 64.8-97.1) versus HyperCVAD (86.7%, 95% CI 69.8-96.6). Among patients subsequently treated with HD MTX and Ara-C, 62.5% proceeded to alloBMT after RII with an additional 12.5% currently undergoing transplant evaluation, while 86.4% proceeded to alloBMT after HyperCVAD. The 1-year RFS and OS following RII were 87.9% (95% CI 59.6-96.8) and 100% compared to 87.5% (95% CI 66.1-95.8) and 95.8% (95% CI 73.9-99.4) following HyperCVAD. Conclusion: RII with dasatinib results in fewer transfusions and less myelosuppression compared to HyperCVAD with a 2nd generation TKI. More patients treated with RII received blinatumomab following high-dose MTX and Ara-C, but the rates of MRD-negativity were comparable between the two regimens. Thus RII with dasatinib followed by MRD-guided follow-up therapy facilitates MRD negative remissions with less toxicity than HyperCVAD. The vast majority of fit patients were able to proceed to alloBMT following either regimen. Transplant outcomes following dasatinib with induction are presented in our concurrent abstract demonstrating a 5-year RFS of 83% (95% CI 59.8-93.5). Disclosures Webster: Amgen: Consultancy; Pfizer: Consultancy. Jain:Bristol Myer Squibb: Other: for advisory board participation; CareDx: Other: Advisory Board; Takeda: Consultancy, Honoraria. Dalton:AbbVie: Research Funding; Eli Lilly: Research Funding. DeZern:Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy. Gojo:Genentech: Research Funding; Amphivena: Research Funding; Merck: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Bolanos-Meade:Incyte: Other: DSMB Fees. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; AbbVie: Consultancy; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Borrello:Celgene: Research Funding; Aduro: Patents & Royalties; WindMIL Therapeutics: Other: Founder , Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levis:Menarini: Honoraria; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding.

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Association between Quality of Response and Outcome in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

Blood ◽

10.1182/blood-2018-99-111044 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1873-1873

Author(s):

Paolo Strati ◽

Mariela Sivina ◽

Ekaterina Kim ◽

Michael J. Keating ◽

William G. Wierda ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Treatment Initiation ◽

Treatment Discontinuation ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Genetics Research ◽

Baseline Characteristics

Abstract Introduction. In the context of chemoimmunotherapy, complete remission (CR) is more common and is associated with improved survival in patients with chronic lymphocytic leukemia (CLL). CR is less frequent in CLL patients treated with ibrutinib, and the prognostic significance of achieving CR with ibrutinib is indeterminate. Methods. We prospectively analyzed 208 CLL patients treated on a phase 2 study (NCT02007044) of first-line (deletion 17p only; n=27) or salvage ibrutinib (n=181), with or without rituximab, between 12/2013 and 01/2018. Response was assessed by international workshop on CLL 2018 guidelines. Categorical variables were compared using the χ2 or Fisher exact tests. Progression-free survival (PFS) was defined as time from treatment initiation to disease progression and/or death, and Kaplan-Meier curves compared using the log-rank test. A landmark analysis at median time of CR achievement (best response) was performed for PFS. Results. After a median follow-up of 34 months (range, 3-48 months), response was evaluable in 194 patients, overall response rate (ORR) was 99%, and CR rate was 24%, with negative minimal residual disease (MRD) in 3% of patients; median time to response was 10 months (range, 3-45 months) and median time to CR was 21 months (5-45 months). None of the patients' baseline characteristics associated with achievement of CR (Table). Among the 47 patients in CR, 7 (15%) discontinued treatment, after a median time from treatment initiation of 19 months (range, 10-39); the main cause of discontinuation was toxicity (5 patients), with second cancer (metastatic melanoma) and disease progression prompting treatment discontinuation only in 2 patients. Among the 145 patients in PR, 50 (34%) discontinued treatment, after a median time from treatment initiation of 14 months (range, 4-45 months); while the main cause of discontinuation was again toxicity (26 patients), 2nd cancers and progressive disease prompted treatment discontinuation in 5 and 14 patients, respectively. Remaining causes of treatment discontinuation among patients in PR were loss to follow-up (3 patients) and consolidation therapy (2 patients). Median PFS was not reached and 28 patients (13%) progressed and/or died. Achievement of CR significantly associated with prolonged PFS (4-year PFS 98% vs 78%, p=0.03)(Figure). The association between CR and prolonged PFS was also confirmed on a landmark analysis (21 months)(p=0.05). Among baseline characteristics shown in the Table, the only factor associated with prolonged PFS was absence of complex karyotype (4-year PFS 80% vs 40%, p=0.05). Median OS has not been reached and 16 (8%) patients have died; of these, only 1 patient was in CR (and cause of death was metastatic melanoma), whereas the remaining 15 were in PR. Among patients in PR, causes of death were: infections in 7 patients, 2nd cancers in 2 patients, Richter transformation in 2 patients and other in 4 patients (small bowel obstruction, colon perforation, intracranial hemorrhage, bradyarrhythmia). Conclusions. This is the first study showing that achievement of CR is a desirable endpoint for patients with CLL treated with ibrutinib, associating with prolonged PFS. Our results support the development of future combination studies, aimed at achieving higher rates of CR in patients treated with ibrutinib. Figure. Figure. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Jain:Infinity: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Infinity: Research Funding; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Adaptive Biotechnologioes: Research Funding; Celgene: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:Adaptive Biotechnologies: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Lenalidomide In Combination With R-CHOP (R2-CHOP) In Patients With High Burden Follicular Lymphoma: Phase 2 Study

Blood ◽

10.1182/blood.v122.21.248.248 ◽

2013 ◽

Vol 122 (21) ◽

pp. 248-248 ◽

Cited By ~ 5

Author(s):

Herve Tilly ◽

Franck Morschhauser ◽

Olivier Casasnovas ◽

Thierry Jo Molina ◽

Nicolas Mounier ◽

...

Keyword(s):

Complete Remission ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Tumor Burden ◽

Phase 2 ◽

Advisory Committees ◽

High Burden ◽

Grade 3

Abstract Background Single-agent studies of lenalidomide in relapsed/refractory follicular lymphoma (FL) have demonstrated significant activity. Recent studies reported that the combination of lenalidomide and rituximab yields high response rates in patients with FL. Three recent phase 1 studies have shown that lenalidomide administered on 10 to 14 days of 21-day cycle of R-CHOP could be safe in the initial treatment of aggressive or indolent B-cell lymphomas. Two of these studies determined 25 mg of lenalidomide as the recommended daily dose. This multicenter, open label, phase 2 trial (NCT01393756) investigated the combination of lenalidomide with R-CHOP in patients (pts) with high burden FL. Methods Pts with previously untreated FL grade 1, 2 or 3a and a high tumor burden according to GELF criteria were eligible. Pts received an induction therapy with 6 cycles of R2-CHOP given every 3 weeks (25 mg oral lenalidomide on days 1-14) followed by two additional rituximab infusions. Pegfilgrastim was administered on day 4 and oral aspirin prophylaxis (100 mg) was given daily during the cycles. Lenalidomide dose was adapted to toxicities. Pts responding to induction therapy received rituximab maintenance every 8 weeks for 2 years. The primary endpoint was the complete remission (CR/CRu) rate, according to IWRC 99, at the end of induction treatment. Secondary endpoints were safety, progression free survival, duration of response and overall survival. Results Eighty pts were enrolled from 16 LYSA centres between December 2010 and January 2012. Median age was 57 y (range 29-71); 50% were male; 92% Ann Arbor stage III-IV; 28% B symptoms, 69% ECOG performance status = 0; 25% mass >10cm; 53% bone marrow involved; 40% LDH elevated; 63% FLIPI 3-5. Sixty-eight pts (85%) received the complete induction regimen. Median interval between R2-CHOP cycles remained 21 days during treatment. Thirty-three pts (41%) experienced at least one dose reduction of lenalidomide. The complete remission (CR/CRu) rate was 74% (CI 95%: 63%-83%) and ORR was 94% (CI95%: 86%-98%).Current median follow-up is 13 months. So far, 9 pts (11%) experienced a progression/relapse. Hematologic toxicity was in the range of that observed with R-CHOP regimen with 65% grade 4 neutropenia; 12.5% grade 4 thrombocytopenia; 7.5% febrile neutropenia and no toxic death. Grade 1-2 sensory neuropathy was observed in 28 pts (36%), one pt had a grade 3 neuropathy. Twenty-nine pts (36%; grade 1-2: 27; grade 3: 2) had reversible skin toxicity, usually during the course of the first cycle. Five episodes of thrombosis occurred during treatment or follow-up, 3 were related to venous access devices and only one required discontinuation of lenalidomide. Three cases of neoplasm were observed during follow-up. Conclusion The combination of 25mg of lenalidomide for 14 days with 21-day R-CHOP cycles is well tolerated and yields a high rate of complete remission in patients with high tumor burden follicular lymphoma. Disclosures: Tilly: Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Off Label Use: Use of lenalidomide to enhance R-CHOP efficacy in follicular lymphoma. Morschhauser:Celgene: advisory boards Other, Honoraria, Research Funding, Speakers Bureau. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding. Molina:Merck: Honoraria. Salles:roche: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Haioun:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Impact and Safety of Chimeric Antigen Receptor T Cell Therapy in Vulnerable Older Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2019-125162 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1603-1603 ◽

Cited By ~ 3

Author(s):

Richard J Lin ◽

Stephanie M Lobaugh ◽

Martina Pennisi ◽

Jason T Chan ◽

Yakup Batlevi ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

B Cell Lymphoma ◽

Tumor Burden ◽

Advisory Committees ◽

Comorbidity Burden ◽

Car T ◽

Equity Ownership

The development of chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of relapsed refractory diffuse large b-cell lymphoma (DLBCL). However, its impact in vulnerable older patients, especially those with multi-morbidity and functional limitations, has not been explored. Moreover, the Centers for Medicare & Medicaid Services (CMS) has recently proposed Coverage with Evidence Development for CAR T, emphasizing the need for evidence in older patients. We retrospectively examined outcomes of older patients referred for commercial CAR T products, axicabtagene ciloleucel and tisagenlecleucel, at our institution from January 2018 to March 2019. Forty-two consecutive older patients (≥65yo) were included in the analysis of post-relapse (last documented relapse or refractory state) overall survival (PR-OS) accounting for time of CAR T entry. Geriatric assessment, including comorbidity, basic and instrumental activities of daily living, prior falls, and weight loss, was performed either by a geriatrician prior to admission, or by interdisciplinary clinical staff on the day of admission. In parallel, we compared the safety and toxicities of CAR T between older (≥65yo, n=24) and younger (<65yo, n=25) patients. Among the 42 patients ≥65yo, 18 did not receive CAR T due to clinical ineligibility and/or death during the pre-requisite clinical evaluation. Their gender distribution, comorbidity burden, measured by Deyo/Charlson Comorbidity Index (DCI/CCI), and Karnofsky Performance Status (KPS) were comparable to the 24 older patients who received a CAR T product. With a median follow-up of 291 days (range 162 - 572) for survivors, the PR-OS favored the group of older patients who had received CAR T with estimated 1-year PR-OS of 0.67 (95% CI: 0.43, 0.99) versus 0.44 (95% CI: 0.27, 0.75) for patients who did not receive CAR T (p=0.04) (Figure). We next compared the safety and toxicity profiles among older (≥65yo, n=24) versus younger patients (<65yo, n=25) who received a CAR T. Baseline characteristics were similar among the two groups including: KPS, the prevalence of functional impairment, prior fall, and weight loss, and pre-treatment tumor burden measured by LDH (Table). The older group had more females (p<0.001) and higher comorbidity burden measured by DCI/CCI (p=0.04) (Table). Numerically more younger patients (84%) received axicabtagene ciloleucel compared to tisagenlecleucel versus older patients (63%; p=0.11). Importantly, the two groups had similar incidences of cytokine release syndrome (CRS) and neurotoxicity (NT) of all grades (Table). We also examined the incidence of grade 3-4 hematologic and non-hematologic toxicities by CTCAE v5.0 and found that numerically, older patients appeared to have less infection and cytopenia, and more metabolic and other toxicities (Table). In addition, the rate of Intensive Care Unit admission was similar. At the time of last follow-up, we observed only 1 treatment-related death, a 69-year-old female with a history of prior allogeneic hematopoietic cell transplantation who died of influenza pneumonia 129 days after CAR T infusion. Although limited by small sample size, retrospective design, and possible patient selection bias regarding disease biology, our results highlight potential benefits of CAR T in selected older patients even with functional limitation, multi-morbidity, and significant tumor burden; and the lack of excessive CRS, NT, and other high-grade toxicities. These findings extend beyond published results of older patients in ZUMA-1 and JULIET trials, and support that, with meticulous management of CAR T toxicities, older patients should not be excluded from CAR T based on chronologic age alone. Detailed geriatric assessment and correlation with toxicities should allow better selection of older adults who could benefit from this curative treatment. In addition, the biology of CAR T response in older adults may warrant additional investigation in the context of aging-associated changes in the immune system. Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giralt:Jazz Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Kite: Consultancy. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Noble Insights: Consultancy; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties. Santomasso:Kite/Gilead: Consultancy; Novartis: Consultancy; Juno/Celgene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyte/Gilead: Research Funding; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Cost Evaluation Study of Management and Surveillance, and Review of the Recent USA and UK Guidelines

Blood ◽

10.1182/blood-2021-153675 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4014-4014

Author(s):

Aia S Mehdi ◽

Rachel O'Connell ◽

Michael Potter ◽

Chris Marshall ◽

Liza Van Kerckhoven ◽

...

Keyword(s):

Health Care ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Breast Implant ◽

Large Cell ◽

Post Treatment ◽

Advisory Committees ◽

Surveillance Imaging

Abstract Introduction Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a T-cell lymphoma associated with textured breast implants, recently recognized by the revised WHO Classification. Recommended management for BIA-ALCL involves a multidisciplinary team (MDT) approach with breast surgery, haemato-oncology, pathology, radiology and oncoplastic input. Definitive management for the 'effusion-only' subset is surgical implant and capsule removal; systemic therapy is reserved for 'mass-forming' and 'advanced-disease' cohorts. Overall prognosis is excellent with the vast majority achieving remission. Although the diagnostic and treatment paradigm is established, post treatment surveillance and follow-up guidance varies widely (globally); over-utilisation of imaging tests compromises the patient pathway, impacts limited health-care resources and is associated financial burdens on patients and providers. Recently, newly published consensus guidelines (UK MHRA and USA NCCN clarify follow-up and surveillance imaging (Table 1). The aim of this study was to review our BIA-ALCL specialist centre institutional practise; to quantify the direct economic cost (EC) of imaging surveillance and indirect EC of outpatient clinic (OPC) assessment compared EC if recent guidelines were followed. The secondary aim is to highlight and raise awareness of the latest international guidance to promote the standardisation of practise. Methods A retrospective analysis of a prospectively maintained patient database between July 2015 to October 2019 was conducted, with Institutional Review Board Approval. Data collection included patient demographics, tumour subset, treatment, clinical and imaging surveillance. Follow-up and imaging undertaken for symptomatic concerns / non-BIA-ALCL related pathology was excluded. Imaging costs were calculated using UK NHS tariffs. Results Eleven patients were treated for BIA-ALCL during the study period, with a median age of 49 at diagnosis (range 30-82years). Patients were diagnosed with: effusion-only (n=7), effusion and mass (n=2), mass-only (n=2) subtypes, at a median time of eleven years from implant insertion (IQR 8-12). All patients underwent explantation and en-bloc capsulectomy, with 1 patient required neo-adjuvant (CHOP, Brentuximab) and 1 adjuvant (CHOP) therapy (CHOP. Surveillance with imaging and OPC detected no disease recurrence to date (overall median follow-up 38 months, IQR 12-47). Post treatment episodes of surveillance imaging or follow-up related to patient symptoms were excluded. 8 patients underwent surveillance imaging at our institute (Table 2). Total cost of imaging was £10,396 ($14,396) with a median cost of £1,953 ($2,705) per patient [IQR £526-2029 ($728-2,810)]. 7 patients had completed at least 24 months follow-up since surgery during the study period (Table 3), with 3 patients having not yet completed their follow-up period of two years. Of those with completed follow-up, the median OPC follow-up per patient was 48 months (IQR 38-52), median number of OPC was 7 (IQR 6-11) and the median cost of clinic review was £982 (IQR 804-1395). The surplus cost per patient compared with recommended follow-up was £118 ($164) [IQR £0-531 ($0-738)]. Conclusions Our data shows the variable BIA-ALCL surveillance practise pattern and the associated additional direct and indirect EC of unnecessary asymptomatic surveillance imaging, with an excessive number of follow-up OPC and period of clinical follow-up after complete remission. With no recurrence detected in our patient cohort to date, this data supports the new UK and updated USA NCCN Guidelines (extrapolated from data in other NHLs, and analogous to principles of the ASH Choosing Wisely Campaign) that routine post-treatment surveillance imaging should not be performed in BIA-ALCL patients. Routine asymptomatic post-treatment surveillance imaging is clinically unnecessary and potentially leads to a 'Cascade Effect' of further tests, with increased radiation exposure, excess costs and impact on limited health-care resources. We also support open-access follow-up for patients in remission, to reduce unnecessary follow up appointments. With UK and USA guidelines now available for BIA-ALCL, we support training and education of health-care professionals, global consensus guidelines and a registry, for this rare however increasingly recognised new entity. Figure 1 Figure 1. Disclosures Iyengar: Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: conference support; Janssen: Other: conference support, Speakers Bureau. Nicholson: Pfizer: Consultancy; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; BMS/Celgene: Consultancy; Novartis: Consultancy, Other: Conference fees. El-Sharkawi: Kyowa Kirin: Other: Ad boards; Beigene: Other: Ad boards; ASTEX: Other: Ad boards; Novartis: Other: Travel Support; Takeda: Honoraria; Roche: Honoraria; Janssen: Honoraria, Other: Ad boards; AstraZeneca: Honoraria, Other: Ad boards; AbbVie: Honoraria, Other: Travel Support, Ad boards. Tasoulis: BMJ: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cunningham: Roche: Research Funding; Clovis Oncology: Research Funding; Celgene: Research Funding; Eli Lilly: Research Funding; Bayer: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees; 4SC: Research Funding; AstraZeneca: Research Funding; MedImmune: Research Funding.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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Preclinical Evaluation of Gilteritinib on NPM1-ALK Driven Anaplastic Large Cell Lymphoma Cells

Blood ◽

10.1182/blood-2019-130633 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2865-2865

Author(s):

Sudhakiranmayi Kuravi ◽

Janice Cheng ◽

Kishore Polireddy ◽

Gabrielle Fangman ◽

Roy A Jensen ◽

...

Keyword(s):

Tyrosine Kinase ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Advisory Board ◽

Advisory Committees ◽

Apoptotic Protein ◽

Large Cell Lymphoma ◽

Alk Positive

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin's lymphoma (NHL) comprising 2-8% of adult and 10-20% of pediatric and adolescent NHL. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL express (nucleophosmin1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The self-dimerization of fusion kinase NPM1-ALK mediates constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for lymphoma cell proliferation and survival. The current standard treatment regimen for ALK+ ALCL is CHOP (cyclophosphamide, hydroxy doxorubicin, vincristine, prednisone) chemotherapy. Oftentimes, resistance and failure of remission occur with CHOP therapy, making it a suboptimal treatment regimen for many patients. Therefore, an alternative therapeutic approach is warranted to better address the needs of the ALK+ ALCL population. Gilteritinib is a recently FDA approved tyrosine kinase inhibitor for the treatment of FMS-like tyrosine kinase (FLT3) mutation-positive acute myeloid leukemia. Along with inhibition of FLT3, gilteritinib also inhibits other tyrosine kinases such as AXL and ALK. In this study, for the first time, we demonstrated gilteritinib mediated growth inhibitory effects on NPM1-ALK driven ALCL cells. We have used a total of five cell lines in our study: NPM1-ALK endogenously expressing human ALCL cell lines (SUDHL-1, SUP-M2, SR-786, and DEL), and our laboratory generated ectopically overexpressing Ba/F3-FG-NPM1-ALK, a murine cell line. Gilteritinib treatment (5-20 nM) inhibited NPM1-ALK fusion kinase phosphorylation, which resulted in downregulation of downstream survival signaling pathways including AKT, ERK1/2, and STAT3 leading to induced apoptosis and decreased clonogenic survival. Gilteritinib mediated apoptosis was associated with caspase 3/9 and poly (ADP-ribose) polymerase cleavage with increased pro-apoptotic protein BAD and decreased anti-apoptotic protein MCL-1. Increased expression of c-Myc is associated with ALK-positive ALCL and gilteritinib treatment decreased c-Myc levels in a dose dependent manner. Cell cycle analysis demonstrated gilteritinib treatment induced cell cycle arrest at the G0/G1 phase with a concomitant decrease in G2/M and S phases. In summary, our preclinical results suggest gilteritinib has therapeutic potential for the treatment of ALCL cells expressing NPM1-ALK and other ALK /ALK-fusion driven hematologic or solid malignancies. Disclosures Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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