Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3526-3526

Abstract: Introduction: The standard of care for patients with stage IE indolent B-cell lymphoma (BCL) of the ocular adnexa is external beam radiotherapy (RT) to 24-30 Gy. Even with these moderate doses, ocular morbidity is common. Indolent BCL is radiosensitive, with reports of complete response (CR) to 4 Gy. We sought to evaluate the efficacy of a response adapted strategy for the treatment of orbital indolent BCL with upfront ultra-low dose (ULD) orbital RT (4 Gy) and an additional 20 Gy for incomplete responders. Methods: We conducted a phase II single arm study in patients with stage I-IV indolent BCL involving the orbit. Patients were treated with ULD RT to 4 Gy in 2 fractions to the affected orbit(s). Response was assessed clinically and/or radiographically 3 months after ULD RT. Patients with a CR were observed. Patients without CR were evaluated in 3-4 month intervals and offered an additional 20 Gy if they had two consecutive visits with no tumor reduction. The primary endpoint was local control (LC) within the RT field defined from the last day of RT. Secondary endpoints included CR rate, freedom from distant relapse (for stage I patients) and overall survival. We hypothesized that this response adapted strategy would yield equivalent LC to that of standard therapy (24 Gy up front). CR was defined as clinical and/or radiographic resolution of orbital disease. In patients with pre-therapy PET-CT avid disease, CR was defined as a 5PS of 1-3 with or without a residual mass. Partial response (PR) was defined as a decrease in clinical or radiographic disease burden by ≥50% by sum of the disease parameters. Minimal response (MR) was defined as & lt; 50% in orbital disease burden. Stable disease (SD) and progressive disease (PD) were defined as no change or increasing disease, respectively. Results: Between July 2015 and January 2021, 51 patients were enrolled. The median age was 63 years (range 29-88); 62% were female (n=31). Diagnoses included MALT lymphoma (65%, n=33), follicular lymphoma (FL) (24%, n=12), and unclassified low-grade BCL (12%, n=6). Thirty-two patients (63%) had disease confined to one or both orbits at enrollment (stage I); 37 (73%) had newly diagnosed, untreated lymphoma. All patients received 4 Gy in 2 fractions to the affected orbit(s) (bilateral, n=8). Treatment was well tolerated without grade 3 or higher toxicity. One patient did not return for follow up. For 50 evaluable patients, at a median follow up of 21.9 months (95% CI 16.2 - 27.6), 44 patients achieved a CR to ULD therapy (88%) at a median time of 3.4 months (IQR 3, 3.9). Nine patients (20%) had residual disease at the first follow up visit but subsequently had resolution of orbital lymphoma in future follow up. No patient who experienced CR to ULD RT had an in-field orbital relapse (freedom from local relapse rate = 100%, Figure 1a). At the time of follow up #3, 7 patients had not experienced CR and had evidence of disease (Figure 2). Among these 7 patients, 1 achieved CR with continued observation (without intervening therapy) and 2 are being observed with stable disease. Ultimately 4 patients were recommended additional RT to 20 Gy; two patients received the recommended RT, one refused additional RT, one was treated with rituximab for systemic disease progression. After an additional 20 Gy, one patient has stable disease at 21 months and the other patient has pending follow-up. Of the 50 evaluable patients, 31 had stage I disease (MALT = 25, FL=4, low grade BCL =2) that was either untreated (n=25) or had relapsed or progressed in the orbit (n=6) after rituximab (n=2), surgical excision (n=2) or contralateral RT (n=2). Twenty-eight stage I patients (90%) had a CR to ULD RT; of these, the 2-year freedom from local recurrence rate was 100% (Figure 1b) and the freedom from distant relapse rate was 87% (Figure 1b). Distant relapses in the mediastinum, lung, contralateral orbit and mesentery were salvaged successfully with bendamustine/rituximab, rituximab, contralateral 4 Gy orbital RT and rituximab, respectively. None of the 3 patients that did not completely respond to ULD RT experienced distant relapse. Conclusions: In the first prospective study evaluating this novel approach of response adapted ULD orbital RT, orbital outcomes were compelling with minimal toxicity. Additional follow up is required to evaluate long term LC. Response adapted ULD orbital RT is an effective and promising strategy for the definitive management of indolent BCL of the ocular adnexa. Figure 1 Figure 1. Disclosures Pinnix: Merck Inc: Research Funding. Nastoupil: Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; MorphoSys: Honoraria; Gilead/Kite: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; IGM Biosciences: Research Funding; TG Therapeutics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; ADC Therapeutics: Honoraria; Bayer: Honoraria; Caribou Biosciences: Research Funding. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Steiner: Rafael Pharmaceuticals: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding. Jain: kite: Consultancy; Lilly: Consultancy. Westin: Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Umoja: Consultancy; Iksuda Therapeutics: Consultancy; Curis: Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Wang: BioInvent: Research Funding; Celgene: Research Funding; Molecular Templates: Research Funding; Lilly: Research Funding; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Oncternal: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; Juno: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Genentech: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; CStone: Consultancy; Bayer Healthcare: Consultancy; BGICS: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Scripps: Honoraria; Physicians Education Resources (PER): Honoraria; OMI: Honoraria; Newbridge Pharmaceuticals: Honoraria; Mumbai Hematology Group: Honoraria; Moffit Cancer Center: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Imedex: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Epizyme: Consultancy, Honoraria; Dava Oncology: Honoraria; Clinical Care Options: Honoraria; Chinese Medical Association: Honoraria; CAHON: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Samaniego: Arog: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees. Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flowers: Karyopharm: Consultancy; SeaGen: Consultancy; Genentech/Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Acerta: Research Funding; Biopharma: Consultancy; Genmab: Consultancy; 4D: Research Funding; Denovo: Consultancy; Spectrum: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Epizyme, Inc.: Consultancy; Bayer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; EMD: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-154172

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1776-1776

Abstract: Double hit lymphoma (DHL), defined as aggressive B-cell Lymphoma with MYC and BCL2 or BCL6 rearrangement, is associated with dismal outcomes. We report our experience at MD Anderson Cancer Center over the last 15 years. This retrospective study is to serve as a historical control, and was approved by Institutional Review Board. Method We reviewed medical records of patients (pts) with aggressive B-cell lymphoma diagnosed between 1998 and 2012. DHL was defined by presence of MYC gene rearrangement with IGH gene or amplification, determined by fluorescence in situ hybridization or cytogenetic analysis, in addition to similar genetic abnormality of BCL2. Result We identified an initial group of 56 cases of DHL, diagnosed between 1998 and 2012. Median age was 62 years (range 18-84). Fifty pts (89%) had stage III/IV disease. Serum LDH was elevated in 37 pts (66%). IPI score was ≥3 in 42 pts (75%). Six pts (11%) had a history of low-grade lymphoma prior to the diagnosis of DHL. C-MYC rearrangement and amplification was observed in 51 (91%) and 5 (9%), respectively. BCL2 rearrangement and amplification was observed in 54 (96%) and 2 (4%), respectively. BCL6 rearrangement was tested in 9 cases, and rearrangement was observed in 2 (4%) cases (triple hit). Initial regimens were CHOP±rituximab (R) (n=24, complete response [CR] rate 50%), hyper-CVAD alternating with methotrexate plus cytarabine ± R (n=20, CR rate 68%), EPOCH+R (n=6, CR rate 83%) and others (n=6, CR rate 50%). A total of 32 (57%) pts achieved CR. Median progression free survival duration was 9 months. Median overall survival (OS) duration was 18 months. The 3-year OS rate was 31% for all pts (Figure A), 50% for pts who achieved CR after initial therapy, and 5% for pts who did not achieve CR. Among pts who did not achieve CR, one pt is alive (4%) beyond 2.5 years after proceeding to allogeneic stem cell transplant (allo-SCT) immediately after achieving partial response to initial therapy. In the 6 pts with early stage disease, 5 (83%) achieved CR after initial induction therapy and did not undergo frontline SCT. One of them had recurrent disease and underwent autologous SCT (auto-SCT) but died of disease. One pt who achieved only PR after initial therapy proceeded to allo-SCT, and remains in remission beyond 2.5 years after SCT. Overall, in pts with early stage disease, 3-year OS rate was 75%. In pts with advanced stage disease (n=50), 27 (54%) pts achieved CR. Median OS duration was 13 months. 3-year OS rate was 25%, Among pts achieving CR after initial treatment (n=27), 9 underwent consolidative auto- (n=8) or allo- (n=1) SCT (median age 53, range 34-68) and 18 did not (median 61, range 18-84). Among pts undergoing frontline SCT, only 1 pt has experienced recurrence so far (4 months after auto-SCT) with a median follow up duration 17 months. However, 2 died without disease progression; one with treatment related lung toxicity (1 month post auto-SCT) and one with other comorbidities (14 months after auto-SCT). In pts achieving CR and undergoing frontline SCT, the 3-year OS rate was 66%. In pts achieving CR and not undergoing frontline SCT, the 3-year OS rate was 43%, but the difference was not statistically significant (Figure B. log-rank test 0.87, hazard ratio 0.82 for frontline SCT [95% CI 0.17-3.94, p=0.8)] . Among 10 pts who had transplant for refractory or relapsed disease (auto n=7, allo n=3), one pt who underwent allo-SCT is alive 5 years after transplant. All others (n=9) died of disease. Conclusion DHL is associated with poor outcome, except rare cases with early stage diseases. Particularly those who do not respond to initial chemotherapy have a uniformly dismal prognosis. In our limited experience, pts with recurrence typically do poorly following SCT, except rare cases of “cure” from allo-SCT. Thus, effective initial induction therapy leading to CR seems to be most effective path to the long-term survival. Consolidative frontline SCT, either autologous or allogeneic, in pts responding to the initial treatment may play a role in disease control. But in our small subset of pts, survival curve of pts undergoing frontline SCT was not significantly different from those who did not, affected by death of other cause. Further identification and analysis of additional pts with DHL is ongoing. Moreover, well designed prospective clinical trial with novel therapeutic approach is desired. Disclosures: Off Label Use: sirolimus - mTOR inhibitor vorinostat - HDAC inhibitor.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1776.1776

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1594-1594

Abstract: Introduction: We have previously reported the results of cohort A from a single arm, phase II clinical trial of lenalidomide with rituximab (R2) as frontline treatment for patients with previously untreated follicular lymphoma (FL), Fowler N et al Lancet Oncology 2014. Recent randomized studies (RELEVANCE) did not demonstrate superiority of either R2 or R-Chemo in untreated, high GELF FL, but follow up is short. We now report outcomes of an additional extended dosing cohort (12 mo of R2) and the long term follow up of the both dosing schedules in untreated FL. Methods: A total of 154 pts were included in the original clinical trial (FL, n=80; MZL, n=31; SLL, n=43). Characteristics were collected at the time of starting R2 treatment. Patients received lenalidomide 20 mg/day on days 1-21 of each 28-day cycle and rituximab 375 mg/m2 on day 1 of each cycle (6 cycles; schedule A) and lenalidomide 20 mg/day on days 1-21 of each 28-day cycle for cycles 1-6 then lenalidomide 10 mg/day on days 2-22 for cycles 7-12 with rituximab 375mg/m2 IV x1 weekly on cycle 1 and day 1 of every subsequent cycle (12 cycles; schedule B). Responders continued treatment for at least 6 but up to 12 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were complete and partial response (CR, PR), safety, and progression free survival (PFS). PFS was defined as time from starting treatment to disease progression or death, event free survival included time from starting treatment to discontinuation due to any cause and overall survival (OS) was defined from the time of initial diagnosis of FL to death/last follow up. Results: Eighty pts with FL were enrolled in study and followed a median of 86 months. Median age was 58 years (range, 29 to 84); 50% were males. 61% pts had grade 1 FL and 39% had grade 2 FL. Schedule A was administered in 50 pts and schedule B in 30 pts. Seventy seven pts were evaluable for initial response assessment and 76 (98%) responded. The best response rate was 95% (87% CR/CRu). At the time of last follow up, 23 patients experienced disease progression, 13 lost to follow up (all had CR as best response and had completed tx), 4 came off study due to pt choice/financial and 4 due to intolerance (2 arterio-thrombotic event, 1 respiratory failure, 1 intolerance) during therapy. After a median follow up of 86 mo, 23 pts (29%) progressed, 5 yr PFS was 75%. Five yr PFS was 70% and 82% for pts on cohort A vs B respectively (P=.30). Overall, 2 pts died, with a 5 year survival 97%, Figure-1 (A-B). The median event free survival in pts with FL was 85 months with a 5 year EFS of 59%. Subgroup analysis showed no statistically significant difference in PFS with FLIPI score, bulky disease and by initial bone marrow involvement. Pts who achieved CR had significantly longer PFS compared to those who did not achieve CR (not reached vs 78 months; p = 0.004), however the OS was not significantly different between the two groups Figure-1 (C-F). Grade 3 or 4 hematologic AEs included neutropenia (28%), thrombocytopenia (3%), and no anemia. Count recovery occurred in all pts with follow up and/or dose modification. Nine pts developed second primary cancers, including one melanoma in-situ, 3 localized skin cancers, and 2 secondary hematologic malignancies. Conclusions: A combination of lenalidomide with rituximab produced durable responses in pts with FL. At a follow up of 7 years, the majority of pts remain in remission and patients who achieved CR had the best outcomes. Five year PFS may be longer in pts who received 12mo of therapy, but will need larger analysis to confirm. Further studies are ongoing to analyze mutation dynamics and genomic profile to identify molecular biomarkers. Disclosures Fowler: Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Nastoupil:Novartis: Honoraria; Juno: Honoraria; Gilead: Honoraria; TG Therappeutics: Research Funding; Spectrum: Honoraria; Janssen: Research Funding; Merck: Honoraria, Research Funding; Karus: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Wang:Kite Pharma: Research Funding; Novartis: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding. Samaniego:ADC Therapeutics: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-119592

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 447-447

Abstract: Introduction Given the relapsing nature of indolent non-Hodgkin lymphomas (iNHL), the prolonged natural history suggests many patients will undergo multiple lines of therapy over the course of their disease. Combination approaches with rational selection of synergistic mechanisms of action are desirable to improve outcomes and minimize overlapping toxicity. Rituximab and lenalidomide (R2) has resulted in favorable efficacy and manageable toxicity in phase II and III studies (Fowler et al, Lanc Oncol 2014; Fowler et al, ASCO abstract 2018) in untreated iNHL. Ibrutinib, a BTK inhibitor and active B-cell receptor signaling pathway inhibitor, is an attractive agent to build upon R2 given the therapeutic activity in the microenvironment via enhanced T cell activation and function, reduction in inflammatory cytokines, and diminished interaction with macrophages (Niemann et al, Clin Can Res 2015). We hypothesized that the addition of ibrutinib to R2 (IR2) would result in enhanced efficacy; the concern from the Phase I study was the potential for excess grade 3 rash (Ujjani et al, Blood 2016). In an attempt to reduce the incidence of grade 3 rash observed in the phase 1 study, an alteration in the cycle 1 dose of lenalidomide was done to assess the efficacy and safety of IR2 in untreated follicular (FL) and marginal zone lymphoma (MZL) in an open-label phase II, single center study. Methods In this phase II study, adults with untreated stage II, III, or IV FL (grade 1, 2, or 3a) or MZL, who were in need of therapy, received an initial cycle of lenalidomide 15mg/day (days 1-21 of a 28 day cycle), ibrutinib 560mg/day, and 4 weekly doses of rituximab (375mg/m2). For cycles 2-12, patients received 20mg of lenalidomide on days 1-21, 560mg of ibrutinib daily, and rituximab (375mg/m2) on day 1 of each cycle. The primary endpoint was progression-free survival (PFS) at 2 years. Secondary endpoints include: complete response (CR), partial response (PR), overall response (ORR), duration of response (DOR) and overall survival (OS). Results Forty-eight patients with FL (N=38) and MZL (N=10; nodal MZL N=4; splenic ZML N=3; MALT N=3) were enrolled. Median age was 60 years (range 37-81), 67% were male (N=32), 3 (6%) had stage II disease, 12 (25%) stage III, and the remainder had stage IV disease (69%). With a median follow up of 19 months, the estimated 2 year PFS rate was 76% (95% CI: 60-96%). Among FL patients, the ORR according to Lugano criteria was 97%, with a CR rate of 78%. Among MZL patients, the ORR was 80% with a CR rate of 60%. No deaths have been observed to date. Seven (15%) subjects discontinued therapy due to treatment related adverse events (AEs), 3 due to recurrent grade 3 rash, 2 due to pneumonitis (1 grade 2, 1 grade 3), 1 due to pneumonia (grade 3), and 1 due to ventricular arrhythmia (grade 4). The most common grade ≥3 AEs were rash (46%), neutropenia (15%), and diarrhea (13%). The majority of patients with grade 3 rash were managed with interruption in study drugs and antihistamines with successful re-challenge. The most common grade 2 AEs included fatigue (23%), diarrhea (15%), myalgias (17%), rash and edema (each 10%). One patient experienced atrial fibrillation (grade 2) and 1 had an upper GI bleed (grade 3); both successfully resumed treatment without dose reduction. Correlative and minimal residual disease studies are currently underway and will be presented at the meeting. Conclusions Ibrutinib in combination with rituximab and lenalidomide for untreated FL and MZL was associated with promising efficacy. The toxicity profile was manageable. Modification of lenalidomide dose did not significantly impact the incidence of grade 3 or higher rash. Biomarkers are underway to identify patients most likely to benefit from triplet therapy. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; TG Therappeutics: Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Spectrum: Honoraria; Genentech: Honoraria, Research Funding; Karus: Research Funding; Juno: Honoraria. Westin:Celgen: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Samaniego:ADC Therapeutics: Research Funding. 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; Novartis: Membership on an entity's Board of Directors or advisory committees; 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. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113721

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 96-96

Abstract: Background Axicabtagene ciloleucel (axi-cel) is an autologous CD19-specific CAR T-cell therapy product that was FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy. In the pivotal ZUMA-1 study, the best overall response (ORR) and complete response (CR) rates observed in 108 patients treated with axi-cel were 82% and 58%, respectively. At a median follow-up of 15.4 months, 42% of the patients remain in ongoing response (Neelapu et al. N Eng J Med 2017). Analysis of efficacy outcomes in patients 〈 65 years (N=81) and ³65 years (N=27) showed that the ORR and ongoing response at 12 months were comparable between the two subgroups (Neelapu et al. N Eng J Med 2017). Whether the safety is also comparable between the two subgroups is unknown. Here, we report safety outcomes in elderly patients (³65 years) with large B-cell lymphoma treated with axi-cel at our institution. Methods We retrospectively analyzed and reviewed the data from patients treated with axi-cel at our institution. Patients had a diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and transformed follicular lymphoma (TFL). Patients were treated with conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days followed by axi-cel infusion after 2 days of rest at a dose of 2 x 106 CAR+ T cells/kg body weight. Patients were monitored for toxicities for at least 7 days in the hospital after CAR T infusion and those who had at least 30 days of follow-up after axi-cel were considered to be evaluable for safety. Cytokine release syndrome (CRS) and neurological toxicity termed as CAR-related encephalopathy syndrome (CRES) were graded according to the CARTOX grading system (Neelapu et al. Nat Rev Clin Oncol 2018). Results A total of 61 patients with relapsed or refractory large B-cell lymphoma who received axi-cel at our institution were included. Of these, 44 (72%) patients were 〈 65 years of age and 17 (28%) patients were ³65 years of age. The baseline characteristics of the patients are summarized in Table 1. ORR and CR rates at Day 30 were comparable between the two groups. CRS was common in both groups and was observed in 83% and 91% of the patients in the older and younger age groups, respectively. But most CRS events were grade 1-2. Grade 3 or higher CRS was observed in 18% vs. 11% in the older vs. younger age groups (P=0.67). One patient with a history of autoimmune disease in the elderly group died of hemophagocytic lymphohistiocytosis (HLH). CRES was observed in 58% and 71% of the patients in the older and younger age groups, respectively. Grade 3 or higher CRES was observed in 29% vs. 39% in the older vs. younger age groups (P=0.58). Median hospitalization period for axi-cel CAR T-cell therapy was comparable between the two groups. Conclusions Our results suggest that response rates are comparable between the elderly and younger age groups at day 30 after axi-cel therapy. Importantly, toxicities due to CRS and/or CRES after axi-cel CD19 CAR T cell therapy are comparable between the elderly (³65 years) and younger ( 〈 65 years) patients with relapsed or refractory large B-cell lymphoma. Table 1 Table 1. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; Juno: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Samaniego:ADC Therapeutics: Research Funding. Wang:Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-120013

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1609-1609

Abstract: Introduction: Commercially available chimeric antigen receptor (CAR) T-cell therapy has improved the outcomes for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma. Many pts have highly symptomatic, rapidly progressive disease that untreated could be fatal during the 3-4 week manufacturing interval. We examined the outcomes of pts treated with axicabtagene ciloleucel (axi-cel) and bridging interventions, including systemic therapy (ST) and radiation therapy (RT). Methods: We reviewed clinical efficacy and toxicity outcomes for 80 pts who underwent apheresis for axi-cel therapy between 12/2017 and 1/2019 at a single institution. Disease specific survival (DSS), progression free survival (PFS), toxicity free survival (TFS) and overall survival (OS) were defined from the date of CAR T-cell infusion. For the pts who received bridging treatment (defined as therapy given between apheresis and CAR T cell infusion), baseline clinical, treatment and toxicity characteristics were compared between cohorts that received ST versus RT. All comparisons were 2 sided. Results: Of the 80 pts who underwent apheresis, 73 (91%) received CAR T-cell therapy. Among these 73, 32 (44%) received bridging therapy and 41 (56%) did not. Pts who received bridging therapy were more likely to have an IPI of ≥3 at the time of apheresis (72%) compared to those that did not (39%; p=0.009). Of the 32 pts who received bridging therapy, 24 (75%) were treated with ST (corticosteroids [n=3], targeted therapy [n=4] and chemotherapy [n=17]) and 8 (25%) with RT. RT was administered to a median dose of 44.6 Gy (range 9-46 Gy) with a median fraction size of 2.5 Gy (range 1.8 -3 Gy). The median time between the end of RT and the CAR T-cell infusion was 16 days (range 0 -21). The median age of the entire bridging therapy cohort was 59 (range 24 - 85 years). Twenty five pts (78%) were male, 23 had DLBCL (72%). Comparing the ST (n=24) to the RT (n=8) cohort, there were no differences in ECOG PS ≥2 (p=0.296), IPI of ≥3 (p=0.654), double hit or triple hit status by IHC (p=0.378) or FISH (p=0.578), bulky disease (≥10 cm, p=1.0), or elevated LDH at the time of apheresis (p=1.0). Upon completion of bridging therapy, cytopenias requiring G-CSF administration prior to initiation of fludarabine/cyclophosphamide conditioning occurred in 18 pts with no difference between ST and RT cohorts (p=0.252). The median WBC and absolute lymphocyte count after bridging therapy and just prior to conditioning was 5.3 K/uL (range 1.5 -20.6) and 0.59 K/uL (range 0.07 - 1.9) respectively and was not statistically different between the ST and RT cohorts (p=0.851 and p=0.317). Twenty pts (62.5%) required G-CSF ≥ 14 days post CAR-T cell therapy infusion and did not differ between the groups (p=1.00). Rates of grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (ICANS) were 25% in the RT cohort and 63% in the ST group (p=0.106). Rates of grade ≥ 3 cytokine release syndrome (CRS) were 12.5% in the RT cohort compared to 16.7% among ST treated bridging patients (p=1.00). Rates of ICU admission were not significantly different between the groups (p=0.423). At a median follow up of 6.1 months (95% CI 4.0 - 6.9), there have been 13 deaths; the median OS for the entire bridging cohort has not been reached. Five deaths occurred due to toxicity (5/24 in the ST cohort and 0/8 in the RT group, p=0.296) as a result of infectious complications (n=3), ICANS (n=1) and hemophagocytic lymphohistiocytosis (HLH, n=1). Eight deaths occurred due to lymphoma (6/24 in the ST cohort and 2/8 in the RT cohort, p=1.00). For the entire bridging group of 32 pts, 13 experienced lymphoma progression with a median DSS of 4.4 months. The median DSS was 4.43 months among the ST cohort and not reached in the RT cohort (p=0.644). The PFS was 3.5 months for all bridging pts with a median PFS of 3.5 months among the ST treated pts and not reached for the RT pts (p=0.314). Conclusion: Bridging therapy is often utilized at physician discretion to temporize aggressive disease and facilitate successful CAR T-cell infusion. In this single institutional study, judicious use of bridging therapy permitted 91% of patients to undergo CAR-T cell infusion. This preliminary data suggests that RT can be an effective bridging tool for pts with R/R large B cell lymphoma prior to axi-cel therapy. Larger cohorts are required to determine if RT bridging strategies may result in lower rates of treatment related mortality and improved disease control. Figure Disclosures Pinnix: MD Anderson Cancer Center: Employment; Merck and Company: Research Funding; International Journal of Radiation Oncology Biology and Physics: Honoraria; Global Oncology One: Consultancy. Hawkins:Novartis Pharmaceuticals: Other: advisory panels. Westin:Curis: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Unum: Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding. Fowler:Abbvie: 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; Celgene: 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; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Iyer:Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Genentech/Roche: Research Funding; Arog: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Kite Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Juno Therapeutics: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Aviara: Research Funding; BeiGene: Research Funding; Loxo Oncology: Research Funding. Neelapu:Poseida: Research Funding; Cell Medica: Consultancy; Precision Biosciences: Consultancy; Celgene: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS: Research Funding; Acerta: Research Funding; Incyte: Consultancy; Novartis: Consultancy; Karus: Research Funding; Cellectis: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Allogene: Consultancy. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-131499

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 147-147

Abstract: Introduction: Mantle cell lymphoma (MCL) is a rare and incurable subtype of B-cell lymphoma. Intense chemo-immunotherapy with 8 cycles of Rituximab-HyperCVAD alternating with Rituximab-Methotrexate-Ara C is associated with an overall survival of 10.7 years but the 10-year cumulative incidence of therapy-related myeloid neoplasm was 6.2%. The ibrutinib-rituximab combination has produced durable responses in 88% of patients with relapsed and refractory MCL with acceptable toxicity. This gives rise to a "Window" of opportunity to use chemotherapy-free induction with ibrutinib plus rituximab followed by fewer cycles of chemo-immunotherapy consolidation in young and fit patients with newly-diagnosed, untreated MCL. Methods: Enrolment began in June 2015 for a Phase II single-center clinical trial consisting of an initial chemotherapy-free phase (window) of ibrutinib and rituximab combination treatment in Part 1 until best response, followed by a shortened course of intense chemo-immunotherapy in Part 2 among young newly diagnosed MCL patients of ≤65 years. The primary objective was to evaluate the response rate of ibrutinib plus rituximab. The secondary objectives were to evaluate the progression free survival (PFS) of ibrutinib plus rituximab after consolidation with a shortened number of cycles of intense chemo-immunotherapy, and to further evaluate the toxicity profile. Ibrutinib is dosed at 560 mg orally, daily, continuously. Rituximab is dosed at 375 mg/m2 IV weekly x 4 during cycle 1 (28 days cycle), then day 1 of cycles 3-12. Intense chemo-immunotherapy consists of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD); alternating every 28 days with rituximab plus high-dose methotrexate-Ara C. If in complete remission (CR) after initial ibrutinib and rituximab treatment, a total of 4 additional treatments of intense chemo-immunotherapy are given. If the patient is in partial response or progression, and if responding to intensive chemo-immunotherapy, a total of 2 cycles of chemo-immunotherapy therapy are administered beyond achievement of CR. Results: As of August 2, 2016, we have completed the target enrolment by accruing 50 out 50 patients with newly-diagnosed untreated MCL. Forty one (n=41) patients have begun treatment and 36 are evaluable for response. Of the 36 evaluable patients, overall response rate (ORR) to Part 1 alone (Ibrutinib plus rituximab) is 100% (n=36) with PR in 28% (n=10) and CR in 72% (n=20). Nineteen 19 patients have completed both Part 1 (ibrutinib and rituximab) and Part 2 (chemo-immunotherapy). The ORR to both Part 1 and Part 2 (n=19) was 100% and was equal to the CR rate (100%, n=19), i.e. all have achieved a CR to Part 1 and Part 2. Toxicities are recorded as the number of patients experiencing a certain adverse event. Regardless of their relation to study drug in Part 1, the most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=40), diarrhea (n=25), rash (n=24), myalgia (n=22), oral mucositis (n=17), peripheral neuropathy (n=15), nausea (n=14), blurred vision (n=14), edema (n=13), constipation (n=12), headache (n=11), dry eyes (n=9), dizziness (n=9) and watery eyes (n=6). Grade 3 non-heme AEs included fatigue (n=3), nausea (n=0), rash (n=1), pleural effusion (n=1), infection (n=2) and dyspnea (n=1). There was no grade 4 or grade 5 non-heme toxicities in Part 1. In part 2, common grade 1-2 hematological (heme) AEs was anemia (n=13). Grade 3-4 haematological AEs included neutropenia (n=2), ALT increase (n=1) and febrile neutropenia (n=1). In Part 2, there was no grade 5 hematologic toxicity. The toxicity after intensive immune-chemotherapy in shortened cycles are much improved compared to historical controls but longer follow-up is needed. Conclusions: Preliminary data indicate that the chemotherapy-free induction with ibrutinib and rituximab in newly diagnosed, young MCL patients was efficacious and well-tolerated. This unprecedented efficacy and safety may provide a window of opportunity for less chemo-immunotherapy needed for consolidation. Table Preliminary findings form the Window Study: a phase II clinical trial Table. Preliminary findings form the Window Study: a phase II clinical trial Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.147.147

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cancer, Wiley, Vol. 122, No. 20 ( 2016-10-15), p. 3145-3151

Abstract: Very elderly fit patients (age ≥ 80 years) have survival outcomes similar to those of younger patients with standard‐dose anthracycline‐based regimens. Patient education and close monitoring with sufficient supportive therapy during treatment are imperative for preventing treatment‐related mortality.

Type of Medium: Online Resource

ISSN: 0008-543X , 1097-0142

URL: Issue

URL: Article

DOI: 10.1002/cncr.v122.20

DOI: 10.1002/cncr.30173

Language: English

Publisher: Wiley

Publication Date: 2016

detail.hit.zdb_id: 1479932-7

detail.hit.zdb_id: 2599218-1

detail.hit.zdb_id: 2594979-2

detail.hit.zdb_id: 1429-1

In: PLOS ONE, Public Library of Science (PLoS), Vol. 13, No. 3 ( 2018-3-14), p. e0191461-

Type of Medium: Online Resource

ISSN: 1932-6203

URL: Article

URL: Article

URL: Article

URL: Article

URL: Article

URL: Article

URL: Article

DOI: 10.1371/journal.pone.0191461

DOI: 10.1371/journal.pone.0191461.g001

DOI: 10.1371/journal.pone.0191461.g002

DOI: 10.1371/journal.pone.0191461.g003

DOI: 10.1371/journal.pone.0191461.t001

DOI: 10.1371/journal.pone.0191461.s001

DOI: 10.1371/journal.pone.0191461.s002

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2018

detail.hit.zdb_id: 2267670-3

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 13, No. 2 ( 2013-04), p. 99-105

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2012.11.002

Language: English

Publisher: Elsevier BV

Publication Date: 2013

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3