Outcomes for Patients with Primary or Secondary Central System Lymphoma Treated with Ibrutinib: A Multicentre Retrospective Analysis

Background Primary and secondary central nervous system lymphoma (PCNSL/SCNSL) are rare brain malignancies with an aggressive clinical course and dismal outcomes. The BTK inhibitor ibrutinib has activity in a range of B-cell lymphomas. Phase I and II studies of ibrutinib monotherapy in relapsed/refractory PCNSL have demonstrated promising results, with response rates of up to 81%. Response rates of up to 69% have also been seen in SCNSL. Ibrutinib has been combined with other systemic agents (e.g. rituximab and methotrexate) in phase 1 trials with promising results (Grommes et al Blood 2019); combination with more intensive combination chemotherapy regimens also appears efficacious but has exhibited a potentially limiting toxicity profile, in particular invasive fungal infections. (Lionakis et al Cancer Cell 2017). However, data for ibrutinib in PCNSL and SCNSL outside the clinical trial setting are scarce. Methods We performed a national, multicentre, retrospective study of the clinical outcomes and safety of patients (pts) with PCNSL and SCNSL who received ibrutinib between December 2015 and June 2019. Results The baseline characteristics of the 16 eligible pts are summarised in the table (Figure 1a). 88% (n=14) had relapsed/refractory disease, with two patients receiving ibrutinib as a component of multiagent frontline therapy. The most common target daily dose was 560mg (range 420-840mg); this was reached in all pts. Among all pts, the objective response rate (ORR) was 69%, with a complete remission (CR) rate of 63%. Both patients receiving ibrutinib in combination frontline therapy achieved a CR. ORR in PCNSL pts was 50% (n=4) and SCNSL pts was 88% (n=7), (P=0.28). ORR was 80% (n=4) when ibrutinib was administered as monotherapy, 80% (n=4) when administered with chemotherapy and 75% (n=3) when administered concomitant with whole brain radiotherapy. MYD88L265P mutation at time of starting ibrutinib was only tested in two patients with PCNSL and none with SCNSL. The mutation was detected in both PCNSL cases, and both later attained a CR. With a median follow up of 14 months, calculated using median observation period among patients alive at last follow-up, median progression free survival (PFS) and overall survival (OS) were not reached. 12 month PFS was 56% for the entire cohort (95% confidence interval [CI] 29-76); 50% for PCNSL (95% CI 15-77) and 60% for SCNSL (95% CI 20-85%) (Figure 1b). 12 month OS was 66% for the entire cohort (95% CI 36-85) ; 50% for PCNSL (95% CI 15-77) and 80% for SCNSL (95% CI 20-97%) (Figure 1c). Ten pts had PFS >6 months (longest 41.3 months), and 11 pts (69%) remained alive, with 9/11 being free from disease progression. Seven pts remain on ibrutinib at time of data analysis, 3 with PCNSL and 4 with SCNSL. Nine pts (56%) have discontinued therapy; 6 due to progressive disease (PD), 1 due to atrial fibrillation with hypotension requiring inotropic support and 2 in remission, one of whom subsequently underwent autologous stem cell transplant. Dose interruptions or reductions were required in 6 pts (37%), due to bleeding (n=2), infection (n=3) and neutropenia (n=1). Grade 3/4 adverse events were infection (31%, n=5), neutropenia (25%, n=4), febrile neutropenia (12%, n=2) and one each (6%, n=1) of atrial fibrillation, thrombocytopenia, and anaemia. No invasive fungal infections were observed, despite use of 8-16mg daily dexamethasone immediately prior to or during ibrutinib therapy in 10 pts (62%). Conclusions In this small real-world, majority methotrexate-refractory population, ibrutinib demonstrates encouraging efficacy and durable responses despite doses lower than used in clinical trials. No unexpected adverse events were observed. Invasive fungal infections were not seen, despite most patients receiving concurrent dexamethasone and/or chemotherapy. We observed substantial variety in additional therapy during ibrutinib treatment, and the optimal way to use ibrutinib in this heterogenous patient group remains unclear. Disclosures Manos: NovoNordisk Pharmaceuticals: Other: Travel; Janssen: Honoraria. Ho:Celgene: Consultancy, Other: Advisory role. Grigg:Abbvie: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel. Gandhi:Amgen: Honoraria; Bristol Myers Squibb: 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; Gilead: Honoraria, Research Funding; Roche: Honoraria, Other: Travel Support; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Hawkes:Astra Zeneca: Research Funding; Mundi pharma: Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Merck Sharpe & Dohme: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding, Speakers Bureau. Cheah:Roche: Other: Travel expenses; Roche, Janssen, MSD, Gilead, Loxo Oncology, AstraZeneca, TG Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Roche, Abbvie: Research Funding. OffLabel Disclosure: Ibrutinib is not currently approved for use in DLBCL/CNS lymphoma.

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A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Blood ◽

10.1182/blood-2019-131045 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 348-348 ◽

Cited By ~ 6

Author(s):

Nathan H Fowler ◽

Loretta J. Nastoupil ◽

Collin Chin ◽

Paolo Strati ◽

Fredrick B. Hagemeister ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Advisory Board ◽

Indolent Lymphoma ◽

Advisory Committees ◽

Grade 3

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

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The Use of Venetoclax for Acute Myeloid Leukemia in a Real-Life Setting: A Multicenter National Experience

Blood ◽

10.1182/blood-2019-128583 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5098-5098

Author(s):

Jacopo Nanni ◽

Giacomo Gianfaldoni ◽

Gianluca Cristiano ◽

Giovanni Marconi ◽

Matteo Piccini ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Real Life ◽

Advisory Committees ◽

The Real ◽

Real Life Setting ◽

Treatment Naïve ◽

Grade Iii

Background The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor venetoclax has shown strong activity in R/R AML in controlled clinical trials, and recently impressive results in treatment-naïve AML elderly patients with acute myeloid leukemia. However, limited data are available in the real-life setting. Methods This is a multi-center (n=4), retrospective study involving patients with treatment-naïve or Relapsed/Refractory (R/R) AML treated with Venetoclax in combination with HMAs. Data were collected after anonymous aggregation, in accordance with GCP and Helsinky declaration. Adverse events (AEs) were graded according CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results Forty-four patients have been prescribed Venetoclax from March 2018 to June 2019 and completed at least 1 course of venetoclax (range 1-8, median 2, IQR 2.0 - 4.0), being evaluable in this analysis. Patients's characteristics are summarized in Table 1. Five/44 (11.4%) patients had a low risk AML, 21/44 (47.7%) had an intermediate risk AML and 14/44 (31.8%) patients had a high risk AML, according to ELN 2017 risk stratification (4 patients had no available ELN risk at baseline). Six out of 44 (13.6%) patients received Venetoclax in combination with HMAs as first line of therapy, whereas 14/44 (31%) as first line rescue for resistant AML, 15/44 (34.1%) at first relapse, 9/44 (20.5%) for second or further R/R AML. Among R/R patients who received Venetoclax, 17/38 (44.7%) and 21/38 (55.2 %) had received chemotherapy or HMAs as induction therapy, respectively. Overall, Venetoclax was combined with azacitidine in 19/44 patients (43.2%), with decitabine in 19/44 patients (43.2%), with Low-dose of Cytarabine in 5/44 (11.4%), and was performed in monotherapy in 1/44 (2.3%) patient. Three out of 44 patients (6.8%) received a maximum dosage of 100 mg daily, 2/44 (4.5%) received 200 mg, 37/44 (84.1%) received 400mg and 2/44 (4.5%) received 600 mg. Fifteen out of 44 (34.1%) patients reduced the dosage of venetoclax for concomitant Azole administration. The median follow-up is 75.5 (IQR 45.2 - 178.5) days for patients who received upfront venetoclax therapy, while 143 (IQR 49.2 - 235.7) days for R/R patients. In the first-line setting, no patients reduced venetoclax dosage for concomitant adverse events; two neutropenia grade IV and two thrombocytopenia grade III have been documented. In the R/R setting, 14/38 (36.6%) patients reduced venetoclax dosage for concomitant adverse events. Specifically, we reported 22 adverse events, of which 10 were grade III-IV (5 neutropenia grade IV, 2 pancytopenia grade IV, 1 neutropenia grade III and 2 febrile neutropenia grade III). The overall CR rate is 16.7 % in newly-onset AML patients and 28.9 % in R/R patients, respectively. Two out of 6 treatment-naive patients had an evaluable response at 2 months after the beginning of Venetoclax treatment, and 2/6 had an evaluable 4-months response: 1 stable disease (SD) and 1 disease progression (PD) at 2 months,1 SD e 1 complete remission (CR )at 4 months. Thirty-one out of 38 R/R patients had an evaluable response at 2 months and 21/38 had an evaluable 4-month response: 10 CR, 1 complete response with incomplete hematologic recovery (CRi), 14 SD and 6 PD at 2 months; 6 CR, 10 SD and 3 PD at 4 months have been documented. After a short follow-up period (75.5 days), no patients who received Venetoclax as upfront therapy underwent an allogeneic hematopoietic stem cell transplantation (HSCT). On the other hand, after a longer follow-up period (143 days), 5 out of 38 patients (13.2%) received a HSCT after Venetoclax therapy among R/R patients. Median Overall Survival was not reached in the newly-onset cohort. In R/R setting, median OS was 253 days (95% C.I. 157-349). Interpretation These data extend to the real-life setting some previous evidence obtained from trials. In particular, our data confirm that venetoclax plus HMAs or LDAC has an acceptable toxicity profile and is safe and manageable. However, especially in the R/R setting, hematological toxicity represents the most frequent adverse event, arising some concerns about the optimal drugs management. Although our data suggest a similar clinical activity of venetoclax combinations to that reported in clinical trials, further studies from the real-life setting are highly warranted to confirm venetoclax efficacy under normal clinical practice. GG and JN equally contributed CP and AC equally contributed Disclosures Boccadoro: Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: 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. Papayannidis:Shire: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Teva: Honoraria. OffLabel Disclosure: Venetoclax is not approved to treat Acute Myeloid Leukemia in Italy

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Clinical Features, Treatments and Outcomes of HIV-Associated Diffuse Large B-Cell Lymphoma: A Single-Center Experience

Blood ◽

10.1182/blood-2020-143253 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-20

Author(s):

Tylan Magnusson ◽

Greer Burkholder ◽

Nathan Erdmann ◽

Amitkumar Mehta ◽

Mayur Narkhede ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Cd4 Count ◽

Advisory Committees ◽

Entire Cohort ◽

Large B Cell Lymphoma ◽

Extranodal Disease ◽

Hiv Negative

INTRODUCTION Recent studies have suggested that the prognosis of HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) may be improving with advances in anti-retroviral therapies (ART). A pooled analysis of clinical trial data showed that EPOCH may be associated with superior outcomes as compared to CHOP (Barta et al. Blood. 2013), but about two-third of patients in the combined analysis were treated without rituximab. A recent French study, however, showed similar overall survival (OS) between R-CHOP and R-EPOCH treated patients (Besson et al. AIDS 2017) and a phase III trial showed similar efficacy of R-CHOP vs. R-EPOCH in HIV-uninfected DLBCL (Bartlett et al. JCO 2019). The optimum frontline therapy in HIV-DLBCL is unknown as most clinical trials exclude HIV-infected patients or restrict accrual to those with undetectable HIV viral load and minimum CD4 count cut-off. Moreover, most existing studies include a majority (>60%) Caucasian population, and there is a paucity of studies on outcomes in African-American population. In this retrospective study, we describe the clinical features and outcomes of HIV-DLBCL patients seen at our institution and compare them with HIV negative DLBCL patients. METHODS We conducted a retrospective review of HIV+ DLBCL cases diagnosed and treated at our institution from 2008-2020. We used the Kaplan-Meier method to assess overall survival (OS). Univariate and multivariate analyses were performed to assess prognostic factors. HIV-DLBCL patients were matched 1:2 with HIV negative DLBCL by age and stage of lymphoma at diagnosis. Comparison of OS analysis was conducted using log-rank method and predictors of progression or death using Cox proportional hazards regression. RESULTS We included a total of 33 patients with HIV-DLBCL in our study. Median age was 46.6 years (IQR 40-53.3), 25 (76%) were males, and 20 (61%) were African-Americans (Table). 28 (85%) patients had stage III/IV and 24 (73%) had extranodal disease at diagnosis. The median CD4 count at diagnosis was 252 (IQR 89.5-409). 6 (18%) had CNS involvement at diagnosis, for which the median OS was 8.3 months. First-line treatment included rituximab-chemotherapy combinations in 25 (76%) patients. All patients continued ART during first line treatment. Median follow up duration of the entire cohort was 2.06 years (IQR 0.53-5.02 years) and 5 (15.2%) were lost to follow up. The 2-year OS for R-CHOP treated patients was 63% vs. 38% for R-EPOCH treated patients, although this failed to reach statistical significance (p=0.125). On multivariate analysis, the only factor significantly associated with difference in event free survival (EFS; progression or death) was female sex (HR 19.86; [2.652-148.7]; p=0.004). Trends were seen towards shorter EFS among patients who were tobacco smokers at time of DLBCL diagnosis (HR 2.69; 0.463-15.6]; p=0.271), CD4+ count <200 at time of DLBCL diagnosis (HR 2.39; [0.519-11.0]; p=0.264), IPI score >3 (HR 2.98; [0.480-18.5]; p=0.241), and presence of MYC gene rearrangement (HR 3.93; [0.569-27.2]; p=0.165). Treatment type (R-CHOP, R-EPOCH), ART use prior to lymphoma diagnosis, race, and insurance status were not correlated with EFS. 11 (33.3%) patients died within 1 year of diagnosis. The 2-year OS for the entire cohort was 64% vs. 68% in matched HIV-negative DLBCL patients (p=0.651). Median OS for HIV+ patients was 2.14 years (IQR 0.23-5.77) vs 2.97 years (IQR 0.76-6.48) in matched HIV-negative DLBCL patients (p=0.3996). One patient died from acute hypoxemic respiratory failure prior to starting treatment. Four patients died of complications during their first inpatient chemotherapy administration. CONCLUSION In our cohort, most HIV-DLBCL patients were African-Americans, presented with advanced stage and extranodal disease. The survival of HIV-associated DLBCL was similar to HIV-negative counterparts. All HIV-DLBCL continued ART during chemotherapy, suggesting the feasibility of this approach. There was no difference in OS between patients treated with R-CHOP vs. R-EPOCH, however there was a trend towards increased OS in patients treated with R-CHOP. CNS involvement at diagnosis was frequently seen. Despite limited sample size, we observed a significant association with gender, and a trend toward significant factors including tobacco use and low CD4 count at time of diagnosis. Disclosures Mehta: TG Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Merck:Research Funding;Roche-Genentech:Research Funding;Kite/Gilead:Research Funding;Innate Pharmaceuticals:Research Funding;Seattle Genetics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Oncotartis:Research Funding;Gelgene/BMS:Research Funding;Juno Parmaceuticals/BMS:Research Funding;fortyseven Inc/Gilead:Research Funding;Takeda:Research Funding;Incyte:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Affimed:Research Funding.

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The Impact of Atrial Fibrillation on Subsequent Survival of Patients Receiving Ibrutinib As Treatment of Chronic Lymphocytic Leukemia (CLL): An International Study

Blood ◽

10.1182/blood.v128.22.3242.3242 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3242-3242 ◽

Cited By ~ 6

Author(s):

Philip A Thompson ◽

Vincent Levy ◽

Constantine S. Tam ◽

Chadi al Nawakil ◽

Francois Xavier Goudot ◽

...

Keyword(s):

Atrial Fibrillation ◽

Overall Survival ◽

Ischemic Stroke ◽

Board Of Directors ◽

Cardiac Failure ◽

Research Funding ◽

Pulmonary Hemorrhage ◽

Bleeding Events ◽

Advisory Committees

Abstract Introduction Atrial fibrillation (AF) occurs in 5-9% of patients treated with ibrutinib for CLL. We previously reported on the clinical characteristics and management outcomes of 56 patients with ibrutinib-associated AF (n=52) or atrial flutter (n=4) retrospectively identified from centers of the FILO group (French Innovative Leukemia Organization, France/Belgium, n=29), MD Anderson Cancer Center (USA, n=21), and Peter MacCallum Cancer Centre (Australia, n=6) (Thompson et al BJH 2016). We found that (1) the median time from the initiation of ibrutinib to AF was 3.8 months (range: 6 - 1410 days); (2) AF recurred or became persistent in 63% despite medical management; (3) AF and its management was associated with serious sequelae including severe cardiac failure (n=3, 1 fatal), ischemic stroke (n=3) and severe bleeding events (n=8); (4) immediate cessation of ibrutinib therapy was required in 22/56 (39%). Given the reported poor outcomes for patients who discontinue ibrutinib for toxicity, we update the results of this cohort with respect to CLL outcomes and survival. Aim To describe long term overall and disease-specific outcomes in patients who develop ibrutinib-associated AF. Methods This is an update of an international, retrospective cohort of patients who developed ibrutinib-associated AF. Patients are managed according to local best standard practice. The median follow-up from onset of AF is 21 months. Results The median overall survival after development of AF is 43 months. Twenty-two (39%) patients stopped ibrutinib at the time of AF. Among these patients, 7 (32%) eventually died from CLL progression (n=3), infection (1), cardiac failure (1), pulmonary hemorrhage (1) and colon cancer (1). Of the 34 patients who initially continued ibrutinib, 5 (15%) died; causes of death were: Richter transformation (RT) (n=2), septic shock (1), CLL progression (1), and stroke in the context of AF (1). In order to gain insight into disease control in relationship to AF and its management, we examined PFS from the time of AF onset. The following features had no impact on PFS: single AF episode vs paroxysmal/permanent AF or time from ibrutinib initiation to onset of AF. However, patients who had ibrutinib interrupted at the time of AF onset (n=22) had a significantly inferior PFS (median 19 months) compared with those who had dose reduction without interruption (n=13) or those who continued full dose ibrutinib (n=21, median 27 months, p=0.023, Figure 1). There was a trend toward inferior overall survival in those who interrupted ibrutinib (62% at 3 years) compared with those who continued without interruption (74% at 3 years, p=0.10), but this did not reach statistical significance at the time of analysis. Only 3 of 22 (14%) patients who had initial interruption of ibrutinib successfully restarted ibrutinib following control of AF; all 3 remain in continuous partial remission. Four other patients restarted ibrutinib, but subsequently discontinued due to pulmonary hemorrhage (n=1), stroke (1), CLL progression (1) and RT (1). Among patients who discontinued Ibrutinib permanently, only 9 did so solely because of uncomplicated AF. The others discontinued because of: (a) complications of AF or its management such as cardiac failure (n=1), recurrent AF (n=5) and bleeding events (n=4; one each of hemopericardium, pulmonary hemorrhage, subdural hematoma and gastrointestinal hemorrhage); (b) complications related to CLL such as CLL progression (n=1) and RT (n=2); or (c) other causes such as lung cancer (n=1) or unknown reasons (n=2). Altogether, 21 patients were still on Ibrutinib among 44 patients alive at last follow-up. Conclusion Occurrence of AF at any time during ibrutinib treatment was associated with an initial discontinuation rate of 39%, and only 37.5% of patients remain alive and on drug after a median of 21 months follow-up. Patients who interrupted ibrutinib at the time of AF onset have an inferior PFS compared to those who continued ibrutinib or were managed with dose reductions. This inferior outcome in CLL control is likely related to the low rate of patients (14%) who subsequently successfully restarted ibrutinib. Development of AF was associated with serious complications, including hemorrhage, ischemic stroke and cardiac failure. Management of ibrutinib-associated AF is complex and requires international consensus guidelines and a multidisciplinary approach. Figure 1 Figure 1. Disclosures Thompson: Pharmacyclics: Consultancy, Honoraria. Levy:Abbive: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Tam:janssen: Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Quinquenel:janssen: Honoraria, Research Funding. Dupuis:ABBVIE: Membership on an entity's Board of Directors or advisory committees; janssen: Honoraria. Cymbalista:Roche: Honoraria; Abbvie: Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Research Funding.

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Antifungal Prophylaxis: Impact on Outcomes of Newly Diagnosed AML Patients Treated with a Hypomethylating Agent and Venetoclax

Blood ◽

10.1182/blood-2021-148717 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4126-4126

Author(s):

Evan C. Chen ◽

Yiwen Liu ◽

Eric S. Winer ◽

Marlise R. Luskin ◽

Martha Wadleigh ◽

...

Keyword(s):

Fungal Infection ◽

Board Of Directors ◽

Research Funding ◽

Fungal Infections ◽

Hematologic Malignancy ◽

Antifungal Prophylaxis ◽

Newly Diagnosed ◽

Advisory Committees ◽

Entire Cohort ◽

Hypomethylating Agent

Abstract Introduction: The Phase 3 VIALE-A study established the combination of venetoclax and a hypomethylating agent (VEN/HMA) as a new standard of care option for acute myeloid leukemia (AML) patients who are ineligible for intensive chemotherapy due to age (≥ 75 years) or comorbidities. The NCCN recommends antifungal prophylaxis (AFP) for relapsed/refractory AML patients receiving VEN/HMA, but its role in newly diagnosed AML patients treated with VEN/HMA remains controversial. Additionally, the impact of VEN dose-reduction due to concomitant azole use on AML outcomes and rates of fungal infection remains unclear. We evaluated the pattern of AFP use and its association with infectious and AML outcomes in patients receiving VEN/HMA at our institution. Methods: Consecutive patients aged ≥18 who received frontline VEN/HMA for newly diagnosed AML at the Dana-Farber Cancer Institute between 2016-2021 were identified in the Hematologic Malignancy Data Repository for retrospective chart review. Antibacterial and antifungal prophylaxis use at any time during VEN/HMA therapy and reasons for hospitalizations were recorded. Invasive fungal infections (IFIs) were adjudicated as "possible," "probable," or "proven" according to consensus guidelines (Donnelly, Clin Infect Dis 2020). Rates of complete remission (CR) and CR with incomplete hematologic recovery (CRi) per European LeukemiaNet (ELN) criteria were determined. Descriptive statistics on patient characteristics were compared between groups via nonparametric testing including Wilcoxon rank-sum, chi-squared, and the Fisher's Exact tests. Overall survival (OS) was estimated using the method of Kaplan and Meier, and log-rank tests were used to compare survival between groups. Multivariable Cox proportional-hazards models were used to obtain hazard ratios between groups. Results: 131 patients met inclusion criteria, of which 22 patients (16%) received AFP at any time. For the entire cohort, the median age at AML diagnosis was 72 (range 22-89), and the majority of patients were <75 years old (66%), had ELN adverse risk (70%), and had secondary AML (sAML)/sAML-like disease (73%; "sAML-like" defined per Lindsley, Blood 2015). Frequently mutated genes include TP53 (37%), ASXL1 (22%), and RUNX1 (19%). These baseline characteristics did not differ between patients who did and did not receive AFP. However, compared to patients who never received AFP, patients receiving AFP at any time were more likely to have received HMA therapy for an antecedent hematologic malignancy (41% vs. 13%, p=0.004) and concomitant antibacterial prophylaxis at any time (82% vs. 54%, p=0.016). Among the 171 hospitalizations that occurred in 90/131 patients, bacterial infection was suspected or identified in 139 admissions, and possible/probable/proven IFIs were identified in 21. Receiving AFP prior to admission was not associated with fewer hospitalizations in which an IFI was suspected or identified (Table, p=0.36). 3/21 IFIs were deemed "probable" or "proven." All 21 IFIs prompted antifungal therapy. No patient experienced more than one hospitalization involving an IFI. After a median of two cycles (range 1-15), best response (CR/CRi) for the entire cohort was 49%. Receiving AFP at any time was associated with lower CR/CRi than never receiving AFP (57% vs. 32%, p=0.014). The median OS for the entire cohort was 11.0 months (95% CI 8.8-14.6) and did not differ based on AFP use (11.9 months for patients without AFP, 8.1 months for those receiving AFP; p=0.23). In a multivariable model that included patient age, ELN risk, and AML ontogeny, AFP use was not significantly associated with OS (HR 1.40, p=0.22). Conclusion: AFP use and incidence of invasive fungal infection were overall low at our institution. Receiving AFP was not associated with improved OS nor with decreased number of hospitalizations for a suspected or confirmed IFI. At an institution where the incidence of fungal infections is low, there is presently no clear role for antifungal prophylaxis in newly-diagnosed AML patients receiving HMA with venetoclax. Figure 1 Figure 1. Disclosures Winer: Takeda: Consultancy; Novartis: Consultancy; Abbvie: Consultancy. Lane: AbbVie: Research Funding; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; N-of-One: Consultancy, Honoraria. Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Other: Stock ownership. DeAngelo: Blueprint Medicines Corporation: Consultancy; Takeda: Consultancy; GlycoMimetics: Research Funding; Autolus: Consultancy; Abbvie: Research Funding; Shire: Consultancy; Amgen: Consultancy; Agios: Consultancy; Forty-Seven: Consultancy; Pfizer: Consultancy; Incyte Corporation: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding. Stone: Syros: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; GlaxoSmithKline: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Aprea: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Janssen: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Foghorn Therapeutics: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Boston Pharmaceuticals: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Celgene: Consultancy; Macrogenics: Consultancy. Garcia: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

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Long-Term Durable Responses after Autologous Stem Cell Transplantation in POEMS Syndrome

Blood ◽

10.1182/blood-2018-99-115710 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4606-4606

Author(s):

Neeraj Y Saini ◽

Romil Patel ◽

Ankur Varma ◽

Qaiser Bashir ◽

Omar Hasan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Median Number ◽

Castleman Disease ◽

Poems Syndrome ◽

Bone Lesions ◽

Advisory Committees ◽

Entire Cohort ◽

The Mean

Abstract Abstract: Background: POEMS syndrome is a constellation of symptoms of polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Other features often present in this syndrome include papilledema, extravascular volume overload, sclerotic bone lesions, Castleman disease, high vascular endothelial growth factor (VEGF) levels and thrombocytosis/polycythemia. The standard of care has not been established in the management of the disease. We had previously reported on the role of auto-HCT in a smaller cohort of POEMS patients at our institution1. Here, we present an updated analysis in a larger cohort of POEMS patients who underwent auto-HCT. Methods: We retrospectively reviewed the outcomes of POEMS patients who underwent auto-HCT at our institution from the period of January, 1999, through June, 2018. The Kaplan-Meier method was used to caculate progression-free survival (PFS) and overall survival (OS). Hematologic response was defined as per the International Myeloma Working Group (IMWG) criteria. OS was defined as the duration from the date of transplant to death or last date of follow-up in alive patients. PFS was defined as the duration from the date of transplant to either progressive disease or death, whichever occurred first. Results: 16 patients (13 males, 3 females) with POEMS syndrome received a total of 17 auto-HCTs. One patient underwent auto-HCT two times for multiple relapses. The median age at auto-HCT was 48 years (range: 18-75). The median time from diagnosis to auto-HCT was 15 months (2-141 months). All 16 (100%) patients had peripheral neuropathy and monoclonal gammopathy: IgG lambda in 7, IgA lambda in 6, IgG kappa in 2 and light chain in 1 patient. Other features were: osteosclerotic bone lesions in 13 (81%), endocrinopathy in 10 (69%), skin involvement in 8 (50%) and extravascular fluid overload in 7 (44%). Three (18%) patients had biopsy-proven co-existent Castleman disease. Among patients with available data (n=7), the mean serum VEGF level pre-transplant was 389 pg/ml (268-1622). The median HCT-CI (comorbidity index) score available for 15 patients was 2 (range 0-7). The median number of chemotherapies received before the transplant was 1 (range 1-3). Table 1 summarizes the prior systemic chemotherapies received before auto-HCT. Two patients also received plasmapheresis, and eight patients received radiation therapy for bone disease. The mobilization regimens used for collecting peripheral blood stem cells were granulocyte colony-stimulating factor (G-CSF) alone, cyclophosphamide+G-CSF and G-CSf+plerixafor in 16, 2 and one patient, respectively. The median number of CD34+ stem cells collected was 3.43 X 106 cells/kg (range 1.73 - 6.5). The overall response rate, as per the IMWG criteria, for the entire cohort was 94% (16/17): 5 (29.4%) CR, 4 (23.5%) nCR, 1 (5.8%) VGPR, and 6 (35.2%) PR. The mean serum VEGF levels improved from 389 pg/ml before transplant to a level of 35 pg/ml (31-86) post-transplant. Engraftment syndrome was seen only in 1 patient who required corticosteroid use. One-year transplant-related mortality was 0%. Median follow-up among surviving patients is 52 months (5-120 months). The median PFS and OS have not been reached yet. All 16 patients had a complete or partial resolution of their clinical symptoms after auto-HCT. 4-year PFS and OS rate for the entire cohort is 80.2% and 100% respectively. At ten years, PFS and OS rate is 59.4% and 80% respectively. Fourteen out of 16 patients were alive at the time of the last follow-up. One patient died six years after his auto-HCT secondary to gastrointestinal bleeding unrelated to his underlying disease, and the second patient died after 11 years post auto-HCT of unknown cause. Conclusions: Upfront Auto-HCT provides durable chemotherapy free remission and significant clinical improvement in patients with POEMS syndrome. References: Patel, K. et al. Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome. Bone marrow transplantation49, 465-6 (2014). Figure. Figure. Disclosures Thomas: Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Array Pharma: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Poseida: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Consultancy, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Patel:Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

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Comparison of Splenectomy and Treatment Failure Incidence in Nonsplenectomized Patients with Immune Thrombocytopenia (ITP) Receiving Romiplostim or Medical Standard of Care: 1-Year Treatment and 6-Month Safety Follow-up.

Blood ◽

10.1182/blood.v114.22.679.679 ◽

2009 ◽

Vol 114 (22) ◽

pp. 679-679 ◽

Cited By ~ 2

Author(s):

David J Kuter ◽

Mathias J Rummel ◽

Ralph Vincent Boccia ◽

B. Gail Macik ◽

Ingrid Pabinger ◽

...

Keyword(s):

Platelet Count ◽

Adverse Events ◽

Treatment Failure ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Actual Incidence

Abstract Abstract 679 Chronic ITP is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production. Immunosuppressive ITP therapies have variable response rates and may be associated with substantial side effects, limiting their use for long-term treatment. Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to thrombopoietin, and is approved for the treatment of chronic ITP. We present final results from a phase 3b, randomized, open-label study, comparing the incidence of splenectomy and treatment failure in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). Patients were randomized (2:1) to romiplostim or SOC. Eligible patients had a platelet count <50 × 109/L. Once-weekly subcutaneous romiplostim was administered with dose adjustments to target a platelet count between 50 and 200 × 109/L. SOC treatments were prescribed according to standard institutional practices or therapeutic guidelines; the only treatments not allowed were investigational agents (rituximab was allowed) or other thrombopoietic agents. Patients received romiplostim or SOC for 52 weeks, and those who did not subsequently transfer to another romiplostim study completed a 6-month off-treatment safety follow-up. Co-primary endpoints of the study were: the incidence of splenectomy and the incidence of treatment failure (defined as: platelet count ≤20 × 109/L for 4 consecutive weeks at the highest recommended dose and schedule, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms). Patients who discontinued study during the treatment period were counted as having had splenectomy or treatment failure. To assess the impact of treatment discontinuation on the primary endpoints, a sensitivity analysis was conducted to determine the actual incidence of splenectomy or treatment failure. A total of 234 patients were randomized (romiplostim, 157; SOC, 77); 83% of romiplostim and 66% of SOC patients completed the study. Patients had been diagnosed with ITP for a median of 2 years (range 0.01 to 44 years) and 73% had received ≥2 prior ITP therapies. Patient characteristics were similar between treatment groups. The efficacy of romiplostim was significantly greater than that of SOC in both primary endpoint analyses. The incidence of splenectomy was 9% (14/157) in the romiplostim group compared to 36% (28/77) in the SOC group (OR, 0.17; 0.08, 0.35; p<0.0001), and the incidence of treatment failure was 12% (18/157) in the romiplostim group compared to 30% (23/77) in the SOC group (OR, 0.31; 0.15, 0.61; p=0.0005). Sensitivity analyses confirmed the primary endpoint analyses: the actual incidence of splenectomy was significantly lower in the romiplostim group (2/157, 1%) than the SOC group (15/77, 20%) [p<0.0001], and the actual incidence of treatment failure was significantly lower in the romiplostim group (6/157, 4%) than the SOC group (10/77, 13%) [p=0.009]. The incidence of bleeding events with a worst grade score ≥3 appeared lower for patients in the romiplostim group (3%) than the SOC group (7%). Safety analyses included only patients who received ≥1 dose of romiplostim or 1 type of SOC. During the 52-week treatment period, adverse events occurred in 96% (147/154) of patients receiving romiplostim and 92% (69/75) of patients receiving SOC. Serious adverse events occurred in 23% (35/154) of romiplostim and 37% (28/75) of SOC patients; serious adverse events were considered treatment-related in 5% (7/154) of romiplostim and 8% (6/75) of SOC patients. During the 6-month safety follow-up period, 36% (11/31) of romiplostim and 43% (18/42) of SOC patients experienced an adverse event; treatment-related adverse events occurred in none of the romiplostim patients and 2 of the SOC patients. Overall, 6 patients died: 1 (1%) in the romiplostim group and 5 (7%) in the SOC group. None of the deaths were considered related to study treatment or the underlying ITP. No patients tested positive for neutralizing antibodies to romiplostim or TPO. One romiplostim-treated patient showed an increase in bone marrow reticulin that was still within the normal range (Grade 2). In summary, romiplostim significantly reduced incidences of splenectomy and treatment failure in nonsplenectomized ITP patients compared to SOC. The safety profile of romiplostim was similar to SOC. Disclosures: Kuter: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Esehi: Consultancy; Shionagi: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria, Speakers Bureau; MGI Pharma: Consultancy, Research Funding; Ligand: Honoraria, Speakers Bureau. Rummel:Amgen Inc.: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Boccia:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Macik:Amgen Inc.: Research Funding; Eisai Inc.: Research Funding. Pabinger:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Selleslag:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodeghiero:Amgen Inc.: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Shionogi: Speakers Bureau. Chong:Commonwealth Serum Laboratory (CSL): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Beiβenhirtz:Amgen Inc.: Consultancy. Gehl:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

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Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.508.508 ◽

2015 ◽

Vol 126 (23) ◽

pp. 508-508 ◽

Cited By ~ 27

Author(s):

Ajai Chari ◽

Sagar Lonial ◽

Attaya Suvannasankha ◽

Joseph W. Fay ◽

Bertrand Arnulf ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Institutional Research ◽

Advisory Committees ◽

Multicenter Phase ◽

Phase 1B ◽

Grade 3

Abstract Introduction : Daratumumab (DARA) is a human anti-CD38 IgG1κ monoclonal antibody with remarkable safety and activity as monotherapy in heavily treated relapsed and refractory (RR) multiple myeloma (MM) (Lokhorst HM. J Clin Oncol 2014;32 Suppl:abstr 8513. Lonial S. J Clin Oncol 2015;33 Suppl:abstr LBA8512). DARA has demonstrated clinical activity in combination with lenalidomide (LEN) and dexamethasone (D) in relapsed or RR MM (Plesner T. Blood 2014;124(21):84). This ongoing 4-arm, multicenter, phase 1b study (NCT01998971) evaluated the safety and efficacy of DARA in combination with various backbone therapies and pomalidomide plus D (POM-D). Results in newly diagnosed patients treated with DARA and backbone therapies were previously reported (Mateos MV, et al. Haematologica 2015;100(s1):84). Methods : Patients in the DARA + POM-D arm had relapsed or RR MM with ≥2 prior lines of therapy including ≥2 consecutive cycles of LEN and bortezomib. During 28-day treatment cycles patients received DARA 16 mg/kg qw for 2 cycles, then q2w for 4 cycles, and q4w until disease progression (PD). Pomalidomide 4 mg was administered qd for 21 days with D 40 mg qw (20 mg for patients >75 years of age). The primary endpoint was safety and tolerability of DARA in combination with POM-D. Overall response rate (ORR) was a secondary endpoint. Disease responses were evaluated by an independent data safety monitoring board. Results: A total of 77 patients were enrolled into the DARA + POM-D arm. The median (range) age was 64 (35-86) years and the median number of prior therapies was 3.5 (2-10). Sixty-five percent of the patients were refractory to bortezomib, 30% to carfilzomib, 88% to lenalidomide, and 65% to both a PI and IMiD. With a median (range) duration of follow-up of 72 (1-423) days, 28 (36%) patients have discontinued treatment due to PD (15 [20%]), adverse events (AEs; 6 [8%]), death or physician's decision (3 [4%] each), and one (1%) patient withdrawal. The median (range) duration of treatment was 69 days (1-416), and the median (range) number of infusions was 7.5 (1-25). Forty-nine (64%) patients continue on study treatment and enrollment is ongoing. There was little additional toxicity when DARA was added to POM-D other than DARA-specific infusion related reactions (IRRs; 47/77 patients). Most occurred on Cycle 1 Day 1 (45/47 patients), and the most common (>10%) IRRs were chills (13%), cough (13%), and dyspnea (11%). The most common (>10%) and grade ≥3 adverse events (AEs) are presented in Table 1. Five patients died within 30 days of receiving study treatment due to AEs (4[5%]) or progressive disease (1 [1%]). In 53 patients with >1 post-baseline assessment, the ORR was 58.5%, with 3 stringent complete responses (sCR), 1 complete response (CR), 12 very good partial responses (VGPR), 15 partial responses (PR), 2 minimal responses, 18 stable disease, and 2 PD. Many responses deepened over time. Median (range) time to first response was 30 (28-92) days. After a median follow-up of 148 days, 4 out of 31 responders developed PD. Among the evaluable double refractory patients (n = 40), there was 1 sCR, 1 CR, 10 VGPRs, and 11 PRs with an ORR of 57.5%. Conclusions : The addition of DARA to POM-D was well tolerated and did not result in additional toxicities with the exception of DARA-related infusion reactions. Deep and durable responses were observed quickly, along with a high response rate. Study enrollment is ongoing and data will be updated at the meeting. Table 1. Most Common (>10%) Adverse Events (N = 77) Adverse Event, n (%) Any Grade Grade ≥3 Neutropenia 42 (54.5%) 39 (50.6%) Anemia 28 (36.4%) 16 (20.8%) Fatigue 28 (36.4%) 4 (5.2%) Cough 24 (31.2%) 0 Nausea 21 (27.3%) 0 Dyspnea 20 (26.0%) 5 (6.5%) Diarrhea 19 (24.7%) 1 (1.3%) Leukopenia 19 (24.7%) 12 (15.6%) Thrombocytopenia 17 (22.1%) 8 (10.4%) Pyrexia 16 (20.8%) 1 (1.3%) Dizziness 15 (19.5%) 0 Chills 14 (18.2%) 0 Nasal Congestion 14 (18.2%) 0 Upper Respiratory Tract Infection 14 (18.2%) 1 (1.3%) Back Pain 13 (16.9%) 2 (2.6%) Constipation 13 (16.9%) 0 Tremor 13 (16.9%) 2 (2.6%) Insomnia 12 (15.6%) 1 (1.3%) Lymphopenia 11 (14.3%) 7 (9.1%) Muscle Spasms 11 (14.3%) 0 Vomiting 11 (14.3%) 0 Arthralgia 9 (11.7%) 1 (1.3%) Pruritus 9 (11.7%) 0 Throat Irritation 9 (11.7%) 0 Anxiety 8 (10.4%) 0 Headache 8 (10.4%) 0 Hypertension 8 (10.4%) 4 (5.2%) Musculoskeletal Chest Pain 8 (10.4%) 2 (2.6%) Peripheral Edema 8 (10.4%) 1 (1.3%) Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Novartis: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Onyx: Consultancy, Research Funding. Lonial:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Suvannasankha:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Arnulf:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Qin:Janssen: Employment. Masterson:Janssen: Employment. Nottage:Janssen: Employment. Schecter:Janssen: Employment. Ahmadi:Janssen: Employment. Weiss:Janssen and Millennium: Consultancy; Janssen and Onclave: Research Funding. Krishnan:Millenium: Speakers Bureau; BMS: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Lentzsch:Celgene: Consultancy; Janssen: Consultancy; Axiom: Honoraria; Novartis: Consultancy; BMS: Consultancy.

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A Phase I/II Trial of Brentuximab Vedotin (BV) Plus Rituximab (R) As Frontline Therapy for Patients with Immunosuppression-Associated CD30+ and/or EBV+ Lymphomas

Blood ◽

10.1182/blood-2019-127390 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 351-351 ◽

Cited By ~ 1

Author(s):

William Pearse ◽

Barbara Pro ◽

Leo I. Gordon ◽

Reem Karmali ◽

Jane N. Winter ◽

...

Keyword(s):

Peripheral Neuropathy ◽

T Cell ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees ◽

Lymphoid Malignancies ◽

Frontline Therapy

Background: Immunocompromised patients (pts) face an approximate 6-fold increase in lifetime risk of lymphoid malignancies compared with immunocompetent counterparts. Additionally, up to 80% of post-transplant lymphoproliferative disease (PTLD) cases are driven by EBV-associated mechanisms of tumorigenesis. Approximately 70% will express CD30 and over 80% will express CD20. Recent studies of chemoimmunotherapy (CIT) have reported median overall survival (OS) of 2-4 years and treatment-related mortality (TRM) rates of 13-50%. Moreover, solid organ transplant (SOT) pts are at significant risk of graft rejection when CIT is employed, possibly due to "off target" depletion of regulatory T-cell populations. R monotherapy induction, followed by response-stratified use of CIT, has been evaluated (Trappe, et al, JCO, 2016). However, ~75% of pts had an inadequate response to R alone and required subsequent CIT; 2-yr OS for the population as a whole was ~70%. BV is an anti-CD30 antibody-drug conjugate that received accelerated FDA approval for previously untreated CD30+ T-cell lymphoma and Hodgkin lymphoma. We hypothesized that a combination of BV and R would yield improved breadth and depth of response compared with R monotherapy induction, would spare pts subsequent exposure to CIT, and result in favorable OS. Methods: We report here results of a phase I/II multicenter study investigating the efficacy and safety of BV+R as frontline therapy in pts diagnosed with immunosuppression-associated CD30+ and/or EBV+ lymphoid malignancies. Induction consisted of R 375 mg/m2 given days 1, 8, 15, 22 and BV 1.2 mg/kg given days 1, 8, 15, of a 28-day cycle, followed by restaging. Those with progression were removed from study. Pts with stable disease were offered study discontinuation or completion of one consolidation cycle followed by repeat disease assessment. Pts with partial response or complete response (CR) could receive either consolidation followed by maintenance therapy (MT) or move directly to MT without consolidation. Consolidation was identical to induction dosing; MT consisted of BV 1.8 mg/kg every 3 weeks and R 375 mg/m2 every 6 weeks for up to 1 year of therapy. Toxicity was defined using CTCAE 4.0 and response (Cheson, 2007) was assessed at the end of induction, consolidation (if given), and after cycles 4 and 7 of BV. Results: A total of 22 pts were entered in the trial. Toxicity and response data are available for 20 pts. Median age was 67 years (range, 30-79) and 14 pts (64%) were male (range, 30-79 years). Fourteen pts (64%) had received either a SOT or hematopoietic allograft requiring immunosuppression, 3 pts required immunosuppression for underlying rheumatologic conditions, and 3 pts were found to have EBV-associated lymphoid malignancies in the absence of iatrogenic immunosuppression (Table 1). Overall response rate was 70%, including a CR rate of 60%. With median follow-up of 26.1 month, the probability of progression-free survival at 1 year was 75.2% and 67.6% at 3 years (Fig 1). Probability of OS was 89.2% at both 1-year and 3-year follow-up (Fig 1). Median time to best response was 28 days. Three pts withdrew consent after induction, 2 pts died (1 death related to treatment), and 1 patient was lost to follow-up. Seven pts (31%) required dose adjustments or delay of medication administration during induction therapy and 45% required discontinuation of therapy due to toxicity within 1 year. The most frequent grade 3/4 toxicities were peripheral neuropathy, neutropenia, lymphopenia, and pancreatitis. The most frequent adverse events of any grade were fatigue, nausea, abdominal pain, pancytopenia, and peripheral neuropathy (Table 2). Conclusions: The combination of BV + R had an acceptable safety profile and appeared effective in achieving early remissions when used as frontline therapy for PTLD and other immunosuppression-related lymphomas. Specifically, over half of pts achieved CR, and 75% have been spared exposure to multi-agent cytotoxic chemotherapy. Furthermore, survival and PFS data were encouraging compared with historical controls. However, nearly half of pts discontinued therapy within 1 year due to toxicity suggesting poor long-term tolerance of the regimen and that earlier cessation of therapy may be warranted. Further studies are needed to confirm these efficacy results and to determine optimal BV+R dosing regimens and durations. Disclosures Pro: Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria. Gordon:Gilead: Other: Advisory Board; Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution. Winter:Merck: Consultancy, Research Funding. Ma:Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Xeme: Research Funding; Bioverativ: Consultancy; Beigene: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy; Abbvie: Research Funding; Incyte: Research Funding; Juno: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Novartis: Research Funding. Behdad:Pfizer: Other: Speaker; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees. Petrich:AbbVie: Employment, Equity Ownership. Smith:Portola Pharmaceuticals: Research Funding.

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Hypomethylating Agent and Venetoclax Combination Therapy Yields Superior Outcomes When Compared to Hypomethylating Agent Monotherapy in Patients ≥70 Years with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-127772 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1368-1368 ◽

Cited By ~ 1

Author(s):

Yumeng Zhang ◽

Hannah H Asghari ◽

Onyee Chan ◽

Dasom Lee ◽

Martine Extermann ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Entire Cohort ◽

Response Data

Background: Older patients with acute myeloid leukemia (AML) have inferior outcomes when compared to younger patients. Hypomethylating agents (HMA) were established as the standard of care for patients who are unfit for intensive induction chemotherapy until HMA and venetoclax (HMA+ven) combination approval by the FDA in December 2018. Approval of HMA+ven was based on an early phase study which produced high response rates; however, the combination was not compared head-to-head with HMA alone. A randomized phase 3 study is currently underway. There is no data available comparing HMA+ven to HMA monotherapy in older patients (age ≥70 years), thus we aimed to characterize responses in older patients when treated with these two regimens. Methods: We retrospectively reviewed clinical and molecular data on 225 patients at Moffitt Cancer Center and Memorial Health System with newly diagnosed AML who were ≥ 70 years old and were treated with HMA monotherapy or HMA+ven combination. Clinical data was abstracted in accordance with institutional review board approved protocol. Patients were then divided in two subgroups: Cohort A) HMA monotherapy and B) HMA+ven combination. We calculated overall response rates (ORR) defined as patients achieving complete remission (CR), CR with incomplete hematologic recovery (CRi) or morphologic leukemia free state (MLFS). Fisher's Exact method was utilized to determine significance for categorical variables. All reported p-values are two sided. Next generation sequencing (NGS) results were analyzed using the TruSight Myeloid-54 gene panel with a sensitivity of 5%, and were characterized in patients treated in cohort B. Results: Among the 225 patients, 87% (n=196) were in cohort A and 13% (n=29) in cohort B. In cohort A, 36.7% were females compared to 27.6% in cohort B. Median age in both cohorts was 76 years (range: 70-90 years in cohort A) (range: 72-86 years in cohort B). Overall, 26% of the patients had adverse risk disease as defined by European Leukemia Net (ELN) classification in cohort A and 51.7% in cohort B. Baseline characteristics are described in Table 1. Overall response rate (ORR) of the entire cohort was 43.6% (n=92) (Table 2). ORR in cohort A was 25.5% (n=47) compared to 66.7% (n=18) in cohort B (p<0.001). The median time to response in cohort A was 3.8 mos and was 1.9 mos in cohort B. Looking only at the 66 patients with ELN-defined adverse risk, response data were available in 62 patients, and the ORR in both cohorts was 25.8% (n=16), and was significantly lower in cohort A compared to B (14.9% vs. 60%, respectively, p=0.001) (Figure 1). Among the 136 patients with favorable or intermediate risk disease, response data were available in 127 patients, and the ORR was 35.4% (n=45). In cohort A the ORR in favorable/intermediate patients was 28.9% (n=37), and in cohort B it was significantly higher at 100% (n=8) (p<0.001). Ten responding patients in cohort B had NGS data available at diagnosis and at the time of best response. Mutations cleared from the bone marrow in 60% (n=6) of these patients. With a median follow up of 11.7 months, the median overall survival (mOS) of the entire cohort was 15.03 months. The median follow-up time in cohort A is 46 months and in cohort B is 5.4 months, making assessment of relapse free survival or overall survival in cohort B premature. Early mortality rate was not different between the two cohorts (1.5% vs 3.4%, p=0.42). Conclusion: Our data provides convincing support that HMA+ven combination yields significantly higher response rates when compared to HMA monotherapy in newly diagnosed AML patients ≥70 years of age; an observation that is further strengthened by the short duration of follow-up in the HMA+Ven cohort. Responses are particularly striking in favorable and intermediate risk patients when treated with HMA+Ven. Overall our data supports the use of HMA+ven in the upfront setting for older patients with newly diagnosed AML. Additional follow-up in HMA+ven arm is needed to evaluate survival outcomes. Disclosures Kuykendall: Incyte: Honoraria, Speakers Bureau; Abbvie: Honoraria; Janssen: Consultancy; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Talati:Celgene: Honoraria; Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria. Sweet:Pfizer: Consultancy; Incyte: Research Funding; Jazz: Speakers Bureau; Stemline: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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