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

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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Ponatinib for Chronic Phase (CP) CML Failing Two or More Tyrosine Kinase Inhibitors (TKI) or Harboring a T315I Mutation in the Real Life: Pearl Observational Study

Blood ◽

10.1182/blood.v126.23.4039.4039 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4039-4039

Author(s):

Franck E. Nicolini ◽

Mael Heiblig ◽

Stéphane Morisset ◽

Denis Caillot ◽

Valérie Coiteux ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Real Life ◽

Compassionate Use ◽

Advisory Committees ◽

The Real ◽

Real Life Setting ◽

Tobacco Abuse ◽

T315i Mutation ◽

Grade 3

Abstract Background Ponatinib, a third generation TKI, induces high rates of cytogenetic and molecular responses in heavily pre-treated CML patients (pts) resistant to ≥2 TKI and/or with a T315I mutation, especially in CP (J. Cortes at al., NEJM 2013). This agent induces diverse non-severe adverse events (AEs), a substantial proportion of pts experience severe arterial thrombotic events [(ATE) 17% by 3 years, J. Cortes et al., Haematologica 2015]. This agent is now licensed and it is mandatory to explore the rates of responses and ATE in the real-life setting. Aims We took the opportunity of the French ponatinib compassionate use program between May 2013 (end of PACE inclusions) and January 2014 (ponatinib license) to evaluate different outcomes in real-life conditions. Methods This is a multicenter observational retrospective study, designed to examine safety and efficacy of ponatinib in CML (any phase) resistant/intolerant to prior TKIs, in university and non-university hospitals, benefiting from the national ponatinib compassionate use program. Data were captured and validated following the rules and regulations of observational studies in France. Pts were analyzed in intention-to-treat, Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL are expressed as % IS in all centers. Standard clinical [gender, age, weight, body mass index (BMI), cardiovascular risk factors (previous events, tobacco abuse, high blood pressure, diabetes)], onset of any CV events before and during ponatinib treatment) and metabolic biological parameters (cholesterol, triglycerides) were collected. Results Thirty-five observations were collected in CP, 4 in AP and 5 in BC. We focused our analysis on the 35 CP pts only. There were 16 (46%) males and 19 females, with a median age of 53 (18-76) years at CML diagnosis and 59 (20-82) years at ponatinib initiation. Sokal scores were high in 13 (37%), intermediate in 12 (34%), low in 4 (12%) and unknown in 6 (17%); Euro scores were high in 6 (17%), intermediate in 15 (43%), low in 3 (9%) and unknown in 11 (31%); Eutos scores were high in 7 (20%), low in 20 (57%) and unknown in 8 (23%) pts. All pts harbored "major" BCR-ABL transcripts except one (e19a2). Regarding cardiovascular risk factors (CVRF) prior to ponatinib, 12 pts (34%) were treated for hypertension, 1 was diabetic, 6 (17%) had dyslipidemia (all on statins). Tobacco abuse was present in 8 (23%) pts and 14 pts had some pre-existing CVRF in total. Median weight just prior ponatinib was 66 (48-107) kg, and BMI was 24.2 (17.85-33) kg/m2. Thirteen (37%) pts were on anti-aggregants or anti-coagulants (AAG/C) prior to ponatinib. All pts had received imatinib first-line for a median of 29.5 (4-123) months, 20 (57%) dasatinib and 14 (40)% nilotinib as second-line, one pt developed a T315I after imatinib only; 21 (60%) had received all 3 TKIs prior to ponatinib. At ponatinib initiation, 7 (20%) harboured a T315I mutation, 7 (20%) other mutation(s) 20 (57%) none. In one case mutation screen was not performed. The trigger for ponatinib was resistance (hematologic, cytogenetic or molecular progression) in 26 (74%) pts, intolerance in 7 (20%) pts and both in 2 (6%) pts. Pts were initiated at a median of 45 (30-45) mg daily after a median of 79.5 (12-217) months of disease duration. The median follow-up on ponatinib was 26 (2-37) months. The cumulative incidence of major molecular responses was 29% at 3, 42% at 6, 56% at 12 and 70% at 18 months. The overall survival is shown in figure 1. Four pts died, 3 of disease progression and 1 of myocardial infarction. Six (17%) pts had grade 3-4 hematologic AEs imposing transient ponatinib withhold, and 14 (40%) had diverse grade 1-2 non-hematologic, non-CV AEs (pancreatic, hepatic, skin toxicities, no grade 3-4). ATEs occurred in 19 (54%) pts after a median of 5.8 (0.7-21.7) months of ponatinib, without CVRF in 10 (53%) pts and without AAG/C in 13 (68%) pts. CVRF and AAG/C had no significant influence here on ATEs onset in univariate Cox model (p=0.76 and 0.37 respectively). Lipids and HbA1c were not modified on ponatinib. Overall 43% of pts stopped ponatinib for toxicity. Conclusion In the French compassionate use program in CP-CML patients resistant or intolerant to previous TKIs, ponatinib displayed strong efficacy, as previously described. In this unselected population of patients, ATEs were confirmed to represent the main tolerance concern in the real life setting. Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coiteux:Novartis: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau. Charbonnier:Novartis: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau. Huguet:Novartis: Consultancy, Research Funding; PFIZER: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau. Legros:Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Amé:BMS: Speakers Bureau; Novartis: Speakers Bureau. DeFrance:Ariad: Consultancy. Mahon:ARIAD: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rea:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

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Pomalidomide 3rd Line Versus 4th Line for RRMM

Blood ◽

10.1182/blood-2018-99-115449 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5633-5633

Author(s):

Cécile Gruchet ◽

Stephanie Guidez ◽

Valentine Richez ◽

Cyrille Hulin ◽

Eric G. Voog ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Financial Support ◽

Research Funding ◽

Real Life ◽

Disease Stage ◽

Advisory Committees ◽

The Real ◽

Safety Issues ◽

Line P

Abstract Background. Pomalidomide in association with dexamethasone is approved for RRMM in 3rd line and beyond based on the MM-003 multicenter international phase 3 study that demonstrated greater efficacy for Pomalidomide plus dexamethasone over high dose dexamethasone. However, MM-003 mainly recruited advanced RRMM with a median of 5 prior lines. Few data is available regarding real life Pomalidomide-based treatment in 3rd and 4th line RRMM. The aim of this study was to study efficacy and safety of Pomalidomide-based treatment in 3rd and 4th line RRMM. Methods. We studied 108 consecutive RRMM treated with Pomalidomide-based treatment in 3rd and 4th line in a multicenter-based study. All assessment made according to IMWG. Results. The median age was 62.5 (range, 30-86), with 36% older than 65 years, sex ratio M/F 1.25 and ISS disease stage 2 or 3 in 58%. 100% were exposed to bortezomib and refractory to Lenalidomide. 52 patients (48%) had pomalidomide-based therapy as 3rd, and 56 (52%) as 4th line. 73% of patients received a double-based therapy (Pomalidomide plus Dexamethasone) and 27% received a triple based therapy (Pomalidomide, Cyclophosphamide and Dexamethasone). Overall ORR was 55%, with 20% ≥VGPR including 5% CR, and was not statistically different in 3rd versus 4th line, and with PCd versus Pd, although the former was always better. With a median f-up of 45 months, overall 77% and 49% had relapsed and died, respectively, with significantly less in benefit to combination and 3rd line compared to Pd and 4th line (p=0.020). The median PFS was 6 (CI95% 2.3;9.6) and 9 (5.5;12.5) months in 3rd and 4th line (p=0.04), and 6 (CI95% 2.8;9.2) and 12 (8.5;15.5) months in Pd and PCd (p=0.04), respectively. Interestingly, the estimated 3 years PFS for 3rd line and PCd was 34% and 32% respectively, greatly superior to 4th line and Pd, 13% and 18%, respectively. Similarly, the median OS from start of Pomalidomide was not reached in 3rd and in PCd lines versus 23months (5;49), (p=0.04), and 32 months (5;-) for 4th line and Pd use, respectively. Pomalidomide was never permanently discontinued for safety issues, but 30 (28% of patients had to reduced pomalidomide dose, 25% to N-1 that is 3mg/d and 3% at N-2 that is 2mg/d. Expectedly, more patients (increased by 10%) had to reduce pomalidomide dose in 4th line compared to 3rd line, although it was not statistically significant, but not with PCd versus Pd. Indeed Cyclophosphamide but not pomalidomide is reduced in modified in dose or scheme when facing safety issues. No patient died related to adverse events. AEs leading to pomalidomide-based modification in schema included hematological in 40% and non hematological AEs in 12% of patients. Overall, the most common adverse events grade 3 or 4 were neutropenia (22%), anemia (11%), thrombocytopenia (7%) and infectious disease (5%). Conclusion. Pomalidomide-based therapy demonstrates efficacy in the real life with a manageable safety profile. We demonstrate herein that early use and combination improves MM on pomalidomide in the real life. Further prospective studies are warranted to confirm this data on a larger MM population. Disclosures Hulin: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Perrot:Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Macro:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress. Laribi:Hospira: Other: Grant; Amgen: Other: Personal fees; Novartis: Other: Grant and personal fees; Gilead: Other: Personal fees; Roche: Other: Grant; Takeda: Other: Grant and personal fees; Sandoz: Other: Grant; Teva: Other: Grant. Leleu:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Car-Bird [Carfilzomib, Clarithromycin(Biaxin®), Lenalidomide/(Revlimid®), Dexamethasone) for Newly-Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.4761.4761 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4761-4761 ◽

Cited By ~ 1

Author(s):

Tomer M Mark ◽

Abbe Schickner ◽

John N. Allan ◽

Adriana C Rossi ◽

Roger Pearse ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Maximum Response ◽

First Line ◽

Advisory Committees ◽

Cell Harvest ◽

Grade Iii

Abstract Background: Carfilzomib (Cfz), lenalidomide, and dexamethasone synergize to provide an impressive overall response rate (ORR) in upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The ORR to Cfz+dexamethasone (Cfz-Dex) as first-line therapy is unknown. We hypothesized that sequential treatment with Cfz-dex and BiRD would improve provide similar ORR and improve tolerability. A protocol of Cfz-Dex, consolidation with BiRd (Clarithromycin(Biaxin¨), Lenalidomide/(Revlimid¨), dexamethasone), and lenalidomide maintenance (Len) was conducted to evaluate ORR and safety as induction therapy for MM. Methods: Forty patients (pts) with symptomatic untreated MM were enrolled in a phase 2 study of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 min on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each dose thereafter and dex 40mg on D1, 8, 15, 22. After the first 26 pts were enrolled, the protocol was amended to increase the Cfz from 45 to 56mg/m2. Echocardiography and spirometry were performed prior to study entry and serum brain natriuretic peptide (BNP) was followed monthly to evaluate for heart or lung toxicity. Cfz-dex was continued until plateau in disease response, defined as unchanged M-protein for 2 cycles. Elective stem cell collection was then performed in transplant eligible pts and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg on D1, 8, 15, 22 of 28-day cycle. BiRd was continued until a 2nd response plateau after which lenalidomide maintenance (Len) at 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results: 36 pts completed at least 1 cycle and were evaluable for response. 58% of pts were ISS II/III. High-risk cytogenetics and unfavorable MyPRS score were found in 62% and 21% of pts, respectively. Median study follow-up was 66.2 weeks (range 3.7-114.7). Maximum response to the Cfz-dex, BiRd, and Len is shown in Table 1. Median time to PR was 1 cycle. Median time to maximum response with Cfz-dex, BiRD, and Len was 2, 2, and 4 cycles respectively. At last audit, 8 (22%) pts remain on Cfz-Dex; 21 (58%) reached plateau and received BiRd. Of the pts that received BiRd, 9 (43%) improved categorical response and 19 (90.5%) received Len. Two (11%) pts deepened response to CR while on Len. 97.5% of pts are alive and 82.5% without progression at last follow-up. One pt died after coming off study (withdrew consent) from sepsis during elective autologous stem cell transplant. Pts with high risk cytogenetics had a trend towards a shorter progression free survival (PFS), with median 71.7 weeks vs not reached (NR) (P = 0.058). Similar results were seen with unfavorable MyPRS score with a shorter median PFS at 71.7 weeks vs NR (P = 0.094). 17 pts had stem cell harvest following Cfz-dex. All collected stem cells to support at least two transplants, with median 14.5 x 10^6 (range 7.06-27) CD34/kg in a median of 1 (range 1-2) apheresis session. 18 pts (46.2%) have come off study, 6 (15%) for disease progression (2 during CfzDex , 1 during BiRD, 3 during Len) and 5 pts (12.5%) due to toxicity: 3 pts for renal failure [2 Grade 2, I grade 3, all with renal recovery after discontinuation, all attributable to Cfz]; 1 pt due to Grade III CHF [attributable to Cfz with recovery]; 1 pt with Grade III Thromboembolic [attributable Len]. There was no correlation between pre-study cardiac and lung function, or serial BNP, with toxicities. Seven (17.9%) pts came off study for noncompliance, lost to follow up, investigator discretion, or withdrew consent (Cfz-dex: 4, BiRD: 1, Len: 2). Discussion: This is the first prospective study evaluating induction response to Cfz/Dex in MM. Cfz/Dex is safe and active, with ORR of 91.7% and rate of >=VGPR of 55.6%, despite the majority with a high-risk cytogenetics. Cfz-dex did not hinder stem cell harvest. ORR improved with lenalidomide-based consolidation and maintenance, with CR rate > 50%. Baseline heart/lung function or serial BNP change did not predict emerging toxicities. Table 1: Maximum Response For Car-BiRD Phase: Response Category Car-Dex BiRD Lenalidomide N = 36 N = 21 N = 19 PD 0 1 (4.8) 0 SD 3 (8.3) 0 0 PR 13 (36.1) 1 (4.8) 1 (5.3) VGPR 17 (47.2) 12 (57.1) 8 (42.1) CR 1 (2.8) 0 0 SCR 1 (2.8) 5 (23.8) 8 (42.1) ICR 1 (2.8) 2 (9.5) 2 (10.5) >=PR 91.7 95.2 100 >=VGPR 55.6 90.4 94.7 >=CR 8.4 33.3 52.6 Disclosures Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for first-line treatment of myeloma. . Rossi:Celgene: Speakers Bureau. Pekle:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Onyx: Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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

Blood ◽

10.1182/blood-2019-125730 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1620-1620

Author(s):

Katharine L Lewis ◽

Kate Manos ◽

John Casey ◽

Julie Crawford ◽

Shir-Jing Ho ◽

...

Keyword(s):

Atrial Fibrillation ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Fungal Infections ◽

Invasive Fungal Infections ◽

Advisory Committees ◽

Entire Cohort ◽

Frontline Therapy

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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Car-Bird [Carfilzomib, Clarithromycin(Biaxin(R)), Lenalidomide/(Revlimid(R)), Dexamethasone) For Newly-Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.3216.3216 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3216-3216 ◽

Cited By ~ 2

Author(s):

Tomer M Mark ◽

John N. Allan ◽

Geoffrey Marano ◽

Adriana C Rossi ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Disease Response ◽

M Spike ◽

Grade Iii

Abstract Background Carfilzomib (Cfz) synergizes with lenalidomide and dexamethasone (Len-dex) to provide impressive response rates as upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The addition of clarithromycin to Len-dex has shown superior time to progression compared to Len-dex alone (Gay et al 2010). We hypothesized that sequential treatment with Cfz-dex and BiRD would lead to enhanced efficacy, response duration, and tolerability. We thus tested a sequential approach of upfront carfilzomib / dexamethasone, consolidation with BiRd, and lenalidomide maintenance to evaluate overall response and safety as first line therapy for MM. Methods Twenty-four patients (pts) with symptomatic untreated MM were enrolled in a single institution study to evaluate the efficacy and tolerability of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 minutes on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each successive dose thereafter and dex 40mg on D1, 8, 15, 22. Cfz-dex was continued until plateau in disease response defined as unchanged M-protein for 2 cycles. Elective autologous stem cell collection was then performed per physician and patient discretion and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg daily D1, 8, 15, 22 of 28-day cycle. Therapy was continued until a 2nd plateau in disease response after which lenalidomide maintenance at a dose of 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results 24 pts have currently been enrolled; 23 have completed at least 1 cycle of therapy and were evaluable for response. Sixteen pts (67%) harbored high-risk cytogenetics, as defined by the presence of one or more of the following on iFISH: del 17p, gain 1q, del 1p, t(4;14), t(14;16), or complex karyotypic abnormalities. Median study follow-up was 30.8 weeks (range 4.5-62.2). Response to the Car-BiRD regimen was: overall response rate (ORR) 87%, stringent complete response (sCR) 13%, very good partial response (VGPR) 48%, partial response (PR) 26%, stable disease (SD) 13%. Maximum response to the Cfz-dex induction was: ORR 87%, sCR 9%, VGPR 39%, PR 35%, SD 13%. Median time to PR and maximum response with Cfz-dex was 2 cycles (range 1-2) and 4 cycles (range 1-5) respectively. Median M-spike percentage decrease with Cfz-dex was 92% (range 13-100%). Twelve pts thereafter received BiRD consolidation with 5 pts (41%) further decreasing the M-spike by a median of 8% (range 1-45%). A median of 3 cycles (range 2-7) of BiRD was given until a 2nd response plateau was achieved. Seven pts subsequently received lenalidomide and all have maintained their response after a median of 5 cycles (range 1-8) of follow-up. Seven pts (30%) have come off study, 2 (8%) secondary to disease progression (1 during Car-Dex and 1 during BiRD) and 5 pts (22%) due to toxicity (2 pts due to Grade III renal failure, both attributable to Cfz, and 2 pts due to Grade III CHF during Cfz-Dex, 1 attributable to Cfz; 1 pt with Grade III Thromboembolic event during BiRD, attributable to Len-dex). Discussion This is the first prospective study evaluating the response to induction Cfz/Dex in treatment-naïve MM. Cfz/Dex therapy appears safe and effective in newly diagnosed myeloma patients. Responses deepen with subsequent IMiD(R)-based consolidation and maintenance. Toxicities due to each component of the regimen were manageable. The ORR of 87% and rate of VGPR or better of 61% in group with a high percentage of unfavorable cytogenetics compares favorably to similar studies using 1st generation proteasome inhibitor combinations, and may continue to improve with longer study follow-up. Disclosures: Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for front line use in myeloma. Rossi:Celgene: Speakers Bureau. Zafar:Onyx: Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Long-Term Subgroup Analyses from Azacitidine Vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the Pethema Registry

Blood ◽

10.1182/blood-2021-150649 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1256-1256

Author(s):

Jorge Labrador ◽

Adolfo de la Fuente ◽

David Martínez-Cuadrón ◽

Rebeca Rodríguez-Veiga ◽

Josefina Serrano ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Subgroup Analysis ◽

Myeloid Leukemia ◽

Research Funding ◽

Real Life ◽

Advisory Committees ◽

Baseline Characteristics

Abstract INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs have demonstrated efficacy in monotherapy and in combination with targeted therapies. However, there is little direct comparative data on AZA and DEC in first-line treatment, and we do not know which group of patients might benefit from each drug. Results of the full analysis set (FAS) were presented previously (Labrador J, et al. ASH 2020). Here, we report long-term clinical efficacy from prespecified patient subgroup analyses. METHODS We conducted a retrospective study to compare real-life clinical outcomes between AZA and DEC in patients with AML ineligible for intensive chemotherapy included in the PETHEMA registry, and analyzed clinical variables associated with response and overall survival (OS) between AZA and DEC. RESULTS A total of 626 patients were included for the FAS between 2006 and 2019. 487 (78%) received AZA and 139 (22%) received DEC. Baseline characteristics were comparable in both groups, except for the percentage of bone marrow blasts (44% vs. 34% in the DEC group compared to AZA, p=0.010). In the FAS, there was no difference in the CR, CR/CRi or ORR (CR/RCi + PR) rate: 18%, 20.5% and 32% with AZA vs. 23%, 25% and 39.5% with DEC (p=0.20, p=0.27 and p=0.12). In the subgroup analysis, DEC was associated with higher CR/CRi rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.088 - 0.801), bone marrow blast count < 50% (95% CI: 0.293 - 0.965), secondary AML (95% CI: 0.223 - 0.918) and adverse cytogenetics (95% CI: 0.171 - 0.857) (Figure 1A). DEC was associated with higher ORR rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.116 - 0.782), leukocytes < 10 x10 9/L (95% CI: 0.321 - 0.920) and bone marrow blasts < 50% (95% CI: 0.321 - 0.920) (Figure 1B) 120 days-mortality was 25.4% after AZA and 27.1% after DEC, p=0.70. Patients who did not achieve at least a PR had significantly higher 120-day mortality with both HMAs (OR 8.85 and 8.22 for AZA and DEC, respectively). In the subgroup analysis, patients with leukocytes ≥ 10 x10 9/L (95% CI: 1.069 - 4.157) and those with estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m 2 (95% CI: 1.249 - 4.664) had higher 120-day mortality with DEC than with AZA (Figure 1C) With a median follow-up of 12 months, median OS was 10.4 months (95% CI: 9.2 - 11.7) for AZA vs. 8.8 months (95% CI: 6.7 - 11.0) for DEC (p = 0.455). The subgroup analysis revealed that patients ≥ 80 years (95%: CI 1.005 - 2.341), with leukocytes ≥ 10 x10 9/L (95% CI 1.039 - 2.062), platelet count <20 x10 9/L (95% CI: 1.150 - 3.422) and those with eGFR ≥ 45 mL/min/1.73m 2 (95% CI: 1.040 - 2.059) did benefit for treatment with AZA compared to DEC (Figure 1D). CONCLUSIONS Our study provides real-life data on the outcomes of AML patients treated with AZA compared to DEC in a large retrospective cohort with long-term follow-up. In addition, we identify for the first time some baseline characteristics that could benefit from AZA or DEC in terms of responses, 120-day mortality and OS. These findings could help us to choose the most appropriate HMA in monotherapy or for the development of new combinations. Figure 1 Figure 1. Disclosures de la Fuente: Novartis: Research Funding; Abbie: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Tolero Pharmaceutical: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Agios: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

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A Phase I/II Study of AZD2811 Nanoparticles (NP) As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory AML/MDS Patients Not Eligible for Intensive Induction Therapy

Blood ◽

10.1182/blood-2019-130635 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3919-3919

Author(s):

William B. Donnellan ◽

Ehab L. Atallah ◽

Adam S. Asch ◽

Manish R. Patel ◽

Jay Yang ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Slow Release ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Naïve ◽

Equity Ownership ◽

Refractory Aml

Background: Aurora kinases (AurK) represent potential targets for anticancer therapy in hematological malignancies and solid tumors. AurK B inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of AurKB, when given as 2-4hr IV on days 1 and 4, offers a prolonged drug exposure in vivo, mimicking the AZD1152 7-day continuous IV infusion. This is an update on the first-in-man dose-escalation study of AZD2811NP in pts with relapsed/refractory AML/MDS or treatment-naïve patients (pts) not eligible for intensive induction therapy (NCT03217838). The primary objectives are to determine the Maximum Tolerated Dose (MTD) and safety profile of AZD2811NP monotherapy and in combination with azacitidine. The secondary objectives are to evaluate the pharmacokinetic (PK) profile, Biologically Effective Dose (BED), and preliminary efficacy (CR, CRi, PR, 6 month OS). Methods: Pts received a 2-hour IV infusion on Day 1 and 4 of each 28-day cycle (Cy) for doses up to 600mg, extending to a 4 h IV infusion for dosages > 600 mg. In the ongoing dose escalation, 3-6 pts have been sequentially enrolled in cohorts ranging from 100 mg to 800 mg per infusion (Day 1 & 4), i.e. from 200 mg to 1,600 mg per cycle in monotherapy setting, according to a modified continuous reassessment method (mCRM) dose escalation design. AZD2811NP was also combined with azacitidine (75 mg day 1 to 7 or the 5-2-2 schedule) starting at an AZD2811NP dose of 400 mg D1 and D4 every 4 weeks. Study treatment was continued until disease progression, intolerability, or when discontinuation criteria were met. Results: Currently, 30 pts have enrolled of which 29 pts (12 females and 17 males) received study treatment in 5 monotherapy cohorts and 2 azacitidine combination cohorts, with ages ranging from 53 to 85 years. Nineteen pts had relapsed/refractory AML, 9 pts had MDS and 1pt had MDS/MPN. Monotherapy cohort 5 (800 mg D1 & D4) and combination cohort 4c (600mg D1 & D4 + Azacitidine) are currently enrolling. Of the 19 pts in monotherapy cohorts 1-5, 18 pts discontinued (due to consent withdrawal [2], early disease related deaths [2], other reason [1], or completed follow up [13; 11 pts after Cy1, 2 pts after Cy2]) and 1 pt is still on therapy. Nine pts were treated in combination with azacitidine, and of these, 3 pts are still on therapy and 6 pts have discontinued AZD2811NP (due to death [1], consent withdrawal [2], or completed follow up [3; 2 pts after Cy2, 1 pt after Cy4]). Adverse events that occurred in ≥ 20% of pts were mainly myelotoxicity, nausea and fatigue. One dose-limiting toxicity (DLT) has been observed in the monotherapy arm (esophageal infection) and one DLT in the combination setting (late neutropenia recovery). Two deaths were due to the underlying disease and 1 due to a serious adverse event of Gr 5 sepsis not related to study drug. AZD2811 total and released blood PK exposure appears broadly dose proportional with a terminal t1/2 of ~ 30-50 hours. Released blood PK exposure is ~ 1% of total PK exposure. Conclusion: AZD2811NP is documented to be well tolerated at doses up to 600 mg on Day 1 & 4 every 28 days in monotherapy setting and up to 400 mg (D1 & 4) in combination with azacitidine. The monotherapy and combination therapy dose escalations are ongoing. Updated results including preliminary efficacy data will be presented. Additional dose finding and expansion cohorts of AZD2811NP in combination with venetoclax are planned. Disclosures Atallah: Pfizer: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy. Yang:AstraZeneca: Research Funding; Agios: Consultancy. Eghtedar:Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Verastem Oncology: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Borthakur:Merck: Research Funding; Oncoceutics: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Eisai: Research Funding; Novartis: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding. Charlton:AstraZeneca: Employment; GSK: Equity Ownership. MacDonald:AstraZeneca: Employment, Equity Ownership. Korzeniowska:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment, Equity Ownership. Strickland:Sarah Cannon Development Innovations: Employment. Overend:AstraZeneca: Employment, Equity Ownership. Adelman:AstraZeneca: Employment, Equity Ownership. Fabbri:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment, Equity Ownership. Pease:AstraZeneca: Employment, Equity Ownership. Cosaert:AstraZeneca: Employment. OffLabel Disclosure: AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of Aurora Kinase B (AurKB), is an investigational agent in clinical trials for human cancers including AML/MDS.

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Prognostic Comparison Between ISS and R-ISS in Real-Life Setting of Myeloma Patients: An Example of Utilization of Electronic Biobank Database

Blood ◽

10.1182/blood.v128.22.5645.5645 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5645-5645

Author(s):

Samu Kurki ◽

Klaus Tamminen ◽

Tatu Miettinen ◽

Kari Remes

Keyword(s):

Board Of Directors ◽

Real Life ◽

Hazard Ratio ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Kaplan Meier ◽

Real Life Setting ◽

First Line Treatment

Abstract Introduction: Identification of patients with high-risk (HR) multiple myeloma (MM) is important to optimise their treatment. In 2015, revised International Staging System (R-ISS) guidelines were published (Palumbo, 2015) where HR cytogenetics (CG) and elevated serum lactase dehydrogenase (LDH) were added to the traditional ISS staging criteria. Thus, R-ISS stage III includes one of the HR CG abnormalities or elevated LDH, ISS stage I patients have no HR CG and normal LDH; the rest of patients belong to R-ISS stage II. There are limited data on the prevalence of R-ISS groups in comparison to the old ISS grouping and impact on clinical outcomes in the real-life setting. The aim of the present analysis was to use structured longitudinal electronic health records (EHR) provided by the Finnish Auria Biobank to compare the prevalence and survival outcome between patients in ISS and R-ISS groups in a real-life patient cohort of 100 patients treated at Turku University Hospital. Auria Biobank covers roughly 15% of the population of Finland and collects samples with the associated data from all diseases treated at Turku University Hospital based on the Finnish Biobank Act. Methods: Auria Biobank database was analysed retrospectively for all MM-patients diagnosed between 2008-2013 (incident cohort) and whose fluorescence in situ hybridization analysis was performed at the time of diagnosis. Data for age, gender, LDH, creatinine, ISS, R-ISS, CG, time to next treatment and overall survival were collected from Auria Biobank. Classification into ISS groups was done based on data at the time of diagnosis and OS. Classification into R-ISS staging was done according to IMWG (Palumbo, 2015). For HR CG at least one of the following CG abnormalities was required: del(17), t(4:14), or t(14:16). Estimated glomerular filtration rate was calculated by using the CKD-EPI formula. Drug treatments were classified as conventional (e.g. melphalan + prednisolone) or novel (proteasome inhibitors, IMIDs). Descriptive methods and Kaplan-Meier survival analysis were used for comparison of the groups. Results: The median age of the 100 patients was 64 yrs (range: 37 - 80), and 43% were female. At the time of diagnosis, 17% of patients had high risk CG status, 32% had at least moderate kidney failure (estimated glomerular filtration rate <60ml/min) and 26 % had elevated LDH. 41% patients received autologous stem cell transplant and 64% and 14% were treated with novel and conventional treatments in first line, respectively. 26%, 48% and 26% were classified to ISS stage I, II and III groups respectively, and 21%, 63% and 16% to R-ISS stage I, II and III groups, respectively. Criteria to include patients into R-ISS III were HR CG in 62 %, elevated LDH in 69 % and 31 % fulfilled both criteria. Neither ISS- nor R-ISS staging had any influence on first line treatment decisions between novel and conventional treatments. In all patients 2-year OS (from diagnosis) was 82% (median OS not yet reached). The 2-year OS in ISS I, II and III groups was 90%, 88%, and 60% respectively, and in R-ISS I, II and III groups 87%, 85% and 42%, respectively. R-ISS had a statistically significant effect on survival time (log rank P=0.032), with R-ISS III patients having a 3.8-fold risk of death compared to R-ISS I (Fig 1). R-ISS III patients had also shorter (ns) treatment free survival than R-ISS I patients (HR 2.1, log rank P=0.479) (Fig 2). No statistically significant difference was observed between the survival curves stratified by ISS staging groups. Conclusion: The new R-ISS staging system, using additional information including CG-profile and serum LDH, separated in our real-life setting more profoundly patients with poor prognosis than the old ISS staging. Structured EHRs can successfully be used to derive useful clinical and prognostic data from real-life MM patients. Figure 1 Kaplan-Meier curves for overall survival in different R-ISS groups. Time is measured from diagnosis to death or end of follow-up. Log rank P=0.032. R-ISS III vs. R-ISS I hazard ratio 3.8. Figure 1. Kaplan-Meier curves for overall survival in different R-ISS groups. Time is measured from diagnosis to death or end of follow-up. Log rank P=0.032. R-ISS III vs. R-ISS I hazard ratio 3.8. Figure 2 Kaplan-Meier curves for time to next treatment in different R-ISS groups. Time is measured from beginning of first line treatment to beginning of second line treatment or end of follow-up. Log rank P=0.479. R-ISS III vs. R-ISS I hazard ratio 2.1. Figure 2. Kaplan-Meier curves for time to next treatment in different R-ISS groups. Time is measured from beginning of first line treatment to beginning of second line treatment or end of follow-up. Log rank P=0.479. R-ISS III vs. R-ISS I hazard ratio 2.1. Disclosures Tamminen: Aava Healthcare group: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Roche: Employment; Takeda: Employment. Remes:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Haploidentical Transplantation Using High Dose Post-Transplant Cyclophosphamide for Patients with Aplastic Anemia : The European Group for Blood and Marrow Transplantation Experience

Blood ◽

10.1182/blood-2018-99-114033 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 486-486

Author(s):

Pedro H Prata ◽

Boris Afanasyev ◽

Dirk-Jan Eikema ◽

Frans Smiers ◽

Cora Knol ◽

...

Keyword(s):

Aplastic Anemia ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Advisory Committees ◽

Platelet Recovery ◽

Post Transplant ◽

Haploidentical Transplantation ◽

Grade Iii

Abstract The outcome of patients with severe aplastic anemia (SAA) has greatly improved in recent years but is still poor for patients who failed or relapsed after immunosuppressive therapy (IST) and don't have a matched donor. Recent use of eltrombopag shows blood count improvements in 40% of cases, but most patients refractory to immunosuppressive therapy, are also unresponsive to eltrombopag. In this situation, hematopoietic stem cell transplantation (HSCT) using alternative donor sources (mismatched unrelated donors, cord blood, and haploidentical family donors) may be curative but are also associated with a high risk of morbidity and mortality. Moreover, ethnic minorities have limited access to an alternative donor, especially in the adult population. Haploidentical transplantation using post-transplant cyclophosphamide (Haplo-PTCy) has been shown to facilitate engraftment and shows GvHD rates comparable to those of matched sibling HSCT in hematologic malignancies. However, few papers have been published on Haplo-PTCy in the context of aplastic anemia. We conducted a retrospective analysis of 36 patients (72% male), who received an haplo-PTCy for aplastic anemia in 22 EBMT centers from June 2010 to March 2017. Haplo-PTCy was the first transplantation for 81% patients (second, 11%; third, 8%). The non-myeloablative preparatory regimen included anti-thymocyte globulin in 33% of patients and low dose TBI in 58% of patients. Donors were father (n=12, 35%), mother (n=12, 35%), brother (n=5, 15%), sister (n=3, 9%), cousin (n=1, 3%) and daughter (n=1, 3%). The stem cell source was mainly bone marrow (55%). All patients received cyclophosphamide 50mg/kg/day IV on days +3, and +4 post-transplant and 75% received tacrolimus or cyclosporine plus mycophenolic acid. The primary endpoint was the probability of OS. Secondary study endpoints included probability of neutrophil recovery (ANC 500/ μL for at least 3 consecutive days), platelet recovery (platelets 20 000/ μL for at least 3 consecutive days, and 7 days after the last transfusion), cumulative incidences of acute and chronic GVHD and relapse-free survival without Grade III-IV acute GvHD and without extensive chronic (GRFS). Thirty-two patients were diagnosed with moderate (7%), severe (52%) or very severe idiopathic aplastic anemia (41%), while 4 patients were transplanted for congenital aplastic anemia (3 Fanconi Anemia and 1 Diamond Blackfan). The median age was 19.4 years (range 2.5-45.4 years; 58% adults). Median disease duration before haplo-PTCy was 11.3 months (1.9-201.2). Thirty patients (83%) received pretreatment (77% anti-thymocyte globulin plus cyclosporine, 12% eltrombopag, and 1 patient (3%) received androgens). Cumulative incidence (CI) of neutrophil recovery at day 60 was 78% (64-91) with a median time of 21 days (18-26). Cumulative incidence (CI) of platelet recovery at day 60 was 60% (44-76) with a median time of 31 days (22-185). The CI of grade II-IV acute GvHD was 26% (12-41%) (grade II 19% (7-32%), grade III 6% (0-13%) and no grade IV). CI of chronic GvHD was 17% (5-30) at 1 year (6% (0-13%) extensive) and a CI of 22% (7-37) at 2 years (only limited, there was no new case of extensive cGvHD after one year). With a median follow-up of 24.6 months (15.9 - 38.2), the estimated probability of overall survival (OS) was 78% (64-91) at 1 year and 74% (60-89) at 2 years. Of note, among the 4 patients with inherited disorders, 2 died [1 infection (Diamond Blackfan) and 1 aGvHD (Fanconi Anemia)] and 2 are alive at month 12 and month 15 of follow-up, respectively. Nine patients died during the study. The main cause of death was infection (n=6, 67%). Finally, the GRFS (alive, full donor chimerism, without previous grade III-IV GvHD and without extensive cGvHD) was 58% (41-75) at 2 years. In conclusion, with a median follow-up of 2 years, Haplo-PTCy leads to 74% overall survival in 36 patients with aplastic anemia, with almost 60% of the patients being free from GvHD complication. In a population with no other therapeutic options, our data suggests haplo-PTCY is a feasible option. However, prospective well-designed trials are urgently needed before the inclusion of Haplo-PTCy in the treatment strategy of aplastic anemia. Disclosures Bloor: Janssen: Research Funding; AbbVie: Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Russell:Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Speakers Bureau; Daiichi Sankyo: Consultancy. Kerre:Celyad: Consultancy; BMS: Consultancy; Celgene: Consultancy, Research Funding. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

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