Survival Implications of Opioid Use after Blood and Marrow Transplantation

B ackground Premature death from opioid-related causes imposes an enormous public health burden across the United States. Between 2001 and 2016, the number of opioid-related deaths in the United States increased by 345%, from 9489 to 42 245 deaths (33.3 to 130.7 deaths per million population. Moreover, opioids may have immunosuppressive properties independent of their psychotropic effects; opioid use has been associated with increased invasive pneumococcal disease in a nested case-control study of 1233 Medicaid patients from Tennessee. In liver transplant recipients, opioid use disorder has been associated with increased mortality after transplant. The impact of opioid use disorder on patients receiving blood and marrow transplant (BMT) remains to be defined. Methods We performed a retrospective analysis of all consecutive adult patients who had BMT (autologous and allogeneic) from 1/1/2008 through 1/1/2018 at the James Comprehensive Cancer Center. Overall survival (OS) was measured from the date of transplant to the date of death, censoring at date of last follow up if alive. Progression free survival (PFS) was measured from the date of transplant to the date of disease progression or the date of death, whichever occurred first, censoring at last follow up if no event. OS and PFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Opioid use (OU) was defined as a binary yes/no variable if an opioid was prescribed upon discharge from the hospital after BMT. The impact of OU, along with other patient, disease, and BMT related factors, on PFS/OS, was analyzed using Cox regression method. Results A total of 1585 patients were included in the analysis (Table 1). The median age at BMT was 58 (range=18-79) years; 59% were males; 60% had autologous transplants; and 58% were prescribed opioids upon discharge from the hospital. OU was significantly more in patients who were younger, have had allogeneic transplant, reduced intensity conditioning, had acute myeloid leukemia (AML), or higher BMT comorbidity index (CMI). On univariable analysis, OU was not associated with cumulative incidence of relapse (CIR) or PFS however it was associated with inferior OS; hazard ratio (HR)=1.25, 95% CI: 1.06-1.49; p=0.01 (Figure-1). There were no differences in CIR, PFS, or OS when autologous and allogeneic transplants were analyzed separately. Upon multivariable analysis of OS, OU lost statistical significance after controlling for age, diagnosis, type of transplant, intensity of conditioning regimen, CMI, and disease risk index (DRE). Of interest, OU independently predicted for superior OS at 100 days and 365 days post-BMT; HR=0.29, 95% CI 0.16-0.50 (p=<.0001) and HR=0.47, 95% CI 0.32-0.69 (p<0.001); respectively. Conclusion: Our results suggest that opioid use (OU) may have a long term negative impact on survival in BMT patients. The apparently protective effects of OU early on after BMT is elusive but may be possibly related immunomodulatory effects of opioids. A major limitation of our study is that OU is analyzed at a single time point at hospital discharge after BMT. We plan to undertake a more detailed analysis of ongoing OU after discharge and its impact on survival outcomes after BMT. Disclosures Brammer: Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Efebera:Celgene: Research Funding; Ohio State University: Current Employment; Pharmacyclics: Research Funding; Takeda: Honoraria, Speakers Bureau. Mims:Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Novartis: Speakers Bureau. Chaudhry:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Khan:Amgen: Consultancy; Janssen: Consultancy. Devarakonda:Janssen: Consultancy. Jaglowski:Novartis: Consultancy, Research Funding; CRISPR: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. William:Kyowa Kirin: Consultancy, Honoraria; Merck: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Guidepoint Global: Consultancy; Dova: Research Funding; Celgene: Consultancy, Honoraria.

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Body Mass Index and Survival of Patients with Lymphoma

Blood ◽

10.1182/blood-2020-139402 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 2-3

Author(s):

Dai Chihara ◽

Melissa C. Larson ◽

Dennis P. Robinson ◽

Carrie A. Thompson ◽

Matthew J. Maurer ◽

...

Keyword(s):

Body Mass Index ◽

At Risk ◽

Board Of Directors ◽

Body Mass ◽

Research Funding ◽

B Cell Lymphoma ◽

The United States ◽

Advisory Committees ◽

The Impact

Background: Obesity is increasing worldwide, with the highest prevalence in the United States. High or low body mass index (BMI) is a well-established risk factor for increased all-cause mortality and also has been associated with cancer-specific mortality. However, the impact of BMI on survival following diagnosis with lymphoma currently remains controversial. We leveraged a prospective cohort of lymphoma patients to assess the relationship of BMI two years prior to diagnosis (BMI-2), at diagnosis (BMI-dx), and three-years post-diagnosis (BMI+3) with lymphoma-specific survival (LSS) as the primary endpoint and with event-free survival (EFS) and overall survival (OS) as secondary endpoints. Patient and Method: Patients were prospectively enrolled at lymphoma diagnosis to the SPORE Molecular Epidemiology Resource (MER) cohort at Mayo Clinic and University of Iowa from 2002-2015. BMI-2 and BMI+3 were self-reported in patient questionnaires, while BMI-dx was extracted from the medical chart. Patients with extreme BMI (BMI <14 and BMI ≥50) were excluded from the analysis. BMI change from BMI-2 to BMI-dx and from BMI-dx to BMI+3 was categorized as no change (-5% to 5%), decrease (>-5%), and increase (>+5%). Person-time at risk was assessed from lymphoma diagnosis until death or last follow-up, except for analyses of BMI change from BMI-dx to BMI+3, which started person-time at risk when the 3-year (+/- 6 months) follow-up questionnaire was returned. Cause of death was assigned by a study clinician. For all lymphoma patients combined and in the most common subtypes, we evaluated the association of BMI at each time point and change in BMI with EFS, LSS, and OS using hazard ratios (HRs) and 95% confidence intervals (CI) from multivariable adjusted Cox models. Results: A total of 4,009 lymphoma patients (including 670 diffuse large B-cell lymphoma [DLBCL], 689 follicular lymphoma [FL] and 1018 chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL] and 1,632 others) with data on BMI-dx were included. Among them, 2,955 patients had BMI-2 and 2,004 had BMI+3 and were evaluable for change in BMI. The median age of all patients at diagnosis was 61 years (range 18-92 years), and 94% of patients had ECOG performance status <2. At the time of diagnosis, 28% were normal weight (BMI 18.5-25), 1% were underweight (BMI <18.5), 39% were overweight (BMI 25-30) and 32% were obese (BMI ≥30). With a median follow-up of 108 months from diagnosis (IQR 83-143 months), 1320 deaths were observed, 48% of which were due to lymphoma. Patients with FL who were obese at BMI-2 had significantly shorter LSS (HR: 3.02, 95%CI: 1.43-6.41, p=0.004). Associations between obesity at BMI-2 and LSS were not evident for DLBCL (HR: 1.04, 95%CI: 0.62-1.76, p=0.879) or CLL/SLL (HR: 1.10, 95%CI: 0.71-1.70, p=0.668) (Table). BMI-dx was not associated with LSS in any lymphoma patients, except that DLBCL patients who were underweight at BMI-dx (n=10) experienced shorter LSS (HR: 3.52, 95%CI: 1.22-10.1, p=0.020). This correlated significantly with presence of B symptoms (p=0.004) and may signify aggressive disease. Across all subtypes, >5% decrease in BMI from BMI-2 to BMI-dx was associated with significantly shorter LSS in patients with (HR: 2.02, 95%CI: 1.65-2.48, p<0.001). However, only for FL patients, >5% increase in BMI from BMI-dx to BMI+3 also was associated with significantly shorter LSS in subsequent years (HR: 3.74, 95%CI: 1.30-10.8, p=0.014). The associations reported for LSS generally were similar for EFS and OS. Conclusions: FL patients with obesity prior to diagnosis or who experienced increasing BMI after the diagnosis had significantly shorter LSS. The impact of weight control after the diagnosis of FL patient outcomes warrants investigation. Figure Disclosures Maurer: Celgene / BMS: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Flowers:Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy; Kite: Research Funding; Bayer: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; National Cancer Institute: Research Funding; AbbVie: Consultancy, Research Funding; V Foundation: Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding.

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The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Blood ◽

10.1182/blood-2021-146722 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2552-2552

Author(s):

Franck E. Nicolini ◽

Vincent Alcazer ◽

Stephanie Dulucq ◽

Sandrine Hayette ◽

Jean-Michel Cayuela ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chronic Phase ◽

Median Dose ◽

First Line ◽

Advisory Committees ◽

French Group ◽

Treatment Free Remission ◽

The Impact

Abstract Aims: The absolute number of chronic phase CML patients (pts) reaching the treatment-free remission (TFR) criteria has been substantially increased by the use of second-generation TKI (TKI2), initiated since diagnosis, comparing to Imatinib first-line. However, the relative rate of unsuccessful TFR (i. e. pts loosing their MMR after TKI2 cessation) still remains around 50% at 2 years and beyond, whatever the TKI2 was. The aim of this study is to analyse the rate of successful TFR in pts receiving Nilotinib (Nilo) or Dasatinib (Dasa) first-line obtaining the appropriate criteria. Methods: Observational retrospective study in 3 reference centers of the French group of CML lead between 2010 and 2021. Eligible pts were CP CML pts initiating either Nilo 300 mg BID or Dasa 100 mg daily since diagnosis, until cessation for sustained MR4.5 (i.e. ≥2 years on ≥4 datapoints). Data were retrospectively collected according to the national regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2009, 2013 and 2020 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) for TFR. In this regard, the TKI2 was resumed in case of loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. All patients were harbouring major BCR-ABL1 transcripts. The primary endpoint was the survival without loss of MMR after TKI2 cessation. The secondary endpoints were the kinetics of MMR loss, and the identification of factors influencing MMR loss. Results: Seventy-two pts were reported (47 Nilo, 25 Dasa) with 57% females with a median age at diagnosis of 48 (36.75-61.25) years. The median follow-up since diagnosis was 9.26 (3.75-13.75) years (8.8 for Nilo and 9.47 for Dasa p=ns) and after TKI2 cessation 3.94 (0.7-8.8) years (3.92 for Nilo and 3.90 for Dasa p=ns). Sokal scores were 42% Low, 41% Intermediate, 17% High in Nilo and 39% L, 25% I and 35% H in Dasa pts (p=ns). ELTS scores were 50% L, 22% I, 9.5% H (18.5% Uk) in Nilo and 46.5% L, 28.5% I and 3.5% H (21.5% Uk) in Dasa pts (p=0.95). Five (9%) pts harboured ACA at diagnosis in the Nilo group and 2 (7%) in the Dasa group (p=1.00). The median time from TKI2 initiation to sustained MR4.5 was 19 (3.12-36) months in the Nilo group and 16 (6.3-39) months in the Dasa group (p=0.644). The duration of sustained MR4.5 until cessation was 3.04 (1.5-9.3) years for Nilo and 2.65 (1.11-7.95) for Dasa (p=0.96). The median dosing of Nilo was 600 (300-800) mg daily and 80 (20-100) mg at TKI2 cessation. None of these patients switched to another TKI during the follow-up. TKI2 cessation occurred after 60.5 (43-74.5) months in the Nilo group and 68 (39-90) months in the Dasa group (p=0.581). Thirty-seven pts out of 47 (79%) were BCR-ABL1 undetectable at Nilo cessation 18/25 (72%) at Dasa cessation (p=0.60). At M3 after discontinuation, 58% of pts remained undetectable after Nilo cessation and 30.4% after Dasa cessation (p=0.05).The median survival of pts without loss of MMR was not reached in the Nilo group, and was 14 (4.73-NR) months in the Dasa group, (p=0.042) as analysed by the KM method (Figure 1.). Two patients died (1 Nilo, 1 Dasa) from competing events (solid tumours) after unsuccessful TFR. Twenty-eight pts (14 Dasa, 14 Nilo) restarted their TKI2 after MMR loss and all regained ≥ MMR after 3 months of Dasa at a median dose of 75 (40-100) mg daily and all except one (who regained MMR at M12) after resumption of Nilo at a median dose of 350 (300-600) mg daily. Univariate analysis identified pts with H+I Sokal (as compared to low) as an unfavourable factor for successful TKI2 cessation [HR=0.35 (0.15-0.83), p=0.017] and type of TKI2 (Nilo as reference vs Dasa) was discriminant [HR=2.1 (1.01-4.35), p=0.047]. Multivariate analysis identified the type of TKI2 as a significant factor impacting on TFR outcome [HR 2.11 (0.97-4.55], p=0.05]. Conclusions: As it is likely that no prospective head-to-head comparison will be performed in this setting, on this limited series of pts, we conclude that the outcome of TFR seems to be different according to the TKI2 used since diagnosis, suggesting the impact of distinct biological variables modified by the type of TKI2 on the long run (such as immunological system, BM micro-environment, others) on TFR outcome. Figure 1 Figure 1. Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Enestnd 4-Year (y) Update: Continued Superiority of Nilotinib Vs Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v120.21.1676.1676 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1676-1676 ◽

Cited By ~ 13

Author(s):

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

Surapol Issaragrisil ◽

Richard E Clark ◽

Josy Reiffers ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Molecular Responses ◽

The Difference ◽

The Impact

Abstract Abstract 1676 Background: Pts treated with nilotinib in the ENESTnd phase 3 trial achieved higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular responses (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), significantly lower rates of progression to accelerated phase/blast crisis (AP/BC), and fewer CML-related deaths compared with imatinib by 1, 2, and 3 y. Here, we report data with a minimum follow-up of 3 y; efficacy and safety data based on longer follow-up of 4 y will be presented to further assess the impact of nilotinib vs imatinib in pts with newly diagnosed Ph+ CML-CP. Methods: Adult pts (N = 846) with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID; n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD; n = 283). MMR, MR4, MR4.5, time to progression to AP/BC, progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Significantly higher rates of MMR, MR4, and MR4.5 by 3 y were achieved in nilotinib- vs imatinib-treated pts (Table). Nilotinib led to the achievement of higher rates of molecular responses regardless of Sokal risk group or age. The difference in the rates of both MR4 and MR4.5 continued to be significantly higher for nilotinib, with the difference in favor of nilotinib increasing from 1 to 3 y (MR4: 9%-14% difference by 1 y, 18%-24% difference by 3 y; MR4.5: 6%-10% difference by 1 y, 13%-17% difference by 3 y). Among patients who achieved MMR, more pts achieved MR4 or MR4.5 on nilotinib 300 mg BID (68%) and nilotinib 400 mg BID (62%) compared with imatinib (49%). No pt in any arm progressed after achieving MR4.5. Significantly fewer pts progressed to AP/BC on nilotinib vs imatinib (Table). No new progressions occurred on core treatment between the 2-y and 3-y analyses. When events occurring after treatment discontinuation were included, the rates of progression to AP/BC were also significantly lower with nilotinib vs imatinib (Table). Nearly twice as many pts had emergent mutations on imatinib (n = 21) vs either nilotinib arm (n = 11 in each arm), with 5 pts overall developing mutations between 2 and 3 y. OS remained similar in all groups at 3 y, but fewer CML-related deaths occurred in both the nilotinib 300 mg BID (n = 5) and 400 mg BID (n = 4) arms vs imatinib (n = 14). Both drugs were well tolerated. Few new adverse events (AEs) and laboratory abnormalities were observed between 2 and 3 y. Rates of discontinuation due to AEs were 10%, 14%, and 11% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib arms, respectively. Conclusions: Nilotinib continues to demonstrate superiority vs imatinib, yielding faster and deeper molecular responses and a significantly decreased risk of progression. Results of ENESTnd support the use of nilotinib as a standard of care option in newly diagnosed adult pts with Ph+ CML-CP and should be considered to replace imatinib as the standard-of-care frontline therapy for patients with Ph+ CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kim:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Research Funding. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reiffers:BMS: Expense reimbursement for travel expenses Other; Novartis: Expense reimbursement for travel expenses, Expense reimbursement for travel expenses Other. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

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Registry Of Patients Treated With Protein C Concentrate (Human) In The United States and Europe: Interim Results

Blood ◽

10.1182/blood.v122.21.1146.1146 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1146-1146

Author(s):

Marilyn J. Manco-Johnson ◽

Paul Knoebl ◽

Amy D. Shapiro ◽

Maureen Finnerty ◽

Leman Yel ◽

...

Keyword(s):

United States ◽

Board Of Directors ◽

Research Funding ◽

Protein C ◽

The United States ◽

Employment Equity ◽

Advisory Committees ◽

Protein C Concentrate ◽

Concentrate Treatment ◽

Equity Ownership

Abstract Background Protein C (PC) is a naturally occurring, vitamin-K dependent anticoagulant produced by the liver. Deficiency of PC, which can be congenital or acquired, results in a hypercoagulable state. Patients with severe PC deficiency may manifest severe, often life-threatening, disseminated intravascular coagulation (DIC), purpura fulminans (PF), and/or thromboembolism. Highly purified protein C concentrate prepared from human donor plasma (Ceprotin; Baxter Healthcare Corporation, Westlake Village, CA) is an approved therapy for prevention and treatment of venous thrombosis and PF in patients with severe congenital PC deficiency (SCPCD) in the United States. It is indicated in patients with SCPCD for PF and coumarin-induced skin necrosis, and short-term prophylaxis in the European Union and other countries. Use of protein C concentrate (human) has been reported in patients with acquired PC deficiency. The Ceprotin Treatment Registry is a prospective, international, multi-center, open-label, non-interventional, observational study designed to examine the long-term safety and effectiveness of protein C concentrate (human) in the clinical setting. This is the first large, real-world assessment of the treatment of a rare disease with protein C concentrate (human). Here we report data from the first interim analysis in June 2013 covering a 3-year enrollment period. Methods Patients of any age who received, or were initiating/receiving protein C concentrate are included. The study duration is 5 years (3-year enrollment period plus 2 years of follow-up). All study visits/assessments are in accordance with standard of care, with protein C concentrate dose, dose frequency, duration and route of administration determined by the investigator. The study objectives are to determine the most common medical diagnoses associated with protein C concentrate treatment, protein C concentrate treatment regimens, and safety information based on all serious adverse events (SAEs) and rate of treatment-related AE. Other objectives include: an examination of the relationship between protein C concentrate treatment and outcomes in all registry participants, as well as various subgroups. Descriptive statistical analyses are used. Results At the time of data extraction, 34 patients were enrolled from 26 centers; 10 centers in the United States and 16 centers in Europe. Half of the patients were males. The primary diagnosis of PC deficiency was congenital in 25 patients (73.5%) and acquired in 9 patients (26.5%). The median age at diagnosis was 0.03 years (range 0–19.9). Mean plasma PC activity level was 9% (range 1–40.0). The most common (in ≥3 patients) thrombotic disease-associated conditions were PF (50.0%); blindness (44.1%); thromboembolic disease (41.2%), which included deep vein thrombosis, arterial thrombosis and DIC; stroke (32.4%), and renal dysfunction (8.8%). Of the 23 patients being treated with protein C concentrate, 15 were administered protein C concentrate intravenously, and 8 patients received protein C concentrate subcutaneously. The body weights of patients receiving subcutaneous treatment ranged from 10.0 kg to 57.9 kg. A total of 15 patients received an anticoagulant treatment in addition to protein C concentrate. Eight patients reported 23 SAEs, all of which were considered not related to treatment. Eighteen (52.9%) patients reported 72 AEs; only 1 of them, an episode of upper respiratory infection, was considered possibly treatment-related. In 18 patients in whom PC activity recovery was determined after protein C concentrate treatment, there were no patients documented with poor recovery. Protein C concentrate was used during 18 surgeries/invasive procedures and considered effective in all interventions for which data were available. Conclusions Data from the first interim analysis of the Ceprotin Treatment Registry demonstrate that patients with both congenital and acquired severe PC deficiency who are treated with protein C concentrate (human) have a low incidence of treatment related SAEs and AEs, and treatment with protein C concentrate appears to be effective when used during surgery/invasive procedures. Further patient follow up will shed light onto clinical treatment outcomes. Disclosures: Manco-Johnson: CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Research Funding. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria. Shapiro:Cangene: Research Funding; Biogen Idec: Research Funding; Baxter BioScience: Research Funding; Bayer HealthCare: Research Funding. Finnerty:Baxter: Employment, Equity Ownership. Yel:Baxter: Employment, Equity Ownership. Gelmont:Baxter: Employment, Equity Ownership.

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Chronic Exposure to Cytoreductive Treatment Shapes Clonal Evolution in Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2021-152622 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3620-3620

Author(s):

Lin-Pierre Zhao ◽

Nabih Maslah ◽

Rafael Daltro De Oliveira ◽

Emmanuelle Verger ◽

Juliette Soret-Dulphy ◽

...

Keyword(s):

Board Of Directors ◽

Mutation Rate ◽

Chronic Exposure ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Clonal Evolution ◽

Advisory Committees ◽

Cytoreductive Treatment ◽

The Impact

Abstract Introduction: Myeloproliferative neoplasms (MPN) are a heterogeneous group of chronic myeloid malignancies resulting from the combination of a driver mutated gene (JAK2, MPL or CALR) and a variety of acquired additional somatic mutations. Although next-generation sequencing (NGS) has identified high molecular risk mutations associated with adverse prognosis (Vannucchi et al., Leukemia, 2013 , Guglielmelli et al., Leukemia, 2014 ), the clonal evolution of these mutations remains poorly described. Chronic exposure to cytoreductive treatment, especially genotoxic drugs such as hydroxyurea (HU), could impact clonal evolution. A previous study suggested that Interferon-α (IFN) could limit the accumulation of cytogenetic abnormalities compared to HU (Mondello et al., Blood, 2018). The objective of our study was to describe the long-term evolution of the mutational landscape in the era of NGS in a large cohort of MPN patients. Methods: A total of 1538 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and January 2021. This study included 1039 of them in whom a NGS molecular analysis targeting 36 myeloid genes with a sensitivity of 1% was performed at diagnosis and/or during follow-up. Patients with only one NGS (n=588), AML/MDS transformation at either the first (n=3) or the second NGS (n=2) were excluded from the analysis. Serial NGS data obtained in chronic MPN phase were thus analyzed for 446 patients. Clinical and biological characteristics at time of diagnosis and follow-up were collected from medical charts and electronic medical records. Mutation rates per year were calculated for each gene as the difference in the number of mutations between first and last NGS divided by the time interval (in years) between both NGS. Results : Median age at MPN diagnosis in our whole cohort was 51 years [IQR 41-60]. Our cohort included 167 (37%), 205 (46%) and 64 (14%) patients with Polycythemia Vera (PV), Essential thrombocythemia (ET) and primary myelofibrosis (MF) respectively. 279 patients (63%) had at least one additional mutation at first NGS, and respectively 27 (6%) and 104 (23%) patients had TP53 and high molecular risk mutations. Median interval between MPN diagnosis and the first NGS was 6.5 years [IQR 1.7-13] while median time between the first and the last NGS was 2.5 years [IQR 1.6-4, range 0.3-14.3]. Overall, 178 patients (39.9%) acquired an additional mutation at last NGS evaluation, most frequently involving TET2, DNMT3A, ASXL1, TP53 and NFE2 genes . To study the impact of chronic MPN therapy on clonal evolution, we focused on patients who electively received HU (n=112) or IFN (n=92) as a monotherapy, or did not receive any cytoreductive treatment (n=119) between the first and the last NGS. The remaining patients received ruxolitinib (n=44), anagrelide (n=10), vercyte (n=7) or polytherapy (n=62). At last follow-up, 74 patients receiving IFN (80.4%) and 65 (58%) treated with HU had a complete hematological response. When combining all additional mutations, the global mutation rate per year did not significantly differ between treatment groups. When analyzing individual genes, TP53 mutation rate was higher in patients treated with HU compared to the patients receiving IFN (p=0.014) or not treated (p=0.008) (Figure). MDS/AML evolution occurred in 4 patients (3.6%) treated with HU, 2 (1.7%) without cytoreductive therapy versus none of the 92 patients treated with IFN (ns). In the whole cohort, MDS/AML evolution was significantly increased in patients harboring TP53 mutations (p= 0.004). In contrast, DNMT3A mutation rate was significantly increased in patients receiving IFN compared to patients treated with HU (p=0.045) (Figure). The latest result is in line with previous observations showing that loss of DNMT3A could confer resistance to IFN in a JAK2-V617F mouse model (Stetka et al., Blood, 2020). Conclusion: Our results highlight the impact of chronic cytoreductive therapy on clonal evolution shaping in MPN. IFN limits the emergence of TP53 mutated clones compared to HU, thus potentially reducing the risk of leukemogenesis. Emergence of DNMT3A mutated clones under IFN therapy requires further exploration and could potentially play a role in therapeutic resistance. This study on a large clinically and biologically annotated cohort illustrates how serial NGS analysis may guide therapeutic options for MPN patients. Figure 1 Figure 1. Disclosures Raffoux: PFIZER: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Kiladjian: AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees. Benajiba: Pfizer: Research Funding; Gilead: Research Funding.

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Disease and Clinical Characteristics of Patients with Essential Thrombocythemia Enrolled in the MOST Study

Blood ◽

10.1182/blood-2018-99-112183 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4306-4306

Author(s):

Abdulraheem Yacoub ◽

Roger M. Lyons ◽

Srdan Verstovsek ◽

Ryan Shao ◽

David Tin Chu ◽

...

Keyword(s):

United States ◽

Observational Study ◽

Board Of Directors ◽

Essential Thrombocythemia ◽

Research Funding ◽

Clinical Characteristics ◽

The United States ◽

Advisory Committees ◽

History Of ◽

Equity Ownership

Abstract Introduction: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by clonal platelet production and an increased risk for thrombotic and hemorrhagic events. Limited real-world data exist regarding the clinical characteristics and treatment patterns of ET in the United States; most prior data have been generated outside the United States. The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) is an ongoing observational study being conducted to describe contemporary demographics, burden of disease, clinical management, and patient-reported outcomes in patients with specific risk categories of myelofibrosis (MF) or ET in the United States. This analysis describes the clinical characteristics of patients with ET currently enrolled in MOST. Methods: MOST is a multicenter, noninterventional, prospective, observational study in patients with a clinical diagnosis of specific risk categories of MF or ET (NCT02953704). Eligible patients with ET included high-risk patients (≥ 60 years of age and/or a history of thromboembolic events [TEs]), or low-risk patients currently receiving ET-directed therapy. Key exclusion criteria included participation in blinded investigational drug studies, life expectancy ≤ 6 months, or diagnosis of other malignancy. Data regarding disease and clinical characteristics are collected at usual-care visits over a planned 36-month observation period. Patient demographics and clinical characteristics at enrollment were described with descriptive statistics. Results: At data cutoff (May 18, 2018), 793 eligible patients were enrolled from 85 sites since November 29, 2016. The median age at enrollment was 70 (range, 24-95) years, 66.5% were female, and 89.8% were Caucasian. The median time from ET diagnosis to enrollment was 4.2 (range, 0.0-42.1) years with a proportion of patients diagnosed within 1 year (19.5%), 1 to < 5 years (35.0%), 5 to < 10 years (21.7%), or ≥ 10 years (23.8%) of enrollment. Approximately 40% of patients were retired and 42.7% were working full- or part-time at enrollment. A total of 212 patients (26.7%) had a history of TE at the time of enrollment. The type of TE was available for 148 patients, the most common was arterial events (53.4%); 33.1% had venous, and 13.5% of patients had both arterial and venous events. Six hundred and eighty-eight patients (86.8%) were classified as high-risk. Assessments at the time of ET diagnosis, among evaluable patients, included bone marrow biopsy (51.4%; 393/765) and mutational testing (77.2%; 590/764). Three hundred and forty-nine patients had mutation test results reported at the time of diagnosis; of patients with JAK2 V617F test results reported at the time of diagnosis (n = 313), 78.6% were positive for JAK2 V617F (Table 1). Laboratory values and peripheral blood counts were reported for patients with available data (Table 2). The majority of patients (87.9%) had received at least 1 ET-directed therapy prior to enrollment, which in some cases was the same medication the patient was receiving at the time of enrollment. At the time of enrollment, 740 patients (93.3%) were receiving at least 1 current ET-directed therapy, including HU (71.6%; 530/740), anagrelide (13.1%; 97/740), ruxolitinib (4.7%; 35/740), interferon (3.0%; 22/740), and busulfan (0.3%; 2/740). Of 793 patients, the most frequently occurring relevant comorbid conditions were hypertension (52.7%), history of smoking (44.7%), and hyperlipidemia (24.1%). Among 761 patients with ET-related symptoms assessed at diagnosis, the most common symptoms documented by healthcare providers included constitutional (22.9%), vasomotor (16.0%), and spleen-associated symptoms (3.9%), and pruritus (2.6%). Conclusions: Prior real-world data in ET has predominately been generated outside of the United States or has been reported from single institutional experiences. The MOST study will provide a more complete picture of the patient characteristics and outcomes of patients receiving ET-directed therapy in the United States. Ultimately, these data will be important for determining ET treatment gaps and areas of unmet need. Disclosures Yacoub: Cara Therapeutics: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ardelyx, INC.: Equity Ownership; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Shao:ASH: Membership on an entity's Board of Directors or advisory committees; ASCO: Membership on an entity's Board of Directors or advisory committees. Agrawal:Incyte: Speakers Bureau. Sivaraman:Incyte: Employment. Colucci:Incyte: Employment, Equity Ownership. Yao:Incyte: Employment. Mascarenhas:Celgene: Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Janssen: Research Funding.

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Anatomical Predictors of Venous Thromboembolism Recurrence after Isolated Superficial Vein Thrombosis

Blood ◽

10.1182/blood.v126.23.651.651 ◽

2015 ◽

Vol 126 (23) ◽

pp. 651-651

Author(s):

Jean-Philippe Galanaud ◽

Marie-Antoinette Sevestre ◽

Céline Genty ◽

Susan R Kahn ◽

Gilles Pernod ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

Superficial Vein ◽

Advisory Committees ◽

Vein Thrombosis ◽

Superficial Vein Thrombosis ◽

The Impact

Abstract Background: Isolated superficial vein thrombosis (iSVT) (i.e. without concurrent deep-vein thrombosis or pulmonary embolism) is a frequent event. Its clinical significance and management are controversial. Data on long-term follow-up are scarce and the impact of anatomical characteristics of iSVT on the risk of venous thromboembolism (VTE) (DVT and/or PE) recurrence has not been assessed. Objective: To determine the impact of anatomical characteristics of iSVT on the long-term risk of VTE recurrence. Methods: Using data from the The OPTIMEV (OPTimisation de l'Interrogatoire dans l'_evaluation du risque throMbo-Embolique Veineux) study, a prospective, observational, multicenter study, we assessed at 3 years in patients recruited for an objectively confirmed iSVT i) cumulative rates of DVT, PE and SVT recurrences using the Kaplan-Meier method; and ii) anatomical predictors of VTE recurrence (SVT involving the sapheno-femoral junction (i.e. ≤3 cm), SVT of the trunk of the great saphenous vein, bilateral SVT, SVT occurring in a varicose vein (i.e. C≥2 according to CEAP classification) using a Cox multivariable model adjusted for age, sex, cancer and personal history of VTE. At baseline, all patients with SVT underwent a complete bilateral swhole leg ultrasound to exclude concurrent DVT and during follow-up, all suspected VTE recurrences were confirmed/ruled out with objective tests. All recurrences were centrally adjudicated by the study's expert committee. Results: Among the 479 recruited patients with iSVT, 12.5% (n=60) had a thrombotic recurrence during the 3 years of follow-up. Cumulative rates of recurrence as a PE, DVT and iSVT were 1.9%, 4.8% and 5.8%, respectively. In multivariate analysis, a thrombus involving the sapheno-femoral junction at baseline independently increased the risk of VTE recurrence (HR=3.34 [1.5-7.2]). Presence of varicose veins also increased the risk but this result did not reach statistical significance (HR=1.8 [0.9 - 3.9], p=0.11). Conclusion: In an unselected population of patients with iSVT, long-term risk of VTE recurrence is substantial. Involvement of the sapheno-femoral junction is a strong independent predictor of VTE during the subsequent 3 years. Our results suggest the need for more aggressive management and follow-up of patients with iSVT exhibiting this anatomical characteristic. Disclosures Galanaud: Daichi: Membership on an entity's Board of Directors or advisory committees, Research Funding; bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sevestre:bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pernod:pfizer: Consultancy; leo: Consultancy; bristol meyers: Consultancy; Daichi: Consultancy; bayer: Consultancy. Brisot:bayer: Membership on an entity's Board of Directors or advisory committees; daichi: Membership on an entity's Board of Directors or advisory committees. Quéré:3-M: Research Funding; thuasne: Research Funding; aspen: Research Funding; daichi: Membership on an entity's Board of Directors or advisory committees; bayer: Membership on an entity's Board of Directors or advisory committees; leo: Membership on an entity's Board of Directors or advisory committees.

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No Difference in Survival Among Black Patients with Mycosis Fungoides and Sézary Syndrome: A Multicenter Retrospective Analysis

Blood ◽

10.1182/blood-2021-151911 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2441-2441

Author(s):

Pamela Allen ◽

Subir Goyal ◽

Irl Brian Greenwell ◽

Jane Scribner ◽

Sunil Rangarajan ◽

...

Keyword(s):

United States ◽

Board Of Directors ◽

Mycosis Fungoides ◽

Median Survival ◽

Systemic Therapy ◽

Research Funding ◽

The United States ◽

Insurance Status ◽

Stage At Diagnosis ◽

Advisory Committees

Abstract Introduction Black (B) patients with Mycosis fungoides and Sézary Syndrome (MF/SS) have inferior survival and distinct clinical presentations, including many high risk features compared to non-black (NB) patients with MF/SS in large registry studies from the United States. We sought to characterize clinical differences in presentation, treatment, and outcomes to identify drivers of disparities among B patients with MF/SS. Methods We performed a retrospective review of 417 patients with MF/SS diagnosed between 1990 and 2020 at 6 academic institutions in the United States that serve populations with large numbers of Blacks and minorities. Patients with pathologic review and a confirmed histopathologic diagnosis of MF or SS with a stage >1B as their highest TNMB stage were eligible for inclusion. The primary objective was to assess differences in clinical characteristics, treatment patterns, and survival between B and NB patients. Clinical variables included demographics, insurance, zip code, tumor characteristics, and treatment. Descriptive analysis was performed for each variable. Comparison between B and NB patients utilized ANOVA for numerical covariates and chi-square test or Fisher's exact test for categorical covariates. Kaplan-Meier curves for OS were generated, and subgroups were analyzed separated. Results Among 417 patients, 204 (48.9%) were Blacks, 196 (47.0%) were White, and (4.1%) were other races (8 Asian, 5 unknown, 4 Hispanic). The diagnosis was MF in 366 (87.8%), SS in 47 (11.3%), and other 4 patients. Stage at diagnosis was available for 384 patients. 37 (9.6%) were stage 1A, 165 (43%) were stage 1B, 34 (8.9%) were stage 2A, 58 (15.1%) were stage 2B, 44 (11.5%) were stage 3, and 46 (12%) were stage 4 at diagnosis. The median survival of the whole cohort (n=417) was B patients were younger (median 50.1 years in B vs. 60.5 in NB, p<0.001), more often female (49.5% in B; 35.7% in NB, p=0.004), had higher rates of reported lymphadenopathy (78.5% vs. 70%, p=0.039), longer delays from symptom onset to diagnosis (2.0 years in Black vs. 1.2 years in NB, p=0.014), and higher rates of bacteremia at any time in their disease course (19.7% in Black, vs. 6.6% in NB, P< 0.001) compared to NB patients. There was no difference in insurance status (private, Medicare/Medicaid, or uninsured) or comorbidities by race. There was also no differences in overall TNMB stage at diagnosis (p=0.14) compartment stage, or highest stage (p=0.076). Progression to a higher T, N, M, or B stage occurred at similar frequencies in B and NB patients (n=83 (43.2%) in Black and n=73 (38.8%) in NB, p=0.38). Time to first therapy, time to systemic therapy, or total lines of therapy also did not differ by racial group. A greater fraction of B compared to NB patients received systemic therapy but this did not reach statistical significance (72.6% in Black vs. 62% in NB, p=0.060). There was no difference in large cell transformation at any point, or white blood cell count (WBC), lactate dehydrogenase (LDH), or T-cell receptor (TCR) clonality in skin/blood at diagnosis. On univariate analysis, race was not associated with survival; the median survival was 10.5 years (95% CI 8-13.2) in B patients and 10.9 years (95% CI 7.2-14.1) in NB patients. Covariates associated with inferior survival included older age (p<0.001), number of comorbidities (p< 0.001), bacteremia (p< 0.001), higher overall TNMB stage, higher individual T, N, M and B stage, progression to a higher N or M stage, positive TCR in the blood, WBC value, and LDH value. Insurance status and year of diagnosis (prior to 2010, vs. following 2010) were not associated with survival. On multivariate cox proportional hazard model, age at diagnosis, comorbidities, extra-cutaneous disease, bacteremia, TNMB stage at diagnosis, and progression to a higher nodal stage remained statistically significant for survival. Conclusions We present the first multicenter analysis of racial disparities in MF/SS, with nearly 50% B patients. B patients had distinct presentations, delay in diagnosis, and higher rates of bacteremia compared to NB patients. In contrast to US-registry studies, there was no difference in survival between B and NB patients. This finding could be explained by access to academic centers and/or higher rates of insurance coverage among B patients in our cohort. Additional analyses will be updated at the time of the presentation. Figure 1 Figure 1. Disclosures Allen: ADC Therapeutics: Consultancy; Kyowa Kirin: Consultancy; Secure Bio: Consultancy. Mehta: Seattle Genetics; Incyte; TG Therapeutics: Consultancy; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding. Huen: Rhizen: Research Funding; Elorac: Research Funding; Kyowa Kirin: Research Funding; Tillium: Research Funding; Innate: Research Funding; Galderma: Research Funding; Miragen: Research Funding. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

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Dasatinib Versus Imatinib in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Not Achieved an Optimal Response to 3 Months of Imatinib Therapy: Dascern

Blood ◽

10.1182/blood-2018-99-111978 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 788-788 ◽

Cited By ~ 4

Author(s):

Jorge E. Cortes ◽

Qian Jiang ◽

Jianxiang Wang ◽

Jianyu Weng ◽

Huanling Zhu ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Tolerability Profile ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Molecular Responses ◽

Optimal Response ◽

Grade 3 ◽

The Impact

Abstract Introduction: Treatment with dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has resulted in high rates of cytogenetic and molecular responses for pts with CML-CP, both as initial therapy and after failure of other therapies. A reduction in BCR-ABL1 transcript levels to ≤ 10% on the International Scale (IS) at 3 mo is associated with an improved probability of deep molecular responses and superior progression-free and overall survival (PFS and OS). In DASISION, considerably more pts treated with dasatinib achieved BCR-ABL1 ≤ 10% IS compared to imatinib. BCR-ABL1 ≤ 10% IS at 3 mo is considered an optimal response by international guidelines; however, approximately one-third of pts with CML-CP on first-line (1L) imatinib will not achieve this threshold. Clinical studies exploring the potential benefit of early switching to dasatinib in pts with less than optimal responses on initial imatinib treatment have not been reported. Methods: DASCERN (NCT01593254) is a randomized, open-label, international phase 2b trial in adult pts with CML-CP who had achieved complete hematologic response (CHR) but who had BCR-ABL1 > 10% IS at 3 mo after initial treatment with 400 mg imatinib once daily (QD). Imatinib must have been started within 6 mo of the initial CML-CP diagnosis. Pts were randomized 2:1 to receive 100 mg dasatinib QD or continue imatinib at ≥ 400 mg daily with the option for dose escalation. Pts initially randomized in the imatinib cohort who met European LeukemiaNet 2013 failure criteria after randomization and without dasatinib-resistant mutations were crossed over to the dasatinib arm. The primary endpoint in DASCERN is the rate of MMR (BCR-ABL1 < 0.1% IS) at 12 mo after day 1 initiation of 1L imatinib (9 mo after randomization). Secondary endpoints include time to MMR, OS, and PFS (progression was defined as transformation to accelerated/blast phase or death). Tertiary endpoints include safety and tolerability profile of both treatment arms and cytogenetic response over time. Results: All 260 randomized pts (dasatinib: n = 174; imatinib: n = 86) had a minimum follow-up of ≥ 12 mo from the last pts 1st visit (Sokal scores: 28% low, 30% intermediate, 24% high, 18% unknown; median age 37 y [range 18-82, 95% were < 65 y]; 78% male; 73% Asian). All pts had e13a2 or e14a2 transcript types. At the time of analysis, 84% of pts were continuing in the study. Median daily dose was 100 mg QD (range 26-142) for dasatinib and 400 mg QD (range 129-825) for imatinib. Median treatment duration was 111 wk (774 d) in the dasatinib arm and 68 wk (477 d) in the imatinib arm; 42 (49%) imatinib-randomized pts crossed over to dasatinib. Rate of MMR at 12 mo in the intent-to-treat population was 29% (95% confidence interval [CI] 22, 36) for dasatinib and 13% (95% CI 7, 22) for imatinib (P = 0.005); median time to MMR was 14 mo (range 12-18) for dasatinib vs 20 mo (range 14-26) for imatinib (P = 0.053). No differences in the rate of progression or OS were observed between treatment arms. No new safety signals were observed for either treatment arm and the early switch to dasatinib did not increase the toxicity rate. Treatment-emergent pleural effusion (PE; any grade) occurred in 11 (6%) pts randomized to dasatinib and 3 (7%) imatinib-randomized pts who crossed over to dasatinib; treatment-emergent PE grade 3/4 occurred in 1 (1%) pt randomized to dasatinib and 2 (5%) pts randomized to imatinib who crossed over to dasatinib. Hematologic toxicity was similar between treatment arms: neutropenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and 12 (29%) pts randomized to imatinib who crossed over to dasatinib; thrombocytopenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and in 7 (17%) pts randomized to imatinib who crossed over to dasatinib. Two dasatinib-treated pts discontinued due to hematologic toxicity (1 neutropenia, 1 thrombocytopenia). Conclusions: Early results from DASCERN show that pts with suboptimal responses to imatinib at 3 mo who switched to dasatinib had a significantly increased rate of MMR at 12 mo compared to pts who remained on imatinib. Longer follow-up is required to assess the impact of early switching on PFS and OS, and achievement of deep molecular responses. Disclosures Cortes: Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding. Kim:BMS: Research Funding; Ilyang: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Gurnani:Bristol-Myers Squibb: Employment.

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Pre-CAR Blinatumomab Is Associated with Increased Post-CD19 CAR Relapse and Decreased Event Free Survival

Blood ◽

10.1182/blood-2020-139260 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-14

Author(s):

Agne Taraseviciute ◽

Seth M. Steinberg ◽

Regina M. Myers ◽

Lia Gore ◽

Adam J. Lamble ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Car T Cell ◽

Increased Risk ◽

Car T ◽

The Impact ◽

Cd19 Expression

Introduction: Both CD19 CAR T-cells (CD19 CAR) and blinatumomab (blina) effectively induce remission in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r ALL). However, blina use prior to CD19 CAR has raised concerns for increased relapse risk and/or CAR non-response due to selective pressure on CD19. The tisagenlecleucel registration trial in pediatric ALL excluded patients who had received prior blina. Thus, there is limited data regarding the impact of blina on long-term outcomes in patients receiving subsequent CD19 CAR. Methods: This retrospective, multicenter study was performed to evaluate the impact of pre-CAR blina on subsequent CD19 CAR outcomes in pediatric and young adult patients with r/r ALL < 25 years at diagnosis. The primary objective was to evaluate relapse (RFS) and event free survival (EFS) at 6 months following CD19 CAR stratified by blina use. Secondary objectives included: evaluation of RFS at 12 months and response to CD19 CAR. All patients had their first CAR T-cell infusion between the years 2012-2019 and had at least 30 days of follow-up (or an event prior to 30 days). Descriptive statistics were used for baseline demographics and comparison between cohorts. Kaplan-Meier estimates were used to evaluate survival. Results: A total of 420 patients from 7 centers received 1 of 3 CD19 CAR T-cell constructs. (Table 1) The median age at diagnosis and at CAR infusion was 7.1 years and 12.4 years, respectively (range, 0.6-30 years). Amongst 412 patients evaluable for response, a total of 375 (91.0%) patients achieved a complete remission (CR); 363 (96.8%) of whom were minimal residual disease (MRD) negative (by flow cytometry). Thirty-seven (9.0%) of evaluable patients were CD19 CAR non-responders. With a median potential follow-up of 2.3 years (IQR, 1.6-3.3 years), 164 (43.7%) patients experienced relapse. Seventy-five (17.8%) patients received blina prior to CD19 CAR. The median time from last blina use to CD19 CAR was 129 days (IQR, 79-304 days). Blina was associated with an increased risk of CAR non-response; 13/71 (18.3%) blina patients versus 24/341 (7.0%) non-blina patients were non-responders (p=0.0052). Ten of 71 (14.1%) were non-responders to both CD19 CAR and blina; 19 of 29 (66%) blina non-responders achieved remission with subsequent CD19 CAR. Baseline disease status did not differ between blina and non-blina patients at CAR T-cell infusion, although a higher fraction of blina patients harbored KMT2Ar cytogenetics (11/75 (14.7%) versus 22/345 (6.4%), p=0.03). Pre-CAR blina was associated with worse EFS and RFS, but not overall survival (OS). The 6-month RFS for blina and non-blina patients was 63.4% (95% CI, 49.6-74.4%) and 81.1% (95% CI, 76.3-85.0%), respectively (Figure 1A). The 6-month EFS for blina and non-blina patients was 49.7% (95% CI, 37.8-60.5%) and 72.1% (95% CI, 67.1-76.6%), respectively (Figure 1B). Analysis excluding KMT2Ar patients to evaluate for the possibility that these patients represented a higher-risk subgroup and could skew the data, revealed similar EFS and RFS. Amongst 408 patients with pre-CAR CD19 analysis, 6/69 (13.0%) of blina patients versus 21/339 (6.2%) of non-blina patients had CD19 dim/partial/negative disease (p=0.07). Serial CD19 evaluation pre/post blina revealed that 6/52 (11.5%) had CD19 evolution to dim expression. Conclusions: This large, multicenter analysis demonstrate an association with blina use and 1) increased risk of CAR non-response; 2) worse RFS and EFS and 3) a trend towards a higher incidence of pre-CAR CD19 dim disease. While blina non-response did not preclude CD19 CAR response, blina non-responders had lower remission rates to CD19 CAR and a cohort of patients were refractory to both, potentially suggesting resistance to immunotherapeutic CD19 targeting. Additionally, we found that blina may impact CD19 expression, which could subsequently affect response and relapse. Mechanisms of resistance to CD19 CAR include antigen escape or an inherent resistance to T-cell mediated killing. Our data suggest that 1) patients relapsing after or refractory to blina who proceed to CD19 CAR may have an inherent resistance and 2) blina may impact CD19 expression. Ongoing analysis includes detailed analysis of low/dim/partial CD19 expression to delineate the potential impact of blina exposure on leukemic blasts and evaluation of the role of HSCT. Disclosures Gore: Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Brown:Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Laetsch:Bayer: Consultancy, Research Funding; Cellectis: Consultancy; Pfizer: Research Funding; Novartis: Consultancy, Research Funding. Gardner:Novartis: Honoraria. Rheingold:Pfizer: Research Funding. Pulsipher:Mesoblast: Honoraria; Novartis: Honoraria; Adaptive: Research Funding; Miltenyi: Honoraria, Research Funding; Bellicum: Honoraria; Jasper: Honoraria.

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