Primary Central Nervous System Involvement at Initial Diagnosis Remains an Independent Risk Factor for Relapse in Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplantation in CR1

Abstract Background: A recent study from the Acute Leukemia Working Party of EBMT demonstrated that outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adults with acute lymphoblastic leukemia (ALL) have improved significantly over time and that total body irradiation (TBI) should be considered as the preferable type of myeloablative conditioning (MAC). This study, however, did not compare outcomes of allo-HCT in patients with CNS involvement (CNS-pos) vs. those without CNS disease (CNS-neg). Study population: Here, we evaluate post allo-HCT outcomes of 547 patients (CNS-pos at initial presentation=96, CNS-neg=451) who underwent the procedure in first complete remission (CR1) between 2009 and 2019 at an EBMT participating transplant center. The distribution of ALL subtypes were as follows: CNS-pos (Ph-neg B ALL=28%, Ph-pos B ALL=27%, and T-cell ALL=45%) and for CNS-neg (Ph-neg B ALL=21%, Ph-pos B ALL=44%, and T-cell ALL=35%), p=0.01. The primary endpoint was leukemia-free survival (LFS). Results: The median follow up was not statistically different between the CNS-pos (78.7 months) and the CNS-neg group (67.2 months), p=0.58. Patients in the CNS-pos group were younger (median age 31.3 vs. 39.7 years, p=0.004), received the procedure more recently (median year 2012 vs. 2010, p=0.003), were less likely to have a Karnofsky score of equal or higher than 90 (70.8% vs. 81.9%, p=0.017), or to have received peripheral blood stem cells (PBSC) (61.5% vs. 72.7%, p=0.028). The groups did not differ in regards to donor source (URD, 50% vs. 56.5%, p=0.24) or the intensity of the preparative regimen (MAC, 82.3% vs. 85.6%, p=0.41). In multivariate analysis, CNS-pos were associated with higher cumulative incidence of relapse (HR=1.58 (95%CI=1.06-2.35), P=0.025) and a trend for an inferior leukemia-free survival (LFS) (HR=1.38 (95%CI=0.99-1.92), p=0.057), but did not adversely impact overall survival (OS) (HR=1.28 (95%CI=0.89-1.85), p=0.18). A subgroup multivariate analysis limited to patients with CNS-pos showed that prescribing a TBI MAC regimen (vs. others) results in a lower cumulative incidence of relapse (HR=0.35 (95%CI=0.15-0.79), p=0.012) and better LFS (HR=0.43 (95%CI=0.22-0.83), p=0.01) and OS (HR=0.44 (95%CI=0.21-0.92), p=0.03). Use of PBSC (vs. BM) was also independently associated with better OS (HR=0.53 (95%CI=0.29-0.99), p=0.046). Conclusion: Notwithstanding the inherent limitations of registry data, particularly ascertaining the absence of CNS involvement in the CNS-neg group, our results show CNS involvement as an independent risk factor for relapse following allo-HCT. Our data support, nonetheless, the choice of a TBI-based MAC regimen in this group of patients but stresses the need for close monitoring of relapse after allo-HCT. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Mielke: Immunicum: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Miltenyi: Other: Data safety monitoring board; Novartis: Speakers Bureau; Celgene/BMS: Speakers Bureau. Socie: Alexion: Research Funding. Huynh: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Peric: Therakos, Servier, MSD, Astellas, Novartis, Abbvie, Pfizer: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

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Retrospective Comparison between 12-Gray and 8-Gray Total Body Irradiation (TBI) before Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Lymphoblastic Leukemia in First Complete Remission

Blood ◽

10.1182/blood-2021-145100 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1783-1783

Author(s):

Alexandros Spyridonidis ◽

Myriam Labopin ◽

Bipin B. Savani ◽

Sebastian Giebel ◽

Christoph Schmid ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Free Survival ◽

Total Body ◽

First Complete Remission

Abstract Introduction: Total body irradiation (TBI) continues to be an important part of the conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in acute lymphoblastic leukemia (ALL). Previous dose escalation studies showed that higher than 12-Gray (Gy) was toxic and did not provide any apparent survival benefit - at least in patients (pts) transplanted in first complete remission (CR1) - thus establishing 12-Gy as the standard TBI dosage. Whether 8-Gy instead of 12-Gy TBI is sufficient in ALL CR1, as has been prospectively demonstrated for AML CR1 (Lancet Oncol 2012; 13: 1035-1044), has not yet been studied. Methods : In this registry-based retrospective study of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (ALWP-EBMT), we compared outcomes of ALL-CR1 pts who underwent a matched-sibling donor (MSD) or matched-unrelated donor (MUD) allo-HCT (94% peripheral blood stem cells) with TBI-based conditioning at a total dose of 12-Gy vs 8-Gy. Patients included in this analysis had received fludarabine (Flu) as the sole chemotherapy counterpart of TBI (12-Gy vs 8-Gy TBIFlu). Results: The median follow up for the whole cohort (n=639 pts) was 22.5 months (95% CI, 17.2-24.1) and did not differ between the 8-Gy (n=494) and 12-Gy (n= 145) TBIFlu treated pts. 25% pts had B-precursor ALL, 54% Philadelphia (Ph)-positive ALL and 21% T-ALL (p=0.008 between groups). Patients conditioned with 8-Gy TBIFlu were older than 12-Gy TBIFlu treated pts (median 55.7 vs 40.3 years, IQR 50.2-61.3 vs 27-50.2 years, <0.0001) and more frequently received in vivo T-cell depletion (71% vs 40%, <0.0001). All other characteristics were well balanced between 8-Gy vs 12-Gy groups including time from diagnosis to HCT (5.5 vs 5.8 months), Karnofksy <90% (34% vs 26%), minimal residual disease (MRD) positivity at HCT (37% vs 43%), MUD (72% vs 68%) and type of GvHD prevention. Engraftment failure was low and below 2% in both groups. Overall, 29% and 27% of 8-Gy vs 12-Gy treated patients died, with the main causes of death not differing between groups (relapse 41% vs 44%, infections 26% vs 24%, GVHD 12.6% vs 12.7%, respectively). Both in univariate and in the age-adjusted Cox proportional-hazards analysis, relapse (REL), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were not influenced by TBI dose (Figure 1, Table 1). These results were confirmed when we focused on pts aged <55 years (median age 47 years; 8-Gy 229 pts vs 12-Gy 131 pts). In the multivariate analysis, an incremental age of 10 years was associated with increased NRM risk (hazard ratio [HR] 1.66, 95% CI, 1.25-2.22) and reduced OS (HR 1.32, 1.09-1.59). Ph+ and T-ALL pts had significantly better survival outcomes than Ph- B-ALL pts, mainly due to significantly fewer relapses (Table 1). Conclusion: Although there were limitations to this study (TBI dose and age were correlated; missing data on TBI fractionation; missing MRD data for nearly one-third of the pts) this retrospective analysis was able to investigate the effect of TBI total dose independently from the chemotherapy counterpart (TBIFlu regimen only) and suggests that 12-Gy and 8-Gy results in similar outcomes in ALL patients transplanted in CR1. Whether this is also true for more advanced disease (>=CR2) and/or young adults) cannot be answered, as our study included only CR1 pts, few of whom were below 25 years of age. The reduced REL risk of Ph+ B-ALL pts is probably due to the increased use of tyrosine kinase inhibitors (TKIs) pre- and post-transplant. Clinically, these results suggest 8-Gy TBI as sufficient for ALL patients transplanted in CR1 with no additional benefit of augmenting the conditioning intensity to 12-Gy, a finding which should be validated in prospective trials. Figure 1 Figure 1. Disclosures Spyridonidis: Menarini: Current Employment. Labopin: Jazz Pharmaceuticals: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Peric: Therakos: Honoraria; servier: Honoraria; MSD: Honoraria; Astellas: Honoraria; NOVARTIS: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria; Prothena: Honoraria, Other: Travel grants; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Stelljes: Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Schroeder: JAZZ: Honoraria, Research Funding. McDonald: BioCryst Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ganser: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria. Wulf: Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees.

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Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment

Blood ◽

10.1182/blood-2020-137489 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-30

Author(s):

Josep-Maria Ribera ◽

Olga García ◽

Pau Montesinos ◽

Pilar Martinez ◽

Jordi Esteve ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Molecular Response ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Allogeneic Hsct ◽

Central Artery

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was <2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

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Patient Reported Financial Toxicity in Acute Leukemia

Blood ◽

10.1182/blood-2018-99-119163 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4796-4796 ◽

Cited By ~ 1

Author(s):

Thomas G. Knight ◽

Myra Robinson ◽

Michael R. Grunwald ◽

Lauren M. Bohannon ◽

Erin Blackwell ◽

...

Keyword(s):

Acute Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Financial Toxicity ◽

Advisory Committees ◽

Data Safety ◽

Safety Monitoring Board ◽

Data Safety Monitoring

Abstract Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Treatment of acute leukemia is associated with heavy healthcare utilization and high costs. The purpose of this study was to define rates, risk factors, and mortality implications for FT in patients with acute leukemia using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based leukemia practice, were surveyed prior to each visit over a six-month period. All patients were aged ≥18 years and were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 4 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Demographic data and disease characteristics were abstracted from the medical record. Model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity. Correlation of numerical financial toxicity scores with PROMIS scores and with mortality data was assessed using linear regression. Results: Of the 106 patients, 58 (54%) met the definition of exhibiting FT. The factors associated with incidence of FT included: age, race, and insurance type. The odds of FT in those patients <65 years of age were 2.7 times the odds of FT in those ≥65, adjusting for race, insurance, and time since first treatment (95% CI: 0.884 - 8.438, p = .081). The odds of FT in African American patients were 4.3 times the odds of FT in Caucasian patients, adjusting for age, insurance, and time since first treatment (CI: 0.408 - 44.824, p = .150). The odds of FT in patients with Medicaid insurance were 14.2 times the odds of FT in patients with commercial insurance, adjusting for age, race, and time since first treatment (CI: 1.658 - 121.862, p = .106). Gender, distance from the hospital, type of acute leukemia, history of blood/marrow transplant, and history of relapsed disease were not found to be significant. There was a significant correlation for both the PROMIS global physical (p < .001) and mental (p < .001) scores with the FT score. Lower FT score (higher degree of FT) was associated with lower mental and physical scores. There was no statistically significant difference in survival between patients with FT scores >4 compared to patients with FT scores <=4; however, there was a trend toward decreased survival in those with lower FT scores (Figures 1 and 2). Conclusions: Patients with acute leukemia represent an extremely vulnerable population for financial toxicity with rates of distress even higher than other reported malignancies. Urgent interventions are indicated in this population. Disclosures Grunwald: Medtronic: Equity Ownership; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Janssen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees. Symanowski:Five Prime Therapeutics: Other: Data Safety Monitoring Board ; Boston Biomedical: Other: Data Safety Monitoring Board ; Eli Lily & Co: Other: Data Safety Monitoring Board; Immatics: Other: Data Safety Monitoring Board.

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Systematic Review of the Published Evidence on the Pharmacokinetic Characteristics of Factor VIII and IX Concentrates

Blood ◽

10.1182/blood.v124.21.2818.2818 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2818-2818

Author(s):

Menchen Xi ◽

Tamara Navarro-Ruan ◽

Sunil Mammen ◽

Victor S. Blanchette ◽

Cedric R. Hermans ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Advisory Committees ◽

Safety Monitoring Board ◽

Population Pk ◽

Viii And Ix ◽

Factor Concentrate

Abstract Introduction: The efficacy of factor VIII and IX concentrates administered to prevent bleeding episodes in patients with hemophilia A and B is correlated with the plasma levels measured over time after the infusion. The inter-patient variability of pharmacokinetic (PK) parameters is large, and it is difficult to assess individual PK profiles due to the need for multiple time points. This is often not feasible, particularly for pediatric patients. Population PK modeling potentially provides a practical solution to this problem. The successful modelling of PK parameters at the population level requires knowledge of disposal characteristics and relevant covariates. We performed a systematic review of the available evidence in order to identify available PK data for factor VIII and IX concentrates to facilitate the implementation of a population PK approach. Methods: We conducted a literature search in MEDLINE and EMBASE from January 1997 to May 2014, using the keywords "hemophilia" and "pharmacokinetic". We included only articles that published original PK data for factor VIII and IX concentrates in humans and published in English. Two authors independently screened the studies and extracted the relevant data. Results: We retrieved 237 unique articles published between 1998 and 2013. We excluded 185 articles that did not meet our research criteria. We included 52 articles, with a total of 1365 patients included in PK analyses. 26 articles reported PK data on factor VIII concentrates, 18 articles report PK data on factor IX concentrates, and one article reported on both factor VIII and IX concentrates. Seven articles reported pharmacokinetic data on both factor VIII and Von Willebrand factor concentrates. We extracted the following data: number of patients, type and severity of hemophilia, patient age, factor concentrate infused, dose infused, sampling data points, half-life, clearance, recovery and the model used for pharmacokinetics, and inclusion of patients undergoing surgery or with inhibitors. The main results are summarized in table 1. Conclusions: This review provides the first systematic appraisal of the methods and results of published papers in the field. The data gathered confirms the intra-patient variability of factor concentrate PK and provides useful information on which to build population based PK models. *3 FIX articles and 2 FVIII articles did not report lab test; one article reported PK data for both FIX and FVIII †11 articles reported FVIII PK data for both one-stage clotting and chromogenic assays ǂPapers reporting on long-acting FVIII and FIX were included in the review, but not summarized in the table. For this reason, not all 1365 patients are accounted for in the table §Estimate of the range of the means found in the papers Disclosures Xi: Baxter: Research Funding. Navarro-Ruan:Baxter: Research Funding. Mammen:Baxter: Research Funding. Collins:Baxter: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL: Consultancy, Honoraria, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Neufeld:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: data safety monitoring board, data safety monitoring board Other; Biogen IDEC: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Pfiser: consultancy, data and safety monitoring board Other; Octapharma: Research Funding. Dunn:CSL Behring,: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfiser: Membership on an entity's Board of Directors or advisory committees. Iorio:Baxter: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; NovoNordisk: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Pfiser: Honoraria, Research Funding.

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Poor Outcomes with Hyper CVAD Induction for T-Cell Lymphoblastic Leukemia/Lymphoma

Blood ◽

10.1182/blood.v126.23.3762.3762 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3762-3762 ◽

Cited By ~ 6

Author(s):

Vamsi K Kota ◽

Amanda Redden Hathaway ◽

Bijal D. Shah ◽

Deniz Peker ◽

Ling Zhang ◽

...

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Cancer Center ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research

Abstract Background: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in adults is an aggressive bone marrow malignancy that historically has a poor prognosis. Hyper-CVAD/methotrexate-cytarabine (hyper CVAD) regimen is a commonly used induction regimen following the protocol developed at MD Anderson Cancer center. Recent reports from Swedish Cancer Registry showed that relapse rates were much higher than expected with this regimen. We report our retrospective experiences across three different centers, Winship Cancer Institute of Emory University (Atlanta), University of Alabama Cancer Center (Birmingham) and Moffitt Cancer Center, (Tampa), with the use of this regimen for management of T-ALL/LBL. Methods: We conducted a retrospective chart review of all adult T-ALL/T-LBL cases at three large cancer centers between the years 2005-2015, treated at the physician's discretion. Data collected included patient demographics, tumor characteristics (white count at diagnosis, flow cytometry, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. Since hyper CVAD is a commonly used regimen outside of clinical trials, we focused our analysis on outcomes with this regimen. This regimen consisted of 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8). CNS prophylaxis was given to all patients as per standard of care recommendations. All patients eligible for maintenance received 2 years of POMP (6 mercaptopurine, methotrexate, vincristine and prednisone) maintenance. Relapse-free survival (RFS) and overall survival (OS) were examined looking at medians and interquartile ranges of times to events. Kaplan Meier curves provided a graphical representation of the survival probability. Results: The final analysis included 95 adult patients with 64/95 (67%) patients receiving hyper-CVAD induction. Among the hyper-CVAD patients the median age at diagnosis was 30 (range 17-74). 71% of patients were male. Median white cell count (WBC) was 13.6/mm3 (1.7-500). Cytogenetic analysis revealed diploid in 36, complex (1 or more abnormalities in 16) and was not available in 12. WBC count was > 100,000/mm3 in 9 patients. 14 patients had mediastinal disease while 7 had CNS disease at diagnosis. Hyper-CVAD was the primary induction regimen in 56/64. Other patients either started on non-hyper CVAD induction prior to switching (n=3) or had asparaginase added to induction (n=5). The median number of cycles given as 7 (range 2-10) with 27(45%) patients receiving the planned 8 cycles. 37 patients did not complete 8 cycles due to stem cell transplant in remission (n=12), progressive disease (n=10) and unclear reasons (n=15). After induction therapy, remission status was unknown in 3 patients while 43/61 patients (70%) achieved remission. Maintenance with POMP was started in 21 patients that were in remission while 12 patients were taken to transplant without starting on maintenance. At the time of analysis, 23/64 (35%) patients are alive. The median relapse free survival was 387 days (12.9 months) and the median overall survival was 536 days (17.6 months). Excluding one patient lost to follow up, 44/63 (69.8%) relapsed. There was no difference in relapse versus non relapse patients in terms of median age (30 vs 33 years), median WBC at diagnosis (13.2 vs 13.6 mm3). Relapse rate was lower in patients with diploid karyotype (22/36, 61%) as compared to those with complex karyotype (14/16). Median survival in patients post relapse was 150 days. Only 9 patients were able to go for transplant after relapse with post transplant survival also being low (6 deaths). For the entire group, the two year survival was 35%. Conclusion: Our multi-institutional retrospective review shows that outcomes are poor across various centers in patients outside of clinical trials. This is the largest reported series of patients with adult T-ALL/T-LBL treated with hyper-CVAD outside of clinical trials. This data warrants investigation with newer agents to improve outcomes in this disease. Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Disclosures Kota: Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hathaway:OnQ Health: Research Funding. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acetylon: Membership on an entity's Board of Directors or advisory committees; PLexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria; Rosetta Genomics: Research Funding; Seattle Genetics: Research Funding. Jillella:Seattle Genetics, Inc.: Research Funding. Borate:Genoptix: Consultancy; Seattle Genetics: Research Funding; Gilead: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau.

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Hemophilia Prophylaxis No Longer Just for Children without Inhibitors - Increasing Use of Prophylaxis in Other Groups (children with inhibitors and adults with and without inhibitors)

Blood ◽

10.1182/blood.v126.23.3535.3535 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3535-3535 ◽

Cited By ~ 2

Author(s):

Manuel Carcao ◽

Maria L. Avila ◽

Victor S. Blanchette ◽

Elena Santagostino ◽

Carmen Escuriola-Ettingshausen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Advisory Committees ◽

Data Safety ◽

Safety Monitoring Board ◽

Data Safety Monitoring ◽

Adults And Children

Abstract Background: Long-term prophylaxis is standard of care in children with severe hemophilia A (SHA) and B (SHB) without inhibitors. Studies have shown benefit from long-term prophylaxis in adults with SH and in both adults and children with SH and inhibitors. Yet there is little data on the prevalence of prophylaxis in these groups. Aim/Methods: To understand the current use of long-term prophylaxis in these groups of patients in countries capable of underwriting the high cost of prophylaxis we surveyed (2013) hemophilia treatment centers (HTCs) in countries where long-term prophylaxis in children is routinely used. Results: 134 HTC from 14 countries in North America, Australasia, and Western Europe reported on 4,763 adults with SH (4,011 SHA; 752 SHB) and on 751 children and adults with inhibitors. Prophylaxis use in these groups is shown in table 1: Table 1. Prophylaxis use in adults with SH (without inhibitors). Adults without inhibitors Children and adults with inhibitors HA HB In ITI setting In non-ITI setting % on Prophylaxis 59 49 29 28 Most common regimen EOD 2 d/wk FEIBA EOD or 3 d/wk FEIBA EOD or 3 d/wk EOD, every other day Adults without inhibitors: A higher proportion of SHA (59%) vs SHB adults (49%) were on prophylaxis (Χ2 p<.001). This was particularly true in the age group of 18-30 y [74% (SHA) vs 60% (SHB)]. For SHA the use of prophylaxis was progressively less in older age groups: 31-40 y (55%), 41-50 y (47%), 51-70 y (39%) and >70 y (29%). There was little drop in the proportion of SHB adults on prophylaxis with increasing age. 67% of SHA adults on prophylaxis were receiving ≥3 infusions/wk while 80% of SHB adults on prophylaxis were receiving ≥2 infusions/wk. Once/wk prophylaxis was reported in 3% of SHA and by 19% of SHB patients on prophylaxis. Daily prophylaxis was rarely reported in both groups. Children and adults with inhibitors: Data was available on 407 children and 344 adults with SH and inhibitors. Table 2 shows the proportion of children and adults on/not on Immune tolerance induction (ITI) and on/not on bypassing agent prophylaxis (BA-P). Most children (78%) were on either ITI (with or without BA-P) or on BA-P alone and as such were having some bleed protection. In contrast only 28% of adults were on either ITI (with or without BA-P) or on BA-P and as such most adults with inhibitors are not on any bleed protection. Table 2. Use of ITI and of BA-P in children and adults with SH (+ inhibitors). 403 children 344 adults On ITI. Not on BA-P 43% 8% On ITI. On BA-P 17% 4% Not on ITI. Not on BA-P 23% 71% Not on ITI. On BA-P 18% 16% In total, 185 patients had received FEIBA prophylaxis while 70 had received rFVIIa prophylaxis. FEIBA prophylaxis was particularly more common (vs. rFVIIa prophylaxis) in the non-ITI setting [FEIBA (n=107 pts) vs rFVIIa (n=33 pts)]. The most common prophylactic FEIBA regimen was EOD or 3/wk while the most common rFVIIa prophylaxis regimen was daily. Conclusions: This survey captured data on 4,763 adults with SHA/SHB and on 751 adults and children with SH and inhibitors. This is the largest survey of prophylaxis in these 2 groups of patients. Given the benefits of prophylaxis in children it is reassuring to observe that prophylaxis in adults (without inhibitors) is more prevalent than previously reported. Use of BA-P in patients with inhibitors still however lags far behind the use of prophylaxis in non-inhibitor patients - particularly in adults. FEIBA is more commonly used for prophylaxis than rFVIIa. Our survey did not capture longterm patient outcome data; this needs evaluation. Note: This abstract includes data presented as separate abstracts at the ISTH 2015 meeting. The data has been combined and analyzed in this abstract to show the increasing use of prophylaxis outside of children without inhibitors. Disclosures Blanchette: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Data Safety Monitoring Board; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Board, Research Funding. Santagostino:CSL Behring: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Biogen/Sobi: Speakers Bureau; Bayer: Speakers Bureau; Novo Nordisk: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Kedrion: Speakers Bureau; Biotest: Speakers Bureau; Octapharma: Speakers Bureau; Roche: Speakers Bureau. Leissinger:Bayer: 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; 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, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Aledort:Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: DSMB Participation; Kedrion BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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MCL-1 and PKA/AMPK Axis Fuel Venetoclax Resistance in Lymphoid Cancers

Blood ◽

10.1182/blood-2019-131336 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1284-1284

Author(s):

Vivian M. Liu ◽

Romain Guièze ◽

Daniel Rosebrock ◽

Alexis A Jourdain ◽

María Hernández-Sánchez ◽

...

Keyword(s):

Transcription Factor ◽

Board Of Directors ◽

Cell Lines ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Advisory Board ◽

Advisory Committees ◽

Data Safety ◽

Genome Wide

Venetoclax, the first approved BH3 mimetic targeting BCL2, demonstrates high response rate in chronic lymphocytic leukemia (CLL) but resistant cases are emerging. Aside from BCL2 mutations affecting venetoclax binding, multiple lines of mounting evidence suggest a role for non-mutational mechanisms underlying resistance to this drug. By applying both CRISPR-Cas9 knock-out and ORF overexpression screens in the lymphoma cell line OCI-Ly1, we previously reported the identification of MCL-1 overexpression and of the AMPK/PKA signaling axis in altering energy metabolism underlying venetoclax resistance (Guieze, ASH 2018). Here, we report further in-depth exploration of the impact of these findings, discovered through the analysis of lymphoid cell lines, and of specimens collected from CLL patients developing venetoclax resistance. The resistant lymphoma cell lines that we generated (OCI-Ly1 and SU-DHL4 cells) displayed increased oxidative phosphorylation (OXPHOS) compared to the parental lines, measured by Seahorse assay. We instead observed that venetoclax rapidly perturbs OXPHOS in sensitive cells. This process is dependent on mitochondrial outer membrane permeabilization, as this effect is abrogated in BAX/BAK1 double knockout (KO) cells. Targeting OXPHOS was shown to synergize with venetoclax in vitro and in vivo, as combination of venetoclax and oligomicin (an inhibitor of the ATP synthase, the complex V of the mitochondrial electron transport chain), was more effective than each drug alone in reducing tumor growth of a subcutaneous NSG xenograft model based on OCI-Ly1. Among the candidate markers driving resistance identified from the genome-wide screens, we focused on AMP pathway members (AMPK and PKA) and the ID3 transcriptional regulator, given that ID3 KO cells demonstrated similar transcriptomic changes than the resistant OCI-Ly1 cells. We found that PRKAR2B (encoding a PKA subunit), already highlighted in our ORF screen, was the top transcript overexpressed when knocking out ID3. To clarify how the dominant-negative transcription factor ID3 regulates PRKAR2B expression, we performed ATAC-seq of the ID3 OCI-Ly1 knockout (vs control) lines in order to determine differential signatures of chromatin accessibility and transcription factor engagement. We showed that ID3 repression leads to genome-wide increased accessibility associated with motifs of the lymphoid transcription factor TCF3. TCF3 has previously been shown to interact with ID3 and to be involved in the transcription of ADIPOQ, which was identified in the GOF screen. TCF3 binding sites were confirmed to be present within putative enhancer regions of PRKAR2B in a B cell context. We then investigated whether our findings could be validated in patient samples. By whole-exome sequencing of matched pretreatment and venetoclax-resistant CLL samples collected from 6 patients, we did not detect any recurrent somatic mutations associated with resistance. The resistant samples from three of 6 patients, however, harbored subclones with 1q amplification in a common region encompassing the MCL1 locus. We identified 4 additional CLL cases relapsing on venetoclax with leukemia samples collected before and after relapse. By immunohistochemical staining of 9 of 10 cases for which tissue was available, we detected increased MCL-1 expression at relapse in 6 of 9 cases (p = 0.026). We furthermore confirmed the involvement of AMPK signaling by detecting evidence of AMPK, ACC and p-ACC expression in 4 of 9 patients (all p = 0.0062). ID3 expression was decreased at matched relapse samples (p = 0.0001), supporting the presence of the resistance circuit we identified above. Taken together, our results identified the increased MCL-1 expression and PKA/AMPK activation as underlying mechanisms for venetoclax resistance. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance. Disclosures Guièze: Abbvie: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Brown:AbbVie: Consultancy; Acerta Pharma: Consultancy; Loxo: Consultancy, Research Funding; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Juno/Celgene: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding. Wierda:Xencor: Research Funding; Cyclcel: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Gilead Sciences: Research Funding; KITE pharma: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Acerta Pharma Inc: Research Funding; GSK/Novartis: Research Funding; Miragen: Research Funding; Loxo Oncology Inc.: Research Funding; Juno Therapeutics: Research Funding. Letai:AbbVie, AstraZeneca, Novartis: Consultancy, Research Funding; Zeno Pharmaceuticals, Vivid Bioscience, Flash Therapeutics, Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder or Advisory Board member. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Mootha:Jansen Pharmaceuticals: Other: SAB, compensation; 5am Ventures: Other: SAB, compensation; Raze Therapeutics: Other: Founder, SAB, equity. Getz:MuTect, ABSOLTUE, MutSig and POLYSOLVER: Patents & Royalties: MuTect, ABSOLTUE, MutSig and POLYSOLVER; Pharmacyclics: Research Funding; IBM: Research Funding. Wu:Pharmacyclics: Research Funding; Neon Therapeutics: Other: Member, Advisory Board.

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Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Blood ◽

10.1182/blood-2020-141143 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 46-48 ◽

Cited By ~ 1

Author(s):

Armin Ghobadi ◽

Kahee A Mohammed ◽

Rawan Faramand ◽

Hagop M. Kantarjian ◽

Elias Jabbour ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Chronic Gvhd ◽

Philadelphia Chromosome ◽

Advisory Board ◽

Adult Patients ◽

Advisory Committees ◽

Free Survival ◽

Advisory Role

Introduction: Allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) is the standard of care for adult patients with Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL). The addition of tyrosine kinase inhibitors (TKI) to therapy have resulted in significantly higher rates of complete molecular remissions (CMR) and better overall outcomes. Given the increased toxicity associated with HCT, we aimed to study the benefit of HCT in adult patients with Ph+ ALL in CR1 in CMR. Methods: We performed a multi-institutional, retrospective analysis of 186 patients ≥18 years of age who received induction therapy including TKI for Ph+ ALL from January 2001 through December 2018 and achieved a CMR CR1. Patients achieving CMR within 3 months of diagnosis were included. Sixty-six patients underwent HCT consolidation (HCT group) and 120 patients did not receive HCT in CR1 (no HCT group). Primary outcomes of interest were overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and GVHD free relapse free survival (GRFS). GRFS was defined as being alive without grade III-IV acute GVHD, extensive or systemic chronic GVHD requiring therapy, or relapse. Although GRFS in no HCT group should be exactly as RFS, GRFS comparison was done to compare the composite outcome of quality of life in addition to survival in two groups. Landmark analysis was performed at 3 months to ensure CMR in all subjects at time 0. Survival end points were estimated using Kaplan-Meier method and analyzed with the log-rank test and Cox proportional hazard regression models. Gray's test was used for the comparison of cumulative incidence between cohorts. Results: Patient characteristics at diagnosis are summarized in Table 1. Compared to the non-transplanted patients, HCT patients were younger (median age 45 years vs. 56 years, p <0.001) and had better performance status at diagnosis (Karnofsky score > 90% in 90% of patients vs. 60%, p<0.001). Among patients in the no HCT group, 92.5% were treated with TKI as maintenance therapy with 43% receiving the treatment for more than 3 years. In the HCT group, 86.4% underwent myeloablative conditioning, 81.8 % had a matched related or unrelated transplant, and 47% had TKI as maintenance therapy after transplantation. The rates of patients with transplantation-comorbidity index (HCT-CI) of 0, 1-2, and 3 or more at transplant were 26.7%, 33.3% and 40% respectively. Median follow-up for survivors was 73.2 months (range, 4.3-206 months). Among transplant patients, 65.2% developed acute GVHD with 48.8% of them having a maximum grade of 2. Additionally, 51.6% developed chronic GVHD. In both univariate and multivariate analysis, there was no statistically significant difference in OS or RFS between the two treatment groups (Figure 1A and 1B). Compared to the non-transplanted patients, HCT patients had higher rates of NRM (HR: 3.57; 95% CI: 1.62-7.85), lower rates of CIR (Figure 1C), and a trend toward lower GRFS (Figure 1D). Five-year estimates of the probabilities of OS, RFS, CIR, and GRFS were 65%, 59%, 21%, and 38% for allo-HCT group and 58%, 54%, 28%, and 54% for no allo-HCT group, respectively. Conclusions: Comparing transplant versus chemotherapy only consolidation in CR1, this multicenter retrospective study shows that adult patients with Ph+ ALL in CMR have similar estimates of OS and RFS. Lower CIR in the HCT group was offset by higher NRM, resulting in similar RFS. Results of this study need to be confirmed in a prospective randomized trial. Disclosures Ghobadi: Kite: Consultancy, Research Funding; BMS: Consultancy; Amgen: Consultancy, Research Funding; EUSA: Consultancy; WUGEN: Consultancy. Kantarjian:Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; Sanofi: Research Funding; Oxford Biomedical: Honoraria; BMS: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; BioAscend: Honoraria; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Delta Fly: Honoraria. Jabbour:AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Uy:Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria; Agios: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Takeda: Patents & Royalties; Cytonus: Consultancy; Omeros: Consultancy. Ravandi:Macrogenics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Kebriaei:Amgen: Other: Research Support; Jazz: Consultancy; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support.

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Blinatumomab Is Well Tolerated Maintenance Therapy Following Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-125931 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1298-1298 ◽

Cited By ~ 4

Author(s):

Partow Kebriaei ◽

Pinaki P Banerjee ◽

Christina Ganesh ◽

Mecit Kaplan ◽

Vandana Nandivada ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Checkpoint Inhibitors ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Active Disease

Background: Patients with high-risk or multiply relapsed B-lineage acute lymphoblastic leukemia (ALL) have a very high rate of relapse, even after allogeneic hematopoietic cell transplantation (HCT). In an effort to reduce the risk for relapse, we investigated the role of blinatumomab (Blin), a bi-specific T cell immunotherapy targeting CD19, as maintenance therapy following allogeneic HCT for adult patients with advanced B ALL. We rationalized that this is an ideal agent with little cytotoxicity, and the potential to provide immune protection against disease relapse during the first year post HCT when graft versus leukemia (GVL) is still maturing. Methods: Adult patients with B-ALL deemed high risk for relapse defined as disease stage beyond CR1, any active disease including MRD, or presence of high risk molecular mutations or karyotype at time of HCT, or patients with evidence of MRD immediately following HCT, were eligible for study enrollment; prior Blin treatment was allowed. Patients with active disease defined as >5% malignant blasts or active GVHD requiring steroid therapy post HCT were excluded. Patients were scheduled to receive 4 cycles of Blin as a continuous intravenous infusion at the dose of 28 microgram/24 hours over 4 weeks, with the first cycle to be administered within the first 3 months post HCT after count recovery; the subsequent cycles were administered at 6, 9, and 12 months following HCT (day of hematopoietic progenitor cell infusion). Dose escalation for cycle 1 and hospitalization for observation during cycles 1 and 2 followed standard FDA issued guidelines. Results: 14 patients enrolled to date with 12 patients treated with median age 30 years (range, 21-65 years); two patients did not proceed with treatment due to graft versus host disease (GVHD). Patient characteristics and outcomes are listed in Table 1. The median days to start of therapy post HCT was 84 (range, 38-105 days). The treatment was well tolerated with no reported cytokine release syndrome, GVHD, graft failure, or grade 5 adverse events (AE). A cumulative 26 cycles of Blin were administered with 7 Blin-related grade 3 or 4 AEs reported (leukopenia n=4, transaminitis n=2, rash n=1). Grade 2 neurotoxicity manifesting as confusion and dysphagia requiring temporary suspension of therapy and short course steroids noted in 1 patient. Median follow up was 8.5 months post HCT (range 2-35 months). All 4 patients who were MRD positive prior to start of Blin have progressed and 2 have died. None of the 8 patients who were MRD negative post transplant has relapsed. We performed multiparametric flow cytometry studies on serial peripheral blood patient samples collected prospectively at multiple time points to measure T cell subsets, T-cell function and cell surface expression of various checkpoint inhibitors including PD1, TIGIT, Tim3, 2B4 and CD160. Samples were studied on an X-20 Fortessa, and the data analyzed using Kaluza software. Interestingly, the 4 patients who progressed on Blin maintenance had lower CD8 to CD4 ratio compared to non-progressors (17:60 vs. 46:42) (Figure 1). Furthermore, compared to healthy controls, we observed higher levels of checkpoint molecules as multiple checkpoints per cell. PD1 and TIGIT upregulation and co-expression were more common in progressing patients compared to non-progressors (Figure 2). Conclusion: We observed that Blin maintenance following allogeneic HCT for B ALL is well tolerated. More patients need to be treated to confirm the efficacy of this approach. This approach is encouraging for high risk ALL patients who are MRD negative post transplant. Strategies to increase CD8 levels and blockade against checkpoint inhibitors may overcome resistance to therapy. Disclosures Kebriaei: Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Ravandi:Xencor: Consultancy, Research Funding; Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding. Jabbour:Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding. Champlin:Sanofi-Genzyme: Research Funding; Johnson and Johnson: Consultancy; Actinium: Consultancy.

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A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Hematopoietic Cell Transplantation for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: CALGB Study 10701 (Alliance)

Blood ◽

10.1182/blood.v128.22.2782.2782 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2782-2782 ◽

Cited By ~ 3

Author(s):

Matthew J. Wieduwilt ◽

Jun Yin ◽

Meir Wetzler ◽

Geoffrey L. Uy ◽

Bayard L Powell ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Advisory Committees ◽

Allogeneic Hct ◽

Cns Prophylaxis ◽

Autologous Hct

Abstract Background: Potent inhibitors of BCR-ABL1have improved remission results and altered post-remission therapy for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Dasatinib plus dexamethasone followed by hematopoietic cell transplantation (HCT) promises high response rates, reduced toxicity, and durable remissions. Methods: We conducted a Phase II trial at 17 U.S. centers with the primary objective being to estimate the 3-year overall survival and disease-free survival of patients with Ph+ ALL treated with dasatinib and dexamethasone for remission induction and intensification, central nervous system (CNS) prophylaxis, consolidation with reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or etoposide and cytarabine, and dasatinib-based maintenance. Eligible patients had untreated Ph+ ALL, were ≥18 years old, and had normal cardiac function. Induction (Course I) used dasatinib 140 mg oral daily and dexamethasone 10 mg/m2/day oral or intravenous (IV) days 1-7. For patients with ≤20% blasts in the Course I, Day 15 bone marrow biopsy, intensification (course II) continued daily dasatinib with another 7 days of dexamethasone. Those with >20% lymphoblasts also received vincristine (VCR) and daunorubicin (DNR). Patients (n=3) not in CR/CRi after Course II received a second induction (Course III) with dasatinib, cyclophosphamide, VCR, DNR, and dexamethasone. After Course II or III, CNS prophylaxis (Course IV) consisted of IV VCR and IV, oral, and intrathecal methotrexate (MTX). Dasatinib was restarted at serum [MTX] <0.05 microM. Course V consisted of HCT or chemotherapy. Patients aged 18-70 years with an HLA-matched donor underwent RIC allogeneic HCT; otherwise they underwent autologous HCT. Allogeneic HCT conditioning used fludarabine 30 mg/m2/day IV day -7 through -3, alemtuzumab 20 mg/day IV day -7 through -3, and melphalan 140 mg/m2 once on day -2. GVHD prophylaxis with tacrolimus began day -2. Patients undergoing autologous HCT received etoposide 10 mg/kg/day (age >65 years, 5 mg/kg/day) continuous IV for 4 days and cytarabine 2 g/m2 (age >65 years, 1 g/m2) IV every 12 hours for 8 doses (EA) then G-CSF for mobilization. Autologous HCT conditioning used melphalan 100 mg/m2/day on days -2 and -1. Patients >70 years or unable to undergo HCT received EA alone. Dasatinib maintenance (Course VI) began on day 30 of Course V and continued for 12 months and until 2 consecutively negative bone marrow BCR-ABL1RT-PCR assays 3 months apart or until relapse. Dasatinib levels were measured on day 15 of induction. Results: Sixty-six patients enrolled from 12/15/2010 to 11/14/2014; 65 received dasatinib and are evaluable. Median age was 60 years (22-87); 49% were male. Median presenting WBC count was 23.1 x 103/ul (0.3-453.6). No deaths occurred during induction or intensification. CR or CRi occurred 31 patients (48%) by Day 15 of induction and in 62 patients overall (95%; CR 86%). Median dasatinib levels in serum and CSF on Day 15 of induction were 30.3 ng/mL (<3-308) and 0.29 ng/mL (<0.2-1.37), respectively suggesting approximately 1% of plasma dasatinib penetrates into the CSF, less than the unbound fraction (6%). Fifty-four patients started Course IV, 38 Course V, and 37 Course VI. Fourteen patients continue on protocol therapy. Of 38 patients receiving Course V, 22 had allogeneic HCT, 6 had autologous HCT, and 10 had EA chemotherapy. Median age of allogeneic HCT recipients was 61 years (31-69). Robust autologous stem cell mobilization was observed [median CD34+ cell count, 90 x 106/kg (31-166, n=6)]. Dasatinib maintenance was feasible after allogeneic HCT, autologous HCT, and chemotherapy alone with no missed doses in 59%, 83%, and 63% of cycles, respectively. Ten patients have relapsed with one isolated CNS relapse. No relapses have occurred after allogeneic HCT with 3 relapses after autologous HCT and one after Course V EA alone. Median follow up for survivors is 22.8 months (longest, 51 months). There have been 23 deaths: 5 treatment-related (4 after allogeneic HCT, 1 after course V EA), 16 disease-related and 2 unrelated. Conclusions: Dasatinib with dexamethasone yields CR rates comparable to those reported with tyrosine kinase inhibitors combined with conventional chemotherapy. Post-remission therapy with reduced-intensity allogeneic HCT, autologous HCT, or chemotherapy followed by dasatinib maintenance is feasible. Survival follow up is maturing. Disclosures Stock: Sigma-Tau: Honoraria, Research Funding; Royalties for a chapter in Up to Date: Patents & Royalties; ADC Therapeutics: Honoraria; Amgen: Honoraria; Gilead Sciences: Honoraria. Beumer:Bristol-Myers Squibb: Research Funding. Stone:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Sunesis Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Astellas: Consultancy, Research Funding.

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