Comparing Exercise-Induced Musculoskeletal Bleeding in Murine Models of Hemophilia A and B

Abstract Background: Hemophilia A and B are recessive X-linked bleeding disorders characterized by the deficiency in coagulation factor VIII and factor IX. Patients with the severe form of the disease can experience bleeding into the joints and muscle either spontaneously or after provoking events including sporting injuries of different degree. Patients are prone to bleeding in the musculoskeletal system. While most research is focused on hemarthrosis, muscle hematomas are not well studied although being the second most common complication of hemophilia, accounting for 10-25% of diagnosed bleeding episodes. There is limited consensus regarding optimal diagnosis and treatment of muscle hematomas in patients with hemophilia. We are investigating the effect of physical activity on muscle and joint bleeds in mouse models of hemophilia. Aim: The objective of this study was to compare the severity of exercise-induced skeletal bleedings in two mouse models of hemophilia A and B. Methods: Hemophiliac F8-KO and F9-KO mice, aged from 8-12 weeks old, were subjected to either mild or moderate daily treadmill exercise for 5 days. The speed was set at 10 meters per minute for the mild intensity group and 15 meters per minute for the moderate intensity group; and the animals were exercised for 30 minutes daily. Mechanical stimulus with a brush was used to encourage the animals to run. Animals were monitored daily and on day 6 (24 hours after the treadmill exercise) the animals were sacrificed to assess bleeding events. The mice skin was carefully removed and the body was macroscopically evaluated for presence of bleeds. If muscle bleedings were present, they were assigned a score in accordance with a previously published protocol (Tranholm M et al., JTH 2015 Jan;13(1):82-91) with minor modifications. Results: The animals were closely monitored during the study periods, and all completed the study. Normal behaviour and appearances were observed. No external bleeding was recorded. No muscle hematoma was observed in the wild-type C57-strain, thus the group received the bleeding score of 0. For the mild exercise group, the mean muscle bleeding score of F8-KO strain was 5.50 (standard error = 2.81), while the mean muscle bleeding score of F9-KO strain was 1 (standard error: 2). The two-tailed P value between the hemophilia A and B group was significant (p<0.01). For the moderate exercise group, the mean muscle bleeding score of F8-KO strain was 4.667 (standard error = 3.51), while the mean muscle bleeding score of F9-KO strain was 2.8 (standard error = 2.86). The two-tailed P value between the hemophilia A and B group was 0.33. Discussions: The preliminary analysis of our data showed that musculoskeletal bleeding induced by exercise appears to be more severe in hemophilia A mice than hemophilia B. This is in accordance with previous observations that hemophilia B may be clinically milder than hemophilia A. In our study, there appears to be a more significant difference between the hemophilia A and B mice when the mice were subject to milder form of exercise. No statistical significance was found between the two groups when moderate exercise was given. Overall, this exercise model can be a useful tool to study the pathophysiology of musculoskeletal bleeding as well as to evaluate new therapeutic strategies in the prevention and management of muscle hematomas in hemophilia. Figure 1 Figure 1. Disclosures Gross: Leo Pharma: Honoraria; Bayer: Honoraria; BMS-Pfizer: Honoraria; Valeo: Honoraria. Matino: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Spark: Other: research grants; Octopharma: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: personal fees.

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Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽

10.1182/blood.v128.22.3778.3778 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3778-3778

Author(s):

Amy L. Dunn ◽

Alexis A. Thompson ◽

Werner Engl ◽

Marlies Sharkhawy ◽

Brigitt E. Abbuehl

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Pediatric Patients ◽

Hemophilia A ◽

Point Estimate ◽

Severe Hemophilia ◽

Advisory Committees ◽

The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

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Perioperative Outcomes Associated with Inhibitor Status in Patients with Hemophilia - a Retrospective Cohort Study

Blood ◽

10.1182/blood-2021-147550 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4990-4990

Author(s):

Omotola O. Olasupo ◽

Charles Nakar ◽

Alfonso Iorio ◽

Craig Haddix ◽

Thushara Mathew ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Advisory Board ◽

Clotting Factor ◽

Perioperative Outcomes ◽

Clotting Factors ◽

Advisory Committees ◽

Research Grants ◽

Increased Risk

Abstract Background The development of antibodies (inhibitors) to clotting factors compromises the treatment of people with Hemophilia A (HA) and B (HB), and results in ineffective clotting-factor therapy, higher risk of complications, and need for bypassing agents to achieve hemostatic control. Objectives To evaluate the association between presence of inhibitors and peri-operative hemostatic control, complications, and deviations from pre-surgery plans. Methods We conducted a retrospective study using data from the Indiana Hemophilia and Thrombosis Center (IHTC) surgical database (1998 - 2019). Association between specified outcomes and inhibitor status at surgery was assessed using generalized linear models while controlling for patient and procedural characteristics. Results A total of 1,492 surgeries were conducted in 539 patients with HA or HB, 4.8%(72/1492) of which were conducted in 20 (15 HA; 5HB) patients with inhibitors. Of the 72 surgeries involving inhibitors, 30 were high-titer, 10 low-titer and 32 with unreported inhibitor titers. Adjusting for patient's age, hemophilia diagnosis, surgery setting, and surgery type, the risk of achieving perioperative hemostasis was lower in surgeries involving inhibitors compared to non-inhibitor surgeries (65.6% vs 91.4%; aRR=0.78; 95% CI= 0.61-0.99; p=0.038). Complications including hemorrhage, fever, pain, thrombosis, and infections occurred more frequently in surgeries involving inhibitors (31.7% vs 14.6%; aRR= 1.67, 95% CI= 1.07 - 2.63; p=0.025). Deviation from pre-surgical plans, usually due to the development of complications including lack of effective hemostatic control, also occurred more frequently in surgeries involving inhibitors compared to those without inhibitors (70.8 vs 39.5%; aRR= 1.63, 95% CI= 1.33 - 2.01; p<0.001). Conclusion Procedures involving patients with inhibitors have increased risk of adverse perioperative outcomes compared to those without inhibitors. Key Words: Inhibitors, Hemophilia, Surgery, Perioperative outcomes, Database. Disclosures Iorio: McMaster University: Current Employment; Bayer (funding to the institution): Research Funding; BioMarin (funding to the institution): Research Funding; NovoNordisk (funding to the institution): Research Funding; Octapharma (funding to the institution): Research Funding; Pfizer (funding to the institution): Research Funding; Roche (funding to the institution): Research Funding; Sanofi (funding to the institution): Research Funding; Sobi (funding to the institution): Research Funding; Takeda (funding to the institution): Research Funding. Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy. Matino: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Spark: Other: research grants; Octopharma: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: personal fees. Shapiro: Pfizer: Research Funding; Novartis: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; Daiichi Sankyo: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Glover Blood Therapeutics: Research Funding; Kedrion Biopharma: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Prometric BioTherapeutics: Research Funding; Octapharma: Research Funding; OPKO: Research Funding; Agios: Research Funding; BioMarin: Research Funding; Takeda: Research Funding.

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Management of Secondary Prevention in Venous Thromboembolism: Use of Reduced Doses of Rivaroxaban and Apixaban in Extended Therapy

Blood ◽

10.1182/blood-2020-141908 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-17

Author(s):

Desiree Campoy ◽

Katia Flores ◽

Gonzalo Artaza ◽

César A Velasquez ◽

Tania Canals ◽

...

Keyword(s):

Venous Thromboembolism ◽

Secondary Prevention ◽

Board Of Directors ◽

Dose Reduction ◽

Standard Dose ◽

Control Group ◽

Advisory Committees ◽

The Mean ◽

D Dimer

BACKGROUND After a standard anticoagulation period (3-6 months), the risk of venous thromboembolism recurrence (RVTER) needs to be considered. Such risk is higher in unprovoked events and patients with persistent risk factor. The increase of D-dimer (DD) levels during the therapy seems to be strongly associated to RVTER. The use of rivaroxaban 10 mg/day and apixaban 2.5mg/12h as an extended therapy (ET) after the standard anticoagulation period has been proven to be an effective strategy to prevent recurrence without increasing bleeding events. AIM To assess the effectiveness and safety of reduced doses of rivaroxaban and apixaban as ET in patients with RVTER and to compare their DD levels with those of a control group on anticoagulant therapy at a standard dose. METHODS From April 2016 to June 2020, we included patients with venous thromboembolism (VTE) who received ET with rivaroxaban and apixaban with/at reduced doses. Dose reduction was performed following the clinical algorithm of our unit (Fig. 1). The DD values were determined using HemosIl D-Dimer HS-500 and the cut-off value was established at 500 µg/L DD levels were compared with a control group of 235 patients with VTE who received ET with standard doses of anticoagulation. DD levels were measured at the time of diagnosis (D1), initiation of treatment (D2) and 3 months after treatment (D3). RESULTS From a total of 116 patients (65.5% women), 77.6% (n=90) received rivaroxaban 10 mg/24h and 22.4% received apixaban 2.5 mg/12h as an ET. The mean duration of the initial anticoagulant therapy was 12 +/- 8.8 months. The mean DD value prior to the ET was 388 µg/L. In this group, 63.8% (n=74) was an unprovoked VTE and 17.2% (20) had hereditary thrombophilia. The mean of follow-up time was 6.9 +/- 8.3 months. No recurrences of VTE were observed during the follow-up and only one major bleeding event was reported in a high-bleeding risk patient. We observed a progressive decrease of DD levels from the VTE diagnosis to the last visit, with D1, D2, and D3 values of 987 µg/L ± 324, 388 µg/L ± 134, and 288 µg/L ± 98, respectively. There were no differences in d-dimer concentrations between patients with reduce doses of rivaroxaban or apixaban and the control group with standard doses (D1: 85.6% vs 81%, p =0.22; D2: 10.2% vs 8.0%, p =0.14; and D3: 9.1% vs 9.5%, p =0.18). CONCLUSIONS Our data indicated that an ET strategy with reduced doses of rivaroxaban or apixaban is effective and safe. We did not observe significant differences in DD levels at follow-up compared to the control group receiving a standard dose of anticoagulation. Further studies are needed in order to select and standardize dose reduction criteria in secondary prevention. Figure 1 Disclosures Campoy: boehringer ingelheim: Consultancy; Daiichi Sankyo: Speakers Bureau. Sierra:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Olivera:Daiichi Sankyo: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BAYER: Consultancy.

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Effect of Moderate and Severe Hemophilia a on Daily Life in Children and Their Caregivers: A CHESS Paediatrics Study Analysis

Blood ◽

10.1182/blood-2020-134658 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-45

Author(s):

Kate Khair ◽

Francis Nissen ◽

Mariabeth Silkey ◽

Tom Burke ◽

Aijing Shang ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Disease Burden ◽

Hemophilia A ◽

Daily Life ◽

Social Activity ◽

Publicly Traded ◽

Advisory Committees ◽

Lost Work ◽

Hours Of Work

Introduction: Hemophilia A (HA) is a congenital bleeding disorder, caused by a deficiency in clotting factor VIII (FVIII) and characterized by uncontrolled bleeding and progressive joint damage. This analysis assesses the impact of disease burden on the daily life of children with hemophilia A (CwHA) and their caregivers, addressing a deficit of current research on this topic. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey in a Paediatric Population (CHESS Paediatrics) is a retrospective, burden-of-illness study in children with moderate and severe HA (defined by endogenous FVIII [IU/dL] relative to normal; moderate, 1-5%; severe, <1%) across France, Germany, Italy, Spain and the UK. CwHA were recruited and stratified by both age group (0-5 years:6-11 years:12-17 years=1:1:1) and disease severity (severe:moderate=approximately 2:1, prioritizing children with severe HA [CwSHA]). Data for this analysis were captured from physicians, children, and their caregivers. Physicians completed online case report forms for treated children, and the child and/or their caregivers completed a paper-based questionnaire utilizing 5-point Likert scales. For CwHA aged 0-7, the questionnaire was completed by the caregiver, while for CwHA aged 8-17, children and caregivers completed different sections. Hours of care provided by the caregiver and work lost by the caregiver were reported as median values due to non-normal data distribution. Informed consent was obtained for all participants. Upon review, the study was approved by the University of Chester ethical committee. Results: Data from child/caregiver questionnaires were available for 196 CwHA (moderate, 25.5%; severe, 74.5%); the majority of these children, as expected, were receiving prophylaxis (72.4%), and did not have FVIII inhibitors (89.8%; Table 1). There was a direct impact of disease burden on CwHA, particularly with regard to physical and social activities (Figure 1). Overall, it was agreed or strongly agreed by the child or caregiver that 48.0% and 57.5% of children with moderate HA (CwMHA) and CwSHA respectively, have reduced physical activity due to HA, and 46.0% and 57.5%, respectively, have reduced social activity due to HA. A total of 36.0% and 61.0% of CwMHA and CwSHA, respectively, had adapted their treatment in anticipation of physical or social activity (Table 1). Furthermore, 34.0% of CwMHA and 55.4% of CwSHA were frustrated due to their disease, and many (CwMHA, 36.0%; CwSHA, 50.7%) felt that they had missed opportunities (Figure 1). For 66.0% of CwMHA and 76.0% of CwSHA, it was reported that their daily life was compromised due to their HA. Caregivers provided a median (interquartile range [IQR]) of 19.0 (10.0-59.5) and 12.0 (5.0-20.0) hours a week of care for the hemophilia-related needs of their CwMHA (n=30) or CwSHA (n=105), respectively. Of those who responded, 17.4% (n=4/23) and 25.0% (n=20/80) of caregivers to CwMHA or CwSHA, respectively, stated they have lost work due to their caregiving duty. This was more than twice as common for caregivers in families with multiple CwHA (42.9%, n=9/21 responses) compared with those in families with one CwHA (18.5%, n=15/81 responses). Median (IQR) hours of work per week estimated to be lost were 20.0 (17.0-22.0) for caregivers of CwMHA (n=4) and 12.5 (4.50-20.0) for caregivers of CwSHA (n=20). Conclusions: In conclusion, both children and caregivers make sacrifices in their daily lives due to HA; many CwHA reported reduced physical and social activities, fewer opportunities and feelings of frustration due to their HA. Caregivers reported spending a significant number of hours caring for their child and some reported losing work due to their caring responsibilities. However, some outcomes may be limited by the small number of respondents and narrow response options, particularly those regarding the caregiver burden. Responses on the hours of work lost may be subject to selection bias, as caregivers who have lost work may be more likely to respond to this question. Additionally, as this question is targeted at caregivers in employment, it is unknown if some caregivers have left employment due to their caregiving responsibilities. According to this analysis, children/caregivers are frequently required to adapt the child's treatment before the child engages in activities. Overall, the burden of disease was similar in children with moderate and severe HA. Disclosures Khair: Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Haemnet: Membership on an entity's Board of Directors or advisory committees. Nissen:GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Silkey:Aerotek AG: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Burke:HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Shang:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Noone:Research Investigator PROBE: Research Funding; Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees.

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Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-134237 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-14

Author(s):

Alexander Coltoff ◽

Joseph G. Jurcic ◽

Peter Campbell ◽

Daniel J. Lee ◽

Mark L Heaney ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Median Overall Survival ◽

Residual Disease ◽

Institutional Research ◽

Negative Group ◽

Advisory Committees ◽

Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie: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, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

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High-Risk Population Screening for Gaucher Disease: Final Results and Key Learnings from an Italian Multicenter Observational Study

Blood ◽

10.1182/blood-2020-141527 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

Irene Motta ◽

Christian Benedetto ◽

Marina Stroppiano ◽

Elena Cassinerio ◽

Dario Consonni ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Acid Sphingomyelinase ◽

High Risk Population ◽

Exclusion Criteria ◽

Advisory Committees ◽

Risk Population ◽

Multicenter Observational Study ◽

The Mean ◽

Beta Glucosidase

Background:Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder due to the deficiency of beta-glucosidase enzyme. Its prevalence in the non-Ashkenazy Jewish population is 1:40.000-100.000, whereas in Ashkenazy Jewish 1:500-1000. Patients present several hematological symptoms, including splenomegaly (86%), anemia (64%), thrombocytopenia (56%), bleeding, and MGUS, leading them to consult a hematologist on their diagnostic pathway. However, an international survey showed that only 20% of hematologists included GD in the differential diagnosis of a patient with anemia, thrombocytopenia, hepatomegaly, splenomegaly, and bone pain (Mistry PK, Am J Hematol 2007). Indeed, GD is underdiagnosed, patients experience long diagnostic delays, and misdiagnoses, leading to inappropriate procedures, treatments, and complications that often cannot be reversed by treatment. Half of the patients are diagnosed through bone marrow biopsy, although the diagnostic gold standard is the activity of beta-glucosidase on leukocytes or fibroblasts. Among the crucial obstacles to diagnosis, physicians identify the outsourced diagnostic test and, more importantly, the lack of awareness. Thus, ten years ago, a panel of experts published two diagnostic algorithms, one for the Ashkenazi and one for the non-Ashkenazi Jewish population, to facilitate the diagnosis of GD for hematologists (Mistry PK, Am J Hematol. 2011). Newborn screening has been experimented, showing an incidence of 1:22.205 (Burlina AB, J Inherit Metab Dis 2018). However, the large-scale implementation of newborn screening should be carefully evaluated. We hypothesized that an approach that combines the use of a diagnostic algorithm and a simple and cheap test could facilitate the diagnosis. Preliminary results of this study on 196 patients have been previously published, showing a prevalence of 3.6% of GD in a high-risk population (Motta I, Eur J Haem 2016). Aim:The aim of this study was to evaluate the prevalence of GD in a high-risk population presenting to the hematologist for splenomegaly and/or thrombocytopenia associated with other hematological signs or symptoms suggestive for GD. Methods:We designed a multicenter observational study among hematology centers in Italy. The study enrollment started in September 2010 and closed in December 2018. Inclusion and exclusion criteria were based on the published algorithm for the non-Ashkenazi population: Inclusion criteria: Splenomegaly and/or thrombocytopenia plus at least one among bone pain history, anemia, MGUS, polyclonal gammopathy in under 30 yrs, splenectomy;Exclusion criteria: onco-hematological diseases, portal hypertension due to liver diseases, hemoglobinopathies or chronic hemolytic anemias. The beta-glucosidase activity tests on Dried Blood Spot (DBS) were centralized at Ospedale Gaslini, Genoa (Italy). Results:500 subjects have been enrolled. 45 have been excluded because they did not fulfill the inclusion and exclusion criteria. The mean age at enrollment was 46.9±17.4 years, 31.9% (145/455) were females. The majority of enrolled patients had splenomegaly (89.7%), and approximately half (47.9%) thrombocytopenia associated with the other signs/symptoms. Anemia was the most frequent adjunctive sign (23.1%). The prevalence of GD was 3.3% (15/455, IC 95%: 1.9-5.4) in this high-risk population. In 14/15 of these patients, the molecular analysis of GBA gene identified the mutations. GD patients showed a significantly lower PLT count compared to non-GD patients (84.000/mm3 vs. 131.000/mm3, p<0.001) and significantly higher serum ferritin levels (551 ng/dL vs. 139 ng/dL, p<0.001). The mean Hb value was 12.9±2.1 g/dL in the GD and 13.3±2.4 in the non-GD group. Interestingly, in the non-GD group, a patient was diagnosed with Acid Sphingomyelinase Deficiency (ASMD), previously known as Niemann Pick type B, which presents with similar signs and symptoms as GD. Conclusions:High-risk population testing is effective in identifying Gaucher disease patients who present to the hematologist because of splenomegaly and/or thrombocytopenia. The use of DBS as a first-level tool is essential to facilitate patient testing. Because of the overlapping features of GD and ASMD, patients fulfilling the criteria applied to this protocol should be tested for both beta-glucosidase and acid-sphingomyelinase activity. Disclosures Motta: Sanofi Genzyme:Honoraria.Barcellini:Agios:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis:Honoraria, Other: invited speaker , Research Funding;Bioverativ:Membership on an entity's Board of Directors or advisory committees;Incyte:Membership on an entity's Board of Directors or advisory committees;Alexion:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding.Cappellini:BMS:Honoraria;Genzyme/Sanofi:Honoraria, Membership on an entity's Board of Directors or advisory committees;CRISPR Therapeutics, Novartis, Vifor Pharma:Membership on an entity's Board of Directors or advisory committees.

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Infections in Patients with Lymphoproliferative Diseases Treated with Target Therapy. Italian Multicentric Retrospective Study Seifem 2017

Blood ◽

10.1182/blood-2018-99-111518 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4164-4164 ◽

Cited By ~ 3

Author(s):

Gianpaolo Nadali ◽

Gessica Marchesini ◽

Davide Facchinelli ◽

Francesca Farina ◽

Maria Chiara Tisi ◽

...

Keyword(s):

Respiratory Tract ◽

Board Of Directors ◽

Bacterial Infections ◽

Viral Infections ◽

Life Experience ◽

Cell Lymphoma ◽

Real Life ◽

P Value ◽

Advisory Committees ◽

Tract Infections

Abstract Introduction: in the last 5 years new "target drugs" to treat lymphoproliferative disorders have been introduced in clinical practice, such as monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab), BTK inhibitors (ibrutinib) and PI3K inhibitors (idelalisib). Efficacy and safety of these drugs were assessed in registrative trials and data regarding infectious complications in the "real life" experience are currently unavailable. We aimed to assess the incidence of major infections in patients treated with the above mentioned drugs. Methods: 555 patients were treated, for registered indications, with idelalisib, ibrutinib, brentuximab, ofatumumab and obinutuzumab (single agents or in combination as licensed) in 13 hematology centres in Italy, from time of their commercial availability to December 2016. The observation period was one year after study entry. Patients in clinical trials or treated within patient named programs were excluded as well as patients with active infections at beginning of treatment. Results: in 132/555 patients (24%) infections occurred for a total number of 187 events, 56% of whom were of grade 3. The median age was 64 years (range 20-86), 46,2% (61/132) of patients were treated with 3 or more previous lines of therapy, 55/132 (42%) experienced 2 or more infective episodes. A bacterial cause of infection was reported in 35% of cases, viral in 22% and an invasive fungal infection (IFI) in 9% (17/187). In 2% of cases the infection was of mixed origin (bacterial/viral or bacterial/fungal) while in 32% of cases there was not microbiological documentation. The lower respiratory tract was the most frequent site of infection in 39% of cases (73/187) while the upper respiratory tract was involved in 30% of events (39/187). The urinary tract infections were 13% (24/187). Other sites involved were skin and soft tissue 7%, sepsis 7%, gastrointestinal site 5%, central nervous system 2% and fever of unknown origin 6%. Patients treated with idelalisib were 106 (80% affected by chronic lymphocytic leukemia - CLL- and 20% follicular lymphoma) and 35 (33%) experienced one ore more infections for a total of 49 episodes. The incidence of bacterial infections was 37%, of viral infections 37% and of IFI 6%. In 235 patients treated with ibrutinib, 70 (30%) had one ore more events for a total of 102 infective episodes. 60/70 (86%) patients had CLL and 10/70 (14%) had indolent or mantle cell lymphoma The incidence of bacterial infections was 50%, viral 20% and IFI 16%. Focusing on IFI, 17 events were reported in 15 patients. According to the EORTC criteria, 11 cases (4 possible, 1 probable, 6 proven) were reported in patients treated with ibrutinib, 3 cases of possible IFI in patients treated with idelalisib and 3 cases of proven IFI in patients treated with brentuximab. The incidence of IFI in patients treated with ibrutinib (11/102 events) and idelalisib (3/49 events) was not different (11% vs. 6% respectively; p-value = 0.55) even considering proven/probable cases only (3% in ibrutinib vs. 0% in idelalisib p-value = 0.11). The incidence of bacterial infections in patients treated with ibrutinib (35/102) was not statistically different compared to patients treated with idelalisib (18/49) (34% vs. 37% respectively p-value =0.87). Noteworthy, the incidence of viral infections in patients treated with idelalisib (18/49) was significantly higher compared to patients treated with ibrutinib (14/102) (37% vs. 14% respectively; p-value =0.015). Brentuximab was used in 175 patients, 70% of cases for Hodgkin Lymphoma and 30% for T cell lymphoma. The rate of infections was 11% for a total of 27 infection episodes. The incidence of bacterial, viral and fungal infections was 37%, 30% and 11% respectively. In 22% of cases the cause of infection could not be established. Patients treated with ofatumumab or obinutuzumab were 39 and in 7/39 (18%) an infective episode was reported (four of bacterial origin, one viral and four undetermined). All patients were affected by CLL. Conclusions: this "real life" experience confirm that the incidence of infections in patients treated with "target drugs" is not negligible. Ongoing analysis that take into account patient's clinical and demographical characteristics, may give insights on risk factors that will contribute to better characterizing patients at different risk levels. Figure. Figure. Disclosures Cattaneo: GILEAD: Other: Advisory Board. Candoni:Pfizer: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau. Fanci:Gilead: Honoraria; Pfizer Pharmaceuticals: Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau. Del Principe:Gilead: Membership on an entity's Board of Directors or advisory committees. Busca:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merk: Honoraria, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria; Novartis: Speakers Bureau.

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Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽

10.1182/blood-2019-127270 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2409-2409

Author(s):

Tiffany Lin Lucas ◽

Shveta Gupta ◽

Joanna A. Davis ◽

Fernando F. Corrales-Medina

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hemophilia A ◽

The United States ◽

Haemophilia A ◽

Advisory Committees ◽

Inhibitor Development ◽

Increased Risk ◽

Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

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Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽

10.1182/blood-2019-126659 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1126-1126

Author(s):

Karen L. Zimowski ◽

Glaivy M. Batsuli ◽

Paulette Bryant ◽

Jenny McDaniel ◽

Kelly Tickle ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Bleeding ◽

Severe Hemophilia ◽

Bleeding Events ◽

Advisory Committees ◽

Acute Bleeding ◽

Fviii Activity ◽

Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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Hypogammaglobulinemia during Rituximab Maintenance after Transplantation Is a Surrogate Marker for Disease Control in Patients with Mantle-Cell Lymphoma, an Analysis from the LyMa Trial

Blood ◽

10.1182/blood-2020-139990 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-42

Author(s):

Louise Bouard ◽

Catherine Thieblemont ◽

Krimo Bouabdallah ◽

Thomas Gastinne ◽

Anne Moreau ◽

...

Keyword(s):

Immune Deficiency ◽

Disease Control ◽

Board Of Directors ◽

Research Funding ◽

P Value ◽

Immune Recovery ◽

Advisory Committees ◽

Post Transplant ◽

Rituximab Maintenance ◽

Mantle Cell

Introduction Rituximab maintenance (RM) (375mg/m2 per infusion every 2 months for 3 years) in transplanted patients with mantle-cell lymphomas (MCL) prolongs disease control (LyMa trial, Le Gouill et al NEJM; NCT00921414). However, post-transplant RM might also induce long-term immune deficiency and thus increases risk of infection. To address these issues, we performed an ancillary pre-planned study based on the LyMa trial, a phase III trial that compared RM versus observation (Obs) after ASCT in MCL patients. We compared post-transplant immune-deficiency and its impact on PFS and OS in the RM vs Obs groups. Method All transplanted and randomized patients enrolled in the LyMa trial were eligible for the present study. The following data were collected during the post-ASCT period and monitored according to protocol procedure: febrile event, clinically documented infection, hospitalization for infection, neutropenia, hypogammaglobulinemia and T CD4 lymphocytes count. We also retrospectively collected the use of immune globulin (Ig) substitution. In the LyMa trial, patients were randomized between RM vs Obs after transplantation. To decipher the implication of ASCT or RM in immune recovery, treatment periods were divided in 4: < 6 months after randomization, from 6 to 12 months after randomization, from one to two year after randomization, and from 2 to 3 years after randomization (respectively periods A, B, C and D). Chi-square or Fisher's exact tests were used as appropriate to investigate differences between arms in each treatment period. For all tests, a two-sided p-value<0.05 was considered statistically significant Results 240 patients were eligible, 120 in each arm. Patients' characteristics at diagnosis and inclusion were similar in the two arms. Number of hospitalizations due to infections was not statistically different in RM vs Obs in all periods. As previously shown, grade 3/4 infections incidence did not differ in the 2 arms. However, febrile events were more frequent in the RM arm (32 pts vs 11; 38 events vs 12) but this was statistically significant only in C and D periods; p=0,03 for the 2 periods. In all, 51 infections in 44 pts were reported in Obs vs 127 events in 82 pts in RM arm. This difference was also only statistically significant during the C period, p=0,001. Grade 4 neutropenia incidence and T CD4 count did not differ between the two arms in all tested periods. Hypogammaglobulinemia was statistically more frequent in RM during C and D periods (p=0,0001 and p< 0,0001, respectively). Mean level of gammaglobulinemia on D period was 6,50 g/L (range 0,6-11,7) in obs arm versus 4,99 (range 1,0-9,5) in RM arm (p< 0,0001). 36 pts in RM arm vs 10 pts in obs arm were substituted with Ig and the difference was statistically significant only in period D, p<0,0001. Febrile and infectious episodes; neutropenia and T CD 4 lymphopenia did not modify PFS and OS. Patients with gammaglobulinemia < 6g/L in RM arm and in the whole cohort had longer PFS compared to pts who did not present hypogammaglobulinemia : 3-years PFS 93,2% vs 63,5% in RM arm HR = 0,294, 95% CI (0,113-0,767 and), p=0,01 and 3-years PFS 85,6% vs 63,6% in the whole cohort, HR adjusted on treatment arm=0,488 95% CI (0,287-0,830), p=0,008 . PFS was not modified by gammaglobulin level in the Obs arm and it did not modified OS in both arms. We performed a multivariate analysis to determine which data were predictive of infectious events and delayed immune recovery (neutropenia, hypogamma, T CD 4 lymphopenia). This included all univariate parameters with p value < 0,2, among clinical and biological characteristics at diagnosis, response after induction and number of rituximab injections. Interestingly, among others expected parameters, complete response assessed by TDM was predictive of hypogamma with Odd Ratio 2,972 (1,263-6,994) p=0,0126. No value was predictive of neutropenia or T CD4 cytopenia. Conclusion As compared to observation, the use of post-transplant RM does not increase risk of neutropenia and T CD4 lymphopenia. However febrile and infectious events, hypogammaglobulinemia and Ig substitution are more frequent after one year post transplantation. Hypogamma < 6g/L is associated with longer PFS and complete morphologic response. This suggests that hypogammaglobulinemia could be a surrogate for disease response quality and duration. Our findings deserve to be confirmed. Disclosures Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Cellectis: Speakers Bureau; Janssen: Honoraria; University Employement: Current Employment. Bouabdallah:Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Oberic:Roche, Janssen: Other: Travel, Accommodations, Expenses; Roche: Honoraria; Roche, Janssen: Consultancy. Hermine:AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Celgene BMS: Consultancy, Research Funding; Novartis: Research Funding; Alexion: Research Funding; Roche: Consultancy. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria.

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