Prophylactic Antibiotic Use and Risk of Meningococcal Infections in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Eculizumab Who Received Meningococcal Vaccination: Results from the International PNH Registry

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) patients treated with eculizumab have an increased susceptibility to serious meningococcal infections. In the largest safety data set to date, representing >10 years of postmarketing pharmacovigilance surveillance of eculizumab for the treatment of PNH, the reported meningococcal infection rate was 0.24 per 100 patient-years (PY); cumulative exposure to eculizumab in PNH was 21,016 PY (Socié G, et al. Br J Haematol. 2019). To reduce infection risk, it is recommended that PNH patients receive meningococcal vaccination ≥2 weeks prior to the first dose of eculizumab; patients vaccinated <2 weeks prior to eculizumab initiation are treated with appropriate prophylactic antibiotics (P-Abx) until 2 weeks after vaccination. However, some patients may still experience meningococcal infections, as vaccination reduces but does not eliminate the risk of meningococcal infection; thus, some physicians use long-term P-Abx in addition to meningococcal vaccination to lower infection risk. The real-world use of P-Abx is not well characterized, and their effect on the incidence of meningococcal infection is unknown. The objective of this study was to assess meningococcal infection rates in PNH patients who received eculizumab with or without P-Abx. METHODS This was a cohort study consisting of eculizumab-treated PNH patients from the International PNH Registry (NCT01374360). Eligible patients received meningococcal vaccination within 6 months prior to or up to 1-month post-eculizumab initiation; had a known birth date, sex, enrollment date, and status of P-Abx use; and were evaluable for infection during the study period. To prospectively assess the rates of meningococcal infections, the start of the follow-up period was defined as the later of the registry enrollment date or eculizumab treatment start date and the end of the follow-up period was defined as the earlier of the last eculizumab treatment follow-up date or date of the first meningococcal infection (i.e., patients were censored when they developed the first meningococcal infection after registry enrollment). To compare the demographic and disease characteristics between patients who started P-Abx and those who did not (No P-Abx), data were summarized at the later of the eculizumab start date, P-Abx start date, or enrollment date for patients with P-Abx use or at the last eculizumab treatment follow-up for No P-Abx patients. Event rates and corresponding 95% CIs were calculated for meningococcal infections for patients with and those without P-Abx using Poisson regression with an offset for the log of the treatment duration. RESULTS As of January 8, 2019, 1,815 eculizumab-treated patients were enrolled in the International PNH Registry, of whom 1,231 met all inclusion criteria for this study. Of the eligible patients, 501 received P-Abx and 730 did not. For the P-Abx and No P-Abx groups, the mean age of PNH onset (37.3 vs 36.8 y, respectively) and mean age at eculizumab initiation (44.4 vs 43.1 y, respectively) were similar. P-Abx use was higher in Europe (76.6%) than in other regions (Table 1). Both P-Abx and No P-Abx groups had similar medical event histories; the mean duration of the study period was 4.3 years (SD, 2.28 years) for the P-Abx group and 3.8 years (SD, 2.48 years) for the No P-Abx group. The mean duration of P-Abx use during the study period was 0.4 years (SD, 1.01 years). The most commonly used P-Abx was penicillin (314 of 500 patients). In total, 7 patients (3 from the P-Abx group and 4 from the No P-Abx group) experienced a meningococcal infection during the study period. In these 7 patients, the mean time from meningococcal vaccination to eculizumab initiation was 0.7 months (SD, 0.23 months) for the P-Abx group and 2.4 months (SD, 1.20 months) for the No P-Abx group. The estimated rates of meningococcal infection per 100 PY were 0.1 (95% CI, 0.0-0.4) for the P-Abx group and 0.1 (95% CI, 0.1-0.4) for the No P-Abx group (Table 2). CONCLUSIONS Rates of meningococcal infection were consistent with previously reported rates and were similar in PNH patients who received eculizumab therapy with or without P-Abx. It is important to note the small number of meningococcal infections and the limited details of P-Abx use reported in the registry. Further work will assess if patients were on P-Abx at the time of infection, and what meningococcal serotypes were identified. Disclosures Patriquin: Apellis: Consultancy, Honoraria, Research Funding; Ra Pharma: Consultancy, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding. Kulasekararaj:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Wilson:Alexion Pharmaceuticals Inc.: Employment. Jain:Alexion Pharmaceuticals Inc.: Employment. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

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Eculizumab Protects Against TE and Prolongs Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Study

Blood ◽

10.1182/blood.v120.21.3480.3480 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3480-3480

Author(s):

Gérard Socié ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Jeffrey Szer ◽

Alvaro Urbano-Ispizua ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Advisory Committees ◽

Significant Protective Effect ◽

Rbc Transfusion

Abstract Abstract 3480 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic and life-threatening hematopoietic stem cell disorder characterized by uncontrolled complement-mediated hemolysis. PNH, in large part due to chronic hemolysis and platelet hyperactivation, is associated with thromboembolism (TE), one of the leading causes of disease mortality. Eculizumab, a monoclonal antibody that inhibits terminal complement activation, has been shown in clinical trials to reduce hemolysis and the incidence of TE. The International PNH Registry provides the opportunity to understand from real world experience the impact of eculizumab on TE reduction in PNH patients. Aim: To assess the risk factors for TE and mortality in PNH patients enrolled in the Registry and to assess the effectiveness of eculizumab in reducing PNH-associated TEs. Methods: Patients are eligible for the Registry if they have a detectable PNH clone, regardless of disease severity, comorbidities, or treatments (past, current or planned). As of June 30, 2012, there were 1547 patients enrolled from 25 countries on 5 continents. Patients were excluded from analysis if they were missing key demographic variables or dates of eculizumab use, or did not yet have follow-up information. The cumulative incidence of TE was determined using competing risks methods to take into account bone marrow transplantation and death, while Kaplan-Meier methods were used for the cumulative incidence of mortality. Risk factors for TE and mortality were explored using a Cox proportional hazards model with stepwise selection (the significance level was relaxed to P=0.20 due to the small number of events for analysis). Variables examined in the models included: ethnicity; prior TEs, bone marrow disorders, impaired renal function, impaired hepatic function (IHF), abdominal pain, dysphagia, dyspnea, easy bruising/bleeding, fatigue, headache, hemoglobinuria, Karnofsky performance score, granulocyte clone size and lactate dehydrogenase (LDH) at enrollment, red blood cell (RBC) transfusions 6 months prior to enrollment as a marker for hemolysis, and treatments after enrollment (eculizumab and warfarin/heparin). Results: The mean age of the 1047 patients eligible for analysis was 45 years; 537 patients (51.3%) were female and 868 were Caucasian (82.9%). Anti-coagulants (heparin/warfarin) were used by 28% of patients and eculizumab was used by 51% during follow-up (18% used both). During a mean (SD) follow-up of 22.5 (18.4) months, 16 patients had a TE and 51 were deceased. Patients taking eculizumab during follow-up had a cumulative incidence of TE at 1 year of 0.41% and 1.35% at 2 years, while patients not taking eculizumab had TE incidence of 1.70% and 2.61% at 1 and 2 years, respectively. In the multivariate Cox model, the greatest associations with TE were RBC transfusions in the 6 months before enrollment (hazard ratio [HR]=9.61), history of IHF (HR=4.78), dyspnea (HR=2.42) and headache (HR=2.33) at enrollment. While controlling for these variables, eculizumab had a significant protective effect (HR=0.23, 95% CI = 0.08–0.66). The cumulative incidence of mortality in eculizumab-treated patients was 2.31% and 4.21% at 1 and 2 years, while in untreated patients it was 4.40% and 7.01%, respectively. In the multivariate model of mortality, the greatest associations were age 60+ years (HR=4.72), Karnofsky score <80 (HR=2.34), fatigue at enrollment (HR=1.94), and recent RBC transfusion (HR=1.75). While controlling for these variable, eculizumab had a significant protective effect (HR=0.41, 95% CI = 0.23–0.73). Conclusions: This analysis of a large international cohort of ‘real world’ patients with PNH showed that eculizumab is associated with a significantly reduced risk of TE and mortality, consistent with prior research. Recent RBC transfusion, a surrogate marker for hemolysis, was associated with increased risk of TE and mortality. Several symptoms and hepatic dysfunction also showed increased risks for these outcomes. As might be expected, older age and low performance status were associated with mortality. These data should be interpreted within the context of a contemporary cohort of PNH patients who may or may not be treated (with either eculizumab and/or anticoagulation). These analyses are limited due to small number of TE and mortality outcomes. Disclosures: Muus: Alexion Pharmaceuticals : Sat on advisory board of Alexion Pharmaceuticals. Other. Urbano-Ispizua:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Kanakura:Shire: Consultancy. Rosse:Alexion Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara:Alexion Pharmaceuticals, Inc: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Analysis Of Warfarin Drug-Drug Interactions With Antibiotics In The Ambulatory Care Setting

Blood ◽

10.1182/blood.v122.21.1143.1143 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1143-1143

Author(s):

Nathan P Clark ◽

Thomas Delate ◽

Catherine S Riggs ◽

Daniel M Witt ◽

Elaine M Hylek ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Warfarin Dose ◽

Acute Illness ◽

Control Groups ◽

Advisory Committees ◽

Antibiotic Group ◽

The Mean ◽

Excessive Anticoagulation

Abstract Background The typical effect of antibiotic initiation on the international normalized ratio (INR) in a real-world, stable warfarin population has not been adequately described. In addition, the influence of acute illness on the risk of excessive anticoagulation is not known. Methods This retrospective, longitudinal cohort study evaluated patients who received stable warfarin therapy between January 1, 2005 and March 31, 2011. The protocol for patients receiving warfarin and initiating antibiotic therapy during the study time-frame was to continue the warfarin dose unchanged and measure an INR within 3 to 7 days. Patients who purchased an antibiotic (antibiotic group) were compared to those purchasing a warfarin refill (stable controls) and patients with upper respiratory infection who did not purchase an antibiotic (sick controls). Primary outcomes included the mean INR change between the last INR prior to study inclusion (pre-index INR) and the first follow-up INR as well as the percentage of patients with a follow-up INR ≥ 5.0. The influence of interaction mechanism on the risk of a follow-up INR ≥ 5.0 was evaluated and predictors of a follow-up INR ≥ 5.0 were identified. Results A total of 5905 (49.0%), 5579 (46.2%), and 570 (4.8%) patients were included in the antibiotic, stable control, and sick control groups, respectively. The mean age was 68.3 years and the median pre-index INR was 2.5 (IQR 2.2-2.9). The mean change in INR was greater in the antibiotic group compared to the stable and sick control groups (both p< 0.05) but the increase was not clinically relevant (i.e., mean increase was less than 0.1 INR units). There were 3.2%, 2.6%, and 1.2% of patients with a follow-up INR ≥ 5.0 in the antibiotic, sick, and stable groups respectively (antibiotics v. stable and sick v. stable p<0.001; antibiotics v. sick p=0.434). Antibiotics interfering with warfarin metabolism were more likely to result in a follow-up INR ≥ 5.0 (9.6%) than those disrupting Vitamin K synthesis (3.1%) and those without a known interaction with warfarin (2.1%) (p<0.01) (Table). Antibiotic use, acute illness, cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR ≥ 5.0. Conclusion In the absence of antibiotics, acute illness alone increases the risk of excessive anticoagulation in previously stable warfarin patients. The risk of an INR ≥ 5.0 was greatest among antibiotics interfering with warfarin metabolism. In addition to antibiotics and acute illness, patients with cancer, elevated baseline INR, and females were most susceptible to excessive anticoagulation. Disclosures: Hylek: Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy. Garcia:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Roche Diagnostics: Consultancy; CSL Behring: Consultancy. Crowther:Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Consultancy; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood-2018-99-115710 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4606-4606

Author(s):

Neeraj Y Saini ◽

Romil Patel ◽

Ankur Varma ◽

Qaiser Bashir ◽

Omar Hasan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Median Number ◽

Castleman Disease ◽

Poems Syndrome ◽

Bone Lesions ◽

Advisory Committees ◽

Entire Cohort ◽

The Mean

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

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Stable FIX Expression and Durable Reductions in Bleeding and Factor IX Consumption for up to 4 Years Following AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B

Blood ◽

10.1182/blood-2019-122535 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2059-2059 ◽

Cited By ~ 5

Author(s):

Wolfgang Miesbach ◽

Karina Meijer ◽

Michiel Coppens ◽

Peter Kampmann ◽

Dr. Klamroth ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

First Year ◽

Severe Hemophilia ◽

Advisory Committees ◽

The Mean ◽

Second Year

Background: The aim of gene therapy is to provide long-term therapeutic effect from a single administration, yet information on response durability is currently limited. AMT-060 is an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human factor IX (FIX) gene and liver-specific promoter. AMT-060 is being analyzed in an ongoing study of 10 participants with severe/moderate-severe hemophilia B (Phase 1/2 study, NCT02396342). Aim: To describe efficacy and safety outcomes from a planned interim analysis at up to 4-years post-AMT-060. Methods: Adult males with FIX activity ≤2% and a severe bleeding phenotype received a single intravenous infusion of AMT-060 (5x1012gc/kg, Cohort 1, n=5) or (2×1013 gc/kg, Cohort 2, n=5). Assessments included FIX activity, FIX replacement use, annualized bleeding rate (ABR), treatment-related adverse events (TRAE), immunological and inflammatory biomarkers up to 4 years (Cohort 1) and 3.5 years (Cohort 2). Results: As of 8 May 2019, for Cohort 1 the mean yearly FIX activity (annualized to 4 years) was 6.0 as compared to 4.4% in the first year, 6.8% in the second year and 7.3% in the third year. Mean yearly FIX activity for Cohort 2 at 3 years was 7.9% as compared to 7.1% in the first year and 8.4% in the second year. Factor IX activity for each patient over the length of follow up is shown in Figure 1. Eight of 9 participants using prophylaxis at baseline were able to discontinue use. During the last 12 months of observation, the mean annualized bleed rate (ABR) was 1.7 for Cohort 1 and 0.7 for Cohort 2. Respectively, these represent a reduction in mean ABR to the year prior to treatment of 88% and 83%. During this same period the consumption of FIX replacement therapy declined 93% and 96% relative to pre-treatment respectively for Cohort 1 and Cohort 2. No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. TRAE were mainly reported in the first 3.5-months after treatment, including three participants who experienced transient mild elevations in alanine aminotransferase as previously described. One new TRAE (joint swelling post-exercise) was observed during the last 12 months of observation post-treatment. Updated data, up to 4-years of observation, will be presented for the first time. Conclusions: Long-term stable endogenous FIX activity and reductions in ABR and FIX replacement use were observed following a single treatment with AMT-060. There were no additional safety concerns with longer term follow-up. These findings support the ongoing Phase III study of the enhanced construct, AMT-061, which encodes the highly active Padua FIX variant. Figure 1 Disclosures Miesbach: Bayer, BioMarin, CSL Behring, Chugai, Freeline, Novo Nordisk, Octapharma, Pfizer, Roche, Takeda/Shire, UniQure: Consultancy; Bayer, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire: Research Funding; Bayer, Chugai, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire, UniQure: Speakers Bureau. Meijer:Pfizer, Sanquin, Uniqure: Research Funding; Uniqure, BMS, Aspen, Boehringer Ingelheim, Sanquin, Bayer: Consultancy, Honoraria; Sanquin: Research Funding; Bayer: Research Funding. Coppens:Pfizer: Honoraria; Portola Pharmaceuticals, Inc: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Uniqure: Research Funding; Boehringer Ingelheim: Research Funding; Sanquin Blood Supply: Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Kampmann:Uniqure BV: Research Funding. Klamroth:Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, Takeda: Consultancy; Bayer, Novo Nordisk, SOBI: Research Funding. Schutgens:Baxalta Shire, Novo Nordisk, Bayer, CSL Behring, Pfizer, UniQure BV: Research Funding. Castaman:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Seifried:Medac: Other: BSD owns IP and is contract manufacturer; Uniqure BV: Research Funding. Schwaeble:Uniqure BV: Research Funding. Bönig:Celgene, Novartis, Sandoz Hexal: Consultancy; Kiadis Pharma: Other: Contract manufacturing of ATIR101; Sandoz Hexal, Uniqure: Research Funding; Miletenyi: Speakers Bureau. Sawyer:Uniqure BV: Employment. Leebeek:CSL Behring: Research Funding; UniQure: Consultancy; Shire/Takeda: Research Funding; Novo Nordisk: Consultancy; Sobi: Other: Travel grant; Shire/Takeda: Consultancy.

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Baseline Characteristics of Patients in Peak: A Global, Longitudinal Registry of Patients with Pyruvate Kinase Deficiency

Blood ◽

10.1182/blood-2020-136634 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Rachael F. Grace ◽

Audra Boscoe ◽

Chris Bowden ◽

Bertil Glader ◽

Hitoshi Kanno ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Chelation Therapy ◽

Treatment Patterns ◽

Missense Mutations ◽

Private Company ◽

Advisory Committees ◽

The Mean

Background: Pyruvate kinase (PK) deficiency is a rare, inherited hemolytic anemia caused by autosomal recessive mutations in the PKLR gene, whereby a glycolytic defect causes a reduction in adenosine triphosphate generation. Current treatment options are supportive and include splenectomy, blood transfusions, and iron chelation therapy. To better understand the natural history, treatment patterns, and burden of disease, the observational PK Deficiency Natural History Study (NHS) (NCT02053480) enrolled 254 adult and pediatric patients with PK deficiency at 30 sites in 6 countries between 2014 and 2017 and followed patients for 2 years. The Peak Registry (NCT03481738) was developed to continue and expand on this research. This retrospective and prospective observational registry aims to enroll 500 adult and pediatric patients at ~ 60 sites in up to 20 countries over 7 years, with 2-9 years of follow-up. Objective: This analysis aimed to characterize the baseline demographics and clinical characteristics of patients with PK deficiency enrolled in the Peak Registry as of 24March2020. Methods: Demographic, diagnostic, medical history, laboratory, treatment, and other relevant data were collected from participating clinicians via electronic case report forms. To be eligible for inclusion in this analysis, patients were required to have genetically confirmed PK deficiency and available demographic information. All analyses reported here are descriptive and based on data as of the date of enrollment in the registry. Continuous variables are summarized by the number of non-missing observations, mean, standard deviation (SD), median, and range. Categorical variables are summarized as counts and percentages. Results: A total of 141 patients met the inclusion criteria, across 11 countries in North America and Europe. A summary of baseline demographics and clinical characteristics is shown in the Table. Fifty patients (35.5%) had completed 2 years of follow-up in the NHS and then moved to the Peak Registry; the remainder were newly recruited to the Peak Registry. The mean age of study participants at enrollment was 25.5 years (SD 19.1); 78 patients (55.3%) were female. Mean reported age at first symptoms was 5.8 years (SD 13.2) and mean age at diagnosis was 11.7 years (SD 16.0). Fifty-seven percent of patients were classified as having missense/missense mutations, 34.4% as having missense/non-missense mutations, and 8.6% as having non-missense/non-missense mutations. The mean hemoglobin at enrollment was 8.8 g/dL (range: 5.8-12.9 g/dL). Mean reticulocyte count was 19.8% (range: 2.2-42.4%), mean lactate dehydrogenase was 382 IU/L (range: 135-849 IU/L), and mean indirect bilirubin was 4.3 mg/dL (range: 0.8-23.1 mg/dL). Among the 45.2% of patients who had been splenectomized, the mean age at splenectomy was 7.2 years. Chelation therapy had been previously prescribed to 40.3% of patients. Among the 27 patients for whom ferritin data were available, the mean was 867.9 ng/L (range: 78.1-2499.0 ng/L), and 18 patients (66.7%) had a level > 500 ng/L. Ninety-nine patients (70.2%) had received at least one transfusion in their lifetime. Among the 45 patients who were known to have received at ≥ 1 transfusion in the 12 months prior to enrollment, the mean number of transfusions during that period was 5 (SD 4.3), with 18 of those patients (40.0%) having received ≥ 6 transfusions. Conclusions: New data emerging from the Peak Registry will provide valuable insights into the patient characteristics, treatment patterns, and burden associated with PK deficiency. The population is demographically heterogenous and represents a broad geography. Patients have a wide range of hemoglobin levels, and iron overload is common. The substantial rates of splenectomy, cholecystectomy, transfusions, and chelation use are indicative of a high disease and treatment burden in patients with PK deficiency. This abstract is presented on behalf of the Peak Registry Steering Committee and Peak Registry Investigators. Disclosures Grace: Novartis: Research Funding; Pfizer: Research Funding; Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees. Boscoe:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Bowden:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Glader:Agios Pharmaceuticals, Inc.: Consultancy. Layton:Cerus: Membership on an entity's Board of Directors or advisory committees; Novartis: 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. van Beers:Novartis: Research Funding; Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yan:Agios Pharmaceuticals: Consultancy. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor.

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Outcome of Very Young (≤ 40 years) Patients with Immunoglobulin Light Chain Amyloidosis (AL): A Case Control Study

Blood ◽

10.1182/blood.v128.22.5576.5576 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5576-5576

Author(s):

Jithma P Abeykoon ◽

Miriam Hobbs ◽

Jonas Paludo ◽

Dirk R Larson ◽

Angela Dispenzieri ◽

...

Keyword(s):

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Cardiac Involvement ◽

Case Control Study ◽

Years Of Life Lost ◽

Advisory Committees ◽

The Mean ◽

Control Study

Abstract BACKGROUND Light-chain amyloidosis (AL) is the most common form of systemic amyloidosis, with an incidence of approximately 1 case/100,000 person-years. Clinically relevant data with regard to the very young (≤ 40 years) patients (pts) are scant. We present a case-control study of very young pts with AL seen at a single institution. METHODS We reviewed the medical records of all pts with AL who were consecutively evaluated at Mayo Clinic, Rochester, MN between 01/01/1995 and 12/31/2015. The clinical characteristics and survival outcomes of very young pts at the time of AL diagnosis (cases) were compared to a 2:1 matched cohort of pts (controls) with AL who were 65 years or older and matched by the time of diagnosis. Upfront autologous stem cell transplantation (ASCT) was defined as transplantation within 6 months of the diagnosis of AL. The Kaplan-Meier method was used to all time-to-event analyses. The average years of life lost was computed by subtracting the mean survival from diagnosis observed in the cohort from the mean survival expected in the population based on life-tables. RESULTS Of 3433 pts with AL, 50 (1.5%) pts were ≤ 40 years of age at diagnosis (cases). Fatigue, peripheral edema, dyspnea and bleeding were less common at presentation in cases compared to controls (table A). The cases were also more likely to have liver or GI involvement (OR= 3.45, 95% CI: 1.6-7.2). Unusual initial clinical features in the cases included unprovoked splenic rupture (2%) and erectile dysfunction (4%) observed 6-15 months prior to the diagnosis of AL in cases; no such features were observed in the control group. The median time between the onset of symptoms and definitive diagnosis was 0.4 years (95% CI: 0.3-0.7) for the cases and 1 year (95% CI: 0.8-1.2) for controls (p<0.0001). The ECOG performance score at diagnosis was ≥2 in 51% of cases compared to 78% of the controls (OR= 0.29, 95% CI: 0.14-0.63). The involvement by 3 or more organs at diagnosis was comparable [24 (48%) cases compared to 34 (34%) controls (p=0.11)]. Concomitant myelomatous (AL-CRAB) features were evident in 12% of each group and 27 (54%) cases and 37 (41%) controls had >10% BMPCs without active myeloma (AL-PCMM) (p=0.16). Monoclonal light chain involvement without involvement of heavy chain was seen in 23 cases (50%) and 31 controls (32%), (OR= 2.1, 95% CI: 1.04-4.37). The median follow-up was similar for cases and controls, [10.9 years (95% CI: 7.6-12) vs 9.9 years (95% CI 8-14)], respectively. The estimated average years-of-life lost was 8.6 years over 20 years of follow-up in cases, (Figure 1a). In cases, 1 and 10-year overall survival (OS) from diagnosis was 73% and 51%, respectively (median OS 12.7 years; 95% CI: 4.0-NR) while, in controls, 1 year and 10 year OS was 62% and 15% respectively (median OS 2.1 years; 95% CI (1.0-3.6), p<0.001), (Figure 1b). Cardiac involvement was associated with a worse OS in both cohorts, (cases: median OS was 3.2 years with cardiac involvement (95% CI: 0.6-8.7) vs NR (95% CI: 8.0-NR) in those without; p=0.003; controls: median OS was 1.1 years with cardiac involvement (95% CI: 0.53-1.6) vs 4.8 years (95% CI: 3.7-8.1) in those without; p=0.02. Thirty one of 47 (66%) cases were eligible and 20 of 79 (25%) controls were eligible for upfront ASCT. In cases, upfront ASCT was associated with a longer OS. Median OS was NR (95% CI: NR-NR) in pts who underwent upfront ASCT (n=25) vs 4.0 years (95% CI: 0.5-8) in pts who did not, p≤0.0001. For controls, the median OS was 9 years (95% CI: 0.5-11) for pts who underwent upfront ASCT (n=7) vs 1.6 years (95% CI: 1.0-2.8) for pts who did not (n=93), p=0.26. In cases, six (12%) pts underwent solid organ transplantation (kidney 5, heart 1) and none in the control arm. CONCLUSIONS AL amyloidosis is infrequently encountered at the age of ≤40 years, but the loss of productive years of life and the disease burden are substantial in this cohort. A substantial delay in diagnosis from the onset of symptoms was noted in our study in the control population. Cardiac involvement remains a primary determinant of prognosis irrespective to age. Although over one-half of young pts are alive 10 years after the diagnosis (contrast ≈15% ≥ 65 years), early mortality remains substantial irrespective of age. An ASCT-based approach is associated with superior outcome in the young. A greater proportion of the young pts is fitter and ASCT-eligible at diagnosis, and should therefore be offered this approach. Disclosures Dispenzieri: Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding. Kumar:Array BioPharma: Consultancy, Research Funding; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding.

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Sickle Cell Disease Burden in North Lebanon

Blood ◽

10.1182/blood-2019-128311 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1022-1022

Author(s):

Adlette Inati ◽

Chadi Al Alam ◽

Cristel El Ojaimi ◽

Taghrid Hamad ◽

Hemanth Kanakamedala ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Disease Burden ◽

Leg Ulcers ◽

Newly Diagnosed ◽

Advisory Committees ◽

Study Population ◽

The Mean ◽

Diagnosis Date

Background: Sickle cell disease (SCD) is one of the most prevalent hemoglobinopathies in Lebanon, where 0.1% of the population are affected by the disease, with the highest prevalence in North Lebanon. SCD burden has not been well characterized in this patient population. Moreover, there is limited understanding of the factors associated with complications of SCD. We hereby report on characteristics, complications, treatments and survival of a SCD cohort treated at a comprehensive SCD referral clinic in North Lebanon. Methods: Data were extracted from the health records and electronic registry of 335 SCD patients treated at the comprehensive SCD clinic of Nini hospital, Tripoli, North Lebanon between 2009 and 2019. The study population consisted of referred and newly diagnosed patients. Patients were considered to be newly diagnosed with SCD if there was a gap of ≤ 60 days between SCD diagnosis date and their first clinic visit date. Patients were regularly seen in the clinic at intervals ranging from every 2 months to 1 year depending on their age and disease severity. Patient characteristics, complications, treatment choices, and mortality were evaluated during follow-up. Follow-up was defined as the time between SCD diagnosis and last visit to the clinic. Complications included vaso-occlusive crisis (VOC), acute splenic sequestration (ASS), stroke, dactylitis, joint necrosis, priapism, leg ulcers, sepsis, iron overload and mortality. VOC events, defined as the composite of pain and/or acute chest syndrome (ACS), were only reported if they resulted in a hospitalization. Since history of VOC events was not well documented among referred patients, VOC events were assessed among patients newly diagnosed at the clinic. Results: The mean age of the study population at SCD diagnosis was 2.9 years (standard deviation [SD]: 4.3), with 73.1% of patients diagnosed within 3 years of age. Mean age at first visit to the clinic was 8.6 years (SD 10.0). 159 (47.5%) patients were female. The most common genotypes were Hemoglobin SS (233 [69.6%]), Hemoglobin Beta-0 Thalassemia (62 [18.5%]), and Hemoglobin Beta + thalassemia (27 [8.1%]). The mean number of follow up years between SCD diagnosis date and latest visit date to the clinic was 13.7 (SD: 10.5). 132 (39.4%) patients were newly diagnosed at the time of their first visit to the clinic. The most frequently encountered SCD clinical events were pain (189 [56.4%]) followed by ACS (135 [40.3%]), ASS (115 [34.3%]) and joint necrosis (55 [16.4%]). The incidence of stroke, pulmonary hypertension, priapism, leg ulcers and sepsis was low (3.3%, 4.2%, 6.0%, 3.0% and 3.9%). Persistent splenomegaly beyond 6 years was seen in 57 (17%) patients, 36 (63.2%) of these patients were of SS genotype. 276 (82.4%) patients required at least one hospitalization during their follow-up. Among newly diagnosed patients, 63% experienced at least one VOC event that led to a hospitalization with a mean of 0.4 (SD: 0.6) hospitalized VOC events per patient per year. 15 (4.5%) patients died during follow-up. The most common cause of death was stroke (3 [20%]). 84 (25.1%) and 76 (22.7%) patients underwent a cholecystectomy and surgical splenectomy respectively, and 30 (9.0%) patients underwent both. 236 (70.5%) patients were treated with Hydroxyurea. The mean age at introduction of Hydroxyurea was 11.5 years (SD: 10.1) and median starting dose was 15.2 mgs/kg/day. 281 (84%) patients received at least one blood transfusion during their follow-up. 37 (11.0%) patients received iron chelation during their follow up. 3 (0.9%) patients underwent bone marrow transplant and were cured of their disease. Conclusion: This first SCD study from North Lebanon demonstrates that SCD burden in North Lebanon is significant. Despite the high disease burden and the low community resources in this region, survival rate of this SCD patient population is relatively high. This can be attributed to the young age at diagnosis, the close comprehensive follow-up and the regular parent/patient education. The low rate of stroke, priapism and leg ulcers in this population warrants further investigation via disease associated markers and genetic determinants. As for priapism, it may be underreported due to social stigma in a conservative country as Lebanon. Noteworthy, Iron overload is under recognized and sub optimally treated. The association between specific risk factors and disease complications will be further addressed. Disclosures Inati: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Global Blood Therapeutics: Research Funding. Kanakamedala:Novartis: Consultancy; Genesis Research: Employment. Pilipovic:Novartis Pharma AG: Employment, Equity Ownership. Sabah:Novartis: Employment.

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Infection Risk in Lymphoproliferative Diseases (LPD) Treated with Targeted Drugs. Geltamo Real-Life Experience

Blood ◽

10.1182/blood-2020-134729 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-40

Author(s):

Maria Stefania Infante ◽

Ana Fernandez-Cruz ◽

Lucia Nuñez ◽

Cecilia Carpio ◽

Ana Jimenez-Ubieto ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Drug Exposure ◽

Real Life ◽

Infection Risk ◽

Targeted Drugs ◽

Upper Respiratory Tract ◽

Advisory Committees ◽

Tract Infections

Introduction:Recently there has been a renewal of therapeutic tools for the treatment of lymphoid neoplasms to increase the antitumor efficacy and reduce the toxicity generated by conventional chemotherapies, which adds to the intrinsic immunological dysfunction of the disease itself. To date, few data are published about infection risk of these new drugs, and the need for infectious prophylaxis is unknown. The aim of the study is to analyze the infectious complications in patients with LPD treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab and pembrolizumab), BTK inhibitors (ibrutinib, acalabrutinib) and PI3K inhibitors (idelalisib). Methods: Multicenter retrospective study in patients with LPD treated with targeted therapies (single agents or combination) in 18 Hematology centers in Spain, from the time of their commercial availability to March 2020. Patients in clinical trials were excluded as well as patients with active infections at the beginning of treatment. Results:During the study period, 380 patients were included.Baseline characteristics of the entire cohort are shown in Table 1.Median follow-up was 17.3 months (range 0-103), the longest follow-up corresponding to CLL patients (24 months, range 0-98) and the shortest to LBCL (5 months, range 0-25). Median exposure to target drugs was 8 months (range 0-72).Ibrutinib was administered to 219 patients(1 FL, 147 CLL, 27 MCL, 10 DLBCL, 1 TL and 32 WM, 1 HL),Brentuximab to 49(31 HL, 14 TL and 4 DLBCL) andIdelalisibto 35 patients (16 affected by chronic lymphocytic leukemia - CLL, 15 FL and 1 DLBCL, 1 WM, 1MCL, 1HL).Obinutuzumabcombinations were used in 10 (6 CLL, 3 FL, 1 MCL) and 5 HL patients (of which 4/5 underwent previous BMT) receivedNivolumab. A total number of 237 infectious events occurred in 148/380 patients (38.9%), 39% of which were grade 3 and 54/148 (36.4%) experienced 2 or more infective episodes: of those 54, 21 (38%) had underwent 3 or more lines of therapy and 28 (51%) had hypogammaglobulinemia. Hospitalization was required in 59.2% events. A bacterial cause of infection was reported in 40% of cases, and viral in 16%, including 11/237 (4,6%) SARS-CoV-2 infection. Invasive fungal infection (IFI) occurred in 3.3% (8/237). Noteworthy, no case of PJP was identified. Lung was the most frequent site of infection in 24% of cases (57/237) while the upper respiratory tract was involved in 17% of events (41/237). Urinary tract infections were diagnosed in 10% (24/237). Other sites involved were skin and soft tissue 7%, gastrointestinal tract 5,4%, bloodstream infections 3% and catheter related infections 2,5%. Considering drugs individually, 86 patients that receivedIbrutinib(39.2 %)experienced a total of 137 infectious episodes: 30% bacterial, 19% viral, 5% fungal and 45% clinical and image-based infections; the 17(34.6%of those who received Brentuximab, experienced a total of 16 infectious episodes: 56% bacterial, 37.5% viral infections and one catheter-related sepsis. Of those who receivedIdelalisib,18 (51.4%)experienced a total of 28 episodes: 42% bacterial, 14% viral and 7% fungal. Four patients treated withObinutuzumabcombinations (40%) experienced one infection during treatment (25% bacterial and 75% viral). Only one patient treated withNivolumabexperienced more than three infections, he was also under corticosteroid treatment. Focusing on IFI (Table 2): 7/8 infections were identified in CLL patients, 6 out 7 being on ibrutinib treatment and 1/7 on Idelalisib.Aspergilluswas the fungus most frequently isolated. The targeted drug was discontinued temporarily in 4 patients and indefinitely in 3. Twenty three (6%) patients died due to infection in our series. Conclusions: 1. We identified 38.7% infections in our LPD patients treated with targeted drugs, with a median drug-exposure time of 8 months (range 0-72), with a non-negligible incidence of bacterial infections. 2. The highest rates of infection were found in patients treated with with Idelalisib and Ibrutinib (51.4% and 39.2% respectively). 3. IFI (3.3%) occurred with low frequency, mostly in CLL patients during ibrutinib treatment, leading to its temporal discontinuation in most of the cases. 4. No case of PJP was identified in our cohort. 5. An analysis to determine risk factors for infection and the optimal monitoring and prophylaxis for these patients is ongoing. Disclosures Hernandez-Rivas: Janssen:Membership on an entity's Board of Directors or advisory committees;Abbvie:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Membership on an entity's Board of Directors or advisory committees;Gilead:Membership on an entity's Board of Directors or advisory committees;Celgene/BMS:Membership on an entity's Board of Directors or advisory committees;Rovi:Membership on an entity's Board of Directors or advisory committees.Lopez-Guillermo:novartis:Consultancy;celgene:Consultancy, Research Funding;roche:Consultancy, Research Funding;gilead:Consultancy, Research Funding.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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