A Global Registry of Patients with Paroxysmal Nocturnal Hemoglobinuria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3007-3007
Author(s):  
Robert Brodsky ◽  
Hubert Schrezenmeier ◽  
Petra Muus ◽  
Monica Bessler ◽  
Jeffrey Szer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Natural History ◽  
Board Of Directors ◽  
Research Funding ◽  
Health Care Services ◽  
Clinical Symptoms ◽  
Marrow Transplant ◽  
Advisory Committees ◽  
Care Services ◽  
History Of

Abstract Abstract 3007 Poster Board II-983 Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis which can lead to life-threatening complications including thrombosis, kidney disease, and pulmonary hypertension. The natural history of PNH is highly variable and has previously been captured by retrospective assessment. However, the clinical presentation and prognosis of the disease has changed with the increased awareness of PNH, the increased use of more sensitive diagnostic tests, and the availability of new treatment. Specifically, the development of targeted but potentially life-long therapies, such as terminal complement blockade, necessitates the collection of long-term outcomes data in this patient population. We have established a global PNH Registry in order to redefine the natural history of PNH capturing a wide range of patients from all over the world. The goal of the present analysis is to describe the data collected for the patients in the Registry and demonstrate its use as an ongoing repository of information on symptoms, course, complications and treatment in patients with a PNH clone. The first patient was enrolled in January 2005, with data contributed from 62 clinical sites in 12 countries on 4 continents as of July 2009. Patients are included in the Registry regardless of amount of clone, bone marrow pathology, symptoms, or treatments. Sites collect data at enrollment and every 6 months including demographics, diagnostics and flow cytometry, other lab tests including LDH, medical conditions such as bone marrow pathology and major adverse vascular events (MAVE), clinical symptoms, medications and transfusions, qualitative assessments, bone marrow transplant, and mortality. Patients complete a questionnaire every 6 months including health-related quality-of-life, symptoms, and use of health care services. As of July 2009 there were 368 enrolled patients in the Registry (51% female, 49% male). Mean age at enrollment was 43.6 ±16.7, while mean age at first PNH symptoms was 35.9±16.7. At enrollment, median GPI-deficient granulocyte percentage (GPI-DG) was 80.4%, while 10% of patients had a GPI-DG <10. Of those patients with a GPI-DG <10, 81% had bone marrow pathology (62% with aplastic anemia, 16% with myelodysplastic syndrome, 3% other pathology) compared to 38% of patients with GPI-DG 350. MAVE was increased in patients with GPI-DG 350 compared to <10 (22% vs. 8%), as were LDH levels (median 1042 vs. 239 U/L). Patients with GPI-DG <10 reported high levels of significant clinical symptoms (fatigue 59%; dyspnea 52%; abdominal pain 41%) and symptom reporting was generally increased in patients with higher GPI-DG levels. Treatment in the year prior to Registry enrollment primarily consisted of transfusions (42%), anticoagulation therapy (30%), eculizumab (29%), and immunosuppression (23%), although these varied by GPI-DG level. Clinicians assessed 14% of patients with a Karnofsky score of 70 or lower (i.e., not capable of work or normal activity). Patients' assessment of their overall health, social functioning, and fatigue worsened and use of health care services increased with higher GPI-DG. At this time, median follow up is 12.8 months, although 25% of patients have been followed for at least 30 months. Two patients received a bone marrow transplant and 8 are deceased. In conclusion, preliminary data show that greater GPI-DG is associated with less underlying bone marrow pathology, more hemolysis, more thromboses, and more patient-reported symptoms. New clinical sites and geographic regions are encouraged to participate in the Registry ([email protected]). This global PNH Registry should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Brodsky: Alexion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Muus:Alexion: Membership on an entity's Board of Directors or advisory committees. Bessler:Alexion: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees. Rotoli:Author Deceased: Author Deceased. Maciejewski:Celgene: Speakers Bureau; Gemzyne: Research Funding; Taligen: Membership on an entity's Board of Directors or advisory committees. Socie:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua:Alexion: Membership on an entity's Board of Directors or advisory committees. Rosse:Alexion: Membership on an entity's Board of Directors or advisory committees. Karnell:Alexion: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Observational Prospective Registry for the Assessment of the Clinical Impact of Starting Anti-Myeloma Treatment at Biological Relapse

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4765-4765
Author(s):  
Adrian Alegre ◽  
Merche Gironella ◽  
Juan Miguel Bergua ◽  
Esther Gonzalez ◽  
Fernando Escalante ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Marrow Transplant ◽  
Clinical Relapse ◽  
First Line ◽  
Advisory Committees ◽  
Free Survival

Abstract Introduction: Despite the great medical advances associated with the introduction of thalidomide, bortezomib (BORT), and lenalidomide (LEN) for the treatment of multiple myeloma (MM), it remains an incurable disease. Most patients (pts) show disease progression, consistent with the clinical evolution of MM, and only a low percentage achieve long-term responses and extended progression-free survival (PFS). The heterogeneous nature of MM in both the clinical and biological setting is reflected in the heterogeneity of MM relapses. The International Myeloma Workshop Consensus Panel (Rajkumar, Blood 2011) states that treatment (Tx) shall begin either at clinical relapse with symptoms (clinR), or in the event of asymptomatic relapse with significant paraprotein relapse, biological relapse (BR). The purpose of this Spanish registry is to describe MM relapse patterns comparing the impact of Tx decisions in pts who meet the criteria for biological relapse (BR) according to IMWG criteria with those in whom Tx was delayed until clinical relapse (clinR). Here, the preliminary results of this study are presented. Methods: MM pts in (or previous to) first or second BR who have achieved ≥ PR since their last Tx are eligible for inclusion in this observational prospective registry at the time BR is detected. Evaluations performed at least bi-monthly are mandatory. A total of 41 Spanish sites participated in the registry following approval from their independent ethics committees, with 410 pts expected to be included, without physician’s decision of prescribing Tx affecting the inclusion. The main objective of the registry is to assess the time to progression (TTP) from the start of anti-MM Tx at the onset of asymptomatic BR vs. the start of Tx at the time of clinR. Secondary objectives are to describe demographics of BR; to assess the median time elapsing from BR to clinR; to assess overall response rate (ORR), event-free survival (EFS), PFS, overall survival (OS) at BR and at clinR (if appropriate); to asses safety and quality of life (QoL) using 2 validated questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-MY24); to document the tolerability profile of the Tx; and to describe the use of associated resources. Here, we summarize baseline characteristics and preliminary results from 83 pts (out of 126 registered pts) who had basal data in the registry at the time of this report. Results: Overall, 79% of pts presented with a BR and 21% were in a bi-monthly watchful waiting follow up. The mean age of pts was 67 years, 53% were female, 57% were in first relapse, 43% and 27% had an ECOG performance status (PS) of 0 and 1, respectively, while the ECOG PS was unknown in 30% of pts at the time of this report. In total, 30% of pts had ISS stage I, 26% had ISS stage II, and 22% had ISS stage III, while ISS stage data were not available or unknown for 12% and 10% of pts, respectively. MM types were IgG Κ (37% of pts), IgG λ (23%), IgA Κ (13%), IgA λ (9%), and type was unknown in 17% of pts. 28% of IgG/IgA MM types were Bence-Jones. Cytogenetic risk assessments were available in 66% of pts. Among those pts with a BR, 51% received active Tx without waiting for a ClinR. First-line Tx was BORT-based in 70% of pts. Overall, 55% of pts had undergone autologous stem cell transplantation, 15% had received consolidation Tx and 34% had received maintenance Tx. After first-line Tx, 17% of pts achieved a stringent complete response (sCR), 31% achieved a CR, 24% achieved a very good partial response (VGPR), and 10% achieved a PR. The median time to BR was 24.53 months. Most (63%) pts who registered after second relapse received LEN-based Tx. Conclusions: To our knowledge, this is the first prospective study in MM to evaluate BR as well as the effects of Tx based on the decision to start Tx at BR vs. clinR. In this preliminary cohort, the physicians’ decision to start active Tx at BR, before the onset of clinR in 50% of cases, was noteworthy. Further follow-up is needed to identify the differences between these two strategies. Updated clinical results will be presented at the meeting. MM-BR Study, Spanish Myeloma Group-GEM/PETHEMA Bibliography Alegre A, et al. Haematologica. 2002;87:609-14. Brioli A, et al. Blood. 2014;123:3414-9. Fernández de Larrea C, et al. Bone Marrow Transplant. 2014;49:223-7. Lenhoff S, et al. Haematologica. 2006;91:1228-33. Rajkumar SV, et al. Blood. 2011;117:4691-5. Zamarin D, et al. Bone Marrow Transplant. 2013;48:419-24. Disclosures Alegre: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ruiz:Celgene: Celgene Stock options as part of the employee's compensation plan Other, Employment. Vilanova:Celgene: Contracted by Celgene Other.

scholarly journals RON Kinase Is a Novel Therapeutic Target for Philadelphia-Negative Myeloproliferative Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1462-1462
Author(s):  
Lindsay Meg Gurska ◽  
Rachel Okabe ◽  
Meng Maxine Tong ◽  
Daniel Choi ◽  
Kristina Ames ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Marrow Transplant ◽  
Jak Inhibitor ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Stat Signaling ◽  
Genetic Deletion

Abstract The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineage compartments. Activation of JAK/STAT signaling is a major driver of all Ph-negative MPNs. During disease progression, MPN patients experience increased pro-inflammatory cytokine secretion, leading to remodeling of the bone marrow microenvironment and subsequent fibrosis. The JAK inhibitor ruxolitinib is an approved targeted therapy for MPN patients and has shown promise in its ability to reduce splenomegaly and the cytokine storm observed in patients. However, JAK inhibitors alone are not sufficient to reduce bone marrow fibrosis or to eliminate the JAK2-mutated clone. Furthermore, JAK inhibitor persistence, or reactivation of JAK/STAT signaling upon chronic JAK inhibitor treatment, has been observed in both MPN mouse models and MPN patients. Therefore, there is an urgent need for new treatment options in MPN. The tyrosine kinase RON, a member of the MET kinase family, has well-characterized roles in erythroblast proliferation and pro-inflammatory cytokine production. RON can be phosphorylated by JAK2 to stimulate erythroblast proliferation. However, the role of RON in MPN pathogenesis is unknown. We found that the ALK/MET/RON/ROS1 inhibitor crizotinib inhibited colony formation by MPN patient CD34+ cells, regardless of their disease subtype, mutation status, or JAK2 inhibitor treatment history (Figure 1A). To determine whether this is due to inhibition of the JAK/STAT signaling pathway, we performed phospho-flow cytometry of STAT3 and STAT5 in myelofibrosis patient erythroblasts treated with crizotinib ex vivo as well as Western blot analysis in the JAK2-mutated cell lines SET2 and HEL. We found that crizotinib inhibits the phosphorylation of JAK2, STAT3, and STAT5 (Figure 1B). Since crizotinib has not been reported to directly inhibit JAK2, we asked whether these effects of crizotinib in MPN cells could be explained by RON inhibition. Consistent with this hypothesis, we observed that shRNA knockdown of multiple RON isoforms also decreases the phosphorylation of JAK2, STAT5, and STAT3 in HEL cells (Figure 1C-D). To determine whether crizotinib can alter the MPN disease course in vivo, we tested crizotinib by oral gavage in the MPLW515L bone marrow transplant murine model of myelofibrosis at 100mg/kg daily for 2 weeks. We showed that crizotinib decreased the disease burden of MPL-W515L mice, as evidenced by decreased spleen and liver weights (Figure 1E). To determine the effects of RON genetic deletion on MPN pathogenesis, we tested whether genetic deletion of Stk (mouse gene for RON) impairs disease progression in the JAK2V617F bone marrow transplant MPN model by transplanting Stk-/- c-Kit+ bone marrow cells transduced with the JAK2V617F-GFP retrovirus into lethally irradiated recipients. We observed a significant delay in disease onset in Stk-/- transplant recipients compared to WT controls (Figure 1F). However, we found that Stk-/- mice have normal numbers of hematopoietic stem and progenitor cells, and normal bone marrow myeloid colony forming capacity, suggesting that RON is a safe therapeutic target. To determine whether RON plays a role in the JAK inhibitor persistence phenotype, we generated persistent cells by treating SET2 cells with increasing doses of ruxolitinib over 8 weeks, and confirmed persistent proliferation and JAK/STAT activation. Interestingly, we found that RON phosphorylation is enhanced in JAK inhibitor persistent cells, and that dual inhibition of RON and JAK2 overcomes JAK inhibitor persistence in SET2 cells (Figure 1G-H), suggesting that RON may potentiate the JAK2 persistence phenotype in response to ruxolitinib. Importantly, we showed by immunoprecipitation that phospho-RON and phospho-JAK2 physically interact in JAK inhibitor persistent SET2 cells, and that this interaction is disrupted by crizotinib (Figure 1I). In summary, our data demonstrate that RON kinase is a novel mediator of JAK/STAT signaling in MPNs, and that it plays a particularly important role in JAK inhibitor persistence. Our work suggests that therapeutic strategies to inhibit RON, such as crizotinib, should be investigated in MPN patients. Figure 1 Figure 1. Disclosures Halmos: Guardant Health: Membership on an entity's Board of Directors or advisory committees; Apollomics: Membership on an entity's Board of Directors or advisory committees; TPT: Membership on an entity's Board of Directors or advisory committees; Eli-Lilly: Research Funding; Advaxis: Research Funding; Blueprint: Research Funding; Elevation: Research Funding; Mirati: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gritsman: iOnctura: Research Funding.

scholarly journals Transfusion Requirements in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria with or without a History of Bone Marrow Disorder Receiving Ravulizumab and Eculizumab: Results from a Phase 3 Non-Inferiority Study Extension

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-33
Author(s):  
Antonio Risitano ◽  
Jun-Ho Jang ◽  
Lee Gyeong-Won ◽  
Wanchai Wanachiwanawin ◽  
Hubert Schrezenmeier ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sample Size ◽  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Complement Inhibitor ◽  
Phase 3 ◽  
Advisory Committees ◽  
Treatment Groups ◽  
History Of

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder leading to hemolytic anemia, which can occur concomitantly with bone marrow disorders (BMD), such as aplastic anemia (AA) and myelodysplastic syndrome (MDS). Accordingly, patients with PNH often require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow failure. After demonstrating a non-inferior efficacy and safety profile in two of the largest clinical trials to date, ravulizumab was approved as a treatment for adults with PNH, including patients with an underlying history of bone marrow disease, who are transfusion dependent or independent. Aims: To assess the efficacy of ravulizumab in patients with PNH with or without an underlying pathology of AA or MDS, and to investigate the impact of ravulizumab on transfusion burden as measured by number of transfusions and total packed RBC (pRBC) units transfused over a 52-week period. Methods: This phase 3 multicenter, randomized, active-controlled, open-label study (study 301, NCT02946463) enrolled complement-inhibitor-naïve patients with PNH. Patients were aged ≥ 18 years with a confirmed diagnosis of PNH by flow cytometry and lactate dehydrogenase (LDH) level ≥ 1.5x the upper limit of normal (ULN; 246 U/L). Patients received either ravulizumab or eculizumab for 26 weeks; after which all patients received ravulizumab from week 26 to week 52. Efficacy outcomes included the proportion of patients achieving transfusion avoidance (TA), number of pRBC units transfused and the number of pRBC or whole blood transfusions (WBT) received from baseline to 26 and 52 weeks of treatment. In this retrospective analysis, outcomes were analysed for the following subgroups: AA, MDS or no BMD (medical history of AA or MDS was determined by the investigator at screening). Descriptive statistics were calculated for continuous (means) and categorical variables (numbers and percentages). Formal hypothesis testing for significance between treatment groups was not performed. Results: Of the 246 patients included in the study, 79 had a history of AA (32.1%) and 13 (5.3%) had a history of MDS. Baseline characteristics were comparable between treatment groups. From baseline to week 26, a comparable proportion of patients with AA achieved TA to those with no BMD; 75.6% for patients with AA and no BMD receiving ravulizumab, and 60.5% and 73.7% for patients with AA and no BMD receiving eculizumab, respectively (Table 1). Importantly, TA was maintained through 52 weeks, with similar proportions of patients with AA (87.1‒91.3%) maintaining TA to patients without BMD (85.7‒91.5%). More specifically, 65.9% of patients with AA and 69.2% of patients without BMD achieved TA through 52 weeks of ravulizumab treatment, and 55.3% and 63.2% of patients with AA and without BMD, respectively, achieved TA on eculizumab followed by ravulizumab. The proportion of patients with MDS who achieved TA appeared numerically lower compared with patients with AA or no BMD, however, this subgroup sample size was small. Furthermore, a lower proportion of patients on ravulizumab with AA or MDS received any transfusion from baseline to weeks 26 and 52 compared with those treated with eculizumab followed by ravulizumab: for week 26, 24.4% and 57.1% for ravulizumab versus 39.5% and 100.0% for eculizumab in patients with AA and MDS, respectively, and for week 52, 29.3% and 57.1% for patients with AA and MDS receiving ravulizumab for 52 weeks versus 44.7% and 100.0% for patients with AA and MDS treated with eculizumab followed by ravulizumab. In addition, ravulizumab-treated patients with AA or MDS had numerally fewer transfusions and units of pRBC/WBT compared with those who received eculizumab followed by ravulizumab. Overall, the exploratory nature of the analysis and small sample size means that interpretation of the data is limited. Conclusions: This analysis demonstrates that majority of patients with PNH and AA who received ravulizumab avoided the need for transfusion up to 52 weeks of treatment. Patients treated with ravulizumab for the 52-week period had numerically fewer transfusions and units of pRBC/WBT transfused compared with patients who received eculizumab followed by ravulizumab. Overall, these findings support the use of ravulizumab in complement-inhibitor-naïve patients with PNH, with or without a history of BMD. Disclosures Risitano: Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; RA pharma: Research Funding; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Yonemura:Alexion Pharmaceuticals: Honoraria, Research Funding. Munir:Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Pavani:Alexion Pharmaceuticals: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sicre de Fontbrune:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Röth:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding.

Natural History Of Hemophilic Joint Disease Using Sensitive Imaging With Magnetic Resonance Imaging (MRI)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 209-209
Author(s):  
Thomas J Glorioso ◽  
John M Kittelson ◽  
Michael L Manco-Johnson ◽  
Bjorn Lundin ◽  
Walter Hong ◽  
...  
Keyword(s):  
Natural History ◽  
Board Of Directors ◽  
Research Funding ◽  
Healthcare Research ◽  
Rate Of Change ◽  
Advisory Committees ◽  
On Demand ◽  
Age Related ◽  
History Of ◽  
Bleeding Episodes

Abstract Introduction Arthropathy, the most costly chronic complication of severe hemophilia A (HemA) can be prevented by routine replacement of factor VIII (FVIII) when initiated prior to joint bleeding (primary prophylaxis) [NEJM;357:535]. However, the efficacy of prophylaxis initiated after the onset of recurrent hemarthroses or with established arthropathy (secondary or tertiary prophylaxis) is unknown. This individual patient meta-analysis was performed to derive the natural history of arthropathy in HemA patients treated only in response to acute bleeding (on demand therapy) as a baseline for future work to estimate the amelioration of arthropathy attributable to secondary or tertiary prophylaxis. Methods Data from individual participants in 3 studies who received on demand therapy were aggregated into a single database. Eligibility for this analysis included FVIII ≤ 2%, negative history for inhibitor, bleeding history for 12 months prior to study data acquisition and assessment of both ankles, knees and elbows; joints were assessed using physical examination (PE) and T2* gradient echo MRI scored as previously described using the World Federation of Hemophilia Gilbert score and the 45 point extended MRI scales [Haemophilia;6:649; ISTH OP Mon 7/1/13, 9 am]. MRI data were divided into soft tissue and osteochondral changes. Bleeding and Gilbert data for all 6 joints and MRI data for knees and ankles were analyzed using standard descriptive statistics and regression methods to quantify the rate of change in scores of joint damage with age. Results The 3 studies included the Joint Outcome Study [NEJM;357:535] and the JOS Continuation Study (JOSc), the Spinart Study baseline results [JTH;11:1119] and a Cross-Sectional MRI study [Haemophilia;189 Suppl3:117]. The 3 studies provide data on 275 individuals aged 1 to 50 years. Clinical, Gilbert and MRI data were extracted and analyzed from multiple joints in each of 157 individuals who were receiving on-demand treatment only. The median age was 21 (range 1 – 50), and across all studies the median number of bleeding episodes in the prior 12 months was 18 (range 0 to 82). The rate of change in outcomes as a function of age is shown in Table 1 and Figure 1. The number of bleeding episodes was approximately constant at 20 bleeding episodes per year regardless of age (Figure 1a; p = 0.72 for relationship with age). Gilbert scores showed a steeper rise in young patients but did not increase after the late teens (Figure 1b; change of 0.34 Gilbert points/year of life, p=0.07). MRI scores, in contrast to bleeding rates and Gilbert scores, showed continued age-related deterioration (Figure 1c; change of 2 MRI points/year of life, p < 0.0001). Age-related total and osteochondral deterioration on MRI increased steadily with age (on average 2 MRI-points/year of age, p < 0.0001 for each), whereas soft tissue scores increased rapidly to approximately 9 by age 20, and then plateaued at a score of approximately 10 for ages 20-50 (0.08 MRI points/year, p =0.28). Conclusions Individual patient meta-analysis of bleeding frequency, joint PE and MRI joint structure was useful to determine the natural history of hemophilic arthropathy in patients treated with on-demand therapy, and showed a continuous increase in joint bone and cartilage abnormalities across the age span despite an early leveling in bleeding rate and joint physical function. These data will be critical to determine the quantitative effects of prophylaxis on mitigation of joint deterioration when initiated at various ages following the onset of joint bleeding. Disclosures: Manco-Johnson: Bayer HealthCare: Research Funding. Lundin:Bayer HealthCare: Research Funding. Hong:Bayer HealthCare: Employment. Oldenburg:Octapharma AG: Consultancy, Investigator Other. Manco-Johnson:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; NovoNordisk: Membership on an entity’s Board of Directors or advisory committees; Eisai: Research Funding.

Use of Blood Transfusions In Paroxysmal Nocturnal Hemoglobinuria Patients with and without Aplastic Anemia Enrolled In the Global PNH Registry

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2241-2241
Author(s):  
Hubert Schrezenmeier ◽  
Robert A Brodsky ◽  
Petra Muus ◽  
Monica Bessler ◽  
Jeffrey Szer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Employment Equity ◽  
Advisory Committees ◽  
Clone Size ◽  
History Of ◽  
Equity Ownership ◽  
To Receive

Abstract Abstract 2241 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis which can lead to life-threatening complications including thrombosis, kidney disease, pulmonary hypertension, pain, anemia, and severe fatigue. PNH clones occur in a number of patients with concomitant aplastic anemia (AA) and other bone marrow disorders (BMD). Some patients with PNH and/or BMD may require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow hypoplasia. Aims: To characterize the use of RBC transfusions among PNH patients with and without underlying AA. Methods: Enrollment data from 117 clinical sites participating in the observational PNH Registry in 16 countries on 5 continents was analyzed. Patients are included in the Registry regardless of the proportion of cells with deficiency of glycosylphosphatidyl-inositol anchored proteins (GPI-AP), bone marrow pathology, symptoms, or treatments. Sites collect clinical history at enrollment and additional data every 6 months. Demographic data, use of transfusions and other treatments, lab results, and symptoms are summarized for PNH patients with and without AA. Results: As of June 30, 2010 there were 655 enrolled patients in the Registry (53% female, median age 43). At enrollment, 28% of patients had history of AA and 45% had no history of BMD. Patients with underlying AA had lower median GPI-AP deficient granulocytes than those without BMD (median = 53% vs. 86%, respectively, p<.01) and patients in both groups had similar evidence of hemolytic activity when stratified by clone size (median LDH fold above normal upper limit was 0.90 vs. 0.94, p=.39 for patients with and without AA and clone size <10%; median = 3.41 vs. 4.84, p=.08 for AA vs. no BMD and clone size ≥50%). Not all PNH patients required transfusions: 56% of all patients required transfusions in the year prior to enrollment. Although patients with and without AA were equally likely to be treated with blood transfusions in the year prior to study enrollment overall, some differences emerged when stratified by clone size. For patients with clone size <50%, AA patients were almost twice as likely to receive transfusion in the previous year as patients without BMD (39% vs. 20%, p=.08). However, regardless of underlying AA, the proportion of patients receiving transfusions, in the prior year increased as clone size increased (29%, 31%, and 69% for clone sizes <10%, 10–49%, and ≥50%, respectively, p<.01). When patients were stratified by percent reticulocytes at enrollment (below vs. above the median value of 4.16%), 45% vs. 75% received transfusion in the prior year (p<.01). Among patients receiving a transfusion in the year prior to enrollment, the mean number of RBC units transfused was 9.6 for patients with underlying AA and 7.9 for patients with no BMD (p=.10). However, approximately twice as many patients with AA received 20+ RBC units in that year compared to patients without BMD (20% vs. 11%, p=.09). Number of transfused units in that year was similar by clone size (mean 9.5 vs. 8.6 for clone size <50% vs. ≥50%, p=.57). Concomitant treatment with anticoagulants or immunosuppressants was similar among patients who had received a transfusion in the past year compared to patients with no transfusions (39% vs. 33%, p=.13 and 26% vs. 22%, p=.25 respectively). Patients with AA had more bruising and bleeding while patients without BMD had more hemoglobinuria, dysphagia, and abdominal pain. Transfused patients with AA had more fatigue than non-transfused patients with AA (68% vs. 48%, p=.02). Conclusions: A substantial proportion (56%) of patients with PNH, but not all, required at least one transfusion in the year prior to enrolling in the registry, independent of underlying AA. The proportion of patients who had at least one transfusion increased with clone size. Among patients who had at least one transfusion, there was a trend for patients with underlying AA to receive more RBC units than patients without BMD. PNH patients with AA have fewer GPI-AP deficient granulocytes but demonstrate elevated hemolysis similar to patients without history of BMD when patients with similar clone sizes were compared. This Global PNH Registry, which remains open to accrual ([email protected]), should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Schrezenmeier: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brodsky: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Muus: Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bessler: Alexion Pharmaceutical Inc: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy. Szer: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Maciejewski: Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. Socié: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua: Alexion: Membership on an entity's Board of Directors or advisory committees. Kanakura: Alexion: Membership on an entity's Board of Directors or advisory committees. Hoechsmann: Alexion: Speakers Bureau. Rosse: Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Karnell: Alexion Pharma International: Employment, Equity Ownership. Bedrosian: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hillmen: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Classical Hodgkin Lymphoma Patients Have an Increased Incidence of Idiopathic Acquired Aplastic Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5098-5098
Author(s):  
Taylor Linaburg ◽  
Adam R. Davis ◽  
Noelle V. Frey ◽  
Daniel J. Landsburg ◽  
Stephen J. Schuster ◽  
...  
Keyword(s):  
Bone Marrow ◽  
General Population ◽  
Aplastic Anemia ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Advisory Board ◽  
Classical Hodgkin Lymphoma ◽  
Advisory Committees ◽  
History Of

Abstract Idiopathic acquired aplastic anemia (AA) is a rare immune-mediated bone marrow aplasia of unknown etiology. Interestingly, we noted several cases of AA developing after a previous diagnosis of classical Hodgkin lymphoma (HL). Due to the rarity of both HL and AA, we hypothesized that their co-occurrence represents a non-random association that may be etiologically significant. To evaluate this potential association, we analyzed the prevalence, incidence and characteristics of patients with co-occurring AA and HL at our institution and through a systematic literature review. Using a defined search of electronic medical records for patients seen at our institution between 2005 and 2018, we identified 4 patients with severe AA who were also diagnosed with HL. The prevalence of AA in patients with HL at our institution (0.2%; 4 of ~2040) was in agreement with the prevalence of AA in published cohorts of HL patients (e.g., 1 in 138 - 200; p 0.205). Using a conservative incidence measure of AA, we found that patients with HL have a striking, over 20-fold higher incidence of AA compared to the published incidence of AA in the general population (4 in 26,497 person-years vs 2.2 to ~7 in 1,000,000 person-years; p=0.0001). To determine the clinical and pathologic characteristics of AA in patients with a history of HL, we expanded our study by performing a systematic literature review. Using the search terms "Hodgkin lymphoma", "Hodgkin disease", "aplastic anemia" and "pancytopenia" in the PubMed database, we identified 7 cases of associated AA and HL diagnoses published between 1956 and 2007. Patients with other HL complications, such as post-chemotherapy myelosuppression, infections, myelodysplastic syndrome, acute leukemia, and hemophagocytic syndrome were excluded. Of the 11 total cases of AA also diagnosed with HL, the median age at AA diagnosis was 31.5 years (range of 12-49 years), with 80% of patients being male (Figure 1, Table 1). Ten of the 11 patients developed AA after or concurrent with a HL diagnosis. The median interval between HL diagnosis and AA onset was 2 months, ranging from concurrent presentation in 5 patients to a maximum of 14 years after an initial HL diagnosis. Of the 10 patients initially presenting with HL, 3 were treated with ABVD, 4 with MOPP-related regimens, and 2 patients required salvage therapy. There were no unusual hematological or other toxicities due to chemotherapy. At the time of AA diagnosis, none of the patients had marrow involvement with HL, and 5 of 10 patients were in complete remission from HL. Five patients for whom cytogenetic information was available had no cytogenetic abnormalities at AA diagnosis. Among the 4 cases from our institution, 2 had a diagnosis of marginal zone lymphoma (1 treated by splenectomy, 1 by rituximab monotherapy), and 1 had a remote history of testicular carcinoma treated by orchiectomy; all 3 cases were in remission prior to HL diagnosis. There was no family history indicative of bone marrow failure or inherited cancer syndromes. The 10 patients who developed AA concurrent with or after HL had dramatically poor outcomes, with a median survival of 14 months (range of 1 month to not reached) (Figure 1, Table 1). Of these 10 patients, 4 were treated with immunosuppression, 2 with eltrombopag, and 2 received allogeneic bone marrow transplants. Of the 4 patients who received immunosuppression, 1 evolved to MDS/AML 4 months after AA diagnosis. Five patients presented with both diagnoses concurrently: 1 was refractory to immunosuppression and achieved complete remission after receiving an allogenic bone marrow transplant, while 4 were unable to receive standard therapy for either condition. Of the historical cases, 5 of the 7 patients received supportive therapy only; the median survival for these patients was 14 months (range of 1 month to 84 months). In conclusion, the data suggest that patients with HL have a significantly higher incidence of AA compared to the general population. The underlying reason for this association is not known; however, the development of AA after HL, a unique B-cell neoplasm associated with a marked inflammatory component, without having received prior cytotoxic therapy in half of the cases, points to secondary immune dysregulation as the possible etiologic factor for AA pathogenesis. Recognition of this syndrome and improved management algorithms are needed for the management of AA presenting in patients with HL. Disclosures Frey: Novartis: Consultancy; Servier Consultancy: Consultancy. Landsburg:Curis: Consultancy, Research Funding; Takeda: Consultancy. Schuster:Dava Oncology: Consultancy, Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Svoboda:Kyowa: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy; TG Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding. Olson:Novartis: Other: participated in 2 advisory boards in 2018; Merck: Other: participated on an advisory board in 2018; BluebirdBio: Other: participated in an advisory board in 2018.

scholarly journals Characteristics and Outcomes of Adolescent and Young Adult (AYA) Patients with Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML): A Single-Center Retrospective Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3687-3687
Author(s):  
Shehab Fareed Mohamed ◽  
Tareq Abuasba ◽  
Kelly S. Chien ◽  
Guillermo Montalban-Bravo ◽  
Faezeh Darbaniyan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retrospective Study ◽  
Young Adult ◽  
Myelodysplastic Syndrome ◽  
Board Of Directors ◽  
Research Funding ◽  
Marrow Transplant ◽  
Adolescent And Young Adult ◽  
Research Support ◽  
Advisory Committees

Abstract Introduction Myelodysplastic syndrome (MDS) is mainly a disease of the elderly, with a median age of 72 years. There is little information regarding Adolescent and Young Adult (AYA) Patients with Myelodysplastic syndrome (MDS). AYA cancer patients are defined as those patients ages between 15-39 years according to NCCN guidelines. This retrospective study describes the general characteristics, cytogenetics, mutational profiles, treatments, and outcomes of AYA with MDS Diagnosis. Methodology We analyzed the clinical database of a single tertiary care center for patients with MDS ages between 18- 39 years from January 2012 through December 2020. We used 18 years as age cut-off, and not 15, due to the structure of our cancer center. Results In this retrospective study, 65 patients were identified. The median age was 30 (18-39) years, with female sex predominance (n=37) (57%). Baseline laboratory findings: median hemoglobin (HgB) was 9.45gm/dL (6.2-14.8), white blood cells (WBC) (3.4x10e9/L [0.3-136.9], platelets 63,000 (5,000-479,000), bone marrow blast 4% [0-17], IPSS was low in 11 patients (17%), intermediate- 1 in 23 (35%), intermediate- 2 16(25%) and high 8 (12%). 58 patients (89%) had MDS and seven (11%) had CMML. Twenty patients (30.7%) had a previous history of other cancers, with sarcomas being the most frequent with 6 cases (9.2%). Therapy-related MDS (t-MDS) was observed in 18 patients (27.6%). Ten patients (15.3%) had bone marrow failure syndrome, with GATA2 syndrome being the most frequent. Fanconi anemia and Schwachman-Diamond Syndrome was documented in two patients respectively. The most recurrent cytogenetics alterations were diploid in 20 patients (30.7%), followed by complex in 11 (16.9%). The most frequent mutations were RUNX1 (somatic)15%, followed by DNMT3A, TP53, NRAS, GATA2 and TET2, as shown in the Figure 1. Hypomethylating agents (HMAs) were the most frequent first line treatment used in 16 patients (24.6%). Forty-three patients (66%) underwent an allogeneic bone marrow transplant with a median OS (95% CI) of 27 months (9-45). While for the group of patients who didn't receive transplant, it was 21 months (7-69) (p=0.19) vs patients who didn't receive transplant. Allogeneic transplantation in TP53-mutated patients resulted in a Median OS (95% CI) of 21 months (12-65). Patients who progressed into AML had an inferior median OS (95% CI) of 21 months (12-65) for vs 28 months (11-47) for those who did not progressed to AML(p=0.025). In multivariate analysis expression of RUNX1 and NOTCH1, was associated with inferior outcomes (p-value=0.035, 0.004 respectively) (Figure 2,3 and 4) Conclusion In our cohort, MDS occurred as part of marrow failure syndrome or consequence of therapy t-MDS. Somatic RUNX1 was the most frequent mutation in AYA group with MDS. RUNX1, NOTCH1 and Tp53 mutated patients had worse outcome. Most patients underwent bone marrow transplant Figure 1 Figure 1. Disclosures Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Daver: Abbvie: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Amgen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Hanmi: Research Funding; Sevier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Kadia: Liberum: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Other; Jazz: Consultancy; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Pulmotech: Other; Genentech: Consultancy, Other: Grant/research support; Aglos: Consultancy; Sanofi-Aventis: Consultancy; Genfleet: Other; Astellas: Other; Ascentage: Other; AstraZeneca: Other; AbbVie: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; Cellonkos: Other. Pemmaraju: LFB Biotechnologies: Consultancy; Incyte: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Celgene Corporation: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Roche Diagnostics: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Plexxicon: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Sager Strong Foundation: Other; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Kantarjian: NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Precision Biosciences: Honoraria; BMS: Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; Ascentage: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria.

scholarly journals Peripheral Blood Haploidentical Allogeneic Stem Cell Transplantation in Older Adults with AML/MDS Demonstrates Excellent Long Term Overall Survival, Results from the Australasian Bone Marrow Transplant Recipient Registry

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2929-2929
Author(s):  
Edward Abadir ◽  
Jad Othman ◽  
John Kwan ◽  
David J Gottlieb ◽  
Glen A Kennedy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Marrow Transplant ◽  
Donor Age ◽  
Bone Marrow Transplant Recipient ◽  
Advisory Committees ◽  
Cmv Reactivation

Abstract Background: Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-HCT) is an established therapy using alternative donors for patients with Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS). There is a limited body of evidence for older patients undergoing Haplo-HCT in AML and MDS. Studies describing Haplo-HCT in older patients have used a high proportion of bone marrow (BM) derived grafts and a variety of conditioning regimens. In this setting, Haplo-HCT demonstrates acceptable Non-Relapse Mortality (NRM) and chronic Graft Versus Host Disease (cGVHD) rates of less than 10% (Ciurea. Biology of Blood and Marrow Transplantation. 2018 Jun 1;24(6):1232-6.). In Australia and New Zealand, Haplo-HCT is predominantly performed using peripheral blood (PB). We performed a retrospective national registry study to examine the outcomes of Haplo-HCT using PB in older patients. Methods: Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB Haplo-HCT for AML/MDS between January 2010 and July 2020. Cumulative incidence functions were used for engraftment, CMV reactivation, acute GVHD, chronic GVHD, relapse, and NRM. The competing risk for engraftment, CMV reactivation and GVHD was death. Relapse and NRM were competing risks for each other. Overall survival (OS), relapse-free survival (RFS), and composite GVHD and RFS (GRFS) were calculated using Kaplan-Meier analyses. The impact of pre-transplant factors on these endpoints was analyzed using Cox regression. Results: A total of 44 patients were included in the analysis. The median follow-up time was 734 days. The median age was 68 (range 65-74) with a median Karnofsky Performance Status of 90. Thirty patients (68.2%) had AML while 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was non-myeloablative fludarabine, cyclophosphamide and TBI (73.8%), the remainder of the patients received either melphalan or busulfan based regimens, the majority were reduced intensity with only 2 patients undergoing myeloablative conditioning. All patients received post-transplant cyclophosphamide and mycophenolate mofetil with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporin (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients, at a median of 18 days while platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of CMV reactivation and CMV disease were 52.5% and 5.1% at 1 year The incidence of Grade 2-4 aGVHD was 18.2%. The incidence of cGVHD at 2 years was 40.7%, with extensive cGVHD occurring in 17.7% of patients. The incidences of relapse and NRM at 2 years were 8.8%. and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year OS was 74%. RFS and GRFS at 2 years was 70% and 48% (Figure 1). Recipient age, donor age or disease type (AML vs MDS) had no significant impact on OS or GRFS. Conclusion: These results confirm the safety and effectiveness of Haplo-HCT for AML/MDS in older patients. The rates of cGVHD were higher than expected given the lower rates reported in other studies using PTCy GVHD prophylaxis. Haplo-HCT using a PB graft demonstrates good long-term disease control with reasonable rates of NRM and cGVHD for older patients with AML/MDS. Figure 1 Figure 1. Disclosures Bajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Perera: Abbvie: Speakers Bureau; BMS: Speakers Bureau. Greenwood: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Diagnosis of Myelodysplastic Syndromes and Related Conditions: Rates of Discordance between Local and Central Review in the NHLBI MDS Natural History Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4370-4370 ◽  
Author(s):  
Ling Zhang ◽  
Donald M Stablein ◽  
Pearlie Epling-Burnette ◽  
Alexandra M. Harrington ◽  
Lynn C. Moscinski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Natural History ◽  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Diagnostic Errors ◽  
Advisory Committees ◽  
Natural History Study ◽  
Oncology Research ◽  
Blast Count

Abstract Background Myelodysplastic syndromes (MDS) are a collection of hematopoietic disorders with widely variable prognoses and treatment options. Pathologic diagnosis can be challenging and misdiagnosis can impact patient therapy and outcome. How commonly misdiagnosis occurs, and the severity of diagnostic errors, is not known. Here, we report interim analyses of patients (pts) with cytopenia and suspected MDS from the NHLBI National MDS Natural History Study (https://thenationalmdsstudy.net ClinicalTrials.gov: NCT02775383) assessing MDS occurrence and rates of agreement on classification of MDS/MDS-related disorders by local and centralized review. Methods Pts with cytopenias and clinically suspected MDS were identified between 6/16 and 6/18 from 84 participating centers in this ongoing multi-Institutional Cooperative Group study, with a goal of recruiting 2000 MDS (WHO 2016 subcategories), MDS/MPN or low blast count acute myeloid leukemia (AML, <30% blasts without core binding factor) and 500 cases with idiopathic cytopenia of undetermined significance (ICUS) from both NCI community oncology research program (NCORP) and lead academic participating sites. Centrally submitted clinical and pathologic data and bone marrow samples were analyzed by pathologists in the central laboratory & biorepository (CL/B) blinded to the original site's diagnosis, with a third-level review for cases with disagreement between the local and CL/B assignment. Disagreements in the 5 categories detailed in Figure 1 were considered clinically meaningful. Cases were assigned to longitudinal (MDS, MDS/MPN, ICUS, low blast count AML) versus cross-sectional (other cytopenias or cancers) cohorts after central classification based on clinical, pathologic, and cytogenetic features. Interrater-agreement was evaluated with the Kappa statistic. Results Of 375 pts for whom data and samples were submitted with completed classification, 88 (23%) had MDS, 15 (4%) MDS/MPN, 12 (3%) ICUS, 23 (8%) AML, and 237 (63%) other cytopenias (Figure 1). The median age of all pts was 71 years (range, 20-92), 44% were female, and median baseline blood counts and other baseline measures are in Figure 2. MDS pts had single lineage dysplasia (SLD, 0), SLD with ring sideroblasts (RS, 9 (10%)), multi-lineage dysplasia (MLD, 17 (19%)), MLD -RS (18 (20%)), excess blasts I (EB, 14 (16%)), EBII (19 (22%)), del(5q) (6 (7%)), and MDS-U (5(6%)). IPSS-R categories were defined in 51 of 88 MDS cases (58%): Very Low (27%), Low (43%), Intermediate (27%), High (16%), and Very High (14%). Overall site/central agreement on diagnosis occurred in 225 cases (60%) with inconsistency associated with recognized site coding errors resolved in 54 cases (14%) without 3rd party review. Seventy-eight others (21%) were referred to 3rd level review; confirmation of CL/B classification occurred in 49/78 cases (63%), agreement with site in 13/78 (17%), and a different diagnosis in 16/78 (21%). Clinically meaningful changes in diagnoses between local and central review occurred 26% of the time (Figure 1, n=97/375 kappa =.53 95% CI (.45, .61)). Site assigned MDS was changed to ICUS or other cytopenia in 35% (n=34/99); and to AML in 3% (n=3/99). For cases with site assignment to other causes of cytopenias (225 of 375 cases, 60%), central assignment identified ICUS in 3, MDS/MPN overlap in 8, AML in 2 and MDS in 22, totaling a change in diagnosis in 16%. Of note, 60% (15/25) of ICUS diagnosed locally were interpreted as reactive marrow or normal according to central review. Within MDS cases diagnosed locally, the greatest discrepancy was observed in the MDS-U classification, reported 31 times (31/99 31%) but confirmed in only 2 cases (6%), with 22 (71%) found to not have MDS. Across the study when compared to local assignment, central review changed the follow-up cohort assignment for 87 pts (23%). Conclusions In this well-characterized series of pts evaluated for MDS with bone marrow biopsy and paired site/central morphologic assessment, 40% of site diagnoses were changed at central review and site coding errors were common. In 26%, the changes were clinically meaningful, potentially affecting patient treatment and prognosis. In particular, site designation of MDS-U was an unreliable classification category, which could only partially be attributed to miscoding errors at the local site. Incorporating genomics data might help refine MDS diagnoses. Disclosures Bejar: Genoptix: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Honoraria; Modus Outcomes: Consultancy; Astex/Otsuka: Consultancy, Honoraria; AbbVie/Genentech: Consultancy, Honoraria; Foundation Medicine: Consultancy. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Scott:Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy, Research Funding; Alexion: Consultancy. Gore:Celgene: Consultancy, Research Funding. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Trends in Iron Overload over Past Two Decades: Results from the Natural History of Iron Burden Study with the SQUID Biosusceptometer

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 961-961
Author(s):  
Ashutosh Lal ◽  
Roland Fischer ◽  
Elliott Vichinsky ◽  
Marcela Weyhmiller
Keyword(s):  
Natural History ◽  
Longitudinal Data ◽  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Iron Status ◽  
Advisory Committees ◽  
Liver Iron ◽  
Non Invasive ◽  
History Of

Established in 2002, the Iron Overload Program in Oakland relies on a biosusceptometer (Ferritometer®, model 5700, Tristan Technologies, San Diego, USA) utilizing low temperature SQUID technology to quantify liver iron concentration (LIC). The procedure is non-invasive and patients as young as 2 years can be been measured without sedation. The measurement and analysis are rapid (30 - 45 min) and the results have been validated against biopsy. Over 3500 measurements have been performed on 1055 patients at risk of iron overload. Longitudinal data were acquired under the natural history of iron burden by non-invasive measurement techniques study since November 2002. Patients were referred for liver iron assessment at intervals determined by their providers. Seventy-one patients had ≥10 measurements, 34 had ≥15 measurements, and 7 had ≥20 measurements. Over the course of the study, the average age at enrollment fell from 23 +/- 17 years (range 2 - 88 years) to 18 +/- 15 years (2 - 73 years). There was an increase in the proportion of patients with non-transfusion dependent thalassemia and those with iron overload from red cell transfusions associated with chemotherapy or stem cell transplantation. In comparison to the first five years (2003 - 2008) in the most recent five years (2014 - 2018) chelation has shifted from deferoxamine to deferasirox and there has been an increase in the simultaneous use of two chelators. We observed an overall decrease in mean LIC from 2400 to 1800 micrograms Fe/g liver wet weight (14.4 to 10.8 mg/g liver dry weight). Ferritin to LIC ratios were 0.46 in non-transfused thalassemia, 0.85 in intermittently transfused (&lt; 7 mL/Kg/month), and 1.10 in transfusion-dependent (≥7 mL/Kg/month). A subgroup analysis of longitudinal data in transfusion-dependent thalassemia with multiple measurements was conducted. The mean (±s.d.) LIC decreased by 42% from 15.8 ± 10.2 at the first measurement to 9.2 ± 9.7 mg/g at the last visit. At the same time, mean ferritin decreased from 2629 to 2115 ng/mL, a change of 20%. In this group of patients ferritin levels now overestimate LIC by a significant amount (Figure). This reflects either a change in transfusion practices or the type of chelation. These results show a positive impact of oral chelators and combined chelation regimens leading to a significant improvement in iron overload in thalassemia. The development of organ complications from iron toxicity is expected to decrease, but there is a risk of over-chelation if ferritin is the sole measure of iron status. Liver biosusceptometry has been a valuable method to assess diverse conditions associated with iron overload and to monitor chelation treatment in patients across all ages. Figure Disclosures Lal: Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Terumo Corporation: Research Funding; Insight Magnetics: Research Funding; bluebird bio: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding. Vichinsky:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Agios: Research Funding.

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