Geriatric Assessment Metrics Are Associated with Hospital Length of Stay in Pre-Bone Marrow Transplant Myeloma Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3200-3200 ◽  
Author(s):  
Ashley E Rosko ◽  
Craig C Hofmeister ◽  
Yvonne A Efebera ◽  
Don M Benson ◽  
Douglas W Sborov ◽  
...  
Keyword(s):  
Physical Activity ◽  
Social Support ◽  
Bone Marrow ◽  
Length Of Stay ◽  
Physical Function ◽  
Research Funding ◽  
Marrow Transplant ◽  
Objective Measures ◽  
Moderate Fatigue ◽  
Transplant Evaluation

Abstract A geriatric assessment (GA) is a global approach to improve healthy aging, wherein occult problems are assessed and intervened upon using a multidisciplinary method. A GA is feasible and can predict chemotherapy-induced toxicity and overall survival in cancer patients. Biomarkers of aging are also being explored as objective and reproducible measures of health and fitness. p16INK4a (p16) is a marker of cellular senescence that rises exponentially with chronologic age and is influenced by factors such as physical activity, smoking, and solid tumor chemotherapy. Here, we investigated the relationship of both the GA and molecular (i.e. p16) metrics in pre-bone marrow transplant (BMT) multiple myeloma (MM) patients. We selected this group for our studies as BMT patients are a vulnerable cohort in which transplant eligibility is subjective and age related. BMT patients are also at high risk for adverse events and treatment toxicity. In this preliminary analysis, we explored the predictive value of GA metrics and p16 with inpatient length of stay (LOS) during autologous BMT. Methods: We performed a pilot prospective cohort study on 55 MM patients during their pre-transplant evaluation. MM patients >18 years completed GA assessments related to physical function, distress, comorbidities, social support, and cognition. Patients completed surveys using the Brief Fatigue Inventory (BFI) (scale 1-10; moderate fatigue 4-6, severe fatigue 7+); Hospital Anxiety and Depression (HADS) (borderline case 8-10, definite case 11+); medical outcome study-social support survey (MOS-SSS) (scale 0-100, higher scores indicated greater support), Human Activity Profile (HAP) maximum activity score (MAS) and HAP-adjusted activity score (AAS), a 94-item questionnaire ranking tasks according to energy use validated in the BMT population, with higher scores indicating higher activity (Herzberg BBMT 2010). Objective measures of physical activity were measured using the Short Physical Performance Battery (SPPB) (range 0-12; impairment <9) and cognition was evaluated using the Modified Mini Mental Status exam (3MS). At the pre-transplant evaluation, p16 mRNA was measured in peripheral blood T-cells using established laboratory techniques (Liu Aging Cell 2009). The association between GA metrics and p16 were evaluated using Spearman's correlation coefficient. Univariable generalized linear models were fit to model LOS as a function of GA metrics or p16. Results: The median patient age was 61 (range 42-76). Most patients exhibited early stage disease (ISS Stage 1 53%) with minimal comorbidities (HCT-CI median 1; range 0-8) and a median of 2 prior lines of treatment (range 1-11). Pre-transplant Karnofsky Performance Status (KPS) was reported as 70% (n=10), 80% (n=10), 90% (n=15) and 100% (n=12). 7 patients did not proceed with BMT, 1 inpatient for BMT. Patients reported moderate fatigue by BFI (median 4.3; range 0-9.8), with minimal anxiety or depression as measured by the HADS. Self-reported physical activity by HAP-MAS was 73 (range 30-94) and HAP-AAS was 64 (range 20-94). Patients reported high levels of social support (median 86.7%; range 18.2-100) by MOS-SSS. Objective measures of physical function were also high as measured by the SPPB (median 10; range 4-12) and no cognitive impairment was identified by the 3MS. p16 expression was adjusted for age and did not correlate with GA tools including BFI, HADS, HAP-AAS, HAP-MAS, MOS-SSS, SPPB or 3MS. The median length LOS during transplant was 16 days (range 12-36). Univariate analysis revealed that SPPB score was significantly associated with LOS, where each one unit increase in physical performance corresponded to an average LOS decrease of 0.63 days (p=0.04). Self-reported activity by HAP-AAS also correlated with LOS (p=0.05). LOS was not influenced by p16, age, KPS or HCT-CI. Age and HCT-CI had no relationship with SPPB scores, but KPS did (p=0.03727). Conclusions: A comprehensive GA can be used to identify factors that contribute to BMT outcomes. Physical function appears to be most predictive of hospital LOS as measured by SPPB or a detailed self-report of physical function. Baseline p16 levels had no relationship with GA metrics in this selected population. A standardized approach for determining patient fitness including SPPB and HAP-AAS assessments may improve treatment tolerance, reduce hospital LOS, and decrease the risk for adverse outcomes in BMT populations. Disclosures Jaglowski: Immunomedics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Seattle Genetics: Consultancy.

Social Support and Depression among Bone Marrow Transplant Patients

2008 ◽  
Vol 13 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Julie D. Jenks Kettmann ◽  
Elizabeth M. Altmaier
Keyword(s):  
Social Support ◽  
Bone Marrow ◽  
Bone Marrow Transplant ◽  
Marrow Transplant ◽  
Transplant Patients

The Use of a Bone Marrow Transplant Program Public Website for Patient Education and Reporting of Outcomes: Increased Use Resulting in Improved Patients’ Trust and Assurance.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5592-5592
Author(s):  
Elissa F. Malcolm ◽  
Linda J. Patchett ◽  
Thomas F. Fitzmaurice ◽  
John M. Hill ◽  
Kenneth R. Meehan
Keyword(s):  
Bone Marrow ◽  
Patient Education ◽  
Length Of Stay ◽  
Bone Marrow Transplant ◽  
Marrow Transplant ◽  
Outcome Data ◽  
Patient Specific ◽  
Disease Specific Survival ◽  
Quality Reports ◽  
Disease Specific

Abstract To promote patient education, the Dartmouth Bone Marrow Transplant (BMT) Program created a website focusing on Quality Reports, highlighting outcomes and patient satisfaction data. In an attempt to address areas most important to potential patients, the development of the website involved Transplant physicians and nurses, outside reviewers and recently transplanted patients. Based on these assessments and interviews, the BMT website was designed to provide various outcome data, including disease-specific overall- and disease-free survival, length of stay, and incidence of nausea. The website became public in January 2004. The use of the public website was evaluated 18 months after initiation. There was a 300% increase in external user visits to the Dartmouth BMT Website (comparing 3 month averages). Eighty percent of the information accessed was in the topic of “Safe and Effective Care”, which addresses patient-specific data, including survival statistics, length of stay, or toxicities during the transplant. The remaining 20% of interest was satisfaction measures addressing patients’ view of their overall care, opinions addressing nursing care or physician interaction. Of the top ten measures that were evaluated by users, the first 9 were disease-specific survival statistics and the remaining was “Average Length of Hospital Stay”. Individual interviews with patients (n=16) indicate that the information provided on the web site increased the trust of the institution. In addition, patients felt re-assured concerning their selection of our institution. In conclusion, the initiation of the Dartmouth BMT Quality Reports Website (http://www.dhmc.org/QualityReports) that focuses on outcome data resulted in a marked increased use of the Dartmouth BMT Website within 18 months. Patients were most interested in disease-specific survival statistics, followed by transplant patients’ opinions of their care. Patients report that the “transparency” of outcome results and the patient education provided by the website improve their trust of our BMT program/hospital and foster assurance of our institution’s reputation.

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.

The Combination of Cyclophosphamide-Bortezomib-Dexamethasone (CYBOR-D) Is a Highly Effective and Well Tolerated Regimen that Produces Rapid and Complete Hematological Response In Patients with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3063-3063
Author(s):  
Joseph R. Mikhael ◽  
Steven R. Schuster ◽  
Victor H Jimenez-Zepeda ◽  
Nancy Bello ◽  
Jacy Spong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplant ◽  
Research Funding ◽  
Autologous Bone Marrow ◽  
Marrow Transplant ◽  
Al Amyloidosis ◽  
Autologous Bone Marrow Transplant ◽  
Treatment History ◽  
Hematological Response ◽  
Autologous Bone

Abstract Abstract 3063 Background: The combination of Cyclophosphamide, Bortezomib, and Dexamethasone (CYBOR-D) is proven to be highly active and effective in multiple myeloma. (Reeder, Leukemia 2009) We aim to evaluate the safety and efficacy of this regimen in a separate plasma cell neoplasm, AL Amyloidosis. The primary endpoint of this study is hematologic response. Complete hematologic response is defined as normalization of the free light chain ratio with no evidence of a monoclonal protein by immunofixation. Partial hematologic response is defined as a 50% reduction in M-spike or absolute light chain level (Gertz Am J Heme 2006). Methods: We report a series of patients with symptomatic AL Amyloidosis who received treatment with a combination of Bortezomib (1.3mg/m2 on days 1, 4, 8, and 11 every 28 days or 1.5 mg/m2 weekly), Cyclophosphamide (300 mg/m2 orally weekly) and Dexamethasone (40 mg weekly). We include patients in this study regardless of autologous bone marrow transplant candidacy or previous treatment history. Results: Fifteen patients with AL amyloidosis received two to six cycles of CYBOR-D. The treatment history, bone marrow transplant candidacy prior to treatment, hematological response, and status of transplant after therapy are shown in table 1. Of note, 8 (53%) had symptomatic cardiac involvement all of whom had elevated levels of both cardiac biomarkers (Troponin T and B-natriuretic peptide). Complete hematological response occurred in 11 patients (73.3%) with partial hematological response in 3 patients (20.0%). One patient (6.6%) did not achieve a partial response but did receive autologous bone marrow transplant after treatment with CYBOR-D. Median time to response was 2 months. Six patients (40%) had objective evidence of kidney response to therapy with a greater than 50% decrease in proteinuria. Conclusions: CYBOR-D produces a rapid and complete hematological response in the majority of patients with AL amyloidosis regardless of previous treatment history or bone marrow transplant candidacy. Overall, it is well tolerated with few side effects that included peripheral neuropathy and infectious complications. Two patients originally determined to be not eligible for transplant improved sufficiently on CYBOR-D to become eligible and then went on to receive autologous bone marrow transplant. The retrospective nature and small sample size limit this study, and prospective, randomized studies are needed to further elucidate the role of this regimen in AL amyloidosis. Disclosures: Stewart: Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding; Celgene: Honoraria. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy.

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 Comparative Cost Analysis of Therapy in Sickle Cell Anemia: Supportive Care Vs. Bone Marrow Transplant

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4466-4466 ◽  
Author(s):  
Pooja Lothe ◽  
Tiffany Pompa ◽  
Maneesh Jain ◽  
Parshva Patel ◽  
Yayu Liang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Length Of Stay ◽  
Bone Marrow Transplant ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Hospital Admissions ◽  
Marrow Transplant ◽  
Cell Disease ◽  
The Cost

Abstract Objective: A comparative cost analysis of sickle cell admissions vs. stem cell transplants in sickle cell patients. Hypothesis: We believe the overall cost of a bone marrow transplant for a sickle cell patient will be less than that of a patient with multiple sickle cell admissions. Background: Sickle cell disease remains an increasing burden to the cost of health care and health care providers. The disease results in a variety of serious organ system complications that can lead to life-long disabilities and/or early death. Despite the advent of hydroxyurea, sickle cell admissions and cost have been increasing over the course of several years. Various contributing factors may include socioeconomic status, complications of sickle cell anemia itself, narcotic dependence and noncompliance with medications. Bone marrow transplants were introduced in 1982 as an option for the treatment of sickle cell anemia, and are currently the only curative option in this disease. A study conducted at the NIH from 2004-2013, found that bone marrow transplant reversed the disease in 26 of 30 patients (87%) (Hseih et al, N Engl J Med 2009; 361:2309-2317). The patients ultimately had a normal hemoglobin, fewer hospitalizations, and lower use of narcotics to treat pain from the disease. However, the underutilization of bone marrow transplant continues to exist and may in part be secondary to a lack of fully matched donors. To overcome this challenge, the Johns Hopkins group developed a nonmyeloablative bone marrow transplantation platform using HLA haploidentical donors for patients using posttransplant cyclophosphamide. As a result, 17 patients were successfully transplanted, 14 from HLA-haploidentical and 3 from HLA-matched related donors (Meade et al, Blood. 2012; 120(22):4285-4291). Due to this, most patients with sickle cell disease have the potential to undergo a successful bone marrow transplant. However, an analysis comparing the cost of admissions vs. transplant has yet to be determined. In order to create an effective cost comparison, we utilized a nationwide database. Methods: US hospital admissions were identified from discharge data from the Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality from 1998 to 2011 using ICD9 codes. Admissions were included if they had an ICD9 code for Sickle cell anemia (282.5). Results: Table 1. Year 1998 1999 2000 2001 2002 2003 2004 Length of Stay (Days) 6.21 6.13 6.37 6.19 6.46 6.31 6.05 Cost ($) 15,724.00 16,465.00 18,654.00 18,750.00 22,587.00 24,501.00 23,743.00 Table 2. Year 2005 2006 2007 2008 2009 2010 2011 Average Length of stay (Days) 6.16 6.13 6.00 5.91 5.62 5.71 5.61 6.04 Cost ($) 25,129.00 27,471.00 28,425.00 27,314.00 29,767.00 29,929.00 31,683.00 24,687.00 The cost per hospitalization has almost doubled since 1998, despite a slight decrease in length of stay from an average of 6.5 days to 5.6 days from 1998-2011. According to the data base from our study, the average cost per patient per hospitalization was $24,687. The average number of admissions per year for a single patient with sickle cell anemia is 6 (Ballas et al, Am J Hem 2009) for an estimated overall cost per year of $148,000. However, this value underestimates the true cost since this does not include emergency room visits, medicine costs, and readmission rates. Conclusion: In the age of cost effective medicine, clinicians struggle to find a balance between low cost and optimal patient care. An underutilized modality of care and even cure for sickle cell disease is bone marrow transplant. The sickle cell information center website estimates the cost of the transplant process for most patients to be $150,000 to $250,000 which includes pre-transplant evaluation, transplant stay, and post-transplant follow-up (https://scinfo.org). We estimate that a bone marrow transplant is approximately equivalent to the cost of ten sickle cell hospital admissions. According to this analysis, undergoing a bone marrow transplant would ultimately prove to be more cost efficient while decreasing the rate of complications associated with this debilitating disease. Disclosures No relevant conflicts of interest to declare.

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