scholarly journals Prediction of Early Mortality with Non-Intensive Acute Myeloid Leukemia (AML) Therapies: Analysis of 1336 Patients from MRC/NCRI and SWOG

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 220-220
Author(s):  
Xu Wang ◽  
Ian Thomas ◽  
Cono Ariti ◽  
Mike Dennis ◽  
Priyanka Mehta ◽  
...  
Keyword(s):  
Research Funding ◽  
Regression Models ◽  
Early Death ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Publicly Traded ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
Logistic Regression Models ◽  
Multivariable Models

Abstract Background: Therapeutic resistance and treatment tolerance vary greatly in patients with AML, likely due to the advanced age and genetic diversity in pharmacokinetics of those affected. Undoubtedly, tools to accurately predict outcomes of individual therapies for patients could inform decision-making and improve response rates. To this end, several scoring systems have been developed aimed at identifying patients at high risk of poor outcome after intensive chemotherapy. Similar tools for use after non-intensive therapies are currently not available. As such therapies are increasingly effective and more widely utilized we sought to develop tools to predict early death and survival for patients treated with non-intensive therapies. Patients and Methods: We developed prediction models for all-cause death by day 28, 42, 56, and 100 from enrollment using data from 796 patients enrolled on MRC/NCRI trial LI-1, which we then validated in a cohort of 540 patients treated on SWOG trials S0432, S0703, and S1612. Treatments included: Low dose Ara-C (LDAC) alone, sapacitabine alone and LDAC in combination with vosaroxin, tosedostat or ganetespib (MRC/NCRI); Azacytidine (AZA) alone, tipifarnib alone, and AZA in combination with mylotarg, midostaurin, and nivolumab (SWOG). The following covariates were available in the MRC/NCRI and SWOG cohorts to build multivariable logistic regression models (quantitative unless specified otherwise): age, performance status (PS; 0-1 vs. 2-4), secondary AML (vs. de novo AML or high-risk myelodysplastic syndrome), white blood cell and platelet counts, and percentage of bone marrow blasts - all assessed at enrollment. The regression coefficients from the model fit in the MRC/NCRI cohort were used to derive a score and applied to each patient in the SWOG cohort. The models' prognostic accuracies were assessed using the area under the receiver operating characteristic curve (AUC). For the MRC/NCRI cohort, additional covariates were available: cytogenetic risk (per Grimwade 2011), FLT3-ITD, and NPM1 mutation and patient-reported outcomes using the QLQ-C30 instrument. Logistic regression models with these covariates were fit and optimism-corrected AUC estimated to assess prognostic performance for early death. Results: Both patient cohorts were largely composed of older individuals (median age of 75 [range: 60-91] for MRC/NCRI and 77 [60-94] for SWOG, respectively. A substantial subset in each had a PS of 2-4 (MRC/NCRI: 20%; SWOG: 37%) and/or secondary AML (MRC/NCRI: 26%; SWOG: 41%). Overall, the ability to predict early death either by day 28, 42, 56, or 100 was limited in the MRC/NCRI cohort. Subscales of the QLQ-C30 had univariate AUC=0.67, the highest among all covariates evaluated. Multivariable models with just clinical covariates had optimism-corrected AUCs ranging from 0.63-0.65; adding cytogenetic risk and FLT3-ITD and NPM1 mutation status led optimism-corrected AUCs ranging from 0.64-0.66; addition of two QLQ-C30 subscales (fatigue and appetite loss) led to optimism-corrected AUCs ranging from 0.66-0.69. The SWOG cohort did not collect QLQ-C30 or mutational data on all patients and only the clinical multivariable models could be evaluated. The models had a similar performance in the SWOG cohort with AUCs ranging from 0.65-0.68. Conclusion: Our ability to predict early death in older patients treated with lower intensity AML therapies is limited with routinely available clinical variables. Inclusion of cytogenetic risk, FLT3-ITD, and NPM1 mutation status minimally improved the prognostic accuracy as did some of the QLQ-C30 subscales. Our data highlight the difficulties in predicting outcomes with non-intensive AML therapy with routinely available baseline clinical information. Improving the clinical utility of these models may require more complete characterization of patient comorbidities (including frailty index, cognitive function, renal and hepatic function, comorbidity scores) or additional PRO measures since some QLQ-C30 subscales had the strongest univariate signals. Support: NIH/NCI grants CA180888 and CA180819; Blood Cancer UK grant 13041 and Cardiff University. Figure 1 Figure 1. Disclosures Assouline: Novartis: Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; Gilead: Speakers Bureau; Johnson&Johnson: Current equity holder in publicly-traded company; Jewish General Hospital, Montreal, Quebec: Current Employment; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding. Walter: Jazz: Research Funding; Pfizer: Consultancy, Research Funding; Selvita: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Othus: Daiichi Sankyo: Consultancy; Celgene: Other: Data safety monitoring board; Merck: Consultancy; Biosight: Consultancy; Glycomimetics: Other: Data safety monitoring board.

scholarly journals Single-Cell Multi-Omics Reveals That Pegylated Interferon-Alfa Treatment Differentially Redirects Mutated and Wildtype Hematopoietic Cell Differentiation Trajectories in CALR-mutated Essential Thrombocythemia (ET) Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 57-57
Author(s):  
Shira Rosenberg ◽  
Andrea Kubas-Meyer ◽  
Neelang Parghi ◽  
Nathaniel D. Omans ◽  
Neville Dusaj ◽  
...  
Keyword(s):  
Cell Cycle ◽  
High Throughput ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Myeloid Differentiation ◽  
Cell Identity ◽  
Mutation Status ◽  
Lymphoid Development ◽  
Cd34 Cells

Abstract Interferon-alpha (IFN), the first approved immunotherapy for cancer, remains an effective therapy for patients with myeloproliferative neoplasms (MPN). The mechanisms of action of IFN on MPN cells are poorly understood, particularly in patients with CALR mutated (MUT) MPNs, who often exhibit clinical but not molecular responses. Previously, by developing Genotyping of Transcriptomes (GoT) that captures mutation status and single-cell RNA-seq (scRNA-seq) in high-throughput, we observed that CALR mutations led to cell identity-dependent effects on CD34 + cells, including a strong megakaryocytic progenitor (MkP) differentiation bias and fitness. We hypothesized that the IFN effects may be cell identity and mutation status dependent; thus we applied GoT to serial bone marrow aspirates (BM) from 5 patients with CALRmutated ET treated with pegylated-IFN-alfa2a who participated in MPD-RC-111/112 clinical trials. To capture the transcriptional impact of IFN, we removed experimental batch effects with Cell Hashing, in which CD34 + cells from serial BM were uniquely labeled and combined for the same GoT experiment (Fig. 1A). Cell clustering based on transcriptomic data alone revealed that the cells on active treatment clustered based on cell identity and IFN effects (Fig. 1B). When off therapy for 3 weeks, the strong transcriptional effects of IFN were largely lost (Fig. 1B). Next, we batch corrected and integrated across time points for each BM sample (Fig. 1C). We observed that IFN caused large shifts in the composition of wildtype (WT) and MUT cell subsets (Fig. 1D). IFN resulted in a dramatic expansion of WT lymphoid progenitors with a corresponding diminution of other progenitors (Fig. 1E). MUT cells at baseline were enriched for MkPs, compared to WT cells; after treatment, we observed an expansion of the immature myeloid (IMP) and neutrophil progenitors, with a less striking expansion of lymphoid progenitors (Fig. 1E). As IFN has been reported to induce cell cycling of murine hematopoietic progenitor cells, we examined whether a differential increase in proliferation by IFN underlies the differentiation shifts in WT and MUT cells. Cell cycle gene expression of ProB cells increased after treatment similarly in MUT and WT cells, while cell cycle expression of IMPs was increased to a greater extent in MUT cells (Fig. 1F), consistent with the differential shifts in populations. Next, we performed differential expression analysis between baseline and treated WT and MUT cells, respectively. We observed enrichment of the IFN pathways post-therapy, whereas TNF-a signaling was downregulated (Fig. 1G). Uniquely in the MUT cells, TGF-b signaling was downregulated, which may underlie improvements in marrow fibrosis following IFN therapy (Fig. 1G). Finally, as the differentiation biases of IFN persisted after discontinuation, we hypothesized that IFN results in chromatin remodeling of the earliest hematopoietic stem progenitor cells (HSPCs), with respect to transcription factor (TF) accessibility. We leveraged single nuclei chromatin accessibility (snATAC-seq) as a powerful measure of TF regulatory activities. We developed GoT-ATAC, an adaptation of the Multiome platform (10x Genomics), to capture snRNA-seq, snATAC-seq and somatic genotyping within the same cells in high-throughput (Fig. 1H). We applied GoT-ATAC to CD34 + cells from the same clinical trial cohorts (Fig. 1I, n = 3 patients: 3 baseline, 2 treated) and identified the expected enrichment of IRFs and STAT2 in treated HSPCs (Fig. 1J). Accessibility of BCL11A, critical for early lymphoid development, was increased in treated MUT and WT HSPCs. We also identified enhanced motif accessibility of PU.1 which can associate with IRF and is essential for myeloid and lymphoid differentiation. Uniquely within the treated MUT cells, we observed enhanced CEBPA motif enrichment, which regulates myeloid differentiation, together with PU.1. In conclusion, GoT revealed that IFN reshapes the differentiation landscape by promoting early lymphoid development and, uniquely in MUT cells, myeloid differentiation, providing a novel mechanism of actions underlying the effects of IFN in MPN patients. Downregulations of TNF-a and TGF-b signaling were other key molecular consequences of IFN. Lastly, GoT-ATAC demonstrated that IFN governs master regulators of hematopoietic differentiation as a function of the underlying mutational status. Figure 1 Figure 1. Disclosures Mimitou: Immunai: Current Employment. Smibert: Immunai: Current Employment. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding.

scholarly journals Rusfertide (PTG-300) Induction Therapy Rapidly Achieves Hematocrit Control in Polycythemia Vera Patients without the Need for Therapeutic Phlebotomy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 390-390
Author(s):  
Yelena Ginzburg ◽  
Kamini Kirubamoorthy ◽  
Sinari Salleh ◽  
Sung-Eun Lee ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Polycythemia Vera ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Low Risk ◽  
Publicly Traded ◽  
The Mean ◽  
Mean Time

Abstract Background. Polycythemia (PV) patients with hematocrit above 45% are at increased risk of thrombotic complications and are treated with phlebotomy and/or cytoreductive therapy to reach a hematocrit target below 45%. Rusfertide (PTG-300) is a peptidic mimetic of hepcidin that is being developed for treatment of polycythemia vera (PV). A Phase 2 trial has indicated that rusfertide is effective at reducing the number of phlebotomies and maintaining hematocrit below 45% without phlebotomy in PV patients who are either high-risk or low-risk, patients treated with cytoreductive therapy (hydroxyurea, interferon, ruxolitinib) and patients treated with phlebotomy alone (Kremyanskaya, ASH 2020). The current trial (PTG-300-08) tested the ability of rusfertide to normalize hematocrit in PV patients with elevated hematocrit without instituting phlebotomy treatment to normalize hematocrit to below 45% in PV patients without requiring phlebotomy and/or cytoreductive treatment. Methods. Eligible study subjects were diagnosed with PV (in accordance with the WHO 2016 criteria), had baseline hematocrit above 48%, and a history of 3 or more hematocrit values above 48% in the year prior to enrollment. High-risk and low-risk subjects treated with phlebotomy alone or with concurrent cytoreductive therapy were eligible. Rusfertide was added on to each subject's current therapy. The initial rusfertide dose was 40 mg administered subcutaneously twice weekly. When each subject's hematocrit was below 45%, the dosing schedule was changed to weekly and the rusfertide dose was adjusted to maintain hematocrit below 45%. Results. Sixteen subjects (12 male and 4 females) have been enrolled. The mean age is 56.1 years; the mean time since diagnosis is 3.74 years; 10 subjects are low risk PV; 12 subjects are receiving concurrent hydroxyurea and 4 subjects were not receiving cytoreductive therapy. Baseline values (mean, min-max) HCT (51.0%, 47.4 - 59), WBC (12,338/µL, 7,000 - 24,600), RBCs (5.9x10 6/µL, 4.3 - 7.6), platelets (486,500/µL, 242,000 - 904,000). All subjects had rapid decreases in hematocrit to below 45% without the use of phlebotomy (Figure 1a). Hematocrit levels remained well controlled after falling below 45% as investigators reduced rusfertide dose to maintenance once weekly regimen. Hemoglobin (Figure 1b) fell rapidly. Erythrocyte counts (Figure 1c) also fell rapidly, indicating that decreased hematocrit is due to decreased erythrocytosis. For the 11 subjects with adequate follow-up, the mean rate of absolute hematocrit decrease was 1.76% per week (median: 1.81%/week; min - max: 0.65 - 2.69%) and the mean time to reach goal hematocrit below 45% was 4.79 weeks (median: 4.14 weeks, min - max: 3.57 - 8.14). Eight subjects reported adverse events (AEs). Injection site reactions (ISRs) occurred in 7 subjects and were mild or moderate in severity. The most common ISRs were erythema (n=7), induration (n=5) and pruritis (n=2). Adverse events other than ISRs that occurred in 2 or more subjects were hypertension (n=2), pyrexia (n=2) and thrombocytosis (n=2). There were two serious adverse events (worsening migraine and pleuritic chest pain) and both were considered unrelated to rusfertide. Overall, rusfertide was well tolerated. Conclusions. This study demonstrates that induction therapy with twice weekly rusfertide administration was effective in rapidly achieving target hematocrit below 45% without phlebotomy in all PV patients which was then successfully maintained with weekly rusfertide treatment. Moreover, the twice weekly injections of rusfertide used to rapidly lower hematocrit levels were safe and well tolerated. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Gupta: Protagonist Therapeutics: Current Employment. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Hoffman: Kartos Therapeutics, Inc.: Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Novartis: Other: Data Safety Monitoring Board, Research Funding; AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding.

BTK and/or PLCG2 Mutations in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Ibrutinib: Characteristics and Outcomes at the Time of Progression

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3050-3050 ◽  
Author(s):  
Paul J. Hampel ◽  
Timothy G. Call ◽  
Sara J. Achenbach ◽  
Kari G Rabe ◽  
Wei Ding ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Resistance Mutation ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Data Safety ◽  
Safety Monitoring Board ◽  
Progression Of Disease ◽  
Richter’S Transformation ◽  
Richter's Transformation

INTRODUCTION Mutations in BTK and PLCG2 have been reported to occur in ~80% of CLL patients (pts) who have progression of disease on ibrutinib therapy (Woyach, JCO 2017; Ahn, Blood 2017). These mutations are described as appearing months before actual relapse and thus considered as a potential predictive biomarker for future relapse (Quinquenel, Blood 2019). However, the outcomes of these pts after disease progression are not well described. In this study, we seek to investigate time to next therapy and overall survival (OS) following progression among CLL pts on ibrutinib therapy with and without these resistance mutations. METHODS Between 10/2012 and 6/2019, we identified 34 pts in the Mayo Clinic clinical CLL resource who progressed while receiving ibrutinib therapy and also had testing for BTK and PLCG2 mutation performed as part of routine clinical practice at either NeoGenomics Laboratories or The Ohio State University. OS was calculated from time of ibrutinib progression to last known alive or death date; OS was plotted using Kaplan Meier methods and was compared using the log-rank test between various groups (e.g., mutation positive vs negative; CLL progression vs Richter's). Cumulative incidence of time to next treatment in those who had a treatment after progression was adjusted for the competing risk of death. RESULTS Of 34 pts who progressed while receiving ibrutinib, 26 pts experienced CLL progression and 8 pts had Richter's transformation; baseline characteristics in Table 1A. The presence of a BTK or PLCG2 mutation was found in 20/34 (59%) pts (specific mutations in Table 1B). BTK mutation alone was present in 9 pts, 7 pts had PLCG2 mutation alone, and 4 pts had both mutations. Median time between a positive test and start of next therapy was 4 months (range 1-19 months) and did not vary between BTK vs PLCG2 mutations. Among the 26 pts with CLL progression, 18 (69%) pts had a mutation present: BTK alone (n=8), PLCG2 alone (n=6), both (n=4). Therapy following progression on ibrutinib in these pts was as follows: venetoclax (n=16; 11 pts who continued ibrutinib in combination), idelalisib (n=4), investigational treatments (n=2), continued ibrutinib alone (n=2), dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; n=1), and unknown (n=1). Twelve of the 26 pts with CLL progression on ibrutinib, including 8 pts with a prior resistance mutation detected, had subsequent progression of disease on the aforementioned next line therapy. Treatment of these patients consisted of the following: restarted ibrutinib in addition to current treatment of venetoclax (n=5), venetoclax (n=2), pembrolizumab (n=2; 1 pt with continued ibrutinib), obinutuzumab with continued ibrutinib (n=1), gemcitabine and vinorelbine with continued ibrutinib (n=1), and no further treatment (n=1). Among the 8 pts with Richter's transformation as the initial progression event on ibrutinib after mutation testing, 1 pt had a BTK mutation and 1 pt had a PLCG2 mutation. Treatments following progression on ibrutinib included multi-agent chemoimmunotherapy (n=3; 2 pts received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP] with continued ibrutinib and 1 pt received doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD] alone), pembrolizumab (n=3; 1 pt in combination with continued ibrutinib), venetoclax in combination with continued ibrutinib (n=1), and venetoclax and obinutuzumab (n=1). The median time to next treatment (second line of treatment beyond ibrutinib) for the 31 pts who started another therapy following progression on ibrutinib was 16.7 months (95% CI 9.6-NE; Figure 1A) and was not significantly different for pts with or without a resistance mutation (p=0.57). Median OS for all 26 pts with CLL progression was 28.7 month and there was no difference according to presence or absence of a resistance mutation (median 28.7 months vs 18.2 months, p=0.53; Figure 1B). The 8 pts with Richter's transformation had a median OS of 7.1 months (95% CI 2.0-NE). CONCLUSION Approximately 60% of pts tested in this progression cohort had a BTK or PLCG2 mutation at time of or preceding progression on ibrutinib therapy. OS and time to next therapy did not differ statistically between pts with mutated vs non-mutated clones; however, caution should be applied with the conclusions given the limited sample size. Disclosures Ding: DTRM Biopharma: Research Funding; Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Parikh:Ascentage Pharma: Research Funding; Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding.

a Randomized, Double-Blinded, Placebo Controlled Study of IVIG Vs. IVIG with High Dose Methylprednisolone in Rapidly Augmenting Platelet Counts in Childhood ITP

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 868-868
Author(s):  
Manuel Carcao ◽  
Mariana Silva ◽  
Michele David ◽  
Robert J. Klaassen ◽  
MacGregor Steele ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Blood Type ◽  
Data Safety ◽  
Platelet Counts ◽  
Safety Monitoring Board ◽  
Life Threatening ◽  
Double Blinded

Abstract The combination of intravenous (IV) methylprednisolone (IVMP) and IV immune globulin (IVIG) is often used in children with immune thrombocytopenia (ITP) to rapidly increase platelet counts (PCs) to a safe hemostatic level. However, there are no controlled data to support the use of combination therapy over IVIG alone in children with severe thrombocytopenia [PC <20 x109/L] and/or life-threatening bleeding. We conducted a randomized, double-blinded, placebo controlled, multicenter, prospective study to evaluate 2 regimens: IVMP (Solu-Medrol®, UpJohn) 30 mg/kg (max. 1 gram) over 1 hour (h) followed by IVIG 1 g/kg (Gammunex 10%, Bayer) given at a rapid infusion rate (over a maximum of 3 h), vs IV placebo over 1 h followed by IVIG 1 g/kg in children with primary ITP. The goal was to evaluate the rapidity of the PC increment and associated adverse events with both regimens. Eligible patients were children [ages: 1 to 17 years (y)] with acute (defined at the time of study initiation as <6 months (mo.) since diagnosis) or chronic primary ITP (>6 mo.), with PCs <20x109/L in whom it was decided to treat with IVIG. Exclusion criteria included: previous splenectomy, life/organ threatening hemorrhage, renal disease, diabetes, hypertension, sepsis, fever >38.5°C, disseminated intravascular coagulation, pregnancy or a previous documented lack of response to IVIG. Baseline studies included: a complete blood count (CBC), a reticulocyte count, Coombs test and renal and liver function tests. CBCs were repeated at the end of the IVIG infusion, at 8±1h, 24±2h, 72±4h, day 7±2 day (d) and day 21±3d following the start of the placebo/IVMP. The primary outcome measure was the PC increment over the first 24 h following the administration of therapy; the main secondary outcome measures were the attainment of a PC of ≥20x109/L and ≥50x109/L at times + 8, +24 and +72h. Sample size was estimated based on the assumption that patients treated with placebo + IVIG would attain a mean PC at +24h of 30x109/L vs. 50x109/L for those treated with IVMP + IVIG. For 80% power to show a difference in PC of 20x109/L (at +24h)with an a of 0.025 (two-sided) and a b of 0.2, 32 patients were required. Patients were stratified by block randomization according to type of ITP (acute vs. chronic) and according to center. The trial was registered in ClinicalTrials.gov. (NCT00376077). Thirty two patients were enrolled (ages: median 8 y; min. 1.2 y; max: 17.5 y; 22 male: 10 female; 16 acute: 16 chronic; 11 were blood type O; 14 blood type A and 7 blood type B). Fourteen patients were randomized to IVMP+IVIG while 18 were randomized to placebo+IVIG. Randomization was not equal as 1 patient was randomized and then immediately declined to participate and another patient was incorrectly assigned; both were assigned to the placebo group. PCs for the 2 groups of patients at the different time points are shown in table 1. The difference in PC was statistically significant at the 24 hr time point (p<0.0001). At this time the proportion of patients achieving a PC of ≥50x109/L was 77% in the IVMP+IVIG vs 50% in the placebo+IVIG. No patient experienced a severe bleed or an unexpected severe adverse event during the study. There was a statistically significant drop in mean Hb post-treatment among all patients (baseline 133.3 (13.6) g/L to 121.6 (14.2) g/L at time +8h) but there was no difference between O and non-O blood type patients or between treatment groups. This study showed that PCs increased rapidly following administration of IVIG with or without IVMP such that by 8h post initiation of therapy 55% (17/31) of all patients had achieved a PC ≥20x109/L. The mean PC was significantly different between the groups at time +24h. Our findings provide level 1 evidence to support the use of combination therapy (IVMP+IVIG) in life threatening situations where it is deemed to important to attain as rapidly as possible a hemostatic platelet count. Table 1 Table 1. Disclosures Blanchette: Shire: Consultancy, Other: Member of a Data Safety Monitoring Board, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL-Behring: Research Funding; Octapharna: Other: Member of a Data Safety Monitoring Board; Biogen Idec: Research Funding; Bayer Healthcare: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Patient Reported Financial Toxicity in Acute Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4796-4796 ◽  
Author(s):  
Thomas G. Knight ◽  
Myra Robinson ◽  
Michael R. Grunwald ◽  
Lauren M. Bohannon ◽  
Erin Blackwell ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Financial Toxicity ◽  
Advisory Committees ◽  
Data Safety ◽  
Safety Monitoring Board ◽  
Data Safety Monitoring

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

scholarly journals A Role for TNF-α in Chronic Lymphocytic Leukemia Bone Marrow Hematopoietic Dysfunction

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4276-4276
Author(s):  
Bryce A Manso ◽  
Jordan Krull ◽  
Kimberly Gwin ◽  
Petra Lothert ◽  
Charla R Secreto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Ex Vivo ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Lymphocytic Leukemia ◽  
Cell Contact ◽  
Short Term ◽  
Tnf Α

The current paradigms of known peripheral immune abnormalities in B-Chronic Lymphocytic Leukemia (CLL) are not able to consistently explain patient complications and it is difficult to correct a given CLL patient's immune status. Here, we expand on our initial report demonstrating bone marrow (BM) hematopoietic dysfunction in untreated CLL patients (Manso et al., Leukemia volume 33, pages 638-652, 2019). CLL patient BM had significantly reduced frequencies and short-term functional capacity of hematopoietic stem and progenitor cells (HSPCs). Additionally, the remaining progenitors exhibited increased protein levels of the key hematopoietic transcriptional regulators GATA-2 and PU.1. We further evaluated the frequency and function of myeloid stem cells from controls and untreated CLL patients by limiting dilution analysis in long-term culture-initiating cell (LTC-IC) assays. Over the 5 week duration of the assay, we observed delayed and partial recovery of myelopoiesis from CLL-derived HSPCs (Figure 1A). These data suggest that removal of HSPCs from the CLL leukemic microenvironment partially recovers their ability to sustain myelopoiesis. A known inflammatory mediator and hematopoiesis-modulating cytokine that is constitutively produced by CLL cells, TNF-α, induced increased expression of GATA-2 and PU.1 in specific HSPC subsets and reduced formation of short-term colony forming units in vitro. Addition of TNF-α to LTC-IC assays resulted in a striking ablation of myelopoiesis in a dose-dependent manner, partially reproducing the ex vivo results (Figure 1B). To further assess the direct impact of CLL cells on HSPC biology, isolated HSPCs from controls were exposed in vitro to leukemic CLL cells. The co-culture induced overexpression of GATA-2 and PU.1 in distinct HSPC populations, recapitulating our ex vivo findings (Figure 1C-D). When cell-cell contact was inhibited by use of Transwell inserts, an intermediate increase in GATA-2 and PU.1 was observed, highlighting the contributions of both soluble mediators and cell-cell contact to HSPC alterations. In both direct and Transwell co-culture conditions, overexpression of GATA-2 and PU.1 was reversed when TNF-α was neutralized (Figure 1E-F). Taken together, these findings indicate a significant role for CLL-derived TNF-α in HSPC modulation and expand our previous observations of BM dysfunction in untreated CLL patients. This data offers new molecular insight into the contribution of the leukemic microenvironment to altered hematopoiesis, contributing to immunodeficiency in CLL, and identifies TNF-α as a potential therapeutic target for correction of hematopoiesis in CLL disease. Disclosures Ding: Merck: Research Funding; DTRM Biopharma: Research Funding. Parikh:AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria. Novak:Celgene Coorperation: Research Funding. Kay:Agios: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; MorphoSys: Other: Data Safety Monitoring Board.

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

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2818-2818
Author(s):  
Menchen Xi ◽  
Tamara Navarro-Ruan ◽  
Sunil Mammen ◽  
Victor S. Blanchette ◽  
Cedric R. Hermans ◽  
...  
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Advisory Committees ◽  
Safety Monitoring Board ◽  
Population Pk ◽  
Viii And Ix ◽  
Factor Concentrate

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

scholarly journals Results from a First-in-Human, Proof-of-Concept Phase 1 Trial in Pretreated B-Cell Malignancies for Loxo-305, a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 501-501 ◽  
Author(s):  
Anthony R. Mato ◽  
Ian W. Flinn ◽  
John M. Pagel ◽  
Jennifer R. Brown ◽  
Chan Y. Cheah ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Phase 1 ◽  
Acquired Resistance ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Proof Of Concept ◽  
Wild Type ◽  
B Cell Malignancies

Introduction: Bruton Tyrosine Kinase inhibitors (BTKis) have transformed the treatment of patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies by inducing durable responses, improving quality of life and prolonging overall survival. Prolonged use of BTKi in the real-world setting is limited by toxicity and acquired resistance. Discontinuation rates for BTKis may be as high as 40% in relapsed/refractory CLL, with BTK C481-mediated resistance evident in many progressing patients. Alternative therapies such as venetoclax are associated with on-target (BCL2) acquired resistance. We hypothesized that a selective, non-covalent BTKi would benefit patients with B-cell malignancies in the setting of acquired resistance and/ or unacceptable toxicities following an irreversible BTKi. LOXO-305 is a next-generation, highly selective, oral, non-covalent BTKi that inhibits wild-type and C481-mutated BTK preclinically. Here, we report results from a first-in-human, proof-of-concept phase 1 trial in patients with B-cell malignancies. Methods: This multicenter phase 1/2 trial (NCT 03740529) enrolled patients with advanced B-cell malignancies who had failed or were intolerant to &gt; 2 prior therapies. LOXO-305 was dosed orally in 28-day cycles, using a standard 3+3 dose-escalation design with a primary endpoint of MTD/RP2D identification. Results: As of 26 July 2019, 13 patients (9 CLL and 4 MCL) were enrolled to 3 dose levels: 25mg (n=5), 50mg (n=5) and 100mg (n=3) QD. Median age was 65 (range 51-79) years and the median number of prior therapies was 3 (range 2-6). 12 patients (8 CLL, 4 MCL) received prior chemotherapy + anti-CD20 antibody; 2 MCL patients underwent prior autologous stem cell transplantation; 5 CLL patients received prior umbralisib; 10 patients (7 CLL, 3 MCL) received prior ibrutinib (5 intolerant, 5 relapsed), including 1 who had also received venetoclax. 6 CLL patients displayed high-risk genetic features, including unmutated IGHV (4), complex karyotype (4) and del17p (3). Molecular characterization was available in 7 patients (6 CLL, 1 MCL) and revealed: BTK C481S mutations (in 2 CLL patients post-ibrutinib), a BCL2 G101V mutation (in a CLL patient post-venetoclax), and a TP53 mutation (in an MCL patient post-ibrutinib). At doses ≥50 mg QD, LOXO-305 exposure exceeded the calculated IC90 for wild-type and C481S mutated BTK. No DLTs were reported and all TEAEs are grade 1-2. Clinical activity was noted within the first cycle of therapy and at the first dose level of 25mg QD. The first eight patients were evaluable for initial response and 7 tumor responses (87.5%) were observed (by disease-defined criteria): 5/5 CLL patients (1 PR and 4 PR-L including one with BTK C481S mutation after ibrutinib and one with BCL2 G101V mutation after venetoclax) and 2/3 MCL patients (2 PR and 1 PD with a preexisting TP53 mutation). 2 additional CLL patients were awaiting initial radiologic assessment but had already demonstrated treatment-induced lymphocytosis. 12/13 patients remain on therapy, the longest 5+ months. Conclusion: Phase 1 data with LOXO-305 demonstrate a favorable safety profile and provide proof-of-concept evidence of efficacy in heavily pretreated CLL and MCL patients, including patients with acquired resistance to available BTKis and venetoclax. Disclosures Mato: DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Brown:Teva: Honoraria; Janssen: Honoraria; Sunesis: Consultancy; Juno/Celgene: Consultancy; Gilead: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Loxo: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Octapharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Acerta Pharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; AbbVie: Consultancy. Cheah:Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Roche, Abbvie: Research Funding; Roche: Other: Travel expenses. Coombs:Medscape: Honoraria; Covance: Consultancy; Cowen & Co.: Consultancy; H3 Biomedicine: Honoraria; Dedham Group: Consultancy; Loxo: Honoraria; Abbvie: Consultancy; Octopharma: Honoraria; Pharmacyclics: Honoraria. Rothenberg:LOXO Oncology Inc.: Employment. Tsai:Eli Lilly and Company: Employment. Ku:Eli Lilly and Company: Employment. Wang:BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Dava Oncology: Honoraria; Aviara: Research Funding.

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

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2901-2901
Author(s):  
Mohamed A. Kharfan-Dabaja ◽  
Myriam Labopin ◽  
Ali Bazarbachi ◽  
Urpu Salmenniemi ◽  
Stephan Mielke ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Independent Risk Factor ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Cns Involvement ◽  
Advisory Committees ◽  
Free Survival

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

Preferences for breast cancer prevention among BRCA mutation carriers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17018-17018
Author(s):  
J. Jacobson ◽  
P. Patel ◽  
A. Bharthuar ◽  
D. Hershman ◽  
K. Hill ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Regression Models ◽  
Pairwise Comparisons ◽  
Carrier Status ◽  
Health States ◽  
Mutation Status ◽  
Logistic Regression Models ◽  
Mutation Carriers ◽  
Brca 1

17018 Purpose: Breast cancer screening with MRI is a new option available to patients with BRCA 1/2 mutations. We analyzed preferences for this modality and 10 other breast cancer- related health states and preventive measures among women without cancer or known high risk and women with BRCA mutations. Methods: Following IRB approval, we administered a time trade-off questionnaire to mutation carriers and to women without breast cancer or known high risk. We used Kruskal-Wallis test to compare the two groups with respect to continuous variables, chi-square tests to compare proportions, and the Wilcoxon signed rank test for pairwise comparisons. We then developed logistic regression models to analyze the association of mutation carrier status and demographic factors with willingness to trade time for each of the 11 health states. Results: Two-hundred-four women (44 mutation carriers and 160 without breast cancer or known high risk) responded to the questionnaire. Both groups assigned the highest preference rating to mammography and the next-highest to MRI, but the differences in ratings were not statistically significant. Both groups assigned the lowest preference ratings to having a child with a mutation and the next lowest to ovarian cancer. In pairwise comparisons, both groups ranked oophorectomy higher than ovarian cancer (p <0.01), but mutation carriers did not rank prophylactic mastectomy significantly differently from breast cancer (p=0.38). In the logistic regression models, mutation carrier status was not a statistically significant predictor of willingness to trade time for any health state, but younger age, lower income, and nonwhite race/ethnicity were associated with willingness to trade time for certain health states. Conclusion: Our data indicate that MRI is as acceptable as mammography to respondents, and that the preferences of BRCA 1/2 mutation carriers are similar to those of other women. Age and other demographic factors may be more important than mutation status in determining preferences. The preference ratings of individuals should not be inferred from demographic characteristics or mutation status. However, such ratings can help to clarify the quality of life implications of clinical decision-making and health care policy regarding breast cancer prevention. No significant financial relationships to disclose.

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