scholarly journals Impact of Letermovir Prophylaxis on Voriconazole Exposure in Allogeneic Hematopoietic Cell Transplant Recipients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Issam S. Hamadeh ◽  
Michael R. Grunwald ◽  
Allison Martin ◽  
Jai N. Patel ◽  
Alexandra Shillingburg ◽  
...  
Keyword(s):  
Trough Concentration ◽  
Research Funding ◽  
Multivariate Logistic Regression Analysis ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Advisory Committees ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Trough Plasma Concentration ◽  
Cmv Reactivation ◽  
Trough Plasma

Introduction: Letermovir is a terminase complex inhibitor that was recently approved for prevention of cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (HCT). Its favorable side effect profile makes it an attractive alternative to other anti-CMV agents. Nevertheless, its use may present other challenges secondary to enzyme induction, leading to clinically significant drug-drug interactions. Voriconazole is widely used for prophylaxis against invasive fungal infections in the setting of HCT. By virtue of its hepatic metabolism mediated by CYP2C19, the package insert recommends close monitoring of voriconazole trough concentration when given concomitantly with letermovir. The objective of this study was to characterize the extent of interaction between voriconazole and letermovir in allogeneic HCT recipients. The study was approved by the institutional review board. Methods: Patient selection and data collection: An institutional database was queried to identify patients who underwent allogeneic HCT and received antifungal prophylaxis with voriconazole from November 2018 through July 2020. Per the institutional standard operating procedure (SOP), patients initially received intravenous micafungin 50 mg daily which was switched to voriconazole when oral drug administration became feasible. The voriconazole prophylactic dose was guided by CYP2C19 phenotype. Rapid metabolizers (harboring the gain of function variantCYP2C19*17) received 300 mg twice daily whereas others received 200 mg twice daily. Further dose adjustment was warranted if trough concentration, measured at least 5 days after starting voriconazole, did not fall within target range of 1 to 5.5 mg/L. Patients at risk for CMV reactivation who underwent HCT after SOP revision (November 2019) received prophylaxis with letermovir 480 mg daily on day +6 post HCT. After a retrospective review of electronic medical records, HCT recipients were divided into two cohorts;cohort 1included patients who received letermovir prophylaxis whereascohort 2comprised those who did not. Data extracted from medical records included: demographics, hematological disorder, voriconazole dose and trough concentration, and date of letermovir initiation. Statistical analysis: The Student's t-test was used to compare mean voriconazole trough plasma concentration between cohorts 1 and 2. The chi-squared/Fisher's exact test was used to compare rate of subtherapeutic voriconazole trough concentration. Multivariate logistic regression analysis was performed to determine the association between letermovir use and subtherapeutic voriconazole concentration after adjusting for age, gender, race, weight and voriconazole dose. All statistical analyses were performed in SAS (version 9.4) Results: 64 patients were identified (23 in cohort 1 and 41 in cohort 2). Baseline characteristics were comparable except for age (62.0±8.7 years in cohort 1 vs. 58.0±12.2 years, p=0.01); 39% of patients in cohort 1 and 30% in cohort 2 received voriconazole 300 mg twice daily upfront for prophylaxis due to the rapid CYP2C19 metabolizer phenotype whereas the rest received voriconazole 200 mg twice daily (p=0.6). There was no significant difference in mean voriconazole trough plasma concentration (p=0.5) or frequency of subtherapeutic trough (p=0.16) between cohorts 1 and 2 (Figure 1). Multivariate logistic regression analysis indicated that letermovir prophylaxis had no impact on subtherapeutic voriconazole concentration (OR: 0.4, 95% CI: 0.1-1.4, p=0.1). In the subgroup of patients who received voriconazole at 300 mg twice daily, the rate of subtherapeutic concentration did not differ significantly between cohorts 1 and 2 (p=1.0), whereas a non-significant trend in rate of subtherapeutic voriconazole concentration was noted in subgroup of patients who received the 200 mg dose (p=0.1,Figure 2) Conclusions: Our single center experience suggests there may not be a significant interaction between voriconazole and letermovir. Notably, patients receiving the 300 mg dose upfront may not require an additional dose increase to achieve a voriconazole trough within the recommended range despite the concomitant use of letermovir. Our group is collaborating with other centers to corroborate these findings, particularly in patients receiving the standard voriconazole prophylactic dose of 200 mg. Disclosures Grunwald: Forma Therapeutics:Research Funding;Agios:Consultancy;Abbvie:Consultancy;Trovagene:Consultancy;Daiichi Sankyo:Consultancy;Astellas:Consultancy;Daiichi Sankyo:Consultancy;Trovagene:Consultancy;Trovagene:Consultancy;Premier:Consultancy;Astellas:Consultancy;Astellas:Consultancy;Genentech/Roche:Research Funding;Premier:Consultancy;Genentech/Roche:Research Funding;Genentech/Roche:Research Funding;Premier:Consultancy;Janssen:Research Funding;Merck:Consultancy;Forma Therapeutics:Research Funding;Incyte:Consultancy, Research Funding;Celgene:Consultancy;Incyte:Consultancy, Research Funding;Incyte:Consultancy, Research Funding;Pfizer:Consultancy;Celgene:Consultancy;Celgene:Consultancy;Cardinal Health:Consultancy;Merck:Research Funding;Daiichi Sankyo:Consultancy;Agios:Consultancy;Abbvie:Consultancy;Merck:Consultancy;Amgen:Consultancy;Merck:Consultancy;Amgen:Consultancy;Abbvie:Consultancy;Pfizer:Consultancy;Amgen:Consultancy;Pfizer:Consultancy;Agios:Consultancy;Cardinal Health:Consultancy;Forma Therapeutics:Research Funding;Cardinal Health:Consultancy;Janssen:Research Funding.Ai:Incyte:Speakers Bureau;Celgene:Speakers Bureau.Knight:Foundation for Financial Planning:Research Funding.Chojecki:Incyte:Research Funding;Novartis:Other: Investigator Meeting Attendance.Avalos:Juno:Membership on an entity's Board of Directors or advisory committees;Best Practice-Br Med J:Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia.Copelan:Amgen:Membership on an entity's Board of Directors or advisory committees.

Use of CMV Unselected Blood Products Does Not Increase the Risk of CMV Reactivation in Patients Undergoing Hematopoetic Stem Cell Transplant (HSCT)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2346-2346
Author(s):  
Jayne Peters ◽  
Jonathon Elliott ◽  
Adrian Bloor ◽  
Michael Dennis ◽  
John Murray ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Cell Transplant ◽  
Blood Products ◽  
Advisory Committees ◽  
Hematopoetic Stem Cell ◽  
Before And After ◽  
Key Factor ◽  
Full Intensity ◽  
Cmv Reactivation

Abstract Introduction: Conventionally patients receiving allogeneic HSCT (AlloHSCT) have received CMV negative blood products to obviate the risk of transfusion related CMV transmission. In the era of leucodepletion with more than log 4 reduction in blood product WBC content, the utility of this practice has been questioned and, in line with SABTO (Safety of Blood, Tissues and Organs) guidance, most UK transplant centers have adopted the policy of using unselected blood products for this patient cohort. At this center, our policy was changed to conform to recommended national practice in April 2013. This analysis was carried out to evaluate if this change has resulted in an increased incidence of CMV reactivation. Methods: 868 (M: 561; median age: F: 307; median age:) patients who received HSCT from January 1998 to November 2014 were included in analysis. Transplant types included AutoHSCT (n=384), AlloHSCT-Sibling (n=217) and AlloHSCT-MUD (n=267). Diagnosis was Ac Leukaemia (n=313), Chr Leukaemia (n=36), Myeloma (n=216), Lymphoma (n=261) or other malignancies (n=42). Commonest indication for AutoHSCT was myeloma or lymphoma. TBI based condition was used in 225 AlloHSCT and 50 AutoHSCT cases. RIC was used in 268 cases and full intensity in 215 cases (unknown in 1). Alemtuzumab or ATG was used in conditioning for 274 cases. Source of stem cell was PBSC (AutoHSCT: 363, AlloHSCT: 382), BM (AutoHSCT: 7, AlloHSCT: 97), both (AutoHSCT: 2, AlloHSCT: 9) and 8 AlloHSCT were UCB grafts. Results: 26, 345 blood PCR results were evaluated. 3100 tests were requested in AutoHSCT patients and 109 (3.6%) were positive. There were no differences in the incidence of positive CMV PCR results before and after use of CMV unselected blood products. Further analysis was limited to AlloHSCT patients. AlloHSCT patients were divided in two groups, GrpA: 1998 to 2013 and GrpB: 2013 to 2014 to evaluate the effect of using CMV unselected blood products. In AlloHSCT group, 9.1% of 23278 samples tested for CMV PCR were positive (Median log: 2.7, range: 0.3-7.3). Incidence of CMV reactivation was not different in GrpB as compared to GrpA (47.7% vs. 48.1%, p=0.93). There was no difference with gender (M: 45.8% vs. F: 53.1%, p=0.13), type of donor (Sibling: 48.6% vs. MUD: 47.9%, p=0.98), use of Alemtuzumab/ATG (50.6% vs. 45.4%, p=0.51), source of stem cells (BM: 36.4% vs. PBSC: 51.3%, p=0.07), use of TBI (43.8% vs. 52.3%, p=0.06). Higher incidence was observed with use of RIC transplant (53.2% vs. 42.3%, p=0.02) and donor-recipient CMV mismatch (NP: 24.5%, PN: 80%, PP: 90.8%, p<0.0001). Conclusion: This analysis suggests that the risk of CMV reactivation is related to the donor-recipient CMV mis-match and the transplant intensity. Use of CMV unselected blood products does not increase the risk of CMV reactivation and careful selection of donors using CMV sero-status is the key factor to reduce the risk of CMV reactivation post AlloHSCT. Disclosures Cavet: Janssen: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Somervaille:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Use of Post-Transplant Cyclophosphamide (PTCy) with Mycophenolate Mofetil and Tacrolimus in HLA Matched Allogeneic Hematopoietic Cell Transplant Is Safe and Associated with Acceptable Transplant Outcomes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1950-1950 ◽  
Author(s):  
Brian T Hess ◽  
Feng Gao ◽  
John F. DiPersio ◽  
Peter Westervelt ◽  
Ravi Vij ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Transplant Outcomes ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Transplant Patients ◽  
Gvhd Prophylaxis ◽  
Grade Ii

Abstract Background: The use of post-transplantation cyclophosphamide (PTCy) as a single agent for graft-versus-host disease (GVHD) prophylaxis in HLA matched transplant patients has had varied results. Two recent studies at Johns Hopkins University noted favorable incidences of both GVHD and non-relapse mortality (NRM) in both matched related and unrelated donor allogeneic hematopoietic cell transplant (allo-HCT) recipients (Kanakry CG, et al, JCO, 2013 and Kanakry CG et al, Blood, 2014). In contrast to this data, a phase II study at MD Anderson reported higher rates of grade II-IV acute GVHD and NRM, with worse overall survival in patients receiving PTCy as the sole GVHD prophylaxis compared to their matched cohort receiving a calcineurin-inhibitor (CNI) and methotrexate (MTX) as immunosuppression (Alousi AM et al, BBMT, 2015). Another study in Australia had to be stopped for safety reasons due to high GVHD and NRM when using PTCy as sole GVHD prophylaxis (Bradstock KF, BBMT, 2015). There is no published data on the use of MMF plus tacrolimus in combination with PTCy in HLA matched allo-HCT recipients. We hypothesized that addition of MMF and Tacrolimus to PTCy in HLA matched allo-HCT recipients will lead to significantly improved transplant outcomes. To answer this question we retrospectively analyzed data from patients who received this regimen at a single institution. Methods. We performed a retrospective analysis of 31 HLA matched allo-HCT patients who received PTCy at 50 mg/m2 on days +3 and +4 in addition to MMF and tacrolimus immunosuppression from December 2012 till June 2015 at Washington University School of Medicine in Saint Louis. All of these patients received G-CSF mobilized peripheral blood grafts. Patients included AML (n=13), ALL (n=5), MDS (n=5), CML (n=2), aplastic anemia (n=2) and NHL (n=1), myelofibrosis (n=1). Twelve of the patients underwent a matched related donor (MRD) transplant and 19 underwent a matched unrelated donor (MUD) transplant. Two of the MUD transplants had a HLA match grade of 8 of 10 and the other 17 were a 10 out of 10 match. Twenty-eight of the patients received a graft collected via peripheral blood stem cell mobilization and the other three had a donor graft collected via bone marrow harvest. Cumulative incidence of aGVHD was estimated using Gray's sub-distribution method to account for death without aGVHD as a competing event, and the cumulative incidences of non-relapse mortality (NRM) and relapse were estimated treating each other as competing event, while OS was estimated using Kaplan-Meier limit method. Results: This regimen was associated with acceptable GVHD in our patients. Incidence of grade II-IV acute GVHD was 28% (21.3% for MRD; 31.5% for MUD) at day 100 and 28% at 1 year. Incidence of Grade III-IV acute GVHD was 13.5% at both 100 days and 1 year. Limited chronic GVHD was 25.9% and extensive GVHD was 14.8% at 1 year. Similarly we found acceptable NRM and relapse in these patients, NRM was 10.2% and 19.7% at 100 days and 1 year respectively and cumulative incidence of relapse at 100 days and 1 year were 17.8% and 29.0% respectively. Overall survival at 1 year for all patients was 52%. Summary: Here we report favorable results from a regimen combining MMF and Tacrolimus on PTCy platform in HLA matched MRD and MUD transplant recipients. Relatively low GVHD and NRM results are particularly encouraging in view of almost exclusive use of G-CSF mobilized T cell replete grafts with much higher T cell content. Though limited by the relatively small number of patients, our results suggest combining MMF plus Tacrolimus with PTCy platform in HLA matched allogeneic transplant patients is safe and associated with acceptable transplant outcomes. Disclosures Vij: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy; Merck: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Schroeder:Celgene: Other: Azacitidine provided for this trial by Celgene; Incyte: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.

The patient's BCR-ABL1 Kinase Domain Mutation History Is Important for Decisions Regarding Tyrosine Kinase Inhibitor Therapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1692-1692
Author(s):  
Wendy T Parker ◽  
Alexandra L Yeoman ◽  
Bronte A Jamison ◽  
David T Yeung ◽  
Hamish S Scott ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Research Funding ◽  
Direct Sequencing ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Advisory Committees ◽  
Imatinib Resistant

Abstract Abstract 1692 Introduction. BCR-ABL1 kinase domain mutations are the most common known cause of resistance to tyrosine kinase inhibitors (TKIs) in CML. Some imatinib resistant mutations also confer resistance to second generation TKIs nilotinib and/or dasatinib. Therefore, it is recommended that mutation analysis be performed before changing therapy. However, BCR-ABL1 mutant clones are often de-selected upon TKI cessation or change of therapy, and may become undetectable (Hanfstein et al, Haematologica 2011). It is not known whether treatment discontinuation or long term alternative TKI therapy leads to eradication of these mutant clones. If mutant clones persist at sub-clonal levels they have the potential to be re-selected and expand clonally given favorable conditions, such as change to a TKI for which they confer resistance. We examined longitudinal data of patients with imatinib resistant mutations that became undetectable by direct sequencing to determine whether these “long dormant” mutations could reappear, and the circumstances related to reappearance. Method. All chronic phase patients who had been monitored at our institution since starting imatinib, and had mutations detectable by sequencing during imatinib therapy were analyzed; 49 patients, median follow up since starting imatinib was 4.3 years (range 0.6–11.6 years). Sensitive mutation analysis using mass spectrometry (detection limit 0.2% mutant) was performed at selected times when the mutations became undetectable by direct sequencing (detection limit 10–20%). Results. Of the 49 patients with mutations detected by sequencing during imatinib therapy, mutations became undetectable by sequencing in 21 patients (29 mutations), at a median of 2 months after changing therapy (range 1–20 months). This was associated with increased imatinib dose (3 mutations), stopping imatinib (2), hematopoietic cell transplant (6), chemotherapy (1), switching to nilotinib (3), or switching to dasatinib (14). All mutations that became undetectable by sequencing when the patient switched to nilotinib or dasatinib were those known to be sensitive to the inhibitor received (e.g. F359V in a patient treated with dasatinib). In 16 of the 21 patients whose mutations became undetectable by direct sequencing, the mutations have not been detected again with 0.1 to 6.9 years of follow up since the mutations were last detected (median 1.1 years). Of these 16 patients, 15 maintained a stable complete cytogenetic response and 1 lost a major cytogenetic response. In the other 5 patients, the same mutations as those originally detected (identical nucleotide exchange) became detectable by sequencing between 1.7 and 5.4 years after last detection (median 4.4 years), Figure. The original mutations in 4 of these patients confer resistance to nilotinib as well as imatinib (Y253H and F359V), and their reappearance was associated with initiation of nilotinib therapy, Figure. Three of these 4 patients died of their disease, and 1 lost a major cytogenetic response. Sensitive mutation analysis could detect the mutation in 1 of these patients during the time of “dormancy” and before nilotinib therapy. The 5th patient received an autologous hematopoietic cell transplant upon detection of F359V, and the mutation became undetectable by sequencing. The patient subsequently received dasatinib for 3 years and the mutation remained undetectable. Dasatinib therapy was stopped due to intolerance and F359V rapidly reappeared while the patient was off TKI therapy, having been undetectable for 4.8 years. Using sensitive mutation analysis, F359V could be detected at low levels after the transplant, suggesting that the mutant clone had not been eradicated. Conclusion. The data suggest that some BCR-ABL1 mutations may persist at sub-clonal levels for many years after changing therapy. This could lead to clonal expansion under the selective pressure of a TKI for which the mutation confers insensitivity. Alternatively, the reappearance of the mutation could be a new occurrence of the same mutation. The study highlights the importance of knowing the mutation history of individual patients to enable informed therapy choices. Disclosures: Yeung: Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid: Consultancy.

scholarly journals Impact of TBI-Based Conditioning Regimen on Outcomes of Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplant: Systematic Review and Meta-Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4773-4773
Author(s):  
Mudit Dutta ◽  
Rahul Mhaskar ◽  
Hany Elmariah ◽  
Taiga Nishihori ◽  
Bijal Shah ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Inclusion Criteria ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Conditioning Regimens

Introduction: Allogeneic hematopoietic cell transplant (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation(TBI)-based and chemotherapy only (non-TBI) transplant conditioning regimens have been utilized. But the optimal conditioning regimen for all-HCT in ALL remains unclear. We performed a systematic review to assess the totality of evidence pertaining to the efficacy of TBI-based vs- non-TBI conditioning regimens. Methods: We searched PubMed and Embase databases for all studies comparing TBI-based vs. non-TBI conditioning regimens in patients who received allo-HCT for ALL. Two authors independently reviewed all references for inclusion and extracted data related to overall survival (OS), progression free survival (PFS), non-relapse mortality (NRM), relapse, acute- and chronic graft-versus-host disease (GVHD) whenever available. We restricted inclusion criteria to studies published only as peer-reviewed manuscripts which included ALL only patients (both T-ALL and B-ALL) who received a myeloablative conditioning; pediatric only studies were excluded. We also assessed outcomes in subgroups of patients 16 years of age and older which were majority of the included studies. Results: Seven studies were included in the final analysis that met our inclusion criteria. The quality assessment rating for each study was good based on its study type. The results for all patients in these observational studies revealed that TBI-based regimen was significantly favorable (all p<.05) to non-TBI conditioning regimen with regards to OS (HR=0.74, 95% CI [0.62, 0.88], 6 studies, 4300 patients), PFS (HR=0.72, 95% CI [0.61, 0.85], 6 studies, 4300 patients), and relapse (RR=0.73, 95% CI [0.61, 0.86], 5 studies, 4664 patients). The TBI-based regimen did not increase (all p>.05) the risks of NRM (RR=1.09, 95% CI [0.75, 1.58], 6 studies, 4251 patients), grade II-IV acute GVHD (RR=1.11, 95% CI [0.90, 1.36], 5 studies, 4725 patients) or grade III-IV acute GVHD (RR=1.20, 95% CI [0.89, 1.63], 2 studies, 3248 patients). However, TBI-based regimen increased the risk of chronic GVHD (RR=1.12, 95% CI [1.02, 1.23], 5 studies, 4219 patients). Subgroup comparison of patients 16 years of age and older (range 16-70) showed similar results as shown in Table 1a-d. Conclusion: This meta-analysis represents evidence supporting the use of TBI-based conditioning regimens for allo-HCT in patients with ALL as it offers significantly lower risk of relapse and better survival yet acceptable NRM as compared to non-TBI regimens. Disclosures Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria. Bejanyan:Kiadis Pharma: Other: advisory board.

Pretransplant Factors That Influence Intravenous Busulfan Kinetics in Adult Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3350-3350
Author(s):  
Ali McBride ◽  
Karen Fancher ◽  
Jongphil Kim ◽  
Donn Davis ◽  
Michelle Conwell ◽  
...  
Keyword(s):  
Research Funding ◽  
Plasma Concentrations ◽  
Multivariable Analysis ◽  
Population Based ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Time Curve ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Concurrent Use ◽  
Artery Disease

Abstract Abstract 3350 Poster Board III-238 We performed a retrospective review of intravenous busulfan (Bu) pharmacokinetic (PK) parameters and pretransplant characteristics on patient receiving Bu and fludarabine (40mg/m2/day x 4) (BuFlu) prior to allogeneic hematopoietic cell transplant (HCT) in order to determine the predictive value of pretransplant characteristics on Bu area under the concentration time curve (AUC). Included in this analysis are 265 pts transplanted between 7/04 and 12/08 who received 130 or 145mg/m2/day for 2 doses then had doses 3 and 4 adjusted based on first dose PK parameters (from 5 plasma concentrations) to achieve a target AUC of 5300 micromole*min/L. Pretransplant variables collected included: gender, age, ethnicity, height, actual body weight (ABW), body surface area (BSA), body mass index (BMI), underlying diseases states (hypertension, diabetes mellitus, coronary artery disease and liver disease), transplant diagnoses, prior chemotherapy, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), serum creatinine (SCr), measured creatinine clearance (CrCl) and concomitant medications administered up to 24 hours prior to first Bu dose. Median first dose AUC was 5252 micromole*min/L (2633-21400 micromole*min/L). Univariable and multivariable analyses were utilized to identify prognostic factors that may affect AUC levels based on first dose kinetics. In univariable analyses, BMI and CrCl were negatively correlated with Bu AUC while AST and SCr were positively correlated. In addition, the use of azole antifungals, metronidazole proton pump inhibitors, doxycycline, and choice of antiseizure prophylactic medication also had a significant effect on Bu AUC. Multivariable analysis demonstrated BMI and CrCl were negatively associated with AUC (p=0.008 and 0.005, respectively) while AST was positively associated (p=0.035). The use of fluconazole, metronidazole and doxycyline was associated with higher AUCs (p=0.011, 0.021, and 0.004, respectively) while concurrent use of voriconazole was associated with lower AUC (p=0.011). Based on these data, pts with large BMI, increased CrCl, or on concomitant voriconazole may require larger doses of busulfan to achieve a target AUC whereas pts with an elevated AST or taking fluconazole, metronidazole and doxycyline may require less. In order to validate these findings, we are developing a population based dosing model that will require testing in a prospective pt sample. Disclosures: Field: PDL BioPharma: Research Funding. Perkins:PDL BioPharma: Research Funding. Off Label Use: IV busulfan and fludarabine for pretransplant conditioning.

Analysis of Impact of Comorbidities Constituting the HCT-CI Score on the Outcome of Patients Undergoing Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3201-3201
Author(s):  
Fotios V. Michelis ◽  
Hans A. Messner ◽  
Naheed Alam ◽  
Vikas Gupta ◽  
Dennis Dong Hwan Kim ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
P Value ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Cardiac Disorder

Abstract The Hematopoietic Cell Transplant Co-morbidity Index (HCT-CI, Sorror et al 2005) was developed as a prognostic tool for overall survival (OS) and non-relapse mortality (NRM) in allogeneic hematopoietic cell transplant (HCT) patients. The prognostic significance of the score for patients with acute myeloid leukemia (AML) undergoing HCT has been demonstrated, however reports are conflicting. The purpose of this single-center study was to retrospectively investigate the prognostic impact of the individual component co-morbidities of the HCT-CI on the outcome of 418 patients that underwent HCT for AML at our center between 2000 and 2013. Patients underwent HCT in first (CR1, n=303) and second (CR2, n=115) complete remission. Median age at HCT was 50 years (range 18-71), 212 (51%) patients were female. Myeloablative conditioning (MAC) was used in 283 (68%) patients, reduced-intensity (RIC) in 135 (32%) patients. Donors were related for 236 (56%) patients, unrelated for 182 (44%) patients. Grafts were peripheral blood stem cells (PBSC) in 339 (81%) patients and bone marrow in 79 (19%) patients. Median follow-up of patients alive was 62 months (range 12-168). Cytogenetics at diagnosis were available for 84% of patients, of which 31 (7%) were favorable, 246 (59%) were intermediate and 74 (18%) were unfavorable risk (MRC classification). HCT-CI scores were grouped as 0 (n=109, 26%), 1-2 (n=157, 38%) and ≥3 (n=152, 36%). A total of 171 patients (41%) underwent HCT during the years 2000-2006 and 247 patients (59%) during the years 2007-2013. The observed frequency of the co-morbidities composing the HCT-CI is summarized in Table 1. Univariate analysis for OS demonstrated the following significant variables: Age (HR=1.02, 95%CI=1.01-1.03, p=0.0002), CR status (HR=1.42 for CR2, 95%CI=1.08-1.87, P=0.01), donor type (HR=0.73 for related, 95%CI=0.57-0.94, p=0.02), HCT-CI group (overall p-value=0.004). For OS, univariate analysis of the impact of individual co-morbidities was performed for the components of the HCT-CI score that were observed in ≥5% of the patients (Table 1). All variables with a p-value ≤0.2 were introduced into the multivariable analysis (not including the HCT-CI itself), and these included cardiac disorder (CAD, CHF, MI or EF≤50%) (HR=1.65, 95%CI=1.17-2.32, p=0.004), prior solid tumor (HR=1.56, 95%CI=1.06-2.30, p=0.02) and diabetes (HR=1.40, 95%CI=0.89-2.19, p=0.14). In the multivariable analysis for OS, none of the aforementioned co-morbidities demonstrated independent prognostic relevance. For NRM, univariate analysis demonstrated cardiac disorder (HR=1.89, 95%CI=1.27-2.81, p=0.002), diabetes (HR=1.94, 95%CI=1.20-3.12, p=0.007) and moderate pulmonary (FEV1 and/or DLCO 66-80% or dyspnea on slight activity) (HR=1.31, 95%CI=0.93-1.84, p=0.12) to meet the significance criteria for inclusion in the multivariable analysis, which finally demonstrated diabetes (HR=2.17, 95%CI=1.31-3.60, p=0.003) and cardiac disorder (HR=1.78, 95%CI=1.15-2.76, p=0.01) to be independent predictors of NRM post-transplant. In conclusion, among the pre-transplant co-morbidities included in the HCT-CI, diabetes and cardiac dysfunction are independent prognostic indicators for NRM but not for OS. Pulmonary dysfunction does not seem to negatively influence outcomes in this cohort of patients. Disclosures Kim: Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

5-Day Decitabine with Mini Fludarabine and Busulfan Yields Comparable Outcomes to Mini Flu/Bu but with Increased Incidence of Severe Acute GvHD

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3422-3422
Author(s):  
Melissa Baker ◽  
Tracy Andrews ◽  
Scott D. Rowley ◽  
Andrew L. Pecora ◽  
Alan P Skarbnik ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Control Group ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Advisory Committees ◽  
Disease Response

Abstract Background: Studies have shown that hypomethylating agents (HMAs), including 5-AZA and decitabine (Dac) are well-tolerated antileukemic agents (Kantarjian et al, JCO, 2012). Despite its myelosuppressive effect, Dac has low extramedullary toxicities, making it an attractive drug for allogeneic hematopoietic cell transplant (HCT). Reports suggest that HMAs selectively upregulate tumor associated antigens (TAAs) on malignant cells without expression in healthy tissue (Cruijsen, 2016). We previously reported on a series of 20 patients (pts) in a phase I study of 5-day Dac plus mini fludarabine and busulfan (DacMiniFluBu) in elderly or medically infirm pts (Baker et al, Blood, 2012). In the current analysis, we compared updated results from our DacFluBu study with a historical MiniFluBu control group in pts with MDS or AML. Methods: Pts were evaluated to assess engraftment, toxicity, disease response, PFS and OS. Pts received Dac 20 mg/m2/day on days (d) -15 to -11, Flu 30 mg/m2/day, on d -7 to -3 and Bu 130 mg/m2 on d -4 and -3. The control group received Flu 30 mg/m2 on d -6 to -2 and Bu 130 mg/m2 on d -3 and -2. Both groups received thymoglobulin 2 mg/kg IV on d -3, -2 and -1, followed by infusion of donor stem cells on d 0. Immunosuppression consisted of tacrolimus starting on d -2 and MTX 5 mg/m2 IV on d +1, 3, 6, and 11. Results: 107 pts were analyzed between 5/2009 and 8/2015; 36 pts received DacMiniFluBu; 17 with MDS, and 19 with AML. 23 (64%) had unrelated donors (URD); 13 (36%) had sibling donors. 71 pts were included in the MiniFluBu control group for comparison; 33 with MDS, and 38 with AML. 53 (75%) had URD; 18 (25%) had sibling donors. Median age was 68.5 yrs compared to 66 yrs, respectively. Cohorts were comparable for gender, disease and graft source. The incidence of severe (gr III/IV) acute GVHD (aGvHD) was 22% compared to the control group of 6% (p=0.0195). Moderate or severe cGVHD was seen in 7 pts vs 22 in the control group (p=0.2535). The median follow-up in the DacMiniFluBu group was 262 d, OS was 35%, relapse incidence was 28%, and NRM at 6 mos was 22%. In the control group, the median follow-up was 424 d (p=0.2213), OS was 34%, relapse was 41%, and NRM was 15%. Median time to relapse in the study vs control group was 142 and 149 d (p=0.8722). There were 22 deaths after DacMiniFluBu and 43 after MiniFluBu (p=0.7382). 6 pts in the study group received DLI at a median of 170 d post HCT for either relapse (n=3) or falling chimerism (n=3) compared to 16 pts in the control group at a median of 183 d. Multivariate analysis was performed to estimate the cumulative incidence of severe aGvHD by regimen. Results showed that conditioning regimen (HR=3.98, 95% CI, p=0.0197), degree of match (HR=1.365, p=0.039) and non-hematologic (heme) gr IV events (HR= 4.266, p=0.029) were all significant independent factors predicting a higher incidence of severe aGvHD. Conclusions: There were no significant differences in the cumulative incidences of relapse or survival between pts receiving DacMiniFluBu and MiniFluBu. However, the risk of severe aGvHD was 4 times greater in DacMiniFluBu recipients when controlling for infections, degree of match, and non-heme gr IV events. Findings were confirmed in univariate and multivariate analyses. This may be explained by the increased expression of TAAs in healthy tissues in response to Dac, which evoke T cell responses. This is the first report showing that adding Dac to the MiniFluBu regimen was an independent risk factor for severe aGvHD. Other findings in our analysis linking age, risk stratification, and degree of match to GvHD are consistent with prior reports. The differences between our results and those of other studies warrant larger validation analyses. Dac as part of a conditioning regimen should only be used in context of a clinical trial. Table Table. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Skarbnik: Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Vesole:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Goy:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau.

scholarly journals Rheological Assessments of Sickle Cell Patients Post Allogeneic Hematopoietic Cell Transplant

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 996-996 ◽  
Author(s):  
Tami D John ◽  
Madeleine Lu ◽  
Celeste K. Kanne ◽  
Minke A.E. Rab ◽  
Richard van Wijk ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Donor Chimerism ◽  
Hematology Analyzer ◽  
Rbc Deformability

Introduction: Mixed donor chimerism (MDC) occurs in nearly 35% of patients with sickle cell disease (SCD) post allogeneic hematopoietic cell transplant (alloHCT). Donor myeloid engraftment of &gt;20% is considered necessary to support disease resolution. However, in a disease known for its clinical variability, we hypothesize that patients (pts) with a severe pre-HCT phenotype may have abnormal RBC rheology at a level of chimerism and %HbS believed to be consistent with a cure. RBC rheology is markedly abnormal in SCD; these abnormalities are associated with SCD related clinical complications. Even fully oxygenated, sickle RBC are less deformable than those of HbAA or HbAS individuals; upon deoxygenation, deformability further declines. Sickle RBC morphology reflects the tendency to polymerize, with characteristic sickle forms. Sickle RBC are more adherent to the endothelial cell lining of the vasculature than HbAA or HbAS RBCs. The goal of any cell-based therapy of curative intent should be normalize the red cell rheology. To determine if the rheology of blood from SCD pts post-HCT with varying degrees of donor chimerism fall into the HbSS range of values, we propose to functionally assess the peripheral blood from a series of 6 post alloHCT SCD patients using a battery of rheological tests measuring deformability, sickling, adherence, percent dense cells (%DRBC), and RBC morphology. Methods: Peripheral blood samples (EDTA) from 6 SCD pts post alloHCT with a matched sibling donor were collected and immediately analyzed using oxygenscan (Lorrca), artificial microvascular network (AMVN), microfluidic image acquisition, and an ADVIA hematology analyzer. The Lorrca with oxygenscan measures RBC deformability (elongation index EI), under a range of pO2 (150-0 mmHg). EImax is the deformability of the oxygenated sickle RBC; EImin is the deformability of deoxygenated RBCs. The point of sickling (PoS) is the pO2 at which RBC deformability rapidly declines. RBC adhesiveness is measured by the difference in rate of perfusion of RBC through the AVMN coated with adhesive proteins (adherent AVMN) and a non-adherent, uncoated AVMN. %DRBC was measured by an ADVIA hematology analyzer. Microscopic RBC images were acquired and classified to determine the fraction of sickled RBCs in well-oxygenated samples. Additional clinical data including Hb profile, donor chimerism, and symptoms were obtained via chart review. Reference ranges were generated as described above using n=45 HbSS samples ages 2-21, on hydroxyurea, chronic transfusion, or untreated; n=14 HbAS, and n=43 HbAA. Results: In Figure 1, we show the measurements obtained by the Lorrca with oxygenscan on 5 pts post-alloHCT with a range of donor chimerism, as well as typical values for HbAA, HbAS, and HbSS patients. Patient 1 and 3 exhibit normal rheology; both were transplanted with a HbAA donor, with high chimerism and no detectable HbS. Patient 2 has 40% whole blood chimerism, well above the 20% threshold described with myeloid chimerism, and a HbS less than 50%, yet their plot resembles that of an untransplanted HbSS pt; the donor to Patient 2 exhibits the expected HbAA deformability. Patients 5 and 6 exhibit rheology in the HbAS range; they have intermediate chimerism from a HbAS donor. Clinical details and biomarker panel values for all 6 pts analyzed are in Table 1, as well as ranges of values for HbSS and HbAS subjects generated in the Sheehan and Shevkoplyas labs. Patient 2 is the only subject with values in the HbSS range, and the only subject with SCD symptoms. Conclusions: Our rheological tests identified a pt with values consistent with a HbSS pt of moderate severity or treated with hydroxyurea despite variable donor chimerism above the 20% threshold and HbS &lt;50% thought to be sufficient for cure. The pt reported pain events beginning two years prior, indicating a clinical correlation supporting the validity of the rheological tests we propose to use to distinguish cure from persistent SCD. Current post-HCT evaluation depends on chimerism and hemoglobin profiles, and would not detect the significant functional abnormalities visible by Lorrca with oxygenscan biomarkers that indicate that Patient 2 is at risk for SCD related complications. Our results suggest that this functional analysis may help with management of post alloHCT SCD pts, and may be even more essential to assessing new gene-based therapy approaches to curing patients with SCD. Disclosures Rab: RR Mechatronics: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding. Shevkoplyas:SSS: Research Funding; New Health Sciences: Consultancy.

scholarly journals Letermovir and its role in the prevention of cytomegalovirus infection in seropositive patients receiving an allogeneic hematopoietic cell transplant

2020 ◽  
Vol 11 ◽  
pp. 204062072093715
Author(s):  
Terri Lynn Shigle ◽  
Victoria Wehr Handy ◽  
Roy F. Chemaly
Keyword(s):  
Organ Transplant ◽  
Primary Prophylaxis ◽  
Lessons Learned ◽  
Hematopoietic Cell ◽  
Solid Organ ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Cmv Reactivation

Cytomegalovirus (CMV) reactivation is one of the most common infections affecting allogeneic hematopoietic cell transplant recipients. Although available anti-CMV therapies have been evaluated for the prevention of CMV reactivation, their toxicity profile makes them unfavorable for use as primary prophylaxis; thus, they are routinely reserved for the treatment of CMV viremia or CMV end-organ disease. Pre-emptive CMV monitoring strategies have been widely accepted, and although they have been helpful in early detection, they have not affected the overall morbidity and mortality associated with CMV. Letermovir is a novel agent that was approved for primary prophylaxis in CMV-seropositive adult allogeneic hematopoietic cell transplant recipients. This review focuses on letermovir’s novel mechanism; clinical trials supporting its United States Food and Drug Administration (FDA) approval and subsequent follow-up analyses; clinical considerations, with an emphasis on pharmacology; and lessons learned from solid organ transplant recipients, as well as potential future directions.

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