scholarly journals Neither COVID-19, Nor Cryopreservation, Prevented Allogeneic Product Infusion: A Report from the National Marrow Donor Program

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 478-478
Author(s):  
Heather E. Stefanski ◽  
Jeni Newman ◽  
Jennifer Novakovich ◽  
Jacklyn Barten ◽  
Jason Oakes ◽  
...  
Keyword(s):  
Product Quality ◽  
Research Funding ◽  
Positive Culture ◽  
Patient Choice ◽  
Study Cohort ◽  
Cell Transplant ◽  
Patient Death ◽  
Hematopoietic Cell Transplant ◽  
Cell Counts ◽  
Significant Downward Trend

Abstract The COVID-19 pandemic posed numerous logistical challenges in the way that the National Marrow Donor Program (NMDP) delivered allogeneic products to patients undergoing hematopoietic cell transplant (HCT). Prior to COVID-19, fresh bone marrow (BM) and peripheral blood stem cell (PBSC) grafts were infused into patients at the time of transplant in more than 90% of cases. Due to the pandemic, graft products could no longer be reliably delivered fresh and required cryopreservation given patient safety issues as well as logistical issues in ensuring timely delivery of a fresh product. Given these challenges, the NMDP as well as other donor registries pivoted to providing cryopreserved products. We sought to evaluate the effect of cryopreservation on the infusion of allogeneic products, analyzing all allogeneic products collected from March 17, 2020 through June 30, 2021. A total of 9294 products were collected from both related donors (RDs) and unrelated donors (URDs). Of these, a total of 8702 products were infused both domestically and internationally: 476 were RDs and 8226 were URDs. One main difference between fresh and cryopreserved products is that transplant centers (TCs) can wait to infuse the product depending on the status of the patient, patient's preference of when to receive HCT, and other factors. Moreover, TCs also can assess the product quality both at the time of product receipt and after cryopreservation thaw, thereby allowing the TC to determine if they will infuse a patient based on product quality. Due to this nuance for cryopreservation, 370 products are pending infusion. Over the last 18 months, only 222 products were not infused for a variety of reasons including patient death, patient choice, poor product quality (low cell counts, clumps in the product, viability or a positive culture) or unknown reasons. The number of products collected and infused on average per month was 544, while the number of products that were not infused each month averaged 14. Figure 1 shows the number of products infused, pending and not infused each month. We hypothesized that as TCs and apheresis centers became more adept at cryopreservation and infusing cryopreserved products, fewer products not infused would decrease. To determine if there was a difference in the number of products that were not infused in the first half of the pandemic compared to the latter half of the pandemic, we compared the first 5 months (March-July 2020) to the last 5 months (March-July 2021) using the Kruskal-Wallis test to compare the two timeframes. As shown in Figure 2, a significant downward trend (p<0.04) was noted in non-infused products by domestic TCs (p<0.02), but not international TCs, most likely reflecting low volume from the international TCs. In the study cohort, we were also able to analyze the effect of COVID-19 on product infusion. Since March 2020, a total of 34 COVID-19 positive cases were noted with 33 being PCR positive and one being antibody positive. In the PCR positive cases, 16 had a donor that tested positive for COVID-19 post-donation: 12 products were infused and 4 were not infused based on the TC's preference. Thirteen (13) had a donor with COVID-19 concerns that caused the collection to be stopped and 4 were uncharacterized. In the patients that had products infused, there were no known infections of COVID-19 or deleterious effects on engraftment. Taken together this analysis demonstrates that despite cryopreservation, a surprisingly low number of products were not infused. Moreover, patients that received products from a COVID-19 positive donor did not become infected with COVID-19 nor suffered deleterious effects. This preliminary data may help inform donors to aid them in making choices about donation as well as guide TCs and donor centers in future crises or instances when a donor's allogeneic products need to be cryopreserved Figure 1 Figure 1. Disclosures Stefanski: Novartis: Honoraria. Devine: Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Sanofi: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding.

Association of Iron Overload with Survival and Complications in Allogeneic Hematopoietic Cell Transplant Recipients: Prospective Cohort Study Using R2-MRI Measured Liver Iron Content

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1961-1961
Author(s):  
Bryan J Trottier ◽  
Todd E. Defor ◽  
Linda J Burns ◽  
Sarah Cooley ◽  
Navneet S. Majhail
Keyword(s):  
Iron Overload ◽  
Research Funding ◽  
Immune Reconstitution ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Liver Iron ◽  
Allogeneic Hct ◽  
Liver Iron Content ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 1961 Elevated pre-transplant ferritin levels have been associated with increased mortality and transplant-related complications in hematopoietic cell transplant (HCT) recipients. However, attempts to define the impact of iron overload on transplant outcomes using ferritin are confounded by its lack of specificity. Using liver magnetic resonance imaging (R2-MRI) to quantify liver iron content (LIC), we designed a prospective cohort study to determine the impact of iron overload on outcomes following allogeneic HCT. Our primary study objective was to determine the impact of pre-transplant iron overload on overall survival (OS); secondary objectives included cumulative incidence of non-relapse mortality (NRM) and post-HCT complications. Adult patients with hematologic malignancies being considered for allogeneic HCT were recruited for this study. Enrolled patients underwent baseline, pre-transplant ferritin measurements; patients with ferritin levels > 500 ng/ml had LIC quantified using liver R2-MRI. Patients were defined as no-iron overload (ferritin ≤ 500 or LIC ≤ 1.8 mg/gdw) and iron overload (LIC > 1.8). Of the 112 patients recruited for the study, 24 were excluded (disease progression=12, unable to complete MRI=9, transplant delays due to pre-HCT complications=3) and 88 were included in the final analysis (no-iron overload=28, iron overload=60). Four patients had ferritin >500, but on MRI had LIC ≤ 1.8 and were included in the no-iron overload group. Median ferritin in the two groups was 290 (range, 52–2023) and 1732 (range, 510–7137), respectively. The median LIC in the iron overload group was 4.3 (range, 1.9–25.4). Baseline ferritin moderately correlated with LIC (Spearman's R=0.58). There was no significant difference in recipient age, conditioning intensity, graft source, or HCT comorbidity index scores between the two groups. Patients with iron overload were more likely to have acute leukemia (55% vs 15%) and less likely to have high risk disease (40 vs 75%). We observed no significant difference in OS, NRM, relapse, acute or chronic graft-versus-host disease, organ failure, bacterial infections, viral infections, or fungal infections among patients without and with iron overload (see Table). We also found no difference in the composite endpoint of NRM, any infection, organ failure or hepatic veno-occlusive disease (1 yr cumulative incidence 71% vs 80%, P=0.44). In multivariate analyses that adjusted for other important prognostic variables, iron overload status did not impact risks of overall mortality (relative risk 2.3 (0.9–5.9) for iron overload vs. no-iron overload). We also evaluated outcomes based on an LIC threshold of ≤ 5 vs > 5 and observed similar results (see Table). Immune reconstitution studies were done in 55 patients at 3, 6 and/or 12 months post-HCT (no-iron overload=19, iron overload=36). On generalized linear mixed modeling, presence of iron overload was not associated with delay in recovery of absolute lymphocyte count, total NK cells, total T cells, CD4 cells, CD8 cells, or regulatory T cells. In conclusion, we did not find an association between pre-transplant iron-overload defined by R2-MRI measured LIC and OS, NRM, complications or immune reconstitution after allogeneic HCT in adults. Pre-transplant ferritin levels only moderately correlated with LIC. Future studies of iron overload in HCT should consider LIC to define iron overload instead of ferritin. Table. Outcomes by Iron-Overload Status Prob (95% CI) Prob (95% CI) P-value Ferritin ≤ 500 or LIC ≤ 1.8 LIC > 1.8 N 28 60 2 yr OS 78% (57–90) 58% (44–70) 0.12 2 yr NRM 18% (4–33) 21% (10–32) 0.91 1 yr Bacterial Infection 11% (0–22) 13% (5–22) 0.72 1 yr Fungal Infection 7% (0–17) 12% (4–20) 0.49 LIC ≤ 5.0 LIC > 5.0 N 65 23 2 yr OS 62% (49–73) 73% (49–87) 0.42 2 yr NRM 20% (10–30) 19% (3–35) 0.82 1 yr Bacterial Infection 12% (4–20) 13% (0–27) 0.98 1 yr Fungal Infection 12% (4–20) 4% (0–12) 0.28 Disclosures: Burns: Novartis Pharmaceuticals: Research Funding. Majhail:Novartis Pharmaceuticals: Research Funding.

In the Era of Bortezomib-Based Chemotherapy the Presence of Minimal Residual Disease Predicts Progression Free Survival after Autologous Hematopoietic Cell Transplant

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5493-5493
Author(s):  
Robert F Cornell ◽  
Jade E Jones ◽  
Claudio A. Mosse ◽  
Heidi Chen ◽  
Laura Dugger ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Research Funding ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Free Survival ◽  
Kaplan Meier ◽  
Minimal Residual

Abstract Background: Retrospective studies have shown that achieving minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) is predictive of outcomes in multiple myeloma (MM). Modern induction therapies including bortezomib (V), lenalidomide (R) followed by autologous hematopoietic cell transplant (AHCT) have resulted in substantial improvements in progression free survival (PFS) and overall survival (OS). The impact of bortezomib-based therapy on end of induction chemotherapy MRD status and post-AHCT MRD status is not well defined. We designed a prospective clinical trial (NCT01215344) to study the incidence of MRD negativity at end of induction and following AHCT, and its association with PFS and OS. Patients and Methods: Twenty patients with newly diagnosed, symptomatic MM were enrolled. They received four cycles of VRd induction therapy followed by AHCT. Dose modifications of VRd were controlled during the clinical trial. MRD status by MFC was evaluated at the end of induction chemotherapy and at day 100 post-AHCT. The MFC cut-off to determine MRD negativity was defined as 10-4. Outcomes analyzed included MM disease status, PFS and OS. Results: Three cohorts of patients were identified; patients achieving MRD negative status at the end of induction (cohort 1, 50%), those achieving MRD negative status only after AHCT (cohort 2, 15%) and patients never achieving MRD negative status (cohort 3, 35%). All patients achieving MRD negative status at the end of induction remained MRD negative post-AHCT. There were no significant differences in median age, renal function, disease stage, cytogenetic risk and maintenance chemotherapy post-AHCT between cohorts. The table summarizes characteristics of these cohorts. Patients who never achieved MRD negative status after AHCT had significantly shorter PFS (cohort 3) compared with patients who achieved MRD negative status (cohorts 1 and 2, p=0.008) (figure). The median PFS for cohort 3 was 2.64 years and not yet reached for the other cohorts. There were no significant differences in OS. Median follow-up for survivors was 2.53 years (range, 0.73-4.04). Conclusions: In this study, bortezomib-based therapy resulted in half of patients achieving MRD negative status with induction chemotherapy alone. AHCT improved the depth of response with 30% of patients who were MRD positive after induction therapy converting to MRD negativity following AHCT. Achieving a negative MRD state, pre- and at D100 post-AHCT resulted in improved PFS. These findings were independent of molecular cytogenetics or ISS stage. MRD positive status at day 100 post-AHCT is highly predictive of earlier disease progression, and may help identify patients for alternative management approaches. Delay of AHCT may be considered as a potential management option for patients with MRD negative status at the end of induction therapy, as being studied in the IFM DFCI study (NCT01208662). As some patients with MRD positive disease at the end of induction therapy become MRD negative with AHCT, these patients may benefit from AHCT and this population warrants further investigation. Table. Descriptive analysis Cohort 1 MRD -/- (%) (n=10) Cohort 2 MRD +/- (%) (n=3) Cohort 3 MRD +/+ (%) (n=7) Test Statistic Median Age 55 54 60 0.31 ISS Stage III 40 33 14 0.52 DS Stage III 89 67 60 0.14 Median Serum creatinine 0.90 0.60 0.88 0.10 Serum M-spike 2.0 1.9 2.1 0.80 Bone marrow plasma cells 14 44 14 0.18 Cytogenetics 0.37 Standard risk 40 0 57 Intermediate risk 50 67 43 High risk 10 33 0 Figure 1. Kaplan-Meier curve of progression-free survival comparing patients achieving MRD negative disease with MRD positive disease. Figure 1. Kaplan-Meier curve of progression-free survival comparing patients achieving MRD negative disease with MRD positive disease. Disclosures Cornell: Prothena: Research Funding. Jagasia:Takeda Inc: Research Funding.

scholarly journals Age-Based Probability of Ten-Year Overall Survival (OS) of Acute Myeloid Leukemia (AML): A National Cancer Database (NCDB) Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Vijaya R. Bhatt ◽  
Valerie K Shostrom ◽  
Nabin Khanal ◽  
Chakra P Chaulagain ◽  
Fiona He ◽  
...  
Keyword(s):  
Older Patients ◽  
Research Funding ◽  
Clinical Trial Data ◽  
Older Age ◽  
New Drugs ◽  
Cell Transplant ◽  
Short Term ◽  
Hematopoietic Cell Transplant ◽  
Logistic Regression Models

Background: Clinical trial data suggest excellent short-term outcomes for younger patients and a subset of fit older patients. Translating findings of clinical trials into the real-world practice has challenges, and longer-term data are often not available. Hence, we utilized NCDB to determine age-based probability of ten-year OS of unselected cohorts of adults with AML. Methods: NCDB captures about 70% of all new diagnosis of cancer. We utilized NCDB to analyze ten-year OS of 15,646 patients aged ≥18 years, who were diagnosed with AML during the years 2004-2007. Univariate and multiple logistic regression models were used to determine factors associated with ten-year OS. Kaplan Meier curves were generated for OS analysis. Results: Ten-year OS was 12.7% for patients aged 18-59 years treated with chemotherapy without hematopoietic cell transplant (HCT) (Table 1, Fig. 1). Older age, male, Charlson-Deyo comorbidity score >0, insurance other than private, subtypes other than core-binding factor AML were associated with lower ten-year OS. Ten-year OS was 24.3% for patients aged 18-59 years treated with chemotherapy and HCT (Fig 2). Older age, male, and insurance other than private were associated with lower ten-year OS. Ten-year OS was 16.1% and 2.2% for patients older than 60 years and treated with and without HCT, respectively; multivariate analysis was not performed for older patients because of low sample size (HCT group) or low survival (non-HCT group). Detailed analysis will be presented. Conclusions: Long-term OS of adults with AML is low with less than a quarter of patients being alive at ten years. Ten-year OS is particularly poor for older patients who are treated with chemotherapy alone. Whereas recent advances and approval of eight new drugs will likely improve short-term OS at 2-3 years, innovative strategies are necessary to improve long-term OS and cure. Further study to identify the cause of death will be insightful. Disclosures Bhatt: Takeda: Consultancy; Partnership for health analytic research: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero: Research Funding; Rigel: Consultancy; Agios: Consultancy; Omeros: Consultancy. Chaulagain:Sanofi Genzyme: Honoraria. Gundabolu:BioMarin: Consultancy; Bristol Myers Squibb pharmaceuticals: Consultancy.

scholarly journals Treatment of Persons with Multiple Myeloma in Underprivileged Circumstances: Real-World Data of a Prospective Study in a Single Institution

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5707-5707
Author(s):  
Iván Murrieta-Álvarez ◽  
David P. Steensma ◽  
Juan Carlos Olivares-Gazca ◽  
Jesús Mauricio Olivares-Gazca ◽  
Andrés A. León-Peña ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Population Data ◽  
Mantel Test ◽  
Novel Agents ◽  
P Value ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Real World Data ◽  
Term Survival

Background The treatment of patients with multiple myeloma (MM) has evolved in recent years, and the disease-associated prognosis has improved substantially. This improvement has been driven largely by the approval of novel agents, many of which are expensive and not universally available. Less expensive but effective approaches would be of value globally. Patients and methods All consecutive MM patients diagnosed in the Centro de Hematología y Medicina Interna de Puebla after 1993 were prospectively entered in this study. Patients were given oral thalidomide (T), 100 mg/day, oral dexamethasone (D) (36-40 mg/week) and aspirin 100 mg/day. Bortezomib (V) (1.75 mg subcutaneously every week) was administered to those who could afford it. After 4-6 weeks of treatment, patients were offered an outpatient-based hematopoietic cell transplant (HCT). After the recovery of granulocytes following the HCT, patients continued indefinitely on T; those who failed to tolerate were switched to lenalidomide (R) (25 mg/day). The assessment of overall survival (OS) for all groups was achieved through the Kaplan-Meier method using the Cox-Mantel test. All the statistical analyses used a p value <0.05 to considered them statistically significant. Results Among 108 patients with MM who were prospectively accrued in the study (47 females and 61 males), the median age was 57 years (range 33 to 90). IgG myeloma represented 60% of patients and 49% had International Scoring System (ISS) stage III disease. The median (OS for all patients has not been reached and is >157 months. The median OS of patients who did not receive HCT was similar to those who did, with a trend for better outcomes with HCT (A). The response rate (complete remission or very good partial remission) was 71.8% for those given TD versus 88.3% for those given VTD before HCT, but OS was not different (B, C and D). As post-HCT maintenance, 37 patients received T; 26 of those (70%) could be maintained indefinitely with T, whereas 11 were switched into R after a median of 7 months; median OS of patients maintained after HCT with T or R was not different. Comparing the current population data with those obtained between 1983 and 1993 in the same institution employing only MP, the prognosis of MM patients was noted to have improved substantially. In our previous experience in the same institution, the median OS of patients treated solely with MP was 33 months, with a 72-month survival of 30%, whereas in this study of patients given IMiDs +/- HCT, median OS has not been reached and the 72-month OS is 60%, twice that obtained with MP. When analyzing the OS of patients included in this study and separated by 5-year intervals, survival continued to improve since 1993. Conclusions In this series, a regimen incorporating low cost novel agents and outpatient HCT was associated with excellent long-term survival in the treatment of persons with MM. This approach may be a model for treatment of MM in middle-income countries. Figure Disclosures Steensma: Aprea: Research Funding; Arrowhead: Equity Ownership; Summer Road: Consultancy; Astex: Consultancy; Onconova: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.; Stemline: Consultancy; Pfizer: Consultancy.

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.

Ivosidenib (IVO) prior to hematopoietic cell transplant for patients with IDH1-mutant relapsed or refractory acute myeloid leukemia (R/R AML).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7521-7521
Author(s):  
Courtney Denton Dinardo ◽  
Eytan Stein ◽  
Arnaud Pigneux ◽  
Jessica K. Altman ◽  
Robert Collins ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Mononuclear Cells ◽  
Survival Rates ◽  
Digital Pcr ◽  
Hematopoietic Cell ◽  
Study Cohort ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Entire Study

7521 Background: Allogeneic hematopoietic cell transplantation (HCT) provides a potentially curative option for patients (pts) with R/R AML. Disease status at the time of transplant is a major determinant of long-term prognosis, with pts typically receiving salvage chemotherapy prior to HCT to induce a remission. However, older and/or heavily pre-treated pts frequently cannot tolerate intensive chemotherapy (IC) or do not obtain adequate disease control to permit an HCT. IVO is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with newly diagnosed AML ≥75 y of age or ineligible for IC, and those with R/R AML. We assessed HCT outcomes in pts with m IDH1 R/R AML who proceeded to HCT after treatment with IVO in a phase I study (NCT02074839). Methods: Baseline characteristics, clinical response (including CR, CRi/CRp, MLFS), and overall survival (OS) for the subgroup of pts with m IDH1 R/R AML who received IVO 500 mg QD, responded to treatment and then underwent HCT are reported. m IDH1 variant allele frequency (VAF) from bone marrow mononuclear cells was assessed using BEAMing digital PCR (0.02–0.04% VAF detection limit). Results: Among 179 pts with R/R AML treated with IVO, 18 proceeded to HCT: median age, 61.5 y (range 36–68); 56% male; 16.7% had secondary AML; 27.8% had ≥3 prior regimens; 11.1% had a prior HCT. The median duration of IVO treatment prior to HCT was 3.9 mo (range 2.1–15.2). The last reported response prior to HCT was 50.0% CR. Six- and 12-mo post-HCT survival rates were 77.8% and 50.0%; median relapse-free survival post HCT was 7.3 mo (range 2.6–NE). Median OS from start of IVO was 16.8 mo (95% CI 9.2, NE) for HCT pts vs 9.0 mo (95% CI 7.1, 10.2) in the entire study cohort; median follow-up time, 33.2 mo (range 3.2–41.9). Eight HCT pts were censored for OS: 5 are in remission, 2 relapsed and are in survival follow-up, and 1 was lost to follow-up. Median OS was not estimable (95% CI 9.1, NE) for the 12 HCT pts who achieved CR after IVO therapy and was 20.5 mo (95% CI 16.4, NE) for the 31 CR pts who did not undergo HCT. m IDH1 was undetectable in 1/18 (6%) pts; 4/18 (22%) pts had reduction below 1% VAF in ≥1 at the last assessment prior to HCT. Conclusions: IVO monotherapy is a putative treatment option to induce remissions prior to HCT for m IDH1 R/R AML pts who are not considered candidates for intensive salvage therapy. Post-transplant survival rates are encouraging and warrant further investigation of IVO monotherapy or combination salvage therapies prior to HCT. Clinical trial information: NCT02074839 .

Pharmacokinetically Targeted Intravenous Busulfan Combined with Fludarabine (BuFlu) as Conditioning Prior to Allogeneic Peripheral Blood Hematopoietic Cell Transplant: Pretransplant Predictors of Outcomes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3347-3347
Author(s):  
Janelle Perkins ◽  
Jongphil Kim ◽  
Claudio Anasetti ◽  
Mohamed A Kharfan-Dabaja ◽  
Ernesto Ayala ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Disease Risk ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Increased Risk ◽  
Multivariable Analyses ◽  
Standard Risk ◽  
Risk Of Relapse

Abstract Abstract 3347 Poster Board III-235 We report here our experience with 145 consecutive patients (pts) treated with IV busulfan and fludarabine (BuFlu) as conditioning prior to allogeneic hematopoietic cell transplant (HCT). Bu was dosed at 130mg/m2/day on days 1 and 2 with pharmacokinetic (PK) targeting for days 3 and 4; the dose of Flu was 40mg/m2/day for 4 days. The median age was 48 (range 22-68) years. Median HCT Comorbidity Index (HCT-CI) was 3 (range 0-9) and median Karnofsky performance status (KPS) was 100% (60-100%). Sixty-two pts received grafts from HLA matched siblings, 61 from matched unrelated donors (MUD), and 22 from 1 antigen/allele mismatched MUD (mMUD). Disease status was categorized in 50 pts as standard risk (acute leukemia in CR1 or CML in CP1) and in 91 pts as high risk (including acute leukemias > CR1, CML.>.CP1, MDS, MPD, lymphoma, myeloma, and CLL). 4 pts had aplastic anemia. Bu doses were targeted to a daily area under the concentration time curve (AUC) value of 5300 uM*min. Median actual AUC after the first dose was 5002 uM*min (range 3609-8190 uM*min) and doses 3 and 4 were adjusted in 92 pts (63%) to achieve the overall target AUC. Median total Bu dose to achieve AUC target was 520 mg/m2 (range 332-1040 mg/m2). Median Bu clearance (Cl) was 2.7 ml/min/kg (range 1.5-5.2 ml/min/kg). Maximum Bu concentrations (Cmax) after the first dose was 3315 ng/ml (range 1135-4848 ng/ml). First dose Bu AUC, Cmax, and Cl were not correlated with age, race, ethnicity, KPS, or HCT-CI. Women had significantly higher Cl than men (median 2.9 vs 2.6 ml/min/kg; p=0.001). Grade 3 or 4 elevations in hepatic transaminases occurred in 15 pts (10%), hepatic VOD/SOS in 6 pts (4%), and interstitial pneumonitis in 4 pts (3%). None of these toxicities were associated with any of the PK parameters measured. 100 day and 1 year non-relapse mortality (NRM) were 7% and 23% respectively. In multivariable analyses, neither first dose Bu AUC nor Bu Cl were associated with NRM. Having an unrelated donor (MUD: HR 2.68; p=0.025 and mMUD: HR 3.64; p=0.009) and a diagnosis of CML (HR 3.82; p<0.001) or lymphoma (HR 5.15; p=0.005) were associated with increased NRM. In multivariable analyses of relapse, only first dose AUC was significantly associated, with >6000 uM*min predictive of an increased risk of relapse (HR 2.66; p=0.007). The only significant predictor of overall and progression-free survival in multivariable analysis was disease risk. Overall and progression -free survivals at 2 years for the standard risk vs high risk groups were 61% and 57% vs 39% and 32% (p=0.04 and p=0.03, respectively). The increased risk of relapse in the high first dose AUC group may be related to an association between Bu Cl and uptake into malignant cells or the presence of a larger proportion of patients in this group with high risk features other than the predefined disease risk. We conclude that PK targeting of Bu provides a safe method of delivering high doses given that increased toxicity and NRM were not seen in pts with high first dose AUC due to dose adjustment. Disclosures: Perkins: PDL BioPharma: Research Funding. Off Label Use: IV Busulfan and Fludarabine for pre-transplant conditioning. Fernandez:Otsuka: Consultancy. Field:PDL BioPharma: Research Funding.

Temporal Changes in Plerixafor Administration Do Not Impact Hematopoietic Stem Cell Mobilization Efficacy: Results of a Prospective Clinical Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2988-2988
Author(s):  
R. Donald Harvey ◽  
Sagar Lonial ◽  
Heather Renfroe ◽  
Rajni Sinha ◽  
Christopher R Flowers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Published Data ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Dosing Interval ◽  
Cell Counts ◽  
Cd34 Cells

Abstract Abstract 2988 Objectives: Plerixafor (AMD3100, Mozobil) with filgrastim (G-CSF, Neupogen) is approved for hematopoietic stem cell (HSC) mobilization in patients with non-Hodgkin Lymphoma and multiple myeloma (MM). Plerixafor pharmacokinetics (PK) and pharmacodynamics (PD) are well described, with linear, dose-dependent PK following subcutaneous (SC) administration, peak concentrations 30–60 mins post-injection and an elimination half-life (t1/2) of 5.3 hr. In pharmacodynamic studies of plerixafor in conjunction with filgrastim in healthy volunteers, peak CD34+ cell counts occur 10–14 hours following administration, however, data is limited in the 14–24 hr timeframe. Plerixafor labeling requires SC dosing approximately 11 hours prior to apheresis, which translates into dosing 10 :00 PM the night before apheresis, and 54% of MM patients collect ≥ 6 × 106 CD34+ cells/kg following a single apheresis procedure. The current regimen is inconvenient for patients and requires additional health care resources. Based on PK and PD, we hypothesized that plerixafor given at 3 :00 PM (17 hr prior to apheresis) would yield equivalent CD34+ HSC yield to 10 :00 PM dosing in MM patients. Methods: In a Simon's two-stage design, we enrolled MM patients undergoing cytokine-only HSC mobilization. All subjects received filgrastim 7.5 mcg/kg SC BID for 4 days followed by plerixafor (0.24 mg/kg SC daily) for up to 4 days beginning at 3 :00 PM the day prior to the first day of a 24-liter apheresis procedure at 8 :00 AM. Target CD34+ HSC collection for stem cell transplant (SCT) was ≥ 10 × 106 CD34+ cells/kg. Blood samples for CD34+ fluorescence-activated cell sorting analysis were collected prior to the first plerixafor dose and at 1, 3, and 17 ± 1 hr, then daily prior to apheresis as needed. Results: Thirty patients (17 female, median age 59 years [range 44–70]) were evaluable; 27 received 1 pre-mobilization regimen (RVD n=20, VTD n=2, VD n=2, V/PLD/D n=1, VT n=1, RD n=1) for a median of 4 (1–6) cycles. Three received 2 regimens [CMF × 6 (breast cancer), then VTD × 5; RD × 4, then RVD × 4; and V/PLD × 1 with maintenance R]. Six patients received prior radiation. Mean (± SD) CD34+ cell counts in peripheral blood pre-plerixafor and 1, 3, and 17 hr post-first dose increased through the dosing interval (Figure). Twenty-two (73%) patients collected target cell numbers in 1 day of apheresis, 7 (23%) in 2 days, and 1 (3%) in 3 days. Twenty-seven (90%) patients collected ≥ 6 × 106 CD34+ cells/kg in 1 day. Institutional data with filgrastim 7.5 mcg/kg SC BID for 4 days alone in MM in 22 subjects showed a day 1 collection of ≥ 10 × 106 CD34+ cells/kg in 18% of patients (Renfroe H, et al. Transfusion Feb 2011). Adverse events were generally mild and consistent with known side effects of the combination [gastrointestinal disorders (diarrhea, nausea) and injection site reactions]. To date, 16 (53%) patients have proceeded to autologous SCT with melphalan conditioning and all patients have engrafted, with median time to an ANC ≥ 500/mm3 of 13 (range 11–15) days and platelets ≥ 20, 000/mm3 of 16 (range 11–21) days. Conclusion: This is the first prospective trial demonstrating the safety and efficacy of plerixafor given 17 hr prior to apheresis. Pharmacodynamic data showed the peripheral blood CD34+ cell population increased throughout the dosing interval, with a 4.6-fold increase over pre-plerixafor counts at 17 hr. Comparison with historical institutional controls and published data suggests this regimen yields at least equivalent, if not superior, collection rates with one apheresis procedure. Disclosures: Flowers: Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding.

scholarly journals High Incidence of Herpes Zoster after Cord Blood Hematopoietic Cell Transplant Despite Longer Duration of Antiviral Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4556-4556
Author(s):  
Elisabetta Xue ◽  
Hu Xie ◽  
Wendy Leisenring ◽  
Louise E Kimball ◽  
Sonia Goyal ◽  
...  
Keyword(s):  
Herpes Zoster ◽  
Cord Blood ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Cell Transplant ◽  
Antiviral Prophylaxis ◽  
Post Herpetic Neuralgia ◽  
Research Support ◽  
Hematopoietic Cell Transplant

Introduction Herpes zoster (HZ) after hematopoietic cell transplant (HCT) is a well-known complication with a peak incidence during the first year post-HCT. Cord blood transplant (CBT) recipients are at increased risk for viral infections and historically have a cumulative incidence of HZ approaching 80% by 2.5 years in the context of short-term peri-HCT antiviral prophylaxis. In 2009, international guidelines for prevention of infections after HCT recommended maintaining HZ prophylaxis for at least 1 year after HCT. We retrospectively studied the impact of longer-term antiviral prophylaxis on the incidence of HZ after CBT. Methods Between 2006 and 2016, we performed 360 CBT at our Institution. Patients who were seronegative for varicella zoster virus (VZV) or received the live varicella vaccine (i.e. Varivax®) pre-CBT without a history of chickenpox or HZ were excluded. From 2006-2008, CBT recipients received acyclovir (ACV) 800 mg BID or valacyclovir (VACV) 500 mg BID for HSV and VZV prophylaxis. From 2008-2016, patients who were CMV seropositive received higher-dose prophylaxis with VACV 2g TID through day +100. Before 2009, institutional guidelines recommended to continue prophylaxis until the end of immunosuppression; after 2009, prophylaxis was recommended for at least 1 year and until 8 months after immunosuppression ends. For patients discharged from our center, data were collected through standardized questionnaires and medical records. We abstracted HZ events and other variables for up to 5 years post-CBT. We calculated the cumulative incidence of HZ after CBT, treating death and second HCT as competing risk events. Variables were evaluated for an association with development of HZ using Cox proportional hazards regression; those of biological interest and with a P value ≤ 0.3 in univariable analyses were considerate for multivariable model. Results The study cohort consisted of 227 CBT recipients with a median follow up of 25.4 months (interquartile range [IQR], 6.8 - 49). Follow up time was truncated at the time of death (n=113), second HCT (n=13) or last available records (n=32). Cohort characteristics are shown in Table 1. Among 1-year survivors, 91% were still receiving prophylaxis for a median duration of 20.6 months post-CBT (IQR, 14.1 - 29.4). HZ occurred in 44 patients (19%) at a median of 23.6 months (IQR, 16.1 - 30.3). Most patients (n=31/44, 70%) were not taking antiviral prophylaxis when HZ developed. The cumulative incidence of HZ by 1-year post-CBT was low (1.8%; 95% CI, 0.1%-4%) but increased starting from the second year and reached 26% (95% CI, 19%-33%) by 5 years (Figure 1). Disseminated HZ occurred in 5 cases (11%), and post-herpetic neuralgia occurred in 14 cases (31.8%). Of the 13 HZ episodes that occurred in patients reportedly taking antiviral prophylaxis, 6/13 had clear documentation of ongoing antiviral prophylaxis and 5/13 were still receiving immunosuppressive treatment for graft-versus-host disease (GvHD). All patients responded to antiviral treatment, which consisted of ACV (n=18), VACV (n=16), and famciclovir (n=1). In a multivariable analysis, patients who received myeloablative conditioning or had acute GvHD grades 2-4 had a higher risk of HZ, whereas the use of antiviral prophylaxis was associated with a lower risk of HZ (Table 2). Among 35 patients who discontinued prophylaxis before completing immunosuppressive therapy, 28.5% developed HZ. We found no association between CD4+ T cell counts at 1-year after-CBT and HZ risk. Conclusions In this cohort of 227 CBT recipients with up to 5 years of follow up, the cumulative incidence of HZ was 26% at 5 years, despite antiviral prophylaxis for &gt;1 year in the majority of patients. Furthermore, these patients had high rates of post-herpetic neuralgia and disseminated VZV. Antiviral prophylaxis protected against HZ but there were breakthrough cases. Given that a high number of patients interrupted prophylaxis while still receiving immunosuppressants, adherence to antiviral prophylaxis should be emphasized by health care providers. Based on our findings, the lack of alternative prophylactic strategies at this time, and the safety of ACV/VACV, longer duration of prophylaxis should be considered, especially in patients with ongoing immunosuppression. Recent data demonstrating the safety and efficacy of the HZ subunit vaccine after autologous HCT support future study of HZ vaccination after allogeneic HCT. Disclosures Delaney: Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Boeckh:Chimerix: Research Funding; GSK: Other: Personal fees; GSK: Research Funding; Merck: Research Funding; Merck: Other: Personal fees; Clinigen: Other: Personal fees. Milano:ExCellThera: Research Funding; Amgen: Research Funding. Hill:Takeda: Other: research support; Karius: Other: research support; Amplyx: Consultancy; Nohla Therapeutics: Consultancy, Other: research support.

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.

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