scholarly journals Pharmacogenomics of Fludarabine in Pediatric HCT Recipients: Preliminary Results

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 908-908
Author(s):  
Nam H.K. Nguyen ◽  
Vivek M. Shastri ◽  
Ying Lu ◽  
Beth Apsel Winger ◽  
Janel R. Long-Boyle ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Cumulative Incidence ◽  
Conflicts Of Interest ◽  
Chemotherapeutic Agents ◽  
Ongoing Study ◽  
Variant Allele ◽  
Cell Transplant ◽  
Pathway Gene ◽  
Conditioning Regimens ◽  
Transplantation Outcomes

Abstract Introduction: Total Body Irradiation (TBI) conditioning regimens are considered standard of care for pediatric hematopoietic cell transplant (HCT) recipients. However, TBI has many long-term effects, so avoiding it in young HCT recipients is critical. Fludarabine is frequently used in combination with other chemotherapeutic agents like busulfan and/or thiotepa in non-TBI based conditioning regimens. While multi-drug conditioning aims to avoid TBI-related late-effects, little is known about the effect of variations in genes that metabolize these drugs (pharmacogenomics/PGx) on clinical outcomes including engraftment, relapse, and acute drug-related toxicities. In this study, we investigated the pharmacogenomic effects on HCT outcomes such as event-free outcomes and re-transplantation outcomes, as well as fludarabine's pharmacokinetics (PK). Methods: This ongoing study included pediatric patients from a nationwide multi-center study who received fludarabine in combination with other agents as busulfan and thiotepa. From literature searches and PharmGKB databases, we selected 70 SNPs in 30 candidate pharmacological genes for these drug pathways. SNPs with a minor allele frequency of 10% were further selected for analysis with different endpoints such as: 1) Cumulative incidence with disease relapse with re-transplantation (using Gray's methods, controlling for competing risks); 2) fludarabine PK with cumulative area under the curve (cAUC); 3) 1-month-post-transplant chimerism levels defined as sufficient (CD3 ≥80% and CD14/15 ≥95% chimerism) and insufficient (CD3 <80% and CD14/15 <95% chimerism); and 4) event-free outcomes (comparing patients alive and well vs. others) OR alive re-transplantation outcomes (alive with vs. without re-transplantation). SNPs with an association p-value <0.05 were considered significant using generalized linear models from the SNPassoc R package. Results: Total of 87 patients included in the analysis had a median age of 3.5 (0.2 - 17.9) years, 63% were male, 48% were Caucasian, 85% had received allogenic HCT, and 43% had malignant hematologic disease (Table 1). For SNP rs2277119 in CYP39A1, presence of T allele was associated with greater cumulative incidence of re-transplantation (TC-TT vs. CC genotype: HR=3.64 (95% CI=1.14-11.62), p=0.02, Figure 1A); and SNP rs4715354 in GSTA5, presence of G allele was associated with lower cumulative incidence of re-transplantation (AG-GG vs. AA: HR=0.32 (95% CI=0.11-0.95), p=0.037, Figure 1B). In 79% of patients with available fludarabine cAUC (median of 3.72 mg•hr/L), we evaluated fludarabine pathway gene SNPs for association with cAUC. Within SNPs rs3925058 in CMPK1 and rs11853372 in the uptake transporter SLC28A1, presence of variant allele was associated with higher fludarabine cAUC (rs3925058: GA-AA vs. GG, p=0.049, Figure 2A, and rs11853372 GG-GT vs. TT, p=0.003, Figure 2B); and for a 3'-UTR SNP rs2037067 in TENM3/DCTD, the variant allele was associated with lower fludarabine cAUC levels (CT-CC vs. TT, p=0.005, Figure 2C). In an exploratory analysis with event-free outcomes, patients with variant allele for SNPs rs9937 in RRM1, rs2072671 in CDA, rs324148 in SLC29A1, and rs7533657 in CTPS1 had higher odds of having an event compared to patients with the reference allele; while rs11577910 in CTPS1 had a better outcome with presence of variant allele. With respect to patient's status being alive with re-transplantation outcomes, variants SNPs with rs507964 in SLC29A1, rs4244285 in CYP2C19, rs1021737 in CTH, rs1561876 in STIM1, and rs1130609 in RRM2 have high odds of re-transplantation. At 1-month follow-up, variant SNP rs12144160 in CTPS1 was associated with sufficient chimerism in CD3 and CD14/15. Conclusions: In this study, we have identified a number of SNPs that predict interpatient variability in clinical outcomes and fludarabine levels in pediatric HCT recipients. Results so far showed potential to predict outcomes and develop strategies that will consider pharmacogenomics when determining fludarabine doses in pediatric HCT recipients. Our ongoing study is focused on establishing and validating the pharmacogenetic markers predictive of pharmacokinetics of busulfan, fludarabine and thiotepa and clinical outcomes in pediatric HCT recipients. Acknowledgements: This study was supported by Florida Department of Health - Live Like Bella Discovery Award (9LA04). Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Comparison of Outcomes After Allogeneic HSCT for Adult Patients with AML in Remission Using in the Conditioning Regimen Either I.V. Busulfex (BU) Plus Cyclophosphamide (Cy) or TBI Plus Cy: An- ALWP-EBMT Survey.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 195-195
Author(s):  
Arnon Nagler ◽  
Myriam Labopin ◽  
Avichai Shimoni ◽  
Liisa Volin ◽  
Donald W. Bunjes ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Post Transplantation ◽  
Allogeneic Hsct ◽  
Reduce Relapse Rate ◽  
Conditioning Regimens ◽  
Wbc Count ◽  
Transplantation Outcomes

Abstract Abstract 195 TBI/CY and oral (p.o) Bu/Cy are the traditional allogeneic HSCT (alloHSCT) myeloablative conditioning regimens for adults with AML with comparable survival and relapse probabilities. Intravenous (i.v.) Bu in contrast to p.o Bu has more predictable pharmacokinetics and a more favorable toxicity profile. Post transplantation outcomes with i.v. Bu/Cy, thus, may be superior to those achieved with TBI/Cy. In order to address these issues, the ALWP of the EBMT performed a survey comparing i.v. Bu/Cy to TBI/Cy as conditioning regimen for adult pts. with AML undergoing alloHSCT. Overall, 603 alloHSCT were analyzed. One hundred pts. underwent alloHSCT with Bu/Cy while 503 with TBI/Cy. Age was 41 (range, 18–57) and 41 (range, 16–61) years and median transplant year was 2004 (2000 – 2005) and 2003 (2000 – 2005) for the Bu/Cy and TBI/Cy groups, respectively. Disease status at alloHSCT were CR1 – 81% vs. 78% and CR2–19% vs. 22% for the Bu/Cy and TBI/Cy groups, respectively. WBC count at diagnosis was 11×109/L and 15×109/L, respectively. Regarding the cytogenetic classification, 10% and 10% were good, 60% and 55% were intermediate and 9% and 6% were poor risk, respectively (data were NA for 21%–26% of pts). Sixty nine percent and 68% of both groups underwent alloHSCT from sibling donors, while 31% and 32% from MUD, respectively. Length of follow up was 37(15–86) and 57 (1–105) months for both groups, respectively. Sixty nine percent and only 41% of the Bu/Cy and TBI/Cy groups received PB, while 31% and 59% received BM grafts, respectively (p<0.0001). Engraftment was similar in the Bu/Cy vs. the TBI/Cy groups, 95% and 96%, respectively. Cumulative incidence of TRM at 2y was 17+4% and 23+2%, respectively (p=0.23). Acute GVHD (II–IV) was also similar between the 2 groups, 28% and 32%, respectively. Two year relapse incidence was 30+5% and 22+2% for Bu/Cy vs. TBI/Cy, respectively (p=0.03) while LFS was comparable 57+5% and 61+2%, respectively (p=0.5). In multivariate analysis Cy/TBI was found to be an independent good prognostic factor for reduce relapse rate (p=0.03, HR-1.67) and there was a trend for higher TRM (p=0.16). Poor prognostic factors for LFS and TRM were age >40y, disease status (CR2 vs. CR1) and MUD vs. Sib. donor. In conclusion, in this retrospective EBMT survey outcomes of alloHSCT in adult pts. with AML in CR using either i.v Bu/Cy or TBI/Cy were comparable. Disclosures: No relevant conflicts of interest to declare.

The Effect Of CMV Reactivation On Relapse and Survival In Patients With AML and MDS After Allogeneic Stem Cell Transplant (allo-HCT)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4531-4531
Author(s):  
Armin Ghobadi ◽  
Amir Hamdi ◽  
Piyanuch Kongtim ◽  
Denai Milton ◽  
Amin Alousi ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Conflicts Of Interest ◽  
Group Differences ◽  
Rank Test ◽  
Cancer Center ◽  
Published Data ◽  
Cell Transplant ◽  
Transplant Outcomes ◽  
Cmv Reactivation ◽  
Cmv Antigenemia

Introduction The effect of CMV reactivation after allo-HCT on relapse and overall survival (OS) in patients with acute myeloid leukemia (AML) and myelodysplatic syndrome (MDS) is controversial (Green et al blood 2013, Elmaagacli et al Blood 2011, and Erard et al Hematologica 2006). Methods We retrospectively analyzed the effect of CMV reactivation on OS and cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) in AML and MDS patients older than > 18 years who had received allo-HCT between 2005-2011 and had not died within 30 days of receiving allo-HCT at MD Anderson Cancer Center. The effect of any CMV antigenemia on allo-HCT outcomes was evaluated by comparing any CMV antigenemia with no CMV antigenemia. Because of potential immunomodulatory effect of CMV infection, the effect of prolonged antigenemia (defined as CMV antigenemia with duration more than 12 days, the median duration of antigenemia for the cohort) on transplant outcomes was analyzed by comparing patients with prolonged antigenemia with patients with no CMV antigenemia or CMV antigenemia with ≤ 12 days. All patients underwent surveillance by pp65 antigenemia test. Preemtive therapy was initiated for > 3 pp65 Ag cells/million WBC's. Kaplan-Meier survival curves were used to estimate OS and the log-rank test was used to assess group differences. CIR and NRM were determined using the competing risks method; competing risk for CIR was death and for NRM was relapse. Group differences in CIR and NRM were assessed using Gray's test. Results Table 1 shows baseline characteristics. Comparing R+/D+, R-/D-, R-/D+, and R+/D- groups, the incidence of any CMV antigenemia after HCT was 48%, 16.7%, 13.5%, and 50.9%, respectively (p<0.0001) and the incidence of CMV disease was 1.0%, 1.9%, 2.7%, and 4.5%, respectively (p = 0.05). When any CMV antigenemia was compared with no CMV antigenemia post allo-HCT, CMV reactivation had no effect on OS (p > 0.15) and CIR (p > 0.61) in all cohort as well as AML and MDS subgroups. Comparing any antigenemia vs. no antigenemia, CIR at 3 years was 34.6% vs. 35.2% in all cohort, 36.7% vs. 36.6% in AML patients, and 29.5% vs. 30.0% in MDS patients, respectively. In patients with CMV antigenemia, duration of antigenemia ranged from 1 to 535 days (median 12 days). We then investigated the effect of prolonged CMV antigenemia on transplant outcomes. Patients with CMV antigenemia > 12 days compared with combined group of ≤ 12 days or no CMV antigenemia had a lower cumulative incidence of relapse and a higher NRM, resulting in a similar OS (Fig. 1). Such a difference was seen in AML but not in MDS subgroup. We then investigated the effect of duration of CMV antigenemia in patients with CMV reactivation. Comparing 1-12 days of antigenemia vs. more than 12 days of antigenemia, CIR at 3 years was 41.9% vs. 26.7% (p = 0.003) in all cohort, 45.8% vs. 26.4% (p = 0.001) in AML patients, and 32.1% vs. 27.4% (p = 0.68) in MDS patients, respectively. Conclusion Prolonged CMV antigenemia is associated with decreased relapse in patients with AML, but not in MDS. Lower relapse is offset by increased NRM resulting in no change in OS. In contrast with published data, lower rate of relapse was not found when any antigenemia was compared with no antigenemia. Disclosures: No relevant conflicts of interest to declare.

Influence of NPM1 and FLT3-ITD Status On Outcome in Relapsed/Refractory AML Patients with Normal Karyotype and Receiving Salvage Therapy Including Gemtuzumab Ozogamicin (GO).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3110-3110
Author(s):  
Patrice Chevallier ◽  
Thomas Prebet ◽  
Arnaud Pigneux ◽  
Mathilde Hunault ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Gemtuzumab Ozogamicin ◽  
Chemotherapeutic Agents ◽  
Cell Transplant ◽  
Salvage Regimen ◽  
Leukemia Diagnosis ◽  
Major Interest ◽  
Refractory Aml

Abstract Abstract 3110 Poster Board III-47 The aim of this study was to investigate the influence of the NPM1/FLT3-ITD status on outcome in relapsed/refractory AML patients with normal karyotype who received a salvage regimen using GO as monotherapy or in combination with other agents. For this purpose, we analyzed the outcome of 57 AML patients with normal karyotype treated between 2001 and 2009. Patients received GO as monotherapy or in combination with other chemotherapeutic agents at time of relapse (n=36) or in the setting of refractory disease (n=21). There were 26 males and 31 females with a median age of 52 (range, 20-70) years at time of leukemia diagnosis. The FAB distribution included 2, 13, 15, 11, 12 and 1 AML cases from the M0, M1, M2, M4, M5 and M6 subgroups, respectively. Three cases were considered as unclassified. In addition, 5 patients had secondary AML. All patients were CD33 positive with a median CD33 expression level of 98%. As salvage treatment, 46 patients received the MIDAM regimen (GO: 9 mg/m2 at day 4 + Cytarabine 1g/m2/12 hours day 1-5 + Mitoxantrone 12 mg/m2/day day 1-3).3 In 2 patients receiving the MIDAM regimen, Mitoxantrone was omitted to avoid cardiac toxicity. Four patients received GO as monotherapy at 9 mg/m2 (n=3) or at 6 mg/m2 (n=1). The 5 remaining patients received GO 3 to 9 mg/m2 combined with other chemotherapeutic agents (Cytarabine + VP16 + GO, n=2; Cytarabine + Idarubicine + GO, n=2; Cytarabine + Amsacrine + GO, n=1). After salvage therapy, 25 patients could proceed and receive consolidation with an allogeneic stem cell transplant. In this series, all patients could be screened in the blood or bone marrow for mutations in the NPM1 and in the FLT3 gene (ITD mutations) at diagnosis. Numbers of patients according to NPM1/FLT3-ITD status were as follow: (+/−): n=14, (+/+): n=9, (−/−): n=19, (−/+): n=15. The same proportion of refractory patients was observed in the favourable NPM1+/FLT3-ITD- sub-group as compared to the other sub-groups (36%, n=5/14 vs 37%, n=16/43). With a median follow-up of 23.3 (range, 2.3-94.5) months for surviving patients, OS was 46.5% (95%CI, 33.6-59.9%) at 2 years. CR, relapse and death rates according to NPM1/FLT3-ITD status were as follow: CR: (+/−): 85%, (+/+): 66%, (−/−): 47%, (−/+): 73%, P=NS; Relapses: (+/−): 33%, (+/+): 33%, (−/−): 33%, (−/+): 54%, P=NS; Deaths: (+/−): 28%, (+/+): 78%, (−/−): 58%, (−/+): 66%, P=0.02 Also, the death rate was significantly lower in FLT3-ITD- patients as compared to FLT3-ITD+ cases (45% vs. 71%, P=0.05). OS was significantly higher in the NPM1+/FLT3-ITD- sub-group as compared to other patients (78% vs. 36% at 2 years, P=0.026). In conclusion, and although this needs to be confirmed in a prospective setting, refractory/relapsed AML patients combining a normal karyotype and a NPM1+/FLT3-ITD- molecular status are likely to remain in a “favorable prognosis” category when receiving salvage therapy. Such information is of major interest for patients counselling and for the design of salvage therapy approaches. Disclosures No relevant conflicts of interest to declare.

Association of Cyclophosphamide (CY) and Fludarabine (FLU) Pharmacokinetics with Treatment Related Mortality (TRM) after Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1153-1153
Author(s):  
Anthony C. Wiseman ◽  
Kinjal Sanghavi ◽  
Qing Cao ◽  
Erica D. Warlick ◽  
Claudio G Brunstein ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Active Metabolite ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Systemic Exposure ◽  
Chemotherapeutic Agents ◽  
Unrelated Donor ◽  
Increased Risk ◽  
The Relationship

Abstract CY and FLU are chemotherapeutic agents often used in RIC regimens. RIC regimens may yield lower transplant related complications and toxicities as compared to myeloablative conditioning. However TRM at 12 months still approximates 30%. We previously reported that high F-ara-A (active metabolite of FLU) exposure was associated with more TRM at a FLU dose of 40 mg/m2, but the relationship is unknown at lower doses. Similarly, phosphoramide mustard (PM, the active metabolite of CY) may influence clinical outcomes. Thus we studied the relationship between clinical outcomes and systemic exposure of F-ara-A at lower doses and PM. Forty adults undergoing allogeneic RIC HCT were prospectively studied from March 2013 to May 2014. All patients received FLU, CY and TBI as conditioning and cyclosporine or sirolimus, plus mycophenolate for posttransplant immunosuppression. Median age was 62 years (21-72). 22 were male and 18 female. The stem cell sources were sibling or unrelated donor PBSC (n=22, 55%), cord blood (n=13, 32.5%) or bone marrow (n=5, 12.5%). CY 50mg/kg was administered IV over 2 hrs on day -6. Pharmacokinetic samples were obtained at predose and 2, 4, 6, 21, 24 and 45 hrs after the end of infusion. PM was derivatized with diethyldithiocarbamate and measured by ultraviolet detection with HPLC. PM area under the curve (AUC0-last), AUC0-6 and AUC0-24 were calculated using non-compartmental methods (Phoenix WinNonlin Professional 6.3). Fludarabine dosing was 30 mg/m2/d (n=35), 32 mg/m2/d (n=1), 35 mg/m2/d (n=2) and 40 mg/m2/day (n=2) x 5 doses depending on protocol and was administered IV over 1 hr on days -6 to -2. In addition, F-ara-A troughs were obtained at 24 hours after the start of the first infusion on day -6 and 24 hours after start of 2nd infusion. F-ara-A quantification was performed using HPLC-UV. TRM was defined as death due to any cause other than relapse or disease progression. GVHD was staged and graded according to the standard GVHD criteria based on clinical and pathological criteria Recursive partitioning regression analysis was used to determine optimal cut points for PM and F-ara-A pharmacokinetic measures towards TRM at day 100, 6 months and 12 months and the incidence of acute graft vs host disease (GVHD). The cumulative incidence of engraftment, TRM and acute GVHD (II-IV and III-IV) was calculated using death prior to event as a competing risk. The proportional hazards model of Fine and Gray was used to assess the association of F-ara-A exposures towards TRM, acute GVHD and engraftment. The incidence of TRM at day 100 was 13%, 20% at 6 months and 47% at 12 months. The incidence of grades 2-4 and 3-4 acute GVHD was 39% and 25%. In univariate analysis, day 100 TRM risk was significantly higher in patients with a PM AUC0-24 ≥85 ug-hr/ml (relative risk (RR) 36%, [95% CI 9-64%]) vs. AUC0-24 <85 ug-hr/ml (4% [0-11%] (p<0.01). Risk of TRM at 6 months was also associated with a PM AUC0-24 ≥85 ug-hr/ml (47% [17-77%]) vs. <85 ug-hr/ml (14% [0-28%]) (p=0.02) while there was no effect of AUC0-24 on 12 month TRM. Patients with F-ara-A trough concentration after the second dose ≥75 ng/ml had significantly higher risk of day 100 TRM as compared to patients in whom F-ara-A was <75 ng/mL (33% [4-63%] vs 7% [0-15%])(p=0.01). F-ara-A troughs were not associated with TRM at 6 and 12 months. PM and F-ara-A exposures did not influence risks of acute GVHD. Engraftment rates were high (93%, CI 82-99%) so an insufficient number of failure events were available for evaluation. Higher PM exposures were associated with increased risk of TRM at day 100 and 6 months. Higher F-ara-A exposures were associated with greater risk of TRM at day 100. No associations were observed towards acute GVHD. These data for the first time show that TRM is associated with high PM exposure. These data also support our earlier findings that overexposure to F-ara-A may be harmful in RIC regimens. Multivariate models adjusting for other important clinical factors will be evaluated as enrollment continues to a larger cohort. In the future predictive pharmacokinetic models may be beneficial in personalizing fludarabine and cyclophosphamide doses. Disclosures No relevant conflicts of interest to declare.

Utility of Plerixafor In Addition to Chemotherapy and G-CSF Mobilization Regimens

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4443-4443
Author(s):  
Farrukh Awan ◽  
David Deremer ◽  
Elaine Mebel ◽  
Samith Thomas Kochuparambil ◽  
Anand P. Jillella
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Chemotherapeutic Agents ◽  
Phase Iii ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Significant Difference

Abstract Abstract 4443 Introduction: Various chemotherapeutic agents particularly cyclophosphamide (CY) are utilized in combination with growth factors in an attempt to increase the number of stem cells available for collection in the peripheral blood. Plerixafor (P) is a reversible antagonist of CXCR4 and interrupts its interaction with SDF-1. This results in a rapid release of hematopoietic stem cells from the marrow to the circulation. Recent pivotal phase III trial data has established the efficacy of P in combination with G-CSF (G) in patients who had failed prior attempts at stem cell collection. However, there is limited data about the utility of plerixafor in patients who are being mobilized with chemotherapy and G. Method: In this single institution study of uniformly treated patients we describe our experience with the use of P as a salvage option in patients who fail to optimally mobilize CD34+ cells (>5 × 106 CD34+ cells/kg). Patients received CY (3-4 g/m2) followed by GCSF (10 mcg/kg) from day 1 to day 10. Thirteen patients (6 NHL, 4 MM, 2 Hodgkin lymphoma, 1 Ewings sarcoma) received salvage P from 2008–2010. Their outcomes were compared with 10 matched, historic controls mobilized with (CY n=8; CY + etoposide n=1; CY + topotecan n=1) plus G-CSF (10mcg/kg/d) identified from our institutional database. Data was collected on mobilization and transplant outcomes and analyzed utilizing SPSS version 13.0. Patients receiving P were closely matched to historic controls (CY+G). Result: Both groups were similar with regards to age, gender, disease type, prior therapies and performance status (p>0.05 for all). Patients in the P arm received a median of 2.5 doses (range 1–8). The mean CD34+ count was 21.5cells/ul in the P arm and 32.5 cells/ul in the CY+G arm (p=0.2). Similarly, no significant difference was observed in the average number of apheresis sessions in the P vs. CY+G arms (4.2 vs. 4.4, p=0.8) or the total number of CD34+ stem cells collected (4.0×106/kg vs. 3.9×106/kg, p=0.9). However, 7 out of the 13 patients who received P did have an increase of >10 CD34+ cells/ul in their peripheral blood. Utilizing a cut-off of 5×106 CD34+/kg, 3 (23%) patients in the P arm and 3 (30%) patients in the CY+G arm had a successful harvest. Three NHL patients required >4 doses of P, but all eventually collected >2 × 106 CD34+ cells/kg. Neutrophil and platelet engraftment dynamics were similar in both groups of patients. Median time to neutrophil engraftment was 10 days for both groups, p=0.8, and to platelet engraftment was 22 days vs. 20.5 days, p=0.1, respectively for P vs. CY+G. Conclusion: Our limited single-center retrospective case-controlled outcomes data, suggests that when compared with CY+G, the addition of P as a salvage agent does not significantly improve mobilization outcomes. Further evaluation is needed to combine P with CY+G in terms of optimal timing and potentially dosing of chemotherapy agents utilized. We suggest that the combination P+G would provide better potential outcomes such as improved collection and less hospitalization and reduce the use of chemo-mobilization prior to an Autologous Hematopoietic Stem Cell Transplant. Disclosures: No relevant conflicts of interest to declare.

Comparative Efficacy Analysis of Busulfan Dose Intensity Between Two Reduced Intensity Conditioning Regimens (FB2 vs. FB4) for Allogeneic HCT for AML in First Complete Remission: A Report From the EBMT Acute Leukemia Working Party

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4153-4153
Author(s):  
Mohamed A Kharfan-Dabaja ◽  
Myriam Labopin ◽  
Ali Bazarbachi ◽  
Rose-Marie Hamljadi ◽  
Didier Blaise ◽  
...  
Keyword(s):  
Complete Remission ◽  
Cumulative Dose ◽  
Cumulative Incidence ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Allogeneic Hct ◽  
Conditioning Regimens ◽  
First Complete Remission ◽  
Donor Source

Abstract Abstract 4153 Background: better understanding of the bona fide immunological benefits derived from the donor immune effector cells resulted in development of reduced-toxicity regimens, which are associated with lesser toxicities and improved non-relapse mortality (NRM). However, reducing the toxicity of allogeneic hematopoietic cell transplantation (HCT) conditioning regimens without compromising its efficacy remains an imperative goal to broaden applicability of allogeneic HCT. We compare outcomes of two preparative regimens, known as FB2 and FB4, in patients (pts) with AML transplanted in first complete remission (CR1) at EBMT participating centers. Materials and methods: between 2003 and 2010, 437 (FB2=225 (51%), FB4=212 (49%)) pts with a median age of (FB2=57 (21–75) years, FB4=41 (18–68) years, p<0.0001), with AML in CR1, underwent allogeneic HCT. FB2 comprised intravenous (IV) busulfan cumulative dose of 6.4 ± 10% mg/kg, while FB4 cumulative dose was 12.8 ± 10% mg/kg. Cytogenetic risks groups were comparable: FB2 (good=8, int=144, poor=24) and FB4 (good=7, int=54, poor=9), p=0.27. For pts treated with FB2, donor source consisted of matched-related donors (MRD)= 112, matched unrelated donor (MUD)=80, mismatched unrelated donors (MMUD)=16, unknown=17. For FB4, donor source was MRD=160, MUD=29, MMUD=15, and unknown=8. Use of peripheral blood stem cells (PBSC) was higher in the FB2 group (96% vs. 83%, p <0.0001). Use of anti-thymocyte globulin (ATG) was also higher in FB2 group (79% vs. 33%, p<0.0001). FB4 allograft recipients (80% vs. 67%, p=0.003) and donors (77% vs. 56%, p<0.0001) had higher incidence of CMV seropositivity. Results: median follow-up time was 28 (2–89) months. Median time to absolute neutrophil count engraftment (days) was 17 (2–110) and 15 (7–45), for FB2 and FB4, respectively (p<0.0001). For pts <50 yrs. of age (n=208; FB2=56, FB4=152), the 2-year leukemia-free survival (LFS), cumulative incidence of relapse (CI-R), and of NRM was: LFS (FB2=60±7% vs. FB4=64±4%, p=0.45), CI-R (FB2=32±6% vs. FB4=20±4%, p=0.04), and NRM (FB2=7±4% vs. FB4=16±3%, p=0.17). Conversely, for pts aged ≥50 yrs. (n=229, FB2=169, FB4=60), outcomes were: LFS (FB2=63±4% vs. FB4=42±7%, p=0.02), CI-R (FB2=22±3% vs. FB4=29±6%, p=0.42), and NRM (FB2=15±3% vs. FB4=29±6%, p=0.06). Cumulative incidence of acute (≥grade 2) and chronic GVHD were similar: acute (FB2=51 (23%) and FB4=53 (26%), p=0.54) and chronic (FB2=48 ±3, FB4=44±2, p=0.51). Conclusion: in pts < 50 years of age, FB2 results in worse 2-year CI-R compared to FB4, but with similar 2-year NRM and LFS. For pts ≥50 years of age, FB2 results in superior 2-year LFS likely due to lower NRM. FB2 is a reasonable preferred option in pts ≥50 years with AML in CR1. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Response Kinetics of Daratumumab-Based Regimens in Patients with Newly Diagnosed or Refractory/Relapsed Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3806-3806
Author(s):  
Jiasheng Wang ◽  
Raul Arroyo-Suarez ◽  
William Tse
Keyword(s):  
Multiple Myeloma ◽  
Clinical Outcomes ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Late Response ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Hematopoietic Cell Transplant ◽  
Significant Difference

Abstract Background: It is controversial in multiple myeloma (MM) whether early and late responders to therapies have similar clinical outcomes. Daratumumab (DARA) is a human anti-CD38 antibody that has been increasingly used in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). The association between response kinetics to DARA and clinical outcomes remains unexplored. Methods: Individual-participant data were obtained from phase 3 trials: POLLUX (Dimopoulos, NEJM, 2016), CASTOR (Palumbo, NEJM, 2016), and MAIA (Facon, NEJM, 2019). Patients were divided into early and late response groups based on the median time to the response of interest. Modified PFS (mPFS) and OS (mOS) were calculated from the time of first response of interest. Minimal residual disease (MRD) negativity was defined as less than 10 5 tumor cells by NGS assays. Results: After a median follow up of 16.1 months, 670 patients achieved a response of very good partial response (VGPR) or better, and 213 achieved MRD negativity. The median time to achieving VGPR or better was similar between NDMM and RRMM (86 vs. 84 days, respectively), while the median time to MRD negativity was longer among NDMM than RRMM (407 vs. 197 days, respectively). Among patients achieving VGPR or better, there was no significant difference of mPFS (HR 1.00, 95%CI 0.69 to 1.44) (fig. a), duration of response (DOR) (HR 1.02, 95%CI 0.68 to 1.53) (fig. b), or mOS (HR 0.98, 95%CI 0.54 to 1.75) (fig. c) between early and late responders. In the subgroup analysis, no significant difference of DOR was observed across all prespecified groups, including sex, age, cytogenetic risk groups, lines of previous therapy, types of measurable disease, NDMM vs. RRMM, prior treatment with autologous hematopoietic cell transplant, immunomodulatory drugs, or proteasome inhibitors. Among patients with NDMM achieving MRD negativity, there was no significant difference of mPFS (p=0.66) (fig. d), DOR (p=0.21) (fig. e) or mOS (p=0.87) (fig. f) between early and late responders. However, among patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS (p=0.038) (fig. g) and DOR (p=0.043) (fig. h) than early responders; mOS was not significantly different (fig. i). In the multivariable Cox analysis among patients achieving MRD negativity, only lower baseline LDH level, NDMM, and IgG type MM were independently associated with later response. Conclusions: For patients with NDMM or RRMM achieving VGPR or better, early and late responders had similar survival; for patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS and DOR. Our data support that in patients who failed to achieve an early or deep response to daratumumab based regimens, therapies should be continued with the goal of achieving ongoing and stepwise improvement of response. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Outcomes of Post Allogeneic Stem Cell Transplant Splenectomy in Primary Myelofibrosis for Delayed Engraftment

2021 ◽  
Vol 27 (3) ◽  
pp. S428-S429
Author(s):  
Lindsey Pelke ◽  
Mark R. Litzow ◽  
Mithun V. Shah ◽  
William J. Hogan ◽  
Hassan B. Alkhateeb
Keyword(s):  
Stem Cell ◽  
Clinical Outcomes ◽  
Stem Cell Transplant ◽  
Primary Myelofibrosis ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant
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