Comparison of continuous versus intermittent infusion cyclosporine and impact on transplant related outcomes in allogeneic transplant recipients

2020 ◽  
pp. 107815522097060
Author(s):  
Jeff A Engle ◽  
Justin A Wasko ◽  
John Rogosheske ◽  
Todd E Defor ◽  
Armin Rashidi
Keyword(s):  
Overall Survival ◽  
Continuous Infusion ◽  
Medical Center ◽  
Chronic Gvhd ◽  
Intermittent Infusion ◽  
University Of Minnesota ◽  
Allogeneic Hct ◽  
Increased Risk ◽  
Administration Method ◽  
Grade Ii

Introduction Continuous infusion (CIVI) cyclosporine (CsA) is an alternative for allograft recipients intolerant of twice daily infusions (TDI). The importance of achieving therapeutic levels of CsA early after allogeneic HCT has been demonstrated in previous studies. Our study evaluated the incidence of acute graft versus host disease (GVHD) and survival among patients receiving CIVI vs. TDI CsA during their first allogeneic HCT. Methods A retrospective study of adult patients undergoing first allogeneic HCT at the University of Minnesota Medical Center between 2011 and 2017. Patients were grouped according to the administration method. The primary outcome was the occurrence of acute grade II-IV GVHD by day +180. Secondary outcomes included the 1-year incidence of chronic GVHD, relapse, and overall survival. Results 42 patients intolerant of TDI CsA received CsA via CIVI for >48 hours for a median of 9 days (range, 3–32 days). CsA concentrations were similar between groups. We found no difference between the rates of grade II–IV acute (45% vs 53%, p = 0.59) or chronic (17% vs 30%, p = 0.20) GVHD or overall survival (57% vs 67%, p = 0.10). Subgroup analysis of patients that received myeloablative conditioning or umbilical cord blood did not reveal significant differences in GVHD or overall survival. Cumulative incidence of relapse was higher among the continuous infusion group (39% vs. 23%, p < 0.01). Conclusion Due to the finding of increased risk of relapse, cyclosporine should be administered as traditional twice daily infusion unless necessary. A prospective clinical trial is needed to confirm these results.

Unrelated Male Donors Versus Sibling Parous Female Donors: Impact on Transplant-Related Outcomes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 70-70
Author(s):  
Anita J Kumar ◽  
Soyoung Kim ◽  
Michael Hemmer ◽  
Mukta Arora ◽  
Steve Spellman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Increased Risk ◽  
Donor Type ◽  
Unrelated Donors ◽  
Recipient Age ◽  
Grade Ii ◽  
Related Mortality

Abstract Introduction: Optimal donor selection is critical to reduce morbidity and mortality from allogeneic hematopoietic cell transplant (HCT). HLA identical female parous sibling donors (pSIB) confer an increased risk of chronic graft vs. host disease (cGVHD) compared to male sibling donors, possibly from alloimmunization and exposure to fetal antigens during pregnancy. Unrelated donors (URD) also confer higher GVHD risk than sibling donors. While both pSIB and URD donors confer increased GVHD risk, they have never been directly compared. This study compares incidence of acute GVHD (aGVHD), cGVHD, survival, and treatment- related mortality in patients who received transplants from pSIB donors to male unrelated donors (mURD). Methods: A retrospective cohort study was completed using the Center for International Bone Marrow Transplant Registry (CIBMTR). We identified patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) who underwent a non-T cell depleted HCT from an HLA identical pSIB or a matched mURD between 2000-2012. Recipients were at least 25 years at time of transplant to ensure female sibling donors had biological opportunity to become parous. Primary outcome was Grade II-IV aGVHD, cGVHD, and overall survival (OS). Secondary outcomes were relative risk (RR) of leukemia free survival (LFS), transplant related mortality (TRM) and relapse. Results: We identified 892 pSIB donors and 1921 mURD donors. Median recipient age at transplant was 49 (pSIB) and 50 (mURD), p=0.14. Median donor age was higher in pSIB than mURD (48 vs. 32, p<0.001). Cumulative incidence of aGVHD was higher in mURD than pSIB at 100 days, 46% vs. 35%, p<0.001. Incidence of cGVHD at 100 days was also higher in mURD (9% vs. 4%, p<0.001), but was not different at 1 year (mURD 50%, pSIB 50%, p=0.99) or 2 years (mURD 56%, pSIB 56%, p=0.77). In multivariate analysis adjusting for other risks of GVHD (prophylaxis, graft source, gender, and transplant year), mURD had a 1.6 times higher risk of grade II-IV aGVHD (p<0.0001) and 1.23 times higher risk of cGVHD (p=0.0003) than pSIB donors (Table 1). A greater proportion of pSIB recipients were alive at 100 days (88% vs. 82%, p<.001), 1 year (62% vs. 57%, p=0.02), and 2 years (51% vs. 47%, p=0.02). However, in multivariate analysis donor type did not significantly affect OS (RR mURD 1.10, p=0.072), LFS (RR mURD 1.04, p=0.47), TRM (RR mURD 1.04, p=0.59), or relapse (RR mURD 1.03, p=0.62). Variables associated with OS included increasing recipient age (p<0.0001), Karnofsky performance status <90% (RR 1.37, p<0.0001), disease status at HCT (p<0.0001), and year of HCT (p<0.0001) (Table 2). Conclusion: Male URD confer a higher risk of grade II-IV acute and chronic GVHD compared to HLA-identical female parous sibling donors. Donor type does not significantly affect OS, LFS, TRM, or disease relapse. When available, female pSIB should be utilized rather than mURD donors to minimize toxicity of GVHD. Table 1. GVHD Outcomes Table 1. GVHD Outcomes Table 2. Overall Survival Table 2. Overall Survival Disclosures No relevant conflicts of interest to declare.

scholarly journals The Impact of Marital Status on Hematopoietic Stem Cell Transplant (HCT) Recipient Outcomes: A Surrogate for Consistent Caregiver. a CIBMTR Registry Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4788-4788 ◽  
Author(s):  
Jason Tay ◽  
Ruta Brazauskas ◽  
Naya He ◽  
Sara Beattie ◽  
Christopher Bredeson ◽  
...  
Keyword(s):  
Social Support ◽  
Overall Survival ◽  
Marital Status ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Allogeneic Hct ◽  
Increased Risk ◽  
The Impact

Abstract Background Current literature suggests that the presence and quality of social support may provide meaningful benefits in overall survival of HCT recipients. Further, studies in general oncology and renal transplantation population suggest that married patients have favorable outcomes. Caregivers of HCT recipients are an important source of both instrumental and emotional support, and a reasonable surrogate for presence of social support. Using data from Center for International Blood and Marrow Transplant Research (CIBMTR), we examined the potential influence of marital status (surrogate for caregiver) at the time of HCT on outcomes of HCT. Methods Patients, >40 years of age who underwent either autologous or allogeneic-HCT from 2008 to 2015 were included. Marital status was defined as either 1) Married, 2) Single, never married, 3) Separated/divorced, and 4) Widowed. The probability of OS at 5 years, Grade 2-4 acute GVHD at 100 days and chronic GVHD at 2 years were estimated as appropriate using the Kaplan-Meier method with the log-rank test used for univariate comparisons. Multivariate analysis was performed to determine the association of marital status with these outcomes, while adjusting for clinical and sociodemographic variables. Results We identified 10,226 allogeneic and 5,714 autologous HCT patients; the median follow-up of survivors was 37 months (range 1-102 months) and 40 months (range 1-106 months) respectively. In the allogeneic population, there were n=7,999 married, n=741 single, n=1,175 separated/divorced and n=311 widowed patients. There were n=4,308, n=478, n=695 and n=233 respectively in the autologous population. The baseline characteristics amongst the 4 groups of marital status were comparable. In the allogeneic population, the 5-year probability of OS, 100-day Grade 2-4 acute GVHD, 2-year probability of chronic GVHD were 38% [95%CI (36-39%)], 16% [95%CI (15-17%)]and 46% [95%CI (45-47%)] respectively; while the 5-year probability of OS in the autologous population was 63% [95%CI (61-64%)]. When compared with married patients, single, separated/divorced and widowed patients were not at an increased risk of death [HR 1.09, 95%CI (0.98-1.2); HR 1.01, 95%CI (0.93-1.09); HR 1.09, 95%CI (0.98-1.2)] in the allogeneic setting. Similarly, there was no association of marital status and OS in the autologous setting [HR 1.10, 95%CI (0.92-1.33); HR 1.17, 95%CI (1.01-1.36); HR 1.08, 95%CI (0.86-1.37)] respectively. In contrast, marital status in the allogeneic setting was associated with an increased risk of grade 2-4 acute GVHD in patients who are divorced/separated as compared to married patients [HR 1.13, 95%CI (1.03-1.24)] but not chronic GVHD [HR 0.90, 95%CI (0.80-1.02); HR 0.94, 95%CI (0.86-1.04); HR 0.82, 95%CI (0.68-0.99)] respectively. We did not identify an interaction between marital status and gender. Conclusions Our data suggest the marital status in patients undergoing either autologous or allogeneic HCT is not associated with overall survival or chronic GVHD, while the risk of acute GVHD maybe increased in patients who are divorced/separated. Taken together, the effect of marital status on post-HCT outcomes is negligible when other patient, disease and transplant variables are considered. Alternatively, marital status maybe an imperfect marker for positive social support. Future research should consider measuring social support using validated scales and assess health related quality of life together with health care utilization outcomes to better appreciate the potential impact of social support. Disclosures No relevant conflicts of interest to declare.

Killer Immunoglobulin-Like Receptor and NOD2/CARD15 Polymorphisms Independently Influence Survival after Allogeneic Hematopoietic Stem Cell Transplanation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2167-2167
Author(s):  
Sebastian Giebel ◽  
Aleksandra Holowecka-Goral ◽  
Izabela Nowak ◽  
Tomasz Czerw ◽  
Jerzy Wojnar ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Kir Genes ◽  
Increased Risk ◽  
Grade Ii ◽  
Card15 Gene ◽  
Grade Iii

Abstract Background: Activating and inhibitory killer immunoglobulin-like receptors (KIRs) regulate function of NK cells and a subset of T cells. KIR genotype, in particular the content of activating KIR genes is highly polymorphic. NOD2/CARD15 protein is broadly expressed in APCs and lymphocytes. Single nucleotide polymorphisms (SNPs) of this gene have been reported to impair the pathogen elimination and trigger pathologic immunologic reactions like GvHD. The goal of this prospective study was to evaluate the impact of donor’s and recipient’s KIR and NOD2/CARD15 genotypes on outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT). Pateints and methods: One-hundred-two consecutive patients with hematological malignancies, aged 32(18–58)y, treated with alloHSCT from HLA-matched related (n=34) or matched unrelated donor (MUD) (n=68) were included. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of CsA, Mtx, and, in case of MUD-HSCT, pre-transplant ATG. Donors and recipients were tested for 11 KIR genes as well as SNP8,12,13 of the NOD2/CARD15 gene. In addition, immune reconstitution including KIR expression on T cells, was analyzed on days +28, +56, +100, +180, and +360. Results: Overall survival (OS) rate at 2y was significantly lower in alloHSCT with at least one activating KIR mismatch compared to transplants with full compatibility (62% vs. 86%, p=0.01). In particular, the presence of at least one activating KIR in the donor with its absence in the recipient (D+R−) was associated with decreased probability of OS (60% vs. 78%, p=0.01) and DFS (58% vs. 82%, p=0.005), as well as increased incidence of non-relapse mortality (NRM) (27% vs. 7%). KIR2DS1 and KIR3DS1 D+R− mismatches resulted in increased risk of grade II–IV acute GvHD, whereas KIR2DS3 and KIR2DS2 D+R− mismatches were associated with increased risk of chronic GvHD. The presence of at least one activating KIR D+R− mismatch was associated with increased CD8+/CD4+ T cell ratio up to day +100. In all cases of incompatibility regarding KIR2DS1, KIR2DS2 and KIR3DS1, T cells with expression of respective receptors could be detected up to 360 days after alloHSCT. The presence of SNP8 of the NOD2/CARD15 gene in the recipient was associated with decreased probability of OS (20% vs. 70%, p=0.005) and DFS (20% vs. 70%, p=0.01) as well as increased incidence of NRM (60% vs. 17%) and grade III–IV acute GvHD (67% vs. 8%). In a multivariate analysis including KIR and NOD2/CARD15 polymorphisms together with other potential risk factors, increasing number of D+R− activating KIR mismatches as a linear variable appeared to independently influence OS (HR: 1.3, p=0.02), DFS (HR: 1.3, p=0.008), NRM (HR: 1.4, p=0.02), grade II–IV acute GvHD (HR: 1.4, p=0.001), and chronic GvHD (HR: 1.2; p=0.02). Recipient SNP8 of NOD2/CARD15 was predictive for OS (HR: 5.5, p=0.003), DFS (HR: 4.4, p=0.008), NRM (HR: 5.9, p=0.006), grade III–IV acute GvHD (HR: 6.1, p=0.02), and chronic GvHD (HR: 3.7; p=0.03). Conclusions: Both activating KIR D+R− mismatches and recipient SNP8 of NOD2/CARD15 appear to enhance alloreactivity and independently influence survival after alloHSCT. Evaluation of these polymorphisms may contribute to better donor selection and optimization of the alloHCT procedure.

Delayed Cytomegalovirus (cmv) Infection Following Hematopoietic Cell Transplantation (HCT): City of Hope (COH) Experience.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1155-1155
Author(s):  
Alexandra Schaible ◽  
Allison Mays ◽  
Can-Lan Sun ◽  
Liton Francisco ◽  
Lennie Wong ◽  
...  
Keyword(s):  
Immunosuppressive Therapy ◽  
Chronic Gvhd ◽  
First Year ◽  
Unrelated Donor ◽  
Cmv Infection ◽  
Allogeneic Hct ◽  
Increased Risk ◽  
Related Donor ◽  
Autologous Hct ◽  
One Year

Abstract Patients undergoing HCT are at an increased risk of developing primary and/or reactivated CMV infection, although the magnitude of risk of CMV disease has decreased with the widespread use of preemptive ganciclovir. Most episodes of reactivation occur within the first year post-HCT and are associated with risk factors such as CMV serostatus of donor and recipient, development of acute graft vs. host disease (GVHD): and the immunosuppressive therapy used for its management. Because of prolonged periods of immunosuppression post-HCT, patients may be at risk for delayed CMV infection one or more years after HCT. However, the magnitude of risk of delayed CMV infection and characteristics of those at increased risk has not been described. Given the high morbidity and mortality associated with post-HCT CMV infection, identifying patients at high risk of delayed CMV could be useful for effective management. This report includes 2700 consecutive patients who survived more than one year after undergoing HCT at COH between 1976 and 2003; these included 1404 autologous HCT recipients and 1296 allogeneic HCT recipients (1043 related donor; 253 unrelated donor recipients). Median age at HCT was 38 years (range, 0.6 to 79 years) and 59% of the cohort was males. Median follow-up time from HCT until delayed CMV infection/disease, death, or end of study period (12/31/2006), whichever occurred first, was 4.3 years (range:1–26.6 years). Medical records from COH and/or outside facilities were the main source of data for CMV occurrences. In total, 33 patients (1%) developed delayed CMV infection after surviving at least one year post-HCT (1 autologous and 32 allogeneic [20 related donor and 12 unrelated donor HCT]) developed a total of 40 episodes of delayed CMV that included pneumonia (n=16), gastrointestinal disease (n=8), retinitis (n=2), hepatitis (n=1), concurrent pneumonia and hepatitis (n=1), and asymptomatic reactivation (n=12). The overall cumulative incidence of delayed CMV infection was 1.3% (95% Confidence Interval [CI], 0.9–1.8%) at 5 years from HCT. For autologous HCT recipients, the incidence was 0.07% at 1 year based on 1 event. Among allogeneic HCT recipients, the cumulative incidence at 5 years post-HCT was 2.1% [95%CI, 1.2–3.0%] for related donor HCT recipients; and 5.0% [95%CI, 2.2–7.7%] for unrelated donor HCT recipients. Among allogeneic HCT recipients, the risk factors for the development of delayed CMV infection included unrelated donor HCT (hazard ratio [HR] = 2.5, 95% CI, 1.1–5.7) and CMV seropositive status of the recipient (HR=7.7, 95% CI 1.0–57.0) (Figure). Interestingly, donor CMV status was not associated with increased risk of delayed CMV. All 32 allogeneic HCT recipients experienced chronic GVHD, with prolonged exposures to corticosteroids (median=494 days), and cyclosporine (median=380 days). Thirty patients with delayed CMV infection (94% of the allogeneic HCT recipients with delayed CMV) were receiving immunosuppressive therapy for management of chronic GVHD at onset of delayed CMV. A total of eight patients with delayed CMV did not have a history of CMV infection in the first year, and were characterized by the following clinical and demographic features: 6 (75%) were male; median age at HCT was 35 years; one was an autologous HCT recipient, who relapsed 10 months post-HCT for non-Hodgkin lymphoma, received further chemotherapy and radiation, including Rituximab and then developed late CMV, just over one year post-HCT. The seven allogeneic HCT recipients had chronic GVHD, and were CMV serostatus positive prior to HCT, with 4 also having CMV seropositive donors. Of the 33 patients with delayed CMV in this study, 26 expired; median survival after the development of delayed CMV was 46 days. This study describes the magnitude of risk of delayed CMV infection in autologous and allogeneic HCT recipients and identifies at risk patients as those who are seropositive for CMV, undergoing unrelated HCT, and those with prolonged exposures to immunosuppressive therapy for cGVHD (Figure), suggesting the need for a close surveillance of these patients at high risk. Figure Figure

scholarly journals Post-Transplant Cyclophosphamide after Matched Sibling, Unrelated and Haploidentical Donor Transplants in Patients with Acute Myeloid Leukemia, a Comparative Study of the ALWP EBMT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3274-3274
Author(s):  
Jaime Sanz ◽  
Jaques-Emmanuel Galimard ◽  
Boris V Afanasyev ◽  
Emanuele Angelucci ◽  
Fabio Ciceri ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Advisory Board ◽  
Free Survival ◽  
Increased Risk ◽  
Matched Sibling ◽  
Grade Ii

Introduction: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. Although PTCy-Haplo has been compared with different transplant platforms, there is no information on the impact of donor types using homogeneous prophylaxis with PTCy. Methods:We retrospectively analysed outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n=215), MUD (n=235) and Haplo (n=789) donors registered in the EBMT database between 2010 and 2017. The median follow up period of the entire cohort was 2 years. Results: Median age of patients was 52 years (range, 18-76), 693 (56%) were male and 928 (78%) were CMV seropositive. AML was de novo in 1,046 (84%) patients, while 47 (6%),543 (66%) and 239 (29%) had standard, intermediate and high risk cytogenetics, respectively. Peripheral blood (PB) was used as the stem cell source in 814 (66%) patients. Regarding conditioning, 962 (78%) were chemotherapy based regimens and 500 (41%) patients received reduced intensity conditioning (RIC). Preferred conditioning regimens were thiotepa, busulfan, fludarabine for Haplo (n= 371; 47%) and busulfan, fludarabine for MSD (n= 83; 39%) and MUD (n= 102; 43%). Patients received a variety of PTCy containing immune suppressive regimens, the most frequently used being PTCy, calcineurin inhibitor and mycophenolate mofetil in Haplo (n= 684; 87%) and PTCy and calcineurin inhibitor alone in MSD (n= 52; 24%) and MUD (n= 74; 31%). In-vivo T-cell depletion (TCD) was used in 164 (13%) patients. Compared to MSD and MUD, Haplo patients were older and less frequently received RIC, TCD and PB but the distribution of cytogenetic risk group was similar between the donor types. Cumulative incidence of neutrophil recovery at 60 days was 95% (95% CI 94-96). The cumulative incidence of 100 day acute GVHD grade II-IV and III-IV, and 2-year chronic and chronic extensive GVHD were 25% (95% CI 23-28), 9% (95% CI 7-10), 31% (95% CI 28-34) and 12% (95% CI 10-14), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality (NRM) and the probability of leukemia-free survival (LFS) and overall survival (OS) were 25% (95% CI 22-28), 19% (95% CI 17-21), 56% (95% CI 53-59) and 63% (95% CI 60-66), respectively. On multivariable analysis, outcomes were not significantly different for MSD and MUD. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) but the risk was not significant for chronic GVHD (HR 1.2; 95% CI 0.8-1.8). Haplo-SCT carried a higher risk of NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no change in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). The most frequent cause of death was relapse for MSD (n= 36, 53%) and MUD (n= 41, 48%) and infection for Haplo (n = 107, 39%). Interestingly, the use of PB was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). Other variables that had an impact on LFS were: poor risk cytogenetics (HR 1.4; 95% CI 1.1-1.7), use of MAC-Chemo (HR 0.7; 95% CI 0.6-0.9), Karnofski performance status <90 (HR 0.8; 95% CI 0.6-0.99), older patient age (HR 1.1 by 10 year increase; 95% CI 1.02-1.2) and CMV seropositivity of recipient (HR 1.3; 95% CI 1.0-1.6). Conclusions:The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD and Haplo is safe and effective and rates of GVHD are low, especially chronic. HLA mismatch in Haplo has a negative impact on acute GVHD and NRM in this setting but also offers increased anti-leukemic efficacy. As seen in other transplant scenarios, PB is associated with more GVHD and less relapse. Figure Disclosures Angelucci: Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

scholarly journals Utilizing Organ-Sparing Marrow Irradiation to Condition Patients Prior to Allogeneic Hematopoietic Cell Transplant with High-Risk Hematologic Malignancies: Results of a Pilot Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2856-2856
Author(s):  
Sumithira Vasu ◽  
Meghan Kromer ◽  
Qiuhong Zhao ◽  
Hannah Choe ◽  
Karilyn Larkin ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Advisory Committees ◽  
High Incidence ◽  
Grade Ii

Abstract Background: Total body irradiation (TBI) has long been incorporated as part of the conditioning regimen prior to hematopoietic stem cell transplant (HSCT). While the myeloablative TBI conditioning is associated with a lower relapse rate in high risk diseases such as Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), it is also associated with substantial toxicities, and increased NRM so use of this regimen is limited to young patients with excellent performance status. In this study, we used a linac-based volumetric modulated arc therapy (VMAT) technique to deliver standard myeloablative radiation to high risk body sites while sparing radiation sensitive organs (Organ Sparing Marrow Targeted Irradiation, OSMI). We hypothesized that this technique would be feasible and safe in patients who are older or who have higher transplant specific comorbidity index (HCT-CI), typically ineligible for standard TBI conditioning. Methods: This is a single-arm prospective study. Patients from age 18-75 with high risk AML, MDS or ALL were eligible. There are 3 cohorts: (1) age 18-50 with HCT-CI of 3/4; (2) age 51-65 with HCT-CI of ≤ 3; and (3) age 66-75 with HCT-CI of ≤ 2. Patients receive OSMI to a total dose of 1200 cGy delivered twice daily for 6 fractions for a total of 7200 cGy. Clinical tumor volume includes total skeletal bone marrow and any sanctuary or high-risk areas. Graft-versus-host disease (GVHD) prophylaxis originally was tacrolimus and methotrexate. Given high incidence of bacterial infections related to mucositis, prophylaxis was changed to tacrolimus and sirolimus without methotrexate. All patients received Keratinocyte growth factor for prevention of mucositis. The primary objective was to assess feasibility and tolerability of OSMI based HSCT as defined by transplant-related mortality (TRM) at day 30 (D30) as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. Results: Patient demographics for the 24 patients are shown in Table 1. Median age of recipients was 56.5 years. No graft failures were observed. The most common grade II or III Bearman toxicities include mucositis (grade 2: n=4), and diarrhea (grade 2: n=4). Clinical outcomes are shown in Figure 2. With a median follow-up of 3.3 years, overall survival (OS) and relapse-free survival (RFS) at 2 years was 78% and 74% respectively. Among the 5 patients who were not in complete remission at the time of transplant, 2-year OS and RFS rate was 40%. Incidence of Grades II-IV acute GVHD was 79% and Grades III-IV GVHD was 30%. Relapse incidence was 4% at 2 years. Incidence of Thrombotic microangiopathy by day 100 (TMA) as defined by Jodele's criteria was 17%. Incidence of chronic GVHD was 45% and severe chronic GVHD was 16%. One year non-relapse mortality was 22%, likely due to higher incidence of GVHD. Conclusions: Selected patients who are older or with higher HCT-CI, who are typically not candidates for standard TBI conditioning, were able to receive a radiation-based myeloablative conditioning regimen with 2 year overall survival rates of 78%. We observed a high incidence of TMA, possibly related to use of tacrolimus and sirolimus as GVHD prophylaxis, and a high incidence of Grade II-IV acute GVHD. Low incidence of relapse was observed. OSMI-based conditioning was feasible in this cohort with median age of 56 years and was associated with low rates of relapse and favorable 2 year overall survival. Figure 1 Figure 1. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

Gemtuzumab Ozogamicin (GO) and Continuous Infusion Cytarabine (ARA-C) for Relapsed/Refractory Acute Myeloid Leukemia (AML) Prior to Allogeneic Stem Cell Transplantation (SCT).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 952-952
Author(s):  
Amer Zeidan ◽  
Wei Tan ◽  
Gregory Wilding ◽  
LaurieAnn Ford ◽  
Theresa Hahn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Continuous Infusion ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Bone Marrow Aspiration ◽  
Infectious Complications ◽  
Unrelated Donor ◽  
Increased Risk ◽  
Unrelated Donors ◽  
Refractory Aml

Abstract The question whether to re-induce AML patients (pts) in first or subsequent relapse to reduce leukemia disease burden prior to SCT is not well studied. Several groups reported a 28–30% disease-free survival rate at five years for matched related donor SCT in first relapse without re-induction. Finally, re-induction regimen choices prior to SCT are relatively limited. Specifically, GO-containing regimens have been suspected to be associated with increased incidence of liver sinusoidal occlusive syndrome (SOS) when used prior to SCT. We evaluated our institutional experience of using GO and ARA-C for relapsed/refractory CD33-positive AML pts prior to allogeneic SCT. A total of 18 pts (median age 45.4 years; range 28–66) with relapsed/refractory AML were treated with GO/ARA-C. The median initial complete remission duration was 4.4 (range 0.5–14.5) months. The median time from relapse to GO/ ARA-C was 57 (range 6–142) days. Pts received GO (6 mg/m2 on day 1, 4 mg/m2 on day 8) and continuous infusion ARA-C (100 mg/m2) daily for 7 days. Bone marrow aspiration and biopsy were performed at a median of 15 (range 11–39) days post induction (one pt had >20% peripheral blasts on day 14 and therefore did not undergo bone marrow aspiration and biopsy). Three (17%) pts developed infectious complications following re-induction and one pt had disease progression that prevented them from undergoing bone marrow aspiration and biopsy and continuing on to SCT. Marrow aplasia (defined as <5% blasts and <20% cellularity) was reached in six of 14 (43%) evaluable pts. Three pts (all without achieving marrow aplasia) developed infectious complications that precluded SCT. A total of 11 pts proceeded onto SCT at a median of 30 (range 21–73) days after re-induction, including six pts who achieved marrow aplasia and five who did not. Six pts underwent matched unrelated donor SCT (two were mismatched at one allele) and five received matched sibling SCT. Reduced intensity preparatory regimens (fludarabine/melphalan) were used in all but one pt who received a fully myeloablative regimen (busulfan/cyclophosphamide). Engraftment to absolute neutrophil count ≥0.5x109/L for three days was achieved in all 11 pts at a median of 15 (range 9–21) days. During SCT, all pts were treated with prophylactic enoxaparin 40 mg subcutaneously once daily to prevent SOS of the liver. The two pts with mismatched unrelated donor SCT died three and nine days after achieving count recovery from pulmonary infiltrates and severe graft versus host disease (GVHD), respectively. Acute GVHD grade II-IV developed in six of the pts with matched donors (three related and three unrelated donors). Chronic GVHD developed in four (one related and three unrelated donors) of the pts. None developed liver SOS. Four pts are alive from starting GO/ARA-C at a median of 7.2 (range 1.2–52.7) months; two of them with and two of them without GVHD. Marrow aplasia prior to SCT was achieved in two of them. In summary, the question of whether to re-induce pts with relapsed/refractory AML to reduce leukemia burden prior to allogeneic SCT remains controversial. However, if one chooses to proceed with re-induction, then the combination of GO/ARA-C represents a feasible re-induction strategy with acceptable toxicity, achievement of marrow aplasia in approximately half of evaluable pts, and no increased risk of liver SOS in the setting of enoxaparin prophylaxis and low intensity conditioning regimens.

Graft-Versus-Host Disease (GVHD) and Survival Outcomes after HLA-Haploidentical (Haplo) Bone Marrow Transplant (BMT) Compare Favorably with Matched Related Donor (MRD), and Matched Unrelated Donor (MUD) BMT Utilizing High-Dose Posttransplantation Cyclophosphamide (PTCy)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 730-730 ◽  
Author(s):  
Shannon R. McCurdy ◽  
Christopher G. Kanakry ◽  
Yvette L. Kasamon ◽  
Javier Bolanos Meade ◽  
Hua-Ling Tsai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Chronic Gvhd ◽  
Lower Probability ◽  
Survival Outcomes ◽  
High Dose ◽  
Grade Ii ◽  
The Impact ◽  
Grade Iii

Abstract Background: High-dose PTCy has been shown to effectively reduce acute (a) and chronic (c) GVHD after MRD and MUD BMT and to enable the safe implementation of haplo BMT. However, GVHD-related risk factors and survival outcomes, the impact of donor type, and novel composite endpoints, such as cGVHD-free relapse-free survival (cGFRFS), have not been fully characterized in BMT with PTCy. Methods: We retrospectively analyzed 582 consecutive adult pts with advanced or poor-risk hematologic malignancies who received allogeneic BMT with PTCy at Johns Hopkins from 2002-2012. All pts received a T-cell replete bone marrow graft and PTCy (50 mg/kg/d IV) on D+3 and +4. Platforms consisted of: 1) myeloablative conditioning (MAC) with Busulfan/Fludarabine or Busulfan/Cy followed by MRD (n = 193; 33%) or MUD (n=119; 20%) allografting and PTCy as sole GVHD prophylaxis; or 2) nonmyeloablative (NMA) conditioning with Fludarabine/Cy/TBI followed by related haplo (n = 270; 46%) allografting and PTCy, mycophenolate mofetil D5-35, and tacrolimus D5-180. Results: The median follow up was 4 (range 0.3-11.4) years (y). The median pt age at time of BMT was 49 (range 18-66) in the MAC cohort and 54 (range 18-73) in the NMA cohort. On competing risk analysis, the D200 probability of grade II-IV aGVHD was 27% after haplo, 37% after MRD, and 50% after MUD BMT, and grade III-IV aGVHD was 4%, 11%, and 14% respectively. The 3-y probability of cGVHD was 12% after haplo, 8% after MRD, and 19% after MUD BMT. On multivariate analysis adjusted for age and original disease risk index (DRI), MRD and MUD BMT were associated with a statistically significantly higher risk of grade II-IV and grade III-IV aGVHD compared to haplo BMT (each p ≤ 0.001). Compared to haplo BMT, MUD, but not MRD, BMT was also associated with a significantly higher risk of cGVHD (p = 0.009). On multivariate analysis, female into male allografting was independently associated with a higher risk of cGVHD (p = 0.007), whereas age and CMV serostatus of the pt and donor were not statistically significantly associated with risks of acute or chronic GVHD. Pts with grade II-IV aGVHD or cGVHD had a lower probability of relapse, but a higher probability of nonrelapse mortality (NRM) at 3 y compared to pts without GVHD. Among pts with GVHD, an HCT-CI score ≥ 5 was associated with significantly inferior overall survival compared to lower HCT-CI scores. Although MAC matched BMT was associated with less relapse risk than NMA haplo BMT, the 3-y probabilities of NRM, DFS, and overall survival were comparable between the transplant platforms (Table). On multivariate analysis adjusted for pt age and DRI, there were no statistically significant differences in DFS, OS, or cGFRFS in MAC related or unrelated BMT compared to NMA haplo BMT. Conclusions: High-dose PTCy safely modulates acute and chronic GVHD across multiple BMT platforms. The apparently lower risk of aGVHD after NMA haplo BMT with PTCy likely reflects the reduced conditioning intensity and longer duration of immunosuppression utilized. Despite the limitations inherent to a retrospective analysis, these data suggest that key outcomes after BMT with PTCy are comparable across donor types and conditioning intensities. Notably, in all these settings, 3-y estimates of cGFRFS appeared to approach those of DFS. Thus, PTCy may minimize the late morbidity and mortality of cGVHD and allow earlier implementation of novel posttransplantation strategies for relapse prevention. TableOutcomes of BMT with PTCy3-y probabilitiesNMA HaploMAC MRD*MAC MUD*NRM141717DFS384144OS495856cGFRFS313533 * p = NS for all comparisons to haplo BMT on multivariate analysis Disclosures Off Label Use: High-dose posttransplantation cyclophosphamide.

Sarcomas of nasal cavity and paranasal sinuses: chondrosarcoma, osteosarcoma and fibrosarcoma

1994 ◽  
Vol 108 (11) ◽  
pp. 947-953 ◽  
Author(s):  
V. Koka ◽  
R. Vericel ◽  
E. Lartigau ◽  
A. Lusinchi ◽  
G. Schwaab
Keyword(s):  
Overall Survival ◽  
Nasal Cavity ◽  
Paranasal Sinuses ◽  
Primary Tumour ◽  
Local Failure ◽  
Distant Failure ◽  
Increased Risk ◽  
Grade Ii ◽  
Male Sex ◽  
Grade Iii

AbstractForty-two patients were treated for sarcoma of the nasal cavity and paranasal sinuses at the Institut Gustave Roussy, Paris, between 1960 and 1993. Twelve patients had chondrosarcoma (CS), 14 had osteosarcoma (OS) and 16 had fibrosarcoma (FS). Ten patients had grade I, six grade II and 26 grade HI tumours.All but 10 patients had surgery for the primary tumour. A significantly increased risk of local failure was associated with the male sex (p <0.01), grade III tumours (p <0.02) and patients excluded from surgery (p <0.04). The overall incidence of local and distant failure was 76 and 12 per cent respectively. Overall survival was 28 per cent at three years and 23 per cent at five years. Eight patients (20 per cent) were alive more than 10 years later. The factors significantly influencing survival were sex (p <0.01), grade (p <0.05) and local failure (p<0.01).

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