Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia (AML) with Complex Karyotypes (CK): A Retrospective Study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) and MD Anderson Cancer Center (MDACC)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3479-3479
Author(s):  
Stefan O. Ciurea ◽  
Myriam Labopin ◽  
Emmanuelle Polge ◽  
Piyanuch Kongtim ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Prognostic Factors ◽  
Relapse Rate ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Secondary Aml ◽  
Equity Ownership ◽  
Active Disease

Abstract Introduction CK AML patients have high relapse rate and poor outcomes when treated with conventional chemotherapy. Allogeneic hematopoietic stem cell transplantation (AHSCT) may cure this disease; however, relapse rate remains a major limitation and survival is one of the worst amongst AML patients. Here we aimed to identify prognostic factors associated with survival in patients with AML and CK using combined data from the EBMT and MDACC. Methods A total 1,342 consecutively transplanted patients with CK (>3 cytogenetic abnormalities) AML reported to EBMT (N=1,118) and at MDACC (N=224) between 01/2000-12/2015 were included.The median age was 52 years (range 18-76 years), 335 patients (25%) were older than 60 years. Seven hundred and twenty-nine patients (54.3%) were male, 239 patients (17.8%) had secondary AML. Disease status before transplant was CR1, CR2 and activediseasein 877 (65.3%), 77 (5.7%) and 388 (29%), respectively. Donors were matched related (MRD), matched unrelated (MUD) and mismatched unrelated (MMUD) in 749 (55.8%), 513 (38.2%) and 80 (6%), respectively. Conditioning regimens were various, mostly eitherbusulfan-based (53.7%) or TBI-based (26.7%). Seven hundred and thirty-nine patients (55%) and 603 patients (45%) receivedmyeloablativeconditioning (MAC) and reduced intensity conditioning (RIC), respectively. The main stem cell source was peripheral blood (81%). In vivo T-cell depleted (TCD) methods were used in 665 patients (50%). Median time from diagnosis to transplant was 5.1 months (range 2-387 months) while the median follow-up duration was 35.5 months (range 8-174 months). Results Engraftment occurred in 96.3%, 69.7% and 30.3% had full and mixed donorchimerism, respectively. At 2 year post-transplant, the cumulative incidence (CI) of acute GVHD grade II-IV and grade III-IV was 26.3% and 8.4%, respectively, whereas CI of chronic GVHD was 30.9% with extensive chronic GVHD 17.8%. Leukemia free survival (LFS), overall survival (OS), CI of relapse, non-relapse mortality (NRM) at 2 years for the whole group was 31.3%, 36.8%, 51.1% and 17.6%, respectively, while 2-year GVHD-free, relapse-free survival (GRFS) was 19.8%. LFS, OS, GRFS, CI of relapse and NRM at 2 years for patients transplanted in CR1 was 38.4%, 44.5%, 23.8%, 46% and 15.7%, respectively. For patients with active disease these outcomes were 14.6%, 18.5%, 9.6%, 63.5% and 21.9%, respectively (Figure A, B). Patients ages 40-60 years transplanted in CR1 with MAC demonstrated lower relapse (40.2% vs. 51% with RIC, p=0.005), offset by a higher NRM (18.2% vs 9.8% RIC, p=0.037), associated with higher incidence of acute GVHD, and a non-significant difference in LFS (Figure C, D). In multivariable analysis (MVA) for the entire group, advanced age, transplantation in active disease, secondary AML and presence of deletion or monosomy 5 or 7 predicted poor LFS and OS. All of these factors as well as year of transplant (before 2010) also predicted poor GRFS, while conditioning intensity (MAC vs RIC) and donor type did not influence survival outcomes. Prognostic factors for relapse were age, secondary AML, active disease at transplant and presence of deletion or monosomy 5, while prognostic factors for NRM were older age, active disease, use of a mismatched unrelated donor and deletion or monosomy 7. Conclusions In this largest analysis of complex karyotypes AML patients, relapse remains the most common cause of treatment failure with 45% for patients in CR1 and 63.5% for patients not in remission relapsing after transplant. The only modifiable factorsat this time are performing transplantation in CR1 as soon as the donor is available. Control of GVHD might allow younger patients receiving MAC to have a lower NRM and improved LFS. Novel approaches are needed to decrease relapse rate and improve survival in these patients. Table Multivariable analysis for patients with CK AML. Table. Multivariable analysis for patients with CK AML. Figure A. CI of relapse for all patients and patients in CR; B. LFS for all patients and patients in CR; C. CI of relapse for patients age 40-60 years in CR with MAC, RIC; D. LFS for patients age 40-60 years in CR with MAC, RIC. Figure. A. CI of relapse for all patients and patients in CR; B. LFS for all patients and patients in CR; C. CI of relapse for patients age 40-60 years in CR with MAC, RIC; D. LFS for patients age 40-60 years in CR with MAC, RIC. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Patients Aged 65 Years or Older with AML and MDS.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2301-2301 ◽  
Author(s):  
Marcos de Lima ◽  
Munir Shahjahan ◽  
Jorge Alamo ◽  
Patricia Williams ◽  
Brigitte von Wolff ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Stem Cell Source ◽  
One Year ◽  
Active Disease

Abstract Allogeneic HSCT is a potentially curative treatment for AML/MDS, but aging is generally associated with poorer outcomes. The incidence of AML/MDS, however, increases after the 7th decade of life, and there is limited data with transplantation in this age group. Here we review our experience treating such patients. Methods: Retrospective analysis of outcomes of patients aged 65 or older treated from 1996 to 2004 with allogeneic HSCT (n=40; median age 67 years, range 65–75 years). Diagnosis was MDS in 5 cases and AML in 35 patients. Cytogenetics were high-risk in 50% and intermediate risk in 50%; 80% of the patients had active disease at HSCT (n=32). All preparative regimens contained fludarabine 100–150 mg/m2, combined with cytarabine 4 gm/m2, and idarubicin 36 mg/m2 (n=12); or with busulfan (n=8); with melphalan 140 or 180 mg/m2 (n=12); and with melphalan 140 mg/m2 and Mylotarg 2 or 4 mg/m2 (n=8). ATG was added in unrelated donor (MUD) HSCT. All but 2 patients received tacrolimus and methotrexate for graft-versus host disease (GVHD) prophylaxis. Stem cell source was bone marrow in 11 cases and peripheral blood in the others. Donors were related in 27 cases and unrelated in 13 cases (33%). Results: 35 patients engrafted (88%); complete remission (CR) rate was 72%, 6 patients died early and 3 did not respond. Eleven patients are alive at a median of 12.5 mo (range, 2.6–59 mo), 10 of them in CR. One-year overall survival was 30% for the whole group, 26% for recipients of MUD and 32% for recipients of related donor HSCT (MUD x sibling, P=NS). One-year event-free survival was 28%. Median survival and disease-free survival was 4.5 and 2.5 mo, respectively; 42% of the patients in CR post HSCT have relapsed (n=13). Acute and chronic GVHD rates were 45% and 48%, respectively. Non-relapse mortality (NRM) was 40%. Figure shows survival of patients with and without circulating blasts at the time of transplant. Figure shows survival of patients with and without circulating blasts at the time of transplant. Conclusions: Here we expanded our previous observations indicating that allogeneic HSCT is a treatment option for selected patients in this age range. In this cohort with advanced stage disease (80% with active disease at transplant), NRM was high, but survival after sibling and unrelated donor transplants was similar.

scholarly journals Prognostic Factors on the Graft-versus-Host Disease-Free and Relapse-Free Survival after Adult Allogeneic Hematopoietic Stem Cell Transplantation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Yao-Chung Liu ◽  
Sheng-Hsuan Chien ◽  
Nai-Wen Fan ◽  
Ming-Hung Hu ◽  
Jyh-Pyng Gau ◽  
...  
Keyword(s):  
Stem Cell ◽  
Prognostic Factors ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Hematologic Malignancy ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host ◽  
Disease Free

The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including graft-versus-host disease (GVHD), relapse, and death. A novel composite endpoint of GVHD-free/relapse-free survival (GRFS) in which events include grades 3-4 acute GVHD, chronic GVHD requiring systemic therapy, relapse, or death is censored to completely characterize the survival without mortality or ongoing morbidity. In this regard, studies attempting to identify the prognostic factors of GRFS are quite scarce. Thus, we reviewed 377 adult patients undergoing allogeneic HSCT between 2003 and 2013. The 1- and 2-year GRFS were 40.8% and 36.5%, respectively, significantly worse than overall survival and disease-free survival (log-rankp<0.001). European Group for Blood and Marrow Transplantation (EBMT) risk score > 2 (p<0.001) and hematologic malignancy (p=0.033) were poor prognostic factors for 1-year GRFS. For 2-year GRFS, EBMT risk score > 2 (p<0.001), being male (p=0.028), and hematologic malignancy (p=0.010) were significant for poor outcome. The events between 1-year GRFS and 2-year GRFS predominantly increased in relapsed patients. With prognostic factors of GRFS, we could evaluate the probability of real recovery following HSCT without ongoing morbidity.

Allogeneic Stem Cell Transplantation for Relapsed Follicular Non-Hodgkin’s Lymphoma: Single Centre Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5054-5054
Author(s):  
Amir Peyman ◽  
Stephen Couban ◽  
Kara Thompson ◽  
Louis Fernandez ◽  
Donna L. Forrest ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Follicular Lymphoma ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Grade 3

Abstract Between 1993 and 2005, 57 patients with follicular lymphoma underwent high-dose chemo/radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), 49 Allogeneic, (16 Bone Marrow and 33 Peripheral Blood), 6 MIN, 2 MUD. Median age was 47 years. Median days to neutrophil and platelet engraftment after HSCT were 18 and 13 days respectively. Twenty-five patients experienced Acute GVHD and thirty-four had Chronic GVHD (12 mild and 22 extensive). Thirty-three patients were in grade 1, 17 in grade 2, 4 in grade 3 and 3 grade 4. As of their FLIPI score, 4, 14, 21 and 18 patients were calculated to have score of 0, 1, 2 and 3 respectively. Forty-one patients are alive. Two patients have relapsed, one a year and the other two years after HSCT. The 5 year survival was 71.9% (95% CI 57.5–82.2%) and 5 year survival was 67.2% (95% CI 52.3–78.5%). Transplant related mortality rate (TRM) in 5 year was 22.4% (95% CI 63.6–86.8%). No significant differences was found among FLIPI groups 0,1,2 and 3 in terms of overall, relapse-free survival, TRM Allogeneic HSCT for patients with progressive follicular lymphoma is feasible and may result in prolonged disease-free survival.

IL10-592 CC Genotype In the Donor Is Associated with a Significant Decrease of Relapse Rate and a Significant Increase of Event-Free Survival and Overall Survival After Allogeneic Hematopoietic Stem Cell Transplantation In Children with Hematological Malignancies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4459-4459
Author(s):  
Bernd Gruhn ◽  
Janine Voigt ◽  
Nadine Pfaffendorf-Regler ◽  
Ilona Wolff ◽  
Felix Zintl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Event Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Il10 Gene

Abstract Abstract 4459 IL10 is a pivotal immunomodulatory cytokine and is usually regarded as a suppressor of the immune responses. However, IL10 has been shown to have some immunostimulatory effects. The IL10-592 CC genotype is associated wit higher production of IL10. Because IL10 may promote the development of alloimmunity we hypothesized that the IL10-592 CC genotype in the donor reduces the risk of relapse after hematopoietic stem cell transplantation (HSCT). A cohort of 211 children (median age, 12 years) with acute lymphoblastic leukemia (n=100), acute myeloid leukemia (n=62), myelodysplastic syndrome (n=30) or chronic myeloid leukemia (n=19) who underwent allogeneic bone marrow (n=153) or peripheral blood stem cell transplantation (n=58; T-cell depleted: n=26) in a single center and/or their respective donors was genotyped of IL10 gene for rs1800872 using TaqMan real-time polymerase chain reaction. The donor was HLA-matched unrelated in 48% of transplants and HLA-identical related in 42% of transplants. Conditioning regimen was myeloablative in all cases. Two forms of post-transplant immunosuppression predominated, cyclosporine A and methotrexate in 69% of transplants and cyclosporine A alone in 17% of transplants. Cell samples from the donor were available in 174 cases and from the patient in 197 cases. The IL10-592 CC genotype was present in 82 of the 174 donors (47.1%) and in 104 of the 197 patients (52.8%). Interestingly, we found a significantly reduced incidence of relapse in patients who were transplanted from a donor with the IL10-592 CC genotype (15.9% versus 30.4%; p=0.016). In addition, we observed a significant increase of event-free survival (52.4% versus 33.7%; p=0.019) and a significant increase of overall survival (54.9% versus 37.0%; p=0.040) if the IL10-592 CC genotype was present in the donor. The occurrence of the IL10-592 CC genotype, in either donors or recipients, had no significant impact on treatment related mortality, acute and chronic graft-versus host disease. In conclusion, IL10-592 CC genotype in the donor is associated with a significant decrease of relapse rate and a significant increase of event-free survival and overall survival after HSCT in children with hematological malignancies. This is the first study to describe an association of IL10 gene polymorphism with relapse rate after HSCT. Selecting a donor with the IL10-592 CC genotype could be a useful therapeutic strategy for improving the final outcome after allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

A Novel Chemotherapy-Based Allogeneic Hematopoietic Stem Cell Transplant Regimen for Very Young Children with Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3149-3149
Author(s):  
Susan E. Prockop ◽  
Nancy A. Kernan ◽  
Elizabeth G Klein ◽  
Rachel Kobos ◽  
Andromachi Scaradavou ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Young Children ◽  
Cord Blood ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant

Abstract Abstract 3149 Young children in need of allogeneic hematopoietic stem cell transplant (HSCT) are at increased risk of unacceptable side effects from total body irradiation (TBI) and have historically been considered candidates for non-TBI containing regimens. However, disease free survival (DFS) has been poorer in cohorts of very young patients transplanted without TBI and novel chemotherapy based regimens are needed. We report results in a cohort of 14 children all under three years of age at the time of transplant (6 – 32 months; median 19.8 months) using a clofarabine-based ablative regimen. Fourteen patients in this age group have undergone transplant with a regimen consisting of clofarabine 20 mg/m2/day × 5, thiotepa 10 mg/Kg/day × 1 and melphalan 70 mg/m2/day × 2. All patients had high risk disease. Seven (7) pts were transplanted for ALL, 6 for AML and 1 for JMML. Patients with ALL or AML in first remission (CR1) or CR2, were categorized as patients with good risk disease while all other pts were considered as poor risk irrespective of all other factors. Transplant risk was good for 6/7 with ALL, and 3/6 with AML. The patient with JMML had stable disease. Stem cell grafts consisted of unmodified bone marrow (BMT) (N=6), double cord blood (dCBT) (N=7) and T cell depleted PBSCT (N=1). Donors were matched unrelated (N=5) or mismatched unrelated (N=9) including 7 double umbilical cord blood grafts, and one T cell depleted graft. Graft versus host disease (GvHD) prophylaxis was with tacrolimus and methotrexate for unmodified BMT, tacrolimus and mycophenolate for dCBT or T cell depleted HSCT. Two patients died early post transplant of infection (1) and acute GvHD (1). Neutrophil engraftment for the 13 evaluable patients was at a median of 13 days (10 –29 days) for PBSC and BM grafts and 17.5 days (12 –23 days) for recipients of CB grafts. Platelet engraftment for the 12 evaluable patients was at a median of 23 days (16 – 36 days) for recipients of PBSC and BM grafts and 43.5 days (36 –66 days) for recipients of CB grafts. In all five patients developed grade II-IV GvHD, and two patients chronic GvHD. Seven patients developed transaminitis which resolved in all cases. No patients developed Grade IV mucositis. One patient (AML) died after relapsing 5.5 months post transplant. Two patients are alive after relapsing at 1.3 months (AML) and 10.8 months (JMML) post-transplant. Nine of the 14 patients are alive in continuous complete remission seven of whom are greater than 36 months from transplant (40.2 – 71 months). The seven patients without chronic GvHD have had robust immune reconstitution, have responded to vaccination, and continue to meet growth and developmental milestones. Only one patient (transplanted at 14 months of age) has mild neurocognitive deficits. This novel chemotherapy based regimen is associated with durable engraftment of unmodified and cord blood HSCT grafts and promising disease free survival in very young children with leukemia. Based on the low toxicity profile in this cohort of patients higher dosing of clofarabine will be explored as a possible way to improve leukemia remission in the highest risk patients. Disclosures: Off Label Use: Clofarabine.

Allogeneic Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia in Remission: Comparison of Intravenous Busulfan Plus Cyclophosphamide (Cy) Versus Total-Body Irradiation Plus Cy As Conditioning Regimen—A Report From the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

2013 ◽  
Vol 31 (28) ◽  
pp. 3549-3556 ◽  
Author(s):  
Arnon Nagler ◽  
Vanderson Rocha ◽  
Myriam Labopin ◽  
Ali Unal ◽  
Tarek Ben Othman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Total Body Irradiation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Multivariable Analysis ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Total Body

Purpose Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable bioavailability and a safer toxicity profile than the oral formulation. Comparative studies of outcomes have been performed between oral Bu/Cy and Cy/TBI, but there have been no comparative trials in the era of IV Bu. Patients and Methods We performed a retrospective registry-based study comparing outcomes of patients with AML in first or second remission after alloSCT from sibling donors who underwent IV Bu/Cy (n = 795) or Cy/TBI (n = 864) conditioning. Results Engraftment rate was 98% and 99% after IV Bu/Cy and Cy/TBI, respectively. Grade 2 to 4 acute graft-versus-host disease (GVHD) was significantly lower in the IV Bu/Cy compared with Cy/TBI group (P < .001). Similarly, chronic GVHD was significantly lower in the IV Bu/Cy compared with Cy/TBI group (P = .003). Cumulative incidence of 2-year nonrelapse mortality (NRM; ± standard deviation [SD]) was 12% ± 1% in the IV Bu/Cy group and 15% ± 2% in the Cy/TBI group (P = .14), and 2-year relapse incidence (RI; ± SD) was 26% ± 3% and 21% ± 1%, respectively (P = .012). Leukemia-free survival (LFS) rate (± SD) was 61% ± 2% after IV Bu/Cy and 64% ± 2% after Cy/TBI (P = .27). In multivariable analysis, adjusting for differences between both groups, patients who received IV Bu/Cy had lower acute and chronic GVHD, higher RI, and a trend toward lower NRM. LFS was not statistically different between the two conditioning regimens. Conclusion This retrospective study shows that final outcomes after myeloablative conditioning using IV Bu/Cy were not statistically different from those after Cy/TBI.

scholarly journals High Resolution Donor/Recipient HLA Matching Level in Unrelated Hematopoietic Stem Cell Transplantation and Impact on the Transplant Outcome: The Italian Experience on Behalf of GITMO, IBMDR and Aibt

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4642-4642
Author(s):  
Alessandra Picardi ◽  
Nicoletta Sacchi ◽  
Valeria Miotti ◽  
Francesca Lorentino ◽  
Elena Oldani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hla Matching ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Grade 3 ◽  
Italian Origin ◽  
Advisory Role

Abstract Introduction: HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). To elucidate the effect and the potential identification of "permissive" and "non permissive" I and II class HLA mismatching (mm) loci on the early and long term transplant outcome, we conducted a retrospective/prospective observational analysis on 1789 patients transplanted with unmanipulated haematopoietic stem cells from a volunteer unrelated donor (URD). Methods Between January 2012 to December 2015, 1789 adult patients with a median age of 49 years (18-70) affected by haematological malignant diseases, performed an unrelated HSCT, coordinated by the Italian Bone Marrow Donor Registry (IBMDR). All patients have been typed by high resolution (HR) HLA typing for HLA-A/B/C/DRB1/DQB1 loci, at the start of the donor's search process. Patient and donor characteristics are shown in Table 1. As conditioning regimen and GVHD prophylaxis, 71% of patients received a myeloablative conditioning and 76% a combination of anti-Thymoglobuline, Cyclosporine and Metotrexate short course. Total Body Irradiation was part of conditioning regimen in 14% of cases and PBSC was used as stem cell source in 80% of transplants. Median follow for survivors was 38 months (1-76). Regarding to the allelic compatibility, 890 (50%) of donor/recipient (D/R) pairs were 10/10 HLA matched, 677 (38%) showed 1 mm for A, B, C, DRB1 or DQB1 in 249, 141, 173, 2 and 112 cases, respectively and 222 (12%) received HSCT from a 8/10 or less HLA matched donor. Results: Overall 90% and 79% of patients achieved PMN and PLTS engraftment within 30 and 90 days, respectively. Probabilities of 3-y Overall Survival (3-yr OS), Progression Free Survival (3-yr PFS), and Graft Relapse Free Survival (3-yr GRFS) were 52%, 42%, and 30%, respectively. The 3-y CI of Transplant Related Mortality (TRM) was 26%, with a 100-days CI of acute GVHD ≥2 of 26%, whereas the 3-yr CI of chronic GVHD was 30%, of which 10% extensive. Cox multivariate analysis showed that, compared to 10/10 HLA-matched HSCT, 9/10 and ≤8/10 HLA-matched HSCT were associated with worse outcomes in terms of OS (HR 1.16, p=0.04 and HR 1.3, p=0.007, respectively), GRFS (HR 1.2, p=0.005 and HR 1.2, p=0.07, respectively), TRM (HR 1.3, p=0.007 and HR 1.6, p<0.0001, respectively), grade 3-4 aGVHD (HR 1.8, p=0.0001 and HR 1.8, p=0.01, respectively) and cGvHD (HR 1.3, p=0.005 and HR 1.1, p=0.35, respectively). Notably, no significant differences occurred through the comparison between ≤8/10 and 9/10 matching. Univariate comparisons are shown in Figure 1. Moreover, in order to identify permissive and non permissive allelic mismatching, we analyzed the donor/recipient pairs with a single HLA mm with a frequency > 5%: the presence of A02:01 in the patient's HLA, after adjustment for HLA matching at the other loci and other clinical variables known to affect HSCT outcome, was associated with significant higher risk of TRM (HR 1.9, p= 0.03) and worst OS (HR 1.7, p=0.04). Patient's age > 49 years (p<0.0001), advanced disease stage (p<0.0001), presence of 1 or more co- morbidity according to the Sorror Hematopoietic Cell Transplant-Comorbidity Index (p=0.01) were associated with a hazard risk of 1.4, 2, 1.2 for OS and 1.6, 1.75, 1.4 for TRM. Moreover, the Italian origin of recipient and donor resulted in reduced grade 2-4 acute (HR=0.6, p=0.001) and chronic GVHD (p=0.002, HR=0.4). Finally, the Transplant Program expertise (>10 HSCT/year) is associated with reduced TRM (HR 0.8, p=0.0001), HSCT from female donor to male recipient was associated with higher risk of extensive cGvHD (HR 1.4, p=0.03), and CMV negative/negative status versus other combinations had protective effect on development of grade 3-4 aGVHD (HR 0.56, p=0.04). Conclusions: Our large cohort data of homogeneously treated 1789 URD transplants, show that 10/10 HLA matching remains a significantly favorable prognostic factor for OS, TRM, GRFS and acute/chronic GVHD, whereas there are no significant differences between 8/10 and 9/10 matching transplants. Moreover, the HLA A02:01 as single mm seems to play a "non permissive" role. Finally the Italian origin of recipient and donor is related to a reduced development of GVHD probably due to the matching of the extended MHC haplotypes in individuals of the same geographic origin. Disclosures Rambaldi: Amgen Inc.: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Omeros: Consultancy; Roche: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy. Vago:Moderna TX: Research Funding; GENDX: Research Funding. Patriarca:Janssen: Other: Advisory role; Jazz: Other: Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; MSD Italy: Other: Advisory Role.

scholarly journals The 17-Gene Leukemic Stemess Score Can Predict Treatment Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3299-3299
Author(s):  
Dennis Dong Hwan Kim ◽  
Taehyung Kim ◽  
Tracy Murphy ◽  
Steven M Chan ◽  
Mark D. Minden ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hct ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

Introduction: A 17-gene stemness score (LSC17 score) had been reported to determine the risk of therapy resistance in acute myeloid leukemia (Nature 2016), and this was replicated successfully in 5 independent cohorts (n=908). When the patients were stratified according to the median value of the LSC17 score, allogeneic hematopoietic stem cell transplantation (HCT) did not affect overall survival (OS) from initial diagnosis for either high- or low-score patients (p=0.2 for high and p=0.06 for low LSC17 score groups). In the present study, we aimed to further perform a subgroup analysis confined to the patients receiving allogeneic HCT and determine whether the LSC17 score at leukemia diagnosis was associated with treatment outcomes including OS, leukemia-free survival (LFS), non-relapse mortality (NRM), relapse incidence (RI), and acute/chronic GVHD following allogeneic HCT. Methods and patients: Out of 452 patients with available LSC17 scores, 123 patients were included into the final analysis who received allogeneic HCT using matched (n=104, 84.6%) or mismatched/haploidentical donors (n=19, 15.4%). 80 patients were from the previous study (Nature 2016), while 43 patients were a prospectively accrued cohort during 2016-2018. Patients and transplant characteristics were: male/female (n=61/62); median age, 51 (17-73); CR status prior to HCT, CR1 (n=93, 75.6%), CR2 (n=30, 24.4%); Conditioning regimen, reduced intensity/myeloablative conditioning (n=59, 48.0% vs n=64, 52.0%); GVHD prophylaxis using post-transplant cyclophosphamide (PTCy; n=45, 36.6%) or T cell depletion (n=62, 50.4%); Cytogenetic risk, favorable (n=10, 8.1%), intermediate (n=70, 56.9%), adverse (n=26, 21.1%), inconclusive or not done (n=17, 13.8%). The LSC17 score for each patient was measured in a diagnostic sample using a NanoString assay and compared to the high/low threshold of a reference AML cohort (Ng et al, Nature 2016 and unpublished data). Transplant outcomes were compared according to the LSC17 risk group for OS, LFS, NRM and RI. Univariate and multivariate analyses were conducted for OS and LFS using Cox's proportional hazard model or for NRM and RI using Fine-Gray model, respectively. The following variables were included in the model: the LSC17 score group (high vs low LSC17 score), chronic GVHD, CR status (CR2 vs CR1), Cytogenetic risk (adverse vs favorable/intermediate/inconclusive), GVHD prophylaxis (PTCy vs others, T-cell depletion vs others), Age (above 60 vs others), donor type (mismatched/haploidentical vs matched donors). Results: With a median follow-up duration of 22 months among survivors after HCT, 23 patients experienced relapse (n=23, 18.7%) while 63 deaths (51.2%) were noted. Out of 123 patients, 58 (47.1%) had a low LSC17 score and 65 (52.9%) had a high LSC17 score. There was no difference in the distribution of LSC17 scores between the group who received HCT (n=123; 0.479±0.026) vs not (n=229; 0.456±0.019; p=0.491). LFS survival was significantly better in the low LSC17 score group (51.5 vs 32.4% for 2-year LFS rate, p=0.0219), and there was a trend to higher OS rate in the low LSC17 group (48.1%) compared to the high LSC17 group at 2 years (34.2%, p=0.09). Furthermore, patients with a low LSC17 score had a significantly lower RI (14.9% vs 27.3% for 2-year relapse incidence, p=0.028). There is no difference of NRM between the groups (37.2% vs 38.2% at 2 years, p=0.647). Multivariate analysis confirmed that the high LSC17 score group was associated with worse LFS (HR 1.874 [1.080-3.249], p=0.025). However, it was not confirmed with respect to OS or relapse incidence. As expected, it was not associated with NRM. Conclusion: A low 17-gene stemness score is associated with better leukemia-free survival and lower relapse incidence after allogeneic HCT, and is suggested to be associated with OS. The high LSC17 score group may be considered for novel therapeutic strategies to reduce the risk of relapse after allogeneic HCT. Figure Disclosures Chan: Celgene: Honoraria, Research Funding; AbbVie Pharmaceuticals: Research Funding; Agios: Honoraria. Minden:Trillium Therapetuics: Other: licensing agreement. Michelis:CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria. Wang:Pfizer AG Switzerland: Honoraria, Other: Travel and accommodation; Pfizer International: Honoraria, Other: Travel and accommodation; Trilium therapeutics: Other: licensing agreement, Research Funding; NanoString: Other: Travel and accommodation.

Photopheresis As Part of Conditioning Reduces Incidence of Severe Graft Versus Host Disease: Fourteen Year Follow-up of a Novel Reduced Intensity Regimen for Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5924-5924
Author(s):  
Esha Kaul ◽  
Gunjan L Shah ◽  
Aaron S. Rosenberg ◽  
Raymond L. Comenzo ◽  
Hedy Smith ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Chronic Gvhd ◽  
P Value ◽  
Hematopoietic Stem ◽  
Entire Cohort ◽  
Stem Cell Source ◽  
Remission Status ◽  
Antigen Presenting ◽  
Active Disease

Abstract Background: Reduced intensity conditioning (RIC) regimens have allowed the use of allogeneic hematopoietic stem cell transplantation (HSCT) in older and high risk individuals, though Graft versus Host Disease (GVHD) remains an issue. Host antigen presenting cells have been implicated in the pathogenesis of GVHD. Extracorporeal photopheresis (ECP) has been shown to modulate host antigen presenting cell function. Tufts Medical Center developed a novel RIC regimen incorporating ECP, pentostatin and reduced dose total body irradiation (PPT). We now report our 14 year experience with this regimen in 206 consecutive patients not eligible for a myeloablative HSCT. Methods: The Tufts BMT database, the Center for International Bone Marrow Transplantation Registry (CIBMTR) database, and chart review were used to gather data. All patients received a conditioning regimen consisting of ECP administered on days -6 and -5, pentostatin 4mg/m2 by continuous infusion over 48 hours on days -4 and -3, a total dose of 600 cGy TBI administered in 3 fractions on days -2 and -1. No antithymocyte globulin was given. All patients received GVHD prophylaxis with cyclosporine and 2 doses of methotrexate. Supportive care was provided per institutional guidelines. Overall survival (OS) was calculated from day 0 using the Kaplan Meier method. Cumulative incidence of non-relapse mortality (NRM) was calculated treating death due to primary hematologic malignancy or relapse as competing risks. Univariate associations between patient characteristics and outcomes were estimated using logistic regression or Cox proportional hazards models as appropriate. Results: 206 patients (56% males) underwent allogeneic HSCT with the PPT regimen between October 1999 and December 2013. Median age at transplant was 53 years (19-70 years) with 45% being older than 55 years. 31% had a prior autologous HSCT. Median time from diagnosis to transplant was 17 months (range 1-180 months). 59% of the transplants were from matched siblings and 41% were from unrelated donors. Marrow was utilized as the source of stem cells in 72% of the transplants. 92% transplants were HLA matched with 8% mismatched at one antigen. The most common indications for transplant were Acute Myelogenous Leukemia (AML) (35%), Myelodysplastic Syndrome (MDS) (16%) and Non-Hodgkin Lymphoma (NHL) (12%). Of the 73 patients with AML 33% were in first complete remission (CR1), 18% were in a second or greater complete remission (CR ≥2) and 49% had active disease at the time of transplant. Median times to neutrophil and platelet engraftment were 17 and 19 days, respectively. 17% of the patients never dropped their platelet counts below 20,000/mm3. The estimated 5 year overall survival (OS) for the entire cohort was 29% [95% CI (23%-36%)]. The estimates of OS by diagnosis are shown in Figure 1. The estimated non-relapse mortality (NRM) at 100 days was 17% [95% CI (13%-23%)]. The incidence of grade 3-4 acute GVHD was 20%. 54% of the patients developed chronic GVHD, of which only 17% were extensive stage. On univariate analysis for the entire cohort, the variables significant for a higher risk of death were 1-antigen mismatch [HR 1.96, p-value=0.01] and KPS <80 [HR 10.66, p-value <0.001]. Age, stem cell source and having an unrelated donor were not found to be significant. On multivariate analysis in the AML cohort, advanced age [aHR 1.37, p-value=0.02] and active disease [aHR 3.02, p-value=0.002] were significant factors for death. OS by remission status in the AML cohort is shown in Figure 2. Conclusions: PPT was well tolerated with low NRM and survival outcomes comparable to other RIC regimens. OS was independent of graft type (related versus unrelated) or stem cell source. Rates of severe acute and extensive chronic GVHD were low, possibly due to the use of ECP and its modulation of the host antigen presenting cells. OS in patients with AML was comparable to other RIC regimens despite almost half of the patients having active disease at the time of transplant. Our long term follow-up data of 14 years shows that PPT remains a novel regimen for patients not eligible for full intensity conditioning. Figure 1. Overall Survival of Patients Receiving PPT Conditioning by Diagnosis Figure 1. Overall Survival of Patients Receiving PPT Conditioning by Diagnosis Figure 2. Overall Survival of AML Patients by Remission Status. Figure 2. Overall Survival of AML Patients by Remission Status. Disclosures No relevant conflicts of interest to declare.

Evaluation of Graft Versus Host Disease and Relapse Free Survival As Novel Endpoint in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Joint Naples-Paris Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2285-2285
Author(s):  
Simona Pagliuca ◽  
Antonio M Risitano ◽  
Sylvie Chevret ◽  
Flore Sicre de Fontbrune ◽  
Alienor Xhaard ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host

Abstract The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Classical endpoints such as overall survival (OS), desease free survival (DFS) and non relapse-mortality (NRM) had become more and more unsuitable for transplant research because of their inability to a dynamic mesure of transplant-associated comorbidity. For this reason several composite endpoints taking into account also GVHD-associated comorbidity were proposed in the last years. GVHD free/relapse free survival (GRFS), proposed by Holtan et al (Blood 2015), includes grades 3-4 acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse , or death for any cause considered as events. This endpoint seems to completely characterize the survival without mortality or ongoing morbidity. With the intent to analyse the outcomes of our transplanted cohort, we retrospectively analysed GRFS of 959 consecutive patients receiving HSCT at Federico II University in Naples (n=119) and Saint-Louis Hospital (n=840) in Paris between 2007 and 2014, identifying prognostic factors associated with a better outcome and estimating the incidences of all components of this endpoint: rates of acute and chronic GVHD, disease relapse and death. Patient, disease and transplant characteristics are listed in table 1. Median duration of follow-up after HSCT was 22.1 months (IQR: 5.6-51 months). Cumulative incidence at day 100 of grade II-IV acute GVHD and grade III-IV were 42% and 16%, respectively. Cumulative incidence of chronic GVHD requiring systemic treatment at 1 and 5 years was 23% and 33%, respectively, diagnosed according to NIH criteria [14% of patients had score 1 (mild), 58% score 2 (moderate) and 27% score 3 (severe)cGVHD]. Cumulative incidence of relapse (considering all malignant and non-malignant diseases) was 26.7% (N=219) at 5 years. Overall survival for the whole population was 57% (95%CI, 53.3-60.8) at 5 years and Disease free survival (DFS) and non-relapse mortality (NRM) were respectively 50% (95%CI, 46.6-53.8) and 23% at 5 years. GRFS was 25% (95%CI, 21.8-28.5) at 5 years. Factors identified as influencing GRFS based on univariate analyses were age higher than 45 years (HR=1.64, 95%CI, 1.40-1.92), bone marrow (BM) as stem cell source (HR=0.40, 95%CI, 0.32-0.50); reduced intensity conditioning (RIC) (HR=0.63, 95%CI, 0.53-0.74); disease type [non-malignant disorders: HR=0.24, 95%CI, 0.17-0.33; myelodysplastic and myeloproliferative syndromes (MPN/CML/MDS): HR=1.34, 95%CI, 1.10-1.63; whereas other diagnosis did not influence GRFS] and than unrelated donor (matched: HR=1.71, 95%CI, 1.41-2.07;mismatch:HR=1.81, 95%CI, 1.48-2.23). Based on a multivariable Cox model, only diagnoses (non-malignancies, HR=0.27, 95%CI, 0.19-0.38 and MPN/CML/MDS, HR= 1.35, 95%CI, 1.11-1.65), and HLA unrelated graft (matched, HR=1.42, 95%CI, 1.17-1.73 and mismatched, HR=1.55, 95%CI, 1.26-1.92) remained associated with the outcome (Figure 1 and 2). GRFS could represent the ideal endpoint following HSCT. It differs significantly based upon type of disease and donor type, essentially. This composite indicator yields more information regarding complications of HSCT than the simpler measurement of OS or DFS. Its use willbetter compare these clinically important outcomes that accompany disparate HSCT techniques. All examined prognostic factors could enhance our ability to optimally judge the risk and the probability of true recovery after allogeneic HSCT. Our data support the use of this composite endpoint to describe HSCT outcome, and also pave the way for the investigation of novel endpoints, which may also track the dynamic changes of post-transplant events in the long-term. These retrospective data represent the background to investigate the impact of novel strategies of HSCT aiming to improve the outcome of HSCT, as detectable, by using more sensitive endpoints, tracking clinical events associated with detrimental long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Novartis: Research Funding; Alnylam: Research Funding; Rapharma: Research Funding. Peffault de Latour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document