Donor Type, Chronic Gvhd Subtype , and the Severity of Chronic Gvhd at the Time of Initiation of Chronic Gvhd Treatment Affect Failure-Free Survival in the Patients with Chronic Gvhd

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3139-3139
Author(s):  
Jieun Uhm ◽  
Elizabeth Shin ◽  
Marc Poch Martell ◽  
Fotios V. Michelis ◽  
Auro Viswabandya ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Overlap Syndrome ◽  
Unrelated Donor ◽  
Free Survival ◽  
Unrelated Donors ◽  
Severe Grade

Abstract Introduction: Chronic graft versus host disease (cGVHD) is one of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). Several prognostic factors have been proposed to predict the outcomes of cGVHD including progressive type onset, extensive skin involvement, thrombocytopenia and NIH global score (NIH GS). Most studies have been focusing on the factors at the diagnosis of cGVHD without consideration of baseline characteristics prior to allo-HCT. We attempted to evaluate the prognostic factors for the outcomes of cGVHD treatment including the characteristics at the start of cGVHD treatment as well as prior to HCT. Method: We retrospectively reviewed 668 consecutive patients who underwent allo-HCT between 2004 and 2012 at the Princess Margaret Cancer Centre, Toronto, Canada, among whom 277 patients diagnosed as cGVHD and received systemic corticosteroids as a frontline cGVHD therapy. Chronic GVHD was classified and graded using the NIH consensus criteria. We evaluated non-relapse mortality (NRM), relapse and failure-free survival (FFS). FFS was defined as time to a switch in systemic therapy, NRM or relapse. The Kaplan-Meier method was used for FFS. The cumulative incidences of NRM, relapse and the treatment switch (TS) were calculated considering competing risks. Multivariate analysis was performed using the Cox proportional hazard regression model for FFS. Results: With a median follow-up duration of 26 months, the median time from HCT to cGVHD treatment was 183 days (range, 61-828). 102 patients (36.8%) were classified as classical cGVHD and 175 (63.2%) as overlap syndrome. At the start of cGVHD treatment 25 patients (9.0%) had mild cGVHD by the NIH GS, 189 (68.2%) moderate and 63 (22.7%) severe. Median age at allo-HCT was 51 year-old (range, 19-70). 162 patients (58.5%) were males and 65 (23.5%) patients were gender match of female donor to male recipient. 257 patients (92.8%) received peripheral blood stem cells (PBSC).175 grafts (63.2%) were from matched sibling donors (MSD). 180 patients (65%) received myeloablative conditioning. GVHD prophylaxis was calcineurin inhibitor (CNI) and methotrexate (n=82, 29.6%), CNI and mycophenolate mofetil (n=141, 50.9%), CNI and T-cell depletion (n=37, 13.5%) or others (n=17, 6.1%). The median FFS was 255 days (95% CI, 218-321). The severity of cGVHD, NIH GS correlated with FFS: median FFS was 164 days in severe vs 238 days in moderate vs 304 days in mild (p=0.001). The overlap syndrome was associated with a shorter FFS than classical cGVHD (223 vs 329 days, p=0.015). Patients receiving MSD graft showed longer FFS (329 days) than unrelated donor (196 days; p=0.004). The cumulative incidence of TS was 47.7% at 1 year. The NRM was 7.1% and relapse rate was 6.8% at 1 year. The MSD was associated with a lower 1-year NRM than the unrelated donors (4.2% vs 12.3%, p=0.003) while no difference between 2 groups for TS (p=0.731) or relapse at 1 year (p=0.565). Patients with overlap syndrome had higher NRM at 1 year than with classical cGVHD (10.0% vs 2.2%, p=0.009), but no differences in TS or relapse at 1 year (p=0.167 and p=0.138). Chronic GVHD severity by NIH GS showed a significant correlation with TS (28% in mild, 51.9% in moderate, and 43.8% in severe grade at 1 year, p=0.02) and NRM (4% in mild, 3.6% in moderate, and 19.1% in severe grade at 1 year, p<0.001), but with relapse (p=0.784). Multivariate analysis for FFS confirmed that the use of unrelated donor showed a worse FFS (hazard ratio (HR) 1.660, p=0.001). FFS was also associated with the severity of cGVHD, NCC GS (mild vs moderate vs severe; HR 1 vs 2.1 vs 2.9, p=0.002) and the cGVHD subtype (classical vs overlap, HR 1 vs 1.39, p=0.028). We then assigned score 0 for NIH GS mild, 1 for moderate, and 2 for severe; for NIH subtype, score 0 for classical and 1 for overlap; for donor types, score 0 for MSD and 1 for unrelated donors. After summation of the scores, we regrouped them into low (score 0, n=11, 3.9%), intermediate (score 1-2, n=168, 60.6%), and high risk groups (score 3-4, n=98, 35.3%). The risk stratification model correlated nicely with FFS (FFS duration, 1977 days in low vs 341 days in intermediate, and 150 days in high risk group, p<0.001). Conclusion: the use of unrelated donor, overlap subtype of chronic GVHD and severe grade of chronic GVHD at the time of initiation of chronic GVHD treatment affect adversely on failure-free survival. Disclosures Kim: Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

Higher Leukemia Free Survival after Post-Induction Hematopoietic Cell Transplantation Compared to Consolidation Therapy in Patients >60 Years with Acute Myelogenous Leukemia (AML): Report from the AML 2004 East German Study Group (OSHO)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 280-280 ◽  
Author(s):  
Dietger Niederwieser ◽  
Haifa Kathrin Al-Ali ◽  
Rainer Krahl ◽  
Christoph Kahl ◽  
Hans-Heinrich Wolf ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Normal Karyotype ◽  
Mutation Status ◽  
Free Survival ◽  
Flt3 Mutation ◽  
Unrelated Donors ◽  
The Difference

Abstract Treatment of elderly patients with AML remains challenging. While increasing doses of induction and consolidation chemotherapy have failed to improve outcome, efforts to decrease relapse rates using the graft-versus-leukemia effect have shown promising results in phase II studies. In the present analysis of the prospective OSHO 2004 study we evaluated the effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML. The OSHO 2004 study is part of the German intergroup study. Upon achieving complete remission (CR) after induction, patients were assigned to CT or HCT depending on the availability of a matched related or unrelated donor. Unrelated, single antigen mismatched donors were accepted in high risk situations. By April 2014 from 817 eligible patients, 505 entered CR (62%) after one or two induction therapies. From the 452 patients who received consolidation in CR 1, 31 patients (7%) relapsed and 10 (2%) died of complications during consolidation. No further therapy for medical reasons was given to 73 patients, 206 patients received second consolidation with cytarabine (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m² d1-2) and 132 patients underwent HCT. Most frequent conditioning regimens for HCT were low dose TBI (83%) and treosulfan/fludarabine (12%). Most of the patients received HCT from unrelated (80%) donors and the majority received grafts from HLA-identical (78%) donors. Our analysis was restricted to the 315 patients <75 years receiving either CT or HCT. Probabilities for overall survival (OS) and leukemia free survival (LFS) were estimated according to the Kaplan-Meier method and differences tested by the log-rank test. Relapse incidence (RI) and non relapse mortality (NRM) were described by estimating the cumulative incidence and testing the differences using the Gray's test. Multivariate Cox regression models and competing risks regression models were used to identify independent prognostic variables for outcomes. The median age was 67 (60-74) and 65 (60-74) years in the CT and the HCT groups (p<0.0005), respectively. There were no differences between CT and HCT regarding gender, AML type (de novo, secondary or therapy related) and FLT3 mutation status. However more patients with mutated NPM1 were observed in the CT as compared to the HCT group (39% vs 28%; p=0.07) and more patients entered into remission after one induction in the CT as compared to the HCT group (89% vs. 81%; p=0.05). Low risk cytogenetics and normal karyotype were present more frequently in the CT than in the HCT arm (p<0.0005). The interval from CR to CT was 50 days and from CR to HCT 72 days (p<0.0005). Patients receiving related or unrelated matched/mismatched HCT had superior LFS than those receiving CT (32±5% vs. 13±4% at 8 years, respectively; p<0.0005). The difference was more distinct when only those patients with matched related or unrelated donors were compared to those receiving CT (36±6% vs. 13±4% at 8 years; p<0.0005). Similar figures were obtained for overall survival [OS, 35±5% matched/mismatched HCT vs. 24±4% for CT (p=0.18) and 41±6% for matched HCT patients vs. 24±4% for CT (p=0.09)]. RI was lower after HCT (40±5%) than after CT (79±5%; p<0.0001). In contrast, NRM was higher in HCT patients (28±7%) than in CT patients (9±11%; p<0.0001). Subpopulation analyses identified no difference in LFS and OS between matched related versus unrelated HCT. The difference in LFS between HCT and CT was highest in patients with normal karyotype, high risk cytogenetics and patients with non-monosomal karyotyp. Prognostic factors for LFS, OS, RI and NRM were analyzed in a multivariate analysis. Significant prognostic factors for LFS were cytogenetic risk (p=0.04), HCT (p=0.01) and FLT3 mutation status (p=0.07). OS was determined by cytogenetics p<0.01) with a trend for lower age (p=0.07) and HCT (p=0.14). Prognostic factors for RI were cytogenetics (p< 0.0006), FLT3 mutation status (p<0.03) and HCT (p<0.0005). NRM was influenced by HCT (p=0.002). Conclusions: HCT from related or unrelated donors improved LFS and OS in patients with AML over the age of 60 years and in particular in those with high risk cytogenetics or normal karyotype disease. The LFS of over 30% after 8 years achieved by HCT represents a marked improvement in the prognosis of patients with AML aged 60-75 years in CR1. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Maschmeyer:Celgene: Consultancy.

One Antigen HLA-Mismatched Related and 8/8 Allele Matched Unrelated Donors Are Associated with Similar Survival after Hematopoietic Cell Transplantation for Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 965-965
Author(s):  
David Valcarcel ◽  
Fangyu Kan ◽  
Tao Wang ◽  
Stephanie J. Lee ◽  
Stephen R Spellman ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Related Donor ◽  
Disease Free

Abstract Patients in need of an allogenetic hematopoietic cell transplant but who lack an HLA genotypically identical sibling donor, are faced with the decision to consider a single HLA antigen mismatched related donor, or a search for a suitable 8/8 matched unrelated donor. We compared the outcomes of adult patients (≥18 years old) receiving a transplant for the treatment of AML or ALL in first or second remission from either a one-antigen mismatched related donor (MMRD group, N=89) reported to the CIBMTR or an 8/8 HLA-A, B, C and DRB1 allele matched unrelated donor (UD group, N=700) facilitated by the NMDP between 1995–2005. MMRD group was typed by serological or DNA-based methods for HLA-A, -B and –DR with all results verified by lab report review. The UD group was retrospectively typed for HLA-A, B, C and DRB1 by high resolution typing methods. Most received myeloablative conditioning regimens (77%), calcineurin inhibitor-based GVHD prophylaxis (100%) and T cell replete grafts (100%). 13% received ATG with the conditioning regimen. Median follow-up was 54 and 38 months in the MMRD and UD groups, respectively. The MMRD group was younger (median age 35 vs 43, p=0.002), had more ALL patients with low-risk cytogenetics (43% vs 18%, p=0.005), had older donors (median age: 38 vs 34, p=0.047), were more likely to receive methotrexate for GVHD prophylaxis (89% vs 77%, p=0.014) and were more likely to be transplanted prior to 2001 (62% vs 24%; p<0.001). There were no differences in patient or donor gender, diagnosis, disease-status, cytogenetic-risk of AML, time from diagnosis to transplant, stem cell source, conditioning regimen, use of ATG and Karnofsky index. Univariate comparisons (MMRD vs. UD) showed: 3-year OS (42% vs 44%, p=0.647), 3-year DFS (41% vs 41%, p=0.931), 3-year TRM (39% vs 31%, p=0.136), 3-year incidence of relapse (20% vs 28%, p=0.094), grade III–IV acute GVHD by 100 days (22% vs. 15%, p=0.147), chronic GVHD by 1 year (35% vs 47%, p=0.029). All multivariate analyses were adjusted for patient and transplant characteristics and are shown in the table below. In summary, transplants utilizing one-antigen mismatched related and 8/8 allele-matched unrelated donors did not significantly differ in overall survival or disease free survival, but chronic GVHD was more frequent after UD transplantation. Outcome RR (MMRD vs. UD) 95% CI p-value Survival 0.99 0.73–1.34 0.94 Disease-free survival 1.06 0.80–1.41 0.69 Treatment related mortality 1.14 0.77–1.69 0.52 Relapse 0.81 0.50–1.30 0.38 Acute GVHD III–IV 1.53 0.91–2.57 0.11 Chronic GVHD 0.58 0.39–0.85 0.006

Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2002-2008 ◽  
Author(s):  
Ann E. Woolfrey ◽  
Claudio Anasetti ◽  
Barry Storer ◽  
Kristine Doney ◽  
Laurie A. Milner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Marrow Transplant ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Conditioning Treatment ◽  
Unrelated Donors ◽  
Total Body

Abstract Acute lymphoblastic leukemia (ALL) is the most common indication for transplantation of marrow from unrelated donors in children. We analyzed results of this procedure in children with ALL treated according to a standard protocol to determine risk factors for outcome. From January 1987 to 1999, 88 consecutively seen patients with ALL who were younger than 18 years received a marrow transplant from an HLA-matched (n = 56) or partly matched (n = 32) unrelated donor during first complete remission (CR1; n = 10), second remission (CR2; n = 34), third remission (CR3; n = 10), or relapse (n = 34). Patients received cyclophosphamide and fractionated total-body irradiation as conditioning treatment and were given methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Three-year rates of leukemia-free survival (LFS) according to phase of disease were 70% for CR1, 46% for CR2, 20% for CR3, and 9% for relapse (P &lt; .0001). Three-year cumulative relapse rates were 10%, 33%, 20%, and 50%, respectively, and 3-year cumulative rates of death not due to relapse were 20%, 22%, 60%, and 41%, respectively, for patients with CR1, CR2, CR3, and relapse. Grades III to IV acute GVHD occurred in 43% of patients given HLA-matched transplants and in 59% given partly matched transplants (P = .10); clinical extensive chronic GVHD occurred in 32% and 38%, respectively (P = .23). LFS rates were lower in patients with advanced disease (P &lt; .0001), age 10 years or older (P = .002), or short duration of CR1 (P = .007). Thus, in addition to phase of disease, age and duration of CR1 were predictors of outcome after unrelated-donor transplantation for treatment of ALL in children. Outcome was particularly favorable in younger patients with early phases of the disease.

Varying Importance of Prognostic Factors in Subgroups of Myelodysplastic Syndromes Defined by Blast Count, Cytogenetic Risk Group, or WHO Classification.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2776-2776
Author(s):  
Andrea Kuendgen ◽  
Corinna Strupp ◽  
Kathrin Nachtkamp ◽  
Barbara Hildebrandt ◽  
Rainer Haas ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Univariate Analysis ◽  
Risk Groups ◽  
High Risk Group ◽  
Intermediate Risk ◽  
Blast Count

Abstract Abstract 2776 Poster Board II-752 Introduction: We wondered whether prognostic factors have similar relevance in different subpopulations of MDS patients. Methods: Our analysis was based on patients with primary, untreated MDS, including 181 RA, 169 RARS, 649 RCMD, 322 RSCMD, 79 5q-syndromes, 290 RAEB I, 324 RAEB II, 266 CMML I, 64 CMML II, and 209 RAEB-T. The impact of prognostic variables in univariate analysis was compared in subpopulations of patients defined by medullary blast count, namely <5%, ≥5% (table), ≥10%, and ≥20% (not shown), as well as 3 subpopulations defined by the cytogenetic risk groups according to IPSS (table). Multivariate analysis of prognostic factors was performed for cytogenetically defined subgroups and WHO-subtypes. Results: Strong prognostic factors in all blast-defined subgroups were hemoglobin, transfusion dependency, increased WBC, age, and LDH. However, all variables became less important in patients with ≥20% blasts (RAEB-T) and increased WBC was rare. Platelet count and cytogenetic risk groups were relevant in patients with <5%, ≥5%, and ≥10% marrow blasts, but not in RAEB-T. Marrow fibrosis was important in patients with <5% or ≥5% blasts, but not ≥10%. Gender and ANC <1000/μl were significant only in patients with a normal blast count. Furthermore, we looked for the effect of the karyotypes, relevant for IPSS scoring (-Y, del5q, del20q, others, del7q/-7, complex), and found a comparable influence on survival, irrespective whether patients had < or ≥5% marrow blasts. In subpopulations defined by cytogenetic risk groups, several prognostic factors were highly significant in univariate analysis, if patients had a good risk karyotype. These included hemoglobin, sex, age, LDH, increased WBC, transfusion need, and blast count (cut-offs 5%, 10%, and 20%). In the intermediate risk group only LDH, platelets, WBC, and blasts were significant prognostic factors, while in the high risk group only platelets and blast count remained significant. Multivariate analysis was performed for the cytogenetic risk groups and for subgroups defined by WHO subtypes. The analysis considered blast count (</≥5%), hemoglobin, platelets, ANC, cytogenetic risk group, transfusion need, sex, and age. In the subgroup including RA, RARS, and 5q-syndrome, LDH, transfusion, and age in descending order were independent prognostic parameters. In the RCMD+RSCMD group, karyotype, age, transfusion, and platelets were relevant factors. In the RAEB I+II subgroup, the order was hemoglobin, karyotype, age, and platelets, while in CMML I+II only hemoglobin had independent influence. In RAEB-T none of the factors examined was of independent significance. Looking at cytogenetic risk groups, in the favorable group, several variables independently influenced survival, namely transfusion, blasts, age, sex, and LDH (in this order). Interestingly, in the intermediate and high risk group, only blast count and platelets retained a significant impact. Conclusion: Univariate analysis showed prognostic factors (except ANC) included in IPSS and WPSS are relevant in most subgroups defined by marrow blast percentage. However, they all lose their impact if the blast count exceeds 20%. Regarding cytogenetic risk groups, several prognostic factors lose their influence already in the intermediate risk group. This underscores the prognostic importance of MDS cytogenetics. Multivariate analysis showed MDS subpopulations defined by WHO types also differ with regard to prognostic factors. In particular, CMML and RAEB-T stand out against the other MDS types. Disclosures: Kuendgen: Celgene: Honoraria. Hildebrandt:Celgene: Research Funding. Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials. Germing:Novartis, Celgene: Honoraria, Research Funding.

Prognostic Factors of Infections and Effect of Primary Anti-Infectious Prophylaxis in MDS Patients Treated with Azacitidine (AZA): A Prospective Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1917-1917
Author(s):  
Marie Sebert ◽  
Claire Aguilar ◽  
Sylvie Chevret ◽  
Lionel Ades ◽  
Olivier Lortholary ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Fungal Infection ◽  
Predictive Factors ◽  
Invasive Fungal Infection ◽  
Research Funding ◽  
Pulmonary Infection ◽  
Influenza B ◽  
Fatal Infection

Abstract Background: Hypomethylating agents, especially AZA, have become the reference first line treatment of high-risk MDS. Myelosupression, although less important than with chemotherapy, is however observed, leading to potentially life threatening infections. A retrospective study found unfavorable (unfav) cytogenetics and low platelet counts to be predictive factors of infections in high risk MDS and AML patients (pts) receiving AZA (Merkel and al, Am j Hemat 2012). However, prognostic factors of infections, and whether infection prophylaxis would be useful in this situation, has not been prospectively evaluated. Methods: Between June 2011 and March 2013, 120 high-risk MDS pts were included in a randomized phase II trial seeking the most promising drug association with AZA by comparison with AZA alone in higher risk MDS (including AML with 20 to 30% marrow blasts and CMML with > 10% marrow blasts) (NCT01342692). Pts received AZA (75mg/m²/dx7d every 4 weeks) alone (N=40), with Valproic acid (N=40) or with Lenalidomide (N=40) (10mg/dx14d every 4 weeks). G-CSF was not used. Infectious events (IE) (diagnosed as such by the treating physician), hospitalizations for sepsis and pts receiving antimicrobial prophylaxis were reported at each cycle. Predictive factors of the occurrence of IE were analyzed. Results: 75 (62.5%) pts developed 259 IE, including 61 requiring hospitalization in 46 pts (61.3% of infected patients). The number of IE and of infected patients were similar in the 3 study arms. 39 pts died during the study, 12 of them because of infection, none of whom had responded to AZA (4 progressions, 4 failures and 4 deaths before evaluation). IE were more common during the first two cycles of therapy, with 86 (31.3%), 52 (23.5%) 45 (18.9%), 26 (15%), 15(19.2%) and 24 (19.7%) IE during cycles 1, 2, 3, 4, 5, and 6, respectively. Fever of unknown origin (FUO) (39.6%) and pneumonia (28.8%) were the most common type of infections followed by ENT (9.9%), urinary tract (8.1%), skin (5.4%), dental (4.5%) and intra-abdominal (3.6%). 6,3% were bacteriemia. Among the 26 microbiologically documented IE, 13 were CG+ (4 staph aureus, 4 enteroccus species, 4 coag neg staph and 1 other), 9 were BG- (6 E Coli, 1 pseudomonas and 2 others) and 3 were viral (HSV1, influenza B, Hepatitis E) and only one patient had documented invasive fungal infection (asp fumigatus). Overall, 23 (19%), 22 (18%), 10(8%) pts received bacterial (Levofloxacine), fungal (posaconazole) and viral (Valaciclovir) prophylaxis resp. Predictive factors of IE were unfav karyotype (79.5% infections vs. 50.8% in pts with fav or int karyotype; p=0.005) and platelets (PLT) < 20 G/L (92.3% infections vs. 58.9% for platelets > 20 G/L; p=0.03). In multivariate analysis, only unfav karyotype was predictive of IE (p=0.01). Other baseline parameters (including ANC, IPSS, age, sex, Hb level, and BM blast %) and bacterial, fungal or viral prophylaxis had no significant predictive value on the occurrence of IE. In multivariate analysis, predictive factors of pulmonary infection were anemia at baseline (p=0.04) and unfav karyotype (p<0.001), while prophylaxis had no significant impact. Infected pts had significantly more hospitalizations and deaths than non-infected pts (p<0.0001 and p=0.028 resp.). In multivariate analysis, unfav karyotype (p<0.001) and PLT <20 G/L (p=0.05) were significantly predictive of hospitalization for infection, while baseline Hb <10g/dL (p=0.02), and unfav karyotype (p=0.03) were predictors of fatal infection. Conclusion: 62.5% of the 120 pts developed infections during AZA treatment, mainly during the first 2 cycles, and 10% of the pts died from infection. Only one invasive fungal infection was documented. Unfav karyotype was strongly predictive of IE, hospitalization for infection and fatal infections. Other significant predictive factors were baseline anemia for pulmonary infection and fatal infection, and thrombocytopenia for hospitalization for infection, while ANC was not a significant factor. Moreover, prophylaxis was not associated with a decrease of IE in our study, but the small number of pts who received it precludes any conclusion. Disclosures Ades: celgene: Research Funding; Novartis: Research Funding. Fenaux:Novartis: Research Funding; celgene: Research Funding; Janssen: Research Funding.

scholarly journals Comparable Outcomes after Hematopoietic Stem Cell Transplantation from Mother Donors and Matched Unrelated Donors in Patients with Hematopoietic Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3463-3463
Author(s):  
Rui MA ◽  
Xiao-Jun Huang ◽  
Lan-Ping Xu ◽  
Kaiyan Liu ◽  
Xiaohui Zhang ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Donor Selection ◽  
Unrelated Donor ◽  
Donor Group ◽  
Hematopoietic Stem ◽  
Hematopoietic Recovery ◽  
Unrelated Donors ◽  
Transplantation Outcomes

Abstract BACKGROUND Haploidentical donor (HID) transplantations have achieved comparable survival as HLA fully matched unrelated donor (URD) transplantations. However, previous studies usually consider the two donor sources as whole populations when making the comparison, although there are actually subgroups within each. Based on current knowledge regarding donor selection, offspring and sibling donors were prioritized over parental donors in unmanipulated haplo-transplant settings, and maternal donors were considered as "the worst donors" under the Beijing Protocol due to the increased probabilities of GVHD and inferior survival. To compare efficacies of "the worst" mother donors and URDs would help to acquire a further understanding on donor selection of HIDs versus URDs. PATIENTS AND METHODS 43 and 92 patients who underwent transplantations with URDs or mother donors from June 2012 to June 2015 were enrolled. Their transplantation outcomes, including hematopoietic recovery, acute and chronic GVHD, relapse, transplant related mortality (TRM), overall survival (OS) and leukemia-free survival (LFS) were compared. Univariate and multivariate analysis were performed to explore risk factors for transplantation outcomes. RESULTS Both 2-year OS and 2-year LFS were comparable between the mother donor group and the URD group (74.8% versus 72.9%, p=0.937 and 71.7% versus 67.0%, p=0.580). Higher incidences of grade 2 to 4 acute GVHD and chronic GVHD were observed in the mother donor group than that in the URD group (43.5% versus 14.0%, p=0.001 and 58.8% versus 37.1%, p=0.013), although incidences of grade 3 to 4 aGVHD were similar between groups (mother donor group: 12%, URD group: 7%, p=0.374). Multivariate analysis indicated increased rates of acute GVHD were associated with mother donor transplantations (HR ratio: 2.049, p=0.017) and chronic GVHD was related to lower dose of CD34 cells infused (HR ration: 1.834, p=0.035) and female to male donations (HR ration: 1.733, p=0.047). The 2-year cumulative incidences of relapse were significantly decreased in the mother-donor group (7.6% versus 20.9%, p=0.036). Incidences of relapse were associated with donor types (URD vs mother donor: HR ratio 2.524, p=0.035) and disease status before transplantation (CR1 vs other: HR ratio 0.201, p=0.001) in multivariate analysis. These two groups were comparable in hematopoietic recovery and TRM (mother donor group: 21.1%, URD group: 11.6%, p=0.173). CONCLUSIONS Our findings suggest that mother donor transplantations could achieve comparable survival to unrelated donor transplantations, and exhibited decreased rates of relapse but increased rates of GVHD under the Beijing Protocol. This study not only shed light on donor selection by using one modality (the Beijing Protocol) to answer the universal question of HIDs versus URDs, but was also of practical significance due to possible shortage of unrelated donors, sibling donors and other suitable HIDs, especially in contemporary China with the one family one kid policy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allotransplants for Patients 65 Years or Older with High-Risk Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4667-4667
Author(s):  
Paul Lin ◽  
Lauren Westfall Veltri ◽  
Katy Rezvani ◽  
Betul Oran ◽  
Sairah Ahmed ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Group ◽  
Morphological Evidence ◽  
Consolidation Chemotherapy ◽  
Medical Event ◽  
History Of

Abstract Outcome of persons >65 years with acute myeloid leukemia (AML) is poor. Allogeneic transplant can cure some of these patients but is associated with substantial transplant-related mortality (TRM) and high relapse risk. We analyzed 185 consecutive patients >65 years with high-risk AML between 2010 and 2015 who had measurable residual disease (MRD) and molecular risk assessments and who received myeloablative conditioning (MAC, n=42) or reduced-intensity conditioning (RIC, n=143) and a transplant from an HLA-identical sibling (n=66) or a 10/10 loci HLA-matched unrelated donor (MUD, n=119) in order to identify patients who would benefit from allotransplant. MRD was assessed by flow cytometry in bone marrow samples. AML cytogenetic and molecular risk were defined using the 2017 European Leukemia Net genetic risk stratification. The patients who were MRD-negative at time of transplant had a better 2-year cumulative incidence of relapse (CIR 17.6%) and a 2-year overall survival (OS, 69.4%) as compared to the patients in remission but MRD-positive (55.6% CIR, 21.5% OS) or the patients who had morphological evidence of leukemia prior to transplant (48.7% CIR, 19.9% OS), (p<0.0001). Multivariate analysis for 2-year CIR showed that having detectable leukemia at time of SCT (defined as MRD-positive or morphological evidence of leukemia) (HR=14.5, CI=3.4-61.4, p<0.0001), having received <3 cycles of chemotherapy prior to SCT (HR=1.8, CI=1.1-2.8 p=0.01), and high-risk genetics were independent predictors of relapse. However, high-risk genetics only had a deleterious effect on outcomes for MRD-negative patients (HR=9.4, CI=2.0-43.6, p=0.004), and did not affect the outcome of patients with detectable leukemia (HR=1.1, CI=0.7-1.9, p=0.61). Patients who received RIC (Flu-Mel-RIC or Bu-Flu-RIC) or MAC (Bu-Flu-MAC) had similar proportion of MRD-negative patients (p=1.0). However, MRD-negative patients who received Flu-Mel-RIC had a superior OS than patients who received Bu-Flu-RIC (adjusted HR=1 vs 5.3, p=0.02) or patients who received Bu-Flu-MAC (HR=1 vs 5.093, p=0.04), which is explained by a significantly lower relapse rate in patients receiving Flu-Mel-RIC (adjusted HR=1 vs 4.8, p=0.03) and a significantly lower TRM as compared to patients receiving Bu-Flu-MAC (adjusted HR= 5.1, p=0.01). Patients who had major medical complications (MMC), defined as a medical event requiring admission to the intensive care unit for ventilatory or inotropic support or a medical event that prolonged the patient hospitalization for more than 2 weeks, during induction or consolidation chemotherapy preceding the transplant, had a higher day +100 mortality (30.6% vs 6.0%, p<0.0001), 2-year TRM (55.6% vs 16.8%, p<0.0001) and lower 2-year OS (8.3% vs 44.6%, p<0.0001). Multivariate analysis for 2-year OS showed that history of delayed hematological recovery during induction or consolidation chemotherapy prior to transplantation (HR=1.5, CI=1.0-2.3, p=0.04), high risk genetics (HR=1.8 CI:1.2-2.6, p=0.006), donor-recipient HLA-DRβ3/4/5-DP mismatch (HR=2.2, CI=1.3-3.6, p=0.001), history of cardiovascular disease (HR=1.7, CI=1.1-2.6, p=0.02) were independent predictors for OS. Other variables such as secondary leukemia, CMV sero-status, FEV1 or creatinine clearance prior to SCT, sex mismatch, ABO group mismatch, donor type, or stem cell source did not have a significant impact on OS or TRM. Outcomes were also similar between patients transplanted in CR1 or in ≥ CR2 or in CR or CRi. We sought to identify those patients who may clearly benefit from a SCT. To that end, we classified patients according to the MRD status prior to transplantation and the presence or absence of the other prognostic factors identified in the multivariate analysis. As seen in the Figure, the High risk group which includes patients with detectable leukemia and >1 additional adverse prognostic factors (or a MMC), had a 2-year OS of 7.7% (CI=3.1-17.8). In comparison, the Low risk group which includes MRD-negative patients with ≤3 other prognostic factors (and no MMC), had a 2-year OS of 76.2% (CI=63.3-85.6). Finally, the Intermediate risk group which constituted the remaining patients, had a 2-year OS of 32.2% (CI=22.1-44.3, p<0.00001). These data indicate the possibility to identify persons >65 years with high-risk AML likely to benefit from an allotransplant. Figure. Figure. Disclosures Rezvani: Affirmed GmbH: Research Funding. Oran:ASTEX: Research Funding; Celgene: Consultancy, Research Funding; AROG pharmaceuticals: Research Funding. Shpall:Affirmed GmbH: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

scholarly journals Post-Transplant Cyclophosphamide and Sirolimus in Matched Related and Unrelated Allogeneic Transplant with a Treosulfan-Based Conditioning

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4662-4662
Author(s):  
Jacopo Peccatori ◽  
Serena Albanese ◽  
Raffaella Greco ◽  
Francesca Lorentino ◽  
Fabio Giglio ◽  
...  
Keyword(s):  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Introduction: Post transplant cyclophosphamide (PT-Cy) has recently emerged as a very promising pharmacological strategy to overcome human leukocyte antigen (HLA) barriers in the setting of haploidentical hematopoietic cell transplant (HCT). We recently reported a promising preliminary experience on the use of PT-Cy and sirolimus as graft-versus-host disease (GVHD) prophylaxis in matched allo-HSCT (Greco R et al, Blood 2016). Herein we describe long-term outcomes of matched allogeneic HSCT, using treosulfan-based conditioning, and GVHD prophylaxis with PT-Cy and sirolimus. Methods: In our center, we collected 104 adult patients (pts) receiving matched HSCT for high-risk hematological malignancies, mainly acute myeloid leukemia (n=43). Donor was matched related (MRD) for 45 pts, 10/10 matched unrelated (MUD) for 39 pts and 9/10 MUD for 20 pts. Median age was 48 years (range 19-78). At HSCT, 51% of patients were not in complete remission (CR), 39% were in CR1 and 11% in subsequent CR. Graft source was mainly PBSCs (95%). All pts received a conditioning regimen based on treosulfan and fludarabine; 89% received an intensified conditioning with the addition of melphalan. All pts received PT-Cy (50 mg/kg/day) on days 3 and 4. Sirolimus was given from day 5, and withdrawn 3 months after HSCT. Mycophenolate mofetil (MMF) was added from day 5 to day 30, only in MUD. All patients were treated according to current institutional programs upon written informed consent for transplant procedures. Results: Median follow up was over 16 months (range 3-51). Median CD34+ and CD3+ cell doses were 5.6x10^6/Kg (range, 1.5-10.9) and 2.0x10^8/Kg (range, 0.2-8.0), respectively. All the recipients of allo-HSCT experienced a sustained donor cell engraftment. The cumulative incidence of grades II-IV and III-IV acute GVHD at 100 days was 21% and 9%, respectively. The cumulative incidence of chronic GVHD was 25% at 2 years; we observed severe chronic GVHD only in 4% of pts. The cumulative incidences of relapse and non-relapse mortality (NRM) were 33% and 8% at 2 years, respectively. Two-year overall survival (OS) was 67% and progression free survival (PFS) 59%. The composite end point of GVHD-free/relapse-free survival (GRFS) was 52% at 2 years, in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death. There was a longer OS, 2-year OS was 77% (p = 0.05), and a trend towards higher PFS and GRFS, 63% (p=0.07) and 58% (p=0.06) respectively, for pts with CR status at HSCT. We did not found a significant effect of HLA-matching (9/10 versus 10/10) or donor type (related versus unrelated) on major transplant outcomes (NRM, PFS, GRFS, relapse, acute and chronic GvHD). Conclusion: These outcomes confirmed that matched allogeneic HSCT using treosulfan-based chemotherapy, PT-Cy and sirolimus, is associated with low NRM and acceptable severe GVHD, providing relevant long-term survival in high-risk diseases. A randomized trial comparing this strategy with other kind of in-vivo T-cell depletion (i.e. ATG) is warranted. Disclosures Vago: Moderna TX: Research Funding; GENDX: Research Funding.

scholarly journals Triple Post-Transplant Cyclophosphamide (PTCY) Based Gvhd Prophylaxis for HLA Matched or HLA Haploidentical Transplants

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4881-4881
Author(s):  
Eugenio Galli ◽  
Elisabetta Metafuni ◽  
Sabrina Giammarco ◽  
Maria Assunta Limongiello ◽  
Idanna Innocenti ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Age Over 60 ◽  
Disease Free ◽  
Related Mortality

Abstract We report a retrospective analysis of 198 consecutive allogeneic stem cell transplant (HSCT) recipients, who received post transplant cyclophosphamide (PTCY), cyclosporine and mycophenolate mofetile as g raft-versus-host-disease (GVHD) prophylaxis. The donor was either HLA matched (n=78) (siblings -32- or unrelated -46) , or a haploidentical relative (HAPLO) (n=120). End points of the study were acute and chronic GVHD, transplant related mortality (TRM), relapse, disease free survival (DFS) and graft versus host and relapse free survival (GRFS). The two groups were comparable except for an older age (49 vs 56 years) in the haplo-HLA group. The diagnosis was mainly acute leukemia (57%), myelofibrosis (21%) or lymphoma (12%). Conditioning was myeloablative in 77% and 73% respectively (p=0.57). Acute GVHD grade II-IV developed in 10% of the HLA matched transplants vs 27% in the HAPLO group (p=0.005). The latter also had more moderate-to-severe cGVHD (4% vs 23%, p&lt;0.001). The cumulative incidence of transplant related mortality (TRM) at 1 year for the HLA matched vs HAPLO patients, was 10% vs 21% (p=0.04) (Fig.1) , with age over 60 years being the major negative predictor in multivariate analysis. Relapse at 1 year was 24% for HLA matched vs 10% for HAPLO transplants (p=0.051) (Fig.1). Disease free survival (DFS) at 1 year was 65% and 68% in matched and HAPLO patients, respectively (p=0.85) (Fig.1) and GRFS 55% vs 49% (p=0.18). In multivariate analysis, age over 60 years was the strongest predictor of DFS and GRFS (HR 1.73, p=0.03 and HR 1,65, p= 0.02). In conclusion: when using the same triple PTCY based GVHD prophylaxis, HLA matched grafts are associated with significantly less acute and chronic GvHD, if compared with HAPLO grafts. There is a trend for reduced TRM at 1 year, especially in chronic myelo-lymphoproliferative disorders, and a trend for increased relapse, resulting in identical disease free survival. Figure 1 Figure 1. Disclosures Laurenti: Gilead: Honoraria; Roche: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Sica: Pfizer: Honoraria.

scholarly journals Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3980-3980
Author(s):  
Jae-Ho Yoon ◽  
Sung-Soo Park ◽  
Young-Woo Jeon ◽  
Sung-Eun Lee ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Median Time ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Advisory Committees

Abstract Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD. Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043). Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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