The NIH Chronic Gvhd Global Score and the CIBMTR Risk Score Correlate Well with Failure Free Survival Following Frontline Systemic Corticosteroid Therapy for Chronic Gvhd

Abstract Introduction: While the National Institutes of Health (NIH) consensus criteria (NCC) on diagnosis and staging of cGVHD are now widely used, minimal attempts have been made to validate its ability to predict the outcomes of cGVHD treatment. Arora et al. analyzed data from the Center for International Blood and Marrow Transplant Registry (CIBMTR) and suggested that the CIBMTR risk score is a predictive factor for overall survival (OS) and non-relapse mortality (NRM). The failure free survival (FFS) has been recently proposed as an endpoint for clinical trials on treatment of cGVHD. With this study we aimed to evaluate if the cGVHD global score by the NCC and the CIBMTR risk groups (RG) could predict the treatment outcomes of frontline systemic steroid therapy for cGVHD. Method: We retrospectively reviewed 668 consecutive patients who underwent allo-HCT between 2004 and 2012 at the Princess Margaret Cancer Centre, Toronto, Canada. We then identified 312 patients who had a diagnosis of cGVHD and received at least one systemic treatment for this. Thirty-five patients were excluded from the analysis as they were not treated with systemic corticosteroids and the remaining 277 patients were included in the final analysis. Chronic GVHD was reclassified and graded using the NCC. The CIBMTR risk score was also calculated and patients were stratified into 3 RGs accordingly. We evaluated the treatment outcomes including OS, NRM, relapse and FFS. FFS was defined as time to a switch in systemic therapy (i.e. failure of the treatment), NRM or relapse. The Kaplan-Meier method was used for OS and FFS. The cumulative incidences of NRM and relapse were calculated considering competing risks. Multivariate analysis was performed using the Cox proportional hazard regression model for OS and FFS. The Fine-Gray method was used for the incidences of NRM and relapse in multivariate analysis. Results: With a median follow-up duration of 26 months among survivors, the median to onset of cGVHD was 140 days (range, 45-381). One hundred and two patients (36.9%) were classified as classical cGVHD and 175 patients (63.1%) as overlap syndrome. At the onset of cGVHD 90 patients (32.5%) had mild cGVHD by the NIH global score (NIH GS), moderate in 143 patients (51.6%) and severe in 44 patients (15.9%). Thirty-three patients (11.9%) presented with progressive type onset (PTO). The CIBMTR risk score was available in 227 patients and we were able to stratify them into those with RG1 (score 0-2; n=32, 14.1%), RG2 (score 3-6; n=162; 71.4%) and RG3-6 (score ≥7; n=33, 14.5%). The median FFS of the 277 patients was 255 days. A severe GS correlated with the worst FFS: median FFS duration was 164 days in severe vs 238 days in moderate vs 304 days in mild (p=0.001). The CIBMTR RG also reflected the prognosis of patients after cGVHD treatment: the higher the RG the shorter the median duration of FFS: 166 days in RG3-6 vs 291 days in RG2 vs 501 days in RG1 (p=0.003). The OS at 2 years from the onset of cGVHD was 74.3%. A severe GS was associated with a worse OS: 55.1% in severe vs 79.9% in moderate vs 76% in mild grade (p<0.001). The CIBMTR RG was predictive of OS: 92% in RG1 vs 81.5% in RG2 vs 38.9% in RG3-6 (p<0.001). The cumulative incidence of NRM was 7.6% at 2 years. The NIH GS was predictive of NRM. The 2-year NRM rate was lowest with a mild GS at 2.4%, intermediate with a score of moderate at 4.8%, but significantly higher with a severe score at 27.5% (p<0.001). The CIBMTR RGs were also predictive of NRM: 0% for RG1, 6.1% for RG2 and 21.9% for RG3-6 (p=0.001). The cumulative incidence of relapse at 2 years was 9.2% and it was not associated with either the NIH GS or CIBMTR RGs.. Multivariate analysis confirmed that an NIH GS of severe and the CIBMTR RG3-6 and the overlap syndrome were associated with worse FFS: A severe NIH GS hazard ratio (HR) 1.65, p=0.011; CIBMTR RG3-6, HR 2.39, p=0.006; overlap syndrome, HR 1.38, p=0.058. A NIH GS of severe and CIBMTR RG3-6 were verified as adverse risk factors for NRM: A severe NIH GS, HR 6.31, p=0.001; CIBMTR RG3-6, HR 3.44, p=0.0081. CIBMTR RG3-6 and PTO were identified as unfavorable factors for OS: CIBMTR RG3-6, HR 5.14, p=0.002; PTO, HR 3.20, p<0.001. Conclusion: The NIH GS and CIBMTR RG for cGVHD correlated well with FFS and NRM following first line systemic treatment for cGVHD with corticosteroid-based regimens. Disclosures No relevant conflicts of interest to declare.

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Risk Factors for Major Transplant Related Outcomes In Pediatric Patients with Chronic Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v116.21.211.211 ◽

2010 ◽

Vol 116 (21) ◽

pp. 211-211

Author(s):

David A. Jacobsohn ◽

Mukta Arora ◽

John P. Klein ◽

Joseph H. Antin ◽

Brian J. Bolwell ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Blood Cell ◽

Immune Suppression ◽

Peripheral Blood ◽

Cumulative Incidence ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Peripheral Blood Cell ◽

Myelogenous Leukemia

Abstract Abstract 211 The adverse impact of chronic GVHD (cGvHD) on health and quality of life is especially critical in children because of their longer life expectancy and problems impacting growth and development. Although risk-factors for developing cGvHD in children are reported, little is known about risk factors for non-relapse mortality (NRM) in children with cGvHD. Identification of predictors for mortality in children with cGvHD could permit risk-adapted therapy, help plan for clinical trials and assist in counseling. We performed a multivariate analysis using data from CIBMTR to identify transplant- and cGvHD-related risk factors for NRM and survival in a cohort of 1117 subjects aged 0–20 years, transplanted from related donors, unrelated donors (URD), or unrelated cord blood (UCB) in 1995–2004 for acute myelogenous leukemia (AML), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). Median age was 12 years. Characteristics of cGvHD at diagnosis were: progressive onset (49%), total bilirubin >2 mg/dL (16%), thrombocytopenia (platelets <100 × 109/L, 32%) and Karnofsky/Lansky (KPS/L) score <80 (24%). Probabilities of NRM at 1, 3, and 5 years after diagnosis of cGvHD were 17% (95% CI: 14–19%), 22% (20-25%) and 24% (21-27%), respectively. Multivariate analysis indentified four factors significantly associated (p<0.01) with higher NRM: (1) HLA-partially-matched or -mismatched URD; (2) peripheral blood cell graft; (3) KPS/L <80 at cGVHD diagnosis; and (4) platelets <100 × 109/L at cGVHD diagnosis. Survival after diagnosis of cGVHD at 1-, 3- and 5-years was 75% (72-77%), 63% (60-66%), and 59% (56-62%). Factors significantly associated with worse survival were: (1) age >10 years; (2) transplant from an HLA-partially-matched or -mismatched URD; (3) advanced disease at transplant; (4) KPS/L <80; and (5) platelets <100 × 109/L. The cumulative incidence of NRM at 5 years was higher for children with KPS/L <80 (46%; CI: 40–52%) than for those with a higher KPS/L score (15%; CI: 12–18%; p<0.001). This translated to poorer survival of 42% (36-48%) vs. 66% (CI: 63–70%; p<0.001), respectively. 5 year cumulative incidence of NRM was also higher in children with platelets <100 × 109/L: 37% (32-43%) vs. 15% (CI: 12–18%; p<0.001). This also resulted in poorer survival (47%, CI: 42–52%; vs. 67%, CI: 63–71%; p<0.001). Cumulative incidence of discontinuation of systemic immune suppression (death and relapse treated as competing risks) at 1, 3 and 5 years after diagnosis of cGvHD were 22% (20-25%), 34% (31-37%), and 37% (34-40%). In conclusion, we identified several factors adversely correlated with NRM and survival children with cGvHD. The correlation between peripheral blood cell grafts and increased NRM without poorer survival may be explained by fewer relapses. This is the first large study elucidating factors affecting outcome after diagnosis of cGvHD in children. Our results may be useful for risk stratification.SurvivalNRMRelative Risk95% CIPRelative Risk95% CIPAge (baseline: 0–9 years) 10-191.321.091.600.005NSKPS/L (baseline: 80–100)<.001<.001 <801.891.522.34<.0013.012.293.96<.001 unknown1.341.001.780.051.641.122.430.015Platelets (x10e9/L) (baseline: ≥ 100)<.001<.001 <1001.631.322.01<0.0012.321.763.07<.001 Unknown1.330.991.780.061.731.182.520.005Donor (baseline: HLA-identical siblings)0.003<0.001 Other related1.681.132.520.0111.670.962.960.07 HLA-well-matchedunrelated1.401.021.940.041.250.801.960.33 Partially matched unrelated1.691.232.310.0011.941.282.940.002 Mismatched unrelated1.751.272.42<0.0012.311.493.59<0.001No data1.020.641.620.941.220.602.130.71Disease State (baseline: Early)<0.0010.005 Intermediate0.960.781.180.700.650.500.850.07 Advanced1.561.192.040.0010.920.631.350.68Graft (baseline: BM)0.002 BloodNS1.761.282.41<0.001 Cord BloodNS1.070.671.700.78NS=Not SignificantCumulative Incidence of NRM by Platelets and KPS/L at Diagnosis of cGvHDCumulative Incidence of NRM by Platelets and KPS/L at Diagnosis of cGvHDSurvival and Cumulative Incidence of Discontinuation of Immune SuppressionSurvival and Cumulative Incidence of Discontinuation of Immune Suppression Disclosures: No relevant conflicts of interest to declare.

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The Disease Risk Index Predicts Outcomes Including Relapse and Survival in CD34-Selected Allogeneic HCT for Acute Leukemia and Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v128.22.3498.3498 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3498-3498

Author(s):

Christina Cho ◽

Patrick Hilden ◽

Jonathan U. Peled ◽

Scott T. Avecilla ◽

Pere Barba ◽

...

Keyword(s):

Multivariate Analysis ◽

Cumulative Incidence ◽

Disease Risk ◽

Risk Index ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Relapse Free Survival ◽

Free Survival ◽

Donor Type ◽

Very High

Abstract INTRODUCTION: T-cell depleted allogeneic peripheral blood stem cell transplant (TCD PBSCT) using CD34 selection achieves relapse rates comparable to those of unmodified grafts (Pasquini et al., JCO 2012), but disease-related predictors of outcome have not been fully characterized in the TCD setting. We evaluated the prognostic utility of the refined Disease Risk Index (DRI; Armand et al., Blood 2014) in TCD PBSCT. METHODS: This was a retrospective analysis of patients who underwent first allogeneic HCT with TCD PBSCT for AML, ALL, or MDS at a single center between 1/2000 and 12/2015. Overall survival (OS), relapse-free survival (RFS), and chronic GVHD/relapse-free survival (CRFS) were estimated by the Kaplan-Meier method. Cumulative incidence of relapse, non-relapse mortality (NRM), acute GVHD (aGVHD), and chronic GVHD (cGVHD) were estimated using the cumulative incidence method for competing risks. The univariate association between variables of interest and OS/RFS/CRFS was evaluated using the log-rank test; Cox regression models assessed the adjusted effect of significant covariates on OS and RFS. Given only 1 patient with very high DRI, the high/very high DRI groups were combined. Similarly, given few patients with low DRI, the low/intermediate groups were combined in multivariate analysis. RESULTS: The analysis comprised a total of 519 patients. Median age was 55 years (range 18-73). There were 302 patients (58%) transplanted for AML, 144 (28%) for MDS, and 73 (14%) for ALL. Seventeen patients had low DRI scores (3%), 431 intermediate (83%), and 71 high/very high (14%). Median follow-up among survivors was 53.1 months (range 4.6-171.0). Two-year estimates for outcomes of interest were OS 62.8% (95% CI 58.5, 66.9), RFS 58.1% (95% CI 53.7, 62.3), and CRFS 54.0% (95% CI 49.5, 58.2). The cumulative incidence of relapse at 2 years was 17.3% (95% CI 14.2, 20.7). There were 0 relapse events in patients with low DRI, whereas intermediate and high/very high DRI scores were associated with a significantly increased incidence of relapse (p < 0.001), with 2 year estimates 14.7% (95% CI 11.5, 18.3) and 37.1% (95% CI 25.8, 48.4), respectively. The cumulative incidence of NRM was 24.6% (95% CI 20.9, 28.4) at 2 years. The cumulative incidence of aGVHD at 100 days was 12.5% (95% CI 9.8, 15.5) for grade 2-4 and 2.5% for grade 3-4 (95% CI 1.4, 4.1); with a cumulative incidence of cGVHD of 4.7% (95% CI 3.1, 6.7) at 1 year. NRM, aGVHD, and cGVHD did not vary with DRI. In univariate analysis, DRI was associated with significant differences in OS, RFS, and CRFS (Table 1; Figure). Additional factors associated with poorer OS in univariate analysis were HCT-CI score > 0, KPS < 90, donor type (matched unrelated or mismatched vs. matched related donor), and age > the median of 55.3 years; HCT-CI and KPS also correlated with significant differences in RFS. On multivariate analysis (Table 2), high/very high DRI corresponded to significantly greater risk of death (HR 1.72 for OS, [95% CI 1.24, 2.40]) and relapse or death (HR 1.86 for RFS [95% CI 1.35, 2.55]), compared with low/intermediate DRI. Multivariate analysis also showed that KPS < 90 was associated with worse OS and RFS, as did a higher HCT-CI score. Neither age nor donor type was significantly associated with OS in multivariate analysis. CONCLUSION: In a large cohort of patients undergoing first TCD PBSCT at a single center for acute leukemia or MDS, DRI score significantly correlated with relapse incidence as well as OS, RFS, and CRFS. We have previously shown that the HCT-CI score, which incorporates patients' baseline comorbidities, is also predictive of outcomes after TCD PBSCT. Combining these prognostic tools will serve to better select appropriate patients for TCD PBSCT, a transplant approach currently under investigation in a multicenter phase 3 trial (BMT CTN 1301). Disclosures Koehne: Atara Biotherapeutics: Consultancy.

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CD34+Selected Hematopoietic Stem Cell Transplants Conditioned with a Myeloablative Regimen Is Well Tolerated and Results in Good Outcomes in Patients with Myelofibrosis

Blood ◽

10.1182/blood-2018-99-113166 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4636-4636

Author(s):

Jeong-Ok Lee ◽

Jessica Flynn ◽

Molly Maloy ◽

Ann A. Jakubowski ◽

Esperanza B. Papadopoulos ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Systemic Treatment ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Grade Ii

Abstract Background: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the only curative treatment for myelofibrosis (MF). Due to high incidence of non-relapse mortality (NRM) in patients with MF who underwent allo-HCT with myeloablative conditioning (MAC), transplants in these patients are mostly done by utilizing a reduced intensity conditioning regimen with calcineurin inhibitors for graft versus host disease (GVHD) prophylaxis. We previously published very good outcomes in patients with acute leukemia (AML and ALL) and myelodysplastic syndrome (MDS) who underwent Ex- vivo CD34+-selected T-cell depleted (TCD) allo-HSCT following MAC regimens (Barba P et al. BBMT 2017; Tamari R et al. BBMT 2018). Aim: To study retrospectively the outcomes of patients with primary or secondary myelofibrosis (PMF or SMF) who underwent a CD34+ cell-selected Allo-HSCT. Methods: Twenty-one MF patients who underwent a CD34+-selected Allo-HSCT at a single center between October 2010 and November 2017 were included in this retrospective analysis. All patients received MAC regimen including busulfan, melphalan and fludarabine and antithymocyte globulin to prevent graft rejection. None of the patients received post-transplant GVHD prophylaxis. G-CSF mobilized peripheral blood stem cell grafts were depleted of T-cells using immunomagnetic CD34+ selection by CliniMACS device. Overall survival (OS), relapse free survival (RFS), relapse, NRM and the composite endpoint of GVHD-free/relapse-free survival (GFRS: defined as grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death) were estimated using the Kaplan-Meier and cumulative incidence method, with death considered a competing risk for relapse. Log-rank and Gray's tests were used to assess differences in patient and treatment characteristics. Results: Patient's and donor's characteristics are summarized in table 1. Neutrophils engraftment occurred in all patients at a median of 11 days (range: 8 - 14) and 90% (N = 19) achieved platelet engraftment at a median of 24 days (range, 14 - 77). Another patient achieved platelet engraftment only after splenectomy which was performed on post-transplant day 54. With a median follow-up of 54.06 months, the estimated 3-year OS and RFS were 84.4 % (95% CI, 69.6% to >99.9%) and 74.7% (95% CI, 57.6 to 96.9%), respectively (figure 1). The cumulative incidence of grade II-IV acute GVHD at day 100 was 33.3% (95% CI 11.2-54.1%); majority (N=5) had grade II and 2 patients had grade III (N=1) and grade IV (N=1) acute GVHD. Chronic GVHD developed in 2 patients including only 1 case requiring systemic treatment. The 3-year cumulative incidence rate of relapse was 9.5% (95% CI, <0.1 to 22.4%); three relapse cases include 2 patients with molecular/cytogenetic relapse and 1 patient with clinical relapse. Patients who relapsed were treated with donor lymphocyte infusion (DLI) (N=1), with azacytidine plus DLI (N=1) and both are alive with minimal molecular disease. The 3rd patient is alive without evidence of disease recurrence 43 months after second unmodified Allo-HSCT from the original donor. NRM at 3 years was 15.6% (95% CI, <0.1% to 32.4%) and the cause of all deaths (n=3) was primarily attributed to acute GVHD. The estimated 3-year GRFS was 66.7% (95% CI, 49.3 to 90.2%) (figure 2). TCD boost and unmodified boost were conducted successfully for patients with poor graft function (N=1) and late graft failure (N=1). Six patients received 8 DLIs for the following indications: mixed chimerism (N=3), relapse (N=3) and poor immune reconstitution (N=2). Conclusions: In this analysis we demonstrate that CD34+ selected Allo-HSCT following a chemotherapy only based MAC regimen is well-tolerated and an effective treatment for patients with myelofibrosis. We noted higher incidence of acute GVHD when compared to our reported outcomes in patients with acute leukemia and MDS undergoing a CD34+ selected allo-HSCT and all cases of mortality in this analysis were secondary to GVHD. This may suggest differences in the biology of the diseases and a more inflammatory milieu in pts with MF. Relapse incidence was notably low and all patients who relapsed were salvaged with further cellular therapy suggesting a strong graft-versus-leukemia effect in this disease. Disclosures Sauter: Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees.

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Allogeneic Hematopoietic Stem Cell Transplantation for Adult AML Patients with Granulocytic Sarcoma

Blood ◽

10.1182/blood.v118.21.2035.2035 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2035-2035

Author(s):

Hiroaki Shimizu ◽

Takayuki Saitoh ◽

Masatsugu Tanaka ◽

Takehiko Mori ◽

Nobutaka Kawai ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

Stem Cell ◽

Prognostic Factors ◽

Stem Cell Transplantation ◽

Treatment Outcomes ◽

Cell Transplantation ◽

Chronic Gvhd ◽

Granulocytic Sarcoma ◽

Free Survival

Abstract Abstract 2035 Background: Recently, we described that adult AML patients with granulocytic sarcoma (GS) at diagnosis presented unique characteristics including younger age, higher WBC counts, and higher frequency of French-British-American M4 and M5 morphology than those without GS. Furthermore, GS adversely affected the relapse rate and disease free survival. However, the appropriate therapeutic strategy, especially indication of allogeneic hematopoieteic stem cell transplantation (allo-HSCT), has remained unclear. Here, we present a large-scale retrospective analysis of 503 adult AML patients who underwent allo-HSCT that compared the clinical characteristics and treatment outcomes of patients with GS to those without GS. Patients and Methods: This study included 503 consecutive adult AML patients (median age 44 (15–73), male/female; 301/202), excluding patients with acute promyelocytic leukemia, who received allo-HSCT for the first time between January 2000 and December 2008 at 9 institutions participating in the Kanto Study Group for Cell Therapy (KSGCT). GS group was consisted of patients in whom GS occurred any time in the clinical course until transplantation, such as at diagnosis, relapse, and disease progression. The c2-test was used for comparison of binary variables. The Mann-Whitney U test was used for comparison of continuous variables. overall survival (OS) and leukemia free survival (LFS) were estimated by the Kaplan-Meier method, and compared using the log-rank test. The Cox proportional hazards regression model was used for multivariate analysis of prognostic factors. P < 0.05 was considered as statistically significance. Results: Of the 503 patients, 44 patients (8.7%) had GS before transplantation. All factors including patients' characteristics and transplantation procedure were not significantly different in each group, but the patients in GS group were significantly younger (GS: median 34 years; range, 17–60 years vs. non-GS: median 46 years; range, 15–73 years; p=0.002). Treatment outcomes, GS vs. non-GS: The cumulative incidences of grade II-‡W acute GVHD, chronic GVHD, and NRM at 1 year were not significantly different in each group. The 5-year OS rate did not differ significantly between the GS and non-GS groups (47% vs. 44%, respectively; p=0.621). The 5-year LFS rate also did not differ significantly (41% vs. 38%, respectively; p=0.646). Since patients in GS group were significantly younger as mentioned above, we performed a subgroup analysis on 336 patients aged 50 or younger; 37 patients in GS group and 298 in non-GS group. Age was not significantly different between the two groups. In this subgroup, too, there was no significant difference in both the 5-year OS rate and the 5-year LFS rate. Treatment outcomes in GS group: Patients in CR at allo-HSCT achieved the significantly superior 5-year OS rate and LFS rate compared to those in non-CR, (OS: 75% vs. 24%, respectively; p=0.002), (LFS: 60% vs. 24%, respectively; p=0.046). In contrast, the prognosis of 10 patients who performed allo-HSCT with accompanying GS was dismal; 9 patients experienced a relapse within 6 months. 5-year OS rate and LFS of 8 patients, who received prior local irradiation for GS, did not significantly differ from those who did not. Both acute and chronic GVHD did not significantly affect the OS and LFS rates, respectively. Twenty-four patients (55%) experienced a relapse after allo-HSCT. Regarding the sites of relapse, only GS, only bone marrow, and both bone marrow and GS were involved in 1 patient (4%), 13 (54%), and 10 (42%), respectively. In 10 patients (91%) out of 11 with GS at relapse, GS occurred at the same site between before and after allo-HSCT. Multivariate analysis identified age and disease status as independent prognostic factors for OS. Conclusion: Patients with GS, who treated with allo-HSCT, could achieve the comparable prognosis to those without GS despite poor prognosis of GS. Notably, an excellent treatment outcome was brought about in patients received allo-HSCT in CR. This study suggests that allo-HSCT during an appropriated period may overcome this unfavorable disease. Disclosures: No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood.v126.23.3139.3139 ◽

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.

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GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia

Blood Advances ◽

10.1182/bloodadvances.2018030171 ◽

2019 ◽

Vol 3 (9) ◽

pp. 1441-1449 ◽

Cited By ~ 3

Author(s):

Rohtesh S. Mehta ◽

Shernan G. Holtan ◽

Tao Wang ◽

Michael T. Hemmer ◽

Stephen R. Spellman ◽

...

Keyword(s):

Multivariate Analysis ◽

Acute Leukemia ◽

Pediatric Patients ◽

Hematopoietic Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Chronic Gvhd ◽

Cox Proportional Hazards ◽

Relapse Free Survival ◽

Free Survival ◽

Grade Iii

Abstract We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy–requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen–mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation–based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.

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Chimerism Analysis Is Predictive of Relapse-Free Survival After Allogeneic Transplantation for MDS

Blood ◽

10.1182/blood.v116.21.1332.1332 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1332-1332

Author(s):

Sanjay R. Mohan ◽

Lisa Rybicki ◽

Matt Kalaycio ◽

Ronald Sobecks ◽

Brian J. Bolwell ◽

...

Keyword(s):

T Cell ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

Lower Probability ◽

Unrelated Donor ◽

Univariable Analysis ◽

Relapse Free Survival ◽

Free Survival ◽

Chimerism Analysis

Abstract Abstract 1332 Chimerism analysis permits evaluation of the extent of donor engraftment following allogeneic hematopoietic cell transplantation (HCT) via differentiation between donor- and recipient-derived cells. Though relapse remains a major cause of treatment failure post-HCT for hematologic malignancies, the clinical utility of chimerism analysis for the early detection of morphologic relapse varies between different diseases and remains controversial. The predictive value of chimerism analysis for relapse rates and mortality in myelodysplastic syndromes (MDS) is not well-described. We reviewed serial chimerism results for 72 consecutive patients (pts) who underwent allogeneic HCT for MDS between 1999 and 2009; 9 pts were excluded from analysis due to lack of appropriately timed chimerism studies. Donor engraftment was initially assessed 28 days post-HCT and then at 2-week intervals through day 100. Chimerism studies were performed with peripheral blood using a short tandem repeat assay by PCR-based analysis. Acute and chronic GVHD rate, relapse-free survival (RFS), and overall survival (OS) were assessed for patients with donor leukocyte chimerism and T-cell chimerism ≥95% and <95%. The median age was 51 years (range 20–70) and 52% were male. The median time from MDS diagnosis to HCT was 5.4 months; 9 pts (14%) were in complete remission at the time of HCT, 11 (18%) were in partial remission, 17 (27%) had relapsed or refractory disease, and 26 (41%) were untreated. HCT-comorbidity index was low in 25 pts (40%), intermediate in 18 (29%), and high in 20 (32%). 31 pts (49%) received sibling donor HCT and the remainder received an unrelated donor graft. 40 (63%) received bone marrow and 23 (37%) received peripheral stem cells. Myeloablative (MA) busulfan- or cyclophosphamide-based preparative regimens were used in 47 pts (75%) and a non-myeloablative (NMA) regimen with fludarabine and TBI was given to the remaining pts. 61 pts achieved ≥95% donor leukocyte chimerism at a median of 29 days and 39 evaluable pts achieved ≥95% donor T-cell chimerism at a median of 42 days. Two pts did not achieve donor leukocyte chimerism ≥95% and 9 did not achieve donor T-cell chimerism ≥95% at any timepoint. Univariable analysis of prognostic factors for relapse showed that donor leukocyte chimerism ≥95% was significantly associated with lower probability of relapse (hazard ratio [HR] 0.11, 95% confidence interval [CI] 0.02–0.51, p=.005), whereas prior exposure to radiation therapy (excluding exposure during HCT preparative regimen) was associated with increased probability of relapse (HR 3.48, 95% CI 1.14–10.60, p=.028). Multivariable analysis implicated donor leukocyte chimerism <95% as the only independent risk factor for relapse. Transplant type (MA vs NMA) and cell source did not significantly impact the likelihood of relapse. Donor leukocyte chimerism ≥95% was not associated with acute or chronic GVHD. Univariable analysis of risk factors for survival showed that donor leukocyte chimerism ≥95% was associated with improved RFS (HR 0.29, 95% CI 0.09–0.97, p=.045) but not OS, both findings of which were confirmed on multivariable analysis. Donor T-cell chimerism ≥95% was not significant in univariable analysis; however, in multivariable analysis, controlling for comorbidity scores, donor T-cell chimerism <95% was associated with lower risk of chronic GVHD (HR 0.18, 95% CI 0.04–0.88, p=.034) but did not significantly impact relapse, RFS, or OS. In conclusion, achievement of a high donor leukocyte chimerism post-HCT for MDS is associated with improved RFS. Donor T-cell chimerism, however, is not predictive of outcome and its routine use for MDS pts should be reevaluated. Pts with donor leukocyte chimerism <95% might be considered for immunologic interventions such as withdrawal of immunosuppression or donor lymphocyte infusion. Disclosures: No relevant conflicts of interest to declare.

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CMV-Replication After Allogeneic Stem Cell Transplantation Is Associated with a Gvhd-Independent Reduced Relapse Risk in Lymphoma

Blood ◽

10.1182/blood.v120.21.1635.1635 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1635-1635

Author(s):

Ahmet H Elmaagacli ◽

Michael Koldehoff ◽

Nina K. Steckel ◽

Yael Hegerfeldt ◽

Markus Ditschkowski ◽

...

Keyword(s):

Overall Survival ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Disease Stage ◽

Aggressive Lymphoma ◽

Independent Effect ◽

Free Survival ◽

Pp65 Antigenemia ◽

Cmv Reactivation

Abstract Abstract 1635 Background: We have previously showed that a CMV- reactivation after allogeneic HSCT is associated with a reduced risk for leukemic relapse and improved overall survival in patients with AML (Elmaagacli et al Blood 2011). Further, experimental data in a lymphoma mice model reported from Erlach et al. showed that coinfection with murine CMV revealed a strong anti-lymphoma effect by induction of apoptosis in lymphoma cells and improving rate of overall survival in mice after transplant. Methods: This prompted us to investigate the influence of early replicative CMV infection in 94 (median age [years]: 45, 18 – 70) patients with lymphoma, who received transplants from unrelated (n=67) or related (n=27) donors. Patients were transplanted from HLA-identical (n=74), HLA-mismatched (n=20). 13 patients were transplanted for indolent lymphoma (FL n=11, CLL n=2), 67 patients for aggressive lymphoma (B-lineage n=35, T-lineage n=27, transformed n=5), 11 patients for MCL and 3 patients for HD. The disease stages of patients at HSCT were CR in 20 patients, PR in 40 patients, refractory in 30 patients and untested in 2 patients. 55 patients (59%) received previous autograft and 82 patients (87%) were treated prior to transplant with at least 3 chemotherapy lines. The hematopoietic cell transplantation specific comorbidity index (HCT-CI) were 0–2 in 76 patients (81%) and 3+ in 18 patients (19%). Myeloablative preparative regimen was applied in 60 patients (64%) while 34 patients (36%) received a RIC. Sixty-eight % of patients (n=48) were at risk for CMV reactivation based on either patient or donor pretransplant CMV serostatus. CMV replication as detected by pp65 antigenemia assay occurred in 34 patients (36%). Results: Taking all competing risks into account, the cumulative incidence of progressive free survival (PFS) at 5 years after alloSCT was 38 % (95 % confidence limit [95 % CL]: 31 – 45) in patients without as compared to 20 % (95 % CL: 9 – 31) in patients with early pp65 antigenemia (p<0.018). In multivariate analysis including parameters as grades II-IV acute graft-versus-host disease (GvHD), chronic GvHD, disease stage, chemorefractory, previous chemotherapy lines and pp65 antigenemia, CMV replicative status was confirmed as a strong independent predictor of PFS (hazard ratio [HR]: 0.29, 95 % CL: 0.08 – 1.00, p<0.049) together with chronic GvHD (HR: 0.32, 95 % CL: 0.13 – 0.80, p<0.016), and chemorefractory HR: 3.3, 95 % CL: 1.28 – 8.4, p<0.013). The anti-lymphoma effect was detectable across all lymphoma subsets and was most pronounced in patients with chemotherapy refractory lymphoma or refractory disease of lymphoma. However, Overall survival rate did not differ in both groups (51.9% for patients with CMV-replication versus 50.7% without n.s.) Conclusions: This is the first report which demonstrates a strong and independent effect of early CMV replication on the PFS in patients with lymphoma. This effect deserves further and more comprehensive studies with regard to its clinical relevance and the underlying anti-lymphoma mechanisms. Cumulative incidence of progression-free survival (PFS) stratified by posttransplant HCMV pp65-antigenemia and cell type of aggressive lymphoma. Disclosures: No relevant conflicts of interest to declare.

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Significance of Busulfan Dose Intensity On Outcomes of Hematopoietic Cell Allografting for AML in Second Complete Remission or Beyond: A Report From the EBMT Acute Leukemia Working Party

Blood ◽

10.1182/blood.v120.21.1929.1929 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1929-1929

Author(s):

Ali Bazarbachi ◽

Myriam Labopin ◽

Mohamed A. Kharfan-Dabaja ◽

Gérard Socié ◽

Nicolaus Kröger ◽

...

Keyword(s):

Complete Remission ◽

Cumulative Dose ◽

Cumulative Incidence ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

Hematopoietic Cell ◽

Unrelated Donor ◽

Number Of Patients ◽

Donor Source

Abstract Abstract 1929 Background: Allogeneic hematopoietic cell transplantation (HCT) is associated with inferior outcomes in patients with more advanced stage AML. In such cases, reducing the ablative intensity of the preparative regimen could potentially compromise its efficacy. We hereby compare transplant outcomes of two preparative regimens, known as FB2 and FB4, in patients (pts) with AML transplanted in second complete remission (CR2) or beyond at EBMT participating centers. Materials and methods: Between 2003 and 2010, 128 (FB2=88 (69%), FB4=40 (31%)) pts with a median age of (FB2=60 (22–70) years, FB4=42 (19–65) years, p<0.0001), with AML in ≥CR2 (FB2 (CR2=85 (97%), CR3=3 (3%)); FB4 (CR2=38 (95%), CR3=2 (5%)), p=0.67, underwent allogeneic HCT. FB2 comprised intravenous (IV) busulfan cumulative dose of 6.4 ± 10% mg/kg, while FB4 cumulative dose was 12.8 ± 10% mg/kg. Cytogenetic risks groups were similar: FB2 (good=17, int=31, poor=6) and FB4 (good=6, int=7, poor=0), p=0.35. For pts treated with FB2, donor source consisted of matched-related donors (MRD)=32, matched unrelated donor (MUD)=39, mismatched unrelated donors (MMUD)=8, unknown=9. For FB4, donor source consisted of MRD=17, MUD=15, MMUD=6, unknown=2. Use of peripheral blood stem cells (PBSC) was higher in the FB2 group (92% vs. 70%, p=0.001). Administration of anti-thymocyte globulin (ATG) was also higher in FB2 conditioned patients (89% vs. 45%, p<0.0001). Results: Median follow-up time was 24 (3–76) months. Median time to absolute neutrophil count engraftment (days) was 16 (5–38) and 16 (9–29) days, for FB2 and FB4, respectively (p=0.45). The 2-year leukemia-free survival (LFS), cumulative incidence of relapse (CI-R), and of non-relapse mortality (NRM) was: LFS (FB2=47±5% vs. FB4=70±8%, p=0.01), CI-R (FB2=27±5% vs. FB4=19±7%, p=0.24), and NRM (FB2=25±5% vs. FB4=10±5%, p=0.06). The 2-year cumulative incidence of chronic GVHD was similar (FB2=41±6% vs. FB4=43±8%, p=0.8). On multivariable analysis, favorable impact on 2-year LFS was observed with FB4 conditioning (HR 0.66 (95%CI: 0.46–0.97), p=0.03) and with longer interval from diagnosis to transplantation (> median) (HR=0.49 (95%CI: 0.29,0.85), p=0.01). When the analysis was performed by age groups, the statistical advantage of FB4 on LFS was lost, likely because of small numbers in each subgroup. Indeed, for pts <50 yrs. (n=43; FB2=16, FB4=27), LFS was (FB2=50±13% vs. FB4=72±9%, p=0.11), whereas for pts ≥50 yrs. (n=85, FB2=72, FB4=13), LFS was (FB2=47±6% vs. FB4=67±13%, p=0.18). Conclusion: Although limited by the small number of patients, these results suggest that FB4 is a reasonable preferred conditioning in patients with AML in ≥CR2. Disclosures: No relevant conflicts of interest to declare.

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Unmanipulated Haploidentical Bone Marrow Transplantation and Post-Transplant Cyclophosphamide for Hematologic Malignanices Following A Myeloablative Conditioning.

Blood ◽

10.1182/blood.v120.21.3034.3034 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3034-3034

Author(s):

Andrea P Bacigalupo ◽

Anna Maria Raiola ◽

Alida Dominietto ◽

Maria Teresa Van Lint ◽

Francesca Gualandi ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Myeloablative Conditioning ◽

Free Survival ◽

Disease Free ◽

Active Disease ◽

Related Mortality

Abstract Abstract 3034 Despite a large number of unrelated donors (UD), not more than 30% of patients who have activated a donor search, undergo an allogeneic UD stem cell transplant. HLA haploidentical family members are being increasingly considered as an alternative donors, both using T cell depleted or T cell replete grafts. Post-transplant high dose cyclophosphamide (PT-CY), introduced by the Baltimore group, has shown very promising results following non myeloablative conditioning regimens. We are now reporting 50 patients with high risk hematologic malignancies, who received a myeloablative regimen, followed by unmanipulated haploidentical bone marrow transplant (hBMT) and PT-CY. The myeloablative conditioning consisted of thiotepa (10 mg/kg), busulfan (9,6 mg/m2̂), fludarabine (150 mg/m2̂)(n=35), or total body irradiation (9,9–12 Gy), fludarabine (120 mg/m2̂) (n=15). The median age was 42 years (18–66); 23 patients were in remission and 27 had active disease; 10 patients were receiving a second allograft. Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median nucleated cell dose was 3.6 ×108̂/kg (range: 1,4 – 7,7). The median time to neutrophil counts of >0.5×109/L was 18 days (range, 13–30 days) and to platelet counts of >20×109/L 23 days (range, 14 – 58 days), respectively. There was no correlation between infused number of nucleated cells and days of neutrophil engraftment. The cumulative incidence of engraftment was 90%for neutrophils and 86% for platelets. Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full donor chimerism on day +30. The cumulative incidence of grade II-III acute GvHD was 12%, and of moderate chronic GvHD 10%. With a median follow up for surviving patients of 333 days (149–623), the cumulative incidence of transplant related mortality is 18%, and the rate of relapse 26%. The actuarial 22 months disease free survival is 68% for patients in remission and 37% for patients with active disease (p<0.001). Causes of death were pneumonia (n=3), haemorrhage (n=3), sepsis (n=3) and relapse (n=7). In conclusion, a myeloablative conditioning regimen followed by h-BMT with PT-CY, results in a low risk of acute and chronic GvHD and encouraging rates of transplant related mortality and disease free survival. Disclosures: No relevant conflicts of interest to declare.

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