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

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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Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT

Journal of Clinical Oncology ◽

10.1200/jco.19.00396 ◽

2020 ◽

Vol 38 (18) ◽

pp. 2062-2076 ◽

Cited By ~ 1

Author(s):

Rohtesh S. Mehta ◽

Shernan G. Holtan ◽

Tao Wang ◽

Michael T. Hemmer ◽

Stephen R. Spellman ◽

...

Keyword(s):

Multiple Testing ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

Pairwise Comparison ◽

Unrelated Donor ◽

Relapse Free Survival ◽

Free Survival ◽

Graft Versus Host ◽

Alternative Donor

PURPOSE There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]–bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor. METHODS We report composite end points of graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) and chronic GVHD (cGVHD)–free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant. RESULTS In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group. CONCLUSION Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.

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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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Ex Vivo T Cell-Depleted Haploidentical HCT for Children with Acute Leukemia after a Reduced-Intensity Preparative Regimen Containing Low-Dose TBI

Blood ◽

10.1182/blood.v128.22.4673.4673 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4673-4673

Author(s):

Yeon Jung Lim ◽

Ho Joon Im ◽

Sung Han Kang ◽

Hyery Kim ◽

Kyung-Nam Koh ◽

...

Keyword(s):

T Cell ◽

Acute Leukemia ◽

Low Dose ◽

Pediatric Patients ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Reduced Intensity

Abstract Background: Recent advances in haploidentical hematopoietic cell transplantation (HHCT) enabled this transplant using haploidentical family donor to be a viable option for pediatric patients lacking matched related or unrelated donor. In our center, HHCT using ex vivo T cell-depleted (TCD) grafts after reduced-intensity conditioning (RIC) was conducted since 2008. The safety and efficacy of this transplantation modality for pediatric with acute leukemia were investigated. Methods: Thirty-one pediatric patients with acute leukemia received ex vivo T cell-depleted HHCT at Asan Medical Center Children's Hospital between July 2008 and June 2016. Four patients received CD3-depleted grafts and 27 received TCRαβ-depleted stem cells. Among 31 patients, 9 had ALL (3 CR1, 6 CR2-3), 22 had AML (18 CR1-3, 4 NR). Seven patients had relapsed after previous allogeneic HCT. All 31 patients underwent a uniform RIC regimen consisting of low-dose total body irradiation (LD-TBI; 600 cGy), fludarabine (FLU; 180 mg/m2), cyclophosphamide (CY; 100 mg/kg), and rabbit anti-thymocyte globulin (r-ATG; 3 mg/kg). Results: The median age at HHCT was 14 years (range, 1-19). All 31 patients achieved sustained neutrophil engraftment at a median of 10 days (range, 9-17) post-transplant. The cumulative incidence of acute GVHD grade II-III and III were 30% and 21%, respectively. None developed grade IV. Two of 26 evaluable patients developed extensive chronic GVHD. As of July 2016, 18 of the 31 patients survive free of disease with a median follow-up of 26 months (range, 2-98 months). Ten patients have died. Causes of death were relapse (n=9) and disseminated tuberculosis (n=1). Only one patient died of non-relapse cause, leading to TRM of 5.3% at 1 year. EFS and OS at 2 years for all patients were 51% and 60%, respectively. Sixteen patients with AML who received a first HHCT in any CR showed a favorable outcome (EFS of 85%), whereas, 6 patients with ALL who received a first HHCT in CR showed a poor EFS of 28%. In addition, all patients (6 with AML and 3 with ALL) who received a subsequent HCT in CR or were not in remission developed relapse. Conclusions: This study demonstrated that our ex vivo T cell-depleted HHCT using RIC is a feasible therapy with low TRM for pediatric patients with acute leukemia. The outcome of patients with AML who received their first transplant in CR was excellent in this treatment modality. However, the outcome of ALL was poor suggesting that more intensified conditioning regimen may be required for those diseases. Furthermore, an innovative treatment strategy is warranted to improve the outcome for patients with relapsed or refractory acute leukemia. Disclosures No relevant conflicts of interest to declare.

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Second Transplants in Relapsed Multiple Myeloma (MM): Autologous (AHCT) Versus Non-Myeloablative/Reduced Intensity (NST/RIC) Allogeneic Transplantation (AlloHCT)

Blood ◽

10.1182/blood.v118.21.824.824 ◽

2011 ◽

Vol 118 (21) ◽

pp. 824-824 ◽

Cited By ~ 1

Author(s):

Cesar O. Freytes ◽

David H. Vesole ◽

Xiaobo Zhong ◽

Jennifer Le-Rademacher ◽

Angela Dispenzieri ◽

...

Keyword(s):

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Allogeneic Transplantation ◽

Lower Probability ◽

Unrelated Donor ◽

Karnofsky Performance Score ◽

Risk Of Death ◽

Significant Difference ◽

Reduced Intensity

Abstract Abstract 824 There is no standard therapy for MM relapsing after autologous hematopoietic cell transplantation (AHCT). A second AHCT can result in additional progression-free survival (PFS). Nonmyeloablative/reduced intensity conditioning (NST/RIC) allogeneic transplantation (AlloHCT) has the advantages of a tumor-free graft and the potential of a graft-versus-myeloma (GVM) effect. Few studies have compared second AHCT vs. NST/RIC AlloHCT. We compared the outcome of second AHCT or NST/RIC AlloHCTafter relapse from prior AHCT in patients with MM reported to the CIBMTR from 1995–2008. Recipients of planned tandem transplants, AlloHCT for graft failure or second malignancies and myeloablative alloHCT were excluded. 137 patients underwent second AHCT and 152 underwent NST/RIC AlloHCT (32 HLA-identical sibling and 120 unrelated donor). The table below illustrates clinical characteristics and patient outcomes. AlloHCT recipients were significantly younger (median 53 years [yrs] of age vs. 56 yrs in the AHCT cohort (p < 0.001). The groups were similar in Karnofsky performance score (KPS) and gender. Conditioning regimens differed between groups. In the AHCT cohort, 85% were melphalan based. In the NST/RIC alloHCT cohort, 38% received melphalan + other drugs and 24% received total body irradiation +/− other drugs but no melphalan (p <0.001). Time from 1st to 2nd transplant was significantly shorter for the AlloHCT cohort (30 vs. 23 months, p = 0.014). Acute graft-versus-host disease (GVH) was 35% at 60 days while chronic GVHD was 44% at 36 months.Patient CharacteristicsAutologousAllogeneicP-valueNumber of patients137152Age at 2nd transplant, median (range), years56 (28–65)53 (32–65)0.001*Gender Male84 (61)90 (59)0.720Karnofsky Score pre-transplant ≥90%68 (50)76 (50)0.884Time from 1st to 2nd transplant, months, median (range)30 (6–122)23 (6–78)0.014* 6–24 months44 (32)78 (51)0.001* >24 months93 (68)74 (49)OutcomesTreatment-related Mortality (TRM)12 months2 (1–5)13 (8–19)<0.001*60 months4 (2–8)15 (10–21)<0.001*Relapse/Progression12 months51 (43–58)72 (64–79)<0.001*36 months82 (76–88)80 (73–86)0.655Progression-free survival12 months47 (40–54)15 (10–21)<0.001*36 months13 (9–19)6 (3–10)0.038*Overall Survival (OS)12 months83 (77–89)51 (42–58)<0.001*36 months46 (37–54)20 (14–27)<0.001*60 months29 (21–38)9 (5–15)<0.001**Significant difference The most common cause of death in both cohorts was progression of MM. On multivariate analysis risk of death was higher for alloHCT (HR 2.38, p < 0.001), KPS < 90 (HR 1.96, p < 0.001), and year of transplant (2004 or earlier, HR 1.77, p = < 0.001). AlloHCT was associated with significantly higher risk of TRM (HR 7.14, p < 0.001). Durie-Salmon Stage III was associated with a higher risk of relapse (HR 2.70, 95% CI: 1.93–3.80, P<0.001) and treatment failure in the alloHCT group (HR 3.05, 95% CI: 2.20–4.22, p < 0.001). We conclude that patients with MM who underwent NST/RIC alloHCT after AHCT failure experienced higher TRM and lower probability of survival compared with those who received second AHCT. Because genetic risk data were not available for these patients, we cannot exclude the possibility that the alloHCT population was a higher risk population. Despite this limitation, our data demonstrate that the value of alloHCT after relapse from prior AHCT is limited. Disclosures: No relevant conflicts of interest to declare.

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Split Mixed Donor Chimerism Early after T-Cell Depleted Reduced Intensity Conditioned Allogeneic Haematopoietic Stem Cell Transplantation Predicts Survival

Blood ◽

10.1182/blood.v124.21.423.423 ◽

2014 ◽

Vol 124 (21) ◽

pp. 423-423 ◽

Cited By ~ 1

Author(s):

Francesca A M Kinsella ◽

Amy Gudger ◽

Charlotte F Inman ◽

Graham Mc Ilroy ◽

Sandeep Nagra ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

High Risk ◽

Chronic Gvhd ◽

Haematopoietic Stem Cell ◽

Prognostic Impact ◽

Relapse Free Survival ◽

Free Survival ◽

Donor Chimerism ◽

Risk Of Relapse

Abstract The significance of mixed donor chimerism as a hallmark of an unsuccessful graft versus leukaemia effect and disease relapse is unclear. Whilst some studies have described changes in PBMC and T cell chimerism that may predict relapse, patients at high risk are not identifiable at a stage to permit early intervention. In this retrospective study, the prognostic impact of early “split” PBMC and T cell chimerism in 212 patients who underwent T cell depleted RIC-SCT at 2 UK centers is described. 118 and 94 patients were transplanted using PBMC grafts from matched unrelated or sibling donors respectively. 169 received fludarabine and melphalan, 24 other fludarabine containing regimes, 17 BEAM, and 2 TLI. 203 underwent TCD with alemtuzumab, whilst 9 received ATG. Overall survival by day 3773 days post-SCT was 67.1%, and relapse-free survival was 58.9%. 28.7% experienced acute GvHD (grade 2 or above), and 22.8% developed chronic GvHD. Patients were grouped according to percentage donor PBMC and T cell chimerism at a median of 49 days post SCT (25% and 75% percentiles, 31 and 61 days respectively). 68 Patients exhibited “split” chimerism (SC) in whom PBMC chimerism was >99%, but T-cell chimerism <98%. SC patients demonstrated comparable overall survival to the 81 patients with full donor chimerism (FC) in whom both haematopoietic compartments displayed donor chimerism >99% (HR 1.36, 95% CI 0.697 - 2.638, log-rank p= 0.3698). In contrast, 63 patients with chimerism of <98% in both compartments (MC) exhibited significantly worse overall survival, than the SC cohort (HR 2.10, 95% CI 1.13 - 3.92, log-rank p=0.019). Of that MC cohort, those entering HSCT with intermediate or high risk disease had 3 times the relative risk of relapse compared to MC patients with low risk disease. Multivariate analysis confirmed the predictive value of early SC versus MC status. Despite differences in overall survival SC and MC patients displayed comparable relapse free survival. It was therefore hypothesised that SC patients experienced improved OS compared to MC patients by responding to donor lymphocyte infusion (DLI). In this cohort, 11 original FC, 28 SC, and 33 MC patients underwent DLI at medians of 808, 325 and 227 days post SCT respectively. There were no differences between the groups in the proportion of patients receiving DLI for molecular relapse versus the presence of residual host haematopoiesis. SC patients displayed significantly improved OS after DLI than MC patients (HR 0.37 95% CI 0.15 - 0.91, log-rank p= 0.03), where all deaths were due to disease. To conclude, this is the first study to show that early “split” chimerism post SCT predicts overall survival after HSCT in a T deplete setting, and identifies patients with mixed PBMC and T cell donor chimerism at day 50 to be at significantly greater risk of relapse. This data supports a rationale to intervene early in MC patients post SCT, particularly those with an intermediate or high pre-SCT disease risk. Work to elucidate targetable mechanisms is underway. Disclosures No relevant conflicts of interest to declare.

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Impact of KIR/HLA Incompatibilities after Posttransplant Cyclophosphamide Based T Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-125243 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3340-3340

Author(s):

Sarah Lindner ◽

Tobias Berg ◽

Christian Seidel ◽

Franziska Kalensee ◽

Michael A. Rieger ◽

...

Keyword(s):

T Cell ◽

Nk Cells ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Free Survival ◽

The Impact

Introduction: Posttransplantation cyclophosphamide (PTCy) based T cell-replete haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) is a valid option for patients with indication for allogeneic HSCT without a human leucocyte antigen (HLA) matched donor. However, selection criteria to determine the optimal among several available haplo donors are still a matter of debate. Especially, the impact of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA) incompatibilities (inc) in the setting of PTCy T cell-replete haplo HSCT is unclear. PTCy has been reported to eliminate most mature donor NK cells infused with the graft, including single KIR+ NK cells, thereby blunting NK cell alloreactivity in this setting (Russo et al., Blood 2018). Willem et al. (J Immunol 2019) reported (i) a significant loss of KIR2DL2/3+ NK cells at day +30 in patients with inhibitory KIR/HLA incompatibility (inc.) suggesting that PTCy might target responsive KIR NK cells and (ii) a correlation of genetic KIR2DL/HLA inc. with less relapse, but more graft-versus-host-disease (GvHD). Similarly, NK alloreactivity defined as KIR receptor-ligand mismatch or group B KIR haplotype with the presence of KIR2DS2 has been correlated with improved survival (Salomon et al., BBMT 2018). Aims of our study were to evaluate the impact of (i) HLA/KIR inc, (ii) donor KIR genotype and (iii) HLA-DP mismatch status on survival and incidence of relapse, acute and chronic GvHD in our homogeneously treated, independent patient cohort. Patients and methods: We retrospectively analyzed the outcome of 51 consecutively transplanted patients (AML/MDS (n=28/5), ALL (n=9), HD (n=2), NHL (n=5), CML (n=1), PMF (n=1)) receiving a PTCy based T cell-replete haplo HSCT between 01/2011-12/2018. All patients received a myeloablative conditioning regimen (fludarabine/total body irradiation (FTBI) or thiotepa/busulfan/fludarabine (TBF)) with unmanipulated bone marrow (98%) as the preferred graft (median CD34+ cells: 3.02 x 106/kg (range, 1.50-6.90) and median CD3+ T cells: 3.54 x 107/kg (range 1.52-43.74)). GvHD prophylaxis with ciclosporin A started on day 0, mycophenolate-mofetil on day +1, PTCy was applied on day +3 and +5. Results: Patient, donor and transplant characteristics as detailed in table 1 were well balanced between the inh. KIR/HLA inc. group (n=29) vs. no inh. KIR/HLA inc. group (n=22) with the exception of the median donor age (41.7 (range, 23.4-73.7) vs. 33.6 years (range, 19.0-56.2), resp. All patients engrafted. At day +28 (range, 20-29; n=26) CD3+ cells were 88.5/nL (range, 3-665), CD3+CD4+ cells 22.5/nL (range, 0-277.0), CD3+CD8+ cells 117.0/nL (range, 7-478), CD19+ cells 1.0/nL (range, 0-12), CD56bright cells 74.4/nL (range11.1-93.4), CD56dim cells 25.5/nL (range, 6.4-88.9) measured by flow cytometry and without differences between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. Cytomegalovirus (CMV) reactivation occurred in 73.3% of patients at risk and median time of occurrence was 32 days (range, 12-97) without difference between groups. Median follow-up for surviving patients was 26.1 months (range, 2.8-92.8) and we found no significant differences in 2-year overall survival (OS; 65.3±10.3 vs. 89.6±7.0, p=0.311), 2-year relapse-free survival (RFS; 66.0±9.4 vs 77.8±10.2, p=0.235), GvHD- and relapse-free survival (GRFS; 48.4±9.8 vs 60.5±12.0, p=0.182) as well as cumulative incidence (CI) of relapse (23.3% vs 16.2%, p= 0.283), acute GvHD grade 2-4 (27.6% vs 31.8, p=0.563), moderate-severe chronic GvHD (22.2% vs. 9.9%, p=0.227) and NRM (16.3% vs 5.3%, p=0.283) between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. This was also the case for donor KIR genotype AA vs AB (n=46; 2-y OS: 74.9±13.0% vs. 73.0±9.9%, p=0.844; 2-y RFS: 60.0±14.8% vs 74.5±8.4%, p=0.645) and HLA-DP-identical/permissive mismatch (MM) vs non permissive MM (n=45; 2-y OS: 70.7±10.0% vs 72.7±13.4%, p=0.945; 2-y RFS: 73.2±8.2% vs 63.6.0±14.5%, p=0.798) Conclusion: Our outcome data support the hypothesis of PTCy eliminating mature donor NK cells infused with the graft and thereby reducing the impact of alloreactivity in this setting. However, our patient number is quite small and the findings need to be validated in larger cohorts and preferably prospective studies. Disclosures Lindner: Celegene, Sanofi, Neovii: Honoraria, Research Funding. Berg:Riemser Pharma GmbH: Consultancy, Honoraria; Incyte, Abbvie, Astellas, Alexion and Celgene: Other: travel support. Bug:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants. Schwaeble:Uniqure BV: Research Funding. Ullrich:CellGenix: Honoraria, Research Funding; Novartis: Research Funding.

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Comparison of Outcomes Between 2-Year Survivors After Myeloablative and Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.3307.3307 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3307-3307

Author(s):

Ronald Sobecks ◽

Robert Dean ◽

Lisa Rybicki ◽

Matt Kalaycio ◽

Brad Pohlman ◽

...

Keyword(s):

Chronic Gvhd ◽

Multivariable Analysis ◽

Secondary Malignancy ◽

Disease Relapse ◽

Cmv Infection ◽

Relapse Free Survival ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Free Survival ◽

Reduced Intensity

Abstract Abstract 3307 Poster Board III-195 Myeloablative (MA) and reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) are both effective treatment approaches for patients with otherwise incurable hematologic diseases. However, patients who survive beyond 2 years are still at risk for significant morbidity and mortality. Differences in these later post-transplant outcomes may exist between those patients who received MA and RIC regimens. We therefore investigated outcomes on 677 patients (590 MA and 87 RIC) with hematologic diseases who underwent alloHSCT at our institution from 1/90-12/06. 235 MA and 37 RIC patients survived >2 years (40% vs. 42%, respectively, p=0.63). Factors predictive for surviving >2 years on multivariable analysis included younger age, greater Karnofsky performance status (KPS) at transplant, related donor and HLA matched donor. For > 2 yrs survivors, as compared to those treated with MA conditioning the RIC patients were older (median age 55 vs. 39 yrs, p<0.001), had better KPS at transplant (p<0.001), more commonly had lymphoid diagnoses (24 [65%] vs. 62[28%], p<0.001), had longer median time from diagnosis to transplant (19 vs. 6 mos, p<0.001), had more prior chemotherapy (p<0.001) and radiation therapy (p=0.036), more often received a TBI-based preparative regimen (100% vs. 15%, p<0.001) and peripheral blood stem cells (100% vs. 5%, p<0.001). There were no differences between the groups regarding gender, race, comorbidity index score, donor relationship, donor to recipient gender, HLA matched transplants, incidence or severity of acute or chronic GVHD, CMV infection, other infections or overall survival. Disease relapse was higher in the RIC group (6[16%] vs. 22[9%], p=0.048). Currently, for these >2 yr survivors 178 (76%) MA and 28 (76%) RIC patients remain alive at median follow-ups of 72 (range, 3-196) vs. 33 mos (range, 5-86), respectively (p<0.001). Death occurred most commonly for the MA pts due to relapse, then chronic GVHD, pulmonary toxicity, infection and secondary malignancy, while relapse and secondary malignancy were the most common causes for RIC pts. As compared to those with lymphoid diseases those with myeloid diseases had superior relapse-free survival (RFS) (Figure, p=0.012) and tended to have better overall survival (OS) (p=0.09). Myeloid disease status was also predictive of lower disease relapse (p=0.005) and better relapse-free survival (p=0.014) on multivariable analysis. However, no differences in CMV infection, other infections, incidence and severity of chronic GVHD, relapse, RFS or OS were found when comparing MA vs. RIC patients for myeloid and lymphoid diseases independently. We conclude that the majority of MA and RIC patients surviving >2yrs after alloHSCT remain alive and relapse-free. The superior RFS for patients with myeloid diseases is likely related to a more robust graft-vs-malignancy effect. Further strategies with novel approaches to decrease late relapses for these patients are warranted. Disclosures No relevant conflicts of interest to declare.

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Comparison of Outcomes for Non-Myeloablative (NMA) and Myeloablative (MA) Conditioning for Adults with Acute Lymphoblastic Leukaemia (ALL) in First and Second Complete Remission (CR): a Center for International Blood and Marrow Transplant Research (CIBMTR) Analyisis.

Blood ◽

10.1182/blood.v114.22.872.872 ◽

2009 ◽

Vol 114 (22) ◽

pp. 872-872 ◽

Cited By ~ 3

Author(s):

David I. Marks ◽

Tao Wang ◽

Waleska S. Peréz ◽

Donald W. Bunjes ◽

John F. DiPersio ◽

...

Keyword(s):

Multivariate Analysis ◽

T Cell ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Cell Depletion ◽

Unrelated Donor ◽

Conditioning Group ◽

T Cell Depletion ◽

Hematopoietic Stem ◽

Donor Transplant

Abstract Abstract 872 The efficacy of reduced intensity or NMA conditioning for allogeneic hematopoietic stem cell transplantation (HCT) for adults with ALL is uncertain. Using CIBMTR data we compared the outcomes of 92 patients ≥16 years who had NMA conditioning with 1421 patients who had myeloablative conditioning (MC) for allografts using sibling and unrelated donors for ALL in CR1 or CR2. Conditioning in the NMA group included regimens containing busulfan ≤ 9 mg/kg (27), melphalan ≤ 150 mg/m2 (23) or low-dose total body irradiation (36) and others (7). The NMA conditioning group were older (median 45 vs. 28 years, p<0.001) and more received peripheral blood grafts (73% vs. 43%, p<0.001). Other major potential prognostic factors were similar in the two groups. After a median follow-up of 54 vs. 38 months respectively, the NMA vs. MA conditioning groups had slightly less acute grade 2-4 graft-vs-host-disease (GVHD), less chronic GVHD but similar transplant-related mortality (TRM). However the NMA conditioning group experienced slightly more relapse (35% vs. 26%, p=0.08) yet similar overall survival (OS) (Figure): Outcome:MANMAP-value Acute GVHD @ 100 days, grades (2-4)46 (43-49)39 (29-49)0.16 Chronic GVHD @ 3 years42 (39-44)34 (24-44)0.16 TRM @ 3 years, %33 (31-36)32 (23-43)0.86 Relapse @ 3 years, %26 (23-38)35 (25-46)0.08 Leukemia-free survival (LFS) @ 3 years, %41 (38-44)32 (22-43)0.12 OS @ 3 years, %43 (40-46)38 (28-49)0.39 Multivariate analysis showed that a low Karnofsky score (KPS) and T cell depletion were associated with higher TRM but conditioning intensity had no impact on TRM (RR with NMA 0.97, P=0.89). Relapse risk with NMA conditioning was slightly, but not significantly higher ( (RR)=1.34, p=0.15) as was a CR2, particularly with a short (<12 months) initial CR (RR=2.74; longer remission (12 months) RR1.51, P<0.0001). Multivariate analysis demonstrated significantly improved OS with: KPS>80, CR1, lower WBC, no extramedullary disease, a well matched unrelated or a sibling donor, transplant since 2001, in younger patients (<30y), conditioning without TBI and GVHD prophylaxis without T-cell depletion. However ATG use did not affect survival.. The most common cause of death was relapse; which was similar in MA and NMA HCT (46% vs. 35%). Despite the older age in the NMA group, OS and LFS at 3 years was similar to those receiving MA HCT. In comparing the outcomes of NMA and MA conditioning in sibling vs. unrelated donor transplant recipients we found that there was slightly, but not significantly more relapse with NMA [34 (18-52)% vs. 26 (23-30)%, p=NS and 36 (24-49)% vs. 25 (22-28)%, p=NS respectively]. This was associated with similar OS of 40 (23-59)% vs. 50 (45-54)% and 37 (25-50) vs. 38 (34-41)% in the sibling and unrelated donor groups. Conclusions: These data suggest that NMA conditioning is worthy of investigation in prospective clinical trials of adult ALL. These trials should include both well matched unrelated and related donors, but importantly, NMA conditioning may not fully overcome the adverse impact of poor pre-HCT KPS on outcome. >Disclosures: No relevant conflicts of interest to declare.

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Evidence of Effect Modification of Graft-Versus-Leukemia Effect of Cytomegalovirus By Alemtuzumab in Myeloid Malignancies Undergoing Unrelated Donor Transplantation

Blood ◽

10.1182/blood.v124.21.5927.5927 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5927-5927

Author(s):

Mohamed Shanavas ◽

Jieun Uhm ◽

Naheed Alam ◽

Eshetu G Atenafu ◽

John Kuruvilla ◽

...

Keyword(s):

T Cell ◽

Cumulative Incidence ◽

Low Dose ◽

Effect Modification ◽

Cell Depletion ◽

Unrelated Donor ◽

Relapse Free Survival ◽

T Cell Depletion ◽

Free Survival ◽

Myeloid Malignancies

Abstract Several studies have suggested a beneficial effect of CMV seropositivity and or reactivation on relapse risk after allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies. Inability to replicate this finding in T cell depleted HCT is suggestive of a potential effect modification between TCD and CMV in this setting, but this has not been addressed in previously published studies. We have retrospectively analyzed transplant outcomes in 192 patients with myeloid malignancies who have undergone unrelated donor HCT at our center during January 2006 –November 2013. Among this 111 patients received in vivo TCD with low dose (30 mg) alemtuzumab and 81 patients received non-TCD transplants. Recipients were CMV seropositive in 57% of TCD transplants and 59% of non-TCD transplants. Analysis showed a significant effect modification (p=0.03 for interaction) between alemtuzumab and CMV serostatus on relapse risk, and stratified analysis based on recipient CMV status showed inferior outcomes with alemtuzumab in CMV seropositive recipients but not in CMV seronegative recipients. In CMV seropositive recipients alemtuzumab was an independent predictor of higher relapse (Hazard Ratio=13.95, p=0.008), inferior relapse free survival (HR=2.30, p=0.002), and inferior overall survival (HR= 2.04, p=0.008). There was no difference in NRM between CMV seropositive and CMV seronegative groups, or between TCD and non-TCD transplants. These findings suggest the presence of an effect modification by TCD on CMV's effect on relapse, resulting in inferior transplant outcomes with low dose Alemtuzumab in CMV seropositive recipients, but not in seronegative recipients. Figure 1. CIR, NRM, RFS, and OS showing differential effects of T cell depletion between CMV seropositive and seronegative recipients (A-B) Cumulative incidence of relapse, (C-D) Non-relapse mortality, (E-F) Relapse free survival, and (G-H) Over all survival. Figure 1. CIR, NRM, RFS, and OS showing differential effects of T cell depletion between CMV seropositive and seronegative recipients. / (A-B) Cumulative incidence of relapse, (C-D) Non-relapse mortality, (E-F) Relapse free survival, and (G-H) Over all survival. Disclosures Off Label Use: Alemtuzumab for GVHD prophylaxis.

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Low-Dose Anti-Thymocyte Globulin for Graft-Versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplant

Blood ◽

10.1182/blood.v128.22.5782.5782 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5782-5782

Author(s):

Adam Bryant ◽

Ranjeeta Mallick ◽

Lothar B. Huebsch ◽

David S. Allan ◽

Harold Atkins ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Relapse Free Survival ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Free Survival ◽

Related Donor

Abstract Background Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic in-vivo T-Cell depletion with antithymocyte globulin (ATG) has recently been reported as leading to decreased GVHD rates in matched unrelated and related donor HSCT, without increases in relapse or death. Understanding that higher rates of GVHD are observed with matched unrelated versus matched related donor HSCT, we have always had a local policy to give ATG as part of GVHD prophylaxis in patients undergoing HSCT from an unrelated donor. Here we report and compare clinical outcomes of patients who did and did not receive ATG at our transplant center using a unique, substantially lower ATG dose than previously reported. Methods We conducted a retrospective single-center database study comparing outcomes in 110 matched unrelated donor (MUD; ATG-exposed) and 78 matched related donor (MRD; ATG-unexposed) HSCT patients transplanted for any malignant indication at The Ottawa Hospital from 2009 to 2014. Patients were exposed to a rabbit ATG formulation (Thymoglobulin ®) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1 prior to stem cell infusion, to total 2.5 mg/kg. Primary outcomes assessed were incidence of acute and chronic GVHD, defined as new-onset GVHD requiring systemic immunosuppressive therapy at less or more than 100 days post HSCT, respectively. Secondary outcomes included disease relapse and survival. Results At baseline there were no significant differences in median age at transplant, sex, disease indication or risk index, graft source, conditioning regimen and intensity between ATG exposed (MUD) and unexposed (MRD) cohorts. The majority of patients in both cohorts had intermediate or high disease risk index. There were significant baseline differences between the ATG exposed and unexposed cohorts with respect to proportion of 7/8 mismatched unrelated donor transplants (14 v 6% respectively, p = 0.015) and median CD34+ dose (4.9 v 7.6 x 108 cells; p < 0.001). No differences were noted in platelet engraftment. ATG exposed patients had significantly shorter time to neutrophil engraftment than the unexposed cohort (16 v 19 days respectively; p=0.007). ATG exposed patients had significantly lower rates of GVHD compared to the unexposed cohort (57 v 79%; p=0.005), with differences noted predominantly in rates of chronic GVHD (18 v 44%, p= 0.009). The proportion of patients off immune suppression one year after HSCT was not significantly different between the cohorts.At median follow-up of 13 (1-73) months for the ATG exposed cohort and 20 (0-69) months for the ATG unexposed cohort, no significant differences in overall survival (median overall survival not met for either cohort), cumulative incidence of relapse (26 v 29%; p=0.73) or relapse-free survival (not met in ATG exposed; 26.2 months in ATG unexposed, p=0.22) were observed between groups (Figure 1). Significant differences were observed with respect to GVHD-Free Relapse-Free Survival (GRFS) between ATG exposed and unexposed cohorts, with a two-year GRFS of 23 v 3% respectively (p = 0.003). There were no significant differences between cohorts in proportion of patients with post HSCT infectious episodes or ICU admissions. Conclusions Here we report significantly lower rates of chronic GVHD and significant improvement in GVHD-free relapse-free survival in our ATG exposed MUD HSCT cohort compared to our ATG unexposed MRD. These findings were observed without differences in relapse or survival outcomes, infectious complications or ICU admissions. While in keeping with other recent reports on ATG use for GVHD prophylaxis, our findings indicate that a lower dose of ATG may be effective in preventing GVHD. Our study suggests that a broader exploration into the optimal dosing of this prophylactic GVHD agent is warranted. Disclosures Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees. Sabloff:Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Research Funding; Alexion: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding.

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