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

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

Blood ◽

10.1182/blood.v128.22.2285.2285 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2285-2285

Author(s):

Simona Pagliuca ◽

Antonio M Risitano ◽

Sylvie Chevret ◽

Flore Sicre de Fontbrune ◽

Alienor Xhaard ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Graft Versus Host

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

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Tacrolimus/Sirolimus Vs. Tacrolimus/Methotrexate for Graft-Vs.-Host Disease Prophylaxis After HLA-Matched, Related Donor Hematopoietic Stem Cell Transplantation: Results of Blood and Marrow Transplant Clinical Trials Network Trial 0402

Blood ◽

10.1182/blood.v120.21.739.739 ◽

2012 ◽

Vol 120 (21) ◽

pp. 739-739 ◽

Cited By ~ 12

Author(s):

Corey Cutler ◽

Brent R. Logan ◽

Ryotaro Nakamura ◽

Laura Johnston ◽

Sung W. Choi ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Graft Vs Host Disease ◽

Grade Ii ◽

Related Donor

Abstract Abstract 739 The combination of a calcineurin inhibitor and methotrexate has been the standard of care in graft-vs.-host disease (GVHD) prophylaxis for over 25 years, with resultant rates of grade II-IV acute GVHD between 30–50%. The mTOR inhibitor, sirolimus, has demonstrated promise in a number of Phase II trials as an immunosuppressant used for GVHD prophylaxis. The BMT CTN, sponsored by the NHLBI and NCI, conducted a multicenter, randomized controlled trial comparing the combination of tacrolimus and sirolimus (Tac/Sir) with tacrolimus and methotrexate (Tac/Mtx) as GVHD prophylaxis after matched, related donor (MRD) hematopoietic stem cell transplantation (HSCT). Methods: Eligible patients were between ages 2 – 60 years, and had acute leukemia in remission, myelodysplasia or chronic myeloid leukemia in chronic or accelerated phase. All had adequate organ function, and a 6/6 HLA-A, B, DRB1 matched sibling donor. 304 patients were randomly assigned to either Tac/Sir (n = 151) or Tac/Mtx (n = 153) as GVHD prophylaxis after TBI-based conditioning and MRD HSCT. An intent-to-treat analysis was performed on the primary endpoint of Grade II-IV GVHD-free survival 114 days from randomization. Ten subjects who received busulfan-based conditioning and were previously reported were excluded from analysis. Three subjects who did not undergo HSCT are included in the primary analysis, but not secondary analyses. Results: Treatment groups were well balanced. The median age of participants was 44 years (range 13 – 59) and 83% had acute leukemia. Neutrophil and platelet engraftment were both faster in the Tac/Sir group (14 vs. 16 days, p < 0.001; 16 vs. 19 days, p = 0.03, respectively), but this did not affect the time to first hospital discharge (20 vs. 21 days, p = 0.37). The incidence of grade II-IV and grade III-IV acute GVHD at 100 days were lower in the Tac/Sir group (26 vs. 34%, p = 0.17; 8 vs. 15%, p = 0.05). Day 100 treatment-related mortality was no different between groups (7 vs. 7%, p = 0.43). The primary endpoint of 114-day acute GVHD-free survival was not statistically different between groups (67 vs. 62%, p = 0.38, Figure). The cumulative incidence of relapse at 2 years from transplantation was not different between groups (27 vs. 30%, p = 0.81). The competing-risk cumulative incidence of chronic GVHD was higher in the Tac/Sir arm (54 vs. 43%, p =0.044). Overall toxicities were not different between groups, with two notable exceptions. The peak and average OMAS oral mucositis scores were lower in the Tac/Sir arm (peak 0.70 vs. 0.96, p < 0.001; average 0.31 vs. 0.47, p < 0.001), however, there was an increased rate of the endothelial injury syndromes, veno-occlusive disease (11 vs. 4%, p = 0.03), and thrombotic microangiopathy (5 vs. 1%, p = 0.05) in the Tac/Sir arm. Causes of death were not different between groups. At 2 years from transplantation, disease-free (DFS) and overall survival (OS) were not different between study arms (DFS 53 vs. 53%, p = 0.76; OS 60 vs. 61%, p = 0.44). Conclusions: No difference in 114-day acute GVHD-free survival was noted between treatment arms. Compared with Tac/Mtx in MRD HSCT, Tac/Sir is associated with more rapid engraftment, less severe acute GVHD and oral mucositis, excess chronic GVHD and endothelial injury syndromes, and similar long-term outcomes. Understanding the trade-offs between regimens, Tac/Sir can be used as an alternative to Tac/Mtx in MRD HSCT. Disclosures: Cutler: Pfizer, inc: Research Funding; Astellas, Inc: Consultancy, Research Funding. Off Label Use: Sirolimus - Prevention of GVHD Tacrolimus - Prevention of GVHD. Waller:Outsuka: Research Funding.

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Time-Restricted Versus Standard Duration Immunosuppression after Allogeneic Hematopoietic Stem Cell Transplantation: Results from the Prospective Randomized Phase III HOVON-96 Trial

Blood ◽

10.1182/blood-2019-130872 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 371-371

Author(s):

Cornelis N. De Jong ◽

Ellen Meijer ◽

Katerina Bakunina ◽

Erfan Nur ◽

Marinus van Marwijk Kooij ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Phase Iii ◽

Standard Regimen ◽

Hematopoietic Stem ◽

Free Survival ◽

Post Transplant ◽

Grade Ii

Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality. The current standard Dutch regimen for prevention of GVHD in T-cell replete (TCR) alloHSCT following reduced intensity conditioning (RIC) consists of mycophenolic acid (MA) and cyclosporine A (CyA) for three and six months post-transplant, respectively. However, as approximately 30% of patients will never develop GVHD, immunosuppressive overtreatment is of concern and might impair outcome. Aims In the present prospective randomized, multicenter, phase III trial we set out to compare time-restricted immunosuppression versus a standard immunosuppressive regimen. The primary objective was to increase the proportion of patients with non-severe GVHD (either acute GVHD grades I-II without gut involvement or chronic GVHD not requiring systemic treatment) within 180 days after transplantation and to reduce the relapse rate, without increasing severe GVHD. Secondary endpoints included time to acute and chronic GVHD, progression-free survival (PFS), GVHD-free/relapse-free survival (GRFS), overall survival (OS), and adverse events. Methods Hematological patients planned to undergo TCR alloHSCT with a related or unrelated 8/8 HLA matched donor were included. The trial randomized patients between three treatment arms. The current analysis includes all patients randomized between arms A and B. Immunosuppression consisted of CyA twice daily aiming for serum trough levels of 250-350 µg/L and MA 16 mg/kg twice daily with a maximum dose of 2160 mg a day. The standard regimen (arm A) prescribed to discontinue MA at day 84 post-transplant and CyA was continued until day +120 followed by tapering until day +180. In those randomized for the time-restricted regimen (arm B) MA was discontinued at day 28 post-transplant and CyA was continued until day +84 followed by tapering. Results A total of 389 patients were randomized 1:1 between arms A and B, of whom 95% (184 in arm A versus 185 in arm B) proceeded to transplant. The median age was 55 (range: 18-71), 57% were male. Fifty-one patients received myeloablative conditioning and 318 (86%) patients RIC. Donors were matched siblings for 135 patients and matched unrelated donor (MUD) for 233 patients. The majority of patients received peripheral blood stem cells, consisting of median 6.46x106/kg CD34+ cells/kg (range: 0.94-26.3) and median 230x106/kg CD3+ T cells (range: 0-936). Baseline patient and transplantation characteristics were equally distributed between the treatment arms. The proportion of patients developing non-severe GVHD within 180 days post-alloHSCT was 24% in both treatment arms, with an odds ratio (OR) of 1.01 (95% confidence interval 0.61-1.67, p 0.98). The cumulative incidence (CI) of grade II-IV and grade III-IV acute GVHD at 6 months post-alloHSCT was not significantly different between the two arms (47% and 15% versus 52% and 18%), nor was the maximum grade or organ involvement of acute GVHD. In addition, no difference was seen in the two-year CI of chronic extensive GVHD between the two treatment arms (51% versus 49%). The three-year estimate of PFS was 51% (44-59%) versus 52% (44-59%), respectively. The three-year CI of progression/relapse was 28% in arm A versus 27% in arm B. OS at three years was 59% (0.51-0.66%) versus 57% (0.50-0.64%). The one-year estimate of the composite endpoint GRFS was 14% (9-19%) in arm A, and 17% (12-22%) in arm B. Incidences and nature of adverse events were comparable in both arms. Conclusion A time-restricted combination of MA and CyA did not increase the proportion of patients with non-severe GVHD within 180 days after transplantation and resulted in similar outcome as compared to standard immunosuppression following alloHSCT using sibling and well-matched unrelated donors. Given the observed high CI of acute grade II-IV and chronic extensive GVHD and low GRFS for both the time-restricted and standard regimen, recipients of TCR RIC alloHSCT should be considered for more intensive immunosuppression. Figure Disclosures Nur: Novartis: Consultancy. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Greater HLA Disparity Is Associated with Reduced Risk of Relapse and Improved Event-Free Survival after Nonmyeloablative, HLA-Haploidentical BMT with Post-Transplantation High-Dose Cyclophosphamide

Blood ◽

10.1182/blood.v112.11.150.150 ◽

2008 ◽

Vol 112 (11) ◽

pp. 150-150 ◽

Cited By ~ 1

Author(s):

Yvette L. Kasamon ◽

Mary S. Leffell ◽

Jeanne Kowalski ◽

Hua-Ling Tsai ◽

Nancy Rossiter ◽

...

Keyword(s):

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Class I ◽

High Dose ◽

Post Transplantation ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

One Year

Abstract Background: Although a lower relapse risk has been reported after allogeneic BMT with increasing HLA disparity, this potential benefit has been offset by higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). However, it is possible that the type of GVHD prophylaxis could influence the balance between GVHD toxicity and relapse. Patients and methods: We retrospectively analyzed the outcomes of 185 patients with poor-risk hematologic malignancies enrolled on three similar clinical trials of related-donor, haploidentical BMT incorporating high-dose post-transplantation cyclophosphamide (Cy) for GVHD and graft rejection prophylaxis (as published in BBMT2008;14:641–50). Molecular typing was at an allele level for HLA-A, -B, -Cw, and -DRB1 and at an allele group level for -DQB1. All received Cy (14.5 mg/kg IV on days −6, −5), fludarabine (30 mg/m2 IV on days −6 to −2), total body irradiation (200 cGy on day −1), and non-T-cell depleted bone marrow infusion. GVHD prophylaxis consisted of Cy (50 mg/kg IV) either once (on day 3; n = 48) or twice (on days 3, 4; n = 137), mycophenolate mofetil for 35 days, and tacrolimus for up to 6 months, with filgrastim begun after the last dose of Cy. Most patients (median age 50, range 1–71) had advanced disease and 49 (26%) had failed autologous BMT. Diagnoses were MDS (22), CMML (3), acute leukemia or lymphoblastic lymphoma (58), CML (11), CLL (15), multiple myeloma (9), non-Hodgkin lymphoma (42), and Hodgkin lymphoma (25). Results: Median follow-up after BMT is 20 months (range, 2–71 months) in those without events. Nonengraftment attributed to primary graft failure or to residual bone marrow malignancy occurred in 29 of 177 evaluable patients (16%). Cumulative incidences of grade II–IV acute GVHD and chronic GVHD were 31% and 15%, respectively. Cumulative incidences of NRM and relapse or progression at one year were 15% and 50%, respectively. Actuarial event-free survival (EFS) at one year was 35%, with grade II–IV acute GVHD by day 100 associated with a trend toward lower cumulative incidence of relapse (p = 0.08) but a significantly higher cumulative incidence of NRM (p = 0.002) on subgroup analysis. Notably, increasing degrees of HLA mismatch at either class I or class II loci had no significant effect on cumulative incidence of acute or chronic GVHD or NRM. In contrast, the presence of a DRB1 antigen mismatch in the GVH, but not host-versus-graft (HVG), direction was associated with a significantly lower cumulative incidence of relapse (Figure a; p = 0.04) and improved EFS (Figure c; p = 0.009), whereas DQB1 antigen and class II allele mismatch status had no effect. Additionally, the presence of two or more class I allele mismatches (composite of A, B, and Cw) in either direction was associated with a significantly lower cumulative incidence of relapse (Figure b; p = 0.045 for GVH direction, p = 0.01 for HVG direction) and improved EFS (Figure d; p = 0.07 for GVH direction, p = 0.001 for HVG direction). Conclusion: Greater HLA disparity appears to be beneficial after nonmyeloablative, HLA-haploidentical BMT that incorporates high-dose post-transplantation Cy. These results suggest an anti-tumor effect of partially HLA-mismatched BMT that is irrespective of clinically significant GVHD. Potential effectors of anti-tumor immunity include HLA-DRB1 reactive CD4+ T-cells, class I reactive CD8+ T-cells, and/or natural killer cells recognizing missing self. Since most patients have several potential HLA-haploidentical related donors, the results support a strategy of choosing a donor who is incompatible for both HLA-DRB1 antigen and multiple HLA class I alleles. Figure Figure

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Long-Term Follow-up of Hematopoietic Stem Cell Transplantation with the Modified Peking Regimen for the Treatment of Acute Leukemia

Blood ◽

10.1182/blood-2019-124419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2034-2034

Author(s):

Xi Yang ◽

Chenglong Li ◽

Rong Zhang ◽

Hong Zheng ◽

Qing Wei ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Acute Leukemia ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Free Survival

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment strategy for patients with acute leukemia. The ATG-based transplantation system initiated by Peking University people's hospital, known as the Peking regimen, has become a mainstream transplant system worldwide. Here, based on the Peking regimen, we report a modified protocol:(1)add Fludarabine and replace ATG with ATG-F in the conditioning regimen; (2)transfuse higher-dose cell collections from granulocyte-colony stimulating factor(G-CSF) primed bone marrow and peripheral blood samples; (3) add Basiliximab (a CD25-antibody) on day +3 for acute GVHD prophylaxis. In this study, 265 patients (158 patients with haplo-SCT and 107 patients with sibling-SCT) underwent allo-HSCT with our modified protocols. All patients achieved sustained full-donor chimerism. The incidence of grade II-IV and III-IV acute GVHD in haplo-SCT comparing with sibling-SCT was 36.1%(57/158) vs 17.8%(19/107)(P=0.001) and 13.3% (21/158) vs 9.3%(10/107)(P>0.05) respectively. The 2-year cumulative incidence of total chronic GVHD and extensive chronic GVHD in haplo-SCT was 41% (65/158) and 15% (24/158) respectively. The 3-year cumulative incidence of non-relapse mortality (NRM) in haplo-SCT and sibling-SCT was 6.3% (10/158) and 4.7%(5/107) respectively(P>0.05). The 100-day cumulative incidence of CMV viremia in haplo-SCT and sibling-SCT was 35.5% (56/158) and 23.4%(25/107) respectively(P=0.036). A total of 36 patients in haplo-SCT group and 24 patients in haplo-SCT group had recurrent disease, reaching a cumulative incidence of relapse of 20.8% in haplo-SCT and 23.4% in sibling-SCT at 3 years respectively(P>0.05). The relapse ratio of haplo-SCT and sibing-SCT in the 1st year, between the 1st and the 2nd year and after 2 years was 21.5% vs 14.1%(P>0.05), 1.3%(2/158) vs 0%(P>0.05) and 0% vs 6.5%(P=0.009) respectively. The 3-year overall survival(OS) and leukemia-free survival(LFS) rates in haplo-SCT and sibling-SCT was 78.8% vs 74.2% and 76.8% vs 75.04% respectively(P>0.05) by the Kaplan-Meier estimate. The 3-year GVHD-free and leukemia-free survival rates (GRFS) in haplo-SCT and sibling-SCT were 43.4% vs 69.5%(P=0.045) respectively. Lower OS in haplo-SCT was associated with III-IV aucte GVHD and lower MNC(<19×10^8/L) in grafts by Cox regression analysis. In a word, the results from our experience showed that the modified protocol based on the Peking Regimen is safe and reliable for acute leukemia patients and brings on a long-stage survival post transplantation. Disclosures Zheng: Pfizer: Research Funding.

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Multicenter, Prospective Study of Tacrolimus Plus Methotrexate As Graft-Versus-Host Disease Prophylaxis in HLA-Matched Sibling Peripheral Blood Stem Cell Transplantation: Comparison with Cyclosporine Group As Control

Blood ◽

10.1182/blood.v120.21.4177.4177 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4177-4177

Author(s):

SeungHwan Shin ◽

JaeHo Yoon ◽

SeungAh Yahng ◽

SungEun Lee ◽

ByungSik Cho ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hazard Ratio ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Grade Ii

Abstract Abstract 4177 Background Graft-versus-host disease (GVHD) is an immunologic complication after allogeneic hematopoietic stem cell transplantation (HSCT) with significant mortality and morbidities. Allogeneic peripheral blood stem cell transplantation (PBSCT) has high risk of GVHD, especially chronic GVHD compared to bone marrow transplantation. Only limited data are available comparing the efficacy of FK506 with that of cyclosporine (CsA) in human leukocyte antigen (HLA)-matched sibling PBSCT. Methods Thirty-nine patients with various hematologic disease received PBSCT with FK506+methotrexate (MTX) as GVHD prophylaxis were compared to ninety-four historical control with CsA+MTX GVHD prophylaxis. Results The 1-year cumulative incidence of grade II-IV acute GVHD was significantly lower in patients who received FK506 than those in the CsA group (10.3% vs 28.2%, p=0.036). The female donor-male recipient pair (hazard ratio; 4.828, 95% CI; 17.84-13.06, p=0.002) and CsA prophylaxis (hazard ratio; 3.279, 95% CI; 1.14–9.43, p=0.027) were significant risk factor of acute GVHD in multivariate analysis. But, there was no difference in the 3-year cumulative incidence of chronic GVHD between the FK506 and the CsA group (77.6% vs 69.6%, p=0.793). The 3-year cumulative incidence of relapse (33.9% vs 23.1%, p=0.505) and 3-year treatment-related mortality (18.9% vs 28.4%, p=0.187) of the two groups were similar. The patients in the FK506 arm had a similar event-free survival (EFS) and overall survival (OS) with patients in the CsA arm (3-year EFS; 53.2% vs 55.1%, p=0.706, 3-year OS; 60.7 vs 61.5%, p=0.610). The age over 35 years (hazard ratio; 4.12, 95% CI; 1.95–8.70, p=0.001), female donor-male recipient pair (hazard ratio; 2.66, 95% CI; 1.52–4.65, p=0.001) and advanced pre-HSCT disease status (hazard ratio; 3.13, 95% CI; 1.72–5.71, p=0.001) were significant prognostic factors associated with OS in multivariate analysis. Conclusion These results demonstrated that the FK506+MTX can significantly reduce grade II-IV acute GVHD compared to CsA+MTX in sibling PBSCT with similar incidence of chronic GVHD, and comparable outcome in EFS, OS, relapse rate and TRM rate between two groups. Disclosures: No relevant conflicts of interest to declare.

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Investigating the Relationship between CD34+and CD3+ Cell Doses, One-Year Graft-Versus-Relapse-Free-Survival, Graft-Versus-Host Disease, and Overall Survival in Haploidentical Hematopoietic Stem Cell Transplantation: A Single Center Experience

Blood ◽

10.1182/blood-2019-129647 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2051-2051 ◽

Cited By ~ 1

Author(s):

Mindy Hsiao ◽

Anastasia Martynova ◽

George Yaghmour ◽

Chris Foss

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Optimal Dose ◽

Relapse Free Survival ◽

Free Survival ◽

Improved Outcomes ◽

The Mean ◽

Related Mortality

Background: Haploidentical hematopoietic cell transplantation (haplo-HCT) has emerged as a popular alternative to traditional HLA-matched hematopoietic cell transplant. As the number of haplo-HCT's rises, investigating the factors that may affect outcomes is necessary in order to improve overall survival and reduce transplant-related mortality. The optimal dose of CD34+ cells used during haplo-HCT to ensure favorable outcomes using PTCy has not yet been reported though a range of 2 to 5.00x106 cells/kg is commonly used.Furthermore, the optimal dose of CD3+ cells is unknown however recent data has suggested less than 3.00x108 cells/kg may prevent the development of acute GVHD. The importance of studying the impact of CD34+/CD3+ cell dosing may help to improve outcomes in this setting. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 21) who received haplo-HCT from 2014 to 2019. The primary end-point assessed was 1-year GVHD-free/relapse-free survival (GRFS) defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the first post-HCT year. Secondary end-points included 1-, 2-, and 3-year relapse-related mortality (RRM) and overall survival (OS) in addition to 1-year transplant related mortality (TRM) and incidence of both acute and chronic GVHD. Results: A total of 67 adult haplo-HCT recipients were reviewed. Of the patients evaluated, approximately 50% (n = 33) were male and 49% (n = 32) were female. The age range was 21-71 years old (median = 44), and the most common underlying hematologic disorders included AML (40%), ALL (38%), aplastic anemia (7.7%), and others (MDS, lymphoma, myelofibrosis, and HLH) (13.8%). 67% of patients received myeloablative conditioning regimens while 33% received reduced intensity regimens. 70% (n = 47) of patients received peripheral blood as a stem cell source with 30% (n = 20) receiving bone marrow. The mean CD34+ dose infused was 6.07x106 cells/kg and the mean CD3+ dose was 2.94x108 cells/kg. The mean time to recovery of platelets, neutrophils, and lymphocytes was 25, 18, and 37 days respectively. CD34+ stem cells ≥5.00x106 cells/kg was significantly associated with shorter time to lymphocyte recovery (p = 0.0265) though recovery less than 30 days was not significantly associated with OS (p = 0.5268). Incidence of 1-year GRFS was 71% (n= 46) and 1-, 2-, and 3-year RRM were 4.6%, 6%, and 7.7% respectively. 1-year TRM was 15.3% with 50% of deaths from acute GVHD. 1-, 2-, and 3-year OS were 80%, 78%, and 77% respectively. Factors significantly associated with increased mortality included use of RIC regimen (p = 0.004) and disease status at time of transplant (p = 0.04). Cumulative incidence of GVHD was 63% (n = 42) with 33% (n = 22) and 30% of patients (n = 20) with acute and chronic GVHD respectively. Lack of mild chronic GVHD was associated with increased mortality (p = 0.0029) and use of a myeloablative regimen (p = 0.0029) was significantly associated with GVHD. Subgroup analysis of those who received CD34+ dose ≥7.00x106 cells/kg (n = 24) and ≥10x106 cells/kg (n = 7) were found to have 1-year OS of 87.5% and 85.7% compared with 77% and 80% in those that received lower doses (p= 0.2229 and p = 1.00) respectively however this was not found to be significantly associated with increased incidence of GVHD, relapse, or mortality. Discussion: Our results demonstrate improved outcomes specifically 71% survived 1 year without experiencing at least 1 GRFS event compared with 24-35% reported by CIBMTR, Holtan et al 2015, and Solh et al 2016 with 3-year OS of 77% when compared with a previously reported 48%. The mean CD34+ cell dose of our population is higher than the standard range which may account for the improved outcomes however the dosing of CD34+/CD3+ cells were not significantly associated with our primary and secondary end-points. It was significantly associated, however, with shorter time to lymphocyte recovery, a factor that has been reported to be associated with decreased RRM and therefore improved OS. Furthermore, subgroup analysis of higher CD34+ dose did show a better 1-year OS though this was not statistically significant. Limitations of this study include small sample size and short follow-up period. Further research with a prospective study identifying the optimal CD34+/CD3+ cell dose in addition to comprehensive evaluation of immune recovery is warranted in order to improve haplo-HCT outcomes. Figure Disclosures Yaghmour: Jazz Pharmaceutical company: Consultancy, Speakers Bureau; Astella company: Speakers Bureau; Takeda: Speakers Bureau.

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Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party

Blood ◽

10.1182/blood.v128.22.4655.4655 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4655-4655 ◽

Cited By ~ 1

Author(s):

Kavita Raj ◽

Eduardo Olavarria ◽

Diderik-Jan Eikema ◽

Liesbeth C de Wreede ◽

Linda Koster ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Cell Source ◽

Mismatched Donor

Abstract Background: Allogeneic stem cell transplantation is a treatment option for patients with advanced myelofibrosis. Problems encountered include an increased risk of delayed or poor engraftment and in the mismatched unrelated donor setting a higher rate of GVHD and particularly poor outcomes. As for other indications for allogeneic stem cell transplants, patients for whom either a matched sibling or matched unrelated donor is not available are considered for either a double umbilical cord blood, a mismatched unrelated donor or haploidentical stem cell transplant. Data on the latter option are limited and we reviewed registry data on all family mismatched donor transplants performed between 2001 and 2015 and reported to the EBMT registry. Results: Records retrieved 69 patients with myelofibrosis transplanted between November 2001 and November 2015. 44 (64%) were male. 50 (74%) had primary myelofibrosis,18 (27%) had secondary myelofibrosis (6 from ET, 5 from PRV and 7 others) and unknown 1(2%). Of 25 patients for whom the JAK2 V617F mutation status was known, 15 (22%) harboured the mutation. Patient Karnofsky performance status was > 70% in 98%. Of the mismatched family donors, 47 (68%) were male and 22 (31%) female. Donors were HLA mismatched at 1 locus in 12 (17%) and 2 or more loci in 48 (69%). Donor-recipient serology combinations were CMV -/- in 8 (12%), +/- in 4 (6%), -/+ in 15 (22%) and +/+ in 34 (49%) missing 8 (12%). Bone marrow was the stem cell source in 34 (49%) and peripheral blood in 35 (51%). The median total nucleated cell count (TNC) infused was 7.5x108/kg (range 2.3-21x108/kg) from data available in 17 patients. The median CD34+ cell dose was 6.9x106/kg (range 1.9-18.18x106/kg) from data available in 19 patients. Conditioning was myeloablative in 48 (70%) and RIC in 21 (30%) The conditioning regimes were varied but the predominant ones were Fludarabine, Busulphan, ATG (FBATG) and Thiotepa, Busulphan, Fludarabine (TBF). TBI was administered in 8 (12%) and in vivo T cell depletion in 22 (32%), ex-vivo T cell depletion in 5 (7%) patients. GVHD prophylaxis varied with post transplant Cyclophosphamide administered in 34/67 (49%) and ATG in 19/67 patients (28%). Neutrophil engraftment was established in 53 (82%) at a median of 20 days (range 11-83). Primary graft failure occurred in 8 (12%) and secondary graft failure in 4 (6%). This occurred at a median of 12 months (range 4.5-35 months). Eleven of these patients had a second allograft at a mean interval of 6.4 months. Responses to the first allograft (censoring for patients who had a second allograft) with data available in 45 patients, showed that complete remission was achieved in 35 patients (78%), 6 (13%) were never in CR and 4 (9%) were not evaluable. The cumulative incidence of grade II-IV acute GvHD at 100 days was 12% (95% CI 4-21%) and for grade III-IV acute GvHD at 100 days it was 5% (95% CI 3-11%). Data for chronic GVHD was valid in 49 patients. The cumulative incidence of chronic GvHD at 2 years was 62% (95% CI 47-76%). The cumulative incidence of limited cGvHD was 45% (95% CI 31-59%) whereas the cumulative incidence of extensive cGvHD was 10% (95% CI 2-19%). The median follow up was 24 months (95% CI 13-35 months). The 2-year OS was 51% (95% CI 37-76%) and the 5-year OS was 38% (95% CI 21-55%). The 2-year RFS was 44% (95% CI 30-59%) and the 5-year RFS was 31% (95% CI 15-48%). The 2 year cumulative incidence of relapse was 14% (95% CI 5-24%). The 2 year NRM was 41% (95% CI 28-55%), which increased to 54% (95% CI 37-72%) at 5 years. The main causes of death were infection (16, 24%), GVHD (7, 10%) organ damage or failure (3, 5%), relapse/disease progression (1, 2%) and secondary malignancy or PTLD (1, 2%). On univariate analysis there was no significant effect of recipient gender, donor gender, degree of HLA mismatch 1 vs >1 Ag MM, CMV matching between donor and recipient, primary or secondary MF, disease stage at transplant (chronic versus advanced phase), conditioning intensity, conditioning regimen, GVHD prophylaxis with ATG or post transplant cyclophosphamide or stem cell source on overall survival. Conclusion: Concerns regarding engraftment and secondary graft failure have excluded patients with myelofibrosis from clinical trials of mismatched related donor transplant. The data suggest that engraftment is feasible, and PFS and OS can be attained with limited severe chronic GVHD with family mismatched donors in this setting. Disclosures Ciceri: MolMed SpA: Consultancy.

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

Blood ◽

10.1182/blood.v110.11.2167.2167 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2167-2167

Author(s):

Sebastian Giebel ◽

Aleksandra Holowecka-Goral ◽

Izabela Nowak ◽

Tomasz Czerw ◽

Jerzy Wojnar ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Kir Genes ◽

Increased Risk ◽

Grade Ii ◽

Card15 Gene ◽

Grade Iii

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

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Absolute Lymphocyte Count Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Clinical Outcome

Blood ◽

10.1182/blood.v124.21.2499.2499 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2499-2499

Author(s):

Haesook T Kim ◽

Philippe Armand ◽

David Frederick ◽

Emily Andler ◽

Corey S Cutler ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Acute Gvhd ◽

Progression Free Survival ◽

Absolute Lymphocyte Count ◽

Threshold Value ◽

Hematopoietic Stem ◽

Free Survival ◽

Grade Ii ◽

Conditioning Intensity

Abstract To determine the impact of absolute lymphocyte count (ALC) recovery on clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT) and to determine the threshold value of ALC, we conducted a retrospective study of 1109 adult patients who underwent a first allogeneic HSCT from 2003 through 2009, excluding patients who died or relapsed before D30. The median age was 51 years (range: 18-74) with 52% undergoing reduced intensity HSCT and 48% myeloablative intensity HSCT with T-replete PBSC (93.7%) or marrow (6.4%) grafts; 41% receiving HLA-matched related donors, 51% HLA-matched unrelated donors, and 8.5% HLA-mismatched transplantation. The median follow-up time was 6 years (range: 2.5 – 9.8 years). To determine the threshold value, we randomly split the entire cohort into a training set and a validation set in a 1:1 ratio stratified by conditioning intensity, and then applied a restricted cubic spline (RCS) smoothing method to obtain relative hazard estimates of the relationship between ALC at 1 month and log hazard of progression-free survival. Based on this approach, ALC was categorized as low (≤0.2x 109 cells/L) or normal (>0.2x109 cells/L). For patients with low ALC at 1, 2, or 3 months after HSCT, excluding relapse or death prior to each time point to rule out the direct influence of relapse on the ALC, the overall survival (OS) (p≤0.0001) and progression-free survival (PFS) (p≤0.0002) were significantly lower and non-relapse mortality (p≤0.002) was significantly higher compared to patients with ALC >0.2x109 cells/L at each timepoint, but there was no difference in relapse. Since patients with newly low ALC at 2 or 3 months post HSCT had equally poor outcome as those whose ALC was low at 1 month post HSCT, we combined patients who had low ALC at 1, 2 or 3 months post HSCT and compared their outcome to that of patients who had ALC>0.2x109 cells/L at 1, 2, and 3 months after HSCT. The 5-year OS for patients with low ALC was 28% vs 46% for patients without low ALC (p<0.0001); the corresponding 5-year PFS were 21% vs 39%, p<0.0001 and NRM 40% vs 18%, p<0.0001 (Figure A-C). This result was consistent when other prognostic factors, including occurrence of grade II-IV acute GVHD, were adjusted for in multivariable Cox models stratified by conditioning intensity: HR for OS was 1.52 , p≤0.0001; for PFS, 1.42, p=0.0008; and for NRM, 2.4 p<0.0001 for patients with low ALC within 3 months of HSCT. Low ALC was not significantly associated with relapse (HR 1.01, p=0.92) in the multivariable model. Low ALC early after HSCT is an independent risk factor for increased NRM and poor survival independent of grade II-IV acute GVHD. ALC assessment early after HSCT may be useful to identify high-risk patient cohorts that may benefit from additional therapeutic interventions. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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