Hematopoietic Stem Cell Transplantation (HSCT) after a Myeloablative Conditioning Regimen in Children with Refractory Cytopenia (RC): Results of a Retrospective Analysis from the EWOG-MDS Group.

Abstract RC is one of the most common variants of childhood MDS, characterized by clonal ineffective hematopoiesis and sustained peripheral cytopenia. Allogeneic HSCT represents a widely employed, curative treatment for children with RC. We analyzed the outcome of 48 children (33 males, 15 females; median age at transplantation 11 years, range 2.9–19) affected by RC, given allogeneic HSCT after a myeloablative preparative regimen and reported to the European Working Group on Childhood MDS (EWOG-MDS). Karyotype analysis was available in all patients, but 4. Clonal abnormalities were detected in 17 patients, involving chromosome 7 in 13 children. Bone marrow cellularity was reduced in 34, normal in 8 and increased in the remaining 6 patients. Nineteen patients were transplanted from an HLA-identical sibling, while the remaining 29 were given HSCT from an unrelated donor (UD). Bone marrow, cord blood and peripheral blood stem cells were employed in 38, 1 and 9 patients, respectively. Busulfan (BU) and cyclophosphamide (CY) were used as preparation to the allograft in 12 patients, while 36 children were given a regimen including BU, CY and melphalan (L-PAM). Cyclosporine-A (Cs-A) alone was mainly used as graft-versus-host disease (GvHD) prophylaxis in children transplanted from a relative, while the majority of patients transplanted from an UD were given the combination of Cs-A, short-term methotrexate and anti-thymocyte globulin. All patients engrafted, the median time to neutrophil and platelet recovery being 16 days (range, 9–79) and 26 days (range, 10–170), respectively. Two patients had secondary graft failure at 74 and 93 days after HSCT, respectively; one of them was successfully re-transplanted. The cumulative probability of developing grade II-IV acute GVHD was 37% (95% CI, 26–54%). Thirteen out of the 41 patients at risk developed chronic GVHD, which was limited in 8 patients and extensive in 5. The cumulative incidence of chronic GVHD was 35% (95% CI, 23–55%). With a median follow-up of 3.5 years (range 4 months-7.8 years), 39 patients are alive with sustained donor engraftment (1 after a second transplant), 9 patients having died for either transplant-related complications (8 patients) or disease recurrence (1 child). The 5-year probability of disease-free survival (DFS) is 77% (95% CI, 65–89%). In patients transplanted from an HLA-identical sibling and from an UD the DFS probability at 5 years is 78% (95% CI, 59–97%), and 76% (95% CI, 60–91%), respectively (P=n.s). The 5-year probability of DFS was 61% (95% CI, 38–83%) and 86% (95% CI, 74–99%) for children who did or did not experience grade II-IV acute GvHD (P=0.04). The outcome of patients prepared with either BU/CY or BU/CY/L-PAM was 92% (95% CI, 76–100%) and 71% (95% CI, 56–86%), respectively (P=n.s). These data indicate that a myeloablative allogeneic HSCT is able to cure a large proportion of children with RC, especially if GvHD is successfully prevented. Transplantation-related mortality represents the main cause of treatment failure, while relapse is rarely observed. The addition of L-PAM does not offer any advantage in comparison to BU/CY. Outcome of children with RC given allogeneic HSCT from either a relative or an UD is similar.

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Anaerobic Antibiotics and the Risk of Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-125080 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1992-1992

Author(s):

John Tanaka ◽

Rebecca Young ◽

Lisa Spees ◽

Kirsten Jenkins ◽

Anthony D. Sung ◽

...

Keyword(s):

Stem Cell ◽

Febrile Neutropenia ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Research Support ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Graft Versus Host ◽

Grade Ii

Background: The gut microbiota interacts extensively with the host immune system and thus may modify the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). During the post-transplant neutropenic period, the majority of allogeneic HSCT recipients receive empirical broad-spectrum antibiotics for febrile neutropenia. We hypothesized that receipt of an antibiotic regimen with an anaerobic spectrum of activity is associated with a higher risk of grade II-IV acute GVHD than receipt of a non-anaerobic antibiotic regimens. Methods: In this single-center retrospective cohort study, we evaluated associations between peri-transplant receipt of antibiotics with an anaerobic spectrum of activity and the risk and severity of GVHD among 877 adults who received an allogeneic HSCT between January 1, 2005 and December 31, 2016. We identified 609 patients who developed febrile neutropenia after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n=333) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, ceftazidime, or cefepime; n=276). Antibiotics received by patients between 7 days before and 28 days after allogeneic HSCT and GVHD diagnoses were verified via manual review of medication orders and provider notes in electronic medical records. Results: Receipt of anaerobic antibiotics was associated with an increased risks of grade II-IV acute GVHD (hazard ratio (HR): 1.41; 95% confidence interval (CI): 1.10-1.79; P=0.01) and acute GVHD mortality (HR: 1.87; 95% CI: 1.13, 3.11; P=0.02). This hazard was primarily associated with acute GVHD of the gut or liver (HR: 1.38; 95% CI: 1.06, 1.79; P=0.02). The association remained with even short (<7 days) courses of anaerobic antibiotics. Anaerobic antibiotic exposure was not associated with acute skin GVHD (HR: 0.97; 95% CI: 0.69, 1.37; P=0.88), chronic GVHD diagnosis (HR: 0.93; 95% CI: 0.70, 1.23; P=0.43), or chronic GVHD mortality (HR: 0.89; 95% CI: 0.44, 1.81; P=0.76). Conclusions: Receipt of anaerobic antibiotics for febrile neutropenia post-HSCT is associated with an increased risks of acute GVHD of the gut or liver and acute GVHD mortality. Limiting use of antibiotics with an anaerobic spectrum of activity after allogeneic HSCT may reduce acute GVHD incidence and mortality. Disclosures Sung: Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding. Martin:Novartis Pharmaceuticals: Other: research support; Jazz Pharmaceuticals: Other: research support.

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Higher Rate of Thrombotic Thrombocytopenic Pupura (TTP) Associated with Graft Versus Host Disease (GVHD) and Unrelated Donor Bone Marrow Transplantation (BMT).

Blood ◽

10.1182/blood.v106.11.1111.1111 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1111-1111

Author(s):

B. Oran ◽

A. Aleman ◽

E. J. Shpall ◽

C. Hosing ◽

M. Korbling ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Stem Cell ◽

Median Time ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Lymphoid Malignancies ◽

Gvhd Prophylaxis

Abstract TTP is one of the complications of allogeneic hematopoietic stem cell transplantation (HSCT). In contrast to idiopathic cases, post-transplantation TTP may not be associated with severe von Willebrand factor-cleaving protease deficiency but rather a diffuse endothelial injury. Our aim was to define incidence, risk factors and mortality of TTP following allogeneic HSCT. 1312 patients with lymphoid malignancies (n=605), myeloid malignancies (n=688) or aplastic anemia (AA, n=18) who were treated with ablative preparative regimens (n=614) or reduced intensity regimens (n=697) followed by HSCT from an HLA matched related (MRD, n=694) or unrelated donor (MUD; n=461) and 1–3 antigen mismatched related (MMR, n=99) or unrelated donor (MMUD, n=57) between December 1997 and December 2004 were studied. Patients with prior allogeneic HSCT or graft failure were excluded. GVHD prophylaxis was tacrolimus-based in 1276 (97.3%) and cyclosporine based in 15 (1.1%) patients. Twenty patients did not receive GVHD prophylaxis per protocol. Anti-thymocyte-globulin (ATG) was added in 350 patients. Stem cell sources were bone marrow (n=626), peripheral blood (n=635) or cord blood (n=50). The following variables were evaluated: age, gender, primary diagnosis, disease status before HSCT, intensity of preparative regimen, stem cell source and acute GVHD(aGVHD) grade ≥2 (time dependent variable). Of the 1312 patients with a median follow-up from transplantation of 11.4 months (range, 5 days-7.2 years), 77 developed TTP (6%). The actuarial risk of developing TTP was 6.5% at 1 year. The median time of the onset of TTP was 67 days post HSCT (range, 11–1812) with 27 cases (35%) presenting after day 100. Female gender, lymphoid malignancies, unrelated or antigen mismatched related donor and aGVHD grade ≥2 were found to be independent risk factors. (Table1). Among the patients who had aGVHD grade≥2, the median time of interval between the onsets of two events was 25 days (range, 2–335 days). All patients were treated with therapeutic plasma exchange (PE). Of the 77 patients only 1 died of TTP (intracranial hemorrhage). The overall one-year survival after TTP was 29% and the most common cause of death were acute or chronic GVHD (n=35, 55%) and primary disease progression (n=10, 16%). Stem cell donors other than MRD, lymphoid malignancies and aGVHD≥2 have been established as risk factors associated with development of TTP and therapeutic PE has been shown to decrease TTP related mortality. Risk factors for TTP after allogeneic HSCT Variables sample size events HR 95% CI p Male 793 33 1.0 Female 518 44 2.2 1.3–3.6 0.002 Myleoid malignancy 688 33 1.0 Lymphoid malignancy 605 42 1.9 1.1–3.3 0.03 AA 18 2 1.3 0.2–8.0 0.75 MRD 694 28 1.0 MUD 461 40 2.9 1.6–5.1 <0.001 MMR 99 7 2.4 0.9–6.0 0.06 MMUD 57 2 1.7 0.4–7.6 0.5 aGVHD ≥2 370 39 3.3 2.0–5.5 <0.001

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Sirolimus-Containing Graft-Versus-Host Disease Prophylaxis and High- Resolution HLA Typing Improves the Outcome of Mismatched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v112.11.2216.2216 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2216-2216

Author(s):

Ronald J. Maggiore ◽

Dennis L. Cooper ◽

Francine M. Foss ◽

Warren D. Shlomchik ◽

Stuart E. Seropian

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Disease Recurrence ◽

Hla Typing ◽

Unrelated Donor ◽

Prophylactic Regimen ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Kaplan Meier ◽

Gvhd Prophylaxis

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors can cure a variety of hematologic diseases; however, decreased survival and graft versus host disease (GVHD) are associated with mismatches at HLA class I and class II loci. Beginning in 2004, we have employed a modified three-drug sirolimus-based GVHD prophylactic regimen (Antin JH et al., Blood2003;102:1601) for all patients undergoing unrelated donor allogeneic HSCT with any antigen or allele mismatch at HLA A, B, C, DR, or DQ in the GVHD direction. Outcomes of 22 patients undergoing mismatched unrelated donor (MMUD) allogeneic HSCT (sirolimus(+) group) were retrospectively reviewed in comparison to 14 patients receiving MMUD allografts between 2000–2004 who received a tacrolimus-based two-drug GVHD prophylactic regimen (sirolimus(−) group). Median age (45 vs. 51), disease status, donor gender, and type of transplant conditioning (reduced-intensity, 9 vs. 8) were similar between the two groups. Seven of 14 patients in the sirolimus (−) group received bone marrow grafts whereas all patients in the sirolimus + group received peripheral blood stem cells. Nine patients in the sirolimus – group had antigen-level typing at HLA A, B, C and DQ loci and allele level typing at HLA DRB1 and 5 patients had allele-level typing at all loci. Patients in the sirolimus+ group had allele-level typing at all loci. One subject was mismatched at HLA DRB1 and DQ at the allele level; the remaining subjects had a single allele or antigen mismatch. GVHD prophylaxis for the sirolimus(−) group included tacrolimus and mycophenolate (n=11) or tacrolimus and low-dose methotrexate x 3 doses (n=3). GVHD prophylaxis for the sirolimus (+) group included sirolimus, tacrolimus and post- transplant methotrexate for 2 or 3 doses, totaling 15mg/m2. Median follow-up for surviving patients was 1921 days (1781–2295) in the sirolimus-group and 447 days (53–1122) in the sirolimus(+) group. The day +100 cumulative incidence of grades II-IV and III-IV acute GVHD were, respectively, 71% and 43% in the sirolimus(−) group, and 14% and 5% in the sirolimus(+) groups (p=0.002; p=0.02). Kaplan-Meier estimates of the probability of chronic GVHD or late onset acute GVHD at two years were 51% in the sirolimus(–) group and 70% in the sirolimus(+) group. Graft failure occurred in 2 patients each in both groups and was successfully treated in two patients by retransplantation or pentostatin plus donor lymphocyte infusion. Adverse effects of sirolimus included 8 patients with renal dysfunction (36%), 4 with thrombotic microangiopathy (TMA) (18%), and 3 with dyslipidemia requiring medical therapy (14%). Deaths in the sirolimus(−) group were due to disease recurrence (n=3), graft failure (n=1), and GVHD (n=7). Deaths in the sirolimus(+) group were due to disease recurrence (n=2), TMA (n=1) and GVHD (n=4). The Kaplan-Meier estimates of disease free (DFS) and overall survival (OS) at 3 years were 21% and 21% for the sirolimus(−) group and 53% and 56% for the sirolimus(+) group. The Kaplan-Meier estimates of non-relapse mortality (NRM) at day +100 and day +365 were 22% and 50% for the sirolimus (−) group and 5% and 13% for the sirolimus(+) group. Summary: High-resolution HLA typing and GVHD prophylaxis with sirolimus, tacrolimus, and low-dose methotrexate in patients undergoing MMUD allogeneic HSCT is associated with low rates of severe acute GVHD and non-relapse mortality. Renal dysfunction and TMA appear more common with sirolimus, and, as in prior studies with this regimen, a lower rate of acute GVHD did not result in less chronic GVHD. Nonetheless, DFS and OS appear to compare favorably to recently reported registry data for MMUD allograft recipients (Lee SJ et al., Blood;110:4576), and a prospective trial has been initiated to further study this regimen in MMUD recipients.

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HLA-DRB4 Mismatch Is Associated with Worse Outcomes in Unrelated Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Blood ◽

10.1182/blood.v120.21.4540.4540 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4540-4540 ◽

Cited By ~ 1

Author(s):

Marie Y. Detrait ◽

Ibrahim Yakoub-Agha ◽

Valerie Dubois ◽

Françoise Dufossé ◽

Myriam Labalette ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Stem Cell Source ◽

Cell Source

Abstract Abstract 4540 Introduction The impact of HLA DRB3 and DRB4 allele mismatch after allogeneic HSCT using unrelated donors is unclear. We therefore examined retrospectively the outcome of 35 patients who received HLA-10/10 unrelated hematopoietic stem cell transplantation with a DRB3 or DRB4 mismatch between 2005 and 2011. This cohort of 35 patients was a part of a cohort of 132 consecutive patients who underwent allogeneic HSCT between 2005–2011 with a 10/10-HLA matched donor. There were 18 males (51.4%) and 17 females (48.6%) with a median age of 48 years (range, 6–64), there were 13 (37%) AML, 9 (26%) ALL, 4 (11.5%) MDS, 3 (8.5%) multiple myeloma and 6 (5.7%) other (CML, CLL, NHL). Twenty patients (57%) received a myeloablative conditioning (MAC) and 15 (43%) received a reduced intensity conditioning (RIC). At transplantation, 21 patients (60%) were in complete remission (CR), 4 patients (11.5%) in partial remission (PR) and 10 (28.5%) in relapse; 13 (37%) patients received peripheral blood stem cell (PBSC) and 22 (63%) received bone marrow (BM). Twelve (34%) patients had a mismatched DRB4 donor and 23 (66%) patients had a mismatched DRB3 donor. In the remains of 97 patients, there were 55 male (57%) and 42 female (43%), 28 (29%) patients received a MAC and 69 (71%) a RIC as regimen before allogeneic HSCT. The stem cell source was BM for 32 (34%) patients and PBSC for 65 (66%). At transplantation, 34 (35%) patients are in CR and 63 (65%) were in PR. The distribution of diagnosis was acute leukaemia and MDS for 44 (45%), CLL for 2 (2.5%) and other diagnosis (aplastic anemia, NHL, CML, MPS) for 51 patients (52.5%). Results After HSCT, 124 (94%) patients engrafted. After a median follow-up of 11.5 months (range, 0–76), the cumulative incidence of acute GvHD≥2 at 3 months was 20% (95%CI,16.5–24) and the cumulative incidence of chronic GvHD at one year was 19 % (95%CI, 15–22). In univariate analysis, the mismatch DRB3 or DRB4 had no effect on engraftment and no effect on acute GvHD (p=0.08) or chronic GvHD (p=0.63). There was no impact of DRB3 or DRB4 mismatch on relapse (p=0.33 and p=0.53, respectively) and on PFS (p=0.63 and p=0.07, respectively). We found an impact of the DRB4 mismatching (p=0.016) on overall survival. The median survival for patient without DRB3 or DRB4 mismatch was 23 months (14-NR), for patients with DRB3 mismatch 32 months (12-NR), and for DRB4 mismatched patients 5 months (3-NR). The probability of survival at 24 months, for patients without mismatch DRB3 or DRB4 is 47% (36–61), for patients with DRB3 mismatch 51% (32–82) and for DRB4 mismatched patients 19% (6–66%). (figure1). The multivariate analysis that studied age, type of disease, DRB3 or DRB4 mismatch, sexmatching, TBI, ATG, disease status at transplantation and type of conditioning and stem cell source showed a significant impact of mismatch DRB4 on survival (HR= 2.5 [95%CI, 1.2–5.5] p=0.019); there was no impact for DRB3 mismatch (HR= 1.3 (95%CI,0.5–3.9 p=0.58). We found also an impact of the DRB4 mismatch on TRM (HR= 3.5; [95%CI, 1.6 –8] p= 0.026). The incidence of TRM at 24 months for patients without DRB3 or DRB4 mismatch is 29% (24–34), for patients with DRB3 mismatch 17% (9–26%) and for DRB4 mismatched patients 50% (34–66%). (figure 2). Conclusion The HLA DRB4 matching donor is relevant for survival of patients who undergo allo-HSCT from unrelated donor in the HLA-10/10 matching settings. In view of the important impact of these loci mismatches on clinical outcome, it seems to be important to consider this matching loci in the unrelated donor selection. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults.

Blood ◽

10.1182/blood.v106.11.1134.1134 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1134-1134 ◽

Cited By ~ 1

Author(s):

Masamitsu Yanada ◽

Tomoki Naoe ◽

Hiroatsu Iida ◽

Yoshiko Atsuta ◽

Kazuhito Yamamoto ◽

...

Keyword(s):

Survival Rate ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Philadelphia Chromosome ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Younger Age ◽

Grade Ii ◽

Risk Of Relapse ◽

Grade Iii

Abstract The prognosis for Philadelphia chromosome-positive ALL (Ph+ALL) is quite poor, and allogeneic hematopoietic stem cell transplantation (HSCT) is currently considered the only established procedure with curative potential. It is therefore quite important to clarify what are essential elements of the success of allogeneic HSCT. Thus, we performed a retrospective study covering 197 Ph+ALL cases aged 16 years or older who underwent allogeneic myeloablative HSCT to identify factors affecting the transplant outcome. The subjects comprised 120 males and 77 females, and their median age was 37 years (range, 16 to 59 years). Transplantation during complete remission (CR) accounted for 57% (112 cases), and only 19 patients received transplantation during their second or subsequent CR. The 5-year survival rates were 34% for patients in first complete remission (CR), 21% for those in second or subsequent CR, and 9% for those with active disease (p<0.0001). Multivariate analysis showed four pre-transplant factors as significantly associated with better survival: younger age, CR at the time of transplantation, conditioning with total body irradiation (TBI), and human leukocyte antigen (HLA)-identical sibling donor (p<0.0001, p<0.0001, p=0.0301, p=0.0412, respectively). Next, we investigated whether development of graft-versus-host disease (GVHD) had a significant influence on survival. The presence or absence of each type of GVHD (grade II-IV acute GVHD, grade III-IV acute GVHD, any form of chronic GVHD, and extensive chronic GVHD) was included separately in the Cox model containing the four significant pre-transplant risk factors. Although the survival rate was almost identical for patients with and without grade II-IV acute GVHD, grade III-IV acute GVHD had a significant impact on survival (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.34 to 0.98; p=0.0430). For patients developing any form of chronic GVHD, there was a non-significant increase in survival rate compared with those who did not (HR, 1.40; 95% CI, 0.85 to 2.32; p=0.1877). As for extensive chronic GVHD, the survival advantage was statistically significant (HR, 2.10; 95% CI, 1.13 to 3.88; p=0.0179). The 5-year survival rate was estimated to be 51% for those with extensive chronic GVHD, and 29% for those without. Chronic GVHD was associated with a lower risk of relapse without increasing the risk of treatment-related mortality (TRM), whereas acute GVHD was associated with a higher risk of TRM without diminishing the risk of relapse. From the analysis of the data for 197 Ph+ALL patients who had undergone allogeneic myeloablative HSCT, we identified four prognostic pre-transplant factors. Younger age, CR at the time of transplantation, TBI conditioning, and HLA-identical sibling donor were found to be associated with significantly better survival. Chronic GVHD reduces the risk of relapse without increasing the risk of TRM, and development of extensive chronic GVHD even prolongs survival. These findings should be helpful for achieving the success of allogeneic HSCT for Ph+ALL.

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Non T-Depleted Bone Marrow Transplantation From Haploidentical Related Donor in Hematological Malignancies.

Blood ◽

10.1182/blood.v114.22.2291.2291 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2291-2291 ◽

Cited By ~ 2

Author(s):

Stella Santarone ◽

Gottardo De Angelis ◽

Erminia Di Bartolomeo ◽

Pasqua Bavaro ◽

Mauro Montanari ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Platelet Recovery ◽

Prognostic Features ◽

Grade Ii

Abstract Abstract 2291 Poster Board II-268 Haploidentical bone marrow transplantation (BMT) is an alternative treatment to patients with high-risk hematologic malignancy lacking a HLA-matched donor and those urgently need transplantation. We used a haploidentical-BMT protocol without ex vivo T cell depleted based on the knowledge that marrow grafts have 10 times fewer lymphocytes compared to peripheral blood stem cell grafts and granulocyte colony-stimulating factor (G-CSF) donor priming reduce the incidence of acute GvHD. Materials and Methods: 40 patients (median age of 32, 12-63) with advanced disease or leukemia with poor prognostic features underwent unmanipulated haplo-BMT: 22 with AML, 9 with ALL, 3 with CML, 3 with Hodgkin lymphoma and 3 with plasmacell leukemia. Status at disease: 22 early (first or second comple! te remission), 18 advanced (progressive or refractory disease). All pairs of donors and recipients were identical for one HLA haplotype and incompatible at 2 or 3 loci.The myeloablative conditioning regimens used were different; antithymocyte globuline, cyclosporine, metotrexate, mycophenolate mofetil and basiliximab were used for GvHD prophylaxis. Donors were primed with filgrastim at 4 micrograms/Kg/d for 7 consecutive days. Bone marrow cells were harvest on the 8 day and were infused unmanipulated. Results: the median dose of total nucleated, CD34+ and CD3+cells was 7×10e8/Kg (1.01-28.7), 2.3×10e6/Kg (1.17-6.0) and 23.3×10e6/Kg (9.7-66.6) respectively. 1 patients had a primary graft failure and 5 patients died early prior to engraftment. In the remaining 34 patients, engraftment was seen with median time to granulocyte and platelet recovery of 22 and 27 days respectively; acute GvHD was grade 0 in 17 patients (50%), grade I in 9 (26%), grade II in 7 (20%) and grade IV in 1 (3%). In 29 evaluable patients, chronic GvHD was limited in 3 (10%) and extensive in 1 (3%). Transplant-related mortality at 6 months for early and advantage stage was 22% and 35% respectively. After a median follow up of 18 (3-42) months, 8 patients relapsed; 11 patients (50%) in the early stage and 4 (22%) in advanced phase are now living in haematological remission. The 1-year Kaplan-Meyer probability of disease-free survival is 45% for all patients. Conclusion: the high engraftment rate, low incidence of grade II-IV acute GvHD and an acceptable TRM suggest that G-CSF-primed marrow grafting along with sequential immunosuppression could provide an excellent alternative for patients who lack matched donors. Disclosures: No relevant conflicts of interest to declare.

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Post-Transplantation High Dose Cyclophosphamide As Gvhd Prophylaxis in 9/10 HLA-Matched Unrelated Donors Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.3135.3135 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3135-3135 ◽

Cited By ~ 1

Author(s):

Rohtesh S. Mehta ◽

Rima M Saliba ◽

Julianne Chen ◽

Gabriela Rondon ◽

Aimee E Hammerstrom ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Hla Class I ◽

Conventional Group ◽

Unrelated Donor ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Grade Iii

Abstract Background: Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent GVHD after haploidentical or HLA-matched related or unrelated donor hematopoietic stem cell transplantation (HSCT). Our study aim was to determine its efficacy in HLA-mismatched unrelated donor (MMUD) HSCT. Methods: We included 113 consecutive adult patients with high risk hematological malignancies who underwent one-antigen MMUD (9/10-matched) bone marrow (BM) or peripheral blood (PB) HSCT after myeloablative or reduced-intensity conditioning at our institution from 2009-2013. Outcomes were compared between (a) conventional GVHD group (n=71) that received in-vivo T-cell depletion with ATG, tacrolimus and methotrexate and (b) PTCy group (n=41) that received PTCy (50 mg/kg/day IV on days 3 and 4) with tacrolimus and MMF. After exclusion of 29 patients with isolated HLA-DQ mismatches, a separate analysis was performed in 84 patients with 7/8 HLA-MUD HSCT; 38 patients received PTCy while 46 patients received conventional prophylaxis. Results: Patients in the conventional group were marginally older (median 54 years; range 19-74) than those in the PTCy group (median 50 years; range 20-64). PB was used more frequently as a graft source in the conventional group (38% vs 17%, p=0.02). PTCy group included more patients with HLA class-I mismatches (87.8%) compared to conventional group (56.9%). There were no other differences between the groups. Incidence of grade II-IV (37% vs 36%, p=0.8) or grade III-IV (17% vs 12%, p=0.5) acute GVHD at day 100 post-transplant was not different between the groups. [Figure 1] Incidence of grade II-IV acute GVHD at day 30 was significantly lower after PTCy compared with conventional prophylaxis (0% vs 15%, p <0.001). Correspondingly, incidence of grade III-IV GVHD at day 30 was 0% in the PTCy group and 8% in the conventional group (p=0.08). Cumulative incidence of chronic GVHD was similar between the two groups at 6 months (20% vs 15%), 1-year (30% vs 31%) or 2-years (30% vs 42%). Risk factors analysis showed that use of PTCy was the sole independent predictor of lower risk of grade II-IV acute GVHD at day 30 (p=0.01). None of the risk factors evaluated, including PTCy use, were shown to predict the rate of grade II-IV acute GVHD within day 100. Two-year cumulative incidences of NRM (35% vs 25%), disease progression (20% vs 31%), DFS (42% vs 38%) and OS (52% vs 40%) were similar in the PTCy and the conventional groups, respectively. [Figure 1] Median times to neutrophil (18 vs. 12 days, p<0.001) and platelet (25.5 vs. 18 days, p=0.05) engraftment were prolonged in PTCy group. Disease recurrence/persistence was the leading cause of death in both groups, accounting for about 46% of all deaths. Subgroup analysis restricting to patients with BM grafts produced similar findings. In patients with HLA class-I mismatch, PTCy was associated with significantly reduced risk of grade II-IV, but not grade III-IV, acute GVHD at day 30 (p=0.01). However, there were no differences in acute grade II-IV GVHD (HR 1.1, 95% C.I. 0.5-2.5, p=0.7) or acute grade III-IV GVHD (HR 1.5, 95% C.I. 0.4-5.4, p=0.5) by day 100 between the groups. Comparing patients with 7/8-HLA-MUD HSCT, no patient in PTCy group developed acute GVHD at day 30 compared with 8 patients in conventional group (p=0.005). There were no differences in incidence of grade II-IV (HR 1, 95% C.I. 0.5-2.1, p=0.9) or grade III-IV (HR 1.1, 95% C.I. 0.3-3.3, p=0.9) acute GVHD at day 100, chronic GVHD at 6 months (HR 0.8, 95% C.I. 0.2-2.9, p=0.7), 1-year (HR 0.8, 95% C.I. 0.3-2.2, p=0.6) or 2-years (HR 0.7, 95% C.I. 0.2-1.9, p=0.5) between the groups. Conclusion: Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HSCT. Disclosures Alousi: Therakos, Inc: Research Funding.

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Impact of KIR B/X Genotype and Missing KIR Ligands in HLA-Matched Unrelated Donor HSCT

Blood ◽

10.1182/blood.v118.21.4488.4488 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4488-4488

Author(s):

Weiyang Li ◽

Jun He ◽

Xiaojing Bao ◽

Lina Zhou ◽

Wu Depei ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Prognostic Impact ◽

Matched Unrelated Donor ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Significant Difference ◽

Group A ◽

Group B

Abstract Abstract 4488 Objective To study the prognostic impact of missing ligands for inhibitory killer immunoglobulin-like receptor(KIR) and donor KIR B/X genotype in HLA-matched hematopoietic stem cell transplantation(HSCT) using unrelated donor. Methods HLA genotype of 51 patients (ALL 22 cases,AML 13 cases,CML 14 cases,MDS 1 case and HAL 1 case) and their matched unrelated donors was determined by polymerase chain reaction sequence oligonucleotide probes(PCR- SSOP) and sequence specific primers (PCR-SSP).The KIR genotype was determined by PCR-SSP. Results Patients were divided into two groups. Group A consisted of 16 patients with donor KIR B/X genotype and missing HLA class I ligands for donor inhibitory KIR, and group B consisted of 35 patients without KIR B/X or missing KIR ligands.The 3-year overall survival(OS) rate for group A was 93.8%, and the OS rate for group B was 61.7% (P=0.058).The 3-year continuous complete remission(CCR) rate for the two groups was 83.3% and 57.2%,respectively(P=0.098).There was no significant difference in neutrophil and platelet recovery,≥ III° acute GVHD(6.3% vs 20.0%,P>0.05) and extensive chronic GVHD (25.0% vs 17.1%,P>0.05) between the two groups. Conclusions In HLA-matched unrelated donor HSCT,donor KIR B/X genotype and missing KIR ligands may be associated with decreased severely acute GVHD,improved CCR and OS. Disclosures: No relevant conflicts of interest to declare.

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Association of Donor and Recipient Interleukin-1 Gene Single Nucleotide Polymorphisms with Outcome after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood

Blood ◽

10.1182/blood-2021-150895 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3902-3902

Author(s):

Bernd Gruhn ◽

Susan Wittig ◽

Katharina Kämpfner

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Acute Gvhd ◽

Interleukin 1 ◽

Chronic Gvhd ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Travel Costs ◽

Grade Ii

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for hematological malignancies, genetic diseases, and severe immune deficiencies. Despite the matching of the human leucocyte antigens (HLA), HSCT is still associated with a considerable rate of morbidity and mortality caused by infections, relapse, and graft-versus-host disease (GVHD). Therefore, non-HLA polymorphisms like cytokines and their receptors are considered as important contributing factors. Interleukin-1 (IL-1) is a cytokine that initiates and maintains the immune response as well as the development of GVHD in the recipient. Single nucleotide polymorphisms (SNPs) of the IL-1 gene are associated with a higher risk of malignancies, an elevated death rate because of infections, and a higher chance to suffer from autoimmune or chronic diseases. This study aimed to analyze the association of IL-1 gene SNPs with outcome in a pediatric population undergoing allogeneic HSCT. Methods: We included 270 pediatric patients with a median age of 9 years who underwent an allogeneic HSCT and their respective donors. We used TaqMan real-time polymerase chain reaction to analyze the SNPs IL-1-alpha rs1800587 (-889, A/T), IL-1-beta rs1143627 (-31, A/T), and IL-1-beta rs16944 (-511, A/T). The underlying diseases were acute lymphoblastic leukemia (n=89), acute myeloid leukemia (n=63), chronic myeloid leukemia (n=10), juvenile myelomonocytic leukemia (n=9), myelodysplastic syndrome (n=29), lymphoma (n=7), solid tumor (n=11), genetic disease (n=41), and aplastic anemia (n=11). The stem cell sources were bone marrow (n=178), peripheral blood (n=90) or umbilical cord blood (n=2). Two hundred donors were HLA-matched, and 70 donors were HLA-mismatched. Conditioning regimen was myeloablative in all cases and based on chemotherapy in 180 children or total body irradiation in 90 children. The predominant post-transplant immunosuppression was cyclosporine A and methotrexate in 148 patients or cyclosporine A alone in 55 patients. The genotyped SNPs were compared using the Kaplan-Meier method for event-free survival (EFS) and overall survival (OS) and the Gray test for acute GVHD, chronic GVHD, relapse rate (RR), and transplant-related mortality (TRM). Results: We observed a significant association between the SNP IL-1-alpha rs1800587 (-889, A/T) of the donor and the rate of acute GVHD. The genotypes of IL-1-alpha rs1800587 had the following distributions in the donor: CC genotype n=132 (49%), CT genotype n=114 (42%), and TT genotype n=24 (9%). Overall, 63 children (23%) suffered from moderate to severe acute GVHD (grade II-IV). We found a significantly increased incidence of moderate to severe acute GVHD (grade II-IV) if the patient was transplanted from a donor with the CC/CT genotype compared to the TT genotype (25% versus 4%; p=0.028). We found no significant associations of the SNP IL-1-alpha rs1800587 (-889, A/T) for chronic GVHD, RR, TRM, EFS, and OS. In addition, we observed no significant associations of the other studied genotypes IL-1-beta rs16944 (-511, A/T) and rs1143627 (-31, A/T) in either donors or recipients for acute and chronic GVHD, RR, TRM, EFS, and OS. Conclusion: Our study identified the IL-1-alpha rs1800587 CC/CT genotype of the donor as a genetic risk factor for the development of moderate to severe acute GVHD (grade II-IV) in pediatric allogeneic HSCT recipients. After confirmation in further studies, these findings could implicate the adjustment of prophylactic measures to reduce the risk of acute GVHD in children. Disclosures Gruhn: AmgenGmbh: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel costs; Bellicum Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees, Other: travel costs; EUSA Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: travel costs; Novartis Pharma Inc.: Honoraria, Other: travel costs; pfizer: Honoraria; servier: Honoraria, Other: travel costs; Neovii Biotech GmbH: Other: travel costs; medac GmbH: Other: travel costs.

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Depletion of donor lymphocytes by counterflow centrifugation successfully prevents acute graft-versus-host disease in matched allogeneic marrow transplantation

Blood ◽

10.1182/blood.v67.5.1302.bloodjournal6751302 ◽

1986 ◽

Vol 67 (5) ◽

pp. 1302-1308

Author(s):

T de Witte ◽

J Hoogenhout ◽

B de Pauw ◽

R Holdrinet ◽

J Janssen ◽

...

Keyword(s):

Bone Marrow ◽

Marrow Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Host Disease ◽

Allogeneic Marrow Transplantation ◽

Primary Graft Failure ◽

Acute Graft

Bone marrow from 22 histocompatible siblings was depleted of 98% of the lymphocytes using a combination of density flotation centrifugation followed by counterflow elutriation. Even with the marrow suppressive influence of methotrexate (MTX), the viability of the hematopoietic stem cells was not affected, as indicated by the normal repopulation after grafting in the evaluable patients. One patient (UPN 9) showed a primary graft failure, possibly resulting from persisting septicemia and long-term antibiotic therapy. Two patients have persistent host lymphocytes, one of whom was examined during relapse; the other remains in remission. Two patients did not receive immunosuppression after bone marrow transplantation (BMT), and acute graft-v-host disease (GVHD) developed in both. Nine patients received MTX as immunosuppression following BMT. GVHD did not develop in any of them, but fatal infections in the immediate posttransplant period developed in five patients. Eleven patients received cyclosporine (CsA) after transplantation. Beginning in week 5 after BMT, CsA was gradually replaced by MTX. Acute GVHD, substantial chronic GVHD, or fatal infections did not develop in any of these patients. Removal of 98% of the lymphocytes by counterflow centrifugation prevents development of acute GVHD, provided that immunosuppression is administered after BMT. Graft rejection was not observed, but the number of evaluable patients is limited at present.

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