Evaluation of Three Different Cyclosporine-Based Graft Versus Host Disease (GVHD) Prophylaxis Regimens Following Nonmyeloablative Hematopoietic Stem Cell Transplantation (NST).

Abstract Acute GVHD is a major contributor to morbidity and mortality following NST. A high incidence of grades II–IV GVHD occurs when cyclosporine A (CSA) alone is used as prophylaxis. Consequently, we investigated the effect of combining either mycophenolate mofetil (MMF) or methotrexate (MTX) with CSA on the incidence and severity of acute GVHD. Between 11/97 and 07/04, 185 consecutive patients (solid tumors n=116, hematologic malignancies n=48, non-malignant hematologic disorders n=21) underwent nonmyeloablative conditioning with fludarabine (125mg/m2) and cyclophosphamide (120mg/kg), followed by a G-CSF mobilized peripheral blood hematopoietic stem cell transplant from an HLA identical (n=177: 96%) or 5/6 antigen-matched (n=8: 4%) related donor. Twenty-four patients with a history of heavy RBC transfusions or those receiving a 5/6 HLA-matched transplant had anti-thymocyte globulin (40mg/kg/d x 4 days) added to their conditioning regimen. The initial cohort of patients (Group 1, n=66), received CSA alone (dose adjusted to maintain therapeutic serum levels) as GVHD prophylaxis. Due to the high incidence of severe acute GVHD in this group subsequent patients received CSA with either MMF (1 gram po bid; Group 2, n=82) or MTX (5mg/m2 days +1, +3, +6; Group 3, n=37). In all three groups, decisions regarding discontinuation of immunosuppression were based on the degree of donor T cell chimerism, presence of GVHD, and disease status in those with malignant diseases. In the absence of grade II–IV GVHD and disease progression, CSA (+/− MMF) was tapered slowly beginning on day +60. Baseline characteristics of patients in the three groups were compared using the Wilcoxon test for continuous variables and chi-squared tests for discrete variables. The three groups did not differ significantly in terms of age, sex, sex mismatch (female into male) and CD34 cell dose. Median follow-up in groups 1, 2 and 3 was 1901 days, 1248 days and 346 days respectively. The cumulative incidence of grades II–IV GVHD in these three groups was 56% (95% CI 44%–68%), 59% (95% CI, 48%–70%), and 34% (95% CI 18%–50%, p=0.11) respectively. The cumulative incidence of grades III–IV GVHD (30% vs. 34% vs. 16%, p=0.2) and the incidence of chronic GVHD (46% vs. 57% vs. 50%, p=0.49) were also similar in the three groups. Transplant related mortality was 15% (95% CI, 6%–24%) in group 1, 12% (95% CI, 5%–19%) in group 2 and 5% (95% CI, 0%–13%) in group 3 patients (p=0.44). The cumulative incidence of death from acute GVHD was 9% (95% CI, 0%–16%) and 2% (95% CI, 0–5%) respectively in groups 1 and 2, while no deaths from acute GVHD occurred in group 3. Overall survival in the three groups did not differ significantly (log-rank test, p=0.48), with medians 244 days (95% CI 196–402), 486 days (95% CI 306–620) and 438 days, (95% CI 210–662) respectively. The impact of adding MMF or MTX to CSA on disease-specific outcome in patients with malignant diseases was not assessed. Conclusion: There was a trend towards a lower incidence of grades II–IV GVHD in group 3 patients. However, despite the addition of either MMF or MTX to CSA, severe grade III–IV acute GVHD remains a major morbidity complicating NST. Additional strategies aimed at preventing GVHD and optimizing the management of established GVHD are needed to improve outcome following this approach.

Download Full-text

Reduced Incidence of Acute Graft Versus Host Disease (GVHD) and Transplant-Related Mortality (TRM) with the Addition of Short-Course Mini-Dose Methotrexate (MTX) to Cyclosporine (CSA) as GVHD Prophylaxis Following Nonmyeloablative Hematopoietic Stem Cell Transplantation (NST).

Blood ◽

10.1182/blood.v110.11.2990.2990 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2990-2990 ◽

Cited By ~ 1

Author(s):

Ramaprasad Srinivasan ◽

Haley Hedlin ◽

Rose Goodwin ◽

Aleah Smith ◽

Catalina Ramos ◽

...

Keyword(s):

Lower Incidence ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Dose Methotrexate ◽

Gvhd Prophylaxis ◽

High Incidence ◽

Group 3 ◽

Group 2 ◽

Related Mortality ◽

Group 1

Abstract Acute GVHD is a major cause of morbidity and mortality following NST. A high incidence of aGVHD occurs when CSA alone is used as prophylaxis. We investigated the effect of combining either mycophenolate mofetil (MMF) or an abbreviated course of low dose MTX with CSA on the incidence and severity of aGVHD. Between 11/97 and 07/07, 230 consecutive patients (pts) (solid tumors n=127, hematologic malignancies n=57, non-malignant hematologic disorders n=46) underwent conditioning with fludarabine (125mg/m2) and cyclophosphamide (120mg/kg), followed by a G-CSF mobilized PBSC transplant from an HLA identical (n=222: 96%) or 5/6 HLA-matched (n=8: 4%) related donor. Forty-eight pts with a history of heavy RBC transfusions or those receiving a 5/6 HLA-matched transplant had ATG (40mg/kg/d × 4 days) added to their conditioning. The initial cohort of pts (Group 1, n=66), received CSA alone (dose adjusted to maintain therapeutic serum levels) as GVHD prophylaxis. Due to the high incidence of severe aGVHD in this group, subsequent pts received CSA with either MMF (1 gram po bid; Group 2, n=82) or an abbreviated course of mini-dose MTX (5mg/m2 days +1, +3, +6; Group 3, n=82). In all three groups, decisions regarding discontinuation of CSA and MMF were based on donor T cell chimerism, presence of GVHD, and disease status. With a median follow-up of 2963, 2317 and 894 days in the three consecutive cohorts, a comparison was undertaken using competing risk analysis. The incidence of grades II–IV and III–IV GVHD was significantly higher in pts receiving CSA alone or CSA+MMF compared to those receiving CSA+MTX; the cumulative incidence of grades II–IV GVHD in the three groups was 56%, 59%, and 37% (p=0.05) while grades III–IV GVHD occurred in 30%, 34%, and 15% (p=0.019) respectively. The incidence of chronic GVHD (45% vs. 57% vs. 46%, p=0.27) was similar in the three groups. The lower incidence of aGVHD associated with MTX use was accompanied by a significantly improved TRM in group 3 pts; transplant related mortality was 21% in group 1, 21% in group 2 and 5% in group 3 pts (p=0.019). The impact of adding MMF or MTX to CSA on disease-specific outcome in pts with different malignant diseases could not be assessed due to small sample sizes. Conclusion: The addition of an abbreviated course of mini-dose methotrexate to CSA was associated with a significantly lower incidence of grades II–IV and III–IV aGVHD as well as lower TRM compared with CSA used alone or in combination with MMF in pts undergoing NST. To our knowledge this is the first report demonstrating a benefit of adding mini-dose MTX for GVHD prophylaxis in patients undergoing NST. Group 1 (N=66) Group 2 (N=82) Group 3 (N=82) P value Cumulative Incidence of Grade II–IV aGVHD (95% CI) 56% (44%–68%) 59%(48%–70%) 37%(25%–49%) 0.05 Cumulative Incidence of Grade III–IV aGVHD (95% CI) 30%(19%–41%) 34%(22%–46%) 15%(7%–23%) 0.019 Transplant Related Mortality(95% CI) 21%(11%–31%) 21%(12%–30%) 5%(0%–7%) 0.019 Proportion of Evaluable Pts with Chronic GVHD (%) 24/53 (45%) 43/75(57%) 34/74(46%) 0.274

Download Full-text

Addition of More Immunosuppressive Drugs As Graft-Versus-Host Disease (GVHD) Prophylaxis Does Not Improve Gvhd Outcomes in Reduced Intensity Allogeneic Hematopoietic Cell Transplantation from Unrelated Donors

Blood ◽

10.1182/blood.v128.22.5786.5786 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5786-5786

Author(s):

Mauricette Michallet ◽

Mohamad Sobh ◽

Fiorenza Barraco ◽

Xavier Thomas ◽

Marie Balsat ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Immunosuppressive Drugs ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Unrelated Donors ◽

Group 3 ◽

Group 2 ◽

Related Mortality ◽

Group 1

Abstract Background: Reduced-intensity conditioning (RIC) regimens have led to a dramatic reduction of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The concept of RIC is to deliver adequate immunosuppression with manageable graft-versus-host disease (GVHD) and the eventual development of a potent graft-versus-leukemia effect. Nevertheless, GVHD prophylaxis remains a challenging task after allo-HSCT. While the combination of cyclosporine A (CsA) and a short course of methotrexate (Mtx) after transplantation is considered as the gold standard for GVHD prophylaxis after conventional myeloablative allo-HSCT from HLA-identical siblings, there is no consensus on the optimal preventive GVHD prophylaxis after RIC allo-HSCT. On the other hand, recent and ongoing studies are evaluating a promising GVHD prophylaxis strategy using post-transplantation cyclophosphamide (PTCy). The aim of this study is to evaluate the impact of different GVHD prophylaxis used after RIC allo-HSCT in patients receiving peripheral blood stem cells (PBSC) from unrelated donors for hematological malignancies. Patients and methods: We evaluated 127 consecutive patients with hematological malignancies who received RIC allo-HSCT and were followed in our center between January 2008 and January 2016; 74 (58%) were males, median age was 58 years (range: 18-70), 52 (41%) had acute myeloid leukemia, 36 (28%) myelodysplastic syndrome, 12 (10%) myeloproliferative syndrome, 9 (7%) Non-Hodgkin lymphoma, 9 (7%) chronic lymphocytic leukemia, 6 (5%) multiple myeloma and 3 (2%) chronic myeloid leukemia. At transplantation, 65 (51%) patients were in complete response (CR) or chronic phase (CP). RIC regimen consisted on fludarabine, intermediate doses of IV busulfan and anti-thymocyte golbulins (ATG) (Thymoblobulin) in 56 (44%) patients and a sequential FLAMSA regimen in 71 (56%) patients and who also received similar doses of ATG (Thymoglobulin). PBSC donors were 10/10 HLA matched in 81 (64%) patients and 9/10 HLA mismatched in 46 (36%) patients. Patients were divided according to GVHD prophylaxis into 3 groups: group 1 consisted on CsA alone with 23 (18%) patients, group 2 include patients who received either CsA + mycophenolate mofetil (MMF), n= 64 (50%) or CsA + Mtx, n= 20 (16%) or CsA + cyclophosphamide n= 5 (4%), and group 3 included patients receiving CsA + MMF + tacrolimus n= 15 (12%) patients. Results: After transplantation, all patients in group 1 engrafted after a median of 17 (3-25) days, 81/89 (91%) engrafted in group 2 after a median of 17 (5-58) days and 14/15 (94%) engrafted in group 3 after a median of 16 (9-24) days. We did not observe any significant impact of the type of GVHD prophylaxis on the 100-day incidence of grade II to IV acute GVHD, which occurred in 6/15 (40%), 34/81 (42%) and 7/14 (50%) for the groups 1, 2 and 3 respectively (p=0.18). Grade III-IV acute GVHD occurred in 3 (20%), 24 (29%) and 5 (33%) in the three groups respectively (p=0.11). Similarly, cumulative incidence of 1 year chronic GVHD was not different between groups 1, 2 and 3 reaching 46%, 43% and 46% respectively (p=0.6) among them 3/15 (20%), 18 (22%) and 3/14 (21%) patients had an extensive form. After a median follow-up of 22 months for surviving patients, although there was no significant difference between the three groups in terms of non-relapse mortality, we observed more infection-related mortality with 45% and 83% in groups 2 and 3 respectively compared to 47% in group 1. The cumulative incidence of relapse at 2 years was 22%, 31 and 26% for the three groups respectively (p=0.23). Overall survival rates at two years were 43%, 31% and 44 % for groups 1, 2 and 3 respectively (p=0.42). The multivariate analysis taking into account the type of disease, donor HLA matching, disease status at transplantation, type of RIC and the type of prophylaxis, showed that the incidence of acute GVHD was influenced only by the use of FLAMSA regimen from mismatched donors, HR= 2.2 [1.3-3.1], p=0.05 which had also the same impact on the occurrence of chronic GVHD. Conclusion: Despite its limitations and the need for prospective randomized studies, the results of our study suggest that in the RIC allo-HSCT from unrelated donors, the different GVHD prophylaxis associations lead to similar GVHD outcomes. Patients with more immunosuppressive drugs had a higher incidence of infection-related mortality and in which PTCy could be a better option. Disclosures Nicolini: BMS: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Impact of Peripheral Blood Stem Cell Recruitment on Outcome of Single or Double Autologous Hematopoietic stem Cell Transplantation for Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.5221.5221 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5221-5221

Author(s):

Mauricette Michallet ◽

Quoc-Hung Le ◽

Anne-Sophie Michallet ◽

Anne Thiebaut ◽

Emmanuelle Tavernier ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Stem Cell ◽

Light Chains ◽

Hematopoietic Stem ◽

Group 4 ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Multiple myeloma remains one of the best indication for intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoT). Intensive therapy followed by autologous transplantation is superior to conventional chemotherapy and it was demonstrated that two autoT were superior to one except for patients in very good partial response or in complete response after the first autotransplant. Peripheral blood stem cells (PBSC) can be used as well as bone marrow as HSC source with the same efficacy but very few data have been reported regarding PBSC recruitment. The main goal of our work was to study the impact on overall and event-free survival (OS and EFS) of PBSC recruitment using either growth factors (GF) alone (steady state) or chemotherapy followed by GF. Secondly, we performed a multivariate analysis studying influence on OS and EFS of sex, age, lines of therapy, pretransplant status, TBI, PBSC recruitment and number of autoT. We have analyzed 193 PBSC autoT (1 autoT=160, 2 autoT=33) performed for 160 MM patients [81 males and 71 females, mean age: 55 years (39–71)]. At diagnosis, 88 patients presented a MM Ig G (70k and 18l), 28 Ig A (16k and 12l), 3 Ig D (1k and 2l), 21 light chains k and 13 light chains l, 3 non secreting and 4 with plasmocyte leukemias. According to Durie and Salmon classification 75% of patients were in stage III, 15% in stage II and 10% in progressive I. Before transplantation, patients have received 1 line of poly-chemotherapy (n=141), 2 lines (n=15) or 3 lines (n=4) and 154 were evaluated for the response with 11 complete remission, 113 partial remission and 30 stable or evolutive disease just before transplant. As HSC (n=189), patients received PBSC which were recruited by GF alone (n=105) or cyclophosphamide+GF (n= 84). Conditioning (n=189),consisted in melphalan and TBI (n=51), melphalan alone (n=132), melphalan associated to cyclophosphamide or busulfan (n=6). We divided the population into 4 groups : group 1 who received one autoT of PBSC recruited by GF (n=76), group 2 one autoT of PBSC recruited by chemotherapy+GF (n=50), group 3 two autoT of PBSC recruited by GF (n=16) and group 4 two autoT of PBSC recruited by chemotherapy+GF (n=17). The median follow-up (FU) of the 4 groups were different with shorter FU (group 3: 9.9 months, group 4: 13 months) for patients who received tandem autoT because of the recent character of this strategy as compared to a long term follow-up for patients who received only one transplant (group 1: 35months, group 2: 55.3 months). Probabilities of OS and EFS at 2 years were 76% (95%CI 67–87) and 60% (95%CI 49.5–73) for group 1, 77% (95%CI 65–90.5) and 70% (95%CI 57.5–85) for group 2, 87.5% (95%CI 73–100) and 72.9% (95%CI 49–100) for group 3, 100% and 66.7% (95%CI 36–100) for group 4. The difference was not significant because of follow-up differences between the 4 groups and small number of patients in groups 3 and 4. In addition, multivariate analysis did not show any significant influence of the different studied parameters on OS and EFS. Nevertheless, because of these interesting preliminary results, a longer follow-up is warranted for definitive conclusions.

Download Full-text

Leukemic and Hematopoietic Stem Cells Compete for the Same Functional Marrow Niche in a MLL-AF9 Murine Leukemia Model

Blood ◽

10.1182/blood.v120.21.4897.4897 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4897-4897

Author(s):

Ronan G. Desmond ◽

Taha Bat ◽

Olena Kamenyeva ◽

Benjamin Mizukawa ◽

James C. Mulloy ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Murine Model ◽

Leukemic Cells ◽

Hematopoietic Stem ◽

Group 4 ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Abstract 4897 Much is known regarding the location, cellular composition, signaling pathways, and functional role of the normal hematopoietic stem cell (HSC) niche in the bone marrow microenvironment. Microenvironmental cells including osteoblasts, other specialized mesenchymal cells, and vascular endothelial cells exert control over HSC self-renewal, differentiation, and engraftment. Niche occupancy appears to be competitive and limiting in terms of controlling the number of HSCs per organism. Leukemia stem cells (LSCs), through their inherent properties of quiescence and resistance to chemotherapeutic agents, are thought to be one of the principal mechanisms underlying disease relapse in patients. Much less is known regarding the interaction of LSCs and the marrow microenvironment. It is not clear whether LSCs localize to the same niches as HSCs, compete with HSCs for niche occupancy, or share dependence on niche signals, and whether those signals affect tumor responses to chemotherapy. Using a human pre-B ALL xenograft mouse model, Colmone et al (Science 2008) recently showed that leukemic cells may alter the normal microenvironment, resulting in initial homing of transplanted normal HSPCs in distinct atypical niches. Shiozawa et al (JCI 2011) showed that metastatic prostate cancer cells, a tumor type known to target bone, impeded HSC engraftment in a murine model, suggesting competition for the same niche. To investigate the relationship between HSC and LSC niche localization and functional occupancy, we used murine progenitor cells transduced with an MLL-AF9 vector expressing GFP in a murine syngeneic competitive transplantation model. MLL-AF9 cells are highly enriched for LSCs, particularly the c-kit+ compartment (Somervaille Cancer Cell 2006). We found that between approximately 21% and 24% of cells were c-kit+ by FACS in 2 separate experiments. In our model, mice transplanted with unsorted MLL-AF9 cells (1×107) died of AML with a latency of 11–14 days. We cotransplanted a fixed number of MLL-AF9-GFP cells (1×106) with increasing numbers of normal mouse whole bone marrow (WBM) cells, derived from dsRed transgenic mice to facilitate distinction from the GFP+ MLL-AF9 cells, into mice irradiated with 1000 rads: 1×105 [group 1], 1×106 [group 2], 1×107 [group 3], 5×107 [group 4]. Control groups received 1×105 and 1×106 normal WBM cells only. Survival was monitored daily. The control group receiving 1×105 cells only all died with median time to death of 16.5 days from lack of count recovery, those receiving 1×106 cells are still alive 35 days after transplant, indicating that 1×106 cells is adequate to rescue from irradiation. Mice were bled weekly until death and samples were analyzed by flow cytometry. Complete blood counts, blood smears, and splenic sections were obtained from these mice. As expected, there were no circulating blasts detected 7 days post transplant and all mice were healthy. However, 14 days after transplant the percentages of GFP+ leukemic cells detected in the blood were inversely proportional to the number of normal dsRed WBM cells transplanted (group 1 vs. group 2 vs. group 3 vs. group 4 mean percentage of GFP+ cells, 83.97 v 66.53 v 18.73 v 9.275 p< 0.0001). At day 15, mice from group 1, but not from groups 2 to 4, became moribund and were sacrificed. Spleens in this group were heavier than in those mice transplanted with 1×105 normal WBM cells alone and 2 out of 3 showed leucocytosis compared to leucopenia in all mice in the group transplanted with normal cells alone. When mice in the other groups had blood samples taken for analysis while moribund, GFP+ cells were greater than 80% suggesting that mice in group 1 died from complications relating to leukemic infiltration. Confocal microscopy confirmed the colocalization of normal HSPCs and MLL-AF9-GFP LSCs in the niche. Most interestingly, survival was proportional to the numbers of normal WBM cells transplanted, with a continuous delay in leukemic death proportional to the number of normal WBM cells cotransplanted with the same dose of MLL-AF9 cells (Figure 1). Hence, this murine model of leukemia suggests that normal and leukemic cells compete for the same functional niche, that manipulation of the niche could impact on response to anti-leukemic therapies, and that cell dose in the context of stem cell transplantation for leukemia may have an impact on outcome via niche competition. Figure 1 Figure 1. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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

Blood ◽

10.1182/blood-2018-99-113166 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4636-4636

Author(s):

Jeong-Ok Lee ◽

Jessica Flynn ◽

Molly Maloy ◽

Ann A. Jakubowski ◽

Esperanza B. Papadopoulos ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Systemic Treatment ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Grade Ii

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

Download Full-text

Correlation of Acute GVHD with CD4+CD25+ Regulatory T Cells of the Donates and Receipients in Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v106.11.5235.5235 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5235-5235

Author(s):

Zhai Zhi Min

Keyword(s):

T Cells ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Normal Control ◽

Acute Gvhd ◽

Hematopoietic Stem ◽

Group 2 ◽

Group 1

Abstract Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). CD4+CD25+ T cells are characterized in suppression of autoimmunity and induction of transplantation tolerance. Recently several studies have shown that CD4+CD25+ T cells from donor are able to effectively suppress acute GVHD (aGVHD) in murine models. However the relationship of aGVHD with the levels of CD4+CD25+ T cells in donor and receipients undergoing aHSCT in human is not clear. Here we examined the CD4+CD25+ T cells in both donors and receipients after aHSCT. Methods: donors and receipients were divided into two groups: group 1 without or with grade I aGVHD and group 2 with aGVHD above grade II. Age match with donors and receipients of normal peoples were taken as control separately. aGVHD was diagnosised and graded according to standard criteria. The peripheral blood was obtained from the donors 1 week before aHSCT, and receipients 4weeks after aHSCT for treatment of malignancy, mostly chronic myelogenous leukemia. CD4+CD25+ T cells and CD4+CD25+ bright were assessed by double color immunoflurecence labeling and FACScan. The ratio of CD4+CD25+ T cells and CD4+CD25+ bright in CD4 T cells was calculated. Results: There is no difference in CD4+CD25+ T cells between normal control and group 1 of the donors who’s stem cells were infused into the receipients underwent grade I aGVHD. CD4+CD25+ T cells were significantly decreased in group 2 of donors compared to normal control and group 1 of donors (see table 1). CD4+CD25+ T cells and the CD4+CD25bright T cells subpopulations in group 2 of receipients were significantly lower than normal control and group 1 of receipients (see table 2). Summary: the severity of aGVHD is correlated to the levels of CD4+CD25+ T cells in both donors and receipients after aHSCT. aGVHD occur less in the donor with normal levels of CD4+CD25+ T cells. Lower levels of CD4+CD25+ T cells in receipients indicate high incidents of server aGVHD. These data suggested that CD4+CD25+ T cells could have important role in prevention of aGVHD. Table 1. lymphocytes, CD4+ T cells, CD4+CD25+ and CD4+CD25bright T cells (%) in donates lymphocytes lymphocytes CD4+ CD4+CD25+ CD4+CD25bright *P<0.01 vs normal control and group 1. **P< 0.001 vs normal control and group 1 Normal control n=10 34.27±8.62 37.25±5.38 11.29±1.89 1.36±0.53 Group 1 donate n=6 33.65±10.06 36.43±9.50 11.23±1.69 1.41±0.76 Group 2 donate n=4 23.90±11.67 32.57±3.40 5.64±1.57** 0.69±0.48* Table 2. WBC count, CD4+CD25+ and the CD4+CD25bright T cells in receipients (%) WBC(×109) CD4+CD25+ CD4+CD25bright *P<0.01 vs normal control and group 1. **P< 0.001 vs normal control and group 1 Normal n= 10 6.38±1.23 11.29±1.89 1.36±0.53 Group 1 n= 6 5.16±4.49 17.10±4.19 2.23±1.52 Group 2 n=4 4.34±2.85 1.52±0.61** 0.00±0.00*

Download Full-text

Affect of Age on Survival and Complications after Hematopoietic Stem Cell Transplantation in Children with β-Thalassemia Major

Blood ◽

10.1182/blood-2019-126596 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4591-4591

Author(s):

Yiqi Xu ◽

Yongsheng Ruan ◽

Yuelin He ◽

Jianyun Wen ◽

Xiaoqin Feng ◽

...

Keyword(s):

Stem Cell ◽

Age Groups ◽

Thalassemia Major ◽

Oral Infection ◽

Hematopoietic Stem ◽

Kaplan Meier ◽

Group 3 ◽

Group 2 ◽

Family Donor ◽

Group 1

Background/Objective:Adolescents are considered to be a high-risk group by pediatricians, and have long been regarded as high-risk patients by adult hematologists. Foreign related studies show that the degree of damage to the organ in older children after hematopoietic stem cell transplantation (HSCT) is more serious and late complications are more common in them. Considering this finding, we conducted an analysis on the age, the survival rate and complications among children who had had β-thalassemia major and received HSCT. Methods:Among the children who had β-thalassemia major and were treated with HSCT in the Pediatrics Department of the Nanfang Hospital of Southern Medical University, we collected the data of 332 valid β-thalassemia children patients from January 1st, 2012 to June 30th, 2018 and following up the cases until September 30th, 2018. 281 β-thalassemia patients received allo-HSCT from HLA-matched sibling or unrelated donor and 51 β-thalassemia children patients received haplo-identical family donor. Based on the age of the children patients, the case data was divided into three groups for discussion and comparison: group 1 for ≤4 years, group 2 for 5 to 8 years and group 3 for over 8 years. For the three age groups, the correlation between the age and the incidence of GVHD, grade I & II, III and IV aGVHD, cGVHD and some complications such as infection, septicemia, convulsion, EVB infection, etc, was analyzed. Furthermore, the survival curves of the OS and the ESF of all age groups were compared. Results:In 281 HLA-matched cases, OS and ESF after transplantation was 94.3% and 93.2% respectively and deaths in 16 cases(figure1). OS of group 1, 2 and 3 is 97.5%, 95% and 88.5%, respectively. OS of group 3 compared with group 1 is statistically significant with P-value =0.028 (P<0.05) and with group 2 is P=0.096(Kaplan-Meier estimator). EFS of group 1, 2 and 3 are 96.2%, 95% and 85.2%, respectively. EFS of group 3 compared with group 1 is P=0.020 (P<0.05) and with group 2 is P=0.018 (P<0.05)(Kaplan-Meier estimator). The age correlated with the incidence of GVHD, chronic GVHD, grade I & II acute graft-versus-host disease (Kaplan-Meier estimator), convulsion, oral infection and EVB infection (P < 0.05, χ2 test). In particular, the incidence was significantly higher in children above age 8 years as compared to the children under 8 years. In 51 haploidentical family donor cases, OS and ESF after transplantation were 94.1% and 90.2% respectively, the total deaths in 3 cases, the incidence of grade I & II acute GVHD and EVB infection correlated with the age(P<0.05, χ2 test). Conclusions:For HSCT of thalassemia, in HLA-matched cases, OS and ESF rates were lower in children above 8 years than the children below 8 years. In terms of GVHD, cGVHD, aGVHD grade I & II, seizure, oral infection, and EVB infection, the incidence was high in children aged above eight years as compared to below 8 years old, while the lowest incidence was observed in children aged below four years, which is statistically significant. In haplo-identical family donor cases, the incidence of aGVHD grade I and II was highest in children aged above eight years while lowest in children below four years old. Figure 1 Disclosures No relevant conflicts of interest to declare.

Download Full-text

Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001818 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001818 ◽

Cited By ~ 1

Author(s):

Chantal Saberian ◽

Noha Abdel-Wahab ◽

Ala Abudayyeh ◽

Hind Rafei ◽

Jacinth Joseph ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Myelodysplastic Syndromes ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Checkpoint Inhibitors ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Acute Myeloid

BackgroundImmune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT.MethodsA retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed.ResultsFour patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2–4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01).ConclusionsICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.

Download Full-text

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.

Download Full-text