Haploidentical Stem Research Articles

Value of the Assessment of Interleukin 6 level in Allogenic T-cell Replete Haploidentical peripheral blood haematopioetic stem cell transplantation using post-transplant cyclophosphamide as a predictor for the occurrence of acute Graft versus Host Disease

Value of the Assessment of Interleukin 6 level in Allogenic T-cell Replete Haploidentical peripheral blood haematopioetic stem cell transplantation using post-transplant cyclophosphamide as a predictor for the occurrence of acute Graft versus Host Disease

Improved Outcome of Haploidentical Peripheral Blood Stem Cell Transplant Treating Severe Aplastic Anemia

Improved Outcome of Haploidentical Peripheral Blood Stem Cell Transplant Treating Severe Aplastic Anemia

Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора

Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора

Akut Lösemi Hastalarında Haploidentik ve Akraba Dışı Kök Hücre Nakli Sonuçlarının Karşılaştırılması

Akut Lösemi Hastalarında Haploidentik ve Akraba Dışı Kök Hücre Nakli Sonuçlarının Karşılaştırılması

Grade III-IV cytokine release syndrome is associated with inferior survival in patients undergoing haploidentical donor stem cell transplants.

7546 Background: Haploidentical transplant (HIDT) with post-transplant cyclophosphamide (pCY) is being increasingly used because of the universal availability of donor and rapid graft acquisition time. Cytokine release syndrome (CRS) is one of the commonly occurring complications in this population. The information on the impact of CRS on the post-HIDT outcomes is limited. Methods: We retrospectively evaluated 91 patients who underwent HIDT between June 2012 and June 2019 for the onset and severity of CRS. CRS was graded per ASTCT guidelines. The primary objective was to compare RFS (relapse-free survival), NRM (non-relapse mortality), OS (overall survival) and GVHD in patients with no CRS, CRS grade 1-2 and 3-4. Results: All received peripheral blood stem cells and pCY/tacrolimus/mycophenolate as GVHD prophylaxis. Fifty-six (62%) received reduced intensity and 35 (38%) received full intensity conditioning regimen. Ten (10.9%) had no CRS, 74 (81.3%) developed grade 1-2 CRS and seven (7.7%) experienced grade 3-4 CRS. Median time to onset of CRS was one day post-transplant. The most common symptoms were fever (87%), fatigue (30%), nausea/vomiting (24%), rigors (24%), diarrhea (20%) and rash (11%). Fifteen (20%) with grade 1-2 and six (85%) with grade 3-4 CRS received tocilizumab. Day +100 cumulative incidence of grade III-IV acute GVHD for no CRS, grade 1-2 and grade 3-4 CRS was 0%, 2.7%, and 14.3%, respectively (P = 0.36). One-year cumulative incidence of chronic GVHD for no CRS, grade 1-2 and grade 3-4 CRS was 30%, 31.9% and 14.3%, respectively (P = 0.70). One-year NRM for no CRS, grade 1-2 and grade 3-4 CRS was 30%, 16.5%, and 57.1%, respectively (P = 0.002). One-year RFS for no CRS, grade 1-2 and grade 3-4 CRS was 48%, 63.4% and 28.6%, respectively (p = 0.03). OS at 1-year for no CRS, grade 1-2 and grade 3-4 CRS was 60%, 73.9%, and 28.6%, respectively (P = 0.008). Multivariable analysis revealed that grade 3-4 CRS was associated with significantly higher NRM (HR 5.54, P = 0.002), worse RFS (HR 3.41, P = 0.011) and worse OS (HR 4.91, P = 0.001). Conditioning regimen, degree of HLA match and disease risk index did not affect post-transplant outcomes and were not predictors for developing CRS. Conclusions: Our study showed that grade 3-4 CRS was associated with inferior post-transplant outcomes. However, no impact on acute or chronic GVHD was noted. Therefore, early recognition and prompt management of CRS may help improve outcomes.

A Trial to Assess Haploidentical T-depleted Stem Cell Transplantation in Patients With SCD

A Trial to Assess Haploidentical T-depleted Stem Cell Transplantation in Patients With SCD

Characterization of Immune Cells Producing Regulatory Cytokines That Mediate Engraftment in Sickle Cell Disease Patients after Haploidentical Peripheral Blood Stem Cell Transplantation

Sickle cell disease (SCD) is an inherited blood disorder in which red blood cells are sickle-shaped as a result of an amino acid alteration from glutamate to valine at the sixth position of the β-globin chain. Hematopoietic stem cell transplant (HSCT) is a curative option for SCD, with both HLA-matched and haploidentical transplant being viable approaches. Stable mixed chimerism and tolerance induction are sufficient to reverse the sickle phenotype. Graft rejection and graft versus host disease may occur following nonmyeloablative haploidentical peripheral blood stem cell transplantation (PBSCT). Various regulatory cytokines have been identified as biomarkers of engraftment in graft transplantation. Previously, we observed that TGF-β, interleukin (IL)-7, and IL-10 cytokines were elevated in engrafted SCD patients as compared to those who rejected their grafts following haploidentical PBSCT. Now, we aim to identify the immune cell populations responsible for producing the above cytokines in both engrafted and rejected patients. The plasma samples of 21 SCD patients who underwent nonmyeloablative haploidentical PBSCT at the National Institutes of Health between March 2010 and September 2015 were evaluated previously by multiplexed magnetic bead enzyme linked immune sorbent assay. Here, we analyzed various immune cells which produce the above regulatory cytokines through multi-color flow cytometry in 8 out of the 21 patients (four engrafted and four rejected). We evaluated the cytokine producing capabilities via intracellular cytokine detection among T regulatory (Treg, CD3+CD4+CD25+Foxp3+) cells, Type 1 regulatory (Tr1, CD3+CD4+Foxp3-CD45RA-CD49+LAG3+) T cells, T helper 1 (Th1, CD3+CD4+Foxp3-CD45RO+CXCR3+) cells, T helper 17 (Th17, CD3+CD4+Foxp3-CD45RO+CCR6+) cells, natural killer (NK, CD3-CD56+NKG2D+) cells, B regulatory (Breg, CD3-CD56-CD19+CD24hiCD38hi)cells, polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs, CD45+CD14-CD15+CD11b+), monocytic-MDSCs (CD45+CD14+CD15-HLADRlow), early-MDSCs (CD45+Lin-HLADR-CD11b+CD33+), myeloid dendritic cells (mDCs, CD45+CD3-CD56-HLADR+CD11c+CD123-), and plasmacytoid dendritic cells (pDCs, CD45+CD3-CD56-HLADR+CD11c-CD123+). Cytokine producing cell frequencies were measured at five timepoints: baseline (day 0) and days 30, 60, 100, and 180 post-transplant (PT). Percentages of intracellular cytokine and cell population frequencies were assessed through flow cytometry analysis and statistical significance was determined by Student's t-test. We noted IL-10-producing Tregs were significantly elevated in engrafted patients at PT day 100 (p< 0.01, see Figure 1). Further, IL-10-producing Th1 cells were significantly higher in engrafted patients on PT day 30 (p< 0.01) and day 100 (p< 0.01). However, rejected patients had significantly higher amounts of IL-10-producing PMN-MDSCs (p< 0.01), and myeloid DCs (p< 0.01, see Figure 2), but their levels were lower than IL10-producing Tregs and Th1 cells of engrafted patients. There were no significantly different alterations of IL-10-producing cell frequencies among other cell populations (Tr1, Th17, NK, Breg, early-MDSCs, monocytic-MDSCs, and pDCs). In addition, there were no significant variations in TGF-β- and IL-7-producing cell frequencies in any of the immune cell populations tested. Overall, the engrafted patients showed higher IL-10-producing Tregs and Th1 cells at PT day 30 and/or day 100, which suggest that the immunosuppressive cytokine IL-10 may play an important role in engraftment. Further analyses with a larger sample size are indicated to evaluate whether IL-10 producing immune regulatory cells may serve as a biomarker to predict transplant outcome. Taken together, continuous regulatory cytokine analysis at serial time points pre- and post-transplant may aid in establishing mechanisms of successful engraftment and tolerance induction. Disclosures No relevant conflicts of interest to declare.

Incorporation of Posttransplant Cyclophosphamide (PCy) As Part of Standard Immunoprophylaxis (IP) for All Allogeneic Transplants: A Retrospective, Single Institution Study

Background: The incorporation of PCy in IP has allowed transplantation of stem cells from haploidentical (HI) family members such that nearly all patients have a potential donor. Thus far, HI stem cell transplantation with PCy appears to yield comparable results to matched unrelated (MUD) and matched sibling donors (MSD) who have been treated with conventional GVHD regimens, but with less chronic GVHD (cGVHD). Particularly in light of the low incidence of cGVHD, which has not been achieved with other IP strategies after T cell-replete products, PCy is being investigated after MUD and MSD transplantation where complications from cGVHD remain the major cause of non-relapse mortality. A recent study from the BMTCTN showed that in patients conditioned with reduced intensity regimens and who received MSD and MUD stem cells, the addition of PCy to standard IP (SIP) was superior to either bortezomib or maravoric in the composite endpoint of graft-versus-host disease-free, relapse-free survival (GRFS). However, this study did not include patients who received ablative conditioning regimens and did not report on the percentage of patients who were disease-free and off immunosuppression (DFOI) at 1 year after transplant. In the present study, we have compared our experience with the addition of PCy for essentially all allogeneic stem cell transplants treated over a 2 year period with the results of patients treated with SIP in the prior two year span. Outcomes of interest included one-year overall survival (OS) and one-year GRFS as well as the percentage of patients DFOI at one year. Methods: With the exception of patients receiving umbilical cord blood transplants, beginning in April 2016, all but two patients who received allogeneic transplants were given mobilized peripheral blood stem cells and then treated with PCy on days +3 and +4 followed by tacrolimus and mycophenolate on day 5. In the absence of GVHD, mycophenolate was stopped at days +35-50 and tacrolimus was tapered beginning after day +100 unless there was low donor chimerism or a suspicion of relapse in which case tacrolimus could be tapered sooner. In order to have at least one-year follow-up, the last patient included in the study was treated before April 2018. During this time period, MSD were prioritized over MUD which in turn were chosen over haploidentical donors. For comparison, we looked at the prior 2 year period (2014-2016) in which patients were treated with SIP (including ATG in patients who received MUD stem cells). Because of a higher percentage of patients with an advanced disease risk index (DRI) in the years 2014-2016, we restricted our analysis in the SIP cohort to those patients with low and intermediate risk disease but included all patients in the more recent period who received PCy. Results: There were 68 patients treated in the PCy group, including 2 patients who received PCy after HI transplants in the years 2014 and 2015. After eliminating patients with high DRI there were 40 patients in the earlier SIP cohort of patients. The resulting patient groups were similar with respect to median age (53) and diagnosis (approximately 80% of patients with AML and ALL). There was a slightly higher percentage of patients in the SIP group with hematopoietic cell transplantation-comorbidity index scores of 3 or more (52.5 vs 48.5). In the PCy group the number of patients with early, intermediate and advanced DRI were 2, 53 and 13, whereas in the (modified) SIP category 2 patients had a low DRI and 38 had intermediate DRI. In the PCy group, HI donors comprised 26.5% of the total compared to 19.1% MSD and 54.4% MUD donors. In the SIP group, MSD and MUD donors accounted for 30% and 70% of the donors. One-year percentages of OS, GRFS and DFOI were 79.4, 47.1 and 44.1 in the PCy group compared to 72, 45 and 35 in the SIP cohort. If the analysis of the PCy group is limited to the 50 patients with MSD and MUD donors (as in the SIP cohort), the one-year OS, GRFS and DFOI are 88, 52 and 52. Conclusions: PCy in combination with SIP resulted in at least comparable results as SIP despite the inclusion of 19% of patients with a high DRI and 26.5% HI donors. The results with the addition of PCy are excellent in patients with MSD and MUD donors with more than half of the patients GRFS and DFOI at one year. Future studies on GVHD prophylaxis should report DFOI as the latter status may be the best platform for posttransplant strategies aimed at eliminating minimal residual disease and for improving QOL. Disclosures No relevant conflicts of interest to declare.

Risk Factors and Different Therapeutic Patterns of Late-Onset Hemorrhagic Cystitis after Haploidentical Allogeneic Stem Cell Transplantation

Introduction Late-onset hemorrhagic cystitis (LOHC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with an incidence ranging from 6.5% to 70% and leads to prolonged hospitalization and even death (Silva Lde P et al, Haematologica, 2010; LAM et al, Transpl Infect Dis, 2017). The pathogenesis of LOHC remains obscure, but in our previous study, viral infections and acute graft-versus-host disease (aGVHD) have frequently been shown to be associated with its development (Han et al., Am. J. Hematol, 2014). Therapeutic strategies for LOHC are still not standardized due to the complicated clinical background and given the paradoxical phenomenon that immunosuppressive agents, such as steroids, are necessary for aGVHD but cause an immunosuppressive state. We aimed to investigate the incidence, risk factors and outcomes of LOHC after allogeneic stem cell transplantation. Additionally, for the first time, we propose four therapeutic patterns and their impact on prognosis of LOHC to aid in clinical decision making. Methods This retrospective, nested, case-control study reviewed data from 2158 patients who received allo-HSCT from January 2014 to December 2018. In total, 364 (16.87%) patients were diagnosed with LOHC. Individual matching was performed by randomly selecting 3 controls from the same cohort for each identified LOHC patient according to the time of allo-HSCT. Standard basic measures included hyperhydration, forced diuresis, insertion of a vesical catheter for intermittent or continuous bladder irrigation and evacuation of clots. Patients with grade III-IV LOHC were divided into four groups according to immunosuppressant use (steroid, MMF and Basiliximab) 1 week before and after the onset of LOHC: an intensified-intensified (I-I) group, intensified-not intensified (I-N) group, not intensified-intensified (N-I) group and not intensified-not intensified (N-N) group. "Intensified" was defined as an increase in any immunosuppressant, and "not intensified" was defined as maintenance or tapering of all immunosuppressants. Data concerning the baseline characteristics, incidence, treatment patterns and outcomes were recorded. Results In total, 364 patients developed LOHC at a median of 29 days (range, 23-37.75 days), with a cumulative incidence of 16.87%. AML (HR =0.493 95% CI, 0.244-0.997; p=0.049), AA (HR =0.444, 95% CI,0.18-1.096; p=0.078), HLA match(HR =0.149, 95% CI, 0.036-0.616; p=0.009), days to platelet engraftment(HR =1.023, 95% CI, 0.998-1.049;p=0.069)and CMV viremia (HR =2.365, 95% CI, 1.179,4.733;p=0.015)were associated with LOHC. Only HLA match (HR =0.111, 95% CI, 0.014-0.878; p=0.037)remained significant in the multivariate analysis. 6.5%, 12.9%, 48.39% and 32.26% patients with III-IV LOHC were divided into I-I, I-N, N-I and N-N groups, respectively. There were no significant differences in overall survival (p=0.05) and the incidence of CMV viremia (p=0.187) among the four groups. The incidence of relapse (p=0.007) and the incidence of aGVHD (p=0.01) was highest in the I-I group, followed by the N-I, I-N and N-N groups. 50% of the patients in N-I group showed the improvement of LOHC, which is significantly highest among the four groups(p=0.000). However, no statistical significance was found regarding the CMV viremia turning shade or the improvement of aGVHD. Non-relapse mortality (NRM) was observed in 25% of patients without resolution of LOHC. NRM was 0% among patients without intensified immunosuppression but was 25%, 0% and 50% among those with intensified immunosuppression before LOHC, after LOHC and before and after LOHC, respectively. Conclusion The independent risk factors for LOHC after allo-HSCT were HLA mismatch. Avoiding intensified immunosuppression that damages endothelium or reactivates the related virus may improve transplant outcome. The N-N pattern could reduce the incidence of CMV viremia or aGVHD in the LOHC patients, and the N-I pattern might be more promising as a therapeutic strategy for LOHC. Disclosures No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.

Safety Study and Preliminary Efficacy of Infusion Haploidentical Mesenchymal Stem Cells Derived From Bone Marrow for Treating Recessive Dystrophic Epidermolysis Bullosa

Safety Study and Preliminary Efficacy of Infusion Haploidentical Mesenchymal Stem Cells Derived From Bone Marrow for Treating Recessive Dystrophic Epidermolysis Bullosa

Unmanipulated haploidentical peripheral blood stem cell transplantation for patients with Philadelphia-negative acute lymphoblastic leukaemia in first complete remission

Haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) is a promising treatment option for patients with Ph-negative acute lymphoblastic leukemia (ALL). In this study, we retrospectively analyzed data from Ph-negative ALL patients who underwent haplo-PBSCT during their first complete remission (CR1), and compared the long-term outcomes between the standard-risk and high-risk patients. The 3-year probability of relapse was 7.6% and 16.7% for the standard- and high-risk group (p = .274). The 3-year probability of disease-free survival (DFS) and overall survival (OS) for the standard-risk versus high-risk groups were 84.6% versus 50% (p = .0063) and 92.3% versus 61.1% (p = .046), respectively. Univariate analysis showed that a diagnosis of high risk with fusion/mutation genes were associated with worse outcomes, which was confirmed by multivariate analysis (p = .016). In summary, haplo-PBSCT may be a promising alternative for patients with Ph-negative ALL in CR1, although the fusion/mutation genes in high-risk patients may relatively impair the long-term efficacy compared with standard-risk patients.

Efficacy analysis of haploidentical allogeneic hematopoietic stem cell transplantation combined with third-party umbilical cord blood infusion in treatment of high-risk lymphoblastic malignancies

Objective To evaluate the efficacy of haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HSCT) combined with third-party umbilical cord blood (UCB) infusion in treatment of high-risk lymphoblastic malignancies. Methods The clinical data of 20 patients with high-risk lymphoblastic malignancies who received Haplo-HSCT from April 2012 to April 2015 in Shanghai General Hospital were retrospectively analyzed, which were compared with the data from 15 patients who underwent matched unrelated donor HSCT (MUD-HSCT) or 14 matched sibling donor HSCT (MSD-HSCT) during the same period. The efficacy of Haplo-HSCT combined with UCB infusion in treatment of high-risk lymphoblastic malignancies was evaluated. The preparative regimen mainly consisted of teniposide, cyclophosphamide and total body irradiation (TBI). Graft versus host disease (GVHD) preparative regimen included cyclosporine and a short term of methotrexate. The patients who received Haplo-HSCT combined with UCB infusion and MUD-HSCT were treated with antithymocyte globulin (ATG). Results After the transplantation, one patient in MUD-HSCT group and one in MSD-HSCT group died within 21 days, and other patients were engrafted successfully. The median time of neutrophil engraftment was 13 days (10-18 d), 12 days (9-16 d) and 12 days (9-14 d) in Haplo-HSCT + UCB group, MUD-HSCT group and MSD-HSCT group, respectively; the median time of platelets engraftment was 11 days (9-18 d), 12 days (10-23 d) and 12 days (9-14 d), respectively. There were 10, 3, 3 cases of grade Ⅱ-Ⅳ acute GVHD at day 100 in the three groups, respectively, and there were 6, 4, 3 cases of chronic GVHD in the three groups, respectively. The 2-year cumulative incidence of relapse was 40.6%, 66.2% and 26.7%, respectively. The predicted 2-year overall survival rate was 37.9%, 42.9% and 55.4%, respectively. All these data had no significant difference (all P > 0.05). Conclusion The efficacy of Haplo-HSCT combined with UCB infusion is similar to that of MUD-HSCT or MSD-HSCT in treatment of high-risk lymphoblastic malignancies, which should be recommended to the patients with high-risk lymphoblastic malignancies and without matched donors. Key words: Lymphoblastic malignancies; Allogeneic hematopoietic stem cell transplantation; Fetal blood

Reduced-intensity conditioning haploidentical peripheral blood hematopoietic stem cell transplantation without T-cell depletion in vitro for treatment of relapsed Hodgkin lymphoma after autologous hematopoietic stem cell transplantation: report of one case

Reduced-intensity conditioning haploidentical peripheral blood hematopoietic stem cell transplantation without T-cell depletion in vitro for treatment of relapsed Hodgkin lymphoma after autologous hematopoietic stem cell transplantation: report of one case

Managing Drug Interactions in Cancer Therapy: A Guide for the Advanced Practitioner

Mrs. P is a 30-year-old woman who presented to our bone marrow transplant program with myelodysplastic syndrome (MDS). She received a haploidentical allogeneic stem cell transplant with a conditioning regimen consisting of busulfan and cyclophosphamide. This treatment was followed by post-transplant immunosuppression for graft-versus-host disease (GVHD) with cyclophosphamide, mycophenolate mofetil (MMF), and tacrolimus (see Table 1 for medication list). Tacrolimus levels were monitored twice a week with adjustment to a goal range of between 5 and 10 ng/mL. We initiated tacrolimus at a dose of 0.03 mg/kg by mouth twice daily (rounded to 2 mg by mouth twice daily). Drug interactions were assessed by the clinical pharmacist prior to admission, routinely with medication changes, and then upon discharge.

Related Haploidentical Peripheral Blood Stem Cell Transplantation as a Rescue after Double Cord Blood Unit Graft Rejection in an Anti-HLA-Immunized Patient

Related Haploidentical Peripheral Blood Stem Cell Transplantation as a Rescue after Double Cord Blood Unit Graft Rejection in an Anti-HLA-Immunized Patient

Hemophagocytic syndrome following haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide.

Hemophagocytic syndrome (HPS) is a rare but serious complication after allogeneic transplantation which has been reported to be particularly high after unrelated cord blood transplantation. We report on the incidence, risk factors and outcome of HPS in 51 patients (age 2-64 years) after haploidentical peripheral blood stem cell (PBSC) transplantation with post-transplantation cyclophosphamide (PTCY). The incidence of HPS was 12.2 %, occurring at a median of 18 days. The non-relapse mortality in patients with HPS was 83.3 % compared to 11.6 % in patients without HPS. Complete donor chimerism was documented in all patients with HPS. Definite infective etiology was identified in two patients only. The others were refractory to multiple lines of treatment and 3 patients underwent a second transplant. Even though the symptoms and biochemical markers of HPS showed prompt response in 2/3 patients undergoing a second allograft, they succumbed to infections before haematological recovery. The others succumbed to multi-organ failure or infections. Age < 10 years, transplantation for non-malignant disease and high CD34 content of the graft were identified as risk factors for HPS. Considering the fact that post-transplant HPS is usually a refractory and fatal condition, we discuss further attempts at deciphering the pathogenesis, developing modalities to prevent this complication and improve the outcome.

The First Case of Ganciclovir-Resistant Cytomegalovirus Colitis with a 597-600 Deletion inUL97Gene after Stem Cell Transplantation in Korea

Human cytomegalovirus (CMV) infection has been a major concern in hematopoietic stem cell transplant recipients. Ganciclovir (GCV) resistance results mostly from mutations within the protein kinase UL97 gene. The three hot spots for GCV resistance (codons 460, 520, and 590-607) were well known. We describe a case of GCV-resistant CMV colitis caused by a 597-600 deletion in UL97 after haplo-identical peripheral blood stem cell transplantation (h-PBSCT) in a 46 year-old man with myelodysplastic syndrome. On post-PBSCT day 28, CMV antigenemia turned positive. Treatment of GCV was started and continued for 12 weeks but CMV antigenemia did not respond to the treatment and CMV colitis was worsened. The UL97 showed the in-frame deletion between codons 597 and 600 by direct sequencing. The treatment was switched to foscarnet and the antigenemia test was consecutively negative twice, and clinical symptoms improved. Despite the recovery of the patient from CMV colitis, the patient expired post-PBSCT day 146 from acute liver failure, hepatorenal syndrome and septic shock. This case is a first report of a deletion 597-600 in CMV UL97 in Korea. A 597-600 deletion in UL97 was responsible for the GCV resistance while preserving susceptibility to foscarnet. (Ann Clin Microbiol 2015;18:64-67)

Micafungin Versus Fluconazole Or Itraconazole For Prophylaxis Against Invasive Fungal Infections During Neutropenia In Patients Undergoing Haplo-Identical Hematopoietic Stem Cell Transplantation

Objectives Over the past decade, invasive fungal infections (IFI) have remained an important problem in patients undergoing hematopoietic stem cell transplantation (HSCT). The optimal approach for prophylactic antifungal therapy has yet to be determined. Patients and Methods we conducted a retrospective, bi-institutional comparative clinical study, (Institut Paoli-Calmettes at Marseille France and Humanitas cancer center at Rozzano, Italy), and we compared the efficacy and safety of Micafungin 50mg/day (iv) with those of fluconazole (400mg/day) or itraconazole 200mg/day (iv) as prophylaxis for adult patients with various haematological diseases receiving haplo-identical allogeneic stem cell transplantation (haplo-SCT). Patients received prophylaxis with the beginning of the transplant conditioning regimen until the hospital discharge, or until occurrence of an IFI. We compared the incidence of proven or probable IFI (the primary end point) between the micafungin and fluconazole or itraconazole groups; death from any cause and time to death was secondary end points. Patients were followed for 100 days after haplo-SCT and for 30 days after the last dose of the prophylaxis drug administrated. Results From January 2009 to May 2013, a total of 99 patients were identified; 30 patients received micafungin, and 69 patients received fluconazole or itraconazole. 81 patients (82%) received a non myeloabaltive conditioning regimen (NMA), with Fludarabine, Cyclophosphamide and Total body irradiation (TBI) 2 Gy based , or Fludarabine, Busulfan, and Cyclophosphamide based (3%) or other (9%), while five patients (5%) received a thiotepa-based conditioning regimen. The patients and transplant details are shown in the table 1. Proven or probable invasive fungal infections were reported in 2 patients (7%) in the micafungin group and 8 patients (12%) in the fluconazole or itraconazole group (absolute reduction in the micafungin group, −5%; 95% confidence interval, 0.0565-3.1395, P=0.72). Fewer patients in the micafungin group had invasive aspergillosis (1 [3%] vs. 5 [7%], P=0.6). A total of 4 (13%) patients in the micafungin group and 23 (33%) patients in the fluconazole or itraconazole group received empirical antifungal therapy (P = 0.14). No serious adverse events related to treatment were reported by patients and there was no treatment discontinuation because of drug related adverse event in both groups. Overall Survival and disease free survival were similar among the two groups (P = 0.97). 6 patients (20%) in the micafungin group died within 100 days, as did 10 patients (14%) in the fluconazole or itraconazole group (P = 0.57). Interestingly the transplant related mortality (TRM) at 100 days was 0% in the micafungin group vs 13% in the second group [CI 95% (0-22)] (p=0,06), whereas the relapse or progression rate at 100 days was 27% vs. 8% respectively [CI 95% (14-44)] (p=0,14). Conclusions In patients undergoing to haplo-SCT, antifungal prophylaxis with micafungin is well tolerated and effective to prevent IFI. Furthermore, the incidence of IFI and invasive aspergillosis seems lower even if this did not attend statistical power, probably due to low number of patients. Disclosures: No relevant conflicts of interest to declare.

Nonengraftment Haploidentical Cellular Therapy for Hematologic Malignancies

Much of the therapeutic benefit of allogeneic transplant is by a graft versus tumor effect. Further data shows that transplant engraftment is not dependant on myeloablation, instead relying on quantitative competition between donor and host cells. In the clinical setting, engraftment by competition alone is not feasible due to the need for large numbers of infused cells. Instead, low-level host irradiation has proven to be an effective engraftment strategy that is stem cell toxic but not myeloablative. The above observations served as the foundation for clinical trials utilizing allogeneic matched and haploidentical peripheral blood stem cell infusions with minimal conditioning in patients with refractory malignancies. Although engraftment was transient or not apparent, there were compelling responses in a heavily pretreated patient population that appear to result from the breaking of tumor immune tolerance by the host through the actions of IFNγ, invariant NK T cells, CD8 T cells, NK cells, or antigen presenting cells.

Haploidentical non-myeloablative stem cell transplantation as Salvage for graft failure in a patient with juvenile myelomonocytic leukemia

Haploidentical non-myeloablative stem cell transplantation as Salvage for graft failure in a patient with juvenile myelomonocytic leukemia