Matched Sibling Donor Hematopoietic Stem Cell Transplantation Research Articles

Unmanipulated haploidentical transplantation for adult patients with hematological malignancies.

Unmanipulated haploidentical transplantation for adult patients with hematological malignancies.

PS1558 COMPARISON OF THE INCIDENCE AND OUTCOMES OF TRANSPLANT‐ASSOCIATED THROMBOTIC MICROANGIOPATHY BETWEEN HAPLOIDENTICAL AND MATCHED SIBLING DONOR HEMATOPOIETIC STEM CELL TRANSPLANTATION

Background:Transplant‐associated thrombotic microangiopathy (TA‐TMA) is an early complication of hematopoietic stem cell transplantation (HSCT) that usually occurs within the first 3 months and has a high mortality rate of approximately 50–75%. TA‐TMA is less common in autologous (0–27%) than in allogeneic HSCT (6–76%). We previously reported risk factors and mortality of TA‐TMA with concomitant acute graft versus host disease (aGvHD) (Xiao Liu, Eur J Haematol, 2018). Recently, the use of haploidentical (HID) donors has continued to increase, but no information is available on the incidence and outcomes of TA‐TMA patients after HID allo‐HSCT.Aims:To compare the incidence and outcomes of TA‐TMA in HID recipients with those of matched sibling donor (MSD) transplantation.Methods:In this retrospective, nested case‐control study, 102 consecutive TA‐TMA patients (HID: 87 patients, MSD: 15 patients) were identified from a total of 3726 patients who underwent allo‐HSCT at Peking University People's Hospital between 2009 and 2018. Patients with TA‐TMA and controls were matched for follow‐up time after transplantation (total n = 278). TA‐TMA were diagnosed based on the clinical suspicion of the physician according to the diagnostic criteria for overall TMA (Byung‐Sik Cho, Transplantation, 2010). Upon diagnosis of TA‐TMA, all CNIs were discontinued, and monoclonal antibodies, TPE and other supportive treatments were used as required by the patients’ condition. Cox regression was used to identify independent risk factors associated with the occurrence and outcomes of TMA.Results:The 10‐year cumulative incidence of TA‐TMA occurrence in HID recipients was 3.5%, which was significantly higher than that of the MSD group (Figure 1, p < 0.001). A total of 60.5% of TA‐TMA events occurred in the first 3 months after HSCT. TA‐TMA patients in the HID group were younger, more likely to receive additional anti‐human T‐lymphocyte immunoglobulin during conditioning and had more ABO mismatches and more concomitant aGvHD. The time from transplantation to the TA‐TMA diagnosis was comparable between the two groups (p = 0.365). In the multivariate Cox regression analysis, concomitant aGvHD ≥ grade 3 (HR 2.629, 95%CI 1.363–5.069, p = 0.004), higher doses of corticosteroids administration (HR 1.005, 95%CI 1.002–1.007, p < 0.001), but not the HID/MSD donor type, were each associated with an increased risk of TA‐TMA development in HSCT patients. With a median follow‐up of 374 days, the 1‐week, 1‐month, and 1‐year probabilities of overall survival (OS) of the TA‐TMA patients were 92.6%, 56.9% and 16.5% in the HID patients and 53.3%, 20.0% and 19.3% in the MSD patients, respectively. The main cause of death was disease‐related. Multivariate analysis showed that the only significant predictive factor was the time from HSCT to aGvHD (HR 0.845, 95% CI 0.934–2.661, p = 0.009). HLA mismatch showed no significant correlation with either long‐term OS (p = 0.464) or nonrelapse mortality (p = 0.322).Summary/Conclusion:TA‐TMA is more common in HID than in MSD HSCT. However, HID is not an independent risk factor of the occurrence of TA‐TMA, and OS is comparable between the groups. Further studies on the role of HID in the setting of TA‐TMA are required to confirm these findings.image

Graft Versus Host Disease Following HLA-Matched Sibling Donor Compared with Matched Related Donor for Hematopoietic Stem Cell Transplantation for the Treatment of Severe Combined Immunodeficiency Disease.

One of the limiting factors for successful hematopoietic stem cell transplantation (HSCT) is graft versus host disease (GVHD). The EBMT/ESID guidelines for HSCT in severe combined immunodeficiency (SCID) recommend no GVHD prophylaxis for a matched sibling donor (MSD). To determine the risk of GVHD in MSD HSCT for SCID patients compared to matched related donor (MRD). This retrospective cohort study compares MSD with MRD and the outcome of GVHD in all SCID patients who underwent HSCT between 1993 and 2013. All statistical analyses were done using IBM SPSS statistics software. One hundred forty-five SCID patients underwent 152 HSCTs while 82 (54%) received GVHD prophylaxis. GVHD occurred in 48 patients (31.5%); 20/48 (42%) had GVHD prophylaxis compared to 28/48 (58%) that did not, P = 0.022. Acute GVHD occurred at a higher trend in MSD, 37/120 (30.8%), compared to MRD, 6/32 (18.8%), P = 0.17. We also analyzed the outcome according to the period of HSCT. The first period was 1993 to 2003, 48 HSCTs, 43 MSD, 5 MRD; all patients had GVHD prophylaxis, and there was no difference in GVHD. The second period was 2004 to 2013: of 104 HSCTs, 77 had MSD and 27 had MRD; GVHD prophylaxis was used in 22.1% of MSD and 63% of MRD, P = 0.000. GVHD was significantly higher in the MSD (40.2%) compared to MRD (18.5%) patients, P = 0.041. GVHD prophylaxis in MSD transplant should be considered in SCID patients.

Association of Matched Sibling Donor Hematopoietic Stem Cell Transplantation With Transcranial Doppler Velocities in Children With Sickle Cell Anemia

In children with sickle cell anemia (SCA), high transcranial Doppler (TCD) velocities are associated with stroke risk, which is reduced by chronic transfusion. Whether matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) can reduce velocities in patients with SCA is unknown. To determine the association of MSD-HSCT with TCD velocities as a surrogate for the occurrence of ischemic stroke in children with SCA. Nonrandomized controlled intervention study conducted at 9 French centers. Patients with SCA were enrolled between December 2010 and June 2013, with 3-year follow-up ending in January 2017. Children with SCA were eligible if younger than 15 years, required chronic transfusions for persistently elevated TCD velocities, and had at least 1 sibling without SCA from the same 2 parents. Families agreed to HLA antigen typing and transplantation if a matched sibling donor was identified or to standard care in the absence of a matched sibling donor. MSD-HSCT (n = 32), compared with standard care (n = 35) (transfusions for ≥1 year with potential switch to hydroxyurea thereafter), using propensity score matching. The primary outcome was the highest time-averaged mean of maximum velocities in 8 cerebral arteries, measured by TCD (TCD velocity) at 1 year. Twenty-five of 29 secondary outcomes were analyzed, including the highest TCD velocity at 3 years and normalization of velocities (<170 cm/s) and ferritin levels at 1 and 3 years. Sixty-seven children with SCA (median age, 7.6 years; 35 girls [52%]) were enrolled (7 with stroke history). In the matched sample, highest TCD velocities at 1 year were significantly lower on average in the transplantation group (129.6 cm/s) vs the standard care group (170.4 cm/s; difference, -40.8 cm/s [95% CI, -62.9 to -18.6]; P < .001). Of the 25 analyzed secondary end points, 4 showed significant differences, including the highest TCD velocity at 3 years (112.4 cm/s in the transplantation group vs 156.7 cm/s in the standard care group; difference, -44.3 [95% CI, -71.9 to -21.1]; P = .001); normalization rate at 1 year (80.0% in the transplantation group vs 48.0% in the standard care group; difference, 32.0% [95% CI, 0.2% to 58.6%]; P = .045); and ferritin levels at 1 year (905 ng/mL in the transplantation group vs 2529 ng/mL in the standard care group; difference, -1624 [95% CI, -2370 to -879]; P < .001) and 3 years (382 ng/mL in the transplantation group vs 2170 ng/mL in the standard care group; difference, -1788 [95% CI, -2570 to -1006]; P < .001). Among children with SCA requiring chronic transfusion because of persistently elevated TCD velocities, MSD-HSCT was significantly associated with lower TCD velocities at 1 year compared with standard care. Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up. ClinicalTrials.gov Identifier: NCT01340404.

Assessment of Calcineurin Inhibitor-Associated Neurotoxicity in Patients with Sickle Cell Disease Receiving a Matched Sibling Donor or T-Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation

Introduction: Sickle cell disease (SCD) is one of the most prevalent monogenic hematological disorders leading to progressive multi-organ damage and reduced life expectancy despite a significant improvement of conventional and supportive care. Allogeneic hematopoietic stem cell transplantation (HSCT) with a matched sibling donor (MSD) represents currently the only curative treatment option, limited by a donor availability <20%. In a pilot study, we compared α/β/CD19 and CD3/CD19, respectively T-cell depleted haploidentical HSCT (T-haplo-HSCT) with MSD HSCT in patients (pts) with advanced stage SCD, using almost identical HSCT regimens for both donor groups.Neurotoxicity (NT) contributes significantly to HSCT-associated morbidity and mortality. Calcineurin inhibitor (CNI) related NT after HSCT is mostly caused by cyclosporine A (CsA) and tacrolimus (FK506) with an overall frequency between 4.2% - 28.8%, and severe NT in 4% - 11%, such as posterior reversible encephalopathy syndrome (PRES), seizures, visual disturbance, cortical blindness, aphasia or ataxia.Particularly in hemoglobinopathies (thalassemia, SCD) the reported incidence is around 30%, possibly also due to impaired hepatic metabolization of CsA and FK506 based on iron overload. However, also infusion modalities might impact on NT, since it was more frequently reported after 4-hours bolus injections (10.3%) than continuous infusion (3.3%). However, the excessive NT observed in SCD might be also related to the systemic vasculopathy, increasing with age and pro-inflammatory triggers after allo-HSCT.Methods: A total of 30 pts aged 3 to 31 years with homozygous SCD or HbS 0/+ ß-Thal were treated between 2012 and 2018. Nine pts received a MSD bone marrow (BM) graft, 21 pts received T-haplo-HSCT from a relative (1 second T-haplo-HSCT due to graft rejection) with a α/β CD19 or CD3/CD19 depleted graft. Post-HSCT immunosuppression consisted of either CsA in 6 MSD and 16 T-haplo-HSCT pts or FK506 in 3 MSD and 6 T-haplo-HSCT pts, both mostly in combination with mycophenolate mofetil (MMF). FK506 was administered as a 20-hours continuous infusion, while CsA was given as 4-hours bolus injections. Dosage was adjusted according to usual target levels (CsA: 120ng/ml; FK506: 7ng/ml). Duration of immunosuppression was >6 months in T-haplo-SCT and <6 months in MSD, depending on chimerism. All pts developing neurological symptoms indicative for severe CNI-related NT underwent neuroradiological imaging (MRI/CT) with consecutive symptomatic treatment as indicated.Results: Overall CNI-related NT was observed in 32.3% of our HSCT pts. Severe NT such as PRES and visual disturbance combined with aphasia was present in 16.1% (Table 1). Overall, NT was more prevalent in MSD (n=5, 55.5%) than in T-haplo-HSCT pts (n=5, 22.7%). The majority of NT events was observed under CsA prophylaxis (8/10; 80%) and in only 22% (2/9) pts with FK506. All 5 cases of severe NT, particularly all PRES, occurred on CsA. Complete recovery of neurologic symptoms was achieved in all pts spontaneously or after switching CsA to FK506 or everolimus (Table 1). Moreover, 60% of pts with NT was >18 years, and 90% >12 years suggesting an increasing risk with age while a third of patients with pre-existing NT experienced no post-HSCT NT. Of note, 4 of 5 pts with severe NT also experienced a mild acute GvHD (Table 1). The overall (OS) and disease-free survival (DFS) with a median follow-up of 17 months in T-haplo-HSCT pts and 22 months in 9 MSD HSCT pts was 90% vs. 100%, respectively.Conclusions: Our data confirm an elevated risk for NT in SCD pts following allo-HSCT. Importantly, the incidence of NT events seems to be related to age (90% of pts with NT were >12years), donor source (MSD vs. T-Haplo; 55.5% vs 22.7%) and CsA rather than FK506 (CSA 80% vs. FK506 20%). All severe NT (particularly all PRES) were observed in pts with CsA prophylaxis, while the continuous infusion of FK506 might have levelled concentration peaks. Nevertheless, the NT observed with CsA post-HSCT could be the consequence of predominantly CsA-related vascular complications inflicting systemically pre-damaged vessels of SCD pts. The mechanism of action could be similar to other systemic endotheliopathies such as sinusoidal obstruction syndrome (VOD/SOS), transplant-associated microangiopathy (TAM) and acute GvHD which was observed in 4/5 pts with severe NT, compared to an overall GvHD rate of 29%. [Display omitted] DisclosuresCorbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria.

Stem Cell Transplantation in Advanced Stage Sickle Cell Disease with Haploidentical T-Cell Depleted PBSC Yields Comparable Outcomes to Matched Sibling Donor Bone Marrow: Results of a Pilot Study

Background: Sickle cell disease (SCD) is an inherited disorder with an estimate of 300,000 affected newborns per year worldwide. Despite improvements in preventive measures and conventional therapy, substantial morbidity and mortality, resulting in a reduced life expectancy persist. Allogeneic hematopoietic stem cell transplantation (HSCT) with a matched sibling donor (MSD) is currently the curative standard of care. However, matched donor availability is <20% and unrelated donor (MUD) HSCT is associated with unacceptably high rates of severe graft-versus-host disease (GvHD). A T-cell depleted HSCT from a haploidentical relative (T-haplo-HSCT) expands donor availability while exhibiting low GvHD rates and thus could offer cure to the remaining 80% of SCD patients (pts).Methods: We report the results of 29 pts with advanced stage SCD transplanted with either a T-cell depleted haploidentical regimen (20 pts, median age 13 years, range 3-31 years) or with bone marrow from a matched family donor (MSD, 9 pts, median age 14, range 9-25 years). Indication for HSCT was advanced stage SCD related complications. Pts with a MSD received a bone marrow (BM) graft. Pts requiring an alternative donor were transplanted with an αß/CD19 (n=5) or CD3/CD19 (n=15) depleted graft from a haploidentical family donor. The conditioning regimen for both groups was identical except that antithymoglobulin (ATG-Neovii®) was given upfront on day -10 to -8 in T-haplo-HSCT and on day -3 to -1 in MSD. Chemotherapy consisted of thiotepa 2 x 5 mg/kg, fludarabine 4 x 40 mg/m2 and treosulfan 3 x 14 g/m2, given between days -10 and -2. Post-HSCT immunosuppression consisted of mofetil mycophenolate and tacrolimus or cyclosporine A for a duration >6 months in T-haplo-HSCT and <6 months in MSD, depending on chimerism. The MSD group received a graft containing a median of 2.4 x 108 cells/kg body weight (BW). The T-haplo-SCT group received a peripheral stem cell allograft with a median of 13.1 x 106 CD34+ cells/kg BW.Results: The conditioning regimen was well tolerated in all pts with no high-grade transplant related toxicity. The overall (OS) and disease-free survival (DFS) with a median follow-up of 17 months in 20 advanced stage mostly adolescent and adult T-haplo-HSCT pts and 22 months in 9 MSD HSCT pts was 90% vs. 100%, respectively. Engraftment was achieved in most pts with stable chimerism over 90%, except for 4 pts with a stable MC in the T-haplo SCT group and 1 patient in the MSD group off immunosuppression. All pts presented a complete BM engraftment of red cell precursors. Only one patient in the T-haplo-HSCT group with a mixed chimerism is still under immunosuppression.The post-HSCT bacterial infectious complications were comparable in both groups and the most common observed viral infections were systemic cytomegaly virus (CMV), adenovirus (ADV), polyomavirus (BKV) and Epstein Barr virus (EBV) reactivations which were successfully treated with intravenous antiviral drugs or virus specific T-cells.Two patients in the T-haplo-HSCT group achieved a DFS off immunosuppression but succumbed to post-HSCT complications. One developed a rotavirus gastroenteritis and an uncontrolled CMV pneumonitis. The other a late graft failure and succumbed to a macrophage activation syndrome.None of our pts developed a Glucksberg Grade III-IV acute GvHD and in the T-haplo SCT group 4 pts (20%) and in the MSD group 2 pts (22%) developed a steroid sensitive mild to moderate cGvHD (fasciitis/oral as well as mild cutaneous GvHD). No extensive cGvHD was observed.To our knowledge this is the largest group of advanced stage SCD pts transplanted with either a T-haplo-HSCT or a MSD approach, according to donor availability, with an almost identical regimen in a direct comparative design. These preliminary results demonstrate increasing evidence for the feasibility, safety and efficacy of a T-haplo-HSCT using CD3/CD19 or αβ/CD19 depleted grafts, in order to offer a curative option to the majority of pts with SCD. A prospective, stratified non-inferiority trial is in preparation (EudraCT number 2018-002652-33) in order to confirm these preliminary results in a large prospective cohort. DisclosuresCorbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria.

Role of thymoglobulin in matched sibling allogeneic hematopoietic stem cell transplantation with busulfan and fludarabine conditioning in myeloid malignanicies.

In vivo T-cell depletion using anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation (HSCT) for prophylaxis of GvHD. We investigated the influence of thymoglobulin dose (an ATG) on GvHD following matched sibling donor (MSD) HSCT with a busulfan and fludarabine preparative regimen. Medical records of 180 patients who received MSD HSCT with a conditioning regimen of busulfan, fludarabine, and ATG (BuFluATG) were reviewed retrospectively. The median age was 53 years (range 18-68). Initial diagnoses were acute myeloid leukemia (73.3%) and myelodysplastic syndrome (26.7%). Forty-four and 68 patients (24.4 and 37.7%) experienced acute and chronic GvHD of any grade, respectively. High-dose (⩾4.5 mg/kg) ATG was independently associated with decreased risk of acute GvHD (hazard ratio=0.36, 95% confidence interval (CI): 0.15-0.84, P=0.019) compared to low-dose ATG (<4.5 mg/kg). Although ATG dose was associated with the risk of acute GvHD, it was not associated with the risk of chronic GvHD in our study. A higher dose (⩾4.5 mg/kg) of ATG decreases the risk of acute GvHD but had no significant impact on disease-free survival in MSD HSCT patients conditioned with BuFluATG. The optimal dose of ATG should be further investigated in a large prospective study context.

Haploidentical Hematopoietic Stem Cell Transplant Compared with Matched Sibling and Unrelated Transplants in Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia in First Complete Remission

Matched-sibling donor (MSD) and matched unrelated donors (MUD) hematopoietic stem-cell transplantation (HSCT) have been recommended for the adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1). However, it is not defined for this portion of patients whether HLA haploidentical donor (HID) transplants can achieve equivalent outcomes compared to MSD and MUD transplants. From 2009 to 2014, 379 adult patients with Ph-negative ALL in CR1 underwent HID HSCT (n = 159), or MSD HSCT (n = 135), or MUD HSCT (n = 85). Among HID, MSD and MUD transplants, the 100-day incidences of acute graft-versus-host disease (aGVHD) Grade III-IV were 11.0%, 8.4% and 10.6% respectively (P>0.05), and 2-year chronic GVHD (cGVHD) were 38.9%, 28.5% and 35.6% respectively ( P>0.05 ). At 5 years, the incidences of relapse were 19.0%, 24.0% and 23.4% in HID, MSD and MUD transplants respectively (P>0.05). The 5-year transplant related mortality (TRM) of HID was higher than MSD transplants (16.5% vs 10.9%, P = 0.032), and no difference compared with MUD transplants (16.5% vs 18.1%, P > 0.05). However, the 5-year overall survival (OS), disease-free survival (DFS) did not differ among HID, MSD and MUD transplants (OS 70.9%, 72.0%, 65.4% respectively, P > 0.05; DFS 67.3%, 66.0%, 62.0%, respectively, P > 0.05).Our results indicate that outcomes of adult patients with Ph-negative ALL in CR1 from HID transplants are comparable to MSD and MUD transplants. DisclosuresLin:National Natural Science Foundation of China 81400141: Research Funding; National Natural Science Foundation of China 81270647: Research Funding; Science and technology planning project of Guangdong Province 2014B020226004: Research Funding; The project of health collaborative innovation of Guangzhou City 201400000003-4: Research Funding.

Single-center clinical research of matched sibiling donor and haploidentical hematopoietic stem cell transplantation for treatment of malignant hematopathy

Objective To evaluate the safety and efficacy of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of malignant hematopathy, through comparison with matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT). Methods From January 2011 to May 2015, a total of 68 patients who had accepted related donor hematopoietic stem cell transplantation (HSCT) in Department of Hematology, First Affiliated Hospital of Chongqing Medical University were enrolled into this retrospective study as study subjects. According to different types of related donor HSCT, 68 cases of patients were divided into MSD-HSCT group (n=33) and haplo-HSCT group (n=35). All the cases were conformed to the diagnostic criteria of Standard of Diagnosis and Curative Effect of Hematology (3rd edition). The inclusion criteria of this study: patients' diagnosis were conformed to the diagnostic criteria of malignant hematopathy and clinical data were complete. Exclusion criteria: clinical data were not complete. Clinical data of donors and patients of the two groups were retrospectively analyzed. Implantations of hematopoietic stem cells in two groups after HSCT were tested. HSCT schemes, the number of input hematopoietic stem cells and outcome of engraftment, transplant related complications, overall survival (OS) rate, disease free survival (DFS) rate, incidence of relapse and mortality were compared and analyzed statistically. The study protocol was approved by the Ethical Review Board of Investigation in Human at First Affiliated Hospital of Chongqing Medical University. There were no statistically significant differences of patients' clinical data, such as gender ratio, preprocessing solution type, type of stem cell transplantation and donors' age between two groups (P>0.05). Results ①There were no statistical differences of patients' disease, disease status, blood type between donors and recipients between the two groups (χ2=2.313, 2.809, 3.420; P=0.678, 0.094, 0.331). But the patients in MSD-HSCT group were older than haplo-HSCT group with statistical significance (t=2.534, P=0.010). ②There were no statistical differences of the input of mononuclear cells (MNC)[(15.0±3.8)×108/kg vs (16.3±4.2)×108/kg)]and the CD34+ cells[(5.8±3.1)×106/kg vs (6.8±2.7)×106/kg]between the two groups (t=1.277, 1.062; P=0.206, 0.294). ③In MSD-HSCT group, average time of neutrophils count over 0.5×109/L[(12.7±2.9) d]was significantly earlier than that of haplo-HSCT group[(16.1±4.8) d](t=3.510, P=0.001). Average time of platelets count over 20×109/L[(12.7±4.9]d]was also significantly earlier than that of haplo-HSCT group[(16.1±7.9) d](t=2.094, P=0.016). All of the 68 patients obtained hematopoietic reconstruction and achieved chimeric state. ④There were no statistical differences of cumulative incidence of acute graft versus host disease (aGVHD) (18.2% vs 22.9%), cumulative incidence of chronic graft versus host disease (cGVHD) (39.3% vs 26.9%), incidence of engraftment syndrome (ES) (0 vs 2.9%), hemorrhagic cystitis (HC) (24.2% vs 45.7%), thrombotic microangiopathy (TMA) (3.0% vs 2.9%), hepatic veno-occlusive disease (VOD) (3.0% vs 2.9%), capillary leak syndrome (CLS) (0 vs 2.9%), herpes (24.2% vs 14.3%), bacterial infection (33.3% vs 20.0%), fungal infection (12.1% vs 20.0%), cytomegalovirus (CMV) infection (9.1% vs 5.7%), secondary tumors (3.0% vs 0), reversible posterior leukoencephalopathy syndrome (RPLS) (0 vs 2.9%) between the two groups (χ2=0.227, 1.551, 0.957, 3.429, 0.002, 0.002, 0.957, 1.089, 1.551, 0.778, 0.284, 1.076, 0.957; P=0.634, 0.336, 0.328, 0.064, 0.966, 0.966, 0.328, 0.297, 0.213, 0.378, 0.594, 0.299, 0.328). ⑤Up to September 1st, 2015, there were 21 patients survived in MSD-HSCT group, and the mortality was 36.4%, relapse rate was 18.2%. Mean survival time was (34.7±4.2) months, and OS and DFS rate of 3 years were 60.6%, 56.0%, respectively. Twenty-three patients survived in haplo-HSCT group, and the mortality was 34.3%, relapse rate was 5.7%. Mean survival time was (27.3±3.2) months, and OS and DFS rate of 3 years were 61.9%, 58.5% respectively. There were no statistical differences between relapse rate and mortality between two groups (χ2=2.543, 0.032; P=0.111, 0.858). There was also no statistical difference of mean survival time between two groups (t=1.537, P=0.129). There were no statistical differences between OS and DFS rate of 3 years (χ2=0.137, 0.032; P=0.706, 0.694). Conclusions The hematopoietic reconstruction time of neutrophils and platelets in malignant hematopathy patients who received MSD-HSCT treatment were earlier than those malignant hematopathy patients who received haplo-HSCT treatment, but they got a similar rate of OS, DFS, relapse, mortality and graft versus host disease (GVHD). Safety and efficacy of haplo-HSCT in treatment of malignant hematopathy is similar with MSD-HSCT. Key words: Hematopoietic stem cell transplantation; Hematologic disease; Comparative effectiveness research

Evolving hematopoietic stem cell transplantation strategies in severe aplastic anemia.

Significant improvements in unrelated donor hematopoietic stem cell transplantation (HSCT) in recent years have solidified its therapeutic role in severe aplastic anemia (SAA) and led to the evolution of treatment algorithms, particularly for children. Advances in understanding the genetics of inherited bone marrow failure syndromes (IBMFS) have allowed more confidence in accurately diagnosing SAA and avoiding treatments that could be dangerous and ineffective in individuals with IBMFS, which can be diagnosed in 10-20% of children presenting with a picture of SAA. Additionally long-term survival after matched sibling donor and matched unrelated donor HSCT now exceed 90% in children. Late effects after HSCT for SAA are minimal with current strategies, and compare favorably to late effects after upfront immunosuppressive therapy, except for patients with chronic graft versus host disease. Careful assessment for signs or symptoms of IBMFS, along with genetic screening for these disorders, is of major importance. Matched sibling donor HSCT is already considered the standard of care for upfront therapy and some groups are evaluating matched unrelated donor HSCT as primary therapy. Ongoing studies will continue to challenge treatment algorithms and may lead to an even more expanded role for HSCT in SAA.

Hematopoietic reconstitution and prognosis of different types of hematopoietic stem cell transplantation for severe aplastic anemia

目的比较HLA相合同胞供者造血干细胞移植(MSD-HSCT)、亲缘半相合HSCT(Haplo-HSCT)、无关供者HSCT(UD-HSCT)和脐血HSCT(UCB-HSCT)四种不同移植方式治疗重型再生障碍性贫血(SAA)造血重建以及预后的差异。方法回顾性分析2008年5月8日至2013年12月13日在苏州大学附属第一医院接受HSCT治疗的63例SAA患者临床资料，分别比较不同移植方式对移植后造血重建、移植物抗宿主病(GVHD)发生及5年总生存(OS)率的影响。结果53例行MSD-HSCT、Haplo-HSCT和UD-HSCT的患者全部获得造血重建，其中性粒细胞和血小板植入时间比较，差异无统计学意义(P=0.111和0.577)。UCB-HSCT中性粒细胞和血小板植入时间分别为19(18~29) d及32(24~70) d，明显长于其他移植方式(P值均<0.01)；植入率分别为42.0％及42.0%，明显低于其他移植方式(P值均<0.01)。但是造血重建失败的4例UCB-HSCT患者在一段时间后均出现自体造血重建。MSD-HSCT、Haplo-HSCT、UD-HSCT和UCB-HSCT 5年预期生存率分别为70.0%、81.0%、88.9%和77.8%，差异均无统计学意义(P>0.05)。结论MSD-HSCT、Haplo-HSCT和UD-HSCT 3种移植方式造血重建及预后方面差异均无统计学意义。UCB-HSCT虽然造血重建率明显低于其他移植方式，但总体预后无明显差异，因此对于无HLA相合同胞供者的SAA患者，Haplo-HSCT、UD-HSCT及UCB-HSCT作为替代治疗疗效与MSD-HSCT相当。

The diagnosis and treatment of aplastic anemia: a review.

Aplastic anemia is a rare disorder characterized by suppression of bone marrow function resulting in progressive pancytopenia. A trigger-related abnormal T cell response facilitated by some genetic predisposition has been postulated as the pathogenetic mechanism leading to the overproduction of bone marrow-inhibiting cytokines. Immuno-mediated pathogenesis is confirmed by the response to immunosuppressive treatment (IST) (cyclosporin A+ATG), which represents the first-choice therapy for patients <40 years when a matched sibling donor (MSD) is not available for transplant. MSD hematopoietic stem cell transplantation (HSCT) is associated with cure in ~90 % of patients. IST up-front provides an overall survival (OS) rate of above 90 %, but a response rate of about 60 %. Front-line matched unrelated donor (MUD) appears to be a viable option in children with similar OS and event-free survival to that in MSD HSCT. MUD HSCT post-IST failure proved to be a very good rescue strategy. Haploidentical donors/cord blood transplants or alternative immunosuppressive therapies, such as alemtuzumab, may represent valid tools for resistant/relapsing cases. New promising strategies, such as eltrombopag, are now under investigation. Patients should be offered an accurate diagnostic work-up in order to rule out other underlying disorders, primarily constitutional marrow failures, which may require different approaches.

Outcomes of matched sibling donor hematopoietic stem cell transplantation for severe sickle cell disease with myeloablative conditioning and intermediate-dose of rabbit anti-thymocyte globulin.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) in children. Despite excellent outcomes of matched sibling donor (MSD) HSCT, there is still 5-10% chance of rejection and transplant related mortality (TRM) with 12-23% incidence of graft versus host disease (GVHD). We postulated that an intermediate dose of rabbit anti-thymocyte globulin (r-ATG, 10 mg/kg cumulative) would be effective in preventing both rejection and GVHD. Fifteen patients, median age 5 (range 1.5-18) years, underwent MSD HSCT using busulfan (≥ 12.8 mg/kg with first dose pharmacokinetics), cyclophosphamide (total 200 mg/kg) and r-ATG. Bone marrow was the stem cell source; tacrolimus and methotrexate were given for GVHD prophylaxis. All patients achieved donor engraftment and there was no TRM. One patient rejected donor cells at 2 months post-transplant. Majority of the patients had high and sustained level of donor chimerism. None of the patients developed ≥ Grade II GVHD. Incidence of CMV (10%) and EBV (9%) reactivations was low with rapid immune-reconstitution. Overall survival was 100% with event free survival of 93%. Eliminating the risks of TRM and GVHD by optimizing the regimen may lead to further acceptance of HSCT for SCD.

Paroxysmal Nocturnal Hemoglobinuria Clones in Children with Acquired Aplastic Anemia: A Multicentric Study

AbstractAbstract 1269 Introduction.Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic disorder characterized by the clonal expansion of a PIG-A mutated stem cell and consequent defective synthesis of glycosil phosphatidyl-inositol-anchored proteins, complement-mediated hemolysis, increased incidence of thrombosis, bone marrow failure. PNH and acquired aplastic anemia (AA) are closely related and a reciprocal progression is possible. A relative resistance of the PNH stem cell to the immune-mediated damage can explain the PNH clonal expansion in AA. High resolution flow cytometry analysis (FCA) has revealed a high incidence of minor PNH clones in adult AA patients at diagnosis, predictive for some Authors of a favourable response to the immunosuppressive therapy (IST) (Maciejevki et al, 2001; Ishiyama et al, 2003; Sugimori et al, 2006). “Pure” PNH is a very rare disease in children. Only a few studies have so far evaluated longitudinally PNH clones in pediatric AA patients. Materials and Methods.Ninety AA patients diagnosed in 8 AIEOP (Italian Association of Pediatric Hematology-Oncology) Centers (age at diagnosis 1–20 years, median =10.8, 51 severe AA, 30 very severe AA, 9 non severe AA) were studied: forty-one since diagnosis, 25 during IST, 20 off therapy and 4 selected cases after hematopoietic stem cell transplantation (HSCT). Among the patients followed since diagnosis, 8 received an HLA matched sibling donor HSCT as first line therapy, whereas the other 33 patients were treated with IST according to EBMT protocols (anti-lymphocyte globulin/anti-thymocyte, ciclosporin ± granulocyte colony stimulating factor). The study started in 1998. Peripheral blood PNH cells were detected by lack of CD59 expression on granulocytes by a two-color FCA for CD59 (clone p282-FITC Becton-Dickinson) and CD11b (clone D12-PE Becton-Dickinson); at least 105 cells were analyzed, for a total of 1104 tests. The presence of a population CD11b+/CD59- > 0.15% was defined as abnormal; the cut off value was established in 1998 by evaluating 87 normal controls (PNH clones: median = 0.001%, mean+2SD=0.10%). Since 2009 FCA results were confirmed by more sensitive techniques with three or six-color sequential gating analysis for CD45/33/66b or CD45/33/15/24/14/FLAER. Results.A PNH+ clone was observed in 15 patients (36.6%) at diagnosis (clone size 0.17–10.4%), in 10 patients (40%) during IST (clone size 0.16–12.6%) and in 8 patients (40%) off-therapy (clone size 0.16–4.0%). The presence of a PNH+ clone at diagnosis did not predict a favourable response to IST, both in ALG and ATG-treated patients. In 33 patients (16 at diagnosis, 9 in IST, 8 off therapy), the presence of the PNH clone was sporadic or intermittent, whereas in 13 patients (9 at diagnosis, 3 in IST, 1 off therapy) the clone persisted for more than 3 following controls (follow up 6–60 months). Among the 26 PNH- patients at diagnosis, in 10 a PNH clone (clone size 0.16–1.7%) appeared later during IST. Among the 25 patients studied during IST, in one patient PNH clone appearance was associated with the tapering of cyclosporine (figure 1), in two with the relapse when off therapy. In one out of 4 patients treated with HSCT, a PNH clone appeared at time of relapse and disappeared after starting IST with cyclosporine (figure 2). A mild hemolysis was observed in the only 2 patients with a major PNH clone (clone size 12.6 and 10.4% respectively). No thrombotic events were reported. Conclusions.We have observed a significant incidence of minor PNH clones in pediatric AA at diagnosis, as reported in adults. Whereas previous studies in adults correlated the presence of pre-treatment minor PNH clones with a favourable response to IST, we do not confirm those observations both in the present multi-centre as in our previous single-centre study (Timeus et al, 2010), in agreement with Yoshida et al (2008) and Scheinberg et al (2010). The appearance of a PNH clone in a PNH- patient at diagnosis is described as uncommon (Sugimori et al, 2009), however in our series this was observed in 38% of previously PNH- patients. In AA the presence of PNH clones seems related to complex interactions between stem cells, immune-mediated damage and immunosuppressive therapy. A periodic screening for PNH clones in patients with AA is recommended, permitting modulation in IST, early identification of major PNH clones and prompt diagnosis of a frank PNH. [Display omitted] [Display omitted] Disclosures:Timeus:Alexion Pharma Italy s.r.l.: Research Funding. Dufour:Pfizer: Consultancy.

Favorable Outcomes After Allogeneic Hematopoietic Stem Cell Transplantation in Children With High-risk or Advanced Acute Myeloid Leukemia

The role of allogeneic hematopoietic stem cell transplantation (HSCT), including transplantation from an alternative donor (AD), has not been clearly defined for children with high-risk or advanced acute myeloid leukemia (AML). We retrospectively reviewed outcomes in 29 children (median age at HSCT, 6.7 y; range, 1.0-16.2 y) with high-risk or advanced AML who underwent allogeneic HSCT at the Asan Medical Center between 1998 and 2008. Donors included a matched sibling donor (MSD) for 7 patients (24%), an unrelated volunteer for 21 patients (72%), and a haploidentical mother for 1 patient (3%). The 3-year estimates of overall survival and event-free survival (EFS) were 77% [95% confidence interval (CI), 65%-99%] and 70% (95% CI, 57%-93%), respectively, whereas the cumulative incidences of relapse and transplant-related mortality were 33% (95% CI, 5%-58%) and 7% (95% CI, 0%-44%), respectively. The 3-year EFS rates did not differ between MSD and AD HSCT. Univariate analysis showed that age ≥ 10 years at diagnosis was the only factor associated with poorer EFS. Development of acute graft-versus-host disease predicted a significantly lower incidence of relapse. These findings may provide further evidence that allogeneic HSCT is a curative therapy for children with high-risk or advanced AML, and suggest the efficacy of AD transplantation.

Safety and efficacy of targeted busulfan therapy in children undergoing myeloablative matched sibling donor BMT for sickle cell disease

Busulfan influences engraftment and toxicities during hematopoietic stem cell transplantation (HSCT). We report our single-institution experience of targeted busulfan therapy for myeloablative, matched sibling donor (MSD) HSCT for sickle cell disease (SCD) and assess the relationships of busulfan levels to engraftment and toxicities. Twenty-seven patients with SCD underwent MSD HSCT from 1993 to 2007, 25 with busulfan measurements. The conditioning regimen was busulfan (initial dose 0.875 mg/kg for 16 doses), CY and antithymocyte globulin. Busulfan area under curve (AUC) was determined with the first dose, and dose adjustments were made to target the desired AUC range. Median AUC was 963 μmol min/L (range 780-1305 μmol min/L). Engraftment occurred in all cases: 21 (84%) full donor chimerism (> 95% donor cells), 4 (16%) partial donor chimerism. Hepatic veno-occlusive disease (VOD) occurred in 8 (32%) patients. Lower AUC was seen with partial donor chimerism (862 ± 73 μmol min/L) versus full donor chimerism (AUC 1018 ± 122 μmol min/L) (P = 0.022). VOD was not associated with busulfan AUC (P = 0.153). Of 25 patients, 24 survived with median follow-up of 4.9 years. Our experience shows that targeting busulfan AUC above the range used in previous multicenter trials appears safe and may contribute to sustained engraftment in SCD.