Indication Of Stem Cell Translantation In Nonmalignant Hematologic Disorders

Sickle cell disease(SCD)is the most common inherited hemoglobinopathy worldwide. The goal when performing HSCT is to replace the patient’s marrow with genetic functional cells before major organ dysfunction and complications it has been demonstrated that patients transplanted at a young age have a better 3-year OS and 3-year EFS, with lower incidence of aGvHD and cGvHDNonmalignant indications, however continue to grow, most importantly HCT for hemoglobinopathies by 36%, equally for thalassemia and sickle cell disease. In late 1990s, the Pesaro group has proposed a risk classification for pediatric patients undergo- ing MFD HSCT for TM . Limitations to this risk stratification include the interobserver variability regarding hepatomegaly and the lack of clear definition of adequate iron chelation. very-high- risk group was identified in Pesaro class 3 patients if liver size is > 5 cm below the costal margin and if the patient age is > 7 years. Transient elastography (FibroScan) and T2 MRI have been shown to be reliable noninvasive methods to predict liver fibrosis secondary to iron overload. effective and safe haploidentical transplant procedure for TM patients. The use of TCD graft was associated with high rate of infections and increased risk of graft failure due to allo-sensitization and hyperactive marrow . This was overcome by pretransplant over-transfusion and immunosuppressive therapy and post transplant infusion of transduced donor T-cells BU, CY, TT, and FLU as conditioning regimen and ATG HLA identical sibling HSCT is an estab-i lished treatment option for SCD. HSCT should be performed as early as possible, preferably at pre-school age, and BU, CY, and ATG should be used as conditioning regimen. Match family donor allo-HSCT is cur- rently considered the only curative standard therapeutic approach for thalas- semia major, which despite holding its own risks, could release the patient from lifelong treatments and possible iron accumulation complications. Despite encouraging results of gene therapy, its use in TM is currently limited to clinical trials. bone marrow failure syndrome Disease such as MDS, Myelofibrosis, hypocellular acute leukemia , inherited bone marrow failure and telomeropathies need to be excluded. Cytogenetic abnormalities can be found in up to 10% of true SAA.in case of transfusion requirement or if the criteria for SAA are met, treatment should begin with no delay. Early bone marrow HSCT after a conditioning regimen with CY, ATG, and GVHD prophylaxis combining CSA and MTX promotes excellent engraftment (95%) and OS (90% at 2 years) In the absence of sign of intravascular hemolysis, patient’s treatment algorithm is similar with or without PNH. Recently some factors were found to positively affect OS after MUD HSCT including age ≤ 30 years, transplant within the first year after diagnosis ,use of BM vs PB, and CMV status . presence of a PNH clone does not change the treatment algorithm of SAA. Eculizumab is currently the standard of care for all PNH patients presenting with symptomatic hemolytic and/or thromboembolic disease; occasionally, when this occurs concomitantly with a BMF, the anticomplement treatment may be considered. Fanconi’s anemia Indications for transplant include marrow failure (transfusion dependency or severe neutropenia) and myelodysplasia/leukemia. Since the outcome is dependent on age at trans- plant, the decision to proceed to transplant should be individualized . Current conditioning regi- mens generally contain FLU (cumulative dose 150 mg/m2), in combination with reduced doses of CY (up to 50 mg/kg cumulative) . C. Díaz de Heredia et al. Key PointsPatient– Evaluate carefully hematologic and extra-hematologic manifestations of the disease prior to transplantDonor– The best donor is MSD; however, it is mandatory to test the genetic defect in the donor since some IBMFS may present different clinical and hematologic expression in members of the same family– Consider MUD in case of no appropriate MSD– Mismatched related and UD and unrelated CB only in experienced centers and preferentially in clinical trialsSource of stem cellsBM is the best source of stem cells Matched related CB is a good option PB is associated with higher risk of cGVHD and should be avoidedCell doseIt is important for graft failure prevention:NC > 3 × 108/kg recipient bw for BM NC > 3 × 107/kg recipient bw for related CBNC > 4 × 107/kg recipient bw for unrelated CBConditioning regimenMAC or RIC depending on the type of IBMFIrradiation should be avoided owing to the known risk of cancerPatients with Fanconi’s anemia and dyskeratosis congenita must receive a RICGVHD prophylaxisGVHD must be avoidedInclude two immunosuppressive drugs Serotherapy for UD transplantsLong-term follow-up– It is mandatory owing to high risk of secondary malignancies, extra- hematologic manifestations and iron overload– Patients should be followed-up by a multidisciplinary team Philadelphia-negative myeloproliferative neoplasms The evidence of graft-versus-myelofibrosis effect was documented by responses to DLI after failure of allo-HSCT .The EBMT published results of 103 patients who received a BU/FLU-based RIC fol- lowed by related or unrelated HSCT. The median age was 55 years, and the NRM at 1 year was 16%. Cumulative incidence of relapse was 22% at 3 years. PFS and OS at 5 years were 51% and 67%, espectively. A recent update of the study after a median fol- low-up of 60 months showed an 8-year OS. Splenomegaly is a hallmark of myelofibrosis and may have an impact on engraftment and graft function after HSCT. Spleen size prior to transplantation, but high morbidity and even mortality have been reported. Spleen irradiation to reduce spleen size has been reported success- fully in single cases prior to conditioning. Since ruxolitinib is approved for myelofibrosis, the drug can be used prior to transplantation to improve constitutional symptoms and to reduce spleen size. Primary or post-ET/PV myelofibrosis can only be cured by allo-HSCT which can induce molecular remission and resolution of bone marrow fibrosis. Major risk factors for worse outcome are advanced age and not fully HLA- matched donor. Patients with intermediate-1 risk can be considered for allo-HSCT if other high-risk features such as ASXL1 mutation, more than 2% peripheral blasts, refractory transfusion-dependent anemia, or adverse cytogenetics according to DIPSS plus are present.