Is Mixed Chimerism Post-allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoid Leukemia a Prognostic Factor for Relapse?

Hematopoietic stem cell transplantation (HSCT) has been considered curative for children with high-risk acute leukemia (ALL), offering better survival. Short tandem repeat has been used as a marker of chimerism status after HSCT. The appearance of recipient cells >1% post-allogeneic stem cell transplant is defined as mixed chimerism (MC). Chimeric studies post-HSCT are dynamic. This study aimed to investigate the significance of recipient cells in post-HSCT pediatric ALL patients as a predictor of relapse of their primary disease. The rate of MC was 51.4% (19 out of 37 recipients). It was 48.6% (n = 18) during Day+100 and 12.9% (4 out of 31 recipients) during post-Day+100 follow-up until two years. No significant association was noted between MC and all grade overall acute graft-versus-host disease. A mortality rate of 35.1% (n = 13) and a median follow-up of 56.9 months (95% CI: 39.7-74.2) were observed for all but four (16.7%) of the survivors in remission. Regarding causes of death, transplant-related mortality was recorded in only 2 of 13 expired patients (15.4%); both succumbed to sepsis. No significant association was found between MC and primary causes of death. The cumulative probability of five-year overall survival and event-free survival was not found to be statistically significantly different for MC (≤1.0% vs. > 1.0%). In conclusion, our data did not show MC testing alone as an effective prognostic marker for detecting relapse; molecular and flow cytometric analyses should be considered in children with ALL post-HSCT for monitoring relapse.

Clofarabine in Pediatric Acute Relapsed or Refractory Leukemia: Where Do We Stand on the Bridge to Hematopoietic Stem Cell Transplantation?

Background: Despite pronounced improvement in overall survival (OS) in pediatric leukemia, a proportion of patients continue to suffer from lack of response or relapse, and the management of such patients is exceedingly difficult. Immunotherapy and engineered chimeric antigen receptor (CAR) T-cell therapy have shown promising results in the course of relapsed or refractory acute lymphoblastic leukemia (ALL). However, conventional chemotherapy continues to be utilized for re-induction purposes whether independently or in combination with immunotherapy. Methods: Forty-three pediatric leukemia patients (age < 14 years at diagnosis) consecutively diagnosed at our institution and got treated with clofarabine based regimen at a single tertiary care hospital between January 2005 and December 2019 were enrolled in this study. ALL comprised of 30 (69.8%) patients of the cohort while the remaining 13 (30.2%) were with acute myeloid leukemia (AML). Results: Post-clofarabine bone marrow (BM) was negative in 18 (45.0%) cases. Overall clofarabine failure rate was 58.1% (n = 25) with 60.0% (n = 18) in ALL and 53.8% (n = 7) in AML (P = 0.747). Eighteen (41.9%) patients eventually underwent hematopoietic stem cell transplantation (HSCT); 11 (61.1%) were from ALL group and remaining seven (38.9%) were AML (P = 0.332). Three- and 5-year OS of our patients was 37.7±7.6% and 32.7±7.3%. There was a trend of better OS for ALL patients compared to AML (40.9±9.3% vs. 15.4±10.0%, P = 0.492). Cumulative probability of 5-year OS was significantly better in transplanted patients (48.1±12.1% vs. 21.4±8.4%, P = 0.024). Conclusions: Though almost 90% of our patients proceeded to HSCT with complete response post-clofarabine treatment, yet clofarabine-based regimens are associated with the significant burden of infectious complications and sepsis-related deaths.

Hematopoietic Stem Cell Transplantation Stabilizes Cerebral Vasculopathy in High-Risk Pediatric Sickle Cell Disease Patients: Evidence From a Referral Transplant Center.

Background: Severe sickle cell disease (SCD) can present with different vaso-occlusive manifestations with cerebral vasculopathy (CV) as one of the most serious complications. Hematopoietic stem cell transplant (HSCT) is the ultimate therapy for this complication. The aim of this study was to assess the outcome and impact of HSCT on severe SCD patients with CV complications. Methods: Twenty-five consecutive transplants-naive pediatric SCD patients with CV complications underwent HSCT at our institution between 1993 and 2015, using bone marrow as stem cells source from fully match related donors were included. Neurologic evaluation was done both clinically and radiologically before transplantation and regularly following the HSCT. Results: With a median follow-up of 52.2 ± 5.8 months, the cumulative probability of overall survival (OS) at 3 years was 92.0% and event-free survival (EFS) was 88%. Significant neurologic improvements were observed in most of the patients clinically. Different neurologic complications were assessed. The neurologic manifestations before and after HSCT were hemiparesis (11, 1), seizures (13, 8), focal neurologic deficit (4, 2), loss of conscious (2, 1) headache (6, 1), and psychological symptoms (5, 2). Post-HSCT radiological imaging was done in 15 patients, which showed stabilization of CV among all. Conclusions: Allogeneic HSCT in patients with severe SCD presenting with CV complications including moyamoya vasculopathy showed favorable outcome with significant clinical neurologic improvement and stabilization of the disease. None of the patients with severe vasculopathy underwent neurological vascular by-pass surgery prior to HSCT.

Essential Thrombocythemia in Children: A Retrospective Study.

BACKGROUND: Essential thrombocythemia (ET) is one of the "classic" Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms characterized by sustained thrombocytosis, increased megakaryopoiesis and high risk of vascular complications. ET is very rare in childhood. The annual incidence is approximately 1 per 10,000,000 in children less than 14 years, and about 60 times lower than adults. The genetic landscape and clonal features in childhood ET has not been well defined. There is no evidence-based guidance on the diagnosis of childhood ET. METHODS: Medical records of 28 pediatric patients (age ≤ 14 years at diagnosis) with ET were reviewed and evaluated to characterize the different mutation profiles and to evaluate the treatment modalities used and the potential long-term outcome. RESULTS: More than half of the patients were found to have positive history of parental consanguinity (57.1%) whereas positive family history was documented for more than a quarter of our patients (28.6%). Janus kinase 2 gene (JAK2) V617F mutation was positive in two of 26 patients (7.7%). Myeloproliferative leukemia virus oncogene (MPL) exon 10 and calreticulin (CALR) mutations were tested in eight patients, which were negative for all of them. Treatment included low-dose aspirin (LDA) in seven patients (50%), combination of LDA with hydroxyurea in three patients (21.4%), hydroxyurea in two patients (14.3%), combination of platelets apheresis with LDA and anagrelide in one patient each (7.1%). During the treatment, two patients experienced stroke (7.1%), one patient developed Budd-Chiari syndrome (3.6%) and one patient developed azoospermia (3.6%). CONCLUSIONS: The incidence of ET in children is extremely low in Saudi Arabia. Most of the children with ET were asymptomatic, and thrombocytosis was often discovered incidentally. JAK2 V617F mutation has no known impact on the prognosis or on the outcome of the disease in the pediatric age group that is in contrast to the adult ET. Children less than 1 year are at high risk for complications particularly during acute precipitating infectious episode. The potential complications and clinical course of pediatric ET are unpredictable.

Does Mixed Chimerism After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients With Fanconi Anemia Impact on Outcome?

Fanconi anemia (FA) cells are characterized by genomic instability, which places FA patients at risk for malignancies such as leukemia and oropharyngeal/urogenital cancers. The risk of development of leukemia is theoretically eliminated after hematopoietic cell transplantation (HCT). Mixed chimerism (MC) in FA patients might have a unique implication because the persistent existence of FA cells might give rise to a malignant clone. We have studied a large population of FA patients who underwent allogeneic HCT at our institution and report here the outcome according to chimerism status. Patients with FA who had evidence of progressive bone marrow failure and were blood products-transfusion dependent (packed red blood cells, platelets, or both) were included in the study. Those who had myelodysplasia (MDS) or an abnormal clone or evidence of leukemia were excluded. All but 3 patients had normal renal and cardiac function at the time of transplantation. In total, 160 patients with FA underwent allogeneic HCT at our center from January 1995 to December 2017; mean age at HCT was 8.4. Chimerism data at last follow-up visit were available on 97 patients who are the subjects of this analysis (no day +100 chimerism data on one of them). On day +100, 46 patients (47.9%) had full chimerism (FC) and 50 (52.1%) had MC, whereas at last follow-up 50 (51.5%) exhibited FC and the remaining 47 (48.5%) had MC. Cumulative incidence of all grades acute graft-versus-host disease (GVHD) was 13.4% and that of grade III to IV GVHD was 4.1%. Chronic GVHD was seen in eight (8.0%) patients. Incidence of severe acute GVHD (grade ≥ III) and that of chronic GVHD were not significantly associated with FC or MC measured at day +100 (P values = .347 and .254, respectively), nor at the last follow-up. Graft failure occurred in 2 patients; both from the MC at day +100 group. No graft failures occurred in the FC at day +100 group (P value = 1.00). At a median follow-up of 83.8 months (95% confidence interval, 51.0-116.6; range, 19.3-181.1 months) the cumulative probability of overall survival (OS) at 5 years was 95.7% ± 2.1%. Mean follow-up time in our cohort was 90.7 months. Five-year overall survival was not significantly associated with FC or MC evaluated at day +100 (95.7% ± 3.0% versus 95.6% ± 3.1%, P value = .908) nor at the last follow-up (96.0% ± 2.8% versus 95.4% ± 3.2%, P value = .925). No patient in either group developed MDS/leukemia during the follow-up period. We conclude that mixed chimerism in patients with FA appears to have no adverse effect on outcome in our follow-up period. A longer follow-up period is needed, however, to confirm the validity of this statement.

Successful Outcome in Patients with Fanconi Anemia Undergoing T Cell-Replete Mismatched Related Donor Hematopoietic Cell Transplantation Using Reduced-Dose Cyclophosphamide Post-Transplantation.

Allogeneic hematopoietic cell transplantation (HCT) has been shown to restore normal hematopoiesis in patients with Fanconi anemia (FA), with excellent results in matched related donor HCT. Outcomes of alternative donor HCT are less favorable, however. In patients without FA, several reports have documented stable engraftment and/or a low risk of graft-versus-host disease (GVHD) using unmanipulated HLA-mismatched related donors and post-HCT cyclophosphamide (PT-CY) for GVHD prophylaxis. Data on the use of this approach in patients with FA are scarce, and thus we launched a study of HLA-mismatched related donor HCT in these patient. Here we report our findings in 19 patients. The conditioning was fludarabine 30 mg/m2/day for 5 days, antithymocyte globulin 5 mg/kg/day for 4 days, and total body irradiation (total dose, 200 cGy). GVHD prophylaxis was cyclosporine and mycophenolate and reduced doses of PT-CY, 25 mg/kg, on days +3 and +5. All patients exhibited absolute neutrophil count recovery. Grade III-IV acute GVHD occurred in 3 patients, and chronic GVHD occurred in 1 patient. At a mean follow-up of 38.3 ± 5.8 months, the 5-year probability of overall survival for our patients was 89.2% ± 7.2%. The regimen was well tolerated; hemorrhagic cystitis occurred in 7 patients, and severe mucositis occurred in 5 patients. There were 2 deaths; the primary cause of death was severe GVHD in 1 patient and leukemia recurrence in the other. We conclude that in patients with FA lacking a matched related donor, the use of mismatched related HCT with low-dose PT-CY is a viable option; it is well tolerated, with a high rate of engraftment and an acceptable incidence of GVHD.

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.

BACKGROUND: 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). OBJECTIVE: To determine the risk of GVHD in MSD HSCT for SCID patients compared to matched related donor (MRD). METHODS: 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. RESULTS: 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. CONCLUSION: GVHD prophylaxis in MSD transplant should be considered in SCID patients.

Factors Determining the Outcome of Hematopoietic Stem Cell Transplantation in Patients With Acute Lymphoblastic Leukemia at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Medical records of 82 patients with acute lymphoblastic leukemia (ALL) who underwent hematopoietic cell transplantation (HCT) at our institution from 2005 to 2011 were reviewed. Forty-five patients were male (54.8%). The median age at HCT was 7.46 years (range, 0.98 to 14.31 y), the median time to HCT after diagnosis was 12.56 months. Ten patients were below the age of 1 year (12%). All patients were in complete remission at the time of HCT. In 83 transplants, 64 patients received HCT from human leukocyte antigen-identical-related donors and 19 from other donors. Stem cell source was bone marrow in 65 (78%) and cord blood in 18 (22%). Five-year overall survival was 58.8% and event-free survival was 54.3%. The cumulative incidence of acute graft versus host disease was 4.8%±2.3% and of chronic graft versus host disease was 8.9%±3.2%. The median time to absolute neutrophil count and platelet recovery was 17 days (range, 12 to 43 d) and 28 days (range, 15 to 98 d), respectively. One patient acquired CMV infection after transplant. No one developed venoocclusive disease, hemorrhagic cystitis, or other complication. Patient's age at diagnosis, sex, donor's human leukocyte antigen status and sex, source of transplant and complete remission status at HCT did not affect overall survival and event-free survival. Our results show a favorable outcome to HCT for acute lymphoblastic leukemia patients comparable to published data, and no single factor was associated with superior outcome.

Chimerism Analysis of Cell-Free DNA in Patients Treated with Hematopoietic Stem Cell Transplantation May Predict Early Relapse in Patients with Hematologic Malignancies.

Background. We studied DNA chimerism in cell-free DNA (cfDNA) in patients treated with HSCT. Methods. Chimerism analysis was performed on CD3+ cells, polymorphonuclear (PMN) cells, and cfDNA using 16 small tandem repeat loci. The resulting labeled PCR-products were size-fractionated and quantified. Results. Analyzing samples from 191 patients treated with HSCT for nonneoplastic hematologic disorders demonstrated that the cfDNA chimerism is comparable to that seen in PMN cells. Analyzing leukemia patients (N = 126) showed that, of 84 patients with 100% donor DNA in PMN, 16 (19%) had evidence of clinical relapse and >10% recipient DNA in the plasma. Additional 16 patients of the 84 (19%) showed >10% recipient DNA in plasma, but without evidence of relapse. Eight patients had mixed chimerism in granulocytes, lymphocytes, and plasma, but three of these patients had >10% recipient DNA in plasma compared to PMN cells and these three patients had clinical evidence of relapse. The remaining 34 patients showed 100% donor DNA in both PMN and lymphocytes, but cfDNA showed various levels of chimerism. Of these patients 14 (41%) showed laboratory or clinical evidence of relapse and all had >10% recipient DNA in cfDNA. Conclusion. Monitoring patients after HSCT using cfDNA might be more reliable than cellular DNA in predicting early relapse.

Factors affecting the outcome of related allogeneic hematopoietic cell transplantation in patients with Fanconi Anemia.

Hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi Anemia (FA), and it is generally accepted that these patients should receive low-intensity conditioning because of the underlying DNA repair defect in their cells. Outcomes for recipients of matched related HCT have generally been favorable, but only a few studies have scrutinized the factors that may affect the eventual outcome of these patients. This retrospective analysis of 94 pediatric patients with FA who underwent related HCT at King Faisal Specialist Hospital & Research Center was carried out to attempt to identify factors that may affect outcome. Results showed overall survival (OS) probabilities of 92.5%, 89%, and 86% at 1, 5, and 10 years, respectively. In univariate analysis, use of higher dose cyclophosphamide (CY) (60 mg/kg) conditioning was associated with a better 10-year OS than lower dose CY (20 mg/kg) conditioning (91% versus 82%, respectively; P = .035), and use of radiation-containing regimens was associated with a significantly lower 10-year OS than nonradiation regimens (76% versus 91%, respectively; P = .005). Of the 4 regimens used in this study, the fludarabine-based regimen was associated with the highest survival (95.2%; P = .034). The use of the higher dose CY (60 mg/kg) was associated with a significantly increased incidence of hemorrhagic cystitis (HC) (20% versus 5.6% respectively; P = .049). Three patients (3%) developed squamous cell carcinoma (2 oropharyngeal and 1 genitourinary), at 9.4, 5.4, and 13.3 years after HCT; 2 of them had radiation-containing conditioning. In conclusion, our data suggest that although using a higher dose CY (60 mg/kg) conditioning regimen may be associated with better survival, it is also associated with a significantly increased risk of HC. The addition of fludarabine to the low-dose CY (20 mg/kg) is associated with the best survival. On the other hand, radiation-containing regimens are associated with significantly lower survival.

Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration.

PURPOSE: Magnetic resonance imaging (MRI)-based techniques for assessing liver iron concentration (LIC) have been limited by single scanner calibration against biopsy. Here, the calibration of spin-density projection-assisted (SDPA) R2-MRI (FerriScan®) in iron-overloaded ß-thalassemia patients treated with the iron chelator, deferasirox, for 12 months is validated. METHODS: SDPA R2-MRI measurements and percutaneous needle liver biopsy samples were obtained from a subgroup of patients (n = 233) from the ESCALATOR trial. Five different makes and models of scanner were used in the study. RESULTS: LIC, derived from mean of MRI- and biopsy-derived values, ranged from 0.7 to 50.1 mg Fe/g dry weight. Mean fractional differences between SDPA R2-MRI- and biopsy-measured LIC were not significantly different from zero. They were also not significantly different from zero when categorized for each of the Ishak stages of fibrosis and grades of necroinflammation, for subjects aged 3 to <8 versus ≥8 years, or for each scanner model. Upper and lower 95% limits of agreement between SDPA R2-MRI and biopsy LIC measurements were 74 and -71%. CONCLUSION: The calibration curve appears independent of scanner type, patient age, stage of liver fibrosis, grade of necroinflammation, and use of deferasirox chelation therapy, confirming the clinical usefulness of SDPA R2-MRI for monitoring iron overload.

Allogeneic hematopoietic cell transplantation for fanconi anemia in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome, or acute leukemia.

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi anemia (FA). Data on outcomes in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome (MDS), or acute leukemia have not been separately analyzed. PATIENTS AND METHODS: We analyzed data on 113 patients with FA with cytogenetic abnormalities (n = 54), MDS (n = 45), or acute leukemia (n = 14) who were reported to the Center for International Blood and Marrow Transplant Research from 1985 to 2007. RESULTS: Neutrophil recovery occurred in 78% and 85% of patients at days 28 and 100, respectively. Day 100 cumulative incidences of acute graft-versus-host disease grades B to D and C to D were 26% (95% CI, 19% to 35%) and 12% (95% CI, 7% to 19%), respectively. Survival probabilities at 1, 3, and 5 years were 64% (95% CI, 55% to 73%), 58% (95% CI, 48% to 67%), and 55% (95% CI, 45% to 64%), respectively. In univariate analysis, younger age was associated with superior 5-year survival (≤ v > 14 years: 69% [95% CI, 57% to 80%] v 39% [95% CI, 26% to 53%], respectively; P = .001). In transplantations from HLA-matched related donors (n = 82), younger patients (≤ v > 14 years: 78% [95% CI, 64% to 90%] v 34% [95% CI, 20% to 50%], respectively; P < .001) and patients with cytogenetic abnormalities only versus MDS/acute leukemia (67% [95% CI, 52% to 81%] v 43% [95% CI, 27% to 59%], respectively; P = .03) had superior 5-year survival. CONCLUSION: Our analysis indicates that long-term survival for patients with FA with cytogenetic abnormalities, MDS, or acute leukemia is achievable. Younger patients and recipients of HLA-matched related donor transplantations who have cytogenetic abnormalities only have the best survival.

Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).

Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined hyperinflammatory syndrome caused by uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, and macrophages. STXBP2 mutations have recently been associated with FHL5. To better characterize the genetic and clinical spectrum of FHL5, we analyzed a cohort of 185 patients with suspected FHL for mutations in STXBP2. We detected biallelic mutations in 37 patients from 28 families of various ethnic origins. Missense mutations and mutations affecting 1 of the exon 15 splice sites were the predominant changes detectable in this cohort. Patients with exon 15 splice-site mutations (n = 13) developed clinical manifestations significantly later than patients with other mutations (median age, 4.1 year vs 2 months) and showed less severe impairment of degranulation and cytotoxic function of NK cells and CTLs. Patients with FHL5 showed several atypical features, including sensorineural hearing deficit, abnormal bleeding, and, most frequently, severe diarrhea that was only present in early-onset disease. In conclusion, we report the largest cohort of patients with FHL5 so far, describe an extended disease spectrum, and demonstrate for the first time a clear genotype-phenotype correlation.

The Saudi experience in fludarabine-based conditioning regimens in patients with Fanconi anemia undergoing stem cell transplantation: excellent outcome in recipients of matched related stem cells but not in recipients of unrelated cord blood stem cells.

Low-dose cyclophosphamide (CY) is now considered the backbone of many of the conditioning regimens used in patients with Fanconi anemia undergoing allogeneic stem cell transplantation (SCT). To reduce the risk of rejection and improve results, CY is usually used in combination with other agents/modalities, such as antithymocyte globulin (ATG), busulfan, radiation, and, more recently, fludarabine (Flu). In this study, we used a uniform Flu-based conditioning regimen (ie, CY, Flu, ATG) in 26 pediatric patients with Fanconi anemia undergoing SCT. The median patient age at the time of SCT was 7.8 years, and the stem cell source was an HLA-matched related donor in 19 patients and partially HLA-matched unrelated cord blood in 7 patients. The CY, Flu, ATG regimen was well tolerated overall, with a remarkably low incidence of graft-versus-host disease and hemorrhagic cystitis. All 19 patients in the matched related donor group engrafted and were alive and transfusion-independent at a median follow-up time of 19 months, compared with only 2 of 7 patients in the unrelated cord blood group. We conclude that the combination of CY, Flu, and ATG in the doses used in this study is well tolerated, and that the proclaimed positive effect of adding Flu to the conditioning regimens of patients with Fanconi anemia undergoing SCT is most pronounced in recipients of HLA-matched related transplants. Its value in unrelated cord blood transplantation probably depends on other factors, such as the degree of HLA matching and the cell dose.

Advances in allogeneic stem cell transplantation for hemoglobinopathies.

Hematopoietic stem cell transplantation (SCT) is currently the only potential curative therapy for thalassemia and sickle cell disease. A myeloablative conditioning regimen has been in use to eradicate the disease. Nowadays, improved preparative and conditioning methods are used including reduced intensity conditioning regimens. Such developments have allowed transplantation of more advanced hemoglobinopathy diseases. Stem cell transplant sources became more accessible including umbilical cord blood and alternate donor. However, donor human leukocyte antigen (HLA) disparity still carries a significant risk of morbidity and mortality.

Outcome of allogeneic stem cell transplantation with a conditioning regimen of busulfan, cyclophosphamide and low-dose etoposide for children with myelodysplastic syndrome.

BACKGROUND AND OBJECTIVES: Allogeneic stem cell transplantation (SCT) offers the best chance of cure and long-term survival for children with myelodysplastic syndromes (MDS). DESIGN AND SETTING: Retrospective analysis of pediatric patients with primary MDS treated with allogeneic SCT at a single institution treated between January 1993 and December 2008. PATIENTS AND METHODS: Of 16 consecutive children who received allogeneic SCT for treatment of MDS in our center, 14 patients met the criteria of MDS according WHO I and II criteria. The median age was 4.8 years (range, 1-14 years) and 64% were male. The median time from diagnosis to transplant was 6 months. MDS stage was refractory cytopenia (RC) in 9, refractory anemia with excess blasts (RAEB) in 5. Monosomy 7 was present in 35% of the patients. The majority of patients (11/14) were conditioned with a busulfan-based myeloablative (MA) regimen with addition of low-dose of etoposide (30 mg/kg). All but one received a bone marrow graft. RESULTS: Nine patients achieved complete remission (CR), and seven remain alive. At a median follow-up of 3 years (range, 2-14 years) the OS and EFS was 57% (95%CI, 0.28-0.78). Cumulative EFS at 10 years was 43% (95% CI, 0.14-0.70). Relapse-related mortality was 21.4%; nonrelapse mortality (NRM) was 28.57%. All the survivors had etoposide in their conditioning regimen. Patients younger than 10 years had better survival (P=.001). CONCLUSION: Children with MDS achieve encouraging OS and EFS following allogeneic SCT. A busulfan-based regimen with a lower dose of etoposide is an effective and less toxic regimen. The outcomes are best in younger patients.

Cytomegalovirus infections in unrelated cord blood transplantation in pediatric patients: incidence, risk factors, and outcomes.

BACKGROUND AND OBJECTIVES: Stem cells from umbilical cord blood (CB) have increasingly become a viable alternate source of progenitor cells for hematopoietic cell transplantation (HSCT). Cytomegalovirus (CMV) is thought to contribute significantly to HSCT morbidity and mortality. DESIGN AND SETTING: Retrospective case-control study in patients at tertiary care center. PATIENTS AND METHODS: We determined the incidence, risk factors and outcomes for CMV infection and disease after unrelated cord blood transplantation (UCBT) in children. RESULTS: Between 2003 and 2007, 73 pediatric patients underwent UCBT and 68% of recipients were CMV seropositive. The overall incidence of CMV infection, early and late CMV infection was 58.9% (43/73), 62.8% (27/43), and 37.4% (16/43), respectively. in patients with early CMV infection, 6 of 27 (22%) patients progressed to develop CMV end-organ disease including pneumonitis and retinitis. High levels CMV antigenemia ≥70 infected cells by pp65 antigenemia assay + PMNs, P=.237) were associated with a higher risk of progression to CMV disease. The development of CMV infections was higher in CMV-seropositive recipients (P<.001) and in those who developed graft-versus-host-diseases (GVhD) (P<.001). other risk factors for CMV infection include the use of high-dose corticosteroids (P<.001) and older age of the recipient at the time of transplant (P<.002). Late CMV infection was strongly associated with a previous history of early CMV infection (P<.001). CONCLUSION: CMV infection is a significant complication in UCBT recipients in pediatric patients and is associated with an increase in transplant-related morbidity and mortality. Risk factors for CMV infections after UCBT include GvHD, use of corticosteroids, underlying diseases (hematologic malignancies) and older age. Late CMV infection was strongly associated with a previous history of CMV infection.

Hematopoietic stem cell transplantation in the Eastern Mediterranean Region (EMRO) 2008-2009: report on behalf of the Eastern Mediterranean Bone Marrow Transplantation (EMBMT) Group.

BACKGROUND: The Eastern Mediterranean Bone Marrow Transplantation (EMBMT) Group has accumulated over 25 years of data and experience in hematopoietic stem cell transplantation (HSCT), most particularly in hemoglobinopathies, severe aplastic anemia (SAA), and inherited metabolic and immune disorders, in addition to hematologic malignancies peculiar to the region and where recent updates in trends in activities are warranted. OBJECTIVES: To study trends in HSCT activities in the World Health Organization-Eastern Mediterranean (EM) region surveyed by EMBMT between 2008 and 2009. STUDY DESIGN: Retrospective analysis of the survey data, mainly of the cumulative number of transplants, types of transplants (autologous vs. allogeneic), types of conditioning as myeloablative (MAC) vs. reduced intensity conditioning (RIC) and trends in leukemias, hemoglobinopathies, SAA, inherited bone marrow failure syndromes amongst others. RESULTS AND DISCUSSION: Fourteen teams from ten Eastern Mediterranean Region Organization (EMRO) countries reported their data (100% return rate) to the EMBMT for the years 2008-2009 with a total of 2608 first HSCT (1286 in 2008; 1322 in 2009). Allogeneic HSCT represented the majority (63%) in both years. The main indications for allogeneic HSCT were acute leukemias (732; 44%), bone marrow failure syndromes (331, 20%), hemoglobinopathies (255; 15%) and immune deficiencies (90; 5%). There was a progressive increase in the proportions of chronic myeloid leukemia (CML) cases transplanted beyond the first chronic phase (3; 7% of all CML cases in 2008 vs 13; 29% in 2009). The main indications for autologous transplants were plasma cell disorders (345; 36%) Hodgkin disease (256; 27%), non-Hodgkin lymphoma (207; 22%) and solid tumors (83; 9%). RIC continued to show a progressive increase over the years (7% in 2007, 11% in 2008 and 13% in 2009), yet remained relatively low compared to contemporary practices in Europe published by EBMT. The vast majority (95%) of allo-HSCT sources were from sibling donors with a continued dominance of peripheral blood (PB) (1076; 63%), while cord blood transplant (CBT) increased to 83 (5% of allo-HSCT), matched unrelated donor (MUD) remained underutilized (1; 0%) and there were no haploidentical transplants reported. Large centers with >50 HSCT/year showed a plateau of the total number of allo-HSCT over the last 5 years that may be related to capacity issues and needs further study. CONCLUSIONS AND RECOMMENDATIONS: There is an overall increased rate of HSCT in the EMRO region with a significant increase in utilization of CBT and allogeneic PB-HSCT as a valuable source. However, further research on outcome data and development of regional donor banks (CB and MUD) may help facilitate future planning to satisfy the regional needs and increase collaboration within the group and globally.