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.
3100 Background: 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 due to the underlying DNA repair defect in their cells. Outcomes of recipients of matched related HCT have generally been favorable, but only few studies have scrutinized the factors that may impact on the eventual outcome of these patients. Thus, the current study was designed to use data from King Faisal Specialist Hospital & Research Center (KFSHRC) to evaluate the impact of different key variables on outcome of related HCT in these patients. Patients and Methods: This is a retrospective analysis of 94 pediatric patients (age ≤ 14 years) with FA who underwent related HCT at KFSHRC from 1993 to 2011. Overall survival (OS) probability was estimated using the Kaplan-Meier method. Univariate analyses were conducted to evaluate the impact of key variables on survival as well as on the incidence of graft failure, graft versus host disease (GVHD), and hemorrhagic cystitis. The small sample size precluded multivariate analysis. Forty-six (48.9%) were male. Eleven had evidence of myelodysplasia and/or abnormal cytogenetic clone (MDS) in bone marrow pre-HCT. Two doses of cyclophosphamide (CY) were used in the conditioning: CY 60 mg/kg, when used alone with ATG (N= 40) and CY 20 mg/kg when used in combination with ATG, and radiation (total body irradiation -TBI-; N=12, or thoraco-abdominal irradiation -TAI-; N=22), or when used in combination with ATG and fludarabine (N=21). Donor source was HLA-matched sibling in 86 patients, HLA-matched parent in 3, and HLA-class I single-antigen-mismatched sibling or parent in 5. Results: Absolute neutrophil count (ANC) recovery occurred in all patients, median of 14 days (range, 9–33 days). Platelet-transfusion independence occurred in 92 patients, median of 29 days (range, 14–97 days). The cumulative incidences of acute GvHD grade II-IV and III-IV were 8.51 % (95% CI: 8.35%-8.67%), and 5.32% (95% CI: 5.12%-5.42%), respectively. Chronic GvHD cumulative incidence was 9.8% (95% CI: 9.6% to 9.10%). Cumulative incidence of secondary graft-failure was 4.3% (95% CI 4.2%-4.4%). Survival probabilities (OS) were 92.5%, 89%, and 86% at 1, 5, and 10 years, respectively. In univariate analysis, survival was not affected by any of the following variables: age at HCT (< 10 years vs. 10–14 years), recipient or donor gender, presence of MDS pre-HCT, use of fludarabine in the conditioning regimen. Only two variables significantly affected survival: use of higher dose CY (60mg/kg) conditioning was associated with a better 10-year OS than lower dose CY (20mg/kg) conditioning (91 % vs. 82 %, respectively; P =0.035), and use of radiation-containing regimens was associated with a lower 10-year OS than non-radiation regimens (76 % vs. 91 %, respectively; P =0.005). Incidence of graft failure, and GVHD was not affected by any of the variables analyzed, but use of higher dose of CY (60mg/kg) was associated with a significantly increased incidence of hemorrhagic cystitis (20% vs. 5.6% respectively; P=0.049). Three patients (3%) developed squamous cell carcinoma (2 oropharyngeal and one genitourinary), at 9.5, 5.5, 14 years post HCT; 2 of them had radiation containing conditioning. Conclusion: Our analysis indicates that related HCT for pediatric FA patients is associated with excellent long-term survival, and suggests that, for patients transplanted ≤ 14 years, early HCT (below 10 years vs. 10–14 years) does not improve survival. Our data also suggest that a higher dose CY (60 mg/kg) conditioning regimen is associated with better survival but is also associated with a significantly increased risk of hemorrhagic cystitis. On the other hand, radiation-containing regimens are associated with significantly lower survival. Our data also show, that in our patient cohort, the presence of pre-HCT MDS does not adversely affect survival. Disclosures: No relevant conflicts of interest to declare.
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.
Post-transplant erythrocytosis is an ominous complication of kidney transplantation, occurring in the first 8 to 24 months after surgery in 10% to 15% of transplant recipients; this is frequently associated with significant thromboembolic events and sometimes death. In patients undergoing allogeneic hematopoietic cell transplantation (HCT), erythrocytosis has not been previously well described. At our institution, we observed that some aplastic anemia (AA), and Fanconi anemia (FA) patients developed progressively increased hemoglobin (HB), hematocrit (HCT) and RBC readings on long term follow up. Thus, this study was conducted to assess the validity of this observation in AA/FA patients post HCT, and its impact on their health. Patients and Methods From January 1993 until December 2011, 144 pediatric patients underwent successful allogeneic HCT for AA or FA; median age at HCT 11.6 years (range, 6.6 -15). All patients included were alive at the time of the analysis, and had sustained engraftment; all have had a follow up time of ≥ 12 months. For those who underwent more than one HCT, only events after the last HCT were included. We retrospectively examined the HB levels as an indicator for erythrocytosis (Corresponding RBC, HCT, WBC, and platelet counts were also collected). HB values of 150, and 160 gm/l were considered the trigger value in females and males, respectively. Patients who reached this value were studied for higher values on follow up, and only those whose HB persisted for at least 3 months above trigger value were included in the analysis; 29 patients (15 females, 14 males) were identified after causes of secondary erythrocytosis were ruled out. Erythrocytosis was defined as HB ≥ 160 gm/l in females, a HB ≥ 170 gm/l in males. Results Median time to trigger HB was 51.4 months (range, 15-121) in females, and 65 months (range, 23.3-114) in males, and median age at trigger HB was 14.7 years (range, 8.6-21.4) in females, and 16.9 years (range, 13.4-20.6) in males. Median highest HB reached was 160 gm/l (range, 151-162) in females, and 172 gm/l (range, 164-189) in males, with a median time of 67 months (range, 17-164) in females, and 103 months (range, 23.3-206) in males; the median age at highest HB was 16 years (range, 9.7-24.8) in females, and 20.2 years (range, 13.4-27.4) in males. Upon follow up, the HB fell below the trigger level in 16 patients (9 females, 7 males) (55.2%), at a median time of 37.2 months from the trigger value (range, 3.6-104). Seventeen patients qualified for the diagnosis of erythrocytosis (12%); 8 females, and 9 males. In all 8 females and in 4 males, HB fell below the erythrocytosis value upon follow up. All HB values correlated positively with HCT and RBC, no correlation was detected with platelet count or WBC. On univariate analysis, patients with older age at HCT (≥ 10 years) appeared to be more likely to develop elevated HB (P=0.003); and those who had radiation in the conditioning regimen were less likely to develop elevated HB (P=0.008). Three of the males with persistent erythrocytosis were tested further and all 3 had normal erythropoietin levels and were negative for JAK-2 mutations. None of the 29 patients had any adverse clinical symptoms during the follow up visits, and no thromboembolic events were reported. Conclusion A proportion of patients with AA/FA who undergo HCT may experience elevated HB on long term follow up; 12% subsequently qualifying as erythrocytosis, with the highest reading requiring between 1.5-2 years to evolve. Unlike erythrocytosis post renal transplant, the phenomenon we are describing in our patient cohort does not appear to be associated with any adverse symptoms, or any increased risk of thrombosis. More in depth investigation to study the potential pathophysiology behind it is currently underway at our institution, together with further exploration of this observation in patients with other illnesses undergoing allogeneic HCT. Disclosures: No relevant conflicts of interest to declare.
Background Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children occurring most commonly in the head and neck region. The treatment involves using a multimodality approach including chemotherapy, surgery, and radiation therapy. Survival for patients with localized disease has improved markedly, but the treatment of advanced disease remains a challenge. We report the clinical characteristics and outcome for patients treated at a tertiary care center in Saudi Arabia. Methods Patients aged 0–14 years diagnosed with RMS between 2005 and 2018 were included. Statistical analysis was performed using SPSS software. Kaplan–Meier method was used to calculate overall and event free survival. Cox proportional hazards model was used for multivariate analysis. Results One hundred and twenty‐four patients were analyzed. The median age was 5.7 years with male predominance (2.4:1). The most common primary sites were head/neck (30%) and the genitourinary tract (25%). Embryonal RMS was present in 81%; alveolar in 19%. Most patients had intermediate risk disease (60%). The 5‐year overall and event free survivals were 64.3% and 53.3%, respectively. Survival was influenced by primary tumor site, histology, and clinical risk group. Unfavorable primary site, high risk stratification, and poor initial response to therapy predicted a poor outcome. Conclusion This study provides an insight on the current management outcomes for our patients with RMS. Cytogenetics and molecular diagnostics need to be incorporated as standard of care in the therapeutic approach of our patients. In addition, there is a need for national collaborative efforts to improve the outcome of RMS in children and adolescents.
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