Cytogenetic abnormalities predict survival after allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia: a PDWP/EBMT study.

Poor-risk (PR) cytogenetic/molecular abnormalities generally direct pediatric patients with acute myeloid leukemia (AML) to allogeneic hematopoietic stem cell transplant (HSCT). We assessed the predictive value of cytogenetic risk classification at diagnosis with respect to post-HSCT outcomes in pediatric patients. Patients younger than 18 years at the time of their first allogeneic HSCT for AML in CR1 between 2005 and 2022 who were reported to the European Society for Blood and Marrow Transplantation registry were subgrouped into four categories. Of the 845 pediatric patients included in this study, 36% had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 16% had other PR cytogenetic abnormalities. In a multivariable model, 11q23 (hazard ratio [HR] = 0.66, P = 0.03) and other PR cytogenetic abnormalities (HR = 0.55, P = 0.02) were associated with significantly better overall survival when compared with monosomy 7/del7q or monosomy 5/del5q. Patients with other PR cytogenetic abnormalities had a lower risk of disease relapse after HSCT (HR = 0.49, P = 0.01) and, hence, better leukemia-free survival (HR = 0.55, P = 0.01). Therefore, we conclude that PR cytogenetic abnormalities at diagnosis predict overall survival after HSCT for AML in pediatric patients.

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.

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.

Successful hematopoietic cell transplantation in Fanconi anemia patients with renal impairment using ultra-reduced doses of cyclophosphamide and fludarabine.

Hematopoietic cell transplantation (HCT) remains until now the only curative modality for hematological manifestations in patients with Fanconi anemia (FA). The doses of alkylating agents used in the conditioning of this patient population before HCT are usually significantly decreased due to the genomic instability of the FA cells. FA patients with renal impairment represent a dilemma because of the need to further modify the conditioning regimen according to the degree of renal impairment to avoid additional toxicity. At our institution, we successfully transplanted three FA patients using an ultra-modified regimen.

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.

Hematopoietic stem cell transplant for hyper-IgM syndrome due to CD40L defects: A single-center experience.

HIGMI is a disease with a high risk for morbidity and mortality. HSCT has been shown to be a curative option. This study retrospectively reviewed and analyzed data from five patients who received HSCT at King Faisal Specialist Hospital & Research Centre (KFSH&RC) in Riyadh, Saudi Arabia, between 2005 and 2013. Five patients with HIGMI syndrome underwent HSCT at a median age of 41 months (range, 9-72 months). The median time from diagnosis to transplantation was 30 months (range, 5-58 months). For all five patients, the donors were HLA-identical siblings. In three patients, the conditioning regimen was composed of BU and CY. Fludarabine and melphalan with either ATG or alemtuzumab was used in two patients. For GVHD prophylaxis, cyclosporine was used in two patients, and the combination of cyclosporine and MTX was used in three patients. The survival rate was 100%, with a median follow-up of 69 months (range, 13-100 months). All patients engrafted. Two patients developed acute GVHD. Four patients showed complete immune recovery with positive CD40L expression in activated T cells and discontinued IVIG replacement. HSCT in early stage from an HLA-matched sibling donor is potentially effective at curing the disease.

Outcome of pediatric patients with lymphoma following stem cell transplant: a single institution report.

Hematopoietic stem cell transplant (HSCT) is recommended for pediatric patients with relapsed/refractory lymphoma even though the evidence for this is limited. We retrospectively reviewed records of 57 patients (29 Hodgkin lymphoma [HL], 28 non-Hodgkin lymphoma [NHL]) who underwent HSCT between 1995 and 2012. All demonstrated chemoresponsiveness prior to HSCT and 44 patients had a complete response. All underwent myeloablative conditioning, 38 chemotherapy-based and 19 total body irradiation-based. Forty-one patients received autologous and 16 allogeneic HSCT. Twelve (21%) died within 100 days post-HSCT, and 25 patients relapsed at a median of 1.6 months post-HSCT. Three patients developed second malignant neoplasms. Five-year overall survival (OS) was 50.5% and event-free survival (EFS) was 43.4%. Outcomes for HL were significantly better than those for NHL (OS 61.9% vs. 38.7% [p = 0.005] and EFS 60.4% vs. 26% [p = 0.008]). In summary, approximately half of all pediatric patients with lymphoma who failed first-line therapy and demonstrated chemosensitivity to second-line therapy can be salvaged with HSCT.

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.

Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers.

BACKGROUND: Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. OBJECTIVE: We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. METHODS: We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. RESULTS: Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. CONCLUSION: IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations.

Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia in Saudi Arabia: a multi-institutional retrospective national collaborative study.

BACKGROUND: Treatment of childhood acute lymphoblastic leukemia (ALL) has been available in Saudi Arabia (SA) for over 30 years; however, only limited data have been published from there. This study was conducted to establish processes for collaborative data collection and provide clinical characteristics and outcome of children with ALL in SA. PROCEDURE: Clinical data for patients diagnosed from 2004 to 2008 were retrospectively collected at eight institutions and entered remotely into a custom-built database. Statistics regarding clinical and genetic characteristics and treatment outcome were calculated. RESULTS: The 594 evaluable patients had a median age of 4.37 years and 56.4% were boys. Majority of patients had B-precursor ALL while 10.7% had T-ALL. CNS leukemia was present in 5.2% of patients. The distribution of common genetic abnormalities was similar to that reported from western populations, with 24.6% hyperdiploidy, 21% RUNX1-ETV6 positivity, 4.2% BCR-ABL1 positivity, and 2.5% with MLL gene rearrangement. Patients received risk-adapted therapy according to various protocols, although treatment strategies for the majority were similar. Five-year OS, RFS and EFS were 86.9%, 79.1%, and 73.3%, respectively. The OS for patients with pre-B ALL was significantly higher than for T-ALL (88.0% vs. 71.8%; P = 0.019, Log-Rank test). Patients with pre-B ALL categorized as low-risk by NCI/Rome criteria and those with hyperdiploidy had OS of 93.4% and 95.8%, respectively. CONCLUSIONS: The characteristics of childhood ALL in SA are similar to those observed in developed countries. Future prospective studies utilizing unified national protocols are needed to further improve the outcome of our patients.

Idiopathic colonic calcification: a case report.

We describe diffuse colonic calcification detected on CT scan of the abdomen in a young female patient who presented to our clinic with vague intermittent abdominal pain of four weeks duration. Her investigative profile was normal and her colonoscopy did not reveal any mucosal changes. Colonic calcification has been known to occur mostly as a result of ischemic phenomenon but the index case had no such features or any other predisposing factor. The patient is currently symptom-free and is following our clinic for the last 8 months. After the review of literature and thorough investigations her colonic calcification remains unexplained.