Low‐dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high‐risk pediatric acute myeloid leukemia

The dismal prognosis of pediatric acute myeloid leukemia (AML) relapsing after hematopoietic stem cell transplantation (HSCT) requires exploration of novel strategies to prevent relapse. Azacitidine (AZA) maintenance therapy could potentially reduce the recurrence rate post HSCT. Here, we presents the cases of three children with high‐risk AML post HSCT who were treated with low‐dose AZA maintenance therapy, demonstrating the feasibility of this therapy. Currently, all three are in complete remission for 13–41 months despite their high‐risk characteristics. Our encouraging data warrant larger prospective studies to assess the efficacy and safety of low‐dose AZA maintenance therapy post HSCT for pediatric patients with high‐risk AML.     

Efficacy and safety of azacitidine in pediatric patients with newly diagnosed advanced myelodysplastic syndromes before hematopoietic stem cell transplantation in the AZA-JMML-001 trial

Here we report efficacy, pharmacokinetics, and safety data obtained in treatment-naive, pediatric patients with newly diagnosed advanced MDS receiving azacitidine in the AZA-JMML-001 study. The primary endpoint was response rate (proportion of patients with complete response [CR], partial response [PR], or marrow CR, sustained for ≥4 weeks). Of the 10 patients enrolled, one had an unconfirmed marrow CR and none had confirmed responses after three cycles; the study was therefore closed after stage 1. Azacitidine was well tolerated. The lack of efficacy of azacitidine in pediatric patients with newly diagnosed advanced MDS highlights the need for effective new treatments in these patients.     

Azacitidine as a bridge to allogeneic hematopoietic cell transplantation in a pediatric patient with Fanconi anemia and acute myeloid leukemia

HCT is the definitive therapy for patients with FA and AML. Conventional cytotoxic agents cause potential DNA damage, and currently, there is no established regimen for these patients prior to HCT. A 13‐year‐old male with FA and refractory AML was given azacitidine, achieved morphologic remission and underwent HCT. At 95 days after HCT, he relapsed. Azacitidine along with DLI was used as first salvage therapy. Azacitidine was overall well tolerated with minimal side effects. In patients with AML and FA, azacitidine can be considered an alternative to conventional chemotherapy.     

Sorafenib as treatment for relapsed or refractory pediatric acute myelogenous leukemia

The prognosis for children with acute myelogenous leukemia (AML) has improved with overall survival rates of up to 65% [Pui et al. J Clin Oncol 2011; 29: 551-565]. However, the cure rate for AML lags behind that of acute lymphoblastic leukemia. Advances in AML leukemogenesis are leading to refined risk stratification. FMS like tyrosine kinase 3 (FLT3) mutations are independently associated with a poor prognosis. Newer kinase inhibitors, including sorafenib, have shown promise in adult studies. We report three pediatric patients with relapsed AML who achieved a sustained remission with sorafenib. Further trials are necessary to understand the role of sorafenib in pediatric AML.     

A paediatric case of successful non‐myeloablative bone marrow transplantation after azacitidine therapy for non‐Down syndrome acute megakaryoblastic leukaemia with monosomy 7

We report a patient with non‐Down syndrome AML, also known as AMKL, with monosomy 7, who was also obese and had a hearing impairment and mental retardation. Non‐myeloablative bone marrow transplantation was performed successfully after the patient received less aggressive azacitidine treatment, without the usual intensive induction chemotherapy regimen for AML.     

Sustained remission with azacitidine monotherapy and an aberrant precursor B‐lymphoblast population in juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) has a poor prognosis in general, with hematopoietic stem cell transplant (HSCT) remaining the standard of care for cure. The hypomethylating agent, azacitidine, has been used as a bridging therapy to transplant. However, no patients have been treated with azacitidine without an HSCT post azacitidine. We report on an infant with JMML with somatic KRAS G12A mutation and monosomy 7 who achieved sustained remission following azacitidine monotherapy. He also developed an aberrant B‐lymphoblast population which declined with similar kinetics as his JMML‐associated abnormalities, suggesting that a B‐lymphoblast population in JMML does not always progress to acute leukemia.     

Preventive antibiotics in pediatric patients with acute myeloid leukemia (AML)

Background

Treatment of acute myeloid leukemia (AML) comes with a significant risk of life‐threatening infection during periods of prolonged severe neutropenia. We studied the impact of preventive intravenous (IV) antibiotic administration at onset of absolute neutropenia on the incidence and outcome of life‐threatening infections during treatment of childhood AML.

Procedures

This is a retrospective study on pediatric patients (aged 0–18 years) consecutively diagnosed with de novo AML and treated at a single institution from April 2005 through February 2013. Patients were treated on the Children's Oncology Group (COG) AAML0531 protocol or with a modified United Kingdom Medical Research Council (UK MRC) AML 10 regimen. Pertinent data were extracted from hard copy or electronic chart review.

Results

A total of 76 chemotherapy phases were analyzed from 29 patients. In each phase reported, preventive antibiotics were initiated when the daily absolute neutrophil count was <500 cells/mcl, before onset of fever. Seven episodes of bacteremia were documented with predominantly coagulase‐negative staphylococci and viridans group streptococci. One infection‐related death occurred, attributed to progressive respiratory failure occurring months after documented candidal pneumonia.

Conclusions

Initiation of preventive antibiotics at the onset of absolute neutropenia was associated with no mortality from bacteremia. This preventive approach appears feasible and safe. Pediatr Blood Cancer 2015;62:1149–1154. © 2015 Wiley Periodicals, Inc.     

Chromosomal rearrangement in Down syndrome with acute myeloid leukemia

The incidence of acute leukemia in children with Down syndrome (DS) is high as compared to general population. Recent findings have demonstrated that DS children with acute myeloid leukemia (AML) have the highest event free survival rates with high dose cytosine arabinoside (Ara-C). We present 3 year-old DS female child with AML-M5, whose chromosomal analysis revealed constitutional t(21;21) alongwith del(5)(q31q33) and a unique translocation t(16;20)(q13;q12). After chemotherapy, child achieved complete clinical remission. Karyotype analysis of remission marrow showed disappearance of abnormal clone of der(20) t(16;20)(q13;q12), del(5q) indicating cytogenetic remission too. This case alongwith supportive literature indicate that pediatric DS-AML is a distinct biologic sub-group differs from that of non-DS-AML with respect to chemosensitivity.     

Outcome of hematopoietic stem cell transplantation for pediatric patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome

BACKGROUND: Therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) carry a poor prognosis. We analyzed the results of allogeneic HSCT in 38 children to determine which factors, if any, affected outcome. PROCEDURE: The effects of demographic, donor, and disease-related factors were analyzed to determine their effects on overall and disease-free survival (OS, DFS), relapse, and non-relapse mortality (NRM). RESULTS: OS and DFS for t-AML and t-MDS were similar. Three-year OS and EFS were the same (15.4 +/- 5.8%) and the 3-year NRM was 59.6 +/- 8.4%. The 1-year cumulative risk of grade III-IV acute graft-versus-host disease (GVHD) and relapse were 23.7 +/- 7.0% and 18.7 +/- 6.5%, respectively. The percentage of pre-transplant bone marrow (BM) blasts was positively associated with relapse (P = 0.05), while the percentage of BM blasts at diagnosis of therapy-related disease tended to associate with NRM (P = 0.07). Alternative donor and matched sibling donor grafts had similar outcomes. NRM was higher among patients who did not develop acute GVHD as compared to those with grade 1-2 acute GVHD (69.2 +/- 14.2% vs. +/- 12.7%, respectively), while NRM was 100% in patients with grade III-IV acute GVHD (P = 0.007). CONCLUSIONS: The percentage of BM blasts is associated with relapse in these disorders. High rates of NRM negatively impact the outcome of allogeneic HSCT for children with t-AML and t-MDS. Future studies should focus on reducing NRM.     

Use of oral immunoglobulins to treat diarrhea in pediatric kidney transplant recipients—Single‐center experience and review of the literature

Effective treatment modalities for diarrhea in solid organ transplant recipients are lacking. We evaluated the effect of oral IgG on clinical course of diarrhea in pediatric kidney transplant recipients. We retrospectively studied all pediatric kidney transplant recipients who required hospitalization for diarrhea between January 1, 2015, and December 31, 2017. We divided the recipients into two groups based on whether they had received oral IgG to treat diarrhea. Sixteen pediatric kidney transplant recipients required hospitalization for diarrhea over 3 years. Median age at admission was 9.25 years (IQR:12.54). Fifty‐six percent of recipients were male, and 81% were white. Four patients received oral IgG for prolonged diarrhea. Oral IgG recipients had longer diarrheal duration before admission (median (days) 14.5 vs1; P .02), a trend for greater weight loss at admission (median (kilogram) 1.4 vs 0.2; P .3), and a trend for higher acute kidney injury (>75% reduction in glomerular filtration rate: 100% vs 42%; P .36). Diarrhea resolved completely in 3 (75%) oral IgG recipients and 7 (58%) non‐oral IgG patients by discharge (P .99). One oral IgG recipient showed partial improvement but also had biopsy evidence of mycophenolate‐induced colitis. All patients tolerated oral IgG well. No patients required re‐hospitalization within 30 days of discharge. Oral IgG may be used safely and effectively to treat prolonged diarrhea in pediatric kidney transplant recipients. A larger, randomized, prospective study is needed to further assess the efficacy of oral IgG in the treatment of diarrhea.