Early post-induction augmented therapy improves outcome in children and adolescents with T-cell acute lymphoblastic leukemia.

INTRODUCTION: T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of all newly diagnosed ALL in children and adolescents and is associated with worse outcomes compared to pre-B ALL. We aimed to decrease T-ALL relapses by intensifying our regimen. METHODS: Patients with T-ALL were treated using two different regimens; before September 2014, patients were treated per St. Jude Total XV protocol; subsequently, a major change was adopted by adding two intensive blocks: FLAG and Reintensification. Cranial radiation was limited to patients with WBC ≥ 100 k/µl at diagnosis and/or patients with CNS2/CNS3 status. RESULTS: Between June 2005 and April 2020, a total of 100 patients (76 males) were treated and followed up for a median of 70 months (range 14-181). Median age at diagnosis was 9 years (range 0.5-17.8). Forty-eight patients were diagnosed after September 2014 and received the augmented regimen; their median follow up was 46 months (range 14-74). The 5-year-EFS estimates for patients who received the augmented regimen versus standard regimen were 87% ± 4.9% versus 67% ± 6.8% (p = .03); and the 5-year-OS estimates were 87% ± 5.1% versus 71% ± 6.3% (p = .06), respectively. Treatment related mortality (TRM) was reported in two patients treated per standard regimen but none for patients who received the augmented regimen. CONCLUSIONS: We implemented a novel approach with early intensification added to a backbone of modified St. Jude Total-XV regimen for patients with T-ALL that resulted in improved outcome with no treatment related mortality.

Neuraminidase Inhibitors and Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine Treatment Effectiveness Among Patients Hospitalized With Nonfatal 2009 Pandemic Influenza A(H1N1) Virus Infection.

BACKGROUND: The effect of neuraminidase inhibitor (NAI) treatment on length of stay (LoS) in patients hospitalized with influenza is unclear. METHODS: We conducted a one-stage individual participant data (IPD) meta-analysis exploring the association between NAI treatment and LoS in patients hospitalized with 2009 influenza A(H1N1) virus (A[H1N1]pdm09) infection. Using mixed-effects negative binomial regression and adjusting for the propensity to receive NAI, antibiotic, and corticosteroid treatment, we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Patients with a LoS of <1 day and those who died while hospitalized were excluded. RESULTS: We analyzed data on 18 309 patients from 70 clinical centers. After adjustment, NAI treatment initiated at hospitalization was associated with a 19% reduction in the LoS among patients with clinically suspected or laboratory-confirmed influenza A(H1N1)pdm09 infection (IRR, 0.81; 95% CI, .78-.85), compared with later or no initiation of NAI treatment. Similar statistically significant associations were seen in all clinical subgroups. NAI treatment (at any time), compared with no NAI treatment, and NAI treatment initiated <2 days after symptom onset, compared with later or no initiation of NAI treatment, showed mixed patterns of association with the LoS. CONCLUSIONS: When patients hospitalized with influenza are treated with NAIs, treatment initiated on admission, regardless of time since symptom onset, is associated with a reduced LoS, compared with later or no initiation of treatment.

Analysis of KRAS and NRAS Gene Mutations in Arab Asian Children With Acute Leukemia: High Frequency of RAS Mutations in Acute Lymphoblastic Leukemia.

BACKGROUND: KRAS and NRAS gene mutations are frequently observed in childhood leukemia. The objective of this study was to determine the frequency of RAS mutations and the association between RAS mutations and other genetic aberrations in Arab Asian children with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). METHODS: Diagnostic samples of 485 patients (<18 years) with acute leukemia from Iraq and Jordan were obtained, using Flinders Technology Associates filter papers. Polymerase chain reaction and direct sequencing were performed in Japan. RESULTS: RAS mutations were detected in 86/318 (27%) of ALL cases and 35/167 (21%) of AML cases. The frequency of NRAS mutation was similar to that of KRAS mutation in ALL. Two RAS mutations were detected in nine patients. Among 264 Iraqi patients with ALL, RAS mutation was significantly associated with lower initial white blood cell count. Of 57 patients with chimeric transcripts, only two patients with either TEL-AML1 or E2A-PBX1 had KRAS mutation. The frequency of NRAS mutation was four times higher than that of KRAS mutation in AML. FAB-M4 and M5 subsets were associated with RAS mutation. Among 134 Iraqi patients with AML, 18 patients had RAS mutations and other genetic aberrations. In particular, 9 of 25 (36%) with MLL-rearrangement had RAS mutations. CONCLUSION: The prevalence of oncogenic RAS mutations was higher among Arab Asian children than in other countries. RAS mutations in AML were found to coexist with other genetic aberrations, particularly MLL rearrangement.

Safety of inadvertent administration of overdose of intrathecal Cytarabine in a pediatric patient.

PURPOSE: To describe a medication error of intrathecal Cytarabine overdose that was managed conservatively with no apparent toxicities. SUMMARY: An 11-year-old girl was diagnosed with bone marrow relapsed precursor B-cell acute lymphoblastic leukemia. According to her chemotherapy protocol, she was started on triple intrathecal chemotherapy consisting of Methotrexate, Cytarabine and Hydrocortisone on day 1 of the protocol. After the intrathecal therapy being administered to the patient, the pharmacist who checked the medication realized that the wrong formulation of Cytarabine was used to prepare the intrathecal therapy; this error resulted in five times overdose of Cytarabine. The patient was then managed conservatively without cerebrospinal fluid exchange. Our patient remained clinically and neurologically stable without apparent toxicities and was discharged safely from hospital. CONCLUSION: Supportive care without the need for invasive procedures such as cerebrospinal fluid exchange may be adequate for managing intrathecal Cytarabine overdose.

Frequent coexistence of RAS mutations in RUNX1-mutated acute myeloid leukemia in Arab Asian children.

BACKGROUND: RUNX1 mutation plays an important role in adult leukemic transformation. However, its contribution to the development of childhood leukemia remains unclear. In the present study, we analyzed point mutations of RUNX1 gene in children and adolescents with acute myeloid leukemia (AML) from Iraq and Jordan. PROCEDURE: Bone marrow and/or peripheral blood samples were collected from 178 patients of Arab Asian ethnicity (aged ≤17 years) newly diagnosed with AML: 145 samples from Iraq and 33 samples from Jordan. Direct DNA sequencing was performed on six genes including RUNX1 gene (exons 3-8). RESULTS: RUNX1 point mutations were identified in 10 (5.6%) of 178 patients. One patient possessed biallelic mutations of RUNX1 gene. C-terminal area was the predominant site of RUNX1 mutations (eight in C-terminal and two in N-terminal). Patients with RUNX1 mutations were significantly older than those with wild-type of the gene. Additionally, AML M0 subtype was more frequently found in patients with RUNX1 mutations. Both RUNX1 mutations and RAS mutations were identified in 4 of 10 children. Three patients with RUNX1 mutation had FLT3-ITD. On the other hand, 36 (21.4%) and 25 (14.9%) of 168 patients with wild-type of the gene had a RAS mutation and FLT3-ITD, respectively. Eight of 10 patients with RUNX1 mutations died of hematological relapse. CONCLUSION: The incidence of RUNX1 mutations in Arab Asian children and adolescents with AML was 5.6%. Further studies are required to clarify whether RAS mutations contribute to the development of pediatric AML associated with RUNX1 mutations.

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data.

BACKGROUND: Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS: We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS: We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each day's delay). INTERPRETATION: We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING: F Hoffmann-La Roche.

Childhood acute lymphoblastic leukemia in the Middle East and neighboring countries: a prospective multi-institutional international collaborative study (CALLME1) by the Middle East Childhood Cancer Alliance (MECCA).

BACKGROUND: Little is known about childhood ALL in the Middle East. This study was undertaken by MECCA as initial efforts in collaborative data collection to provide clinical and demographic information on children with ALL in the Middle East. PROCEDURE: Clinical and laboratory data for patients with ALL between January 2008 and April 2012 were prospectively collected from institutions in 14 Middle East countries and entered into a custom-built-database during induction phase. All laboratory studies including cytogenetics were done at local institutions. RESULTS: The 1,171 voluntarily enrolled patients had a mean age of 6.1 ± 3.9 years and 59.2% were boys. T-ALL represented 14.8% and 84.2% had B-precursor ALL. At diagnosis, 5.6% had CNS disease. The distribution of common genetic abnormalities reflected a similar percentage of hyperdiploidy (25.6%), but a lower percentage of ETV6-RUNX1 translocation (14.7%) compared to large series reported from Western populations. By clinical criteria, 47.1% were low/standard risk, 16.9% were intermediate risk, and 36% were high risk. Most patients received all their care at the same unit (96.9%). Patients had excellent induction response to chemotherapy with an overall complete remission rate of 96%. Induction toxicities were acceptable. CONCLUSIONS: This first collaborative study has established a process for prospective data collection and future multinational collaborative research in the Middle East. Despite the limitations of an incomplete population-based study, it provides the first comprehensive baseline data on clinical characteristics, laboratory evaluation, induction outcome, and toxicity. Further work is planned to uncover possible biologic differences of ALL in the region and to improve diagnosis and management.

Prognostic effect of blood transfusion in children with acute lymphoblastic leukemia.

BACKGROUND: Most children with acute lymphoblastic leukemia (ALL) receive blood transfusions. Transfusions may affect ALL outcomes through transfusion-related immunomodulation (TRIM). METHODS: We analyzed overall survival (OS) and event-free survival (EFS) in relation to leukocyte reduced and irradiated (LR/IRR) blood products transfused during the induction phase in 136 children with ALL. Hazard ratios (HRs) for death and relapse were estimated through Cox regression analysis. RESULTS: One hundred and twenty patients (89%) were transfused with packed red blood cells (PRBCs) and 79 (58%) with single donor platelets (SDPs). The median number of transfusions was 2 (interquartile range [IQR]=1-3 events) and 1 (IQR=0-3 events) for PRBCs and SDPs, respectively. Patients who had white blood cell (WBC) count >50,000×10(9)/L, were classified as high risk according to the high National Cancer Institute criteria, displayed a T cell phenotype, or were minimal residual disease-positive at end of induction were more likely to receive >3 transfusions during induction (P=0.001, 0.002, 0.03, and 0.01, respectively). In univariate analysis, PRBC, SDP, and fresh frozen plasma transfusions did not have any significant association with relapse or death. For PRBC transfusions, the HRs for EFS and OS were 1.02 (95% CI, 0.85-1.24; P=0. 76) and 1.03 (95% CI, 0.83-1.27; P=0.76), respectively. For SDP transfusions, HRs were 1.03 (95% CI, 0.90-1.18; P=0.64) and 0.98 (95% CI, 0.80-1.20; P=0.87) for EFS and OS, respectively. CONCLUSION: LR/IRR blood products may not confer a TRIM effect in childhood ALL and are unlikely to affect outcome.

Hematopoietic stem cell transplant versus chemotherapy plus tyrosine kinase inhibitor in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

BACKGROUND: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) remained until recently the molecular genetic abnormality associated with the worst outcome. Hematopoietic stem cell transplant (HSCT) was considered the treatment of choice, however, recent data have indicated that chemotherapy plus tyrosine kinase inhibitor (TKI) maybe an alternative effective therapy. METHODS: We conducted a retrospective analysis of children (<18 years) with Ph+ ALL who were treated at King Hussein Cancer Center (KHCC) from January 2003 till December 2011. RESULTS: Over a 9 year period, 411 children were diagnosed and treated for ALL at KHCC. Twenty three (6.6%) had Ph+ ALL; 16 males and 7 females. Median age at diagnosis was 9.5 years (range 1.67-17). The median white blood cell count was 58.6×10(3)/µL (range 1.6-459). Twelve patients underwent HSCT from a full matched related donor; and 10 were treated with intensive chemotherapy plus TKI (imatinib). Those who underwent HSCT were significantly older (P=0.004) and had a higher leukocyte count at diagnosis (P=0.53). After a median follow up of 42.2 months (range 12.7-107), the estimated 5 year event free survival (EFS) and overall survival (OS) were 75% and 91.6%, respectively, for those who underwent HSCT as primary therapy and 49.3% and 83.3%, respectively, for those treated with chemotherapy plus imatinib. There was no significant difference in EFS (P=0.98) or OS (P=1) between the two treatment modalities. CONCLUSIONS: Our results indicate that chemotherapy plus TKI may be a reasonable treatment option for some children with Ph+ ALL.

6-Mercaptopurine-induced recurrent acute pancreatitis in children with acute lymphoblastic leukemia/lymphoma.

Two children with acute lymphoblastic leukemia/lymphoma developed recurrent acute pancreatitis during treatment; the etiology was presumed to be secondary to 6-mercaptopurine (6MP). Both had no further attacks after discontinuation of 6MP. Acute pancreatitis secondary to 6MP is extremely rare in acute leukemia/lymphoma although it has been reported in patients with other conditions like inflammatory bowel disease; the reason for this difference is not clearly understood.

Outcome of childhood acute lymphoblastic leukemia in Jordan.

BACKGROUND: Accurate data about childhood acute lymphoblastic leukemia (ALL) in low- and middle-income countries are lacking. Our study is designed to assess survival of childhood ALL at King Hussein Cancer Center (KHCC) using modified St. Jude Children's Research Hospital protocols. PATIENTS AND METHODS: We reviewed the medical records of children 1-18 years of age who were diagnosed with ALL and treated at KHCC from January 2003 through December 2009. Disease characteristics and outcome were analyzed. RESULTS: Over a 7-year period, 300 children with ALL were treated. One hundred and seventy-three (57.7%) were males and 127 (42.3%) were females. The median age at diagnosis was 5 years. One hundred and fifty-seven (52.3%) children were classified as low-risk, 118 (39.3%) were standard-risk and 25 (8.3%) were high-risk. Two hundred and sixty-two (88.5%) children had pre-B cell phenotype and 34 (11.5%) had T-cell phenotype. Two hundred and seventy-three (91.3%) children were classified as having CNS I disease, 24 (8%) had CNS II, and 2 (0.67%) had CNS III. Cytogenetic abnormalities included: t(12;21) in 30 (12%) children and t(9;22) in 18 (7.4%). Four (1.3%) children died in induction, 6 (2%) died in first remission and 27 (9%) relapsed. After a median follow-up of 34.5 months (range 0.32-84.5), the estimated 5-year event free survival and overall survival were 80% and 89%, respectively. CONCLUSION: Treatment protocols developed by major cooperative groups and institutions to treat childhood ALL was successfully adapted and suggest that such an approach may be useful in other low- and middle-income countries.

Retrospective analysis of pediatric cancer patients diagnosed with the pandemic H1N1 influenza infection.

BACKGROUND: Limited data are available on disease characteristics and outcome of children with cancer who contracted the H1N1 influenza infection during the 2009 pandemic. METHODS: All 76 pediatric patients with cancer and documented H1N1 infection who presented to the Pediatric Department at King Hussein Cancer Center (KHCC) between October 1 and December 1, 2009 were reviewed for clinical characteristics and course of the disease. RESULTS: Two-thirds of the patients had hematological malignancies and half were receiving non-intensive chemotherapy at the time of infection. With the exception of two patients who needed pediatric intensive care unit admission, the course of the remaining patients was uneventful whether they were hospitalized or not. No deaths related to H1N1 influenza infection were reported. Sixty-three percent of patients became afebrile within 48 hr of receiving oseltamivir. One-third of hospitalized patients were discharged in < 3 days. CONCLUSION: The course of H1N1 influenza infection in children with cancer appears to be mild in most cases.