Infection-related complications during treatment for childhood acute lymphoblastic leukemia.

Background: Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking. Patients and methods: We evaluated infection-related complications that were grade ≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period. Results: Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n = 389), followed by ear (n = 151), bloodstream (n = 147), and gastrointestinal tract (n = 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n = 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P = 0.002) during induction and febrile neutropenia and documented infection (both P < 0.001) during later continuation. White race was associated with documented infection (P = 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P < 0.001) and documented infections (P = 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P < 0.001). Conclusions: The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.

Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait.

We performed a genomewide association study (GWAS) of primary erythrocyte thiopurine S-methyltransferase (TPMT) activity in children with leukemia (n = 1,026). Adjusting for age and ancestry, TPMT was the only gene that reached genomewide significance (top hit rs1142345 or 719A>G; P = 8.6 × 10-61 ). Additional genetic variants (in addition to the three single-nucleotide polymorphisms [SNPs], rs1800462, rs1800460, and rs1142345, defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype. Clinical mercaptopurine tolerability in 839 patients was related to TPMT clinical genotype (P = 2.4 × 10-11 ). Using 177 lymphoblastoid cell lines (LCLs), there were 251 SNPs ranked higher than the top TPMT SNP (rs1142345; P = 6.8 × 10-5 ), revealing a limitation of LCLs for pharmacogenomic discovery. In a GWAS, TPMT activity in patients behaves as a monogenic trait, further bolstering the utility of TPMT genetic testing in the clinic.

Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy.

To determine the clinical significance of minimal residual disease (MRD) in patients with prognostically relevant subtypes of childhood acute lymphoblastic leukemia (ALL), we analyzed data from 488 patients treated in St Jude Total Therapy Study XV with treatment intensity based mainly on MRD levels measured during remission induction. MRD levels on day 19 predicted treatment outcome for patients with hyperdiploid >50 ALL, National Cancer Institute (NCI) standard-risk B-ALL or T-cell ALL, while MRD levels on day 46 were prognostic for patients with NCI standard-risk or high-risk B-ALL. Patients with t(12;21)/(ETV6-RUNX1) or hyperdiploidy >50 ALL had the best prognosis; those with a negative MRD on day 19 had a particularly low risk of relapse: 1.9% and 3.8%, respectively. Patients with NCI high-risk B-ALL or T-cell ALL had an inferior outcome; even with undetectable MRD on day 46, cumulative risk of relapse was 12.7% and 15.5%, respectively. Among patients with NCI standard-risk B-ALL, the outcome was intermediate overall but was poor if MRD was ⩾1% on day 19 or MRD was detectable at any level on day 46. Our results indicate that the clinical impact of MRD on treatment outcome in childhood ALL varies considerably according to leukemia subtype and time of measurement.

A revised definition for cure of childhood acute lymphoblastic leukemia.

With improved contemporary therapy, we reassess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia (ALL) to determine when cure can be declared with a high degree of confidence. In six successive clinical trials between 1984 and 2007, 1291 (84.5%) patients completed all therapies in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% (P<0.001)) and overall survival (76.5% vs 81.1% vs 91.7% (P<0.001)) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5% and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years of therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with ALL may relapse after completion of treatment, and those who remain in remission at 4 years post treatment may be considered cured (that is, less than 1% chance of relapse).

Successful challenges using native E. coli asparaginase after hypersensitivity reactions to PEGylated E. coli asparaginase.

PURPOSE: Asparaginase is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. However, asparaginase-induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Here, we report successful challenges using native Escherichia coli asparaginase after previous hypersensitivity reactions to both PEGylated E. coli asparaginase and Erwinia asparaginase. PATIENTS AND METHODS: The two patients included in this case report were diagnosed with B-precursor ALL at St. Jude Children's Research Hospital and were treated with a common regimen. Both patients developed hypersensitivity reactions to PEGylated E. coli asparaginase and Erwinia asparaginase early in treatment, and they were challenged with native E. coli asparaginase. Serum samples were collected for estimating the pharmacokinetic parameters of each patient during native E. coli asparaginase therapy. RESULTS: Challenges with native E. coli asparaginase were successful, and asparaginase serum concentrations above therapeutic levels were attained in both patients. CONCLUSIONS: These two cases suggest that some patients can be given native E. coli asparaginase after hypersensitivity reactions to PEGylated asparaginase and achieve therapeutic concentrations of the drug in serum.

Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature B-cell malignancies.

Children with ataxia-telangiectasia (A-T) and cancer have a poorer prognosis due in part to increased treatment-related toxicity. We piloted a curative intent approach in five children with A-T who presented with advanced stage (III, n = 2; IV, n = 3) B-NHL (diffuse large B-cell lymphoma, n = 4; Burkitt leukemia, n = 1) using a modified LMB-based protocol. Two achieved sustained CCR (one, CCR at 6 years; one, pulmonary death after 3 years in CCR). Two died from toxicity during induction and 1 failed induction with progressive disease. Novel therapeutic approaches which overcome drug resistance and are less toxic are needed for children with A-T and B-NHL.

Imaging of acute invasive fungal rhinosinusitis in a patient with gorlin syndrome and acute lymphocytic leukemia.

Gorlin Syndrome (GS), also known as nevoid basal cell carcinoma syndrome, is a rare autosomal dominant condition characterized by developmental abnormalities and predisposition to certain neoplasms. Acute invasive fungal rhinosinusitis (AIFRS) is an uncommon clinical entity characterized by high morbidity and mortality. In immunocompromised patients, computed tomography plays a critical role in screening for suspected AIFRS. However, due to the association between exposure to ionizing radiation and subsequent development of malignancies in patients with GS, patients with GS and suspected AIFRS present a unique and challenging clinical scenario. We present a case of a pediatric patient with GS and acute lymphocytic leukemia (ALL) diagnosed with AIFRS; to the best of our knowledge, it is the only case described in the literature.

Results of treatment of advanced-stage lymphoblastic lymphoma at St Jude Children's Research Hospital from 1962 to 2002.

BACKGROUND: Reliable prognostic factors have not been established for advanced-stage pediatric lymphoblastic lymphoma (LL). We analyzed treatment outcomes and potential risk factors in children and adolescents with advanced-stage LL treated over a 40-year period. PATIENTS AND METHODS: From 1962 through 2002, 146 patients (99 boys and 47 girls) with stage III (n = 111) or stage IV (n = 35) LL were treated at St Jude Children's Research Hospital. The five treatment eras were 1962-1975 (no protocol), 1975-1979 (NHL-75), 1979-1984 (Total 10 High), 1985-1992 (Pediatric Oncology Group protocol), and 1992-2002 (NHL13). Age at diagnosis was <10 years in 65 patients and ≥10 years in 81. RESULTS: Outcomes improved markedly over successive treatment eras. NHL13 produced the highest 5-year event-free survival (EFS) estimate (82.9% ± 6.1% [SE]) compared with only 20.0% ± 8.0% during the earliest era. Treatment era (P < 0.0001) and age at diagnosis (<10 years versus ≥10 years, P = 0.0153) were independent prognostic factors, whereas disease stage, lactate dehydrogenase level, and presence of a pleural effusion were not. CONCLUSIONS: Treatment era and age were the most important prognostic factors for children with advanced-stage LL. We suggest that a better assessment of early treatment response may help to identify patients with drug-resistant disease who require more intensive therapy.

Frequent mutations in SH2D1A (XLP) in males presenting with high-grade mature B-cell neoplasms.

X-linked lymphoproliferative syndrome (XLP) is caused by mutations in SH2D1A, and is associated with overwhelming infectious mononucleosis, aplastic anemia, hypogammaglobulinemia, and B-cell lymphomas. However, the frequency of SH2D1A mutations in males who present with B NHL is unknown. Five cases of XLP were diagnosed among 158 males presenting with B NHL (approximately 3.2%). Four of the patients had two episodes of B NHL and one had a single episode of B NHL followed by aggressive infectious mononucleosis. Prospective screening for XLP in males with B-cell lymphoma at the time of initial diagnosis should be considered.

Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia.

Hypersensitivity to asparaginase is common, but the differential diagnosis can be challenging and the diagnostic utility of antibody tests is unclear. We studied allergic reactions and serum antibodies to E. coli asparaginase (Elspar) in 410 children treated on St. Jude Total XV protocol for acute lymphoblastic leukemia. Of 169 patients (41.2%) with clinical allergy, 147 (87.0%) were positive for anti-Elspar antibody. Of 241 patients without allergy, 89 (36.9%) had detectable antibody. Allergies (P=0.0002) and antibodies (P=6.6 × 10(-6)) were higher among patients treated on the low-risk arm than among those treated on the standard/high-risk arm. Among those positive for antibody, the antibody titers were higher in those who developed allergy than in those who did not (P<1 × 10(-15)). Antibody measures at week 7 of continuation therapy had a sensitivity of 87-88% and a specificity of 68-69% for predicting or confirming clinical reactions. The level of antibodies was inversely associated with serum asparaginase activity (P=7.0 × 10(-6)). High antibody levels were associated with a lower risk of osteonecrosis (odds ratio=0.83; 95% confidence interval, 0.78-0.89; P=0.007). Antibodies were related to clinical allergy and to low systemic exposure to asparaginase, leading to lower risk of some adverse effects of therapy.

ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy.

ETV6-RUNX1 fusion is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL). To evaluate whether outcomes for this drug-sensitive leukemia are improved by contemporary risk-directed therapy, we studied clinical features, response and adverse events of 168 children with newly diagnosed ETV6-RUNX1-positive ALL on St Jude Total Therapy studies XIIIA (N=36), XIIIB (N=38) and XV (N=94). Results were compared with 494 ETV6-RUNX1-negative B-precursor ALL patients. ETV6-RUNX1 was associated with age 1-9 years, pre-treatment classification as low risk and lower levels of minimal residual disease (MRD) on day 19 of therapy (P<0.001). Event-free survival (EFS) or overall survival (OS) did not differ between patients with or without ETV6-RUNX1 in Total XIIIA or XIIIB. By contrast, in Total XV, patients with ETV6-RUNX1 had significantly better EFS (P=0.04; 5-year estimate, 96.8±2.4% versus 88.3±2.5%) and OS (P=0.04; 98.9±1.4% versus 93.7±1.8%) than those without ETV6-RUNX1. Within the ETV6-RUNX1 group, the only significant prognostic factor associated with higher OS was the treatment protocol Total XV (versus XIIIA or XIIIB) (P=0.01). Thus, the MRD-guided treatment schema including intensive asparaginase and high-dose methotrexate in the Total XV study produced significantly better outcomes than previous regimens and demonstrated that nearly all children with ETV6-RUNX1 ALL can be cured.

Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma.

BACKGROUND: Children with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients. PATIENTS AND METHODS: This study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered. RESULTS: There were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths. CONCLUSIONS: MIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.

Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia.

We analyzed the long-term outcome of 1011 patients treated in five successive clinical trials (Total Therapy Studies 11, 12, 13A, 13B, and 14) between 1984 and 1999. The event-free survival improved significantly (P=0.003) from the first two trials conducted in the 1980s to the three more recent trials conducted in the 1990s. Approximately 75% of patients treated in the 1980s and 80% in the 1990s were cured. Early intensive triple intrathecal therapy, together with more effective systemic therapy, including consolidation and reinduction treatment (Studies 13A and 13B) as well as dexamethasone (Study 13B), resulted in a very low rate of isolated central nervous system (CNS) relapse rate (<2%), despite the reduced use of cranial irradiation. Factors consistently associated with treatment outcome were age, leukocyte count, immunophenotype, DNA index, and minimal residual disease level after remission induction treatment. Owing to concerns about therapy-related secondary myeloid leukemia and brain tumors, in our current trials we reserve the use of etoposide for patients with refractory or relapsed leukemia undergoing hematopoietic stem cell transplantation, and cranial irradiation for those with CNS relapse. The next main challenge is to further increase cure rates while improving quality of life for all patients.

Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1.

To evaluate the impact of contemporary therapy on the clinical outcome of children with pre-B acute lymphoblastic leukemia (ALL) and the t(1;19)/TCF3/PBX1, we analyzed 735 patients with B-cell precursor ALL treated in four successive protocols at St Jude Children's Research Hospital. The 41 patients with the t(1;19) had a comparable event-free survival to that of the 694 patients with other B-cell precursor ALL (P=0.63; 84.2+/-7.1% (s.e.) vs 84.0+/-1.8% at 5 years). However, patients with the t(1;19) had a lower cumulative incidence of any hematological relapse (P=0.06; 0 vs 8.3+/-1.2% at 5 years) but a significantly higher incidence of central nervous system (CNS) relapse (P<0.001; 9.0+/-5.1% vs 1.0+/-0.4% at 5 years). In a multivariate analysis, the t(1;19) was an independent risk factor for isolated CNS relapse. These data suggest that with contemporary treatment, patients with the t(1;19) and TCF3/PBX1 fusion have a favorable overall outcome but increased risk of CNS relapse.

Effective treatment of advanced-stage childhood lymphoblastic lymphoma without prophylactic cranial irradiation: results of St Jude NHL13 study.

There has been a steady improvement in cure rates for children with advanced-stage lymphoblastic non-Hodgkin's lymphoma. To further improve cure rates whereas minimizing long-term toxicity, we designed a protocol (NHL13) based on a regimen for childhood T-cell acute lymphoblastic leukemia, which features intensive intrathecal chemotherapy for central -nervous system-directed therapy and excludes prophylactic cranial irradiation. From 1992 to 2002, 41 patients with advanced-stage lymphoblastic lymphoma were enrolled on the protocol. Thirty patients had stage III and 11 had stage IV disease. Thirty-three cases had a precursor T-cell immunophenotype, five had precursor B-cell immunophenotype and in three immunophenotype was not determined. Out of the 41 patients, 39 (95%) achieved a complete remission. The 5-year event-free rate was 82.9+/-6.3% (s.e.), and 5-year overall survival rate was 90.2+/-4.8% (median follow-up 9.3 years (range 4.62-13.49 years)). Adverse events included two induction failures, one death from typhlitis during remission, three relapses and one secondary acute myeloid leukemia. The treatment described here produces high cure rates in children with lymphoblastic lymphoma without the use of prophylactic cranial irradiation.

Clinical consequences of hyperglycemia during remission induction therapy for pediatric acute lymphoblastic leukemia.

Hyperglycemia adversely affects outcome in adult patients with acute lymphoblastic leukemia (ALL), but its impact on children with this disease is unknown. We evaluated the relationship between hyperglycemia during remission induction therapy and clinical outcomes among pediatric patients with ALL. We reviewed the records of patients enrolled on four consecutive ALL protocols (Total Therapy protocols XIIIA, XIIIB, XIV and XV) at St Jude Children's Research Hospital from 1991 to 2007 and identified those who experienced hyperglycemia (glucose >or=200 mg per 100 ml) during remission induction. Complete remission (CR) rates at the end of induction, event-free survival (EFS), overall survival (OS), cumulative incidence of relapse and occurrence of infections were compared between those who did and did not experience hyperglycemia. Of 871 patients analyzed, 141 (16%) experienced hyperglycemia during remission induction. Patients with hyperglycemia were significantly older than the other patients (P<0.0001). There was no significant difference in CR rate (P=0.92), EFS (P=0.80), OS (P=0.28), cumulative incidence of relapse (P=0.59) or in the probability or types of infection between patients who did and did not experience hyperglycemia. Pediatric patients with or without hyperglycemia during remission induction for ALL have similar clinical outcome. Occurrence of hyperglycemia does not warrant alteration of the antileukemic regimen.

Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation.

To assess the prognosis of overt testicular disease at diagnosis of acute lymphoblastic leukemia, and any therapeutic role of irradiation for this involvement, we reviewed the data of 811 boys treated on St Jude studies Total X--XI (early period) and Total XII-XIV (recent period). In all, 19 boys (2.3%) had testicular disease at diagnosis. In the early period, patients with testicular leukemia had a poorer overall survival (OS) (P=0.003), event-free survival (EFS) (P=0.064), and higher cumulative incidence of relapse (P=0.041) than did other patients. During the recent period, patients with and without overt testicular leukemia did not differ in OS (P=0.257), EFS (P=0.102), or cumulative incidence of relapse (P=0.51). In a multivariate analysis, OS was lower for patients with testicular disease than for those without the involvement in the early period (P=0.047) but not in the recent one (P=0.75). Both patients who received irradiation for residual testicular disease at the end of induction subsequently died of leukemia. Of the other 17 patients who did not receive irradiation, only one developed testicular relapse in combination with bone marrow relapse. In conclusion, the prognostic impact of overt testicular disease has diminished. Irradiation appears to provide no survival advantage to this patient population.

Low-dose oral etoposide-based induction regimen for children with acute lymphoblastic leukemia in first bone marrow relapse.

We evaluated the clinical response to low-dose etoposide in relapsed acute lymphoblastic leukemia (ALL). Of the 45 patients with ALL in first bone marrow relapse enrolled on the ALL R15 protocol, 44 had received epipodophyllotoxins during frontline therapy. In the first week of remission induction therapy, patients received etoposide (50 mg/m(2) per day) administered orally as a single agent once or twice daily. On Day 8, patients started to receive dexamethasone, vincristine, and L-asparaginase. Etoposide was administered until Day 22. Two courses of consolidation therapy were followed by continuation therapy or hematopoietic stem cell transplantation. After 7 days of single-agent etoposide treatment, peripheral blast cell counts (P=0.013) and percentages of bone marrow blasts (P=0.016) were significantly reduced. In all, 38 (84.4%) attained second remission. Only time to relapse was significantly associated with outcome (P=0.025): the 5-year event-free survival estimates (+/-se) were 52.0+/-9.6% for those with late relapse and 20.0+/-8.0% for those with early relapse. We conclude that low-dose etoposide administered orally has a cytoreductive effect in relapsed ALL.

Rationale and design of Total Therapy Study XV for newly diagnosed childhood acute lymphoblastic leukemia.

The current cure rate of 80% in childhood acute lymphoblastic leukemia (ALL) attests to the effectiveness of risk-directed therapy developed through well-designed clinical trials. The ongoing Total Therapy Study XV at St. Jude Children's Research Hospital was designed to further increase cure rate and to improve quality of life. The study consists of intensive systemic and intrathecal therapy but does not include cranial irradiation, irrespective of a patient's risk features. The intensity of postremission consolidation, continuation and reinduction therapy is based on the level of minimal residual disease at the end of induction, as measured by both flow cytometric detection of aberrant immunophenotypes and polymerase-chain-reaction amplification of clonal antigen-receptor gene rearrangements. Status of thiopurine methyltransferase is determined prospectively for treatment modification. Pharmacogenetic, pharmacodynamic, gene expression and proteomic profiling studies of host normal cells and leukemic cells are performed in parallel to elucidate the mechanisms of drug resistance and to advance our understanding of leukemogenesis.