Bassem I. Razzouk

Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial

BACKGROUND We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment. METHODS From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m(2), n=113) or low-dose (2 g/m(2), n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084. FINDINGS Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34%vs 42%, p=0.17). The 6-month cumulative incidence of grade 3 or higher infection was 79.3% (SE 4.0) for patients in the high-dose group and 75.5% (4.2) for the low-dose group. 3-year event-free survival and overall survival were 63.0% (SE 4.1) and 71.1% (3.8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0.1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2.41, 95% CI 1.36-4.26; p=0.003) and overall survival (2.11, 1.09-4.11; p=0.028). INTERPRETATION Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML. FUNDING National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC).

Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia

PURPOSE To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). RESULTS The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade > or = 3 were febrile neutropenia, anorexia, hypotension, and nausea. CONCLUSION Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital

We present the long-term results of three consecutive clinical trials (total therapy studies 11, 12 and 13a) conducted for children with newly diagnosed acute lymphoblastic leukemia (all) between 1984 and 1994. in study 11 (1984–1988), the overall event-free survival rates (±1 s.e.) were 71.8 ± 2.4% and 69.3 ± 2.4%, and the cumulative risks of isolated central nervous system (cns) relapse 5.6 ± 1.2% and 5.9 ± 1.3%, at 5 and 10 years, respectively. in study 12 (1988–1991), event-free survival rates were 67.6 ± 3.4% and 61.5± 9.0%, and isolated cns relapse rates were 10.4 ± 2.3% and 10.4 ± 2.3%, respectively. early intensive intrathecal therapy in study 13a (1991–1994) has yielded a very low 5-year isolated cns relapse rate of 1.2 ± 0.9%, boosting the 5-year event-free survival rate to 76.9 ± 3.3%. factors consistently associated with an adverse prognosis included male sex, infant or adolescent age group, leukocyte count >100 × 109/l, nonhyperdiploidy karyotype and poor early response to treatment. Risk classification based on age and leukocyte count had prognostic significance in B-lineage but not T-lineage ALL. Early therapeutic interventions or modifications for patients with specific genetic abnormalities or persistent minimal residual leukemia may further improve long-term results.

Late Effects of Treatment in Survivors of Childhood Acute Myeloid Leukemia

PURPOSE To investigate the incidence of and risk factors for late sequelae of treatment in patients who survived for more than 10 years after the diagnosis of childhood acute myeloid leukemia (AML). PATIENTS AND METHODS Of 77 survivors (median follow-up duration, 16. 7 years), 44 (group A) had received chemotherapy, 18 (group B) had received chemotherapy and cranial irradiation, and 15 (group C) had received chemotherapy, total-body irradiation, and allogeneic bone marrow transplantation. Late complications, tobacco use, and health insurance status were assessed. RESULTS Growth abnormalities were found in 51% of survivors, neurocognitive abnormalities in 30%, transfusion-acquired hepatitis in 28%, endocrine abnormalities in 16%, cataracts in 12%, and cardiac abnormalities in 8%. Younger age at the time of diagnosis or initiation of radiation therapy, higher dose of radiation, and treatment in groups B and C were risk factors for the development of academic difficulties and greater decrease in height Z: score. In addition, treatment in group C was a risk factor for a greater decrease in weight Z: score and the development of growth-hormone deficiency, hypothyroidism, hypogonadism, infertility, and cataracts. The estimated cumulative risk of a second malignancy at 20 years after diagnosis was 1.8% (95% confidence interval, 0.3% to 11.8%). Twenty-two patients (29%) were smokers, and 11 (14%) had no medical insurance at the time of last follow-up. CONCLUSION Late sequelae are common in long-term survivors of childhood AML. Our findings should be useful in defining areas for surveillance of and intervention for late sequelae and in assessing the risk of individual late effects on the basis of age and history of treatment.

Favorable Impact of the t(9;11) in Childhood Acute Myeloid Leukemia

PURPOSE To determine the impact of MLL rearrangements on the outcome of children with acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed the clinical and biologic features of 298 infants and children with primary AML treated on four consecutive institutional clinical trials. The Kaplan-Meier method was used in survival analysis and the Cox proportional-hazards model was used to analyze the effect of potential prognostic factors on event-free survival (+/- 1 SE). RESULTS Molecular studies of 152 cases detected 42 with MLL rearrangements. The karyotypes of these 42 revealed the t(9;11) (15 cases), abnormalities of chromosomes 10 and 11 (nine cases), the t(11;19) (four cases), other abnormalities of 11q23 (seven cases), and miscellaneous rearrangements (seven cases). Among these 42 patients, the 15 whose leukemic cells carried the t(9;11) had a better outcome (66% +/- 15%) than the other 27 (25.9% +/- 11.2%; P =.004). Cases with the t(9;11) were also characterized by M5 AML morphology (21 of 23 cases). Of the 63 patients with M5 AML, the 21 whose leukemic cells demonstrated the t(9;11) had a better outcome (71.1% +/- 11%) than the other 42 (25.8% +/- 7.9%; P =.0004). The only independent factors indicating a favorable prognosis were presenting leukocyte count less than 50 x 10(9)/L (relative risk of relapse, 0.73; 95% confidence interval, 0.55 to 0.97; P =.03) and the t(9;11) (relative risk of relapse, 0.32; 95% confidence interval, 0.16 to 0.64; P =.002). CONCLUSION We conclude that the t(9;11) is the most favorable genetic factor for patients with AML treated at our institution.

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse.

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD ⩾0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2±12.3% for the 19 MRD-positive patients and 27.9±12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1±17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5±14.4% (n=12) and 25.0±13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.

Clinical significance of residual disease during treatment in childhood acute myeloid leukaemia

Summary. In children with acute myeloid leukaemia (AML), morphological and karyotypic studies cannot precisely assess response to treatment, and less than one‐third of patients have genetic markers for molecular studies of residual disease. We determined the usefulness of a four‐colour flow cytometric strategy developed in our laboratory to study residual disease. We first compared the immunophenotypes of AML cells obtained from 54 children at diagnosis with those of cells from 59 normal or regenerating bone marrow samples. Forty‐six of the 54 AML cases (85·2%) had immunophenotypes that allowed detection of 0·1–0·01% residual leukaemic cells. Of 230 bone marrow samples obtained from those 46 patients during and off treatment, 61 (26·5%) had ≥ 0·1% AML cells by flow cytometry. We found that core binding factor‐associated AML had a significantly better early treatment response. Mean (± standard error) 2‐year survival estimate was 33·1 ± 19·1% for patients with ≥ 0·1% AML cells by flow cytometry after induction therapy, but 72·1 ± 11·5% for those with < 0·1% AML cells (P = 0·022); overt recurrence of AML within the subsequent 6 months was significantly more likely in the former group. The assay described here holds promise for guiding the choice of post‐remission treatment options in children with AML.

Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital

To characterize the biology and optimal therapy of acute mixed-lineage leukemia in children, we reviewed the pathologic and clinical features, including response to therapy, of 35 patients with mixed-lineage leukemia. The majority of cases (91%) had blasts cells that simultaneously expressed either T-lineage plus myeloid markers (T/myeloid, n = 20) or B-lineage plus myeloid markers (B/myeloid, n = 12). Overall survival rates for the B/myeloid and T/myeloid subgroups were not significantly different from each other or from the rate for acute myeloid leukemia (AML) but were inferior to the outcome in children with acute lymphoblastic leukemia (ALL). Patients who failed to achieve complete remission with AML-directed therapy could often be induced with a regimen of prednisone, vincristine, and L-asparaginase. Analysis of gene-expression patterns identified a subset of biphenotypic leukemias that did not cluster with T-cell ALL, B-progenitor ALL, or AML. We propose that treatment for biphenotypic leukemia begin with one course of AML-type induction therapy, with a provision for a switch to lymphoid-type induction therapy with a glucocorticoid, vincristine, and L-asparaginase if the patient responds poorly. We also suggest that hematopoietic stem cell transplantation is often not required for cure of these patients.

Nocturnal Awakenings, Sleep Environment Interruptions, and Fatigue in Hospitalized Children With Cancer

PURPOSE/OBJECTIVES To describe nocturnal awakenings and sleep environment interruptions experienced by children and adolescents hospitalized for two to four days to receive chemotherapy and to assess the relationships among nocturnal awakenings, sleep environment interruptions, sleep duration, and fatigue. DESIGN Longitudinal, descriptive design. SETTING St. Jude Childrens Research Hospital and Texas Childrens Cancer Center. SAMPLE 25 patients with solid tumors and 4 with acute myeloid leukemia. METHODS Actigraphy, fatigue instruments, sleep diary, room entry and exit checklists, and blood samples. MAIN RESEARCH VARIABLES Nocturnal awakenings, sleep environment interruptions, sleep duration, and fatigue. FINDINGS The number of nocturnal awakenings per night as measured by actigraphy ranged from 0-40. The number of room entries and exits by a staff member or parent was 3-22 times per eight-hour night shift. The number of nocturnal awakenings was related to fatigue by patient report; patients who experienced 20 or more awakenings had significantly higher fatigue scores than those with fewer awakenings. Nocturnal awakenings also were significantly associated with sleep duration by patient and parent report. CONCLUSIONS Hospitalized pediatric patients with cancer who experience more nocturnal awakenings are more fatigued and sleep longer. IMPLICATIONS FOR NURSING Nurses may be able to control some of the factors that contribute to nocturnal awakenings and sleep environment interruptions that affect fatigue and sleep duration in hospitalized pediatric patients with cancer.

Bacillus cereus Bacteremia and Meningitis in Immunocompromised Children

Two cases of Bacillus cereus meningitis in immunocompromised children at our hospital within a 2-month period prompted us to review B. cereus--related invasive disease. We identified 12 patients with B. cereus isolated in blood cultures from September 1988 through August 2000 at our institution. Three of these patients also had B. cereus isolated from CSF specimens; 1 additional patient had possible CNS involvement (33%, group A), whereas 8 patients had no evidence of CNS involvement (67%, group B). Patients in group A were more likely to have neutropenia at the onset of sepsis and were more likely to have an unfavorable outcome. They were also more likely to have received intrathecal chemotherapy in the week before the onset of their illness. Two patients from group A died. One survived with severe sequelae. The fourth patient had mild sequelae at follow-up. No sequelae or deaths occurred among patients in group B. In patients with unfavorable outcomes, the interval from the time of recognition of illness to irreversible damage or death was short, which demonstrates a need for increased awareness, early diagnosis, and more-effective therapy, particularly that which addresses B. cereus toxins.