Bassem I. Razzouk

PURPOSE: Effective regimens are needed for children with relapsed acute myeloid leukemia (AML). AAML1421 is a phase I/II study of CPX-351, a liposomal preparation of daunorubicin and cytarabine. AAML1421 sought to determine the recommended phase II dose (RP2D) of CPX-351 and the response rate after up to 2 cycles of therapy. PATIENTS AND METHODS: Children > 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding; those in first relapse were eligible for the efficacy phase. Dose-limiting toxicity (DLT) assessment occurred during cycle 1. Two cycles of therapy were offered (cycle 1: CPX-351; cycle 2: FLAG [fludarabine 30 mg/m²/dose on days 1-5; cytarabine 2,000 mg/m²/dose on days 1-5; and granulocyte-colony stimulating factor 5 µg/kg/dose, days 1-5 and day 15 through absolute neutrophil count > 500/µL]). Response was assessed after each cycle. RESULTS: Thirty-eight patients enrolled: 6 in the dose-finding phase and 32 in the efficacy phase. During dose finding, 1/6 patients experienced a DLT (grade 3 decrease in ejection fraction). The RP2D was 135 units/m² on days 1, 3, and 5. Toxicities of grade ≥ 3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 complete response (CR; 54%), 5 CR with partial recovery of platelet count (CRp; 14%), and 5 CR with incomplete blood count recovery (14%). Twenty-one of 25 with CR/CRp had no detectable residual disease (RD; 84%) by flow cytometry. Hematopoietic stem cell transplantation (HSCT) was used as consolidation in 29/30 responders (96.7%); 20/25 (80%) had no RD before HSCT. CONCLUSION: The RP2D of CPX-351 is 135 units/m²/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.

Li-Fraumeni patients have germline mutations in the TP53 gene resulting in increased risk of developing one or more malignant tumors. In children, osteosarcomas and rhabdomyosarcomas are the most common tumors outside the central nervous system (CNS). Primary CNS tumors in these patients include glioblastomas, choroid plexus carcinomas and medulloblastomas. We present an unusual case of a 15 year old boy who had a left tibial osteosarcoma resected 4 years ago, then treated with chemotherapy, without any recurrence or metastatic disease. His two younger male siblings both have the same mutation, and one sibling has already developed an osteosarcoma. Interestingly, the mutation is present in the mother, who has no neoplasm to date. Annual radiological studies of the CNS were normal until February 2017; but it was 13 months until the next scan, which revealed a large tumor in the lateral cerebellum. The patient was asymptomatic and a surgical resection was performed. The operative report described a well-circumscribed mass in the lateral cerebellum with little parenchymal involvement bringing up the possibility of metastatic disease. Neuropathological evaluation showed a densely cellular tumor with large and markedly pleomorphic nuclei as well as numerous mitoses. No cerebellar tissue was seen. Immunohistochemical (IHC) studies were complicated by the widely overlapping antigenicity of osteosarcomas and medulloblastomas. Next Generation Sequencing found abnormalities in SMO, DDX3X, TP53, and MYCN amplification, which are associated with SHH-activated medulloblastomas. Both GAB1 IHC and FISH studies for YAP1 were positive. In summary we report a rare case of an SHH-activated medulloblastoma, large cell/anaplastic type in a 15 year-old boy with a germline TP53 mutation and history of resected osteosarcoma.

BACKGROUND: The discovery of new, effective non–anthracycline‐based reinduction regimens for children with recurrent acute myeloid leukemia (AML) is critical. In this phase 1/2 study, the tolerability and overall response rate of clofarabine in combination with cytarabine was investigated in children with recurrent/refractory AML.METHODS: AAML0523 enrolled 49 children with AML in first recurrence or who were refractory to induction therapy. The study consisted of a dose‐finding phase (9 patients) and an efficacy phase (40 patients). Two children received clofarabine at a dose of 40 mg/m²/day and 47 children at a dose of 52 mg/m²/day.RESULTS: Toxicities typical for intensive chemotherapy regimens were observed at all doses of clofarabine. The recommended pediatric phase 2 dose of clofarabine in combination with cytarabine was 52 mg/m²/day for 5 days. Of 48 evaluable patients, the overall response rate (complete remission plus complete remission with partial platelet recovery) was 48%. Four patients met conventional criteria for complete remission with incomplete count recovery. Twenty‐one of 23 responders subsequently underwent hematopoietic stem cell transplantation. The overall survival rate at 3 years was 46% for responders compared with 16% for nonresponders (P < .001). Patients found to have no minimal residual disease at the end of the first cycle by flow cytometric analysis had superior overall survival after 1 year (100% vs 38%; P = .01).CONCLUSIONS: The combination of clofarabine and cytarabine yielded an acceptable response rate without excess toxicity in children with recurrent AML. The nearly 50% survival rate reported in responders is highly encouraging in these high‐risk patients and suggests that this combination is an effective bridge to hematopoietic stem cell transplantation. Cancer 2014;120:2482–2489. © 2014 American Cancer Society.

The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, PThis study was registered with ISRCTN code: 94206677.

Purpose: In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group. Patients and Methods: Patients with relapsed or primary refractory non–French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years). Results: The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups. Conclusion: DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.

Background: The discovery of effective re‐induction regimens for children with more than one relapse of acute lymphoblastic leukemia (ALL) remains elusive. The novel nucleoside analog clofarabine exhibits modest single agent efficacy in relapsed ALL, though optimal combinations of this agent with other active chemotherapy drugs have not yet been defined. Herein we report the response rates of relapsed ALL patients treated on Children's Oncology Group study AAML0523, a Phase I/II study of the combination of clofarabine and cytarabine.Procedure: AAML0523 enrolled 21 children with ALL in second or third relapse, or those refractory to re‐induction therapy. The study consisted of two phases: a dose finding phase and an efficacy phase. The dose finding portion consisted of a single dose escalation/de‐escalation of clofarabine for 5 days in combination with a fixed dose of cytarabine (1 g/m²/day for 5 days). Eight patients received clofarabine at 40 mg/m²/day and 13 patients at 52 mg/m²/day.Results: Toxicities observed at all doses of clofarabine were typical of intensive chemotherapy regimens for leukemia, with infection being the most common. We did not observe significant hepatotoxicity as reported in other clofarabine combination regimens. The recommended pediatric Phase II dose of clofarabine in combination with cytarabine for the efficacy portion of AAML0523 was 52 mg/m². Of 21 patients with ALL, 3 (14%) achieved a complete response (CR). Based on the two‐stage design definition of first‐stage inactivity, the therapy was deemed ineffective.Conclusion: The combination of clofarabine and cytarabine in relapsed/refractory childhood ALL does not warrant further clinical investigation. Pediatr Blood Cancer 2013; 60: 1141–1147.

Despite recent studies failing to demonstrate the value of routine chest radiography (CXR) in the initial evaluation of the febrile neutropenic patient with cancer, this screening test is advocated by some experts. We evaluated the benefits of CXR for early diagnosis of pulmonary infection at St. Jude Children’s Research Hospital (SJCRH) with emphasis on early recognition of mould infections.

Aim: To identify gene-expression signatures predicting cytarabine response by an integrative analysis of multiple clinical and pharmacological end points in acute myeloid leukemia (AML) patients. Materials & methods: We performed an integrated analysis to associate the gene expression of diagnostic bone marrow blasts from acute myeloid leukemia (AML) patients treated in the discovery set (AML97; n = 42) and in the independent validation set (AML02; n = 46) with multiple clinical and pharmacological end points. Based on prior biological knowledge, we defined a gene to show a therapeutically beneficial (detrimental) pattern of association of its expression positively (negatively) correlated with favorable phenotypes such as intracellular cytarabine 5´-triphosphate levels, morphological response and event-free survival, and negatively (positively) correlated with unfavorable end points such as post-cytarabine DNA synthesis levels, minimal residual disease and cytarabine LC50. Results: We identified 240 probe...

BACKGROUND: Granulocyte–colony‐stimulating factor (G‐CSF) is effective in accelerating neutrophil recovery after intensive chemotherapy for acute myeloid leukemia (AML). However, the optimal G‐CSF dosage for patients with AML has not been determined. To the authors' knowledge, G‐CSF dosages have not been compared in a randomized AML study.METHODS: Patients who were enrolled on the St. Jude AML97 protocol and remained on study after window therapy were eligible to participate. The effect of the dosage of G‐CSF given after induction chemotherapy Courses 1 and 2 was analyzed in 46 patients who were assigned randomly in a double‐blinded manner to receive either 5 μg/kg daily or 10 μg/kg daily of G‐CSF. The number of days of G‐CSF treatment, neutropenia (an absolute neutrophil count 9/L), and hospitalization; the number of episodes of febrile neutropenia, grade 2 through 4 infection, and antimicrobial therapy; transfusion requirements; the cost of supportive care; and survival were compared between the 2 study arms.RESULTS: No statistically significant differences were observed between the 2 arms in any of the endpoints measured.CONCLUSIONS: The higher G‐CSF dosage (10 μg/kg daily) offered no greater benefit than the lower dosage (5 μg/kg daily) in patients who were receiving intensive chemotherapy for AML. Cancer 2011. © 2010 American Cancer Society.

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.