Frank Alvaro

High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1–18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)–Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.

Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment‐related mortality of 8%. Leukaemia‐free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre‐HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre‐HSCT (LFS 41%, OS 64%, P < 0·0001) or post‐HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B‐other ALL had more relapses (CIR 50%, LFS 41%) than T‐ALL and the main precursor‐B subtypes including BCR‐ABL1, KMT2A (MLL), ETV6‐RUNX1 (TEL‐AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B‐other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post‐HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post‐HSCT therapy.

Outcomes of haematopoietic stem cell transplantation for inherited metabolic disorders: a report from the Australian and New Zealand Children's Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry.

We report a retrospective analysis of 53 haematopoietic stem cell transplants for inherited metabolic disorders performed at ANZCHOG transplant centres between 1992 and 2008. Indications for transplant included Hurler syndrome, ALD, and MLD. The majority of transplants utilized unrelated donor stem cells (66%) with 65% of those being unrelated cord blood. Conditioning therapy was largely myeloablative, with Bu plus another cytotoxic agent used in 89% of recipients. Primary graft failure was rare, occurring in three patients, all of whom remain long‐term survivors following the second transplant. The CI of grade II‐IV and grade III‐IV acute GVHD at day +100 was 39% and 14%, respectively. Chronic GVHD occurred in 17% of recipients. TRM was 12% at day +100 and 19% at one yr post‐transplant. OS at five yr was 78% for the cohort, 73% for patients with ALD and 83% for patients with Hurler syndrome. There was no statistically significant difference in overall survival between unrelated marrow and unrelated cord blood donor groups. The development of interstitial pneumonitis was an independent variable shown to significantly impact on TRM and OS. In summary, we report a large cohort of patients with inherited metabolic disorders with excellent survival post‐allogeneic transplant.

Allogeneic bone marrow transplant improves outcome for juvenile myelomonocytic leukaemia

Objective: To correlate clinical presentation and therapeutic outcomes in children with a diagnosis of juvenile myelomonocytic leukaemia.

Two cases of hypereosinophilia and high-risk acute lymphoblastic leukemia.

with normal karyotype. In contrast, AML secondary to chronic MPDs is usually characterized by a poor prognosis. This clinical course is even more remarkable, considering that the patient was over 67 years old when the AML diagnosis was carried out, an age associated with a poor prognostic likelihood. NPMcþ AML is unlikely to have been related to the previous hydroxyurea therapy, as cytoplasmic-mutated NPM is rarely associated with therapy-related AML. Moreover, the leukaemogenic role of hydroxyurea in chronic MPDs remains controversial. In conclusion, we report for the first time on a case of NPMcþ AML developing in a JAK2-V617Fþ PMF. Although no definitive conclusion can be drawn about the cell of origin of AML in our patient, the finding that the blast cells lacked JAK2V617F and displayed all distinctive features of NPMcþ AML suggests that the leukaemic transformation may have occurred de novo in a normal stem cell. Recognition of cases such as the one described in this study is clinically important since AMLs developing in chronic MPDs may be molecularly heterogeneous and their prognoses may vary according to the underlying genetic lesion.

Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors

The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Childrens Cancer Study Group--VETOPEC I, Baby Brain 91, and VETOPEC II--have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen.

Childhood acute lymphoblastic leukaemia presenting as jaundice

ABSTRACT An unusual presentation of acute lymphoblastic leukaemia (ALL) in a 6‐year‐old girl is reported. She presented with unilateral cervical lymphadenopathy, a mixed obstructive/cholestatic jaundice and a progressive pancytopenia. Ultrasound examination revealed an obstructed common bile duct with gross thickening of the wall of the duct and intrahepatic bile duct dilatation. The jaundice resolved with high dose intravenous (i.v.) methylprednisolone. It is postulated that this was due to infiltration of the common bile duct, given the failure to demonstrate any other cause for the bile duct pathology.

High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment

Acute lymphoblastic leukemia (ALL) remains a leading cause of cancer-related death in children and young adults. Since the 1960s, improvements in the treatment of children with ALL have led to 10-year survival rates now exceeding 85%.[1][1] Philadelphia-like (Ph-like) ALL is characterized by a gene

Treatment of children with poor risk solid tumors by further escalation of the VETOPEC regimen including very high-dose cyclophosphamide and peripheral stem cell support: An Australian and New Zealand children's hematology and oncology group study†‡

Children with solid tumors deemed to be poor risk at diagnosis and those who fail to respond or recur after chemotherapy have adverse outcomes. We sought to increase the dosage of cyclophosphamide (CPA) in the VETOPEC regimen (vincristine, etoposide, and CPA) with a view to improving the response rate and survival.

Family history-taking practices and genetic confidence in primary and tertiary care providers for childhood cancer survivors

There is growing impetus for increased genetic screening in childhood cancer survivors. Family history‐taking is a critical first step in determining survivors’ suitability. However, the family history‐taking practices of providers of pediatric oncology survivorship care and the confidence of these providers to discuss cancer risks to relatives are unknown.