Associate Professor Rishi S. Kotecha

Increased Body Mass Index during Therapy for Childhood Acute Lymphoblastic Leukemia: A Significant and Underestimated Complication

We undertook a retrospective review of children diagnosed with acute lymphoblastic leukemia (ALL) and treated with modern COG protocols to determine...

Rare childhood cancers—an increasing entity requiring the need for global consensus and collaboration

Rare childhood cancers have not benefited to the same extent from the gains that have been made for their frequently occurring counterparts.

Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy.

Lessons learnt from influenza vaccination in immunocompromised children undergoing treatment for cancer

Influenza infection contributes substantially to global morbidity and mortality, with children undergoing treatment for cancer among the most vulnerable due to immunosuppression associated with disease and treatment. However, influenza remains one of the most common vaccine-preventable diseases.

Survival Outcomes of Children with Relapsed or Refractory Myeloid Leukemia Associated with Down syndrome

Children with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population.

Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy

Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required.

Characterization of mesenchymal stem cells in pre-B acute lymphoblastic leukemia

Components of the bone marrow microenvironment (BMM) have been shown to mediate the way in which leukemia develops, progresses and responds to treatment. Increasing evidence shows that leukemic cells hijack the BMM, altering its functioning and establishing leukemia-supportive interactions with stromal and immune cells.

Pre-Clinical Evaluation of the Hypomethylating Agent Decitabine for the Treatment of T-Cell Lymphoblastic Lymphoma

T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10-20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing.

The evolution of clinical trials for infant acute lymphoblastic leukemia

Despite initial improvements in survival of infants with ALL since establishment of the first pediatric cooperative group ALL trials, the poor outcome has...

Hepatic sinusoidal obstruction syndrome during chemotherapy for childhood medulloblastoma: Report of a case and review of the literature

Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group

Medulloblastoma is curable in approximately 70 % of patients. Over the past decade, progress in improving survival using conventional therapies has stalled...

Morbidity in survivors of child and adolescent meningioma

Given the paucity of data concerning long-term outcome, the authors undertook a meta-analysis to analyze morbidity in survivors of this disease.

Childhood craniopharyngioma: 20-year institutional experience in Western Australia

Although neurocognitive, psychological and behavioural problems were noted for some patients during medical review, only 20% of patients were formally assessed.

Efficacy of acute myeloid leukemia therapy without stem-cell transplantation in a child with blastic plasmacytoid dendritic cell neoplasm

Our case demonstrates that AML therapy, without HSCT, can be sufficient to treat this rare disease in children.

Molecular characterization of identical, novel MLL-EPS15 translocation and individual genomic

Acute Lymphoblastic Leukemia (ALL) occurring in the first year of life is rare.

Chemotherapy increases amenability of surgical resection in congenital glioblastoma

Brain tumors presenting in infancy, especially during the first 6 months of life.

Pre-natal, clonal origin of t(1;11)(p32;q23) acute lymphoblastic leukemia in monozygotic twins

Investigation of this rare mixed lineage leukemia cytogenetic abnormality aims to provide further evidence of the genetic changes that underpin this leukemia.

Meningiomas in children and adolescents: a meta-analysis of individual patient data

The epidemiological, prognostic, and therapeutic features of child and adolescent meningioma are poorly defined...

Pediatric meningioma: Current approaches and future direction

With improvement in leukemia therapy, central nervous system (CNS) tumors are the leading cause of cancer mortality in children and the most expensive...

Updates in infant acute lymphoblastic leukemia and the potential for targeted therapy

Outcomes for infants diagnosed under 1 year of age with KMT2A-rearranged acute lymphoblastic leukemia (ALL) have remained stagnant over the past 20 years. Successive treatment protocols have previously focused on intensification of conventional chemotherapy, but increased treatment-related toxicity and chemoresistance have led to a plateau in survival.

Cardio-Oncology Recommendations for Pediatric Oncology Patients: An Australian and New Zealand Delphi consensus

Cardio-oncology is a new multidisciplinary area of expertise that seeks to pre-emptively and proactively address cardiac complications that emerge during and following cancer therapy. Modern therapies including molecular targeted therapy and immunotherapy have broadened the agents that can cause cardiac sequelae, often with complications arising within days to weeks of therapy.

Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia

Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study.

COVID-19 vaccination in children and adolescents aged 5 years and older undergoing treatment for cancer and non-malignant haematological conditions: Australian and New Zealand Children’s Haematology/Oncology Group consensus statement

The Australian Technical Advisory Group on Immunisation and New Zealand Ministry of Health recommend all children aged ≥ 5 years receive either of the two mRNA COVID-19 vaccines: Comirnaty (Pfizer), available in both Australia and New Zealand, or Spikevax (Moderna), available in Australia only. Both vaccines are efficacious and safe in the general population, including children. Children and adolescents undergoing treatment for cancer and immunosuppressive therapy for non-malignant haematological conditions are particularly vulnerable, with an increased risk of severe or fatal COVID-19.

Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study.

Acute Lymphoblastic Leukemia in Infants: A Distinctive, High-Risk Subtype of Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) in infants younger than 1 year of age is an aggressive, high-risk subtype of childhood ALL. Infant ALL with KMT2A-r is characteristically poorly responsive to chemotherapy and hematopoietic stem cell transplantation. New strategies, such as molecularly targeted therapies and immunotherapies, are in development and show promise in preclinical models and early phase studies.

Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia

Patients whose leukemias harbor a rearrangement of the Mixed Lineage Leukemia (MLL/KMT2A) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics.

Prospective longitudinal evaluation of treatment-related toxicity and health-related quality of life during the first year of treatment for pediatric acute lymphoblastic leukemia

Pediatric acute lymphoblastic leukemia (ALL) therapy is accompanied by treatment-related toxicities (TRTs) and impaired quality of life. In Australia and New Zealand, children with ALL are treated with either Children's Oncology Group (COG) or international Berlin-Frankfurt-Munster (iBFM) Study Group-based therapy.

Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia.

Successful treatment of a child with acute monoblastic leukaemia who relapsed with T-cell acute lymphoblastic leukaemia: A rare lineage switch

Blinatumomab as bridging therapy in paediatric B-cell acute lymphoblastic leukaemia complicated by invasive fungal disease

Invasive fungal disease (IFD) remains a challenging complication of treatment for paediatric acute leukaemia. Consensus fungal treatment guidelines recommend withholding chemotherapy to facilitate immune recovery in this setting, yet prolonged delays in leukaemia therapy increase risk of relapse.

Acute Leukaemia of Ambiguous Lineage Presenting as a Focal Bone Lesion: a Case Report

Acute leukaemia is the most common childhood malignancy. Almost all cases are classified as acute lymphoblastic leukaemia or acute myeloid leukaemia. Acute leukaemia of ambiguous lineage (ALAL) is a rare form of acute leukaemia that cannot be classified by a single lineage. Like other acute leukaemias, ALAL typically presents with nonspecific symptoms such as fatigue, fever, or bleeding.

The Bone Marrow Microenvironment in B-Cell Development and Malignancy

B lymphopoiesis is characterized by progressive loss of multipotent potential in hematopoi-etic stem cells, followed by commitment to differentiate into B cells, which mediate the humoral response of the adaptive immune system.

Antifungal use in children with acute leukaemia: state of current evidence and directions for future research

Invasive fungal disease (IFD) remains a common and serious complication in children treated for leukaemia. Antifungal prescription in children with leukaemia presents unique challenges, particularly due to variation in IFD risk between and within leukaemia treatment protocols, drug toxicities and interactions between antifungals and chemotherapeutic agents.

The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression

Rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome.

Pediatric pineoblastoma: A pooled outcome study of North American and Australian therapeutic data

Pineoblastoma is a rare brain tumor usually diagnosed in children. Given its rarity, no pineoblastoma-specific trials have been conducted. Studies have included pineoblastoma accruing for other embryonal tumors over the past 30 years.

RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism.

Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol

Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide).

Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol

Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide).

The bone marrow microenvironment of pre-B acute lymphoblastic leukemia at single-cell resolution

The bone marrow microenvironment plays a key role in leukemia progression, but its molecular complexity in pre-B cell acute lymphoblastic leukemia (B-ALL), the most common cancer in children, remains poorly understood. To gain further insight, we used single-cell RNA sequencing to characterize the kinetics of the murine BMM during B-ALL progression.

Defining the fetal origin of MLL-AF4 infant leukemia highlights specific fatty acid requirements

Infant MLL-AF4-driven acute lymphoblastic leukemia (ALL) is a devastating disease with dismal prognosis. A lack of understanding of the unique biology of this disease, particularly its prenatal origin, has hindered improvement of survival. We perform multiple RNA sequencing experiments on fetal, neonatal, and adult hematopoietic stem and progenitor cells from human and mouse.

Viridans Group Streptococci in Pediatric Leukemia and Stem Cell Transplant: Review of a Risk-stratified Guideline for Empiric Vancomycin in Febrile Neutropenia

Viridans group streptococci (VGS) are an important cause of sepsis in immunosuppressed children. We reviewed the effectiveness of risk-stratified addition of vancomycin to empiric febrile neutropenia therapy among 107 children with leukemia or undergoing an allogeneic transplant.

Invasive fungal disease in children with acute myeloid leukaemia: An Australian multicentre 10-year review

Invasive fungal disease (IFD) is a common and important complication in children with acute myeloid leukaemia (AML). We describe the epidemiology of IFD in a large multicentre cohort of children with AML.

Therapeutic targeting of the leukaemia microenvironment

In recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia. However, high-risk patients continue to have inferior outcomes, where chemoresistance and relapse are common due to the survival mechanisms utilised by leukaemic cells.

Case Report: Long-Term Survival of a Pediatric Patient With an Intra-Abdominal Undifferentiated Carcinoma of Unknown Primary

This report provides detailed characterization of carcinoma of unknown primary (CUP) in a young child and in the absence of defined therapeutic guidelines for pediatric CUP, the successful treatment strategy described should be considered for similar cases.

Outcomes for Australian children with relapsed/refractory acute lymphoblastic leukaemia treated with blinatumomab

We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B-cell acute lymphoblastic leukaemia (B-ALL) and high-risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2-year progression-free survival (PFS) of 39% and 2-year overall survival of 63%. In total, 83% (n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab (n = 12) or following additional salvage therapy (n = 8).

Are outcomes for childhood leukaemia in Australia influenced by geographical remoteness and Indigenous race?

Presenting features, biology and outcome for childhood leukaemia are known to vary by ethnic origin, geographic location and socioeconomic group. This study aimed to compare presentation patterns, follow-up and clinical outcomes in Indigenous and non-Indigenous children with acute leukaemia in Australia, and to assess the impact of remoteness and area-based socioeconomic disadvantage on outcome.

Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin

The prognosis for high-risk childhood acute leukaemias remains dismal and established treatment protocols often cause long-term side effects in survivors. This study aims to identify more effective and safer therapeutics for these patients.

Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia

Infants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with KMT2A-rearranged ALL.

Malignant Melanoma in Children and Adolescents Treated in Pediatric Oncology Centers: An Australian and New Zealand Children’s Oncology Group (ANZCHOG) Study

Unlike adults, malignant melanoma in children and adolescents is rare. In adult melanoma, significant progress in understanding tumor biology and new treatments, including targeted therapies and immunotherapy have markedly improved overall survival. In sharp contrast, there is a paucity of data on the biology and clinical behavior of pediatric melanoma. We report a national case series of all pediatric and adolescent malignant melanoma presenting to ANZCHOG Childhood Cancer Centers in Australia and New Zealand.

Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia

Infants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with KMT2A-rearranged ALL.

Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia

Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding.

The bone marrow microenvironment of pre-B acute lymphoblastic leukemia at single-cell resolution

The bone marrow microenvironment (BMM) plays a key role in leukemia progression, but its molecular complexity in pre-B cell acute lymphoblastic leukemia (B-ALL), the most common cancer in children, remains poorly understood. To gain further insight, we used single-cell RNA sequencing to characterize the kinetics of the murine BMM during B-ALL progression.

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown.

Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL).

Challenges posed by COVID-19 to children with cancer

Development of standardised guidance by national and regional authorities for reducing the risk of SARS-CoV-2 transmission to children with cancer

Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma

IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that T-ALL and T-LBL patients could benefit from PIM inhibition

Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for ALL and lymphoma in caucasian children

The largest GWAS meta-analysis conducted to date associating SNPs to venous thromboembolism in children and adolescents treated on childhood ALL protocols

Immunogenicity of the inactivated influenza vaccine in children who have undergone allogeneic haematopoietic stem cell transplant

This study provides evidence to support annual inactivated influenza vaccine administration to children following allogeneic haematopoietic stem cell transplant

Optimized peripheral blood progenitor cell mobilization for autologous hematopoietic cell transplantation in children with high-risk and refractory malignancies

Our approach to hematopoietic progenitor cells mobilization resulted in highly effective HPC harvest in children and adolescents with high-risk cancers

Targeting the bone marrow microenvironment: a novel therapeutic strategy for pre-B acute lymphoblastic leukemia

Our findings shed light on the mechanisms of leukemia-induced bone loss

Vaccine-preventable disease following allogeneic haematopoietic stem cell transplant in Western Australia

There is a high incidence of vaccine-preventable morbidity post-allogeneic haematopoietic stem cell transplantation in West Australian children

Primary central nervous system lymphoma: Initial features, outcome, and late effects in 75 children and adolescents

Children with Primary Central Nervous System Lymphoma and no immunodeficiency have a good outcome

A Novel Missense Mutation Affecting the N-terminal Domain of SAP Protein in X-linked Lymphoproliferative Disease

We have revealed a novel SH2D1A gene mutation in a patient with XLP resulting in fulminant refractory EBV-driven HLH, which is a recognized severe complication

Invasive fungal infections in children with acute lymphoblastic leukaemia: Results from four Australian centres, 2003-2013

Invasive fungal infections are more common in children with high-risk acute lymphoblastic leukaemia and in relapsed disease

Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study

Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant acute lymphoblastic leukemia

Romidepsin enhances the efficacy of cytarabine in vivo, revealing HDAC inhibition as a therapeutic strategy for KMT2A-rearranged acute lymphoblastic leukemia

In this study, we investigate the in vivo synergy between romidepsin and cytarabine

Risk factors for symptomatic venous thromboembolism during therapy for childhood acute lymphoblastic leukemia

We found two known risk factors in a large cohort of children treated for ALL and identified other factors associated with venous thromboembolism

New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment

We provide evidence that targeting leukemia-induced bone loss is a therapeutic strategy for pre-B ALL

Immunogenicity and safety of single-dose, 13-valent pneumococcal conjugate vaccine in pediatric and adolescent oncology patients

All children who are receiving therapy for cancer should receive a single dose of PCV13 as soon as possible after diagnosis, regardless of prior PCV exposure.

Regular exercise improves the well-being of parents of children with cancer

Mental health benefits of a pedometer-based exercise intervention for parents of children with cancer were identified.

Molecular-genetic profiling and high-throughput in vitro drug screening in NUT midline carcinoma-An aggressive and fatal disease

Our data emphasize the heterogeneity of NMC and highlights genetic aberrations that could be explored to improve therapeutic strategies.

Immunogenicity and clinical effectiveness of the trivalent inactivated influenza vaccine in immunocompromised children undergoing treatment for cancer

The trivalent inactivated influenza vaccine is safe, immunogenic, provides clinical protection and should be administered annually to immunosuppressed children receiving treatment for cancer

Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin

Present a valuable resource for drug discovery and have identified ROM as a promising therapeutic for MLL-rearranged iALL

Successful Treatment of Congenital Erythroleukemia With Low-Dose Cytosine Arabinoside

We report a term male with congenital acute erythroleukemia who achieved sustained remission with low-dose cytosine arabinoside alone