Pre-Emptive Pharmacogenomic Testing in Paeds Oncology:

Improving Efficacy & Minimising ADR

Rizal Husaini bin Razali, RPh., PhD

Hospital Tunku Azizah,

Kuala Lumpur

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Introduction to Paediatric Oncology

Pre-emptive pharmacogenomic in Paeds Oncology

LCH high risk – Targeted therapy of Dabrafenib

Relapse Pre B ALL – Latest treatment CAR T therapy

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• In Malaysia, the Malaysian National Cancer Registry (2012 - 2016) - 4303 cases of childhood cancer in children between 0 – 19.

• Cancer is rare in children.

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• In Malaysia, the incidence of pediatric cancer is about 77.4 per million children aged less than 15 years.

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• Top 5 cancer in children : leukemia, lymphoma, GCT, CNS & bone ca.

• Leukemia - 30% of all childhood cancers in the country, making it the most common type.

Introduction to Paeds Onco

Introduction to Paediatric Oncology

Pre-emptive pharmacogenomic in Paeds Oncology

LCH high risk – Targeted therapy of Dabrafenib

Relapse Pre B ALL – Latest treatment CAR T therapy

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• Preemptive pharmacogenomic testing - individualized medical treatment with a ↓ in chemotherapy-induced toxicities.

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• Only a few guidelines regarding genetic variation and pediatric chemotherapeutic treatment are available (Scott et al 2020).

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• In clinical practice, dose adjustments are performed for purine treatment, based on the activity of the enzymes thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked nucleoside motif 15 (NUDT15)(Relling et al 2018).

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• Pre-emptive PGx involves testing for multiple genetic variants that could influence commonly used medications.

Introduction

• Scott, Erika N., Hasbullah, Jafar S., Carleton, Bruce C., Ross, Colin J.D., Prevention of adverse drug effects: a pharmacogenomic approach. Current Opinion in Pediatrics 32(5):p 646-653, October 2020.
• Relling, M.V.; Schwab, M.; Whirl-Carrillo, M.; Suarez-Kurtz, G.; Pui, C.H.; Stein, C.M.; Moyer, A.M.; Evans, W.E.; Klein, T.E.; Antillon-Klussmann, F.G.; et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin. Pharmacol. Ther. 2019, 105, 1095–1105

1. Classic example - thiopurine methyltransferase (TPMT) gene- encodes the TPMT enzyme involved in inactivating thiopurines.
2. 6MP often prescribed for pts with ALL.
3. inherits 2 inactive TPMT alleles has deficient TPMT activity → accumulation of high concentrations of the active thioguanine nucleotide metabolite → high risk for life-threatening myelosuppression
4. TPMT genotype before a thiopurine is prescribed : dose reduction is warranted to minimize the risk of myelosuppression and fatal.

TPMT*3C - is the most common variant allele in East Asian and African American populations (frequency approximately 2%). TPMT*3C (Tyr240Cys; rs1142345)

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TPMT*3A - the most common variant allele associated with low TPMT activity in Caucasians (frequency approximately 5%).

TPMT*3B - occurs rarely and contains only the exon 7 SNP

e.g The mutant allele TPMT*2 is defined by a single nucleotide transversion (G238C) in the open reading frame, leading to an amino acid substitution at codon 80 (Ala>Pro)

TPMT Genetic Polymorphism

There have been 138 fatal reports for AZA, 7 for 6-MP, and up to 2008, 3 fatal reports for 6-TG.

MHRA Drug Analysis Print, Azathioprine, Mercaptopurine, thioguanine. (accessed 11 Aug 2009)

Precision medicine Immunotherapy in Children with Acute Lymphoblastic Leukemia

• Mortality in relapsed/refractory (R/R) B-cell ALL (B-ALL) is still high.
• Blinatumomab, a bispecific antibody that binds CD19 + on B cells and CD3 + on T cells.
• Cytokine release syndrome (CRS) and neurological adverse events remain higher in pts treated with Blina.
• Occurred in 15% of pts with R/R ALL and in 7% of pts with MRD-ve ALL

eg. hypotension, ↑AST, ↑ total bilirubin and disseminated intravascular

coagulation (DIC)

• neurological adverse events; eg. headache and tremor

For pediatric patients, premedicate with 5 mg/m² of dexamethasone to a maximum dose of 20 mg prior to the first dose of BLINCYTO^® in the first cycle

Indication:

1st or 2nd CR with minimal residual disease (MRD)

greater than or equal to 0.1% in pediatric ALL patients.

5-year relative survival in patients with ALL by age group, US, 2013–2019

Results from SEER 22 in patients with ALL from 2013–2019

Introduction to Paediatric Oncology

Pre-emptive pharmacogenomic in Paeds Oncology

LCH high risk – Targeted therapy of Dabrafenib

Relapse Pre B ALL – Latest treatment CAR T therapy

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5

• a cancer that starts in cells called neuroblasts.
• most often starts in the neuroblasts in the adrenal glands, located on top of each kidney.
• Approximately one-half of these cases are classified as high risk or Stg IV.

Neuroblastoma in Children

Combination of therapies:

surgery, chemotherapy, radiation therapy, and potentially immunotherapy and targeted therapies.

OLFACTORY Neuroblastoma

• a rare cancer - originates in the olfactory neuroepithelium of the nasal cavity

• specifically - upper part of the nasal cavity, and responsible for the sense of smell.

• 5-year survival rates ranging from 44% - 91%, depending on factors like stage, grade, and treatment.

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Complement-dependent cytotoxicity (CDC)

1. Dinutuximab - monoclonal antibody binds to GD2.
2. GD2 is expressed on the surface of neuroblastoma cells.
3. Binding of dinutuximab to GD2 initiates an immune response that can kill the cells.
1. Cost: RM 350K – RM 400K per pt

(1 vial = RM 52K)

The FDA has approved Dinutuximab in March 2015 as part of first-line therapy for children with High-risk Neuroblastoma.

• The most frequent hypersensitivity reactions included hypotension (42.2%), urticaria (7%) and bronchospasm (1%).
• Cytokine release syndrome was also reported in 32% of the patients.

Introduction to Paediatric Oncology

Genomics-Driven Precision Medicine

LCH – Dabrafenib

Relapse Pre B ALL – Latest treatment CAR T therapy

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CAR-T (Chimeric Antigen Receptor T-cell) therapy for Pre-B acute lymphoblastic leukemia

• is a type of immunotherapy

• that modifies a patient's T cells to target and destroy B-cell ALL
• offering a promising approach for treating certain blood cancers and solid tumors.

• CD19 is a common target antigen for CAR-T therapy in B-

cell ALL.

Cost ??:

The cost of CAR-T therapy in Malaysia is significantly lower than in Europe and the US, suggesting costs between RM200,000 – 300,000 per patient.

UKM wt Hospital Canselor Tunku Muhriz (HCTM) & Plutonet Sdn. Bhd – on study and clinical trial involving Chimeric Antigen Receptor-T Cell (CAR-T) therapy for ALL pts who failed chemotherapy treatment.

CAR-T therapy in Malaysia

• MaHTAS has visit the IMR together with HTA Expert Committee as part of the Health Technology Assessment (HTA) MOH

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• Process Evaluation of CAR-T cell therapy, specifically for the treatment of refractory /relapsed Acute Lymphoblastic Leukemia (ALL) in Malaysia.

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• Expert Committee members comprised of multidisciplinary experts relevant (haematologists, paeds oncologist, pharmacists scientist etc).

• The US Food and Drug Administration (FDA) approved the first CAR T-cell therapy in 2017 to treat children with acute lymphoblastic leukemia (ALL).
• Since then, others have been approved to treat adults with blood cancers like non-Hodgkin lymphoma and multiple myeloma.

(MOH)

FDA-Approved CAR T-cell Therapies

Pharmacy Special Interest Group (PSIG) HKL-HTA-IPR visited Auxi Therapeutics at UMMC.

CAR-T therapy in Malaysia

Introduction to Paediatric Oncology

Genomics-Driven Precision Medicine

LCH high risk – Dabrafenib

Relapse Pre B ALL – Latest treatment CAR T therapy

4

5

• 2 year old boy - admitted with h/o right ear purulent discharge with right swelling that was gradually increasing in size.

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• Pt well without any systemic or neurological symptoms, seen by a general practitioner and was treated as right acute otitis media.

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• The symptoms did not resolve despite multiple doses of oral and topical antibiotics.

right swelling

• rare, heterogeneous disorder, primarily affecting children, characterized by abnormal proliferation of Langerhans cells

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• is an aggressive disease: characterized by chronicity, recurrences, long-term sequelae and even death.

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• Clinical: fever, weight loss, seborrheic skin eruptions on over scalp, cytopenias, hepatosplenomegaly, lymphadenopathy, pulmonary infiltrates, and lytic bone lesions.

Langerhans cell histiocytosis (LCH)- Multisystem

1. 4 y/o boy presented with multiple scalp abscesses and red, scaly rash involving scalp and face of 2 years duration.
2. There was hepatosplenomegaly and painful cervical lymphadenopathy. Note the irregular protrusion of the eyes (exophthalmos).
3. CT skull revealed multiple lytic lesions. Skin and bone marrow biopsies confirmed the diagnosis of multisystem LCH

Within 4 weeks of initiating oral dabrafenib therapy to target the BRAF gene mutation causing the patient’s LCH, tests showed no evidence of disease.

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A few weeks later, a 2nd patient with chemo-resistant LCH responded to dabrafenib in the same way.

Dabrafenib, a targeted therapy, is used to treat Langerhans cell histiocytosis (LCH) by blocking the BRAF protein, which is mutated in some LCH cells, thus inhibiting their growth

Price of Dabrafenib 75mg/ 120’s : RM 8,574

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Treatment duration : 4 years (1 to 7 years)

Infantile Fibrosarcoma

Huge mass

Specialization Training Pharmacotherapy in Pediatric Oncology Pharmacy at McMaster Children’s Hospital, Hamilton, Ontario, Canada in 2007

1. Each year in Ontario approximately 500 children are diagnosed with cancer (Malaysia: 1000 cases/year).
2. ~ 25% of children with cancer in Ontario are enrolled on clinical trials, led by the Children's Oncology Group (COG).
3. COG is the largest clinical trials group in the world devoted exclusively to childhood cancer research.

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Ontario

The POGO 2007 Multi-disciplinary Symposium on Childhood Cancer

Niagara Falls, Canada

Specialization Training Pharmacotherapy in Pediatric Oncology Pharmacy at McMaster Children’s Hospital, Hamilton, Ontario, Canada in 2007

POGO: Pediatric Oncology Group of Ontario

Dr. John T.Wiernikowski

(PharmD)

Thank you