Hematologic Malignancies in Children (Pediatric Leukemias and Lymphomas) National Academy of Infusion Therapy Dallas, 11/7/15 Scott Howard, MD, MSc Professor, University of Memphis Chair, World Child Cancer USA

Learning Objectives Describe the epidemiology and curability of pediatric leukemias and lymphomas Review treatment protocols for pediatric leukemias and lymphomas Highlight infusion reactions that occur in children with leukemias and lymphomas Identify major challenges to curing pediatric leukemias and lymphomas in low- and middle-income countries

Pediatric Leukemias and Lymphomas Outline Incidence and curability Common treatment protocols Infusion reactions Childhood cancer care in low- and middle-income countries Call to action

Pediatric Leukemias and Lymphomas Outline Incidence and curability Common treatment protocols Infusion reactions Childhood cancer care in low- and middle-income countries Call to action

New Cancer Patients per Year in the USA Total: 1,284,900 Site Number Genital 280,000 Digestive 250,600 Breast 205,000 Respiratory 183,200 Urinary 90,700 Lymphoma 60,900 Skin 58,300 Leukemia 30,800 Oral 29,000 Endocrine 22,700 Brain 17,000 Multiple Myeloma 14,600 Pediatric Cancer 12,400

Cancer in Children

Cancer in Children

Epidemiology < 5 years: 58/million 5-9 years: 30/million 0 5 15 20 Years of age

Leukemia Epidemiology in the USA 43 cases/1,000,000 children (3,250 new cases/year) 30% of pediatric cancers ALL 5 times more frequent than AML Childhood leukemia accounts for 12% of leukemias and 60% of ALL Congenital/newborn leukemia is usually AML

Types, incidence, and curability Leukemias Acute lymphoblastic leukemia [ALL] (85%) Acute myeloblastic leukemia [AML] (70%) Lymphomas Hodgkin lymphoma (85%) Non-Hodgkin lymphomas (70-90%)

50 years of progress in hematologic cancers

50 years of progress in lymphoma

How was this dramatic progress made over 5 decades? Improved supportive care Improved Nursing care New medications for leukemia/lymphoma New regimens using old medications New diagnostic methods Good luck

How was this dramatic progress made over 5 decades? Improved supportive care Improved Nursing care New medications for leukemia/lymphoma New regimens using old medications New diagnostic methods Good luck

Chemotherapy in ALL Drugs Year approved in US Mercaptopurine 1953 Methotrexate 1953 Prednisone 1955 Dexamethasone 1958 Cyclophosphamide 1959 Vincristine 1964 Cytarabine 1969 Asparaginase 1978 Daunorubicin 1979 Etoposide 1983 Teniposide 1990 Clofarabina, Nelarabine, Imatinib, Dasatinib

Chemotherapy in ALL Drugs Year approved in US Mercaptopurine 1953 Methotrexate 1953 Prednisone 1955 Dexamethasone 1958 Cyclophosphamide 1959 Vincristine 1964 Cytarabine 1969 Asparaginase 1978 Daunorubicin 1979 Etoposide 1983 Teniposide 1990 Clofarabina, Nelarabine, Imatinib, Dasatinib

Pediatric Leukemias and Lymphomas Outline Incidence and curability Common treatment protocols Infusion reactions Childhood cancer care in low- and middle-income countries Call to action

Chemotherapy in ALL Drugs Year approved in US Mercaptopurine 1953 Methotrexate 1953 Prednisone 1955 Dexamethasone 1958 Cyclophosphamide 1959 Vincristine 1964 Cytarabine 1969 Asparaginase 1978 Daunorubicin 1979 Etoposide 1983 Teniposide 1990 Clofarabina, Nelarabine, Imatinib, Dasatinib

EFS difference by study arm Better use of an old medicine (ASP) improves EFS (p<0.05 except where indicated) Pieters, et al. Cancer (2011) 117:238 EFS difference by study arm P=NS Pieters, et al. Cancer (2011) 117:238 Figure 1. The effect of intensification with asparaginases on event-free survival is shown. EFS indicates event-free survival; Study 1, Silverman2; Study 2, Amylon38; Study 3, Amylon38; Study 4, Rizzari42; Study 5, Pession41; Study 6, Moghrabi40; Study 7, Duval.39;

Chemotherapy for Hodgkin lymphoma ABVD Adriamycin (doxorubicin) Bleomycin Vinblastine Dacarbazine

Chemotherapy for Hodgkin lymphoma ABVD derivatives OEPA Oncovin, Etoposide, Prednisone, Adriamycin DBVE Doxorubicin, Bleomycin, Vincristine, Etoposide VBVP Vinblastine, Bleomycin, Etoposide, Prednisone VAMP Vinblastine, Adriamycin, Methotrexate, Prednisone

Chemotherapy for NHL CHOP and R-CHOP Immunotherapy Rituximab Chemotherapy Cyclophosphamide Adriamycin (doxorubicin) Oncovin (vincristine) Prednisone

NHL Treatment – German protocol for adults with Burkitt lymphoma

NHL Chemotherapy Schema

NHL Chemotherapy Details

Potential Targets on B-Cells = Rituximab Cheson et al, NEJM 2008

Pediatric Leukemias and Lymphomas Outline Incidence and curability Common treatment protocols Infusion reactions Childhood cancer care in low- and middle-income countries Call to action

Role of Infusion Nursing Maintain safe vascular access Avoid extravasation when PIVs are used Manage infusion reactions Early recognition Clinical evaluation Identification of the cause Cause-specific management Immediate supportive care Determination of whether to finish the infusion Determination of whether and how to give subsequent doses

Anti-cancer agents that can cause infusion reactions Drug action Drug name Mechanism Infusion reactions Cytotoxic Doxorubicin DNA damage N/V, extravasation Vincristine Tubulin inhibitor Extravasation Etoposide ??? Anaphylactoid Asparaginase (a protein) Decreased protein synthesis Hypersensitivity, anaphylactoid, ammonia release Immuno-therapy Rituximab (a protein) Binds CD20 and stimulates immune attack Hypersensitivity, anaphylactoid, complement activation

Infusion Reactions Definition Anything that happens during an infusion May or may not be related to the infusion Determining the cause of the infusion reaction is key to manage it correctly Extravasation – infusion-associated adverse event, but not exactly an infusion reaction

Infusion Reactions Types Nausea/vomiting Hypersensitivy reactions Anaphylactoid reactions Complement-mediated reactions Asparaginase ammonia reactions

Infusion Reactions Types – nausea and vomiting Symptoms caused by direct action of the drug on the nausea center in the brain Not mediated by IgE, and therefore can occur with first exposure Safe to continue using the drug Premedications strongly recommended to prevent nausea and vomiting (and avoid development of anticipatory nausea and vomiting as a conditioned response)

Infusion Reactions Types - hypersensitivy reactions Anaphylaxis, non-systemic allergic reactions (e.g. skin only) Mediated by IgE and therefore require prior immunization Get worse with repeated exposure Avoid the drug that caused the reaction (or desensitize if its use is critical) Premedications not advised since they may hide early/mild symptoms until the patient has a severe reaction

Infusion Reactions Types - anaphylactoid reactions Symptoms resemble anaphylaxis (hypotension, urticaria, wheezing Not mediated by IgE, and therefore can occur with first exposure Do not consistently get worse with repeated exposure (and may even get better on 2nd or subsequent courses) Safe to continue using the drug (with close observation of course) Premedications may reduce symptoms

Infusion Reactions Types – complement mediated reactions Symptoms resemble anaphylaxis (hypotension, urticaria, wheezing Not mediated by IgE, and therefore can occur with first exposure Do not consistently get worse with repeated exposure (and may even get better on 2nd or subsequent courses) Safe to continue using the drug (with close observation of course) Premedications may reduce symptoms

Infusion Reactions Types – asparaginase ammonia reactions Symptoms include N/V, anxiety, flushing, neurologic dysfunction, seizure, encephalopathy, and others Caused by rapid production of ammonia during IV asparaginase administration Most likely with the first dose of a series Treatment is supportive until the body clears the ammonia (in severe cases ammonia binders can be used) Ok to continue asparaginase but with a much slower infusion (or IM dosing)

How does asparaginase work?

Amino Acids 20 amino acids are the building blocks of all proteins Proteins are vital for cells to survive and especially for them to divide into daughter cells Proteins are also needed to maintain normal physiology (insulin, insulin receptor, factor VIII, antithrombin, apolipoprotein)

Asparaginase mechanism of action Depletion of asparagine and glutamine Blood Asparagine Asparagine Asparagine Asparagine Glutamine Glutamine Glutamine Glutamine   Normal cell ALL cell

How Asparagine Depletion Therapy Works References: 1. ONCASPAR® [package insert]. Gaithersburg, MD: Sigma-Tau Pharmaceuticals, Inc; 2014. 2. Narta UK et al. Crit Rev Oncol Hematol. 2007;61(3):208-221. 45

Asparaginase mechanism of action Depletion of asparagine and glutamine Blood Asparagine Aspartate + NH3 Asparaginase Glutamine Glutamate + NH3

Asparaginase mechanism of action Depletion of asparagine and glutamine Blood Asparagine Asparagine Asparagine Asparagine Glutamine Glutamine Glutamine Glutamine ? ? Normal cell ALL cell

Asparaginase mechanism of action Depletion of asparagine and glutamine Blood Asparagine Asparagine Asparagine Asparagine Glutamine Glutamine Glutamine Glutamine Unhappy, alive  Normal cell ALL cell

Asparaginase mechanism of action Depletion of asparagine and glutamine Blood Asparagine Asparagine Asparagine Asparagine Glutamine Glutamine Glutamine Glutamine Asn Asp + NH3 Asparagine synthetase No Asparagine synthetase   = cell death Normal cell ALL cell

Which of the following is an allergic reaction to ASP? Vomiting Diarrhea Abdominal pain Cough Wheezing Rhinorrhea Sore throat Muscle spasms Bladder spasm Urticaria Hypotension Petechiae Eye edema Anxiety Seizure Coma Headache Malaise

Reactions to intramuscular versus intravenous Erwinia ASP Toxicity reported Erwinia IM Erwinia IV Comments Hypersensitivity 13% 37% Excess nausea, vomiting, and “hyper-sensitivity” with IV vs IM may be explained by ammonia toxicity Grade 3 or 4 hypersensitivity 9% 3% Nausea 5% 20% Vomiting 17% Erwinaze revised package insert: http://erwinaze.com/ERWINAZEPI.pdf, 12/2014

Reported hypersensitivity rate of 30% is higher than any previous reports of hypersensitivity with PEG-E coli

Ammonia increases very rapidly - very high at 2 hours from the start of ASP infusion Paulides et al, J Leuk 2013: 1-3

6 asymptomatic pediatric patients had serial ammonia measurements Peak ammonia levels were very high (>175 µmol/L, normal range up to 40) in all patients. Paulides et al, J Leuk 2013: 1-3

Very high peak ammonia levels occurred within 2 hours of the start of ASP infusion Paulides et al, J Leuk 2013: 1-3

Red bar = peak ammonia production (60-min infusion) Simulation of ammonia production per minute during asparaginase infusion 60 vs 120 minutes, Erwinia asparaginase 60-minute infusion 120-minute infusion Peak ammonia production of 42 µmole/L/min with 60-min infusion and 30 µmole/L/min with a 120-min infusion. The 120-min infusion has less of an ammonia spike, but still very rapid ammonia production in the first 20 minutes of infusion Red bar = peak ammonia production (60-min infusion)

Ammonia production/min – IV Erwinia Special infusion method Asparaginase Dilute bag in 120 mL Give 1 mL, flush, wait 10 minutes Start slow infusion (0.3 mL/min) for 80 minutes Faster infusion (3 mL/min) for the final 30 minutes

Distinguishing asparaginase-associated infusion reactions Asparaginase IV Administration Wheezing, urticaria, hypotension Nausea, vomiting, anxiety, malaise, abdominal pain, diarrhea, flushing, edema, cough, rhinorrhea, sore throat Seizure, coma, encephalopathy, neuropathy, headache Ammonia Testing Ammonia normal Ammonia elevated Likely hypersensitivity Presumed hypersensitivity Presumed ammonia Likely ammonia

Manage as with hypersensitivity to any other medicine Determine the cause of the infusion reaction* Hypersensitivity Unclear Ammonia Manage as with hypersensitivity to any other medicine Stop infusion, STAT ammonia level Symptoms persist Symptoms improve * Cause can be determined by clinical factors (wheeze/urticarial/hypotension = hypersensitivity) and STAT ammonia level (if elevated without definite signs of hypersensitivity to defer a diagnosis of hypersensitivity) Stop ASP infusion Finish ASP infusion Give subsequent doses over 2 hours (or IM)

Pediatric Leukemias and Lymphomas Outline Incidence and curability Common treatment protocols Infusion reactions Childhood cancer care in low- and middle-income countries Call to action

50 years of progress in lymphoma

Pediatric cancer survival Event-free survival (%) Survival gap for LIC G. Masera, Haematologica 2000; 85:785 62

Childhood cancer survival in low- versus high-income countries Event-free survival (%) Survival gap for LIC Low-income countries 63

Childhood cancer survival in low- versus high-income countries Survival gap High-income countries Event-free survival (%) Survival gap for LIC Low-income countries 64

Definitions of HIC, MIC, and LIC Mean annual per capita income in 2010 US dollars High-income country > $12,276 Medium-income country $1006-12,275 Lower MIC $1006 to $3975 Upper MIC $3976 to $12,275 Low-income country < $1005 http://data.worldbank.org/about/country-classifications 65

Improving Childhood cancer in LMIC How can you help? Training and transferring best practices Safe vascular access Safe drug preparation and administration Hand hygiene, Inclusion in society activities/scholarships/ sharing materials and curricula Fundraising/advocacy

Pediatric Leukemias and Lymphomas Outline Incidence and curability Common treatment protocols Infusion reactions Childhood cancer care in low- and middle-income countries Call to action

World Child Cancer

World Child Cancer – why? Worldwide, cancer is killing more people than HIV/AIDS, tuberculosis and malaria combined In developing countries, less than 20% of children with cancer survive (compared to over 80% in the developed world)

Where we work World Child Cancer supports twinning partnerships around the world. We are currently supporting 9 twinning partnerships across 16 developing countries. Our new Wilms tumour collaborative project and Myanmar project launched Spring and Summer 2014.

How We Work We create and fund international twinning partnerships We assess the need and fund what is required Two-way transfer of medical expertise and skills Only charity dedicated solely to helping children with cancer across the developing world

Together we Save Lives and Reduce Suffering

World Child Cancer USA Income Targets Together We Can Have Amazing Impact World Child Cancer USA Income Targets 2015 2016 2107 $300,000/annum $400,000/annum $800,000/annum 1 child per day receiving treatment 2 children per day receiving treatment How you can help? Corporate / Foundations: Who do you know? Community Events: Organise further events in line with World Cancer Day, International Childhood Cancer Day (February), Children’s Cancer Awareness Month (September) Caitriot/Outlander Chapter: Interact with the US board, open doors, cultivate supporters, speakers network Social Media: Continue to spread awareness

2014 – Our Stats In 2014 we helped 3460 children with cancer. 1,000 healthcare professionals attended training in 2014 Over 8500 children have been supported by World Child Cancer around the world since launching in Malawi in 2009.

THANK YOU Contact: LeAnn Fickes Leann.fickes@worldchildcancer.us www.worldchildcancer.us @wchildcancerUS World Child Cancer USA is a 501(c)(3) non-profit organization. Tax Identification Number 46-0886328

Pediatric Leukemias and Lymphomas Outline Incidence and curability Common treatment protocols Infusion reactions Childhood cancer care in low- and middle-income countries Call to action Questions later? ScottCHoward@Outlook.com