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Leukemia- Past, Present, and the Future Hatel R. Moonat, DO, FAAP Lindsey Zaremba BSN, RN, CPN, CPHON TCH Cancer and Hematology Centers, The Woodlands September 19, 2019
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Objectives I. History of ALL therapy II. Current ALL therapy III. Emerging ALL therapies IV. Supportive Care
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“The road to curing most children with acute lymphocytic leukemia (ALL), the most common childhood cancer, may be the greatest success story in the history of cancer.” –America Society of Hematology (Dec 2008) Photo Credit: National Institute of Allergy & Infectious Diseases
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Acute Lymphoblastic Leukemia Overview https://commons.wikimedia.org
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Clinical Presentation
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Diagnostic Work-up
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Immunophenotyping Antigens identified on the surface of the leukemia cell www.creativebiomart.net
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Cytogenetics
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Non-Favorable Favorable
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I. History of ALL Therapy
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History of ALL Therapy
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History of ALL Therapy With in-depth studying of the cancers, researchers discovered that within what they thought was one type of childhood cancer -> there were multiple variations -> “Treatment Stratification” Current treatment modalities: Chemotherapy +/- radiation +/- immunotherapy
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BIG Wins…
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II. Current ALL Therapy
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Current ALL Therapy
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Current ALL Therapy Children’s Oncology Group (COG) Special populations to consider: -Infants -Adolescents -Down syndrome patients
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Current ALL Therapy Induction (4 weeks)- Goal: remission! Consolidation (4-8 weeks)- Goal: eliminate any undetectable cancer cells that may still be present Interim Maintenance (8 weeks)- Goal: eliminate any resistant cells that may still be left behind Delayed Intensification (8 weeks)- similar drugs as seen in induction/consolidation; Goal: eliminate resistance + prevent recurrence Maintenance (12 week cycles)- Goal: continuation of therapy *From start of IM: 2 years duration for girls; 3 years for boys
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Current ALL Therapy Response to treatment via MRD: *Minimal Residual Disease Threshold = 0.01% (level of 1 in 10,000 cells) *Greater than this is MRD POSITIVE)
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What is the current survival rate? Around 90%
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Chemotherapy Vincristine Dexamethasone PEG-Asparinginase Methotrexate Doxorubicin Mercaptopurine Thioguanine Cytoxan Peripheral Neuropathy Constipation SIADH Osteonecrosis Irritability Weight Gain Anaphylaxis Liver toxicity Neurotoxicity Skin changes Heart Failure VOD Learning Disabilities Nutritional Deficits Hemorrhagic Cystitis Vomiting infection Transfusion reactions Renal injury Delayed Development Acute and Long Term
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III. Emerging ALL Therapy
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Emerging ALL Therapy Immunotherapy- using the patient’s own immune system to fight cancer Targeted therapies- targeting cancer related genes, proteins, tissue environment that contribute to its growth & survival Epigenetic therapies- regulate expression of genes
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Immunotherapy
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Blinatumomab Adapted from original illustration by Paulette Dennis
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Inotuzamab Ozogamacin CD22+ ALL Currently not open for enrollment Combined with frontline chemotherapy in treating young adults with newly diagnosed B-ALL (next phase of trials)
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Nomenclature of Monoclonal Antibodies http://clinchem.aaccjnls.org/content/65/3/393/tab-figures-data
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CAR-T cells Hucks & Rheingold 2019
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KymriahTM (Tisagenlecleucel ) First-ever approved CAR T-cell therapy for children and young adults with advanced ALL. Based on small clinical trial in which 83% of patients achieved a complete remission 3 months after receiving the treatment.
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CAR-T Cell Leukemia Cell IL-6 Cytokine Release Syndrome Fever Malaise Rash Hypotension Respiratory Symptoms Considerations High tumor Burden Can happen on 1st dose Tociluzumab-Immunosuppressant against IL-6 Supportive Care Cytokine Release Syndrome
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Targeted therapy Napper and Watson 2013
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Targeted therapy Tyrosine kinase inhibitors (TKI)- imatinib, dasatinib, nilotinib, FLT3 inhibitors Monoclonal antibodies (Daratumumab, anti-CD38) mTOR inhibitors (rapamycin, temsirolimus, everolimus) JAK 1 & 2 inhibitors Aurora kinase inhibitors- aurora kinase plays a key role in cell division
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Epigenetic therapy Napper and Watson 2013 Epigenetics: “Study of biochemical modifications of chromatin” (Burke and Bhatla 2014) Napper and Watson 2013
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Epigenetic therapy
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The unknowns…
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IV. Supportive Care
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Supportive Care Heme-Onc mouthwash (HOMW) Pneumocystis jirovecii prophylaxis: Bactrim,pentamadine (inhaled/IV), dapsone Neutropenic fever precautions Antifungal prophylaxis for high risk patients Immunoglobulin replacement therapy (IVIG if IgG <500)
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Case 1- G.M. 4yo CM presented to WL Oncology clinic as referral from WL Orthopedics due to “diffuse osteoporosis noted on L femur plain films” History of questionable slow healing L femur fracture, placed in long leg cast x few weeks (May 2017) ROS: “scalp lesions”, LUE pain, loss of appetite
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Case 1- G.M. Labs: WBC 2.75, Hgb 9.1, Platelets 126, ANC 440, ESR 78, Uric acid 6.9, LDH 1082, Ca 15.5 Peripheral smear: “Small population of large lymphoid cells with atypical features concerning for malignancy is present.“ XR leg length and L foot (7-4-17): Healing, nondisplaced pathological fractures secondary to severe osteoporosis. Hematological evaluation may be helpful in further evaluation. XR skull (7-11-17): Diffuse permeative process suggests a diffuse infiltrative process such as leukemia in this clinical setting. Severe anemia can cause a similar appearance due to bone marrow expansion.
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Case 1- G.M. Diagnosis??? A. Severe osteoporosis B. Severe anemia C. Slow healing fracture D. New onset leukemia Leukemia?
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Case 1- G.M. BONE MARROW, BILATERAL ANTERIOR ILIAC CREST CORE BIOPSIES, LEFT ILIAC CREST ASPIRATE, AND PERIPHERAL BLOOD SMEAR (7/14/17): B-ACUTE LYMPHOBLASTIC LEUKEMIA.Comment: “Corresponding flow cytometric studies performed at the Texas Children's Cancer Center show blasts (38%) marked as lymphoid with a precursor B phenotype identified.”
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Case 2- A.D. 14 yo HF initially presented with progressive history of dizziness and fatigue, found to have pancytopenia and was ultimatyel diagnosed with VHR Pre-B ALL, CNS2. TAT AALL 1131 and tolerating chemotherapy well, no concerns for compliance. 8/31/18: Evidence of peripheral blasts (3.4%) 9/4/18: Repeat lab draw negative 9/14/18: Repeat CBC/smear within normal limits
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Case 2- A.D. 9/28/18: Presented for Maintenance Cycle 6 ROV No complaints on physical exam Labs: WBC 70,000 with 83% peripheral blasts
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Case 2- A.D. Diagnosis??? A. Relapsed leukemia (if so, where?) B. False positive C. Infection D. Reaction to maintenance chemotherapy
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Case 2- A.D. S U R G I C A L P A T H O L O G Y R E P O R T FINAL DIAGNOSIS (9/28/18):BONE MARROW, RIGHT ANTERIOR ILIAC CREST, CORE BIOPSY, CLOT AND ASPIRATE, AND PERIPHERAL BLOOD SMEAR: RELAPSED B-ACUTE LYMPHOBLASTIC LEUKEMIA.Comment: “Corresponding flow cytometric studies performed at the Texas Children's Cancer Center showed leukemic blasts (95%) with a precursor B phenotype consistent with relapsed B-acute lymphoblastic leukemia.” CEREBROSPINAL FLUID, CYTOLOGIC EXAMINATION: PERIPHERAL BLOOD ELEMENTS WITH LEUKEMIC BLASTS IDENTIFIED
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Questions???
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References Burke MJ, Bhatla T. Epigenetic Modifications in Pediatric Acute Lymphoblastic Leukemia. Frontiers in Pediatrics (2014), 42(2)1-7. Doi:10.3389/fped.2014.00042/full Children’s Oncology Group. (2011, July). Treating Acute Lymphoblastic Leukemia. Retrieved from https://www.childrensoncologygroup.org/index.php/in-treatment-for-acute-lymphoblastic-leukemia Hucks G, Rheingold SR. The Journey to CAR Tcell Therapy: The Pediatric and Young Adult Experience with Relapsed or Refractory B-ALL. Blood Cancer Journal (2019)9:10. doi:10.1038/s41408-018-0164-6. Jessop E. (2015, Sept 11). The History of Childhood Cancer Research. Retrieved from https://www.stbaldricks.org/blog/post/the-history-of-childhood-cancer-research Maude SL, Frey N, Shaw PA, et al. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. N Engl J Med. 2014. Oct 16; 371(16): 1507-1517. doi:10.1056/NEJMoa1407222. Napper AD, Watson VG. Targeted Drug Discovery for Pediatric Leukemia. Frontiers in Oncology (2013). 3(170)1-13. Doi:10.3389/fonc.2013.00170 NCI Staff. (2017, Sept 18). FDA Approves Inotuzumab for Adults with B-Cell Acute Lymphoblastic Leukemia. Retrieved from https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-inotuzumab-leukemia Pierro J, Hogan LE, Bhatla T, Carroll WL. New Targeted Therapies for Relapsed Pediatric Lymphoblastic Leukemia. Expert Rev Anticancer Ther. 2017. August; 17(8): 725-736. doi:10.1080/14737140.2017.1347507. The American Cancer Society Medical and Editorial Content Team. (2019, Feb 12). Treatment of Children With Acute Lymphocytic Leukemia (ALL). Retrieved from https://www.cancer.org/cancer/leukemia-in-children/treating/children-with-all.html The American Society of Hematology. (2008, Dec). Curing Pediatric Acute Lymphocytic Leukemia. Retrieved from https://www.hematology.org/About/History/50-Years/1530.aspx Wang, Y., Huang, J., Rong, L., Wu, P., Kang, M., Zhang, X., … Fang, Y. (2016). Impact of age on the survival of pediatric leukemia: an analysis of 15083 children in the SEER database. Oncotarget, 7(50), 83767–83774. doi:10.18632/oncotarget.11765