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Similar to 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
Similar to 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 (20)
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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
- 1. Pediatrics Pediatrics 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
- 2. Pediatrics Pediatrics Objectives I. History of ALL therapy II. Current ALL therapy III. Emerging ALL therapies IV. Supportive Care
- 3. Pediatrics Pediatrics “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
- 5. Pediatrics Pediatrics Clinical Presentation Fever Pancytopenia Bone Pain Pallor, Petechiae, Bruising Fatigue
- 6. Pediatrics Pediatrics Diagnostic Work-up LP with Intrathecal chemotherapy Bone marrow aspirate and biopsy Central line placement
- 7. Pediatrics Pediatrics Immunophenotyping • Antigens identified on the surface of the leukemia cell www.creativebiomart.net
- 8. Pediatrics Pediatrics Cytogenetics Number of chromosomes (ploidy) BCR-ABL 1 (Philadelphia positive) Finds chromosomal deletions, translocations
- 9. Pediatrics Pediatrics Hyperdip loidy T(12;21) Trisomy 4, 10, 17 Ph + Hypodipl oidy T(4;11) Non-Favorable Favorable
- 10. Pediatrics Pediatrics • Age <2 or >10 • Initial WBC 50,000 or greater • Positive MRD at the end of induction • Sanctuary Site High Risk • Ages 2-10 • Initial WBC 50,000 or less • Good initial response Standard Risk
- 11. Pediatrics Pediatrics I. History of ALL Therapy
- 12. Pediatrics Pediatrics 1949-1954: Clinical Trials testing combination chemotherapy 1948: Dr. Farber reports findings in NEJM of using folic acid in leukemia 1950: -6-MP development -Use of steroids in cancer Multi-institutional Leukemia Groups developed History of ALL Therapy
- 13. Pediatrics Pediatrics 1960s • St. Jude Children’s conducts trials using new drug combinations; improves response. • Major breakthrough= aggressively treating brain/CSF with XRT and drugs • Ultimately, 50% patients were cured of leukemia. 1970s • The idea that cure of ALL was now possible was published. • Many colleagues thought this was irresponsible and gave false hope. • Better supportive care, NIH/public support, participation in studies 1980s • Bone marrow transplantation outcomes improved for kids • Few new chemotherapy agents were introduced 1990s • Clinical progress had plateaued by early 1990s • Survivors from prior years of therapy started showing effects of high intensity treatments • “New era of investment in the biology of childhood cancer” 2010 • Targeted therapies • Immunotherapies • Etcetera
- 14. Pediatrics Pediatrics 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
- 15. Pediatrics Pediatrics BIG Wins… Combination Chemotherapy Prophylactic intrathecal chemotherapy to prevent CNS relapse Forming the COG/Clinical research
- 17. Pediatrics Pediatrics Current ALL Therapy Based on revised risk stratification (2010): NCI risk group (SR vs. HR) Cytogenetics CNS and/or testicular disease Early treatment response (Day 8 peripheral blood, Day 29 BM)
- 18. Pediatrics Pediatrics Current ALL Therapy •Children’s Oncology Group (COG) •Special populations to consider: -Infants -Adolescents -Down syndrome patients
- 19. Pediatrics Pediatrics 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
- 20. Pediatrics Pediatrics 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)
- 21. Pediatrics Pediatrics What is the current survival rate? Around 90%
- 22. Pediatrics Pediatrics Chemotherapy Vincristine Dexamethasone PEG-Asparinginase Methotrexate Doxorubicin Mercaptopurine Thioguanine Cytoxan SIADH Weight Gain Neurotoxicity Skin changes Heart Failure VOD Nutritional Deficits Transfusion reactions Acute and Long Term
- 24. Pediatrics Pediatrics 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
- 26. Pediatrics Pediatrics Blinatumomab Adapted from original illustration by Paulette Dennis
- 27. Pediatrics Pediatrics 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)
- 28. Pediatrics Pediatrics Nomenclature of Monoclonal Antibodies http://clinchem.aaccjnls.org/content/65/3/393/tab-figures-data
- 29. Pediatrics Pediatrics CAR-T cells Hucks & Rheingold 2019
- 30. Pediatrics Pediatrics 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.
- 31. Pediatrics Pediatrics CAR-T Cell Leukemia Cell 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
- 32. Pediatrics Pediatrics Targeted therapy Napper and Watson 2013
- 33. Pediatrics Pediatrics 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
- 34. Pediatrics Pediatrics Epigenetic therapy Napper and Watson 2013 Epigenetics: “Study of biochemical modifications of chromatin” (Burke and Bhatla 2014) Napper and Watson 2013
- 35. Pediatrics Pediatrics Epigenetic therapy DNA METHYLATION/HYDROXY METHYLATION HISTONE MODIFICATIONS (ACETYLATION, LYSINE METHYLATION) ALTERATIONS IN NON- CODING MICRORNAS (MIRNAS)
- 38. Pediatrics Pediatrics 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)
- 39. Pediatrics Pediatrics 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
- 40. Pediatrics Pediatrics 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.
- 41. Pediatrics Pediatrics Case 1- G.M. Diagnosis??? •A. Severe osteoporosis •B. Severe anemia •C. Slow healing fracture •D. New onset leukemia •Leukemia?
- 42. Pediatrics Pediatrics 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.”
- 43. Pediatrics Pediatrics 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
- 44. Pediatrics Pediatrics 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
- 45. Pediatrics Pediatrics Case 2- A.D. Diagnosis??? • A. Relapsed leukemia (if so, where?) • B. False positive • C. Infection • D. Reaction to maintenance chemotherapy
- 46. Pediatrics Pediatrics 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
- 48. Pediatrics Pediatrics 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
Editor's Notes
- P.2
- p.27
- Definition-risk stratification
- Farber reported his findings in the June 3, 1948, issue of the New England Journal of Medicine. A shift in attitudes led Dr. Farber to become a heralded advocate for cancer research funding, and to the creation of a consortium in 1955 that would focus on childhood cancer with the kind of research that we know today. This consortium would eventually evolve into the Children’s Oncology Group. In 1950, Gertrude Elion and George Hitchings, who subsequently received the Nobel Prize, developed 6-mercaptopurine (6-MP), which was designed to interfere with DNA synthesis and kill rapidly growing cells like leukemia. At about the same time, cortisone-based drugs (corticosteroids) were new and were tried for virtually every disease, including cancer. Both 6-MP and corticosteroids, like methotrexate (another anti-folic-acid drug), resulted in a transient improvement in the duration and quality of survival for children with ALL Still, all of the children treated at this time eventually died because resistance to these drugs invariably developed. Nevertheless, these earlier successes generated a great deal of interest and, more importantly, organized action. Because of the relative rarity of childhood leukemia, investigators from several institutions began to work together. Two multi-institution "Leukemia Groups" were developed to speed up the study of new therapies. Between 1949 and 1954, the first clinical trials that tested combinations of chemotherapy drugs methotrexate, corticosteroids, and 6-MP for childhood ALL were carried out. The latter studies were the first controlled clinical trials in leukemia, perhaps in cancer history, that simultaneously compared two drugs - in this case methotrexate vs. 6-MP. The results were very informative and were accompanied by wide-ranging laboratory research, particularly in animals. ***Patients lived longer with these new combinations of chemotherapy drugs, but all still died, usually within a year.
- 1960s: Series of trials performed at St. Jude Children's Research Hospital that used new combinations of drugs to improve response. Because ALL tended to come back in CNS, a major advance was made by aggressively treating the brain and spinal fluid with radiation and drugs that markedly decreased this form of relapse. These studies proved to be a breakthrough, and, ultimately, one-half of the patients were cured of leukemia. 1970s: The idea that the cure of ALL was now possible was published in 1971 and again in 1972. Many colleagues thought this was irresponsible and gave false hope; thankfully, they were wrong. The 1970s were a fertile time for leukemia investigators throughout the U.S. and Europe. Better control of infection and bleeding, better nursing, increasing resources from the National Institutes of Health and the public, and especially the courage and faith of the children and families who participated in studies, made steady progress possible. Work from then to the present has led to a cure rate now approximating 80 percent. 1980s: bone marrow transplantation outcomes improved for kids and a few new chemotherapy agents were introduced. 1990s: clinical progress had plateaued by the early 1990s. This was a time when men and women who had been pediatric cancer patients years before started showing the effects of harsh, high-intensity treatments. Survivors were experiencing a multitude of issues, including deadly heart problems. 1990s= new era — the era of investment in the biology of childhood cancer. The field had increasing insights, but we didn’t have drugs to target the tumors.
- In deeply studying the cancers, researchers discovered that within what they thought was one type of childhood cancer, there are a multitude of variations. Some of these are more vicious than others and require more intense treatment. Others are less aggressive and require less treatment. Hence treatment stratification RT (cranial irradiation) in T-cell ALL with hyperleukocytosis or those with overt CNS leukemia (CNS3)
- Revised risk stratification is looking at post induction response.
- TXCH Cancer Center is part of the COG so we use protocols based on their recommendations. Special populations due to having high risk leukemia and also due to more susceptibility to infection; thus save your intense chemo for post-induction (in consolidation phase) when hematopoiesis is normal. Same goes for patients with low/SR of relapse- explains why their therapy is laid .
- Lets go through some terminology first. Consolidation 8 weeks for HR/VHR patients. DI also known as “reinduction”. This phase greatly improves a patient’s event free survival. Some patient depending on their subtype of leukemia will get either IM x 1 or IM x 2.
- Currently we monitor MRD via flow cytometry where they are looking for aberrant leukemia specific receptor genes on the surface of cells. Currently trying to test other methods such as deep sequencing to be even more precise and detect below current threshold of 0.01%, so want to catch low level clones of disease before relapse even occurs. This is our strongest predictor of outcome to date. 0.01%= level of 1 in 10,000 cells
- So why do we need to change what we are doing?
- I know it looks messy but objective to show all the side effects/long term effects our current treatment causes
- A lot of these new treatments care currently in relapsed setting only, with hope that it will be frontline once proper data/results have been resulted. Current hot topic right now is of course immunotherapy. Epigenetic therapies- treatments that regulate the expression of genes. There is a dysregulation that occurs that plays a major role in resistance which we know as there are certain mutations we often see at relapse. Targeted therapies: these are all of the different pathways that drive a cancer cell to grow (mTOR, RAS pathway, proteasome inhibitors, monoclonal antibodies, TKI).
- -Because MRD is the result of persistence of B-ALL cells despite multiagent chemotherapy, immunotherapy may circumvent chemotherapy resistance and eliminate MRD. -The recent approval by the US Food and Drug Administration (FDA) of 3 different immunotherapies (blinatumomab, inotuzumab, tisagenlecleucel) for inducing remission in refractory or relapsed B-ALL has intensified interest in these strategies for preventing relapse in MRD1 patients, especially since all 3 treatments are most effective for patients with relatively low burdens of disease at the time of treatment. -CAR T-cells- patient’s own T-cells are engineered to mount a response.
- MOA: bispecific T-cell engaging antibody that directs cytotoxic T cells to CD19+ cells (which is a marker seen in 90% B-ALL cells). So you get increased killing of current cancer cells (cytotoxicity) and then increased T cell proliferation. Is the first of the immunotherapies to be studied in MRD+ adult B-ALL. Approved in 2017 for adults/pediatrics with relapsed or refractory B-cell ALL regardless of Philadelphia chromosome status. The approval was based on the results of a large clinical trial showing that patients treated with the drug had substantial improvement in how long they lived compared with patients treated with chemotherapy. Adverse effect: cytokine release syndrome. Currently at 28day continuous infusion- we typically will do the first 7-10 days in-house and then send families home with it with weekly clinic visits (decreases side effects and increases exposure of cells to the drug). AALL1331- looking at this for reinduction for first relapse (compared to chemotherapy alone).
- CD22 is expressed during intermediate steps of B-cell development (expressed in 90% B-ALL). Antibody-drug conjugate- a type of drug in which an anticancer drug is chemically linked to another molecule (in this case “calicheamicin”- DNA damaging agent) that helps target the drug to cancer cells. This is able to target quiet cancer cells (i.e. stem cells) rather than proliferating cells as other drugs require. AALL1621.
- Diagram of CAR T cell treatment process. The treatment process for patients receiving CAR T cell therapy begins with leukapheresis of the patient’s T cells. Once isolated, autologous T cells are sent for manufacturing to produce genetically modified CAR T cells, which are reprogrammed to facilitate targeted killing of CD19+ B cells. The treatment process is completed with intravenous infusion of CAR T cells back to the patient. Adverse effect: cytokine release syndrome.
- Steroid pre med Need to review cytokine release syndrome at the end (percentage of grade 3 4) most have fever Picture? As we use more targeted therapy-need to be more comfortable Looks like allergic rxn-no EPI use tociluzimab
- Try to target inhibition of cell proliferation or induction of apoptosis. Targeted therapies: these are all of the different pathways that drive a cancer cell to grow. Certain pathways at relapse become activated/converge, thus can be targeted also (Wnt, MAPK, Ras pathway). Aurora kinase overexpression associated with poor prognosis. A lot of work going into improving our technology so we can identify low level clones that are associated with relapse.
- TKIs particularly important as we come to identify specific subgroups also such as “Ph like”. This was the first example of a molecularly targeted therapy for cancer (Gleevec)- inhibitor of TK activity of fusion protein BCR-ABL. With this, survival of pediatric Ph+ ALL has improved to 80% (doubled). MEK inhibitors- affecting the Ras pathway (selumetinib, tremetinib) Wnt inhibitors- early on in study
- In epigenetics, you are not changing the DNA sequence itself, but rather heritable changes that affect activity of genes and their cellular expression -> thus altering how genes are expressed or silenced. So if you silence tumor suppressor genes or activation of oncogenes -> this leads to leukemogenesis. Not altering chromosomal translocation or gene mutation (which is permanent)- a lot of these changes are reversible events. These are key drivers that drive oncogenesis/leukemogenesis and epigenetic modification is the hallmark of many of the more difficult to treat pediatric leukemias. Also gene expression changes from diagnosis to relapse, so idea that certain pathways can be reverted to improve chemosensitivity to diagnosis levels is also key when developing these agents.
- These 3 main areas are the focus of upcoming trials and next phase of therapy, particularly for relapsed patients. HDAC inhibitor (vorinostat)+ DNA methyltransferase inhibitor (decitabine) shows great promise, currently in study a re-induction regimen.
- Take away point: something didn’t fit with his initial presentation -> highly suspicious.
- Take away points: -relapsed while on maintenance therapy is typically very resistant leukemia that likely hard to control. -Have to eliminate compliance issues. -currently in remission (CR2) following multiple chemotherapies including blinatumamab and BMT, ~3 mo out