Alyssa Mellott

 Systemic disease  Diagnosed based on type of white blood cell affected & speed at which it progresses  Acute vs. Chronic  Myelogenous vs. Lymphocytic

 Forms in bone marrow  B & T lymphocytes: a mature form of lymphoblasts that are critical to the immune system  3 subtypes  1. Precursor B cell Adults  2. Mature B cell Genetic changes  3. Precursor T cell* Pediatric*  Invades blood & spreads to lymph nodes & lymphoid organs

 Most common subtype of leukemia  Most common cancer diagnosed in children  More prominent in:  2-10 year olds  White people  Males

 Family history  Chromosome instability disorders  Ex. Down’s Syndrome  Viral infections  Ex. Epstein Barr  Radiation exposure  Previous radiation or prenatal x-rays  Environmental factors

 Neutropenia  Fever  Malaise  Petechiae  Lymphadenopathy  Hemorrhage  Fatigue  Bone/joint pain  Pallor  Enlarged spleen

 Bone marrow produces lymphocytes  ALL: too many lymphocytes & they don’t function properly  Can’t fight infection & overcrowding = less RBC’s & platelets  This causes  Bleeding (lack of platelets)  Fatigue (lack of RBC’s)  Build up of WBC’s in spleen, lymph nodes, & liver = swelling & discomfort

 Both can develop from lymphocytes  ALL starts in the bone marrow & can spread to other parts of the body  Lymphoma starts in lymph nodes & other organs & can spread to the bone marrow

 Radiation, chemotherapy, & bone marrow transplant  Combination or alone  Chemo alone is most common

 Chemo alone  3 steps  1. Induction: intense 2-3 weeks, goal is remission Agents: doxorubicin, methotrexate, vincristine, ect.  2. Consolidation: goal to kill remaining cells Agents: same + cytarbine & etoposide  3. Maintenance: goal to reduce risk of leukemia coming back Agents: mercaptopurine & methotrexate tablets + vincristine injection

 TBI  Conditioning for bone marrow transplant  1200 cGy  6 fractions  German Helmet  cGy  Cranial Spinal + German helmet  Helmet to 2400 cGy  Spine to 1500 cGy  Treatment of testis  cGy  Relapse due to methotrexate  Can be prophylactic

 For patients in fair health  Can do lower dose TBI for weaker patients  Chemotherapy can severely damage normal bone marrow cells  Restore bone marrows ability to make blood  Autogeneic vs. Autologous  Severe side effects

 7 year old male  Presented with lymphadenopathy & petechiae in 2011  ALL  Relapse in 2014  Had chemotherapy & prophylactic cranial radiation to 1200 cGy in 2011  CNS = sanctuary site  Remission  Orchiectomy in June 2014 due to relapsed testicular disease  Testes = sanctuary site  Methotrexate  Started 3 cycles of chemo again  Reinduction Vincristine Steroids Doxorubicin Asparaginase  TBI and testicular boost at MXE in September to prepare for BMT

 TBI  1200 cGy total  6 fractions/BID  6 mV  Boost to testes  1200 cGy total  6 fractions/BID  12 meV

 Antibody therapy  A form of targeted therapy  Radiation and chemotherapy side effects can limit quality of life  Focus on pediatric relapse cases Usually a poor prognosis (~30% in 5 years)

 1. Monoclonal antibodies  In phase III trial for pediatric ALL  Leukemic blasts express antigens on their surface that can be selectively targeted by monoclonal antibodies  This allows directed delivery of highly potent drugs  Advantages over chemo: Longer circulating half-lives Greater accumulation in tumor cells Fewer systemic side effects

 2. Antibody-Drug Conjugates (ADC’s)  Next generation of antibodies  Being tested for ALL & AML  A highly potent cytotoxic agent is bound to an antibody by a linker, resulting in selective targeting of leukemia cells  3. Bispecific T-Cell Engager (BiTE)  Each antibody contains two binding sites One designed to engage the patient’s own immune system and the other to target malignant cells

 Less severe side effects  More “targeted”  Minimal changes over last 50 years in drugs to induce & maintain remission in pediatric leukemia  Could change routine management of this disease  Cannot not penetrate blood-brain barrier  Still a challenge to get these drugs to sanctuary sites CNS & testes  Still in trials

 Busulfan (BU)  Alkylating agent  One of most potent anti-leukemia drugs  Very toxic to normal bone marrow cells but not immunosuppressive Need fludarabine to get new stem cells to engraft  Limited toxicity to organs  Most common alternative to TBI  Study: childhood leukemia survivors  Best conditioning treatment for BMT?  TBI  174 patients vs. Busulfan  66 patients Health status & quality of life? Median follow up = 10.1 years

 Patients that developed more than three late complications  59.2% of TBI patients  44% of BU patients

Side EffectsBUTBI Height growth failure 27.3%49.4% Overweight*22.7%13.8% Hypothyroidism15.2%28.2% Secondary Tumors4.5%11.5% Gonadal Dysfunction 48.1%53.9% Alopecia*25.8%2.9% Cataract4.5%51.7%

 Seems to be equally effective  BU replace TBI?  Children & TBI More damaging to physical and mental development (lower IQ) Higher risk for secondary cancers  Patients considered were all long-term survivors  TBI seems to have more serious side effects in children

 Antibody therapy vs. common chemotherapy agents  Side effects  Relapse/ALL Better prognosis?  BU vs. TBI as conditioning for BMT  Side effects  Long term quality of life  Pediatric development

 Bernard F, Auquier P, Michel G, et al. Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study. Bone Marrow Transplantation [serial online]. May 2014;49(5): Available from: Academic Search Complete, Ipswich, MA. Accessed October 23,  “Childhood Lymphoblastic Leukemia Treatment.” Cancer.gov. National Cancer Institute, n.d. Web. 30 Oct  Hackworth, Ruth. "Pediatric Tumors." Applied Technical Oncology. Lecture  "Intravenous Busulfan Before Stem Cell Transplant." MD Anderson Cancer Center. University of Anderson Texas MD Anderson, n.d. Web. 30 Oct  "Stem cell transplant for acute lymphocytic leukemia." American Cancer Society. American Cancer Society, n.d. Web. 30 Oct  Vedi A, Ziegler D. Antibody therapy for pediatric leukemia. Frontiers In Oncology [serial online]. April 2014;4:1-10. Available from: Academic Search Complete, Ipswich, MA. Accessed October 27, 2014.