ALL
ACUTE LYMPHOBLASTIC
LEUKEMIA
Alyssa Mellott
LEUKEMIA
Systemic disease
Diagnosed based on type of white blood cell
affected & speed at which it progresses
Acute
vs. Chronic
Myelogenous vs. Lymphocytic
ALL
ALL
Forms in bone marrow
B
& T lymphocytes: a mature form of lymphoblasts that are
critical to the immune system
3 subtypes
1.
Adults
2.
Mature B cell
Genetic changes
3.
Precursor B cell
Precursor T cell*
Pediatric*
Invades blood & spreads to lymph nodes & lymphoid
organs
EPIDEMIOLOGY
Most common subtype of leukemia
Most common cancer diagnosed in children
More prominent in:
2-10
year olds
White people
Males
ETIOLOGY
Family history
Chromosome instability disorders
Ex.
Viral infections
Ex.
Downs Syndrome
Epstein Barr
Radiation exposure
Previous
radiation or prenatal x-rays
Environmental factors
PRESENTATION
Neutropenia
Hemorrhage
Fever
Fatigue
Malaise
Bone/joint pain
Petechiae
Pallor
Lymphadenopathy
Enlarged spleen
PHYSIOLOGY & LYMPHATICS
PHYSIOLOGY & LYMPHATICS
Bone marrow produces lymphocytes
ALL: too many lymphocytes & they dont function
properly
Cant fight infection & overcrowding = less RBCs &
platelets
This causes
Bleeding
(lack of platelets)
Fatigue (lack of RBCs)
Build up of WBCs in spleen, lymph nodes, & liver =
swelling & discomfort
ALL VS. LYMPHOMA
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
TREATMENT
Radiation, chemotherapy, & bone marrow
transplant
Combination
or alone
Chemo alone is most common
CHEMOTHERAPY
Chemo alone 3 steps
1.
Agents: doxorubicin, methotrexate, vincristine, ect.
2.
Induction: intense 2-3 weeks, goal is remission
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
RADIATION THERAPY
TBI
Conditioning
for
bone marrow
transplant
1200 cGy
6 fractions
German Helmet
1800-2400
cGy
Cranial Spinal +
German helmet
Helmet
to 2400 cGy
Spine to 1500 cGy
Treatment of testis
2000-2400
cGy
Relapse due to
methotrexate
Can be prophylactic
BONE MARROW TRANSPLANT
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
TBI: PATIENT EXAMPLE
7 year old male
Presented with
lymphadenopathy &
petechiae in 2011 ALL
Relapse in 2014
Testes
= sanctuary site
Methotrexate
= sanctuary site
Remission
Started 3 cycles of chemo
again
Reinduction
Had chemotherapy &
prophylactic cranial
radiation to 1200 cGy in
2011
CNS
Orchiectomy in June 2014
due to relapsed testicular
disease
Vincristine
Steroids
Doxorubicin
Asparaginase
TBI and testicular boost at
MXE in September to
prepare for BMT
TBI: PATIENT EXAMPLE
TBI
1200
cGy total
6 fractions/BID
6 mV
Boost to testes
1200
cGy total
6 fractions/BID
12 meV
TBI: PATIENT EXAMPLE
OPTION 1:
ANTIBODY THERAPY
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)
OPTION 1:
ANTIBODY THERAPY
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
OPTION 1:
ANTIBODY THERAPY
2. Antibody-Drug Conjugates (ADCs)
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 patients own immune
system and the other to target malignant cells
OPTION 1:
CONCLUSIONS
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
OPTION 2:
PRE-BMT BUSULFAN
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
OPTION 2:
CONCLUSIONS
Patients that
developed more
than three late
complications
59.2%
of TBI
patients
44% of BU patients
OPTION 2:
SIDE EFFECTS
Side Effects
BU
TBI
Height growth
failure
27.3%
49.4%
Overweight*
22.7%
13.8%
Hypothyroidism
15.2%
28.2%
Secondary Tumors 4.5%
11.5%
Gonadal
Dysfunction
48.1%
53.9%
Alopecia*
25.8%
2.9%
Cataract
4.5%
51.7%
OPTION 2:
CONCLUSIONS
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
MY OPINION
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
REFERENCES
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):709-716. Available from:
Academic Search Complete, Ipswich, MA. Accessed October 23, 2014.
Childhood Lymphoblastic Leukemia Treatment. [Link]. National Cancer
Institute, n.d. Web. 30 Oct. 2014.
<[Link]
Hackworth, Ruth. "Pediatric Tumors." Applied Technical Oncology. Lecture. 2014.
"Intravenous Busulfan Before Stem Cell Transplant." MD Anderson Cancer Center.
University of
Anderson Texas MD Anderson, n.d. Web. 30 Oct. 2014.
<[Link]
"Stem cell transplant for acute lymphocytic leukemia." American Cancer Society.
American Cancer Society, n.d. Web. 30 Oct. 2014.
<[Link]
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.
