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

Pediatrics
Pediatrics
 I. History of ALL therapy
II. Current ALL therapy
Objectives III. Emerging ALL therapies
IV. Supportive Care

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

Pediatrics
 Acute
Lymphoblastic
Leukemia Overview

https://commons.wikimedia.org
Pediatrics
 Fever

Pancytopenia

Clinical Bone Pain

Presentation
Pallor, Petechiae,
Bruising

Fatigue

Pediatrics
 LP with Intrathecal chemotherapy

Diagnosti
c Work-up Bone marrow aspirate and biopsy

Central line placement

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 Immunophenotyping
• Antigens identified on the surface of the leukemia cell

www.creativebiomart.net

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 Number of chromosomes (ploidy)

Cytogenetics BCR-ABL 1 (Philadelphia positive)

Finds chromosomal deletions, translocations

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 Non-Favorable Hyperdi
T(4;11) ploidy

Favorable
Hypodipl
T(12;21)
oidy

Trisomy
Ph +
4, 10, 17

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 High ●

●
Age <2 or >10
Initial WBC 50,000 or greater
Positive MRD at the end of induction

Risk ●
Sanctuary Site

Standar ●

●
Ages 2-10
Initial WBC 50,000 or less

d Risk Good initial response

●

Pediatrics
 I. History of
ALL Therapy

Pediatrics
 History of ALL Therapy
1949-1954: Clinical
Trials testing
combination
chemotherapy

1950:
-6-MP development
-Use of steroids in
cancer

Pediatrics
 ●
St. Jude Children’s conducts trials using new drug combinations; improves response.
1960s ●
Major breakthrough= aggressively treating brain/CSF with XRT and drugs
●
Ultimately, 50% patients were cured of leukemia.

●
The idea that cure of ALL was now possible was published.
1970s ●
Many colleagues thought this was irresponsible and gave false hope.
●
Better supportive care, NIH/public support, participation in studies

●
Bone marrow transplantation outcomes improved for kids
1980s ●
Few new chemotherapy agents were introduced

●
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”

●
Targeted therapies
2010 ●
Immunotherapies
●
Etcetera

Pediatrics
 • With in-depth studying of the
cancers, researchers
discovered that within what
they thought was one type of
childhood cancer -> there
History of were multiple variations ->
ALL Therapy “Treatment Stratification”
• Current treatment modalities:
Chemotherapy +/- radiation
+/- immunotherapy

Pediatrics
 Combination
Chemotherapy

Prophylactic
intrathecal
BIG Wins… chemotherapy to
prevent CNS
relapse

Forming the
COG/Clinical
research

Pediatrics
 II. Current ALL
Therapy

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)

Pediatrics
 Current ALL Therapy

• Children’s Oncology Group (COG)

• Special populations to consider:
-Infants
-Adolescents
-Down syndrome patients

Pediatrics
 • 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)-
Current ALL similar drugs as seen in
induction/consolidation; Goal:
Therapy 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

Pediatrics
 • Response to treatment via MRD:
*Minimal Residual Disease
Current ALL • Threshold = 0.01% (level of 1 in
10,000 cells)
Therapy *Greater than this is MRD
POSITIVE)

Pediatrics
 What is the current
survival rate?

Around 90%

Pediatrics
 Heart Failure Chemotherapy
y Con Nutritional
t h a s tip Deficits
ro p ati
e u SIADH on
l N

Acute and
r a Re
Vincristine
ip he Methotrexate na
inf Per L i Neurotoxicity
l inj
ec ve ury
tio rt
Dexamethasone
n ox
ici Transfusion
ty reactions
Doxorubicin
Weight Gain

Long Term
De
D lay VOD
y e e
PEG-Asparinginase
ta b il it ve d
lop Thioguanine
Os
teo
Irri me
n
He
m
ne
cro
Le x s
i t Cy orr sis
a a
l Vo s titi ha
r
Dis Mercaptopurine
nin ap h y mi ti SkinCytoxan gic
changes
s
ab g A n ng
iliti
es

Pediatrics
 III. Emerging ALL
Therapy

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

Pediatrics
 Blinatumamab

Inotuzamab
Immunotherapy
Ozogamacin

Chimeric Antigen
Receptor T-cells
(CAR-T cells)

Pediatrics
 Blinatumomab

Adapted from original illustration by Paulette Dennis

Pediatrics
 • CD22+ ALL
• Currently not open for
enrollment
Inotuzamab • Combined with frontline
chemotherapy in treating
Ozogamacin young adults with newly
diagnosed B-ALL (next phase
of trials)

Pediatrics
 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

Pediatrics
 • First-ever approved CAR T-
cell therapy for children and
young adults with advanced
ALL.
KymriahTM • Based on small clinical trial in
(Tisagenlecleucel ) which 83% of patients
achieved a complete
remission 3 months after
receiving the treatment.

Pediatrics
 Cytokine Release Syndrome
CAR-T Cell
Cytokine Release
Considerations Syndrome

• High tumor Burden

• Can happen on 1st
Fever
dose 6
• Tociluzumab- IL- Malaise
Immunosuppressant Rash
Leukemia
against IL-6 Cell Hypotension
• Supportive Care Respiratory
Symptoms

Pediatrics
Targeted therapy

Napper and Watson 2013

Pediatrics
 • Tyrosine kinase
inhibitors (TKI)- imatinib,
dasatinib, nilotinib, FLT3
Targeted inhibitors
• Monoclonal antibodies
therapy (Daratumumab, anti-
CD38)
• mTOR inhibitors
(rapamycin,
temsirolimus,
everolimus)
• JAK 1 & 2 inhibitors
• Aurora kinase inhibitors-
aurora kinase plays a
key role in cell division

Pediatrics
 Epigenetic therapy
Epigenetics: “Study of biochemical modifications of chromatin”
(Burke and Bhatla 2014)

Napper and Watson 2013

Napper and Watson 2013

Pediatrics
 DNA HISTONE MODIFICATIONS
METHYLATION/HYDROXYM (ACETYLATION, LYSINE
ETHYLATION METHYLATION)

ALTERATIONS IN NON-
CODING MICRORNAS
(MIRNAS)

Epigenetic
therapy

Pediatrics
 Long term effects

The
unknowns…
Bridge to transplant?

Pediatrics
 IV. Supportive
Care

Pediatrics
 • Heme-Onc mouthwash
(HOMW)
• Pneumocystis jirovecii
prophylaxis:
Bactrim,pentamadine
Supportive (inhaled/IV), dapsone
Care • Neutropenic fever precautions
• Antifungal prophylaxis for high
risk patients
• Immunoglobulin replacement
therapy (IVIG if IgG <500)

Pediatrics
 • 4yo CM presented to WL
Oncology clinic as referral from
WL Orthopedics due to “diffuse
osteoporosis noted on L femur
plain films”
Case 1- • History of questionable slow
G.M. healing L femur fracture, placed
in long leg cast x few weeks
(May 2017)
• ROS: “scalp lesions”, LUE pain,
loss of appetite

Pediatrics
 • 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
Case 1- pathological fractures secondary to
G.M. 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.

Pediatrics
 Diagnosis???
• A. Severe osteoporosis
• B. Severe anemia
Case 1-
G.M. • C. Slow healing fracture
• D. New onset leukemia
• Leukemia?

Pediatrics
 • BONE MARROW, BILATERAL
ANTERIOR ILIAC CREST CORE
BIOPSIES, LEFT ILIAC CREST
ASPIRATE, AND PERIPHERAL
BLOOD SMEAR (7/14/17): B-ACUTE
Case 1- LYMPHOBLASTIC LEUKEMIA.

G.M. 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.”

Pediatrics
 • 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
Case 2- compliance.
A.D. • 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

Pediatrics
 • 9/28/18:
• Presented for Maintenance
Cycle 6 ROV
Case 2- • No complaints on physical
exam
A.D. • Labs: WBC 70,000 with 83%
peripheral blasts

Pediatrics
 Diagnosis???
• A. Relapsed leukemia (if so,
where?)
Case 2- • B. False positive
A.D. • C. Infection
• D. Reaction to maintenance
chemotherapy

Pediatrics
 • S U R GI CAL PATH O LO GY 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.

Case 2- Comment: “Corresponding flow cytometric

studies performed at the Texas Children's
A.D. 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

Pediatrics
 Questions???

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

Pediatrics