- Sprycel is the first and only second-generation tyrosine kinase inhibitor for pediatric patients for the treatment of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia in combination with chemotherapy
- Approval marks second pediatric leukemia indication for Sprycel 1
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers
Squibb Company (NYSE:BMY) today announced the U.S. Food and Drug
Administration (FDA) has expanded the indication for Sprycel
®
(dasatinib) tablets to include the treatment of pediatric patients one
year of age and older with newly diagnosed Philadelphia
chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in
combination with chemotherapy.1 Sprycel is the only
second-generation tyrosine kinase inhibitor approved for this patient
population. The approval, which was granted following priority review by
the FDA, is based on data from the Phase 2 study, CA180-372
(NCT01460160).
“We recognize the urgency around developing and delivering therapies for
children and young adults living with cancer, and today’s approval is an
important example of our commitment to pediatric oncology,” said Jeffrey
Jackson, Ph.D., development lead, hematology, Bristol-Myers Squibb.
“Building on our previous indication for children with Ph+ chronic
myeloid leukemia in chronic phase, we’re pleased to bring Sprycel
tablets to a second type of pediatric leukemia. This approval will give
physicians another treatment option to offer appropriate pediatric
patients with Ph+ ALL.”
Sprycel is associated with the following Warnings and
Precautions: myelosuppression, bleeding-related events, fluid retention,
cardiovascular events, pulmonary arterial hypertension, QT prolongation,
severe dermatologic reactions, tumor lysis syndrome, embryo-fetal
toxicity and effects on growth and development in pediatric patients.1
Please see detailed Important Safety Information below.
The efficacy of Sprycel tablets in combination with chemotherapy
was evaluated in a single cohort of the Phase 2, multicenter, single-arm
CA180-372 study, which included 78 pediatric patients with newly
diagnosed B-cell precursor Ph+ ALL.1,2 At three years, the
study demonstrated an event-free survival (EFS) binary rate of 64.1%
(95% confidence interval [CI]: 52.4 to 74.7).1 Event-free
survival is defined as the time from the start of Sprycel to lack
of complete response at the end of the third high-risk block, relapse,
secondary malignancy or death from any cause.
Of the 81 patients evaluated for safety, fatal adverse reactions
occurred in three patients (4%), and eight (10%) experienced adverse
reactions leading to treatment discontinuation, including fungal sepsis,
hepatotoxicity of graft versus host disease, thrombocytopenia, CMV
infection, pneumonia, nausea, enteritis and drug hypersensitivity.1 The
most common serious adverse reactions (incidence ≥10%) were pyrexia,
febrile neutropenia, mucositis, diarrhea, sepsis, hypotension,
infections (bacterial, viral and fungal), hypersensitivity, vomiting,
renal insufficiency, abdominal pain and musculoskeletal pain.1
“As treatments have advanced in recent years, we’ve seen improvements in
outcomes for pediatric patients with Ph+ ALL overall, but there remains
a need for additional options,”3 said Stephen Hunger, MD,
lead study author, chief of the division of oncology and director of the
Center for Childhood Cancer Research at Children’s Hospital of
Philadelphia. “The Phase 2 CA180-372 trial was particularly informative
because it was designed to limit the use of cranial irradiation and stem
cell transplant. In the study, Sprycel plus chemotherapy
demonstrated a three-year event-free survival benefit. These
results show that Sprycel is an effective medication for
physicians to consider for children and adolescents with Ph+ ALL.”1,4
Acute lymphoblastic leukemia is characterized by chromosomal
abnormalities and genetic alterations involved in the differentiation
and proliferation of lymphoid precursor cells.5 The most
common childhood cancer in the United States, ALL represents 20% of all
cancers diagnosed in persons aged less than 20 years, or more than 3,000
new cases each year.6 Three percent of children who have ALL
have the Ph+ subtype, which means they have a chromosome alteration that
results in a specific mutation of the BCR-ABL gene.3
“Coping with a pediatric cancer diagnosis, including searching for and
identifying the right treatment regimen, can take a physical and
emotional toll on patients and their families,” said Vickie Buenger,
president of the Coalition Against Childhood Cancer (CAC2). “The
availability of another option is a welcome step forward for those
affected by this disease.”
In addition to this pediatric approval, Sprycel is approved for
use in children one year of age and older with Ph+ chronic myeloid
leukemia (CML) in chronic phase (CP).1
About the Phase 2 CA180-372 Study
In the CA180-372 trial, the 78 patients evaluated for efficacy in cohort
1 received Sprycel at a daily dose of 60 mg/m2 for up
to 24 months, in combination with chemotherapy.1 The backbone
chemotherapy regimen was the AIEOP-BFM ALL 2000 multi-agent chemotherapy
protocol.1 Efficacy was established based on three-year EFS,
defined as the time from the start of Sprycel to lack of complete
response at the end of the third high-risk block, relapse, secondary
malignancy or death from any cause.1 The trial was designed
such that patients with central nervous system 3 disease receive cranial
irradiation.4 Patients were assigned to receive stem cell
transplant (SCT) based on minimal residual disease if they were
considered high-risk.4 Data from the CA180-372 trial were
presented at the 2017 American Society of Hematology Annual Meeting.
The recommended starting dosage for Sprycel in pediatric
patients with Ph+ ALL is based on body weight.1 The
recommended dose should be administered orally once daily, and the dose
should be recalculated every three months based on changes in body
weight, or more often if necessary.1 For pediatric patients
with Ph+ ALL, Sprycel therapy should begin on or before day 15 of
induction chemotherapy, when diagnosis is confirmed, and continue for
two years.1
Sprycel tablets should not be crushed, cut or chewed.1
Tablets should be swallowed whole; however, there are additional
administration considerations for pediatric patients who have difficulty
swallowing tablets whole.1 Five patients with Ph+ ALL 2 to 10
years of age received at least one dose of Sprycel tablet
dispersed in juice on Study CA180-372. The exposure for dispersed
tablets was estimated to be 36% lower as compared to intact tablets in
pediatric patients. Due to the limited available clinical data, it is
unclear whether dispersing Sprycel tablets significantly alters
the safety and/or efficacy of Sprycel.
Select Safety Profile for the CA180-372 Study
In the CA180-372 study, 81 pediatric patients with Ph+ ALL received Sprycel
continuously in combination with chemotherapy.1 The
median duration of therapy was 24 months (range 2 to 27 months).1
Among these patients, the most common adverse reactions (reported in at
least 20% of patients) were mucositis (93%), febrile neutropenia (86%),
pyrexia (85%), diarrhea (84%), nausea (84%), vomiting (83%),
musculoskeletal pain (83%), abdominal pain (78%), cough (78%), headache
(77%), rash (68%), fatigue (59%), constipation (57%), arrhythmia (47%),
hypertension (47%), edema (47%), viral infection (40%), hypotension
(40%), decreased appetite (38%), hypersensitivity (36%), upper
respiratory tract infection (36%), dyspnea (35%), epistaxis (31%),
peripheral neuropathy (31%), altered state of consciousness (30%),
fungal infection (30%), pneumonia (excluding fungal) (28%), pruritus
(28%), Clostridial infection (excluding sepsis) (25%), urinary tract
infection (24%), bacteremia (excluding fungal) (22%), erythema (22%),
chills (21%), pleural effusion (21%), sinusitis (21%), dehydration
(20%), renal insufficiency (20%) and visual impairment (20%).1
INDICATIONS
SPRYCEL® (dasatinib) is indicated for the treatment of adult
patients with:
-
Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid
leukemia (CML) in chronic phase
-
Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with
resistance or intolerance to prior therapy including imatinib
-
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+
ALL) with resistance or intolerance to prior therapy
SPRYCEL is indicated for the treatment of pediatric patients 1 year of
age and older with:
-
Ph+ CML in chronic phase
-
Newly diagnosed Ph+ ALL in combination with chemotherapy
SPRYCEL (100 mg) is a tablet.
IMPORTANT SAFETY INFORMATION
Myelosuppression:
Treatment with SPRYCEL is associated with severe (NCI CTCAE Grade 3/4)
thrombocytopenia, neutropenia, and anemia, which occur earlier and more
frequently in patients with advanced phase CML or Ph+ ALL than in
patients with chronic phase CML. Myelosuppression was reported in
patients with normal baseline laboratory values as well as in patients
with pre-existing laboratory abnormalities.
-
In patients with chronic phase CML, perform complete blood counts
(CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or
as clinically indicated
-
In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly
for the first 2 months and then monthly thereafter, or as clinically
indicated
-
In pediatric patients with Ph+ ALL treated with SPRYCEL in combination
with chemotherapy, perform CBCs prior to the start of each block of
chemotherapy and as clinically indicated. During the consolidation
blocks of chemotherapy, perform CBCs every 2 days until recovery
-
Myelosuppression is generally reversible and usually managed by
withholding SPRYCEL temporarily and/or dose reduction
-
In clinical studies, myelosuppression may have also been managed by
discontinuation of study therapy
-
Hematopoietic growth factor has been used in patients with
resistant myelosuppression
Bleeding-Related Events:
SPRYCEL can cause serious and fatal bleeding. In all CML or Ph+ ALL
clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages,
including fatalities, occurred in <1% of patients receiving SPRYCEL. The
incidence of Grade 3/4 hemorrhage, occurred in 5.8% of adult patients
and generally required treatment interruptions and transfusions. The
incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The
most frequent site of hemorrhage was gastrointestinal.
-
Most bleeding events in clinical studies were associated with severe
thrombocytopenia
-
In addition to causing thrombocytopenia in human subjects, dasatinib
caused platelet dysfunction in vitro
-
Concomitant medications that inhibit platelet function or
anticoagulants may increase the risk of hemorrhage
Fluid Retention:
SPRYCEL may cause fluid retention. After 5 years of follow-up in the
adult randomized newly diagnosed chronic phase CML study (n=258), Grade
3/4 fluid retention was reported in 5% of patients, including 3% of
patients with Grade 3/4 pleural effusion. In adult patients with newly
diagnosed or imatinib resistant or intolerant chronic phase CML, grade
3/4 fluid retention occurred in 6% of patients treated with SPRYCEL at
the recommended dose (n=548). In adult patients with advanced phase CML
or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade
3/4 fluid retention was reported in 8% of patients, including grade 3/4
pleural effusion reported in 7% of patients. In pediatric patients with
chronic phase CML, cases of Grade 1 or 2 fluid retention were reported
in 10.3% of patients.
-
Patients who develop symptoms of pleural effusion or other fluid
retention, such as new or worsened dyspnea on exertion or at rest,
pleuritic chest pain, or dry cough, should be evaluated promptly with
a chest x-ray or additional diagnostic imaging as appropriate
-
Fluid retention events were typically managed by supportive care
measures that may include diuretics or short courses of steroids
-
Severe pleural effusion may require thoracentesis and oxygen therapy
-
Consider dose reduction or treatment interruption
Cardiovascular Events:
SPRYCEL can cause cardiac dysfunction. After 5 years of follow-up in the
randomized newly diagnosed chronic phase CML trial in adults (n=258),
the following cardiac adverse reactions occurred:
-
Cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac
related fluid retention (8.5% dasatinib vs 3.9% imatinib), and
conduction system abnormalities, most commonly arrhythmia and
palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of
peripheral arterial occlusive disease occurred with imatinib and 2
(0.8%) transient ischemic attacks occurred with dasatinib
Monitor patients for signs or symptoms consistent with cardiac
dysfunction and treat appropriately.
Pulmonary Arterial Hypertension (PAH):
SPRYCEL may increase the risk of developing PAH in adult and pediatric
patients, which may occur any time after initiation, including after
more than 1 year of treatment. Manifestations include dyspnea, fatigue,
hypoxia, and fluid retention. PAH may be reversible on discontinuation
of SPRYCEL.
-
Evaluate patients for signs and symptoms of underlying cardiopulmonary
disease prior to initiating SPRYCEL and during treatment. If PAH is
confirmed, SPRYCEL should be permanently discontinued
QT Prolongation:
SPRYCEL may increase the risk of prolongation of QTc in patients
including those with hypokalemia or hypomagnesemia, patients with
congenital long QT syndrome, patients taking antiarrhythmic medicines or
other medicinal products that lead to QT prolongation, and cumulative
high-dose anthracycline therapy.
-
Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL
administration
Severe Dermatologic Reactions:
Cases of severe mucocutaneous dermatologic reactions, including
Stevens-Johnson syndrome and erythema multiforme, have been reported in
patients treated with SPRYCEL.
-
Discontinue permanently in patients who experience a severe
mucocutaneous reaction during treatment if no other etiology can be
identified
Tumor Lysis Syndrome (TLS):
TLS has been reported in patients with resistance to prior imatinib
therapy, primarily in advanced phase disease.
-
Due to potential for TLS, maintain adequate hydration, correct uric
acid levels prior to initiating therapy with SPRYCEL, and monitor
electrolyte levels
-
Patients with advanced stage disease and/or high tumor burden may be
at increased risk and should be monitored more frequently
Embryo-Fetal Toxicity:
Based on limited human data, SPRYCEL can cause fetal harm when
administered to a pregnant woman. Hydrops fetalis, fetal leukopenia, and
fetal thrombocytopenia have been reported with maternal exposure to
SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal
plasma and amniotic fluid at concentrations comparable to those in
maternal plasma.
-
Advise females of reproductive potential to avoid pregnancy, which may
include the use of effective contraception, during treatment with
SPRYCEL and for 30 days after the final dose
Effects on Growth and Development in Pediatric Patients:
In pediatric trials of SPRYCEL in chronic phase CML after at least 2
years of treatment, adverse reactions associated with bone growth and
development were reported in 5 (5.2%) patients, one of which was severe
in intensity (Growth Retardation Grade 3). These 5 cases included cases
of epiphyses delayed fusion, osteopenia, growth retardation, and
gynecomastia. Of these 5 cases, 1 case of osteopenia and 1 case of
gynecomastia resolved during treatment.
Monitor bone growth and development in pediatric patients.
Lactation:
No data are available regarding the presence of dasatinib in human milk,
the effects of the drug on the breastfed child, or the effects of the
drug on milk production. However, dasatinib is present in the milk of
lactating rats.
-
Because of the potential for serious adverse reactions in nursing
children from SPRYCEL, breastfeeding is not recommended during
treatment with SPRYCEL and for 2 weeks after the final dose
Drug Interactions:
Effect of Other Drugs on Dasatinib
-
Strong CYP3A4 inhibitors: The coadministration with strong
CYP3A inhibitors may increase dasatinib concentrations. Increased
dasatinib concentrations may increase the risk of toxicity. Avoid
concomitant use of strong CYP3A4 inhibitors. If concomitant
administration of a strong CYP3A4 inhibitor cannot be avoided,
consider a SPRYCEL dose reduction
-
Grapefruit juice may increase plasma concentrations of
SPRYCEL and should be avoided
-
Strong CYP3A4 inducers: The coadministration of SPRYCEL with
strong CYP3A inducers may decrease dasatinib concentrations. Decreased
dasatinib concentrations may reduce efficacy. Consider alternative
drugs with less enzyme induction potential. If concomitant
administration of a strong CYP3A4 inducer cannot be avoided, consider
a SPRYCEL dose increase
-
St. John’s wort may decrease plasma concentrations of
SPRYCEL and should be avoided
-
Gastric Acid Reducing Agents: The coadministration of SPRYCEL
with a gastric acid reducing agent may decrease the concentrations of
dasatinib. Decreased dasatinib concentrations may reduce efficacy.
Do not administer H2 antagonists or proton pump
inhibitors with SPRYCEL. Consider the use of antacids in place of H2 antagonists
or proton pump inhibitors. Administer the antacid at least 2 hours prior
to or 2 hours after the dose of SPRYCEL. Avoid simultaneous
administration of SPRYCEL with antacids.
Adverse Reactions:
The safety data reflects exposure to SPRYCEL administered as
single-agent therapy at all doses tested in clinical studies (n=2809)
including 324 adult patients with newly diagnosed chronic phase CML,
2388 adult patients with imatinib-resistant or -intolerant chronic or
advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic
phase CML.
The median duration of therapy in a total of 2712 SPRYCEL-treated adult
patients was 19.2 months (range 0–93.2 months). Median duration of
therapy in:
-
1618 adult patients with chronic phase CML was 29 months (range 0–92.9
months)
-
Median duration for 324 adult patients in the newly diagnosed
chronic phase CML trial was approximately 60 months
-
1094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months
(range 0–93.2 months)
In two non-randomized trials in 97 pediatric patients with chronic phase
CML (51 patients newly diagnosed and 46 patients resistant or intolerant
to previous treatment with imatinib), the median duration of therapy was
51.1 months (range 1.9 to 99.6 months).
In a multicohort study of SPRYCEL administered continuously in
combination with multiagent chemotherapy in 81 pediatric patients with
newly diagnosed Ph+ ALL, the median duration of therapy was 24 months
(range 2 to 27 months).
In the newly diagnosed adult chronic phase CML trial, after a minimum of
60 months of follow-up, the cumulative discontinuation rate for 258
patients was 39%.
In the overall population of 2712 adult patients, 88% of patients
experienced adverse reactions at some time, and 19% experienced adverse
reactions leading to treatment discontinuation.
Among the 1618 adult patients with chronic phase CML, drug-related
adverse reactions leading to discontinuation were reported in 329
(20.3%) patients.
-
In the adult newly diagnosed chronic phase CML trial, drug was
discontinued for adverse reactions in 16% of SPRYCEL-treated patients
with a minimum of 60 months of follow-up
Among the 1094 patients with advanced phase CML or Ph+ ALL, drug-related
adverse reactions leading to discontinuation were reported in 191
(17.5%) patients.
Among the 97 CML pediatric subjects, drug-related adverse reactions
leading to discontinuation were reported in 1 patient (1%).
Patients ≥65 years are more likely to experience the commonly reported
adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea,
cough, lower gastrointestinal hemorrhage, and appetite disturbance, and
more likely to experience the less frequently reported adverse reactions
of abdominal distention, dizziness, pericardial effusion, congestive
heart failure, hypertension, pulmonary edema, and weight decrease, and
should be monitored closely.
-
In adult newly diagnosed chronic phase CML patients:
-
Drug-related serious adverse reactions (SARs) were reported for
16.7% of patients. Serious adverse reactions reported in ≥5% of
patients included pleural effusion (5%)
-
Grade 3/4 laboratory abnormalities included neutropenia (29%),
thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%),
hypocalcemia (4%), elevated bilirubin (1%), and elevated
creatinine (1%)
-
In adult patients resistant or intolerant to prior imatinib therapy:
-
Drug-related SARs were reported for 26.1% of SPRYCEL-treated
patients treated at the recommended dose of 100 mg once daily in
the randomized dose-optimization trial of patients with chronic
phase CML resistant or intolerant to prior imatinib therapy.
Serious adverse reactions reported in ≥5% of patients included
pleural effusion (10%)
-
Grade 3/4 hematologic laboratory abnormalities in chronic phase
CML patients resistant or intolerant to prior imatinib therapy who
received SPRYCEL 100 mg once daily with a minimum follow up of 60
months included neutropenia (36%), thrombocytopenia (24%), and
anemia (13%). Other grade 3/4 laboratory abnormalities included:
hypophosphatemia (10%), and hypokalemia (2%)
-
Among chronic phase CML patients with resistance or intolerance to
prior imatinib therapy, cumulative grade 3/4 cytopenias were
similar at 2 and 5 years including: neutropenia (36% vs 36%),
thrombocytopenia (23% vs 24%), and anemia (13% vs 13%)
-
Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4
hypocalcemia, hypokalemia, and hypophosphatemia were reported in
patients with all phases of CML
-
Elevations in transaminases or bilirubin were usually managed with
dose reduction or interruption
-
Patients developing Grade 3/4 hypocalcemia during the course of
SPRYCEL therapy often had recovery with oral calcium
supplementation
-
In pediatric subjects with Ph+ CML in chronic phase
-
Drug-related SARs were reported for 14.4% of pediatric patients
-
Adverse reactions associated with bone growth and development were
reported in 5 (5.2%) of pediatric patients with chronic phase CML
-
In the pediatric studies, the rates of laboratory abnormalities
were consistent with the known profile for laboratory parameters
in adults
-
In pediatric subjects with Ph+ ALL who were administered SPRYCEL in
combination with multiagent chemotherapy
-
Fatal adverse reactions occurred in 3 patients (4%), all of which
were due to infections
-
Eight patients (10%) experienced adverse reactions leading to
treatment discontinuation
-
The most common serious adverse reactions (incidence ≥10%) were
pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis,
hypotension, infections (bacterial, viral and fungal),
hypersensitivity, vomiting, renal insufficiency, abdominal pain,
and musculoskeletal pain
-
Grade 3/4 laboratory abnormalities (≥10%) included neutropenia
(96%), thrombocytopenia (88%), anemia (82%), elevated SGPT (ALT)
(47%), hypokalemia (40%), elevated SGOT (AST) (26%), hypocalcemia
(19%), hyponatremia (19%), elevated bilirubin (11%), and
hypophosphatemia (11%)
Most common adverse reactions (≥15%) in patients receiving SPRYCEL as
single-agent therapy included myelosuppression, fluid retention events,
diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and
musculoskeletal pain.
Most common adverse reactions (≥30%) in pediatric patients receiving
SPRYCEL in combination with chemotherapy included mucositis, febrile
neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain,
abdominal pain, cough, headache, rash, fatigue, constipation,
arrhythmia, hypertension, edema, infections (bacterial, viral and
fungal), hypotension, decreased appetite, hypersensitivity, dyspnea,
epistaxis, peripheral neuropathy, and altered state of consciousness.
Please see full
Prescribing
Information
.
SPRYCEL® is a trademark of Bristol-Myers Squibb Company.
About Sprycel
Sprycel first received FDA approval in 2006 for the treatment of
adults with Ph+ CML in CP who are resistant or intolerant to prior
therapy including imatinib. At that time, Sprycel was also
approved for adults with Ph+ ALL who are resistant or intolerant to
prior therapy. Sprycel is approved and marketed worldwide for
these indications in more than 60 countries.
Sprycel is also an FDA-approved treatment for adults with newly
diagnosed CP Ph+ CML, and in November 2017, Sprycel received FDA
approval for the expanded indication for treatment in pediatric patients
with CP Ph+ CML. The adult indication is approved in more than 50
countries.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission
is to discover, develop and deliver innovative medicines that help
patients prevail over serious diseases. For more information about
Bristol-Myers Squibb, visit us at BMS.com
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References
1. Sprycel Prescribing Information. Sprycel U.S.
Product Information. Last Updated: December 2018. Princeton, NJ:
Bristol-Myers Squibb Company.
2. ClinicalTrials.gov. A Phase 2 Multi-Center, Historically Controlled
Study of Dasatinib Added to Standard Chemotherapy in Pediatric Patients
With Newly Diagnosed Philadelphia Chromosome Positive Acute
Lymphoblastic Leukemia. https://clinicaltrials.gov/ct2/show/NCT01460160?term=CA+180-372&rank=1#wrapper.
Accessed January 2, 2019.
3. PDQ Pediatric Treatment Editorial Board, Childhood Acute
Lymphoblastic Leukemia Treatment, PDQ Cancer Information Summaries. https://www.ncbi.nlm.nih.gov/books/NBK65763/?report=printable.
Last Accessed: November 28, 2018
4. Hunger S, Vaskar S, Devidas M, et al. CA180-372: An International
Collaborative Phase 2 Trial of Dasatinib and Chemotherapy in Pediatric
Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute
Lymphoblastic Leukemia (Ph+ ALL). Presentation at: American Society of
Hematology Annual Meeting; December, 2017; San Diego, CA.
5. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a
comprehensive review and 2017 update. Blood Cancer J. 2017;7(6).
6. Siegel DA, Henley SJ, Li J, et al. Rates and Trends of Pediatric
Acute Lymphoblastic Leukemia-United States, 2001-2014. MMWR Morb
Mortal Wkly Rep. 2017;66:950-954.
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