Acute Lymphoblastic Leukemia

Risk Classification
 The patient’s response to initial therapy is strongly associated
with response to treatment.
 If a patient has many clinical and laboratory features that are
associated with a good response to chemotherapy, then the
clinician may choose to give less-intensive therapy to reduce
the risk of long-term adverse effects.
 Factors:
 Patient characteristics at diagnosis;
 Leukemic cell features at diagnosis;
 Patient response to initial therapy.
Risk Classification
 Patient Characteristics
 National Cancer Institute (NCI) Risk Classification
 Induction therapy is initially selected based on this classification,
which divides children into standard- or high- risk categories
based on age and initialWBC count.
Risk Classification
 Leukemic Cell Characteristics
 Several chromosomal abnormalities are associated with
prognosis.
 Favorable outcomes are associated with 3 copies of
chromosomes 4 and 10, high hyperdiploidy and the ETV6-
RUNX1 cryptic translocation.
 The Philadelphia chromosome which is present in 3-5% of
children and 25% in adults is associated with a poor prognosis.
Risk Classification
 Initial ResponseTo Therapy
 The strongest prognostic factor for outcome of ALL is response
to therapy.
 Children with a reduction of bone marrow lymphoblasts within
14 days of initiating chemotherapy (rapid early responders) have
a more favorable prognosis.
 Molecular measurement of minimal residual disease
(MRD) by either flow cytometry or polymerase chain reaction
has enabled detection of leukemic cells not visible on
morphologic examination to assess treatment response and
detect relapse in children and adults.
Risk Classification
 Initial ResponseTo Therapy
 Detect MRD  intensive therapy  dec risk of relapse
 Risk- and response- based classification of childhood ALL

 NCI Risk Classification is used first to determine initial risk.

 Following induction therapy, risk is reclassified based on the
rapidity and completeness of response to therapy, the presence
or absence of cytogenic abnormalities or CNS involvement.
 Patients are then classified with varying degrees of risk.
 Risk Classification
Low Risk

Standard Risk
Standard- or High-
Post-Induction Risk
NCI Risk Group Risk Remission
Assessment
Induction Therapy
High Risk

Very High Risk

Treatment
 Desired Outcomes
 Short-term goal: rapidly achieve a complete clinical and
hematologic remission
 Complete Remission (CR) – disappearance of all physical
and bone marrow evidence of leukemia, with restoration of
normal hematopoiesis
 Once CR is achieved – the next goal is to maintain the patient
in continuous CR.
 In general, a child is considered to be “cured” after bring in
continuous CR for 5-10 years.
Treatment
 Minimal Residual Disease (MRD) is a strong predictor
of relapse in ALL.
 Response to treatment is determined by intrinsic drug
sensitivity and the patient’s pharmacogenomics and
pharmacodynamics, treatment received, and treatment
adherence.
 Cure rates in children have risen from less than 5%with
treatments used in the 1960s to about 90% by 2005.
 The reason for this improvement lies largely in improved
scheduling of existing drugs, as relatively new drugs have
come to the market since the 1960s.
Treatment
 Although treatment results with adult ALL are worse than
those with childhood ALL, recent use of aggressive
chemotherapy in adult ALL has increased the CR rate from
60 to 85%.
 Long term event-free survival (EFS) in this population,
however, remains low (between 30-40%) because a higher
proportion of adults present with poor risk disease.
 CR rates and EFS vary according to a number of poor
prognostic factors and certain types of ALL are associated
with a very poor outcome.
Treatment Phases
 Treatment for childhood ALL is divided into 5 phases:
 1. induction,
 2. consolidation therapy,
 3. interim maintenance,
 4. delayed intensification,
 5. maintenance therapy.
 CNS prophylaxis is a mandatory requirement component of
ALL treatment regimens and is administered longitudinally
during all phases of treatment.
 Total duration of treatment is around 2-3 years.
Induction
 The goal of induction: to rapidly induce a complete clinical
and hematologic remission.
 The CR rate is 98% for standard-risk children treated with
vincristine, a glucocorticoid (dexamethasone or prednisone),
and asparaginase or pegaspargase.
 Most treatment protocols add daunorubicin to induction
(four-drug induction) for high-risk or very high-risk ALL,
while others add cyclophosphamide, methotrexate, or
cytarabine.
Induction
 Most children achieve a CR in 4 weeks, which would classify
them as rapid early responders.
 Prednisone has historically been the primary
glucocorticoid of choice used in pediatric ALL regimens.
 Dexamethasone is now being used in most standard-risk
protocols because of its longer duration of action and higher
CSF penetration compared to prednisone.
 However, dexamethasone increases the risk of side effects
such as osteonecrosis, mood alteration, steroid myopathy,
hyperglycemia and infections.
Induction
 The incidence of transient hyperglycemia during pediatric
ALL induction therapy has increased.
 Random serum glucose levels
 Asparaginase has historically been available in three forms.
 Asparaginase – no longer manufactured
 Pegaspargase – *pegylated E. coli asparaginase
 Erwinia asparaginase – isolated from E. chrysanthemi
 *Pegylation – prolongs its duration of activity and allows it to
be given less frequently, in addition fewer IM inj, decreased
antibody formation, and superior response rates.
Induction
 Asparaginase products are the chemotherapeutic agents most
likely to cause hypersensitivity reactions.
 Reactions usually occur during post-induction phases of a
therapy when asparaginase has not been given for a
prolonged period of time.
 Reaction of pegaspargase?
 Reaction of Erwinia asparaginase?
Central Nervous System Prophylaxis
 CNS prophylaxis is incorporated throughout in all phases of
therapy.
 The rationale is based on two observations.
 1. Many chemotherapeutic agents do not readily cross the blood
brain barrier.
 2. Results from early clinical trials of ALL showed that 50-85%
of patients with ALL and no CNS involvement at diagnosis
experience a CNS relapse.
 These observations indicate that the CNS is a potential
sanctuary for leukemic cells and undetectable leukemic cells
are present in the CNS of many patients at the time of
diagnosis.
Central Nervous System Prophylaxis
 Goal of CNS prophylaxis: eradicate undetectable leukemic
cells from the CNS while minimizing neurotoxicity and late
effects.
 Once CNS relapse has occurred, patients are at increased risk
of bone marrow relapse and death from refractory leukemia.
 However, this approach is associated with long-term sequelae
including neuropsychological deficits, precocious puberty,
osteoporosis, decreased intellect, thyroid dysfunction, brain
tumors, short stature, and obesity.
Central Nervous System Prophylaxis
 The CNS prophylaxis regimen is selected based on efficacy,
toxicity, and risk of CNS disease.
 Intrathecal chemotherapy, cranial irradiation,
dexamethasone, and high-dose IV methotrexate or cytarabine
can be used to treat or prevent CNS disease.
 Intrathecal therapy consists of methotrexate and cytarabine,
given either alone or in combination. When given together,
hydrocortisone is commonly added (triple therapy) to
decrease the incidence of arachnoiditis.
Central Nervous System Prophylaxis
 Triple intrathecal therapy is typically reserved for children
with refractory CNS disease.
 Doses of this chemotherapy used for childhood ALL are age-
based because of differences in the volume of CSF at various
ages.
Consolidation Therapy
 Consolidation therapy in ALL is started after a CR has been
achieved, and refers to a continued intensive chemotherapy
in an attempt to eradicate clinically undetectable disease in
order to secure (consolidate) the remission.
 Regimens usually incorporate either non-cross-resistant
drugs that are different from the induction regimen, or more
dose-intensive use of the same drugs.
Consolidation Therapy
 Randomized trials show that consolidation therapy clearly
improves patient outcomes in children, but its benefits in
adults is less clear.
 Standard consolidation lasts 4 weeks and usually consists of
vincristine, mercaptopurine, and intrathecal methotrexate.
 Patients who respond slowly to induction therapy are at
higher risk of relapse if they are not treated on more
aggressive regimens.
Consolidation Therapy
 Children with Ph+ ALL, infant MLL, or children who only
achieve a partial remission may undergo allogeneic
hematopoietic stem cell transplantation (HSCT) in first
remission if a suitable donor is available.
Reinduction
 ‘delayed intensification’ and interim maintenance
 One or two delayed intensification phases separated by low-
intensity interim maintenance cycles can be added to
maintenance remission and to decrease cumulative toxicity.
 Delayed intensification usually consists of drugs used during
induction and consolidation or agents that lack cross-
resistance with those already received such as
cyclophosphamide, methotrexate, and limited amounts of
doxorubicin.
Maintenance Therapy
 Maintenance therapy allows long-term drug exposure to
slowly dividing cells, allows the immune system time to
eradicate leukemia cells and promotes apoptosis.
 Goal of maintenance therapy: further eradicate residual
leukemic cells and prolong remission duration.
 Although maintenance therapy is clearly beneficial in
childhood ALL, the benefit in adults has only recently been
demonstrated.
Maintenance Therapy
 Maintenance therapy usually consists of daily mercaptopurine
and weekly methotrexate for 12-week courses, at doses that
produce relatively little myelosuppression, with monthly
“pulses” of vincristine and a steroid for 5 days per month.
 Mercaptopurine cannot be given with milk or milk products
because of the presence of xanthine oxidase.
Philadelphia Chromosome + ALL
 Ph+ ALL has a 45% 7-year EFS and has historically been
treated as very high-risk disease. This includes a four-drug
induction.
 There is the addition of continuous imatinib mesylate, a
signal transduction inhibitor, that inhibits BCR-ABL kinase.
ALL in Infants
 ALL and AML in infants younger than 1 year of age account
for less than 5% of the reported acute leukemias in
childhood, but they are associated with poor outcomes.
 Age younger than 6 months at diagnosis and poor response to
prednisone alone given prior to starting other agents are
poor prognostic factors.
 Although intensive regimens such as high-dose methotrexate
and high-dose cytarabine have improved survival rates they
resulted in unacceptably high mortality rates.
ALL in Adolescents & Young Adults
 Although ALL is relatively uncommon in adolescent and
young adults (15-39 years old), the outcomes are generally
worse than for childhood ALL.
 The adult regimens studies were more myelosuppressive,
while the pediatric regimens intensified steroids and
asparaginase and included earlier and more intensive CNS-
directed therapy.
 Adult regimen or pediatric regimen?
ALL in Adults
 Treatment risk stratification for adult patients differs
depending on age and Ph+ status.
 The National Comprehensive Cancer Network (NCCN)
guidelines recommend different strategies for adolescents
and young adults, adults (40-65 years old) and adults older
than 65 years with or without poor performance status.
 Poorer outcomes in adults have been attributed to differences
in cytogenetic abnormalities, greater drug resistance, higher
risk of treatment-related adverse effects with subsequent
nonadherence, and possibly less effective therapy.
ALL in Adults
 hyperCVAD
 hyper – high dose methotrexate and cytarabine
Alternating with…
 C – fractionated cyclophosphamide
 V – vincristine
 A – doxorubicin
 D – dexamethasone

 hyperCVAD may improve response and survival in adults with

ALL; considerable number of cases occur in patients who are 65
years and older
ALL in Adults
 For patients older than 65 years of age or for those with a
poor performance status, induction regimens may include
concurrent chemotherapy with a tyrosine kinase inhibitor,
either alone or combined with corticosteroids. Based on
these data, the combination of imatinib with concurrent
chemotherapy is currently considered as the standard of care
for first-line therapy.
ALL in Adults
 HSCT plays an important role in the treatment of adult
patients with ALL.
 After HSCT, patients should continue with standard
maintenance therapy that includes a tyrosine kinase inhibitor.
Relapsed ALL
 About 20% of children with ALL will relapse. The most
common site for relapse is the bone marrow (53%), although
isolated relapses can occur in the CNS (19%) or testicles
(5%), in addition to multiple sites of disease.
 Children who fail to achieve a CR by day 29 of initial
remission induction therapy usually receive an additional two
weeks of four-drug induction therapy.
 If the children do not achieve a CR with the additional
therapy, they are usually treated for bone marrow relapse
consisting of intensive induction therapy consisting of at least
three cycles of chemotherapy.
Relapsed ALL
 Patients who have completed treatment and have stayed in
remission for longer periods are more likely to be reinduced
into remission again.
 Patients with more favorable risk initially, and those who
received less intensive initial treatments, are more likely to
respond well to reinduction/salvage regimens.
Late Effects of Treatment
 Leukemia survivors are 3.7 times more likely to develop a
severe or life-threatening chronic health condition as
compared with healthy siblings, and 2.8 times more likely to
report multiple chronic conditions.
 Older ALL regimens that incorporated the intensive use of
topoisomerase II inhibitors (e.g., etoposide and teniposide)
are associated with unacceptably high risks of development of
secondary leukemia.
 Cranial irradiation is also associated with learning deficits,
especially in patients younger than 5 years of age at the time
of treatment.