Term
| pathophysiology of adult leukemias |
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Definition
leukemia may develop at any stage and within any cell line
features common with acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL):
both arise from a single leukemia cell that expands and acquires additional mutations, culminating in a monoclonal population of leukemia cells
failure to maintain a balance between proliferation and differentiation, so that the cells do not differentiate past a particular stage of hematopoiesis, but then proliferate uncontrollably |
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Term
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Definition
| defect in the pluripotent stem cell or a more commited myeloid precursor, resulting in partial differentiation and proliferation of immature precursors of the myeloid blood forming cells |
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Term
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Definition
| proliferation of immature lymphoblasts at the level of the lymphopoietic stem cell or a very early lymphoid precursor |
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Term
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Definition
cause unknown
history of chemotherapy
etoposide and tenoposide treatment in childhood increase the risk of development of AML later in life
history of ionizing radiation
viruses:
human T cell lymphotrophic virus 1 (HTLV-1)
link between RNA or DNA based virus alone as cause of acute leukemia
potential environmental carcinogens:
low dose radiation (controversial)
chemical exposures (ex. benzene)
cigarette smoke
electromagnetic radiation (controversial)
genetic
immunologic predisposition |
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Term
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Definition
need a bone marrow biopsy for diagnosis
percentage of blasts required for diagnosis of AML = 20%
diagnosis of leukemia permitted with < 20% blasts in patients with specific molecular translocations
ANEMIA:
fatigue, malaise, weakness
palpitations, DOE
THROMBOCYTOPENIA:
bruising, petechiae, eccyhmosis
heavy and/or prolonged menses
bleeding - epistasis, gingival bleeding, conjunctival hemorrhage
NEUTROPENIA:
infection
marrow is not producing normal cells; crowded out by malignant cells
SKIN MANIFESTATIONS:
gum or skin infiltration (chloroma)
RENAL INSUFFICIENCY
potentially secondary to TLS
PAIN
bone pain with increased WBC (rare)
pain secondary to leukemic infiltration
DISSEMINATED INTRAVASCULAR COAGULATION:
APML or M5
manifestation = hemorrhage
monitoring parameters - fibrinogen, Pt, aPTT
LEUKOCYTOSIS
PERIPHERAL BLASTS
INCREASED SERUM LACTATE DEHYDROGENASE (LDH)
INCREASED URIC ACID
CNS MANIFESTATIONS:
uncommon in AML
seen with M4 and M5 |
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Term
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Definition
history of PE
WBC count with differential, H/H, platelets
coagulation studies and fibrinogen
electrolytes, SCr, uric acid, calcium, phosphorous
examination of peripheral blood smear, bone marrow biospy, and aspirate |
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Term
| prognostic factors of AML |
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Definition
age:
advanced age (>60) associated with decreased survival
etiology:
MDS (myelodysplastic syndroms) or chemotherapy induced AML associated with lower complete remission rates
cytogenics
response to treatment:
difficulty obtaining complete remission (poor prognosis)
duration of remission < 6 months (poor prognosis)
classification subtype:
M6, M7 (worse prgnosis)
elevated LDH:
> 3 x upper limit of normal (higher disease burden) |
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Term
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Definition
initiate ASAP after definitive diagnosis
treatment strategies may be modified based on patient comorbidities
treatment intent is curative for majority
INDUCTION
CONSOLIDATION
INTENSIFICATION |
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Term
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Definition
GOAL:
induce a complete remission (CR)
eradicate the leukemia clone to allow restoration of normal hematopoiesis
CR criteria:
no peripheral leukemmia cells
peripheral blood ANC > 1500
platelet count > 100 x 10^9/L
bone marrow < 5% blasts
extramedullary leukemia (ex. soft tissue disease) not present
STANDARD INDUCTION THERAPY:
cytarabine + anthracycline (idarubicin, daunorubicin) OR mitoxantrone
dose of cytarabine may be increased for younger patients
patients 60 yoa or older with a good performance status should be considered for clinical trial if available
patients with significant comorbidities causing organ dysfunction not directly related to leukemia should be considered for best supportive care
ADRS OF CYTARABINE = ara-c syndrome, conjunctivitis
anthracycline ADR = cardiac toxicity |
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Term
| AML induction - complications of care |
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Definition
tumor lysis syndrome
myelosuppression: neutropenia, anemia, thrombocytopenia |
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Term
| AML consolidation (adult) |
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Definition
GOAL:
eliminate any residual (undetectable) leukemia cells to maintain remission and prevent recurrence of leukemia
options:
use of the same agents during induction therapy
use of different agents and/or higher doses of agents
consolidation with similar agents used in induction:
survival rates up to 20%
patients 60 yoa and older - standard dose cytarabine +/- anthracyclins x1-3 cycles
patients < 60 yoa - more aggressive regimens |
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Term
| AML intensification (adult) |
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Definition
high dose cytarabine - used preferentially in patients < 60 yoa with intermediate risk or good risk cytogenetics
myeloablative therapy with allogegneic hematopoietic stem cell transplantation
myeloablative therapy and autologous hematopoietic stem cell transplantation
non-myeloablative allogeneic stem cell transplant |
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Term
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Definition
ADRs:
CEREBELLAR DYSFUNCTION:
characterized by ataxia, nystagmus, dysarthria
risk factors = older age, renal dysfunction, dose, schedule, increased alkaline phosphatase
monitoring: neurologic status q8h
management: hold dose with any indication of neurotoxicity
retreatment: may be able to retreat at a reduced dose
OCULAR TOXICITY
PULMONARY EDEMA
GI TOXICITY
SKIN |
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Term
| refractory/relapsed AML (adult) |
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Definition
additional chemotherapy (induction therapy)
myeloablative therapy with allogeneic hematopoietic stem cell transplantation
investigation therapies |
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Term
| acute promyelocytic leukemia (APML) |
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Definition
INDUCTION THERAPY:
all trans retinoic acid (ATRA) + idarubicin or daunorubicin
CONSOLIDATION THERAPY:
idarubicin or daunorubicin x 2 cycles
MAINTENANCE THERAPY:
ATRA +/- 6-mercaptopurine + methotrexate x1-2 years |
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Term
| all trans retinoic acid (ATRA) |
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Definition
causes proliferation of the abnormal clone causing maturation, eventual terminal differentiation, and apoptosis
CR > 90% with newly diagnosed
resistance develops when ATRA used alone in APML
ATRA does not worsen coagulation defects; causes stabilization and improvement of condition within days |
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Term
| acute promyelocytic leukemia (APML) retinoic acid syndrome (RAS) |
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Definition
occurs in 25% of patients
management:
dexamethasone
characteristics:
fever
dyspnea
peripheral edema
serositis - pleural effusion, pericardial effusion
hypotension
edema |
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Term
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Definition
arsenic trioxide:
associated with APML differentiation syndrome (similar to RAS)
cardiac toxicity
T wave abnormalities, 2nd degree heart block, ventricular arrhythmia
EKG monitoring for QTc prolongation
electrolyte management - potassium, magnesium, calcium
after induction, the patient gets a bone marrow transplant
matched sibling allogeneic hematopoietic stem cell transplantation
matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation |
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Term
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Definition
short remission (<1 year):
arsenic trioxide followed by autologous SCT
long remission (> 1 year):
arsenic trioxide or ATRA + anthracycline followed by autologous SCT |
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Term
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Definition
cause unknown in most cases
chemical exposure
genetic conditions:
Down's syndrome
Bloom syndrome
Fanconi anemia
Agnogenic myeloid metaplasia
CML
MDS
Kleinfelter syndrome |
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Term
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Definition
ANEMIA:
fatigue, malaise, weakness
palpitations, DOE
THROMBOCYTOPENIA:
bruising, petechiae, eccyhmosis
heavy and/or prolonged menses
bleeding: epistaxis, gingival bleeding, conjunctival hemorrhage
NEUTROPENIA:
infection
RENAL INSUFFICIENCY
PAIN:
bone pain with increased WBC (rare)
pain secondary to leukemic infiltration
more common with ALL than AML
CNS MANIFESTATIONS
more common with ALL than AML
ANOREXIA AND WEIGHT LOSS
HEPATOMEGALY (50%)
SPLENOMEGALY (75%)
MEDIASTINAL MASS (T-cell ALL)
LEUKOCYTOSIS (67%)
PERIPHERAL BLASTS
INCREASED LDH
INCREASED URIC ACID |
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Term
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Definition
history and PE
WBC count with differential, H/H, platelets
coagulation studies and fibrinogen
electrolytes: potassium, SCr, uric acid, calcium, phosphorous
examination of peripheral blood smear, bone marrow biopsy and aspirate
examination of cerebrospinal fluid (CSF)
immunophenotyping and cytogenics |
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Term
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Definition
increased risk of relapse with the following:
L2, L3 morphology
Philadelphia chromosome positive
abnormal cytogenetics
high WBC count at diagnosis (>30K)
thrombocytopenia at diagnosis (<10K)
age > 30 years
delayed remission reduction (>14 days)
male > female
race: African American
CNS disease
significant hepatomegaly
significant lymphadenopathy
mediastinal mass |
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Term
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Definition
T cell = good prognosis
pre B cell = intermediate prognosis
mature B cell = poor prognosis |
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Term
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Definition
primary goal: cure
initial goal: induction of complete remission
once CR achieved, therapy must be continued to eliminate nondetectable disease
decreased risk of relapse is CR > 2 years
adults: CR achieved in 65-85%, but relapse is common |
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Term
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Definition
CENTRAL NERVOUS SYSTEM
w/o treatment, relapse in CNS seen in > 50% of pts surviving more than 2 years
high risk of CNS relapse: high LDH; high proliferative index of leukemia
standard chemotherapy does not adequately penetrate CNS
INTRATHECAL (IT) administration of chemotherapy
high dose regimens of methotrexate and/or cytarabine IT
radiation therapy
TESTES
isolated testicular relapse occur in 5% of patients in CR
testicular relapse is poor prognostic indicator
symptoms: painless, firm swelling of the testicle |
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Term
| ALL treatment strategies (adult) |
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Definition
INDUCTION
CNS PROPHYLAXIS
CONSOLIDATION/INTENSIFICATION
MAINTENANCE |
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Term
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Definition
common medications:
IV cyclophosphamide
AND
IV daunorubicin
AND
IV vincristine
AND
PO prednisone
AND
IM/SC L-asparaginase |
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Term
| ALL CNS prophylaxis (adult) |
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Definition
common therapy:
IT methotrexate
AND
cranial radiation therapy |
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Term
| ALL consolidation/intensification (adult) |
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Definition
high risk patients may require more aggressive consolidation therapy (HD therapy + alloHSCT)
common medications:
same medications as induction
additional medications may include: 6-mercaptopurine, 6-thioguanine |
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Term
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Definition
common medications:
IV vincristine
AND
PO prednisone
AND
PO 6-mercaptopurine
AND
PO methotrexate |
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Term
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Definition
majority of adult patients will ALL relapse (60-70%)
options:
re-induction with initial regimen
re-induction with high dose chemotherapy (HD cytarabine)
HD chemotherapy with allogeneic HSCT |
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Term
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Definition
adults, 10-25% refractory to induction chemotherapy
options:
alternative agents
HD chemotherapy with allogeneic HSCT |
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Term
| Philadelphia chromosome + ALL |
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Definition
IMATINIB MESYLATE + hyperCVAD
AND
allogeneic SCT
IMPORTANT TO REMEMBER THAT IMATINIB IS USED TO INDUCE REMISSION FOR PHILADELPHIA CHROMOSOME B/C IT IS NOT USED ANYWHERE ELSE
INDUCTION:
imatanib
cyclophosphamide/mesna
vincristine
adriamycin (doxorubicin)
dexamethasone
CONSOLIDATION:
imatinib
methotrexate
cytarabine
CNS PROPHYLAXIS:
IT methotrexate
IT cytarabine
MAINTENANCE:
imantinib
vincristine
prednisone |
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Term
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Definition
most common childhood cancer
peak incidence:
2-3 years for ALL
bimodal peak in AML (children and elderly)
higher incidence in Caucasian vs. AA children
increasing incidence rate over past 20 years |
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Term
| pediatric acute leukemmia etiology |
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Definition
unknown, although several associations
higher incidence associated with radiation exposure (ex. atom bomb survivors)
other associations: electromagnetic fields, pesticides, maternal cigarette smoking |
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Term
| pediatric acute leukemia pathophysiology |
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Definition
replacement of normal bone marrow with accumulation of blasts
disruption of 1 or mmore relationships within the cellular proliferation pathway
immunologic heterogeneity due to leukemic transformation at various stages of differentiation
early pre B cell ALL
pre B cell ALL
T cell ALL |
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Term
| pediatric acute leukemia presentation |
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Definition
non-specific signs and symptoms
s/s reflect uncontrolled growth of the leukemic clone and resultant deficiency in normal bone marrow elements
clinical findings:
fever
bleeding
bone pain
lymphadenopathy
hepatosplenomegaly
WBC normal; low in 59%
WBC differential:
low percentage of neutrophils and bands
marked lymphocytosis (ALL)
normochromic, normocytic anemia and thrombocytopenia in majority of patients |
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Term
| pediatric acute leukemia diagnosis |
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Definition
bone marrow aspirate and biopsy
may only need peripheral blood in patients with markedly elevated WBC
diagnosis of acute leukemia when at least 25% of lymphoid cells in BM are blasts |
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Term
| pediatric acute leukemia treatment prior to chemotherapy |
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Definition
allopurinol + hydration +/- alkalinization
rasburicase (increased uric acid, increased SCr, increased WBC, or renal dysfunction) |
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Term
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Definition
INDUCTION CHEMOTHERAPY (4 weeks):
standard risk (3 drugs)
PO prednisone/dexamethasone
IV vincristine
IM asparaginase/PEG asparaginase
high risk (4 drugs)
standard drugs + daunorubicin
high risk:
CHILDREN < 1 YEAR OR > 9 YEARS
WBC > 50,000/mm^3
T cell ALL
certain translocations
all patients receive intrathecal chemotherapy with methotrexate (+/- cytarabine and hydrocortisone) throughout therapy
BM aspirations at days 7 or 14 and day 28 to assess response
early remission (day 7 or 14) associated with improved long term survival
CONSOLIDATION/INTENSIFICATION:
period of dose intensive chemotherapy following induction therapy
proven important for prevention of relapse
optimum consolidation regimen undetermined
duration typically 25-50 weeks
consolidation common medications:
IV methotrexate
IV cyclophosphamide
IV/SC cytarabine
PO thioguanine
IV vincristine
PO prednisone
IV doxorubicin
asparaginase
MAINTENANCE:
without maintenance, majority of children with ALL will relapse
patients with successful response to induction and consolidation may have a high leukemic cell burden that is undetectable
standard maintenance therapy:
IM/IV/PO methotrexate
PO mercaptopurine
IT methotrexate (q16 weeks)
periodic vincristine, prednisone pulses
dose adjusted to maintain ANC between 500-1500/mm^3 |
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Term
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Definition
CNS relapse:
cranial radiation
re-induction/re-consolidation therapy followed by maintenance
BM relapse:
early relapse
on therapy or within 1 year post completion of chemotherapy
bone marrow transplant
late relapse
chemotherapy
chance of second remission is good
long term survival often < 50% |
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Term
| pediatric ALL radiation therapy |
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Definition
initial therapy (cranial radiation) in children with T cell ALL
CNS relapse (primary use)
historically associated with significant growth deficiencies and impaired intellectual development |
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Term
| pediatric acute myeloid leukemmia (AML) treatment |
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Definition
INDUCTION
daunorubicin/idarubicin + cytarabine (most effective regimen)
courses are repeated 2-4 times with the same or different agents
optimal duration is unclear
all trans retinoic acid (ATRA) added in acute promyelocytic leukemia (APML)
CONSOLIDATION/INTENSIFICATION
BMT usually recommended once CR achieved if matched living related donor available
AE: severe marrow suppression, NV, mucositis
CNS disease lower than ALL
CNS prevention therapy controversial
IT cytarabine q8-12 weeks
maintenance therapy not used in most protocols |
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Term
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Definition
ALL:
~80% long term survivors
relapse > 2 years after completion rare
predictors of long term survival:
age (1-9 years)
initial WBC (< 50,000)
DNA index (hyperdiploid)
translocations
early response
minimal residual disease
AML:
prognosis in children better than adults
prognosis worse than childhood ALL
long term survival ~30-40% (>50% with BMT)
worse prognosis:
< 1 year
WBC > 20,000
best prognosis:
3-10 years old |
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Term
| long term consequences of therapy |
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Definition
anthracycline cardiotoxicity
secondary AML associated with epipodophylotoxins in patients with ALL
decreased bone mineral density (corticosteroids)
leukoencephalopathy (methotrexate) |
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