Transcript SCIENCE MEETS MEDICINE: ACUTE PROMYELOCYTIC LEUKEMIA

SCIENCE MEETS MEDICINE:
ACUTE PROMYELOCYTIC
LEUKEMIA
Nancy Fuller, M.D.
June 23, 2004
• Objectives:
1. Understand the history and presentation of
Acute Promyelocytic Leukemia (APL)
2. Be familiar with the major abnormalities and
genetic factors
3. Understand treatment and prognostic
indicators
4. Be amazed at the achievements gained with
the interaction between basic sciences and
clinical medicine.
• Disclosure:
No outside sources of funding (and inside
sources getting smaller all the time)
25 yo woman presented to clinic in May
-3 week history of spontaneous bruising,
increasing fatigue, and dizziness with
minor exertion like climbing stairs.
-1 nose bleed 3 weeks ago, none since;
no bleeding from gums or per rectum
PMH: previously healthy except for history
of an eating disorder several years ago,
now asymptomatic
-on no meds; she had taken aspirin on a
couple of occasions in the recent past
because of headaches.
-LMP 2 weeks before, heavier than usual
-New sexual partner for past 6 weeks
PE: slim young woman in NAD, VS normal
HEENT: no petechia or bleeding
Pulm: normal CV: II/VI murmur
Abd: splenomegaly, no hepatomegaly
Ext: multiple eccymoses especially over
lower legs but also upper legs, arms.
No petechia noted
Labs:
WBC: 2.4 (27% PMN, 23% lymph, 47%
blasts, 2% NRBC
H/H: 10.6/29 PLTS 18 K
LFTs normal, INR 1.2
Fibrinogen 147 (165-400)
D-Dimer greater than 18 (0-0.5)
Differential: consistent with acute
promyelocytic leukemia (atypical
promyelocytes with folded or dumb-bell
shaped nuclei; large granules, and Auer
rods)
Bone marrow: 100% cellularity, almost all
promyelocytes
Acute Promyelocytic Leukemia
-First described in 1957: “a very rapidly
fatal course of only a few weeks
duration, a white blood cell picture
dominated by promyelocytes, and a
severe bleeding tendency due to
fibrinolysis and thrombocytopenia”
-”seems to be the most malignant form of
acute leukemia”
APL
Most impressive features of APL:
-occurence of a severe bleeding diathesis
:up to 20-30% of patients died rapidly due to
cerebral hemorrhage
-large numbers of promyelocytic malignant cells
found in marrow and peripheral blood with
folded nuclei, azurophilic granules and Auer
rods
1976: FAB nomenclature committee: M3
APL
-accounts for 10-15% of cases of AML
-sometimes occurs after cytoxic treatment
for other malignancies
-median age 30; does occur in children
and elderly
APL
Clinical management difficult because of the
unpredictable onset of life threatening
bleeding disorders; chemo exacerbates the
bleeding diathesis.
2 major causes of bleeding: thrombocytopenia
and fibrinogenopenia
DIC vs primary fibrinolysis, or both?
Features of both exist; etiology is unclear but 2
tumor cell procoagulants may be implicated
APL
Genetic abnormalities:
-identified in the early 1980s: balanced
translocation in long arms of
chromosomes 15 and 17
t (15;17)
APL
Prognostic factors: intensity of
thromobocyopenia, number of WBCs
Low risk: WBC less than 10K plts greater
than 40K
Intermediate risk: WBC less than 10K plts
less than 40K
High risk: WBC greater than 10K
APL
Treatment initially: anthracyclines and platelet
transfusions
-main causes of poor outcome: failure to
achieve remission due to resistance to
chemo, and fatal hemorrhage
By 1988: early mortality due to bleeding 15%,
failure to enter remission 10%= 75% initial
remission rate
Relapse rate within 2 years: 35% =
approximately 30-35% 2 yr survival rate
APL
SCIENCE MARCHES ON!
Concept: certain agents can trigger a
differentiating process in leukemic
cells:malignant changes are not
irreversible.
-more than 100 hundred agents found
that could induce terminal
differentiation for certain types of cells
APL
In APL, all trans retinoic acid (ATRA) was
found to be the most effective in vitro
BUT: not available in Europe or US
APL
The Chinese Connection:
1985: Chinese researcher begins working with a
French researcher in APL, resulting in a close
collaboration between Paris and Shanghai,
where ATRA could be manufactured.
First patients treated in Shanghai with ATRA in
1987:
No worsening of bleeding diathesis (as with
chemo)
Up to 95% remission rate!
APL
1989: Tienammen Square; cessation of
Franco-Sino cooperation
-Roche agrees to make drug but only for
French patients; trials begin in France.
APL
More science:
-retinoic acid receptor alpha (RARA) located on
long arm of chromosome 17
-APL: abnormal RARA receptor gene (called
PML-RARA)
Conclusion: APL is due to the fusion gene PMLRARA and manufacture of protein PML-RARA
which represses the normal job of RARA in
myeloid differentiation
APL
ATRA trials: very favorable results
BUT: rapid relapse after remission
Most favorable results: ATRA + chemo
By 1992: treatment of APL without ATRA
considered ‘unethical’
APL
Problems with treatment:
1. ATRA syndrome (aka RAS, LAS): fever,
respiratory distress, 3rd spacing, renal
failure; up to 25% of patients
2. Secondary resistance to ATRA: usually
reverses after 6-12 months. Due to
increase in cytochrome p450
catabolism of ATRA
APL
ARSENIC?
1995: Chinese researchers investigating
arsenic treatment for various cancers
find effectiveness in APL.
-not useful as first line because of toxicity
issues, but now can be used in relapse
APL
Current treatment recommendations:
ATRA x 3-4, then add anthracycline til remission
Consolidation tx: at least 2 courses of
anthracycline, plus maintance ATRA
Follow PCR for PML-RARA: positive result
predicts relapse (follow for up to 5 years)
Arsenic is indicated for relapsed patients,
especially when treated with ATRA in past 12
months
Relatively poor results with bone marrow trans
APL
Relapse occurs in 20-30% of patients,
with rate dependent on risk levels
initially (WBCs, platelets):
Low risk: 98% 3 year relapse free survival
Intermediate: 89%
High: 70%
APL
Conclusions:
-APL went from being “the most
malignant form of leukemia” to being
curable in at least 75% of patients
-’the first model of a malignant disease to
be treated by drugs targeted on an
oncogenic event that alters the biologic
process of the diseased cells’
APL
More to come? Other leukemias may be
targeted in the same way
:Gleevec for CML
Selected references:
Degos, L. The History of Acute Promyelocytic
Leukemia. British Journal of Haematology,
2003, 122:539-553
-reads like a detective story!
Tallman,M et al. Acute Promyelocytic leukemia:
evolving therapeutic strategies. Blood, 2002,
99:759-767
Au, W et al. Oral arsenic trioxide in the
treatment of relapsed acute promyelocytic
leukemia. Blood,102:407-408