Acute Promyelocytic Leukemia

Treatment
Deepesh Lad
Prof S. Varma

22
nd
March 2012


1957: 6
th
Euro Congress Jaques Caen
fibrinolytic syndrome (Acquired fibrinogenopenia)
1973: Anthracyclines Bernard et al
1976: FAB classification M3 Bennett et al
1976-84: t(15,17) Golomb, Rowley & Larson
1982: microgranular variant McKenna et al
1986: Maintenance 6-MP and MTX Kantarjian et al

1988: CR=75%, early mortality=15%, resistance=10%, RR=35%
Cure=25%
Pre ATRA Period (1957-1988)
ATRA period (1988-1993)
1978: Leo Sachs; concept of differentiation, first culture system
1981: Breitman: showed terminal diff in HL-60 cell lines and APL pts
1988: Dalton: human myeloid leukemia HL-60 cell line, 100 agents were
listed for differentiation (Anthracyclines, Ara-C, RA)
1986-90: Chomienne: primary cultures of malignant cells from APL pts BM,
Etretinate not effective,
ATRA 10 times potent than other 13-cis retinoids.
Only Etretinate was available in EU and 13-cis RA in USA

Eastern philosophy meets
Western medical science
Confucius famous saying: If you use laws to direct the people, and
punishments to control them, they will merely try to evade the
laws, and will have no sense of shame. But if by virtue you guide
them, and by the rites you control them, there will be a sense of
shame and of right.
if cancer cells are considered elements with bad social behavior in
our body, educating rather than killing these elements might
represent a much better solution
1985: Meeting of Wang Zhen Yi, Shanghai Institute of Haematology
& Laurent Degos, Institute of Haematology of the Saint Louis
Hospital Paris (Thanks to Air France)
diff using low dose Ara-C in France and HHG in shanghai
ATRA was approved by Shanghai Municipality for psoriasis and Acne

1987: ATRA first used at Rui-Jin hospital,
Shanghai
First pt was a 5 year girl
1988: first paper: Huang et al, 23/24
CR=95%
Western pharma companies refused to
manufacture ATRA
So chinese students carried it to France.
1989: Chinese revolution, French laws
prohibited co-operation with China
L Degos asked Roche France: make ATRA
Paper at Memor Sloan Kettering Center
Raymond Warrell and Loretta Itri (VP
Roche Nutley, USA)
1990: Castaigne et al. Chomienne et al
(Blood), Editorial by Wiernek

ATRA trials (1990-93)
CR=95%
Relapse= 5 month (cytoP450 metabolism- accelerated clearance)
1992: Fenaux et al: ATRA+ Dauno/Ara-C reduced relapses
1991: APL 91 trial (first RCT) Dauno+ Ara-C vs ATRA f/b Chemo
stopped prematurely, EFS better in ATRA arm (79 vs 50%)
5 yr DFS (69 vs 29%)
1992: any treatment without ATRA was unethical (US and EU)
1993: APL 93: ATRA f/b Chemo vs concurrent ATRA + chemo (results
in favor of simultaneous Rx), favored ATRA maintenance
Results confirmed by US Intergroup trial

1993: APL curable disease (cure=75%)
ATRA studies

Conclusions
ATRA/ CT concurrent superior to CT or ATRA alone
Consolidation: 3 monthly courses of anthracycline based CT (+- HIDAC)
Maintenance Rx: 6-MP+MTX+ ATRA
PML-RARa for MRD assessment
Euro APL
GIMEMA
PETHEMA
JALSG
US inter group
ATRA/DA
ATRA/IDA
Maintenance
No ARA-C
2000 German 51 92 88 High-dose Ara-C GAMLCG37
Arsenic for APL (Chinese story)
1992: Sun et al (Harbin Medical Univ)
reported effect of Ailing-1 (1%
ATO+HgCl2) CR=65%
1996: Chen et al, CR in 9/10 relapsed
APL
1998: Soignet et al, clinical effect
confirmed at MSKCC
Harbin series CR=73% in Rx Nave
SIH series CR=90%
Huang et al oral composite Realgar-
indigo naturalis tablets, CR=96.7%
Single agent ATO studies
Long term sequelae of ATRA +CT
Extramedullary relapse
Second malignancies/ MDS
Cardiomyopathy (reversible cardiac dysfunction with ATRA)
ATO is the single most active agent in APL
Indian study: Mathews et al
WBC<5000, plt>20000, 100% 5yr survival with ATO
High risk pts, EFS=67%

Risk stratification


WBC Plt
Good <5000 >20000
Inter <5000 <20000
High >5000 <20000

Tallman et al. Hematology 2008
ATO in relapsed APL
ATRA + ATO
Historical model
Ablain J and Hugues de The. Blood 2011
Revised model
Ablain J and Hugues de The. Blood 2011
System biology model Ablain J and Hugues de The. Blood 2011

Hughues de the. Nat Rev 2010
ATO+ATRA studies
SIH
MDACC

Shen et al
20 90.0 ATO
20 95.0 ATRA
21 95.2 ATO+ATRA
ATRA +ATO vs ATO alone: Meta-analysis

ATO/ATRA increases CR, shortened time to CR, improved molecular remission after
consolidation and 1 yr DFS
No difference in terms of early death and main adverse events
Wang et al. Leuk Res 2011
Recommendations

European LeukemiaNet. Blood 2009

Induction therapy
Clincial trials if anthracyclins are CI
No difference between Dauno vs Idarubicin (better in younger)
Ara-C ?role, no diff in CR, OS. decreased relapse, increased death

If in doubt about CR, repeat BM after 2-3 weeks while pt is on ATRA. There are no cases of resistant ATRA and
virtually all cases of PML-RARa proven APL achieve CR
How we treat:
ATRA 25mg/m
2
+ ATO 0.15mg/kg (5days/week) x 4-6 weeks
BM after achieving normal hemogram (4-6 weeks)
Consolidation therapy

Therapeutic milestone
No role in CR1
Persistent MRD: (0.4-7% )Candidates for AlloSCT or experimental therapy ATO, Gemtuzumab, Autologous
How we treat: 3 cycles
ATRA 25mg/m
2
+ ATO 0.15mg/kg (5days/week) x 4-6 weeks (total 28 inj ATO)
ATRA 45mg/m
2
High risk WBC>30000, M3V
RTPCR PML-RARa at end of consolidation
Management after consolidation
2 studies for and 2 against
CNS most common site of extramedullary relapse
Postpone CNS prophylaxis until CR, LP is induction is hazardous
IC bleeds have more CNS relapses

Maintenance Rx: intermittent ATRA+ 6-MP+MTX for min 2 years until further studies
How we treat: 2 years,
ATRA 45mg/m
2
15 days/ 3 months
6MP 75mg/m
2
OD
MTX 20mg/m
2
weekly
RTPCR PML-RARa yearly

AIDA0493 protocol GIMEMA, AIEOP, and EORTC Blood. 2011

Grimwade et al.
A positive RT-PCR reading at the end of induction therapy was significantly associated on a
multivariate analysis with an increased risk of relapse (RR=4.9; P-value=0.034).
None of the good risk patients who were RT-PCR negative at the end of induction relapsed.
Majority of the relapses (91%) happened within three years of completion of treatment.

Post achievement of molecular remission the current MRD monitoring strategy was able to
predict relapse in 60% of cases with an overall sensitivity and specificity of 60% and 93.2%
respectively.

David Grimwade Martin Tallman
5% relapse rate versus 12% at 3 years,
associated with improved survival at a cost
of 4700 per quality adjusted life year
use of molecular monitoring to guide
treatment of relapse and inform transplant
choice has been adopted in the
International APL treatment guidelines
marginal benefit for sequential MRD
monitoring in low risk group (1% survival
benefit at 5 years, at a cost of 14,300/
QALY
High risk, relapse risk exceeds 10% and
therefore there is a much greater benefit
for MRD monitoring (10% survival benefit
at 5 years at a cost of 1350/QALY
achieve further refinement of
management, allowing development of
individualized therapy that minimizes
toxicity without compromising disease cure
with such remarkably effective therapy
even among high-risk patients, are
there subgroups which can be identified
for whom molecular monitoring for
MRD is most valuable?
Although it can be done, how
important is it to detect relapse early,
particularly in the ATO era?
Serious doubts can be raised about the
value of molecular monitoring among
patients with low- and intermediate-
risk disease if they are treated with
contemporary strategies and followed
with routine complete blood counts
Molecular monitoring in APL may, in
fact, have become less important for
the majority of patients as therapeutic
strategies have evolved with less MRD
to detect.
Special situations
Mortality rate 19% vs1% in CR
Pseudotumor cerebri in children, Rx LP, discont ATRA, acetozolamide, Prednisone 2mg/kg x 2 weeks

Genetic variants: ATRA resistant (STAT5b-RARa, PLZF-RARA) AML like approaches
ATRA sensitive (NuMA-RARa, NPM1-RARA, FIPL1-RARa)

tAPL: Rx as denovo Apl, Anthracycline use limited
Pregnancy
Relapse management
CR rates with ATO / ATRA+ CT=80-90%
ATO 25day courses x 2-4 + 4 weekly courses of ITM

Before Autologous: HIDAC mobilizing agent + CNS cover
Autologous SCT

Kharfan Dabaja et al, Biol BMT 2007
Autologous SCT
Allogeneic SCT
Allogeneic SCT
Kharfan Dabaja et al, Biol BMT 2007




















Diagnosis and supportive care

Renal failure or respiratory distress requiring ICU
WH if QT >500msec, restart when <460msec
ATRA started in ER
Differentiation syndrome
Diagnosis requires vigilance and
anticipation
s/s: cough, SOB, unexplained
fever/hypotension, wt gain, edema,
ARF, CCF
CXR: Interstitial pulmonary
infiltrates/pleuro-pericardial
effusion
dd: fluid overload, DAH,
pneumonia

Persistent cytokine activity,
activation of endothelium, ICAM1,
VCAM1- tumor cell adhesion
ATRA stimulates chemokine
production
Dexa 10mg IV BD at earliest s/s.
Discontinue ATRA/ATO only in
severe cases viz renal failure/
respiratory distress requiring
admission to ICU or if non
response to dexa
Dexa until disappearance of all s/s
Presumptive therapy can be given
in high risk pts, WBC>30000-
50000
No evidence of morbidity or
mortality benefit
Coagulopathy
High risk for bleeds
WBC>10000
Fibrinogen<10g/l
Raised creatinine
PS>2
Platelet counts dont predict
Risk for thrombosis
WBC>10000, M3V
CD2,bcr3, PML RARa short
isoform, FLT3-ITD
CBC/ coagulogram twice a day
Platelet target>30000-50000
Fibrinogen target > 150mg/dl
Targets reached in only 71 and
40% on day of bleeding
Risk of bleeding till 20 days
Risk of thrombosis: Heparin only if
DVT develops
Avoid CVC
No Lumbar puncture
No leukapheresis for
hyperleukocytosis
No benefit of antifibrinolytics
Breen KA. BJH 2011


Main driver of bleeding is not aberrant TF
expression but 1
0
fibrinolytic activation
hyperfibrinolysis
CP Cancer procoagulant activates factor X and
II
Most imp fibrinolytic activator Annexin A2
IL1/TNFa downregulation of thrombomodulin
and upregulation of TF
ATRA reduces CP, TF and AnnexinA2
Haematologica 2012