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

indicators4. 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 bleedingPulm: normal CV: II/VI murmurAbd: splenomegaly, no hepatomegalyExt: 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”

APLMost 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

APLClinical 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

APLTreatment 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

APLThe 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.

APLMore 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

PML-RARA 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 remissionMost favorable results: ATRA +

chemoBy 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

APLCurrent treatment recommendations: ATRA x 3-4, then add anthracycline til

remissionConsolidation tx: at least 2 courses of

anthracycline, plus maintance ATRAFollow 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