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Acute Promyelocytic Leukemia, Twelve Years Experience at the University Hospital,San Juan, Puerto Rico

Reviewer: Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 23 de marzo del 2007

Presenter: Lopez-Enriquez, A.
Presenter's Affiliation: University of Puerto Rico, Puerto Rico
Type of Session: Scientific

Background

Acute Promyelocytic Leukemias (APL) are a unique entity in the field of carcinogenesis. They result from maturation arrest of cells at the promyelocyte stage, and are associated with a reciprocal chromosomal translocation of portions of chromosomes 15 and 17. This translocation leads to the formation of a fusion product between the PML gene and the alpha retinoic receptor site. The discovery that the compound all-trans-retinoic acid (ATRA) can induce maturation of the promyelocyte has significantly improved the ability to cure this disease. This current study was undertaken to assess the results of treatment using induction chemotherapy for tumor burden reduction, followed by differentiation and maturation of the promyelocytes with ATRA, for patients with APL.

Materials and Methods

• Single institution, single-arm prospective trial
• Patients enrolled from January 1994 to February 2006
• 65 patients with APL analyzed
• All patients received induction chemotherapy as follows:
  • Cytosine-Arabinoside (Ara-C), 100 mg/m2 continuous infusion x 7 days
  • Daunorubicin (Dau), 45 mg/m2 continuous infusion x 3 days
  • ATRA, 45mg/m2 started on day 14 and continued for 120 days
• Consolidation therapy was delivered as one of the four following regimens:
  • High-dose Ara-C q month x 3à standard regimen
  • High-dose Ara-C with Dau
  • Ara-C with Dau
  • Dau alone, 45 mg/m2

Results

Of 65 patients analyzed:

• 63 received 7+3+ATRA
• 1 received ATRA with Arsenic
• 1 received Arsenic only
• 14 of 64 (21%) died early - in the first 2 weeks of induction - due to bleeding and sepsis
• 49/50 (98%) went into Complete Remission (CR)
• 3 patients developed ATRA Syndrome (pulmonary morbidity)
  • All 3 were mistakenly given ATRA in the first few days of induction
  • 2/3 responded to steroids and went into remission
  • 1/3 died with ATRA Syndrome (pulmonary edema)
• 33 of the 49 patients in CR (67%) have remained in CR over range of two to twelve years
• 10 patients (20%) relapsed within the first two years
  • 1/10 was an HIV patient
  • 1/10 relapsed three more times, even despite autologous transplant, and died six years later

Author's Conclusions

• Acute Promyelocytic Leukemias are a potentially curable disease in today’s world.
• Nonetheless, the high early mortality rate still needs to be improved with more aggressive blood factor support.
• A 98% complete remission rate with induction chemotherapy is extraordinary.
• No ATRA Syndrome when ATRA given on day 14 of treatment.
• ATRA on day 14 reduces further morbidity and mortality in this group of patients.
• Four of the ten patients that relapsed received daunorubicin as single agent in consolidation.

Clinical/Scientific Implications

The authors report a very promising regimen of induction chemotherapy followed by ATRA for the treatment of APL. It is important to have an understanding of the criticality of timely diagnosis and treatment in this patient population. Also impressive was the marked effect of ATRA timing on outcome, with significant morbidity if given with induction chemotherapy, but significant improvement of efficacy if given at day 14. In fact, the authors cite reports from the U.S. of up to a 40% rate of ATRA syndrome when ATRA is used on day 1. Finally, the use of a non-standard consolidation regimen of daunorubicin alone resulted in a relapse rate of 60%, suggesting inadequacy of this therapy that is commonly used in some European centers. Ultimately, the future of APL treatment will hinge on continued optimization of combined modality approaches, adding into the armamentarium a variety of biologic agents including ATRA, arsenic trioxide, and kinase pathway inhibitors.