3.  Acute Promyelocytic Leukemia (APL)

3.1             General considerations

Acute promyelocytic leukemia (APL) is a distinctive subtype of acute myeloid leukemia characterized by unique morphological features, by the t(15;17) translocation that fuses the promyelocytic  leukemia (PML) gene to the retinoic and receptor (RAR) alpha gene (PML-RARalpha), and by coagulopathy associated with disseminated intravascular coagulation (DIC) as well as primary fibrinolysis.

The presence of the PML-RAR alpha fusion transcript gene provides the rational for the use of all-trans retinoic acid (ATRA) which results in the differentation of the leukemic cells into mature granulocytes. The incorporation of ATRA in the frontline treatment leads to rapid resolution of life-threatening coagulopathy and- in combination with anthracycline-based chemotherapy- long-term survival and potential cure in at least 60-70% of newly diagnosed patients. Even after relapse the disease is still curable by various approaches including arsenic trioxide, autologous or allogeneic stem cell transplantation, and antibody-targeted chemotherapy.

Literature: for review e.g.

            DOUER, Acta Haematol. 107 (2002): 1-17 (treatment of relapsed APL)

            FRANKEL and POWEL, Cancer Treat. Res. 99 (1999): 125 – 153

            MANDELLI et al, Rev. Clin. Exp. Hematol. 6 (2002): 60-71

            SLACK et al, Oncologist 7 (Suppl 1 ) (2002): 1-13 (focus on arsenic trioxid)

            TALLMAN et al, Blood 99 (2002): 759-767

3.2             Induction therapy

3.2.1      ATRA

Untill CR or for a maximum of 60 days

Remission induction with ATRA results in high CR retes. But of limited duration.

Literature: e.g.

            AGADIR et al, J. Clin. Oncol. 13 (1995): 2517-2523

            CASTAIGNE et al, Blood 76 (1990): 1704-1709

            KANAMARU et al, Blood 85(1995): 1202-1206

            WARREL et al, N. Engl. J. Med. 324 (1991): 1385

3.2.2      Combination of ATRA with intensive chemotherapy

The combination of ATRA with anthracycline-based induction chemotherapy gives better survival than either or the two elements alone. Cytarabine is added some times but may not be necessary. E.g.

AIDA

Literature:

            SANZ et al, Blood 96 (2000): 1247-1253

or

ATRA + daunorubicin + cytarabine

Literature:

            FENAUX et al, Blood 94 (1999): 1192-1200 and leukemia 14 (2000): 1371-1377

3.3             Postremission therapy

Consolidation with anthracycline-based chemotherapy is necessary, and, in contrast to other subtypes of acute myelocytice leukemia, maintenance therapy appears to play a unique role.

Consolidation and maintenance therapy, e.g. PETHEMA- Protocol

Consolidation course 1

            Consolidation course 2

            Consolidation course 3         

            Maintenance

            Literature:

                        SANZ et al, Blood 96 (2000): 1247-1253

3.4             Salvage therapy

3.4.1      Arsenic trioxide

Especially for patients with recurrent ATRA-resistant disease

Up to a cumulative maximum of 60 doses or until visible leukemic cells were eliminated from the marrow. Patients who meet criteria for a clinical CR are eligible to receive an additional course of arsenic as consolidation beginning 3 – 4 weeks after completion of the induction cycle. The dose is the same as that administered during induction and is given for a cumulative total of 25 doses completed within 35 days.

Arsenic trioxide should be used with caution, particularly in those patients with preexisting cardiac abnormalities, because some cases of sudden death have been reported.

Literature:

            BACHLEITNER-HOFMANN et al, Leuk. Lymphoma 43 (2002): 1535 –

            1540 (review)

            NOVICK and WARRELL, Semin. Oncol. 27 (2000): 495-501 (review)

            SHEN et al. Blood 89 (1997): 3354-3360

            SLACK et al, Oncologist 7 (Suppl 1) (2002): 1-13 (review, also covering   

            additional  indications)

SOIGNET et al, N. Engl. J. Med. 339 (1998): 1341-1348 and J. Clin. Oncol. 19 (2001): 3852-3860 (United States multicenter study)

                      *WESTERVELT et al, Blood 98 (2001): 266-271

                  ZHANG, J. Biol. Reg. Homeost. Agents 13 (1999): 195-200 (review)

3.4.2      Stem cell transplantation

In second CR a transplantation can be considered : either with molecularly negative peripheral blood stem cells or allogeneic in younger patients if a suitable donor is available.

Literature :

            MELONI et al. Blood 90 (1997): 1321-1325

            NABHAN et al, Bone Marrow Transplant. 28 (2001): 219-226

3.5             Secondary acute promyelocytic leukemia

APL occurring as a second tumor responds to ATRA + chemotherapy similarly to de novo APL

Literature:

            PULSONI et al, Blood 100 (2002): 1972-1976