APL represents a uniquely homogeneous subset of AML defined by its cytogenetic abnormality, t(15;17), which results in fusion of the retinoic acid receptor (RARA) gene on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15. This abnormality yields the PML/RARA fusion protein, detectable by PCR techniques, which is useful for both diagnosis and evaluation of minimal residual disease. Most patients (80%) with APL have characteristic hypergranular blasts; laboratory evidence of DIC is present in 70% to 90% of patients at diagnosis or shortly after. Hemorrhagic events contribute 10% to 15% excess mortality during induction chemotherapy for APL compared with other AML subtypes. Prompt initiation of ATRA in suspected cases of APL will minimize the coagulopathy and decrease mortality.
Because of the unique biology and specific clinical features of APL, induction and consolidation regimens for APL differ from strategies used for other pathologic subgroups.
Involvement of the RARA gene in the pathogenesis of APL suggested the use of retinoids as therapy. A study from Shanghai showed CR rates of 85% with single-agent ATRA and offered the advantages of a shorter neutropenic period (2 weeks) and slightly faster resolution of DIC (4 vs 7 days), as compared with standard chemotherapy with Ara-C and daunorubicin(Drug information on daunorubicin). Normalization of marrow morphology and cytogenetics requires 30 to 60 days of ATRA.
Initial treatment options
The backbone of APL induction therapy includes an anthracycline and ATRA (Table 6). The French and North American APL trials have also included standard-dose Ara-C as an integral part of induction and consolidation therapies. All three groups report CR rates in excess of 90% in patients with an initial WBC count < 10,000 /μL.
Based on data from the Spanish PETHEMA Group trials, a stratification schema of risk of relapse was constructed using WBC and platelet counts at presentation. Patients with a WBC count < 10,000/μL and a platelet count > 40,000/mL have a DFS of 97%; those with a WBC count < 10,000/μL and a platelet count < 40,000/mL have a DFS of 86%; those with a WBC count > 10,000/μL have a DFS of 78%.
In a comparison of the outcomes from the Spanish LAP 99 trial and the French APL 2000 trial, the CR rates and 3-year survival rates were similar for the low- and intermediate-risk groups, with a lower rate of relapse (4% vs 14%) and fewer days in the hospital (50 vs 72 days) for the group that did not receive Ara-C. In patients with elevated WBC counts ≥ 10,000 μL, Ara-C during induction significantly increased CR rates (95% vs 83%). Survival at 3 years was also higher for the group receiving Ara-C (92% vs 81%), and relapse was lower (9.9% vs 18.8%). In the LAP 99 trial, the use of ATRA along with anthracycline in consolidation significantly decreased the relapse rate among the low- and intermediate-risk groups. All three European cooperative groups currently use cytarabine(Drug information on cytarabine) in the consolidation regimens for high-risk patients.
The most recent North American Intergroup trial showed improved relapse-free survival when 2 cycles of arsenic trioxide(Drug information on arsenic trioxide) were used as the initial component of consolidation. All three groups were monitored for molecular remission at the end of consolidation and at frequent intervals during 2 years of maintenance chemotherapy. In the most recent PETHEMA/HOVON and GIMEMA trials the incidence of molecular positivity at the end of consolidation was between 0.4% and 1.1%. Relapse rates are lower than 5% for low-risk patients, and new trials will evaluate the need for maintenance therapy for this group. The most recent GIMEMA trial did not show a benefit of maintenance ATRA with or without mercaptopurine(Drug information on mercaptopurine)-methotrexate (6MP/MTX) for patients treated on the most recent trial.
Small single-institution series have reported favorable remission and DFS rates in patients induced with arsenic trioxide alone (CR of 86%) or combined with ATRA (95% for low- and intermediate-risk patients). High-risk patients had poorer response rates (CR of 75%) despite the addition of gemtuzumab ozogamicin (9 mg/m2) on day 1 of induction therapy. Arsenic-based therapy is used primarily in the United States for patients who have contraindications to anthrocycline-based therapy but is used more widely in developing countries where arsenic is much less expensive to manufacture. While arsenic trioxide does carry fewer risks of cardiotoxicity and secondary MDS/AML, it is cumbersome and time-consuming to administer and requires careful monitoring of electrolytes (Ca++, Mg++, and K+) with maintenance of these minerals at the upper levels of the normal range to minimize the risks of QTC prolongation and ventricular arrhythmias.
Approximately 25% of patients with APL develop "differentiation syndrome" (formerly known as ATRA syndrome). Symptoms of this syndrome are fever, respiratory distress with pulmonary infiltrates or pleural effusions, and cardiovascular collapse. Temporary pseudotumor cerebri is a fairly common (10%) side effect of ATRA. Although these symptoms most often correlate with leukocytosis (WBC count > 10,000/μL), many patients develop symptoms with WBC counts between 5,000/μL and 10,000/μL. The syndrome is seen in patients treated with arsenic trioxide as well as in those treated with ATRA.
Treatment of this syndrome involves prompt use of high-dose steroids, initiation of conventional Ara-C/daunorubicin chemotherapy to control leukocytosis, and temporary discontinuation of ATRA or arsenic trioxide.
Arsenic trioxide is now the standard reinduction therapy for patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. As a single agent, arsenic trioxide has produced CR in 34 of 40 patients (85%) with relapsed APL, with 86% of patients achieving molecular remission. Relapsed patients who achieved a molecular remission with arsenic trioxide alone had a median relapse-free survival of 18 months; those who received arsenic trioxide followed by autologous transplantation have had relapse-free survivals in excess of 70% at 2 years. Allogeneic transplantation should be reserved for those who do not achieve a molecular remission.
Gemtuzumab ozogamicin is also an effective agent for patients with relapsed APL. In a small series, 91% of patients with a molecular relapse of APL achieved a molecular remission following two doses of gemtuzumab ozogamicin (6 mg/m2). Although this drug is no longer commercially available, efforts are in progress to maintain access to the drug for patients with relapsed APL.
Monitoring response to therapy Reverse-transcriptase PCR for the PML/RARA fusion protein can be used to follow response to therapy. The marker clears slowly, with many patients still testing positive following induction therapy. However, patients with persistence of PML/RARA fusion protein at the end of consolidation therapy are at high risk of relapse, as are those with reemergence of the marker following a period without detectable protein. Salvage chemotherapy should be considered for patients with persistent or recurrent confirmed molecular relapse.
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Abbreviations in this chapter
ALSG = Australian Leukemia Study Group; BFM = Berlin-Frankfurt-Munster; CALGB = Cancer and Leukemia Group B; COG = Children's Oncology Group; ECOG = Eastern Cooperative Oncology Group; FAB = French-American-British Cooperative Group; FDA = US Food and Drug Administration; GIMEMA = Gruppo Italiano per le Malattie Ematologiche dell'Adulto; GLSG = German Leukemia Study Group; MRC = Medical Research Council; PETHEMA = Programa Español de Tratamientos en Hematología; SWOG = Southwest Oncology Group; WHO = World Health Organization