Incidence, Clinical Features and Outcome of Patients with Differentiation Syndrome in Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid (ATRA) Alone Versus ATRA Plus Idarubicin Versus ATRA Plus Arsenic Trioxide.

Differentiation Syndrome (DS) in patients (pts) with acute promyelocytic leukemia (APL) remains a source of significant morbidity and mortality. DS is reported in 2-27% of pts with newly diagnosed APL treated with all-trans retinoic acid (ATRA) alone or in combination with idarubicin (IDA). More recently, arsenic trioxide (ATO) has been used in combination with ATRA as frontline therapy to improve rates of complete remission (CR) and overall survival (OS). It has been postulated that with the use of ATO, the risk of DS may decrease.

To describe the incidence, characteristics and outcome of differentiation syndrome with various modalities of ATRA-based therapy used for APL.

We reviewed the records of 167 pts with newly diagnosed APL treated at our institution from 1992-2009 with three regimens: ATRA + IDA (Group 1), liposomal ATRA (Group 2) and ATRA plus ATO (Group 3). Patients in Group 1 (n=52; 1992-1997) received induction with ATRA 45mg/m² orally daily in two divided doses until CR and IDA 12mg/m² IV daily for 4 days. Group 2 (n=34; 1997-2000) received liposomal ATRA at 90mg/m² IV every other day until CR. Patients in Group3 (n=82; 2002-2009) received 45mg/m² ATRA orally daily in two divided doses, 9mg/m² gemtuzumab ozogamicin if the WBC count exceeded 30 ×10⁹/L in the first 4 weeks of therapy, ATO 0.15mg/kg/day IV starting on day 10 in 47 patients and on day 1 in 35 patients, and methylprednisolone (50 mg daily for 5 days) to prevent DS. A diagnosis of DS was made by the presence of: dyspnea, unexplained fever, weight gain, peripheral edema, unexplained hypotension, acute renal failure or congestive heart failure, and particularly by a chest radiograph demonstrating interstitial pulmonary infiltrates, or pleuropericardial effusion [Sanz MA, Blood. 2009;113(9):1875-91].Patients with ≥4 features were classified as having severe DS and those with ≤3 mild DS. No single sign or symptom was considered sufficient for diagnosis of DS. Patients with a final diagnosis of pneumonia, sepsis, diffuse alveolar hemorrhage and decompensated heart failure were not considered to have DS. Patients who developed DS ≤7 days of starting therapy with ATRA were classified as “early DS” and others as having “late DS”.

Forty one patients (24%) were diagnosed with DS: 14 (27%) in Group 1, 12 (35%) in Group 2, and 15 (18%) in Group 3. Baseline characteristics of patients with DS in each group are shown in Table. Dyspnea, weight gain and pulmonary infiltrates were the most common features of DS in all groups. The median number of days to develop DS after starting ATRA was 3 (1-15) in Group 1, 5 (2-18) in Group 2 and 10 (1-18) in Group 3. ATRA was held in 8 pts (57%) in Group 1, 9 pts (75%) in Group 2, and 8 pts (53%) in Group 3. Intravenous corticosteroids were used for treatment of all patients with DS. CR was achieved in 7 (50%) pts in group 1, 10 (83%) in Group 2 and 14 (93%) in Group 3. The number of patients who died during induction therapy was 6, 2 and 1 in Groups 1, 2 and 3 respectively. There were no deaths directly attributable to DS in any groups. Three-year survival was 65% for pts with DS and 83% for those without DS (p-value: 0.07).

The incidence of DS is higher when ATRA alone is used as frontline therapy for APL. With ATRA + ATO (and prophylaxis with corticosteroids) there is a trend for decreased frequency and more delayed occurrence of DS. The severity of DS appears lower for patients not receiving chemotherapy with ATRA. With adequate management, a diagnosis of DS during induction therapy for APL does not influence outcomes independent of therapy.

Ravandi:Cephalon: Consultancy, Honoraria.