Treatment of Acute Promyelocytic Leukemia in Adults

Abstract

The treatment of acute promyelocytic leukemia (APL) has evolved rapidly in the past two decades after the introduction of highly active drugs, including tretinoin (all- trans-retinoic acid) and arsenic trioxide. It is now possible to treat this disease without the use of traditional cytotoxic chemotherapy. Today’s clinical guidelines include multiple regimens, some of which continue to use cytotoxic chemotherapy. This leaves the practicing oncologist with multiple treatment options when faced with a new case of APL. In an effort to standardize our approach to the treatment of newly diagnosed APL, we sought to develop a set of treatment recommendations at our institution. We identified eight major controversial issues in the treatment of APL. These controversial issues include the optimal dose and schedule of both all- trans-retinoic acid and arsenic trioxide, the optimal regimen for high-risk APL, the need for intrathecal prophylaxis, the use of prophylactic corticosteroids, and the need for maintenance therapy after consolidation. We reviewed the relevant literature and used the Delphi method among the coauthors to reach consensus for recommendations on the basis of the best available data and our own clinical experience. In this clinical review, we present our consensus recommendations, the reasoning behind them, and the grading of the evidence that supports them.

All-Trans Retinoic Acid Inhibits Migration and Invasiveness of Rheumatoid Fibroblast-Like Synoviocytes

“…In effect, the 0.5 mg/kg of ATRA given to these mice leads to peak ATRA concentrations between 0.6 and 3 mM in serum and tissues, as estimated from the available data in mice (Jing et al, 2017). These concentrations are about 1000 times larger than the endogenous concentration found in the plasma of human subjects (Jing et al, 2017), but there is no reason to expect they will be associated with intolerable adverse effects because they are about one-hundredth the concentrations found in plasma with the recommended dose for the treatment of acute promyelocytic leukemia (Castaigne et al, 1993;Sanz et al, 2009;Osman et al, 2018). Therefore, the 5 mM concentration was clearly larger than the endogenous ATRA, sufficient for eliciting significant effects in preclinical arthritis models, and likely to be well tolerated.…”

Acute promyelocytic leukemia (APL): a review of the literature

“…Clinical manifestations associated with this side effect include dyspnea, pulmonary inðltrates, unexplained fever, pleuro-pericardial effusion, hypotension, acute renal failure, and peripheral edema [8,58,59]. Close to 50% of patients undergoing treatment with ATRA will develop differentiation syndrome [8,10,58]. Patients who experience ATRA syndrome have a significantly lower event-free survival (EFS) and overall survival (OS) compared to patients who do not develop this complication of treatment [8,9].…”

“…High-risk patients are defined as having a WBC above 10,000/µL [9]. Although intermediate as well as low-risk patients may be treated without the use of cytotoxic chemotherapy, the combination of ATRA and ATO alone is not sufficient to treat high-risk patients [10]. The treatment of highrisk patients, (defined as having a WBC count greater than 10,000/µL)-involves administration of cytotoxic chemotherapy [10].…”

“…Although intermediate as well as low-risk patients may be treated without the use of cytotoxic chemotherapy, the combination of ATRA and ATO alone is not sufficient to treat high-risk patients [10]. The treatment of highrisk patients, (defined as having a WBC count greater than 10,000/µL)-involves administration of cytotoxic chemotherapy [10]. An evaluation of four clinical trials involving low risk APL patients (WBC count ≤ 10 × 10 9 /L) from 2010-2014 showed overall survival rates (%) ranging from a low of 86% after three years to a high of 99% after 4 years [11][12][13][14].…”

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

“…Recently Sanz et al reported that there are no formal data supporting the use of CNS prophylaxis in the ATO era [124]. Also Larson et al do not recommend intrathecal chemotherapy (ITT) in the treatment of APL for any risk, thus prophylactic ITT was not used in trials that incorporated ATRA and ATO [125][126][127][128].…”