Combining ATRA With ATO With or Without Gemtuzumab Ozogamicin Produces Durable Responses in Patients With Acute Promyelocytic Leukemia

The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), with or without the addition of gemtuzumab ozogamicin (GO), is a safe and effective regimen for patients with newly diagnosed acute promyelocytic leukemia (APL), resulting in a complete remission (CR) rate of 96 percent, according to results of a single-center, long-term study published in Blood. This chemotherapy-free regimen also lowered induction mortality and relapse rates, compared with historical rates seen with ATRA and chemotherapy in this population.

“A [chemotherapy-free regimen] will spare patients the toxicities associated with use of cytotoxic agents, with particular benefit to patients unfit for chemotherapy, including older patients, who account for up to 20 percent of the APL population,” noted Yasmin Abaza, MD, of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, and co-authors.

“This study further confirms that the combination of ATRA and ATO is highly effective and superior to chemotherapy plus ATRA in patients with standard-risk APL, and confirms that ATRA, ATO, [and] GO is at least as effective in high-risk patients,” added corresponding author Farhad Ravandi, MD, in an interview with ASH Clinical News.

A total of 187 patients (median age = 50 years; age range = 14-84 years) who were newly diagnosed with APL (defined as the presence of t(15;17) by standard cytogenetic analysis or the presence of the PML-RARA fusion gene by reverse-transcriptase polymerase chain reaction) at the University of Texas MD Anderson Cancer Center between July 2002 and May 2015 were included in this study.

Patients were excluded if they had: pregnancy; a pretreatment QTc interval >480 ms unrelated to electrolyte imbalance; hepatic and renal dysfunction (unless related to APL); or hemolysis or Gilbert’s disease.

Most patients (n=133; 71%) were considered “low-risk,” defined as having a white blood cell (WBC) count of ≤10×109/L, and 54 patients (29%) were considered “high-risk,” defined as a WBC count of >10×109/L at presentation. Among all patients, the median leukocyte count at presentation was 2.2×109/L (range = 0.3-187.9×109/L).

Low-risk patients were initially treated with ATRA 45 mg/m2 administered in two divided doses daily and ATO 0.15 mg/kg administered intravenously daily 10 days after ATRA. High-risk patients received the same induction regimen, but also received one dose of GO 9 mg/m2 or idarubicin (IDA) 12 mg/m2 on day one (IDA was used for some during a brief period when GO was not available). Low-risk patients whose WBC count increased to >10×109/L during the first four weeks of therapy also received the additional treatment with GO or IDA.

Patients continued treatment until there were <5 percent blasts and no abnormal promyelocytes in the bone marrow; treatment was then discontinued until the patient achieved CR with normalization of peripheral blood counts.

Over a median follow-up of 47.6 months (range = 2.7-159.7 months), 179 patients (96%) achieved CR after the induction course. Nearly all patients (98%; n=176) achieved a confirmed molecular remission. Notably, patients achieved CR quickly, with a median time to CR of 30 days (range = 17-80 days) and a median time to molecular CR of 119 days (range = 20-277 days). (See TABLE for outcomes for high- versus low-risk patients.)

Seven patients (4%) relapsed – five high-risk patients and two low-risk patients. Relapse occurred eight to 80 months after achieving CR; three patients experienced late hematologic relapse, occurring beyond one year. Four patients received salvage therapy with ATRA (with or without ATO plus GO or IDA), and all achieved a second CR and underwent hematopoietic cell transplantation (autologous = 2; matched related donor = 1; haploidentical donor = 1).

Twenty-six patients (14%) died; seven deaths (4%) occurred during induction due to disease-related complications, including infection, hemorrhage, and multi-organ failure (median time to death = 12 days; range = 7-24 days). Two patients died due to relapsed/refractory APL, including one patient with persistent central nervous system relapse. The other 17 patients died in CR from unrelated causes, including second malignancies (n=8), sepsis (n=3), unknown causes (n=3), renal failure (n=2), and cardiac failure/arrest (n=1). Excluding early deaths, the median time to death in the remaining 19 patients was 1,224 days (range = 107-3,281 days).

Rates of five-year, event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) were 85 percent, 96 percent, and 88 percent, respectively (median survivals not yet reached). The survival rates were similar between low- and high-risk patients:

  • five-year EFS: 87% and 81%
  • five-year DFS: 99% and 89%
  • five-year OS: 98% and 86%

The most common treatment-related adverse events included infections (n=44; 23.5%), prolonged QT (n=14; 7.5%), and hemorrhage (n=10; 5%).

Differentiation syndrome occurred in 21 patients (11%) but was successfully managed in all patients when ATRA was withheld and corticosteroids were administered, the authors noted.

The study is limited by its single-arm, single-institution, non-randomized design. In addition, the use of IDA when GO was unavailable may also have confounded results.

“The combination of ATRA, ATO, with or without GO, should be considered as the new standard of care for all newly diagnosed patients with APL, and efforts to reinstate the availability of GO should be encouraged,” Dr. Abaza and co-authors concluded.


Reference

Abaza Y, Kantarjian HM, Garcia-Manero G, et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2016 December 21. [Epub ahead of print]

TABLE. Outcomes for Patients With High- Versus Low-Risk APL
Outcome n
High-Risk Patients (n=54)
Complete remission (CR) 52
Relapsed 5
Died in CR 3
Died in relapse 2
Early death 2
Low-Risk Patients (n=133)*
CR 127
Relapsed 2
Died in CR 14
Early death 5
*One patient was not evaluable.

APL = acute promyelocytic leukemia

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