What Is the Best Method for Cytoreduction in Patients With Acute Myeloid Leukemia and Hyperleukocytosis?

In patients with acute myeloid leukemia (AML), hyperleukocytosis is associated with the oncologic emergency leukostasis as well as inferior outcomes, but there are few data to determine the optimal approach to rapidly bring down the white blood cell count (WBC). Two recent studies evaluated two standard approaches to cytoreduction – high-dose cyclophosphamide and leukapheresis – and seem to suggest that high-dose cyclophosphamide leads to a greater sustained reduction in WBC counts, while the benefits of leukapheresis were brought into question.

In the first study, published in Leukemia & Lymphoma, Jennifer Zhao, PharmD, of Yale New Haven Hospital in Connecticut, and colleagues retrospectively evaluated the use of high-dose cyclophosphamide in 27 patients with AML (n=26) or blast-phase chronic myeloid leukemia (n=1) between 2014 and 2019. In the trial, hyperleukocytosis was defined as a WBC count ≥50×109/L at presentation.

Treatment consisted of single-dose intravenous high-dose cyclophosphamide 60 mg/kg administered over a four-hour period. The investigators reported that 74% of patients had leukostasis symptoms when they presented to the hospital. These included hypoxemia and respiratory distress (66.7%), neurological deficit (11.1%), disseminated intravascular coagulation (7.4%), and acute kidney injury (3.7%).

Three-quarters of patients received cyclophosphamide within one day of hospital admission. Twenty-five received the full dose of cyclophosphamide, while two received a reduced dose of 35 to 40 mg/kg because of comorbidities and poor performance status.

Eight patients (29.6%) died within a seven-day period of hospital admission, all of whom had required admission to the intensive care unit, the authors reported.

At the time of high-dose cyclophosphamide initiation, the median WBC count was 107×109/L. Among the 24 patients evaluable for WBC trends, 18 (75%) experienced sustained reduction in WBC, with a median nadir of 0.25×109/L. This included 17 who achieved a >95% WBC count reduction. Six patients experienced a transient response to high-dose cyclophosphamide, with a corresponding median WBC reduction of 34% followed by a subsequent elevation within three days.

Adverse events (AEs) associated with high-dose cyclophosphamide included tumor lysis syndrome (25.9%), disseminated intravascular coagulopathy (18.5%), and hemorrhagic cystitis (3.7%). The study investigators noted that these toxicities “are similar to expected leukostasis complications” and emphasized the importance of prophylaxis, close monitoring, and supportive care for disseminated intravascular coagulation, tumor lysis syndrome, and organ function.

“[The use of high-dose cyclophosphamide avoids] the complications and logistical challenges associated with leukapheresis.”

—Jennifer Zhao, PharmD

Dr. Zhao and coauthors concluded that high-dose cyclophosphamide appears to be a safe and effective strategy for rapid cytoreduction in this patient population, and one “that enables a faster cytoreduction compared to hydroxyurea while avoiding the complications and logistical challenges associated with leukapheresis.”

The safety and efficacy of leukapheresis for cytoreduction were evaluated in a large retrospective analysis of 779 patients with newly diagnosed AML who presented with hyperleukocytosis (defined as >50×109/L) across centers in the U.S. and Europe from 2006 to 2017. Findings were reported in Leukemia by Maximilian Stahl, MD, from Yale School of Medicine, and colleagues.

Among the 779 patients, clinical leukostasis was reported in 27% and leukapheresis was used in 113 patients (15%). In the entire cohort, 30-day mortality was 16.7%. The median overall survival was 12.6 months among all patients but was substantially shorter among those ≥65 years (4.5 months).

The researchers found that the use of leukapheresis did not significantly affect 30-day mortality, achievement of complete remission, or overall survival.

A univariate analysis demonstrated a statistically significant improvement with leukapheresis in patients with leukostasis, however, these findings did not remain statistically significant in multivariate analysis. “Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value,” the authors concluded.

Study authors report no relevant conflicts of interest.

References

  1. Zhao J, Bewersdorf JP, Jaszczur S, et al. High dose cyclophosphamide for cytoreduction in patients with acute myeloid leukemia with hyperleukocytosis or leukostasis. Leuk Lymphoma. 2020 December 16. [Epub ahead of print]
  2. Stahl M, Shallis RM, Wei W, et al. Management of hyperleukocytosis and impact of leukapheresis among patients with acute myeloid leukemia (AML) on short- and long-term clinical outcomes: a large, retrospective, multicenter, international study. Leukemia. 2020;34(12):3149-3160.

Leukostasis is one of the most dreaded complications of newly diagnosed acute leukemia, occurring more commonly in patients with AML than in those with acute lymphocytic leukemia (ALL). Rapid cytoreduction is necessary to reverse the complications of leukostasis, commonly neurologic and pulmonary in nature.

In their retrospective analysis, Dr. Zhao and colleagues suggest that high-dose cyclophosphamide (HDCy) may be an effective means of cytoreduction in patients with hyperleukocytosis, with sustained reductions in WBC count noted in 75% of evaluable patients. Benefits of HDCy include ease of pharmacy preparation, lack of need for renal or hepatic dose adjustment, and peripheral administration.

Nonetheless, it is notable that eight patients (29.6%) died within seven days of admission of complications related to leukostasis. Small sample size precludes multivariable analysis to help determine which patients benefit most from HDCy. Interpretation of the risk-benefit ratio for this approach is also confounded by the fact that multiple patients received other types of cytoreduction in addition to HDCy, including hydroxyurea and leukapheresis.

A recent large retrospective study by Stahl et al. suggests that leukapheresis, though effective at decreasing peripheral blood blasts, does not improve outcomes in AML, including no difference in remission and mortality rates.

Though no large, randomized studies exist to determine the optimal method of cytoreduction, leukapheresis has already fallen out of favor at many centers due, in large part, to logistical challenges. More studies, preferably randomized, are needed before HDCy takes over as first-line cytoreduction for patients with AML and hyperleukocytosis.

Mary-Beth Percival, MD
Seattle Cancer Care Alliance