Study Finds Thromboembolism Is a Frequent Complication of ALL Treatment

Adolescents and adults with acute lymphocytic leukemia (ALL) are at a “markedly” increased risk for developing thromboembolism (TE), even when treated according to the same protocol as pediatric patients, according to research published in Blood.

Patients 10 years or older at the time of ALL diagnosis were at the highest risk for treatment-related TE and represent a patient population who would be candidates for preemptive antithrombotic prophylaxis, noted the authors, led by Cecilie Utke Rank, MD, of the Pediatric Oncology Research Laboratory at the University of Copenhagen in Denmark.

In this population-based, prospective study, the researchers examined risk factors for TE, as well as its incidence and clinical characteristics, in 1,772 patients with ALL who were treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol between July 2008 and April 2017.

Participants were aged 1 to 45 years; two-thirds of the patient population were diagnosed with ALL between the ages of 1.0 and 9.9 years (n=1,192; 67%), while others were between the ages of 10.0 and 17.9 (n=306; 17%), or 18.0 and 45.9 (n=274; 16%).

In the NOPHO ALL2008 protocol, patients were stratified according to TE risk groups (standard, intermediate, high, or high risk with hematopoietic cell transplantation [HR-HCT] in first complete remission [CR1]).

Children were randomized to receive pegylated asparaginase (pegASP) administered either at two- or six-week intervals (control arm and experimental arm, respectively) from weeks 14 to 33. The protocol did not include any common recommendations for routine antithrombotic prophylaxis, so low molecular– weight heparin twice daily for one to three months was recommended in the case of symptomatic TE, the authors explained. Patients were followed until date of first event (defined as relapse, death in CR1, or second malignant neoplasm), HCT in CR1, or loss to follow-up.

At the end of follow-up (April 1, 2017), patients had been followed for a median of 4.3 years (interquartile range [IQR] = 2.5-6.4 years).

The 2.5-year cumulative incidence of firsttime TE during therapy was 7.9 percent, or 137 TE events. Nearly all of these patients (n=126; 92%) presented with symptomatic TE, with a 2.5-year cumulative incidence of 7.2 percent.

“Not surprisingly, the majority of TE events occurred during treatment phases containing pegASP,” the authors reported, with 72 percent of TE cases (n=99) occurring within four weeks from last pegASP administration. They also found that “TE occurrence altered the subsequently scheduled ALL treatment by truncating pegASP administration in 38 of 128 patients [30%].” When the authors analyzed the data to identify risk factors for TE, they found that the 2.5-year cumulative incidence of any TE was significantly higher in patients at least 10 years old:

  • patients 1.0 to 9.9 years: 3.7%

  • patients 10.0 to 17.9 years: 15.5%

  • patients 18.0 to 45.9 years: 18.1% (p<0.0001)

Of those who developed supra-diaphragmatic TE, 93 percent had indwelling central venous lines (ICVL); among those who developed asymptomatic TE, 64 percent had ICVL. Infections were reported in 42 percent of patients at the time of TE.

The investigators next conducted multivariable analyses of all patients with delayed entry at day 29 (n=1,594 patients with 114 TE events). Again, the adjusted hazard ratio (HR) for TE was significantly higher in adolescents (HR for those aged 10.0 to 17.9 years = 4.9; 95% CI 3.1-7.8; p<0.0001) and adults (HR for those aged 18.0 to 45.9 years = 6.06; 95% CI 3.65-10.1; p<0.0001), than young children with ALL (HR for <10 years = 2.1; 95% CI 1.0-4.3; p=0.04).

Young patients diagnosed with ALL between the ages of 1 and 6 had the lowest adjusted risk for TE, compared with all other patient age groups, including older children (aged 6.0-14.9 years; HR=2.0; 95% CI 1.2-3.5; p=0.01), young adults (15.0-20.9 years; HR=7.74; 95% CI 4.52- 13.2; p<0.0001), and adults (21.0-45.9 years; HR=6.52; 95% CI 3.69-11.6; p<0.001).

The researchers selected age, enlarged lymph nodes, and mediastinal mass to test for associated risk of TE among 1,723 patients (with 132 TE events). Age had the largest absolute risk ratio (RR):

  • age: RR=4.7 (95% CI 3.1-7.1)

  • enlarged lymph nodes: RR=2.0 (95% CI 1.2-3.1)

  • mediastinal mass: RR=1.6 (95% CI 1.0-2.6)

Sixty-seven patients died while in CR1 occurred in 67 patients, 12 of whom had TE, and death was directly attributable to TE in five cases.

TE was associated with a higher likelihood of death in CR1 in younger patients, compared with those without TE (HR for 1.0-9.9 years = 10.1; 95% CI 4.05-25.3; p<0.0001, and HR for 10.0-17.9 years = 4.51; 95% CI 1.39-14.7; p=0.01). However, there was no difference in the risk for death in CR1 outcomes in adult patients with and without TE (HR=1.1; 95% CI 0.2-5.0; p=0.90).

A total of 134 patients had leukemic relapse during CR1, including seven who experienced TE, all of whom were 18 years or older. As with death in CR1, relapse outcomes did not differ in adults with or without TE (HR=0.8; 95% CI 0.4-1.9; p=0.60).

The researchers concluded that the primary causes of the age-related TE risk among adolescents and adults with ALL remain uncertain. “[This association] may involve age-related decline in anticoagulant and fibrinolytic parameters that provides a prothrombotic state likely reflecting the changes in endogenous sex hormones [during puberty],” they explained.

The study is limited by its lack of data on TE-specific risk factors for patients without TE. In addition, analyses were conducted at multiple centers in different countries, which affected the standardization of the study protocol. Lastly, TE screening was not performed, so asymptomatic TE cases were detected by chance and may be underestimated.

The authors report no financial conflicts.

Rank CU, Toft N, Tuckuviene R, et al. Thromboembolism in acute lymphoblastic leukemia: results of NOPHO ALL2008 protocol treatment in patients 1–45 years. Blood. 2018 April 16. [Epub ahead of print]