Aggressive NK Cell Leukemia (ANKL): Experience with 34 Patients and Therapeutic Potentials of L-Asparaginase and Allogeneic Hematopoietic Cell Transplantation - A Japan-Korea Multicenter Study for ANKL (ANKL07) -
Authors: Ishida Fumihiro , Kim Won Seog , Ko Young Hyeh , Suzumiya Junji , Isobe Yasushi , Oshimi Kazuo , Nakamura Shigeo , Suzuki Ritsuro 
Published: October 2019

Abstract
Abstract 3091

Background:
Aggressive NK cell leukemia (ANKL) is a malignant disorder of mature NK cells that is more common in East Asia and is often associated with Epstein-Barr virus (EBV). The prognosis of ANKL is dismal and the survival is one of the shortest among the lymphoid neoplasms. Because of its rarity, the characteristics and optimal managements of this disease are uncertain.
To better elucidate clinicopathologic features and therapeutic modalities for ANKL, a retrospective Japan-Korea multicenter survey of ANKL (ANKL07) was conducted.

Methods:
Eligibility criteria were based on the diagnosis for ANKL according to the WHO classification. Pathological and clinical information including that on chemotherapy and hematopoietic cell transplantation (HCT) was collected. Approval from the institutional review board at each participating institution was obtained for this study.

Results:
Forty-one patients (pts) were registered from 8 hospitals. After central reviews, 34 pts were further analyzed, while 7 pts were excluded.
The median age of the pts was 45 years old (range: 16–79) with 26 males and 8 females. Four pts had a history of preceding disorders including EBV-LPD in childhood, mosquito bite hypersensitivity or EBV-associated liver damage. Three female pts presented during pregnancy. Fever and hepatosplenomegaly were recognized in 100% and 71% of the pts, respectively. Thirty-two pts (94%) showed high or high-intermediate International Prognosis Index. Three types of ANKL cells (type I, II or III) were categorized according to the morphological features. Using this classification, there were 11, 13 and 10 pts with types I, II and III, respectively. EBV was positive in 85% of the pts. Eleven pts showed less than 20% leukemic cells in both peripheral blood (PB) and bone marrow (BM). The clinical characteristics and prognosis of these pts did not differ from those of the pts with more tumor cells in PB/BM except for the incidence of hemophagocytic syndrome.
As initial therapy, anthracycline-based chemotherapies were utilized in 13 pts and L-asparaginase-containing regimens were administered in 5 pts. Although anthracycline chemotherapy was not associated with better outcome by Kaplan-Meier analysis (p=0.64), L-asparaginase chemotherapy resulted in CR or PR in 4 pts and significantly better survival (p=0.03).
A total of 9 HCT, 2 autologous (auto) and 7 allogeneic (allo), were performed in 8 pts; none were in complete remission (CR) at the time of transplant. For allo HCT, the donor source was HLA-matched related bone marrow in two, cord blood in two, PB of HLA-matched unrelated donor in one and HLA-mismatched related PB in two. The conditioning regimen was TBI+CY in three, and fluradabine-based regimen in four. One patient with auto HCT and 4 with allo HCT reached CR after HCT.
The median survival of all 34 pts was 51 days (range: 1-1, 630). Median survivals for the patients with or without HCT were 266 days (range: 80-1, 630) and 36 days (range: 1–324), respectively. Two pts with allo HCT were alive in CR while the other 6 pts with allo HCT died of the disease (5 pts) or infection (1 pt). All pts without HCT died of ANKL. Times from the diagnosis to HCT for the 2 survivors were within 80 days.
In univariate analysis, L-asparaginase administration was the only clinical factor associated with better survival (hazard ratio 0.29, 95% confidence interval: 0.12–0.70, p=0.008). Age (HR 1.02, 95% CI: 0.998–1.08, p=0.07) and the use of etoposide (HR 0.48, 95% CI: 0.22–1.07, p=0.07) were marginal. Multivariate Cox analysis indicated that the use of L-asparaginase was an independently significant factor for better survival (HR 0.33, 95% CI: 0.13–0.83, p=0.02).

Conclusions:
This is the largest case series of ANKL. ANKL cells are morphologically heterogeneous and the main infiltration sites of ANKL are liver, spleen and BM. In addition, ANKL showed poor prognosis regardless of PB/BM tumor cell burden. Although the prognosis of ANKL did not improve significantly compared with those in previous reports, L-asparaginase-containing initial chemotherapy and allo HCT are promising approaches for ANKL. Prospective studies are required to confirm these results.

Disclosures:
No relevant conflicts of interest to declare.