Epidemiology, Clinical Features, and Outcome of HTLV-1 Related Adult T-Cell Leukemia-Lymphoma in a Prevalent Area in the United States

Introduction:

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive, peripheral T-cell neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 infects up to 10 million people worldwideand is most endemic in Southwestern Japan, the Caribbean basin, South America, and Western Africa. South Florida is the continental U.S. region most proximal to the Caribbean, therefore HTLV-1 associated diseases are commonly encountered in Miami. ATLL carries a dismal prognosis and is essentially incurable by conventional drugs. We describe the epidemiology, clinical features, treatment, and disease outcome of ATLL encountered at the University of Miami and affiliated hospitals over the past 3 decades. To our knowledge, this study is the largest of its kind ever conducted in the U.S.

Methods:

We conducted a retrospective analysis of patients (pts) diagnosed with ATLL between January 1987 and December 2016. ATLL cases were classified according to the Shimoyama criteria into acute (A), lymphomatous (L), unfavorable chronic (UC), chronic (C), and smoldering (S). Treatment approaches used as first-line therapy were: 1) chemotherapy alone; 2) combined chemotherapy with zidovudine/interferon-alpha (AZT-IFN) (concurrently or sequentially after chemotherapy); and 3) AZT-IFN alone. Treatment response was assessed according to the consensus report for ATLL published in 2009 by Tsukasaki et al . To be classified as complete response (CR), partial response (PR), and stable disease (SD), these had to persist for a period of at least 4 weeks.

Results:

A total of 203 pts with ATLL were identified. One hundred and ninety-five pts (L=101, A=76, UC=7, S=4, C=3, and unclassified=4) had sufficient data for analysis. Demographic characteristics are shown in Figure 1 and Table 1. Median age at diagnosis was 52 years. Female predominance was observed in aggressive ATLL pts (62% in A vs. 55% in L type, p=0.383). The great majority of pts were Afro-Caribbean (n=147, 77%) originating from Haiti (n=76, 39%) and Jamaica (n=47, 24%). Hypercalcemia was highly associated with A type (74% vs. 22% L type) (p=0.012). HIV co-infection was observed in 17 (9%) cases. The most commonly affected extranodal sites other than peripheral blood and bone marrow in all subtypes were skin 25% (n = 55), bone with lytic lesions 14% (n=27), lung 13% (n=26), liver 13% (n=23), and CNS 6% (n=11). Regimens used during the first 3 treatment attempts are summarized in Table 2. The median survival (MS) times were 4.3 months, 10 months, 67 months, and 72 months for A, L, UC, and C/S forms, with 4-year survival of 13%, 4%, 57%, and 75%, respectively (Figure 2). Among pts diagnosed between 2000 and 2016 when modern conventional therapies were available, the 4-year OS rates were 14% for A (MS 4.4 months), 6 % for L (MS 12.8 months), 67% for unfavorable chronic (MS 67 months), and 75% for C/S. First-line AZT-IFN resulted in overall response (OR) rate of 56% (CR 23%) for A (n=43) vs. 33% (CR 16.5%) for L (n=6), respectively (Table 3). The OR rates after first-line multi-agent chemotherapy alone for A vs. L were 78% (CR 39%) and 67% (CR 33%), respectively (Table 3). Progression-free survival (PFS) rates in pts with aggressive ATLL who achieved CR after AZT-IFN vs. chemotherapy were 48 months vs. 13 months, respectively (p=0.003) (Figure 3). Regarding chemotherapy regimen choice, intensive VCAP-AP-VECP (a modified version of Japanese LSG-15 VCAP-AMP-VECP) trended to yield a higher CR rate (59%, n=17) as compared to EPOCH (19%, n=26) and CHOP-based chemotherapy (35%, n=37). Two of 4 pts with L type ATLL who underwent allogeneic hematopoetic stem cell transplant (allo-HSCT) had PFS of 21 and 28 months.

Conclusion:

ATLL continues to have a poor outcome despite conventional therapies thus urging the development of novel approaches. Our study found higher rates of hypercalcemia and elevated LDH in A type as compared to those previously reported in Japanese pts, which suggests the Afro-Caribbean ATLL variant may present more aggressively. AZT-IFN was highly associated with a superior outcome in pts with aggressive ATLL who achieved CR with this regimen over chemotherapy alone. Altogether, our clinical experience suggests AZT-IFN is a reasonable first line option for aggressive leukemic ATLL types, and may be the best treatment option for UC type. Chemotherapy remains the preferred choice for L type ATLL, and A type when AZT-IFN is not be feasible, with consideration of allo-HSCT upfront.

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