A Prognostic Index for Acute and Lymphoma Type Adult T-Cell Leukemia/Lymphoma

Abstract

1582 Background: Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). HTLV-1 is endemic to the southwestern region of Japan, Caribbean basin, Central and South America, and western Africa. A previous report by the Japan Clinical Oncology Group-Lymphoma Study Group (JCOG-LSG) identified five prognostic factors: advanced performance status (PS), high lactic dehydrogenase (LDH), age of 40 years or older, total involved lesions, and hypercalcemia, based on an analysis of 854 patients with newly diagnosed ATL registered between 1983 and 1987. The JCOG-LSG then proposed 4 clinical subtypes: acute, lymphoma, chronic, and smoldering types. In general, the prognosis of acute and lymphoma type ATL is similarly very poor, whereas that of the chronic and smouldering types is better. It has come to the attention of clinicians that there are diverse clinical courses and treatment outcomes among patients with acute and lymphoma type ATL. Therefore, it is necessary to establish a prognostic index (PI) for a risk-adapted approach and improving the quality of clinical trials. The aim of this study was to develop the first PI for acute and lymphoma type ATL (ATL-PI). Patients and Methods: We conducted a nationwide retrospective survey of ATL patients who were newly diagnosed between January 2000 and December 2009, and 1,270 patients with acute and lymphoma type were registered. Fully eligible 807 individuals excluding patients who have received allogeneic hematopoietic stem cell transplantation were used for this analysis, and randomly split the dataset into training (n=404) and validation (n=403) samples. We applied a multivariable fractional polynomial model using continuous variables, and then developed the simplified one using dichotomizing variables. Results: The overall median survival time (MST) for 807 patients was 7.7 months. The Ann Arbor stage (I - II vs. III - IV), performance status (0–1 vs. 2–4), and the three continuous variables of age, serum albumin, and soluble interleukin-2 receptor (sIL-2R) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (p<0.0001). ATL-PI = 0.65 (if Stage = III or IV) + 0.35 (if PS > 1) + 0.016 × Age (years) − 0.36 × Albumin (g/dL) + 0.37 × log10 (sIL2R (U/mL)) To make the scoring system simpler and clinically practicable, we also simplified the original ATL-PI by dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and subsequently fitted a multivariate Cox model based on these dichotomizations in the training sample. Then, we derived a simplified ATL-PI as follows: Simplified ATL-PI = 2 (if Stage = III or IV) + 1 (if PS > 1) + 1 (if Age > 70) + 1 (if Albmin < 3.5) + 1 (if sIL2R > 20,000) The scores from 0 to 2 were categorized into low risk group, 3 and 4 into intermediate risk, and from 5 to 6 into high risk group. This classification yielded a good separation of OS curves (p<0.0001), and high concordance to the original ATL-PI in the validation sample. Conclusion: We identified 5 prognostic factors in acute and lymphoma type ATL using a multivariable fractional polynomial model, and further simplified it with minimal loss of the original index. The ATL-PI enables us to distinguish 3 different groups by predicting OS at the time of diagnosis. The ATL-PI, the first PI for acute and lymphoma type ATL, may be a promising platform in consideration of the choice of optimal treatment by risk-stratification and for well-controlled clinical trials. Disclosures: No relevant conflicts of interest to declare.

Japan Clinical Oncology Group (JCOG) prognostic index and characterization of long-term survivors of aggressive adult T-cell leukaemia-lymphoma (JCOG0902A)

“…Although we expected to define a favourable prognosis group in the international PI for aggressive NHL, which consists mostly of diffuse large B‐cell lymphoma, the difference in the OS between the two risk groups was small. This finding was similar to a recent retrospective nationwide survey in Japan of all patients with acute or lymphoma type at each institute (Katsuya et al , ). Therefore, the JCOG‐PI could not be used to identify patients with aggressive ATL who could be treated with intensive chemotherapy alone and spared from more intensive therapy, such as allo‐HSCT, as is the case with the ATL‐PI (Katsuya et al , ).…”

“…Recently, an ATL‐PI consisting of Ann Arbour clinical stage, PS, age, serum albumin level and soluble IL2 receptor level was used to identify three risk groups for patients with acute and lymphoma types of ATL (Katsuya et al , ). However, in that study, both the ATL‐PI and the risk grouping in the 1980's were constructed based on the results of questionnaires collected retrospectively; hence the treatments used were diverse and the prognostic factors might not have been evaluated homogeneously, in contrast to present study based on the three prospective trials (Lymphoma Study Group, ; Katsuya et al , ).…”

“…The external validation set consisted of 136 patients who had not participated in prior JCOG studies but had received anthracycline‐containing regimens as initial chemotherapy at three sites (Nagasaki University Hospital, Nagasaki Medical Centre, and Sasebo City General Hospital) under the remit of the JCOG‐LSG. These patients were a subset of those from a previous retrospective study (Katsuya et al , ) and their OS and corrected calcium levels were reviewed.…”

Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T‐cell leukemia/lymphoma

“…According to the Shimoyama classification, ATLL is classified into 4 disease subtypes: smoldering, chronic, lymphoma, and acute . The acute, lymphoma, and chronic types, when accompanied by unfavorable prognostic factors (hypoalbuminemia, high serum blood urea nitrogen, or high serum lactate dehydrogenase), are regarded as aggressive forms of the disease, and generally have an adverse clinical course . In contrast, the indolent type of ATLL, which includes the smoldering type and the chronic type without unfavorable factors, usually presents with a slower clinical course and progresses to an aggressive type of ATLL following additional genetic alterations .…”

“…In contrast, the indolent type of ATLL, which includes the smoldering type and the chronic type without unfavorable factors, usually presents with a slower clinical course and progresses to an aggressive type of ATLL following additional genetic alterations . The prognosis of each clinical subtype varies, and is estimated by clinical parameters of the ATLL prognostic index (ATL‐PI) or the indolent ATL‐PI (iATL‐PI) for the aggressive or indolent type, respectively . Kataoka et al recently reported that several genetic alterations, including IRF4 amplification, 9p24 ( PD‐L1 ) amplification, or 9p21 ( CDKN2A ) deletion, were significantly associated with poor prognosis in patients with the indolent type of ATLL.…”