Lymphoma-type Adult T-cell Research Articles

The clinical impact of the ratio of C-reactive protein to albumin (CAR) in patients with acute- and lymphoma-type adult T-cell leukemia-lymphoma (ATL).

Recently, the ratio of C-reactive protein to albumin (CAR) is used as an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in solid tumors and hematological malignancy. However, no studies of the CAR have been performed in patients with adult T-cell leukemia-lymphoma (ATL). We retrospectively analyzed the clinical features and outcomes in 68 newly diagnosed acute- and lymphoma-type ATL [(acute-(n=42) or lymphoma-type (n=26)] patients in Miyazaki Prefecture from 2013 to 2017. Furthermore, we investigated correlations between pretreatment CAR levels and clinical features. The median age was 67 years (range, 44 - 87). Patients were initially treated by either palliative therapy (n=14) or chemotherapy [n=54; CHOP therapy (n=37)/ VCAP-AMP-VECP therapy (n=17)], and showed median survival durations of 0.5 months and 7.4 months, respectively. The factors affecting OS by multivariate analysis were age, BUN, and CAR. Importantly, we revealed that the high CAR group (optimal cut-off point; 0.553) was a significant indicator of worse OS by multivariate analysis (p< 0.001, HR; 5.46). The median survival of patients with a CAR< 0.553 was 8.37 months, while patients with a CAR>0.553 had a median survival of 3.94 months. The different clinical features between high CAR and low CAR groups were hypoproteinemia and the implementation of chemotherapy. Furthermore, in the chemotherapy group, but not the palliative therapy group, CAR was a significant prognostic marker. Our study indicated that CAR may be a new simple and significant independent prognostic marker in acute- and lymphoma-type ATL patients.

Cytological tumour cell characteristics and reactive small lymphocytes influence patient prognosis in acute and lymphoma type adult T-cell leukaemia/lymphoma.

Acute and lymphoma type adult T-cell leukaemia/lymphoma (ATLL) patients show an aggressive clinical course. While some clinical signs indicate good prognosis, definitive cytohistological prognostic factors have yet to be described. We classified 65 ATLL patients into three groups by tumour cell size and nuclear pleomorphism on fine-needle aspiration and tumour touch smear samples. Semi-quantitative analysis of background small lymphocytes, reactive CD20-positive B cells and CD8-positive T cells was performed. Thirty-one patients had pleomorphic lymphoma with predominantly medium-sized cells and coarse granular nuclei. Another 24 patients showed pleomorphic large cell lymphoma with stippled chromatin. The remaining 10 demonstrated monomorphic large lymphoma cells with fine granular chromatin. Patients with pleomorphic lymphoma with medium-sized cells showed significantly higher serum lactate dehydrogenase and lower CD30 and C-MYC expression in lymphoma cells than the other two groups (P = .0216, P < 0.01, respectively). Patients with pleomorphic medium-sized ATLL had few usual small lymphocytes observed on routine morphological examination and showed less concurrent detection of CD20-positive B cells and CD8-positive T cells, both of which were lower than in the other two groups (P = .006, P = .019, respectively). Furthermore, ATLL patients with predominantly medium-sized lymphocytes exhibited a worse prognosis than patients with pleomorphic large cells (P = .0197). Background small lymphocytes and concurrent detection of CD20-positive B cells and CD8-positive T cells may thus be good prognostic factors (P = .011, P = .021, respectively). Morphological features, size of neoplastic cells and background non-neoplastic lymphocyte (B cells and CD8-positive T cells) volume appear to influence the prognosis of patients with aggressive-type ATLL.

O1-046 - A Prognostic Index for Acute and Lymphoma Type Adult T-Cell Leukemia/Lymphoma

ABSTRACT Purpose The prognosis of acute and lymphoma type adult T-cell leukemia/lymphoma (ATL) has remained very poor, but there is a marked diversity in survival outcomes. The aim of this study was to develop a prognostic index (PI) for acute and lymphoma type ATL (ATL-PI). Patients and methods In a retrospective review, data from 807 patients newly diagnosed with acute and lymphoma type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed an original PI employing the multivariable fractional polynomial model. Results The overall median survival time (MST) for 807 patients was 7.7 months. The Ann Arbor stage (I–II versus III–IV), performance status (0–1 versus 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 (log-rank test, P 1) + 1 (if age > 70) + 1 (if Albumin 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 also yielded a good separation of OS curves (log-rank test, P Conclusion We developed the PI based on five prognostic factors in patients with acute and lymphoma type ATL, and further proposed its simplified version which is clinically accessible and useful. (J Clin Oncol 2012, in press.)

Identification of multiple subclones in peripheral T‐cell lymphoma, not otherwise specified with genomic aberrations

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with genomic aberrations has been shown to resemble lymphoma-type adult T-cell leukemia/lymphoma (ATLL) in terms of its genomic aberration patterns, histopathology, and prognosis. We have shown recently that a majority of patients with acute-type ATLL have multiple subclones that were likely produced in lymph nodes. In this study, we analyzed whether PTCL, NOS with genomic aberrations also has multiple subclones as found in ATLL by means of high-resolution oligo-array comparative genomic hybridization (CGH). Thirteen cases of PTCL, NOS were available for 44K high-resolution array CGH analysis. The results showed that 11 (84.6%) of the 13 cases had a log2 ratio imbalance, suggesting that multiple subclones exist in PTCL, NOS with genomic aberrations. In order to analyze the association between multiple subclones and prognosis, we used previous bacterial-artificial chromosome (BAC) array analyses for 29 cases and found that the existence of multiple subclones was associated with a poor prognosis (P = 0.0279).

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

The prognosis of acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL) is poor, but there is marked diversity in survival outcomes. The aim of this study was to develop a prognostic index (PI) for acute- and lymphoma-type ATL (ATL-PI). In a retrospective review, data from 807 patients newly diagnosed with acute- and lymphoma-type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed a PI using a multivariable fractional polynomial model. Median overall survival time (MST) for the 807 patients was 7.7 months. The Ann Arbor stage (I and II v III and IV), performance status (0 to 1 v 2 to 4), and three continuous variables (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 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 < .001; χ(2) = 89.7, 2 df; log-rank test). We also simplified the original ATL-PI according to dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and developed an easily calculable PI with prognostic discrimination power (P < .001; χ(2) = 74.2, 2 df; log-rank test). The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks.

Array Comparative Genomic Hybridization Analysis of PTCL-U Reveals a Distinct Subgroup with Genetic Alterations Similar to Lymphoma-Type Adult T-Cell Leukemia/Lymphoma

Peripheral T-cell lymphoma, unspecified (PTCL-U) comprises histopathologically and clinically heterogeneous groups. The purpose of this study was to identify subgroups with distinct genetic, histopathologic, and prognostic features. We used array comparative genomic hybridization (CGH) for high-resolution analysis of 51 PTCL-U patients and the array data for examining possible correlations of histopathologic and clinical features. Moreover, we compared the genetic, histopathologic, and prognostic features of the PTCL-U cases with those of 59 cases of lymphoma-type adult T-cell leukemia/lymphoma (ATLL). We identified 32 regions with frequent genomic imbalance, 1 region with high copy number gain at 14q32.2, and 1 region with homozygous loss at 9p21.3. Gains of 7p and 7q and loss of 9p21.3 showed a significant association with poor prognosis. PTCL-U cases with genomic imbalance showed distinct histopathologic and prognostic features compared with such cases without alteration and a marked genetic, histopathologic, and prognostic resemblance to lymphoma-type ATLL. The array CGH enabled us to identify the frequently altered genomic regions with strong prognostic power among PTCL-U cases. A correlative analysis using the array CGH data disclosed a subgroup in PTCL-U with genomic alterations and with histopathologic and clinical relevance. In addition to histopathologic similarity, the strong genetic and prognostic resemblance between PTCL-U cases with genomic imbalance detected by array CGH and lymphoma-type ATLL seems to support the notion that the former may constitute a distinct PTCL-U subgroup.

Overexpression of survivin in primary ATL cells and sodium arsenite induces apoptosis by down-regulating survivin expression in ATL cell lines

AbstractPatients with acute- or lymphoma-type adult T-cell leukemia (ATL) have a poor outcome because of the intrinsic drug resistance to chemotherapy. Protection from apoptosis is a common feature involved in multidrug-resistance of ATL. IAP (inhibitor of apoptosis) family proteins inhibit apoptosis induced by a variety of stimuli. In this study, we investigated the expression of IAP family members (survivin, cIAP1, cIAP2, and XIAP) in the primary leukemic cells from patients with ATL. We found that survivin was overexpressed in ATL, especially in acute-type ATL. Sodium arsenite was shown to down-regulate the expression of survivin at both the protein and RNA levels in a time- and dose-dependent manner, thus inhibiting cell growth, inducing apoptosis, and enhancing the caspase-3 activity in ATL cells. Nuclear factor-κB (NF-κB) enhances the transcriptional activity of survivin. Sodium arsenite suppressed the constitutive NF-κB activation by preventing the IκB-α degradation and the nuclear translocation of NF-κB. These findings suggest that survivin is an important antiapoptotic molecule that confers drug resistance on ATL cells. Sodium arsenite was shown to down-regulate the expression of survivin through the NF-κB pathway, thus inhibiting cell growth and promoting apoptosis of ATL cells.

Serum Levels of Endogenous Thrombopoietin and Granulocyte-Colony Stimulating Factor in Patients with Acute or Lymphoma Type Adult T-cell Leukemia During Multicycle Chemotherapy

Recent multidrug chemotherapy for adult T-cell leukemia (ATL) showed improved findings, however, these protocols often induced persistent myelosuppression. Among 67 patients with acute and lymphoma type ATL treated between January 1996 and December 1998, 42 patients died during this period and showed chemotherapy-induced myelosuppression. To characterize the relation between the severity of myelosuppression and the endogenous thrombopoietin (TPO) or granulocyte-colony stimulating factor (G-CSF) levels in ATL patients, we measured these hematopoietic factors using ELISA method. Nineteen patients with acute or lymphoma type ATL and 16 healthy individuals were examined. During thrombocytopenia, the serum TPO levels were significantly higher than that of controls (P <0.0001) and were inversely correlated with the platelet counts (r = m 0.687 P <0.001). Later in the chemotherapy cycle, severe persistent thrombocytopenia occurred and TPO levels elevated and remained at a high level approximating the TPO levels of exogenous TPO administration (0.3 µ g/kg body weight). On the other hand, the serum G-CSF levels with absolute neutrophil counts (ANC) below 0.5 × 10 9 /L were significantly higher than controls (P =0.009) and inversely correlated with ANC (r = m 0.382 P =0.0034). However, G-CSF levels in six samples obtained after 6 h of G-CSF (100-150 µ g per body) administration was approximately 50-fold higher than that in the neutropenic states. These findings suggested that G-CSF can effectively reduce the severity and duration of intensified chemotherapy-induced neutropenia and higher dose exogenous TPO (higher than 0.6 µ g/kg per day) therapy may be required to enhance platelet recovery after intensive chemotherapy in ATL patients.

Frequent Hepatic Involvement in Adult T Cell Leukemia: Comparison with non-Hodgkin's Lymphoma

We examined 111 patients with acute type- or lymphoma type-adult T-cell leukemia (ATL) and compared them with 106 patients with non-Hodgkin's lymphoma (NHL). In addition to skin involvement and hypercalcemia which are already known to be frequent in ATL, ATL patients showed an higher incidence of hepatic involvement. There was more frequent palpable hepatomegaly, higher total bilirubin, GOT, GPT, lactate dehydrogenase (LDH), and alkaline phosphatase values in ATL than in NHL patients (p < 0.0001). Among 36 autopsied liver samples, invasion of ATL cells was confirmed in 22 cases. ATL patients with impaired hepatic function showed shorter survival times than patients without hepatic dysfunction. Moreover, ATL patients showed a worse performance status (PS), a higher incidence of lytic bone lesions, lower total protein (TP) and serum albumin levels than NHL patients. This invasive characters of ATL cells and consequent impaired general condition seemed to be factors affecting the poor prognosis recorded in ATL.

Major prognostic factors of Japanese patients with lymphoma‐type adult T‐cell leukemia

Fifty-three Japanese patients with the lymphoma-type adult T-cell leukemia (ATL) were analyzed to study the prognostic value of various clinical findings recorded at the time of diagnosis. All patients were positive for human T-cell leukemia virus type I (HTLV-I) antibody and demonstrated monoclonal integration of HTLV-I proviral DNA in their malignant cells. The important individual variables detected in a previous univariate analysis were placed in a multiple regression model to identify the major prognostic factors for survival. This analysis showed that serum lactate dehydrogenase (LDH), calcium, and total protein levels had a strong predictive relationship with the length of survival (in descending order of importance). Among the 53 patients, 46 were dead at the time of analysis. The cause of death in relation to the duration of survival is also reviewed in this article.