Associated Adult T-cell Leukemia/lymphoma Research Articles

First Line Antiviral Therapy Significantly Improves Survival of Patients with Acute, Chronic and Smoldering ATL: a Worldwide Meta-Analysis.

Abstract 108▪▪This icon denotes an abstract that is clinically relevant.HTLV-I associated adult T cell leukemia/lymphoma (ATL) is an aggressive T cells malignancy, with poor prognosis due to chemotherapy resistance. Multiple small studies using zidovudine (AZT) and interferon-α (IFN) showed response in ATL patients. However, the global impact of this innovative antiviral treatment strategy on long-term survival of ATL patients in routine practice remains undetermined. We realized a worldwide meta-analysis on the use of AZT/IFN treatment. Charts of 254 ATL patients treated from 1994 to 2008 in the USA (59 patients), the UK (13 patients), Martinique (111 patients) and France metropolitaine (67 patients) were individually reviewed. Collected data included epidemiological, clinical and biological characteristics, ATL subtype, first line treatment, response to first line therapy, and overall survival. In 231 patients with available survival data, first line therapy was recorded in 207 patients only. Median age was 50 years (range 16 to 95). According to Shimoyama classification, there were 116 acute ATL, 18 chronic ATL, 11 smoldering ATL, 100 ATL lymphoma, and 9 patients with an unknown subtype. Hypercalcemia was present in 48% of patients. Five year overall survival rates were 20% for 77 patients who received chemotherapy alone, 46% for 75 patients who received first line antiviral therapy alone (p=0.012), and 12% for 55 patients who received chemotherapy followed by antiviral therapy. Response rate to first line antiviral therapy was 66%, including 35% complete remission (CR). When overall survival analysis was performed by ATL subtype, patients with acute, chronic, and smoldering ATL significantly benefited from first line antiviral therapy, whereas patients with ATL lymphoma had a better outcome with first line chemotherapy. Achievement of CR with first line antiviral therapy resulted in prolonged survival of more than 10 years in 82% of the acute ATL subgroup. Finally, first line antiviral therapy in chronic and smoldering ATL resulted in 100% overall survival at 10 years. Multivariate analysis using Cox regression showed that first line antiviral therapy significantly improves overall survival of ATL patients. In conclusion, these results confirm that treatment of ATL using AZT and IFN results in a high response and CR rates particularly in acute, chronic and smoldering ATL, but not in lymphoma, resulting in impressive prolonged survival and hence should be considered as gold standard first line therapy. Predictive factors of response are currently under investigations in order to improve prognosis of this still uncurable disease. Disclosures:No relevant conflicts of interest to declare.

Denileukin diftitox: a novel immunotoxin

Objective: To review FDA approved and other potential uses of Ontak, denileukin diftitox. Methods: Information was obtained via the internet and a journal literature review. Results: In 1999, the FDA approved the use of denileukin diftitox for patients with persistent or relapsed CD25-positive cutaneous T-cell lymphoma (CTCL), but Ontak has been reported to be an effective therapy for other neoplastic and non-neoplastic conditions. Oncological uses include therapy for CD25-negative T-cell lymphoma, recurrent and refractory chronic lymphocytic leukemia (CLL), non-Hodgkin's B-cell lymphoma (NHL), and human T-cell lymphotropic virus- 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL). Potential additional uses of Ontak include: therapy of graft-versus-host disease (GvHD) and autoimmune conditions, including psoriasis, rheumatoid arthritis (RA), systemic lupus, scleroderma and vasculitis. Denileukin diftitox's effect has also been studied for patients with hepatocellular carcinoma (HCC) and HIV, but conclusive data are still pending. Conclusion: There are many potential uses for denileukin diftitox, in both malignant and benign disorders. More human trials are needed to demonstrate further efficacy for a wide range of diseases.

Alemtuzumab (Campath 1-H) in Patients with HTLV-1 Associated Adult T-Cell Leukemia/Lymphoma.

This study investigated the antitumor activity of alemtuzumab (Campath 1-H) with regard to response rate, time to progression, overall survival and adverse events in patients with human T-cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/ lymphoma (ATL). In a single institution non-randomized open-label phase II trial, 24 patients with chronic (n=2), acute (n=13) and lymphomatous (n=9) ATL were treated with intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks. Patients received antimicrobial prophylaxis from the initiation of treatment continuing for a minimum of 2 months after treatment, or until the peripheral blood CD4+ T-cells were ≥ 200 cells/μL. Tumor responses were assessed at the end of 4, 8, and 12 weeks. All patients were evaluable for toxicity and one patient was not evaluable for response due to early withdrawal. The overall objective response rate was 10 out of 23 patients (95% CI: 23 to 66%). Based on the 10 patients who responded, median time to response was 1.1 months (range, 1.0 to 3.0 months). The median response duration was 3.9 months. Median progression free survival of patients with chronic subtype was 2.0 months, 1.0 month for lymphomatous subtype and 2.4 months for acute subtype. Median time to treatment failure was 1.7 months. At data cut-off, (April 24, 2008), 6 (25%) patients were alive. Overall median survival was 5.9 months. Median overall survival by subtypes was 3.9 months for chronic, 4.8 months for lymphomatous, and 7.6 months for acute. Median survival for all responders from on study date was 8.4 months. Clinical benefit was observed both in responders and in patients with stable disease. The most common adverse events were related to infusion and were generally grade 1 or 2, occurring mainly in the first week of alemtuzumab administration. All patients developed CMV antigenemia; however, only 3 (12.5%) were symptomatic. Grade 3 or 4 infections were reported in 6 (25%) patients. Median time to recovery of ALC to >200 cells/μL was 1.9 months.

A Worldwide Meta-Analysis on the Use of Zidovudine and Interferon-alpha for the Treatment of Adult T–Cell Leukemia/Lymphoma.

HTLV-I associated adult T cell leukemia/lymphoma (ATL) is an aggressive T cells malignancy, with poor prognosis due to chemotherapy resistance. Multiple small phase II studies using zidovudine (ZDV) and interferon-alpha (IFN) showed response in ATL patients. However, the impact of this therapy on ATL prognosis remains to be determined. Here, we report a worldwide meta-analysis on the use of ZDV/IFN treatment for ATL in 209 patients treated from 1994 to 2006. Patients were recruited in the USA (27 patients), the UK (13 patients), Martinique (102 patients) and France metropolitaine (67 patients). Collected data included geographic origin, age, sex, type of the disease, clinical presentation, LDH levels, calcemia, and lymphocytes number. Median age was 49 years (range 16 to 95). According to Shimoyama classification, there were 98 acute ATL, 20 chronic ATL, 9 smouldering ATL, 75 ATL lymphoma, and 7 patients with an unknown subtype. Hypercalcemia was present in 60% of patients. The data concerning the course of the disease were also collected, particularly the response status, the length of the response, the duration of ZDV+IFN therapy, as well as previous and post chemotherapy treatments. One hundred patients received first line ZDV+IFN therapy. In these patients, response rate was 66%, including 43% of patients achieving complete remission (CR). Median overall survival and 5 year overall survival rate were 24 months and 50% for patients who received first line ZDV+IFN therapy, versus 7 months and 20% for patients who received first line chemotherapy. When analysis was performed by ATL subtype, patients with acute, chronic, and smouldering ATL significantly benefited from first line ZDV+IFN therapy, whereas no additional benefit was achieved in patients with ATL lymphoma. Achievement of CR with first line ZDV+IFN therapy resulted in prolonged survival of more than 10 years in 70% of the study population, and 75% of the acute ATL subgroup. Finally, first line ZDV+IFN therapy in chronic and smouldering ATL resulted in 100% overall survival at 10 years. In conclusion, these results confirm that treatment of ATL using ZDV and IFN results in a high response and CR rates particularly in acute, chronic and smouldering ATL, resulting in impressive prolonged survival and hence should be considered as gold standard first line therapy.

VCAP-AMP-VECP Compared With Biweekly CHOP for Adult T-Cell Leukemia-Lymphoma: Japan Clinical Oncology Group Study JCOG9801

Our previous phase II trial for treating human T-lymphotropic virus type I-associated adult T-cell leukemia-lymphoma (ATLL) with vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP), doxorubicin, ranimustine, and prednisone (AMP), and vindesine, etoposide, carboplatin, and prednisone (VECP) showed promising results. To test the superiority of VCAP-AMP-VECP over biweekly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), we conducted a randomized controlled trial exclusively for ATLL. Previously untreated patients with aggressive ATLL were assigned to receive either six courses of VCAP-AMP-VECP every 4 weeks or eight courses of biweekly CHOP. Both treatments were supported with granulocyte colony-stimulating factor and intrathecal prophylaxis. A total of 118 patients were enrolled. The complete response (CR) rate was higher in the VCAP-AMP-VECP arm than in biweekly CHOP arm (40% v 25%, respectively; P = .020). Progression-free survival rate at 1 year was 28% in the VCAP-AMP-VECP arm compared with 16% in the CHOP arm (P = .100, two-sided P = .200). Overall survival (OS) at 3 years was 24% in the VCAP-AMP-VECP arm and 13% in the CHOP arm (P = .085, two-sided P = .169). For VCAP-AMP-VECP versus biweekly CHOP, grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3 or 4 infection rates were 98% v 83%, 74% v 17%, and 32% v 15%, respectively. There were three toxic deaths in the VCAP-AMP-VECP arm. The longer OS at 3 years and higher CR rate with VCAP-AMP-VECP compared with biweekly CHOP suggest that VCAP-AMP-VECP might be a more effective regimen at the expense of higher toxicities, providing the basis for future investigations in the treatment of ATLL.

Sustained Hematologic and Central Nervous System Remission with Single-Agent Denileukin Diftitox in Refractory Adult T-Cell Leukemia/Lymphoma

Human T-lymphotrophic virus–1–associated adult T-cell leukemia/lymphoma (ATLL) is a rare and often fatal disease. Initials treatment often includes zidovudine/interferon (IFN)–based therapy, although disease remission is typically not complete or durable. This study reports on a 55-year-old man with relapsed/refractory leukemic-phase ATLL including significant central nervous system (CNS) disease with resistance to previous zidovudine/IFN and arsenic trioxide/IFN treatment. The patient experienced a rapid hematologic and CNS clinical response with single-agent denileukin diftitox therapy (18 μg/kg per day for 5 days). He tolerated 8 cycles of denileukin diftitox therapy well and experienced a sustained complete hematologic and CNS remission. The patient subsequently underwent matched sibling reduced-intensity allogeneic transplantation and remains disease free. Further study examining denileukin diftitox in patients with relapsed/refractory ATLL is warranted.

Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity

Arsenic trioxide (ATO) is an effective treatment for acute promyelocytic leukemia (APL) and potentially for human T-cell leukemia virus type I (HTLV-I) associated adult T-cell leukemia/lymphoma (ATL). Many cytotoxic drugs induce apoptosis through the generation and accumulation of the sphingolipid breakdown product, ceramide, a coordinator of the cellular response to stress. We, therefore, investigated the contribution of ceramide to the mechanism of action of ATO in APL and ATL. A human APL-derived cell line (NB4), various ATL-derived lines and an HTLV-I-negative malignant T-cell line were cultured and treated with ATO. Growth and apoptosis assays were conducted. Measurements were made of ceramide, diacylglycerol, sphingomyelinase activity, sphingomyelin mass, glucosylceramide synthase activity and the de novo ceramide synthesis. Treatment of APL and ATL-derived cells with a clinically achievable concentration of ATO induced accumulation of cytotoxic levels of ceramide. The effects of ATO on ceramide levels in APL cells were more potent than those of all-trans retinoic acid (ATRA). ATO downregulated neutral sphingomyelinase activity. In contrast to the effect of ATRA, ATO-induced ceramide accumulation was not due to induction of acidic sphingomyelinase, but rather resulted from both de novo ceramide synthesis and inhibition of glucosylceramide synthase activity. Interestingly, the effects of ATO on de novo ceramide synthesis were similar in APL and ATL-derived cells despite the defective pathway in ATL cells. These results indicate that ATO-induced ceramide accumulation may represent a general mediator of the effects of ATO, which paves the way for new therapeutic interventions that target the metabolic pathway of this important sphingolipid secondary messenger.

Zidovudine and interferon-α treatment induces a high response rate and reduces HTLV-1 proviral load and VEGF plasma levels in patients with adult T-cell leukemia from North East Iran

Human T-cell lymphotropic virus type I (HTLV-I) associated adult T-cell leukemia/lymphoma (ATLL) is endemic in southern Japan, the Caribbean, intertropical Africa, and Brazil. Recently north east Iran, particularly the region of Mashhad, has been recognized as a new endemic region. ATLL is an aggressive T-cell lymphoproliferative disorder. Patients with ATLL have high plasma levels of VEGF that induce angiogenesis. Prognosis of ATLL remains poor because of immunosuppression and intrinsic resistance to chemotherapy. Important advances in the treatment of ATLL were reported with the combination of zidovudine (AZT) and interferon-α. We investigated the effect of AZT/IFN treatment on vascular endothelium growth factor (VEGF) plasma levels and HTLV-I proviral load in ATLL patients from the region of Mashhad. We confirmed that AZT/IFN treatment induces a high response rate and prolonged survival with minimal side effects. We also confirmed that VEGF plasma levels and HTLV-I proviral load are higher in ATLL patients than in asymptomatic carriers. We finally showed that AZT/IFN treatment reduced both HTLV-I proviral load and importantly VEGF plasma levels, suggesting a potential antiangiogenic effect of this therapy. These results provide further evidence for the efficacy and the mechanism of action of AZT/IFN therapy for ATLL in a developing country.

A phase II study of the efficacy and toxicity of alemtuzumab for the therapy of human T cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL)

2535 Background: HTLV-1-associated ATL is an aggressive lymphoproliferative disorder with limited effective therapy. Alemtuzumab is a humanized monoclonal antibody directed against CD52. High levels of CD52 are expressed on the surface of ATL cells. Preclinical studies in the MET-1 mouse model of ATL showed alemtuzumab to be highly active. Methods: A single institution open-label phase II study examining the response and toxicity of alemtuzumab in patients with ATL. Eligibility criteria: HTLV-1-associated ATL (chronic, acute and lymphoma type), ≥10% CD52+ malignant cells, measurable disease, age ≥18 years, AGC ≥1000/μL, platelets ≥50,000/μL, adequate physiologic status and informed consent. Results: Ten (10) patients, 6 with leukemia, 4 with lymphoma, 8 Afro-Caribbean, 1 African-American and 1 Japanese, 7 women, 3 men, median age 49 years (range, 36–62), all having received previous treatments including CHOP (7), other monoclonal antibodies (5), radioimmunotherapy (2), and radiation (1), median WBC 48,500/μL (leukemia Pts.) received alemtuzumab standard induction followed by 30 mg 3 times weekly for a minimum of 4 weeks and maximum of 12 weeks. All patients experienced infusion reactions (grade, 1–3) including hypotension, fever, rigors, chills, pruritus and urticaria; however, no patient required discontinuation of treatment. All patients developed grade 4 lymphopenia, and transient cytomegalovirus (CMV) antigenemia. Four (4) patients with leukemia responded (1 CR, 3 PR). No patient with lymphoma responded. Conclusions: Alemtuzumab has antitumor activity in HTLV-1-associated adult T cell leukemia and is well tolerated. Lymphomatous ATL appears unresponsive to alemtuzumab. The reason for this is unknown; however, antibody levels achieved in lymph nodes may be suboptimal. Accrual continues. No significant financial relationships to disclose.

The efficacy of combined therapy of arsenic trioxide and alpha interferon in human T-cell leukemia virus type-1-infected squirrel monkeys ( Saimiri sciureus)

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATLL) has a poor prognosis owing to its intrinsic resistance to chemotherapy. Although zidovudine (AZT) and alpha interferon (IFN-α) give rise to some response and improve the prognosis of ATLL, alternative therapies are needed. Arsenic trioxide (As 2O 3) has been shown to synergize with IFN-α in arresting cell growth and inducing apoptosis of ATLL cells in vitro. In this study, we evaluated the toxicity and the efficacy of this combined treatment in HTLV-1-infected squirrel monkeys ( Saimiri sciureus) and HTLV-1 infected cell lines derived therefrom. We first show that treatment with As 2O 3 and IFN-α can induce growth arrest in HTLV-1-transformed monkey T-cell lines in vitro. We then show that treatment of squirrel monkeys with As 2O 3 in vivo is highly toxic at 0.9 or 0.3 mg/day but not at 0.14 mg/day for up to 2 weeks. Although the combination of As 2O 3 and IFN-α did not affect significantly the HTLV-1 proviral load in infected monkeys, it reduced the absolute numbers of CD3 +, CD4 + and CD8 + cells during treatment, with a significant reduction in the total number of circulating HTLV-1 flower cells in the infected monkeys with chronic ATLL-like disease.

Infusional Adriamycin Based Chemotherapy Significantly Improves the Survival of Human T-Cell Lymphotropic Virus-I Induced Acute Type Adult T-Cell Leukemia Lymphoma.

Introduction: In this retrospective analysis, we provide a comprehensive account of the pathophysiology, clinical course and outcomes with various therapeutic regimens in HTLV-1 associated Adult T-cell Lymphoma/Leukemia- The Brooklyn Experience.Patients and Methods:We retrospectively reviewed the medical records of all patients identified as having acute type Human T-cell Lymphotropic Virus (HTLV-I) associated Adult T-cell Leukemia/Lymphoma (ATLL), from 1995 to 2005. The diagnosis was made according to REAL and WHO classification and based on clinical presentation, tissue biopsy and positive HTLV-I serology. Since all patients expired during the study, we used analysis of variance to examine the mean survival of these patients and the relationship between types of therapy and the survival.Results:We identified 44 patients with diagnosis of acute type ATLL. The most common disease presentation was lymphomatous in 70% (n=31) and leukemic presentation in 8% (n=3) both leukemia and lymphomatous presentation at diagnosis was seen in 22% (n=10) of patients. The mean survival for the entire group of patients was 31 weeks. The median survival was 16 weeks (range from 1 to 314 weeks). Patients who presented initially without hypercalcemia had a mean survival that was significantly higher than the patients with hypercalcemia 54 weeks versus 20 weeks, p<0.01. Treatment with infusional adriamycin chemotherapy significantly improved survival mean 99 ± 2.2 weeks, compared to CHOP 28 ± 2 weeks and much better than non-adriamycin regimens 21 ± 3 weeks p<0.001. Treatment with infusional adriamycin consistently improved survival in the patients without hypercalcemia 56± 6.6 weeks versus CHOP 21 ± 3.4 versus non-adriamycin containing regimens 10 ± 2.5 weeks, p=0.001. The presence or absence at diagnosis of central nervous system disease, pleural effusion, ascites, extensive liver or skin involvement or blood group were not independently associated with survival after adjusting for either hypercalcemia or infusional adriamycin chemotherapy. In multivariate analysis the presence of hypercalcemia was no longer significant after the therapy with infusional adriamycin.Conclusions: Hypercalcemia portends poor prognosis in all forms of HTLV-1 associated ATLL and should be included in any risk stratification schema for this disease. Our review demonstrates a statistically significant improvement in median overall survival with infusional adriamycin based chemotherapy over traditional CHOP, CVP or the AZT and interferon combination. This superiority in outcomes was evident in patients with or without hypercalcemia at presentation. Although overall survival remains relatively low in the acute form of this disease and most patients remain incurable with current therapies, our findings suggest that the incorporation of infusional adriamycin based regimens in future treatment modalities to include specific and non-specific molecular targeted therapies, would be a prudent strategy in development of more effective therapies for this disease.

Bilateral Orbital Tumor as Initial Presenting Sign in Human T-cell Leukemia Virus-1 Associated Adult T-cell Leukemia/Lymphoma

To report a case of human T-cell leukemia virus type1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATLL) whose initial sign was exophthalmos. Case report. A 64-year-old Japanese man presented with exophthalmos and choroidal folds of the right eye without general symptoms and received ophthalmologic and laboratory examination, magnetic resonance imaging (MRI), and orbital biopsy. Antibodies against HTLV-1 were extremely high but atypical lymphocytes were not present in the peripheral blood. MRI showed multiple tumorous lesions in both orbits. Orbital biopsy revealed an orbital mass that consisted of atypical lymphocytes originally from T cells and established the diagnosis of lymphoadenopathy type of ATLL. Although ocular involvement by ATLL is extremely rare, ATLL can first present in the orbit, and only the results of a biopsy can provide definitive information for its diagnosis.

The Inhibitor of VEGF-Receptors Tyrosine Kinase PTK-787 Blocks the Invasive Potential of Adult T-Cell Leukemia Cells through the Endothelium.

Extravasation of tumor cells through the endothelial barrier is a critical step in cancer metastasis. HTLV-I associated adult T-cell leukemia/lymphoma (ATL) is an aggressive disease characterized by multiple organ invasion. We have shown that ATL-derived cells induce angiogenesis and communicate with endothelial cells through gap junctions. This results in induction of endothelial-derived metalloproteinases, sub-endothelial basement membrane degradation followed by endothelial cell retraction allowing neoplastic lymphocytes extravasation. In this study we have used the specific tyrosine kinase inhibitor of VEGF receptors PTK787, functional blocking antibodies against VEGF and the gap junction communication inhibitor18-a-G to dissect the respective role of VEGF signaling pathway and cell-to-cell communication in endothelial cell retraction and tumor cell extravasation. PTK787 has mild growth inhibitory and cytotoxic effects on both endothelial and tumor cells at a concentration of 50μM and significantly inhibited cell proliferation at 100μM. Hence, 20μM PTK787 which did not exhibit any cytotoxic or antiproliferative effects on both cell types was used in experiments that last 24 hours or longer (in vitro tube formation assay and invasion assay). Endothelial cells monolayers incubated with either ATL derived cells or their cell-free conditioned medium for 48 hours induced in vitro tube formation in Matrigel angiogenesis assay. This was inhibited by both anti-VEGF antibody and 18-a-G and to a greater extent and in a dose dependent manner by PTK787. Importantly, PTK787, and to a lesser extent anti-VEGF antibody and 18-alpha-G significantly attenuated the ability of ATL-derived cells to traverse endothelial cell monolayers in double compartment invasion assays. Signaling cascade that is activated upon VEGF stimulation of endothelial cells was investigated in confluent endothelial cells cocultured with ATL derived cells or cell-free conditioned medium in the absence or presence of PTK787 or anti-VEGF antibody, using phospho-specific antibodies against FAK Tyr 861, FAK Tyr 397, Src, ERK, PLCgamma, and Akt/PKB, known to be signal mediators in the Ras-Raf-MEKK-ERK signaling cascade. The addition of ATL derived cells or cell-free conditioned medium resulted in a transient activation of the above signal mediators with a peak increase at 15 minutes and gradual return to baseline after 60 minutes. This activation was down regulated in the presence of anti-VEGF antibody and to a greater extent in the presence of PTK787. This data establishes a novel role of VEGF signaling in tumor cell invasion and supports the potential use of PTK787 in the treatment of ATL and other hematological malignancies with angiogenic and invasive properties.

Human T-cell lymphotropic virus type I-infected cells extravasate through the endothelial barrier by a local angiogenesis-like mechanism.

Extravasation of tumor cells through the endothelial barrier is a critical step in cancer metastasis. Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is an aggressive disease characterized by visceral invasion. We show that ATL and HTLV-I-associated myelopathy patients exhibit high plasma levels of functional vascular endothelial growth factor and basic fibroblast growth factor. The viral oncoprotein Tax transactivates the promoter of the gap-junction protein connexin-43 and enhances gap-junction-mediated heterocellular communication with endothelial cells. The interaction of HTLV-I-transformed cells with endothelial cells induces the gelatinase activity of matrix metalloproteinase (MMP)-2 and MMP-9 in endothelial cells and down-regulates the tissue inhibitor of MMP. This leads to subendothelial basement membrane degradation followed by endothelial cell retraction, allowing neoplastic lymphocyte extravasation. We propose a model that offers a mechanistic explanation for extravasation of HTLV-I-infected cells: after specific adhesion to endothelia of target organs, tumor cells induce a local and transient angiogenesis-like mechanism through paracrine stimulation and direct cell-cell communication with endothelial cells. This culminates in a breach of the endothelial barrier function, allowing cancer cell invasion. This local and transient angiogenesis-like sequence that may facilitate visceral invasion in ATL represents a potential target for ATL therapy.

Denileukin Diftitox and Hyper-CVAD in the Treatment Human T-Cell Lymphotropic Virus 1–Associated Adult T-Cell Leukemia/Lymphoma

We report a case of human T-cell lymphotropic virus 1 (HTLV-1)–associated adult T cell leukemia/lymphoma (ATL) in clinical remission >1 year after therapy with denileukin diftitox and hyper-CVAD (hyperfractionated cyclophosphamide/doxorubicin/vincristine/decadron). The patient presented with leukocytosis, anemia, and thrombocytopenia, and bone marrow biopsy demonstrated extensive myelofibrosis and infiltration with leukemic T cells. Initial therapy with 4 cycles of denileukin diftitox resulted in restoration of normal hematopoiesis and a reduction in bone marrow myelofibrosis. After disease progression, 4 cycles of hyper-CVAD were administered and a complete clinical remission was achieved. The patient remains free of disease with normal hematopoiesis and has continued maintenance therapy with denileukin diftitox for 1 year. This case demonstrates clinical improvement of myelofibrosis and acute T-cell leukemia after denileukin diftitox administration, suggesting that denileukin diftitox may affect the paracrine secretion of HTLV-1–associated clinical manifestations of ATL.

Alemtuzumab in T-cell malignancies.

Alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen, which is abundantly expressed on all normal and most malignant T-lymphocytes. We summarize the results of our experience using alemtuzumab to treat a range of clinically aggressive, mature, post-thymic, T-cell malignancies, including T-cell prolymphocytic leukemia (T-PLL), cutaneous T-cell lymphoma (CTCL), T-cell large granular lymphocyte (T-LGL) leukemia, and human T-cell lymphotropic virus I (HTLV-I) associated adult T-cell leukemia-lymphoma (ATLL). Alemtuzumab was administered at a dose of 30 mg, three times a week until maximum response. Apart from first-dose reactions, which were common, treatment was well tolerated, the main complication being infection and viral reactivation associated with the prolonged lymphopenia. Overall response rates were 76% (60% complete response) in 39 patients with T-PLL and 100% in 3 patients with CTCL, of duration up to 4 yr. Experience in T-LGL and ATLL is limited to single cases only and further studies are required to better define the role of alemtuzumab in these subgroups. Our results indicate that alemtuzumab has activity in T-cell malignancies, particularly in T-PLL and in patients with predominantly blood and bone marrow disease. It may be possible to prolong response duration by the use of high-dose therapy and stem cell transplantation. Alemtuzumab may also have a role in purging minimal residual disease following other chemotherapy and prior to transplantation. We conclude that treatment with alemtuzumab may offer new hope to patients who otherwise have a bleak prognosis.

Acquired immunodeficiency syndrome-associated T-cell lymphoma: evidence for human immunodeficiency virus type 1-associated T-cell transformation

The majority of lymphomas in the setting of acquired, iatrogenic, or congenital immunodeficiencies are B-cell lymphoproliferations. We describe a rare T-cell lymphoma in a fulminantly ill patient infected with human immunodeficiency virus type 1 (HIV-1). The T-cell nature of the process was defined genotypically (monoclonal T-cell receptor beta-chain [CT beta] rearrangement) and phenotypically (CD45RO+, CD4+, CD5+, CD25+, CD8-, CD3- and negative for a variety of B-cell and monocyte markers). The CD4+, CD25+ (interleukin-2 receptor [IL-2R]) phenotype with production of IL-2 and IL-2R RNA is analogous to human T-lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATLL); however, no HTLV-1 could be detected. Southern blot analysis did demonstrate monoclonally integrated HIV-1 within the tumor genome. Furthermore, the tumor cells were producing HIV p24 antigen as shown by immunohistochemistry. This is the first case of acquired immunodeficiency syndrome (AIDS)-associated non-Hodgkin's lymphoma in which HIV-1 infection may have played a central role in the lymphocyte transformation process.

Acquired immunodeficiency syndrome-associated T-cell lymphoma: evidence for human immunodeficiency virus type 1-associated T-cell transformation

Abstract The majority of lymphomas in the setting of acquired, iatrogenic, or congenital immunodeficiencies are B-cell lymphoproliferations. We describe a rare T-cell lymphoma in a fulminantly ill patient infected with human immunodeficiency virus type 1 (HIV-1). The T-cell nature of the process was defined genotypically (monoclonal T-cell receptor beta- chain [CT beta] rearrangement) and phenotypically (CD45RO+, CD4+, CD5+, CD25+, CD8-, CD3- and negative for a variety of B-cell and monocyte markers). The CD4+, CD25+ (interleukin-2 receptor [IL-2R]) phenotype with production of IL-2 and IL-2R RNA is analogous to human T- lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATLL); however, no HTLV-1 could be detected. Southern blot analysis did demonstrate monoclonally integrated HIV-1 within the tumor genome. Furthermore, the tumor cells were producing HIV p24 antigen as shown by immunohistochemistry. This is the first case of acquired immunodeficiency syndrome (AIDS)-associated non- Hodgkin's lymphoma in which HIV-1 infection may have played a central role in the lymphocyte transformation process.

Detection and characterization of human T-cell lymphotropic virus type I (HTLV-I) associated T-cell neoplasms in an HTLV-I nonendemic region by polymerase chain reaction

Human T-cell lymphotropic virus type I (HTLV-I) associated adult T-cell leukemia/lymphoma (ATLL) occurs endemically in southwestern Japan, the Caribbean, and West Africa, but occurs sporadically in most of the rest of the world. However, because ATLL and non-HTLV-I associated T-cell neoplasms share overlapping clinicopathologic features, the prevalence of ATLL in nonendemic regions is unknown. In this study, 75 T-cell neoplasms randomly procured from the metropolitan New York City area were examined by polymerase chain reaction (PCR) for the presence of integrated HTLV-I proviral sequences. HTLV-I genomic sequences were detected by PCR in 6 of the 75 cases (8%); this result was confirmed by Southern blot hybridization. The clinicopathologic features of the HTLV- I positive and HTLV-I negative T-cell neoplasms were then compared. Although the clinicopathologic features of patients from these two groups overlapped, some findings were more commonly associated with HTLV-I positive neoplasms. Five of the six patients with HTLV-I positive neoplasms were from HTLV-I endemic areas, five were black, five were women, and five were less than 45 years of age, while the majority of the patients with HTLV-I negative T-cell malignancies were elderly white men. The incidence of hypercalcemia and lytic bone lesions was significantly more common among patients with HTLV-I positive T-cell neoplasms (P less than .001 and P = .004, respectively). The immunophenotypes of the HTLV-I positive and negative tumors were similar; however, all HTLV-I positive neoplasms were CD7 negative (P less than .001). In summary, our findings: (1) demonstrate the special clinicopathologic and immunophenotypic features of HTLV-I positive T-cell neoplasms, (2) suggest that most of the rare cases of HTLV-I-associated T-cell neoplasms occurring in HTLV-I nonendemic areas are actually endemic cases; and (3) that PCR is a sensitive, clinically useful technique for identifying HTLV-I associated T-cell neoplasms.

Detection and Characterization of Human T-Cell Lymphotropic Virus Type I (HTLV-I) Associated T-Cell Neoplasms in an HTLV-I Nonendemic Region by Polymerase Chain Reaction

Human T-cell lymphotropic virus type I (HTLV-I) associated adult T-cell leukemia/lymphoma (ATLL) occurs endemically in southwestern Japan, the Caribbean, and West Africa, but occurs sporadically in most of the rest of the world. However, because ATLL and non-HTLV-I associated T-cell neoplasms share overlapping clinicopathologic features, the prevalence of ATLL in nonendemic regions is unknown. In this study, 75 T-cell neoplasms randomly procured from the metropolitan New York City area were examined by polymerase chain reaction (PCR) for the presence of integrated HTLV-I proviral sequences. HTLV-I genomic sequences were detected by PCR in 6 of the 75 cases (8%); this result was confirmed by Southern blot hybridization. The clinicopathologic features of the HTLV-I positive and HTLV-I negative T-cell neoplasms were then compared. Although the clinicopathologic features of patients from these two groups overlapped, some findings were more commonly associated with HTLV-I positive neoplasms. Five of the six patients with HTLV-I positive neoplasms were from HTLV-I endemic areas, five were black, five were women, and five were less than 45 years of age, while the majority of the patients with HTLV-I negative T-cell malignancies were elderly white men. The incidence of hypercalcemia and lytic bone lesions was significantly more common among patients with HTLV-I positive T-cell neoplasms (P less than .001 and P = .004, respectively). The immunophenotypes of the HTLV-I positive and negative tumors were similar; however, all HTLV-I positive neoplasms were CD7 negative (P less than .001). In summary, our findings: (1) demonstrate the special clinicopathologic and immunophenotypic features of HTLV-I positive T-cell neoplasms, (2) suggest that most of the rare cases of HTLV-I-associated T-cell neoplasms occurring in HTLV-I nonendemic areas are actually endemic cases; and (3) that PCR is a sensitive, clinically useful technique for identifying HTLV-I associated T-cell neoplasms.