Andrew Hodson

Use of Zidovudine and Interferon Alfa With Chemotherapy Improves Survival in Both Acute and Lymphoma Subtypes of Adult T-Cell Leukemia/Lymphoma

PURPOSE Adult T-cell leukemia/lymphoma (ATLL) is a mature (post-thymic) T-cell lymphoma associated with human T-lymphotropic virus type 1 infection. Survival in aggressive subtypes remains poor, and treatment resistance is frequent. Use of zidovudine (ZDV) and interferon alfa (IFN-α) has been associated with improved response rates in small studies and prolonged overall survival in leukemic ATLL subtypes in a recent meta-analysis. PATIENTS AND METHODS We report the clinicopathologic characteristics, treatment, and outcome of 73 patients with aggressive ATLL (acute ATLL, 29; lymphoma ATLL, 44) diagnosed and treated in England between 1999 and 2009. The impact of ZDV/IFN-α on treatment response and survival was assessed. RESULTS The overall response rate ranged from 49% with chemotherapy alone to 81% with combined first-line therapy (chemotherapy with concurrent/sequential ZDV/IFN-α). Median overall survival (OS) was 9 months: 7.5 months for acute ATLL and 10 months for lymphoma ATLL. Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and lymphoma ATLL (P < .001) and was the sole factor associated with reduction in risk of death in aggressive ATLL (hazard ratio, 0.23; 95% CI, 0.09 to 0.60; P = .002). Combined first-line therapy prolonged median OS in acute (P = .0081) and lymphoma ATLL (P = .001) compared with chemotherapy alone. CONCLUSION These data support the use of low-dose ZDV/IFN-α with chemotherapy in first-line treatment of acute and lymphoma ATLL.

Pre-morbid human T-lymphotropic virus type I proviral load, rather than percentage of abnormal lymphocytes, is associated with an increased risk of aggressive adult T-cell leukemia/lymphoma

Out of 153 newly referred human T-lymphotropic virus type I infected patients, 42 (27%) had 5% or more abnormal lymphocytes, consistent with the diagnosis of smoldering adult T-cell leukemia/lymphoma. The abnormal lymphocyte percentage was higher in patients with human T-lymphotropic virus type I associated inflammatory disease compared with asymptomatic carriers (P=0.006). Over 4.5 years median follow up, 4 patients, all with 10 or more human T-lymphotropic virus type I DNA copies/100 peripheral blood mononuclear cells at presentation, but only one with 5% or more abnormal lymphocytes at presentation, developed adult T-cell leukemia/lymphoma. Thus, high pre-morbid human T-lymphotropic virus type I proviral load, rather than fulfilment of the classification criteria for smoldering adult T-cell leukemia/lymphoma, was associated with an increased risk of developing aggressive adult T-cell leukemia/lymphoma.

Striving to cure adult T-cell leukaemia/lymphoma: a role for allogeneic stem cell transplant?

Adult T-cell leukaemia/lymphoma (ATL) is an aggressive HTLV-1-related malignancy, rare outside of regions where the retrovirus is endemic. Although the use of antiviral therapy has improved outcomes, particularly for indolent forms of ATL, response to combination chemotherapy is poor and outcomes for aggressive subtypes remains dismal. Consolidation with allogeneic stem cell transplant (alloSCT) has an increasing role in the management of ATL in eligible patients, offering favourable long-term remission rates. However, relatively high-transplant-related mortality and issues with donor recruitment for certain ethnicities remain problematic. In this review, we discuss the rationale for and issues surrounding alloSCT in ATL in the context of conventional and emerging therapies.

Haematological and molecular responses in patients with chronic ATLL treated with zidovudine and interferon-α

The utility of HTLV-1 proviral load and integration site analysis by both a linker mediated PCR assay based on the Universal VectoretteTM System (Sigma Genosys) and by high through-put sequencing (HTPS) to assess the treatment response of four patients with chronic adult T-cell leukaemia/lymphoma (ATLL) undergoing first line treatment with zidovudine and interferon alpha (ZDV/IFN-α) at the molecular level is described. Diagnosis of chronic ATLL was according to the Shimoyama criteria. All patients were Afro-Caribbean, median age 52 years (range 32-63), three were female. Median lymphocyte count was 8.2x109/L (range 9-23.9) and HTLV-1 proviral load (PVL) was 73.8% (72.6-276.2). All patients gave informed consent and treatment was according to clinic protocol. All patients remain alive with median overall survival of 64 (27 -106) months. A dominant clone was detected by vectorette and HTPS in all patients. Complete haematological response (CHR), defined as normal white cell count and lymphocyte count for one month, was observed in all patients within nine months of starting treatment. Two patients were intolerant of therapy long term and a molecular response was not observed with persistence of the dominant clones on vectorette and by HTPS. In the two patients tolerant of therapy a reduction in HTLV-1 PVL was observed 10-40 months after the CHR but the dominant clone remained detectable by vectorette for a further 20 months on treatment. Two patients have relapsed off treatment and two remain in CHR. Following CHR molecular methods reveal residual disease and predict long-term response.

Case reports: combination therapy with proteasome inhibitor Bortezomib and humanized anti-CD25 Basiliximab for treatment of adult T cell leukaemia lymphoma.

Adult T cell Leukaemia Lymphoma [ATL] is a mature T cell neoplasm affecting 2 - 6% of HTLV-1 infected subjects. ATL have been classified into 4 subtypes- smouldering, chronic leukaemia, acute leukaemia and lymphoma subtype. First line treatment with zidovudine (ZDV) and interferon-α (IFN) is recommended for smouldering, acute and chronic leukaemia whilst for lymphoma subtype combination chemotherapy is supplemented with ZDV/IFN. However a substantial proportion of patients do not respond or suffer treatment limiting side effects. Hence there is an urgent need for novel treatment options. Anti-CD25 in combination with bortezomib trialled in a murine ATLL model out performed either agent alone. We report 2 patients with Chronic ATL who were treated with a novel combination of humanized anti-CD25 antibody, Basiliximab and proteosome inhibitor, Bortezomib. Both patients had CD4+CD25+CCR4+CD127-lo ATL phenotype, were Interferon Regulatory Factor-4 negative and had responded to ZDV/IFN but had treatment limiting side effect. Prior to the novel combination baseline lymphocyte counts were 73.5 & 7.1 X 109/L, LDH 398 & 410 IU/L, CD4+CD25+ 97 & 97 % respectively. One patient had disseminated cutaneous lymphoma. Treatment was initially well tolerated and complete haematological remission was achieved after 8-14 weeks but flow cytometry revealed persistence of cells with the aforementioned ATLL phenotype. Discontinuation of Bortezomib in one patient, due to neuropathy, was associated with an immediate increase in CD4 counts. These early data suggest that this combination presents a new targeted therapy option for remission induction in treatment intolerant patients esp. leukemic subtype and warrant further clinical investigation.

The potential of CD127 as a prognostic and residual disease marker in chronic adult T cell leukaemia/lymphoma

Adult T cell Leukaemia Lymphoma [ATL], a mature T-cell neoplasm has been classified into 4 subtypes: smouldering; chronic leukaemia; lymphoma and acute leukaemia. The diagnosis depends on clinical features, the immunophenotype, and demonstration of HTLV-1 infection & ideally of monoclonal proviral integration. The typical immunophenotype of ATL is not specific. The methods used to detect monoclonality are labour-intensive and/or expensive and are not widely available. We developed a flow cytometry assay for diagnosis and monitoring of ATL. We performed 11-colour immunophenotyping, HTLV-1 proviral quantification and proviral integration site [IS] analysis on 53 samples from 36 patients [25 non ATL HTLV-1-infected, 11 chronic/smouldering ATL], 3 uninfected individuals and 2 HTLV-1-immortalized cell lines. The non-ATL patients had CD127+ & CCR7-lo expression in CD4+ CD25+CCR4+ cells, and a polyclonal distribution on IS analysis. FourATL patients had CD127+ & CCR7-lo expression in CD4+CD25+CCR4+ cells and polyclonal distribution on IS analysis. These patients had an excellent outcome achieving remission with either PUVA or no therapy. Eight ATL patients had CD127-lo expression on CD4+ CD25+ CCR4+ cells with mono/oligoclonal distribution on IS analysis. One of nine patients with chronic ATLL had high CCR7 expression. Foxp3 expression was variable. All 8 patients required systemic ATL treatment and longitudinal study of 5 patients found the change in frequency of CD4+CD25+CCR4+ to correlate with PVL whilst CD127 expression correlated with IS analysis (p<0.005) and disease remission status. CD127 expression appears to be useful to identify patients needing treatment and for monitoring the treatment of chronic ATL.

First line treatment of acute and chronic ATLL with zidovudine (AZT) and interferon alpha (IFN-α): haematological and molecular responses

Recent data suggest an important role of zidovudine (ZDV) and interferon-α (IFN-α) in improving response rates and survival in acute ATLL. Treatment of chronic ATLL with ZDV/IFN-α alone has recently been associated with 100% survival beyond five years.

Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma post BTK inhibitor therapy

Mantle cell lymphoma (MCL), an aggressive B-cell malignancy accounting for 6% of non-Hodgkin lymphomas, remains incurable with standard therapy. Despite the approval of bortezomib,[1][1] temsirolimus,[2][2] lenalidomide,[3][3] ibrutinib[4][4] and acalabrutinib,[5][5] patients with relapsed,