Impact of the HIV epidemic and Anti-Retroviral Treatment policy on lymphoma incidence and subtypes seen in the Western Cape of South Africa, 2002-2009: preliminary findings of the Tygerberg Lymphoma Study Group.

The Tygerberg Lymphoma Study Group was constituted in 2007 to quantify the impact of HIV on the pattern and burden of lymphoma cases in the Western Cape of South Africa which currently has an HIV prevalence of 15%. South Africa has had an Anti-Retroviral Treatment (ART) policy and a roll-out plan since 2004 attaining 31% effective coverage in 2009. This study is designed to qualify and establish the impact of HIV epidemic and the ARV roll-out treatment program on the incidence of HIV Related Lymphoma (HRL). Early data document that despite the ART roll out, cases of HRL are increasing in this geographical location, now accounting for 37% of all lymphomas seen in 2009 which is an increase from 5% in 2002. This is in contrast to trends seen in developed environments following the introduction of ART. Also noted are the emergence of subtypes not previously seen in this location such as Burkitt and plasmablastic lymphomas. Burkitt lymphoma is now the commonest HRL seen in this population followed by diffuse large B-cell lymphoma subtypes. The reasons for this observed increase in HRL are not ascribable to improved diagnostic capacity as the tertiary institute in which these diagnoses are made has had significant expertise in this regard for over a decade. We ascribe this paradoxical finding to an ART treatment environment that is ineffective for a diversity of reasons, paramount of which are poor coverage, late commencement of ART and incomplete viral suppression.

Effects of interferon-alpha (IFN) on the expression of interleukin 1-beta (IL-1), interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF) in acute myeloid leukemia (AML) blasts.

Interferon-alpha (IFN) induces the enzyme 2-5 oligoadenylate synthetase (2-5 AS) in cells from patients with hairy cell leukemia and B-cell chronic lymphocytic leukemia and this is associated with a breakdown of certain species of cytokine messenger (m)RNA via the activation of a latent ribonuclease. We have studied the expression of the cytokines interleukin 1-beta (IL-1), interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumour necrosis factor alpha (TNF) as well as of the ribonuclease activator 2-5 AS in the presence and absence of IFN in acute myeloid leukaemia (AML) blast cells from 26 patients. Before monocyte and T-cell depletion there was no expression of IL-1, IL-6 or GM-CSF, and only three of 13 patients studied expressed TNF mRNA. After cell depletion one or more cytokine was expressed in 31-62% of the 26 patients. Expression of one or more mRNA for IL-1, IL-6, GM-CSF and TNF after 18 h incubation was detected in 16 of 26 patients (63%) and this was particularly so in French-American-British (FAB) subtypes M4 and M5. Eight of nine patients with IL-6 mRNA expression and seven of 10 with IL-1 mRNA expression were in the FAB subtypes M4 and M5. Twenty-two of 26 patients showed induction of 2-5 AS mRNA in response to IFN in vitro. Exposure to IFN resulted in reduction of IL-1 mRNA in nine of 12 cases, of IL-6 mRNA in eight of nine, and GM-CSF mRNA in five of seven cases. TNF mRNA was unaffected by IFN despite 2-5 AS induction in 12 of 13 patients expressing this cytokine. In the presence of exogenous IFN, cells from six of seven patients studied showed inhibition of 3H-thymidine incorporation into DNA. DNA synthesis could also be abrogated in six of seven patients with anti-IL-1 monoclonal antibodies (MoAb) and in two of seven with anti-IL-6 MoAb. This inhibitory effect could be reversed in all patients when anti-IL-1 or anti-IL-6 was given in combination with their corresponding cytokine. These data suggest that IFN may exert a therapeutic effect in a proportion of AML patients by blocking IL-1 and IL-6 mediated growth, consequent on activation of the ribonuclease activator 2-5 AS.

Interferon-alpha inducible 2'-5' oligoadenylate synthetase transcripts in lymphoid and myeloid leukemias.

Alpha-interferon (IFN) is effective in the treatment of a proportion of patients with hairy cell leukemia (HCL). B-cell chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML) and multiple myeloma (MM). One of the proteins induced by IFN is the enzyme 2'-5' oligoadenylate synthetase (2-5 AS). Peripheral blood or bone marrow samples treated with IFN in vitro, or from patients treated with IFN were studied for expression of the different 2-5 AS mRNA transcripts. A total of four normal individuals and 31 patients (nine HCL, five CLL, six MM, nine acute myeloid leukemia (AML) and two T-cell acute lymphoblastic leukemia (T-ALL) have been investigated. In normal peripheral blood lymphocytes, only the 1.8 kb transcript was induced with IFN in vitro. In HCL, CLL, and MM all four transcript sizes were induced by IFN in vivo and in vitro. The 1.6 and 1.8 kb forms were equally and predominantly expressed in HCL and B-CLL. On the other hand, the 1.8 kb transcript was predominantly expressed in MM and this increased expression was statistically significant. In acute leukemia, the majority of samples expressed all four transcripts equally but four of eleven samples expressed only the 1.8 kb transcript. These results suggest that the pattern of induction of specific 2-5 AS mRNA transcripts may be related to the underlying disease. Whether these different patterns of 2-5 AS induction have implications for response to IFN treatment, remains to be determined.

Guidelines for the treatment of myelodysplastic syndromes (MDS) in South Africa.

INTRODUCTION: Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal haematopoietic disorders characterised by chronic and progressive cytopenias resulting from ineffective haematopoiesis. Treatment is complicated by differences in disease mechanisms in different subgroups, variable clinical phenotypes and risk of progression to acute myeloid leukaemia. RATIONALE: Changes in disease classification, prognostic scoring systems, the availability of novel treatment options and the absence of South African guidelines for the diagnosis and management of these complex disorders underpinned the need for the development of these recommendations. METHODS: These recommendations are based on the opinion of a number of experts in the field from the laboratory as well as clinical settings and came from both the private and institutional academic environments. The most recent literature as well as available guidelines from other countries were discussed and debated at a number of different meetings held over a 2-year period. RESULTS: A comprehensive set of recommendations was developed focusing on risk stratification, supportive management and specific treatment. Novel agents and their indications are discussed and recommendations are made based on best available evidence and taking into account the availability of treatments in South Africa. CONCLUSION: Correct diagnosis, risk stratification and appropriate therapeutic choices are the cornerstones of success in the management of patients with myelodysplastic syndromes.

Increase in 2',5'-oligoadenylate synthetase caused by deoxycoformycin in hairy cell leukaemia.

2',5'-oligoadenylate synthetase (2-5OAS) has been studied in peripheral blood mononuclear cells from nine patients with hairy cell leukaemia (HCL) receiving therapy with the adenosine deaminase inhibitor deoxycoformycin (dCF) or alpha interferon (alpha-IFN). 2-5OAS mRNA was assayed by dot-blot hybridization. Increase of 2-5OAS mRNA level was seen in six patients with HCL treated with dCF and in one patient treated with alpha-IFN who responded to therapy. A patient with a variant form of HCL treated with dCF and the second patient treated with alpha-IFN did not show an increase of 2-5OAS mRNA and neither responded to therapy. The 15 other patients with T or B-chronic lymphoblastic leukaemia (CLL), T-acute lymphoblastic leukaemia (ALL), adult T-cell leukaemia lymphoma (ATLL), non-Hodgkins lymphoma (NHL), Sezary and T or B-prolymphocytic leukaemia (PLL) treated with dCF did not show an increase in 2-5OAS, though four patients, all with T-cell tumours, responded clinically. 2-5OAS activity is known to be stimulated by alpha-IFN and recent work suggests that this rise in 2-5OAS may result in increased cleavage of mRNA for tumour necrosis factor (TNF) and other cytokines on which autocrine growth and proliferation of the tumour cells are dependent. By analogy, we suggest that one mechanism of action of dCF in hairy cell leukaemia may be to break down an autocrine growth loop for TNF or other cytokines. An alternative explanation for these observations is that cytokines released from hairy cells in the bone marrow killed by dCF induce a rise in 2-5OAS in circulating leucocytes.

[Hydroxyurea, erythrocyte volumes and hemoglobin F]. / Hydroxyurea, Erythrozytenvolumen und Hämoglobin F.

Hydroxyurea is used in the treatment of sickle cell anemia and beta-thalassemia major to increase the content of hemoglobin F (HbF) and presumably ameliorate clinical symptoms. Under therapy with hydroxyurea an increase of the mean corpuscular volume (MCV) of the erythrocytes can be observed. To evaluate a possible estimation of the content of HbF using the increase of MCV under treatment with hydroxyurea, we measured MCV and HbF during therapy with hydroxyurea. The median MCV before therapy was 87.8 fl (range 74.3-95.7) and under hydroxyurea 104.1 fl (81.0-139.5), and the median HbF 1.8% (0.1-5.4). Although both MCV and HbF increased under treatment with hydroxyurea, a linear correlation between these two parameters was not detectable. Therefore, MCV cannot replace the measurement of HbF.

[Late idiopathic pneumopathy following bone marrow transplantation]. / Späte idiopathische Pneumopathie nach Knochenmarktransplantation.

4 of the 198 patients treated by bone marrow transplantation in Basel, Switzerland, with a follow-up of more than one year after therapy, developed a severe restrictive pneumopathy. In none of the 4 patients could an infectious pathogen be isolated, but all of them had signs of a chronic graft-versus-host disease. The 4 cases are described in detail.