Chlorambucil and interferon for low grade non-Hodgkin's lymphoma

Rohatiner, A. Z. S.; Richards, M. A.; Barnett, M. J.; Stansfeld, A. G.; Lister, T. A.

doi:10.1038/bjc.1987.42

Cited by 41 publications

(4 citation statements)

References 18 publications

(14 reference statements)

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“…The effects of IFN-a on bcl-2 expression and apoptosis of CLL cells were unexpected, in view of the known effect of this cytokine in reducing circulating malignant cells in patients with early-stage disease (Rohatiner et al, 1987;McSweeney et al, 1993). It is now clear, however, that other cytokines, including IL-4 and IFN-7, can regulate bcl-2 expression on CLL cells (Danescu et al, 1992;Buschle et al, 1993;Panayiotidis et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

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Interferon‐alpha up‐regulates bcl‐2 expression and protects B‐CLL cells from apoptosis in vitro and in vivo

et al. 1994

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The bcl-2 oncoprotein, which is involved in the t(14,18) translocation, protects cells against apoptosis. We examined the effects of interferon-alpha (IFN-alpha) on bcl-2 protein expression and apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. None of 12 patients with B-CLL examined expressed the t(14,18) translocation; however, all these, and seven other patients, expressed significant levels of bcl-2 protein. In vitro, IFN-alpha (500 U/ml over 18 h) increased bcl-2 expression on CLL cells (to 200 +/- 23% of control MCF, as determined by indirect immunofluorescence and flow cytometry, n = 10, P < 0.001). All of eight patients who received IFN-alpha (3 megaunits subcutaneously three times a week) demonstrated an increase in bcl-2 expression on circulating malignant cells. CLL cells undergo apoptotic cell death when cultured in vitro (35.6 +/- 10.3% DNA fragmentation after 18 h, n = 10). In the presence of IFN-alpha, however, DNA fragmentation was reduced to 6.6 +/- 5.8% (n = 10, P < 0.001). IFN-alpha also protected CLL cells against apoptosis induced by hydrocortisone and gamma irradiation (reducing DNA fragmentation from 63.9 +/- 12.6% to 10.8 +/- 4.5% and from 80 +/- 2.9% to 5.4 +/- 1.6%, respectively, P < 0.001 for both). The protective effect of IFN-alpha was dose dependent, and maintained for up to 24 h. Our data demonstrate that bcl-2 expression and apoptosis of CLL cells can be influenced by cytokines. In addition, it seems unlikely that the observed clinical responses to IFN-alpha in patients with CLL are due to a direct effect on the malignant cells.

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Section: Discussionmentioning

confidence: 99%

“…Interferon-alpha (IFN-a) is effective in the management of hairy cell leukaemia and possibly other B cell malignancies such as low-grade non-Hodgkin's lymphoma (Quesada et al, 1984;Rohatiner et al, 1987). In patients with early-stage B-CLL.…”

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confidence: 99%

Interferon‐alpha up‐regulates bcl‐2 expression and protects B‐CLL cells from apoptosis in vitro and in vivo

et al. 1994

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“…Furthermore, it has been demonstrated that some cytokines, alone or in combination with cytotoxic drugs, have potent antitumour activity that can be used clinically, e.g. (IFN)-a in non-Hodgkin's lymphoma 7 and hairy cell leukaemia. 8 Many cytokines can be classified into one of two broad groups -T-helper type 1 (Th1)-like or T-helper type 2 (Th2)-like -depending on their biological properties and the nature of the T-cell subset that produces those properties.…”

Section: Introductionmentioning

confidence: 99%

Investigation of interleukin 10, 12 and 18 levels in patients with head and neck cancer

et al. 2006

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Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy. It is the most common neoplasm arising in the upper aerodigestive tract. Interleukin (IL) 12 and IL-18 are cytokines which have a major anti-tumour activity via stimulation of a T-helper type 1 (Th1) immune response. Interleukin 10, a potent antagonist of IL-12, is a cytokine which possesses immunosuppressive activity mainly produced via T-helper type 2 (Th2) cells. Studies of other types of cancer have shown that the level of IL-12 in serum or tissues is suppressed and/or the IL-10 level is increased, suggesting that there is an impaired cell-mediated anti-tumour response. The aim of this study was to measure pre-operative serum cytokine concentrations in HNSCC patients in order to detect any changes in IL-10, IL-12 and IL-18, compared with non-tumour controls. The relationship between cytokine levels and standard clinicopathological features, including tumour site, tumour stage and presence of nodal metastasis, was also examined. Fifty-seven patients with primary HNSCC were prospectively recruited, together with 40 non-tumour control patients with a similar age and sex distribution. Serum cytokine levels were measured using commercial quantitative enzyme-linked immunosorbent assay. The HNSCC patients had significantly lower IL-12 levels (median; interquartile range) than controls (42.8 pg/ml, 26.2-61.6 vs 52.3 pg/ml, 37.5-113.7; p=0.018). Also, patients were more likely to have detectable IL-10 levels than were controls, as IL-10 was positive in 27/55 patients but in only 9/39 controls (p=0.011). Furthermore, IL-10 detectability varied according to primary site, being more commonly observed in hypopharyngeal and laryngeal tumours, and IL-10 was more likely to be detected with advanced tumour stage (T3 and T4). No differences in IL-18 levels were observed between patients and controls (p=0.169). These results suggest (in agreement with studies on other solid malignancies) that HNSCC causes a significant change in the serum levels of specific Th1 and Th2 cytokines, producing an in vivo environment that is unlikely to promote an effective cell-mediated anti-tumour response.

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“…In addition, more aggressive chemotherapy regimens have never demonstrated a clear advantage in terms of event‐free and overall survival (Young et al , 1998). Chlorambucil, an alkylating agent, has been considered one of the treatments of choice for the treatment of low‐grade B‐cell lymphoma patients, and this drug, used alone or in combination with prednisolone, can induce a 70% objective regression rate with an approximate CR rate of 30% in newly diagnosed follicular NHL patients and, at the same time, lead to a very low rate of general toxicity (Ezdinli & Stutzman, 1965; Han et al , 1973; Rohatiner et al , 1987). Several schedules have been used for the administration of chlorambucil, but none has demonstrated a clear advantage.…”

Section: Discussionmentioning

confidence: 99%

Chlorambucil in combination with induction and maintenance rituximab is feasible and active in indolent non‐Hodgkin's lymphoma

et al. 2003

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Summary. We investigated the toxicity and efficacy of the chimaeric anti-CD20 antibody rituximab in combination with standard-dose chlorambucil in newly diagnosed and relapsed/refractory indolent B-cell lymphoma patients. A total of 29 patients (15 newly diagnosed and 14 relapsed/ refractory) with low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) were included in this phase II study. Therapy consisted of chlorambucil 6 mg/m 2 /d for 6 consecutive weeks in combination with a standard 4-weekly rituximab administration schedule in the induction phase. Patients responding to the induction therapy received four additional cycles with chlorambucil (6 mg/m 2 /d for 2 weeks/month) plus rituximab (once a month). Twenty-six patients (89%) completed the treatment; only one patient discontinued treatment because of haematological toxicity. At the end of the study, the dose of chlorambucil had to be reduced in seven patients (27%) and six patients (23%) required a delay in further treatment, as a result of toxicity during consolidation therapy. Only one patient was withdrawn from the study because of progressive disease; the 27 patients evaluable for response at the end of consolidation achieved a clinical response (63% complete response and 26% partial response). A significant CD4 + and CD56 + depletion was observed after induction and during consolidation therapy; two herpes zoster virus infections and one perianal abscess represented major infectious morbidities registered during the study. Based on our preliminary data, the combination of chlorambucil with rituximab seemed to be well tolerated and active. Its definitive role in the treatment of low-grade NHL should be further evaluated in randomized trials.

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Chlorambucil and interferon for low grade non-Hodgkin's lymphoma

Cited by 41 publications

References 18 publications

Interferon‐alpha up‐regulates bcl‐2 expression and protects B‐CLL cells from apoptosis in vitro and in vivo

Interferon‐alpha up‐regulates bcl‐2 expression and protects B‐CLL cells from apoptosis in vitro and in vivo

Investigation of interleukin 10, 12 and 18 levels in patients with head and neck cancer

Chlorambucil in combination with induction and maintenance rituximab is feasible and active in indolent non‐Hodgkin's lymphoma

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