Continuous oral cyclophosphamide and prednisolone as a valuable treatment option for peripheral T cell lymphoma

Peripheral T cell lymphomas (PTCL) are rare and frequently associated with a poor clinical outcome, with 5-year overall survival (OS) between 20% and 40%, regardless of the therapeutic approach employed (Coiffier et al, 1990; Ascani et al, 1997). Major improvements were expected from Alemtuzumab, an anti-CD52 monoclonal antibody targeting mature T lymphocytes. However, unlike Rituximab in diffuse large B cell lymphoma, no clear advantage has been obtained so far. In a prospective multicentre phase II trial, 24 patients with newly diagnosed PTCL received CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) combined with Alemtuzumab. Despite the impressive complete remission (CR) rate (71%), the estimated 2-years OS and failure-free survival rates did not appear better than in historical patients treated with CHOP (53% and 48% respectively) because of the high incidence of major infections (Gallamini et al, 2007). Another study combining CHOP with Alemtuzumab was stopped early, despite an overall response rate (ORR) of 80%, due to significant infectious and haematological toxicities (Moon et al, 2007). Upfront autologous stem cell transplantation (SCT) was recently proposed to improve prognosis in PTCL (Reimer et al, 2009). Promising results were reported by an intent-totreat analysis; unfortunately more than one third of the patients could not be transplanted mostly because of early disease progression. Allogeneic SCT is reserved for selected patients and is mainly used after relapse. In a large retrospective French registry series, 5-years OS and eventfree survival were respectively 57% and 53% with significant long-term transplant-related mortality (TRM) (Le Gouill et al, 2008). Given the lack of effectiveness of most conventional treatments successfully employed in aggressive B cell lymphomas, it may be hypothesized that PTCL has an as yet undetected peculiar pathobiology that may be better managed with alternative treatment modalities. Given that anthracycline-containing regimens have never demonstrated a real benefit (Vose, 2005) and because the major cause of treatment failure was early relapse with frequent recurrence of systemic symptoms, particularly fever, during the intervals between chemotherapy cycles, we explored the efficacy of continuous low-dose cytostatic and corticosteroid therapy, aiming at the achievement of long-term disease control rather than disease eradication. We used an oral combination of prednisolone and cyclophosphamide according to a well-established schedule for systemic vasculitis (Fauci et al, 1979) that provides strong and long-acting immunosuppression of the T cell compartment. We retrospectively analysed 55 patients with unspecified PTCL (PTCL-U) or angioimmunoblastic lymphoma (AILD-T) consecutively seen at our Institute from January 1993 to December 2008, and compared their outcome according to treatment received. All histological diagnoses were reviewed according to the World Health Organization (WHO) classification. Eleven patients were excluded because of early death before the start of any treatment (2), loss to follow up (2), stage I disease treated with radiation only (3) and palliative single agent corticosteroid treatment (4). According to the clinical decision of the attending physician, 20 patients (Group PKT) received polychemotherapy [CHOP or CHOP-like in 14 cases, combined with Alemtuzumab in 4 and consolidated with autologous SCT in one, intensified-CHOP in 5 cases and OxaliDHAP (dexamethasone, cytarabine, cisplatin) in one case] and 24 (Group oralCyP) received low-dose oral cyclophosphamide and prednisolone (Fig 1A). Statistical analyses were performed using Graph Pad Prism software. The characteristics of the subgroups of patients subdivided according to the type of treatment received were compared using Fisher’s exact test or Student’s t test, as appropriate (Table I). Log-rank analysis was used to compare actuarial survival curves. No significant differences in stage, B symptoms, and International Prognosis Index score were found between the two groups. Patients treated with oralCyP were significantly older (P = 0Æ038) and had a significantly worse Prognostic Index for PTCL score (P = 0Æ039) (Gallamini et al, 2004). The ORR was 60% versus 54% (P = 0Æ71) and the CR rate 40% versus 21%, in the PKT and oralCyP group, respectively. Fiveyear relapse-free survival (RFS), calculated from the date of remission, and 5-year OS, from the day of diagnosis, were 13% (95%CI ± 12%) and 29% (95%CI ± 13%) in Group PKT versus 26% (95%CI ± 15%) and 31% (95%CI ± 11%) in Group oralCyP respectively, with no differences between the two groups (P = 0Æ73 and P = 0Æ9) (Fig 1B,C). Toxicity of any grade was observed in 73% and 80% of patients, respectively. Grade ‡ IV WHO toxicity occurred in four patients in each group and included infections in five cases [bacterial pneumonia (2), cytomegalovirus (CMV) colitis (1), CMV pneumonia (1), peritonitis (1)], posterior reversible encephalopathy syndrome, pulmonary embolism and oral mucositis in one case each, with no differences between the two groups. Eleven and 14 patients died in the PKT and oralCyP group, respectively. The cause of death was lymphoma in all patients Correspondence