Low activity of the classical complement pathway predicts short survival of patients with chronic lymphocytic leukaemia

Abstract

SUMMARYThe activities of the classical (CP) and alternative (AP) complement pathways as well as the levels of some complement components and circulating immune complexes were measured in 43 patients with chronic Iymphocytic leukaemia (CLL) between 1980 and 1984. Depressed CP activities were frequently found in these patients. Clinical course ofthe disease in the patients was followed until 1992, and compared with the initial complement values. During the follow-up period 36 patients died, death of 33 patients being related to the underlying disease. A strong positive correlation (P < OOI) was found between the length of survival of the patients and the initial CP values. Patients were divided into two groups: group A, short-term survivors, i.e patients who died in CLL-related complications within 3 years after the complement measurements; and group B. longterm survivors who died ^ 4 years after the complement measurements due to any cause, or were alive at the end of the follow-up period. Average CP values in Group B were almost twice those in group \ {P = 0-002), and a similar but less pronounced difference was found in C3 levels {/* = 0-055). These differences were even more marked (/* = 0 0006 and /* = 0 0015, respectively) when only patients in Rai stage 2 and 3 were considered. Low classical pathway activities predicted short survival time: according to the logrank test, patients in Rai stage 2 3 with low (<mean -2 s.d. of the normal values), and normal CP levels survived for 2 0 ± 11, and 4-6 ± 3 0 years, respectively. All the nine and 11/13 patients with low CP and C4 levels, respectively, died within 3 years after the complement measurements were made. These findings indicate that complement measurements performed in CLL patients have a clinical value.

Discovery and Identification of Potential Biomarkers in a Prospective Study of Chronic Lymphoid Malignancies Using SELDI-TOF−MS

“…40 Impaired classical pathway of the complement has been already observed in such patients 41 that could be associated with short survival. 42 In the same way, we found elevated levels of C3a and C4a using SELDI-TOF that correspond to an activation of the classical pathway. As previously studied by Ohishi et al, 43 this activation could be induced by cross-linked membrane IgM of pathologic lymphoid cells, that triggers the classical pathway of the complement.…”

Enhancing the action of rituximab by adding fresh frozen plasma for the treatment of fludarabine refractory chronic lymphocytic leukemia

“…7,8,31,32 Checking the classical complement pathway of CLL patients, decreased C1 and C4 serum levels were found in 50% of CLL patients, 31,32 Varga et al 7 later confirmed that decreased hemolytic activity of the classical complement pathway occurs frequently in CLL, and it predicts a poor survival. Schlesinger et al 8 showed that complement defects did occur in most patients, affecting either the classical and/or the alternative pathway components.…”

“…Patients with CLL cells that have high expression of ZAP-70 or CD38, unmutated IGHV, mutated p53, or adverse cytogenetic features, achieved OR at rates that appeared similar to those who did not have such disease characteristics. With a median followup of 12 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) months, the median OS and PFS have not been achieved.…”

“…Complement deficiencies have been identified in many CLL patients and correlated with disease activity. 7,8 Klepfish et al first reported a remarkable clinical response in five refractory CLL patients by adding fresh frozen plasma (FFP) to rituximab to supply FFP-derived complement and enhance the action of rituximab. 9 Then, we reported the efficacy of rituximab combining with FFP for the treatment in 12 fludarabine refractory patients.…”

The Role of Complement in Tumor Growth

“…Higher complement hemolytic activity and C3 levels have been observed in serum samples from children with neuroblastoma (Carli et al 1979) and elevated complement levels have similarly been reported in patients with carcinomas of the digestive tract (Maness and Orengo 1977) or with brain tumors (Matsutani et al 1984). In vivo alterations in the activation of the classical pathway have been described in patients with chronic lymphatic leukemia (Fust et al 1987 ; Schlesinger et al 1996), with a strong positive correlation between survival and the initial activity of the classical pathway of complement (Varga et al 1995). …”