The Role of Complement Activating Collectins and Associated Serine Proteases in Patients With Hematological Malignancies, Receiving High-Dose Chemotherapy, and Autologous Hematopoietic Stem Cell Transplantations (Auto-HSCT)

Abstract

We conducted a prospective study of 312 patients (194 with multiple myeloma, 118 with lymphomas) receiving high-dose conditioning chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Polymorphisms of MBL2 and MASP2 genes were investigated and serial measurements of serum concentrations of mannose-binding lectin (MBL), CL-LK collectin and MASP-2 as well as activities of MBL-MASP-1 and MBL-MASP-2 complex were made. Serum samples were taken before conditioning chemotherapy, before HSCT and once weekly after (totally 4-5 samples); in minority of subjects also 1 and/or 3 months post transplantation. The results were compared with data from 267 healthy controls and analyzed in relation to clinical data to explore possible associations with cancer and with chemotherapy-induced medical complications. We found a higher frequency of MBL deficiency-associated genotypes (LXA/O or O/O) among multiple myeloma patients compared with controls. It was however not associated with hospital infections or post-HSCT recovery of leukocytes, but seemed to be associated with the most severe infections during follow-up. Paradoxically, high MBL serum levels were a risk factor for prolonged fever and some infections. The first possible association of MBL2 gene 3′-untranslated region polymorphism with cancer (lymphoma) in Caucasians was noted. Heterozygosity for MASP2 gene +359 A>G mutation was relatively frequent in lymphoma patients who experienced bacteremia during hospital stay. The median concentration of CL-LK was higher in myeloma patients compared with healthy subjects. Chemotherapy induced marked increases in serum MBL and MASP-2 concentrations, prolonged for several weeks and relatively slighter decline in CL-LK level within 1 week. Conflicting findings on the influence of MBL on infections following chemotherapy of myeloma and lymphoma have been reported. Here we found no evidence for an association between MBL deficiency and infection during the short period of neutropenia following conditioning treatment before HSCT. However, we noted a possible protective effect of MBL during follow-up, and suspected that to be fully effective when able to act in combination with phagocytic cells after their recovery.

Associations of Ficolins With Hematological Malignancies in Patients Receiving High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantations

“…This study was complementary to our previous paper concerning the role of complement-activating collectins and associated serine protease-2 (MASP-2) in the same cohort of patients and controls (43).…”

“…This group included 194 persons diagnosed with multiple myeloma (MM; 95 females and 99 males; mean age: 58.9 ± 8.9 years) and 118 with Hodgkin's or non-Hodgkin's lymphomas (LYMPH; 46 females and 72 males, mean age: 49.3 ± 13.1). Basic demographic data were published previously (43). All MM patients were newly diagnosed while for LYMPH patients, auto-HSCT was a second-line treatment.…”

“…All MM patients were newly diagnosed while for LYMPH patients, auto-HSCT was a second-line treatment. The standard chemotherapy for MM patients was melphalan, usually at a dosage of 200 mg/m 2 (MEL-200), but in some cases lower MEL-140 or MEL-100 was used (43). Majority of the LYMPH patients were treated with carmustine (300 mg/m 2 ), etoposide (800 mg/m 2 ), cytarabine (1,600 mg/m 2 ), melphalan (140 mg/m 2 ) (BEAM) or (less frequently)-with BeAM (carmustine replaced with bendamustine).…”

“…Majority of the LYMPH patients were treated with carmustine (300 mg/m 2 ), etoposide (800 mg/m 2 ), cytarabine (1,600 mg/m 2 ), melphalan (140 mg/m 2 ) (BEAM) or (less frequently)-with BeAM (carmustine replaced with bendamustine). In some MM and LYMPH cases, chemotherapy was combined with radiotherapy (43). During hospital stay, crucial clinical parameters like white blood cell (WBC) count, absolute neutrophil count (ANC), platelet (PLT) count, inflammatory markers' [C-reactive protein (CRP), fibrinogen (FBG), and procalcitonin (PCT)] levels, and incidence of complications [infections (associated with bacteremia or not), febrile neutropenia (FN); duration of fever >38 • C] were recorded and used for the analyses (43).…”

“…The control group included 267 individuals (unrelated volunteers with no history of cancer, autoimmune diseases, or recurrence of infections; 174 females and 93 males; mean age: 48 ± 13; age range: 18-84) (43). The study was approved by the local ethics committee, and written informed consent from patients and controls was obtained.…”