IgM peak independently predicts treatment-free survival in chronic lymphocytic leukemia and correlates with accumulation of adverse oncogenetic events

Abstract

We examined the significance of IgM peaks in chronic lymphocytic leukemia (CLL), including its association with newly reported MYD88, BIRC3, NOTCH1 and SF3B1 mutations. A total of 27, 25, 41 and 57 patients with monoclonal IgM or IgG peaks (IgM and IgG groups), hypogammaglobulinemia (Hypo-γ group) and normal immunoglobulin serum levels (normal-γ group) were, respectively, included. IgM peaks were mainly associated with Binet stage C and the del(17p). Biased usage of IGHV3-48 was shared by both IgM and IgG groups. IGHV3-74 and IGHV4-39 gene rearrangements were specific for IgM and IgG peaks, respectively. SF3B1, NOTCH1, MYD88 and BIRC3 mutation frequencies were 12%, 4%, 2% and 2%, respectively, being over-represented in IgM, IgG and Hypo-γ groups for SF3B1, and being equal between normal-γ and IgM groups for MYD88. Overall, 76%, 87%, 49% and 42% of cases from IgM, IgG, Hypo-γ and normal-γ groups had at least one intermediate or poor prognosis genetic marker, respectively. By multivariate analysis, IgM peaks were associated with shorter treatment-free survival independently from any other univariate poor prognosis biological parameters, including IgG peaks, Hypo-γ, IGHV status, SF3B1 mutations, cytogenetics and lymphocytosis. Therefore, as with IgG peaks, IgM peaks aggravated the natural course of CLL, with increased accumulation of adverse genetic events.

Incidence and prognostic significance of serum immunoglobulins and paraproteins in patients with chronic lymphocytic leukaemia: another valuable piece of the puzzle

“…In a recent Italian study, the presence of IgG or IgM paraproteins was linked with several unfavourable prognostic factors such as unmutated IGHV genes or TP53 aberrations and correlated with shorter TFS. 22 The present study by Corbigni et al seems to confirm some of the previously published findings, namely association of IgM paraprotein with advanced clinical stages and TP53 abnormalities, as well as significantly shorter TFS in pts with paraprotein or IgG/IgA deficiency (including multivariate analysis). None of these parameters was significant for shorter overall survival in the multivariate analysis; probably due to recent developments of the therapeutic armamentarium, namely novel targeted oral inhibitors such as ibrutinib, idelalisib, and venetoclax, whose introduction has led to marked survival improvement especially in pts with relapsed/refractory CLL.…”

“…16,17 The research of monoclonal immunoglobulins/paraproteins in CLL has attracted much less attention than that of hypogammaglobulinaemia. First publications emerged at the end of 1970s and during the 1980s, 18,19 Pangalis et al 1988, 20 and several larger studies reported the frequency of paraproteins in newly diagnosed CLL pts between 7 and 35%; [21][22][23] results regarding their prognostic value of were again inconclusive. In a recent Italian study, the presence of IgG or IgM paraproteins was linked with several unfavourable prognostic factors such as unmutated IGHV genes or TP53 aberrations and correlated with shorter TFS.…”

Diagnostic framing of IgM monoclonal gammopathy: Focus on Waldenström macroglobulinemia

“…82 An IgM peak may occur in CLL/SLL with a prevalence of 2.5% to 20% according to different studies. [83][84][85] Sometimes, IgM-RD as immune cytopenia may be the main clinical manifestations in otherwise indolent CLL requiring specific therapeutic approaches. 86…”

Monoclonal gammopathy and serum immunoglobulin levels as prognostic factors in chronic lymphocytic leukaemia

“…Survival curves in the c-normal subgroup showed a shorter TFS and overall survival (OS) in UM-CLL compared to M-CLL, consistent with the major prognostic impact of the IGHV mutational status on the outcome of the disease.22, 45-48The presence of unmutated IGHV genes was also associated with shorter TFS both in the IgG (P < 0Á0001)and in the hypogammaglobulinaemia groups (P < 0Á0001) but not with an inferior outcome regarding OS. Moreover, unlike described by Rizzo et al, 36 IgM/CLL was the only group in which the 'protective effect' of mutated IGHV was lost with an inferior TFS and OS both in mutated and unmutated patients. We also investigated whether there was an association between Ig abnormalities and IGHV gene usage, as reported by others.…”