Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia

Abstract

The immunoglobulin heavy chain variable (IGHV) gene mutational status represents a major prognostic marker in chronic lymphocytic leukemia (CLL). Usually, the prognostic implications of IGHV gene analysis can be reliably ascertained but, occasionally, double productive rearrangements have been detected. Clinical presentation and biological features of such cases are unknown. Sixty patients with morphologically and phenotypically monoclonal CLL but double productive IGHV rearrangements were retrospectively identified by mRNA analysis from three Hematology Institutions. Clinical and biological features and survival of these 60 patients were compared with a control group of patients with CLL and single IGHV rearrangement. A prospective registry was used to assess the epidemiology of double productive IGHV among incidental patients with CLL. Using standard criteria to define IGHV-mutated (M) or unmutated (U) cases, 39 of the 60 patients (65%) with double productive IGHV rearrangement had concordant status (23 MM, 16 UU), while 21 (35%) had discordant IGHV status. As compared with M patients, the MM ones had lower CD38 expression, more favorable cytogenetics and more indolent clinical behavior. Cases with UU had similar characteristics of U patients. Discordant cases presented with adverse prognostic features and had an aggressive clinical behavior requiring early treatment, similar to U patients. The prevalence of double IGHV was 3.1%. Patients with CLL with double concordant mutational status (MM or UU) have a clinical course similar to that of the corresponding single IGHV status, while those exhibiting discordant status represent a high risk population. This may help correct stratification within clinical trials. Am.

Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones

“…This might be an explanation for recently published data indicating that patients with discordant status have an adverse clinical course similar to that of IGHV-unmutated cases. 43 Moreover, based on our observations, the gradual prevailing of one clone over other, also in cases with concordant status, was often accompanied by disease progression. We, therefore, advocate repeated testing of IGHV mutational status in MP-IGH CLL since it can indicated changes in disease behavior.…”

Profiling of biological and environmental risk factors in immunogenetic subgroups of chronic lymphocytic leukemia - Czech national study

“…In agreement with other studies 31,33,55 , we observed concordant IGHV mutational status of coexisting clones in almost two-thirds of oligoclonal cases (34/55; 62%). The remarkably high occurrence of concordant IGHV mutational status in oligoclonal cases suggests that coexisting clones experienced the same or similar influences affecting their development.…”

“…In published studies, oligoclonal CLL has been observed in 2 to 24.4% of cases, depending on the detection method used [31][32][33]54 . Prognostication of these oligoclonal cases may be challenging, especially in cases of coexisting clones with discordant IGHV mutational status 54 , and in this area, only limited work has so far been reported [31][32][33]55 . For the IGH rearrangement analysis within the current study, we used Sanger sequencing which has typically lower detection rate of multiple rearrangements.…”

Challenges in the Role of Gammaglobulin Replacement Therapy and Vaccination Strategies for Hematological Malignancy

“…However, it has been suggested that these combination regimens increase synergistically myelosuppression and immunosuppression, which comes to the prize of an increased risk of infections (66, 67). Severe or unusual infections, with higher rates of global infections compared with the historical group of patients treated with FC alone but without significant influence in infection-related mortality have been reported (62).…”