Identification of monoclonal B-cell lymphocytosis among sibling transplant donors for chronic lymphocytic leukemia patients

To the editor:

In patients with chronic lymphocytic leukemia (CLL), a family history of hematologic malignancies is recorded in 12% of cases, half of the latter being CLL.¹  First-degree relatives of CLL patients have an 8-fold greater likelihood of harboring a CLL than members of the general population.²  Monoclonal B cells with a CLL-like immunophenotype, defined as monoclonal B-cell lymphocytosis (MBL),³  identifiable in approximately 3% to 5% of adults with normal blood counts,^4,5  can be found in 13% of first-degree apparently unaffected relatives of CLL patients.⁶ 

Since January 2005 we have routinely investigated all human leukocyte antigen (HLA)–identical siblings of CLL patients candidate to an allogeneic stem cell transplantation (SCT) for the presence of a MBL by 4-color flow cytometry and polymerase chain reaction (PCR) on peripheral blood (PB) cells, as previously described.⁷  Thirteen HLA-matched siblings of 13 CLL patients have been so far evaluated: 9 males and 4 females, median age 52 years (range, 34-70 years). Three cases had a relative affected by a CLL, a chronic myeloid leukemia (CML), and a non-Hodgkin lymphoma, respectively. All donors showed PB counts within the normal range, with an overall lymphocyte count of 1.99 × 10⁹/L (range, 1.06-3.06 × 10⁹/L).

Of the 13 siblings analyzed, 2 were found to have a B-cell clone in the PB by flow cytometry and PCR, giving an overall incidence of MBL of 15.4%. Both were males (40 and 70 years of age). The family history of the first case was positive for CML. The physical examination was normal in both individuals. The B-cell clone accounted for 74 × 10⁹ and 77 × 10⁹ cells/L, respectively, with a λ light chain restriction and a VH4 family usage in both cases. There was no concordance in the VH family usage between donor and patient pairs. The 2 donors were considered ineligible for a stem cell donation.

Although our series is relatively small, it is the first prospective report which identified a MBL in 15.4% of HLA-identical siblings of CLL patients eligible for an allogeneic SCT, in line with the prevalence of MBL in apparently unaffected first-degree relatives of CLL patients.⁶  At present, we know that people with MBL and a lymphocytosis greater than 4000/mm³ develop a CLL requiring treatment at a rate of 1.1% per year.⁵  Little is known about the evolution over the years of a MBL with a normal lymphocyte count. Because the incidence of MBL is 100-fold greater than the incidence of CLL, it can be assumed that in most people, MBL will not progress into a CLL.⁸  Nevertheless, our decision to exclude the donors with MBL from the stem cell collection was determined by the risk of transferring clonogenic B cells, the risk of evolution from MBL to CLL in the context of posttransplantation immunodepression,^9-11  and the possible availability of alternate donors.

Because the age limits of recipients and of their related donors has increased with the advent of nonmyeloablative allogeneic SCT, the likelihood of transferring premalignant hemopoietic clones with the SCT process might be expected to increase. We recommend that flow cytometry analysis of PB be added to the eligibility screening of HLA-matched siblings of patients affected by CLL and candidate to an allogeneic SCT, as has been suggested by others.^12,13  This procedure is cost-effective, due to the relatively high incidence of positive cases, the noninvasive modality of the test, and the need to collect prospective data on the clinical impact of this relatively new issue.