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Background and Objectives Waldenström macroglobulinemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) are IgM-related disorders in which monoclonal B cells harbor a unique clonotypic rearrangement of the immunoglobulin heavy chain gene (IgH). The aim of this study was to characterize IgH rearrangements in a larger series of IgM-related disorders than any previously described.Design and Methods Seventy-two patients with monoclonal IgM disorders (64 with WM and eight with IgM-MGUS) were studied to amplify and sequence both VDJH and DJH rearrangements. Twenty-nine of them were also tested for the existence of class switch recombination (CSR).Results VDJH and DJH rearrangements were detected in 91% and 42% of WM patients and in 100% and 13% of IgM-MGUS patients, respectively. In WM, the most frequently observed VH family and single segment were VH3 and VH3-23 (76% and 29%, respectively), with their frequencies differing markedly from those that would occur if the rearrangements were random. The VH3-23 segment was never selected in IgM-MGUS. The distribution of both DH and JH families in WM did not differ from that in normal B-lymphocytes. Somatic hypermutation with >2% deviation was seen in 90% of cases of WM and in 71% of IgM-MGUS. DJH rearrangements were more frequent in WM than in MGUS (42% and 13%, respectively). All DJH rearrangements were unmutated, which makes them an attractive target for minimal residual disease investigation. IgM clonotypic transcripts were observed in all cases and IgD in 83%. IgA and/or IgG monoclonal isotypes were seen in three WM cases (14%) but in none of the IgM-MGUS patients.Interpretation and Conclusions WM and IgM-MGUS exhibit dissimilarities in VDJH and DJH rearrangements that could suggest different differentiation processes. There is evidence that WM cells are able to undergo CSR in vivo, a fact that was initially thought to be impossible in this disease.

Background and Objectives The detection of PML-RARα by real-time polymerase chain reaction (RQ-PCR) is becoming an important tool for monitoring minimal residual disease (MRD) in patients with acute promyelocytic leukemia (APL). However, its clinical value remains to be determined. Our aim was to analyze any associations between the risk of relapse and RQ-PCR results in different phases of treatment, comparing these data with those yielded by conventional qualitative reverse transcriptase-PCR.Design and Methods Follow-up samples from 145 APL patients treated with the PETHEMA protocols were evaluated by the RQ-PCR protocol (Europe Against Cancer program) and by the RT-PCR method (BIOMED-1 Concerted Action). Hematologic and molecular relapses and relapse-free survival were recorded. We then looked for associations between relapse risk and RQ-PCR results.Results After induction therapy, no association was found between positive RQ-PCR results and relapse. The PCR result here did not imply any change in the scheduled therapy. After the third consolidation course, two out of three cases with positive RQ-PCR relapsed in contrast to 16 out of 119 (13%) patients with negative RQ-PCR. During maintenance therapy and out-of treatment, all patients with >10 PML-RARα normalized copy number (NCN) (n=19) relapsed while all patients with