Clonal immunoglobulin light chain variable region germline gene use in AL amyloidosis: association with dominant amyloid‐related organ involvement and survival after stem cell transplantation

Abstract

Summary. AL (primary or immunoglobulin light chain) amyloidosis (AL) differs from myeloma per se in that tissue deposits of amyloid are found, typically in association with small numbers of clonal plasma cells producing l light chains, and also in that AL patients typically present with a predominantly dysfunctional organ-system. This constellation of features ± ®brillar deposits comprised of light chains, l light chain predominance, and organ-system tropism and dysfunction ± remains unexplained. Select patients with AL respond to haemopoietic stem cell transplantation (SCT) with clinical improvement and extended survival, particularly those who do not have cardiac involvement. In order to ascertain whether the organ-system tropism of AL was associated with immunoglublin light chain variable region (Ig V L ) germline gene utilization, we attempted to clone, sequence and assign germline donors to the clonal Ig V L genes of 62 AL patients, all of whom were treated with SCT. We succeeded in 39 cases, identifying clonal AL genes derived from donors of the lI (n 10), lII (n 5), lIII (n 6), lVI (n 11) and KI (n 7) subtypes. The majority of the donors (IGLV6S1, DPL5, DPL2, DPL23 and LFVK431) were genes that appear in the expressed repertoire <5% of the time, suggesting an intrinsic propensity to form amyloid under certain conditions. Patients whose clones derived from the lVI IGLV6S1 donor uniformly presented with dominant renal involvement while those with other V l or unknown donors often had dominant cardiac or other organ involvement, particularly patients whose clones derived from the lI DPL2 donor. In addition, both early (<3 months) and overall post-SCT survival were signi®cantly better in lVI IGLV6S1 patients compared to patients with other V l donors. These ®ndings indicate that there are important associations in AL amyloidosis among Ig V L gene utilization, organ-system tropism and post-SCT survival.

Hematopoietic stem cell mobilization with intravenous melphalan and G-CSF in patients with chemoresponsive multiple myeloma: report of a phase II trial

“…Median days of grade 3 or 4 neutropenia or thrombocytopenia were 7 (2-20) and 8 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Median mobilization days, CD34 þ cells/kg and total leukaphereses were 16 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), 12.1 million (2.6-52.8), and 2 (1)(2)(3)(4)(5) respectively. Four patients (12.5 %) failed to achieve the target of 4 million CD34 þ cells/kg in five leukaphereses.…”

“…18 Clonal immunoglobulin (Ig) V L and V H genes were identified as previously, using PCR primers for consensus V H and C a or C g regions and for V k and V l subgroups. 18,[28][29][30] Representative samples were obtained from each SCC without manipulation. To estimate the percent of clonotypic cells, limiting-dilution PCR with patient-specific CDR1/CDR3 primers was performed 18,[28][29][30][31][32][33][34] with DNA from 2 Â 10 5 cells per SCC serially log-diluted (ie 10-fold) with buffy-coat DNA (limiting-dilution PCR).…”

“…Of these, two had sufficient cells collected with a sixth leukapheresis and two were collected again with G-CSF mobilization (all four subsequently underwent SCT). The median number of days until initiation of leukapheresis was 16 (range [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. The median number of CD34 þ cells/kg collected was 12.1 million  10 6 (2.6-52.8).…”

High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease

“…To assess the role of k-light chain variable region germline gene usage in our patients, we amplified and sequenced the dominant k-light chain variable germline gene in the baseline marrow cells of four patients using methods described previously. 19,20 Treatment All patients received initial therapy for multiple myeloma prior to undergoing their consolidation with HDM and auto-SCT. The goal of initial therapy in multiple myeloma is the achievement of a low tumor burden prior to the transplant.…”

Biological features of the clone involved in primary amyloidosis (AL)

“…92 A very recent genetic analysis reported, in a selected population undergoing high-dose chemotherapy, an association between the usage of the VI family and predominant or exclusive amyloid involvement of kidney (14/14 cases). 94 This work raised the possibility that the diverse organ tropism that influences the clinical picture of amyloidosis may be ruled by gene usage. We recently undertook the first analysis of V germline gene usage in a general population of AL patients 95 and found that eight of the 11 VI patients (73%) had major or exclusive kidney involvement (Perfetti et al, manuscript in preparation).…”