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Correlation between burden of 17 P 13.1 alteration and rapid escape to plasma cell leukaemia in multiple myeloma

2013; Wiley; Volume: 162; Issue: 4 Linguagem: Inglês

10.1111/bjh.12385

1365-2141

Silvia Mangiacavalli, Lara Pochintesta, Federica Cocito, Alessandra Pompa, Paolo Bernasconi, Mario Cazzola, Alessandro Corso,

PI3K/AKT/mTOR signaling in cancer

Lenalidomide represents a novel effective treatment for multiple myeloma (MM) patients at relapse (Dimopoulos et al, 2009) as well as at the onset (Palumbo et al, 2012). Some poor cytogenetic prognostic factors, particularly alterations of 17p13, seem to maintain their adverse impact in the course of lenalidomide treatment (Reece et al, 2009). Secondary plasma cell leukaemia (sPCL) represents a very aggressive progression of MM characterized by high therapy resistance and consequently, poor outcome (Fernandez de Larrea et al, 2013). Allelic inactivations of 17p13, responsible for the impairment of TP53 tumour suppressor pathways and present in a small fraction of newly diagnosed MM patients, are reported in a remarkable percentage of sPCL with a prevalence up to 75% when considering del (17p13.1) and even higher (83%) when considering coding mutations (van de Donk et al, 2012). The crucial role of TP53 alterations in conferring survival advantage to leukemic plasma cells is well known. There is growing evidence that small clones harbouring the TP53 mutation are already present at the onset, when clonal heterogeneity is higher; selection pressure from subsequent treatment and clonal evolution cause their progressive dominance over time (Chen et al, 2012; Egan et al, 2012; Keats et al, 2012). We report two patients with newly diagnosed symptomatic MM who were not eligible for transplant, treated upfront with lenalidomide plus melphalan and prednisone therapy (MPR) within the CC5013MM015 trial (Palumbo et al, 2012). Table 1 summarizes the baseline clinical data of the patients. Bone marrow samples were collected at the onset and then at progression. Interphase fluorescence in situ hybridization (FISH) was carried out on CD138-positive sorted cells to detect alterations of IGH, 13q14 and of 17p13. Immunophenotypic characterization of bone marrow plasma cells was performed with a gate on CD138+/CD38+ cells using the following panel of monoclonal antibodies: CD13, CD10, CD20, CD15, CD56, CD16, CD9 and CD117. The first patient was a 69-year-old man diagnosed with symptomatic MM (International Staging System score 2) in April 2008. Plasma cell infiltration at bone marrow aspirate was 60%. FISH analysis showed a trisomy 13 with a concurrent deletion of 13q14 in one of the three chromosomes, there was a third signal at locus 17p13 in 30% of examined cells. The patient completed seven MPR cycles reaching PR after three cycles. At the completion of the seventh cycle, there was a progression to plasma cell leukaemia with plasmacytosis accounting for 30% of the total peripheral white cell count of 2·84 × 109/l. Immunophenotypic analysis confirmed a pattern coherent with plasma cell leukaemia with loss of CD56, CD117, and acquisition of CD20 reactivity. FISH analysis at leukaemic transformation confirmed the presence of trisomy 13 with the concurrent deletion of 13q14 in one of the three chromosomes. With respect to baseline, there was a significant expansion of examined cells (60%) carrying the third signal at locus 17p13. This sub-population of plasma cells acquired a trisomy 11 (CCND1) and a deletion of 16q32 (MAF). The second patient was a 69-year-old woman, diagnosed with symptomatic IgG k MM in July 2008. FISH analysis at baseline showed the presence of monosomy 13, variant translocation of locus 14q32, with most of the interphase nuclei carrying deletion of 17p13 (90%). The patient completed eight MPR cycles reaching a PR. At the completion of the eighth cycle, similarly to the first case previously described, there was rapid progression to sPCL with emerging presence of peripheral plasmacytosis (2·3 × 109/l). A bone marrow smear showed massive plasma cell infiltration with typical plasma cell leukaemia antigens expression (i.e. loss of CD56, CD117). FISH analysis confirmed the same complex pattern of alterations detected at baseline, with all cells sorted presenting TP53 deletion (100%). Given that bortezomib administration could partially overcome the negative impact of 17p13 alterations, bortezomib-based therapy, eventually followed by transplant, represent the best available therapy for sPCL (van de Donk et al, 2012; Fernandez de Larrea et al, 2013). The two patients described here were unfit either for stem-cell transplantation or intensive chemotherapy, and were both treated with bortezomib plus dexamethasone therapy. The first patient obtained a transient disease control; the second rapidly died from progressive disease. Trisomy 13 with a del 13q14 (50%) Third signal at 17p13 (30%) Trisomy 13 with a del 13q14 (60%) Third signal at 17p13 (60%) Trisomy 11 (60%) Del16q32 (60%) Monosomy 13 (60%) Trisomy 14q32 (80%) Del 17p13 (90%) Monosomy 13 (80%) Trisomy 14q32 (100%) Deletion 17p13 (100%) These cases illustrate the well-known aggressive course of sPCL, underlying the possible crucial role of TP53 alterations in conferring survival advantage and therapy resistance to the leukemic plasma cell. Similar mechanism of poor outcome following lenalidomide treatment is shared by other haematological malignancies, such as myelodysplastic syndrome (MDS) with deletion of chromosome arm 5q [del(5q)] with associated TP53 mutations. In some of these MDS cases, expansion at leukemic evolution of sub-clones harbouring the TP53 mutation, already present before the onset of lenalidomide treatment, has been described; 5q-MDS patients usually show baseline 17p13 alterations in a small fraction of the neoplastic clones. The presence of low burden of TP53 mutation might explain the long time to leukemic progression (Jadersten et al, 2009; Sebaa et al, 2012). Both cases reported here had a high percentage of baseline myeloma cells harbouring 17p13 alterations (30% and 90%, respectively) with a further expansion at the time of sPCL progression (60% and 100%). This could explain the aggressive pattern of presentation at onset (sudden occurrence of hyper-viscosity symptoms in one patient, extra-medullary mass in the other), the limited response to therapy and the rapid leukemic progression. Given that lenalidomide has low efficacy toward plasma cells harbouring TP53 alterations, it might be hypothesized that, in these two cases, lenalidomide therapy suppressed the fraction of clones sensitive to its action, allowing the expansion of resistant plasma cells. In conclusion, the presence of a high burden of neoplastic MM cells with TP53 alterations could represent a risk factor for early sPLC evolution. Given that sPCL outcome, despite some benefit obtained with bortezomib, still remains extremely disappointing, an accurate analysis of TP53 alteration before therapy starting should help to identify the fraction of MM patients at higher risk for leukemic transformation. These latter patients could benefit most from newer treatment options (second generation proteasome inhibitors and immunomodulatory drugs, histone deacetylase inhibitors, monoclonal antibodies) combined with bortezomib, followed, in eligible patients, by transplant. Data on a larger amount of patients with similar characteristics are warranted to confirm this preliminary observation. SM, LP, AP, FC, PB and AC performed the research. SM, MC, PB and AC designed the study and wrote the paper. The authors declare no conflict of interest.