Plasma Cell Leukemia.
Authors: Fonseca Rafael 
Published: October 2019

Abstract
Abstract SCI-4

Introduction
Plasma cell leukemia (PCL) represents an aggressive variant of multiple myeloma (MM) characterized by the presence of large number of circulating plasma cells (PC) in the peripheral blood. While some boundaries have been defined to establish a diagnosis of PCL (PC in the peripheral blood greater than 2×109/l-1 or 20% of leukocytes being plasma cells), these values are artificial, and most cases of PCL show extreme numbers of circulating plasma cells. PCL is part of a spectrum of the PC neoplasms where increasing numbers of circulating PC identify aggressive MM, yet many cases do not satisfy criteria for PCL. Historically PLC has been divided into “Primary PCL” (pPCL) when it represents the initial manifestation of a PC neoplasm, and “Secondary PCL”, or MM with leukemic transformation (MM-LT). Both entities share biologic and clinical similarities as aggressive variants of MM, but the latter represents a fulminant PC neoplasm with historic survival of only 1-2 months. In contrast, pPCL, while nevertheless aggressive, often will respond to induction treatment and can occasionally result in a durable response.

Biology
Because of the rarity of PCL (1% or less of all MM) the genetic description of the disease has been limited by lack of material for study. Nevertheless most PCL cases harbor IgH translocations (87% of pPCL and 82% in MM-LT). In particularly the t(11;14)(q13;q32) is common; observed in 35 to 70% of cases of pPCL. In contrast MM-LT contains most other genetic aberrations associated with MM pathogenesis, including the more benign genetic variants of the disease (e.g. hyperdiploid MM), and these cells are presumed to have acquired additional genetic features resulting in aggressive clonal proliferation and expansion. When karyotypes are informative (frequently in PCL) they are almost always non-hyperdiploid variant, mostly hypodiploid. Rare cases of hyperdiploid karyotypes have been observed in association with MM-LT. Monoallelic deletions of 17p13.1, at the TP53 locus and similar to those seen in MM, can be detected in 50% of pPCL and 75% of MM-LT. While mutations of TP53 area rare in MM they are common in PCL (24%), contributing to a substantial overall prevalence of TP53 inactivation of 56% in pPCL and 83% in MM-LT. Furthermore, we found the upstream tumor suppressor p14ARF, whose product directly binds MDM2 enhancing p53 function, to be inactivated by methylation in 29% of MM-LT. MYC abnormalities are only observed in 15% of cases and the distribution of chromosome 13 deletion/monosomy is similar to what would be expected for the corresponding karyotypic aberrations (85% in the hypodiploid pPCL and 50% in MM-LT).

Treatment and future directions
Historically the treatment of PCL has been unsatisfactory with few patients achieving durable remissions, and most dying within weeks to months after diagnosis. The impact of more intensive regimens (including autologous and allogeneic stem cell transplant) and of novel agents such as bortezomib and lenalidomide are not known. However, early data suggest, that the historic survival rates of pPCL (∼12 months) and MM-LT (∼1-2 months) will be improved by the aforementioned interventions. It is likely that with increasing survival of MM patients, MM-LT will become an increasingly common and difficult problem to manage.

Disclosures
Fonseca: Various: CME lectures; Halozyme: Consultancy; BMS: Consultancy; Medtronic: Consultancy; AMGEN: Consultancy. Off Label Use: Multiple agents to be used for the treatment of plasma cell leukemia. No agents are specifically approved for this indication although this is a variant of myeloma.