treatment of primary plasma cell leukemia with high doses of cyclophosphamide, bortezomib, and dexamethasone followed by double autologus HSCT

Plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM) characterized by the presence of plasma cells circulating in peripheral blood. It is classified in the primary form (pPCL) if it appears “de novo” in patients without evidence of previous diagnosis of MM, or secondary if it occurs in patients with refractory/relapsed forms of MM despite the treatment in progress. The diagnosis is based on the percentage of plasma cells greater than 20% and in an absolute number greater than 2 × 109/L in peripheral blood [1, 2]. Treatments of pPCL based on the use of alkylating agents, anthracyclines, and steroids are ineffective; therefore, an optimal therapy remains to be defined. Between January 1, 2012 and December 31, 2018, 9 adult patients with a diagnosis of pPCP received the same front line approach: cyclophosphamide (CTX) 1500 mg/mq d 1,8 - bortezomib 1.3 mg/mq d 1,4,8,11 - dexamethasone 40 mg d 1,2,4,5,8,9,11,12 for 3 courses. Those patients that resulted responsive to the induction therapy underwent to a double autologous hemopoietic stem cell transplant (auto-HSCT). After second auto-HSCT, patients received maintenance with continuous lenalidomide 25 mg every day for 21 days followed by 1 week of rest. The complete response (CR) was based on the simultaneous presence of disappearance of peripheral plasma cells, reduction of bone marrow plasma cell infiltrates to < 5%, disappearance of the eventual monoclonal protein by serum/urine immunofixation, and resolution of possible extramedullary localizations present at diagnosis. Patients in whom some, but not all, criteria for CR are fulfilled are classified as partial response (PR), providing the remaining criteria satisfy the requirements for PR. The PR was defined as a reduction ‡50% in peripheral and bone marrow plasmacytosis and as a reduction ‡50% of measurable monoclonal paraprotein, if present. The overall survival (OS) was measured from the diagnosis of pPCL to death or last follow-up. The duration of response (DFS) was measured for patients responding to first-line therapy from the first observation of PR or CR to the time of relapse, censoring the data on the last visit of follow-up or death. All survival data were analyzed using the Kaplan–Meier method to estimate the probability of death (OS) and of relapse (DFS) as a function of time. All patients fulfilled diagnostic criteria with an absolute count of peripheral blood monoclonal plasma cells > 2 × 109/l. The median circulating plasma cell count was 5.646 x 109/l (range 2.400–20.000). Regarding clinical and laboratory characteristic, 7 (78%) patients presented the CRAB criteria at the onset: 4 patients had anemia (median Hb 7.7 g/dl; range 4.7–9.7); 5 patients had hypercalcemia (median 14.2 mg/dl, range 12–17.3); 5 had acute kidney failure with a median creatinine levels of 5.2 mg/dl (range 2.05–14.9); 7 patients had bone osteolysis. Five patients showed a normal karyotype, 1 patient had hypodiploidy, and 3 patients had a complex karyotype. Monoclonal IgG was present in 3 patients, 2 IgA, and the remaining 4 patients had a micro-molecular component (Table 1). Table 1 Clinical characteristics and outcome of 9 cases of pPCL leukemia Full size table All received the same induction therapy for three courses. At the end of the induction treatment, 5 (55%) patients showed a CR, 3 patients showed a PR, and 1 was unresponsive. The overall response rate was 89% (8/9). Four patients (all in CR) underwent stem cell collection after high doses of CTX (4000 mg/mq), while 1 CR patient, which showed an early relapse, 2 PR, and 1 unresponsive, due to the progression of the disease, was considered not eligible for auto-HSCT. Only 3 patients (33%) showed side effects during the induction phase: in 2 patients, infection and neutropenia during induction therapy regressed through appropriate treatment, while another presented a transitory peripheral neuropathy. All patients with acute kidney failure and hypercalcemia at the onset of pPCL presented a complete resolution after induction therapy. The median OS for the whole population was 12 months; at an actuarial 5 years follow-up, 55% of patients could be still alive. Comparing OS of patients who achieved CR with the patients in PR after first-line treatment, a trend of significance could be noted (OS not reached vs. 10 months respectively, p value = 0.055). The median actuarial PFS for only patients achieving CR after induction therapy was 50 months. pPCL is a highly aggressive disease, with unsatisfactory responses to treatment, a poor prognosis, and a median survival reported within a few years ago no longer of 7–8 months [2]. Conventional treatments adapted from those used for MM are usually less effective; as a consequence, a correct approach to this kind of malignancy is unclear. The introduction of novel agents, such as immunomodulatory drugs (IMIDs) or proteasome inhibitors, has considerably improved the prognosis for patients with pPCL, even though the median duration of CR remains short even in the setting of total therapy protocols [3,4,5]. Recently, a prospective phase 2 study has demonstrated that induction therapy with bortezomib-based combinations followed by auto-HSCT led to high response rates and prolonged survival in patients with pPCL [6]. Registry studies that collected 711 pPCLs who received auto-HSCT between 1980 and 2009 showed a higher rate of CR than in MM with a median OS of 25.7 months [7]. Because of the aggressiveness of pPCL, allogeneic transplantation (allo-HSCT) has been proposed for the treatment of younger patients. The Center for International Blood and Marrow Transplant Research experience showed that 19 of 50 patients were alive at 3 years; this study compared also the OS at 3 years between auto-HSCT and allo-HSCT settings. It was 64% in the autologous group and 39% in the allogeneic group; however, the non-relapse mortality (NRM) at 3 years was 5% in the autologous group and 41% in the allogeneic group [8]. The EBMT group described their experience with 85 patients who underwent allo-HSC in comparison with 411 patients who underwent auto-HSCT for primary and secondary PCL, reporting similar OS at 5 years [9]. In our study, we analyzed the efficacy of a treatment that combined old and new drugs for the treatment of pPCL followed by double auto-HSCT. Our data, with all the limits of a low number of cases, show that this approach could improve the prognosis and survival and these poor prognosis patients when compared with other treatments. No patient had relevant lethal side effects in induction or delay in the following treatments. The double auto-HSCT seems effective to reduce the incidence of relapse in this subset of patients. None of our patients received allo-HSCT, but in selected patients with a suitable donor, a myeloablative allogeneic transplantation could be considered. Otherwise, a tandem transplant with an auto-HSCT followed by a reduced-intensity conditioning allo-HSCT, if a related or unrelated donor is available, could be evaluated, but the impact of this treatment also remains to be defined [10].