Progress in the Treatment of Primary Plasma Cell Leukemia
Authors: Pellegrino Musto
Journal: Journal of Clinical Oncology (2016)

Primary plasma cell leukemia (PPCL) is one of the most challenging diseases for hematologists. Despite the younger age of patients with PPCL, we have not obtained, in this rare and aggressive disorder, the same important therapeutic progress seen during past years in multiple myeloma (MM). Nevertheless, a registry study of 445 patients with PPCL showed a modest, but statistically significant improvement in overall survival (OS), which has increased from 5 months in patients diagnosed between 1973 and 2005 to 12 months in those diagnosed between 2006 and 2009 after the introduction of the so-called novel agents (thalidomide, lenalidomide, and bortezomib) in the upfront setting. The most significant benefit was observed in older patients in whom the early mortality rate decreased from 26% to 15%. Literature about PPCL treatment is limited, sometimes conflicting, and often based on case reports or small retrospective series that frequently include both younger and elderly patients or secondary forms of plasma cell leukemia, which is a terminal event in previously diagnosed MM. Further confusion is caused by the reporting of heterogeneous drug combinations and transplantation procedures often collected over long periods that do not reflect contemporary practice. No randomized trials have been performed in PPCL thus far. Studies have suggested that regimens that contain bortezomib, the first-in-class proteasome inhibitor (PI), induce an overall response rate (ORR) of 69% to 89.9% in PPCL, with at least very good partial response (VGPR) in 28.5% to 37.9% of patients and a median OS that ranges from 12.6 months to about 2 years. These results generally compared favorably with PPCL series not treated with bortezomib-based regimens. Other groups, however, did not find a significant improvement in clinical outcome when novel drugs, particularly bortezomib, were used. Among immunomodulatory drugs, lenalidomide was more consistently investigated with low-dose dexamethasone in the first prospective trial in PPCL, which enrolled 23 patients with a new diagnosis (median age, 60 years). In this phase II study, ORR to induction treatment was 74% (VGPR or better, 39%). Four of five responders not eligible for transplantation who started maintenance with low-dose lenalidomide relapsed within 1 year. Nine patients underwent autologous stem cell transplantation (SCT) after induction. With a median follow-up of 34 months, median progression-free survival (PFS) was 14 months, and median OS was 28 months. However, PFS and OS were 27 months and not reached in patients who underwent autologous SCTupfront versus 2 months and 12 months in those who did not, respectively. Three registry studies in 711 patients who underwent transplantation between 1980 and 2009 explored the role of autologous SCT in PPCL and showed that this procedure induced higher rates of complete response than in MM. Notwithstanding, autologous SCT in PPCL was less effective than in MM in the long term due to increased nonrelapse-relatedmortality and short duration of post-transplantation response; particularly, PFS was 14.3 months (median), 34% to 38% at 3 years, and 10% at 5 years, whereas OS was 25.7 months (median), 39.5% to 64% at 3 years, and 25% to 27.2% at 5 years. Furthermore, there was a trend toward superior OS in patients who underwent a double versus single autologous SCT. Other groups reported median OS of 34 to 38 months in patients with PPCL who underwent autologous SCT. Variable efficacy and feasibility of allogeneic SCT have been described in small retrospective series. In addition, two registry studies compared 135 patients with PPCL who underwent allogeneic SCT, with similar populations treated with autologous SCT. Allogeneic SCT was associated with a lower relapse rate but a much higher risk of nonrelapse-related mortality compared with autologous SCT, without evidence of survival benefits. Reported PFS and OS in patients with allografts were 20% and 39% at 3 years and 20% and 32% at 4 years, respectively; OS at 5 years was 19% for reduced-intensity conditioning and 27% for myeloablative conditioning allogeneic SCT. Of note, patients treated with allogeneic SCT plateaued at approximately 20%, similar to that seen in MM but at a lower level. In the article that accompanies this editorial, Royer et al report the second prospective phase II clinical trial in newly diagnosed PPCL, where novel agents and transplantation procedures were combined. Forty patients (median age, 57 years) were planned to receive induction therapy with four alternate cycles of bortezomib, dexamethasone, pegylated doxorubicin or bortezomib, dexamethasone, cyclophosphamide. ORR was 69%; complete response, 10%; and VGPR, 26%. Sixteen responding patients younger than 66 years with an HLA-matched donor received consolidation with a tandem sequence of single autologous SCT followed by reduced-intensity conditioning allogeneic SCT. Six