The Clinical And Biological Characteristics And Prognosis Of Primary Plasma Cell Leukemia

Background and objective:Primary plasma cell leukemia（p PCL）is a rare and highly aggressive hematological malignancy,with an incidence between 0.5 and 4%of multiple myeloma（MM）.In recent years,treatments have been updated and strengthened,but the remission rate,survival and outcome of p PCL are still poor.At present,the most clinical datas of p PCL come from small retrospective studies and vary widely,so we don’t fully clear its unique clinical and biological characteristics and prognostic factors.In the future,it’s necessary to carry out large scale prospective study to explore the clinical and biological mechanisms,related to the occurrence and development of p PCL,and outcome and prognostic factors of p PCL,so that we can understand the characteristics of the disease,discover potential therapeutic targets,develop new agents,improve the effectiveness of treatment strategies,and ultimately improve the poor outcome of p PCL.The aim of this study was to analyze the unique clinical and biological characteristics,and explore the outcome and prognostic factors of p PCL patients in my country by synthesizing the clinical information of p PCL patients in domestic multicenters.Methods:Analyzing the clinical data of 112 p PCL patients diagnosed from June 1997 to July 2020 in 8 centers in China,and comparing them with 856 newly diagnosed multiple myeloma（NDMM）patients diagnosed from February 2003 to December2019 in Cancer Center of the First Hospital of Jilin University.Using SPSS 22.0,Graph Pad Prism 8.0 and R×₆₄ 3.6.3 software for statistical analysis.Comparisons between groups were performed usingχ2 test or Fisher exact tests.The Kaplan-Meier method was used for survival analysis,the Log-rank method was used for univariate analysis,and the Cox model was used for multivariate analysis.P<0.05 indicates the difference is statistically significant.Results:1.Comparison of clinical features of p PCL and MM:The median age of p PCL and MM were 57 and 61 years old respectively,and the male incidence rate was about55%.Compared with MM,the proportion of p PCL patients with ECOG 3-4 points,clinical stage（ISS,R-ISS）III,Cs Ca≥2.75 mmol/L,LDH≥220 U/L,BMPCs≥60%,WBC≥15×10⁹/L,HB<100 g/L and PLT<100×10⁹/L was higher（P<0.05）,while the proportion of albumin<40g/L and osteolytic lesions was lower（P<0.05）.In the M protein typing,the proportion of Ig A type p PCL was lower than that of MM（15.5%vs24.4%,P=0.05）,and the proportion of light chain type was higher,but the difference was not statistically significant（P>0.05）.2.Comparison of biological features of p PCL and MM:Karyotype analysis showed that the proportion of abnormal chromosomal karyotypes in p PCL was significantly higher than that of MM（P<0.05）,with complex karyotypes accounting for 37.0%,which was statistically different from MM（11.2%）（P<0.001）.In addition,the incidence of hypodiploid karyotypes in p PCL was slightly higher,while the proportion of hyperdiploid karyotypes was lower,but proportions did not reach statistical differences（P>0.05）.In terms of cytogenetic abnormalities,except for del（1p）,the incidence of other cytogenetic abnormalities detected by FISH were higher than that of MM.Among them,the difference of incidence of t（14;16）and1q21⁺was statistically significant（P<0.05）,while the proportion of t（11;14）,t（4;14）,del（17p）and del（13q）did not reach statistical difference（P>0.05）.According to the2016 IMWG cytogenetic risk stratification standard,high-risk p PCL and MM patients accounted for 90.2%and 72.2%,respectively,and the difference was statistically significant（P<0.05）.According to the 2018 m SMART 3.0 risk stratification standard,the double-hit and triple-hit ratios of p PCL and MM were 21.4%vs 12.1%,7.1%vs2.2%,but they were not statistically significant（P>0.05）.This indicates that,compared with MM,p PCL is more prone to genetic changes,and they were most have poor prognosis.In the immunophenotype,the positive rate of CD19 and CD20 in p PCL was significantly higher than that of MM,while the positive rate of CD27 was lower,and the difference was statistically significant（P<0.05）.In addition,the positive rate of CD56 was lower than that of MM,but it was not statistically significant（P>0.05）.3.Comparison of response between p PCL and MM:In this study,the objective response rate（ORR）of p PCL patients was 77.6%,and the deep response rate（≥VGPR）was 42.9%.Compared to MM,the deep response rate of p PCL patients was significantly lower（P<0.05）,and the difference in the ratio of s CR was the largest（P<0.05）.The study further found that the ratios of p PCL and MM reaching MRD^-are 20.0%and 45.7%,respectively.Although there was no statistical difference,it further confirmed the poor response of p PCL.4.Comparison of overall survival between p PCL and MM:Overall,the m OS and m PFS of p PCL patients were significantly lower than that of MM（m OS:20 vs 29months,P=0.004;m PFS:6 vs 15 months,P<0.001）.During the entire follow-up period,71（73.2%）p PCL patients died,and 9（9.3%）patients died within 1 month after diagnosed.What’s more,the ratios of p PCL patients died within 3 months,6 months,12 months and 24 months of diagnosis were 25.3%,34.7%,43.3%and 65.0%,which were significantly higher than those of MM（P<0.05）.5.The effect of treatment on p PCL survival:In this study,the m OS of untreated p PCL patients was 2 months,which was significantly lower than that of treated patients（m OS 23 months,P<0.001）.Compared with traditional drugs,new agents（bortezomib,thalidomide/lenalidomide）bring significant benefits to the outcome of patients（m OS:24 vs 6m,P=0.480;m PFS:8 vs 5m,P=0.210）;Among the new drugs,the clinical efficacy of bortezomib is significantly better than thalidomide（m OS:31 vs 5m,P=0.031;m PFS:8 vs 4m,P=0.198）;compared with bortezomib or thalidomide alone,the induction therapy of bortezomib and thalidomide/lenalidomide slightly improved the patients’m OS（24 vs 21m,P=0.387）,and significantly prolonged m PFS（18 vs 6m,P=0.022）.Compared with patients without ASCT,the new drugs induction therapy combined with ASCT significantly improved the survival of patients（m OS:53 vs 21m,P=0.020;m PFS:27 vs 6m,P=0.001）.6.Analysis of prognostic factors of p PCL:univariate analysis showed that LDH≥220U/L had a statistically significant impact on OS in p PCL patients（P<0.05）;ECOG 3-4 points,LDH≥220 U/L,e GFR<40 ml/min/1.73m²,PLT<100×10⁹/L had a statistically significant impact on PFS（P<0.05）.In multivariate analysis,ECOG score 3-4 points,LDH≥220U/L,e GFR<40ml/min/1.73m²,and PLT<100×109/L are not independent prognostic factors for p PCL patients.Conclusions:1.Compared with MM,p PCL has a rapid onset,rapid progress,short course of disease,and combined with severe anemia,hemorrhage,hypercalcemia,advanced stage,and high tumor burden（such as LDH,β2-MG,BMPCs,etc）.In contrast,the incidence of osteolytic lesions is lower than that in MM.Among M protein types,Ig G is the most common type,followed by light chain type.The proportion of Ig A type is higher than that of MM.2.Compared with MM,p PCL patients have more prominent biological changes,and most of them have poor prognosis,such as complex hypodiploid,pseudodiploid karyotype,1q⁺and t（14;16）.3.Compared with MM,the positive rate of CD19 and CD20 of p PCL is higher,while the positive rate of CD27 and CD56 is lower,which results in the characteristics of cloned plasma cells that are extramedullary migration,malignant proliferation,anti-apoptosis,and reduced osteolytic ability.4.Compared with MM,p PCL patients have poorer response to treatment.During the first-line treatment,the ORR of p PCL was about 78%,and the deep remission rate was 43%,which was significantly lower than that of MM（P<0.05）.5.Compared with MM,p PCL has a poorer outcome,with m OS and m PFS of 20vs 29 months and 6 vs 15 months respectively（P=0.004,P<0.001）.6.In terms of treatment,p PCL patients can benefit from PI combined with IMi D induction therapy and ASCT consolidation therapy.