髓外浆细胞瘤P53缺失率较高、自体造血干细胞移植可能延长生存（可编辑）

髓外浆细胞瘤P53缺失率较高、自体造血干细胞移植可能延长生存（可编辑） 髓外浆细胞瘤P53缺失率较高、自体造血干细胞移植可 能延长生存 中国 科 技 论 文 在 线////0>. Extramedullary myeloma associated with P53 deletion and autologous stem cell transplantation may benefit the survival # 5 of this populationDeng Shuhui, Xu Yan, An Gang, Sui Weiwei, Zou Dehui, Zhao Yaozhong, Qi ** Junyuan, Li Fei, Hao Mu, Qiu Lugui Center of Lymphoma &Myeloma, Blood Diseases Hospial,Chinese Academy of Medical Sciences 10 Abstract: Background: In multiple myeloma MM, plasma cells are usually restricted in the bone marrow. But some patients develop extramedullary diseases EMD at diagnosis or during follow-up, showing different clinical characteristics and a dismal prognosis Methods: We studied 834 consecutive MM patients in a single center in China and compared clinical features of patients with or without EMD 15 Results: In general, the prevalence of EMD was 8.6% at diagnosis and 3.4% during follow up, with significant increase in recent years. Patients with EMD at diagnosis were remarkably younger in age, had higher levels of hemoglobin HB and lactate dehydrogenase LDH, more ISS stage ?and more P53 deletion as determined by fluorescence in situ hybridization (FISH ). EMD during follow-up was correlated with EM presentation at diagnosis HR 8.709, P 0.001, IgD subtype HR 5.107, P0.002 20 and light chain type of λ HR 3.645, P0.012. Treatments with bortezomib HR 0.697 and thalidomide HR 1.112, or autologous stem cell transplant after high dose chemotherapy ASCT/HDT HR 1.232 showed no correlation with EMD. With respect to prognosis, EMD was associated with shorter overall survival time 29 versus 40 months, P 0.01 and shorter time to progression 15 versus 25 months, P 0.001. Multivariate analysis showed that strict EMD s-EMD rather than EMD at 25 diagnosis was the independent prognostic factor. In patients receiving ASCT/HDT, EMD/sEMD showed no adverse effects on survival, suggesting that this treatment may be beneficial to the survival of EMD patientsConclusions: EMD portends unique clinical features and poor outcome in MM. Autologous stem cell transplant after HDT may be beneficial to this population in survival. 30 Key words: hematology;multiple myeloma; extramedullary disease; P53 deletion; transplantation 0 Introduction Multiple myeloma MM is a disease with great heterogeneity. Usually myeloma cells are restricted within the bone marrow. However they can disseminate and infiltrate into many 35 extramedullary sites. The infiltration can occur at diagnosis or during follow-up, and portends poor survival. In recent years, studies showed a significant increase of the incidence of [1-4] extramedullary diseases EMDThis increase is mainly attributed to the wide application of more sensitive techniques. But concerns about the possible increase of EMD with the expanding [5-7] use of transplant and biological agents cannot be ignoredThrough the retrospective analysis 40 of the records of 834 patients with MM, this study aimed to show the prevalence and clinical features of EMD in the mainland of China, to investigate the correlation between EMD relapse/progression and the treatment regimes, and to develop adoptive methods of treatment for this unique population 1 Patients and methods 45 834 consecutive MM patients diagnosed at Blood Diseases Hospital of Chinese Academy of Medical Sciences BDH from January 1993 to March 2012 were included in the analysis. EMD in Foundations: 教 育部新教师基金 课题号:206 Brief author introduction:Shuhui Deng (1979-),female ,attending doctor,Hemaology Correspondance author: Lugui Qiu (1964-), male,professor of medicine,Hematology. E-mail: qiulg@//. - 1 - 中国 科 技 论 文 在 线////. patients with MM was defined as the presence of plasma cell tumors outside the bone marrow, either in extraosseous organs or in the form of soft-tissue mass spreading from the bone. To distinguish the two types in the following analysis, we defined the former strict EMD sEMD, and the latter non-strict 50 EMD non-sEMD. Patients with solitary plasmacytoma only were excluded. In most cases the presence of EMD was diagnosed by computed tomography CT scan or other radiographic methodsIn the early period of the study, EMD was diagnosed by physical examination and X-rays. Histologic confirmation was performed whenever possible. And all the results of fluorescence in situ hybridization ( FISH ) were done on the plasma cells of sorted samples. The study was approved by 55 the institutional review board and conducted in accordance with the Helsinki Declaration of 1964, as revised in 2000. Baseline data were extracted from databases and medical records. Follow-up information was collected at each visit. Durie and Salmon criteria were used for diagnosis and stagingThe International Staging System was retrospectively applied to those patients whose albumin and b2-microglobulin at diagnosis were available. Response to therapy was assessed according to the 60 International Myeloma Working Group IMWG uniform response criteria [17]. Complete response CR was defined as negative immunofixation on the serum and urine, less than 5% plasma cells in the bone marrow and disappearance of any soft tissue plasmacytomas if present at baseline; very good partial response VGPR was defined as detectable serum and urine M-component by immunofixation but not by electrophoresis, or ? 90% reduction in serum M-component plus 65 urine Mcomponent 100 mg per 24 hours; partial response PR was defined as ? 50% reduction in serum M-protein, ? 90% reduction in urinary M-protein, or 200 mg per 24 hours, and, if present at baseline, ? 50% reduction in the size of soft tissue plasmacytomas2 Statistical analysis Chi-square test was applied for comparisons of proportions and means. Potential risk factors for the 70 development of EMD during follow-up were examined using a Cox proportional hazards model. Time to progression TTP and overall survival OS were evaluated using the Kaplan?Meier product-limit method. TTP was calculated from the date of diagnosis to the date of disease progression or last follow-up for censored cases. OS was calculated from the date of diagnosis to the date of death or last follow-up for censored cases. The prognostic effect of EM involvement was assessed by means of Cox 75 proportional hazards regression. All analyses were carried out using SPSS 13.0 software. P values ? 0.05 were considered statistically significant3 Results 3.1 Patient categorization The median follow up time of the entire MM population was 17 months range: 1-192 months80 Overall, 90 out of 834 MM patients 10.8% had EMD. 72 /834 patients 8.6% had EMD at the time of diagnosis, and 40/834 patients 4.8% of them were classified as sEMD. 28 of 834 MM patients 3.4% showed EMD spread during follow-up after a median time of 21 months range: 3?76 months from diagnosis, and 24/834 patients 2.9% of them were classified as sEMD. Table 1 showed the representative features of MM patients with or without EMD at diagnosis. It was 85 found that EMD was associated with younger age, higher prevalence in male patients, higher hemoglobin HB and lactate dehydrogenase LDH levels. IgD subtype, ISS stage ?were significantly more common in patients with EMD. Cytogenetics analysis showed that P53 deletion/mutation were more frequent in EMD* Table 1. Clinical features of MM patients with or without EMD at diagnosis - 2 - 中国 科 技 论 文 在 线////. Characteristics at Patients with EMD Patients without EMD P value diagnosis n 72 n 762 Age years, median 0.003 53(26-75) 57(26-86) range Sex, male/female ratio 3.00 1.66 0.04 Type of myeloma, % of patients IgG 37.8% 48.1% NS IgA 24.4% 23.7% NS IgD 8.7% 2.2% 0.001 IgM 0 0.5% NS Light chain 18.8% 20.0% NS Nonsecretory 5.8% 3.1% NS Type of light chain, κ/λ 1.03 0.84 NS ratio Stage Durie?Salmon, %NS of patients ? 4.4% 5.7% NS ? 4.4% 10.6%? 91.2% 83.7%International Staging System, % of patients ? 32.8% 17.6% 0.015 ? 27.9% 38.2% NS ? 39.3% 44.2% NS Hemoglobin g/dl, 0.002 95(46-151 ) 84(27-169) median range Serum albumin g/dl, 3414-52 NS 35(19-54) mean range β2-microglobuling/l 6.91-46.9 7.10.20-60.1 NS mean range Serum M-protein g/dl, 59.41.92-137.00 63.60.37-159.00 NS mean range Bone marrow plasma 33% (0-93.0% ) 36.5% (0-98.5% ) NS cells%, mean range LDH U/l,meanrange 24763-3000 19942-2000 0.012 CD56 expression% 54.8 59.6 NS Chromosome 31.4%11/35 22.0%78/354 NS abnormalities Chromosome 13 deletion 3.8%1/26 7.2%23/321 NS RB1 deletion by FISH 48.1%25/52 50.7%111/219 NS IgH/CCND1 translocation 16.7%8/48 23.9%50/209 NS IgH/FGFR3 translocation 20.4%11/54 23.9%66/276 NS IgH/MAF translocation 4.4%2/45 3.9%8/204 NS 1q21 abnormality by FISH 45.7%21/46 53.6%103/192 NS P53 deletion by FISH 25.0%13/52 11.826/221 0.014 overall response rateORR 78.6% 93.3% 0.001 Plasma cell leukemia 2.8% 5.0% NS 90 * The same trend can be seen in patients with or without s-EMD at diagnosis 3.2 EMD at diagnosis Among the 72 patients with EMD at diagnosis, only 4 of 143 patients 2.8%were diagnosed before year 2003, and 68 of 691 cases9.8% were diagnosed after year 2003. 40 patients55.6% - 3 - 中国 科 技 论 文 在 线////. 95 were classified as sEMD. 50 of 72 patients 69.4% had a single plasmacytoma. 13 patients (18.1% )had three or more sites affected. Sites of EMD were showed in table 2. Induction therapy consisted of thalidomide/lenalidomide in 33 patients 45.8% and bortezomib in 34 47.2% patients. After induction, 9 patients 12.5% received autologous stem cell transplantation ASCT. Radiotherapy on plasmacytoma was performed in 4 patients 5.6%. Of 56 assessable 100 patients, 44 78.6% achieved at least partial response, among whom 19 33.9% achieved complete responses. The response rate was significantly lower compared to patients without EMDIn patients with EMD at diagnosis, sEMD in three or more sites and pleura spread were negatively correlated with treatment response rate3.3 EMD during follow-up 105 Among the 28 patients with EMD spread during follow-up, 24 patients85.7% were classified as sEMD. 4/ 28 patients 14.3% had a single plasmacytoma, while 10 patients 35.7% had three or more sites involved. Sites of EMD were showed in table 2. EMD spread in 10 cases35.7% was not associated with marrow progression. Multivariate analysis demonstrated that EMD spread during follow-up was correlated with EM presentation at diagnosis HR 8.709,P0.001, IgD 110 subtypeHR 5.107,P0.002 and light chain type of λ HR 3.645,P0.012Figure 1. Because of the small number of patients available, analysis showed no correlation between EMD relapse/progression and cytogenetic parameters. But we noticed that in 5 of 28 EMD relapse/progression patients available for analysis of P53 deletion/mutation, 4 were positive during the disease course, with 2 found positive at diagnosis and 2 found positive at the time of disease 115 progression. Prior ASCT HR 1.232, bortezomib HR 0.697 and thalidomide/lenalidomide HR 1.112 had no effect on the risk of EMD spread Table 2. Sites of EMD EMD location EMD at diagnosis72 cases EMD during follow-up28 cases % of affected patients % of affected patients soft tissue 6184.7% 2692.9% pleura 1520.8% 725% liver and/or spleen 34.2% 13.6% skin 34.2% 27.1% central nervous system 34.2% 27.1% lymph nodes 34.2% 13.6% 3.4 Outcomes of patients with EMD 120 Of the 811 patients with complete follow-up data, 348 patients 42.8% were dead, with a median OS of 39.6 months. In the whole population, conventional prognostic factors such as ISS stage and cytogenetic parameters P53 deletion/mutation, FGFR3/IgH translocation, and chromosome 13 aberration showed good correlation with the outcome. Survival analysis showed that both EMD presenting at any time or at diagnosis and sEMD were negatively correlated with 125 patients’ outcomes both OS and TTP Figure 2. However, only sEMD at diagnosis retained its prognostic significance in the multivariate analysis. The OS of patients with and without sEMD at diagnosis were 16.5 and 40 months, respectively P0.001, and the TTP of the two groups were 11.5 and 25 months, respectively P0.001. Within the population with EMD at diagnosis, sEMD, ?3 sites and pleura spread were both correlated with worse outcome in the single variate analysis130 Multivariate analysis showed that sEMD was negatively correlated with OS HR 4.08, P0.031 and pleura spread had negative prognostic impact on both OS and PFS HR 4.517 and 6.346, respectively, P?0.001 We evaluated the outcomes of patients according to their treatments received. For treatments with - 4 - 中国 科 技 论 文 在 线////. thalidomide/lenalidomide or bortezomib, EMD at any time and EMD/sEMD at diagnosis retained 135 their negative effects on both response rate and survival TTP and OS. In contrast, for ASCT/HDT treatment, the response rate and survival TTP and OS were comparable between patients with or without EMD/sEMDFigure 3 and Figure 4. Among patients presenting with EMD at diagnosis, the 9 MM patients treated with ASCT seemed to have better OS and TTP compared to patients without HDT treatment OS: not reach versus 23 months, P 0.098; TTP: 140 not reach versus 21 months, P 0.137, though the difference was not significant. The same trend was seen in the population with EMD at any time, and the population with sEMD at diagnosisA Events/N5-year estimate light chain type of λ18/34611.6% light chain type of κ 5/362 2.6% P0.002 B Events/N5-year estimate sEMD at diagnosis7/37 70.4% no sEMD at diagnosis 20/720 6.8% P0.001 C Events/N5-year estimate IgD subtype 5/2232.0% Non-IgD subtype 21/713 7.5% P0.001 - 5 - 中国 科 技 论 文 在 线////. Figure1: Cumulative incidence of EMD relapse/progression by baseline features145 B A 150 155C D160165 170 Figure 2: Survival according to the presenting of EMD:TTP A and OSB of the patients with sEMD at diagnosis or not; TTP C and OSD of the patients with EMD at any time or not175 Figure 3: OS according to receiving treatment of HDT or not: A OS of the patients with EMD at diagnosis or - 6 - 中国 科 技 论 文 在 线////. not; B OS of the patients with sEMD at diagnosis or not A 180 185 190 195 B 200 205 210Figure 4: TTP according to receiving treatment of HDT or not: ATTP of the patients with EMD at diagnosis or 215 not; BTTP of the patients with sEMD at diagnosis or not4 Discussion Extramedullary plasmocytoma was a rare event in MM. However in recent years it has been reported with an increasing frequency worldwide, with a notable discrepancy compared with the [1-5] bone marrow myelomaTo investigate the incidence, the clinical features, and the prognosis of 220 EMD in MM in the mainland of China, we analyzed 834 consecutive patients in a single centerOverall, 8.6% patients had EMD at diagnosis2.8% before year 2003 and 9.8% after, and 3.4%[1-4,8] patients had EMD during follow-up. This is in accordance with most large cohortsHowever - 7 - 中国 科 技 论 文 在 线////. an epidemiologic study in Taiwan showed a 22% prevalence of EMD at diagnosis in a duration of[4] 25 yearsMore epidemic data may help to resolve the discrepancy in the future225 In this study we adopted a widely accepted definition of EMD, while some researchers suggested a more strict definition of EMD that does not include tumor masses arising from bone [2,7] lesions in the cranial vault, skull base, nose, or paranasal sinusesThe incidences of sEMD was 4.8% at diagnosis and 2.9% during follow-up in our report. To investigate the difference between the two definitions, we compared the clinical features of sEMD versus non-sEMD230 Results showed that sEMD was negatively correlated with patients’ response rates, and was the only independent adverse factor in prognosis. It was believed that EMD arising from the bone in a great part represents the increased tumor load of classical MM, while sEMD may arise in a different biologic background. To prove this hypothesis, more genetic studies of EMD from different loci should be performed235 Analysis of the clinical features of EM MM showed significant difference from the rest of MM population. Patients with EMD at diagnosis tended to be much younger, with IgD subtype, in ISS stage ?, and to have higher levels of HB and LDH. These findings are in accordance with[1,4,9-12] previous reports in the literatureInterestingly, we also noticed EM MM patients showed more P53 abnormality. It is known that aberrant P53 is an adverse risk factor in MM and is related [13-15] 240 to the progression of the diseaseUp to now, its negative effect on prognosis can not be overcome by conventional chemotherapy or auto-transplant after HDT. Neben K et al suggested that administration of bortezomib before and after HDT could improve the outcome of patients[16] with 17p deletionBecause of the low incidence of EMD and the limited data of cytogenetic[17-19] parameters, most previous studies failed to find a correlation between the twoRecently 245 Usmani et al analyzed 1965 MM cases using gene-risk models and found that EMD was related to GEP TP53 deletion in univariate analysis. But the correlation was lost in the multivariate analysis [2]Billecke L et al also found that sEMD and non-sEMD both showed remarkably higher incidences of del17p13 32% for sEMD and 27% for non-sEMD than reported in BM [20] investigations of MM patientsSheth N et al studied P53 abnormalities in paired biopsies from 250 medullary and extramedullary sites of 12 MM patients with EMD. It was found that P53 nuclear accumulations were detected in myeloma cells derived from the EM sites in 9 75% of the 12 [21] cases, whereas only in 1 of 8% 12 bone marrow myeloma specimens P 0.003These studies, together with our results, suggest that aberrant P53 plays an important role in the occur