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Primary plasma cell leukemia
A Surveillance, Epidemiology, and End Results database analysis between 1973 and 2004
Version of Record online: 28 OCT 2009
Copyright © 2009 American Cancer Society
Volume 115, Issue 24, pages 5734–5739, 15 December 2009
How to Cite
Ramsingh, G., Mehan, P., Luo, J., Vij, R. and Morgensztern, D. (2009), Primary plasma cell leukemia. Cancer, 115: 5734–5739. doi: 10.1002/cncr.24700
- Issue online: 2 DEC 2009
- Version of Record online: 28 OCT 2009
- Manuscript Accepted: 20 APR 2009
- Manuscript Revised: 3 APR 2009
- Manuscript Received: 13 JAN 2009
- plasma cell leukemia;
- multiple myeloma;
- Surveillance, Epidemiology, and End Results Program;
- risk factors
Primary plasma cell leukemia (PCL) is a rare plasma cell disorder, and current knowledge regarding survival in this disease is limited to small series of patients. Although there has been significant improvement in the survival of patients with multiple myeloma (MM) over the past few decades, it is not known whether there has been a similar trend for PCL.
The authors analyzed the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the characteristics and survival of patients who had PCL compared with those of patients who had MM.
Among 291 patients with PCL, the median age was 67 years (range, 19-98 years), the distribution of men and women was nearly equal, and the majority of patients were white (79.4%). The median overall survival (OS) was 4 months and the median disease-specific survival (DSS) was 6 months for patients with PCL; the 1-year, 2-year, and 5-year OS rates were 27.8%, 14.1%, and 6.4%, respectively. There were no survival differences noted according to sex or race. Patients aged <60 years were found to have a better median OS compared with patients aged ≥60 years (median OS, 7 months vs 3 months; P = .007), although the 5-year OS was equally poor in both groups (6.3% vs 6.4%, respectively). During the same period, 49,106 patients with MM were identified. Unlike MM, in which there has been a modest but statistically significant improvement in OS and DSS noted over time, no significant improvement was evident for PCL.
The poor long-term outcome and the lack of survival improvement in PCL suggest the need for better therapeutic options for these patients. Cancer 2009. © 2009 American Cancer Society.
Plasma cell leukemia (PCL) is a rare plasma cell disorder with a dismal prognosis. The diagnostic criteria for PCL is a plasma cell count >2000 if the total blood leukocyte count is >10,000/μL or 20% plasma cells if the circulating white cell count is <10,000/μL.1 PCL is considered secondary if it is preceded by a diagnosis of multiple myeloma (MM) and primary if there is no prior history of MM. Secondary PCL usually arises late in the course of MM and has a worse prognosis compared with primary PCL.2
There have been several treatment innovations in MM over the last 20 years, including the use of autologous stem cell transplantation and novel therapies including thalidomide, lenalidomide, and bortezomib.3, 4 These new treatment options have resulted in improved survival, which has been demonstrated in large retrospective studies, including single-institution studies, multicenter studies, and Surveillance, Epidemiology, and End Results (SEER) database analyses.3-5 It remains unknown whether similar trends can be observed in PCL. The objective of the current study was to evaluate demographics and survival in a large cohort of patients with PCL and compare the findings with those in patients with MM.
MATERIALS AND METHODS
We included all patients with PCL and MM who were diagnosed in the SEER database between 1973 and 2004. The SEER Program classifies histology and topography according to the International Classification of Diseases for Oncology (ICD-0). We included all patients with PCL (ICD-0 code 9733) and MM (ICD-0 code 9732). Patients were divided into cohorts based on age, sex, race, and time since diagnosis.
The Pearson chi-square test for 2-way contingency tables was used to exhibit the distributions of death causes among groups of risk factors. A P value <.05 from a chi-square test indicated a significantly uneven distribution. Overall survival (OS) was defined as the time interval between diagnosis and the event of death from any cause (cancer, cardiovascular, myeloma, and others). Disease-specific survival (DSS) was defined as the interval from entrance to the event of death from PCL or MM. The Kaplan-Meier product-limit method was used to estimate survival functions for groups in each risk factor. Kaplan-Meier survival curves graphically illustrated survival differences among groups for a risk factor, and a statistically significant difference was indicated by a P value <.05 from log-rank tests. To determine the independent prognostic ability of each risk factor, multivariate survival analysis was performed using a Cox proportional hazards model. Hazards ratios of risk factors and the corresponding 95% confidence intervals were reported accompanied with P values from Wald chi-square tests. The proportional hazards assumption was examined with graphic plots of model residuals.
The SEER database identified 291 patients with PCL who were diagnosed between 1973 and 2004. The median age was 67 years (range, 19-98 years). At the time of diagnosis, 63.6% of patients were aged ≥60 years. There were no significant differences noted with regard to sex, and the most common race was white (79.4%). We also identified 49,106 patients with MM during the same time period. MM patients had a median age of 70 years (age range, 9-106 years) and an increased number of patients aged >60 years compared with the patients who had PCL (75.5% vs 63.6%; P < .001). There were no other significant differences in demographic variables noted between patients with PCL and MM (Table 1).
|Characteristic||No. of Patients (%)||P*|
|Plasma Cell Leukemia||Multiple Myeloma|
|No. of patients||291||49,106|
|Median age [range], y||67 [19-98]||70 [9-106]||<.001|
|Age group, y|
|<60||106 (36.4)||12,019 (24.5)|
|≥60||185 (63.6)||37,087 (75.5)|
|Women||150 (48.5)||23,292 (47.4)||.7125|
|White||231 (79.4)||38,360 (78.1)|
|Black||51 (17.5)||8045 (16.4)|
|Other||9 (3.1)||2701 (5.5)|
|Year of diagnosis|
|1973-1980||46 (15.8)||6210 (12.6)|
|1981-1990||30 (10.3)||10,060 (20.5)|
|1991-2000||114 (39.2)||18,566 (37.8)|
|2001-2004||101 (34.7)||14,270 (29.1)|
The median OS was 4 months for patients with PCL; and the 1-year, 2-year, and 5-year OS rates were 27.8%, 14.1%, and 6.4%, respectively. Patients aged <60 years had significantly better OS compared with patients aged ≥60 years (Fig. 1). In patients aged <60 years, the median OS was 7 months compared with 3 months in patients aged ≥60 years. The 1-year and 2-year OS was significantly better in patients aged <60 years (41.8% and 21%, respectively) compared with patients aged ≥60 years (20.2% and 10.4%, respectively) (P = .002). However, the 5-year survival rates appeared to be similar (aged <60 years and 6.3% vs aged ≥60 years and 6.4%). There were no survival differences noted with regard to sex or race (Table 2).
|Factor||Overall Survival||P||Disease-Specific Survival||P|
|HR (95% CI)||HR (95% CI)|
|Age ≥60 y/<60 y||1.46 (1.13-1.89)||<.01||1.4 (1.06-1.86)||.02|
|Sex: Men/women||1.1 (0.86-1.41)||.43||1.07 (0.82-1.4)||.61|
|Race: White/black||1.3 (0.94-1.81)||.11||1.27 (0.89-1.8)||.19|
|Year of diagnosis*|
|1981-1990||1.24 (0.78-1.99)||.36||1.35 (0.81-2.24)||.25|
|1991-2000||1.32 (0.93-2.89)||.12||1.29 (0.87-1.9)||.2|
|2001-2004||1.35 (0.92-1.97)||.12||1.39 (0.92-2.1)||.12|
The median DSS was 6 months for patients with PCL, and 76.3% of the patients died of their disease. Patients aged <60 years were found to have a better median DSS (9 months) compared with patients aged ≥60 years (4 months) (P = .01).
The median OS for patients with MM was 2.08 years, and the median DSS was 3 years. A comparison of OS and DSS for patients with PCL using Kaplan-Meier survival curves for different time periods between 1973 and 2004 revealed no improvements with time. This is in contrast to improving OS and DSS for patients with MM noted during the same time interval using Kaplan-Meier survival curves (Table 3) (Fig. 2).
|Multiple myeloma (N=48,371)|
|No. of patients||6074||9869||15,542||14,125|
|Median overall survival, y||1.75||2.00||2.17||2.17||<.0001|
|Median disease-specific survival, y||2.42||2.92||3.0||3.5||<.0001|
|Plasma cell leukemia (N=252)||N=46||N=30||N=114||N=101|
|No. of patients||46||30||114||101|
|Median overall survival, mo||7||2.5||5||4||.53|
|Median disease-specific survival, mo||12||2.5||6||5||.57|
To our knowledge, this is the largest study evaluating the demographics and survival of patients with PCL. The median age of primary PCL patients in the current study was 67 years compared with 54.5 years in a large single-institution cohort.2 PCL has a dismal prognosis, as demonstrated in several case series.2, 6-10 In what to our knowledge was the largest previously published series, the median survival was 11.2 months.2 In the current study, the median OS of 4 months for PCL was significantly lower compared with the previously reported survival, and these differences likely reflect selection bias. We identified younger age as a favorable prognostic factor for PCL. Compared with patients wth MM, the median survival for patients with PCL was significantly lower throughout the diagnostic periods. Unlike MM, in which there was a modest but statistically significant improvement in survival since 1973, outcomes for patients with PCL remained essentially unchanged.
The poorer outcomes for patients who have PCL compared with patients who have MM may be explained by biologic differences. Garcia-Sanz et al reported a series of 26 patients who had primary PCL and compared their clinical and biologic differences with those of patients who had MM.6 In that study, patients with PCL were more likely to have extramedullary disease, increased disease burden, cytopenias, and renal dysfunction. CD20 expression was observed in approximately 50% of patients with PCL compared with 17% of patients with MM. CD56, CD9, CD117, and human leukemic D-related antigen were less common in PCL compared with MM. Chromosomal changes using fluorescence in situ hybridization (FISH) studies revealed significant differences between patients with PCL and those with MM, including an increased percentage of monosomy 13 (86% vs 26%) and a decreased frequency of trisomy 6 (0% vs 32%) and monosomy 9 (0% vs 52%).2 Karyotype analysis performed in a series of 40 patients with primary PCL revealed a high rate of complex and pseudodiploid or hyperdiploid karyotype in patients with PCL in contrast to higher hyperdiploidy observed in patients with MM. There also was a higher incidence of immunoglobulin H gene rearrangement noted on FISH studies in patients who had PCL (80%) compared with patients who had MM (60%).7
The unusually increased survival for patients diagnosed with PCL before 1980 may have been caused by disease misclassification, and some patients actually may have had MM instead of PCL. Nevertheless, despite publication of the first version of the ICD-01 in 1976, 3 years after the first SEER release, the initial SEER classifications were based on the Systematized Nomenclature of Pathology, which was first published in 1965.11 During this time, the criteria and codes for PCL have undergone no significant changes. Therefore, if there were cases of misclassified tumors, they most likely were caused by of problems in disease reporting rather than diagnostic criteria. The number of patients increased over time because of the expansion of the SEER database, which included 10% of the US population from 1973 to 1991, 14% of the US population from 1992 to 1999, and 26% of the US population since the year 2000.
To our knowledge, there are relatively few studies reporting survival with conventional therapy for PCL10 and no multicenter prospective studies, resulting in a lack of established therapies for this population. Dimopoulos et al reported a median survival of 2 months in patients with PCL who received the combination of melphalan and prednisone. Reports on the use of novel agents, such as thalidomide, lenalidomide, and bortezomib,12-18 remain mostly restricted to case reports. However, Musto et al described a 92% response rate in 12 patients who were treated with bortezomib. In that study, the median progression-free survival and OS were 8 months and 12 months, respectively.14 Better results have been achieved with intensive chemotherapy. Dimopoulos et al reported a median survival of 20 months with intensive chemotherapy compared with 2 months in patients who received oral melphalan and prednisone.10 A report on stem cell transplantation in 15 patients, including 6 autologous transplantations and 9 allogeneic transplantations from the International Blood and Marrow Transplant Research database, identified 3 long-term survivors.19 In a more recent report from a large, retrospective European analysis of 272 patients with primary PCL who underwent autologous stem cell transplantation, the median survival was 25.7 months.20 Unfortunately, the lack of data regarding therapeutic agents used in the SEER database prevents the analysis of treatment changes over time and resulting effects on outcome.
In conclusion, PCL continues to be associated with a dismal long-term outcome. Unlike MM, survival with PCL has not improved over time. Prospective multicenter clinical trials exploring more aggressive regimens, including the combination of chemotherapy, immunomodulatory drugs, proteasome inhibitors, and other novel compounds, may be necessary to increase the complete response rates and survival in patients with this rare and highly lethal disease.
Conflict of Interest Disclosures
The authors made no disclosures.
- 1International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003; 121: 749-757.
- 7Cytogenetic, interphase, and multicolor fluorescence in situ hybridization analyses in primary plasma cell leukemia: a study of 40 patients at diagnosis, on behalf of the Intergroupe Francophone du Myelome and the Groupe Francais de Cytogenetique Hematologique. Blood. 2001; 97: 822-825., , , et al.
- 11National Cancer Institute, Surveillance, Epidemiology, and End Results Program. Codes for primary site and histology type. Cancer Surveillance, Epidemiology, and End Results reporting, October 1975. Available at: http://seer.cancer.gov/manuals/historic/ps_hist_1975.pdf. Accessed on January 10, 2009.
- 20Primary plasma cell leukaemia and autologous stem cell transplantation [abstract]. Blood (ASH Annual Meeting Abstracts). 2007; 110: 731. Available at: http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;110/11/731. Accessed on January 10, 2009., , , et al.