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Circulating Plasma Cells By Routine Complete Blood Count Identify Patients With Similar Outcome As Plasma Cell Leukemia
Abstract
Introduction
Plasma cell leukemia (PCL) is a plasma cell dyscrasia that predicts for a shortened survival. World Health Organization (WHO) criteria require the presence of ≥20% circulating plasma cells (CPC) in the peripheral blood, and an absolute plasma cell count ≥2,000/µl (microliter). These criteria for PCL were established by Noel and Kyle in 1974, but subsequent studies to further validate this cut off are lacking. Since the presence of any plasma cells in the peripheral blood is now known to be a poor-risk feature, we sought to compare the overall survival of patients (pts) with any CPC observed on routine complete blood count (CBC) and differential with those that meet the WHO criteria of PCL.
Methods
We evaluated pts that received hyper-CVAD (cyclophosphamide /vincristine/doxorubicin/dex); CBAD (cyclophosphamide/bortezomib/doxorubicin/ dex), and DT-PACE (dexamethasone/thalidomide/ cisplatin /etoposide / doxorubicin/ cyclophosphamide) chemotherapy at The University of Texas M. D. Anderson Cancer Center for multiple myeloma from 2003-2012. We included pts with circulating blasts, plasma cells, or plasmacytoid cells regardless of the percentage (%) and absolute count. Pts were excluded if blasts or plasma cells were seen transiently in the setting of leukopheresis, growth factor support, or during severe sepsis. Overall survival (OS) was defined from the first detection of CPC until death due to any cause. We treated the % of plasma cells in the CBC as a continuous variable in the range from 1% to 20%. Pts with plasma cells below the cut off were defined as the “low” group and their survival was compared to the pts with plasma cells above the cut off that was defined as the “high” group. We conducted a log rank test for difference in survival curves between the two groups for each cut off, and the results were verified with a Cox model and both results were identical.
Results
85 pts were identified with presence of any CPC or PCL diagnosed based on WHO criteria; 19 had primary PCL (pPCL) and 66 pts had secondary PCL (sPCL). At the time of diagnosis, 83 (2 with unknown values) pts had a median CPC of 4% and median absolute plasma cells of 178/µL. 73 pts had cytogenetic abnormalities by florescence in situ hybridization studies, including deletion/monosomy 13 in 32 pts, IgH gene rearrangement in 24 pts and TP53 deletions in 12 pts. 17/19 pts with pPCL received bortezomib based therapy and 14/19 underwent stem cell transplant.
26 pts met the WHO criteria of PCL at some point during their disease, including 11 who met criteria when plasma cells were first detected, and 15 who had CPC < 20% initially, but subsequently met WHO criteria. Of the remaining 57 pts that did not meet the WHO criteria for presence of both absolute plasma cell count and % plasma cells, 13 met one of the criteria during the course of their disease. 44 pts had CPC but did not meet either of the WHO criteria.
Survival data were available for 79/85 pts. Pts with pPCL (either by CPC or met at least one of the WHO criteria) had a median OS of 18.5 months. pPCL pts who only had CPC and did not meet either of the WHO criteria (n=5) had a median OS of 19 months; pPCL patients who met either or both of the WHO criteria (n=13) had a median OS of 18 months. Pts with sPCL (either by CPC or met at least one of the WHO criteria) had a median OS of 5 months (n=61). sPCL pts who only had CPC and did not meet either of the WHO criteria (n=39) had a median OS of 5 months; sPCL patients who met either or both of the WHO criteria (n=22) had a median OS of 4 months.
Based on evaluating plasma cell % as a dichotomous factor with cut-off ranging from 1% to 20%, there was no significant difference in overall survival based on specific levels of plasma cell percent, and verified with a Cox model, however with many cut-offs, the sample size was small potentially limiting analysis.
Conclusion
In our analysis of OS of pts having plasma cells in their peripheral blood, we did not find any statistically significant difference based on their degree of % plasma cells or absolute plasma cells at the time of diagnosis. This supports the hypothesis that, irrespective of quantity, the presence of any plasma cells in the CBC is a poor prognostic indicator, with a similar natural history and a uniformly poor OS. While these findings will need to be validated in a larger, independent dataset, we would propose that these initial data support redefining the diagnostic criteria of PCL to include any pt with CPC observed in a routine CBC.
Disclosures
No relevant conflicts of interest to declare.
... Recent studies have shown that even lower percentages of PCs in peripheral blood may be related to an adverse prognosis in newly diagnosed MM patients, reflecting the need for re-definition of the diagnostic cut-off [19,[22][23][24]. As it has been proven, the presence of ≥5% circulating PCs in patients with MM has similar adverse prognostic impact as PCL defined traditionally, so that this level may be proposed as a new cut-off point [24]. ...
... As it has been proven, the presence of ≥5% circulating PCs in patients with MM has similar adverse prognostic impact as PCL defined traditionally, so that this level may be proposed as a new cut-off point [24]. Interestingly, Rupin et al. in their small retrospective study stated that, irrespective of quantity, the presence of any PC in the peripheral blood is a poor prognostic indicator [22]. Taking into consideration all the issues mentioned above, the International Myeloma Working Group (IMWG) is working on a new definition of PCL. ...
Plasma cell leukemia (PCL) is an aggressive hematological malignancy characterized by an uncontrolled clonal proliferation of plasma cells (PCs) in the bone marrow and peripheral blood. PCL has been defined by an absolute number of circulating PCs exceeding 2.0 × 109/L and/or >20% PCs in the total leucocyte count. It is classified as primary PCL, which develops de novo, and secondary PCL, occurring at the late and advanced stages of multiple myeloma (MM). Primary and secondary PCL are clinically and biologically two distinct entities. After the diagnosis, treatment should be immediate and should include a proteasome inhibitor and immunomodulator-based combination regimens as induction, followed by stem cell transplantation (SCT) in transplant-eligible individuals who have cleared the peripheral blood of circulating PCs. Due to the rarity of the condition, there have been very few clinical trials. Furthermore, virtually all of the myeloma trials exclude patients with active PCL. The evaluation of response has been defined by the International Myeloma Working Group and consists of both acute leukemia and MM criteria. With conventional chemotherapy, the prognosis of primary PCL has been ominous, with reported overall survival (OS) ranging from 6.8 to 12.6 months. The use of novel agents and autologous SCT appears to be associated with deeper response and an improved survival, although it still remains low. The PCL prognostic index provides a simple score to risk-stratify PCL. The prognosis of secondary PCL is extremely poor, with OS of only 1 month.
... It is seen that even lower levels of circulating clonal plasma cells in peripheral blood below the World Health Organization's threshold for defining plasma cell leukaemia had a poor prognosis comparable with that of the strictly defined plasma cell leukaemia. [4,5] ...
Plasma cell leukaemia (PCL) is a rare neoplasm and is the most aggressive form in the spectrum of multiple myeloma. It is classified as primary or de novo and secondary in patient of multiple myeloma. Organomegaly and bleeding tendency are common in primary PCL and less in secondary as in our case. Osteolytic lesions are seen less frequently in Plasma cell leukaemia. The diagnosis is made by an emphasis on the morphological appearances and confirmation by serum electrophoresis and immunophenotyping. In our case the presence of plasma cells in peripheral blood was more than 20 % in young patient at the age of 34 years which is very rare and is further confirmed by immunophenotyping
... In fact, recent studies have evidenced that even lower percentages of PCs in peripheral blood (i.e. ≥ 2-5%) may confer an adverse prognosis in newly diagnosed patients with MM, resembling that of PPCL and highlighting a possible future re-definition of the diagnostic cut-off [10][11][12][13]. ...
Introduction:
Primary plasma cell leukemia (PPCL) is one of the most aggressive hematological malignancies. The prognosis of PPCL patients remains poor, although some improvements have been made in recent years. Areas covered: In this review recent clinical and biological advances in PPCL are reported. Some recommendations for the practical management of these patients are provided, with a particular focus on the role of novel agents and transplant procedures. A brief description of the currently ongoing clinical trials with new drugs is also enclosed. Expert opinion: PPCL still represents a difficult challenge for all hematologists. Here the authors provide a personal view on how the current, generally unsatisfactory results in this neoplastic disorder could be improved. In particular, dedicated studies exploring alternative therapies are necessary and eagerly awaited. Such studies should possibly be based on new biological information that could be of help in identifying novel genetic biomarkers for risk stratification and new actionable molecular targets.
... Recent reports suggest that a lower degree of peripheral plasmacytosis could be sufficient to define this disease entity along with the associated poor clinical outcome. In two independent series of MM patients treated with novel agents-containing regimens, [5,6] circulating plasma cell levels as low as 1-2% predicted a survival similar to classically defined plasma cell leukemia. These findings need to be validated in larger cohorts, and it is not clear if a low degree of plasmocytosis represents a risk factor in MM or defines PCL. ...
Plasma cell leukemia (PCL) is a rare, but very aggressive, plasma cell dyscrasia, representing a distinct clinicopathological entity as compared to multiple myeloma (MM), with peculiar biological and clinical features. A hundred times rarer than MM, the disease course is characterized by short remissions and poor survival. PCL is defined by an increased percentage (>20%) and absolute number (>2 × 10⁹/l) of plasma cells in the peripheral blood. PCL is defined as ‘primary’ when peripheral plasmacytosis is detected at diagnosis, ‘secondary’ when leukemization occurs in a patient with preexisting MM. Novel agents have revolutionized the outcomes of MM patients and have been introduced also for the treatment of PCL. Here, we provide an update on biology and treatment options for PCL.
Due to the rarity and fulminant nature of the condition, there are limited data driving dialogue for optimal treatment strategies for plasma cell leukemia (PCL). Additionally, the current diagnostic definition of PCL has not been prospectively studied which may result in delays to initiating early aggressive treatment due to underdiagnosis. Due to the rarity and fulminant nature of the condition, there are limited data driving dialogue for optimal treatment strategies for plasma cell leukemia (PCL). Additionally, the current diagnostic definition of PCL has not been prospectively studied which may result in delays to initiating early aggressive treatment due to underdiagnosis.
BACKGROUND
Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder characterized by circulating plasma cells and a poor prognosis. Although patients who have pPCL benefit from the use of stem cell transplantation (SCT) and novel agents, their prognosis remains inferior to that of patients who have myeloma.
METHODS
This was a retrospective analysis of 38 consecutive patients with pPCL who were diagnosed between October 2005 and July 2016 and were registered in the Winship Cancer Institute of Emory University database. Baseline characteristics as well as data about treatment and survival outcomes were collected.
RESULTS
The median patient age at diagnosis was 58 years. All patients received a bortezomib‐based induction regimen, and 92% received both bortezomib and an immunomodulatory drug (thalidomide or lenalidomide); in addition, 74% of patients underwent autologous SCT (ASCT), and 61% received maintenance therapy. The best response to first‐line therapy was a partial response or better in 87% of patients, and 45% had a complete response (CR). The achievement of ≥CR was a predictor for prolonged progression‐free survival (PFS) and overall survival (OS). The median PFS was 20 months, and the median OS was 33 months. PFS was prolonged in patients who underwent ASCT compared with those who did not undergo ASCT (25 vs 6 months; P = .004), and patients who received maintenance therapy after ASCT had prolonged median PFS (27 vs 11 months; P = .03) and a trend toward prolonged OS (median, 38 vs 22 months; P = .06) compared with those who did not receive maintenance therapy.
CONCLUSIONS
The current data support the use of regimens combining novel agents in the upfront treatment of patients with pPCL as well as the role of ASCT and maintenance therapy for long‐term disease control.
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