Diagnosis Of Plasma Cell Leukemia Research Articles

Single-Center Experience of Patients with Plasma Cell Leukemia in the Era of New Therapeutics

Introduction: Plasma cell leukemia (PCL) can occur de novo as primary PCL (pPCL), or in patients with prior diagnosis of multiple myeloma (MM) as secondary PCL (sPCL). In 2021, the diagnostic criteria have been revised, establishing a new cut-off of ≥5% plasma cells in the peripheral blood. Lacking specific clinical trials, PCL is treated similarly to MM; however, outcome for patients with PCL remains poor. Here, we report outcomes for patients with pPCL and sPCL in the era of novel agents. Methods: We performed a retrospective analysis and identified 19 patients (11 pPCL, 8 sPCL) who have been treated for PCL between 2010 and 2022 at University Hospital Essen. Results: Patients with pPCL had a median overall survival (OS) of 37.8 months (95% CI: [15.4; 52.3] months) from diagnosis, with a median time to next treatment (TTNT) of 18.4 (2.0; 22.9) months. All patients were treated with a proteasome-inhibitor (PI)-based induction therapy, and the majority was consolidated with an autologous stem cell transplantation (SCT). Five of these patients received a tandem transplantation. Patients with sPCL had a median OS of only 1.5 months after diagnosis of PCL. Only 1 patient achieved a remission with daratumumab and subsequent allogenic SCT. Conclusion: With our study, we add evidence for a PI-based induction therapy followed by a consolidating autologous SCT for patients with pPCL and give further evidence that a tandem transplant concept might be beneficial. The diagnosis of sPCL remains devastating and needs new therapeutic approaches.

Application of the sysmex XN – 3100 automated hematology system in the diagnosis of plasma cell leukemia – case report

Application of the sysmex XN – 3100 automated hematology system in the diagnosis of plasma cell leukemia – case report

Distinct Genetic Features in Peripheral Blood Represent the Characteristics of Circulating Plasma Cells in Primary Plasma Cell Leukemia

Clonal plasma cells in peripheral blood (PB) are crucial for diagnosing plasma cell neoplasm. The diagnostic criteria for plasma cell leukemia (PCL) have recently been revised to 5% or more circulating plasma cells (CPCs) in PB. Considering that CPCs are an independent worse prognostic factor in multiple myeloma (MM), elucidating how many CPCs are sufficient for distinguishing patients between PCL and other plasma cell neoplasm is important yet uncertain. These CPCs have been recently discussed in MM, characterized by more immature phenotype, clonogenic potential, and high expression of cancer stem cell (CTC) markers. Though the exact mechanism of peripheral circulation still needs further studies, MM CTCs are considered subclones of bone marrow (BM) plasma cells. On the other hand, previous studies regarding PB plasma cells in primary PCL (pPCL) have been mainly focused on similar characteristics to BM plasma cells. Considering significant prognostic differences based on CPCs, PB from PCL patients should have distinct features. Previous studies on PCL revealed that high genetic heterogeneity and accumulation of diverse high-risk genetic abnormalities eventually led to the disease. Therefore, we aimed to investigate the genetic profile of CPCs in PCL to exhibit proper evidence for diagnostic criteria and improve the current practices. We retrospectively identified patients diagnosed with PCL from 2015 to 2017 at Seoul National University Hospital. Our study population included 4 pPCL and 2 secondary PCL (sPCL) patients. We retrospectively collected patients' clinical information and laboratory test results and performed targeted sequencing using the NGS panel of 647 genes related to hematologic malignancies. In all analyzed samples, 51 in PB and 40 variants in BM were detected in pPCL. The median number of variants in pPCL patients was 11 per patient (range 5-25) in PB and 10 per patient (range 3-17) in BM. When comparing variant allele frequency (VAF) between the paired samples, there was a moderate correlation (R=0.44, P<0.05). Similarly, a moderate correlation was observed in both pPCL (R=0.41, P<0.05) and sPCL (R=0.47, P<0.05) groups. When comparing paired variants between PB and BM, 38 were commonly detected in both samples in pPCL patients. Fifteen variants were identified in only one of the two samples, 12 in PB and 3 in BM. Most variants showed a heterogeneous distribution of genes. We checked the paired samples using an Integrative genomics viewer. As a result, twelve pPCL and thirteen sPCL variants were identified in the paired samples. These variants were initially excluded in the filtering process because of low VAF. Consequently, three unique variants were identified in each pPCL and sPCL group, which were considered truly unique. In pPCL patients, MED12, VPS13B variant from PB, and ZMYM3 variant from BM were identified in one of the paired samples. In sPCL patients, unique variants were identified in ARID1A, FANCE, and TP53. In addition, we determined that PB VAF is higher than BM VAF in shared variants of pPCL patients. Conversely, BM VAF tended to be higher than PB VAF in sPCL. However, plasma cell% was generally higher in BM than PB, regardless of pPCL or sPCL. Therefore, the differences in the percentage of plasma cells between PB and BM samples cannot explain the unique variants detected in only one of the paired samples. pPCL is an aggressive disease characterized by a markedly high diversity of heterogeneous mutation distribution and high mutational burden. The clinical outcomes of pPCL are still poor in the novel agent era. There is an urgent need to improve the current diagnosis and treatment strategy. As shown in this study, CPCs in pPCL are not simply part of the malignant plasma cells shed from the BM but have characteristics distinct from them. In this study, we exhibited that PB variants had higher VAF than BM variants, and some unique variants were identified only in the PB samples. Conversely, in sPCL, more diverse variants were detected mainly in BM samples, and VAF was also higher in BM than PB. Considering unique variants detected in PB and the high genetic heterogeneity of the disease, PB should be included in the diagnosis of PCL to determine the exact genetic profile.

Racial Disparities in Plasma Cell Leukemia Outcomes Among Hospitalized Patients in the United States.

Plasma cell leukemia (PCL) is a rare, aggressive subtype of multiple myeloma (MM) with a poor prognosis. Prior studies have shown that racial disparities affect MM patients in various ways, which may affect patients' outcomes. In this study, we aimed to investigate racial differences in hospitalization outcomes for PCL using Nationwide Inpatient Sample data. Overall, hospitalization rates for PCL tended to decrease over the past decade. Among hospitalized patients with a primary diagnosis of PCL, there was no statistically significant association between race/ethnicity and hospitalization rates, between NH-White patients and NH-Black patients (OR 1.94; 95%CI 0.3-3.54, p 0.95), and Hispanic patients (OR 0.47; 95% CI 0.05-4.23, p 0.5). Additionally, there was no significant association between race/ethnicity and inpatient mortality. The overall lower incidence of PCL, more significant disease burden, and poor prognosis across all groups may contribute to our findings. With increasing evidence that PCL is cytogenetically distinct from MM, more investigation into biological and sociodemographic factors that affect healthcare utilization and treatment outcomes should be carried out.

High-Risk Gene Expression Subtype Provides Molecular Basis for Different Clinical Presentation of Primary and Secondary Plasma Cell Leukemia

Plasma cell leukemia (PCL) is rare but represents an aggressive, advanced form of multiple myeloma where neoplastic plasma cells (PCs) lose dependence on the bone marrow (BM) and circulate in the peripheral blood (PB). PCL is clinically defined by diagnosis of myeloma with ≥20% circulating plasma cells (CPCs), however, several groups have proposed a ≥5% CPC cutoff. PCL is classified as primary (pPCL) if it presents at myeloma diagnosis or secondary (sPCL) if it arises at a later progression event. These presentations of PCL are clinically distinct, with sPCL patients responding poorly to novel therapies and having inferior outcomes compared to pPCL patients. Despite recent advances in myeloma therapy, PCL prognosis remains poor, and the molecular drivers of PCL remain poorly understood.The MMRF CoMMpass study (NCT01454297) is a longitudinal, observational clinical study of 1171 newly-diagnosed myeloma patients. Tumors were characterized using whole genome (WGS), exome (WES), and RNA (RNAseq) sequencing at diagnosis and each progression event. PCs were isolated from BM-derived tumors and when >5% CPCs were detected, PCs were also isolated from the PB, creating a subcohort of patients with sequencing data from both the BM and PB compartments, with some patients assayed longitudinally.The percent CPCs determined using flow cytometry was reported for 982 patients at myeloma diagnosis and 194 patients at progression. Patients with 5-20% CPCs (median = 19 months) at diagnosis had poor overall survival (OS) outcomes compared to those with less than 5% CPCs (median = 95 months, p<0.001). No outcome difference was observed between patients with 5-20% and >20% CPCs (median = 41 months), confirming the findings of previous independent studies. A ≥5% CPC cutoff identified 947 myeloma, 29 pPCL, and 6 sPCL patients in the CoMMpass cohort. Compared to myeloma, pPCL and sPCL patients had poor OS (p<0.001), and after sPCL detection patients had a median OS of only 53 days (range = 0-169 days). For 10 pPCL patients, the percent CPCs was reported at diagnosis and at least one progression event, and patients with persistent CPCs (n = 5, median = 16 months, p<0.01) had poor OS compared to patients with no detectable CPCs at progression (n = 5, median not met, median follow up = 64 months). This underscores the benefit of early eradication of CPCs and repeated CPC measurements in pPCL.The proliferative (PR) gene expression subtype of myeloma has been previously described and defines a high-risk group of patients with diverse genetic backgrounds and inferior outcomes. For PCL patients, we determined the subtype of all BM and PB tumor samples characterized using RNAseq. There was high subtype concordance between paired BM and PB tumor samples (12/13, 92.3%). Overall, 6/23 (26.1%) pPCL patients were in the PR subtype, and PR pPCL patients had poor OS outcomes (median = 10 months, p<0.001) compared to non-PR pPCL patients (median = 55 months). PR emerged as a robust predictor of risk in pPCL, outperforming other molecular and clinical variables including high BM or PB PCs, plasmacytomas, renal failure, high LDH, high B2M, low platelets, t(11;14), del(1p), amp(1q), del(13q), and del(17p), suggesting that RNA subtyping CPCs may represent a non-invasive tool to predict risk in pPCL.At myeloma diagnosis, all sPCL patients with RNAseq data were classified in non-PR subtypes. However, at sPCL, 5/6 (83.3%) patients were in the PR subtype, indicating that sPCL is associated with transition to PR. Two sPCL patients that transitioned to PR acquired biallelic deletion of CDKN2C, and a third acquired biallelic deletion of RB1. Overall, a subset of pPCL (26.1%) but the majority of sPCL (83.3%) patients were in the PR subtype at PCL diagnosis, providing a molecular basis for the different clinical presentations observed between these two groups, including the highly-aggressive nature of sPCL. In summary, this study supports using a lower percent CPC cutoff to clinically define PCL and highlights the importance of repeated CPC measurements in prognosticating pPCL patients. Further, PR RNA subtype emerged as a predictor of risk in pPCL and, given that the majority of sPCL patients were in the PR subtype, provides a molecular basis for the different clinical features observed between pPCL and sPCL patients. DisclosuresMikhael: Amgen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Oncopeptides: Consultancy.

Spinal Disease Predicts CNS Involvement in Patients with Plasma Cell Leukemia

Background:Plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy with an incidence of approximately 1,200 patients per year in the United States with a median disease-specific survival of 6 months. PCL can either originate de novo (primary PCL) or as a secondary leukemic transformation of multiple myeloma (secondary PCL). A feared complication is infiltration of plasma cells into the central nervous system (CNS), meninges, or cerebrospinal fluid (CSF) which is challenging to treat and most often results in early mortality. We have observed a higher incidence of CNS disease among patients with PCL compared to multiple myeloma and were motivated to conduct a retrospective analysis to identify risk factors for the occurrence of CNS involvement among patients with primary or secondary PCL.Aim:Identify risk factors that should prompt clinicians to obtain a lumbar puncture and neuroimaging to screen for CNS involvement in patients with PCL.Methods:We conducted a retrospective analysis utilizing clinical data from patients who were found to have greater than 5% abnormal plasma cells in their peripheral blood detected by flow cytometry at the Seattle Cancer Care Alliance from 1990 to the present. IRB approval was obtained before data abstraction. Features extracted included laboratory values, radiographic data, pathologic data, treatment regimens, and response outcomes to chemotherapy regimens. The Fisher test was used identify risk factors associated with CNS disease. A P value <0.05 indicated a significantly asymmetrical distribution. The Kaplan-Meier product-limit method was used to estimate survival functions for groups in each risk factor. To determine the independent prognostic ability of each risk factor, multivariate survival analysis was performed using a Cox proportional hazards model.Results:To date, we have studied 21 patients which include 12 males and 9 females. Among this group, 18 patients were Caucasian, 2 patients were African American, and 1 patient's ethnicity was unknown. Four patients were diagnosed with primary PCL and 17 patients had secondary PCL. PCL was detected in the CSF by lumbar puncture in 5 patients (24%). The median overall survival of patients with CNS involvement from the time of PCL diagnosis was 192 days compared to 722 days in patients without CNS involvement. We reasoned that leukemic cells may translocate to the CSF more commonly in patients with spinal disease and evaluated the prevalence of spinal abnormalities. We found that all patients with CNS involvement and only 72% without CNS involvement had one or more spinal abnormalities which included degenerative disc disease, compression fractures of the spine, or lytic lesions of the spine (P < 0.05). We also found a significant correlation between CNS involvement by PCL and Caucasian race, a diagnosis of secondary PCL, and initial treatment with cyclophosphamide and dexamethasone (P < 0.05)Conclusions:In our study population, we observed a high incidence of CNS involvement (24%) among patients with PCL and identified multiple risk factors for the disease including evidence of malignant and non-malignant disease of the spine. These results suggest all patients with PCL should have spinal imaging performed at diagnosis and lumbar puncture should be considered for all patients, especially those with known spinal disease. DisclosuresNo relevant conflicts of interest to declare.

P-031: Importance of flow cytometry assessment of circulating plasma cells and its connection with clinical characteristics of primary and secondary plasma cell leukemia

<h3>Background</h3> Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell (PC) disorder characterized by the presence of circulating plasma cells (cPC) in peripheral blood (PB). Dismal outcome of PCL requires early diagnosis with appropriate analytical tools. Development of flow cytometry (FC) together with some newly analysed antigens may reveal some marker affecting the prognosis of PCL patients. <h3>Aim</h3> Analysis of phenotypic profile of cPC/PCs to find association with clinical outcomes and to evaluate the prognostic value of analyzed markers. <h3>Methods</h3> Total of 33 primary and secondary PCL patients were investigated. PCs quantity and phenotype profile was analysed by polychromatic FC in PB and bone marrow (BM). <h3>Results</h3> Flow cytometry is an excellent method for cPCs identification as a significantly higher number was identified by FC than by morphology. Thus FC should be incorporated as a diagnostic method for preventing late diagnosis of PCL. Although the phenotypic profile of both PCLs did not differ too much, with low level of CD19, CD20, CD27, CD28, CD81 and CD117 expression, some heterogeneously expressed antigens (CD44, CD56, CD200, nestin etc.) may contribute to identification of patients with later extramedullary involvement, high risk of progression and shortened survival. <h3>Conclusions</h3> FC should be incorporated in PCL diagnostics as not only exact method providing number of cPCs, which is surprisingly overcoming morphology assessment. Moreover, PCL phenotype profile could be connected to patient's diagnosis and possible prognosis as well. <h3>Funding</h3> Supported by grant AZV NV18-03-00203.

Efficacy of Daratumumab (Dara)-Based Regimens for the Treatment of Plasma Cell Leukemia (PCL)

Background: PCL is a rare and aggressive form of multiple myeloma (MM). It is associated with high risk cytogenetics, aggressive disease biology and a dismal prognosis. Dara has revolutionized the treatment of MM leading to deep and durable responses as a single agent and in combination with other agents. We evaluated the efficacy of Dara-based regimens in the treatment of PCL. Methods: Clinical charts of primary and secondary PCL patients treated at the Mayo Clinic Cancer Center between 2012-2019 were reviewed. Survival was analyzed with the Kaplan-Meier method. Plasma cell leukemia was defined by ≥5% peripheral blood plasma cells and/or absolute plasma cell count ≥0.5 x109/L (based on IMWG consensus statement).1 Results: Thirty-one patients were identified (55% female) with a median age at PCL diagnosis of 66 y (range 38-83). Fifteen (48%) had primary (p) PCL, while 14 (52%) had secondary (s) PCL. Nineteen (61%) had high risk cytogenetics with 11 (45%) del 17p, 4 (13%) t(14;16), 14 (45%) 1q amplification/duplication and 3(10%) t(4;14). Twelve (39%) had t(11;14). Eighteen (58%) patients had undergone autologous hematopoietic cell transplant (AHCT) with 12 (39%) having undergone AHCT following their diagnosis of PCL. Patients received a median of 2 prior lines of therapy (range 1-9) prior to receiving Dara-based regimens; 15 (42%) were refractory to an immunomodulatory agent (IMiD), 18 (58%) were refractory to a proteasome inhibitor (PI) and 10 (32%) were refractory to both. Twenty-eight (90%) were IMiD exposed, 31 (100%) were PI exposed. Eighteen (58%) were lenalidomide (R) refractory, 5(16%) were pomalidomide (P) refractory, 8 (26%) were carfilzomib (K) refractory and 13(42%) were bortezomib (V) refractory prior to receiving Dara. Four (13%) received Dara + chemotherapy, 8 (26%) received Dara + PI, 11 (35%) received Dara + IMiD, 5 (16%) received Dara + PI + IMiD and 4 (13%) received single agent Dara. Median follow up time was 26 months (m) (95% CI; 13-61) from diagnosis of PCL and 17m (95% CI; 10-23) from initiation of Dara. Overall response rate (ORR) to Dara-based regimens was 65% (20/31 ≥partial response). The median duration of response was 5.5m (95% CI; 5.6-12.7). The median time to first response was 1m (95% CI; 0.57-1.72) and the median time to best response was 1m (95% CI; 0.7-2.5). Since the start of Dara-based treatment, median progression free survival (PFS) was 4m (95% CI; 2-11, Figure 1A) and median overall survival (OS) was 9 m (95% CI; 5-21, Figure 1B). Patients with pPCL had superior PFS (19 m vs. 3m, p=0.0096) and OS (21 vs. 5m, p=0.0068, Figure 1C) following Dara-based treatment compared to those with sPCL, respectively. Being refractory to an IMiD, PI or both when receiving Dara did not affect PFS or OS. Patients with high risk cytogenetics had similar OS as compared to those with standard risk cytogenetics (8m vs.13m, p=0.89) following Dara-based treatment. After performing a landmark survival analysis at 3m, achieving ≥PR to a Dara-based regimen resulted in a trend towards superior OS (13m vs. 9 m, p=0.07, Figure 1D). Patients who underwent AHCT following the diagnosis of PCL had a superior OS (41m vs. 6m, p=0.020) however there were no PFS or OS differences whether Dara-based regimens were given before or after AHCT. Conclusions: Dara-based regimens induce a high ORR in patients with PCL with a rapid time to first response. However, the OS of patients with PCL, particularly sPCL remains dismal. Prospective trials for PCL patients using novel therapeutic strategies are warranted. 1Fernandez de Larrea, et al. Plasma Cell Leukemia: consensus statement on diagnostic requirements, response criteria, and treatment recommendations by the International Myeloma Working Group (IMWG). Leukemia. 2013; 27(4): 780-791. Disclosures Alhaj Moustafa: Acrotech: Consultancy. Kapoor:Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Cellectar: Consultancy; Celgene: Honoraria; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Dingli:Millenium: Consultancy; Sanofi-Genzyme: Consultancy; Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy. Ailawadhi:Phosplatin: Research Funding; Medimmune: Research Funding; BMS: Research Funding; Cellectar: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Takeda: Honoraria; Amgen: Research Funding; Celgene: Honoraria.

Plasma Cell Leukemia: A Retrospective Review of Cases at Monter Cancer Center/Northwell Health Cancer Institute 2014-2019

Title: Plasma Cell Leukemia: A retrospective review of cases at Monter Cancer Center/Northwell Health Cancer Institute 2014-2019 Background: Plasma cell leukemia (PCL) is an aggressive form of multiple myeloma with an acute onset and a median overall survival (OS) of 13 months.1,2 The defining criteria for PCL is in flux. Prior criteria supported diagnosis of PCL based on the presence of at least 20% clonal plasma cells in the peripheral blood3, while more recent data suggest the use of 5% based on cases with 5-19%.1 The benefit of novel targeted therapy in patients with PCL has begun to be elucidated.2,4 It is difficult to perform prospective studies on patients with PCL due to its fulminant course1,2, changing perspectives on diagnostic criteria1,2,3, and the fact that there is no clear guidance as to what treatment regimens work best in these patients. With the emergence of novel treatment options, such as Daratumumab, the impact on survival in these patients is important to evaluate.2 Aim: Our goal is to gather more information about the treatment approach to patients with PCL in an effort to identify regimens associated with better OS. We hypothesize that patients diagnosed with PCL have improved outcomes when treated with newer FDA approved therapies2, such as Daratumumab2,5,6, compared with traditional therapy. Methods: Using a retrospective study approach, we performed a chart review of patients diagnosed with PCL (primary and secondary) in the Northwell Health system from 2014-2019. Patients were identified at a single center site - Monter Cancer Center. Using the electronic medical records (EMR), patient chart analysis was done to collect baseline patient demographics, diagnoses, cytogenetics, fluorescence in-situ hybridization (FISH) results, laboratory results, treatment regimens, time to progression (TTP), progression-free survival (PFS), and OS. All included patients have a diagnosis of PCL, defined as per the Internal Myeloma Working Group (IMWG) diagnostic criteria.7,8,9 We will correlate survival outcomes (PFS and OS) to treatment regimen used. Results: A total of 10 patients with PCL has been identified. Fifty percent of the patients were male. Ages ranged from 47 - 82 years with a mean age of 65.2 and a median age of 62. Further analysis is in progress. Conclusion: PCL is an aggressive malignancy and an area of unmet need.2,4,7 Due to its fulminant course and the lack of prospective clinical trials in PCL, the optimal therapeutic approach remains controversial.2 This study may potentially highlight the impact of newer therapies for PCL. We propose that further multi-institutional prospective studies in PCL will be important to determine better treatment. References Ravi P, Kumar SK. (2018). Revised diagnostic criteria for plasma cell leukemia: results of Mayo Clinic study with comparison of outcomes to multiple myeloma. Blood Cancer, 8(12). Ngu S, et al. (2019). Primary plasma cell leukemia: A case report and review of the literature. Clin Case Rep, 7(9). Kyle RA, et al. (1974). Plasma cell leukemia. Report on 17 cases. Arch Intern Med, 133(5). Gonsalves WI, et al. (2018). Combination therapy incorporating Bcl-2 inhibition with Venetoclax for the treatment of refractory primary plasma cell leukemia with t (11;14). Eur J Haemotol, 100(2). Center for Drug Evaluation and Research. (2019, September 26). FDA approves daratumumab for transplant-eligible multiple myeloma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-transplant-eligible-multiple-myeloma. Center for Drug Evaluation and Research. (2020, May 1). FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-daratumumab-and-hyaluronidase-fihj-multiple-myeloma. De Larrea CF, Kyle RA, et al. on behalf of the International Myeloma Working Group (2013). Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria, and treatment recommendations by the International Myeloma Working Group (IMWG). Leukemia 27. Kumar SK, et al. (2016). International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 17(8), e328-e346. Gundesen MT, et al. (2019). Plasma Cell Leukemia: Definition, Presentation, and Treatment. Cur Oncol Rep. 21(1). Disclosures No relevant conflicts of interest to declare.

Bortezomib-based Regimens Improve the Outcome of Patients with Primary or Secondary Plasma Cell Leukemia: A Retrospective Cohort Study

Objective:The management experience for plasma cell leukemia (PCL) is still limited by PCL’s rare incidence and aggressive course. The goal of this study was to further identify the efficacy of bortezomib-containing regimens for PCL in Chinese patients.Materials and Methods:In this study, 56 consecutive PCL patients [14 primary PCL (pPCL) and 42 secondary PCL (sPCL) cases] were retrospectively enrolled and 42/56 patients received bortezomib-based regimens (BBRs), including 10/14 pPCL and 32/42 sPCL patients. The patients’ survival data, clinical information, and safety data were collected and analyzed.Results:In pPCL and sPCL patients, the overall response rate in the bortezomib group was 90.0% and 25.0%, respectively. The median progression-free survival from PCL diagnosis for pPCL and sPCL was 8.3 months vs. 2.9 months (p=0.043) and median overall survival (OS) from PCL diagnosis was 23.3 months vs. 4.0 months. The OS for patients receiving BBRs was significantly longer for both pPCL (8.3 vs. 1.2 months, p=0.002) and sPCL (4.3 vs. 1.1 months, p<0.001). In multivariate COX analysis, BBR treatment [p=0.008, hazard ratio (HR)=0.38, 95% confidence interval (CI)=0.19-0.77] and very good partial response or better (≥VGPR) (p=0.035, HR=0.19, 95% CI=0.04-0.74) were independent predictors of OS for sPCL patients. For pPCL patients, BBR predicted OS (p=0.029, HR=0.056, 95% CI=0.004-0.745) instead of ≥VGPR (p=0.272, HR=3.365, 95% CI=0.38-29.303).Conclusion:It was found that BBRs could significantly improve OS for both pPCL and sPCL patients.

2157 A Novel Case of Plasma Cell Leukemia Diagnosed by Endoscopic Ultrasound With Fine-Needle Biopsy

INTRODUCTION: There are numerous reports of endoscopic ultrasound (EUS) with fine needle aspiration (FNA) used to diagnose plasmacytoma of the GI tract but, to our knowledge, this is the first report of plasma cell leukemia diagnosed by EUS with fine needle biopsy (FNB). CASE DESCRIPTION/METHODS: A 78 year old woman presented with exertional chest pain, dyspnea, and unquantified unintentional weight loss. CT chest showed bilateral pleural effusions, left pleural soft tissue masses, and multiple paravertebral soft tissue masses. Thoracentesis was non-diagnostic. She re-presented a month later with the same symptoms. Repeat imaging revealed enlargement of the lesions and the decision was made to pursue EUS-FNB to obtain tissue for diagnosis. On endoscopy, the patient was found to have gastric erosions and two non-bleeding, ulcerated nodules in the fundus. Biopsies resulted in chronic gastritis and h.pylori. EUS described one enlarged lymph node visualized in the middle para-esophageal mediastinum, surrounded by hyperechoic hazy soft tissue. The lymph node measured 30.6 mm by 18.5 mm, with irregular, poorly defined margins. A second lymph node was found in the peri-pancreatic region, measuring 19.4 mm × 15 mm. FNB was performed. The pathology report from both nodes identified sheets of atypical plasma cell proliferation which stained positive for CD138 and CD56. Flow cytometry revealed a proportion of 40% IgG Lambda-restricted plasma cell population. These findings, taken in the context of a known M-spike and circulating atypical IgG lambda-restricted plasma cells on peripheral blood smear, established the diagnosis of plasma cell leukemia with soft tissue component. Unfortunately, it was felt that the patient would not be able to tolerate chemotherapy and she was sent home with hospice. DISCUSSION: While EUS-FNA is used frequently to evaluate lesions in the upper GI tract, this is the first reported case, to our knowledge, of EUS-FNB used to diagnose a plasma cell leukemia. In this case, the diagnosis was confirmed, not on peripheral smear or with cytology from pleural fluid, but from the biopsies we obtained. This is a good example of how EUS-FNB can often be the safest and easiest way to obtain adequate tissue samples from intrathoracic or intraabdominal lesions to facilitate diagnosis.

Hemorrhagic Skin Nodules and Plaques: A Diagnostic Clue to Underlying Primary Plasma Cell Leukemia.

Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder characterized by a malignant proliferation of plasma cells (PC) in blood and marrow. Cutaneous involvement is very rare in PCL. We present the case of a 45-year-old lady who presented with multiple hemorrhagic nodules and plaques in the skin. Her total leucocyte count was 2,00,200/cmm with 85% abnormal plasmacytoid cells in peripheral smear. Biopsy of the skin lesions revealed diffuse infiltration by plasma cells with ‘choked’ blood vessels. A diagnosis of plasma cell leukemia with cutaneous involvement was made. On the second day of admission, the patient expired probably because of intracranial bleed due to thrombocytopenia. Post-mortem bone marrow and liver biopsy also showed diffuse infiltration by plasma cells. Monoclonality of the cells was proven by demonstrating the production of only kappa light chains.

Plasma cell leukemia mimicking hairy cell leukemia

A42-year-old female presented with fever and shortness of breath, and was diagnosed with community acquired pneumonia. On presentation she was found to have a white cell count of 13 · 10/L, hemoglobin of 7.1 g/dL and platelets of 51 · 10/L. Peripheral blood smear showed left shift and many cells with hairy projections (56%) (See Fig. 1) that were positive for CD38 and CD138 by peripheral blood flow cytometry. Other laboratory findings included B-2 microglobulin of 15.3 mg/L with normal creatinine and calcium levels. Serum protein electrophoresis evaluation revealed monoclonal gammopathy (IgG-lambda) of 45.87 g/L. Urine protein electrophoresis showed the presence of Ig-G lambda as well as free-lambda light chain monoclonal bands. Bone marrow biopsy showed increased cellularity (95%) with increased number of plasma cells (45%). Flow cytometry showed 44% of the cells to have clonal plasma cell phenotype (CD38+ve, CD138+ve, CD20 ve, CD22 ve, and cytoplasmic lambda light chin restriction). A diagnosis of plasma cell leukemia was made and treatment was started with bortezomib, cyclophosphamide, and dexamethasone. The patient achieved partial remission. Treatment was followed by autologous bone marrow transplantation and then two cycles of lenalidomide and dexamethasone consolidation. The patient subsequently achieved complete remission. She has been on maintenance lenalidomide over the past six months and continues to be in complete remission.

A case of CD138−/CD19+/CD4+ IgD plasma cell leukemia

Plasma cell leukemia (PCL) is an uncommon and aggressive disease caused by the clonal proliferation of atypical plasma cells with phenotypical abnormalities similar to those seen in multiple myeloma (MM), although at different rates. Here, we report a case of IgD PCL with a very unusual CD138-/CD19+/CD4+ phenotype. Peripheral blood and bone marrow samples from a 37-year-old patient afflicted by an aggressive plasma cell dyscrasia were examined and analyzed by conventional morphology, flow cytometry, and immunohistochemistry. Analysis of peripheral blood fulfilled criteria for PCL (more than 20% and more than 2 × 10e9 cells/L). However, flow cytometry and immunohistochemistry phenotyping revealed that the cells were CD138-/CD38+/CD19+/CD4+/CD56-/CD117-. PCL is diagnosed on peripheral blood smear. Immunophenotyping is a tool that can be helpful in diagnosing difficult cases but its atypical findings should not prevent the appropriate PCL diagnosis in clinically and morphologically unquestionable cases. © 2014 International Clinical Cytometry Society.

A case of CD138-/CD19+/CD4+ IgD plasma cell leukemia.

Background: Plasma cell leukemia (PCL) is an uncommon and aggressive disease caused by the clonal proliferation of atypical plasma cells with phenotypical abnormalities similar to those seen in multiple myeloma (MM), although at different rates. Here we report a case of IgD PCL with a very unusual CD138-/CD19+/CD4+ phenotype Methods: Peripheral blood and bone marrow samples from a 37 year old patient afflicted by an aggressive plasma cell dyscrasia were examined and analyzed by conventional morphology, flow cytometry and immunohistochemistry. Results: Analysis of peripheral blood fulfilled criteria for PCL (more than 20% and more than 2x10e9 cells/L). However, flow cytometry and immunohistochemistry phenotyping revealed that the cells were CD138-/CD38+/CD19+/CD4+/CD56-/CD117- Conclusion: PCL is diagnosed on peripheral blood smear. Immunophenotyping is a tool that can be helpful in diagnosing difficult cases but its atypical findings should not prevent the appropriate PCL diagnosis in clinically and morphologically unquestionable cases. © 2014 Clinical Cytometry Society.

Plasma cell leukaemia and HIV co-infection: profile of patients and experience at Universitas Academic Hospital in Bloemfontein, South Africa

Plasma cell leukaemia (PCL) is a rare condition with high mortality. HIV-positive patients have a propensity to develop malignancy; however, the occurrence of PCL with HIV infection in South Africa has not been documented. We describe patients with PCL in Universitas Hospital in Bloemfontein, South Africa, and report two new cases of HIV infection concurrent with PCL. A retrospective case series of PCL patients (2006-2012) seen at our Clinical Haematology unit is reported. Patient files were used to obtain information. The median age of patients (n=9) was 51years, and 66.7% of cases were of African ethnicity. The condition was equally distributed between genders. Two patients were HIV positive. Both received combination antiretroviral therapy. The diagnosis of PCL was usually made as an incidental finding, subsequently confirmed on bone marrow aspirate and trephine. Deranged haematological and biochemical parameters, including severe anaemia, hypoalbuminaemia, and hyper-cellular bone marrow, were observed. Only one patient improved markedly on treatment, and remains alive at the time of writing. PCL shows poor response to treatment and predominates among Africans. The small sample size made it difficult to determine whether co-infection with HIV was a coincidental finding or the two diseases are pathophysiologically linked.

A rare case of plasma cell leukemia in a 35 year old

Plasma cell leukemia is a rare, aggressive form of multiple myeloma. A 35-year-old male presented with backache, generalized weakness, and facial puffiness. His complete blood count showed anemia and a high WBC count with atypical cells on peripheral smear. Bone marrow examination showed more than 90% of atypical plasma cells, confirming a diagnosis of plasma cell leukemia. Patient also had azotemia, hypercalcemia, and hyperuricemia. The patient was started on chemotherapy along with supportive care. Patient improved dramatically and he was discharged on regular follow-up.

Bortezomib as Front-Line Therapy in Primary Plasma Cell Leukemia

Plasma cell leukemia (PCL) is an aggressive, rare variant of multiple myeloma (MM), with peculiar clinical and biological characteristics, which represents about 2–4% of all MM. PCL exists in two forms:primary PCL (about 60% of cases) presents “de novo”, without previous evidence of MM;secondary PCL, which accounts for the remaining 40%, consists of a leukemic transformation occurring in about 1% of patients with a previously diagnosed MM.We have recently shown that bortezomib is an effective agent for the treatment of both primary and secondary PCL, mainly in the setting of pre-treated disease (Musto et al, Cancer 2007). In the present study we conducted a multicenter retrospective survey focused on unselected patients with a diagnosis of primary PCL who had received bortezomib exclusively as first line therapy for the treatment of their disease, outside of clinical trials. To-date, 15 patients, diagnosed according to International Myeloma Working Group criteria, have been collected, 12 of whom (seven male and five female, 49 to 77 year-old) have been so far evaluated for response. Circulating plasma cells ranged from 3 to 95 × 10e9/L. Seven patients had an IgG M-component, two had IgA, two light chains, while one patient was not secretory. Five patients had concomitant extramedullary disease. Unfavourable cytogenetic abnormalities were observed in 4 out of 7 patients with available karyotype. Bortezomib was generally given using the standard schedule of 1.3 mg/sqm days 1, 4, 8, 11, with an interval of 10 days between cycles. Minor modifications were performed, according to tolerance. Three patients received dexamethasone (VD), two dexamethasone and thalidomide (VTD), six doxorubicin and dexamethasone (PAD), and one oral melphalan and prednisone (MPV) in combination with bortezomib, for 2–6 cycles. Three patients underwent autologous, two allogeneic and one a sequence of autologous followed by non-myeloablative allogeneic stem cell transplantation after induction therapy. One out of five eligible patients failed to collect peripheral blood stem cells. Grade 3–4 hematological, neurological, infectious and renal toxicities occurred in 6, 2, 1 and 1 patient, respectively. Other toxicities (diarrhoea, nausea, skin rash) never reached grade 3. According to the International Uniform Response Criteria, 4 partial remissions (reduction of M-component > 50%), 5 very good partial remissions (reduction of M-component > 90%, with positive immunofixation), and 3 complete remissions (negative immunofixation) were achieved (100% overall response). In all patients circulating plasma cells disappeared. One patient with pre-existing renal damage died of progressive disease after 3 months, developing more severe renal failure. Another patient died in CR 6 months after diagnosis, while performing allogeneic stem cell transplantation. Three patients relapsed after 5–8 months and 2 of them died with progressive disease within 4 months from relapse. The remaining 8 patients are alive, and 6 of them maintain their remission phase after 9 to 19 months. One-year progression-free survival and overall survival were 50% and 66.6%, respectively. Primary PCL is usually characterized by poor prognosis. Global response rate to standard chemotherapy is less than 50% and median survival is only 7 months. Stem cell transplantation may be more effective in some, but not all cases. Our findings suggest that, in these patients, the front-line use of bortezomib induces a very high rate of good quality responses, whose duration, however, may be short. This suggests that, in primary PCL, bortezomib should be integrated within more intensive therapeutic programs, including other active drugs and, when possible, stem cell transplantation.

Clinical Efficacy of Bortezomib Based Therapy in Plasma Cell Leukemias.

Introduction Plasma Cell Leukemia (PCL) is characterized by a high number of plasma cells in peripheral blood (>2 × 109/L) and more than 20% of circulating plasmocytes on differential count. Primary PCL or secondary form, after previous multiple myeloma (MM), represent the most aggressive forms of clonal gammapathy with very poor outcome from both conventional chemotherapy and autologous or allogeneic transplant. For this reasons new effective treatment approaches are required. The proteasome inhibitor Bortezomib has been shown to be effective in advanced MM with a rapid response but few reports have been published regarding its potential role on PCL. We report here the clinical results of a serie of PCL patients that received proteasome inhibitor, Bortezomib (Velcade®), as induction therapy.Patients and Clinical Results We describe 10 patients with PCL treated with Bortezomib. Median age was 58 y (30–70). 4 cases were primary, de novoPCL and 6 cases were secondary forms of relapsed or progressive MM. Patients with secondary PCL had received a median of 3 previous lines of therapy including autologous transplantation (5 cases). Bortezomib at standard dose iv: 1.3 mg/m2 days 1,4, 8,11 every 21 days were used alone in 2 patients and in combination with high dose of Dexamethasone +/− Adryamicin in the rest. 3 cases recived the BDD scheme (Bortezomib iv, Pegylated Doxorrubicin iv and oral Dexamethasone). 9 patients were evaluable for drug efficacy with 7 cases showing some grade of favourable response with the first cycle, including 3 cases of CR. 4 patients have died: 1 during first weeks and 3 for progression, 2–3 months after initial response. 3 cases received allogeneic transplant with related donor and reduced conditioning and are alive 12, 14 and 30 months postransplant. The median follow up since PCL diagnosis of 6 alive patients is 14 months (3–39 months). 3 patients received maintenance therapy that included low dose thalidomide. Grade 2 thrombopenia, neutropenia and gastrointestinal symptoms were the main secondary toxicity. No complicated tumoral lysis syndrome were observed.Conclusions and Comments Bortezomib has been shown to be effective by several mechanisms in patients with MM resistant to multiple previous treatments and as induction therapy alone or in combination with other drugs. The favourable responses observed in these cases of PCL; including de novo patients, and the biological ex vivo results in PCL cell lines, suggest the potential efficacy of this agent combined with dexamethasone and doxorubicin. Although more experience is necessary these data support future trials with Bortezomib combined with other drugs for example BDD scheme in the induction treatment of PCL. The role of allogeneic intensification therapy has also to be investigated in young patients after control of PCL with this approach. For maintenance of response, the role of this drug or other new drugs as thalidomide or lenalidomide has to be investigated.

Bortezomib and Plasma Cell Leukemia.

Bortezomib (Velcade) is currently approved in USA and EU for the treatment of resistant/relapsed multiple mieloma (MM). Some reports have suggested that bortezomib is particularly effective for the treatment of extramedullary MM. However, there are very few data about the efficacy of this drug in plasma cell leukemia (PCL), a MM variant usually characterized by very poor prognosis.We retrospectively evaluated 9 patients with PCL diagnosed between October, 2002, and May, 2006, who had received bortezomib for the treatment of their disease (6 males, 3 females; median age 63 years, range 55–74). Six patients had primary and 3 secondary PCL. Eight patients had previously received 1 to 4 lines of chemotherapy, including autologous transplantation (5) and thalidomide (4). One patient was treated at diagnosis. Circulating plasma cells ranged from 2 to 71 x 10e9/L. Median WBC count was 23 x 10e9/L (range 8.1–113). Two patients had a moderate degree of renal failure, 3 had extramedullary disease (jaw, liver, soft tissues). Del 13 was observed in 4 out of 5 patients with available karyotype.Bortezomib was given using the standard schedule of 1.3 mg/sqm days 1, 4, 8, 11, with an interval of 10 days between cycles. Two patients received dexamethasone and thalidomide, 1 thalidomide alone and 3 doxorubicin and dexamethasone in combination with bortezomib. A median of 4 cycles was administered (range 2–6). Grade 3–4 hematological toxicity occurred in 7 patients, while neurological grade 3 toxicity was observed in a single patient. Infections (grade 3) occurred in 4 patients. Other toxicities (diarrhoea, nausea, skin rash) never reached grade 3. Three patients required red cell and/or platelet support. In 3 subjects a reduction of bortezomib dose was required due to hematological or neurological toxicity.Four partial remissions (reduction of M-component > 50%), 3 near-complete remissions (disappearance of M-component at electrophoresis, but positive immunofixation) and 2 complete remissions (negative immunofixation) were achieved (100% overall response), whose duration ranged from 2 to 14 months. In 4 patients autologous transplant procedures were started after response induced by bortezomib. Eight patients are currently alive 7–45 months after diagnosis of PCL. One patient, who had interrupted the treatment after 2 cycles due to herpes zoster, died of progressive disease 7 months later.Our data indicate that bortezomib is very effective in inducing significant responses in patients with primary or secondary PCL and that this drug should be considered for the initial treatment of this disease. Curiously, during the review work, we recorded 3 cases of PCL developed in MM patients under salvage therapies including bortezomib. This intriguing finding, which strongly contrasts with the very good results obtained in patients with previously established PCL, would warrant to be further investigated with “ad hoc” studies.