Plasma cell leukemia: a highly aggressive monoclonal gammopathy with a very poor prognosis
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- Jimenez-Zepeda, V.H. & Dominguez-Martinez, V.J. Int J Hematol (2009) 89: 259. doi:10.1007/s12185-009-0288-3
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Plasma cell leukemia (PCL) is an aggressive variant of multiple myeloma and is characterized by the presence of >20% and/or an absolute number of greater 2 × 10(9)/L plasma cells circulating in the peripheral blood. PCL represents approximately 2–4% of all MM diagnosis and exists in two forms: primary PCL (PPCL, 60% of cases) presents de novo, whereas secondary PCL (SPCL, accounts for the remaining 40%) consists of a leukemic transformation in patients with a previously diagnosed MM. Because the mechanisms contributing to the pathogenesis of PCL are not fully understood, immunophenotyping, genetic evaluation (conventional karyotype, FISH, GEP and array-CGH), and immunohistochemistry are really important tools to investigate why plasma cells escape from bone marrow and become highly aggressive. Since treatment with standard agents and steroids is poorly effective, a combination of new drugs as part of the induction regimens and bone marrow transplant (autologous and allogeneic approaches) could nearly overcome the poor prognosis exhibited by PCL patients.
KeywordsPlasma cell leukemiaMultiple myelomaBone marrow transplant and prognosis
Diagnostic criteria for plasma cell leukemia
1. Plasma cells >2 × 10(9)/L in peripheral blood
2. Plasma cells >20% of blood leukocytes in peripheral blood
3. Primary plasma cell leukemia (PPCL): presents as de novo leukemia
4. Secondary plasma cell leukemia: progression from a pre-existing multiple myeloma
2 Clinical features
Clinical and biological differences between plasma cell leukemia (PCL) and multiple myeloma (MM)
ECOG > _2
BMPC > 40%
LDH > 460 U/L
Albumin < 3.5 g/dl
Creatinine > 2 mg/dl
Calcium > 11 mg/dl
B2 Mg > 6 mg/dl
S-phase PCs > 3%
Overall response rate
3 Immunophenotypic studies
Because PCs are largely confined to the bone marrow, different patterns of adhesion are likely seen in the circulating clonal cells of PCL.
Immunophenotypic characterization of Bone marrow plasma cells is being performed as previously described in MM [8, 18–20]. The following panel of monoclonal antibodies (MoAbs)—whose specificity has been described elsewhere [8, 18, 21]—has been used: Leu 17 (CD38), Leu M7 (CD13), anti-CALLA (CD-10), anti-HLA-DR (Ia), Leu 16 (CD20), Leu M1 (CD15), FMC56 (CD99, Leu 19 (CD56), Leu 4 (CD3), Leu 5b (CD2), Leu 11c (CD16), c-kit (CD117), and B-B4 (CD138). These MoAbs has been used in triple staining, with CD38 included in all combinations for specific identification of PCs [8, 22].
CD38 and CD138 antigens are excellent PC markers in both MM and PCL patients, while CD2, CD3, and CD16 were consistently negative in all cases. In addition, the frequency of CD10+, CD13+, and CD15+ cases is similar in both groups (MM and PCL). By contrast, statistically significant differences have been observed between PCL and MM for the expression of CD20, CD56, CD9, CD117, and HLA-DR antigens. The CD20 antigen displays higher reactivity in PCL, whereas the other four antigens were more frequently present in MM. These findings indicate that although PCL has characteristic immunophenotype that differs from pattern for MM, there is some overlap in antigenic expression .
4 DNA measurements
The DNA index has been reported and calculated previously in samples from Primary PCL . This index has been calculated as the ratio of the modal channel obtained for PCs (CD38+++) and the remaining normal cells (CD38– or CD38+) present in samples; In addition, the proportion of plasma cells in the different cell-cycle phases for both subsets (PCs and residual normal cells) by using the MODFIT software has already been reported and compared to a subset of 404 MM cases. All except one from 26 PCL cases were diploid (DNA index, 1) with the remaining case displaying a DNA index less than 1 . In contrast, most MM cases (57%) showed a DNA index greater than 1. It should be noted that in one PCL case, two PC subpopulations were found, one diploid (DNA index, 1) and the other tetraploid (DNA index, 2). The distribution of cells along the cell-cycle was also different between PCL and MM, with the former showing a higher percentage of S-phase PCs and a lower percentage of S-phase residual normal cells.
5 Genetic changes and PCL
Genomic differences between PCL and myeloma have been recognized. Few large studies address the genomic aberrations underlying PCL or the relationship between PPCL and SPCL . Two European groups investigated the molecular genetic abnormalities underlying PPCL [8, 24]. Tiedemann et al. recently reviewed the Mayo clinic experience of genetic aberrations in PPCL and SPCL,  and Chang et al.  also reported molecular genetic abnormalities including 13q and 17p (p53) deletions and IgH translocations in 14 PCL patients. In two of the largest studies where informative karyotypes were obtained in 34 and 38 patients with PCL, 23 and 24 cases, respectively showed complex hypodiploid or pseudodiploid karyotypes in both studies (67 and 63% respectively) [24, 25]. Sixty-eight and seventy-six percent had monosomy 13 detected by FISH in both studies, respectively, which may account for the poorer prognosis of patients with PCL . Only three patients in both studies had hyperdiploidy (48, 49, and 51 and 47, 54 and 86 chromosomes respectively). These results are in contrast with those published in MM, [27–29] in which hyperdiploidy is observed in approximately 60% of patients, but they confirm previously published analyses in PCL [8, 30].
Analysis of rearrangements of the 14q32 region by FISH revealed significant differences with high cell mass MM–a higher incidence of t(11;14) (33 vs. 16%; p < .025) and of t(14;16) (13 vs. 1%; p < .002) though incidences of t(4;14) were identical and a higher incidence of monosomy 13 (68 vs. 42%; p = .005) .
With the fluorescent in situ hybridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, −13 (86%), ±1 (57%), +18 (43%), and –X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15.
6 The p53 inactivation
Genetic abnormalities detected in plasma cell leukemia
Median OS (months)
14q32 break apart
Biallelic TP53 loss
3′/myc break apart
5′/myc break apart
7 Chromosome 1 abnormalities and t(4;14)
Genomic aberrations such as t(4;14), del 13q14, del 17p, del 1p21 and 1q21 gains are adverse risk factors in MM but their significance in PCL is unclear [38–45]. Recently, Chang et al.  investigated 41 PCL cases aiming to detect chromosome 1q amplifications and 1p deletions, and compared the genetic aberrations with those in 220 myeloma patients. The prevalence of genetic abnormalities was similar in PPCL and SPCL. However, del(17p), del13q14, del1p21, 1q21 amplifications and t(4;14) were more frequent in PCL than MM. The interrelationship of these genetic aberrations was assessed by using the Pearson chi square test. Del 1p21 was associated with 1q21 amplification (p = 0.03) and has a marginal association with del(17p) (p = 0.06). Chang et al.  showed that patients with 1p21 deletions had a shorter OS than those without such deletions (6.2 vs. 33.5 months, p = 0.006). Patients with t(4;14) had a shorter survival than those without t(4;14) (1.5 vs. 21.6 months, p = 0.003). The presence of del 13q14, del (17p), t(11;14) and 1q21 amplification did not influence survival in this cohort. In a multivariate analysis adjusting for all above genetic risk factors as well as CRP, calcium and B2-microglobulin levels, only t(4;14) was an independent predictor for a worse OS (p = 0.008), 1p21 deletions did not retain the prognostic significance (p = 0.14).
8 MYC translocation and RAS mutation
Rearrangement of MYC has been identified by 3′FISH break apart in 33% of PPCL and SPCL tumors and is been complemented by MYC amplification or 5′MYC translocations in 8 and 17% of patients, respectively  MYC rearrangements are associated with a trend toward inferior OS in PPCL (median OS of 8.6 vs. 27.8 months without rearrangements, p = 0.006).
On the other hand, mutations of K-RAS or N-RAS at codons 12, 13 or 61, previously characterized as functionally activating, [47–50] are found in 27% PPCL and 15% SPCL . Activating mutations of RAS are associated with a trend toward poorer outcome in PPCL (p = 0.069). However, the prevalence of K- or N-RAS mutation in SPCL is comparable to that reported in MM (21%),  suggesting little, if any, selective pressure for RAS activation in secondary leukemic transformation from MM.
9 Diagnostic criteria
The disease is diagnosed when a patient has an absolute PC count of greater than or equal to 2 × 10(9)/L in the peripheral blood . Ancillary studies must include a bone marrow aspirate and biopsy with PCLI, a metastatic skeletal survey, including long bones (plain films); complete blood counts (CBCs) with differential; liver function tests, creatinine; peripheral blood labeling index (PBLI); B2-microglobulin; CRP; serum and urine electrophoreses with immunofixation; LDH; and calcium. Cytogenetic prognostic indicators can be obtained by either conventional cytogenetic analysis or interphase FISH .
10 Thrombosis and acquired activated protein C resistance (APC-R)
Recent reports have shown greater incidence of deep venous thrombosis and pulmonary embolism in patients with MM [52–54]. Zangari et al.  reported a higher prevalence of APC-R in a group of patients with newly diagnosed MM (41.7%). Our group reported  one case of APC-R in a SPCL case without evidence of thrombosis events. There is no more data regarding thrombosis and PCL but the APC-R and some other pro-coagulant conditions as well as therapy-related complications lead to support the possible association between PCL and thrombosis and may be to APC-R. Due to the low frequency of cases in PCL the risk of thrombosis remains unclear.
11 Transformation from MM to SPCL and clinical differences between PPCL and SPCL
In SPCL, the median time to leukemic progression from MM is approximately midway (20.8 months) between diagnosis and median survival of MM patients, indicating that transformation from MM to SPCL is not a late event in MM but occurs both early and late. PPCL patients are younger than SPCL and present without a MM prodrome and higher creatinine and B2-microglobulin levels than SPCL. Both PPCL and SPCL are associated with more renal impairment and higher B2-microglobulin levels than MM. Extramedullary disease seems to be more evident at diagnosis among PPCL than SPCL cases, [8, 25] while PPCL is presented with more hepatomegaly, splenomegaly, extra osseus plasmacytoma and adenopathy. By contrast, bone disease is more common in SPCL with a higher prevalence of osteolytic lesions (SPCL 53% vs. PPCL 18%), consisting with its origin from MM . In previous reports, patients with PPCL usually have more severe anemia, thrombocytopenia and higher serum LDH [51, 57, 58].
The clinical presentation of PCL (asthenia, hepatomegaly and splenomegaly, severe anemia and thrombocytopenia) mimics the presentation of acute leukemia and differs from the classic plasma cell myeloma [51, 58].
12 Pathologic findings of PCL
There are relative few reports describing the pathologic findings in PPCL [9, 59]. In some cases reported, most of the cells resemble normal plasma cells with basophilic cytoplasm, prominent Golgi zone, and an eccentric nucleus. Other cases have been lymphoplasmacytoid lymphocytes and only a minority of characteristic plasma cells. Yet, others have more primitive cells with a higher nuclear cytoplasmic ratio, open chromatin, a prominent nucleolus, and a less prominent Golgi zone (plasmablasts) [9, 59, 60]. These latter cases can be difficult to recognize as plasma cells by light microscopy and require immunophenotypic studies. The pattern of infiltration is mostly diffuse in all cases and this infiltration is able to disrupt normal hematopoiesis .
The plasma cells displayed a spectrum of maturity, from small mature plasma cells to large, anaplastic, blastic cells that were difficult to classify. The peripheral blood smear had mainly an increased number of plasma cells, as is part of the definition of PCL. Ancillary studies are essential in making the correct diagnosis in these cases. Immunophenotypically, PCL is positive for CD38 and CD138 [8, 59, 61]. It has been reported that the intensity of CD38 expression progressively decrease from normal plasma cell to clonal PCL .
14 Alkylating agents
Several combinations that include an alkylating agent have been used as sole treatments of PCL or as induction therapy prior to anticipated transplant. Combinations that include an alkylating agent such as melphalan are generally avoided as induction therapy in potential transplant candidates to preserve stem cells for future collection.
A common chemotherapy combination used for induction consists of vincristine, adriamycin, and dexamethasone (VAD) administered for three to four cycles to reduce tumor burden. This scheme has been abandoned as induction therapy in MM and related conditions due to the complications related to the catheter placement required for its administration and the reduced level of responses in comparison with novel agents [64–66].
In a recent study, Tiedemann et al.  reported 21 PPCL patients treated with either VAD or VBMCP and 20 treated with oral melphalan and prednisone. Overall Survival (OS) for PPCL patients treated with VAD or VBMCP (median 15.4 months) was substantially longer than patients who received MP (4.1 months). We reported similar results by showing a median OS of 6.8 months for patients treated with VAD versus 2 months for those who received MP (p < 0.05) .
15 Intermediate doses of melphalan and dexamethasone
Patients with PCL treated with standard alkylating agents and steroids have a short survival, ranging from 2 to 6 months although more intensive chemotherapy induces resposes in 50% of patients with a median survival of 20 months . Vela-Ojeda et al., reported the use of melphalan and dexamethasone at intermediate doses (M-80 protocol) (oral melphalan 80 mg/m2 plus dexamethasone 40 mg/m2) . Patients receiving the M-80 regimen experienced higher platelet toxicity, vomiting and mucositis. Also, the need for red blood cell transfusions was higher in the M-80 group in comparison with those patients treated either with VAD or VMCPA. Patients in the M-80 group exhibited the highest level of response (6/8 vs. 1/4 and 0/12 for VAD and VMCPA). However, the median OS was 60 days for the entire cohort of cases being better for patients achieving complete or partial response. Since this is a small series of cases, it is hard to jump into conclusions but it is clear that even in the setting of intermediate doses therapy, alkylating agents are not enough to improve OS in PCL.
Based on observation that in PCL the response to standard therapy is extremely poor and the use of thalidomide in advanced MM has resulted in marked responses even in patients with advanced diseases, including those who relapsed after high-dose chemotherapy [69–72], some authors have used this promising drug also in patients with PCL [73, 74].
Wohrer et al.  reported the use of thalidomide in a patient with PPCL as a first line therapy achieving a very good partial response rapidly. However, in a different report by Pettrucci et al.  five cases treated with thalidomide for PPCL (N = 2) and SPCL (N = 3) did not show any degree of response to thalidomide used as a single agent. Survival for these cases was very short and all patients died after 40, 45, 60, 75 and 120 days of treatment initiation, respectively. Bauduer et al.  previously have been reported the significant activity of thalidomide in a patient with VAD-refractory PCL, appearing several months after autologous stem cell transplantation for MM. Since, thalidomide is being used in sporadic cases of PCL the role of this drug remains controversial and unclear.
A new class of thalidomide derivatives, called immunomodulatory drugs (IMiDs), was subsequently developed and although they are structurally related to thalidomide, they have different anti-inflammatory, immunomodulatory and antioangiogenic potential and toxicity profile [78, 79]. Lenalidomide (CC-5013, Revlimid, Celgene), the lead compound of the second generation of IMiDs, was fist tested in phase I and II trials in relapsed/refractory myeloma with encouraging results . Lenalidomide has also been studied in other hematological malignancies, and was first approved by the Food and Drug Administration for use in patients with myelodysplastic syndrome (MDS) associated with a 5q-deletion cytogenetic abnormality . Subsequently, on the basis of two large phase III trials, [82, 83], lenalidomide in combination with dexamethasone was approved by the FDA and European Medicines Agency (EMEAS) for the treatment of myeloma patients who had received at least one therapy earlier.
Despite the no conclusive and controversial experience with the use of thalidomide, Benson et al.  evaluated the use of lenalidomide in the management of a patient with relapsed, secondary PCL who had received three prior treatment regimens. This experience strongly supports the idea of further, formal inquiry into the role of lenalidomide in the management of PCL. This patient achieved a very early response showing normalization in the level of WBC without detectable plasma cells in circulation after 7 days of treatment initiation. Patient achieved remission and remains free-disease after 5 months of ongoing therapy with lenalidomide and dexamethasone. Since, this represents a very short follow up the presence of this magnitude of response encourages its use even in the setting of relapse PCL.
There are different reasons why lenalidomide may be an effective therapy for PCL, despite the unclear data from thalidomide. First, lenalidomide is 50–2000 times more potent than thalidomide in stimulating T-cell proliferation triggered via the T-cell receptor (TCR) and is 50 to n100 times more potent in augmenting interleukin-2 and interferon-γ production . Second, the IC50 of lenalidomide is 0.4 mcmol/l (103.6 ng/ml) against multiple myeloma cell lines and primary cells from patients resistant to chemotherapy, whereas the IC50 of thalidomide is 194 mcmol/l (50.2 mcg/ml) in similar settings [86, 87]. Third, lenalidomide is a more potent inducer of apoptosis through upregulation of the pro-apoptosis mediator caspase-8 as well as down-regulation of anti-apoptosis mediators, e.g., cIAP2 and FLICE . Finally, in a human plasmacytoma murine model, lenalidomide inhibits tumor growth, decreases angiogenesis, and prolongs survival as compared to thalidomide .
Therapy for plasma cell leukemia
19 Stem cell transplantation
The optimal treatment for PCL is not yet well defined; however, recent studies have indicated the potential role of autologous or allogeneic stem cell transplant to prolong overall survival [97, 98]. Saccaro et al.  reported 17 new cases of PPCL who underwent stem cell transplantation (2 cases observed by the authors and 15 cases from the International Bone Marrow Transplant Registry (IBMTR)). The first case was diagnosed in a 21 year-old male who presented with leukocytosis and acute renal failure. He was treated with Hyper-CVAD, entered complete remission, and then proceeded to high-dose chemotherapy with peripheral stem cell support. After 23 months of diagnosis and 19 from PBSCT patient remained in CR. The second case observed by authors was a 31 year-old male who presented with leukocytosis and hepatic infiltration with plasma cells. He was treated with VAD chemotherapy and underwent allogeneic bone marrow transplantation from his HLA-identical sister. He remained in CR for 3 years and then developed progressive refractory disease, dying 7 years after initial diagnosis. In addition to these 2 cases, 15 further unpublished cases of PPCL from the IBMTR were reported, 6 were autologous and 9 allogeneic transplants. The conditioning regimen for 8 of the 15 patients included busulfan and cyclophosphamide. Melphalan was included in the conditioning regimen in only 2 patients. Acute graft-versus host reaction ≥grade II was observed in 3/9 patients who had allogeneic transplantation. At last follow up 1/6 patients after autologous transplantation and 2/9 patients after allogeneic transplantation were alive. Most of these are single cases, very small series or single cases within series of cases treated conventionally. Nonami et al.  recently reported the first case of a chemotherapy resistant primary PCL, which was successfully treated with allogeneic HSCT from a haploidentical (2-HLA loci mismatched) sibling donor. In vivo T-cell depletion by anti-thymocyte globulin (ATG) contained in the conditioning regimen might avoid the development of severe graft-versus host disease (GVHD), whereas a graft-versus PCL effect still might be preserved in this case . Considering the aggressive nature of this disease, haploidentical HSCT can be a treatment option based on graft-versus PCL effects in addition to intensive conditioning regimens for patients with PPCL who do not have an HLA-identical donor.
Bisphosphonates are used for the prevention and palliation of bony disease and hypercalcemia associated with PCL/MM. Pamidronate and zoledronic acid are the most common used employed in MM [100, 101]. Although, preliminary investigations have also suggested a direct antitumor effect by bisphosphonates , their antitumor usefulness in PCL is doubtful.
Plasma cell leukemia represents a unique subset of patients with an aggressive plasma cell proliferative disorder which is associated to a poor prognosis, with a shorter survival than for patients presenting with classic myeloma. Genomic and clinical differences between PCL and myeloma have been recognized. The presence of p53 deletion in a high level, 13q deletions, karyotypic complexity, hypodiploidy and 1q gains could define an advance stage on plasma cell disease progression characterized by therapy resistance and a dismal prognosis. PCL requires evaluation of new fields of treatment including novel therapies such proteasome inhibitors, and IMiDs (that at least in preliminary reports appear to be promising), and bone marrow transplant with different approaches including allogeneic HSCT and maintenance therapy.