Primary Plasma Cell Leukemia: Results of a Retrospective Italian Multicentric Survey.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2885-2885
Author(s):  
Livio Pagano ◽  
Caterina Giovanna Valentini ◽  
Valerio De Stefano ◽  
Adriano Venditti ◽  
Giuseppe Visani ◽  
...  

Abstract Abstract 2885 Poster Board II-861 Background: Epidemiological and clinical information on Primary Plasma Cell Leukemia (pPCL) are rarely reported. Aims: To evaluate in patients (pts) with pPCL the clinical features, the prognostic factors, and the efficacy of treatments. Patients and Methods: A multicenter retrospective cohort study was carried out between January 2000 and December 2008 in 26 Italian hematology divisions. A total of 128 cases of PCL were collected, and 73 of them (57%) were classified as primary (M/F 43/30). Results: The median age was 63 years (range 32-86). At diagnosis the median values of peripheral blood plasma cells and bone marrow plasma cell infiltration were 2.7 × 10 9/L (range 0.4-49.9) and 80% (range 37-100), respectively. The median values of hemoglobin, white blood cell count, and platelet counts were 9.1 g/dl (range 4.8-12.9), 13.7 × 10 9/L (range 1.3-56.7), 116 × 10 9/L (range 8-428), respectively. Extramedullary disease was present in ten cases (14%) and included testis, muscular, neuromeningeal, and cutaneous localization. At diagnosis, 64 pts (88%) had at least one CRAB sign, namely 35 pts (48%) had low hemoglobin level, 20 pts (27%) calcium ≥11 mg/dl, 32 pts (44%) creatinine ≥2 mg/dl, and 47 pts (64%) had osteolysis. In 41 pts (56%) cytogenetic study was performed, revealing an unfavourable karyotype in 17 (23%), in 13 of them del(13q-). Seventy-two pts received front-line therapy (1 died early, receiving only support treatments and steroids), that included antracycline-containing regimens in 36 pts (50%), and single alkylating agents in 17 pts (24%, 9 cyclofosfamide and 8 melphalan). In 11 of them Bortezomib (BTZ, n= 7) or Thalidomide (THAL, n= 4) were also employed. Finally, 19 pts (26%) received BTZ (4) or THAL (5) or both (10) as unique treatment. Twenty-one pts (29%) underwent autologous stem cell transplantation (SCT) as part of front-line therapy, followed by allogeneic-SCT in four cases; two additional pts underwent only allogeneic-SCT. A complete or partial remission after front-line therapy was achieved in 20 pts (27%) and 19 pts (26%) respectively (overall response rate 53%). The median overall survival (OS) was 13.1 months (range 0.5-75.8); 30.6 months (range 4.7-75.8) in responder pts and 4.2 months in non-responder ones (range 0.5-75.6, univariable hazard ratio, HR, 0.28, 95% CI 0.11-0.39). In the responder pts the median progression free survival (PFS) was 17.2 months (range 1.4-72.1). Of note, in SCT pts the median OS and PFS were 38.1 months (range 4.8-75.8) and 25.8 months (range 1.4-72.1) respectively, with a significant advantage with respect to non-transplanted pts in OS (median 9.1 months, range 0.5-75.6, HR 0.28, 95% CI 0.16-0.52) and in PFS (median 7.3 months, range 1.7-17.7, HR 0.29, 95% CI 0.04-0.44). The low number of allo-SCTs did not allow a reliable separate statistical analysis. A multivariable Cox proportional hazard regression analysis showed that OS was influenced by lack of initial response (HR 2.62, 95% CI 1.04-6.57), albumin <3 g/dl (HR 3.33, 95% CI 1.64-6.76), and SCT (HR 0.34, 95% CI 0.12-0.98). Pts with hypercalcemia at diagnosis had a shorter PFS (HR 4.0, 95% CI 1.04-15.24); the PFS was favourably influenced by SCT (HR 0.05, 95% CI 0.009-0.28). Overall, the use of BTZ and/or THAL did not influence the OS and PFS. Conclusions: pPCL is a highly aggressive lymphoprolipherative malignancy, characterized by a poor prognosis and a low response rate to conventional therapy. The use of high-dose chemotherapy followed by autologous or allogeneic-SCT is a very effective therapy leading to 66% increase in the OS and to 95% increase in PFS in respect to non-transplanted pts. Apparently, the use of novel drugs such as BTZ and THAL did not produce a further amelioration in the patient outcome. However, those latter findings should be taken with caution, given the relatively low number of treated pts. Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4951-4951
Author(s):  
Pellegrino Musto ◽  
Maria Teresa Petrucci ◽  
Fortunato Morabito ◽  
Francesco Nobile ◽  
Fiorella D'Auria ◽  
...  

Abstract Abstract 4951 Background Primary Plasma Cell Leukemia (PPCL) is an aggressive, rare variant of multiple myeloma, with clinical, molecular and phenotypic peculiarities, which accounts approximately for 2% to 4% of all myeloma diagnoses. The prognosis of PPCL patients is usually poor, with less than half of patients responding to conventional chemotherapy and a median survival of 7 months. Even by using autologous or allogeneic transplant procedures, survival generally does not exceed three years. Bortezomib has recently provided some promising results in this setting, but, given all the above, new treatments for PPCL are greatly awaited. Lenalidomide is a new immunomodulating agent with great efficacy in multiple myeloma, especially when associated with dexamethasone or other drugs. There are, indeed, some sporadic case reports of PPCL patients treated with lenalidomide as salvage therapy, but no data are currently available on the use of this drug as first line therapy in this disease. Patients and Methods On March, 2009, we started an open label, prospective, multicenter, exploratory, single arm, two-stage study aiming to evaluate safety and antitumor activity of the lenalidomide/low dose dexamethasone combination (Rd), as first line therapy in patients with PPCL. The primary endpoint was early response rate according to International Uniform Criteria. The secondary endpoints were TTP, PFS, OS, percentage of eligible PPCL patients able to collect peripheral blood stem cells and to undergo autologous or allogeneic stem cells transplantation after Rd, serious and severe adverse event rate. According to this study protocol, all eligible, newly diagnosed adult patients with PPCL receive Lenalidomide at a dose of 25 mg daily for 21 days every 28 days. Oral dexamethasone is administered at a dose of 40 mg daily on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, patients who achieve at least PR and not eligible for autologous or allogeneic stem cell transplantation, continue with Rd until clinically appropriate (disease progression, unacceptable toxicity, patient's decision to leave the protocol). In these patients, a maintenance dose of lenalidomide alone equal to 10 mg/die days 1-21 every month is considered after at least 8 full dose Rd cycles. Patients responding after 4 Rd cycles and eligible for transplant procedures, proceed according to single Centre transplant policy. Patients not responding after 4 cycles or progressing under Rd treatment are considered off-study. Appropriate contraception methods and anti-thrombotic prophylaxis are planned. Results Four enrolled patients (1 male, 3 female, mean age 65 years, range 58-69) are currently evaluable for early response. All had unfavourable cytogenetics, including del13, t(4;14), t (14;16), or a complex karyotype. Circulating plasma cells ranged from 4.4 to 9.2 ×10e9/l. One patient had at baseline a moderate degree of renal failure (serum creatinine levels 2 mg/dl). After at least 2 Rd cycles (range 2-4), two PR and two VGPR were achieved (overall response rate 100%), with disappearance or near complete reduction of circulating plasma cells in all cases. The most relevant toxicities were grade 3 neutropenia and pneumonia, occurring in one patient and resolved by appropriate lenalidomide dose reduction, introduction of G-CSF and antibiotic therapy. One patient died in PR, due to causes unrelated to PPCL or treatment. As, according to the Simon, two-stage design adopted, more than two responses occurred within the first ten patients enrolled (stage 1), a total of 22 PPCL subjects will be accrued to complete the stage 2 of the trial. Conclusions These findings, though very preliminary, suggest that the combination of lenalidomide and dexamethasone may be a safe and promising initial therapy for PPCL patients, which can rapidly control the disease and could permit to perform following single patient-adapted therapeutic strategies. An update of this study, including molecular data, a larger number of patients and a longer follow-up, will be presented at the Meeting. Disclosures Musto: Janssen-Cilag: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide is approved in Italy for advanced multiple myeloma, not for plasma cell leukemia. This is a clinical trial registered at AIFA (Italian regulatory Agency for Drugs), EudraCT No. 2008-003246 28. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria. Morabito:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Celgene: Honoraria; Janssen-Cilag: Honoraria. Palumbo:Celgene: Honoraria; Janssen-Cilag: Honoraria.


Author(s):  
Roma S Fourmanov ◽  
◽  
Annemiek Joosen ◽  
Lidwine Tick ◽  
Heleen S de Lil ◽  
...  

Background: Multiple myeloma is a relatively common type of plasma cell dyscrasia, in which monoclonal plasma cells proliferate. This frequently leads to anemia, renal failure, hypercalcemia and bone lesions. Primary plasma cell leukemia is a much rarer type of plasma cell dyscrasia, with measurable plasma cells in the blood circulation and usually more acute presenting signs. Case: A 57-year-old woman presented to the emergency department with dyspnea. Because of hypoxemia due to a hemoglobin concentration of 3.1 g/dL (1,9 mmol/L), asystole occurred, and cardiopulmonary resuscitation had to be started. The severe anemia turned out to be due to a primary plasma cell leukemia. Palliative treatment was started with combination chemotherapy with VTD (bortezomib, thalidomide and dexamethasone) with a very good partial response, after which she proceeded to an autologous stem cell transplantation with high dose melphalan conditioning. Conclusion: Primary plasma cell leukemia is a plasma cell dyscrasia with both resemblances and differences from the better-known multiple myeloma. It is less common, but presenting signs often are more acute and more severe. Currently there is no curative treatment. Keywords: Plasma cell leukemia; Hematological emergency; Multiple myeloma; VTD.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2878-2878
Author(s):  
Laura Mosca ◽  
Pellegrino Musto ◽  
Katia Todoerti ◽  
Marta Lionetti ◽  
Luca Agnelli ◽  
...  

Abstract Abstract 2878 Primary plasma-cell leukemia (pPCL) is an aggressive, rare variant of plasma cell (PC) dyscrasia characterized by extra-medullary proliferation of PCs, high genomic instability and very poor prognosis. The present study was aimed at investigating global genomics in 17 pPCL recruited in an open-label, exploratory, single-arm, two-stage study from the GIMEMA myeloma network designed to evaluate the safety and antitumor activity of lenalidomide in combination with low dose dexamethasone as first-line therapy in pPCL. All the samples were characterized for the main chromosomal aberrations by Fluorescence In-Situ Hybridization (FISH). Specifically, 13q and 17p deletions have been identified in 13 (76.5%) and 6 (35.3%) cases, respectively; the presence of t(11;14) translocation was found in 7 patients (41.2%), t(4;14) in 2 (11.8%) and t(14;16) in 7 (41.2%). To better define the chromosomal alterations of this set of patients, we further investigated them by means of Human Mapping 250K Nsp SNP-array (Affymetrix). SNP-array data were fully concordant with FISH results as regards 13q and 17p deletions in the analyzed patients. Among the copy number alterations identified by mapping analysis the most frequently gained chromosomal region was represented by 1q (9 cases, 52.9%); 1p, 8p, 14q, and 16q arms were affected by loss of DNA material in more than 40% of cases. Moreover, four patients showed gain at 7q (23.5%), one case displayed a near tetraploid karyotype and another one had a hyperdiploid-like pattern. Most of the minimally altered regions identified on the different chromosomes encompassed genes that have been reported to be deregulated in PC dyscrasia, such as CDKN2C (mapped to 1p32.3), FAM46C (1p12), CKS1B (1q21.2), PARK2 (6q26), PPP2R2A (8p21.2), RB1 and MIR-15A/16-1 (13q14.2), TRAF3 (14q32.32), CYLD (16q12.1), WWOX (16q23.3-q24.1), and TP53 (17p13.1). The mutational analysis of the most frequently mutated exons (5–9) of TP53 gene revealed the presence of coding mutations in 4 patients (23.5%), three of which carried a monoallelic deletion including the gene locus. This supports the knowledge that the prevalence of TP53 mutations increases in more advanced disease and is strongly associated with hemizygosity. Genome-wide profiling data were then integrated with the transcriptional profiles generated on Gene 1.0 ST array (Affymetrix). Our analysis (Wilcoxon rank-sum test at a P <0.001) identified 134 transcripts whose expression levels strongly correlated with the occurrence of allelic imbalances, all of them in the previously described altered regions; specifically, 42 mapped to gained regions on 1q (40/134=29.9%) and 7q (1.5%), and 92 mapped to deleted regions on 1p (10.4%), 6q (6.7%), 8p (10.4%), 13q (9.7%), 14q (18.7%), 16q (6.0%) and 17p (6.7%). Enriched categories in functional annotation analysis are protein metabolism, transport, catabolic processes as the proteasome ubiquitination pathway (PSMC6, PSMA3, PSMB4 and PSMD4), and telomere organization and maintenance (PINX1, PARP1 and WRN). Overall, our data highlighted a wide gene-dosage effect, suggesting that genomic structural abnormalities in pPCL closely reflect in expression imbalances. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 729-729 ◽  
Author(s):  
Pellegrino Musto ◽  
Vittorio Simeon ◽  
Giovanni D'Arena ◽  
Maria Carmen Martorelli ◽  
Maria Teresa Petrucci ◽  
...  

Abstract Abstract 729 Introduction: The prognosis of primary plasma cell leukemia (PPCL) remains poor. The “novel agents” have recently shown promising results in PPCL patients in case reports or small retrospective series. Here we describe the first prospective, multicenter, phase II clinical trial of PPCL, where lenalidomide in combination with low dose dexamethasone (Ld) was tested as initial therapy in newly diagnosed patients fulfilling the IMWG diagnostic criteria of PPCL. Patients and methods: Ld regimen consisted of lenalidomide 25 mg/d for 21 days and oral dexamethasone 40 mg on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, responding patients not eligible for stem cell transplantation (SCT) continued until 8 cycles of full-dose Ld, followed by a maintenance dose of single agent lenalidomide equal to 10 mg/d on days 1–21 of each 28-day cycle. Patients responding after 4 cycles and eligible for SCT proceeded according to the treatment centre's transplant policy. Patients not responding after 4 cycles or progressing during this treatment were considered off-study. Appropriate dose reductions (in particular for patients with reduced renal function at baseline), double contraception methods and anti-thrombotic/anti-infective prophylaxis were recommended. The primary end-point was early response rate according to IMWG uniform response criteria. Secondary end-points were PFS, OS, feasibility and efficacy of SCT, safety. Results: According to the Simon optimal two-stage adaptive design, twenty-three patients were enrolled in between March 2009 and May 2011. The male/female ratio was 1.1, and median age was 60 years (range 44–80). The median absolute number and percentage of circulating plasma cells were 4.280/μl (range 1.500–114.660) and 34% (range 21–90) respectively. Fifteen patients (65.2%) had abnormal renal function at presentation. Twenty-one patients (91.3%) were tested by FISH analysis and cytogenetic abnormalities were detected in all of them, del13q being the most frequently found (16 patients). Seventeen patients showed multiple chromosomal lesions. Involvement of chromosome 14 was observed in 18 patients, three of whom showed t(4;14). Chromosome 1q gain and del17p were detected in 10 and 7 patients, respectively. In the intention-to-treat (ITT) population, overall response rate (ORR) after at least one Ld cycle was 73.9% (17/23), with 8 patients (34.7%) achieving partial remission (PR), 5 (21.7%) very good PR (VGPR), 3 (13%) complete response (CR), and 1(4.3%) near CR (nCR) (VGPR or better: 39%). In the efficacy-evaluable (EE) population, 14 out of 15 patients who received the initially planned 4 Ld cycles (65.2% of the ITT population) responded (ORR 93.3%), achieving 5 PR (33.3%), 5 VGPR (33.3%), 1 near-CR (6.6%) and 3 CR (20%) (VGPR or better: 59.9%). The maintenance phase was reached and safely performed in 4 responding patients not eligible for SCT, 3 of whom relapsed after 2, 8 and 22 months, respectively. After Ld induction therapy, 8 patients received single (n. 4) or double (n. 4) autologous SCT (ASCT); another patient underwent a sequence of ASCT followed by non-myeloablative allogeneic SCT (AlloSCT). Six eligible patients did not receive ASCT frontline, due to initial Ld failure or adverse events; three of them underwent single ASCT (n. 2) or tandem ASCT/non-myeloablative AlloSCT (n. 1) after a bortezomib-based salvage therapy, achieving 2 CR and 1 PR. After a median follow-up of 23 months, median OS and PFS in ITT population were not reached and 22 months, respectively. All transplanted patients remained alive, although three of them relapsed and started salvage treatments; OS was 12 months in the 11 patients who did not receive ASCT (p < 0.001). The correspondent figures for PFS were 29 and 16 months, respectively (p < 0.01). Considering ITT population, multivariate analyses showed that SCT was positively correlated to both OS and PFS. There were 17 episodes of grade 3/4 non hematological toxicity, which occurred in 13 patients (5 infections, 3 renal, 3 metabolic, 2 gastro-intestinal, 2 skin, 1 fatigue, 1 thromboembolic), causing early interruption of Ld treatment in 4 patients. Grade 3/4 hematological toxicity (mainly neutropenia) occurred in 11 patients (47.8%). Conclusions: Ld may be a feasible and effective initial therapeutic option for PPCL, particularly in patients who receive ASCT after a short course of induction treatment. Disclosures: Musto: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide as first line therapy of plasma cell leukemia. Petrucci:Celgene: Honoraria. Cascavilla:Celgene: Honoraria. Di Raimondo:Celgene: Honoraria. Caravita:Celgene: Honoraria. Morabito:Celgene: Honoraria. Offidani:Celgene: Honoraria. Bringhen:Celgene: Honoraria. Boccadoro:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Celgene: Consultancy, Honoraria.


2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e20048-e20048
Author(s):  
Saad Malik ◽  
Ammad Raina ◽  
Faisal Akbar ◽  
Hafiz Muhammad Fazeel ◽  
Malik Qistas Ahmad ◽  
...  

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3869-3869 ◽  
Author(s):  
Driss Chaoui ◽  
Xavier Leleu ◽  
Murielle Roussel ◽  
Bruno Royer ◽  
Marie-therese Rubio ◽  
...  

Abstract Abstract 3869 Poster Board III-805 Introduction The outcome of patients with plasma-cell leukemia (PCL) is poor. Avet-Loiseau reported on behalf the IFM, our first experience in PCL patients and showed that the median overall survival (OS) was 8 months (Avet-Loiseau, Blood, 2001). Since 1999, novel agents such as Thalidomide, Bortezomib (Velcade) or Lenalidomide (Revlimid) have been widely used in the treatment of multiple myeloma, both at the time of relapse or part of upfront therapy. Patients and methods In this retrospective analysis, we have looked at the outcome of PCL patients treated within the IFM since 1999 in order to study the impact of novel agents on survival. Results 31 cases, 20 males, 11 females, median age 55 years (34-78) were analyzed. Twenty one patients less than 65 years received high-dose therapy as part of frontline treatment : 19 autologous haematopoietic stem cell transplantation (HSCT) and 5 allogeneic transplantation. Novel agents were used part of induction therapy in 6 cases, at the time of relapse for 9 patients, for both induction and relapse in 16 cases. Thirteen patients received 1 novel agent, 11 received 2 and 7 patients received the 3 novel agents. The median number of lines of therapy was 2 (1 to 4). Bortezomib was used as up front treatment in 15 patients and at relapse for 9 patients. Overall response rate according the IMWG criterias was 70% (17/24) including 11 CR or VGPR (45%). PAD (Bortezomib, Adriamycin and Dexamethasone) and VTD (Bortezomib, Thalidomide, Dexamethasone) regimens provided the best response rates. Lenalidomide was used in 13 patients mostly at relapse. A response was obtained in 53% of patients including 2CR and 2 VGPR (30%). Nineteen patients were treated with Thalidomide-based regimens. Overall response rate was 52% (10/19) including 2 CR and 6 VGPR (31%). Overall, for the whole group of patients, the median progression-free survival was 8 months (0-26) and the median OS was 15 months (6-108). When comparing this survival with that described in our previous experience reported before 1999, we clearly showed that the use of novel agents improved the survival of patients with PCL. Conclusion In this retrospective study, novel agents improved the prognosis of P-PCL. Prospective IFM phase II studies are ongoing to confirm these results. Disclosures: No relevant conflicts of interest to declare.


Leukemia ◽  
2011 ◽  
Vol 26 (1) ◽  
pp. 158-159 ◽  
Author(s):  
H Avet-Loiseau ◽  
M Roussel ◽  
L Campion ◽  
X Leleu ◽  
G Marit ◽  
...  

2020 ◽  
Vol 95 (11) ◽  
pp. 1430-1431
Author(s):  
Yorick Sandberg ◽  
Gert T. Verhoeven ◽  
Floor Weerkamp ◽  
Annemiek Broyl ◽  
Jasper Emmering ◽  
...  

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