The Same Type of Crystalline Inclusions in T-Lymphocytes as in Plasma Cells and B-Lymphocytes in Multiple Myeloma A Pathological Clone Originating from a Common Lymphocyte Stem Cell?

2009 ◽  
Vol 26 (4) ◽  
pp. 265-271 ◽  
Author(s):  
P. Stavem ◽  
Ø. Førre
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
T Lymphocytes ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Crystalline Inclusions

scholarly journals Successful treatment of gastric relapse in multiple myeloma with bortezomib after autologous hematopoietic stem cell transplantation (autoHSCT)

2013 ◽  
Vol 5 (1) ◽  
pp. e2013006
Author(s):  
Serdar Sivgin
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Plasma Cells ◽  
University Hospital ◽  
Hematopoietic Stem ◽  
Relapsed Disease

We report a  case of  59-year-old Turkish   man with history of MVR and COPD whom was diagnosed with stage IIIA IgG lambda multiple myeloma (MM) in 1997. He underwent autologous hematopoietic stem cell transplantation following melphalan 200mg per body area(m2)in February 2006. On 18th of February 2011; he was admitted to the emergency service of university hospital with complaints of hematemesis and melena. In gastric biopsy obtained from the lesion; pathological evaluation showed monoclonal lambda light chain infiltration originated from neoplastic plasma cells in gastric mucosa. The patient was considered as local gastric relapsed disease and was treated with 2 cycles of bortezomib. An excellent response was achieved after  2 cycles of BEP regimen, his paraprotein levels dropped below 10 g/L and there was no recurrence of the hematemesis or melena.

Hypocalcemia during Autologous Stem Cell Transplant with Concurrent Biphosphonate Use in Patients with Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4335-4335
Author(s):  
Kitsada Wudhikarn ◽  
Gregory M. Vercellotti ◽  
Mukta Arora
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Serum Calcium ◽  
Plasma Cells ◽  
Remission Rate ◽  
Calcium Supplementation ◽  
Normal Serum ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Autologous Hsct

Abstract Autologous hematopoietic stem cell transplantation (HSCT) is one of the treatment options which has been shown to enhance remission rate and survival in patients with multiple myeloma. Biphosphonates are used in conjunction with standard therapy and can ameliorate and prevent bony complications, i.e. bone pain, hypercalcemia or fracture, via direct inhibition of osteoclasts and possible anti-tumor effects on malignant plasma cells. With more frequent use of biphosphonates, there are increasing reports of noticeable adverse effects such as osteonecrosis of the mandible, renal failure and hypocalcemia. In this study we report three patients with multiple myeloma who received autologous HSCT accompanied with monthly administration of bisphosphonates and developed significant hypocalcemia post HSCT. All three patients had normal serum calcium levels at diagnosis and prior to transplant. The maximum drop in serum calcium was noted four to ten days post HSCT, and corrected by five to 13 days post HSCT. All three patients received biphosphonates eight to 20 days prior to the episode of hypocalcemia. All patients noted resolution of hypocalcemia with oral and intravenous calcium supplementation over three to ten days. Two patients required ongoing oral calcium supplementation for approximately one month after resolution of hypocalcemia. Multiple potential mechanisms can be postulated for the hypocalcemia in these patients undergoing HSCT such as chronic nutritional deficiency, GI losses, renal losses, vitamin D deficiency in addition to bisphosphonate use. Potentially melphalan, IV fluids, and furosemide may also play roles. Osteoclasts, bone marrow stromal cells and myeloma cells all can modulate calcium levels directly or indirectly through cytokine production. Future laboratory and clinical studies will focus on biochemical marker of complication and attention is needed while using bisphosphonates during autologous HSCT in myeloma patients.

Elimination of CD20-Expressing Cells in Multiple Myeloma by Iodine I-131 Tositumomab (Bexxar®) Correlates with Response to Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5176-5176 ◽  
Author(s):  
Andrzej J. Jakubowiak ◽  
Malathi Hari ◽  
Tara Kendall ◽  
Yasser Khaled ◽  
Shin Mineishi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Clinical Outcomes ◽  
Plasma Cells ◽  
Response To Therapy ◽  
Myeloma Cells ◽  
Consolidation Treatment ◽  
Anti Cd20

Abstract It has been proposed that treatment failures in multiple myeloma (MM) are related to the chemoresistance of a subset of malignant myeloma cells with clonogenic potential to the anti-myeloma drugs (Matsui et al., Cancer Research2008, 68:190). Studies suggest that these putative myeloma stem cells (MSC) are CD138neg and express CD20, which is usually absent in more differentiated malignant plasma cells (Matsui et al., Blood2004, 15:2332). These findings provided a rationale for a treatment strategy to eliminate chemoresistant clonogenic MSC using anti-CD20 antibodies. To evaluate the clinical effects of anti-CD20 treatment, we developed a phase II trial with Bexxar as a consolidation treatment for MM. We hypothesized that Bexxar would be more efficacious than unlabeled antibody in the eradication of highly radiosensitive myeloma cells by both direct and cross-fire effects. Preclinical studies showed that tositumomab, the antibody used in Bexxar, inhibited colony formation of clonogenic myeloma cells. To be eligible for Bexxar treatment, patients must have completed at least 4 cycles of therapy (1st to 3rd line) and have measurable disease in a plateau of at least partial response (PR). To date, 10 of 30 patients have been enrolled, of which 5 were treated with Bexxar after completion of initial therapy prior to proceeding to autologous stem cell transplant (ASCT). Patients proceeding to ASCT required hematopoietic stem cells collection prior to Bexxar and 3 months after Bexxar. Eight patients are evaluable for response and toxicities. At 3 months post Bexxar, 1 patient achieved a partial response (PR), 4 patients had stable disease (SD), and 1 patient progressed (PD). At 1 year post Bexxar, 1 patient with initial PR achieved CR and remains in CR, 1 patient is in unconfirmed CR, 2 are in partial response (PR), and 3 remain in SD. After a median 20 months of followup (range 4–24), all patient are alive, 4 in continued response, 3 with SD. Hematological toxicities were mild to moderate (1 patient grade 3 and 4 patients grade 2 thrombocytopenia, 4 patients grade 2 neutropenia). Non-hematological toxicity was limited to HAMA (6 patients). Out of patients who received Bexxar prior to transplant, 3 collected stem cells post-Bexxar without problems, one requires re-collection. Three patients who proceeded to ASCT to date using the post-Bexxar stem cell collection, engrafted at 11–12 days, and had no unexpected toxicities with ASCT. We also analyzed CD20+ cells in bone marrow aspirates (BM) and stem cell collections (SCC) using samples collected from 4 patients before and after Bexxar. Bexxar treatment eliminated a median 80% of CD20+ cells (range 23–97). For a given patient, elimination of CD20+ cells from SCC correlated with elimination of CD20+ cells from BM. The most complete elimination of CD20+ cells from BM was observed in 2 patients who at 1 year achieved CR (94% and 97%), compared to patients who achieved PR (23% and 68%). We conclude that anti-CD20 consolidation treatment of myeloma patients with Bexxar used as targeted therapy against clonogenic myeloma cells is feasible and well tolerated. Clinical outcomes to date are encouraging considering that clonogenic MSC represent <5% of malignant plasma cells and delayed responses observed in this study could be expected. While early, clinical outcomes appear to correlate with the efficacy of the CD20+ cell elimination by Bexxar treatment in myeloma.

Adaptive Immunotherapy In Multiple Myeloma: Epigenetic Modification and Immunomodulation by Sequential Azacitidine and Lenalidomide to Generate Cancer Testis Antigen Specific Cellular Immune Response

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2926-2926
Author(s):  
Amir A Toor ◽  
Kyle Payne ◽  
Harold M Chung ◽  
Catherine H Roberts ◽  
Roy T Sabo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Response ◽  
Stem Cell ◽  
Plasma Cells ◽  
Residual Disease ◽  
Epigenetic Modification ◽  
Post Transplant ◽  
Cell Counts ◽  
Before And After ◽  
Cell Mobilization

Abstract Abstract 2926 Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Maintenance therapy may delay recurrence but is associated with toxicities, highlighting the need for alternative strategies for long-term disease control. Malignant plasma cells in MM patients occasionally express highly immunogenic cancer testis antigens (CTA). CTA expression is regulated by DNA methylation, and may be increased by 5-azacitidine (Celgene corp., Summit, NJ) (Aza), a DNA hypomethylating agent. The addition of lenalidomide (Celgene corp.) (L) may augment any ensuing adoptive CTA-specific immune response. These immune effector cells may then be collected and adoptively transferred in a setting of lympho-depletion and minimal residual disease following SCT, serving a maintenance function. To demonstrate the feasibility of this approach, we initiated a phase II clinical trial of Aza administered sequentially with L in patients with residual disease following initial therapy (NCT01050790). Three cycles of Aza (75 mg/m2 day 1–5 SQ) and L (10 mg PO daily, day 6–21) were administered every 4 weeks; autologous lymphocytes (AL) were collected around day 21 of the 2nd and 3rd cycles of Aza-L and cryopreserved. Subsequent stem cell mobilization was followed by melphalan 200 mg/m2 and SCT. GM-CSF was used post-transplant for hematopoietic engraftment. Autologous lymphocyte infusion (ALI) was performed between day +30 to +60. Twelve patients have been enrolled; median age is 60 years (range 40–69). Eight are African American, 10 had disease in first partial remission (PR) and 2 in very good PR (VGPR) at the time of initiation of therapy. Median of 2 prior regimens had been administered (range 1–2) and 6 had prior therapy with L. Stage at diagnosis was II (n=6) and III (n=6) and 4 had abnormal cytogenetics. Eight patients have completed all three cycles of Aza-L; 2 developed grade 3 neutropenia, no other grade 3 to 4 toxicity has been observed. Eight patients have gone through both AL collections, 21 days following cycles 2 and 3 of Aza-L, yielding 0.90±0.41 and 0.81±0.36 ×108 CD3+ cells/kg (mean ± SD) with the first and second procedures. Three patients had further disease response, (1 near complete remission, 2 VGPR) and 5 had stable disease following three months of Aza-L, representing a median 18% decline in para-protein levels before and after therapy. So far 8 patients have undergone stem cell mobilization with either GCSF alone (n=6) or GCSF + plerixafor (n=2), and have collected 11.2±3.3 ×106 CD34+ cells/kg body weight. To date 6 patients have undergone SCT (tandem SCT in 1). Neutrophil engraftment was at median of 14 days (13–14), and no unexpected post transplant toxicities were observed. Four patients received ALI at a median 42 days following SCT with no immediate or remote infusional toxicities. With a median follow up of 9 months post-transplant, all four ALI recipients are progression free with either complete remission (n=1) or VGPR (n=3). Quantitative RT-PCR evaluating a panel of 10 CTA in unfractionated bone marrow specimens collected before and after Aza-L from five patients demonstrated 6–8 discrete CTA induced in each patient (Figure 1). This expression was seen in CD138+ plasma cells when tested. In one patient with an induced increase in NY-ESO 1 expression following Aza-L, an antigen specific immune response was recorded (IFN-g release assay) when blood mononuclear cells were co-cultured with recombinant NY-ESO 1 pulsed monocyte derived dendritic cells. This response was maintained for several months post-transplant (Figure 2). Consistent with this observation, CD3+ T cell counts before and after ALI demonstrated a marked increase in T cell counts at two (mean 959/μl; n=4) and eight (1277/μl) weeks, compared with baseline (414/μl; P=0.05); no difference was seen in the NK cell counts at these times. Further studies to confirm these observations in the remaining patients are ongoing. In conclusion, we demonstrate the safety and feasibility of epigenetic modification resulting in over-expression of antigenic targets in MM. This may then be exploited in formulating adaptive immunotherapy protocols in these patients. Adoptively transferred cells may maintain long-term surveillance against malignant plasma cells in patients with MM. Disclosures: Toor: Celgene corporation: Research Funding. Off Label Use: azacitidine in multiple myeloma. Manjili:Celgene corporation: Research Funding.

A Morphologic and Immunohistochemical Study of the Bronchus-associated Lymphoid Tissue of Pigs Naturally Infected with Mycoplasma hyopneumoniae

2003 ◽  
Vol 40 (4) ◽  
pp. 395-404 ◽  
Author(s):  
J. Sarradell ◽  
M. Andrada ◽  
A. S. Ramírez ◽  
A. Fernández ◽  
J. C. Gómez-Villamandos ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
B Lymphocytes ◽  
Lamina Propria ◽  
Lymphoid Tissue ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Immunohistochemical Study ◽  
Mycoplasma Hyopneumoniae ◽  
High Morbidity ◽  
Alveolar Septa

Porcine enzootic pneumonia (PEN), caused by Mycoplasma hyopneumoniae (Mh), has been described in pigs in all geographic areas. The disease is characterized by high morbidity and low mortality rates in intensive swine production systems. A morphologic and immunohistochemical study was done to determine the cellular populations present in lung parenchyma of infected pigs, with special attention to the bronchus-associated lymphoid tissue (BALT). Polyclonal and monoclonal antibodies were used for the detection of antigens of Mh, T lymphocytes (CD3+, CD4+, and CD8+), IgG+ or IgA+ lymphocytes, and cells containing lysozyme, S-100 protein, major histocompatibility complex class II antigen or myeloid-histiocyte antigen. Findings in lung tissues associated with Mh infection were catarrhal bronchointerstitial pneumonia, with infiltration of inflammatory cells in the lamina propria of bronchi and bronchioles and alveolar septa. Hyperplasia of mononuclear cells in the BALT areas was the most significant histologic change. The BALT showed a high morphologic and cellular organization. Macrophages and B lymphocytes were the main cellular components of germinal centers. T lymphocytes were primarily located in perifollicular areas of the BALT, lamina propria and within the airway epithelium, and plasma cells containing IgG or IgA at the periphery of the BALT, in the lamina propria of bronchi and bronchioles, in alveolar septa, and around bronchial submucosal glands. The hyperplastic BALT in PEN cases consisted of macrophages, dendritic cells, T and B lymphocytes, and IgG+ and IgA+ plasma cells. CD4+ cells predominated over CD8+ cells. Local humoral immunity appears to play an important role in the infection.

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