Monoclonal Gammopathy After Allogeneic Hematopoietic Stem Cell Transplant As a Marker For GvHD Onset

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5484-5484
Author(s):  
Federico Monaco ◽  
Francesco Zallio ◽  
Gioacchino Catania ◽  
Maria Teresa Corsetti ◽  
Lia Mele ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Monoclonal Gammopathy ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
The Past ◽  
Non Hodgkin Lymphoma

Abstract Background/Aims Transient monoclonal gammopathy is a common alteration of laboratory test after allogeneic stem cells transplantation (alloBMT). However, until now, only scattered works have been published about it. The main paper reported on PubMed, regarding transient monoclonal gammopathy, was presented by the Dana Farber's group at the end of the eighties. The author of that paper showed an apparently strong correlation between development of graft versus host disease (GvHD) and appearance of a monoclonal gammopathy. Starting from that observation, we decided to evaluate among our allogeneic transplanted patients the incidence of M-component and its possible relationship with GvHD. Patient and Method 67 patients undergoing alloBMT at the Haematology Unit of Alessandria (Italy) between 2006 and 2010 were evaluated: 52% of patients were male and 48% were females. Pre-transplantation diagnosis included: 34 acute myeloid leukaemia (50.7%), 8 acute lymphoblastic leukaemia (11.9%), 7 non-Hodgkin Lymphoma (10.4%), 6 chronic leukaemia (9%), 4 myelodysplastic syndrome (6%), 2 Hodgkin lymphoma (3%) and 6 other less common malignancies (9%). All patients had, at least, two pre-transplantation serum electrophoresis with no evidence of pre-existing monoclonal component; for the analysis, we haven’t considered patients submitted to alloBMT for myeloma. Controls of serum electrophoresis were performed at 90, 180 and 360 days after transplantation. In our survey, 17 patients relapsed after alloBMT, 27 patients developed GvHD and 26 patients died. Post-transplantation follow up ranged from 81 to 2514 days with a median of 496 days. Results As a whole, 35/67 (52%) of the patients developed monoclonal gammopathy after transplantation. Comparing patients with or not monoclonal gammopathy after alloBMT, an increased GvHD development (54% vs 34%) and a decreased relapse incidence (19% vs 32%) was observed. Otherwise, analysing the appearance of monoclonal gammopathy at defined time-points, we have not detected any difference in overall survival, GvHD development, relapse incidence and post-transplantation mortality at +90 and +180 days post transplant. Vice versa, an increased GvHD development (50% vs 21% at median +378 days) was observed in patients with an appearance of monoclonal gammopathy at +360 days; so it seems that the presence of a M-component is associated only lately after 360 days to the possibility of GvHD development. Conclusion Evidence for monoclonal B-cell proliferation is common within the first year after alloBMT. The few papers published in the past found this proliferation more frequently associated with GVHD but without any long term adverse effect. Our data would seem to confirm a correlation between appearance of monoclonal gammopathy post-transplantation and GvHD development. In the past, the explanation for the evidence of a monoclonal gammopathy was associated to an aberrant immune reconstitution after alloBMT. Nevertheless in the last year it has been shown that B cells are involved in the pathogenesis of chronic GVHD (cGVHD) and anti-B-cell therapy can be used for the treatment of cGVHD. A prospective study with a larger population should be considered, in order to confirm our results and assay post-transplantation monoclonal gammopathy as an early marker for GvHD development. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1259-1266 ◽  
Author(s):  
Mark S. Kaminski ◽  
Judith Estes ◽  
Kenneth R. Zasadny ◽  
Isaac R. Francis ◽  
Charles W. Ross ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
De Novo ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Cell Transplant ◽  
Non Hodgkin Lymphoma ◽  
Therapeutic Doses ◽  
131I Tositumomab

Abstract CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine 131I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P = .005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine 131I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL.

High dose chemotherapy with autologous stem cell transplant for patients with transformed B-cell non-Hodgkin lymphoma in the rituximab era

2014 ◽  
Vol 55 (10) ◽  
pp. 2319-2327 ◽  
Author(s):  
Yngvild N. Blaker ◽  
Marianne B. Eide ◽  
Knut Liestøl ◽  
Grete F. Lauritzsen ◽  
Arne Kolstad ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Stem Cell Transplant ◽  
High Dose Chemotherapy ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Non Hodgkin Lymphoma

Redox Associated Gene Expression Predicts For Responses To The Pro-Oxidant Molecule Imexon In Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma: Results Of a Multi-Center Phase II Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 89-89
Author(s):  
Paul M. Barr ◽  
Margaret M. Briehl ◽  
Steven H Bernstein ◽  
Jonathan W. Friedberg ◽  
Andrea Baran ◽  
...  
Keyword(s):  
Gene Expression ◽  
Partial Response ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Cell Transplant ◽  
Prior Therapy ◽  
Non Hodgkin Lymphoma ◽  
Antioxidant Defense Enzymes ◽  
Pre Treatment

Abstract Background Imexon is a 1-carboxamido-2-cyan-aziridine isomer investigated as an anti-cancer agent given its pro-oxidant properties. By binding reduced sulfhydryls leading to the accumulation of reactive oxygen species, imexon interferes with the endoplasmic reticulum and mitochondrial reduction-oxidation (redox) balance, inhibiting protein translation and cell growth and inducing apoptosis. Pre-clinical studies demonstrated activity across an array of tumor cells in vitro and increased activity amongst B-cell non-Hodgkin lymphomas (NHL). A partial response in a follicular lymphoma (FL) patient was observed in a previous phase I study. This phase II trial was initiated to further investigate the clinical activity of imexon in patients with relapsed or refractory NHL. Methods Histologically confirmed NHL, > 1 prior therapy, age≥18, ECOG performance status 0–2, measurable disease, signed informed consent, creatinine and bilirubin < 2.0 x IULN as well as G6PD > IULN were required. Patients were treated with imexon 1000 mg/m2 IV daily on days 1-5 of a 21 day cycle for up to 1 year. Messenger RNA analysis was performed on pre-treatment tumor specimens, evaluating 22 genes important for antioxidant enzyme expression, 16 genes previously associated with outcome in NHL as well as 4 immune cell surface markers. Included were 13 genes used to generate a redox signature score, previously demonstrated to correlate with NHL prognosis (Tome, Blood 2005). Results Twenty-two NHL patients [9 FL, 5 diffuse large B cell (DLBCL), 3 mantle cell, 2 transformed follicular, 2 chronic lymphocytic leukemia and 1 Burkitt] with a median age of 64 (range 43-92) completed a median of 2.5 (range 1-13) cycles of therapy. With a median number of 4 prior therapies, 9 patients had undergone a prior stem cell transplant, 10 had stage IV disease and 6 were refractory to prior therapy. Twenty patients were evaluable for response, 2 pts discontinued therapy during cycle 1 due to progressive disease and grade 5 sepsis respectively. Of the 20 evaluable patients, the overall response rate was 30% (6/20) with another 35% achieving stable disease. Responses were observed in 4 FL and 2 DLBCL pts. After a median follow-up of 7 months, the median progression free survival (PFS) was 2.4 mos (range, 0.6 to 19.1 mos) with a median PFS of 6.7 mos (range, 1.2 to 9.0 mos) in FL patients. The median overall survival has not been reached. Grade 3 and 4 toxicities consisted of anemia (7 pts), thrombocytopenia (2 pts), neutropenia (2 pts), sepsis (2 pts), vomiting (2 pts), pneumonia (2 pts), fatigue (2 pts), dehydration (2 pts) as well as hypokalemia, hyperuricemia, transient ischemic attack, increased creatinine, rash and urinary tract infection in 1 pt each. 13 pts had available pre-treatment tumor biopsies, 2 of which attained a partial response with therapy. Patients with a higher redox score were more likely to achieve an objective response (p=0.03). Further, individual genes most predictive of response included CD68, GPX1 and SOD2. Conclusions This is the first trial to demonstrate that targeting the cellular redox environment is a viable therapeutic strategy in NHL and may be particularly effective in FL. The side effect profile may lend imexon to rational combination studies. Lymphomas reliant on antioxidant defense enzymes for proliferation and survival may be more susceptible to redox directed therapy. Evaluation of antioxidant related gene expression as a predictive biomarker is warranted in future investigations of imexon and similar targeted agents. (NCT01314014) Disclosures: Barr: Seattle Genetics: Consultancy; Celgene: Consultancy. Off Label Use: Imexon; being investigated for use in Non-Hodgkin lymphoma. Schwartz:HTG Molecular Diagnostics: Employment. Dorr:Amplimed Corporation: Employment.

scholarly journals SLAMF7 in Primary Effusion Lymphoma, Target for Individualized Therapy?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5300-5300
Author(s):  
Hilmar Quentmeier ◽  
Claudia Pommerenke ◽  
Wilhelm G Dirks ◽  
Vivien Hauer ◽  
Max Koeppel ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Primary Effusion Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Differentiation ◽  
Expression Array ◽  
Non Hodgkin Lymphoma ◽  
Novel Therapeutic Strategies

Abstract Primary effusion lymphoma (PEL) is a rare, aggressive form of B-cell lymphoma. With a median survival time of around six months the prognosis for PEL patients is poor. Therefore, there is a medical need for novel therapeutic strategies. We performed expression array analysis to find potential targets for antibody-based therapy. Unsupervised clustering analysis revealed that PEL cell lines grouped separate from cell lines derived from other B-non Hodgkin lymphoma (B-NHL) entities. Notably, PEL and Hodgkin Lymphoma (HL) cell lines clustered on one arm, separate from all cell lines representing less-differentiated B-NHL variants. PEL and HL cell lines were characterized by a set of common up- and downregulated genes. Typical for PEL and HL was the expression of CCND2 and the absence of Brutons tyrosine kinase and of B-cell markers including CD19, CD20, CD79A and CD79B. Highly expressed in PEL - but not in HL - were CD138, IL-10, SLAMF7 and PRDM1. PRDM1/BLIMP1 is a master regulator of terminal B-cell differentiation. Originally described as repressor, BLIMP1 can also enhance transcription of SLAMF7 in multiple myeloma (MM) and of IL-10 in type 1 regulatory T-cells. Thus, coexpression of the three genes suggests a causal relationship between transcriptionally active PRDM1/BLIMP1 and its targets SLAMF7 and IL-10 also in PEL. Expression of SLAMF7 in PEL is especially noteworthy because a monoclonal antibody targeting SLAMF7 (elotuzumab) has been approved for treatment of patients with MM. We observed that SLAMF7 is comparably expressed in PEL and in MM cell lines. If the results on cell lines can be translated to primary PEL, i.e. if PEL tumor cells express SLAMF7, the patients might benefit from an antibody-based targeted therapy against this antigen. Disclosures No relevant conflicts of interest to declare.

scholarly journals Improved Outcome of Relapsed or Refractory Pediatric B-Cell Non-Hodgkin Lymphoma in Japan

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5078-5078
Author(s):  
Tomoo Osumi ◽  
Tetsuya Mori ◽  
Naoto Fujita ◽  
Akiko M. Saito ◽  
Atsuko Nakazawa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Rate ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Salvage Therapy ◽  
Combined Treatment ◽  
B Cell Lymphoma ◽  
Overall Survival Rate ◽  
Hematopoietic Stem ◽  
Non Hodgkin Lymphoma

Abstract Introduction Relapsed or refractory pediatric B-cell non-Hodgkin lymphoma (B-NHL) has been reported to be extremely difficult to cure. We previously conducted a retrospective study of pediatric relapsed or refractory B-NHL in Japan between 1996 and 2004 and found that the four-year overall survival rate was only 20.5% (Fujita N. e al. PBC. 2008). Rituximab, a chimeric anti-CD20 monoclonal antibody, is expected to be effective in improving the prognosis of pediatric relapsed or refractory B-NHL and was approved for use in 2003 in Japan. Here, we retrospectively assessed the treatment and prognosis of pediatric relapsed or refractory pediatric B-NHL in the rituximab era in Japan. Methods We collected relapsed pediatric B-NHL cases from patients enrolled in our current study, JPLSG B-NHL03 study, which was the first nationwide multicenter trial for newly diagnosed pediatric B-NHL. We collected information on treatment and outcome after induction failure or relapse. Results In 33 patients enrolled this study, the median age at diagnosis was 9.7 years and male predominance was observed. Nine cases were pathologically subclassified initially as diffuse large B-cell lymphoma, 11 as Burkitt lymphoma, 11 as Burkitt Leukemia and two as others. According to initial Murphy staging, most cases were in the advanced stage. The most common site of relapse was abdomen (8 cases), followed by bone marrow (8 cases) and central nervous system (7 cases). Twenty-three cases relapsed in one site while 10 did so in multiple sites. Among them, 20 relapsed within six months after initial diagnosis. Among them, 28 patients received some rituximab combined treatment as salvage therapy. R-ICE (rituximab, ifosfamide, carboplatin and etoposide) regimen was the most popular and used in 22 patients as first-line salvage therapy. As a result, 22 patients (66.7%) achieved complete remission (CR) by some salvage therapy. 23 received hematopoietic stem cell transplantation (HSCT). Their 5-year overall survival rate was 48.5%, which was far more superior to both our previous study (Figure 1) and another on relapsed or refractory B-NHL in childhood. In risk factor analysis for survival, rituximab combined treatment and HSCT did not influence the outcome, but achievement of CR after salvage treatment resulted in significantly better survival (68.2% vs 9.1%, p=0.001). These results suggest that the advent of rituximab induced an improvement of CR rate for relapsed paediatric B-NHL, which resulted in an improvement of the survival rate. Conclusion In conclusion, the prognosis of the pediatric relapsed or refractory B-NHL in a Japanese cohort remained poor but is showing improvement in the rituximab era. Disclosures No relevant conflicts of interest to declare.

Signal-Regulatory Protein-α (SIRP- α) Expression Delineates Distinct Subsets in Monocytes/Macrophages in Normal Tissue and in B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2515-2515
Author(s):  
Ya-Ping Chen ◽  
Zhi-Zhang Yang ◽  
Jose C. Villasboas ◽  
Tammy Price-Troska ◽  
Hyo Jin Kim ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Regulatory Protein ◽  
Normal Tissues ◽  
Non Hodgkin Lymphoma ◽  
Biopsy Specimens

Abstract BACKGROUND Monocytes and macrophages (mo/mΦ) are a key part of the composition of peripheral blood (PB) and tissues and increased numbers of mo/mΦ have been associated with patient outcome in non-Hodgkin lymphoma (NHL). Because CD14 is abundantly expressed on the surface of human mo/mΦ, it is often used to identify or isolate human mo/mΦ, and immunosuppressive CD14+HLA-DRlow monocytes have been shown to be increased in the peripheral blood of NHL patients. However, we have previously shown that CD14 expression on mo/mΦ is substantially lower than CD68 expression suggesting that many CD68+ mo/mΦ are CD14 negative, especially in spleen and lymph node tissues. To characterize both CD14+ and CD14- mo/mΦ in PB and tissues, we isolated all mo/mΦ from B-cell NHL specimens and normal controls and assessed their phenotype and function. METHODS Human mo/mΦ were isolated by negative selection from PB and tissue biopsy specimens (B-cell NHL and normal tissues) using the immunomagnetic isolation (monocyte enrichment kit). Morphological and immunophenotypic characteristics of isolated mo/mΦ were determined by Giemsa stain and flow cytometry. Phagocytosis and migration assays were used to determine the function of isolated mo/mΦ. T cells were co-cultured with mo/mΦ and T cell proliferation was evaluated by CFSE staining and detected by flow cytometry. RESULTS Using a monocyte enrichment kit to isolate all mo/mΦ, the purity of isolated mo/mϕ was 85~99%, which was defined by the percentage of lineage-negative cells (i.e. cells without expression of CD3,CD19, CD20, and CD56). We found that these isolated mo/mΦ constituted 2 populations: a more frequent population of larger cells and a less common population of smaller cells. In contrast to PB, CD14 positive mo/mΦ constituted less than 40% of the tissue mo/mΦ from the isolated population. Furthermore, we found that the cell size from CD14+ mo/mΦ were larger than CD14- mo/mΦ. Using CD14 and SIRP-α, we could identify 3 populations of mo/mΦ: CD14+SIRP-αhigh, CD14-SIRP-αdim and CD14-SIRP-α- cells. CD14+SIRP-αhigh cells and CD14-SIRP-αdim cells typically constituted the population of larger cells, while CD14-SIRP-α- cells constituted the population of smaller cells. CD14-SIRP-α- cells lacked the typical phenotypic markers and had decreased phagocytic and migratory ability compared to CD14+SIRP-αhigh and CD14-SIRP-αdim cells. Furthermore, we found that these 3 populations of mo/mΦ had a differential effect on activated T-cells and that the CD14-SIRP-α- cells appeared increased number in biopsy specimens from NHL when compared to normal tissues. CONCLUSIONS We have identified a unique population of small CD68+ mo/mΦ that lack expression of CD14, SIRP-α, and other FcγR markers. This subset of mo/mΦ is more prevalent in NHL tissues and has limited phagocytic and migratory functions. This CD14-SIRP-α- mo/mΦ subpopulation may play an inhibitory role in anti-cancer and inflammatory responses. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparison of Disposition and Complications in Geriatric (≥ 65 years) and Non-Geriatric (50-64 years) Cancer Patients Receiving Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2408-2408 ◽  
Author(s):  
Achuta Kumar Guddati ◽  
Gagan Kumar ◽  
Robert David Lewis ◽  
Iuliana Shapira
Keyword(s):  
Stem Cell ◽  
Nursing Homes ◽  
Cancer Patients ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Autologous Transplantation ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Discharge Disposition ◽  
The Past

Abstract Background:.The disposition and complications of hematopoietic stem cell transplant (HSCT) in the geriatric population has not been extensively studied and compared with younger patients. We have analyzed a database with nationwide representation for outcomes of HSCT in these patients over a 12 year period. Methods: Data regarding patients who underwent HSCT was extracted from the Nationwide Inpatient Sample (NIS) from 2000 to 2011 using ICD-9-CM codes. HSCT hospitalizations were classified into allogeneic transplantation, autologous transplantation, subsequent hospitalization (s/p transplant) with graft versus host disease (GVHD) and subsequent hospitalization (s/p transplant) with other complications. NIS variables were used to identify in-hospital complications and discharge disposition. Chi square test and Wilcoxon rank test were used to compare categorical and continuous variables respectively. Results: The proportion of elderly patients (≥ 65 years) receiving autologous transplants and being discharged to nursing homes has increased over the past decade when compared to a younger patient population. Notably, the rate of major complications: mechanical ventilation, tracheostomy and requirement of new dialysis are similar in both the patient populations. The trends from 2000 to 2011 are summarized in Table 1. Conclusion: Although the rate of transplant-associated complications are similar in geriatric and non-geriatric populations, a higher percentage of geriatric cancer patients who receive HSCT are discharged to nursing homes. These rates have not significantly changed over the past decade (p > 0.05). More medical services and resources will be required to support the growing elderly population undergoing HSCT. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

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