Appraisal of IgM Kappa/IgM Lambda Variations Using HevyLite® After Rituximab As Consolidation Therapy in Patients with Waldenström's Macroglobulinemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4879-4879
Author(s):  
Jean-Richard Eveillard ◽  
Achouak Achour ◽  
Françoise N'Go Sack ◽  
Adrian Tempescul ◽  
Ronan LE Calloc'h ◽  
...  
Keyword(s):  
Partial Response ◽  
Binding Site ◽  
Light Chain ◽  
Threshold Value ◽  
Light Chains ◽  
Critical Threshold ◽  
Chop Regimen ◽  
Gamma Receptor ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4879 Background: In Waldenström's Macroglobulinemia (WM), response rates to rituximab (RTX) range from 30% to 75%. RTX is also known to generate a transient IgM flare in some patients. Our study aimed to characterize this phenomenon using the newly Hevylite® assay developed by The Binding Site that specifically quantifies IgM-kappa(K) and IgM-lambda(L). Methods: Between 2007 and 2009, 33 WM patients received a 6-course fludarabine-based regimen, 32 as first and 1 as second line. Partial response (PR), defined as a reduction ≥50% but <90% in baseline monoclonal peak (BMP) on serum protein electrophoresis (SPE), was the minimal goal. Two of the 32 patients treated at first line needed further treatment with CHOP regimen to reach the minimal PR. All received 4 consecutive weekly IV injections of 375 mg/m2 of RTX as consolidation. All were tested using the SPAplus analyzer for residual IgM-K and IgM-L at first and fourth injection. Monoclonal IgM-K or IgM-L level variations and IgM-K/IgM-L ratios were analyzed. SPE and immunofixation (IF) were performed 3 months after the fourth RTX injection to evaluate the impact of consolidation on response. Results: Of the 33 tested, at a variation threshold ≥20% relative to baseline IgM levels, 3 subgroups were defined: 15 or 45.5%, the no-flare patients, showed an increase or a decrease <20%, 11 or 33.3%, the flare patients, showed an increase ≥20% while 7 or 21.2%, the anti-flare patients, showed a decrease ≥20%. In the no-flare subgroup, there was no significant difference in monoclonal K (9) and L (6) light chains while in the 18 but 1 patients of the merged flare and anti-flare subgroups, monoclonal K light chain was overrepresented as there were 17 K vs 1 L (p<0.05). A highest initial IgM-K/L ratio (p<0.005) characterized the flare subgroup. No association was seen with demographic and hematologic characteristics and RTX pharmacokinetics. Regarding Fc gamma receptor (FcγR) IIIa-158 polymorphism, 10 patients were defined as VF and 5 as FF in the no-flare subgroup, 3 as VF, 3 as FF and 1 as VV in the anti-flare subgroup, 3 as VF and 8 as FF in the flare subgroup, with no statistically significant difference between the last 2 subgroups (p=0.22). We also analyzed the data without defining a critical threshold in monoclonal IgM level variations. Patients were, then, separated in 2 subgroups: 17 flare patients and 16 anti-flare patients. Monoclonal K light chain was overrepresented in the 2 subgroups, with 13 K vs 4 L in flare patients and 13 K vs 3 L in anti-flare patients; no statistically significant difference was found between them regarding monoclonal K and L light chains (p=0.32). No association was seen with demographic and hematologic characteristics and RTX pharmacokinetics. Regarding FcgR IIIa-158 polymorphism, there was a statistically significant difference (p=0.03) as 12 patients were of the FF subtype and 5 of the VF one in the flare subgroup while 4 were of the FF subtype, 11 of the VF one and 1 of the VV one in the anti-flare subgroup. At response evaluation 3 months after the fourth injection of RTX, all patients were screened for SPE and 22 for IF. When we compared the 17 patients of the flare subgroup to the 16 ones of the anti-flare subgroup, no patient vs 1 reached complete remission defined as disappearance of BMP on SPE and negativity of IF, 1 vs 6 advanced to very good partial response defined as a decrease ≥90% in BMP on SPE and positivity of IF and the remaining 16 vs 9 improved their partial response by a mean additional reduction of 20% (range: 0–30%) vs 18.75% (range: 0–50%) in BMP, but there was no statistically significant difference in this regard (p=0.79). Conclusions: Using Hevylite® assay, monoclonal IgM up and down variations of at least 20% following RTX occurred in up to 54.5% of our patients and this raised to 100% when no threshold value was considered. Such assay provides a reliable and highly sensitive quantitative assessment, especially in patients whose monoclonal IgM was at low concentration. Patients of the flare subgroup were predominantly of the FF subtype of FcgR IIIa-158 polymorphism while patients of the anti-flare subgroup were predominantly of VF subtype, which was statistically significant. It is tempting to hypothesize a difference in RTX mechanism of action, with ADCC predominating in the anti-flare subgroup and CDC in the flare subgroup. It would be of interest to assess such an hypothesis on a larger cohort and to analyze its impact on response profile. Disclosures: Pietrantuono: The Binding Site: Employment.

scholarly journals Downmodulation of Vaccine-Induced Immunity and Protection against the Intracellular BacteriumFrancisella tularensisby the Inhibitory Receptor FcγRIIB

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Brian J. Franz ◽  
Ying Li ◽  
Constantine Bitsaktsis ◽  
Bibiana V. Iglesias ◽  
Giang Pham ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Immune Protection ◽  
Fc Gamma Receptor ◽  
Gamma Receptor ◽  
Significant Difference ◽  
Cytokine Levels ◽  
Iga Production ◽  
Protection Against Infection ◽  
The Impact

Fc gamma receptor IIB (FcγRIIB) is the only Fc gamma receptor (FcγR) which negatively regulates the immune response, when engaged by antigen- (Ag-) antibody (Ab) complexes. Thus, the generation of Ag-specific IgG in response to infection or immunization has the potential to downmodulate immune protection against infection. Therefore, we sought to determine the impact of FcγRIIB on immune protection againstFrancisella tularensis(Ft), a Category A biothreat agent. We utilized inactivatedFt(iFt) as an immunogen. Naïve and iFt-immunized FcγRIIB knockout (KO) or wildtype (WT) mice were challenged withFt-live vaccine strain (LVS). While no significant difference in survival between naïve FcγRIIB KO versus WT mice was observed, iFt-immunized FcγRIIB KO mice were significantly better protected than iFt-immunized WT mice.Ft-specific IgA in serum and bronchial alveolar lavage, as well as IFN-γ, IL-10, and TNF-αproduction by splenocytes harvested from iFt-immunized FcγRIIB KO, were also significantly elevated. In addition, iFt-immunized FcγRIIB KO mice exhibited a reduction in proinflammatory cytokine levelsin vivoat 5 days after challenge, which correlates with increased survival followingFt-LVS challenge in published studies. Thus, these studies demonstrate for the first time the ability of FcγRIIB to regulate vaccine-induced IgA production and downmodulate immunity and protection. The immune mechanisms behind the above observations and their potential impact on vaccine development are discussed.

The Impact of Different Mobilization Strategies in the Setting of Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3254-3254
Author(s):  
Francesco Mazziotta ◽  
Gabriele Buda ◽  
Nadia Cecconi ◽  
Giulia Cervetti ◽  
Lorenzo Iovino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Peripheral Blood ◽  
High Dose ◽  
Roc Curve Analysis ◽  
Cd34 Cells ◽  
Significant Difference ◽  
The Impact

INTRODUCTION Multiple myeloma (MM) is considered an incurable disease. Despite the introduction of novel agents allowed deeper response, high-dose chemotherapy and autologous stem cell transplantation (ASCT) remain the standard of care for patients (pts) in good clinical conditions. The most used strategies to mobilize stem cells from bone marrow (BM) into peripheral blood are high-dose cyclophosphamide (HD-CTX) plus G-CSF and G-CSF plus plerixafor (G-CSF+P). The goal of this retrospective study is to investigate whether the two different mobilization strategies have an impact on the clearance of monoclonal PCs in the apheresis products and on pts' outcome. PATIENTS AND METHODS We analyzed 62 pts (median age 61, range 41-75, 37 males and 25 women) diagnosed with MM and treated with ASCT between Mar 2014 and Mar 2018 at our Hematology Division (Pisa, Italy). All pts received induction therapy with at least 4 cycles of bortezomib, thalidomide and dexamethasone (VTD). 9/62 pts obtained a less than partial response (PR) and received lenalidomide-based regimens. After induction, 8 (12,9%) pts achieved complete remission (CR), 26 (41,9%) were in PR, 28 (45,2%) obtained a very good partial response (VGPR). 43/62 fit pts received HD-CTX (2-3 g/sqm) on day 1 followed by G-CSF (30 MU/day) started on day 4 until day 7, increased to 60 MU/day from day 8 until the end of apheresis. In 19/62 pts, after 4 days of G-CSF (60 MU/day) administration and not sufficient mobilization, we added plerixafor (0,24 mg/kgbw) for up to 4 consecutive days. In 43/62 pts we collected apheresis samples (10μl) analyzed through flow citometry to enumerate clonal residual PCs. The panel used to asses clonality included: CD138 Per-Cp, CD38 APC, CD19 PE-Cy7, CD45 APC-Cy7, cytoplasmic immunoglobulin K chain and L chain. RESULTS At the end of the peripheral blood stem cell (PBSC) collection, pts treated with HD-CTX presented a higher CD34+ absolute count (p=0.0489) and achieved the threshold of 5x106 CD34+ cells/kgbw in a significantly (p=0.006) higher percentage. We found a nearly significant (p=0.0517) lower count of CD34+ PBSCs in pts who received lenalidomide-based regimens before the mobilization. Performing flow citometry on apheresis samples, we observed that the number of the harvested clonal PCs showed a significant correlation (p=0.0115) with the occurrence of post-ASCT relapse. ROC curve analysis investigating the predictive effect of the number of pathological PCs on disease relapse showed an area under the curve of 0,6978 (95% CI 0.5392-0.8564; p=0.0267). Neither BM residual PCs detectable on BM biopsies performed before apheresis (r=-0.1323; p=0.609) nor the type of mobilization scheme (p=0.707) had an impact on the proportion of clonal PCs in the graft. Additionally, we did not observe any statistically significant difference in progression free- (PFS) (p=0.8276) and overall survival (OS) (p=0.2475) between the HD-CTX and G-CSF+P groups. DISCUSSION PBSC mobilization has a succession rate > 85%. Despite the use of HD-CTX to increase PBSC yields and decrease tumor burden, there is not clear evidence of a superior mobilization strategy. Additionally, HD-CTX has a not negligible toxicity and approximately 10% of the pts require hospitalization. Conversely, G-CSF+P is a safe and effective approach also in poor mobilizers. In our study, we observed a significative difference in the apheresis yields (p=0.0489) and in the percentage of pts who achieved the threshold of 5x106 CD34+ cells/kgbw (p=0.006) in favor of HD-CTX. Additionally, the detection of harvested residual clonal PCs could be a promising strategy to recognise pts more likely to relapse after ASCT. Nonetheless, we failed to demonstrate a superior effect of HD-CTX in the clearance of harvested clonal PCs, in agreement with the absence of a different pts' outcome amongst the two mobilization strategies. In conclusion, the choice between the two regimens is challenging and requires careful consideration of multiple factors. Overall, young fit pts, especially in the high-risk setting, should be treated with all appropriate modalities including chemiomobilization followed by double-ASCT. Conversely, in pts candidate to a single-ASCT it is reasonable to use G-CSF+P, since HD-CTX does not improve PFS and OS and add toxicity. The absence of an in-vivo purging effect on apheresis products of chemiomobilization further strengthens a chemotherapy-free mobilization. Disclosures Galimberti: Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau.

Intact Immunoglobulin or Fragments Thereof Can Be Detected in Urine in a Proportion of Patients with Multiple Myeloma and Are Associated with Reduced Survival At Presentation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1828-1828
Author(s):  
Heinz Ludwig ◽  
Philip Young ◽  
Dejan Milosavljevic ◽  
Niklas Zojer ◽  
Wolfgang Hübl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Binding Site ◽  
Light Chain ◽  
Free Light Chain ◽  
Light Chains ◽  
Glomerular Injury ◽  
Female Ratio ◽  
Serum Free ◽  
Serum Free Light Chain

Abstract Abstract 1828 Introduction: Intact immunoglobulin or fragments thereof (intact/fragmented Ig) can be found in the urine due to nephrotic injury or the preferential scavenging of albumin by the renal FcRn receptor leading to immunoglobulin catabolism. Until now the occurrence, frequency and clinical impact of this phenomenon has not been assessed in patients with multiple myeloma (MM). Here we determine the incidence of intact/fragmented Ig in urine and evaluate its prognostic relevance. Patients and Methods: 94 patients with MM, median age 70 years old (range 41–87) with a male / female ratio 28/66, ISS stage I (48), stage II (23), stage III (28), 69 IgG (43 IgGk/26 IgGl) and 25 IgA (15 IgAk/7 IgAl) were enrolled. Serum free light chain concentrations (sFLC) were measured using commercially available immunoassays (Freelite™, The Binding Site, Birmingham, UK) and compared to electrophoresis results (Hydrasys, Sebia, Paris, France). Overall survival was estimated by the product limiting method of Kaplan-Meyer and survival was compared by the log rank test. Results: Overall, sFLC ratios had a greater sensitivity than urine immunofixation (uIFE) for the detection of monoclonal light chains 86/94 vs. 46/94. In 13/46 (28%) uIFE positive patients intact immunoglobulins or significant fragments (intact/fragmented Ig) thereof were detected, 12 IgG, (12/69, 17%) and 1 IgA (1/25, 4%). Three of these patients had normal urine protein concentrations (<250mg/L) and 2/13 patients had glomerular injury identified by increased levels of albumin excretion. There was no difference in creatinine levels between patients with or without intact/fragmented Ig (p=0.673). Analysis of overall survival in patients stratified at presentation according to uIFE results, namely the presence of intact/fragmented Ig, abnormal serum free light chain ratio-, and negative uIFE results revealed significantly shorter overall survival for the intact/fragmented Ig group (median OS: 34.5 vs. 66.0, vs. 80.6 months, respectively, p< 0.048) (figure 1). Discussion: Our findings confirm the superiority of the serum free light chain assay for detection of monoclonal free light chains as compared to urine immunofixation. However, the serum free light chain assay is inadequate for detection of intact/fragmented Ig in urine. The most important finding presented here is the observation that intact and/or fragment immunoglobulin is present in a substantial number of patients with MM. This phenomenon is mainly restricted to IgG isotypes. There are two possible explanations for these findings: first, the presence of glomerular injury, but this phenomenon (increased albumin leakage) was only seen in two patients and hence is unlikely to account for this observation. The second explanation relies upon disruption of the FcRn receptor function in immunoglobulin scavenging. This receptor will preferentially scavenge albumin in the renal setting, but dysfunction may lead to increased immunoglobulin catabolism and the presence of intact and/or fragmented Ig (Sarav, JASN, 20: 1941–1952, 2009). The results may reflect a hitherto unidentified subtle renal dysfunction. In line with this notion overall survival in our patients intact/fragmented Ig was found to be significantly shorter. Conclusion: We observed an unexpected high incidence of intact/fragmented Ig in the urine of our patients with MM. Patients with urinary excretion of intact/fragmented immunoglobulin had significantly shorter survival. These findings should be validated in further studies. Disclosures: Young: Binding Site: Employment. Harding:Binding Site: Employment.

scholarly journals Clathrin assembly involves a light chain-binding region.

1987 ◽  
Vol 105 (5) ◽  
pp. 2011-2019 ◽  
Author(s):  
G S Blank ◽  
F M Brodsky
Keyword(s):  
Monoclonal Antibodies ◽  
Binding Site ◽  
Heavy Chain ◽  
Light Chain ◽  
Intermediate Filament ◽  
Binding Sites ◽  
Light Chains ◽  
Binding Region ◽  
Intermediate Filament Proteins ◽  
Interaction Site

Two regions on the clathrin heavy chain that are involved in triskelion interactions during assembly have been localized on the triskelion structure. These regions were previously identified with anti-heavy chain monoclonal antibodies X19 and X35, which disrupt clathrin assembly (Blank, G. S., and F. M. Brodsky, 1986, EMBO (Eur. Mol. Biol. Organ.) J., 5:2087-2095). Antibody-binding sites were determined based on their reactivity with truncated triskelions, and were mapped to an 8-kD region in the middle of the proximal portion of the triskelion arm (X19) and a 6-kD region at the triskelion elbow (X35). The elbow site implicated in triskelion assembly was also shown to be included within a heavy chain region involved in binding the light chains and to constitute part of the light chain-binding site. We postulate that this region of the heavy chain binds to the interaction site identified on the light chains that has homology to intermediate filament proteins (Brodsky, F. M., C. J. Galloway, G. S. Blank, A. P. Jackson, H.-F. Seow, K. Drickamer, and P. Parham, 1987, Nature (Lond.), 326:203-205). These findings suggest the existence of a heavy chain site, near the triskelion elbow, which is involved in both intramolecular and intermolecular interactions during clathrin assembly.

Depth of response prior to autologous stem cell transplantation to predict survival in light chain amyloidosis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8516-8516
Author(s):  
Iuliana Vaxman ◽  
M Hasib Sidiqi ◽  
Abdullah S. Al Saleh ◽  
Shaji Kumar ◽  
Eli Muchtar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Partial Response ◽  
Induction Therapy ◽  
Light Chain ◽  
Multivariable Analysis ◽  
Al Amyloidosis ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Depth Of Response ◽  
The Impact

8516 Background: The role of induction therapy prior to autologous stem cell transplant (ASCT) in immunoglobulin light chain (AL) amyloidosis remains controversial. Data on the prognostic impact of response to induction in a transplanted cohort are lacking. The aim of this study was to assess the impact of response to induction therapy on survival in patients undergoing ASCT for AL amyloidosis. Methods: We conducted a retrospective study of all newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic, Rochester, Minnesota. Patients receiving only corticosteroids prior to transplant were excluded as were those with an involved light chain of less than 5 mg/dL (not measurable for response). Results: 134 patients met inclusion criteria. The median age at diagnosis was 60 (range 36-74) and 85 (63%) were men. The most commonly used induction regimen was proteasome inhibitor-based (73.1%, n=98). The overall response rate to induction was 83% (complete response 17%, very good partial response 30% and partial response 36%). With a median follow up of 56.5 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS and was independent of the bone marrow plasma cell percentage. The median PFS was not reached for patients achieving ≥VGPR prior to ASCT and 33.8 months for patient achieving PR or less (P=0.001). The median OS was longer in patients with deeper responses (not reached for patients achieving ≥VGPR vs. 128 months for patients achieving PR or less (P=0.02). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR= 0.38; P=0.018) and depth of response prior to transplant (RR 2.52; P=0.039). Conclusions: Hematologic response prior to transplant predicts post-transplant outcomes in patients with AL amyloidosis. [Table: see text]

Factor VIII Procoagulant Protein Interacts with Phospholipid Vesicles Via its 80 kDa Light Chain

1988 ◽  
Vol 60 (03) ◽  
pp. 442-446 ◽  
Author(s):  
G Kemball-Cook ◽  
S J Edwards ◽  
K Sewerin ◽  
L O Anderson ◽  
T W Barrowcliffe
Keyword(s):  
Factor Viii ◽  
Binding Site ◽  
Light Chain ◽  
Binding Sites ◽  
Light Chains ◽  
Phospholipid Vesicles ◽  
Polyacrylamide Gels ◽  
Phospholipid Binding

SummaryIn a previous report, we detailed the fractionation of polyclonal human anti-Factor VIII :C into a component directed exclusively against the phospholipid-binding site on Factor VIII (PL-site antibody) and another directed at other sites (non-PL-site antibody). The location on the F.VIII molecule of its PL-binding site has now been studied by two different methods using this fractionated 125I-labelled anti-F.VIII: C Fab’.The first method was modified from that of Weinstein et al. (Proc Natl Acad Sci USA 1981; 78: 5137-41), involving electrophoresis of F.VIII peptide-125I-Fab‘ A/F.VIII immunocomplexes in SDS-polyacrylamide gels. PL-site antibody reacted with F.VIII peptides of apparent Mr approximately 80 kDa and sometimes 160 kDa in plasma and concentrate, but not with larger peptides. Non-PL-site antibody, however, reacted with a range of peptides of apparent Mr 90 kDa to 280 kDa. In addition, when purified F.VIII containing heavy and light chains (HC + LC), and isolated LC peptides were analysed, PL-site antibody bound to LC peptides whereas non-PL-site antibody did not.The second method used the antibody pools in immunoradiometric assays (IRMA’s) of purified F.VIII peptides. Both labels measured similar amounts of F.VIII: Ag in a sample of purified F.VIII containing both HC and LC; on assaying an HC preparation, however, PL-site label measured only 2% of F.VIII: Ag found by non-PL-site label, indicating that PL-binding sites are absent in HC preparations.These results indicate that F.VIII binds to PL via its 80 kDa light chain.

Threshold effects of exchange rate depreciation and money growth on inflation

2014 ◽  
Vol 41 (2) ◽  
pp. 196-215 ◽  
Author(s):  
Rizki E. Wimanda
Keyword(s):  
Exchange Rate ◽  
Threshold Model ◽  
Threshold Value ◽  
Threshold Effect ◽  
Threshold Effects ◽  
Money Growth ◽  
Content Type ◽  
Significant Difference ◽  
The Impact ◽  
Exchange Rate Depreciation

Purpose – This paper aims to investigate the impact of exchange rate depreciation and money growth to the consumer price index (CPI) inflation in Indonesia. Design/methodology/approach – Using threshold model applied to Phillips curve equation. Findings – Using monthly data from 1980:1 to 2008:12, the econometric evidence shows that there are indeed threshold effects of money growth on inflation, but no threshold effect of exchange rate depreciation on inflation. Even though the threshold value for exchange rate depreciation is found at 8.4 percent, the F-test suggests that there is no significant difference between the coefficient below and that above the threshold value. While two threshold values are found for money growth, i.e. 7.1 and 9.8 percent, and they are statistically different. The impact on inflation is high when money grows by up to 7.1 percent, it is moderate when money grows by 7.1-9.8 percent, and it is low when money grows by above 9.8 percent. Research limitations/implications – This research is using methodology proposed by Hansen which the threshold is based on the minimum SSR. The value of SSR will differ from one model to one model. For example, model using quarterly data will give the different result from that using monthly or yearly data. Also, when the author uses the new data, the result could be different. Practical implications – Even though inflation targeting framework has been adopted by Bank Indonesia (BI) since 2005, BI should not disregard the monetary aggregate variable, especially M1. This is because the growth of money is still matter to influence inflation in the short run. The impact on inflation is found to be larger than the impact of exchange rate depreciation when it is below a certain threshold value. Originality/value – This is the first paper that evaluates the threshold effect of exchange rate and money growth in emerging country, especially in Indonesia.

scholarly journals A Novel Risk-Model to Predict Time to First Treatment (TTT) in Chronic Lymphocytic Leukemia Based on Heavy+Light Chain Immunoparesis and Serum Free Light Chain Analysis: Results from the Israeli CLL Study Group

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1849-1849
Author(s):  
Tamar Tadmor ◽  
Andrei Braester ◽  
Najib Dally ◽  
Ariel Aviv ◽  
Yair Herishanu ◽  
...  
Keyword(s):  
Binding Site ◽  
Light Chain ◽  
Research Funding ◽  
Reference Range ◽  
Lymphocytic Leukemia ◽  
Light Chains ◽  
Normal Reference Range ◽  
Site Group ◽  
Normal Reference ◽  
Time To First Treatment

Abstract Introduction: Chronic Lymphocytic Leukemia (CLL) is frequently accompanied by immune dysregulation. Hypogammaglobulinemia is one of the most important immune defects encountered, and all three classes of immunoglobulins (IgG, A and M) can be involved. Recently, novel heavy+light chain (HLC) immunoassays have become available that quantify the light chain types of each immunoglobulin class (e.g. IgGk and IgGl). These assays are measured in pairs and provide information on the isotype produced by a tumour (the "involved" HLC), the non-clonal ("uninvolved") HLC, and the ratio (e.g. IgGk/IgGl) - which indicates monoclonality. HLC assays have been shown to improve monitoring of plasma cell dyscrasias, but their role in CLL is yet to be studied. Methods This is a multi-center study performed in collaboration with the Israeli CLL Study Group and involved 10 medical centers. The cohort included 122 patients with CLL and 26 healthy controls. Baseline was defined as the time the blood sample was taken. Serum samples were analyzed for levels of IgG subclasses (IgG1, IgG2, IgG3, IgG4), heavy+light chains (HLC) (IgGκ, IgGλ, IgAκ, IgAλ, IgMκ or IgMλ) and free light chains (sFLC). HLC-pair suppression was defined as an abnormal HLC ratio and uninvolved HLC levels below the normal reference range (i.e. in g/L: IgGκ<3.84; IgGλ<1.91; IgAκ<0.57; IgAλ<0.44; IgMκ<0.19; IgMλ<0.12). HLC immunoparesis was defined as HLC isotype levels below the normal reference range, regardless of HLC ratio (i.e. HLC immunoparesis of at least 1 isotype indicates at least one of IgGκ, IgGλ, IgAκ, IgAλ, IgMκ or IgMλ below the normal reference range). Severe HLC-pair suppression or severe HLC immunoparesis was defined as a concentration of the uninvolved HLC or any HLC isotype that is suppressed by >50% below the normal reference range. The association of variables with time to first treatment (TTT) was performed with Cox proportional hazard model. Results Current analysis was performed on 105 CLL patients who had complete data available; median age was 68 years, 64% were males and Binet stage A, B, C, were 80%, 18.1% and 1.9% respectively. Median time from diagnosis to baseline measurements was 27 months (range 0-328 months). An abnormal sFLC ratio was identified in 70% (73/105) patients and summated k and λ concentrations (SFLC) were ≥70 mg/L in 18% of cases. An abnormal HLC ratio was present in 32% (34/105) patients, and 21% had HLC pair suppression of any 1 HLC isotype. HLC immunoparesis of 1, ≥2 and ≥3 isotypes was observed in 74 (70%), 58 (55%) and 36 (34%) of patients, respectively, with severe HLC immunoparesis identified in 40 patients (38%). Patients with IgG2 suppression were more frequently hospitalized due to infection with an Odds Ratio of 3.826 (p=0.031). In multivariate analysis, SFLC ≥70 mg/L and severe HLC immunoparesis were independently associated with TTT (HR 15.3, p<0.001; HR 80, p<0.001 respectively). Using these 2 variables, a risk-stratification model was constructed that separated CLL patients into 3 risk groups (with 0, 1 or 2 risk factors) with significantly different TTT (p<0.001, Figure 1). Patients with both risk factors (SFLC ≥70 mg/L and severe HLC immunoparesis) had the shortest TTT. Conclusions The findings presented here demonstrate that there is considerable potential for the use of HLC and FLC immunoassays to provide prognostic information in CLL. Figure 1. Figure 1. Disclosures Tadmor: PFIEZER: Consultancy; JNJ: Consultancy; ABBVIE: Consultancy; NOVARTIS: Consultancy; ROCHE: Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Herishanu:ROCHE: Research Funding; JNJ: Consultancy; ABBVIE: Consultancy. Shvidel:ROCHE: Consultancy, Research Funding; ABBVIE: Consultancy, Research Funding; JNJ: Consultancy. Rahimi-Levene:ABBVIE: Consultancy. Ruchlemer:ABBVIE: Consultancy; JNJ: Consultancy. Fogl:The Binding Site Group Ltd: Employment. Polliack:ROCHE: Research Funding; ABBVIE: Consultancy. Magal:The Binding Site: Employment. Townsend:The Binding Site Group Ltd: Employment.

scholarly journals Clinical Presentation and Outcomes of Patients with Light Chain Amyloidosis Who Have Non-Evaluable Free Light Chains at Diagnosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3272-3272
Author(s):  
Surbhi Sidana ◽  
Nidhi Tandon ◽  
Angela Dispenzieri ◽  
Morie A. Gertz ◽  
Francis K Buadi ◽  
...  
Keyword(s):  
Partial Response ◽  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Renal Involvement ◽  
Light Chains ◽  
Free Light Chains ◽  
Advisory Committees

Abstract Introduction: Hematologic response criteria for light chain amyloidosis (AL) requires that difference in involved and uninvolved free light chains (dFLC) be at least 5 mg/dL (or 50 mg/L). However, many patients do not meet these criteria and are often excluded from clinical trials. These patients are challenging to follow clinically as organ response takes much longer and therefore response to treatment is difficult to evaluate in the first few cycles. This study aims to evaluate patients who had non-evaluable FLC (dFLC< 5 mg/dL) at diagnosis and compare them to those who had evaluable FLC (dFLC≥ 5 mg/dL). Methods: All patients with newly diagnosed AL seen within 90 days of diagnosis at our institution over a 10-year period (2006-2015) were identified from an institutional database. Data pertaining to demographics, diagnosis, treatment and follow-up was extracted from electronic medical records. Analysis was carried out by chi-square and Fisher's exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Progression free survival (PFS) is defined as time to progression requiring treatment change or relapse requiring re-institution of treatment or death. PFS and overall survival (OS) were analyzed via the Kaplan-Meier method. Results: Of 1336 patients meeting inclusion criteria, dFLC at diagnosis was known in 1290. 85.4% (n=1101) had dFLC ≥ 5 mg/dL, while 14.6% (n=189) had non-evaluable FLC. Median age at diagnosis (65.2 vs. 63.9 years), gender distribution (males 56.1% vs.64.8%) and involved FLC (lambda: 72.2% vs. 72.9%) was similar in FLC < 5 mg/dL and FLC ≥ 5 mg/dL group. Cardiac (38.1 vs. 76.3%, p <0.0001) and liver (10.2% vs. 16.3%, p=0.03) organ involvement were less common in patients with non-evaluable FLC (table 1). NT-ProBNP was significantly lower in the group with dFLC < 5 mg/dL in patients with and without cardiac involvement, as was Mayo cardiac stage (table 1). A trend towards less gastrointestinal (GI) involvement (17.1% vs. 24%, p=0.09) was also seen with dFLC < 5 mg/dL. In contrast, a trend towards higher renal involvement was seen in patients with dFLC < 5 mg/dL (64.6% vs. 55.9%, p=0.08), though this was not statistically significant. Median 24 hour urine protein was significantly higher in all patients (with and without renal involvement) with dFLC < 5 mg/dL compared to dFLC ≥ 5 mg/dL group (table 1). Treatment details are listed in Table 1. ASCT (autologous stem cell transplant) was utilized more commonly in patients with dFLC < 5 mg/dL compared to patients with dFLC ≥ 5 mg/dL(43.2% vs. 26.1%, p <0.0001), including ASCT alone without chemotherapy (35.4% vs. 15.3%, p <0.0001).Rates of cardiac response (53.3% vs. 50.3%, p=0.88), and time to response (27.7 weeks vs. 35.6 weeks, p=0.67), were similar in both groups. Similarly, there was no difference in rates of renal and liver response and time taken to achieve a response (table 1). In patients with evaluable FLC, hematologic response was complete response (27.3%, n=245), very good partial response (21%, n=189), partial response (18%, n=160), no response (8%, n=74), progression (2%, n=15) and not known in 26.1% (n=216). In patients who had follow up data available, 30.6% (44/144) with dFLC < 5mg/dL experienced a relapse/progression with median PFS of 4.1 years (95% confidence interval (CI): 3 to 5.7), while 34.7% (304/875) with FLC ≥ 5 mg/dL experienced a relapse/progression with median PFS of 1.3 years (95% CI 1.1 to 1.5); p<0.0001. Median OS was higher in patients with dFLC < 5 mg/dL at diagnosis at 8.3 years compared to 2.4 years in patients with dFLC ≥ 5 mg/dL (p < 0.0001) as depicted in Figure 1. Conclusions: Patients with non-evaluable FLC at diagnosis have significant differences in organ involvement and survival compared to those with FLC ≥ 5 mg/dL at diagnosis. They have less cardiac and liver involvement and a trend towards less GI involvement, which may be secondary to low serum FLC burden and consequent less organ deposition. However, a trend towards higher renal involvement was seen in dFLC < 5 mg/dL group, with significantly higher urinary protein excretion. Loss of FLC in urine may result in lower serum FLC levels in this group. Survival was significantly better in patients with dFLC < 5 mg/dL, which may be explained by less cardiac involvement, lower cardiac stage and lower median FLC at diagnosis. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Jannsen: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; AbbVie: Research Funding; Noxxon: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

The Tumor Microenvironment Measured by Flow Cytometry Predicts Overall Survival (OS) and Transformation Risk (TR) in Follicular Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2406-2406 ◽  
Author(s):  
Pedro Farinha ◽  
John Han ◽  
Abdulwahab Al-Tourah ◽  
Joseph M. Connors ◽  
Diponkar Banerjee ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
B Cells ◽  
Follicular Lymphoma ◽  
Light Chain ◽  
Clinical Event ◽  
Light Chains ◽  
Biological Variables ◽  
The Impact

Abstract Background: FL is an indolent but heterogeneous lymphoid neoplasm with a variable clinical course. Transformation into an aggressive lymphoma is a dominant clinical event that is frequently followed by shorter survival. There is no consistent biological prognostic marker for TR. Recent studies have highlighted the role of the microenvironment in helping to determine the prognosis of FL. However, its impact on TR is largely unknown. In this study we used diagnostic flow cytometry (FC) analysis to assess the role of non-malignant cells in determining OS and TR in FL. Methods: We identified 567 patients with FL diagnosed at the BCCA over a 5-year period between 1997 and 2001. Of these, 270 cases had diagnostic FC and histological review, of which 137 were nodal and had complete clinical data in our electronic database. FC results were re-analyzed. The antibodies studied included anti-CD3, CD4, CD5, CD8, CD10, CD14, CD19, CD20, CD23, CD45, FMC-7 and IG kappa and lambda light chains. To ensure that biopsies were representative, the sum of the % gated events for CD3 and CD20 had to equal 100% +/− 20%. Light chain restriction was present in all cases and established clonality. The estimate of neoplastic B cells was determined by examining CD19 and CD20 frequency and the ratio of clonal light chain vs non-clonal light chain. Non-neoplastic B cells were estimated using CD19/20 and the amount of non-clonal light chain × 0.5 (λ clonal) or × 2 (κ clonal). Clinical characteristics, different subsets of T cells and the cell content of reactive, non-neoplastic B cells were evaluated using SPSS® software. Results: The median age of the 137 patients was 57 years, 51.8% were male and 38.6% had a high IPI (4/5). There were 97 grade 1, 27 grade 2 and 13 grade 3a FL. The median ratio of CD4/CD8 was 4.4. Patients were given a variety of treatments, including observation if asymptomatic, precluding an analysis of progression-free survival. The median follow-up of the living patients was 5.8 years and the estimated 5-year OS and TR were 70% and 20%, respectively. The IPI was predictive of OS (p<0.0001). Two biological variables showed a significant impact on survival. Firstly, cases in which CD8+ cells represented more than 25% of the total (CD3+) T cells had shorter OS (p = 0.028) and increased TR (p = 0.013). The CD8 ratio (p = 0.026) affected OS independently of IPI (p = 0.046). Secondly, cases with a low content of reactive, non-neoplastic B cells, defined by the ratio between IG light chains >1/15 had shorter OS (p = 0.003) and increased TR (p=0.002). The impact of a reduction in normal reactive B cells (p = 0.014) on transformation risk was independent of the IPI (p = 0.05). Conclusion: Two features of the FL microenvironment studied by diagnostic FC demonstrated an impact on prognosis. The proportion of CD8+ T cells relative to the total T cells and the number of residual, non-neoplastic B cells were both predictors of OS. Importantly, both predict, independently of the IPI, the risk of transformation. These biomarkers are easily measured and may be used to better stratify patients, choose initial treatment options and predict transformation risk in patients with FL. Microenvironment & Transformation Risk in Follicular Lymphoma Microenvironment & Transformation Risk in Follicular Lymphoma

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