Insights Into The Natural History Of Paroxysmal Nocturnal Hemoglobinuria (PNH): Analysis Of The Presenting Clinical, Haematological and Flow Cytometric Features Of 705 Patients Leads To Improved Classification and Prediction Of Clinical Course

Abstract In past 22 years, we have identified using flow cytometry 705 patients with detectable PNH (GPI deficient) populations of granulocytes, monocytes and red cells in the peripheral blood in samples sent for diagnosis. We undertook an analysis of presenting clinical features, blood count data and PNH clone sizes in order to better understand the natural history and provide a more objective classification of disease. Based on serial flow cytometry measurements of PNH clone sizes, we also studied disease stability, frequency of recovery and progression with an aim to guiding future management of individual patients. Clinical classification of patients at presentation was as follows; aplastic anemia (58%), hemolytic anemia (36.1%); myelodysplasia (2.5%); thrombosis (2.4%); hemolysis & thrombosis (0.6%), myeloproliferative neoplasm (0.3%); Fanconi anemia (0.1%). Median age at presentation was 45 years (observed range 0.5 – 90 years) and the Male:Female ratio was 1.05. Descriptive statistical analysis of presenting blood count data revealed novel gender related features not previously described in PNH. At presentation, pancytopenia was found in 61% of male and 47% of female patients; a normal blood count was present in only 0.3% of males and 4% of females. A combined low red blood cell count (RBC) and white cell count (WBC) was the most frequent bicytopenia affecting 19% males and 22% females. Leucopenia as a sole abnormality did not occur in males and was present in<1% of females; Leucocytosis was present in<1% of cases. Platelet counts were low in 79% of patients and normal in 20.3%. Low absolute numbers of RBC (mean 3.002 x 1012/L; IQR 2.52-3.47) were present in 97.6% of males and 87.6% of females (mean 3.009 x 1012/L; IQR 2.60 - 3.42). Similar findings were obtained for hemoglobin (Hb) values: males (mean 100.5 g/L; IQR 85-115): females (mean: 100.7 g/L; IQR 88-116). Unexpectedly, there were no statistically significant differences between male and female values for Hb or RBC counts. In a more detailed comparison, significant differences between aplastic PNH patients (n = 394) and hemolytic PNH patients (n = 245) were identified. Aplastic patients had significantly lower WBC, neutrophil, monocyte and platelet counts, and MCV (all P<0.01), though lymphocyte count was higher than in the hemolytic cohort. No statistical differences could be demonstrated for Hb or RBC counts between disease types or between males and females, confirming earlier results. For PNH clone sizes at presentation, aplastic patients showed a median red cell PNH clone size of 0.34% (IQR 0.05 - 2.14) and a median granulocyte PNH clone size of 2.58% (IQR 0.42 - 12.48). In contrast, hemolytic patients had a median red cell PNH clone size of 32.35% (IQR 22.04 - 51.67) and a median granulocyte PNH clone size of 90.61% (IQR 77.07 - 97.41). Follow up flow cytometry studies of 154 aplastic and hemolytic patients over a minimum period of 18 months (mean follow up 81 months, range 20-216 months), provided important insights into biology of the disease. Firstly, aplastic patients with granulocyte PNH clones of<1% at presentation, did not evolve to hemolytic PNH. Any increase in PNH clone sizes and progression to hemolytic disease within the aplastic cohort was associated with granulocyte clones of >5% at presentation, though this occurred in only 10/154 (6.5%) cases. For patients presenting with hemolytic disease, PNH granulocyte clones continued to increase in size in 44% of cases most likely reflecting a combination of on going selection in favour of the PNH clone and prompt diagnosis. In the 38 patients that presented with >95% granulocyte PNH clones, 92% remained stable over time (mean follow up 80 months (many on Eculizumab therapy)) with only 8% showing a gradual fall in clone size. The study shows that pancytopenia is a consistent feature of hemolytic and aplastic PNH patients. The degree of anemia is the same in both major groups of patients, but appears to be less severe for females. Not only are PNH clone sizes larger in hemolytic patients, but they also show higher platelet and leucocyte counts compared to aplastic patients, most likely reflecting a more active bone marrow. The data support the model that bone marrow failure is the primary underlying pathology in >95% of PNH patients and that sub classification on the basis of degree of aplasia, hemolysis (with or without thrombosis) and PNH clone size at presentation can be a powerful predictor of clinical course. Disclosures: Richards: Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kelly:Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hill:Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hillmen:Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Evolution of GPI-Deficient Clones Predicts Clinical Course in Paroxysmal Nocturnal Haemoglobinuria.

Blood ◽

10.1182/blood.v104.11.172.172 ◽

2004 ◽

Vol 104 (11) ◽

pp. 172-172 ◽

Cited By ~ 5

Author(s):

Stephen J. Richards ◽

Matthew J. Cullen ◽

Anita J. Dickinson ◽

Claire Hall ◽

Anita Hill ◽

...

Keyword(s):

Aplastic Anemia ◽

Clinical Course ◽

Spontaneous Remission ◽

Red Cells ◽

Red Cell ◽

Clone Size ◽

Clinical Behavior ◽

The Mean ◽

Pnh Clone

Abstract Flow cytometric analysis of GPI-linked antigens has had a major impact on the diagnosis of PNH. Significant numbers of patients with aplastic anemia have small PNH clones, and due to the precision in clone size measurement, reliable serial monitoring can now be undertaken although the clinical value of this is not proven. From our series of 234 PNH patients, we analysed clinical correlates between disease type and red cell and granulocyte peripheral blood clone sizes as determined by flow cytometry at presentation. For hemolytic patients (n = 99) the mean PNH clone sizes were: granulocytes 84.8%; red cells 45.3% (type III cells 33.6%). For aplastic patients (no macroscopic hemolysis) the mean clone sizes were: granulocytes 18.5%; red cells 6.4% (type III cells 4.5%). The two groups were statistically different (Mann Whitney U; P<0.001). Monitoring of PNH clones in 86 of these patients who had at least 3 samples over a minimum of 12 months (mean 55 months; range 15–174) not only showed distinct groups of patients with highly characteristic patterns of disease but also provided insights into the incidence of spontaneous remission, progression from aplastic to hemolytic disease, and development of leukemia. Firstly, hemolytic patients that present with >90% granulocyte clones (n = 30; mean follow up 48 months) with virtually all their hematopoiesis maintained from PNH stem cells have clone sizes that remain stable and their clinical behavior suggests that their PNH can persist for up to 40 years. The second group of patients (n = 16) were those with hemolytic PNH with granulocyte clones of <90%. Mean granulocyte clone size at presentation was 68.4% (range 34.7– 90%) with a mean follow-up of 66 months (range 24–164). Of these, 6 showed stable clone sizes, 2 increasing clone size, and 8 showing reductions in granulocyte clone size. The third group were those presenting with aplastic anemia (n = 34). This group showed the most significant variation in clone size and clinical behavior. Of the 12 patients with persistent aplastic anemia, the majority had slowly increasing clone sizes with 5 patients progressing to hemolytic PNH after a variable time period ranging from 26 to 79 months. Only 3 patients developed MDS or AML. Two of these were from the >90% granulocyte clone group (2/30) and developed as a terminal event, one with GPI-MDS, and the second with a rapid emergence of GPI+MDS. One patient in the aplastic group showed progression to AML (1/34). 27% of patients had an improvement in cytopenias with concurrent decrease in PNH clone size. For hemolytic patients with granulocyte clones of <90%, the 8 patients with falling clone sizes had improving blood counts. The PNH granulocyte clone halved in a mean of 74 months. Of the patients with aplastic anemia, 15 showed resolution of anemia with normalization of counts and all but one had an associated fall in granulocyte PNH clone sizes. Eleven patients have been treated in clinical trials of the anti-complement antibody, eculizumab, for a period of up to 2 years and over this period the proportion of PNH granulocytes has remained stable. This data demonstrates that the size and type of granulocyte and red cell PNH clones at presentation predicts the clinical course for individual patients assisting long term clinical management planning. Moreover, regular clone size monitoring predicts the likelihood of spontaneous reduction in the PNH clone and potentially for spontaneous remission.

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IgM-Gammopathies Transformed into Aggressive Lymphoma: Incidence, Basal Clinical Features and Outcome of a Registry Based, Spanish Retrospective Series

Blood ◽

10.1182/blood-2019-123353 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4011-4011

Author(s):

Irene Dogliotti ◽

Cristina Jiménez ◽

Federica Cavallo ◽

Noemi Puig ◽

Gian Maria Zaccaria ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

B Lymphocytes ◽

Clinical Features ◽

Research Funding ◽

Initial Diagnosis ◽

Aggressive Lymphoma ◽

Advisory Committees ◽

Histological Transformation

Background Transformation into aggressive lymphoma (AL) is a rare complication of indolent lymphoproliferative disorders (LPDs) and is characterized by poor outcome. Immunoglobulin M (IgM) gammopathies are a spectrum of conditions, from monoclonal gammopathy of undetermined significance (MGUS) to Asymptomatic Waldenstroem Macroglobulinemia (AWM) and Symptomatic WM (SWM) that can eventually evolve to transformed WM (tWM). Actually, tWM represents a clinical challenge, mainly because of its poor characterization. Aims This registry study aims to better characterize tWM, focusing on prognostic factors heralding transformation to AL. Methods Two registries of IgM-MGUS, AWM and SWM [Owen, Semin Oncol 2003] based in Salamanca and in the region of Castilla and Leon (Spain) were investigated to identify cases with histological transformation. IgM-secreting patients with other LPDs (e.g. chronic lymphocytic leukemia, marginal zone lymphoma, IgM-multiple myeloma) were excluded from the analysis. All patients provided written informed consent in accordance to Helsinki's declaration. Statistical analysis was carried out using R v 3.3.3. tool; survival analyses were performed with Log-Rank method, while group comparison was performed with t-student for continuous variables and Chi-square tests for categorical variables. Results Data from 903 patients with IgM-secreting disorders diagnosed between 1976 and 2019 were analyzed; 587 cases with confirmed diagnosis of IgM-MGUS, AWM or SWM were selected. Out of 587 IgM-gammopathies, 22 cases with histological transformation to AL were identified. Cumulative incidence of tWM was: 1.4% at 5, 3.4% at 10 and 5.3% at 12 years, respectively (figure 1). Clinical features at first diagnosis of patients subsequently developing tWM where then analyzed: 3/22 tWM evolved from previous IgM-MGUS, while the remaining patients originally presented with AWM (6/22) or SWM (13/22). IPSS-WM prognostic score was LR for 5, IR for 12 and HR for 3/20 patients, respectively [Morel, Blood 2009]. Glancing on distributions between groups according to the outcome, tWM differed from not transformed (NT) cases for: lower median age at diagnosis (66 vs 72 years, p=0.018), lower platelets levels (median 188 vs 235 x 10^9/mmc, p=0.017), higher LDH ratio (0.8 vs 0.67, p=0.015), higher incidence of chromosome 6q deletion by FISH (40 vs 14%, p=0.021) and higher clonal B lymphocytes infiltration on marrow aspirate by flow cytometry (15 vs 4.5%, p= 0.022). Moreover, 13/22 patients received anti-WM treatment within 3 months from initial diagnosis, mainly chlorambucil-based; 5/22 patients received rituximab in first line and 13 in second line. From the whole series, after a median follow-up of 80 months, median transformation-free survival was 61 months from initial diagnosis (range: 0-228). Among these, Only 1/22 of tWM patient is still alive; 19/21 deaths were thus related to AL/WM, with a median survival after transformation of 12 months (0-53). In the whole series (n=587), median OS from initial diagnosis of IgM gammopathy was 76 months for the tWM group (6-225), that is shorter than the NT group (128 months, p=0.012, figure 2). Focusing only on patients treated at initial diagnosis, median survival after first treatment (SAFTI) was 62 vs 90 months for tWM vs NT (p=0.011, figure 3), and median time to next treatment was 28 vs 46 months, respectively (p=0.13). Overall, 10/22 tWM patients received ≥3 treatment lines, and median number of lines prior to transformation was 2 (0-3). Finally, in the whole series IPSS-WM score at diagnosis confirmed to impact on survival (median OS=151, 119 and 56 months for LR, IR and HR groups, respectively, p <0.001). However, this was not the case for tWM cases only, where OS was no longer different between groups. Conclusions In this retrospective study, we confirmed dismal outcome for tWM patients; incidence of transformation was comparable to expectations at 5 years, but higher at subsequent follow-up. At initial diagnosis of IgM gammopathy, younger age, low platelets level, high LDH ratio, high B lymphocytes infiltration by flow cytometry and presence of 6q deletion were significantly enriched among patients subsequently developing tWM. IPSS-WM score looked less predictive among tWM patients probably given to the limited numbers of tWM series. Novel prognostic tools are eagerly awaited for tWM patients. Figure Disclosures Cavallo: Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Puig:The Binding Site: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria. Ferrero:Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding.

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“Red Cell Complement Loading In PNH Patients On Eculizumab Is Associated With a C3 Polymorphism Which Influences C3 Function, Predicts For Increased Extravascular Hemolysis and Provides a Rationale For C3 Inhibition.”

Blood ◽

10.1182/blood.v122.21.2466.2466 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2466-2466 ◽

Cited By ~ 8

Author(s):

Praveen Kaudlay ◽

Haiying Hua ◽

Guansheng He ◽

Darren J Newton ◽

Abraham M Varghese ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Red Cells ◽

Complement C3 ◽

Red Cell ◽

Functional Polymorphism ◽

Advisory Committees ◽

Hindiii Restriction Site ◽

C3 Gene

Abstract Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired bone marrow disorder characterised by intravascular hemolysis and hemoglobinuria, potentially life-threatening thrombosis and an association with aplastic anemia. Most of the clinical features and complications of PNH are due to the unopposed activity of complement due to the absence of CD59 and CD55, two key regulators of complement. Eculizumab prevents the cleavage of C5 complement thereby preventing terminal complement activity and protecting PNH cells from lysis. The inhibition of C5 preserves the early part of complement pathway and leads to the build up of C3 on the PNH red cells, perhaps in part due to their lack of CD55. The majority of PNH patients receiving eculizumab have evidence of extravascular haemolysis that can be clinically significant, including with anemia, hyperbilirubinemia and in some a continued requirement for transfusions. This extravascular hemolysis in thought to be due to the C3 loading of PNH red cells. Methods We report the C3-loading of the PNH red cells from 119 patients treated with eculizumab and correlate this with hemoglobin, LDH, bilirubin, reticulocytes and transfusions. We have studied genetic polymorphisms that affect both C3 and FCγR. We have genotyped 46 eculizumab patients for a functional mutation in the C3 gene (rs2230199). The two alleles of this gene can be distinguished by the presence or absence of a HindIII restriction site that distinguishes the electophoretically slow (arg80) from the electrophoretically fast (gly80) allotype. The fast (C3F) allotype allele of this snp is associated with a range of disorders including age-related macular degeneration, IgA nephropathy, systemic vasculitis and partial lipodystrophy. APL-1 is a small cyclic peptide that binds to and inhibits the activation of complement C3. APL-2 is a large conjugate of APL-1 with enhanced bioactivity and a long systemic half-life. APL-1 and APL-2 molecules as well as other complement inhibitors were studied for lysis of red cells and C3 loading in vitro in a modified Ham test in which flow cytometry was used to identify non-lysed cells. Results Out of the 119 Eculizumab treated patients, 55 (46.2%) required at least one transfusion on treatment. 110 patients had C3 detectable by flow cytometry on their PNH red cells (mean of 19.8%; range: <0.1 to 64.6%). C3-loading was not seen on the normal red cells from the same patients on treatment nor on the PNH red cells in patients not receiving eculizumab. The mean LDH (735IU/l) and reticulocyte count (193 x 109/l) were not statistically significantly different for the transfused group compared to the non-transfused group (518 and 163 respectively). Mean PNH C3 and RBC C3 did not differ stastistically between the transfused and non-transfused groups (26.20 Vs 24.78 PNH C3;15.96 vs 15.09 RBC C3 respectively). We studied one functional polymorphism in the Fcγ receptor but this showed no correlation with haemolytic parameters. Conversely, for the C3 polymorphism eculizumab-treated patients homozygous for the slow (C3S) allele had a significantly higher degree of C3 loading on PNH red blood cells with C3S/C3S having a mean of 33.7% C3 loaded PNH red cells (n=26), C3S/C3F 19.0% (n=19) and C3F/C3F 12.8% (n=3)(all P<0.01). Homozygote C3S also had increased reticulocytes (P<0.01) and bilirubin (P<0.01). The C3S allele has previously been shown to be more efficient in a haemolysis assay using sheep erythrocytes. This polymorphism appears to explain much of the variation in C3 loading between different patients with PNH. In vitro experiments show that inhibitors of C5, such as eculizumab, protect the PNH red cells from lysis but lead to a very rapid deposition of C3 on the PNH red cells. However both APL1 and APL2 demonstrated similar protection of PNH red cell lysis with virtually no C3 loading on PNH red cells. Conclusion A significant proportion of patients on eculizumab experience extravascular haemolysis with the majority of patients developing C3 loading. We show for the first time that a functional polymorphism in the C3 gene is associated parameters of hemolysis. The S(low) allele alters the function of C3 protein and appears to be associated with extravascular haemolysis in patients with PNH. The C3 inhibitors, APL-1 and APL-2, protect PNH red cells and prevent C3 loading in vitro and if safe to be given chronically would be expected to reduce extravascular hemolysis significantly. Disclosures: Hill: Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kelly:Alexion: Honoraria. Richards:Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Hillmen:Alexion: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Observational Study Of PNH Clone Size By High Sensitivity Flow Cytometry In High-Risk Patients InA Large Russian Population

Blood ◽

10.1182/blood.v122.21.4867.4867 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4867-4867

Author(s):

Elena Babenko ◽

Alexandra Sipol ◽

Vyacheslav Borisov ◽

Elena Naumova ◽

Elena Boyakova ◽

...

Keyword(s):

Flow Cytometry ◽

High Risk ◽

Research Funding ◽

Surface Membrane ◽

High Risk Patient ◽

High Sensitivity ◽

Clone Size ◽

Hematopoietic Stem ◽

Pnh Clone

Abstract Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematopoietic stem cell disease caused by a partial or absolute deficiency of proteins linked to the cell surface membrane via a glycosylphosphatidyl-inositol anchor, which leads to complement-induced intravascular hemolysis mediated via the membrane attack complex. Multiparameter high-sensitivity flow cytometric measurement of PNH clones is the method of choice for the diagnosis of PNH, as recommended by the International Clinical Cytometry Society (ICCS). After publication of the ICCS guidelines, screening of patients considered at high risk of PNH was commenced in Russia. Data are presented on PNH clone size distribution across patients with relevant ICD-10 diagnostic codes (based on patients′ initial assumed diagnoses). Methods Patients were tested for the presence and size of PNH clones using high-sensitivity flow cytometry across nine laboratories. PNH clone evaluations were performed as described in the ICCS guidelines: CD59/CD235a monoclonal antibodies for RBC; CD45/CD15/CD24/FLAER for granulocytes and; CD45/CD64/CD14/FLAER or CD45/CD33/CD14/FLAER for monocytes. The sensitivity for PNH clone detection was 0.01%. Changes in PNH clone size were evaluated among patients who had follow-up studies after initial measurements. Results 1889 patients were assessed between October 2011 and June 2013 (Table 1). Suspected PNH and bone-marrow disorders (AA, MDS, cytopenia) were the most common reasons for PNH testing. The greatest proportions of patients with PNH clones were among those with of an initial assumed diagnosis of AA or PNH. Notably, around 40% of patients with an initial assumed diagnosis of PNH actually had no detectable PNH clones. Most patients with small clone sizes (< 1%) were in the AA, MDS and hemolytic anemia groups. Overall, mean clone sizes were slightly higher in monocytes (31.5%) than in granulocytes (30.1%) across the diagnostic categories. While there was generally a good correlation between clone size measurements in granulocytes and monocytes (linear regression r2 = 0.9851), 10% of PNH-positive patients had detectable clones only in one of these leucocyte populations (i.e. either in monocytes or in granulocytes, but not both). PNH clones in RBCs were generally lower than in granulocytes. Repeat clone size measurements were performed in 316 patients over a mean follow-up period of 7.8 months. In patients with initial clone sizes <50% the PNH clones tended to decrease over time, whereas in patients with initial clone sizes >50%, clones tended to increase. PNH clones were not changed at all in 98 patients at follow-up, among whom 48% were patients with AA. Conclusion These screening data confirm the utility of high-sensitivity flow cytometry testing in high-risk patient groups to ensure early and accurate diagnosis and to aid in the effective clinical management of patients. Disclosures: Babenko: Alexion: Research Funding. Sipol:Alexion: Research Funding. Borisov:Alexion: Employment. Naumova:Alexion: Research Funding. Boyakova:Alexion: Research Funding. Glazanova:Alexion: Research Funding. Chubukina:Alexion: Research Funding. Pronkina:Alexion: Research Funding. Popov:Alexion: Research Funding. Mustafin:Alexion: Research Funding. Fidarova:Alexion: Honoraria. Lisukov:Alexion: Honoraria. Kulagin:Alexion: Honoraria.

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Prognostic Value of Clone Size in Paroxysmal Nocturnal Hemoglobinuria (PNH) for Thrombotic Events in Untreated Patients in the International PNH Registry

Blood ◽

10.1182/blood-2018-99-111324 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1038-1038

Author(s):

Regis Peffault De Latour ◽

Jaroslaw P. Maciejewski ◽

Austin G. Kulasekararaj ◽

Loree Larratt ◽

Ronald S. Go ◽

...

Keyword(s):

Research Funding ◽

Prognostic Value ◽

Disease Onset ◽

Employment Equity ◽

Advisory Committees ◽

Clone Size ◽

Equity Ownership ◽

The Relationship ◽

Pnh Clone

Abstract Background/Objective: The association between paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size at disease onset and outcomes in patients with PNH remains unclear. Most but not all reports examining the relationship have shown a positive correlation between clone size and thrombotic events [TEs] in patients with PNH, but without a clear temporal association showing the prognostic value of clone size on the risk of TEs. The ongoing International PNH Registry (NCT01374360) is the largest prospective, observational study of patients with PNH conducted to date. The objective of this analysis was to examine the relationship between PNH granulocyte clone size at disease onset and risk of thrombosis after disease onset while untreated with a complement inhibitor in patients enrolled in the Registry. Methods: The current analysis included patients enrolled in the Registry as of April 2018 who had known demographics, were untreated with complement inhibitor therapy at enrollment, and had ≥12 months of untreated follow-up after disease onset. Baseline was defined as disease onset (earliest of a reported PNH clone, date of PNH diagnosis, or reported PNH symptom), and patients were stratified into 5 cohorts based on clone size at baseline (using the earliest reported clone prior to enrollment): cohort 1, clone size: 0.01-1%; cohort 2, clone size: >1-5%; cohort 3, clone size: >5-10%; cohort 4, clone size: >10-50%; cohort 5, clone size: >50%. Event rates for TEs and all major adverse vascular events (MAVEs; including TEs) were calculated for the time period from baseline to last follow-up. Other outcomes of interest included LDH ratio (LDH/LDH upper limit of normal [ULN]), hemoglobin levels, platelet counts, absolute neutrophil counts, and absolute reticulocyte counts at last follow-up. Results: A total of 2489 patients were eligible for the analysis. The majority of patients in the overall study population were female (54.0% [1343/2489]) and white (79.2% [1967/2484]). Mean (standard deviation [SD]) age at PNH start ranged from 36.4 (16.53) in cohort 5 to 44.2 (20.70) in cohort 1. Median time from baseline to last follow-up was 3.7 years in cohort 1, 4.3 years in cohort 2, 4.7 years in cohort 3, 5.6 years in cohort 4, and 6.8 years in cohort 5. Results for the outcomes of interest are summarized in the Table. All cohorts showed a risk of MAVE and TE during follow-up. Although estimated rates of MAVE and TE were highest in the >50% clone size cohort, there was no difference in the rate of MAVE or TE during follow-up across the 4 cohorts with clone size <50% at disease onset. Mean LDH ratio (LDH/LDH ULN) at last follow-up showed a statistically significant difference by clone size at baseline among the cohorts, ranging from a mean (SD) of 1.1 (1.34) in the patients with clone size <1% and increasing to 5.1 (3.81) in the patients with clone size >50% (P<0.0001). No difference in hemoglobin level at last follow-up was observed in the smaller clone size cohorts, although mean hemoglobin level was lower in patients with clone size >50% (P<0.0001). Similar trends were seen in mean platelet and absolute neutrophil counts across the smaller clone size cohorts, while patients with clone size >50% showed higher values (P<0.0001). Mean absolute reticulocyte count at last follow-up was lowest in patients with clone size 0.01-1%, and were incrementally higher in each successive clone-size cohort (P<0.0001). Conclusions: In this study, all patients with a PNH clone at disease onset were at risk for TEs and other MAVEs. Patients in the highest baseline PNH clone size strata (clone size >50%) had an approximately 2-times higher risk of TEs than patients with smaller clone sizes; Patients with small clone sizes (0.01-1%) were older and showed a higher prevalence of BMD. There was no difference in the prognostic value of clone size at disease onset on the risk of TEs and other MAVEs in patients with small (0.01-1% and 1-5%) versus medium-sized (5-10% or 10-50%) clones. Table Table. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Gustovic:Alexion Pharma GmbH: Employment, Equity Ownership. Kulagin:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria.

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Retrospect Reviews of PNH Tests with Long-Term Follow-up in a Single Institution

Blood ◽

10.1182/blood-2019-124896 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 948-948

Author(s):

Weiwei Wang ◽

Gabrielle Meyers ◽

Haibo Li ◽

Ying Wang ◽

Lisong Shen ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Biopsy ◽

Clinical Course ◽

Molecular Cytogenetics ◽

Clone Size ◽

Positive Correlation ◽

Wbc Count ◽

Pnh Clone

I ntroduction : Paroxysmal nocturnal hemoglobinuria (PNH) often presents as hemolysis and/or bone marrow failure. Flow cytometric testing can accurately detect PNH. However, the long term studies on PNH clone size and how it relates to clinical course are few. We sought to understand how PNH clone size correlates with clinical course over time and the impacts on clone size with different treatments. Here we report long term clone size monitoring and clinical data of 57 patients with PNH in a single intuition. Methods : High sensitivity PNH flow cytometry (0.01% limit of detection) was performed with FLAER-FITC, CD64-PE, CD14-ECD, CD15-PC5, CD24-AA7500, CD45-KO for neutrophils & monocytes; CD59-PE and CD235a-AA750 for RBCs. Retrospective analysis was done in the positive PNH cases from 2008-2019 at OHSU. Total 173 cases for 57 patients; including 27 females and 30 males, 52 adults and 5 pediatrics, with a mean age of 45 (range 9-78). We also reviewed results of serum LDH, bone marrow biopsies and molecular/cytogenetics of these patients. Among of these patients, 18 patients (11 females and 7 males, mean age 49.33, age range 29-73) with long term (at least over 4 years) follow-up have more than 3 PNH tests. Besides PNH clone on RBC and PMN, we also reviewed results of WBC count (x103/ul), Hb (g/dL), PLT (x103/ul) serum LDH (U/L), bone marrow biopsy reports and molecular/cytogenetics findings in these patients. Results: Among 57 patients, there are 30 aplastic anemia (AA) patients (53.63%), 7 AA patients progressing to PNH (AA&PNH, 12.28%), 5 myelodysplastic syndromes (MDS, 8.77%), 12 PNH patients (21.05%), 1 pancytopenia, 1 autoimmune disease, 1 thrombosis. The diagnosis of AA and MDS were confirmed by bone marrow biopsy and molecular/cytogenetics. Significantly higher levels of all PNH clones were observed in PNH and AA/ PNH, compared to AA (all P <0.001) and MDS (all P<0.05) shown in Figure A-D. LDH was higher in PNH and AA/PNH than AA and MDS groups (P<0.001, Figure E). LDH demonstrated positive correlation with PNH clone size in RBC-type-III, neutrophils and monocytes (all P<0.0001, R= 0.4447, 0.5469, 0.5711, respectively, Figure F). No correlation was observed between LDH and RBC-type-II. Long term (4-11 years ) follow up include 18 patients were divided into 4 groups: 5 AA treated with immunosuppressant only, 5 AA treated with immunosuppressants and/or eltrombopag, 5 classic PNH or AA that progressed to PNH treated with immunosuppressants and/or eculizumab, and 3 PNH with observation and supplements only. The study showed immunosuppression only has lowest PNH clone size for both RBC and WBC (Figure G-H). As for the Hb and WBC count, there were no statistics differences among 4 groups (Figure I-J). Decreased PLT was detected in eltrombopag group (Figure K). Significantly, increased LDH was observed in the observation/supplement group (Figure L). Interestingly, all these 3 patients without special treatment have high PNH clones and LDH from diagnosis to now over 10 years. Despite receiving basic supportive care, the patients' clinical courses have been stable with only supplementation of vitamin B12 and Folic Acid. Conclusions : Positive PNH test was most frequently seen in AA patients. AA has lower PNH clone size and LDH than those of PNH patients or AA progressed to PNH patients. For all patients, PNH population showed positive correlation with LDH. Our study suggest that it is necessary to follow PNH clone size, as this may impact the decision of when to start therapy with what agents. Figure Disclosures No relevant conflicts of interest to declare.

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Decreased Expression of CD62L and CD54 Correlates with Poor Cytogenetic Risk Group In Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v116.21.2915.2915 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2915-2915

Author(s):

Canan Alhan ◽

Theresia M. Westers ◽

Claudia Cali ◽

Floortje L. Kessler ◽

Monique Terwijn ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Healthy Volunteers ◽

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Risk Category ◽

Advisory Committees ◽

Cd34 Cells

Abstract Abstract 2915 Interactions in the bone marrow (BM) between haematopoietic progenitor cells (HPC) and the BM micro environment are important for the regulation of cell adhesion, proliferation, differentiation and survival. Expression of both CD62L (L-selectin) and CD54 (ICAM-1) on HPC demonstrated to play a role in signal transduction routes for proliferation and growth regulation. Especially CD54 is involved in uncontrolled proliferation and block of apoptosis. Previously, it was described that decreased expression of CD62L in acute myeloid leukemia (AML) was associated with a poor cytogenetic risk profile and an adverse clinical outcome (Graf M et al, Eur J Haematol 2003) Myelodysplastic syndromes are a group of clonal HPC disorders characterized by ineffective hematopoiesis and a propensity to evolve into AML. The International Prognostic Scoring System (IPSS) provides information on both survival and risk of development of an AML. The purpose of our study was to evaluate CD62L and CD54 expression on CD34+ cells in MDS patients by flow cytometry and to assess the value of a CD62L/CD54 ratio for prognostication. Bone marrow samples of 30 newly diagnosed MDS patients (3 RA(RS)/18 RCMD(RS), the <5% blasts group; 5 RAEB-1, 4 RAEB-2, the >5% blasts group), 16 AML patients with prior MDS and 26 healthy volunteers were analyzed for CD62L and CD54 expression on CD34+ cells by using flow cytometry. An adhesion index was calculated as a ratio of the percentage and MFI of CD62L and CD54 positive cells (as was reported by Buccisano et al, Eur J Haematol 2007). The CD62L/CD54 ratio was significantly decreased in MDS with <5% blasts (median 79.09 p<0.0001) as compared to healthy volunteers (median 480.4) and even more decreased in high risk MDS (median 14.67 p<0.0001 and p=0.001 as compared to healthy volunteers and MDS with <5% blasts, respectively) and AML with prior MDS (median 12.54, p<0.0001 and p=0.009 as compared to healthy volunteers and MDS with <5% blasts, respectively). The MDS patients were assigned to the good, intermediate or poor IPSS cytogenetic risk category. Cytogenetics was available for 22 MDS patients. The CD62L/CD54 ratio was significantly lower in the cytogenetic poor risk category compared with the good risk category (median 5.4 and median 70.79 respectively, p=0.018). Moreover, a low CD62L/CD54 ratio correlated significantly with poor cytogenetics, p=0.006. In the group of MDS patients with <5% blasts, 4 developed a refractory anemia with excess of blasts or AML within a follow up period of 12 months. There was a trend for a lower CD62L/CD54 ratio for MDS patients who developed an AML compared with patients who did not. In conclusion, the CD62L/CD54 ratio is significantly decreased in MDS compared with healthy volunteers and even more decreased in AML with prior MDS. Both CD62L and CD54 are involved in regulation of proliferation and apoptosis of the HPC. A decreased adhesion ratio in low risk MDS patients might reflect HPC damage at an early stage of the disease with an increased proliferative capacity and a decreased apoptotic profile. Interestingly, a low CD62L/CD54 ratio showed a significant inverse correlation with the IPSS cytogenetic risk category. Due to an absence of metaphases in a proportion of MDS patients, cytogenetics is not always available. The CD62L/CD54 ratio might serve as a surrogate marker for poor prognosis cytogenetics in case no karyotype is available. Low risk MDS patients who developed an AML within 12 months tended to have a lower CD62L/CD54 ratio. Although these results are promising, sample size and follow up period needs to be extended. The CD62L/CD54 ratio might add to prognostication of MDS patients and might identify MDS patients with <5% blasts who are at risk for development of an AML. Disclosures: Ossenkoppele: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van de Loosdrecht:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Genetic Response to Lenalidomide in the Circulating Progenitor Cell Compartment of MDS Cohort. Preliminary Results of the Multicenter German LE-MON-5 Study

Blood ◽

10.1182/blood.v118.21.1721.1721 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1721-1721

Author(s):

Katayoon Shirneshan ◽

Ulrich Germing ◽

Friederike Braulke ◽

Julie Schanz ◽

Uwe Platzbecker ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cytogenetic Response ◽

Response To Therapy ◽

Fish Analysis ◽

Trisomy 8 ◽

Advisory Committees ◽

Clone Size ◽

Observation Period

Abstract Abstract 1721 Introduction: LE-MON-5 is a multicenter German phase-II study to verify the safety of monotherapy with lenalidomide (LEN) in MDS patients (pts) with IPSS low or Int-1 and isolated del(5q). We report our cytogenetic results after a monitoring period of sixteen months since start of the trial. Methods: For sequential and frequent survey of LEN-treated pts we applied FISH on enriched CD34+ stem cells from peripheral blood (CD34+ pb) every 2–3 months using a panel of 8 to 13 probes. Karyotyping and FISH on bone marrow aspirates was performed at initial screening and every six months. The median number of analyzed metaphases was 25 (4–30) and FISH analyzing was based on 200 interphase nuclei. Results: We have already screened 94 pts and could confirm isolated del(5q) in 76 (81%). Due to our cytogenetic results demonstrating additional changes in 18/94 (19%) pts, these were registered as screening failures and thus excluded from the study. Until now cytogenetic follow-up data for 40 pts is available. After a median follow-up of 9 months (2–16 months) we have observed a significant impact of LEN on the reduction of the clone size (p < 0.05) by FISH-monitoring. Based on cytogenetic remission, we have separated the cohort into three groups: Fast responders (14/40 (35%) pts) showed a very rapid cytogenetic response to therapy with >50% reduction of 5q- clone size within two months. In the second group, the slow responders, we observed >50% reduction of clone size in 9/40 (22.5%) after > two months. However, two pts showed an increase of 5q- clone after 12 and 13 months respectively after initial response in the sense of a relapse. In the third group, the non responders, (11/34 (27.5%)) we could not observe any cytogenetic response during the as yet limited observation period. In six cases (15%) we detected a reduction of the 5q- clone during follow-up, but the emergence of additional aberrations were also observed such as: 1. trisomy 8 in 6.7% of metaphases after 8 months and is reduced to 3.6% after 12 months, 2. trisomy 4 in 6.7% of metaphases after 6 months and is disappeared after 12 months, followed by emergence of trisomy 8 in 8% of interphase cells, 3. finally, two cases showed loss of Y-chromosome after 4 months in 6% and 19% of CD34+ pb cells, respectively. In CD34+ pb cells of another case, trisomy 8 was detectable after two months in 3.5% of cells. All these new secondary abnormalities occurred in cells with normal chromosomes 5 and were slightly above or below our laboratory thresholds (3 times standard variation). In only one case, a new abnormality emerged in the 5q- clone: In this case additional del(20q) occurred after 2 months in 46% of CD34+ pb cells. In this case no reduction of 5q- cells after 4 months of treatment was observed. However, FISH analysis after 6 months of treatment showed a 14% reduction for both aberrations. To date we could not identify any pts who acquired complex anomalies while treated with LEN. Conclusion: FISH analysis of CD34+ pb cells allows a reliable frequent and relevant genetic monitoring of treatment response to LEN. Our results confirm the positive and rapid effects of LEN on clones with del(5q): Thus, already after 2 months, we could observe up to 90% reduction in the 5q- clone size in 35% of pts. In general, remission rates increased with duration of therapy. We suspect that trisomy 4, 8 and Y-loss are fluctuant “mini clones” without any clinical relevance. Inclusion of additional pts and prolonged observation period will help us to better evaluate the clinical response to LEN. Disclosures: Off Label Use: lenalidomide for MDS del(5q) provided by Celgene for this clinical study. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Braulke:Celgene: Honoraria, Research Funding. Schanz:Celgene: Honoraria, Research Funding. Giagounidis:Celgene: Honoraria. Götze:Celgene: Honoraria. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Myelodysplastic Syndromes (MDS) with Erythroid Hyperplasia: Enumerating Blasts from Non-Erythroid Cell Compartment Improves the Risk Stratification of MDS with Excess of Blasts

Blood ◽

10.1182/blood.v126.23.2894.2894 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2894-2894

Author(s):

Leonor Arenillas ◽

Xavier Calvo ◽

Mar Tormo ◽

David Valcárcel ◽

Elisa Luño ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Erythroid Cell ◽

Advisory Committees ◽

Erythroid Hyperplasia ◽

Risk Patients ◽

Blast Cells ◽

Blast Count

Abstract Introduction: WHO classification of MDS is based on cytopenias, dysplasia, percentage of blasts in PB and BM, and cytogenetics. IPSS-R establishes BM blast subgroups (≤2%,2-<5%,5%-10% and >10%) with independent impact in OS. Erythroid hyperplasia (≥50% of total BM cells) is common in MDS. Concerning MDS with expanded erythropoiesis, there is no consensus whether the proportion of BM blasts should be considered on the basis of all nucleated cells (approach-A) or in non-erythroid cells (approach-B). Aim: To elucidate this issue, we reassess percentage of BM blasts of MDS with erythropoiesis ≥50% from the Spanish registry (RESMD), according to both definitions. Methods: We performed a retrospective analysis of 507 primary MDS diagnosed according to WHO 2008. Proportion of red-cells was calculated in 500 nucleated cells. Erythroid hyperplasia was documented in 10.4% of patients from RESMD. Results: Median age of presentation was 74years (25-94years) and 63% were males. Median follow-up was 29.4 months and median OS was 47.14 months. Table 1 shows distribution of WHO subtypes of the series according to both approaches. Of note, following WHO recommendations, RAEB-2 diagnosis was not possible; formally all of them were diagnosed with erythroleukemia. Distribution of patients according to IPSS-R blast-categories by both methods is shown in Table 2. It is noteworthy that 14/389pts (3.6%) with blasts <5% using approach-A were reclassified in 10-<20% category (RAEB-2) when the approach-B was applied. However, their survival did not differ significantly from those who remained in low-count blast categories. Using approach-A, IPSS-R blast categories discriminate significantly OS of blast subgroups <5% (0-2% vs. 2-<5%, 81 vs. 44 months, p =0.011). Nevertheless, categories with ≥5% blasts showed no differences (5-10% vs. 10-20%; 18 vs. 13 months, p =0.39). With approach-B, significant differences were observed among categories with <10% blasts (0-2% vs. 2-<5% vs. 5-10%; 82 vs. 65 vs. 41 months, p =0.032). However, as in IPSS-R, no differences were observed >10% (10-20% vs. >20%; 20 vs. 14 months, p =0.53). Figure 1. Applying approach-A, significant differences in proportion of patients with high-risk karyotype defined by IPSS were seen between ≥5% blasts vs. <5%, but not between 5-<10% and 10-20%. Using approach-B, these differences appeared in 10% cut-off, without differences between 10-<20% and >20%. Therefore, high-risk patients (>10% blasts and high-risk cytogenetics) were better defined by the second method. Conclusion: In agreement with WHO committee recommendations, these results suggest that there is no a uniform criteria for assessment of medullary blasts. Considering percentage of blasts on the basis of non-erythroid compartment might improve the classification and prognostication of MDS with ≥5% blast cells. However in low-blast count patients this approach could overestimate their risk. Disclosures Valcárcel: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ramos:GlaxoSmithKline: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria.

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Impact of sFLC Ratio on Outcome in Patients with MM: Validating the Utility of sFLC in Response Definition

Blood ◽

10.1182/blood-2019-131835 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3080-3080

Author(s):

Nadine Abdallah ◽

S. Vincent Rajkumar ◽

Dragan Jevremovic ◽

Prashant Kapoor ◽

Angela Dispenzieri ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Complete Response ◽

Light Chains ◽

Advisory Committees ◽

Normal Ratio ◽

Abnormal Ratio

Background: The treatment of Multiple Myeloma (MM) has evolved significantly in the past decade with the introduction of novel agents and drug combinations, thus enhancing treatment efficacy and allowing more patients to achieve complete response (CR). This has created a need to identify surrogates for depth of treatment response. Serum free light chain (sFLC) ratio normalization has been shown to be prognostic for progression free survival as well as overall survival in patients achieving a complete response to therapy. Consequently, it has been incorporated as a defining feature for stringent CR, along with lack of clonal plasma cells by immunohistochemistry (IHC) or low sensitivity flow cytometry. The routine use of multiparametric flow cytometry with higher sensitivity to detect residual disease than IHC or the older 4-color flow cytometry, has raised the question as to whether sFLC ratio is still a valid indicator of response depth. Moreover, in nearly half of the patients with an abnormal sFLC ratio after treatment, the abnormality is secondary to suppression of one or both serum light chains. Therefore, we designed a retrospective study to address these issues. Patients and Methods: This is a retrospective study using the Multiple Myeloma Database at Mayo Clinic, Rochester. We included patients who, after any line of therapy, had negative serum and urine immunofixation and absence of clonal bone marrow plasma cells by flow cytometry (PC-PRO), which has a sensitivity of >10-4. Simultaneous sFLC data was also extracted. Patients were grouped into three categories based on their sFLC ratios: 1) normal ratio (normal), 2) abnormal ratio due to suppression of the uninvolved light chain (LC), involved LC, or both (Abn-suppressed) and 3) abnormal ratio due to elevation of the involved LC (Abn-inv elevated). The primary endpoint was the median time to next treatment (TTNT), defined as the time from sample collection to the time of initiation of the subsequent therapy or time of last follow up if a subsequent line of treatment was not initiated. Results: The cohort consisted of 510 patients. 285 (56%) were males and 225 (44%) females. Median age was 61 years (IQR: 55-67). Median Follow-up was 41 months. The last treatments administered prior to data collection included stem cell transplant (SCT) (with or without maintenance) in 290 (57%) patients, and non-SCT regimens in the others. The sFLC ratio was normal in 337 (66%) and abnormal in 173 (34%) patients. Among the patients with abnormal sFLC ratios, 81 had elevated involved LC, 25 had suppression of the involved LC, 45 had suppression of the uninvolved LC and 22 had suppression of both LCs. We first examined the TTNT for the three groups and found that the TTNT was identical for those with a normal ratio and those with an abnormal ratio due to suppression of one or both light chains (Figure 1). So, we combined these two groups (Normal-Abn suppressed) and compared their outcomes to the patients with abnormal sFLC ratio due to elevated involved LC. The Abn-inv elevated group had a shorter TTNT as shown in Figure 2 (log-rank 0.06, Wilcoxon <0.01). The Abn-inv elevated group also had decreased overall survival compared to the other group (log-rank: 0.05, Wilcoxon: 0.01) (Figure 3). Conclusion: This study provides 2 important observations. First, patients with an abnormal ratio due to suppression of one or both LCs have outcomes similar to those with a normal ratio, suggesting a need to clarify the current definition of stringent CR. Second, the study suggests an important prognostic value for an abnormal sFLC ratio due to elevated involved LC, suggesting this as an important surrogate for depth of response. Disclosures Kapoor: Janssen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy; Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

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