Revised International Scoring System Research Articles

Utility of Flowcytometry in the Diagnosis of Myelodysplasia in Routine Laboratories

INTRODUCTION Myelodysplastic syndromes (MDSs) cover a wide range of abnormalities, ranging from subtle morphological changes to overt findings such as prominently skewed morphology. The clinical picture is dominated by cytopenia of one or more lineages, defined by Haemoglobin<100g/L, absolute neutrophil count <1.8 x 10^9/L and platelets less than 100 x 10^9/L. The aberrant features, suggestive of MDS that can be picked up by flow cytometry can occasionally be missed on morphological features. In the presence of clonal haematopoiesis, these features detected by flow cytometry may help us to confidentially apply a label of MDS to an individual. MATERIALS AND METHODS All patients with suspected myelodysplastic syndrome and patients with acute myeloid leukemia (AML) <30% blasts. Profound dominance of myeloid blasts in a patient with AML automatically earns the patient the 2 points needed for the MDS label and the myeloblast dominance inevitably outnumbers B-cell progenitors, which will affect the Ogata scoring.Exclusion criteria: >2% monoclonal lymphocytes by flow cytometry<400 CD34+ events in the collected sample Parameters included: Ogata A simple 4-point scoring system by Ogata. Other features included as per European Leukemia Net guidelines on flow cytometry on MDS We included following nine parameters to be analysed in addition to the Ogata criteria: Myeloid progenitors: Increased expression of CD11bAbnormal expression of CD7 in progenitor cells (CD34/CD117 Positive cells) Monocytic Lineage: Decreased expression of CD11bDecreased expression of HLA-DRDecreased expression of CD14 Myeloid Lineage: Diminished expression of CD45Decreased expression of CD11bDecreased expression of CD13 or CD33 (Any one of them)Decreased expression of CD10 RESULTS In our analysis of normal patients, Ogata score was frequently positive in the category lymphocyte/ myeloblast CD45 ratio. This obviously may affect the sensitivity. In the series of 20 patients we analysed, we had only one patient with combined score of four or less (patient no: 12). Two patients with Ogata score of less than two fulfilled the flow cytometric criteria using the combined criteria (Patient no: 3 and 5). Since our numbers were low, we do not know whether the combined scoring system would gain more significance in a large cohort of patients. In one of the normal patients who presented with cytopenia with high MCV (patient no: 10) the morphological and flow cytometry features were not consistent with myelodysplasia. Moreover, the patient did not have clonal abnormalities. This patient could have classified as myelodysplasia by flow cytomeric criteria if Ogata score alone had been used. The sensitivity of the combined parameters in detecting myelodysplasia is 89.4% and specificity is 90.9%. CONCLUSION We devised this system based on the principles that, the Ogata scoring system is simple and reproducible. Moreover, its sensitivity can be improved by using nine additional markers based on WELLS criteria, which can be analysed based on mean fluorescence intensity (MFI) alone without much complexity. Our methodology was not demanding and it did not involve usage of special fluorescent dyes and hence can be reproduced in any routine diagnostic laboratories. In addition, we found that both sensitivity and specificity of Ogata scoring system has been improved by inclusion of the other parameters in this study. Our scoring system did not show any correlation with reference to the R-IPSS (Revised International Scoring System in myelodysplasia) at diagnosis. Many attempts have been made so far with extensive markers and application of Automated Intelligence strategies for the analysis of more complex combinations of parameters. However, a simplified, user friendly and cost effective method is the need of the hour.

Outcome of Outpatient Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma and Relapsed and Refractory Hodgkin Lymphoma. The Experience of King Fahad Specialist Hospital in Dammam, Saudi Arabia

Background: Autologous hematopoietic stem cell transplants (HSCT) is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (MM) and patients with relapsed and refractory Hodgkin lymphoma (R/R-HL) who achieve chemosensitivity after salvage therapy. Although autologous HSCT is routinely performed in an inpatient setting, the procedure can safely be performed in an outpatient setting. Methods and materials: A retrospective study of patients with MM and R/R- HL who received outpatient autologous HSCT at King Fahad Specialist Hospital (KFSH) in Dammam, Saudi Arabia between the first of April 2017 and the 31st of January 2022 was performed. Results: Over the study period of 4 years and 10 months, a total of 90 outpatient autologous HSCTs were performed for 79 patients (54 patients with MM; 4 of them received planned tandem autografts and 7 other myeloma patients received second autologous HSCTs for relapsed or progressive disease; and 25 patients with R/R-HL) at our institution. The median ages of patients with MM and those with R/R-HL at HSCT were 50.4 years and 27.8 years respectively. At the presentation of their MM, the following high-risk (HR) features were encountered: stage II and III diseases according to the revised international scoring system (RISS) in 53.7%; adverse cytogenetics in 42.6% and extensive bone involvement in 53.7% of patients. In patients with HL at presentation, 48% of patients had stage IV disease according to Ann Arbor staging classification and 84% of patients had B symptoms. Survival for 100 days post-HSCT for all patients with MM and HL who received outpatient autologous transplants was 100%. For patients with MM, the overall survival (OS) rates at 3 years and 4 years post-HSCT were 80% and 67%, while the progression-free survival (PFS) rates over 3 years and 4 years were 58% and 38% respectively. For patients with HL, the OS at 6 years post-HSCT was 95% while the PFS rates at 3 years and 6 years post-HSCT were 84% and 62% respectively. Conclusion: Outpatient autologous HSCT for patients with MM and HL is safe, and feasible and can lead to short-term as well as long-term outcomes that are comparable to autologous transplantation performed in an inpatient setting. Additional benefits of outpatient autologous include saving beds and reducing hospital costs.

The outcome of autologous hematopoietic stem cell transplantation in patients with multiple myeloma. The experience of King Fahad Specialist Hospital in Dammam, Saudi Arabia

Background: Aautologous hematopoietic stem cell transplants (HSCT) is the standard of care for newly diagnosed patients with multiple myeloma (MM) who are eligible for autologous transplantation. Although cryopreservation is routinely employed, autologous HSCT can be performed using non-cryopreserved stem cells. Methods and materials: A retrospective study of patients with MM who received autologous HSCT between the 10th of October 2010 and the 31st of January 2022 at King Fahad Specialist Hospital (KFSH) in Dammam, Saudi Arabia was performed. Results: Over 11 years and 113 days, a total of 135 autologous HSCTs were performed for 119 patients with MM at our institution. Single autologous HSCTs were performed for 119 patients, while 16 of these patients received either planned tandem autologous transplants or second autografts due to either progression or relapse of their myeloma. The median age of patients with MM at autologous HSCT was 51.5 years. At presentation of their MM, the following high-risk (HR) features were encountered: stage III disease according to the revised international scoring system (RISS) in 12.3%; adverse cytogenetics in 31.93% of patients; advanced bone disease in 60.50%; and renal dysfunction or failure in 11.76% of patients. A total of 104 autologous HSCTs (77.04%) were performed without cryopreservation while 31 autografts (22.96%) were performed using cryopreserved apheresis stem cell products. Additionally, 54 autologous HSCTs (40.00%) were done at outpatient while 81 autografts (60.00%) were performed in an inpatient setting. Survival for 100 days post-HSCT for all patients with MM who received autologous transplants including those done at outpatient was 100%. The 4 years overall survival (OS) an progression-free survival (PFS) for patients with MM who received non- cryopreserved or fresh autologous HSCTs were 82% and 68% respectively. Conclusion: Autologous HSCT without cryopreservation is safe, and feasible and can lead to short-term as well as long-term outcomes that are comparable to autologous transplantation with cryopreservation. Non- cryopreserved autologous grafts allow the performance of autologous transplants in an outpatient setting to save beds and reduce costs.

Minimal Residual Disease in Multiple Myeloma—Current Approaches and Future Clinical Implications

The prognosis and clinical outcomes for patients with multiple myeloma have improved significantly over the past two decades. A substantial number of patients now achieve complete remission after induction therapy, and more sensitive methods are needed to assess response. Minimal or measurable residual disease (MRD) has been incorporated in many clinical trials as well as in clinical practice. The importance of MRD assessment and correlation between MRD negativity and prolonged progression-free and overall survival has been confirmed in numerous clinical trials and several meta-analyses. Recent studies have even suggested that MRD negativity can partly overcome the impact of the negative prognostic factors such as high-risk cytogenetics or adverse revised international scoring system (R-ISS) stage. MRD can be measured in the bone marrow via imaging and via emerging blood-based techniques. The most common methods are multicolor flow cytometry and next-generation sequencing of bone marrow samples. Using these methods in optimal settings, MRD negativity with a sensitivity level of 10−6 can be detected. In this review, we discuss the benefits and limitations of these techniques as well as the clinical implications.

A Tangle of Genomic Aberrations Drives Multiple Myeloma and Correlates with Clinical Aggressiveness of the Disease: A Comprehensive Review from a Biological Perspective to Clinical Trial Results.

Multiple myeloma (MM) is a genetically heterogeneous disease, in which the process of tumorigenesis begins and progresses through the appearance and accumulation of a tangle of genomic aberrations. Several are the mechanisms of DNA damage in MM, varying from single nucleotide substitutions to complex genomic events. The timing of appearance of aberrations is well studied due to the natural history of the disease, that usually progress from pre-malignant to malignant phase. Different kinds of aberrations carry different prognostic significance and have been associated with drug resistance in some studies. Certain genetic events are well known to be associated with prognosis and are incorporated in risk evaluation in MM at diagnosis in the revised International Scoring System (R-ISS). The significance of some other aberrations needs to be further explained. Since now, few phase 3 randomized trials included analysis on patient’s outcomes according to genetic risk, and further studies are needed to obtain useful data to stratify the choice of initial and subsequent treatment in MM.

Clinical Course of High-Risk Multiple Myeloma Patients in Korea: A Multicenter Retrospective Study

Introduction: Increased understanding of the pathophysiology of multiple myeloma (MM) and the introduction of new drugs has led to considerable survival improvements in recent years. The International Myeloma Working Group consensus recently updated the definition for high-risk MM based on cytogenetic abnormalities. Moreover, the recent introduction of new therapeutic agents and the revision of insurance reimbursement policies have changed the clinical characteristics of MM patients in Korea. Yet, current epidemiology and the clinical characteristics of MM patients in Korea have not been fully investigated. Therefore, we aimed to understand the characteristics and management of Korean MM patients in a real-world setting by analyzing patients with high-risk cytogenetic abnormalities in the Korean Myeloma Registry. Methods: This is a retrospective observational study using the Korean Myeloma Registry, the web-based multicenter patient registry system established by the Korean Multiple Myeloma Working Party. Patients who are newly diagnosed with MM from 2010 to 2017 with at least one high-risk cytogenetic abnormality [t(4;14), t(14;16), or del(17p)] were included. Primarily, patients were classified by cytogenetic abnormality into three groups: Group 1, t(4;14) or t(14;16); Group 2, del(17p); and Group 3, t(4;14)/del(17p) or t(14;16)/del(17p). These patients were also stratified by the revised International Scoring System (R-ISS) and transplantation history for detailed analysis. We also used the number of cytogenetic abnormalities in an explanatory analysis; in this case, we included gain(1q). Progression-free survival (PFS) and overall survival (OS) were estimated, and the Hazard Ratio with the log-rank test was used for statistical comparison. Results: 391 out of 2170 MM patients from seven hospitals were identified as high-risk patients (men, 49.6%; median age, 63 years old). Median PFS for all patients was 18.9 months (95% CI 17.27-20.33), and the median OS was 44.6 months (95% CI 36.5-60.1). PFS (P<0.001) and OS (P=0.012) between the cytogenetic abnormality groups were significantly different after stratification by transplant history. Patients with t(4;14)/del(17p) or t(14;16)/del(17p) amongst transplant recipients showed the worst outcome, with median PFS 15.5 (95% CI 8.7-20.5) months and median OS 35.6 (95% CI 14.9-N/A) months. Without stratification, there were no significant between-group differences in PFS and OS. OS was also significantly different between cytogenetic abnormality groups stratified by the revised International Staging System (R-ISS) (P=0.003). The lowest median OS durations were 16.9 months (95% CI 6.5-33.6) for del(17p) with R-ISS III, and 21.7 months (95% CI 9.3-N/A) for t(4;14)/del(17p) or t(14;16)/del(17p) with R-ISS III. Patients with higher R-ISS staging in the presence of del(17p) showed worse survival outcomes. Finally, PFS and OS were significantly inversely correlated with the number of cytogenetic abnormalities (P<0.001). Conclusion: In real-world data from the Korean Myeloma Registry, we were able to observe the association of poor prognosis of MM patients with the number of cytogenetic abnormalities (PFS and OS) and R-ISS (OS). Moreover, we were also able to find the association of cytogenetic abnormality del(17p) and poor prognosis in MM patients. Lastly, we believe that this study provides the characteristics and management of MM patients needed to understand the real-world clinical course of high-risk MM patients in South Korea. Disclosures Kim: Amgen, BMS, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; YuhanPharma: Research Funding; Kyowahako Kirin: Research Funding; Amgen: Consultancy, Honoraria. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Lee:AMGEN: Current Employment.

A multicenter retrospective study of 223 patients with t(14;16) in multiple myeloma.

The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the characteristics and outcomes of t(14;16) patients in a large, real-world cohort (n = 223). A substantial fraction of patients had renal impairment (24%) and hemoglobin <10 g/dL (56%) on initial presentation. Combined therapy of both immunomodulatory drug and proteasome inhibitor (PI) in the first line was used in 35% of patients. Autologous stem cell transplantation was performed in 42% of patients. With a median follow up of 4.1 years (95% CI 3.7-18.7), the median progression-free survival (PFS) and overall survival (OS) from first line therapy were 2.1 years (95% CI 1.5-2.4) and 4.1 years (95% CI 3.3-5.5), respectively. Worse OS was predicted by age > 60 years (HR = 1.65, 95% CI [1.05-2.58]), as well as revised International Scoring System (R-ISS) 3 (vs R-ISS 2; HR = 2.59, 95% CI [1.59-4.24]). In conclusion, based on the largest reported cohort of t(14;16) patients, quarter of this subset of MM patients initially presents with renal failure, while older age and the R-ISS 3 predict poor survival.

Improved Outcomes after Allogenic Hematopoietic Stem Cell Transplantation with Fludarabine/Treosulfan for Patients with Myelodysplastic Syndromes.

While allogeneic hematopoietic stem cell transplantation (allo-HCT) currently offers the only curative option for patients with myelodysplastic syndrome (MDS), there is still a high risk of relapse or transplant-related complications. We collected data on all patients who had undergone allo-HCT at our center (Copenhagen University Hospital) between 2000 and 2018. In total, 215 patients with MDS (n=196) or chronic myelomonocytic leukemia (n=19) were included. Estimated 1-year overall survival (OS) was 70.3% (95% confidence interval [CI], 64.2% to 77.0%), and the median survival was 7.7 years (95% CI, 4.7 to indeterminable). There was a significant improvement in OS over time (P=.011, comparing 2000 to 2010, 2010 to 2014, and 2014 to 2018). Treatment was standardized throughout the study period, allowing comparison between patients receiving nonmyeloablative (NMA, n=124), standard myeloablative (SMA, n=36), and fludarabine and treosulfan (FluTreo, n=55) conditioning. FluTreo has myeloablative properties but lower toxicity and replaced standard myeloablative conditioning at our center in 2014. The FluTreo group was significantly older and had more comorbidities than the SMA group but similar disease severity. One-year OS was 84.0% (95% CI, 74.3% to 94.9%), 58.3% (95% CI, 44.3% to 76.9%), and 68.3% (95% CI, 60.2% to 77.5%) for FluTreo, SMA, and NMA, respectively (P=.04). In univariate analysis, Revised International Scoring System (IPSS-R) (high versus low), donor sex mismatch, and cytomegalovirus status mismatch were significant factors for OS. In multivariate analysis of OS including age, IPSS-R, and HCT specific comorbidity index, NMA was borderline inferior to FluTreo (P=.073) while SMA was significantly inferior to FluTreo with a hazard ratio of 6.89 (95% CI, 2.53 to 18.77, P < .001). The introduction of FluTreo allowed us to administer a myeloablative regimen to a broader patient group and shows promising results.

Bone marrow oxidative stress and specific antioxidant signatures in myelodysplastic syndromes

AbstractMyelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response. Our results highlight increased ROS levels in BM nonlymphoid cells and especially in primitive CD34posCD38low progenitor cells. Moreover, we identified a specific antioxidant signature, dubbed “antioxidogram,” for the different MDS subgroups or secondary acute myeloblastic leukemia (sAML). Our results suggest that progression from MDS toward sAML could be characterized by 3 successive molecular steps: (1) overexpression of enzymes reducing proteic disulfide bonds (MDS with <5% BM blasts [GLRX family]); (2) increased expression of enzymes detoxifying H2O2 (MDS with 5% to 19% BM blasts [PRDX and GPX families]); and finally (3) decreased expression of these enzymes in sAML. The antioxidant score (AO-Score) defined by logistic regression from the expression levels of transcripts made it possible to stage disease progression and, interestingly, this AO-Score was independent of the revised International Scoring System. Altogether, this study demonstrates that MDS and sAML present an important disturbance of redox metabolism, especially in BM stem and progenitor cells and that the specific molecular antioxidant response parameters (antioxidogram, AO-Score) could be considered as useful biomarkers for disease diagnosis and follow-up.

Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis

AbstractMyelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.

Benefit of Two Additional Cycles of Bortezomib/Thalidomide/Dexamethasone (VTD) Induction Therapy Compared to Four Cycles of VTD for Newly Diagnosed Multiple Myeloma

IntroductionFour cycles of bortezomib/thalidomide/dexamethasone (VTD) induction therapy followed by autologous stem cell transplantation (ASCT) is one of the standard therapy for patients aged less than 65 years with newly diagnosed multiple myeloma (NDMM). Complete remission (CR) status before ASCT is an important prognostic factor for progression-free survival (PFS). We analyzed whether two additional cycles of VTD improved the pre- and post-transplant responses as well as PFS compared to the four cycles of VTD induction therapy.MethodsA total of 222 patients with NDMM between September 2014 and August 2016 from eleven hospitals in South Korea were included in the current study. The patients received at least four or more cycles of VTD induction therapy before administration of high-dose therapy (HDT, melphalan 200mg/m2) followed by ASCT. VTD regimen was consisted of bortezomib subcutaneous infusion (1.3 mg/m2 on days 1, 4, 8, and 11), thalidomide (100 mg daily), and dexamethasone (40 mg on days 1-4, 8-11), which was administered every 4 weeks.ResultsThe median age was 57 years (range 30−64 years), and 120 patients (61.9%) were male. Revised international scoring system (R-ISS) classified 59 (30.4%), 86 (44.3%), and 49 patients (25.3%) as stage I, II, and III, respectively. VTD induction was administered 4 cycles in 194 patients (VTD4, 67.5%) and more than 4 cycles in 63 (VTD6, 32.5%) before HDT. Patient characteristics at diagnosis did not differ between VTD4 and VTD6. CR rate before HDT was significantly higher in VTD6 than VTD4 (31.7% vs 13.0%, P = 0.003). However, CR rate after HDT/ASCT was similar between VTD4 and VTD6 (69.0% vs 65.5%, P = 0.726). There was no difference in the incidence of peripheral neuropathy (PN) (≥ grade 2 or that required dose reduction) between two groups. The median follow-up duration was 18.0 months (range 7.0-43.8 months). The 2-year PFS did not differ between the two groups (51.7 ±5.7% in VTD4 and 62.1±8.6% in VTD6, P = 0.240). Multivariate analysis revealed that the achievement of CR was a favorable prognostic factor for PFS (HR 0.27 [0.08−0.90], P = 0.034). Deletion 17p (HR 2.87 [1.01−7.92], P = 0.048) and t(4;14) (HR 3.38 [1.76−6.48], P < 0.001) in FISH were adverse prognostic factors for PFS. Patients with stage I/II by R-ISS receiving additional two cycles of VTD showed prolonged PFS (median PFS not reached vs. 27.6 months, P = 0.034). In the multivariate analysis, VTD6 was a favorable prognostic factor for PFS for patients with stage I/II by R-ISS, (HR 0.11 [0.02−0.52], P = 0.005).ConclusionCR rates increased with additional cycles of VTD induction therapy for NDMM. However, the PFS benefit was observed only in patients with R-ISS stage I/II. For patients with high-risk MM, intensive induction therapy that overcome poor prognostic factors should be administered to improve long-term outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Association between Immunoglobulin Isotypes and Cytogenetic Risk Groups in Multiple Myeloma

Introduction:Cytogenetic abnormalities (CAs) in multiple myeloma (MM) have prognostic significance and predict the risk of clonal evolution, disease progression, and response to treatment. The Revised International Scoring System (R-ISS) was recently updated to incorporate high risk CAs, including del(17p), t(14:16), and t(14:20), the presence of which confer a poorer prognosis. Prior studies have demonstrated the prognostic value of specific CAs and MM immunoglobulin isotypes, for example, non-IgG isotypes having been associated with poorer prognosis. However, data showing a link between cytogenetic risk groups and MM isotypes are limited. Thus, we determined whether a relationship exists between higher-risk CAs and MM isotypes, as well as the degree of malignant plasma cell infiltration of the bone marrow (BM).Methods:We performed a retrospective analysis of a multi-institutional commercial pathology repository of 442 MM patients identified according to the International Myeloma Working Group criteria that included assessment of BM infiltration (BM%), MM isotype, CA, and cytogenetic risk group. The study protocol was approved in accordance with IRB standards. As per the R-ISS, the high risk CAs included del(17p), t(14:16), and t(14:20), intermediate risk CAs included t(4;14), del(13q), dup(1q), and hypodiploidy, and standard risk CAs included t(6;14), t(11;14), and hyperdiploidy. Patients with CAs that included more than one risk group were considered to be in the higher risk category. Associations between categorical variables were made using the chi-squared test or Fisher's exact test. The Mann-Whitney test was used to compare groups (MM isoytpe, CAs, or cytogenetic risk group). Statistical significance was considered at p<0.05. Analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).Results:Among the 442 MM patients, isotype groups included 42% IgG, 16% IgA and 42% light chain-only (LCO). There were 184 patients (42%) who had CAs associated with known MM cytogenetic risk groups, of which 34% were standard-risk, 61% were intermediate-risk, and 5% were high-risk. The median BM% of clonal plasma cells was 50% (range 1-95%). When examining the relationship between any CA and BM%, del(13q14), dup(1p32), dup(1q21), t(4;14), trisomy(11q13), and monosomy(16q23) were associated with a significantly higher BM% than patients who were lacking those respective CAs. For example, the median BM% for patients with t(4;14) was 60% compared with 15% in patients lacking this translocation (p<0.0001). LCO isotype was associated with a lower BM% (p<0.04), however there was no significant correlation between IgG/IgA isotypes and BM%. There was a higher median BM% seen in the intermediate risk group (50%, p<0.0001) compared to standard risk group (20%, p<0.04). The high risk group was not significantly associated with BM%. When comparing isotypes to cytogenetic risk groups, IgA isotype was significantly associated with intermediate risk cytogenetics (p<0.03). Conversely, there was a significantly lower rate of standard risk CAs among IgA isotypes (p<0.01). There was no significant correlation between IgG/LCO and cytogenetic risk. IgA isotype correlated with specific CAs, including del(13q) (p<0.02) and del(16q23) (p<0.04). There was a higher rate of t(11:14) in the non-IgA isotype groups. Additionally, IgG isotype was associated with a trisomy(11q13) (p<0.03). LCO isotype also corresponded with a higher rate of del(17p) (p<0.03), t(11:14) (p<0.03), and a lower rate of t(4:14) (p<0.04) and trisomy (11q13) (p<0.01).Conclusions:In MM, CAs are valuable in risk stratifying patients and predicting treatment responses. In this study, data suggest that the IgA isotype is significantly associated with intermediate-risk cytogenetics, including del(13q) and hypodiploidy, and LCO disease correlates with high risk cytogenetics, including del(17p). When taken together this may explain the previously known association of these isotypes with poorer prognosis, and suggests divergent clonal evolution among MM isotypes. Associations between clinical parameters and disease responses remain ongoing. DisclosuresNo relevant conflicts of interest to declare.

Prognostic significance of bone marrow abnormalities in the appendicular skeleton of patients with multiple myeloma

AbstractWe aimed to determine the clinical and prognostic significance of medullary abnormalities detected by low-dose whole-body multidetector computed tomography (MDCT) in the appendicular skeleton (AS) of patients with newly diagnosed symptomatic multiple myeloma (MM). One hundred ninety-six patients underwent low-dose whole-body MDCT as an initial workup. Patients were categorized into 3 groups based on the medullary pattern of the AS: fatty (36.3%), focal (43.4%), and diffuse (20.4%). Medullary abnormalities were associated with Durie-Salmon and revised International Scoring System stage 3, creatinine levels >2.0 mg/dL, and the proportion of bone marrow plasma cells. The median follow-up was 35.4 months. Patients with fatty, focal, and diffuse patterns had a median survival of not reached, 56 months, and 38 months, respectively. Overall survival (OS) was associated with age, Durie-Salmon stage 3, creatinine levels >2.0 mg/dL, ineligibility for autologous stem cell transplantation, and focal and diffuse patterns on univariate analysis. Multivariate analysis showed that age and diffuse pattern (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.12-3.31; P = .018) were independent predictors of progression-free survival. Age and focal (HR, 2.51; 95% CI, 1.14-5.56; P = .023) and diffuse (HR, 4.12; 95% CI, 1.74-9.77; P = .001) patterns were also independent predictors of OS. The addition of marrow pattern to preexisting risk factors was associated with a net reclassification improvement for predicting OS (to 0.37, P = .015). Medullary abnormalities in the AS (detected by low-dose whole-body MDCT) are associated with a poor prognosis, independent of other clinical variables.

Outcome and Risk Factors for Therapy-Related Myeloid Neoplasms Treated with Allogeneic Stem Cell Transplantation

BackgroundTherapy-related myeloid neoplasms (t-MN) have a poor prognosis with conventional chemotherapy and a median survival of ≤1 year. Allogeneic stem cell transplantation (HCT) is considered the only effective treatment. EBMT and CIBMTR analyzed their registry data on HCT against t-MN and reported its outcome and developed scoring systems using identified risk factors in HCT. This study aimed to investigate outcome and risk factors in adult patients with t-MN who underwent HCT in Japan.MethodsData sourceFor this retrospective observational study, recipients' clinical data were provided by the Transplant Registry Unified Management Program of Japan society for Hematopoietic Cell Transplantation.DefinitionTherapy-related myeloid neoplasms include therapy-related AML (t-AML), t-MDS, and t-MDS/MPN occurring as late complications of cytotoxic chemotherapy and/or radiation therapy administered for a prior neoplastic or non-neoplastic disorder. Cases with past history of MDS or MPN were excluded because it was not possible to clearly distinguish their neoplasms from an original myeloid neoplasm or therapy-related neoplasm.The primary outcome of the analysis was overall survival (OS), whereas the secondary endpoints included incidence of relapse and transplantation-related mortality (TRM).Cytogenetic risk groups in AML were classified according to the MRC (2010). In MDS, three risk groups were defined using the revised International Scoring System: favorable (very good and good), intermediate (intermediate), poor (poor and very poor). HLA mismatch was defined as incompatibility between the recipient and donor when at least a single allele mismatch was detected at HLA-A, -B, and -DR in related and unrelated donors. In cord blood, HLA mismatch was defined as at least two antigen mismatches detected at HLA-A, -B, and -DR.Statistical analysisOS was estimated using the Kaplan-Meier method and was compared using the log-rank test. Cox's proportional-hazards regression model was used for multivariate analysis of prognostic factors. Cumulative incidence curves were used in a competing-risk setting to calculate the probability of relapse and TRM. Relapse and therapy-related deaths were considered a competing risk event for each other and were compared using Gray's test.ResultsBetween 1992 and 2012, 641 adult patients who had undergone HCTs for confirmed t-MN (not de novo myeloid neoplasms) were identified. Median age at HCT was 53 (range; 16-80) years, with a female proportion of 49%. In total, 414 (64.6%) patients had AML, 215 (33.5%) had MDS, and 12 (1.9%) had MPN. Approximately 50% of patients had a prior history of lymphoma, 14.6% had acute leukemia, and 13.3% had breast cancer. Karyotype was available in 310 cases. Favorable karyotypes were detected in 11 (3.5%) cases, whereas intermediate and poor karyotypes were detected in 122 (39.4%) and in 177 (57.1%) cases, respectively. HLA mismatched HCT was 25.7%. Bone marrow or peripheral HCT from related donors was used in 189 (28.7%) cases, whereas bone marrow HCT from unrelated donor was used in 228 (35.7%) cases, and cord blood HCT was used in 229 (35.6%) cases. Approximately 30% of patients were in remission at HCT.Overall survival was 45.3% [95% confident interval (CI) 45-48], 33% (CI 29-37), and 28% (CI 24-32) at 1, 3, and 5 years, respectively. In multivariate analysis, the significant factors for poor survival were ECOG Performance Status (PS) 2-4 (HR 1.99; CI 1.45-2.72), disease status of non-remission at the time of HCT (HR 1.82; CI 1.33-2.50), patient age of >55 years (HR 1.72; CI 1.32-2.24), and poor karyotype (HR 1.54; CI 1.15-2.05).The cumulative incidence of non-relapse mortality and relapse at 3 years was 37% and 36%, respectively. In a multivariate analysis, the significant factor for non-relapse mortality was patient age of >55 years (HR 1.48; CI 1.09-2.02). For relapse, poor karyotype (HR 2.29; CI 1.65-3.18) was a significant factor.ConclusionsPS 2-4, non-remission, higher patient age, and poor cytogenetics were predictive of poor survival. The outcome of HCT against therapy-related myeloid neoplasms in Japan was comparable to those of EBMT and CIBMTR. DisclosuresUsuki:Novartis: Other: personal fees, Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Taiho Pharmaceutical: Other: personal fees, Research Funding; Fuji Film RI Pharma: Other: personal fees; Chugai Pharmaceutical: Other: personal fees; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; Shionogi: Other: personal fees; Sanofi: Other: personal fees, Research Funding; MSD: Other: personal fees, Research Funding; SymBio Pharmaceutical: Other: personal fees, Research Funding; Eisai: Research Funding; Otsuka Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Other: personal fees, Research Funding; Shire: Research Funding; Takeda Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Research Funding; Bristol-Myers Squibb: Other; Astellas: Research Funding. Miyazaki:Chugai: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; Shin-bio: Honoraria.