Epidemiology Unknown: Developing an Approach to Identify Potential Smoldering Multiple Myeloma Cases

Abstract Background Smoldering Multiple Myeloma (SMM) is an asymptomatic clonal plasma cell disorder that identifies patients at risk for progression to Multiple Myeloma (MM). The standard of care for SMM has traditionally been observation, but some cancer centers are now treating high-risk SMM before progression to MM. The diagnostic criteria for SMM have also changed in recent years, and current estimates of SMM are derived from large MM databases and observations from tertiary centers. The goal of this study was to develop an approach for identifying SMM cases in a large integrated healthcare delivery system to better characterize the epidemiology of SMM in community-based populations. Methods This retrospective, observational study was conducted in Kaiser Permanente Northern California (KPNC) using KPNC SEER-based Cancer Registry data and information from the electronic health record (EHR). Potential SMM cases from 1/1/2010 to 12/31/2018 were identified using three approaches: Group 1 - identified via the KPNC Cancer Registry based on indicators of 'asymptomatic myeloma', 'evolving myeloma', and 'smoldering myeloma'; Group 2 - identified via the KPNC Cancer Registry as MM cases who had a physician visit note containing the word 'smoldering' but did not begin treatment within 1 year of diagnosis; Group 3 - identified via the KPNC Cancer Registry as MM cases who had a physician visit note containing the word 'smoldering' but did begin treatment within 1 year of diagnosis. Chart review was performed for these potential SMM cases (Groups 1-3) to document initial bone marrow biopsy results (bone marrow plasma cell percentage, BMPC) and skeletal findings (presence or absence of lytic bone lesions) around the time of biopsy. When BMPC was reported as a range, the highest value was captured. Patient demographics (age, sex and race/ethnicity) were obtained from the EHR. Bivariate analyses were performed using the chi-squared test and the Wilcoxon-Mann-Whitney nonparametric test. For binomial comparisons by mode of potential SMM case identification, Groups 1 and 2 were combined and compared to Group 3. Results A total of 471 potential SMM cases were identified, including 178 (37.8%) via Group 1, 35 (7.4%) via Group 2, and 258 (54.8%) via Group 3 (Figure). The median age was 71 years (interquartile range, IQR 62-78) and 40.0% were female. The racial/ethnic distribution included 57.1% White, 17.6% Black, 10.8% Hispanic, 13.6% Asian, and 0.9% other/unknown race. There were no significant differences across groups (Group 1+2 vs Group 3) with respect to age (p=0.07), sex (p=0.85), or race/ethnicity (p=0.81). There were 442 (93.8%) who underwent bone marrow biopsy. Among those with BMPC data, the median BMPC for Group 1 was 20.0% (IQR 10.0%-28.0%); for Group 2 was 25.0% (IQR 12.5%-50.0%), for Group 3 was 28.0% (IQR 15.0%-50.0%) (p<0.001 comparing Groups 1+2, combined median 20.0%, IQR 10.0%-30.0%, vs Group 3, 28.0%, IQR 15.0%-50.0%). The proportion with BMPC ≥60% was 4%, 13%, and 22% for Groups 1, 2, and 3, respectively (Figure). There were 413 (87.7%) who had skeletal imaging (n=405, 86.0% with available results) within 6 months of diagnosis. Of those with imaging results available to view, n=68 were found to have lytic lesions; 7.6% among Group 1, 6.9% among Group 2, 24.9% among Group 3 (p<0.001 comparing Groups 1+2, 7.5%, vs Group 3, 24.9%). Discussion This study used a multifaceted approach to identify potential SMM cases from a large real-world clinical population in an integrated health system. We used an approach similar to prior SMM epidemiological studies and also included those with physician visit notes specifically containing the word 'smoldering' within the text. The vast majority of our cohort had BMPC between 10 and 60%, but those who received treatment within 1 year had greater BMPC and a higher proportion of lytic lesions. This suggests those who received treatment, Group 3, may have actually had a MM diagnosis, and physician visit notes containing the word 'smoldering' may have been intended to communicate something other than a SMM diagnosis. Further analyses will determine the effectiveness of each approach by confirming SMM cases according to the International Myeloma Working Group diagnostic criteria with incorporation of laboratory data and additional clinical findings. Among confirmed cases of SMM, the rate of progression to MM and the severity of end-organ damage at time of progression will be assessed. Figure 1 Figure 1. Disclosures Lo: Novartis: Research Funding; Bristol-Myers-Squibb: Research Funding; CSL-Bering: Research Funding.

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Surgical Control/Cure of 5TGM1 Murine Multiple Myeloma Model By Thyroparathyroidectomy

Blood ◽

10.1182/blood.v124.21.3387.3387 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3387-3387

Author(s):

Maurizio Zangari ◽

Donghoon Yoon ◽

Hanna Yoo ◽

Young Sik Kim

Keyword(s):

Multiple Myeloma ◽

Parathyroid Hormone ◽

Proteasome Inhibitor ◽

Research Funding ◽

Bone Lesions ◽

Post Surgery ◽

Human Multiple Myeloma ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract The 5TGM1 transplanted C57BL6/KaLwRij mouse is widely used to study murine multiple myeloma development. It recapitulates many features of human multiple myeloma including monoclonal paraprotein as well as bone lesions. Using this mouse model we demonstrated the crucial role of the parathyroid hormone 1 receptor (PTH1R) on the survival of mice exposed to proteasome inhibitor drugs such as bortezomib and carfilzomib; specifically the blockage of the PTH1R function by parathyroid hormone antagonist (PTH 7-34) resulted in significant abrogation of the beneficial survival effect of proteasome inhibitor drugs. To further investigate the effect of the parathyroid hormone (PTH) axis on murine myeloma development we performed thyroparathyroidectomy on the C57BL6/KaLwRij mouse before or after 5TGM1 transplantation. Thyroparathyroidectomy was performed by trained personnel in general anesthesia with isoflurane; all surgical/postsurgical procedures and animal welfare followed an IACUC approved protocol at the University of Arkansas. To prevent hypocalcaemia at postsurgery, 1M CaCl2 solution in the drinking bottle was supplemented for a week. All tested mice received 0.5X106 5TGM1 cell infusion by intravenous injection; mice were divided into three groups; Group 1 control mice (n=10) received 5TGM1 infusion at day 0; Group 2 included 15 mice which on day 10 post 5TGM1 cell infusion underwent thyroparathyroidectomy; Group 3 included 15 mice which at 20 days post-surgery received infusion of 5TGM1 cells. 30% of animals experienced post-surgical complications and died in the first 7 days from procedure; those animals were not included in this survival analysis which is based on 10 animals for each cohort. Blood samples were collected at weekly intervals for IgG2 measurements. The survival curves of mice recovered after surgery are shown in the figure. Figure 1 Figure 1. All control mice (group 1) developed myeloma progression and died within 3 weeks post-transplant; 2 mice from group 2 and 5 mice of the third cohort manifested disease. All 7 animal deaths were pathologically and serologically attributed to myeloma progression. Compared to controls thyroparathyroidectomized mice (Group 2 and Group 3) showed significantly longer survival p<0.001 and p=0.003, respectively. The 13 surviving mice are still alive 6 months post-procedure and have not shown any serological or clinical evidence of disease progression. Two mice from previous experiment set are still alive and healthy after more than 2 years follow-up. In conclusion thyroparathyroidectomy achieves durable control and possibly cure of the 5TGM1 murine myeloma model suggesting an endocrinological control of myeloma progression. Currently the mechanism of action is under investigation. Disclosures Zangari: Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding.

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Prognosis Impact of Positive Minimal Residual Disease By Flow Cytometry Prior to Transplant According to the Cut-Off Threshold in Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-139954 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Claudia Nunez-Torron ◽

Fernando Martin Moro ◽

Juan Marquet Palomanes ◽

Miguel Piris-Villaespesa ◽

Ernesto Roldan ◽

...

Keyword(s):

Flow Cytometry ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Allogeneic Transplant ◽

Group 3 ◽

Baseline Characteristics ◽

Group 2 ◽

Minimal Residual ◽

Group 1

Introduction: Patients with Acute Myeloid Leukemia (AML) and positive Minimal Residual Disease (MRD) prior to allogeneic transplant are currently considered to be a group at high risk of relapse. Multiparameter flow cytometry is a standard technique to measure MRD, and generally we use a 0.1% threshold for positivity. The clinical significance of those patients with an MRD levels >0% but <0.1% is uncertain and it is recommended to define the prognosis of this subgroup. Material and methods: We performed a single-center retrospective analysis of 88 patients transplanted between 2012 and 2020. All patients achieved complete remission (CR) with or without hemoperipheral recovery prior to allogeneic transplant. We have divided our cohort into three groups according to MRD state by flow cytometry: Group 1 patients with negative MRD, Group 2 patients with MRD level >0% but <0.1% and Group 3 patients with MRD ≥ 0.1%. The baseline characteristics of each group were compared using the Chi2 test. The survival analysis was performed through Kaplan-Meier method and the risk was calculated with Cox regression. The Overall Survival (OS) was defined as the time from transplantation to death and the Relapse-Free Survival (RFS) as the time from transplantation to either relapse or death. P<0.05 was defined as statistically significant difference. Results: The baseline characteristics of our cohort are reflected in Table 1. We did not find statistical significant differences except for the response to induction. The median follow-up of the entire cohort was 13.5 months (range 6-43.5). The 4-year RFS (4y-RFS) was 47% and the 4-year OS (4y-OS) 50%. The 4y-RFS was 52.5% in Group 1 vs 59% in Group 2 vs 30% in Group 3. The 4y-OS was 60% in Group 1 vs 60% in Group 2 vs 31% in Group 3 (Image 1). The Hazard Ratio (HR) for RFS and OS comparing Group 1 vs Group 2 was 0.9 [95% CI ((0.3-2.5)] and 1.1 [95% CI (0.4-3)] respectively. The HR for the RFS and OS comparing Group 1 vs 3 was 1.2 [95% CI (0.9-1.7)] and 1.2 [95% CI (0.8-1.6)]. We have stratified patients according to the European LeukemiaNet risk classification. In Group 1, the 4y-RFS was 79% in patients with Favorable Risk (FR) vs 55% in those with Intermediate Risk (IR) and 53% in patients with Adverse Risk (AR) [HR 1.2, 95% CI (0.6-2.3)] and the 4y-OS was 79% vs 54% vs 53% respectively [HR 1.3, 95% CI (0.6-2.5)]. In Group 2, the 4y-RFS was 100% in those with FR vs 83% in IR vs 33% in AR [HR 3.9, 95% CI (0.4-30)] and the 4y-OS was 100% vs 82% vs 36% respectively [HR 4, 95% CI (0.5-32%)]. In Group 3, the 4y-RFS in patients with FR was 82% vs 0% in IR vs 0% in AR [HR 2.1, 95% CI (1.1-4.1)] and the 4y-OS was 82% vs 0% vs 0% respectively [HR 1.6, 95% CI (0.8-3.3)] (Image 2). Conclusions: In our cohort, positive MRD >0.1% prior to transplant identified a group with worse RFS and OS compared to those with negative MRD or positive MRD level >0% but <0.1%. Positive MRD >0.1% is especially relevant in the IR and AR groups of the European LeukemiaNet risk classification. In the AR subgroup even any detectable level of positive MRD could identify patients with unfavorable post-transplant OS and RFS outcomes. We must establish post-transplant strategies in these patients to improve survival. Disclosures Garcia-Gutiérrez: Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding.

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Mobilization of Stem Cells from the Bone Marrow Is Required for Neovascularization of Ischemic Limbs in Mice.

Blood ◽

10.1182/blood.v106.11.4233.4233 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4233-4233

Author(s):

Jeong-A Kim ◽

Chang -Hoon Lee ◽

Jin-A. Yoon ◽

Woo-Sung Min ◽

Chun-Choo Kim

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hind Limb ◽

Limb Ischemia ◽

Hind Limb Ischemia ◽

Ischemic Limb ◽

Group 3 ◽

Group 2 ◽

Surgically Induced ◽

Group 1

Abstract We examined whether the injection of bone marrow mononuclear cells (BM-MNCs) or mesenchymal stem cells (MSCs) might augment angiogenesis and collateral vessel formation in a mouse model of hind limb ischemia. C57BL/6 BM-MNCs were isolated by centrifugation through a Histopaque density gradient and MSCs were obtained from C57BL/6 bone marrow and cultured in low-glucose DMEM media. Unilateral hind limb ischemia was surgically induced in C57BL/6 mice (control; n=4), and autologous BM-MNCs (Group 1; n=4, 1.8±0.2 x107/animal) or MSCs (Group 2; n=4, 1.0±0.14 x106/animal) or BM-MNCs and MSCs (Group 3; n=4, 2.3±0.1 x107 and 1.1±0.21 x106/animal) were transplanted into the ischemic tissue. Six weeks after transplantation, the group 1, group 2 and group 3 had a higher capillary/muscle ratio (0.82±0.12 vs 0.85±0.08 vs 0.97 ±0.03) than control (0.46±0.12, p<0.05) (Fig. 1). This result suggested that direct local transplantation of autologous BM-MNCs or MSCs seems to be a useful strategy for therapeutic neovascularization in ischemic tissues. Next, we evaluated whether bone marrow derived stem cells were participated in the process of local injected stem cells forming new vessels. In general, mobilizing stem cells from bone marrow to local site, MMP-9 has been known as an important molecule. So we used the MMP-9 deficient KO mice and wild type, 129SvEv mice were used in the experiments. Autologous BM-MNCs and MSCs were transplanted into the ischemic limb in MMP-9 (−/−) (n=4) after unilateral hind limb ischemia was surgically induced and then the same experiments was done in MMP-9 (+/+) mice (n=4). The number of the injected BM-MNCs and MSCs was 2.2±0.05 x107 and 0.87±0.17 x106/animal in MMP-9 (−/−). And the number of the injected BM-MNCs and MSCs was 2.1±0.17 x107 and 0.98±0.09 x106/animal in MMP-9 (+/+). No difference was seen in the BM-MNCs and MSCs were injected or not (0.52±0.07 vs 0.49±0.03,) in MMP-9 (−/−). But, in the case that BM-MNCs and MSCs were injected, the higher capillary/muscle ratio was seen in MMP-9 (+/+) compared to control (0.86 ±0.09 vs 0.49±0.03, P<0.05) (Fig 2). This data indicated that the mobilization of bone marrow derived stem cells would have an important role in the neovasculrization although the stem cells were injected directly into the muscle of ischemic limb. Figure Figure Figure Figure

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Prophylactic Use of a Combination of an Anticoagulant and Ursodeoxycholic Acid for Sinusoidal Obstruction Syndrome after Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.5755.5755 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5755-5755

Author(s):

Hiroshi Okamura ◽

Mitsutaka Nishimoto ◽

Takahiko Nakane ◽

Hideo Koh ◽

Yasuhiro Nakashima ◽

...

Keyword(s):

Risk Factors ◽

Research Funding ◽

Gemtuzumab Ozogamicin ◽

Adult Patients ◽

Allogeneic Hsct ◽

History Of ◽

Group 3 ◽

Group 2 ◽

Prophylactic Use ◽

Group 1

Abstract Introduction: Sinusoidal obstruction syndrome (SOS) is one of the potentially fatal complications of hematopoietic stem cell transplantation (HSCT). In particular, severe SOS frequently leads to multiple organ failure, and a worse prognosis. Thus, prophylaxis against development of SOS could contribute improved survival after HSCT. Previous reports demonstrated the effectiveness of the prophylactic use of ursodeoxycholic acid (UDCA) or certain anticoagulants, including unfractionated and low-molecular-weight heparin, for SOS. In two randomized controlled trials and two meta-analyses it was reported that UDCA, a hydrophilic bile acid, was an effective and safe drug for prophylaxis against SOS. The usefulness and feasibility of prophylactic use of anticoagulants after allogeneic HSCT are however still controversial. In addition, to our knowledge no study has evaluated the feasibility of usage of UDCA combined with an anticoagulant for SOS prevention after allogeneic HSCT in adult patients. To assess the efficacy and safety of use of UDCA combined with an anticoagulant as SOS prophylaxis, we performed a retrospective cohort study to examine the occurrences of SOS and hemorrhagic events in patients who underwent myeloablative allogeneic HSCT at our institution. We examined use of any anticoagulant together with simultaneous administration of UDCA, in comparison with UDCA alone for the prevention of SOS. Patients and methods: We reviewed the charts of consecutive adult patients in whom myeloablative allogeneic HSCT was performed at our hospital from November 1994 to May 2014, and who received either unfractionated heparin or dalteparin (low-molecular-weight heparin) with UDCA (group 1), danaparoid with UDCA (group 2), or UDCA only (group 3), used for prophylaxis against SOS. Results: A total of 280 patients (group 1: n=52; group 2: n=33; and group 3: n=195) were investigated. The proportions of patients with risk factors for SOS-including non-remission at the time of HSCT, a second or subsequent HSCT, high aspartate aminotransferase (AST) levels before HSCT, high ferritin levels before HSCT, a history of receiving gemtuzumab ozogamicin, and HLA disparity-were similar across the three groups. In group 1, a conditioning regimen containing busulfan was used less frequently (P = 0.002). SOS occurred in seven patients (13.7%) in group 1, five patients (15.2%) in group 2, and 28 patients (14.4%) in group 3, all meeting the Seattle criteria. None of the patients in group 1, two (6.1%) in group 2, and nine (4.6%) in group 3 had SOS diagnosed according to the Baltimore criteria. There was no significant difference in the incidence of SOS among the three groups. In addition, with regard to the cumulative incidence of severe SOS, no statistically significant difference was present among the three groups. The incidence of hemorrhagic events within 30 and 100 days following allogeneic HSCT was not significantly different across the three groups (30 days; 5.8%, 3.0%, 5.1%, P = 0.843, 100 days; 17.6%, 15.2%, 14.4%, P=0.843, respectively). Furthermore, the probabilities of OS and NRM until day 100 after allogeneic HSCT were similar among the three groups (P = 0.733 and P = 0.637, respectively). In a univariate model, a history of gemtuzumab ozogamicin treatment, high serum ferritin levels before HSCT, an HLA mismatched donor, and non-complete remission of disease at the time of allogeneic HSCT were found to be significant risk factors for SOS. Multivariate analysis revealed that a history of gemtuzumab ozogamicin therapy, a mismatched HLA donor, and non-complete remission of disease at the time of allogeneic HSCT were significant and independent risk factors for SOS. In the multivariate as well as univariate analyses, combined administration of UDCA and any anticoagulant for SOS prophylaxis did not have a significant effect on the incidence SOS, when compared to prophylaxis with UDCA alone. Conclusion: Our study results suggest that the combined use of UDCA and an anticoagulant for SOS prophylaxis after myeloablative allogeneic HSCT in adult patients was not beneficial. Establishment of an optimal strategy for prophylaxis against SOS after HSCT is still needed. Disclosures Nakane: Mundipharma KK: Research Funding. Koh:Pfizer: Consultancy, Honoraria. Hino:Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Speakers Bureau; Alexion: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding.

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Feline Leukemia Virus-associated Enteritis—A Condition with Features of Feline Panleukopenia

Veterinary Pathology ◽

10.1177/030098588702400101 ◽

1987 ◽

Vol 24 (1) ◽

pp. 1-4 ◽

Cited By ~ 21

Author(s):

M. Reinacher

Keyword(s):

Bone Marrow ◽

Leukemia Virus ◽

Feline Leukemia Virus ◽

Lymphoid Tissues ◽

Post Mortem ◽

The Third ◽

Histopathological Alterations ◽

Group 3 ◽

Group 2 ◽

Group 1

Infection with feline leukemia virus (FeLV) was demonstrated immunohistologically in 218 necropsied cats suffering from enteritis. The animals were divided into three groups according to histopathological criteria. The first group exhibited the signs of feline panleukopenia in intestine, lymphoid tissues, and bone marrow. Only 1.6% of these animals were FeLV-infected. The animals of the second group had histopathological alterations as seen in cats suffering from feline panleukopenia, but these were found only in the intestine and not in lymphoid tissues or bone marrow. Of these 71.9% were infected with FeLV. The third group consisted of all other cats suffering from enteritis of which 6.3% were FeLV-positive. The association between FeLV infection and the lesions seen in the animals of group 1 (feline panleukopenia) and group 3 (other types of enteritis) is statistically not significant whereas the alterations exhibited by the cats of group 2 are significantly FeLV-associated. Cats with FeLV-associated enteritis (group 2) are of a mean age of about 2.5 years and are significantly older than animals with feline panleukopenia which are of a mean age of about half a year. Thus a FeLV-associated enteritis exists as a histopathologically recognizable condition which sometimes might be mistaken for feline panleukopenia in routine post-mortem investigations.

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EZH2 Upregulation Is Associated with Unfavorable Prognosis in Diffuse Large B-Cell Lymphoma through Potential RUNX3 Downregulation

Blood ◽

10.1182/blood.v128.22.5301.5301 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5301-5301

Author(s):

Denise Peker ◽

Samara Roman-Holba ◽

Yuri Kwon ◽

Jennifer Gordetsky ◽

Amitkumar Mehta ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Rna Expression ◽

Large B Cell Lymphoma ◽

Group 3 ◽

Group 2 ◽

Large B Cell ◽

Group 1

Abstract Introduction: The runt-related transcription factor 3 (RUNX3) is a downstream effector of the transforming growth factor-β (TGF-β) signaling pathway, and has critical roles in apoptosis, angiogenesis, cell migration and invasion. Putative tumor suppressor activity of RUNX3 has been presented extensively in the literature, particularly in solid epithelial tumors and recently in lymphoma with loss of expression favoring tumorigenesis and/or prognosis, but its role in diffuse large B-cell lymphoma (DLBCL) has not been studied. Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, has been shown to mediate silencing of RUNX3. RUNX3 downregulation due to EZH2 upregulation has been shown in various solid tumors. In the present study, we investigated the EZH2 and RUNX3 RNA expression status in DLBCL and its impact on clinical outcome. Methods: A retrospective chart review was performed and 169 cases of DLBCL treated with chemoimmunotherapy between 2003 and 2013 were included. Immunodeficiency- or EBV-associated and MYC+ LBCL were excluded. Archived formalin-fixed-paraffin-embedded tissue samples were retrieved and RNA was extracted using commercially available kits. We correlated the RNA expression levels for EZH2 and RUNX3 in various sites using quantitative real-time PCR (Taqman assay) and custom designed primers for each gene. Control samples included three benign lymph nodes free of a neoplastic process. Results: We identified 66 cases of DLBCL, including25 nodal DLBCL and 41 extranodal DLBCL, with sufficient RNA extracted. Extranodal locations included testis (n=12), orbit (n=6), primary central nervous system (n=5), bone (n=3), breast (n=2) and viscera (n=13). The median age was 64 years (range 29- 81 years) with a female to male ratio of 0.4 (F=20 and M=46). Median overall survival (OS) was 28 months (1-156 months). Immunophenotypic subtype based on cell-of-origin using Hans algorithm was available in 63 cases; 34 cases were germinal center B-cell (GCB) type while 29 were non-GCB type. Treatment data was available in 63 cases and all patients received R-CHOP as initial therapy except three patients who died shortly after diagnosis. Forty-four cases showed higher expression of EZH2 and RUNX3 when compared to normal lymph nodes (p < 0.05). Nineteen out of 44 cases showed increased EZH2 and decreased RUNX3 expression (Group 1) while EZH2 expression was lower than RUNX3 in the remaining cases (Group 2). The remaining 22 DLBCL cases did not show significant correlation for expression (Group 3). Overall survival was significantly low in Group 1 compared to Group 2 and Group 3 (p =0.030 and p=0.026, respectively). There was no difference for OS between Groups 2 and 3 (p>0.05) (Figure 1). Conclusions: Our results showed that decreased RUNX3 RNA expression is associated with EZH2 overexpression and poses an adverse prognostic factor in DLBCL. Larger studies are needed to establish the prognostic and therapeutic utility of EZH2 and/or RUNX3. Disclosures Mehta: Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Medimmune: Research Funding; Roche Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Forero:University of Alabama at Birmingham: Research Funding. Costa:Sanofi: Honoraria, Research Funding.

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Exploration of Survival Stratification of Patients with Multiple Myeloma after First Relapse Using Real World Data

Blood ◽

10.1182/blood.v128.22.2417.2417 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2417-2417 ◽

Cited By ~ 1

Author(s):

Roman Hájek ◽

Jiri Jarkovsky ◽

Walter Bouwmeester ◽

Maarten Treur ◽

Lucy DeCosta ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Treatment Decision ◽

Advisory Committees ◽

Patient Risk ◽

First Relapse ◽

Survival Expectations ◽

Group 2 ◽

Group 1

Abstract Risk stratification tools in multiple myeloma (MM), such as the International Staging System (ISS) and the revised-ISS (R-ISS), have improved understanding of survival expectations using the strongest known predictors at time of diagnosis. Given their value at diagnosis, these have been used to define risk after first relapse in clinical trials and standard practice. Although these tools have not been validated in this setting, their use arises because of the need to better characterize patients in order to define survival expectations and treatment decisions. Once the patient has relapsed, there are additional variables that may need to be considered in order to systematically assess patient risk, understand drivers of disease progression and ensure that treatment strategies are aligned with patient risk. Using data from the Czech Registry of Monoclonal Gammopathies (RMG), this study assessed predictors of overall survival (OS) and developed a new Risk Stratification Tool (RST) to predict OS at time of treatment decision after first relapse (TTD1). The RST was developed by estimating the strongest predictors of OS at both diagnosis and TTD1 to define the final parameters for inclusion. The cut-offs for each parameter reflect conventional cut-offs used in clinical practice and some were supported by evidence using a K-adaptive Partitioning for Survival (KAPS) approach, which stratified data based on distinct survival expectations. The hazard ratio (HR) of the selected predictors was used to assign a score per parameter at a patient level where missing data were entered with a contribution equal to 1. Using the full RMG data set at TTD1 (N=1418) the (KAPS) method was run to define 4 distinct group of patients based on survival expectations. The RST consists of 4 dimensions and 12 item questions based on the strongest predictors of survival at TTD1, "Patient Factors" (age and Eastern Cooperative Oncology Group (ECOG) performance status), "Existing Stratification Factors (R-ISS at diagnosis and ISS at TTD1), "Disease Factors" (calcium level, number of bone lesions, extramedullary disease, thrombocyte count, clonal cells in bone marrow aspiration cytology, lactate dehydrogenase [LDH]) and "Treatment history" (refractory to prior therapy, time-to-next-treatment [from initiation of treatment of first anti-myeloma drug to initiation of treatment at first relapse]) (Table 1). Subsequently, we explored each group based on distribution of frailty-driven measures (age and ECOG) and aggressiveness of the disease (rest of parameters) to understand what is driving stratification. Figure 1 shows the KM curve of survival after TTD1 for each of the 4 groups estimated by KAPS. The new analysis shows strong differentiation in survival expectations between the 4 groups (Table 2), showing significantly different OS for all groups compared with reference. The median OS and Confidence Intervals per group did not overlap, supported by the positive association of HR across groups. The distribution of the Total Score (Figure 2) is between 1 and 2, which shows sufficient sensitivity to differentiate these groups by survival expectations. The RST can then be split into Frailty Score and Aggressiveness Score (Figure 3a & b) to understand what is driving disease severity. The distribution of these two scores shows that group 1 consists of low patient frailty and low disease aggressiveness, whereas group 4 shows high on both elements. Group 2 has an increased score for frailty and marginal increase in aggressiveness compared with group 1, and group 3 stratification is driven by an increase in aggressiveness over group 2. The analysis showed that predictors, patient's experience of prior treatment and level of disease impact at the point of treatment decision after first relapse provided an initial framework to demonstrate strong differentiation between groups based on patient severity and what is driving patient risk (patient frailty vs aggressiveness of disease). The RST has shown promising results when applied to the RMG, however further validation of this work is required using other real-world and clinical trials data. Nevertheless, this analysis is a first step in systematically assessing patient risk to improve the selection of treatments based on improved understanding of patient profiles. Disclosures Hájek: Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; BMS: Honoraria; Takeda: Consultancy; Celgene: Consultancy, Research Funding. Bouwmeester:Amgen: Consultancy. Treur:Amgen: Consultancy. DeCosta:Amgen: Employment, Other: Holds Amgen Stock. Campioni:Amgen: Employment, Other: Holds Amgen Stock. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Raab:BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Schoen:Amgen: Employment, Other: Holds Amgen Stock. Szabo:Amgen: Employment, Other: Holds Amgen Stock. Lucie:Amgen: Consultancy. Gonzalez-McQuire:Amgen: Employment, Other: Holds Amgen Stock.

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Serum Transferrin Receptor Value as a Universal Indicator of Erythropoietic Activity.

Blood ◽

10.1182/blood.v104.11.3682.3682 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3682-3682

Author(s):

Young Soo Lee ◽

Chul Soo Kim ◽

Jong Weon Choi

Keyword(s):

Bone Marrow ◽

Transferrin Receptor ◽

Bone Marrow Cells ◽

Reticulocyte Count ◽

Serum Transferrin Receptor ◽

Group 4 ◽

Universal Indicator ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract The serum transferrin receptor (sTfR) is thought a sensitive and quantitative parameter of tissue iron deficiency as well as an indicator of erythropoietic activity. This study was aimed at the verification of a hypothesis that sTfR is a general indicator of erythropoiesis regardless whatever the cause is. A total of 173 patients in heterogeneous diseases who underwent bone marrow study as a workup for anemia were measured for sTfR, reticulocyte maturity index (RMI), erythroid element proportion of bone marrow cells, and other hematologic parameters (hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, red cell distribution width, absolute reticulocyte count). By immunoenzymometric method sTfR was measured using IDeATMcTfR kids (Orion Diagnostica, Orion, Finland). Reticulocyte count and proportion was measured manually by one expert examiner after standard blood smear and stain. Reticulocyte subpopulation was automatically analyzed by flow cytometry using R-3000 TM (Sysmex, TOA, Japan). RMI was calculated from the equation of (medium fluorescent reticulocyte fraction + high fluorescent reticulocyte fraction) X 100 / low fluorescent reticulocyte fraction. Correlation analysis was done among the variables including sTfR, RMI, erythroid element proportion of bone marrow cells, and other hematologic parameters using SAS 6.12 soft ware. The analysis was carried out for the whole 173 patients to see the general trends and repeated for 4 groups of disease category, arbitrarily divided to group 1 (n=33, iron deficiency or or disease with no predisposition to anemia of chronic disease), group 2 (n=53, hematologic malignancies), group 3 (n=44, solid tumors), and group 4 (n=43, chronic or infectious disease) to see if the trends may be affected by specific diseases. The results showed a solid correlation of sTfR with RMI as well as erythroid precursors in bone marrow, not only in the whole patient population (e.g. sTfR vs RMI, R=0.587, p=0.0001) but also in individual groups (e.g. sTfR vs RMI, R=0.48, p=0.005 in group 1, R=0.69, p=0.0001 in group 2, R=0.58, p=0.0001 in group 3, R=0.81, p=0.0001 in group 4). These findings indicated the significance of sTfR is valid under any clinical setting as a universal indicator of hematopoietic activity. The sTfR can be used as a useful parameter for monitoring of erythropoiesis in a variety disease.

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Impact of Peripheral Blood Stem Cell Recruitment on Outcome of Single or Double Autologous Hematopoietic stem Cell Transplantation for Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.5221.5221 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5221-5221

Author(s):

Mauricette Michallet ◽

Quoc-Hung Le ◽

Anne-Sophie Michallet ◽

Anne Thiebaut ◽

Emmanuelle Tavernier ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Stem Cell ◽

Light Chains ◽

Hematopoietic Stem ◽

Group 4 ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Multiple myeloma remains one of the best indication for intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoT). Intensive therapy followed by autologous transplantation is superior to conventional chemotherapy and it was demonstrated that two autoT were superior to one except for patients in very good partial response or in complete response after the first autotransplant. Peripheral blood stem cells (PBSC) can be used as well as bone marrow as HSC source with the same efficacy but very few data have been reported regarding PBSC recruitment. The main goal of our work was to study the impact on overall and event-free survival (OS and EFS) of PBSC recruitment using either growth factors (GF) alone (steady state) or chemotherapy followed by GF. Secondly, we performed a multivariate analysis studying influence on OS and EFS of sex, age, lines of therapy, pretransplant status, TBI, PBSC recruitment and number of autoT. We have analyzed 193 PBSC autoT (1 autoT=160, 2 autoT=33) performed for 160 MM patients [81 males and 71 females, mean age: 55 years (39–71)]. At diagnosis, 88 patients presented a MM Ig G (70k and 18l), 28 Ig A (16k and 12l), 3 Ig D (1k and 2l), 21 light chains k and 13 light chains l, 3 non secreting and 4 with plasmocyte leukemias. According to Durie and Salmon classification 75% of patients were in stage III, 15% in stage II and 10% in progressive I. Before transplantation, patients have received 1 line of poly-chemotherapy (n=141), 2 lines (n=15) or 3 lines (n=4) and 154 were evaluated for the response with 11 complete remission, 113 partial remission and 30 stable or evolutive disease just before transplant. As HSC (n=189), patients received PBSC which were recruited by GF alone (n=105) or cyclophosphamide+GF (n= 84). Conditioning (n=189),consisted in melphalan and TBI (n=51), melphalan alone (n=132), melphalan associated to cyclophosphamide or busulfan (n=6). We divided the population into 4 groups : group 1 who received one autoT of PBSC recruited by GF (n=76), group 2 one autoT of PBSC recruited by chemotherapy+GF (n=50), group 3 two autoT of PBSC recruited by GF (n=16) and group 4 two autoT of PBSC recruited by chemotherapy+GF (n=17). The median follow-up (FU) of the 4 groups were different with shorter FU (group 3: 9.9 months, group 4: 13 months) for patients who received tandem autoT because of the recent character of this strategy as compared to a long term follow-up for patients who received only one transplant (group 1: 35months, group 2: 55.3 months). Probabilities of OS and EFS at 2 years were 76% (95%CI 67–87) and 60% (95%CI 49.5–73) for group 1, 77% (95%CI 65–90.5) and 70% (95%CI 57.5–85) for group 2, 87.5% (95%CI 73–100) and 72.9% (95%CI 49–100) for group 3, 100% and 66.7% (95%CI 36–100) for group 4. The difference was not significant because of follow-up differences between the 4 groups and small number of patients in groups 3 and 4. In addition, multivariate analysis did not show any significant influence of the different studied parameters on OS and EFS. Nevertheless, because of these interesting preliminary results, a longer follow-up is warranted for definitive conclusions.

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WT1 Levels At Diagnosis and POST-Induction Provide Prognostic Information in Adult De Novo AML. Results From the Spanish Cetlam Group.

Blood ◽

10.1182/blood.v120.21.2524.2524 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2524-2524

Author(s):

Josep F Nomdedeu ◽

Montserrat Hoyos ◽

Maite Carricondo ◽

Elena Bussaglia ◽

Camino Estivill ◽

...

Keyword(s):

Bone Marrow ◽

De Novo ◽

High Dose ◽

Prognostic Impact ◽

Post Induction ◽

Group 3 ◽

Group 2 ◽

De Novo Aml ◽

Intermediate Dose ◽

Group 1

Abstract Abstract 2524 WT1 monitoring is an almost universal target to follow de novo AML. Its exppression in myeloid malignancies is upregulated in parallel to the blast percentage. Recently, WT1 determination has been standardized as result of an European Leukemia Net initiative. Early reports have demonstrated that the best results are obtained when peripheral blood is used to establish clinical predictions. Pediatric studies in AML have shown that raised WT1 levels after induction associate with unfavourable outcome. Despite all the mentioned, WT1 quantitation has not yet gained widespread use, in part because some AML show normal WT1 levels at diagnosis. To investigate the prognostic impact of the normalized bone marrow WT1 levels at diagnosis and post-induction in a consecutive series of de novo AML patients enrolled in the CETLAM group trials. Available bone marrow samples at diagnosis (586 cases) and post induction (367 cases) were obtained in each participating center and sent to the CETLAM repository center at the Hospital de la Santa Creu i Sant Pau for complete immunophenotype and molecular analyses. One μg of RNA was reverse transcribed to cDNA in a total reaction volume of 20μl containing Cl2Mg 5mM, 10× Buffer, DTT 10mM, dNTP's 10mM each, random hexamers 15μM, RNAsin 20 units (Promega) and 200 units of MMLV enzyme. WT1 expression levels were determined by real-time quantitative polymerase chain reaction (RQ-PCR) in an ABI PRISM 7700® Genetic Analyzer (Applied Biosystems, Foster City, CA) using the primers and conditions described by the ELN group (Cilloni et al J. Clin. Oncol 2009;27:5195-201). For WT1 copy number titration, the IPSOGEN® (Marseille, France) plasmid was employed. Results were expressed as copies and four normal bone marrow samples were used as test controls. Patients were treated between 2004 and 2011 according to the CETLAM03 protocol. Adults up to 70 years of age received induction chemotherapy with idarubicin, intermediate-dose cytarabine and etoposide, followed by consolidation with mitoxantrone and intermediate-dose ara-C. Subsequently, patients with favourable cytogenetics at diagnosis received one cycle of high-dose cytarabine.G-CSF priming during induction and consolidation was used. Patients with favorable cytogenetics and high leukocyte counts at diagnosis were treated with autologous transplantation instead of high-dose cytarabine. Furthermore, patients with a normal karyotype but an adverse molecular profile (FLT3 mutations or MLL rearrangements) were allocated to the treatment for unfavorable cases; this included allogeneic transplantation from an HLA-identical donor. Overall survival (OS) was measured from the date of enrolment until the date of death. Leukemia-free survival (LFS) for patients who achieved a CR was calculated from the date of CR to relapse or death. OS and LFS were plotted by the Kaplan-Meier method; differences between curves were analyzed by the log-rank test. The probability of relapse was calculated using cumulative incidence estimates and taking into account the competing risk of death in remission. A WT1 cut-off value of 5065.2 copies at diagnosis was obtained. Two hundred and four samples had WT1 levels greater than this value, whereas 382 samples showed levels below this cut-off. These groups had statistically different OS 55±3 vs 33±5 p<0.001, LFS 52±3 vs 30±6 p:0.004 and CIR 34±3 vs 56±6 p<0.001. As regards the post-induction results, four groups were established: Group 0 (135 patients) with WT1 levels between 0 and 17.5 copies, Group 1 (107 patients) with WT1 values ranging from 17.6 to 76 copies, Group 2 (54 patients) with WT1 between 76.1 and 170.5 copies and Group 3 (71 patients) with WT1 levels after induction greater than>170.6 copies. These groups showed statistically significant differences(p<0.001) in terms of OS: Group 0 59±4 months, Group 1 50±5 months, Group 2 45±7 months and Group 3 23±6 months. LFS was also statiscally different: Group 0: 58±4, Group 1: 46±5, Group 2: 39±8 and Group 3:19±8 (all p<0.001). Lastlly, CIR was markedly different between the four groups: Group 0:25±4, Group 1: 44±5, Group 2: 46±8 and Group 3: 68±8(p<0.001) . WT1 quantitation at diagnosis and post-induction provide a simple and well standardized measurement of the prognostic risk of adult AML patiens. Larger series need to be analyzed to ascertain whether this determination could be incorporated to initial AML risk stratification. Disclosures: No relevant conflicts of interest to declare.

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