Subsequent Malignant Neoplasms of the Gastrointestinal Tract after Blood or Marrow Transplantation - a BMTSS Report

Abstract Background and Purpose: Subsequent malignant neoplasms (SMNs) are a leading cause of non-relapse mortality after blood or marrow transplantation (BMT). Cancers of the gastrointestinal (GI) tract are of special interest since their clinical behavior is often aggressive, but early detection through screening is possible for specific GI malignancies. There is limited information regarding the risk of GI SMNs following BMT. The purpose of this study was to report the risk of GI SMNs after BMT and to identify specific exposures associated with increased risk. Materials and Methods: The BMT Survivor Study (BMTSS) is a multi-institutional retrospective cohort study of patients transplanted between 1974 and 2014, with survival ≥2y. Disease and treatment characteristics were obtained from institutional databases and medical records. GI SMNs were identified by review of the BMTSS survey or death records and confirmed by pathology report and/or medical record review. Standardized incidence ratios (SIRs) were calculated to determine excess risk of GI SMNs compared with the general population. Fine-Gray competing risks models examined the association between treatment exposures and GI SMNs. Results: Clinical/demographic characteristics of the cohort are provided in Table 1. The 6,710 BMT recipients in this cohort contributed 62,479 person-years of follow-up, yielding 148 patients with GI SMNs occurring a median of 8.9y (range, 0.3-36.6y) from BMT. The GI SMNs in the cohort included colorectal (n=45), liver (n=36), pancreatic (n=27), esophageal (n=22), gastric (n=11), and other GI (n=7) cancers. By age 70, the cumulative incidence of a GI SMN was 4.8% for allogeneic BMT recipients vs. 1.9% for autologous BMT recipients (p<0.0001, Fig 1). The SIR for a GI SMN after BMT was 1.95 for allogeneic BMT recipients vs. 1.03 for autologous BMT recipients (p=0.8). The risk of esophageal (SIR=3.19, p<0.01), liver (SIR=3.06, p<0.01) and pancreatic cancer (SIR=1.79, p<0.01) was increased when compared to the general population whereas the risk for gastric (SIR=1.15, p=0.6) and colorectal cancers (SIR=0.86, p=0.3) was not. Radiation exposure: Exposure to TBI at age <30y was associated with significantly higher risk for colorectal (SIR=2.67, p=0.003), stomach (SIR=5.16, p=0.005), and liver (SIR=11.61, p<0.001) cancers; the risks were not elevated when TBI exposure occurred at age >60 (Fig 2). The cumulative incidence of GI SMNs by age 70 was significantly higher (p<0.0001) among patients who received high-dose TBI (≥8Gy: 4.8%) vs. those who received low-dose TBI (<8Gy: 2.5%) or no TBI (2.1%) (Fig 3). High-dose TBI (and not low-dose) was associated with a 2.5-fold higher risk of colorectal cancer (95%CI=1.3-4.7). Pre-BMT abdominal radiation was associated with 9.55-fold increased risk of GI SMN (95%CI=2.5-36.5) among allogeneic BMT recipients; the association was primarily driven by pancreatic and esophageal cancer. Chemotherapeutic agents: Pre-BMT anthracyclines (HR=4.84, 95%CI=1.2-20.4) and etoposide conditioning (HR=2.87, 95%CI=1.6-5.3) were associated with an increased risk of liver cancer. Cytarabine conditioning was associated with increased risk of colorectal cancer (HR=3.08, 95%CI=1.4-6.9). Chronic GvHD: Risk of esophageal cancer was 9.6-fold higher among allogeneic BMT recipients with chronic GvHD (95%CI=3.3-28.4), when compared with those who received an autologous BMT. Conclusions: This study provides evidence that allogeneic BMT survivors are at increased risk for developing GI SMNs in the setting of specific pre-BMT and BMT-related therapeutic exposures and chronic GvHD. In particular, exposure to myeloablative doses of TBI at age <30y and conditioning with cytarabine and etoposide were associated with increased risk. In addition, pre-BMT exposure to abdominal radiation and anthracyclines were associated with specific types of GI SMNs. These findings and the very high risk of esophageal cancer among those with chronic GvHD provide a framework for developing personalized screening recommendations for those at highest risk. Figure 1 Figure 1. Disclosures McDonald: Varian Medical Systems: Consultancy, Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Arora: Syndax: Research Funding; Pharmacyclics: Research Funding; Kadmom: Research Funding.

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Allogeneic Hematopoietic Stem Cell Transplantation for Aplastic Anemia with Pre-Transplant Conditioning Using Fludarabine, Reduced-Dose Cyclophosphamide, and Low-Dose Thymoglobulin:Â Ksgct Prospective Study

Blood ◽

10.1182/blood-2018-99-115105 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2101-2101

Author(s):

Shinichi Kako ◽

Yoshinobu Kanda ◽

Makoto Onizuka ◽

Nobuyuki Aotsuka ◽

Kensuke Usuki ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Low Dose ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

High Dose ◽

Hematopoietic Stem ◽

Reduced Dose ◽

Company Limited ◽

Otsuka Pharmaceutical

Abstract [Background] Allogeneic hematopoietic stem cell transplantation (HSCT) is a potent treatment to cure in patients with aplastic anemia (AA). However, an optimal pre-transplant conditioning remains unclear. The combination of high-dose cyclophosphamide (CY) and anti-thymocyte globulin (ATG) has been used as an effective conditioning, but cardiotoxity due to high-dose CY has been a major concern especially in patients with iron overload by excessive transfusion. In addition, the appropriate dose and timing of ATG use is another unsolved topic in HSCT for AA. Therefore, we performed a prospective study to assess the safety and efficacy of a conditioning regimen using fludarabine (Flu), reduced-dose CY, and low-dose thymoglobulin in HSCT for AA. [Methods] Patients with severe AA, aged between 16 and 65 years, who have an HLA-matched or 1-locus mismatched, related or unrelated donor were prospectively included. A conditioning regimen consisted of Flu 30mg/m2 for 4 days, CY 25mg/kg for 4 days, and thymoglobulin 1.25mg/kg for 2 days (days -4, and -3). In patients who underwent transplantation from unrelated and/or HLA-mismatched donor, 2 Gy of total body irradiation was added. Cyclosporine for an HLA-matched related donor or tacrolimus for the other donors, together with short-term methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Granulocyte-colony stimulating factor was used from 1 day after transplantation. Primary outcome measure was an overall survival at 1 year after HSCT. This study was approved by the Institutional Review Board of all the participating institutions. [Results] Twenty-eight patients were enrolled between 2011 and 2017, and their median age was 36 years (range: 18 - 61y). Sixteen patients were male. A median time from diagnosis to transplantation was 1858 days in patients who had previously received immunosuppressive therapy (IST) using ATG (n = 16) and 121 days in those who had not received IST (n = 12). Sixteen patients received graft form related donors including 1 HLA-mismatched donor, and 12 patients did from unrelated donors including 3 mismatched donors. Stem cell source was bone marrow in 27 out of 28 patients. All patients but one, who died early due to infection, achieved neutrophil engraftment at a median of 19 days after HSCT. Mixed chimerism (MC) was observed in 6 patients at day 30, and 3 out of those 6 patients achieved complete donor chimerism by day 90. On the other hand, MC was newly observed in additional 2 patients at day 90. Only one patient experienced secondary engraftment failure, and which developed with complete donor-type chimerism at day 99. No patients developed grade 2-4 acute GVHD. However, the cumulative incidence of chronic GVHD was 39.9 % at 1 year, and one third of them had extensive type. With a median follow-up period of 1727 days for survivors, overall survival rates (OS) were 96.4 % at 1 year and 82.8 % at 5 years (Figure 1). Cytomegalovirus (CMV) antigenemia was detected in 17 patients, but no patients developed CMV disease. A high Epstein-Barr virus (EBV)-DNA load (more than 1×104 copies/mL) was detected in 2 patients at day 60 and 1 patient at day 90. Neither developed EBV-lymphoproliferative disorder (LPD) within a year. However, another patient, in whom high EBV-DNA load was not detected within 90days after HSCT, developed EBV-LPD and died at three and a half years after HSCT. [Conclusion] HSCT for AA using Flu, reduced-dose CY, and low-dose thymoglobulin as a conditioning regimen was safe and effective. Relatively high incidences of MC and chronic GVHD need further improvement. (This study is registered with www.umin.ac.jp as UMIN000006071.) Disclosures Kako: Takeda Pharmaceutical Company Limited.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Celgene K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kanda:Tanabe-Mitsubishi: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Pfizer: Research Funding; Taiho: Research Funding; MSD: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Otsuka: Research Funding; Asahi-Kasei: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Takara-bio: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria. Usuki:Ono Pharmaceutical: Speakers Bureau; GlaxoSmithKline K.K.: Research Funding; Janssen Pharmaceutical K.K: Research Funding; Sanofi K.K.: Research Funding; Shire Japan: Research Funding; SymBio Pharmaceuticals Limited.: Research Funding; Celgene Corporation: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Takeda Pharmaceutical: Speakers Bureau; Boehringer-Ingelheim Japan: Research Funding; Pfizer Japan: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau. Mori:Astella Pharma: Honoraria; Shire Japan: Honoraria; Janssen: Honoraria; SHIONOGI: Honoraria; Taisho Toyama Pharmaceutical Co: Honoraria; Novartis Pharma: Honoraria; Celgene: Honoraria; Japan Blood Products Organization: Honoraria; Pfizer: Honoraria; CHUGAI: Honoraria; MSD: Honoraria; Eisai: Honoraria; Novartis Pharma: Research Funding; Asahi Kasei: Research Funding; MSD: Research Funding; Kyowa Hakko Kirin: Honoraria; Ono: Honoraria.

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Long Term Infectious Complications Following Reduced Intensity Conditioning (RIC) Allogeneic HLA-Identical Sibling Transplantation (allo-SCT).

Blood ◽

10.1182/blood.v108.11.2850.2850 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2850-2850

Author(s):

Anne Etienne ◽

Mohamad Mohty ◽

Catherine Faucher ◽

Sabine Furst ◽

Jean El-Cheikh ◽

...

Keyword(s):

Low Dose ◽

Chronic Gvhd ◽

Infectious Complications ◽

Prior History ◽

High Dose ◽

Infectious Episode ◽

Donor Bone Marrow ◽

Increased Risk ◽

History Of

Abstract In the setting of RIC for allo-SCT, long term outcomes are still poorly defined. Of note, the epidemiology of long term transplant-related infections is still sparse. This prospective report describes infectious complications occurring beyond 6 months after allo-SCT, in 159 consecutive patients who received a RIC allo-SCT from an HLA-identical sibling. Patients characteristics are as follow: median age was 50 (range, 18–68) years. 68 patients (43%) had a myeloid malignancy, whereas 66 patients (41%) had a lymphoid malignancy. The remaining 25 patients (16%) were treated for metastatic non-hematological malignancies. The majority of patients (n=126, 79%) had an advanced disease with high risk features precluding the use of myeloablative allo-SCT. 24 patients (15%) received donor bone marrow (BM), while the remaining 135 patients (85%) received PBSCs. In addition to fludarabine and busulfan, the RIC regimen included high dose ATG in 20 patients (13%) and low dose ATG in 95 (60%). 24 patients (15%) received fludarabine, busulfan and TLI, while the remaining 24 patients (15%) received fludarabine and low dose TBI. With a median follow-up of 19 (range, 6–90) months, 120 patients (75%) experienced at least one infectious episode (total number of episodes, 366) beyond the first six months after allo-SCT developing at a median of 8 (range, 6–34) months. In all, 212 infectious episodes (58%) required hospitalization (7% in the intensive care unit) for a median duration of 10 (1–91) days. 144 episodes (39%) could be documented (bacterial, n=48; viral, n=78; fungal, n=18). Microbiologically documented infections were distributed as follow: gram negative bacteria (18%), other bacteria (15%), CMV positive antigenemia (17%), HSV (19%), VZV (15%), other viruses (3%), aspergillus (6%), candida species (6%), other (1%). 76% of patients with an infection were under systemic immunosuppressive therapy for chronic GVHD at time of infection. Moreover, 85 patients (71%) experienced more than one infectious episode (median, 2; range, 1–12). In multivariate analysis, active or prior history of extensive chronic GVHD and the use of a BM graft were the strongest factors significantly associated with an increased risk of long term infections (P=0.0003; RR=2.04; 95%CI, 1.4–3.0; and P=0.005; RR=2; 95%CI, 1.2–3.2 respectively), highlighting the raising concern about the deleterious impact of severe chronic GVHD occurring after RIC allo-SCT, but also the protective effect of donor origin immunity based on graft origin and content. In this series of patients surviving at least 6 months after RIC allo-SCT, the overall long term transplant-related mortality was 11% (n=18), of whom 12 deaths were attributed to chronic GVHD and its complications including infections, and 5 deaths solely attributed to infections. In all, these results suggest that, despite reduction in early toxicity associated with the use of RIC regimens, long term debilitating chronic GVHD and its corollary of continuous immunosuppression and subsequent infections are still a matter of concern. Prospective efforts to develop optimal antimicrobial preventive strategies are needed to further improve the safety of the procedure and the overall benefits of RIC preparative regimens before allo-SCT.

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Chronic GvHD decreases antiviral immune responses in allogeneic BMT

Blood ◽

10.1182/blood-2006-04-017442 ◽

2007 ◽

Vol 109 (10) ◽

pp. 4548-4556 ◽

Cited By ~ 22

Author(s):

Mohammad S. Hossain ◽

John D. Roback ◽

Brian P. Pollack ◽

David L. Jaye ◽

Amelia Langston ◽

...

Keyword(s):

T Cells ◽

Chronic Gvhd ◽

Allogeneic Bone Marrow Transplantation ◽

Murine Cytomegalovirus ◽

Allogeneic Bone ◽

Transplant Recipients ◽

Peripheral Tissues ◽

Allogeneic Bmt ◽

Early Protein ◽

Increased Risk

Abstract Chronic graft-versus-host disease (cGvHD) is associated with functional immunodeficiency and an increased risk of opportunistic infections in allogeneic bone marrow transplantation (BMT). We used a parent to F1 model of allogeneic BMT to test the hypothesis that cGvHD leads to impaired antigen-specific antiviral immunity and compared BM transplant recipients with cGvHD to control groups of allogeneic BM transplant recipients without GvHD. Mice with and without cGvHD received a nonlethal dose of murine cytomegalovirus (MCMV) +100 days after transplantation. Recipients with cGvHD had more weight loss and higher viral loads in the spleen and liver. MCMV infection led to greater than 25-fold expansion of donor spleen–derived MCMV peptide–specific tetramer-positive CD8+ T cells in blood of transplant recipients with and without cGvHD, but mice with cGvHD had far fewer antigen-specific T cells in peripheral tissues and secondary lymphoid organs. The immunosuppression associated with cGvHD was confirmed by vaccinating transplant recipients with and without cGvHD using a recombinant Listeria expressing MCMV early protein (Lm-MCMV). Secondary adoptive transfer of lymphocytes from donor mice with or without cGvHD into lymphopenic congenic recipients showed that cGvHD impaired tissue-specific homing of antigen-specific T cells. These results indicate that cGvHD causes an intrinsic immunosuppression and explain, in part, the functional immunodeficiency in allogeneic transplant recipients.

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Surveillance of Colorectal Cancer (CRC) in Cystic Fibrosis (CF) Patients

Gastrointestinal Disorders ◽

10.3390/gidisord3020009 ◽

2021 ◽

Vol 3 (2) ◽

pp. 84-95

Author(s):

Fabio Ingravalle ◽

Giovanni Casella ◽

Adriana Ingravalle ◽

Claudio Monti ◽

Federica De Salvatore ◽

...

Keyword(s):

Colorectal Cancer ◽

Cystic Fibrosis ◽

General Population ◽

Genetic Disorder ◽

The United States ◽

Screening Colonoscopy ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Increased Risk ◽

Speciality Training

Cystic Fibrosis (CF) is the commonest inherited genetic disorder in Caucasians due to a mutation in the gene CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), and it should be considered as an Inherited Colorectal Cancer (CRC) Syndrome. In the United States, physicians of CF Foundation established the “Developing Innovative Gastroenterology Speciality Training Program” to increase the research on CF in gastrointestinal and hepatobiliary diseases. The risk to develop a CRC is 5–10 times higher in CF patients than in the general population and even greater in CF patients receiving immunosuppressive therapy due to organ transplantation (30-fold increased risk relative to the general population). Colonoscopy should be considered the best screening for CRC in CF patients. The screening colonoscopy should be started at the age of 40 in CF patients and, if negative, a new colonoscopy should be performed every 5 years and every 3 years if adenomas are detected. For transplanted CF patients, the screening colonoscopy could be started at the age of 35, in transplanted patients at the age of 30 and, if before, at the age of 30. CF transplanted patients, between the age of 35 and 55, must repeat colonoscopy every 3 years. Our review draws attention towards the clinically relevant development of CRC in CF patients, and it may pave the way for further screenings and studies.

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Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽

10.1182/blood-2019-131332 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3714-3714

Author(s):

Lei Zhang ◽

Huacheng Luo ◽

Jing Li ◽

Hong-Min Ni ◽

Mark Sellin ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Low Dose ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Low Doses ◽

Hematopoietic Stem ◽

Increased Risk ◽

Leukemia Development ◽

Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

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Non-Myeloablative Conditioning Regimen before T-Cell Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Advanced Lymphoma

Blood ◽

10.1182/blood-2019-128004 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4614-4614

Author(s):

Catalina Montes De Oca ◽

Thomas Pagliardini ◽

Stefania Bramanti ◽

Sabine Furst ◽

Jean Marc Schiano de Collela ◽

...

Keyword(s):

Research Funding ◽

Chronic Gvhd ◽

Disease Status ◽

Research Support ◽

Myeloablative Conditioning ◽

Term Survival ◽

Gvhd Prophylaxis ◽

Increased Risk ◽

Low Incidence

Introduction: allogeneic transplantation (allo-HSCT) is a curative treatment for patients with advanced lymphoma. Haploidentical (haplo-SCT) transplantation extended the accessibility to allo-HSCT, overcoming the issue of donor availability. However, alternative donor allo-HSCT is still considered at higher risk of non-relapse mortality due to the HLA disparity and thus an anticipated higher incidence of GVHD. In this context, the use of a non myeloablative conditioning (NMAC) regimen combined with post transplantation cyclophosphamide (PT-Cy) based GVHD prophylaxis may reduce procedure related toxicity. The aim was to evaluate the toxicity and efficacy of haplo-SCT using NMAC with PT-Cy in advanced lymphoma patients. Methods: We here report the retrospective experience of a bicentric transplantation program. We analyzed a cohort of lymphoma patients undergoing Haplo-SCT and homogeneously receiving NMAC and PT-Cy. Inclusion criteria were: 1) first allo-HSCT for advanced lymphoma between 2009 and 2018; 2) haploidentical donor; 3) NMAC (fludarabine cyclophosphamide and 2 gray TBI GVHD prophylaxis consisted of PT-Cy day+3 and +4 , cyclosporine A and MMF starting from day +5. Multivariate analyses included age, disease type (NHL vs HL), HCT-CI (< vs ≥ 3), graft source (PBSC vs BM), disease status at haplo-SCT (CR vs other). Results: One hundred forty seven patients (73 NHL; 74 HL) with a median age of 46 years (range: 19-71) were included. PBSC (peripheral blood stem cell) was used as graft source in 96 patients (65%). Patients received a median number of 3 conventional chemotherapy lines before haplo-SCT (1-8). Sixty-five (44%) had relapse after Auto-HCT. At the time of haplo-SCT, 96 patients (66%) were in complete remission. The cumulative incidences of day+100 grade 2-4 and 3-4 acute GVHD were 30% and 3%, respectively. The cumulative incidences of 2-year chronic and moderate or severe chronic GVHD were 13% and 8%, respectively. With a median follow up of 39 months (6-114), 2-year NRM was 14%, with a trend for higher risk in patients with HCT-CI ≥ 3 (HR 0.39, 95CI [0.15-1.04] p = 0.061) while age was not associated with an increased risk of NRM (HR 1.01, 95CI [0.98-1.05], p = 0.450). Two-year cumulative incidence of relapse (CIR) was 21% and 18% in HL and NHL patients, respectively. Disease status at the time of haplo-SCT was strongly associated with relapse (HR 2.99, 95CI [1.41-6.35], p = 0.004) In HL patients, 2-year PFS, OS and GRFS were 65%, 77% and 57%, respectively, while corresponding values in NHL patients were 65%, 69% and 55%, respectively. Two-year PFS and GRFS were significantly higher in patients who underwent haplo-SCT in CR (PFS: CR vs. no CR: 72% vs. 55%, p=0.045; GRFS: CR vs. no CR: 63% vs. 42%, p=0.010). There was a trend for better 2-year OS in CR (OS: CR vs. no CR: 78% vs. 63%, p=0.063. Conclusion: We confirm the feasibility of haplo-SCT using NMAC and PT-Cy with low incidence of GVHD (notably severe forms) and NRM. In addition, we observed a relatively low incidence of relapse (19%) in this cohort of heavily pretreated patients, underlining a potent graft-versus-lymphoma effect after haplo-SCT, leading to promising survivals, including high rate of GRFS (>50%), suggesting a preserved long term quality of life in survivors. We conclude that NMAC haplo-SCT with PT-Cy should be considered as a valuable curative option for advanced lymphoma patients, with a favorable toxicity profile and promising long term survival. Figure Disclosures Stoppa: celgene: Other: travel fees, lecture fees; takeda: Other: travel fees. Carlo-Stella:MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Boehringer Ingelheim: Consultancy; Genenta Science sr: Consultancy; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Other: Travel, accommodations; Janssen Oncology: Honoraria; AstraZeneca: Honoraria. Chabannon:EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees; Celgene: Other: speaker's fees; Novartis: Other: speaker's fees; Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities. Santoro:Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; BMS: Consultancy. Blaise:Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria.

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VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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P179 Glucocorticoid exposure and link to serious adverse events in patients with ANCA-associated vasculitis

Rheumatology ◽

10.1093/rheumatology/keaa111.174 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

Philip Spearpoint ◽

Cormac Sammon ◽

Antonio Ramirez de ◽

Arellano Serna ◽

Peter Rutherford

Keyword(s):

Cardiovascular Disease ◽

Adverse Events ◽

Renal Disease ◽

Real World ◽

Low Dose ◽

Remission Induction ◽

High Dose ◽

Anca Associated Vasculitis ◽

Increased Risk ◽

New Onset

Abstract Background Remission induction in ANCA-associated vasculitis (AAV) is with high dose glucocorticoids (GC) and immunosuppressants. Patients are exposed to high GC dose and/or prolonged low dose. EULAR/EDTA guidelines target 7.5-10mg at 3 months but acknowledge this is often achieved later. This study used UK real world practice data to examine the scale of GC exposure and associated clinical risks in AAV. Methods The study utilised the Clinical Practice Research Datalink (CPRD) - Hospital Episode Statistics (HES) linked database. AAV patients were identified using specific READ and ICD codes and followed between 01/01/1997 and 01/01/2018. GP prescriptions were used to describe periods of continuous GC use, stop and restart and when high dose (> 30mg/day) and low dose (<30mg/day) was prescribed. Diagnostic codes indicative of infections and adverse events linked to GCs were used to estimate rates in the AAV population using a generalized linear model with a Poisson distribution. Results 450 AAV patients with at least one GC prescription were analysed. The median dose decreased to 9.3 mg (IQR 5.0 - 17.0) at 6 months and 5.1 mg (0.00 - 10.0) at 12 months,50% patients were taking > 10mg at 5 months and 25% were still > 10mg at 12 months. However, within 6 months of achieving 10mg/day, 50% relapse to needing dose >10mg, 75% within 2 years and 90% within 6 years. In adjusted Poisson model (age, gender, year of diagnosis before/after 2013) the rate of infection in AAV patients taking high dose was 2.59 times (CI95 1.95, 3.45) that of those on low dose and lower in those not taking GCs (IRR 0.27 (0.22-0.34)). Increased risk of new onset cardiovascular disease (IRR 2.55 (0.92, 7.04)) and new onset renal disease (IRR 3.4 (1.29-8.96)) were higher in patients receiving high dose. Conclusion AAV patients have significant exposure to high dose GCs and in real world practice, GC dose remains higher than recommended in current clinical guidelines. High dose GCs are associated with high risk of infection and new cardiovascular disease and renal disease. This creates a significant patient burden and has implications for healthcare resource use. Disclosures P. Spearpoint: Corporate appointments; Employee of Vifor Pharma. C. Sammon: Corporate appointments; Employee of PHMR. A. Ramirez de Arellano Serna: Corporate appointments; Employee of Vifor Pharma. P. Rutherford: Corporate appointments; Employee of Vifor Pharma. Shareholder/stock ownership; Vifor Pharma.

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Differential effects on out-of-hospital cardiac arrest of dihydropyridines: real-world data from population-based cohorts across two European countries

European Heart Journal - Cardiovascular Pharmacotherapy ◽

10.1093/ehjcvp/pvz038 ◽

2019 ◽

Vol 6 (6) ◽

pp. 347-355 ◽

Cited By ~ 1

Author(s):

Talip E Eroglu ◽

Grimur H Mohr ◽

Marieke T Blom ◽

Arie O Verkerk ◽

Patrick C Souverein ◽

...

Keyword(s):

Cardiac Arrest ◽

General Population ◽

Calcium Channels ◽

Cardiac Electrophysiology ◽

Low Dose ◽

Population Based ◽

High Dose ◽

Real World Data ◽

Registration System ◽

Hospital Cardiac Arrest

Abstract Aims Various drugs increase the risk of out-of-hospital cardiac arrest (OHCA) in the general population by impacting cardiac ion channels, thereby causing ventricular tachycardia/fibrillation (VT/VF). Dihydropyridines block L-type calcium channels, but their association with OHCA risk is unknown. We aimed to study whether nifedipine and/or amlodipine, often-used dihydropyridines, are associated with increased OHCA risk, and how these drugs impact on cardiac electrophysiology. Methods and results We conducted a case–control study with VT/VF-documented OHCA cases with presumed cardiac cause from ongoing population-based OHCA registries in the Netherlands and Denmark, and age/sex/index date-matched non-OHCA controls (Netherlands: PHARMO Database Network, Denmark: Danish Civil Registration System). We included 2503 OHCA cases, 10 543 non-OHCA controls in Netherlands, and 8101 OHCA cases, 40 505 non-OHCA controls in Denmark. To examine drug effects on cardiac electrophysiology, we performed single-cell patch-clamp studies in human-induced pluripotent stem cell-derived cardiomyocytes. Use of high-dose nifedipine (≥60 mg/day), but not low-dose nifedipine (<60 mg/day) or amlodipine (any-dose), was associated with higher OHCA risk than non-use of dihydropyridines [Netherlands: adjusted odds ratios (ORadj) 1.45 (95% confidence interval 1.02–2.07), Denmark: 1.96 (1.18–3.25)] or use of amlodipine [Netherlands: 2.31 (1.54–3.47), Denmark: 2.20 (1.32–3.67)]. Out-of-hospital cardiac arrest risk of (high-dose) nifedipine use was not further increased in patients using nitrates, or with a history of ischaemic heart disease. Nifedipine and amlodipine blocked L-type calcium channels at similar concentrations, but, at clinically used concentrations, nifedipine caused more L-type calcium current block, resulting in more action potential shortening. Conclusion High-dose nifedipine, but not low-dose nifedipine or any-dose amlodipine, is associated with increased OHCA risk in the general population. Careful titration of nifedipine dose should be considered.

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