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Effect of eculizumab on transfusion needs in PNH patients with and without transfusion history [Meeting Abstract]

Roth, A; Araten, D; Larratt, L; Kulasekararaj, A; Maciejewski, J; Wilson, A; Gustovic, P; Kanakura, Y
Background: Eculizumab, a humanized monoclonal antibody that blocks terminal complement activation at C5, prevents complement-mediated hemolysis and reduces need for transfusions in paroxysmal nocturnal hemoglobinuria (PNH) patients who were transfusion-dependent before treatment initiation; it has also been shown to reduce lactate dehydrogenase (LDH) irrespective of transfusion history. The International PNH Registry (NCT01374360) is an ongoing prospective, multinational, observational study to record the natural history of PNH and evaluate the long-term efficacy and safety of eculizumab.
Aim(s): Evaluate, in a real-world setting, effectiveness of eculizumab on transfusion needs and other parameters in PNH patients with and without history of transfusion at initiation of eculizumab.
Method(s): Patients enrolled in the PNH Registry on or before January 1, 2018, with known demographics and enrollment date, who (1) were treated with eculizumab, (2) had known red blood cell (RBC) transfusion status for 12 months before initiation of eculizumab, and (3) had >=12 months of follow-up after initiation of eculizumab, were included. Numbers of units of packed RBCs received in the year before initiation of eculizumab and during follow-up were calculated and summarized as rates (units/patientyear). Event rates for thromboembolism (TE) and all major adverse vascular events (MAVE; including TE) were calculated from disease start until eculizumab initiation and from eculizumab initiation to last follow-up. Transfusion rates were further stratified by history of bone marrow disease (BMD). LDH ratio (LDH/LDH upper limit of normal [ULN]) was assessed and change from initiation of eculizumab to last treated follow-up was analyzed using general linear mixed models, adjusted for baseline and subpopulation.
Result(s): 596/543 patients had/did not have history of RBC transfusion in the 12 months before initiation of eculizumab, and were included. Mean (SD) age at eculizumab initiation was 44 (17) years in both groups. Both cohorts had >2600 patient-years of follow-up. Results for outcomes of interest are in the Table 1. In patients with a history of transfusion, the transfusion rate (95% CI) decreased from 10.6 (10.3, 10.9) units/year in the year before initiation of eculizumab to 3.3 (3.3, 3.4) for a 70% reduction in transfusions (Table 1). This reduction was more pronounced in patients without history of BMD (80% reduction) versus those with history of BMD (60% reduction). In the overall group with no history of transfusions, the rate (95% CI) of transfusions during follow-up was 1.5 (1.4, 1.5) units/year; the rate in patients with a history of BMD was 2.2 (2.1, 2.3) units/year, as compared with the rate in patients with no history of BMD of 1.1 (1.1, 1.2) units/year. Patients with and without a history of transfusion at initiation of eculizumab showed a significant reduction in hemolysis after initiation of eculizumab (mean change in LDH ratio -5.4 [P<0.0001] and -3.9 [P<0.0001]), and mean LDH was <1.5 xULN in both groups. Rates of TE and MAVE declined by 70% after initiation of eculizumab regardless of transfusion history. Summary and
Conclusion(s): In this analysis of real-world data from the International PNH Registry in patients with PNH, eculizumab was efficacious in reducing transfusion rates, complement-mediated hemolysis, TE, and MAVE, irrespective of prior transfusion history or BMD status. Transfusion rates in patients with no history of transfusion in the year before eculizumab initiation remained low after initiation of eculizumab, regardless of BMD status. (Table Presented)
EMBASE:625922426
ISSN: 2572-9241
CID: 3615382

MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric B-lymphoblastic leukemia

Evensen, Nikki A; Madhusoodhan, P Pallavi; Meyer, Julia; Saliba, Jason; Chowdhury, Ashfiyah; Araten, David J; Nersting, Jacob; Bhatla, Teena; Vincent, Tiffaney L; Teachey, David; Hunger, Stephen P; Yang, Jun; Schmiegelow, Kjeld; Carroll, William L
Survival of children with relapsed acute lymphoblastic leukemia is poor and understanding mechanisms underlying resistance is essential in developing new therapy. Relapse-specific heterozygous deletions in MSH6, a crucial part of DNA Mismatch Repair, are frequently detected. Our aim was to determine whether MSH6 deletion results in a hypermutator phenotype associated with generation of secondary mutations involved in drug resistance or leads to a failure to initiate apoptosis directly in response to chemotherapeutic agents. We knocked down MSH6 in mismatch repair proficient cell lines (697 and UOCB1) and showed significant increases in IC50s to 6-Thioguanine & 6-Mercaptopurine (697: 26- and 9-fold; UOCB1: 5- and 8-fold) in vitro, as well as increased resistance to 6-Mercaptopurine treatment in vivo. No shift in IC50 was observed in deficient cells (Reh & RS4;11). 697 MSH6 knockdown resulted in increased DNA thioguanine nucleotide levels compared to non-targeted cells (3,070 versus 1,722 fmol/mg DNA) with no difference observed in mismatch repair deficient cells. Loss of MSH6 did not give rise to microsatellite instability in cells lines or clinical samples nor did it significantly increase mutation rate, but rather resulted in a defect in cell cycle arrest upon thiopurine exposure. MSH6 knockdown cells showed minimal activation of checkpoint regulator CHK1, ɣH2AX (DNA damage marker) and p53 levels upon treatment with thiopurines, consistent with intrinsic chemoresistance due to failure to recognize thioguanine nucleotide mismatching and initiate mismatch repair. Aberrant MSH6 adds to the list of alterations/mutations associated with acquired resistance to purine analogues emphasizing the importance of thiopurine therapy.
PMCID:5927991
PMID: 29449434
ISSN: 1592-8721
CID: 2958362

Changing prognosis in Paroxysmal Nocturnal Haemoglobinuria disease subcategories; an analysis of International PNH Registry

Socie, Gerard; Schrezenmeier, Hubert; Muus, Petra; Lisukov, Igor; Roth, Alexander; Kulasekararaj, Austin; Lee, Jong Wook; Araten, David; Hill, Anita; Brodsky, Robert; Urbano-Ispizua, Alvaro; Szer, Jeffrey; Wilson, Amanda; Hillmen, Peter
BACKGROUND: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare disease. Although much progress has been made in the understanding of the pathophysiology of the disease, far less is known with respect to the clinical outcomes of the patients with PNH. Few retrospective studies provide survival estimates and even fewer have explored the clinical heterogeneity of the disease. Haemolytic and aplastic anaemia forms have been recognised as main disease categories with the haemolytic form being associated with worst prognosis by the largest studied cohort some years ago. AIMS: To describe mortality and causes of death in PNH overall and by PNH Classification and to evaluate risk factors associated with mortality. METHODS: We analysed data on 2356 patients enrolled in the International PNH Registry with multivariate analyses using time dependent covariates. Patients were classified into haemolytic, aplastic anaemia/PNH syndrome or intermediate PNH. RESULTS: Overall, 122 (5.2%) patients died after enrolment, the incidence according to subcategories being 5.1%, 11.7%, 2.0%, and 4.8% for patients with haemolytic PNH, AA-PNH, intermediate, and insufficient data, respectively. Older age and decreased performance status also affected survival in multivariate analysis. Improved outcome of patients with haemolytic PNH suggests that eculizumab treatment in PNH may be associated with improved survival. CONCLUSIONS: A detailed analysis of clinical presentations and causes of death in patients with PNH, overall and by disease subcategories provide evidence that, in the current era, patients with haemolytic PNH are no longer those who harbour the worst prognosis. This finding differs sharply from what has been previously reported.
PMID: 27305361
ISSN: 1445-5994
CID: 2145172

MSH6 HAPLOINSUFFICIENCY AT RELAPSE CONTRIBUTES TO THE DEVELOPMENT OF THIOPURINE RESISTANCE IN PEDIATRIC B-LYMPHOBLASTIC LEUKEMIA [Meeting Abstract]

Madhusoodhan, Pillai Pallavi; Evensen, Nikki; Meyer, Julia; Chowdhury, Ashfiyah; Araten, David; Nersting, Jacob; Schmeigelow, Kjeld; Carroll, William
ISI:000374306900060
ISSN: 1545-5017
CID: 2380462

Analysis of the mutation rate in T lymphoblastic leukemia cell lines [Meeting Abstract]

Araten, David J; Sherman, Erik; Etra, Aaron
ISI:000371597102376
ISSN: 1538-7445
CID: 2064442

No evidence of hypermutability in red cells from patients with paroxysmal nocturnal hemoglobinuria using the XK gene

Araten, David J; Zamechek, Leah; Halverson, Gregory
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PMCID:4116847
PMID: 24816235
ISSN: 0390-6078
CID: 977462

Selective splenic artery embolization for the treatment of thrombocytopenia and hypersplenism in paroxysmal nocturnal hemoglobinuria

Araten, David J; Iori, Anna Paola; Brown, Karen; Torelli, Giovanni Fernando; Barberi, Walter; Natalino, Fiammetta; De Propris, Maria Stefania; Girmenia, Corrado; Salvatori, Filippo Maria; Zelig, Orly; Foa, Robin; Luzzatto, Lucio
BACKGROUND: PNH is associated with abdominal vein thrombosis, which can cause splenomegaly and hypersplenism. The combination of thrombosis, splenomegaly, and thrombocytopenia (TST) is challenging because anticoagulants are indicated but thrombocytopenia may increase the bleeding risk. Splenectomy could alleviate thrombocytopenia and reduce portal pressure, but it can cause post-operative thromboses and opportunistic infections. We therefore sought to determine whether selective splenic artery embolization (SSAE) is a safe and effective alternative to splenectomy for TST in patients with PNH. METHODS: Four patients with PNH and TST received successive rounds of SSAE. By targeting distal vessels for occlusion, we aimed to infarct approximately 1/3 of the spleen with each procedure. RESULTS: Three of 4 patients had an improvement in their platelet count, and 3 of 3 had major improvement in abdominal pain/discomfort. The one patient whose platelet count did not respond had developed marrow failure, and she did well with an allo-SCT. Post-procedure pain and fever were common and manageable; only one patient developed a loculated pleural effusion requiring drainage. One patient, who had had only a partial response to eculizumab, responded to SSAE not only with an improved platelet count, but also with an increase in hemoglobin level and decreased transfusion requirement. CONCLUSIONS: These data indicate that SSAE can decrease spleen size and reverse hypersplenism, without exposing the patient to the complications of splenectomy. In addition, SSAE probably reduces the uptake of opsonised red cells in patients who have had a limited response to eculizumab, resulting in an improved quality of life for selected patients.
PMCID:3984395
PMID: 24673826
ISSN: 1756-8722
CID: 881852

Leukemic Blasts With The PNH Phenotype: Correlation With Cytogenetics In ALL [Meeting Abstract]

Araten, David J; Loh, Mignon L; Devidas, Meenakshi; Carroll, Andrew J; Heerema, Nyla A; Hunger, Stephen P; Amro, Chris; Zamechek, Leah
ISI:000331385005372
ISSN: 1528-0020
CID: 2380452

The rate of spontaneous mutations in human myeloid cells

Araten, David J; Krejci, Ondrej; Ditata, Kimberly; Wunderlich, Mark; Sanders, Katie J; Zamechek, Leah; Mulloy, James C
The mutation rate (mu) is likely to be a key parameter in leukemogenesis, but historically, it has been difficult to measure in humans. The PIG-A gene has some advantages for the detection of spontaneous mutations because it is X-linked, and therefore only one mutation is required to disrupt its function. Furthermore, the PIG-A-null phenotype is readily detected by flow cytometry. Using PIG-A, we have now provided the first in vitro measurement of mu in myeloid cells, using cultures of CD34+ cells that are transduced with either the AML-ETO or the MLL-AF9 fusion genes and expanded with cytokines. For the AML-ETO cultures, the median mu value was approximately 9.4x10(-7) (range approximately 3.6-23x10(-7)) per cell division. In contrast, few spontaneous mutations were observed in the MLL-AF9 cultures. Knockdown of p53 or introduction of mutant NRAS or FLT3 alleles did not have much of an effect on mu. Based on these data, we provide a model to predict whether hypermutability must occur in the process of leukemogenesis.
PMCID:4524336
PMID: 23748046
ISSN: 0027-5107
CID: 573562

Comparison of the Xk and Pig-a genes as markers for mutations in red cells from mice [Meeting Abstract]

Araten, David J.; Halverson, Gregory; Zamechek, Leah; Csehak, Ken; Kosinska, Wieslawa; Guttenplan, Joseph
ISI:000331220601091
ISSN: 0008-5472
CID: 852602