Publications by authors named "Rebecca Klisovic"

62 Publications

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.

Leukemia 2021 Mar 2. Epub 2021 Mar 2.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.
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http://dx.doi.org/10.1038/s41375-021-01179-4DOI Listing
March 2021

Adherence trajectories in oral therapy for chronic myeloid leukemia: Overview of a research protocol.

Res Nurs Health 2020 09 31;43(5):443-452. Epub 2020 Aug 31.

Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, Georgia.

Over a quarter of chemotherapy regimens now include oral agents. Individuals living with cancer are now responsible for administering this lifesaving therapy at home by taking every dose as prescribed. One type of oral chemotherapy, tyrosine kinase inhibitors (TKIs), is the current recommended treatment for chronic myeloid leukemia. This targeted therapy has markedly improved survival but comes with significant side effects and financial costs. In the study described in this protocol, the investigators seek to understand the dynamic nature of TKI adherence experienced by individuals diagnosed with CML. Using a mixed-method approach in this prospective observational study, funded by the National Cancer Institute, we seek to describe subjects' adherence trajectories over 1 year. We aim to characterize adherence trajectories in individuals taking TKIs using model-based cluster analysis. Next, we will determine how side effects and financial toxicity influence adherence trajectories. Then we will examine the influence of TKI adherence trajectories on disease outcomes. Additionally, we will explore the experience of patients taking TKIs by interviewing a subset of participants in different adherence trajectories. The projected sample includes 120 individuals taking TKIs who we will assess monthly for 12 months, measuring adherence with an objective measure (Medication Event Monitoring System). Identifying differential trajectories of adherence for TKIs is important for detecting subgroups at the highest risk of nonadherence and will support designing targeted interventions. Results from this study can potentially translate to other oral agents to improve care across different types of cancer.
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http://dx.doi.org/10.1002/nur.22069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7742414PMC
September 2020

A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

Am J Hematol 2020 12 19;95(12):1457-1465. Epub 2020 Sep 19.

Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level -1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m cytarabine D5-8, and 8 mg/m idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).
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http://dx.doi.org/10.1002/ajh.25958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821016PMC
December 2020

Phase I study of AR-42 and decitabine in acute myeloid leukemia.

Leuk Lymphoma 2020 06 8;61(6):1484-1492. Epub 2020 Feb 8.

Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.

This phase I trial sought to determine a biologically safe and effective dose of AR-42, a novel histone deacetylase inhibitor, which would lead to a doubling of miR-29b prior to decitabine administration. Thirteen patients with previously untreated or relapsed/refractory AML were treated at 3 dose levels (DL): AR-42 20 mg qd on d1,3,5 in DL1, 40 mg qd on d1,3,5 in DL2 and 40 mg qd on d1,3,4,5 in DL3. Patients received decitabine 20 mg/m on d6-15 of each induction cycle and 20 mg/m on d6-10 of each maintenance cycle. One DLT of polymicrobial sepsis and multi-organ failure occurred at DL3. Two patients achieved a CRi and one patient achieved a CR for an ORR of 23.1%. The higher risk features of this patient population and the dosing schedule of AR-42 may have led to the observed clinical response and failure to meet the biologic endpoint.
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http://dx.doi.org/10.1080/10428194.2020.1719095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375689PMC
June 2020

Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.

Blood 2020 01;135(5):371-380

The Ohio State University Comprehensive Cancer Center, Columbus, OH.

Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.
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http://dx.doi.org/10.1182/blood.2019002697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993016PMC
January 2020

Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study.

Leuk Lymphoma 2020 02 23;61(2):387-396. Epub 2019 Sep 23.

Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m, in adults with R/R AML and in older (age ≥ 60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60 mg (∼35 mg/m) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60 mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.
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http://dx.doi.org/10.1080/10428194.2019.1665664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552944PMC
February 2020

Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3-ITD-positive AML.

Invest New Drugs 2020 04 17;38(2):340-349. Epub 2019 May 17.

Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.

Activating FLT3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has in vitro activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations. Therefore, we conducted a phase I study of pacritinib in combination with chemotherapy in AML patients with FLT3 mutations to determine the pharmacokinetics and preliminary toxicity and clinical activity. Pacritinib was administered at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin (cohort A) or with decitabine induction (cohort B). A total of thirteen patients were enrolled (five in cohort A; eight in cohort B). Dose limiting toxicities include hemolytic anemia and grade 3 QTc prolongation in two patients who received 100 mg. Complete remission was achieved in two patients in cohort A, one of whom had a minor D835Y clone at baseline. One patient in cohort B achieved morphologic leukemia free state. Seven patients (two in cohort A; five in cohort B) had stable disease. In conclusion, pacritinib, an inhibitor of FLT3-ITD and resistant-conferring TKD mutations, was well tolerated and demonstrated preliminary anti-leukemic activity in combination with chemotherapy in patients with FLT3 mutations.
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http://dx.doi.org/10.1007/s10637-019-00786-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858927PMC
April 2020

Ruxolitinib Therapy Followed by Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation for Myelofibrosis: Myeloproliferative Disorders Research Consortium 114 Study.

Biol Blood Marrow Transplant 2019 02 8;25(2):256-264. Epub 2018 Sep 8.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

We evaluated the feasibility of ruxolitinib therapy followed by a reduced-intensity conditioning (RIC) regimen for patients with myelofibrosis (MF) undergoing transplantation in a 2-stage Simon phase II trial. The aims were to decrease the incidence of graft failure (GF) and nonrelapse mortality (NRM) compared with data from the previous Myeloproliferative Disorders Research Consortium 101 Study. The plan was to enroll 11 patients each in related donor (RD) and unrelated donor (URD) arms, with trial termination if ≥3 failures (GF or death by day +100 post-transplant) occurred in the RD arm or ≥6 failures occurred in the URD. A total of 21 patients were enrolled, including 7 in the RD arm and 14 in the URD arm. The RD arm did not meet the predetermined criteria for proceeding to stage II. Although the URD arm met the criteria for stage II, the study was terminated owing to poor accrual and a significant number of failures. In all 19 transplant recipients, ruxolitinib was tapered successfully without significant side effects, and 9 patients (47%) had a significant decrease in symptom burden. The cumulative incidences of GF, NRM, acute graft-versus-host disease (GVHD), and chronic GVHD at 24 months were 16%, 28%, 64%, and 76%, respectively. On an intention-to-treat basis, the 2-year overall survival was 61% for the RD arm and 70% for the URD arm. Ruxolitinib can be integrated as pretransplantation treatment for patients with MF, and a tapering strategy before transplantation is safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339828PMC
February 2019

A novel regimen for relapsed/refractory adult acute myeloid leukemia using a partial tandem duplication targeted therapy: results of phase 1 study NCI 8485.

Haematologica 2018 06 22;103(6):982-987. Epub 2018 Mar 22.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA.

partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. wild type is epigenetically silenced in partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors , sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of wildtype contributes to partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter daily on days 1-10 and vorinostat 400 milligrams daily on days 5-10. Cytarabine was dose-escalated from 1.5 grams/meter every 12 hours to 3 grams/meter every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the partial tandem duplication subset. ().
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http://dx.doi.org/10.3324/haematol.2017.186890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058798PMC
June 2018

Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia.

Oncotarget 2018 Feb 3;9(11):9706-9713. Epub 2018 Jan 3.

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Acute myeloid leukemia (AML) is the second most common type of leukemia in adults. Incidence of AML increases with age with a peak incidence at 67 years. Patients older than 60 years have an unfavorable prognosis due to resistance to conventional chemotherapy. Volasertib (BI 6727) is a cell-cycle regulator targeting polo-like kinase which has been evaluated in clinical trials in AML. We evaluated effects of volasertib in primary patient samples and NK cells. At equivalent doses, volasertib is cytotoxic to AML blasts but largely spares healthy NK cells. We then evaluated the effect of volasertib treatment in combination with BI 836858 on primary AML blast samples using antibody-dependent cellular cytotoxicity (ADCC) assays. Volasertib treatment of NK cells did not impair NK function as evidenced by comparable levels of BI 836858 mediated ADCC in both volasertib-treated and control-treated NK cells. In summary, volasertib is cytotoxic to AML blasts while sparing NK cell viability and function. Higher BI 836858 mediated ADCC was observed in patient samples pretreated with volasertib. These findings provide a strong rationale to test combination of BI 836858 and volasertib in AML.
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http://dx.doi.org/10.18632/oncotarget.23880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839395PMC
February 2018

Psychosocial risk predicts high readmission rates for hematopoietic cell transplant recipients.

Bone Marrow Transplant 2018 11 14;53(11):1418-1427. Epub 2018 Feb 14.

Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA.

Hematopoietic cell transplantation (HCT) is an intensive treatment resulting in disease control however subsequent psychosocial distress is common. Screening for psychosocial risk factors that contribute to morbidity is underutilized; moreover, the value in screening is uncertain. We performed a retrospective study of 395 HCT patients who were screened for psychosocial risk using the Transplant Evaluation Rating Scale (TERS). Patients were classified by psychosocial risk as no-risk (TERS = 26.5, 52%) vs. at-risk (TERS > 26.5, 48%), with at-risk patients stratified by cumulative deficits into mild risk (TERS = 27-35.5, 39%) and moderate risk (TERS > 35.5, 9%). At-risk patients were more likely to be readmitted within 90 days (mild risk HR = 1.62, p = 0.02; moderate risk HR = 2.50, p = 0.002). Prior psychiatric history (HR = 1.81, p = 0.002) and poor coping skills (HR = 1.64, p = 0.04) also influenced readmission. At-risk patients were more likely to be readmitted for infection (no-risk = 12% vs. at-risk = 25%, p = 0.002). Pre-HCT screening with the TERS did not predict survival or length of stay although at-risk patients are at a heighted risk of readmission. Implementing strategies to reduce readmission in higher risk patients is warranted.
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http://dx.doi.org/10.1038/s41409-018-0118-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092254PMC
November 2018

NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017.

J Natl Compr Canc Netw 2017 09;15(9):1091-1102

The prognosis for patients with newly diagnosed acute lymphoblastic leukemia (ALL) has improved with the use of more intensive chemotherapy regimens, tyrosine kinase inhibitors, targeted agents, and allogeneic hematopoietic cell transplantation. However, the management of relapsed or refractory (R/R) ALL remains challenging and prognosis is poor. The NCCN Guidelines for ALL provide recommendations on standard treatment approaches based on current evidence. These NCCN Guidelines Insights summarize treatment recommendations for R/R ALL and highlight important updates, and provide a summary of the panel's discussion and underlying data supporting the most recent recommendations for R/R ALL management.
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http://dx.doi.org/10.6004/jnccn.2017.0147DOI Listing
September 2017

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.

N Engl J Med 2017 08 23;377(5):454-464. Epub 2017 Jun 23.

From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston (R.M.S.); the Division of Biomedical Statistics and Informatics (S.J.M., K.L.) and the Alliance Statistics and Data Center (S.J.M., K.L., S.G.), Mayo Clinic, Rochester, MN; the Alliance Statistics and Data Center, Duke University, Durham, NC (B.L.S.); the Ohio State University Comprehensive Cancer Center, Columbus (S.G., C.D.B., T.W.P., G.M., R.B.K.); Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden (C.T., G.E.), Department of Internal Medicine III, University Hospital of Ulm, Ulm (K.D., R.F.S., H.D.), Hematology and Oncology, University of Leipzig, Leipzig (D.N.), Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover (J.K., A.G.), and Department of Medicine II, Hematology-Oncology, Goethe University Hospital Frankfurt, Frankfurt am Main (H.S.) - all in Germany; the Department of Biomedicine and Prevention, University Tor Vergata, Rome (F.L.-C., S.A.); the Department of Clinical Haematology, Alfred Hospital and Monash University, Melbourne, VIC, Australia (A.W.); Hospital de la Santa Creu i Sant Pau, Hematology Department, Autonomous University of Barcelona, Barcelona (J.S.), and Hospital Universitario la Fe, Hematology Department, Department of Medicine, University of Valencia, Valencia (M.A.S.) - both in Spain; the Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto (J.M.B.); Radboud Institute Molecular Studies, Radboud University Medical Center, Nijmegen, the Netherlands (T.W.); the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle (F.R.A.); the Division of Hematology-Oncology, Stanford Comprehensive Cancer Center, Stanford University, Stanford, CA (B.C.M.); the Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (M.S.T.); and the Department of Medicine, University of Chicago, Chicago (R.A.L.).

Background: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population.

Methods: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival.

Results: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups.

Conclusions: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).
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http://dx.doi.org/10.1056/NEJMoa1614359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190PMC
August 2017

The Effect of Aromatherapy on Insomnia and Other Common Symptoms Among Patients With Acute Leukemia

Oncol Nurs Forum 2017 07 1;44(4):E185-E193. Epub 2017 Jul 1.

Purpose/objectives: To determine if the use of aromatherapy improves insomnia and other common symptoms in hospitalized patients with newly diagnosed acute leukemia.

Design: A randomized, crossover, washout trial.

Setting: An inpatient acute leukemia unit at the Arthur G. James Cancer Hospital and Richard L. Solove Research Institute of the Wexner Medical Center at Ohio State University in Columbus.

Sample: 50 patients who were newly diagnosed with acute leukemia and hospitalized to receive their initial four weeks of intensive induction chemotherapy.

Methods: Patients were offered a choice of three scents to be used during the trial: lavender, peppermint, or chamomile. Each patient was randomized to receive either the chosen aromatherapy intervention or a placebo intervention during alternate weeks, with a washout period in between. Sleep quality and other common symptoms were measured.

Main Research Variables: Aromatherapy, sleep, insomnia, pain, tiredness, drowsiness, nausea, lack of appetite, shortness of breath, depression, anxiety, and well-being.

Findings: Most patients reported poor quality sleep at baseline, but aromatherapy had a statistically significant positive impact. Improvements were noted in tiredness, drowsiness, lack of appetite, depression, anxiety, and well-being because of aromatherapy.

Conclusions: Aromatherapy is a viable intervention for improving insomnia and other symptoms commonly experienced by patients with acute leukemia.

Implications For Nursing: Oncology nurses can employ aromatherapy safely and inexpensively, and with minimal training, as an effective tool in decreasing many symptoms that plague patients with leukemia. Patients can exercise a greater sense of control over their treatment environments through the use of aromatherapy.
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http://dx.doi.org/10.1188/17.ONF.E185-E193DOI Listing
July 2017

Myeloproliferative Neoplasms, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2016 12;14(12):1572-1611

Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF.
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http://dx.doi.org/10.6004/jnccn.2016.0169DOI Listing
December 2016

Novel Chromosome 5 Inversion Associated With PDGFRB Rearrangement in Hypereosinophilic Syndrome.

JAMA Dermatol 2016 12;152(12):1391-1393

Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.

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http://dx.doi.org/10.1001/jamadermatol.2016.3175DOI Listing
December 2016

Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia.

Leuk Lymphoma 2016 09 19;57(9):2100-8. Epub 2016 Jan 19.

c City of Hope Comprehensive Cancer Center , Gehr Family Center for Leukemia , Duarte , CA , USA.

Targeting aberrant tyrosine kinase activity may impact clinical outcome in acute myeloid leukemia (AML). We conducted a phase I study of the tyrosine kinase inhibitor midostaurin with bortezomib alone and in combination with chemotherapy in patients with AML. Patients on dose levels 1 and 2 (DL1 & 2) received midostaurin 50 mg bid and escalating doses of bortezomib (1 to 1.3 mg/m2). Patients on DL3 or higher received midostaurin and bortezomib following chemotherapy with mitoxantrone, etoposide, cytarabine (MEC). None of the patients enrolled to DL1 & 2 had dose-limiting toxicities (DLTs) or a clinical response. Among patients enrolled to DL3 or higher, DLTs were peripheral neuropathy, decrease in ejection fraction and diarrhea. A 56.5% CR rate and 82.5% overall response rate (CR + CR with incomplete neutrophil or platelet count recovery) were observed. The midostaurin/bortezomib/MEC combination is active in refractory/relapsed AML, but is associated with expected drug-related toxicities (NCT01174888).
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http://dx.doi.org/10.3109/10428194.2015.1135435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360182PMC
September 2016

Granulocyte Colony-Stimulating Factor-Mobilized Allografts Contain Activated Immune Cell Subsets Associated with Risk of Acute and Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2016 04 29;22(4):658-668. Epub 2015 Dec 29.

Division of Hematology, Department of Medicine, The Ohio State University and the Ohio State University Comprehensive Cancer Center, Columbus, Ohio. Electronic address:

We defined associations among immune cell subsets in granulocyte colony-stimulating factor (G-CSF)-mobilized allografts and clinical outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Fresh peripheral blood stem cell (PBSC) aliquots from 238 G-CSF-mobilized allografts were extensively characterized by immunophenotype. Subset-specific transplanted cells were correlated with acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), malignant disease relapse, nonrelapse mortality, and overall survival. Of 238 assessable alloHCT recipients, 185 patients (78%) received reduced-intensity conditioning and 152 (64%) antithymocyte globulin-based serotherapy. Incidences of aGVHD and cGVHD were 58% and 48%, respectively. Median follow-up was 21 months (range, 1.4 to 41.1). In multivariable analyses adjusted for relevant clinical factors, allograft activated natural killer (NK) cells (CD56(+)CD16(+)CD69(+)CD158b(+)) were associated with a significantly lower risk of aGVHD (P = .0016; HR, .51; 95% confidence interval, .33 to .78), whereas late-activated HLA-DR(+) CD3(+) cells were associated with significantly higher aGVHD (P < .0005; HR, 2.31; 95% confidence interval, 1.55 to 3.43). In a subgroup of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), receipt of an allograft from an older donor (≥40 years) was associated with a higher incidence of relapse (P = .0042; HR, 2.99); allograft content of early activated CD3(+) cells (CD3(+)CD69(+); P = .0024; HR, .4) and NKT cells (CD3(+)CD56(+); P = .0006; HR, .54) were associated with a lower incidence of relapse. Presence of HLA-Bw4-80Ile(+) genotype was associated with lower relapse incidence. In conclusion, activated NK cells within PBSC allografts associate with lower aGVHD risk, whereas HLA-DR(+) T cells associate with higher aGVHD and cGVHD risk. NKT cells and early activated T cells are associated with lower relapse risk in AML and MDS patients. These findings may have implications in therapeutic targeting of select populations in the allograft to minimize incidence of GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2015.12.015DOI Listing
April 2016

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors.

Biol Blood Marrow Transplant 2016 Mar 19;22(3):432-40. Epub 2015 Oct 19.

MPN Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Electronic address:

The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation.
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http://dx.doi.org/10.1016/j.bbmt.2015.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030817PMC
March 2016

Acute Lymphoblastic Leukemia, Version 2.2015.

J Natl Compr Canc Netw 2015 Oct;13(10):1240-79

Treatment of acute lymphoblastic leukemia (ALL) continues to advance, as evidenced by the improved risk stratification of patients and development of newer treatment options. Identification of ALL subtypes based on immunophenotyping and cytogenetic and molecular markers has resulted in the inclusion of Philadelphia-like ALL and early T-cell precursor ALL as subtypes that affect prognosis. Identification of Ikaros mutations has also emerged as a prognostic factor. In addition to improved prognostication, treatment options for patients with ALL have expanded, particularly with regard to relapsed/refractory ALL. Continued development of second-generation tyrosine kinase inhibitors and the emergence of immunotherapy, including blinatumomab and chimeric antigen receptor T-cell therapy, have improved survival. Furthermore, incorporation of minimal residual disease (MRD) monitoring has shown insight into patient outcomes and may lead to treatment modification or alternative treatment strategies in select populations. This excerpt focuses on the sections of the ALL guidelines specific to clinical presentation and diagnosis, treatment of relapsed/refractory ALL, and incorporation of MRD monitoring. To view the most recent complete version of these guidelines, visit NCCN.org.
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http://dx.doi.org/10.6004/jnccn.2015.0153DOI Listing
October 2015

Atorvastatin for the Prophylaxis of Acute Graft-versus-Host Disease in Patients Undergoing HLA-Matched Related Donor Allogeneic Hematopoietic Stem Cell Transplantation (allo-HCT).

Biol Blood Marrow Transplant 2016 Jan 6;22(1):71-9. Epub 2015 Aug 6.

Division of Hematology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Statins possess potent immunomodulatory effects that may play a role in preventing acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). We performed a phase II study of atorvastatin for aGVHD prophylaxis when given to allo-HCT recipients and their HLA-matched sibling donors. Atorvastatin (40 mg/day) was administered to sibling donors, beginning 14 days before the anticipated start of stem cell collection. Allo-HCT recipients (n = 40) received atorvastatin (40 mg/day) in addition to standard aGVHD prophylaxis. The primary endpoint was cumulative incidence of grades II to IV aGVHD at day 100. Atorvastatin was well tolerated, with no attributable grades III to IV toxicities in donors or their recipients. Day 100 and 180 cumulative incidences of grades II to IV aGVHD were 30% (95% confidence interval [CI], 17% to 45%) and 40% (95% CI, 25% to 55%), respectively. One-year cumulative incidence of chronic GVHD was 43% (95% CI, 32% to 69%). One-year nonrelapse mortality and relapse incidences were 5.5% (95% CI, .9% to 16.5%) and 38% (95% CI, 18% to 47%), respectively. One-year progression-free and overall survival rates were 54% (95% CI, 38% to 71%) and 82% (95% CI, 69% to 94%). One-year GVHD-free, relapse-free survival was 27% (95% CI, 16% to 47%). These results did not differ from our historical control subjects (n = 96). Although safe and tolerable, the addition of atorvastatin did not appear to provide any benefit to standard GVHD prophylaxis alone.
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http://dx.doi.org/10.1016/j.bbmt.2015.07.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706501PMC
January 2016

Tocilizumab for steroid refractory acute graft-versus-host disease.

Leuk Lymphoma 2016 3;57(1):81-5. Epub 2015 Jul 3.

b Division of Hematology, Department of Internal Medicine , James Cancer Hospital, The Ohio State University Comprehensive Cancer Center , Columbus , Ohio , USA.

Acute graft-versus-host-disease (aGVHD) is a frequent and often lethal complication of allogeneic hematopoietic stem cell transplant despite prophylaxis. Tocilizumab is a humanized anti-IL-6 receptor monoclonal antibody that has evidence of activity in patients with steroid refractory (SR) GVHD. We retrospectively report on nine patients with grade 3 or 4 SR aGVHD who received tocilizumab. Eight mg/kg of tocilizumab was administered intravenously every 3-4 weeks. aGVHD grading and responses were based on consensus criteria. Median age at transplant was 48 years. Five patients had alternate donor sources. Median time from aGVHD onset to tocilizumab administration was 44 days. Two patients had complete responses and two had partial responses. Median survival from start of tocilizumab was 26 days (range 13-1054). Our limited experience demonstrated an overall response rate of 44% (CR + PR); however, this response was not durable. Further studies are needed to determine the optimal time for tocilizumab initiation.
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http://dx.doi.org/10.3109/10428194.2015.1045896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698359PMC
October 2016

ROR1-targeted delivery of OSU-2S, a nonimmunosuppressive FTY720 derivative, exerts potent cytotoxicity in mantle-cell lymphoma in vitro and in vivo.

Exp Hematol 2015 Sep 29;43(9):770-4.e2. Epub 2015 Apr 29.

Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA. Electronic address:

Mantle-cell lymphoma (MCL) remains incurable despite numerous therapeutic advances. OSU-2S, a novel nonimmunosuppressive FTY720 (Fingolimod) derivative, exhibits potent cytotoxicity in MCL cell lines and primary cells. OSU-2S increased the surface expression of CD74, a therapeutic antibody target in MCL cells. OSU-2S, in combination with anti-CD74 antibody milatuzumab, enhanced cytotoxicity in MCL. Moreover, MCL tumor antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) targeted immunonanoparticle-carrying OSU-2S (2A2-OSU-2S-ILP)-mediated selective cytotoxicity of MCL in vitro, as well as activity in a xenografted mouse model of MCL in vivo. The newly developed OSU-2S delivery using ROR1-directed immunonanoparticles provide selective targeting of OSU-2S to MCL and other ROR1(+) malignancies, sparing normal B cells.
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http://dx.doi.org/10.1016/j.exphem.2015.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299545PMC
September 2015

Historical views, conventional approaches, and evolving management strategies for myeloproliferative neoplasms.

J Natl Compr Canc Netw 2015 Apr;13(4):424-34

From Northwestern University Feinberg School of Medicine, Chicago, Illinois; Stanford Cancer Institute, Stanford University, Stanford, California; Duke Cancer Institute, Duke University, Durham, North Carolina; University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; University of California, San Francisco, San Francisco, California; Johns Hopkins University School of Medicine, Baltimore, Maryland; Moores Cancer Center, UC San Diego, San Diego, California; University of Colorado Cancer Center, Aurora, Colorado; Fred Hutchinson Cancer Research Center, Seattle, Washington; Dana Farber Cancer Institute, Boston, Massachusetts; Memorial Sloan Kettering Cancer Center, New York; New York; Moffitt Cancer Center and Research Institute, Tampa, Florida; The Ohio State University, Columbus, Ohio; Fred & Pamela Buffett Cancer Center, Omaha, Nebraska; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Roswell Park Cancer Institute, Buffalo, New York; Washington University-Siteman Cancer Center, St Louis, Missouri; St. Jude Children's Research Hospital, Memphis, Tennessee; University of Alabama at Birmingham, Birmingham, Alabama; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; Yale University School of Medicine; New Haven, Connecticut; University of Utah, Salt Lake City, Utah; University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; City of Hope Cancer Center, Los Angeles, California; The University of Texas MD Anderson Cancer Center, Houston, Texas; and Mayo Clinic Cancer Center, Scottsdale, Arizona.

The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article.
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http://dx.doi.org/10.6004/jnccn.2015.0058DOI Listing
April 2015

Decitabine priming enhances the antileukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia.

Blood 2015 Apr 25;125(17):2689-92. Epub 2015 Feb 25.

Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.

The prognosis of acute myeloid leukemia (AML) is poor, highlighting the need for novel treatments. Hypomethylating agents, including decitabine are used to treat elderly AML patients with relative success. Targeting nuclear export receptor (exportin 1 [XPO1]) is a novel approach to restore tumor suppressor (TS) function in AML. Here, we show that sequential treatment of AML blasts with decitabine followed by selinexor (XPO1 inhibitor) enhances the antileukemic effects of selinexor. These effects could be mediated by the re-expression of a subset of TSs (CDKN1A and FOXO3A) that are epigenetically silenced via DNA methylation, and cytoplasmic-nuclear trafficking is regulated by XPO1. We observed a significant upregulation of CDKN1A and FOXO3A in decitabine- versus control-treated cells. Sequential treatment of decitabine followed by selinexor in an MV4-11 xenograft model significantly improved survival compared with selinexor alone. On the basis of these preclinical results, a phase 1 clinical trial of decitabine followed by selinexor in elderly patients with AML has been initiated.
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http://dx.doi.org/10.1182/blood-2014-10-607648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408293PMC
April 2015

Examination of unplanned 30-day readmissions to a comprehensive cancer hospital.

J Oncol Pract 2015 Mar 13;11(2):e177-81. Epub 2015 Jan 13.

The Ohio State University Wexner Medical Center, Columbus, OH

Purpose: The Centers for Medicare and Medicaid Services (CMS), under the Hospitals Readmissions Reductions Program, may withhold regular reimbursements for excessive 30-day readmissions for select diagnoses. Such penalties imply that some readmissions reflect poor clinical decision making or care during the initial hospitalization. We examined factors related to potentially preventable readmissions in CMS patients at a tertiary cancer hospital.

Methods: The medical records of all CMS patients with unplanned readmissions within 30 days of index admission were reviewed over 6 months (October 15, 2011-April 15, 2012). Each readmission was classified as not preventable or potentially preventable. Factors associated with potentially preventable readmissions were sought.

Results: Of 2,531 inpatient admissions in CMS patients over 6 months, 185 patients experienced at least one readmission for 282 total readmissions (11%). Median time to readmission was 9 days (range, 0 to 30 days). The most common causes for first readmission were new diagnoses not present at first admission (n = 43, 23%), new or worsening symptoms due to cancer progression (n = 40, 21%) and complications of procedures (n = 25, 13%). There were 38 (21%) initial readmissions classified as potentially preventable. Use of total parenteral nutrition at the time of discharge was associated with potentially preventable readmission (P = .028).

Conclusion: Most unplanned readmissions to a tertiary cancer hospital are related to progression of disease, new diagnoses, and procedure complications. Minimizing readmissions in complex cancer patients is challenging. Larger multi-institutional datasets are needed to determine a reasonable standard for expected readmission rates.
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http://dx.doi.org/10.1200/JOP.2014.001546DOI Listing
March 2015

Lower dose of antithymocyte globulin does not increase graft-versus-host disease in patients undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell transplant.

Leuk Lymphoma 2015 Apr 20;56(4):1058-65. Epub 2014 Nov 20.

Division of Hematology, Department of Internal Medicine, The Ohio State University , Columbus, OH , USA.

The appropriate dose of antithymocyte globulin (ATG) to be utilized in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplant (alloHSCT) is as yet unknown. We retrospectively compared patients who received 7.5 mg/kg (R-ATG, 39 patients) and 6 mg/kg (r-ATG, 97 patients). The cumulative incidences of acute graft-versus-host disease (aGVHD) grade II-IV at 180 days were 46% and 41% and of aGVHD grade III-IV were 11% and 18% in r-ATG and R-ATG, respectively (p > 0.30). The respective estimated cumulative incidences at 24 months of cGVHD were 42% and 44% (p > 0.30). There was no significant difference in non-relapse mortality (p = 0.22), cumulative incidence of relapse (p = 0.53), progression-free survival (p = 0.69) or overall survival (p = 0.95). In conclusion, a decreased ATG dose of 6 mg/kg was associated with a similar proportion of GVHD to 7.5 mg/kg ATG. Given the increasing number of RIC HSCTs performed worldwide, the correct dose and preparation of ATG should be defined by prospective randomized trials.
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http://dx.doi.org/10.3109/10428194.2014.956314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417073PMC
April 2015