Publications by authors named "Jayesh Mehta"

99 Publications

Changes in Neutrophil-Lymphocyte or Platelet-Lymphocyte Ratios and Their Associations with Clinical Outcomes in Idiopathic Pulmonary Fibrosis.

J Clin Med 2021 Apr 1;10(7). Epub 2021 Apr 1.

Feinberg School of Medicine, Northwestern University, 420 E Superior St, Chicago, IL 60611, USA.

Identification of prognostic and predictive biomarkers in idiopathic pulmonary fibrosis (IPF) could aid assessment of disease severity and prediction of progression and response to treatment. This analysis examined reference ranges for neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in IPF, and the relationship between NLR or PLR changes and clinical outcomes over 12 months. This post hoc analysis included patients with IPF from the Phase III, double-blind trials of pirfenidone, ASCEND (NCT01366209) and CAPACITY (NCT00287716 and NCT00287729). The relationship between change from baseline to Month 12 in NLR or PLR (divided into quartiles (Q1-Q4)) and outcomes (mortality, respiratory hospitalization, declines in lung function, exercise capacity and quality of life) was assessed. Estimated reference ranges at baseline for all patients analyzed ( = 1334) were 1.1-6.4 for NLR and 56.8-250.5 for PLR. Significant trends were observed across NLR and PLR quartiles for all outcomes in placebo-treated patients, with patients manifesting the greatest NLR or PLR changes experiencing the worst outcomes. These results suggest that the greatest NLR or PLR changes over 12 months were associated with worse clinical outcomes. Further research is needed to determine the utility of NLR and PLR as prognostic biomarkers in IPF.
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http://dx.doi.org/10.3390/jcm10071427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037167PMC
April 2021

Revisiting Infectious Complications Following Total Parenteral Nutrition Use During Hematopoietic Stem Cell Transplantation.

J Adv Pract Oncol 2020 Sep-Oct;11(7):675-682. Epub 2020 Sep 1.

Northwestern Memorial Hospital Department of Pharmacy, Chicago, Illinois.

Background: Total parenteral nutrition (TPN) is frequently used to manage caloric needs during hematopoietic stem cell transplantation (HSCT). Previous studies in transplant patients who received TPN have reported widely discordant results with regard to infection and mortality, and risk factors for TPN-related infection remain unclear.

Method: We conducted a retrospective study of all HSCT recipients treated with TPN between 2005 to 2014 at Northwestern Memorial Hospital to determine the incidence and epidemiology of infections. Electronic records were used to identify patients treated with TPN for at least 2 days who developed infection.

Results: Among 198 patients treated with TPN, 30% developed documented infection. Total parenteral nutrition treatment duration (13 vs. 7 days; < .0001) and the timing of TPN initiation (> day 9 post HSCT; < .0001) were significantly higher in patients who received TPN and developed infection. Receipt of an allogeneic transplant was associated with increased risk for infection ( < .0138), and day 60 mortality was significantly higher in TPN-treated patients with infection ( < .0001).

Conclusion: Stem cell recipients who receive TPN, especially from an allogeneic donor, have high rates of infection and mortality. Minimizing TPN exposure may reduce the chance for infection.
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http://dx.doi.org/10.6004/jadpro.2020.11.7.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646632PMC
September 2020

Pembrolizumab and palliative radiotherapy in 2 cases of refractory mycosis fungoides.

JAAD Case Rep 2021 Jan 6;7:87-90. Epub 2020 Nov 6.

Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois.

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http://dx.doi.org/10.1016/j.jdcr.2020.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736700PMC
January 2021

Tacrolimus dose modification in patients receiving concomitant isavuconazole after hematopoietic stem cell transplantation.

J Oncol Pharm Pract 2020 Jul 12:1078155220940416. Epub 2020 Jul 12.

Feinberg School of Medicine and The Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL, USA.

Introduction: Isavuconazole is increasingly being used for antifungal prophylaxis during stem cell transplantation. Isavuconazole is a moderate inhibitor of Cytochrome P4503A4, and tacrolimus levels are anticipated to be elevated when given concomitantly with isavuconazole. We developed and validated a dose-modified tacrolimus regimen to better achieve and maintain target tacrolimus levels.: Allogeneic stem cell transplantation recipients who received concomitant tacrolimus and isavuconazole from September 2017 to September 2018 were included. Tacrolimus was adjusted to achieve a target range 8-12 ng/ml. Intravenous tacrolimus was first initiated at 0.02 mg/kg/day on day 1, and transitioned to oral therapy using a 2:1 conversion ratio ( = 48). Clinical observations showed high interpatient variability. The intravenous dose was then reduced to 0.017 mg/kg/day, and oral:intravenous conversion changed to 3.1:1 ( = 24).

Results: Interpatient variability was high (lower in the 0.017 mg/kg/day group;  < 0.0217). Patients in the 0.017 mg/kg/day group required fewer dose changes ( < 0.023) and had fewer levels >15 ng/ml ( < 0.021). Median tacrolimus dose declined over time; 0.016, 0.012 and 0.011 on days 1, 7 and 10 for patients receiving 0.02 mg/kg/day and 0.017, 0.014 and 0.013 in the 0.017 mg/kg group. Day 10 tacrolimus accumulation factor was 1.42 R in the 0.02 mg/kg/day cohort compared to 1.23 R in the 0.017 mg/kg/day cohort ( < 0.015). When transitioned to oral therapy, a oral:intravenous conversion ratio >3.1:1 was shown to improve chances for achieving target levels ( > 0.0744).

Conclusion: We recommend initiating intravenous tacrolimus dose at 0.017 mg/kg/day and using a 3.1:1 oral:intravenous conversion to reduce interpatient variability, drug accumulation and the number of suboptimal tacrolimus levels. Tacrolimus requires frequent drug level monitoring.
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http://dx.doi.org/10.1177/1078155220940416DOI Listing
July 2020

Variability in Cytogenetic Testing for Multiple Myeloma: A Comprehensive Analysis From Across the United States.

JCO Oncol Pract 2020 10 29;16(10):e1169-e1180. Epub 2020 May 29.

Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL.

Purpose: Multiple myeloma (MM) treatment has changed tremendously, with significant improvement in patient out-comes. One group with a suboptimal benefit is patients with high-risk cytogenetics, as tested by conventional karyotyping or fluorescence in situ hybridization (FISH). Methodology for these tests has been published, but not necessarily standardized.

Methods: We address variability in the testing and reporting methodology for MM cytogenetics in the United States using the ongoing African American Multiple Myeloma Study (AAMMS). We evaluated clinical and cytogenetic data from 1,221 patients (1,161 with conventional karyotyping and 976 with FISH) tested between 1998 and 2016 across 58 laboratories nationwide.

Results: Interlab and intralab variability was noted for the number of cells analyzed for karyotyping, with a significantly higher number of cells analyzed in patients in whom cytogenetics were normal (P 5.0025). For FISH testing, CD138-positive cell enrichment was used in 29.7% of patients and no enrichment in 50% of patients, whereas the remainder had unknown status. A significantly smaller number of cells was analyzed for patients in which CD138 cell enrichment was used compared with those without such enrichment (median, 50 v 200; P, .0001). A median of 7 loci probes (range, 1-16) were used for FISH testing across all laboratories, with variability in the loci probed even within a given laboratory. Chromosome 13-related abnormalities were the most frequently tested abnormality (n5956; 97.9%), and t(14;16) was the least frequently tested abnormality (n 5 119; 12.2%).

Conclusions: We report significant variability in cytogenetic testing across the United States for MM, potentially leading to variability in risk stratification, with possible clinical implications and personalized treatment approaches.
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http://dx.doi.org/10.1200/JOP.19.00639DOI Listing
October 2020

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

Blood Adv 2020 01;4(1):181-190

Division of Cancer Genetics and Epidemiology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.
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http://dx.doi.org/10.1182/bloodadvances.2019000491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960456PMC
January 2020

Aztreonam and Vancomycin for Initial Treatment of Febrile Neutropenia in Penicillin-Allergic Patients During Hematopoietic Stem Cell Transplantation.

J Adv Pract Oncol 2019 Sep-Oct;10(7):685-690. Epub 2019 Sep 1.

Northwestern Memorial Hospital and Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Most patients who undergo hematopoietic stem cell transplantation develop neutropenic fever and are at high risk for developing potentially life-threatening infections. β-lactam antibiotics remain the cornerstone for initial empiric treatment of neutropenic fever. In cancer patients with allergy or intolerance to β-lactams, guidelines recommend using aztreonam with vancomycin (AV) for neutropenic fever treatment. To date, the efficacy of AV for the treatment of neutropenic fever during stem cell transplantation is unknown. A retrospective study was conducted to identify hematopoietic stem cell transplantation recipients who were initially treated with concomitant AV for neutropenic fever between 2007 and 2013. Febrile neutropenia was classified as neutropenia with unexplained fever, neutropenic fever with a local source of infection, or neutropenic fever with a microbiologically documented infection. Seventy-six patients were identified who received AV as initial treatment for neutropenic fever over the study period. Responses to AV for neutropenia with unexplained fever (n = 41), febrile neutropenia with local site of infection (n = 11 [pneumonia = 9, other = 2]), and neutropenic fever with microbiologically documented infection (n = 34) were 75%, 55% (45% pneumonia), and 46% respectively. Infection-related mortality was 5%. Aztreonam with vancomycin was effective in treating neutropenia with unexplained fever. For patients with neutropenic fever and local source or microbiologically documented infection, alternative antibiotic treatments should be considered.
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http://dx.doi.org/10.6004/jadpro.2019.10.7.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517773PMC
September 2019

Prognostic Score and Cytogenetic Risk Classification for Chronic Lymphocytic Leukemia Patients: Center for International Blood and Marrow Transplant Research Report.

Clin Cancer Res 2019 08 28;25(16):5143-5155. Epub 2019 Jun 28.

Seidman Cancer Center, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio.

Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT).

Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research.

Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high ( < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years).

Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697588PMC
August 2019

Patterns of Failure and Survival Outcomes after Total Lymphoid Irradiation and High-Dose Chemotherapy with Autologous Stem Cell Transplantation for Relapsed or Refractory Classical Hodgkin Lymphoma.

Int J Radiat Oncol Biol Phys 2019 06 11;104(2):436-446. Epub 2019 Feb 11.

Department of Radiation Oncology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Purpose: The patterns of failure and long-term outcomes of patients with relapsed or refractory classical Hodgkin lymphoma treated with total lymphoid irradiation (TLI) and high-dose chemotherapy followed by autologous stem cell transplantation (aSCT) are reported.

Methods And Materials: Patients with biopsy-proven primary refractory or relapsed classical Hodgkin lymphoma who received salvage chemotherapy and accelerated hyperfractionated TLI before high-dose chemotherapy and aSCT were included. Patterns of failure were delineated after fusing pretransplant planning computed tomography to the scan reporting the first failure. Survival rates were computed using the Kaplan-Meier method. Multivariate analysis using proportional hazards regression was done to determine prognostic factors for overall survival (OS) and progression-free survival (PFS).

Results: Between 1993 and 2016, 89 patients underwent salvage treatments. Twenty patients failed at a median of 6.1 months after aSCT. Posttreatment scans were available for 16 patients who failed in a combined 43 different sites, 11 of which were extranodal. Patients failed at multiple sites, mostly within radiation fields. The 5-, 10-, and 15-year OS rates were 72.8%, 68.0%, and 58.3%; PFS rates were 73.3%, 68.5%, and 58.7%; event-free survival rates were 72.3%, 67.5%, and 57.8% respectively. The 5- and 10- year actuarial local control rates were both 77.6%. Complete response (CR) to salvage chemotherapy was associated with statistically significant improvements in OS and PFS. Eight patients developed secondary malignancies; 5 were hematologic and 3 were solid tumors.

Conclusions: Most failures were within the irradiated volume, which reflects the treatment-resistant disease biology. As part of a conditioning regimen, TLI yields good survival outcomes, particularly in patients achieving CR before transplant. However, need for RT in this setting should be assessed and new strategies should be developed to combat the treatment-resistant biology, especially in patients with less than CR after salvage chemotherapy.
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http://dx.doi.org/10.1016/j.ijrobp.2019.02.007DOI Listing
June 2019

Bortezomib is safe in and stabilizes pulmonary function in patients with allo-HSCT-associated pulmonary CGVHD.

Bone Marrow Transplant 2018 09 9;53(9):1124-1130. Epub 2018 Mar 9.

Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Pulmonary chronic graft-versus-host disease (p-CGVHD) following allogeneic HSCT is devastating with limited proven treatments. Although sporadically associated with pulmonary toxicity, the proteasome inhibitor bortezomib may be efficacious in p-CGVHD. We sought to establish safety and tolerability of bortezomib in pilot, open-label trial of patients with p-CGVHD. The primary endpoint was adverse events. Efficacy was assessed by comparing FEV1 decline prior to p-CGVHD diagnosis to during the bortezomib treatment period. The impact on pulmonary function testing of prior long-term bortezomib treatment in multiple myeloma (MM) patients was also assessed as a safety analysis. Seventeen patients enrolled in the pilot study with a mean time to p-CGVHD diagnosis of 3.36 years (±1.88 years). Bortezomib was well tolerated without early dropouts. The median FEV1 decline prior to the diagnosis of p-CGVHD was -1.06%/month (-5.36, -0.33) and during treatment was -0.25%/month (-9.42, 3.52). In the safety study, there was no significant difference in any PFT parameter between 73 patients who received bortezomib and 68 patients who did not for MM. Thus, we conclude that bortezomib has acceptable safety and tolerability in patients with compromised pulmonary function. The efficacy of proteosomal inhibition should be assessed in a large trial of chronic p-CGVHD patients.
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http://dx.doi.org/10.1038/s41409-018-0134-4DOI Listing
September 2018

Olanzapine Reduces Chemotherapy-induced Nausea and Vomiting Compared With Aprepitant in Myeloma Patients Receiving High-dose Melphalan Before Stem Cell Transplantation: A Retrospective Study.

Clin Lymphoma Myeloma Leuk 2017 09 20;17(9):584-589. Epub 2017 Jun 20.

Northwestern Memorial Hospital, Chicago, IL; Feinberg School of Medicine, Northwestern University, Chicago, IL.

Introduction: Acute and delayed chemotherapy-induced nausea and vomiting (CINV) occurs in most patients who receive high-dose melphalan and significantly affects patients' quality of life during autologous stem cell transplantation. Faced with unsatisfactory results using an aprepitant-based regimen, an olanzapine-based regimen was initiated, with the hope of improving the incidence of acute and delayed CINV. A retrospective study was conducted to compare the effectiveness of olanzapine- versus aprepitant-based regimens for CINV prevention in adult hematopoietic stem cell recipients who received high-dose melphalan.

Patients And Methods: We compared olanzapine (n = 43) to aprepitant (n = 54) and fosaprepitant (n = 20). Olanzapine was given orally at 5 mg twice daily for 5 days, aprepitant was given at 125 mg on day -1 and 80 mg on days 0 and 1, and fosaprepitant was given at 150 mg on day -1. The dose of 2 concomitant drugs (dexamethasone and 5-hydroxytryptamine type 3 receptor antagonist) was similar in the 2 groups. Nausea prevention was the primary endpoint. A complete response using a composite index of no emesis and no use of rescue medications was the secondary endpoint.

Results: The results showed that olanzapine significantly reduced the number of patients who experienced acute (P < .0001) or delayed (P < .004) nausea and significantly reduced the use of rescue medications for acute-onset (P < .0046) and delayed-onset (P < .0001) CINV compared with aprepitant.

Conclusion: Compared with fosaprepitant, olanzapine reduced the number of patients with acute (P < .0318) and delayed (P < .1519) nausea and reduced the need for rescue medications for acute-onset (P < .0643) and delayed-onset (P < .0024) CINV.
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http://dx.doi.org/10.1016/j.clml.2017.06.012DOI Listing
September 2017

Multicenter phase II study of temozolomide and myeloablative chemotherapy with autologous stem cell transplant for newly diagnosed anaplastic oligodendroglioma.

Neuro Oncol 2017 Oct;19(10):1380-1390

Memorial Sloan Kettering Cancer Center, New York, New York,USA; Northwestern Memorial Hospital, Chicago, Illinois, USA; NorthShore University, Evanston, Illinois,USA; University of Calgary, Calgary, Alberta, Canada; Massachusetts General Hospital, Boston, Massachusetts, USA; MD Anderson Cancer Center, Houston, Texas, USA.

Background: Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are chemotherapy-sensitive tumors with prolonged survival after radiochemotherapy. We report a prospective trial using induction temozolomide (TMZ) followed by myeloablative high-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) as a potential strategy to defer radiotherapy.

Methods: Patients with AO/AOA received 6 cycles of TMZ (200 mg/m2 × 5/28 day). Responding patients were eligible for HDC (thiotepa 250 mg/m2/day × 3 days, then busulfan 3.2 mg/kg/day × 3 days), followed by ASCT. Genomic characterization was performed using next-generation sequencing.

Results: Forty-one patients were enrolled; 85% had 1p/19q codeleted tumors. After induction, 26 patients were eligible for HDC-ASCT and 21 agreed to proceed. There were no unexpected adverse events or toxic deaths. After median follow-up of 66 months, 2-year progression-free survival (PFS) for transplanted patients was 86%, 5-year PFS 60%, and no patient has died. Among all 1p/19q codeleted patients (N = 33), 5-year PFS was 50% and 5-year overall survival (OS) 93%, with median time to radiotherapy not reached. Next-generation sequencing disclosed typical oligodendroglioma-related mutations, including IDH1, TERT, CIC, and FUBP1 mutations in 1p/19q codeleted patients, and glioblastoma-like signatures in 1p/19q intact patients. Aside from IDH1, potentially oncogenic/actionable mutations were variable, depicting wide molecular heterogeneity within oligodendroglial tumors.

Conclusions: TMZ followed by HDC-ASCT can be safely administered to patients with newly diagnosed 1p/19q codeleted AO. This strategy was associated with promising PFS and OS, suggesting that a chemotherapy-based approach may delay the need for radiotherapy and radiation-related toxicities. Raw data for further genomic and meta-analyses are publicly available at http://cbioportal.org/study?id=odg_msk_2017, accessed 6 January 2017.

Clinicaltrials.gov Registry: NCT00588523.
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http://dx.doi.org/10.1093/neuonc/nox086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596171PMC
October 2017

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

Cancer Epidemiol Biomarkers Prev 2016 12 1;25(12):1609-1618. Epub 2016 Sep 1.

Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma.

Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality.

Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles.

Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-1193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524541PMC
December 2016

Intravenous Busulfan-Based Myeloablative Conditioning Regimens Prior to Hematopoietic Cell Transplantation for Hematologic Malignancies.

Biol Blood Marrow Transplant 2016 08 3;22(8):1424-1430. Epub 2016 May 3.

The Ottawa Hospital Blood and Marrow Transplant Program and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Busulfan (Bu)-containing regimens are commonly used in myeloablative conditioning regimens before allogeneic hematopoietic cell transplantation (HCT). Yet, there is considerable variability on how Bu is administered related to frequency (4 times a day [Q6] or daily [Q24]) and combinations with other chemotherapeutic agents (cyclophosphamide [Cy] or fludarabine [Flu]). We performed a prospective cohort study of recipients of Bu-based conditioning according to contemporary practices to compare different approaches (BuCy Q6, n = 495; BuFlu Q24, n = 331; BuCy Q24, n = 96; BuFlu Q6, n = 91) in patients with myeloid malignancies between 2009 and 2011. BuFlu Q24 recipients were more likely to be older and tended to have worse performance status and a higher comorbid burden. The cumulative incidences of hepatic veno-occlusive disease (P = .40), idiopathic pneumonia (P = .50), and seizures (P = .50) did not differ across groups. One-year HCT-related mortality ranged from 12% to 16% (P = .80), 3-year relapse incidence ranged from 32% to 36% (P = .80), and 3-year overall survival ranged from 51% to 58% (P = .20) across groups. This study demonstrates that HCT conditioning regimens using i.v. Bu Q6 or Q24 alone or in combination with Cy or Flu have similar outcomes in the myeloablative setting for treatment of myeloid malignancies.
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http://dx.doi.org/10.1016/j.bbmt.2016.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949158PMC
August 2016

Filgrastim versus TBO-filgrastim to reduce the duration of neutropenia after autologous hematopoietic stem cell transplantation: TBO, or not TBO, that is the question.

Clin Transplant 2015 Dec 22;29(12):1128-32. Epub 2015 Oct 22.

Department of Medicine, Northwestern University, Chicago, IL, USA.

After a hospital-wide formulary change resulted in the replacement of filgrastim with TBO-filgrastim for all on- and off-label indications, we performed a retrospective comparison of patients with myeloma receiving 200 mg/m(2) melphalan with autologous hematopoietic stem cell transplantation to see whether the type of growth factor used post-transplant made a difference. One hundred and eighty-two consecutive patients with myeloma were studied, 91 receiving filgrastim immediately prior to the change and 91 receiving TBO-filgrastim afterward. The CD34(+) cell dose was comparable, as were other characteristics. Although the overall time to neutrophil recovery was similar for both groups, early engraftment (≤ 12 d) occurred more often (p = 0.05), and late engraftment (≥ 14 d) less often (p = 0.09) in filgrastim-treated patients. The number of documented infections was significantly less in the TBO-filgrastim group. Day 100 mortality and hospital stay were similar for the two groups. These data indicate that there is no material difference between filgrastim and TBO-filgrastim in this clinical setting.
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http://dx.doi.org/10.1111/ctr.12637DOI Listing
December 2015

Adverse Events During Hematopoietic Stem Cell Infusion: Analysis of the Infusion Product.

Clin Lymphoma Myeloma Leuk 2015 Nov 2;15(11):e157-62. Epub 2015 Sep 2.

John and Lillian Mathews Center for Cellular Therapy, Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL; Robert H. Lurie Comprehensive Cancer Center, Chicago, IL.

Background: Stem cell transplantation is a treatment option for patients with cancer. However, a risk of adverse events might be associated with the infusion itself. An understanding of the types and grades of adverse events occurring during infusion and the patient and infusion characteristics that might be associated with these events could allow for interventions to minimize these complications. The risk factors associated with transplant-related adverse events are not well understood.

Materials And Methods: We retrospectively analyzed the adverse events occurring within 1 hour after infusion in 460 patients with cancer undergoing stem cell transplantation at the Northwestern University Robert H. Lurie Comprehensive Cancer Center from January 1, 2008 and May 1, 2011. Of the 460 patients, 382 received autologous transplants and 78 allogeneic transplants. The incidence, types, and National Cancer Institute Common Terminology Criteria grade of toxicity for adverse events were noted (primary objective). Univariate analyses were performed to study which patient and infusion characteristics might be associated with the occurrence of adverse events (secondary objectives).

Results: Of the 460 patients, 261 (56.7%) experienced adverse events (66.7% during allogeneic infusion and 54.7% during autologous infusion). Most events were cardiopulmonary. Univariate analysis of the infusion and patient characteristics revealed that a second transplant (P = .005) was associated with more adverse events for autologous transplant patients. For allogeneic transplant patients, a higher infusion red blood cell volume (P = .01) was associated with more adverse events.

Conclusion: Adverse events are common during stem cell infusion and are generally cardiopulmonary.
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http://dx.doi.org/10.1016/j.clml.2015.08.085DOI Listing
November 2015

Immune reconstitution/immunocompetence in recipients of kidney plus hematopoietic stem/facilitating cell transplants.

Transplantation 2015 Feb;99(2):288-98

1 Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, IL. 2 Institute for Cellular Therapeutics, University of Louisville, Louisville, KY. 3 Regenerex, LLC, Louisville, KY.

Nineteen subjects have more than 18 months' follow-up in a phase IIb tolerance protocol in HLA-mismatched recipients of living donor kidney plus facilitating cell enriched hematopoietic stem cell allografts (FCRx). Reduced intensity conditioning preceded a kidney allograft, followed the next day by FCRx. Twelve have achieved stable donor chimerism and have been successfully taken off immunosuppression (IS). We prospectively evaluated immune reconstitution and immunocompetence. Return of CD4 and CD8 T central and effector memory cell populations was rapid. T-cell receptor (TCR) Excision Circle analysis showed a significant proportion of chimeric cells produced were being produced de novo. The TCR repertoires posttransplant in chimeric subjects were nearly as diverse as pretransplant donors and recipients, and were comparable to subjects with transient chimerism who underwent autologous reconstitution. Subjects with persistent chimerism developed few serious infections when off IS. The majority of infectious complications occurred while subjects were still on conventional IS. BK viruria and viremia resolved after cessation of IS and no tissue-invasive cytomegalovirus infections occurred. Notably, although 2 of 4 transiently or nonchimeric subjects experienced recurrence of their underlying autoimmune disorders, none of the chimeric subjects have, suggesting that self-tolerance is induced in addition to tolerance to alloantigen. No persistently chimeric subject has developed donor-specific antibody, and renal function has remained within normal limits. Patients were successfully vaccinated per The American Society for Blood and Marrow Transplantation guidelines without loss of chimerism or rejection. Memory for hepatitis vaccination persisted after transplantation. Chimeric subjects generated immune responses to pneumococcal vaccine. These data suggest that immune reconstitution and immunocompetence are maintained in persistently chimeric subjects.
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http://dx.doi.org/10.1097/TP.0000000000000605DOI Listing
February 2015

Risk of anaphylaxis with repeated courses of rasburicase: a Research on Adverse Drug Events and Reports (RADAR) project.

Drug Saf 2015 Feb;38(2):183-7

Pharmacy Department, Northwestern Memorial Hospital, Chicago, IL, USA.

Background: Rasburicase, a recombinant urate oxidase, is used to rapidly metabolize uric acid in patients with hyperuricaemia. Rasburicase is an immunogenic therapeutic protein, which has been shown to elicit antibody response in 64 % of healthy volunteers within 1-6 weeks after the initial course, with persistent antibodies for over 1 year. Drug labelling indicates that anaphylaxis rarely occurs (in <1 % of patients) after a single course of therapy with rasburicase, but there are no data available on the incidence of anaphylaxis in patients receiving a subsequent rasburicase course.

Objective: The objective of this study was to determine the incidence of anaphylaxis after multiple treatment courses of rasburicase.

Methods: A retrospective chart review was performed on 97 consecutively treated patients who received repeated courses of rasburicase for hyperuricaemia.

Results: None of the 97 patients who were reviewed experienced anaphylaxis during the first rasburicase course; however, six patients (6.2 %) experienced anaphylaxis during a subsequent rasburicase treatment course (p = 0.03).

Conclusion: Anaphylaxis after a second course of rasburicase appears to occur more frequently than described in the US Food and Drug Administration-approved package insert for initial treatment courses. Given the serious nature of anaphylactic events, caution is advised when administering repeated courses of rasburicase.
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http://dx.doi.org/10.1007/s40264-014-0255-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355936PMC
February 2015

F-18 FDG-PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem-cell transplantation for relapsed and refractory Hodgkin lymphoma.

Br J Haematol 2014 Jun 15;165(6):793-800. Epub 2014 Mar 15.

Division of Hematology/Oncology and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Total lymphoid irradiation (TLI) followed by high-dose chemotherapy and autologous haematopoietic stem cell transplant (aHSCT) is an effective strategy for patients with relapsed/refractory classical Hodgkin lymphoma (HL). We report outcomes for patients with relapsed/refractory HL who received TLI followed by high-dose chemotherapy and aHSCT. Pre-transplant fludeoxyglucose positron emission tomography (FDG-PET) studies were scored on the 5-point Deauville scale. Of 51 patients treated with TLI and aHSCT, 59% had primary refractory disease and 63% had active disease at aHSCT. The 10-year progression-free survival (PFS) and overall survival (OS) for all patients was 56% and 54%, respectively. Patients with complete response (CR) by PET prior to aHSCT had a 5-year PFS and OS of 85% and 100% compared to 52% and 48% for those without CR (P = 0·09 and P = 0·007, respectively). TLI and aHSCT yields excellent disease control and long-term survival rates for patients with relapsed/refractory HL, including those with high-risk disease features. Achievement of CR with salvage therapy is a powerful predictor of outcome.
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http://dx.doi.org/10.1111/bjh.12824DOI Listing
June 2014

Dose-intense etoposide-cyclophosphamide without stem cell transplantation for patients with intermediate and high cytogenetic risk primary refractory and relapsed acute myeloid leukemia.

Leuk Res 2013 Aug 4;37(8):872-6. Epub 2013 Jun 4.

Department of Hematology and Oncology, Robert Lurie Cancer Center and Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA .

Dose-intense etoposide-cyclophosphamide (D-I ECy) without stem cell transplantation has been used in salvage regimens for the treatment of resistant acute myeloid leukemia(AML). Previous D-I ECy studies classified AML according to FAB-criteria, before cytogenetic risk was found to be a major determinant of prognosis. Currently the influence of karyotype on response to D-I ECy is unknown. Thus, an observational study was conducted in thirty four patients treated with D-I ECy for resistant AML. The results show this regimen is moderately effective in achieving CR in relapsed AML patients, including those with age >60 and poor cytogenetic risk category.
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http://dx.doi.org/10.1016/j.leukres.2013.05.006DOI Listing
August 2013

Recurrent aleukemic leukemia cutis in a patient with pre-B-cell acute lymphoblastic leukemia.

J Clin Oncol 2013 Jul 3;31(20):e353-5. Epub 2013 Jun 3.

Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N St Clair, Suite 1600, Chicago, IL 60611, USA.

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http://dx.doi.org/10.1200/JCO.2012.46.1939DOI Listing
July 2013

Idarubicin appears equivalent to dose-intense daunorubicin for remission induction in patients with acute myeloid leukemia.

Leuk Res 2013 Aug 31;37(8):868-71. Epub 2013 May 31.

Department of Hematology and Oncology, Robert Lurie Cancer Center and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Daunorubicin has historically been considered the anthracycline of choice at many cancer centers for the treatment of acute myeloid leukemia (AML). Drug shortages have required the substitution of daunorubicin with idarubicin. Randomized studies have shown idarubicin (10-12mg/m(2)) to be comparable or superior to standard dose daunorubicin (45-60mg/m(2)) for achieving complete remission (CR). Whether these results can be extrapolated to dose-intense daunorubicin (90mg/m(2)), recently shown to improve CR rates when compared to standard daunorubicin doses remains uncertain. This observational study was conducted at Northwestern Memorial Hospital (NMH) to compare CR rates. The results suggest idarubicin is equivalent to daunorubicin, and for some subsets of patients, idarubicin may have superior CR rates.
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http://dx.doi.org/10.1016/j.leukres.2013.04.009DOI Listing
August 2013

Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis.

J Immunol 2013 Mar 13;190(6):2966-75. Epub 2013 Feb 13.

Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Epigenetic changes play important roles in carcinogenesis and influence initial steps in neoplastic transformation by altering genome stability and regulating gene expression. To characterize epigenomic changes during the transformation of normal plasma cells to myeloma, we modified the HpaII tiny fragment enrichment by ligation-mediated PCR assay to work with small numbers of purified primary marrow plasma cells. The nano-HpaII tiny fragment enrichment by ligation-mediated PCR assay was used to analyze the methylome of CD138(+) cells from 56 subjects representing premalignant (monoclonal gammopathy of uncertain significance), early, and advanced stages of myeloma, as well as healthy controls. Plasma cells from premalignant and early stages of myeloma were characterized by striking, widespread hypomethylation. Gene-specific hypermethylation was seen to occur in the advanced stages, and cell lines representative of relapsed cases were found to be sensitive to decitabine. Aberrant demethylation in monoclonal gammopathy of uncertain significance occurred primarily in CpG islands, whereas differentially methylated loci in cases of myeloma occurred predominantly outside of CpG islands and affected distinct sets of gene pathways, demonstrating qualitative epigenetic differences between premalignant and malignant stages. Examination of the methylation machinery revealed that the methyltransferase, DNMT3A, was aberrantly hypermethylated and underexpressed, but not mutated in myeloma. DNMT3A underexpression was also associated with adverse overall survival in a large cohort of patients, providing insights into genesis of hypomethylation in myeloma. These results demonstrate widespread, stage-specific epigenetic changes during myelomagenesis and suggest that early demethylation can be a potential contributor to genome instability seen in myeloma. We also identify DNMT3A expression as a novel prognostic biomarker and suggest that relapsed cases can be therapeutically targeted by hypomethylating agents.
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http://dx.doi.org/10.4049/jimmunol.1202493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581585PMC
March 2013

Changing epidemiology of Clostridium difficile-associated disease during stem cell transplantation.

Biol Blood Marrow Transplant 2013 Mar 4;19(3):405-9. Epub 2012 Dec 4.

Feinberg School of Medicine, Northwestern University, 250 E. Superior Street, Chicago, IL 60611, USA.

The incidence and severity of Clostridium difficile-associated disease (CDAD) within the general population has risen dramatically over the past decade, yet little data are available from hematopoietic stem cell transplantation (HSCT) centers. In the present study, we performed a chart review of 822 consecutive autologous and allogeneic HCST recipients treated at Northwestern Memorial Hospital between 2004 and 2008 to determine the incidence of CDAD at our institution. Variables including age, sex, diagnosis, chemotherapy regimen, transplantation type, microbial colonization, coinfections, diet, antibiotic use, neutropenic fever, comorbid conditions, time to engraftment, growth factor administration, and occurrence of graft-versus-host disease were assessed as potential risk factors for the development of CDAD. Eighty-five CDAD cases (10.3%) were identified. Bivariate analysis revealed a significant association between CDAD and neutropenic fever, administration of a neutropenic diet, ciprofloxacin and aztreonam use and duration of therapy, vancomycin and aztreonam use and duration of therapy, receipt of an allogeneic transplantation, bacterial coinfection, and vancomycin-resistant Entereococcus faecium (VRE) colonization. Cox regression analysis identified the following as factors associated with the development of CDAD: age >60 years, allogeneic transplantation, and prior VRE colonization. Allogeneic recipients with CDAD experienced increased higher rates of grades II to IV gastrointestinal graft-versus-host disease and nonrelapse mortality. A risk stratification model was developed to identify HSCT recipients at different levels of risk. With an incidence >10%, CDAD is a significant infectious complication of stem cell transplantation.
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http://dx.doi.org/10.1016/j.bbmt.2012.10.030DOI Listing
March 2013

Variability of cyclosporine concentrations by HPLC and TDX monoclonal assay methods, application of a correction factor, and description of a novel clinical approach to determine the practical consequences of changing assay technique.

Clin Transplant 2013 Jan-Feb;27(1):154-61. Epub 2012 Oct 29.

Northwestern Memorial Hospital, Chicago, IL 60611, USA.

Cyclosporine (CSA) is an immunosuppressant used for the prevention of graft rejection and graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation. Therapeutic drug monitoring (TDM) is recommended to ensure efficacy and prevent toxicity. Several immunoassay assay are commercially available for measuring CSA drug concentrations. Differences in the cross-reactive metabolites measured by specific immunoassay tests contribute to the significant lack of specificity which has been reported between immunoassays and high performance liquid chromatography (HPLC) test results. Inter-assay test results can affect interpretation of CSA drug concentrations and potentially compromise patient outcomes. The current study analyzed 72 paired HPLC-monoclonal TDX (TDXm) CSA drug concentrations and calculated a clinically reliable correction factor which could be applied to HPLC-TDXm results for TDM. A unique concordance-discordance simulation model was utilized to validate the correction factor for clinical use.
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http://dx.doi.org/10.1111/ctr.12037DOI Listing
July 2013

Latexin is down-regulated in hematopoietic malignancies and restoration of expression inhibits lymphoma growth.

PLoS One 2012 27;7(9):e44979. Epub 2012 Sep 27.

Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA.

Latexin is a negative regulator of hematopoietic stem cell number in mice. Its dysregulated expression in other tumors led us to hypothesize that latexin may have tumor suppressor properties in hematological malignancies. We found that latexin was down-regulated in a variety of leukemia and lymphoma cell lines as well as in CD34+ cells from the blood and marrow of patients with these malignancies. 5-aza-2'-deoxycytodine treatment and bisulfite sequencing revealed hypermethylation of latexin promoter in tumor cells. Retrovirus-mediated latexin overexpression in A20 mouse lymphoma cells inhibited their in vitro growth by 16 fold and in vivo tumor volume by 2 fold. Latexin caused growth inhibition of lymphoma cells by significantly increasing apoptosis through the down-regulation of anti-apoptotic genes Bcl-2 and Pim-2. The molecular mechanism underlying latexin-mediated tumor inhibition was not through its canonical carboxypeptidase inhibitor activity. These results are consistent with a tumor suppressor role for latexin and suggest that latexin may have clinical efficacy in the treatment of malignancies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044979PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459965PMC
February 2013

Diffuse large B-cell lymphoma: is there a place for autologous hematopoietic stem cell transplant in first remission in the era of chemo-immunotherapy?

Leuk Lymphoma 2012 Oct 16;53(10):1859-66. Epub 2012 May 16.

Oncology Specialists, SC and Division of Hematology/Oncology, Department of Medicine, Advocate Lutheran General Hospital, Park Ridge, IL 60068, USA.

While rituximab-based chemo-immunotherapy has improved response and long-term survival rates in diffuse large B-cell non-Hodgkin lymphoma (DLBCL), relapse and death from recurrent disease is still the eventual outcome in a significant proportion of patients, especially those with high-risk disease. Autologous hematopoietic stem cell transplant (AHSCT) in first remission, which was studied mainly before the advent of rituximab, has lost its appeal due to several small negative trials. However, definitive data do not exist to determine the role of AHSCT in first remission. In this review, we critically evaluate studies investigating AHSCT in DLBCL in first remission. Most available studies have shortcomings that limit the applicability of their findings. AHSCT in first remission may have a role in selected patients with high-risk DLBCL, but a carefully designed prospective study is required to appropriately evaluate this concept.
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http://dx.doi.org/10.3109/10428194.2012.679265DOI Listing
October 2012