Publications by authors named "Borje S Andersson"

111 Publications

Myeloablative Fractionated Busulfan With Fludarabine in Older Patients: Long Term Disease-Specific Outcomes of a Prospective Phase II Clinical Trial.

Transplant Cell Ther 2021 Jul 28. Epub 2021 Jul 28.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients because of higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for 6 days over a 2-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80 mg/m busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40 mg/m and busulfan IV once daily. The dosing of busulfan was determined from pharmacokinetic analyses to achieve for the course a target area under the curve of 20,000 ± 12% μmol/min, which is close to the average exposure of myeloablative dose of busulfan. One hundred fifty patients with high-risk hematological malignancies up to 75 years were enrolled in this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N = 59 [39.3%]), myelodysplastic syndrome (MDS; n = 29 [19.3%]), and myelofibrosis (MF; N = 22 [14.7%]). Most had an unrelated donor (n = 93 [62%]) and received peripheral blood graft (n = 110 [73.3%]). Over half had an HCT-specific comorbidity index of ≥3 (n = 79 [52.7%]). The median follow-up among survivors was 43.4 months (interquartile range, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3-year overall survival was 66.7% (95% confidence interval [CI], 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancy was 8.7% (95% CI, 4.1-13.2%) at 3 years. Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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http://dx.doi.org/10.1016/j.jtct.2021.07.021DOI Listing
July 2021

T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors.

J Hematol Oncol 2021 06 30;14(1):102. Epub 2021 Jun 30.

Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

T-cell receptor (TCR)-based adoptive therapy employs genetically modified lymphocytes that are directed against specific tumor markers. This therapeutic modality requires a structured and integrated process that involves patient screening (e.g., for HLA-A*02:01 and specific tumor targets), leukapheresis, generation of transduced TCR product, lymphodepletion, and infusion of the TCR-based adoptive therapy. In this review, we summarize the current technology and early clinical development of TCR-based therapy in patients with solid tumors. The challenges of TCR-based therapy include those associated with TCR product manufacturing, patient selection, and preparation with lymphodepletion. Overcoming these challenges, and those posed by the immunosuppressive microenvironment, as well as developing next-generation strategies is essential to improving the efficacy and safety of TCR-based therapies. Optimization of technology to generate TCR product, treatment administration, and patient monitoring for adverse events is needed. The implementation of novel TCR strategies will require expansion of the TCR approach to patients with HLA haplotypes beyond HLA-A*02:01 and the discovery of novel tumor markers that are expressed in more patients and tumor types. Ongoing clinical trials will determine the ultimate role of TCR-based therapy in patients with solid tumors.
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http://dx.doi.org/10.1186/s13045-021-01115-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243554PMC
June 2021

Eltrombopag for Post-Transplantation Thrombocytopenia: Results of Phase II Randomized, Double-Blind, Placebo-Controlled Trial.

Transplant Cell Ther 2021 05 6;27(5):430.e1-430.e7. Epub 2021 Feb 6.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Prolonged thrombocytopenia occurs in up to 37% of patients after hematopoietic stem cell transplantation (HSCT) and is associated with adverse prognosis and increased risk of bleeding. Eltrombopag, a thrombopoietin receptor agonist, can increase platelet counts in thrombocytopenic patients. We conducted a phase II study, adaptively randomizing patients at ≥35 days post-HSCT to receive placebo or eltrombopag at a platelet count ≤20,000/µL for 7 days or platelet transfusion-dependent and a neutrophil count ≥1500/µL. Sixty patients were randomized to eltrombopag (n = 42) or placebo (n = 18) and received at least 1 dose. Fifteen patients (36%) in the eltrombopag arm achieved a platelet count of ≥30,000/µL, compared with 5 patients (28%) in the placebo arm, with a posterior probability of 0.75. (The protocol required this probability to be >0.975 to declare a winner; thus, the results are inconclusive.) However, 9 patients (21%) in the eltrombopag arm achieved a platelet count of ≥50,000/µL, compared with no patients in the placebo arm (P = .046). The overall survival, progression-free survival, relapse rate, and nonrelapse mortality were similar in the 2 arms. In conclusion, compared with placebo, treatment with eltrombopag led to a higher percentage of patients achieving a platelet count of ≥50,000/µL in patients with persistent thrombocytopenia after HSCT.
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http://dx.doi.org/10.1016/j.jtct.2021.02.004DOI Listing
May 2021

Impact of Cell of Origin Classification on Survival Outcomes after Autologous Transplantation in Relapsed/Refractory Diffuse Large B Cell Lymphoma.

Transplant Cell Ther 2021 05 12;27(5):404.e1-404.e5. Epub 2021 Feb 12.

Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

The cell of origin (COO) classification into germinal center B cell (GCB) and non-GCB types has been shown to predict survival outcomes in newly diagnosed diffuse large B cell lymphoma (DLBCL). In the relapsed/refractory (R/R) setting, there is building evidence that COO does not predict prognosis after high-dose chemotherapy and autologous stem cell transplantation (auto-SCT). The present analysis aimed to compare survival outcomes based on COO classification in R/R DLBCL patients who underwent auto-SCT. This retrospective study included adult patients with R/R DLBCL who underwent auto-SCT at MD Anderson Cancer Center between January 2007 and December 2016. The Hans algorithm using CD10, BCL6, and MUM1 markers was used to classify patients by COO. A total of 122 patients with DLBCL (71 GCB, 51 non-GCB) were included in the analysis. There were no significant differences in patient characteristics between the 2 groups, except for older median age in the GCB cohort (64 years versus 58 years; P < .004). The median overall survival (OS) time was 68.5 (95% confidence interval [CI], 51.3 to not reached) months for the total population, 68.5 (95% CI, 44.8 to not reached) for GCB, and not reached for non-GCB. The 3-year OS rate was 0.659 (95% CI, 0.575 to 0.755) for the total population, 0.653 (95% CI, 0.547 to 0.779) for GCB, and 0.666 (95% CI, 0.537 to 0.824) for non-GCB. When adjusted for age and other factors of interest, no statistically significant associations for OS or progression-free survival were observed between the 2 cohorts. Our results confirm that COO loses its prognostic potential in patients with R/R DLBCL who receive high-dose chemotherapy followed by auto-SCT and both GCB and non-GCB types of DLBCL derive similar benefit from auto-SCT. Younger age, female sex, and pretransplantation disease status were associated with better OS.
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http://dx.doi.org/10.1016/j.jtct.2021.02.009DOI Listing
May 2021

Improved outcomes of high-risk relapsed Hodgkin lymphoma patients after high-dose chemotherapy: a 15-year analysis.

Haematologica 2021 May 6. Epub 2021 May 6.

Nuclear Medicine at the University of Texas MD Anderson Cancer Center.

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment of chemosensitive relapsed classical Hodgkin lymphoma (cHL), although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR cHL patients treated with HDC/ASCT at our institution between 01/01/2005-12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring > 1 salvage line, or PET+ disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (N=146), BuMel (N=38), GemBuMel (N=189) and vorinostat/GemBuMel (N=128). The GemBuMel and vorinostat/GemBuMel cohorts had more HRR criteria and more patients with PET+ disease at ASCT. Pre-ASCT BV, anti-PD1, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). Median follow-up is 50 months (6-186). Outcomes improved over time, with 2-year PFS/OS rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016-2019) (P.
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http://dx.doi.org/10.3324/haematol.2021.278311DOI Listing
May 2021

Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy for Hemorrhagic Cystitis Following Allotransplantation.

J Clin Oncol 2021 Aug 30;39(24):2710-2719. Epub 2021 Apr 30.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option.

Methods: We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed.

Results: Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement.

Conclusion: Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.
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http://dx.doi.org/10.1200/JCO.20.02608DOI Listing
August 2021

Acute graft-versus-host disease is the foremost cause of late nonrelapse mortality.

Bone Marrow Transplant 2021 08 12;56(8):2005-2012. Epub 2021 Apr 12.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Despite low nonrelapse mortality (NRM) at day 100 after allogeneic hematopoietic cell transplantation (HCT), NRM at 1 year remains substantial. In this study, we retrospectively analyzed 199 patients who were treated on a phase II clinical trial assessing safety and efficacy of myeloablative fractionated busulfan and fludarabine conditioning regimen for hematologic malignancies. The goal of the study was to identify factors associated with NRM occurring between days 101 and 365 post-HCT and generate a hypothesis for future studies to reduce the risk of NRM at 1 year. We found that a vast majority (83%) of patients who experienced NRM between days 101 and 365 had prior grade II-IV acute graft-versus-host disease (GVHD), which was the leading cause of death either by itself (33.3%) or complicated by infections (37.5%). In multivariate analysis, grade II-IV acute GVHD (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.6, p = 0.01) was the only significant predictor of NRM between days 101 and 365. Measures to reduce the risk of acute GVHD could lower the risk of NRM at 1 year and improve overall survival.
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http://dx.doi.org/10.1038/s41409-021-01274-1DOI Listing
August 2021

Low-dose decitabine as part of a modified Bu-Cy conditioning regimen improves survival in AML patients with active disease undergoing allogeneic hematopoietic stem cell transplantation.

Bone Marrow Transplant 2021 07 26;56(7):1674-1682. Epub 2021 Feb 26.

Department of Stem Cell Transplantation & Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX, USA.

Relapse is the major cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Effective preventive intervention in high-risk AML may be crucial. In this study, we investigated the clinical efficacy and safety of low dose decitabine (DAC) as part of a modified Busulfan-Cyclophosphamide (Bu-Cy) regimen for high-risk AML patients undergoing allo-HSCT to reduce relapse rate. Fifty-nine patients received DAC (20 mg/m/d, i.v.) for 5 days, followed by modified Bu-Cy (DAC group). A matched-pair control (CON) group of 177 patients (matched 1:3) received modified Bu-Cy only. The differences were more substantial among patients with active disease: 2-year OS, 80.7% (DAC) versus 43.5% (CON), P = 0.011 and 2-year LFS, 64.9% (DAC) versus 39.2% (CON), P = 0.024. Median time to relapse was 8 months (DAC) versus 5 months (CON) for the entire groups and 6.5 months (DAC) versus 3.5 months (CON) for patients with active disease. In summary, our data indicated that the conditioning regimen containing low dose DAC may confer a survival advantage in high-risk AML patients with active disease undergoing allo-HSCT, and a prospective randomized trial is warranted to confirm these observations.
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http://dx.doi.org/10.1038/s41409-021-01238-5DOI Listing
July 2021

Fractionated busulfan myeloablative conditioning improves survival in older patients with acute myeloid leukemia and myelodysplastic syndrome.

Cancer 2021 May 20;127(10):1598-1605. Epub 2021 Jan 20.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown.

Methods: Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 μmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 μmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival.

Results: Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01).

Conclusions: A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.
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http://dx.doi.org/10.1002/cncr.33383DOI Listing
May 2021

Production and characterization of haploidentical CD19 CAR T cells: Validated to induce a continuous complete remission in a patient with relapsed refractory B-cell ALL.

Asia Pac J Clin Oncol 2020 Sep 24. Epub 2020 Sep 24.

Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

Aims: The purpose of this study was to design and manufacture CD19 chimeric antigen receptor (CAR)-modified T cells for clinical use in Thailand, as a model for how this technology can be directly applied at individual institutions treating high-risk leukemia patients.

Methods: We constructed second-generation CAR T cells expressing CD19 scFV-CD28-CD3ζ with different lengths of the spacer region: full, intermediate, and short length, by using a lentiviral vector. We wanted to determine whether the difference in length of the spacer would affect the cytotoxic potential of the CD19 CAR T cells against the leukemic cells.

Results: We found that all constructs of CD19 CAR T cells exhibited a similar level of cytotoxicity against several human lymphoma and leukemia cell lines. For the clinical application, we chose the intermediate length spacer construct CD19 CAR T cells, hypothesizing that the highest transduction efficiency coupled with a slower initial proliferation in vitro might lead to effective leukemic cell kill, yet a lower probability for serious clinical side effects. We then tested the clinical efficacy of our CD19 CAR T cells in one patient with refractory/relapsed acute B-cell lymphoblastic leukemia. This patient indeed had minimal clinical side effects after the CAR T-cell infusion, and he remains in an unmaintained, ongoing complete remission 10+ months after his T-cell treatment.

Conclusion: Our CD19 CAR T cells demonstrated efficacies in acute lymphoblastic B-cell leukemia, and will be used to establish an immunotherapeutic program for high-risk B-cell acute lymphoblastic leukemia in Thailand. We propose that this approach can be used as a model for how this new exciting technology can be applied directly at individual institutions that treat (a large number of) patients with high-risk leukemia.
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http://dx.doi.org/10.1111/ajco.13474DOI Listing
September 2020

Targeted-dose of busulfan: Higher risk of sinusoidal obstructive syndrome observed with systemic exposure dose above 5000 µMol⸱min. A historically controlled clinical trial.

Hematol Oncol 2020 Dec 28;38(5):773-781. Epub 2020 Sep 28.

Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.

Busulfan is given in the conditioning regimens preceding hematopoietic stem cell transplantation (HSCT), and plasma levels can be monitored. A targeted, individualized systemic exposure (SE) dose can be achieved by calculating the area under the plasma concentration versus time curve (AUC). The objective of this study was to determine a cutoff value for safety for the AUC for busulfan plasma levels in patients undergoing HSCT. A total of 149 consecutive HSCT patients were studied. After an oral test dose of busulfan, we set target doses of 4000, 5000, or 6000 µMol⸱min/day, and analyzed the AUC of oral or intravenous Bu. These patients were compared with 53 historical control subjects who had received myeloablative conditioning regimen without busulfan pharmacokinetic monitoring. Using a test dose and the administration route had no impact on the sinusoidal obstructive syndrome (SOS) incidence, transplant-related mortality or 1-year overall survival. However, patients receiving busulfan at doses set up at AUC > 5000 had an increased risk to develop SOS after HSCT (hazard ratio 3.39, p = 0.034, 95% CI 1.09-10.52). Adjusting the busulfan dose according to SE levels target dose during conditioning is associated with lower rates of oral severe mucositis and SOS. A cutoff of 5000 µMol⸱min is safe and does not impair survival.
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http://dx.doi.org/10.1002/hon.2789DOI Listing
December 2020

Cytogenetics and Blast Count Determine Transplant Outcomes in Patients with Active Acute Myeloid Leukemia.

Acta Haematol 2021 30;144(1):74-81. Epub 2020 Jun 30.

Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.
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http://dx.doi.org/10.1159/000507012DOI Listing
March 2021

Development and validation of a risk assessment tool for BKPyV Replication in allogeneic stem cell transplant recipients.

Transpl Infect Dis 2020 Oct 14;22(5):e13395. Epub 2020 Jul 14.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: BK polymavirus (BKPyV), a member of the family Polyomaviridae, is associated with increased morbidity and mortality in allogeneic stem cell transplant recipients.

Methods: In our previous retrospective study of 2477 stem cell transplant patients, BKPyV replication independently predicted chronic kidney disease and poor survival. In this study, using the same cohort, we derived and validated a risk grading system to identify patients at risk of BKPyV replication after transplantation in a user-friendly modality. We used 3 baseline variables (conditioning regimen, HLA match status, and underlying cancer diagnosis) that significantly predicted BKPyV replication in our initial study in a subdistribution hazard model with death as a competing risk. We also developed a nomogram of the hazard model as a visual aid. The AUC of the ROC of the risk-score-only model was 0.65. We further stratified the patients on the basis of risk score into low-, moderate-, and high-risk groups.

Results: The total risk score was significantly associated with BKPyV replication (P < .0001). At 30 days after transplantation, the low-risk (score ≤ 0) patients had a 9% chance of developing symptomatic BKPyV replication, while the high-risk (score ≥ 8) of the population had 56% of developing BKPyV replication. We validated the risk score using a separate cohort of 1478 patients. The AUC of the ROC of the risk-score-only model was 0.59. Both the total risk score and 3-level risk variable were significantly associated with BKPyV replication in this cohort (P < .0001).

Conclusions: This grading system for the risk of symptomatic BKPyV replication may help in early monitoring and intervention to prevent BKPyV-associated morbidity, mortality, and kidney function decline.
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http://dx.doi.org/10.1111/tid.13395DOI Listing
October 2020

Optimizing the Conditioning Regimen for Hematopoietic Cell Transplant in Myelofibrosis: Long-Term Results of a Prospective Phase II Clinical Trial.

Biol Blood Marrow Transplant 2020 08 11;26(8):1439-1445. Epub 2020 May 11.

Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m/day on days -3 and -2 ("low dose"); 31 patients received high-dose conditioning, either 100 mg/m/day (days -5 to -2; n = 4) or pharmacokinetic-guided area under the curve of 4000 μmol/min (days -5 to -2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.
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http://dx.doi.org/10.1016/j.bbmt.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547798PMC
August 2020

Letter to the Editor Regarding "Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement".

Biol Blood Marrow Transplant 2020 09 11;26(9):e232-e234. Epub 2020 May 11.

Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1016/j.bbmt.2020.03.022DOI Listing
September 2020

Idiopathic refractory ascites after allogeneic stem cell transplantation: a previously unrecognized entity.

Blood Adv 2020 04;4(7):1296-1306

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.

At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)-related portal hypertension after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient [HVPG] >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension. From our institutional database, we identified 40 patients who developed IRA after allo-HSCT between 2004 and 2018. The patients' median age at the time of allo-HSCT was 54 years (range, 21-73 years). The median time to development of IRA after allo-HSCT was 80 days (range, 16-576 days). The median number of paracentesis was 3 (range, 1-11), and 15 (38%) patients had an intraperitoneal catheter placed for continued drainage of the rapidly accumulating ascites. Portal pressures were measured in 19 patients; 6 (15%) had moderate portal hypertension (HVPG 6-9 mm Hg), and 13 (33%) had severe portal hypertension (HVPG ≥ 10 mm Hg). Liver biopsy was performed in 24 patients. None of the patients met the criteria for classical VOD/SOS (clinical/histological) or cirrhosis (histological). The cumulative incidence of nonrelapse mortality was 63%, and the median survival duration after the development of the IRA was 7 months (range, 0.8-125.6 months). IRA is a poorly understood and often fatal complication of allo-HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2019000638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160275PMC
April 2020

Panobinostat and venetoclax enhance the cytotoxicity of gemcitabine, busulfan, and melphalan in multiple myeloma cells.

Exp Hematol 2020 01 15;81:32-41. Epub 2020 Jan 15.

Department of Stem Cell Transplantation & Cellular Therapy, University of Texas M. D. Anderson Cancer Center, Houston, TX.

Gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) are used for hematopoietic stem cell transplantation. To further improve their efficacy, a preclinical study on their synergism with the histone deacetylase inhibitor panobinostat (Pano) and the BCL2 inhibitor venetoclax/ABT199 was performed. Multiple myeloma cell lines MM.1R and MC/CAR were exposed to ∼IC levels of the drugs. Synergistic cytotoxicity was observed in cells exposed to the five-drug combination as indicated by combination indexes <1, supported by ∼86% inhibition of proliferation and ∼84% annexin V positivity in MM.1R and ∼58% inhibition of proliferation and ∼46% annexin V positivity in MC/CAR cells. Activation of the DNA damage response and apoptosis were suggested by a modest increase in the phosphorylation of ATM and its substrates; significant cleavage of PARP1, caspase 3, and heat shock protein 90; DNA fragmentation; mitochondrial membrane depolarization; and reactive oxygen species production. The five-drug combination significantly decreased the levels of PI3K, AKT, mTOR, RAPTOR, P-P70S6K, and eIF2α, with concomitant increases in P-AMPK and its substrate Tuberin/TSC2, suggesting that the mTOR signaling pathway was compromised. Endoplasmic reticulum stress through activation of the unfolded protein response was also observed as suggested by increases in the levels of calnexin, BiP/GRP78, ERO1-Lα, and protein disulfide isomerase, which may relate to venetoclax-mediated inhibition of BCL2 in the endoplasmic reticulum. This is the first report on the effects of a venetoclax-containing regimen on the unfolded protein response. These results provide a rationale to propose a clinical trial on use of Gem + Bu + Mel + Pano + Venetoclax as part of a conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1016/j.exphem.2020.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023992PMC
January 2020

Hematopoietic Stem Cell Transplantation for Severe Thalassemia Patients from Haploidentical Donors Using a Novel Conditioning Regimen.

Biol Blood Marrow Transplant 2020 06 11;26(6):1106-1112. Epub 2020 Jan 11.

Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.

Patients with severe thalassemia commonly have a survival that is significantly shorter than that of the general population. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pretransplant immune suppression phase (PTIS) and 2 courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine-i.v. busulfan and post-transplant graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia (median age, 12 years; range, 1 to 28 years) with a minimum follow-up of 6 months (median, 15 months; range, 7 to 53 months); the 3-year projected overall and event-free survival is over 96%, and there have been no secondary graft failures. Of the first 31 patients, we had 2 graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific HLA antibodies (anti-DSAs), but after adjusting the PTIS to include bortezomib and rituximab for patients with high titers of anti-DSAs and using pharmacologic dose guidance for busulfan, we had no graft failures in the last 52 patients. Six (7%) of 83 patients developed severe GVHD. We conclude that this is a safe and efficacious approach to allogeneic SCT in thalassemia, yielding results comparable to those available for patients with fully matched donors.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.002DOI Listing
June 2020

CMV-Reactive NK Cells in Pediatric Post-Hematopoietic Stem Cell Transplant.

Transplant Proc 2020 Jan - Feb;52(1):353-359. Epub 2019 Dec 20.

Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.

Background: Immune reconstitution of T cells has been proven to be a protective factor against cytomegalovirus (CMV) reactivation in patients post-hematopoietic stem cell transplant. Recently, more evidence has suggested that natural killer (NK) cells also play role in the protection against CMV reactivation in these patients.

Methods: CMV-specific T cells and CMV-reactive NK cells from pediatric patients undergoing hematopoietic stem cell transplant were examined by flow cytometry. These cells were defined as cells producing interferon gamma (IFNγ) upon stimulation with CMV antigens.

Results: This study demonstrated that NK cells reactive to CMV do exist in pediatric patients after stem cell transplant. These cells vigorously responded to stimulation with CMV peptides (pp65 and IE1) and to a lesser extent to CMV whole lysate by secretion of IFNγ. Patients with CMV reactivation tended to have less CMV-reactive NK cells than those without.

Conclusion: Reconstitution of CMV-reactive NK cells, together with CMV-specific T cells, may play a role in the control of CMV infections in patients after stem cell transplant.
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http://dx.doi.org/10.1016/j.transproceed.2019.11.010DOI Listing
July 2020

Bayesian non-parametric survival regression for optimizing precision dosing of intravenous busulfan in allogeneic stem cell transplantation.

J R Stat Soc Ser C Appl Stat 2019 Apr 16;68(3):809-828. Epub 2018 Dec 16.

Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, USA.

Allogeneic stem cell transplantation (allo-SCT) is now part of standard of care for acute leukemia (AL). To reduce toxicity of the pre-transplant conditioning regimen, intravenous busulfan is usually used as a preparative regimen for AL patients undergoing allo-SCT. Systemic busulfan exposure, characterized by the area under the plasma concentration versus time curve (AUC), is strongly associated with clinical outcome. An AUC that is too high is associated with severe toxicities, while an AUC that is too low carries increased risks of disease recurrence and failure to engraft. Consequently, an optimal AUC interval needs to be determined for therapeutic use. To address the possibility that busulfan pharmacokinetics and pharmacodynamics vary significantly with patient characteristics, we propose a tailored approach to determine optimal covariate-specific AUC intervals. To estimate these personalized AUC intervals, we apply a flexible Bayesian nonparametric regression model based on a dependent Dirichlet process and Gaussian process, DDP-GP. Our analyses of a dataset of 151 patients identified optimal therapeutic intervals for AUC that varied substantively with age and whether the patient was in complete remission or had active disease at transplant. Extensive simulations to evaluate the DDP-GP model in similar settings showed that its performance compares favorably to alternative methods. We provide an R package, DDPGPSurv, that implements the DDP-GP model for a broad range of survival regression analyses.
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http://dx.doi.org/10.1111/rssc.12331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714050PMC
April 2019

Pharmacokinetics analysis results are similar for oral compared to intravenous busulfan in patients undergoing hematopoietic stem cell transplantation, except for the earlier onset of mucositis. A controlled clinical study.

Bone Marrow Transplant 2019 11 14;54(11):1799-1804. Epub 2019 May 14.

Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH, USA.

Busulfan is used in myeloablative schemes for hematopoietic stem cell transplantation (HSCT), with monitoring of dosage through the area under the curve (AUC) of the drug plasma concentration (µMol min). In this study, we compared the complete pharmacokinetics of busulfan administered orally (Bu-Oral) and intravenously (Bu-IV). We evaluated 40 patients who underwent HSCT with different types of conditioning regimens. After one dose, in the Bu-Oral group (n = 21), the median AUC was 1174 µMol min (799-4000), reaching a median of 4440 µMol min (3428-7181.5) during conditioning in 24 h. In the Bu-IV group (n = 19), it was 1244.8 µMol min (1001.2-2021), reaching 5598.0 µMol min (3102-8818) during conditioning in 24 h. Measuring plasma concentration of Bu in patients undergoing HSCT is important, regardless of the formulation, and the inclusion of a pre-HSCT test can predict the optimal dose during conditioning. Pharmacokinetics of the oral administration of busulfan, as well as clearance, are extremely variable, and this can potentially compromise the clinical results of the treatment since it makes it difficult to predict clinical results.
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http://dx.doi.org/10.1038/s41409-019-0521-5DOI Listing
November 2019

Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial.

Lancet Haematol 2019 May 22;6(5):e266-e275. Epub 2019 Mar 22.

Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.

Background: Retrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial.

Methods: The primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m followed by pharmacokinetically adjusted doses on days -7, -6, -5, and -4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m per day on days -2 and -1 (total melphalan dose 140 mg/m), or a melphalan dose of 200 mg/m on day -2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov, number NCT01413178.

Findings: Between Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22·6 months (IQR 15·2-47·1) and 20·2 months (IQR 8·8-46·6) in the melphalan alone group. Median progression-free survival was 64·7 months (32·9-64·7) with busulfan plus melphalan versus 43·5 months (19·9-not estimated) with melphalan alone (hazard ratio 0·53 [95% CI 0·30-0·91]; p=0·022). There were no treatment-related deaths by day 100 in either group. Grade 2-3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group.

Interpretation: These findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma.

Funding: This study was funded in part by the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant (CA016672).
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http://dx.doi.org/10.1016/S2352-3026(19)30023-7DOI Listing
May 2019

Pharmacokinetics: Unique Challenges in Blood Monitoring for Oncology Nurses.

Clin J Oncol Nurs 2019 04;23(2):191-196

University of Texas Health Sciences Center.

Background: Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion of drugs. Many chemotherapeutic agents have a sensitive PK index, in which a small margin in blood concentrations is the difference between nontherapeutic, therapeutic, and adverse outcomes.

Objectives: This article will provide an overview of evidence-based approaches to the collection of PK samples, monitoring of PK levels, and the resulting management of patients undergoing PK testing.

Methods: A case study involving busulfan, an alkylating agent used in the pre-stem cell transplantation setting, will highlight the cross-contamination of samples while a drug is being infused through a central venous catheter with PK sample collection from a proximal peripherally inserted central catheter. The influence of false elevations in drug concentrations on PK-guided dose adjustments will also be emphasized.

Findings: Imprecise blood collections or cross-contamination of samples may lead to inaccurate drug concentration results and, subsequently, undesired low or high drug dosage calculations.
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http://dx.doi.org/10.1188/19.CJON.191-196DOI Listing
April 2019

Reduced intensity vs. myeloablative conditioning with fludarabine and PK-guided busulfan in allogeneic stem cell transplantation for patients with AML/MDS.

Bone Marrow Transplant 2019 08 10;54(8):1245-1253. Epub 2018 Dec 10.

The Departments of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Conditioning regimens contribute significantly to outcomes following allogeneic stem cell transplantation (allo-SCT). Reduced-intensity conditioning (RIC) regimens provide lower toxicity at the cost of reduced efficacy compared with myeloablative conditioning (MAC) regimens. However, because pre-transplant prognostic variables often determine the conditioning regimen, studies of RIC vs. MAC have been inconclusive. We present a retrospective analysis of 242 acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients, 112 of whom were in 56 pairs matched using propensity scores, to account for variation that may confound clinical outcomes. The uniform conditioning regimens consisted of fludarabine with pharmacokinetic (PK)-guided intravenous busulfan (Bu). The RIC and MAC regimens were dosed at the average daily area under the concentration-vs-time curve (AUC) of 4000 µMol min and 5000-6000 µMol min, or total course AUC of 16,000 µMol min and 20,000-24,000 µMol min, respectively; PK-guided dosing removes overlap in systemic Bu exposure. When patients' data were propensity-matched, there was a trend toward significantly increased full donor chimerism and decreased chronic graft vs. host disease in RIC, and no significant differences in progression free survival and overall survival between RIC and MAC. Our results also elucidate the efficacy of PK-guided-dosing in the setting of allo-SCT for AML and MDS.
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http://dx.doi.org/10.1038/s41409-018-0405-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557700PMC
August 2019

Fludarabine with a higher versus lower dose of myeloablative timed-sequential busulfan in older patients and patients with comorbidities: an open-label, non-stratified, randomised phase 2 trial.

Lancet Haematol 2018 Nov;5(11):e532-e542

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Haemopoietic stem-cell transplantation (HCT) conditioning regimens that can reduce risk of relapse without increasing non-relapse mortality are needed. We aimed to test the safety of timed-sequential delivery of low-dose versus high-dose myeloablative busulfan in older patients and patients with comorbidities.

Methods: This non-stratified, open-label, randomised phase 2 trial was done at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients with haematological cancers aged between 5 and 75 years were eligible to participate in the study. Patients who had HIV or uncontrollable infections were excluded. Eligible patients were randomly assigned (1:1 by a computer-generated programme in block sizes of four) to receive a total intravenous busulfan dose to achieve an area under the curve of 16 000 μmol/min (16K group) or 20 000 μmol/min (20K group) on the basis of pharmacokinetic analysis, plus intravenous fludarabine 40 mg/m for 4 days. The investigators and the research nurses were masked to the block size to conceal allocation. The primary outcome was day 100 non-relapse mortality. All analyses were by modified intention to treat, including only patients who received at least one dose of the study drug. No interim analyses were planned and accrual is complete. This study is registered with ClinicalTrials.gov, number NCT01572662.

Findings: Between April 18, 2012, and Dec 9, 2015, 98 patients were enrolled. 49 patients were randomly assigned to the 16K group and 49 to the 20K group, one of which was removed from the study before starting the intervention. Median age was 60 years (IQR 54-67). 50 (52%) patients had an HCT-specific comorbidity index score of 3 or more, and 41 (42%) had a high or very high Disease Risk Index score. Day 100 non-relapse mortality was 4% (95% CI 0-10) in the 16K group and 6% (0-13) in the 20K group (p=0·65). Infection was the most common grade 3-5 toxicity in both the 20K group (25 [52%] of 48 patients) and the 16K group (24 [49%] of 49 participants). Mucositis (nine [19%] of 48 patients vs three [6%] of 49 patients), idiopathic pneumonia syndrome (nine [19%] of 48 patients vs two [4%] of 49 patients), and culture-negative neutropenic fever (16 [33%] of 48 patients vs eight [16%] of 49 patients) were more common in the 20K group than in the 16K group.

Interpretation: Myeloablative doses of busulfan administered in a timed-sequential manner with fludarabine is associated with low non-relapse mortality in older patients and patients with comorbidities. Additional studies are required to show whether this approach can reduce the risk of relapse.

Funding: Cancer Center Support Grant (US National Cancer Institute, National Institutes of Health).
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http://dx.doi.org/10.1016/S2352-3026(18)30156-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317874PMC
November 2018

Impact of a novel prognostic model, hematopoietic cell transplant-composite risk (HCT-CR), on allogeneic transplant outcomes in patients with acute myeloid leukemia and myelodysplastic syndrome.

Bone Marrow Transplant 2019 06 26;54(6):839-848. Epub 2018 Sep 26.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Outcomes after allogeneic stem-cell transplantation (AHSCT) are influenced by both disease- and patient-related factors. Here, we developed a novel prognostic model, hematopoietic cell transplant-composite risk (HCT-CR), by combining the refined disease risk index (DRI-R) and hematopoietic stem-cell transplant comorbidity/age index (HCT-CI/Age) to predict post-transplant survival for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The analysis included 942 AML/MDS patients treated with AHSCT. Patients were stratified into 4 HCT-CR risk groups: Low-risk-patients with low/intermediate DRI-R and HCT-CI/Age ≤3 (N = 272); Intermediate-risk-patients with low/intermediate DRI-R and HCT-CI/Age >3 (N = 168); High-risk-patients with high/very high DRI-R and HCT-CI/Age ≤3 (N = 284); and Very high-risk-patients with high/very high DRI-R and HCT-CI/Age >3 (N = 184). Compared with the low-risk group, intermediate, high, and very high-risk groups had a significantly increased risk of death [adjusted HR of 1.37 (P < 0.04), 2.08 (P < 0.001), and 2.92 (P < 0.001), respectively]. The concordance test showed that the HCT-CR model provided better discriminative capacity for OS prediction compared with all prior models independently, including cytogenetic risk group, DRI-R, and HCT-CI/Age model (C-indices: 0.62, 0.55, 0.60, and 0.54, respectively) (P < 0.001). In conclusion, combining disease- and patient-related factors provides better survival stratification for patients with AML/MDS receiving AHSCT.
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http://dx.doi.org/10.1038/s41409-018-0344-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285649PMC
June 2019

Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells.

Exp Hematol 2018 11 10;67:49-59.e1. Epub 2018 Aug 10.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

The combination of the DNA-alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pretransplantation conditioning therapy for myeloid leukemias. However, it is associated with significant nonrelapse mortality, which prohibits dose escalation to control relapse. We hypothesized that combining these two drugs with an epigenetic modifier would increase antileukemic efficacy without jeopardizing patient safety. A preclinical study was performed to determine the synergistic cytotoxicity of Bu, 4-hydroperoxycyclophosphamide (4HC), and the hypomethylating agent decitabine (DAC) in human acute myeloid leukemia (AML) cell lines. Exposure of KBM3/Bu250 (P53-null) and OCI-AML3 (P53-wild-type) cells to Bu+4HC inhibited cell proliferation by ∼35-39%; addition of DAC increased the inhibition to ∼60-62%. The observed synergistic interactions correlated with DNA damage response activation, increased the production of reactive oxygen species, and decreased mitochondrial membrane potential, release of mitochondrial proapoptotic proteins into the cytoplasm, and induction of caspase-dependent programmed cell death. The Bu+4HC+DAC combination further caused chromatin trapping of DNMT1 with a concomitant increase in DNA damage. In contrast, FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)-positive AML cell lines were not sensitized to Bu+4HC by inclusion of DAC; addition of the FLT3 kinase inhibitor sorafenib sensitized the FLT3-ITD-positive MV4-11 and MOLM13 cell lines to the triple drug combination by inhibiting the FLT3 signal transduction pathway. Our results therefore provide a rationale for the development of personalized conditioning therapy for patients with P53-mutated and FLT3-ITD-positive AML.
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http://dx.doi.org/10.1016/j.exphem.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262883PMC
November 2018

Phase II Trial of High-Dose Gemcitabine/Busulfan/Melphalan with Autologous Stem Cell Transplantation for Primary Refractory or Poor-Risk Relapsed Hodgkin Lymphoma.

Biol Blood Marrow Transplant 2018 08 2;24(8):1602-1609. Epub 2018 Mar 2.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

We conducted a prospective phase 2 trial of gemcitabine, busulfan and melphalan (Gem/Bu/Mel) with autologous stem cell transplantation (ASCT) in patients with primary refractory or poor-risk relapsed Hodgkin lymphoma (HL) (ie, extranodal relapse or within 1 year of frontline therapy). The trial was powered to detect an improvement in 2-year progression-free survival (PFS) from a historical 50% using a BEAM regimen (carmustine/etoposide/cytarabine/melphalan) to 65%. We compared the study population with all other concurrent patients who were eligible for the trial but instead received the BEAM regimen at our center. No patient received post-ASCT maintenance therapy. The Gem/Bu/Mel trial enrolled 80 patients with a median age of 31 years, 41% with primary refractory HL and 59% with relapsed HL (36% extranodal relapses), and 30% with positron emission tomography (PET)-positive lesions at ASCT. The concurrent BEAM (n = 45) and Gem/Bu/Mel cohorts were well balanced except for higher rates of bulky relapse and PET-positive tumors in the Gem/Bu/Mel cohort. There were no transplantation-related deaths in either cohort. At a median follow-up of 34.5 months (range, 26 to 72 months), Gem/Bu/Mel was associated with better 2-year PFS (65% versus 51%; P = .008) and overall survival (89% versus 73%; P = .0003). In conclusion, our data show that Gem/Bu/Mel is safe, in this nonrandomized comparison yielding improved outcomes compared with a concurrently treated and prognostically matched cohort of patients with primary refractory or poor-risk relapsed HL receiving BEAM.
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http://dx.doi.org/10.1016/j.bbmt.2018.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212703PMC
August 2018

Early Post-Transplant Minimal Residual Disease Assessment Improves Risk Stratification in Acute Myeloid Leukemia.

Biol Blood Marrow Transplant 2018 07 12;24(7):1514-1520. Epub 2018 Feb 12.

Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

We studied if the inclusion of early post-stem cell transplantation (SCT) minimal residual disease (MRD) assessments improved prognostication in patients with acute myeloid leukemia (AML). Two hundred sixty-nine AML patients in morphological complete remission (CR) who underwent a first SCT were included if they had evaluable pre-SCT MRD assessment by multiparametric flow cytometry. Post-SCT MRD assessments were performed at days +30, +100, and +180. The primary outcome was 1-year relapse incidence (RI). Of 269 patients in CR, 83 (30.8%) had detectable MRD pre-SCT. Post-SCT, during routine disease assessment time points, 9 of 241 evaluable patients (3.7%) at day +30, 6 of 191 evaluable patients (3.1%) at day +100, and 4 of 133 evaluable patients (3%) at day +180 were MRD positive while in CR. MRD positivity at day +30 predicted the highest risk of relapse at 1 year (group 1, 1-year RI 78%). Among MRD-negative patients at day +30, either adverse risk category by European Leukemia Net (ELN) or intermediate risk who were aged ≥60 years and/or pre-SCT MRD-positive represented the intermediate-risk group (group 2, 1-year RI 29%). The remaining patients represented the low-risk group (group 3, 1-year RI 5%). For patients in CR beyond day +30 post-SCT, detectable MRD at any time point predicted impending relapse within 2 months. Early post-SCT MRD assessment-combined with pre-SCT MRD assessment, ELN risk category, and age-improves risk stratification for relapse in AML patients post-transplant. Studies aimed at preventing impending relapse in this high-risk population are urgently needed.
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http://dx.doi.org/10.1016/j.bbmt.2018.02.003DOI Listing
July 2018
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