Publications by authors named "Vaibhav Agrawal"

40 Publications

T-Cell Acute Lymphoblastic Leukemia-Current Concepts in Molecular Biology and Management.

Biomedicines 2021 Nov 4;9(11). Epub 2021 Nov 4.

Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA.

T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, yet aggressive leukemia that accounts for approximately one-fourth of acute lymphoblastic leukemia (ALL) cases. / and are the most common mutated genes in T-ALL. Children and young adults are treated with pediatric intensive regimens and have superior outcomes compared to older adults. In children and young adults, Nelarabine added to frontline chemotherapy improves outcomes and end of consolidation measurable residual disease has emerged as the most valuable prognostic marker. While outcomes for de-novo disease are steadily improving, patients with relapsed and refractory T-ALL fare poorly. Newer targeted therapies are being studied in large clinical trials and have the potential to further improve outcomes. The role of allogeneic stem cell transplant (HSCT) is evolving due to the increased use of pediatric-inspired regimens and MRD monitoring. In this review we will discuss the biology, treatment, and outcomes in pediatric and adult T-ALL.
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http://dx.doi.org/10.3390/biomedicines9111621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615775PMC
November 2021

Title: Impact of Induction Therapy with VRD vs. VCD on Outcomes in Patients with Multiple Myeloma in Partial Response or Better Undergoing Upfront Autologous Stem Cell Transplantation.

Transplant Cell Ther 2021 Nov 12. Epub 2021 Nov 12.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI. Electronic address:

Background: Bortezomib-based triplet regimens, specifically bortezomib, lenalidomide and dexamethasone (VRD) and bortezomib, cyclophosphamide and dexamethasone (VCD) are the two most common induction regimens used in transplant-eligible patients with NDMM, with conflicting data on comparative efficacy and outcomes in this population.

Objectives: We compared long-term outcomes of multiple myeloma (MM) patients receiving VRD vs. VCD induction prior to autologous stem cell transplant (ASCT).

Study Design: Patients registered with Center for International Blood and Marrow Transplant Registry were included if they underwent ASCT for MM from 01/2013 to 12/2018 within 6 months of diagnosis, received VRD or VCD induction and achieved pre-transplant > partial response. Of 1,135 patients, 914 received VRD and 221 received VCD.

Results: Patients receiving VCD were more likely to have renal impairment and ISS stage III disease and less likely to receive full dose melphalan (200 mg/m) conditioning (69% vs 80%, p<0.001). Very good partial response rates pre-transplant, post-transplant and at best response in VRD vs. VCD were not significantly different. Maintenance use was more common after VRD (88% vs. 76%, p<0.001) with lenalidomide being the most common agent (80% vs 63%). Patients in the VRD group had higher rates of renal recovery, 74% vs. 43% p<0.001, which may be due to rapid reduction of light chains in the VRD group or improvement in renal function with VCD, which allowed switch over to VRD as patients who switched were classified in the VRD group. Patients receiving VRD had better survival on univariate analysis, with median progression-free survival (PFS) from transplant of 44.6 vs 34.1 months, p=0.004 and 5-year overall survival (OS) of 79% and 60%, p<0.001, respectively. On multivariate analysis there was no significant survival difference, with hazard ratio (VCD vs. VRD induction) for PFS being 1.22 (95% CI: 0.96-1.55, p=0.10) and OS being 1.33 (95% CI: 0.93-1.92, p=0.12). Maintenance use was independently associated with superior PFS and OS, along with ISS stage, cytogenetics and pre-transplant response (PFS only).

Conclusions: In patients with MM undergoing upfront transplant after VRD or VCD induction, no independent survival difference was seen based on the induction therapy received after adjusting for other prognostic factors. The use of maintenance treatment was uniformly associated with superior outcomes.
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http://dx.doi.org/10.1016/j.jtct.2021.10.022DOI Listing
November 2021

Male-specific late effects in adult hematopoietic cell transplantation recipients: a systematic review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.

Transplant Cell Ther 2021 Oct 29. Epub 2021 Oct 29.

Department of Internal Medicine, Mayo Clinic, Rochester, MN;; Department of Medicine, Sheikh Shakhbout Medical City, Abu Dhabi, UAE.

Background: Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies, such as prostate, penile, and testicular cancer. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT.

Objective: Here, we provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.

Study Design: We utilized systematic review methodology to summarize incidence, risk factors, screening, prevention and treatment of these complications and provide consensus evidence-based recommendations for clinical practice and future research.

Results: Most of the evidence regarding male GvHD is still based on limited data, precluding strong therapeutic recommendations. We therefore recommend to systematically screen for male genital GvHD regularly and report it to large registries to allow for a better understanding. Future research should also address treatment since little published evidence is available to date. Male-specific endocrine consequences of HCT include hypogonadism which may also affect bone health. Since the evidence is scarce, current recommendations for hormone substitution and/or bone health treatment are based on similar principles as for the general population. Following HCT, sexual health decreases and this topic should be addressed at regular intervals. Future studies should focus on interventional strategies to address sexual dysfunction. Infertility remains prevalent in patients having undergone myeloablative conditioning, which warrants offering sperm preservation in all HCT candidates. Most studies on fertility rely on descriptive registry analysis and surveys, hence the importance of reporting post-HCT conception data to large registries. Although the quality of evidence is low, the development of cancer in male genital organs does not seem more prevalent than in the general population; however, subsequent malignancies in general seem to be more prevalent in males than females, and special attention should be given to skin and oral mucosa.

Conclusion: Male-specific late effects, probably more under-reported than female-specific complications, should be systematically considered during the regular follow-up visits of male survivors who have undergone HCT. Care of patients with male-specific late effects warrants close collaboration between transplant physicians and specialists from other involved disciplines. Future research should be directed towards better data collection on male-specific late effects and on studies about the interrelationship between these late effects, to allow the development of evidence based effective management practices.
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http://dx.doi.org/10.1016/j.jtct.2021.10.013DOI Listing
October 2021

Allogeneic Transplant and CAR-T Therapy After Autologous Transplant Failure in DLBCL: A Noncomparative Cohort Analysis.

Blood Adv 2021 Oct 21. Epub 2021 Oct 21.

Moffitt Cancer Center, Tampa, Florida, United States.

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR) T-cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto) HCT. While the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis we report outcomes of DLBCL patients (≥18 years), undergoing a reduced intensity alloHCT or CAR-T therapy during 2012-2019, after a prior auto-HCT failure, and apply CIBMTR prognostic model to CAR-T recipients. 584 patients were included. The 1-year relapse, non-relapse mortality, overall survival (OS) and progression-free survival (PFS) for CAR-T treatment after autoHCT failure were were 39.5%, 4.8%, 73.4% and 55.7%, respectively. The corresponding rates in alloHCT cohort were 26.2%, 20.0%, 65.6% and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3, respectively (p=0.002). The corresponding rates for low-, intermediate- and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (p<0.001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in subset of DLBCL patients relapsing after a prior autoHCT. The simple, CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high risk patients.
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http://dx.doi.org/10.1182/bloodadvances.2021005788DOI Listing
October 2021

Detection of diabetes from whole-body MRI using deep learning.

JCI Insight 2021 Nov 8;6(21). Epub 2021 Nov 8.

Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.

Obesity is one of the main drivers of type 2 diabetes, but it is not uniformly associated with the disease. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution, such as visceral fat, are closely related to insulin resistance. There might be further, hitherto unknown, features of body fat distribution that could additionally contribute to the disease. We used machine learning with dense convolutional neural networks to detect diabetes-related variables from 2371 T1-weighted whole-body MRI data sets. MRI was performed in participants undergoing metabolic screening with oral glucose tolerance tests. Models were trained for sex, age, BMI, insulin sensitivity, HbA1c, and prediabetes or incident diabetes. The results were compared with those of conventional models. The area under the receiver operating characteristic curve was 87% for the type 2 diabetes discrimination and 68% for prediabetes, both superior to conventional models. Mean absolute regression errors were comparable to those of conventional models. Heatmaps showed that lower visceral abdominal regions were critical in diabetes classification. Subphenotyping revealed a group with high future diabetes and microalbuminuria risk.Our results show that diabetes is detectable from whole-body MRI without additional data. Our technique of heatmap visualization identifies plausible anatomical regions and highlights the leading role of fat accumulation in the lower abdomen in diabetes pathogenesis.
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http://dx.doi.org/10.1172/jci.insight.146999DOI Listing
November 2021

Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults.

Transplant Cell Ther 2021 Nov 21;27(11):923.e1-923.e12. Epub 2021 Aug 21.

Section of Bone Marrow Transplant and Cell Therapy, Rush University Medical Center, Chicago, Illinois.

Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.08.010DOI Listing
November 2021

Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improve Transplantation Outcomes in Older Patients with Myelodysplastic Syndromes.

Transplant Cell Ther 2021 Nov 14;27(11):921.e1-921.e10. Epub 2021 Aug 14.

Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m. The 2 groups, recipients of FluBu (n = 697) and recipients of FluMel (n = 448), were comparable in terms of disease- and transplantation-related characteristics except for the more frequent use of antithymocyte globulin or alemtuzumab in the FluBu group (39% versus 31%). The median age was 67 years in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% versus 44% (P ≤ .0001). Transplantation-related mortality (TRM) was higher in the FluMel group (26% versus 16%; P ≤ .0001). Because the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was better at 1 year and beyond with FluMel compared with FluBu (48% versus 40% at 1 year [P = .02] and 35% versus 27% at 3 years [P = .01]). Overall survival was comparable in the 2 groups at 1 year (63% versus 61%; P = .4) but was significantly improved with FluMel compared with FluBu at 3 years (46% versus 39%; P = .03). Our results suggest that FluMel is associated with superior DFS compared with FluBu owing to reduced RI in older patients with MDS patients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.08.007DOI Listing
November 2021

Survival outcomes and toxicity in patients 40 years old or older with relapsed metastatic germ cell tumors treated with high-dose chemotherapy and peripheral blood stem cell transplantation.

Cancer 2021 Oct 14;127(20):3751-3760. Epub 2021 Jul 14.

Division of Hematology-Oncology, Indiana University Simon Comprehensive Cancer Center, Indianapolis, Indiana.

Background: High-dose chemotherapy (HDCT) plus peripheral blood stem cell transplantation (PBSCT) is effective salvage therapy for relapsed metastatic germ cell tumors (GCTs) but has potential toxicity. Historically, an age of ≥40 years has been associated with greater toxicity and worse outcomes.

Methods: This is a retrospective analysis of 445 consecutive patients with relapsed GCT treated with HDCT and PBSCT with tandem cycles at Indiana University from between 2004-2017 per our institutional regimen. Kaplan-Meier methods and log-rank tests were used for progression-free survival (PFS) and overall survival (OS) analysis.

Results: A total of 329 patients were <40 years of age, whereas 116 patients were ≥40 years of age; HDCT was used as second-line therapy in 85% and 79%, respectively. Median follow-up time was 42.5 months (range, 0.3-173.4 months). Grade ≥3 toxicities were similar between either group, except for greater pulmonary (P = .02) and renal toxicity (P = .01) in the ≥40-years-of-age group. Treatment-related mortality was similar between both age groups: 10 patients (3%) in the <40-years-of-age group and 4 patients (3.5%) in ≥40-years-of-age group died from complications of HDCT. Two-year PFS for <40 years of age versus ≥40 years of age was 58.7% versus 59.6% (P = .76) and 2-year OS was 63.9% versus 61.5% (P = .93). Factors predicting worse PFS included Eastern Cooperative Oncology Group performance status ≥1, platinum refractory disease, nonseminoma histology, and not completing 2 cycles of HDCT. Age was not an independent predictor of worse outcomes.

Conclusions: HDCT plus PBSCT is effective salvage therapy in patients ≥40 years of age with relapsed metastatic GCT. Patients ≥40 years of age experience similar rates of toxicity and treatment-related mortality as those <40 years of age.
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http://dx.doi.org/10.1002/cncr.33771DOI Listing
October 2021

Age no bar: A CIBMTR analysis of elderly patients undergoing autologous hematopoietic cell transplantation for multiple myeloma.

Cancer 2020 12 23;126(23):5077-5087. Epub 2020 Sep 23.

The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Background: Upfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy in the management of patients with multiple myeloma (MM), a disease of older adults.

Methods: The authors investigated the outcomes of AHCT in patients with MM who were aged ≥70 years. The Center for International Blood and Marrow Transplant Research (CIBMTR) database registered 15,999 patients with MM in the United States within 12 months of diagnosis during 2013 through 2017; a total of 2092 patients were aged ≥70 years. Nonrecurrence mortality (NRM), disease recurrence and/or progression (relapse; REL), progression-free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models with age at transplantation as the main effect. Because of the large sample size, a P value <.01 was considered to be statistically significant a priori.

Results: An increase in AHCT was noted in 2017 (28%) compared with 2013 (15%) among patients aged ≥70 years. Although approximately 82% of patients received melphalan (Mel) at a dose of 200 mg/m overall, 58% of the patients aged ≥70 years received Mel at a dose of 140 mg/m . On multivariate analysis, patients aged ≥70 years demonstrated no difference with regard to NRM (hazard ratio [HR] 1.3; 99% confidence interval [99% CI], 1-1.7 [P = .06]), REL (HR, 1.03; 99% CI, 0.9-1.1 [P = 0.6]), PFS (HR, 1.06; 99% CI, 1-1.2 [P = 0.2]), and OS (HR, 1.2; 99% CI, 1-1.4 [P = .02]) compared with the reference group (those aged 60-69 years). In patients aged ≥70 years, Mel administered at a dose of 140 mg/m was found to be associated with worse outcomes compared with Mel administered at a dose of 200 mg/m , including day 100 NRM (1% [95% CI, 1%-2%] vs 0% [95% CI, 0%-1%]; P = .003]), 2-year PFS (64% [95% CI, 60%-67%] vs 69% [95% CI, 66%-73%]; P = .003), and 2-year OS (85% [95% CI, 82%-87%] vs 89% [95% CI, 86%-91%]; P = .01]), likely representing frailty.

Conclusions: The results of the current study demonstrated that AHCT remains an effective consolidation therapy among patients with MM across all age groups.
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http://dx.doi.org/10.1002/cncr.33171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063213PMC
December 2020

Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report.

Blood Adv 2020 07;4(13):3180-3190

Texas Transplant Institute, San Antonio, TX.

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
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http://dx.doi.org/10.1182/bloodadvances.2019001266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362362PMC
July 2020

Effect of Sirolimus levels between days 11 and 20 after allogeneic stem cell transplantation on the risk of hepatic sinusoidal obstruction syndrome.

Bone Marrow Transplant 2021 01 4;56(1):121-128. Epub 2020 Jul 4.

Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.

Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12-58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21-30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57-8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.
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http://dx.doi.org/10.1038/s41409-020-0987-1DOI Listing
January 2021

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Biol Blood Marrow Transplant 2020 08 17;26(8):1459-1468. Epub 2020 May 17.

(7)Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
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http://dx.doi.org/10.1016/j.bbmt.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391266PMC
August 2020

Subsequent neoplasms and late mortality in children undergoing allogeneic transplantation for nonmalignant diseases.

Blood Adv 2020 05;4(9):2084-2094

Division of Hematology/Oncology, College of Medicine, University of Florida, Gainesville, FL.

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.
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http://dx.doi.org/10.1182/bloodadvances.2019000839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218429PMC
May 2020

Survival following allogeneic transplant in patients with myelofibrosis.

Blood Adv 2020 05;4(9):1965-1973

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Carolinas HealthCare System, Charlotte, NC.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.
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http://dx.doi.org/10.1182/bloodadvances.2019001084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218417PMC
May 2020

Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT.

J Clin Oncol 2020 06 4;38(18):2062-2076. Epub 2020 May 4.

Division of Clinical Hematology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.

Purpose: There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]-bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor.

Methods: We report composite end points of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) and chronic GVHD (cGVHD)-free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, < .0071 in multivariable analysis and < .00025 in direct pairwise comparisons were considered statistically significant.

Results: In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group.

Conclusion: Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.
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http://dx.doi.org/10.1200/JCO.19.00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302955PMC
June 2020

Vaccine and Cell-based Therapeutic Approaches in Acute Myeloid Leukemia.

Curr Cancer Drug Targets 2020 ;20(7):473-489

Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.

Over the past decade, our increased understanding of the interactions between the immune system and cancer cells has led to paradigm shifts in the clinical management of solid and hematologic malignancies. The incorporation of immune-targeted strategies into the treatment landscape of acute myeloid leukemia (AML), however, has been challenging. While this is in part due to the inability of the immune system to mount an effective tumor-specific immunogenic response against the heterogeneous nature of AML, the decreased immunogenicity of AML cells also represents a major obstacle in the effort to design effective immunotherapeutic strategies. In fact, AML cells have been shown to employ sophisticated escape mechanisms to evade elimination, such as direct immunosuppression of natural killer cells and decreased surface receptor expression leading to impaired recognition by the immune system. Yet, cellular and humoral immune reactions against tumor-associated antigens (TAA) of acute leukemia cells have been reported and the success of allogeneic stem cell transplantation and monoclonal antibodies in the treatment of AML clearly provides proof that an immunotherapeutic approach is feasible in the management of this disease. This review discusses the recent progress and persisting challenges in cellular immunotherapy for patients with AML.
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http://dx.doi.org/10.2174/1568009620666200502011059DOI Listing
July 2021

A multi-institutional comparison of mitoxantrone, etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia.

Am J Hematol 2020 08 8;95(8):937-943. Epub 2020 May 8.

Division of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.
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http://dx.doi.org/10.1002/ajh.25838DOI Listing
August 2020

Adverse Health Outcomes Among US Testicular Cancer Survivors After Cisplatin-Based Chemotherapy vs Surgical Management.

JNCI Cancer Spectr 2020 Apr 8;4(2):pkz079. Epub 2019 Oct 8.

Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.

We evaluated for the first time, to our knowledge, adverse health outcomes (AHOs) among US testicular cancer survivors (TCS) given chemotherapy (n = 381) vs surgery-only patients (n = 98) managed at a single institution, accounting for non-treatment-related risk factors to delineate chemotherapy's impact. Chemotherapy consisted largely of bleomycin-etoposide-cisplatin (BEP) administered in three or four cycles (BEPx3, n = 235; BEPx4, n = 82). Incidence of at least 3 AHOs was lowest in surgery-only TCS and increased with BEPx3, BEPx4, and other cisplatin-based regimens (12.2%, 40.8%, 52.5%, 54.8%; <.0001). Multivariable modeling assessed associations of risk factors and treatment with hearing impairment, tinnitus, peripheral neuropathy, and Raynaud phenomenon. Risk for each AHO statistically increased with both increasing chemotherapy burden ( < .0001) and selected modifiable risk factors ( < .05): hypertension (odds ratio [OR] = 2.40) and noise exposure (OR ≥ 2.3) for hearing impairment; noise exposure for tinnitus (OR ≥ 1.69); peripheral vascular disease for neuropathy (OR = 8.72); and current smoking for Raynaud phenomenon (OR = 2.41). Clinicians should manage modifiable risk factors for AHOs among TCS.
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http://dx.doi.org/10.1093/jncics/pkz079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065712PMC
April 2020

Infection in an Allogeneic Hematopoietic Stem Cell Transplant Patient Receiving Voriconazole Prophylaxis.

Case Rep Hematol 2020 12;2020:8124137. Epub 2020 Feb 12.

Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.

infection is a rare complication in the allogeneic stem cell transplant patients. Minimal guidance exists on how to appropriately manage histoplasmosis in these patients. We report a patient who developed pneumonia while receiving voriconazole prophylaxis at a therapeutic trough level. The patient experienced significant clinical improvement after initiation of itraconazole pharmacotherapy. We recommend a lower threshold for evaluation for histoplasmosis in allogeneic hematopoietic stem cell transplant recipients who live in endemic regions, regardless of their antifungal prophylactic regimen.
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http://dx.doi.org/10.1155/2020/8124137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039042PMC
February 2020

The Role of Donor Lymphocyte Infusion (DLI) in Post-Hematopoietic Cell Transplant (HCT) Relapse for Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era.

Biol Blood Marrow Transplant 2020 06 14;26(6):1137-1143. Epub 2020 Feb 14.

Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California.

Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) includes tyrosine kinase inhibitors (TKIs) with or without donor lymphocyte infusions (DLIs), but the most effective treatment strategy is unknown. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We retrospectively reviewed all patients reported to the CIBMTR registry from 2002 to 2014 who underwent HCT for CML and were alive 30 days postrelapse. A total of 215 HCT recipients relapsed and were analyzed in the following groups: (1) TKI alone (n = 128), (2) TKI with DLI (n = 48), and (3) DLI without TKI (n = 39). In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). Patients who received a DLI alone compared with a TKI with a DLI had inferior survival (hazard ratio, 2.28; 95% confidence interval, 1.23 to 4.24; P= .009). Those who received a TKI alone had similar survival compared with those who received a TKI with a DLI (P = .81). These data support that despite use of TKIs pretransplantation, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. These data do not suggest that adding a DLI to a TKI adds an improvement in OS.
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http://dx.doi.org/10.1016/j.bbmt.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367282PMC
June 2020

Salvage therapy for relapsed testicular cancer: a need for consensus.

Future Oncol 2019 Dec 12;15(34):3881-3884. Epub 2019 Nov 12.

Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

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http://dx.doi.org/10.2217/fon-2019-0531DOI Listing
December 2019

Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research.

Haematologica 2020 05 26;105(5):1329-1338. Epub 2019 Sep 26.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.
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http://dx.doi.org/10.3324/haematol.2019.220756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193485PMC
May 2020

Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 09 11;25(9):1875-1883. Epub 2019 May 11.

Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.

Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3 T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3 T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3 T cell dose cutoff of 14 × 10 cells/kg identified MSD/low CD3 (n = 223) and MSD/high CD3 (n = 1214), and a dose of 15 × 10 cells/kg identified MUD/low CD3 (n = 197) and MUD/high CD3 (n = 1102). On univariate analysis, the MSD/high CD3 group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3 group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3 group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3 group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3 T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4 T cells, CD8 T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3 T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4 and CD8 T cell doses were not possible given our small sample size.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071947PMC
September 2019

Role network measures to assess healthcare team adaptation to complex situations: the case of venous thromboembolism prophylaxis.

Ergonomics 2019 Jul 30;62(7):864-879. Epub 2019 Apr 30.

b Center for Quality and Productivity Improvement , University of Wisconsin-Madison , Madison , Wisconsin , USA.

Hospitals are complex environments that rely on clinicians working together to provide appropriate care to patients. These clinical teams adapt their interactions to meet changing situational needs. Venous thromboembolism (VTE) prophylaxis is a complex process that occurs throughout a patient's hospitalisation, presenting five stages with different levels of complexity: admission, interruption, re-initiation, initiation, and transfer. The objective of our study is to understand how the VTE prophylaxis team adapts as the complexity in the process changes; we do this by using social network analysis (SNA) measures. We interviewed 45 clinicians representing 9 different cases, creating 43 role networks. The role networks were analysed using SNA measures to understand team changes between low and high complexity stages. When comparing low and high complexity stages, we found two team adaptation mechanisms: (1) relative increase in the number of people, team activities, and interactions within the team, or (2) relative increase in discussion among the team, reflected by an increase in reciprocity.   The reason for this study was to quantify team adaptation to complexity in a process using social network analysis (SNA). The VTE prophylaxis team adapted to complexity by two different mechanisms, by increasing the roles, activities, and interactions among the team or by increasing the two-way communication and discussion throughout the team. We demonstrated the ability for SNA to identify adaptation within a team.
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http://dx.doi.org/10.1080/00140139.2019.1603402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243844PMC
July 2019

Survival Trends in Infants Undergoing Allogeneic Hematopoietic Cell Transplant.

JAMA Pediatr 2019 05 6;173(5):e190081. Epub 2019 May 6.

Division of Blood and Marrow Transplantation, Center for Cancer and Blood Disorders, Children's National Health System, Washington, DC.

Importance: Studies demonstrating improved survival after allogeneic hematopoietic cell transplant generally exclude infants.

Objective: To analyze overall survival trends and other outcomes among infants who undergo allogeneic hematopoietic cell transplant.

Design, Setting, And Participants: In this cohort study, we used time-trend analysis to evaluate 3 periods: 2000 through 2004, 2005 through 2009, and 2010 through 2014. The study was conducted in a multicenter setting through the Center for International Blood and Marrow Transplant Research, which is made up of a voluntary working group of more than 450 transplant centers worldwide. Two groups of infants aged 1 year or younger in 2 cohorts were included: those with malignant conditions, such as leukemia, and those with nonmalignant disorders, including immunodeficiencies. Data analysis was conducted from July 2017 to December 2018.

Exposures: Allogeneic hematopoietic cell transplant.

Main Outcomes And Measures: Survival trends, disease relapse, and toxicity.

Results: A total of 2498 infants with a median age of 7 months (range, <1-12 months) were included. In the nonmalignant cohort (n = 472), survival rates improved from the first to the second period (hazard ratio, 0.77 [95% CI, 0.63-0.93]; P = .007) but did not change after 2004. Compared with infants with nonmalignant diseases (n = 2026; 3-year overall survival: 2000-2004, 375/577 [65.0%]; 2005-2009, 503/699 [72.0%]; and 2010-2014, 555/750 [74.0%]), those with malignant conditions had poorer survival rates, without improvement over time (3-year overall survival: 2000-2004, 109/199 [54.8%]; 2005-2009, 104/161 [64.6%]; and 2010-2014, 66/112 [58.9%]). From 2000 through 2014, relapse rates increased in infants with malignant conditions (3-year relapse rate: 2000-2004, 19% [95% CI, 14%-25%]; 2005-2009, 23% [95% CI, 17%-30%]; 2010-2014, 36% [95% CI, 27%-46%]; P = .01). Sinusoidal obstruction syndrome was frequent, occurring with a cumulative incidence of 13% (95% CI, 11%-16%) of infants with nonmalignant diseases and 32% (95% CI, 22%-42%) of those with malignant diseases. Generally, recipients of human leukocyte antigen-identical sibling bone marrow grafts had the best outcomes.

Conclusions And Relevance: Survival rates have not improved for infants with malignant diseases over the 15-year study period. Infants with nonmalignant diseases had improved survival rates in the earlier but not the later study period. Higher relapses for the malignant cohort and toxicities for all infants remain significant challenges. Strategies to reduce relapse and toxicity and optimize donor and graft selection may improve outcomes in the future.
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http://dx.doi.org/10.1001/jamapediatrics.2019.0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503511PMC
May 2019

Autologous Hematopoietic Stem Cell Transplantation for Male Germ Cell Tumors: Improved Outcomes Over 3 Decades.

Biol Blood Marrow Transplant 2019 06 20;25(6):1099-1106. Epub 2019 Feb 20.

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

The curative potential of autologous hematopoietic cell transplantation (autoHCT) for male germ cell tumors (GCTs) is well established. The optimal timing and number (single transplant [ST] versus tandem transplants [TT] versus triple transplants) of autoHCT are controversial, with wide practice variations. We examined survival trends among 2395 recipients of autoHCT for male GCTs between 1990 and 2015 reported to the Center for International Blood and Marrow Transplant Research. Trends and outcomes were analyzed by year of transplantation for intervals 1990 to 1994 (N = 288), 1995 to 1999 (N = 351), 2000 to 2004 (N = 376), 2005 to 2009 (N = 509), and 2010 to 2015 (N = 871). Multivariate analysis was restricted to the subset from 2000 to 2015 with research-level data (n = 267). The median duration of follow-up was 51 months. The median age at autoHCT was 31 years; 633 patients (26%) had primary extragonadal GCT, and 1167 (49%) underwent TT. The 3-year progression-free (PFS) and overall survival (OS) improved from 24% (95% confidence interval [CI], 18% to 31%) and 35% (95% CI, 29% to 40%), respectively, in 1990 to 1994 to 47% (95% CI, 43% to 50%) and 54% (95% CI, 50% to 57%), respectively, in 2010 to 2015 (P < .0001). TT recipients were more likely than ST recipients to undergo autoHCT as first salvage treatment. The proportion of TTs increased from 38% of all autoHCTs in 2000 to 2004 to 77% in 2010 to 2015. Nonseminoma histology, residual disease at autoHCT, >1 line of pretransplantation chemotherapy, and ST versus TT were associated with inferior PFS and OS. Post-transplantation survival has improved significantly over time for relapsed/refractory male GCT and is associated with the increased use of TTs (compared with STs) and performance of autoHCT earlier in the disease course.
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http://dx.doi.org/10.1016/j.bbmt.2019.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559839PMC
June 2019

Non-GVHD ocular complications after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT.

Bone Marrow Transplant 2019 05 27;54(5):648-661. Epub 2019 Feb 27.

Utah Blood and Marrow Transplant Program Huntsman Cancer Institute, University of Utaah, Salt Lake City, UT, USA.

Non-graft-vs.-host disease (non-GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT), but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment, and ocular toxicities associated with medications. We have summarized incidence, risk factors, screening, prevention and treatment of individual complicastions and generated evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical symptoms, signs and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplant physicians and ophthalmologists should be knowledgeable of non-GVHD ocular complications and provide comprehensive collaborative team care.
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http://dx.doi.org/10.1038/s41409-018-0339-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497536PMC
May 2019

Ocular graft-versus-host disease after hematopoietic cell transplantation: Expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT.

Bone Marrow Transplant 2019 05 7;54(5):662-673. Epub 2018 Dec 7.

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.
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http://dx.doi.org/10.1038/s41409-018-0340-0DOI Listing
May 2019
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