Publications by authors named "Robert Krance"

80 Publications

BK Virus Epidemiology, Risk Factors, and Clinical Outcomes: An Analysis of Hematopoietic Stem Cell Transplant Patients at Texas Children's Hospital.

J Pediatric Infect Dis Soc 2021 Jan 8. Epub 2021 Jan 8.

Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.

Background: BK virus-associated hemorrhagic cystitis (BKV-HC) is a serious complication after hematopoietic stem cell transplantation (HSCT).

Methods: A retrospective review was performed to determine the frequency of BKV-HC and identify risk factors and renal morbidity associated with BKV-HC in pediatric HSCT recipients at our institution.

Results: A total of 314 pediatric recipients underwent allogeneic HSCT for either malignant (173, 55.1%) or nonmalignant disorders (141, 44.9%) from January 1, 2011, to December 31, 2015, with a minimum follow-up of 5 years post-HSCT. Severe BKV-HC (grades 3 and 4) was prevalent in 46 out of 67 (68.7%) recipients. Timing to presentation of severe BKV-HC (grades 3 and 4) occurred at a median of 37 days (26, 74; IQ1, IQ3) post-HSCT, with the duration of macroscopic hematuria lasting a median of 37.5 days (18, 71; IQ1, IQ3). In the first 60 days post-HSCT, peak acute kidney injury (AKI) stages 2 and 3 were seen more frequently in HSCT recipients who developed BKV-HC than those without (P = .004). Similarly, during post-HSCT days 61 to 100, peak AKI stage 3 was also more frequently seen in HSCT recipients who already developed BKV-HC prior to or during this time period than those without BKV-HC (P = .0002). Recipients who developed BKV-HC within 1 year of HSCT had more frequent mild to moderate chronic kidney disease (CKD stages 2-3) than those without BKV-HC (P = .002 and .007, respectively). On multivariate analysis, BKV-HC was associated with all-cause mortality (hazard ratio [HR]: 2.22; 95% confidence interval [CI]: 1.35-3.65). The following clinical variables were associated with time to development of HC on multivariate analysis: age (subdistribution HR [sHR] 1.11; 95% CI: 1.06-1.16) and myeloabalative conditioning regimen (sHR 4.2; 95% CI: 2.12-8.34).

Conclusions: Pediatric HSCT patients with BKV-HC experience significant morbidity and mortality. Renal morbidity, including AKI and CKD, is associated with BKV-HC.
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http://dx.doi.org/10.1093/jpids/piaa147DOI Listing
January 2021

Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS post-allogeneic transplant.

Blood 2020 Dec 3. Epub 2020 Dec 3.

Baylor College of Medicine, Houston, Texas, United States.

Relapse after allogeneic hematopoietic stem-cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusions of unselected donor lymphocytes (DLIs) are used to enhance the graft-versus-leukemia (GVL) effect, as treatment for relapsed disease. However, as the infused lymphocytes are not selected for leukemia-specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease(GVHD) due to the concurrent transfer of allo-reactive lymphocytes. Thus, to minimize GVHD and maximize GVL we selectively activated and expanded stem-cell donor-derived T cells that were reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, NY-ESO-1). Products were successfully generated from 29 HCT donors, and they demonstrated multi-leukemia antigen specificity (mLSTs). In contrast to DLIs, mLSTs selectively recognized and killed leukemia-antigen-pulsed cells with no activity against recipient-derived normal cells in vitro. We have now administered escalating doses of these mLSTs (0.5-10x107 cells/m2) to 25 trial enrollees with AML/MDS after HCT, 17 of whom were at high risk for relapse and 8 of whom had relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD up to a dose of 10x107 cells/m2. We observed anti-leukemia effects in vivo that translated into not yet reached median LFS and OS at 1.9 years of follow-up among survivors, evidence of sustained immune pressure and objective responses in the active disease cohort (1 CR and 1 PR). In conclusion, mLSTs are safe and promising for the prevention or treatment of AML/MDS following HCT.
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http://dx.doi.org/10.1182/blood.2020009471DOI Listing
December 2020

Factors Impacting Time to Engraftment in Patients With High-risk Neuroblastoma Following Autologous Stem Cell Transplant.

J Pediatr Hematol Oncol 2020 10;42(7):e569-e574

Baylor College of Medicine/Texas Children's Hospital Cancer Center, Houston, TX.

Background: Despite advances in supportive measures, myeloablative chemotherapy with stem cell rescue remains limited by toxicity and treatment-related mortality. The purpose of this study was to identify factors influencing the rate of hematopoietic recovery following autologous stem cell transplant in high-risk neuroblastoma.

Procedure: We retrospectively studied 54 patients with high-risk neuroblastoma who received a single autologous stem cell transplant between 2006 and 2016. Race, sex, conditioning regimen, chemotherapy delays and bone marrow involvement were analyzed using Kaplan-Meier Log-Rank test while the amount of cells infused, age, and length of hospital stay were analyzed using univariate Cox Proportional Hazards Regression.

Results: The conditioning regimen administered was significant (P=0.016) for time to engraftment of neutrophils, with busulfan/melphalan (Bu/Mel) at 16.6 days, and carboplatin/etoposide/melphalan at 12.1 days. A delay of chemotherapy during induction (n=24) was significant (P<0.001) for time to platelet engraftment of >75,000/µL. Female patients had a longer time to engraftment (P=0.029).

Conclusion: Patients receiving Bu/Mel as a conditioning regimen, patients who had a delay in induction chemotherapy and patients of female sex were found to be significant for delayed engraftment of neutrophils, platelets, and hemoglobin, respectively, in patients with high-risk neuroblastoma undergoing autologous stem cell transplant. Knowing these factors may lead to new expectations and possible interventions to decrease the morbidity and mortality of treatment and recovery.
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http://dx.doi.org/10.1097/MPH.0000000000001731DOI Listing
October 2020

Incorporation of thiotepa in a reduced intensity conditioning regimen may improve engraftment after transplant for HLH.

Br J Haematol 2020 03 27;188(6):e84-e87. Epub 2020 Jan 27.

Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, TX, USA.

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http://dx.doi.org/10.1111/bjh.16370DOI Listing
March 2020

Assessment of ST2 for risk of death following graft-versus-host disease in pediatric and adult age groups.

Blood 2020 04;135(17):1428-1437

Indiana University School of Medicine, Indianapolis, IN.

Assessment of prognostic biomarkers of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) in the pediatric age group is lacking. To address this need, we conducted a prospective cohort study with 415 patients at 6 centers: 170 were children age 10 years or younger and 245 were patients older than age 10 years (both children and adults were accrued from 2013 to 2018). The following 4 plasma biomarkers were assessed pre-HCT and at days +7, +14, and +21 post-HCT: stimulation-2 (ST2), tumor necrosis factor receptor 1 (TNFR1), regenerating islet-derived protein 3α (REG3α), and interleukin-6 (IL-6). We performed landmark analyses for NRM, dichotomizing the cohort at age 10 years or younger and using each biomarker median as a cutoff for high- and low-risk groups. Post-HCT biomarker analysis showed that ST2 (>26 ng/mL), TNFR1 (>3441 pg/mL), and REG3α (>25 ng/mL) are associated with NRM in children age 10 years or younger (ST2: hazard ratio [HR], 9.13; 95% confidence interval [CI], 2.74-30.38; P = .0003; TNFR1: HR, 4.29; 95% CI, 1.48-12.48; P = .0073; REG3α: HR, 7.28; 95% CI, 2.05-25.93; P = .0022); and in children and adults older than age 10 years (ST2: HR, 2.60; 95% CI, 1.15-5.86; P = .021; TNFR1: HR, 2.09; 95% CI, 0.96-4.58; P = .06; and REG3α: HR, 2.57; 95% CI, 1.19-5.55; P = .016). When pre-HCT biomarkers were included, only ST2 remained significant in both cohorts. After adjustment for significant covariates (race/ethnicity, malignant disease, graft, and graft-versus-host-disease prophylaxis), ST2 remained associated with NRM only in recipients age 10 years or younger (HR, 4.82; 95% CI, 1.89-14.66; P = .0056). Assays of ST2, TNFR1, and REG3α in the first 3 weeks after HCT have prognostic value for NRM in both children and adults. The presence of ST2 before HCT is a prognostic biomarker for NRM in children age 10 years or younger allowing for additional stratification. This trial was registered at www.clinicaltrials.gov as #NCT02194439.
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http://dx.doi.org/10.1182/blood.2019002334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180084PMC
April 2020

Toward Functional Immune Monitoring in Allogeneic Stem Cell Transplant Recipients.

Biol Blood Marrow Transplant 2020 05 10;26(5):911-919. Epub 2020 Jan 10.

Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, and Medicine Baylor College of Medicine, Houston, Texas.

Serious viral infections, due to delayed immune reconstitution, are a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Thus, many transplant centers prospectively track cellular immune recovery by evaluating absolute cell numbers and the phenotypic profile of reconstituting T cell subsets to identify individuals who are at highest risk of infection. Conventional assessments, however, fail to measure either the antigen specificity or functional capacity of reconstituting cells-both factors that correlate with endogenous antiviral protection. In this pilot study, we sought to address this limitation by prospectively investigating the tempo of endogenous immune reconstitution in a cohort of 23 pediatric HSCT patients using both quantitative (flow cytometry) and qualitative (IFNγ ELISpot) measures, which we correlated with either the presence or absence of infections associated with cytomegalovirus, adenovirus, Epstein-Barr virus, BK virus, human herpes virus 6, respiratory syncytial virus, parainfluenza, influenza, and human metapneumovirus. We present data spanning 12 months post-transplant demonstrating the influence of conditioning on immune recovery and highlighting the differential impact of active viral replication on the quantity and quality of reconstituting cells. Judicious use of standard (phenotypic) and novel (functional) monitoring strategies can help guide the clinical care and personalized management of allogenic HSCT recipients with infections.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.005DOI Listing
May 2020

T-Cell Receptor Stimulation Enhances the Expansion and Function of CD19 Chimeric Antigen Receptor-Expressing T Cells.

Clin Cancer Res 2019 12 26;25(24):7340-7350. Epub 2019 Sep 26.

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Texas Children's Hospital, Houston, Texas.

Purpose: Current protocols for CD19 chimeric antigen receptor-expressing T cells (CD19.CAR-T cells) require recipients to tolerate preinfusion cytoreductive chemotherapy, and the presence of sufficient target antigen on normal or malignant B cells.

Patients And Methods: We investigated whether additional stimulation of CD19.CAR-T cells through their native receptors can substitute for cytoreductive chemotherapy, inducing expansion and functional persistence of CD19.CAR-T even in patients in remission of B-cell acute lymphocytic leukemia. We infused a low dose of CD19.CAR-modified virus-specific T cells (CD19.CAR-VST) without prior cytoreductive chemotherapy into 8 patients after allogeneic stem cell transplant.

Results: Absent virus reactivation, we saw no CD19.CAR-VST expansion. In contrast, in patients with viral reactivation, up to 30,000-fold expansion of CD19.CAR-VSTs was observed, with depletion of CD19 B cells. Five patients remain in remission at 42-60+ months.

Conclusions: Dual T-cell receptor and CAR stimulation can thus potentiate effector cell expansion and CAR-target cell killing, even when infusing low numbers of effector cells without cytoreduction.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062259PMC
December 2019

Allogeneic hematopoietic stem cell transplant for relapsed and refractory non-Hodgkin lymphoma in pediatric patients.

Blood Adv 2019 09;3(18):2689-2695

Center for Cell and Gene Therapy, Texas Children's Hospital/Baylor College of Medicine/Houston Methodist Hospital, Houston, TX.

Allogeneic hematopoietic stem cell transplant (HSCT) for relapsed pediatric non-Hodgkin lymphoma (NHL) is often reserved for patients with certain NHL subtypes or high-risk disease whereas the remainder receive autologous HSCT. Given the aggressive nature of pediatric NHL, we performed allogeneic HSCTs for all patients regardless of disease risk. We report overall survival (OS) and prognostic variables in 36 pediatric patients who underwent allogeneic HSCT between 1998 and 2016. OS at 3 years was 67%. The 3-year OS varied based on NHL subtype: 100% for anaplastic large cell lymphoma (n = 14), 63% for diffuse large B-cell lymphoma (n = 8), 17% for lymphoblastic lymphoma (LL; n = 9) and 80% for other subtypes combined (n = 5). Disease status influenced outcome with 3-year OS of 100% for patients in complete remission (n = 15), 59% with partial remission (PR; n = 17), and 0% with progressive/stable disease (n = 3) ( = .004). Of the 17 patients in PR, all 6 with LL died of relapsed disease, whereas the other 11 attained remission after HSCT and remained disease-free. The cumulative incidence of relapse after HSCT for LL was 78% compared with 15% for all other NHL subtypes combined ( < .0001). Cumulative incidence of nonrelapse mortality (NRM) was low in our cohort at 6%. Hence, allogeneic HSCT is a well-tolerated and useful therapeutic option with low rates of NRM and relapse for all NHL subtypes except LL with active disease at HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2018026203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759733PMC
September 2019

"Mini" bank of only 8 donors supplies CMV-directed T cells to diverse recipients.

Blood Adv 2019 09;3(17):2571-2580

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Texas Children's Hospital, Houston, TX.

Cytomegalovirus (CMV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), and standard antiviral therapies are associated with significant side effects and development of drug-resistant mutants. Adoptively transferred donor-derived CMV-specific T cells (CMVSTs) can provide an alternative treatment modality with few side effects but are not widely available due to their patient-specific nature. Here we report the establishment and use of a bank of CMVSTs derived from just 8 CMV-seropositive donors, with HLA types representing the diverse US population, as an "off-the-shelf" therapy to treat drug-refractory infections. To date, we have screened 29 patients for study participation and identified a suitable line, with ≥2 of 8 shared HLA antigens, for 28 (96.6%) patients with a median of 4 shared HLA antigens. Of these, 10 patients with persistent/refractory CMV infections or disease were eligible for treatment; a single infusion of cells produced 3 partial responses and 7 complete responses, for a cumulative response rate of 100% (95% confidence interval, 69.2-100) with no graft-versus-host disease, graft failure, or cytokine release syndrome. Potential wider use of the tested CMVSTs across transplant centers is made more feasible by our ability to produce sufficient material to generate cells for >2000 infusions from a single donor collection. Our data indicate that a "mini" bank of CMVSTs prepared from just 8 well-chosen third-party donors can supply the majority of patients with an appropriately matched line that produces safe and effective anti-CMV activity post-HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2019000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737421PMC
September 2019

Safety and feasibility of virus-specific T cells derived from umbilical cord blood in cord blood transplant recipients.

Blood Adv 2019 07;3(14):2057-2068

Center for Cancer and Immunology Research, Children's National Health System and Department of Pediatrics, The George Washington University, Washington, DC.

Adoptive transfer of virus-specific T cells (VSTs) has been shown to be safe and effective in stem cell transplant recipients. However, the lack of virus-experienced T cells in donor cord blood (CB) has prevented the development of ex vivo expanded donor-derived VSTs for recipients of this stem cell source. Here we evaluated the feasibility and safety of ex vivo expansion of CB T cells from the 20% fraction of the CB unit in pediatric patients receiving a single CB transplant (CBT). In 2 clinical trials conducted at 2 separate sites, we manufactured CB-derived multivirus-specific T cells (CB-VSTs) targeting Epstein-Barr virus (EBV), adenovirus, and cytomegalovirus (CMV) for 18 (86%) of 21 patients demonstrating feasibility. Manufacturing for 2 CB-VSTs failed to meet lot release because of insufficient cell recovery, and there was 1 sterility breach during separation of the frozen 20% fraction. Delayed engraftment was not observed in patients who received the remaining 80% fraction for the primary CBT. There was no grade 3 to 4 acute graft-versus-host disease (GVHD) associated with the infusion of CB-VSTs. None of the 7 patients who received CB-VSTs as prophylaxis developed end-organ disease from CMV, EBV, or adenovirus. In 7 patients receiving CB-VSTs for viral reactivation or infection, only 1 patient developed end-organ viral disease, which was in an immune privileged site (CMV retinitis) and occurred after steroid therapy for GVHD. Finally, we demonstrated the long-term persistence of adoptively transferred CB-VSTs using T-cell receptor-Vβ clonotype tracking, suggesting that CB-VSTs are a feasible addition to antiviral pharmacotherapy.
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http://dx.doi.org/10.1182/bloodadvances.2019000201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650740PMC
July 2019

Purtscher-like retinopathy: A rare presentation of hematopoietic stem cell transplant-associated thrombotic microangiopathy.

Pediatr Transplant 2019 03 20;23(2):e13344. Epub 2019 Jan 20.

Division of Pediatric Hematology Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.

Hematopoietic stem cell transplant (HSCT)-associated (TA) thrombotic microangiopathy (TMA) is an acquired disorder and a potentially life-threatening complication after allogeneic HSCT. TA-TMA causes endothelial damage and results in micro-thrombi in capillaries and arterioles. Early detection and treatment of complications associated with TA-TMA might improve outcomes. Purtscher-like retinopathy (PLR) is associated with micro-thrombi that occlude the retinal arteries and cause retinal injury. PLR has been associated with multiple entities, including HUS and TTP, but has not previously been described in the setting of TA-TMA. Here, we describe an 18-year-old male who underwent a mismatched unrelated donor HSCT for relapsed acute lymphoblastic leukemia. The patient was diagnosed with TA-TMA based on standard defined criteria. He presented with acute onset of blurred vision with findings of multiple white retinal patches, retinal hemorrhages, and macular edema, thought initially to be hypertensive retinopathy. However, on further evaluation using fluorescein angiography and optical coherence tomography, the diagnosis was determined to be PLR. The patient was treated with intravitreal steroid injections (triamcinolone acetonide) with dramatic improvement of vision. The aim of this report is to make clinicians aware of PLR as a potential ocular complication associated with TA-TMA and that prompt intervention might reverse visual impairment.
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http://dx.doi.org/10.1111/petr.13344DOI Listing
March 2019

Monozygotic twins with non-Down syndrome associated MLL-rearranged hematologic malignancy and megakaryoblastic differentiation.

Leuk Lymphoma 2019 04 2;60(4):1083-1086. Epub 2018 Oct 2.

a Department of Pediatrics, Section of Hematology and Oncology , Baylor College of Medicine , Houston , TX , USA.

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http://dx.doi.org/10.1080/10428194.2018.1516883DOI Listing
April 2019

Immunoglobulin prophylaxis in pediatric hematopoietic stem cell transplant.

Pediatr Blood Cancer 2018 12 11;65(12):e27348. Epub 2018 Sep 11.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

Background: After allogeneic hematopoietic stem cell transplantation (HSCT), patients have an increased susceptibility to infections, thought to be due in part to hypogammaglobulinemia. Thus, prophylactic administration of intravenous immunoglobulins (IVIG) has been administered to patients after HSCT as standard of care. This study compares the viral infection rate between dosing IVIG by IgG levels versus by routine monthly administration in pediatric patients after HSCT.

Procedure: In this retrospective chart review, we abstracted from electronic medical records data on pediatric patients undergoing HSCT from 2010 to 2012 for 6 months post-HSCT. We compared rates of infection between patients treated with routine IVIG prophylaxis and patients given IVIG prophylaxis based on IgG tough levels (IgG levels were checked every 2 weeks).

Results: Data were available and reviewed for 50 patients dosed with IVIG every 28 days (Group 1) and 100 patients dosed with IVIG based on IgG level > 400 mg/dl (Group 2). There was no significant difference in age (P = 0.98) or sex (P = 0.42), reason for HSCT, alemtuzumab use (P = 0.602), or reduced intensity conditioning (P = 1.00). Significantly more haploidentical donors were in Group 1 (P = 0.04), otherwise there was no significant difference in donor type between groups. Significantly less acute graft versus host disease occurred (P = <0.001) in Group 2 (P = <0.001). PCR documented viral infections were not significantly different (P = 0.412) (Table 1). Group 2 patients received significantly less IVIG (P < 0.001).

Conclusion: Dosing IVIG to maintain an IgG level > 400 mg/dl is a cost-effective and safe way to prevent viral infections in pediatric patients undergoing HSCT.
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http://dx.doi.org/10.1002/pbc.27348DOI Listing
December 2018

Therapeutic Plasma Exchange does not Improve Renal Function in Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy: An Institutional Experience.

Biol Blood Marrow Transplant 2019 01 23;25(1):157-162. Epub 2018 Aug 23.

Department of Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic stem cell transplant (HSCT) that causes severe multiorgan injury. The kidneys are almost universally affected. There is no proven therapy, but therapeutic plasma exchange (TPE) is commonly used to treat TA-TMA at Texas Children's Hospital (TCH). To date, there have been no studies assessing the long-term efficacy of TPE in preventing the development of chronic kidney disease (CKD) in TA-TMA patients. In this study we retrospectively analyzed the incidence of CKD in TA-TMA pediatric patients treated with TPE to determine if this treatment modality improves renal morbidity. We reviewed records between January 2007 and June 2017 of pediatric HSCT patients diagnosed with TA-TMA, identified through an internal database maintained at TCH. To be included patients must have completed a course of TPE per the "TPE in TA-TMA" institutional protocol at TCH. CKD was defined as kidney damage for at least 3 months and stratified into stages 1 through 5 according to estimated glomerular filtration rate. Stages 4 and 5 were considered "severe CKD." In the 10-year timeframe 15 patients with TA-TMA completed a course of TPE per our institutional protocol and were subsequently followed for a median of 963 days. Fourteen patients developed CKD, and 5 of these 14 patients developed severe CKD. The cumulative incidence of severe CKD development was 33% (95% confidence interval. 11% to 57%). 6 patients required dialysis, and 2 patients received a renal transplant. 5 patients received eculizumab in addition to TPE. In our patients a TPE course of at least 7 weeks (and up to 25 weeks) was not effective in the prevention of CKD. Our data indicate a need for alternative therapeutic measures to prevent the development of CKD in TA-TMA patients.
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http://dx.doi.org/10.1016/j.bbmt.2018.08.016DOI Listing
January 2019

Allogeneic hematopoietic cell transplant following crizotinib monotherapy for relapsed/refractory anaplastic large cell lymphoma.

Pediatr Transplant 2018 08 2;22(5):e13210. Epub 2018 May 2.

Department of Pediatrics, Center for Cell and Gene Therapy, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA.

Relapsed ALK-positive ALCL often is responsive to CRZ monotherapy. The subsequent role of allogeneic HCT after achieving second remission is poorly understood. We report 6 children who underwent allogeneic HCT for relapsed ALCL after CRZ. Age at transplant ranged from 10.7 to 22.6 years. Follow-up ranged from 0.9 to 4.5 years. All patients engrafted. Three of 4 patients that received a reduced-toxicity conditioning regimen containing fludarabine, alemtuzumab, and low-dose irradiation showed progressive mixed chimerism. Five patients remain in remission. One patient developed isolated CNS relapse 3.6 years after HCT despite a lack of previous CNS involvement. No acute transplant-related complications were experienced. One patient developed chronic renal disease secondary to transplant-associated microangiopathy and one patient chronic GVHD secondary to DLI. Ultimately, allogeneic HCT appears safe and potentially curative after remission induction with CRZ. The role of conditioning therapy, ablative or reduced intensity, remains uncertain for patients' post-CRZ monotherapy, and further studies may be warranted.
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http://dx.doi.org/10.1111/petr.13210DOI Listing
August 2018

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

Blood 2018 07 9;132(1):89-100. Epub 2018 Apr 9.

Department of Pediatrics, Baylor College of Medicine, Houston, TX.

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age ( < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy ( < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.
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http://dx.doi.org/10.1182/blood-2017-11-814244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034641PMC
July 2018

High Incidence of Autoimmune Disease after Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease.

Biol Blood Marrow Transplant 2018 08 6;24(8):1643-1650. Epub 2018 Apr 6.

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas. Electronic address:

There is a lack of consensus regarding the role and method of hematopoietic stem cell transplantation (HSCT) on patients with chronic granulomatous disease (CGD). Long-term follow-up after HSCT in these patient population is essential to know its potential complications and decide who will benefit the most from HSCT. We report the outcome of HSCT and long-term follow-up in 24 patients with CGD, transplanted in our center from either related (n = 6) or unrelated (n = 18) donors, over a 12-year period (2003 to 2015), using high-dose alemtuzumab in the preparative regimen. We evaluated the incidence and timing of adverse events and potential risk factors. We described in detailed the novel finding of increased autoimmunity after HSCT in patients with CGD. At a median follow-up of 1460 days, 22 patients were full donor chimeras, and 2 patients had stable mixed chimerism. All assessable patients showed normalization of their neutrophil oxidative burst test. None of the patients developed grades II to IV acute graft-versus-host disease, and no patient had chronic graft-versus-host disease. Twelve of 24 patients developed 17 autoimmune diseases (ADs). Severe ADs (cytopenia and neuropathy) occurred exclusively in the unrelated donor setting and mainly in the first year after HSCT, whereas thyroid AD occurred in the related donor setting as well and more than 3 years after HSCT. Two patients died due to infectious complications after developing autoimmune cytopenias. One additional patient suffered severe brain injury. The remaining 21 patients have long-term Lansky scores ≥ 80. The outcome of HSCT from unrelated donors is comparable with related donors but might carry an increased risk of developing severe AD. A lower dose of alemtuzumab may reduce this risk and should be tested in further studies.
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http://dx.doi.org/10.1016/j.bbmt.2018.03.029DOI Listing
August 2018

Current Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric Acute Lymphocytic Leukemia: Success, Failure and Future Perspectives-A Single-Center Experience, 2008 to 2016.

Biol Blood Marrow Transplant 2018 07 14;24(7):1424-1431. Epub 2018 Mar 14.

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital. Houston, Texas.

Hematopoietic stem cell transplantation (HSCT) is the only curative option for a subset of patients with high-risk or relapsed acute lymphoblastic leukemia (ALL). Given evolving practices, it is important to continually evaluate outcomes for pediatric ALL following HSCT. Outcomes after HSCT are influenced by the type of donor used as this determines the degree and method of T cell depletion used and, consequently, specific transplant-related morbidities. We retrospectively analyzed HSCT data from our center for transplants performed between January 2008 and May 2016, comparing outcomes among different donor types. One hundred and twenty-four pediatric patients underwent HSCT from a matched sibling donor (MSD; n = 48), an unrelated matched donor (UMD; n = 56), or a haploidentical donor (n = 20). We observed a similar 3-year event-free survival (EFS) for MSD recipients (of .64) and for UMD recipients (.62), but a significantly lower EFS for recipients of haploidentical transplants (.35; P = .01). Relapse was the main cause of HSCT failure and was significantly higher in the haploidentical donor group (.47 versus .19 for MSD and .24 for UMD; P = .02). Treatment-related mortality was evenly distributed among the donor groups (.17, .16, and .15 for the MSD, UMD, and haploidentical groups, respectively). Rates of infection-related mortality were lower than previously reported. Relapse is the main obstacle for successful HSCT in the contemporary era, and this effect is most evident in recipients of haploidentical donor grafts. Newer methods to improve graft-versus-leukemia effect are being evaluated and will need to be incorporated into the management of high-risk patients.
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http://dx.doi.org/10.1016/j.bbmt.2018.03.001DOI Listing
July 2018

Intravesicular cidofovir for BK hemorrhagic cystitis in pediatric patients after hematopoietic stem cell transplant.

Pediatr Transplant 2018 05 1;22(3):e13141. Epub 2018 Feb 1.

Baylor College of Medicine, Houston, TX, USA.

BK virus hemorrhagic cystitis is a complication of HCST. Response to IV cidofovir is unpredictable, and treatment carries risk of toxicity. We report the largest series of pediatric patients with BKHC after HSCT successfully treated with intravesicular cidofovir. There was no significant decrease in urine or plasma BK PCR. There was significant decrease in pain score on days 3 and 7, with associated decrease in morphine use. No patients experienced toxicities associated with IV cidofovir. Intravesicular cidofovir appears to be safe and effective for symptomatic treatment of BKHC in pediatric patients after HSCT.
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http://dx.doi.org/10.1111/petr.13141DOI Listing
May 2018

Outcomes after Allogeneic Transplant in Patients with Wiskott-Aldrich Syndrome.

Biol Blood Marrow Transplant 2018 03 28;24(3):537-541. Epub 2017 Nov 28.

Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas. Electronic address:

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Currently, hematopoietic stem cell transplantation (HSCT) is the most reliable curative treatment with excellent results for patients with HLA-matched family or unrelated donors. However, even after fully myeloablative preparative regimens, mixed donor chimerism is a potential concern. We performed a retrospective chart review of 12 children who underwent allogeneic HSCT for WAS to report our experience. The median age at transplant was 10.5 months (range, 3 to 39). The median nucleated cell dose from the marrow was 4.55 × 10/kg (range, .3 to 7.9). The median times to neutrophil and platelet engraftment were 19 days (range, 13 to 27) and 18.5 days (range, 12 to 31), respectively. The rate of overall survival was 92% with median follow-up of 67 months (range, 3 to 146). Two patients developed grade IV acute graft-versus-host disease, and 1 died on day +99. Five of 12 patient's (42%) had mixed donor chimerism (range, 12% to 85%) at day +180. None of the pretransplant patient parameters was predictive of mixed chimerism. Nonetheless, of these 5 patients, 2 had normalization of the platelet count despite the mixed chimerism, 2 had full donor chimerism after receiving a second transplant with the same donor, and 1 remains transfusion dependent awaiting a second transplant. Hence, even with a significant rate of mixed chimerism, HSCT provides substantial benefit to WAS patients, with excellent overall survival.
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http://dx.doi.org/10.1016/j.bbmt.2017.11.019DOI Listing
March 2018

Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2.

Blood 2017 12 3;130(24):2682-2688. Epub 2017 Oct 3.

Department of Pediatrics, Division of Immunology, University Hospitals of Leuven, Leuven, Belgium.

Deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in DADA2 results in variable autoinflammation and vasculopathy (recurrent fevers, livedo reticularis, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency and bone marrow failure. Tumor necrosis factor-α blockade is the treatment of choice for the autoinflammation and vascular manifestations. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. We present a cohort of 14 patients from 6 countries who received HSCT for DADA2. Indication for HSCT was bone marrow dysfunction or immunodeficiency. Six of 14 patients had vasculitis pre-HSCT. The median age at HSCT was 7.5 years. Conditioning regimens were myeloablative (9) and reduced intensity (5). Donors were HLA-matched sibling (n = 1), HLA-matched unrelated (n = 9), HLA-mismatched unrelated (n = 3), and HLA haploidentical sibling (n = 1). All patients are alive and well with no new vascular events and resolution of hematological and immunological phenotype at a median follow-up of 18 months (range, 5 months to 13 years). Plasma ADA2 enzyme activity normalized in those tested post-HSCT (7/7), as early as day +14 (myeloid engraftment). Post-HSCT hematological autoimmunity (cytopenias) was reported in 4 patients, acute graft-versus-host disease grade 1 in 2, grade 2 in 3, and grade 3-4 in 1, and moderate chronic graft-versus-host disease in 1 patient. In conclusion, in 14 patients, HSCT was an effective and definitive treatment of DADA2.
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http://dx.doi.org/10.1182/blood-2017-07-798660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731089PMC
December 2017

Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation.

J Clin Oncol 2017 Nov 7;35(31):3547-3557. Epub 2017 Aug 7.

Ifigeneia Tzannou, Anastasia Papadopoulou, Swati Naik, Kathryn Leung, Caridad A. Martinez, Carlos A. Ramos, George Carrum, Ghadir Sasa, Premal Lulla, Ayumi Watanabe, Manik Kuvalekar, Adrian P. Gee, Bambi J. Grilley, Robert A. Krance, Stephen Gottschalk, Malcolm K. Brenner, Cliona M. Rooney, Helen E. Heslop, Ann M. Leen, and Bilal Omer, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital; Meng-Fen Wu and Hao Liu, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX.

Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.
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http://dx.doi.org/10.1200/JCO.2017.73.0655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662844PMC
November 2017

Activating MAPK1 (ERK2) mutation in an aggressive case of disseminated juvenile xanthogranuloma.

Oncotarget 2017 Jul;8(28):46065-46070

Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA.

Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder that is usually benign and self-limiting. We present a case of atypical, aggressive JXG harboring a novel mitogen-activated protein kinase (MAPK) pathway mutation in the MAPK1 gene, which encodes mitogen-activated protein kinase 1 or extracellular signal-regulated 2 (ERK2). Our analysis revealed that the mutation results in constitutive ERK activation that is resistant to BRAF or MEK inhibitors but susceptible to an ERK inhibitor. These data highlight the importance of identifying specific MAPK pathway alterations as part of the diagnostic workup for patients with histiocytic disorders rather than initiating empiric treatment with MEK inhibitors.
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http://dx.doi.org/10.18632/oncotarget.17521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542249PMC
July 2017

Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes.

J Allergy Clin Immunol 2016 05 24;137(5):1498-1505.e1. Epub 2016 Feb 24.

Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC; Division of Allergy and Immunology, Children's National Medical Center, Washington, DC. Electronic address:

Background: Viral infections are a leading fatal complication for patients with primary immunodeficiencies (PIDs) who require hematopoietic stem cell transplantation (HSCT). Use of virus-specific T lymphocytes (VSTs) has been successful for the treatment and prevention of viral infections after HSCT for malignant and nonmalignant conditions. Here we describe the clinical use of VSTs in patients with PIDs at 4 centers.

Objective: We sought to evaluate the safety and efficacy of VSTs for treatment of viral infections in patients with PIDs.

Methods: Patients with PIDs who have received VST therapy on previous or current protocols were reviewed in aggregate. Clinical information, including transplantation details, viral infections, and use of antiviral and immunosuppressive pharmacotherapy, were evaluated. Data regarding VST production, infusions, and adverse reactions were compared.

Results: Thirty-six patients with 12 classes of PID diagnoses received 37 VST products before or after HSCT. Twenty-six (72%) patients had received a diagnosis of infection with cytomegalovirus, EBV, adenovirus, BK virus, and/or human herpesvirus 6. Two patients were treated before HSCT because of EBV-associated lymphoproliferative disease. Partial or complete responses against targeted viruses occurred in 81% of patients overall. Time to response varied from 2 weeks to 3 months (median, 28 days). Overall survival at 6 months after therapy was 80%. Four patients had graft-versus-host disease in the 45 days after VST infusion, which in most cases was therapy responsive.

Conclusion: VSTs derived from either stem cell donors or third-party donors are likely safe and effective for the treatment of viral infections in patients with PIDs.
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http://dx.doi.org/10.1016/j.jaci.2015.12.1311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860050PMC
May 2016

Risk-Based Therapy for Localized Osteosarcoma.

Pediatr Blood Cancer 2016 Mar 26;63(3):412-7. Epub 2015 Oct 26.

Department of Pediatrics, Baylor College of Medicine, Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.

Background: The outcome of localized osteosarcoma has remained constant over the past 30 years. Histological response to preoperative chemotherapy is the best predictor of outcome. Strategies to alter treatment based on histological response have not resulted in increased survival.

Procedure: Patients with localized osteosarcoma received preoperative chemotherapy with cisplatin, doxorubicin, and methotrexate. Patients whose tumors had a good histological response (≥90% necrosis) continued with the same treatment postoperatively. Patients with poor histological response (<90% necrosis) received three courses of melphalan 100 mg/m(2) on day -4, cyclophosphamide 2,000 mg/m(2) on days -3, and -2 followed by stem cell infusion.

Results: Fifty-two patients were enrolled. Median age was 14 years, and 56% of patients were male. The femur was the most common site. Forty patients underwent limb salvage surgery and amputation was performed in six patients. Forty-eight percent of tumors showed good histological response. Forty patients were evaluable for outcome; 18 patients with poor histologic response received high-dose chemotherapy. The 5-year event-free survival (EFS) and overall survival (OS) for patients treated on the high-dose chemotherapy arm were 28% (95% confidence interval [CI], 10-49) and 48% (95% CI, 23-69), respectively. The 5-year EFS and OS for patients treated on the standard chemotherapy arm were 62% (95% CI, 36-80) and 74% (95% CI, 44-90), respectively. All patients who received high-dose chemotherapy developed grade 3 or higher hematological toxicity. There were no treatment-related deaths.

Conclusions: Postoperative alkylator intensification with high-dose cyclophosphamide and melphalan in patients with localized osteosarcoma with poor histological response failed to improve survival.
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http://dx.doi.org/10.1002/pbc.25808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993185PMC
March 2016

Risk-Based Therapy for Localized Osteosarcoma.

Pediatr Blood Cancer 2016 Mar 26;63(3):412-7. Epub 2015 Oct 26.

Department of Pediatrics, Baylor College of Medicine, Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.

Background: The outcome of localized osteosarcoma has remained constant over the past 30 years. Histological response to preoperative chemotherapy is the best predictor of outcome. Strategies to alter treatment based on histological response have not resulted in increased survival.

Procedure: Patients with localized osteosarcoma received preoperative chemotherapy with cisplatin, doxorubicin, and methotrexate. Patients whose tumors had a good histological response (≥90% necrosis) continued with the same treatment postoperatively. Patients with poor histological response (<90% necrosis) received three courses of melphalan 100 mg/m(2) on day -4, cyclophosphamide 2,000 mg/m(2) on days -3, and -2 followed by stem cell infusion.

Results: Fifty-two patients were enrolled. Median age was 14 years, and 56% of patients were male. The femur was the most common site. Forty patients underwent limb salvage surgery and amputation was performed in six patients. Forty-eight percent of tumors showed good histological response. Forty patients were evaluable for outcome; 18 patients with poor histologic response received high-dose chemotherapy. The 5-year event-free survival (EFS) and overall survival (OS) for patients treated on the high-dose chemotherapy arm were 28% (95% confidence interval [CI], 10-49) and 48% (95% CI, 23-69), respectively. The 5-year EFS and OS for patients treated on the standard chemotherapy arm were 62% (95% CI, 36-80) and 74% (95% CI, 44-90), respectively. All patients who received high-dose chemotherapy developed grade 3 or higher hematological toxicity. There were no treatment-related deaths.

Conclusions: Postoperative alkylator intensification with high-dose cyclophosphamide and melphalan in patients with localized osteosarcoma with poor histological response failed to improve survival.
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http://dx.doi.org/10.1002/pbc.25808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993185PMC
March 2016

CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo.

Sci Transl Med 2015 Apr;7(285):285ra63

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Adoptive transfer of cytomegalovirus (CMV)-specific T cells derived from adult seropositive donors can effectively restore antiviral immunity after transplantation. However, CMV-seronegative donors lack CMV-specific memory T cells, which restricts the availability of virus-specific T cells for immunoprophylaxis. We demonstrate the feasibility of deriving CMV-specific T cells from naïve cells for T cell therapy. Naïve T cells primed to recognize CMV were restricted to different, atypical epitopes than T cells derived from CMV-seropositive individuals; however, these two cell populations had similar avidities. CMV-seropositive individuals also had T cells recognizing these atypical epitopes, but these cells had a lower avidity than those derived from the seronegative subjects, which suggests that high-avidity T cells to these epitopes may be lost over time. Indeed, recipients of cord blood (CB) grafts who did not develop CMV were found by clonotypic analysis to have T cells recognizing atypical CMVpp65 epitopes. Therefore, we examined unmanipulated CB units and found that T cells with T cell receptors restricted by atypical epitopes were the most common, which may explain why these T cells expanded. When infused to recipients, naïve donor-derived virus-specific T cells that recognized atypical epitopes were associated with prolonged periods of CMV-free survival and complete remission. These data suggest that naïve-derived T cells from seronegative patients may be an additional source of cells for CMV immunoprophylaxis.
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http://dx.doi.org/10.1126/scitranslmed.aaa2546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479400PMC
April 2015

Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning.

Br J Haematol 2015 Jun 27;169(5):711-8. Epub 2015 Mar 27.

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

Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.
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http://dx.doi.org/10.1111/bjh.13347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433436PMC
June 2015

The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post-first and post-second hematopoietic stem cell transplant.

Pediatr Transplant 2015 Jun 23;19(4):391-8. Epub 2015 Mar 23.

Department of Pediatric Hematology/Oncology and BMT, Children's Mercy Hospital, Kansas City, MO, USA.

The reported incidence of post-allogeneic HSCT AIHA was between 4.4% and 6% following a single transplant. Cord blood transplantation, T-cell depletion, and chronic GvHD are significantly associated with post-transplant AIHA. During an 11-yr period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post-first and post-second transplants. Demographic, transplant, and post-transplant-related variables were analyzed. Twelve of 500 (2.4%) recipients at a median of 273 days and seven of 72 (9.7%) recipients at a median of 157 days developed AIHA post-first and post-second HSCT, respectively. Post-first HSCT, none of the MRD recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p = 0.04). Four of 12 required a second HSCT to control the AIHA. After the second HSCT, MUD was significantly associated with the development of AIHA. No other variables were associated with the post-second transplant AIHA. The incidence of AIHA post-first and post-second HSCT was less than the reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications, and management of post-transplant AIHA.
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http://dx.doi.org/10.1111/petr.12455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420696PMC
June 2015

Outcomes after Second Hematopoietic Stem Cell Transplantations in Pediatric Patients with Relapsed Hematological Malignancies.

Biol Blood Marrow Transplant 2015 Jul 10;21(7):1266-72. Epub 2015 Mar 10.

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas.

Relapse of hematological malignancies after hematopoietic stem cell transplantation (HCT) is associated with poor prognosis. A second HCT represents one of the few therapeutic options for these high-risk patients. For children undergoing second HCT, the outcome data are particularly limited. We, therefore, conducted a retrospective single-institution study and report the outcomes and prognostic variables associated with overall survival (OS) and relapse in 43 pediatric patients who underwent a second HCT between 2000 and 2013. Eleven of the 43 patients who underwent transplantation remain alive and disease-free at a median follow-up of 49 months (range, 5 to 127 months). The 5-year probability of OS for the entire cohort was 24%. Patients who had early relapse (<6 months) after first HCT had significantly worse OS than those who relapsed late (>6 months), with 5-year OS at 11% versus 34%, respectively (hazard ratio [HR], 2.24; 95% confidence interval [CI], 1.21 to 4.93; P = .013). Active disease at time of second HCT was also associated with a significantly increased risk of relapse (subdistribution hazard ratio [SHR], 2.36; P = .049) for the entire cohort and relapse was the most frequent cause of death (23 of 32; 72%). On subgroup analysis for the 34 patients with leukemia alone, presence of active disease was associated both with a significant decrease in OS (SHR, 2.28; 95% CI, 1.02 to 5.09; P = .044) and significant increase in the rate of relapse (SHR, 2.46; P = .046). By contrast, underlying disease, donor source, conditioning regimen, or development of GVHD did not modify OS or rate of relapse. Hence, a second HCT appears to be a useful therapeutic option in children with relapsed hematological malignancies that is most likely to benefit those individuals with late onset of relapse and with low disease burden at the time of transplantation.
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http://dx.doi.org/10.1016/j.bbmt.2015.02.024DOI Listing
July 2015