Publications by authors named "Julie-An Talano"

33 Publications

Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis.

J Clin Immunol 2020 08 7;40(6):901-916. Epub 2020 Jul 7.

CHU Sainte-Justine, Department of Pediatrics, Department of Microbiology, Infectious Diseases and Immunology, University of Montreal, Montreal, QC, H3T 1C5, Canada.

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.
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http://dx.doi.org/10.1007/s10875-020-00814-6DOI Listing
August 2020

Priorities for Improving Outcomes for Nonmalignant Blood Diseases: A Report from the Blood and Marrow Transplant Clinical Trials Network.

Biol Blood Marrow Transplant 2020 05 5;26(5):e94-e100. Epub 2020 Feb 5.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Nonmalignant blood diseases such as bone marrow failure disorders, immune dysregulation disorders, and hemoglobinopathies often lead to shortened life spans and poor quality of life. Many of these diseases can be cured with allogeneic hematopoietic cell transplantation, but patients are often not offered the procedure because of perceived insufficient efficacy and/or excess toxicity. In 2018, the Blood and Marrow Transplant Clinical Trials Network convened a task force to identify the most urgently needed yet feasible clinical trials with potential to improve the outcomes for patients with nonmalignant diseases. This report summarizes the task force discussions and specifies the network plans for clinical trial development for nonmalignant blood diseases.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.024DOI Listing
May 2020

Partially CD3-Depleted Unrelated and Haploidentical Donor Peripheral Stem Cell Transplantation Has Favorable Graft-versus-Host Disease and Survival Rates in Pediatric Hematologic Malignancy.

Biol Blood Marrow Transplant 2020 03 22;26(3):493-501. Epub 2019 Nov 22.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3/CD19 depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P= .05) and EFS (P= .05). Relapse was more common in children in second complete remission (P = .03). Partially CD3-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.022DOI Listing
March 2020

Hemophagocytic lymphohistiocytosis mimicking neonatal hemochromatosis.

Pediatr Hematol Oncol 2019 Oct 19;36(7):451-456. Epub 2019 Aug 19.

Department of Pediatrics, Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Medical College of Wisconsin , Milwaukee , Wisconsin , USA.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal illness characterized by impaired natural killer (NK) cell and cytotoxic T-cell function. Patients develop systemic inflammation, multisystem organ dysfunction, and if untreated, death. Patients who present in the neonatal period often have atypical presentations with evidence of liver dysfunction and cholestasis; this has a broad differential diagnosis including neonatal infection, congenital liver defects, or other causes of liver dysfunction, such as neonatal hemochromatosis. Here, we present an infant whose diagnosis of familial HLH was confounded by the history of a stillborn sibling with suspected neonatal hemochromatosis, ultimately delaying diagnosis and initiation of curative treatment. This highlights the need to maintain a low threshold for sending HLH work-up concurrently with evaluation of liver diseases in infants with liver dysfunction, to ensure timely diagnosis and initiation of treatment. Clinicians should maintain a high index of suspicion for HLH and be aware that HLH may mimic the findings on liver biopsy seen in neonatal hemochromatosis.
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http://dx.doi.org/10.1080/08880018.2019.1654051DOI Listing
October 2019

First report that prior ECMO therapy does not preclude hematopoietic cell transplantation.

Pediatr Hematol Oncol 2018 May 20;35(4):245-249. Epub 2018 Dec 20.

a Department of Pediatrics, Division of Blood and Marrow Transplantation , Children's Hospital of Wisconsin, Medical College of Wisconsin , Milwaukee , WI , USA.

Hematopoietic stem cell transplantation (HCT) offers a potential cure for patients with high-risk malignancies but carries a risk of death from transplant-related complications. Extracorporeal membrane oxygenation (ECMO) is often considered a contraindication to transplant with the assumption that lung injury puts the patient at risk for pulmonary complications post-HCT. Although patients who have required prolonged intubation show gradual improvement in pulmonary function over time, there is little data on pulmonary functional recovery after ECMO which makes assessment pre-HCT difficult. We present a case series of two patients with high-risk hematologic malignancies, who had previously received ECMO and then underwent reduced-intensity HCT. Although both patients had complications post-HCT, neither patient suffered significant pulmonary toxicity related to their prior ECMO exposure. We conclude that, although patients who have previously been treated with ECMO remain at high risk for complications after transplant, but they should not be excluded from consideration for reduced intensity transplantation.
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http://dx.doi.org/10.1080/08880018.2018.1505989DOI Listing
May 2018

Post-transplantation employment status of adult survivors of childhood allogeneic hematopoietic cell transplant: A report from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Cancer 2019 01 12;125(1):144-152. Epub 2018 Oct 12.

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

Background: Data are scarce regarding employment outcomes of survivors of childhood allogeneic hematopoietic cell transplantation (alloHCT) and the factors that affect their employment status.

Methods: By using the Center for International Blood and Marrow Transplant Research database, the authors studied employment outcomes of ≥1-year survivors of childhood alloHCT who were age ≥18 years at their most recent assessment (year of transplantation, 1985-2010). Employment status was assessed at their attained ages (ages 18-22, 23-27, and 28-32 years) and according to transplantation center (TC) location (United States or International). A multivariable analysis assessing the factors that affected employed status (full-time/part-time work or student) was performed.

Results: Unemployment rates among 2844 survivors were persistently high at all attained ages (United States TCs: ages 18-22 [14%], 23-27 [15%], and 28-32 [13%] years; International TCs: ages 18-22 [56%], 23-27 [53%], and 28-32 [68%] years). The factors associated a with higher likelihood of employment included: older age at alloHCT (ages 5-9-years: hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.65-2.6; ages 10-14 years: HR, 4.43; 95% CI, 3.58-5.47; ages 15-18-years: HR, 7.13; 95% CI, 5.72-8.88), myeloablative conditioning without total body irradiation (TBI) (HR, 1.56; 95% CI, 1.38-1.77), reduced-intensity conditioning with TBI (HR, 1.47; 95% CI, 1.19-1.8) or without TBI (HR, 2.51; 95% CI, 2.15-2.92), and US-based TC (HR, 1.84; 95% CI, 1.62-2.08).

Conclusions: Young adult survivors of childhood alloHCT have high unemployment rates at all studied attained ages after HCT. Future efforts should be directed toward understanding the causes of unemployment their and relation to quality of life using patient-reported outcome measures.
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http://dx.doi.org/10.1002/cncr.31781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310211PMC
January 2019

Reduced-intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies.

Blood 2018 09 11;132(13):1438-1451. Epub 2018 Jul 11.

Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA.

Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced-intensity conditioning with melphalan, fludarabine, and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary end point was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow-up of 20 months, the 1-year OS for transplanted patients was 80.4% (90% confidence interval [CI], 68.6%-88.2%). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI, 52.9%-77.3%). Two patients experienced primary graft failure, and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion [DLI]). At 1 year, the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI, 25.2%-54.6%), and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI, 45.4 %-74.9%). The day 100 incidence of grade II to IV acute GVHD was 17.4% (95% CI, 8.1%-29.7%), and 1-year incidence of chronic GVHD was 26.7% (95% CI, 14.6%-40.4%). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633).
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http://dx.doi.org/10.1182/blood-2018-01-828277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161764PMC
September 2018

Hemophagocytic lymphohistiocytosis in adults.

Leuk Lymphoma 2019 01 3;60(1):19-28. Epub 2018 Jul 3.

a Department of Pediatrics, Division of Hematology/Oncology/BMT , Medical College of Wisconsin , Milwaukee , WI , USA.

Hemophagocytic lymphohistiocytosis (HLH), a rare but life-threatening condition characterized by uncontrolled inflammation, is increasingly recognized in adults. The management of adult onset HLH is challenging, in part due to gaps in current state of knowledge on etiology, clinical presentation, diagnosis, and management. HLH secondary to triggers such as infections, autoimmune disorders, and malignancy are more commonly seen in adults although cases of familial form have also been reported. Underlying conditions such as sepsis, or malignancy could pose as major confounders while applying universal diagnostic criteria, and therefore could lead to delay in diagnosis. Despite advent of newer therapeutic agents, outcomes of adults continue to remain poor. Future efforts need to be orchestrated to develop evidence-based tailored therapies to improve outcomes of this under recognized heterogeneous entity.
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http://dx.doi.org/10.1080/10428194.2018.1482543DOI Listing
January 2019

Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant: Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression.

Biol Blood Marrow Transplant 2018 10 19;24(10):2040-2046. Epub 2018 Jun 19.

Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, CA, USA.

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239928PMC
October 2018

Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation: Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium.

Biol Blood Marrow Transplant 2018 08 9;24(8):1651-1656. Epub 2018 May 9.

Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington.

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m/day (BSA ≤ .5 m), 12 g/m/day (BSA > .5 to 1.0 m), or 14 g/m/day (BSA > 1.0 m) on days -6 to -4; fludarabine 30 mg/m/day on days -6 to -2; and a single fraction of 200 cGy total body irradiation on day -1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.
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http://dx.doi.org/10.1016/j.bbmt.2018.04.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108922PMC
August 2018

Allogeneic Hematopoietic Cell Transplantation for Chronic Granulomatous Disease: Controversies and State of the Art.

J Pediatric Infect Dis Soc 2018 May;7(suppl_1):S31-S39

Division of Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee.

Chronic granulomatous disease (CGD) is a congenital disorder characterized by recurrent life-threatening bacterial and fungal infections and development of severe inflammation secondary to a congenital defect in 1 of the 5 phagocyte oxidase (phox) subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Hematopoietic cell transplant (HCT) is a curative treatment for patients with CGD that provides donor neutrophils with functional NADPH and superoxide anion production. Many characteristics of CGD, including preexisting infection and inflammation and the potential for cure with mixed-donor chimerism, influence the transplant approach and patient outcome. Because of the dangers of short-term death, graft-versus-host disease, and late effects from chemotherapy, HCT historically has been reserved for patients with high-risk disease and a matched donor. However, as advances in CGD and HCT treatments have evolved, recommendations on transplant eligibility also must be amended, but the development of modern guidelines has proven difficult. In this review, we provide an overview of HCT in patients with CGD, including the debate over HCT indications in them, the unique aspects of CGD that can complicate HCT, and a summary of transplant outcomes.
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http://dx.doi.org/10.1093/jpids/piy015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946867PMC
May 2018

Late cardiovascular morbidity and mortality following pediatric allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2018 10 26;53(10):1278-1287. Epub 2018 Mar 26.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

We analyzed late cardiovascular outcomes of 661 patients who survived at least 2 years from hematopoietic cell transplantation for childhood hematologic malignancy between 1995 and 2008. Center for International Blood and Marrow Transplant Research data was supplemented with surveys focused on cardiotoxicity and potential risk factors. The median duration of follow-up was 97 months (range 24-230). 4.2% of survivors experienced at least one of the primary outcomes including coronary artery disease (0.2%), cerebrovascular accident (0.6%), cardiomyopathy (3%), and cardiac-related death (0.5%). Patients who received anthracycline chemotherapy (HR 4.67, p = 0.036) or cranial or chest radiation (HR 5.58, p < 0.0001; HR 2.18, p = 0.0087) were at increased risk for developing one of the primary outcomes. Dyslipidemia was diagnosed in 18% of survivors. Pre-transplant anthracycline (HR 1.74, p < 0.0001) and chest radiation (HR 1.34, p = 0.0371) were risk factors for dyslipidemia. Overweight/obese body mass status was present in 63% of patients at baseline, 65% at 2 years, and 52% at most recent evaluation. Diabetes was diagnosed in 7% of subjects. In conclusion, severe cardiovascular complications were infrequently reported. The incidence of risk factors including obesity and dyslipidemia were significant and will likely increase the risk of cardiovascular disease over time in transplant survivors.
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http://dx.doi.org/10.1038/s41409-018-0155-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158112PMC
October 2018

Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders.

Biol Blood Marrow Transplant 2017 Oct 7;23(10):1669-1677. Epub 2017 Jun 7.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington; Hematology-Oncology, Seattle Children's Hospital, Seattle, Washington.

Hematopoietic cell transplantation (HCT) is effective in the treatment of inherited marrow failure disorders and other nonmalignant diseases. Conventional myeloablative conditioning regimens have been associated with high transplant-related mortality, particularly in patients with comorbid conditions. Here we report on 14 patients with marrow failure disorders (Shwachman-Diamond syndrome, n = 3; Diamond Blackfan anemia, n = 4; GATA2 deficiency, n = 2; paroxysmal nocturnal hemoglobinuria, n = 4; and an undefined marrow failure disorder, n = 1) who underwent HCT on a prospective, phase II, multicenter clinical trial. Patients were given HLA-matched related (n = 2) or unrelated (n = 12) grafts after conditioning with treosulfan (42 g/m), fludarabine (150 mg/m), ± thymoglobulin (n = 11; 6 mg/kg). All patients engrafted. At a median follow-up of 3 years, 13 patients are alive with complete correction of their underlying disease. These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with a low toxicity profile and excellent disease-free survival in patients with marrow failure disorders.
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http://dx.doi.org/10.1016/j.bbmt.2017.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605451PMC
October 2017

Usual and Unusual Manifestations of Familial Hemophagocytic Lymphohistiocytosis and Langerhans Cell Histiocytosis.

Pediatr Clin North Am 2017 Feb;64(1):91-109

Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Medical College of Wisconsin, 8701 Watertown Plank Road, MFRC 3018, Milwaukee, WI 53226, USA. Electronic address:

Familial hemophagocytic lymphohistiocytosis (FHL) and Langerhans cell histiocytosis (LCH) are histiocytic diseases that occur most commonly in young children. Improvements in recognition and treatment have been substantial for both diseases in the past decade, although early and late morbidity continue to be major concerns. These two diagnoses behave differently, although the clinical spectra for both diseases are diverse and can lead to confusion and delays in diagnosis and treatment. This article focuses on the clinical and genetic spectrum of FHL as well as the clinical and treatment variations of LCH.
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http://dx.doi.org/10.1016/j.pcl.2016.08.006DOI Listing
February 2017

Salvage therapy for refractory hemophagocytic lymphohistiocytosis: A review of the published experience.

Pediatr Blood Cancer 2017 04 27;64(4). Epub 2016 Oct 27.

Children's Cancer Center, Staten Island University Hospital at Northwell Health, Staten Island, New York.

Hemophagocytic lymphohistioytosis (HLH) is a severe, life-threatening hyperinflammatory disorder that requires prompt diagnosis and treatment. Approximately, 25-50% of patients with HLH fail to achieve remission with established regimens that include dexamethasone and etoposide, or methylprednisolone and antithymocyte globulin (ATG). Some of these patients may require salvage or alternative therapeutic approaches. There is a paucity of literature regarding effective salvage therapies for patients with refractory HLH. In this review, we summarize the published experience of four therapeutics reported for using at least two patients with HLH refractory to dexamethasone and etoposide or methylprednisolone and ATG.
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http://dx.doi.org/10.1002/pbc.26308DOI Listing
April 2017

Successful treatment of recurrent CNS disease post-bone marrow transplant in children with familial hemophagocytic lymphohistiocytosis.

Pediatr Blood Cancer 2016 12 27;63(12):2154-2158. Epub 2016 Aug 27.

Department of Pediatric Hematology/Oncology, Children's Hospital of Wisconsin, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin.

Background: Central nervous system (CNS) involvement is a major cause of morbidity and mortality in patients with hemophagocytic lymphohistiocytosis (HLH). Current standard of care for CNS disease utilizes high-dose systemic dexamethasone plus intrathecal methotrexate and hydrocortisone prior to transplantation. However, the morbidity and mortality remains high and there are no clear guidelines posttransplantation for screening and treatment of CNS disease.

Procedure: We report a single-center retrospective case series of five patients with familial HLH (FHLH) who had CNS involvement post-bone marrow transplantation (BMT). All patients were monitored with monthly lumbar punctures (LPs) prior to developing neurologic symptoms. Treatment utilized systemic dexamethasone for CNS disease control.

Results: Five patients were monitored with monthly or bimonthly surveillance LPs and treated with systemic dexamethasone to control CNS relapse post-BMT. All patients are alive, a median of 34 months posttransplant (range 14-66 months). Four patients have mild neurological deficits, including mild speech delay (3) and one patient who exhibited brainstem herniation on day 0, due to CNS HLH, has made a substantial recovery of function with residual deficits of focal weakness on the right side. One patient has no deficits.

Conclusion: Our data support vigilant screening posttransplant for occult CNS disease prior to the development of symptoms and the use of systemic dexamethasone to reverse disease progression. Future prospective trials are needed to evaluate this treatment strategy.
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http://dx.doi.org/10.1002/pbc.26175DOI Listing
December 2016

Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience.

Blood 2016 07 23;128(3):440-8. Epub 2016 May 23.

Department of Paediatric Immunology, Great North Children´s Hospital, Newcastle Upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.

Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR αβ/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.
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http://dx.doi.org/10.1182/blood-2016-03-704015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957165PMC
July 2016

Curative treatment for severe sickle cell disease: allogeneic transplantation.

Clin Adv Hematol Oncol 2015 Apr;13(4):249-56

Medical College of Wisconsin, Milwaukee, Wisconsin.

Sickle cell disease is an inherited hematologic disorder that in its severe form can result in substantial morbidity and early mortality. Patients with this disorder can suffer from severe pain, lung disease, and strokes, resulting in chronic debilitating conditions, end organ dysfunction, and organ failure. The health care costs of caring for these chronically ill patients are substantial. Allogeneic transplantation is a modality that has the potential to cure these patients. To date, matched sibling donor transplantation is widely accepted as a standard of care for pediatric patients. Utilizing alternative donors for transplant is still under investigation, as is transplant for adult patients with sickle cell disease. This review focuses on the most recent data for hematopoietic cell transplantation for patients with sickle cell disease.
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April 2015

Transplant Outcomes for Children with T Cell Acute Lymphoblastic Leukemia in Second Remission: A Report from the Center for International Blood and Marrow Transplant Research.

Biol Blood Marrow Transplant 2015 Dec 29;21(12):2154-2159. Epub 2015 Aug 29.

Stem Cell Transplant Program, Department of Pediatrics, Vanderbilt University, Nashville, TN.

Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P = .005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted.
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http://dx.doi.org/10.1016/j.bbmt.2015.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654112PMC
December 2015

Smoothing the crescent curve: sickle cell disease.

Hematology Am Soc Hematol Educ Program 2014 Dec 18;2014(1):468-74. Epub 2014 Nov 18.

Department of Pediatrics, Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, and Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY.

Sickle cell disease (SCD) is an inherited disorder secondary to a point mutation at the sixth position of the beta chain of human hemoglobin that results in the replacement of valine for glutamic acid. This recessive genetic abnormality precipitates the polymerization of the deoxygenated form of hemoglobin S that induces a major distortion of red blood cells (sickle red blood cells), which decreases sickle red blood cell deformability, leading to chronic hemolysis and vasoocclusion. These processes can result in severe complications, including chronic pain, end organ dysfunction, stroke, and early mortality. The only proven curative therapy for patients with SCD is myeloablative conditioning and allogeneic stem cell transplantation from HLA-matched sibling donors. In this review, we discuss the most recent advances in allogeneic stem cell transplantation in SCD, including more novel approaches such as reduced toxicity conditioning and the use of alternative allogeneic donors (matched unrelated donors, umbilical cord blood transplantation, haploidentical donors) and autologous gene correction stem cell strategies. Prospects are bright for new stem cell approaches for patients with SCD that will enable curative stem and genetic correction therapies for a greater number of patients suffering from this chronic and debilitating condition.
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http://dx.doi.org/10.1182/asheducation-2014.1.468DOI Listing
December 2014

Hematopoietic stem cell transplantation for sickle cell disease: state of the science.

Eur J Haematol 2015 May 10;94(5):391-9. Epub 2014 Oct 10.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.

Sickle cell disease (SCD) is an inherited disorder secondary to a point mutation at the sixth position of the beta chain of human hemoglobin resulting in the replacement of valine for glutamic acid. This recessive genetic abnormality precipitates the polymerization of the deoxygenated form of hemoglobin S inducing a major distortion of red blood cells (S-RBC), which decreases S-RBC deformability leading to chronic hemolysis and vaso-occlusion. These processes can result in severe complications including chronic pain, end-organ dysfunction, stroke, and early mortality. The only proven curative therapy for patients with SCD is myeloablative conditioning and allogeneic stem cell transplantation from HLA-matched sibling donors. In this review, we discuss the most recent advances in allogeneic stem cell transplantation in patients with SCD including more novel approaches such as reduced toxicity conditioning and the use of alternative allogeneic donors, including matched unrelated donors (MUDs), unrelated cord blood donors (UCBT), and familial haploidentical (FHI) donors. The results to date are very encouraging regarding allogeneic stem cell transplantation for patients with SCD including high survival rates and enabling a greater number of patients suffering from this chronic and debilitating condition to receive curative allogeneic stem cell therapies. However, we still have several areas to investigate and barriers to overcome to successfully cure the majority of patients with severe SCD through allogeneic stem cell therapies.
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http://dx.doi.org/10.1111/ejh.12447DOI Listing
May 2015

Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial.

Biol Blood Marrow Transplant 2014 Dec 6;20(12):1996-2003. Epub 2014 Sep 6.

Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.

Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with treosulfan (total dose, 42 g/m(2)), fludarabine (total dose, 150 mg/m(2)), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.
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http://dx.doi.org/10.1016/j.bbmt.2014.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324724PMC
December 2014

Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients.

Biol Blood Marrow Transplant 2014 Feb 8;20(2):229-35. Epub 2013 Nov 8.

Division of Pediatric Hematology, Oncology, Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.

Severe steroid-refractory acute graft-versus-host disease (aGVHD) is related to significant mortality and morbidity after allogeneic stem cell transplantation. Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with severe aGVHD resistant to multiple immunosuppressive agents showed promising results. In this study, we evaluated the risk/benefit profile of remestemcel-L (Prochymal), a third-party, off-the-shelf source of hMSCs, as a rescue agent for treatment-resistant aGVHD in pediatric patients. Children with grade B-D aGVHD failing steroids and, in most cases, other immunosuppressive agents were eligible for enrollment. Patients received 8 biweekly i.v. infusions of 2 × 10(6) hMSCs/kg for 4 weeks, with an additional 4 weekly infusions after day +28 for patients who achieved either a partial or mixed response. The enrolled patients compose a very challenging population with severe disease that was nonresponsive to the standard of care, with 88% of the patients experiencing severe aGVHD (grade C or D). Seventy-five patients (median age, 8 yr; 58.7% male; and 61.3% Caucasian) were treated in this study. Sixty-four patients (85.3%) had received an unrelated hematopoietic stem cell graft, and 28 patients (37.3%) had received a cord blood graft. At baseline, the distribution of aGVHD grades B, C, and D was 12.0%, 28.0%, and 60.0%, respectively. The median duration of aGVHD before enrollment was 30 d (range, 2 to 1639 d), and patients failed a median of 3 immunosuppressive agents. Organ involvement at baseline was 86.7% gastrointestinal, 54.7% skin, and 36.0% liver. Thirty-six patients (48.0%) had 2 organs involved, and 11 patients (14.7%) had all 3 organs involved. When stratified by aGVHD grade at baseline, the rate of overall response (complete and partial response) at day +28 was 66.7% for aGVHD grade B, 76.2% for grade C, and 53.3% for grade D. Overall response for individual organs at day +28 was 58.5% for the gastrointestinal system, 75.6% for skin, and 44.4% for liver. Collectively, overall response at day +28 for patients treated for severe refractory aGVHD was 61.3%, and this response was correlated with statistically significant improved survival at day +100 after hMSC infusion. Patients who responded to therapy by day +28 had a higher Kaplan-Meier estimated probability of 100-d survival compared with patients who did not respond (78.1% versus 31.0%; P < .001). Prochymal infusions were generally well tolerated, with no evidence of ectopic tissue formation.
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http://dx.doi.org/10.1016/j.bbmt.2013.11.001DOI Listing
February 2014

The use of novel Therakos™ Cellex® for extracorporeal photopheresis in treatment of graft-versus-host disease in paediatric patients.

Br J Haematol 2013 Nov 21;163(3):357-64. Epub 2013 Aug 21.

Division of Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.

Extracorporeal photopheresis (ECP) is an established second line treatment option for graft-versus-host disease (GVHD) post-haematopoietic progenitor cell transplant. At our centre, the Therakos™ Cellex(®) has replaced the Therakos™ UVAR-XTS™ machine for ECP since 2009. We reviewed the records of 385 procedures using the Therakos™ Cellex(®) for safety and tolerability. Nine patients underwent ECP for GVHD. The median age was 13·5 years (range 3·7-24) and weight was 49·2 kg (range 18·5-86·3). The mean duration per procedure was 106 min (range 60-205). Fifteen (3·9%) procedures were cancelled and 10 (2·6%) were delayed, with central venous line (CVL) issues being the most frequent problem. With the use of prophylactic tissue plasminogen activator, fewer CVL-related occlusions were observed (4·7% vs. 2·3%). There was one episode of a CVL-associated thrombosis and one episode of delayed bleeding. There were four episodes of viral reactivation, four CVL-associated infections (1142 catheter days) and one episode of systemic inflammatory response syndrome. No patient experienced symptomatic hypotension. This is the first report outlining the safety and tolerability of the Therakos™ Cellex(®) device for ECP in children and young adults.
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http://dx.doi.org/10.1111/bjh.12535DOI Listing
November 2013

Clinical outcomes of children receiving intensive cardiopulmonary support during hematopoietic stem cell transplant.

Pediatr Crit Care Med 2013 Mar;14(3):261-7

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

Objective: We investigated the short-term and 1-year clinical outcomes of 129 children who received intensive cardiopulmonary support during hematopoietic stem cell transplant. Intensive cardiopulmonary support was defined as receiving at least one of the following interventions: continuous positive pressure ventilation, dopamine infusion greater than or equal to 10 mcg/kg/minute, or the use of any other vasoactive infusion. Duration of intensive cardiopulmonary support, survival to hospital discharge, and predictors of these outcome variables were compared with 387 hematopoietic stem cell transplant patients who did not receive intensive support during the same period. We also report the 1-year survival; presence of chronic graft-versus-host disease; and renal, cardiac, and pulmonary function for all patients.

Design: A multicenter retrospective cohort study.

Setting: The ICU and hematopoietic stem cell transplant unit of nine pediatric tertiary care centers.

Patients: Children undergoing hematopoietic stem cell transplant who required intensive cardiopulmonary support.

Interventions: None.

Results: Predictors of the need for intensive support included unrelated donor allogeneic transplant, glomerular filtration rate less than 85 mL/minute/1.73 m, and nonmalignant disease as the indication for transplant. The survival to discontinuation of intensive support for all patients was 62% and 58% for patients who received invasive mechanical ventilatory support. The duration of mechanical ventilation was not predictive of survival. Predictors of intensive support mortality included macroscopic bleeding, engraftment, and pediatric logistic organ dysfunction score greater than one in two domains. Survival to hospital discharge was 50% for the intensive support group and 99% for the nonintensive support group. Overall 1-year survival was 40% in the intensive support population and 65% in the nonintensive support group. There were no significant differences in the survival, rates of chronic graft-versus-host disease, creatinine, forced expiratory volume in 1-minute, cardiac shortening fraction, or performance status in intensive and nonintensive support patients who survived to hospital discharge.

Conclusion: Intensive cardiopulmonary support plays an important and potentially life-saving role in the care of pediatric stem cell transplant patients. Survivors of intensive support do not have compromised 1-year survival or organ function compared with children who did not receive intensive support.
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http://dx.doi.org/10.1097/PCC.0b013e3182720601DOI Listing
March 2013

Monitoring and prevention of relapse after allogeneic hematopoietic cell transplantation for myeloid malignancies.

Biol Blood Marrow Transplant 2012 Jan;18(1 Suppl):S62-73

Department for Stem Cell Transplantation, University of Hamburg, Germany.

Acute myeloid leukemia and myelodysplastic syndromes are the most common indications for allogeneic hematopoietic cell transplantation. Although this treatment can be curative, even in advanced disease, treatment failure is commonly manifested by relapse of disease, for which treatment is successful in only a minority of patients. There is a necessity for new strategies for prevention of posttransplantation relapse through early disease detection and intervention in order to improve patient outcomes. Detection of minimal residual disease in posttransplantation surveillance is felt to be a necessary component of any strategy. In chronic myeloid leukemia, assessment of the BCR-ABL1 load by quantitative real-time PCR provides an optimal guideline for posttransplantation therapeutic decisions, but in patients with acute myeloid leukemia or myelodysplastic syndromes, the situation is more complex because of the genetic heterogeneity of these disorders. Past strategies for relapse prevention have focused on use of donor lymphocyte infusions with variable success. Peritransplantation and maintenance therapies (eg, azacitidine) are under current investigation. This review summarizes the current status of minimal residual disease monitoring and prevention strategies for both pediatric and adult patients with myeloid malignancies in the transplantation setting and discusses perspectives for further improvement.
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http://dx.doi.org/10.1016/j.bbmt.2011.10.028DOI Listing
January 2012

Treatment of recurrent CNS disease post-bone marrow transplant in familial HLH.

Pediatr Blood Cancer 2012 Jul 13;59(1):189-90. Epub 2011 Jul 13.

Department of Pediatrics, Division of Hematology/Oncology/Blood and Marrow Transplant, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.

CNS involvement in Hemophagocytic Lymphohistiocytosis (HLH) has been reported in 63-73% of children at diagnosis [Haddad et al. (1997); Blood 89: 794-800; Horne et al. (2008); Br J Haematol 140: 327-335]. Patients can present with neurologic symptoms, abnormal CSF cytology, abnormal neuro-imaging, or a combination of these findings. CNS involvement is usually associated with a poor prognosis and increased mortality. The 3 year overall survival is 44% in patients with CNS involvement compared to 67% in patients without CNS involvement at diagnosis [Horne et al. (2008); Br J Haematol 140: 327-335]. We describe a treatment strategy employing systemic dexamethasone to control CNS disease in a patient with familial HLH and persistent CNS disease post Bone Marrow Transplant.
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http://dx.doi.org/10.1002/pbc.23248DOI Listing
July 2012

Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal™) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study.

Biol Blood Marrow Transplant 2011 Apr 8;17(4):534-41. Epub 2010 May 8.

The Pediatric Blood and Marrow Transplant Program, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.

Preliminary studies using directed-donor ex vivo expanded human mesenchymal stem cells (hMSCs) have shown promise in the treatment of acute graft-versus-host disease (aGVHD). However, their production is cumbersome and standardization is difficult. We describe the first experience of using a premanufactured, universal donor, formulation of hMSCs (Prochymal) in children (n = 12; 10 boys; 9 Caucasian; age range: 0.4-15 years) with treatment-resistant grade III and IV aGVHD who received therapy on compassionate use basis between July 2005 and June 2007 at 5 transplant centers. All patients had stage III or IV gut (GI) symptoms and half had additional liver and/or skin involvement. Disease was refractory to steroids in all cases and additionally to a median of 3 other immunosuppressive therapies. The hMSCs (8 × 10(6)cells/kg/dose in 2 patients and 2 × 10(6)cells/kg/dose in the rest) were infused intravenously over 1 hour twice a week for 4 weeks. Partial and mixed responders received subsequent weekly therapy for 4 weeks. HLA or other matching was not needed. The hMSCs were started at a median of 98 days (range: 45-237) posttransplant. A total of 124 doses were administered, with a median of 8 doses (range: 2-21) per patient. Overall, 7 (58%) patients had complete response, 2 (17%) partial response, and 3 (25%) mixed response. Complete resolution of GI symptoms occurred in 9 (75%) patients. Two patients relapsed after initial response and showed partial response to retreatment. The cumulative incidence of survival at 100 days from the initiation of Prochymal therapy was 58%. Five of 12 patients (42%) were still alive after a median follow-up of 611 days (range: 427-1111) in surviving patients. No infusional or other identifiable acute toxicity was seen in any patient. Multiple infusions of hMSCs were well tolerated and appeared to be safe in children. Clinical responses, particularly in the GI system, were seen in the majority of children with severe refractory aGVHD. Given the favorable results observed in a patient population with an otherwise grave prognosis, we conclude that hMSCs hold potential for the treatment of aGVHD, and should be further studied in phase III trials in pediatric and adult patients.
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http://dx.doi.org/10.1016/j.bbmt.2010.04.014DOI Listing
April 2011

Antiviral responses following L-leucyl-L-leucine methyl esther (LLME)-treated lymphocyte infusions: graft-versus-infection without graft-versus-host disease.

Biol Blood Marrow Transplant 2009 Dec 8;15(12):1609-19. Epub 2009 Sep 8.

Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Although allogeneic hematopoietic progenitor cell transplant (HPCT) is curative therapy for many disorders, it is associated with significant morbidity and mortality, which can be related to graft-versus-host disease (GVHD) and the immunosuppressive measures required for its prevention and/or treatment. Whether the immunosuppression is pharmacologic or secondary to graft manipulation, the graft recipient is left at increased risk of the threatening opportunistic infection. Refractory viral diseases in the immunocompromised host have been treated by infusion of virus-specific lymphotyces and by unmanipulated donor lymphocyte infusion (DLI) therapy. L-leucyl-L-leucine methyl ester (LLME) is a compound that induces programmed cell death of natural killer (NK) cells, monocytes, granulocytes, most CD8(+) T cells, and a small fraction of CD4(+) T cells. We have undertaken a study of the use of LLME-treated DLI following T cell-depleted allogeneic HPCT, specifically to aid with immune reconstitution. In this ongoing clinical trial, we have demonstrated the rapid emergence of virus-specific responses following LLME DLI with minimal associated GVHD. This paper examines the pace of immune recovery and the rapid development of antiviral responses in 6 patients who developed viral infections during the time period immediately preceding or coincident with the administration of the LLME DLI.
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http://dx.doi.org/10.1016/j.bbmt.2009.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783272PMC
December 2009