The Division of Blood and Marrow Transplantation Utilizes Reduced-Intensity Transplant Procedures for Pediatric Genetic Disorders

The Division of Blood and Marrow Transplantation at UPMC Children’s Hospital of Pittsburgh, led by Paul Szabolcs, MD, is the only center in the world with the ability to successfully engraft children suffering from sickle cell disease, thalassemia, osteopetrosis, and many other inherited genetic disorders with a reduced-intensity regimen paired with a single-unit, human leukocyte antigen (HLA)-mismatched cord blood graft (ClinicalTrials.gov Identifier: NCT01962415). 

Since 2012, the successful implantation of a CliniMACS® device has supported novel clinical trials with T-cell-depleted autologous transplantation for autoimmune diseases and T-cell-depleted HLA-mismatched allogeneic bone marrow transplantation. These protocols have been approved by the U.S. Food and Drug Administration (FDA) as an Investigational New Drug (IND). 

With all possible transplant modalities available at UPMC Children’s since 2012, the Division has been able to find a suitable donor for all patients regardless of age, weight, or ethnicity.

Clinical Trials Update from the Division of Blood and Marrow Transplantation and Cellular Therapies

• Following the development of the Division’s Crohn’s disease transplant protocol, in 2018 a new prospective trial was designed and opened to offer disease control for another refractory autoimmune disease; “Autologous Stem Cell Transplantation in Patients with Systemic Sclerosis (SSc)” (ClinicalTrials.gov Identfier: NCT03630211). This trial received IRB/FDA approval in 2018 and is open for enrollment for pediatric and adult patients.

• One of the division’s signature protocols (ClinicalTrials.gov Identifier: NCT01962415) has attracted patients from two dozen states, ranging from Florida to Alaska. Patients with about 20 unique genetic diagnoses are enrolled on this reduced-intensity conditioning (RIC) trial. Diagnoses range from sickle cell disease, thalassemia, osteopetrosis, Krabbe disease, and metachromatic leukodystrophy to many primary immune deficiency syndromes such as Bare Lymphocyte Syndrome (BLS) and X-linked inhibitor of apoptosis (XIAP) deficiency. Day 100 nonrelapse mortality has remained exceptionally low. In fact, there have been no deaths during this most vulnerable transplant period. With more than 40 patients enrolled so far, one-year event-free survival exceeds 90 percent in the unrelated cord blood transplant setting, exceeding the results of centers of excellence worldwide.

• In 2016, the Division opened an institutional prospective trial for children and young adults afflicted with high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) employing RIC or myeloablative conditioning for HSCT in AML/MDS (ClinicalTrials.gov Identifier: NCT02626715). To bridge the temporary post-transplant immune-deficient state, the Division has performed therapeutic T-cell infusions with adenovirus hexon-specific interferon gamma-captured cells under IND/Institutional Review Board (IRB)-approved treatment plans. These efforts have paved the way for a virus specific T cell (VST) protocol that is opening in early 2019 and will be accessible for all UPMC solid organ or bone marrow transplant patients beyond UPMC Children’s.

• Autologous Stem Cell Transplantation With CD34-Selected Peripheral Blood Stem Cells (PBSCs) in Pediatric and Young Adult Patients With Severe Crohn’s Disease (ClinicalTrials.gov Identifier: NCT00692939). This study was completely revised in 2017 and is armed with a new conditioning regimen prior to infusion of autologous CD34-selected PBSCs. It is open to pediatric and adult patients who are refractory to all other treatment modalities. The first young adult patient received a CD34+ stem cell infusion in December 2017 and has entered clinical remission. The trial continues to screen for eligibility of both adult and pediatric patients from as far as Florida. 

• Naïve T-Cell Depletion for Prevention of Chronic GVHD in Children and Young Adults. Jesse Barnum, MD, serves as site principal investigator on this CIBMTR study, which is a multicenter, phase II, randomized, controlled trial comparing outcomes in pediatric patients receiving allogeneic HCT with either naïve T-cell-depleted peripheral blood stem cells or T-cell replete bone marrow. The randomized phase of this trial is projected to open at UPMC Children’s in early 2019.

• A Phase II Study of Myeloablative and RIC Regimens for Children with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic HSCT (ClinicalTrials.gov Identifier: NCT02626715). This trial, developed by Randy Windreich, MD, is an institutional protocol for a dual-arm myeloablative and reduced-intensity transplant conditioning regimen for patients with hematologic malignancies and unrelated donors. The objective of this study is to determine safety, preliminary efficacy, and event-free survival at one hundred days and six months post-transplant in pediatric patients receiving a myeloablative or reduced-intensity preparative regimen prior to HSCT for high-risk acute myeloid leukemia and myelodysplastic syndrome. The protocol will expand eligibility for HSCT, particularly for those with serious pre-transplant comorbidities. Subject enrollment is ongoing since September 2015.

• T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease and Thalassemia. (ClinicalTrials.gov Identifier: 03653338) Beth Carella, DO, has initiated this trial which has dramatically broadened eligibility for patients lacking matched sibling donors, hoping to provide access to all severely affected patients to a curative intervention. With mismatched donors, the risk of GVHD is prohibitively high. However, this protocol uses in vitro T-cell depletion combined with post-transplant donor leukocyte infusions to reduce GVHD risk without increasing the incidence of rejection. This reduced-intensity conditioning regimen paired with a calcineurin-free GVHD prophylaxis aims for durable engraftment while minimizing toxicity and preserving fertility.

Recent Speaking Engagements and Lectures

Paul Szabolcs, MD
• “Sequential BOLT + BMT in PID Patients From the Same Deceased Donors.” Immune Dysregulation Think Tank; St. Petersburg, Florida (April 2018).
•  “Immunity and Tolerance after Bilateral Orthotopic Lung Transplant (BOLT) in Tandem with a CD3+/CD19+ Depleted Vertebral Bone Marrow Transplant (BOLT+BMT) From 1 of 8 HLA-Matched Cadaveric Donors.” America Transplant Congress (ATC); Seattle, Washington (June 5, 2018).

Jesse Barnum, MD
•  “Immunodeficiencies and Intestinal Failure: Applications for Combined Bone Marrow and Intestinal Transplantation.” 10th International Pediatric Intestinal Failure and Rehabilitation Symposium; invited speaker (September 2018).
•  “Case Presentation: ICF2.” Oral presentation, Pediatric Immune Deficiency Treatment Consortium Educational Workshop; Philadelphia, Pennsylvania (May 2018).

Craig Byersdorfer, MD, PhD
• “Targeting Immune Cell Metabolism to Decrease Graft-versus-host Disease While Preserving Graft-versus-tumor Responses.”Blood & Marrow Transplant and Cellular Immunotherapy, Moffit Cancer Center; Tampa, Florida (October 2018).

Beth Carella, DO
•  “Basics of Bone Marrow Transplant.” Oral presentation, Division of Allergy/Immunology Grand Rounds, UPMC Children’s Hospital of Pittsburgh; Pittsburgh, Pennsylvania (October 2018).
•  “Donor Leukocyte Infusion for Single Unit Umbilical Cord Blood Transplantation: 5% of Thawed Single Cord Blood Unit Refrozen on Day of Transplant is Safe with Signals of Efficacy in Improving Donor Derived Immunity.” Upcoming poster presentation, American Society of Hematology Annual Meeting; San Diego, California (December 2018).

Xiaohua Chen, PhD
• “Clonal deletion and anergy play dominant role to achieve immune tolerance after reduced intensity unrelated donor cord blood transplantation.” Poster presentation at AAI meeting (2017).
• “Dominant Role of Clonal Deletion in Achieving Immune Tolerance After Unrelated Cord Blood Transplantation.” Oral presentation at ATC meeting (2017).

Randy Windreich, MD
• “CAR T-Cell Therapy for Relapsed/Refractory B-Cell Lymphoblastic Leukemia.” Oral presentation, Department of Pharmacy Conference, UPMC Children’s Hospital of Pittsburgh; Pittsburgh, Pennsylvania (May 2018).
•  “The Novel Use of Deferoxamine in a Neonate With Congenital Dyserythropoietic Anemia Type II.” Poster presentation, American Society of Pediatric Hematology/Oncology annual meeting; Pittsburgh, Pa., May 2018.


Recent Publications from the Division of Blood and Marrow Transplantation and Cellular Therapies

• Byersdorfer CA and P Reddy. Intracellular sensors and cellular metabolism in allogeneic hematopoietic stem cell transplantation. Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation. Socie G, Zeiser R, and Blazar BR, eds. Academic Press, 2018 (in press).

• Beezhold K, Byersdorfer CA. Targeting immuno-metabolism to improve anti-cancer therapies. Cancer Lett. 2018. 414:127. PMID: 29126914.

• Haddad E, Logan BR, Griffith LM, Buckley RH, Parrott RE, Prockop SE, Small TN, Chaisson J, Dvorak CC, Murnane M, Kapoor N, Abdel-Azim H, Hanson IC, Martinez C, Bleesing JJH, Chandra S, Smith AR, Cavanaugh ME, Jyonouchi S, Sullivan KE, Burroughs L, Skoda-Smith S, Haight AE, Tumlin AG, Quigg TC, Taylor C, Dávila Saldaña BJ, Keller MD, Seroogy CM, Desantes KB, Petrovic A, Leiding JW, Shyr DC, Decaluwe H, Teira P, Gillio AP, Knutsen A, Moore TB, Kletzel M, Craddock JA, Aquino V, Davis JH, Yu LC, Cuvelier GDE, Bednarski JJ, Goldman FD, Kang EM, Shereck E, Porteus MH, Connelly JA, Fleisher TA, Malech HL, Shearer WT, Szabolcs P, Thakar MS, Vander Lugt MT, Heimall J, Yin Z, Pulsipher MA, Pai SY, Kohn DB, Puck JM, Cowan MJ, O'Reilly RJ, Notarangelo LD. SCID genotype and 6 month post-transplant CD4 count predict survival and immune recovery: a PIDTC restrospective study. Blood. 2018 Aug 28. pii: blood-2018-03-840702. doi: 10.1182/blood-2018-03-840702 PMID:30154114.

• Forbes LR, Vogel TP, Cooper MA, Castro-Wagner J, Schussler E, Weinacht KG, Plant AS, Su HC, Allenspach EJ, Slatter M, Abinun M, Lilic D, Cunningham-Rundles C, Eckstein O, Olbrich P, Guillerman RP, Patel NC, Demirdag YY, Zerbe C, Freeman AF, Holland SM, Szabolcs P, Gennery A, Torgerson TR, Milner JD, Leiding JW. Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT) or STAT3 mutations. J. Allergy Clin Immunol. 2018 Nov; 142(5): 1665-1669.

• Haddad E, Logan BR, Griffith LM, Buckley RH, Parrott RE, Prockop SE, Small TN, Chaisson J, Dvorak CC, Murnane M, Kapoor N, Abdel-Azim H, Hanson IC, Martinez C, Bleesing JJH, Chandra S, Smith AR, Cavanaugh ME, Jyonouchi S, Sullivan KE, Burroughs L, Skoda-Smith S, Haight AE, Tumlin AG, Quigg TC, Taylor C, Dávila Saldaña BJ, Keller MD, Seroogy CM, Desantes KB, Petrovic A, Leiding JW, Shyr DC, Decaluwe H, Teira P, Gillio AP, Knutsen AP, Moore TB, Kletzel M, Craddock JA, Aquino V, Davis JH, Yu LC, Cuvelier GDE, Bednarski JJ, Goldman FD, Kang EM, Shereck E, Porteus MH, Connelly JA, Fleisher TA, Malech HL, Shearer WT, Szabolcs P, Thakar MS, Vander Lugt MT, Heimall J, Yin Z, Pulsipher MA, Pai SY, Kohn DB, Puck JM, Cowan MJ, O'Reilly RJ, Notarangelo LD. SCID genotype and 6-month posttransplant CD4 count predicts survival and immune recovery. Blood. 2018 Oct 25; 132(17): 1737-1749.

•Dreyzin A, Michaels MG, Vander Lugt MT, Szabolcs P. Oral ribavirin for paramyxovirus infection after alemtuzumab-containing reduced-intensity conditioning HCT regimen. Pediatr Transplant. 2019 Jan 27: e13358.

• Szabolcs P, Chen X, Donnenberg A, Hill M, Rowan J, Mcintyre S, Barnum JL, McDyer J, Kurland G. Immunity and tolerance after Bilateral Orthotopic Lung Transplant (BOLT) in tandem with a CD3+/CD19+ depleted vertebral bone marrow transplant from a 1 of 8 HLA-matched cadaveric donor, International Society of Cell Therapy, Poster Presentation, April 2018.