TCRαβ/CD19 Depletion of Stem Cell Grafts for Transplant

Acute Myeloid Leukemia Clinical Trial

Official title:

A Feasibility Study Using the CliniMACS Device for T-Cell Receptor (TCR) αβ+/CD19+ Depleted Hematopoietic Stem Cells for Patients Undergoing Transplant

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05968170
• Other study ID #: APP-23-03064
• Status: Not yet recruiting
• Phase: N/A
• Start date: December 1, 2023
• Est. completion date: July 1, 2035

Study information

• Verified date: November 2023
• Source: Children's Hospital Los Angeles
• Contact: Elizabeth Kissell, MS
• Phone: 323-361-5286
• Email: ekissell[@]chla.usc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The CliniMACS® device is FDA-approved only for one indication (CD34+ selection). Additional use of this device outside of this indication requires the use of feasibility studies. Children, adolescents and young adults with malignant and non-malignant conditions undergoing hematopoietic stem cell transplants will have stem cells selected using alpha-beta+/CD19+ cell depletion. This is a single arm feasibility study using this processing of peripheral stem cells with alternative donor sources (haploidentical, mismatched, matched unrelated) to determine efficacy as seen by engraftment and graft-versus-host disease (GVHD).

Description:

Hematopoietic stem cell transplantation (HSCT) is recognized as an effective cure for a wide range of diagnoses including hematologic malignancies, bone marrow failure syndromes, red blood cell disorders (sickle cell, beta thalassemia), white blood cell disorders (CGD), and immune deficiency disorders. Current therapy with allogeneic HCT from HLA-matched sibling donors has shown to be a potentially curative option for children with high-risk and/or relapsed hematologic malignancies (ALL/AML) as well as primary immune deficiency disorders (PID), however only 25-30% of patients have an HLA-identical matched sibling. Alternative stem cell sources include matched unrelated donors (MUD) and unrelated cord blood (UCB), however, the likelihood of finding an unrelated match can range between 29-79% depending on the patient's ethnic background. Since 2015, the CHLA Transplant and Cellular Therapy Program has performed approximately 90 ex vivo processed haploidentical transplants. Greater than 80% of our patients belong to racial/ethnic groups with limited unrelated donor availability, relying heavily on haploidentical donors. This lack of matched stem cells represents a significant access disparity for underrepresented minorities with life-threatening hematologic or immunologic conditions to undergo a potentially curative HSCT. The FDA approved the use of the CliniMACS CD34+ Reagent System as a Humanitarian Use Device for the prevention of GVHD in patients with acute myeloid leukemia (AML) in first complete remission undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related donor. The CliniMACS CD34+ Reagent System decreases the risk of developing GVHD by efficiently removing donor T-cells from the graft prior to infusion by enriching CD34+ blood stem cells, which help to repopulate the patient's immune system. FDA approval was based on data from a phase II, single-arm, multi-center study conducted by the Blood and Marrow Transplant Clinical Trials Network that showed after an intensive myeloablative conditioning, receiving a stem cell transplant from a matched related donor processed through the CliniMACS CD34+ Reagent System as a GVHD prophylaxis led to a low incidence of chronic GVHD, about 19% at 2 years post-transplant. However, removal of all cells except CD34+ selected complicates immune recovery (delay in CD4+ cells) leading to higher rates of opportunistic viral infections and transplant-related mortality. The use of CD34+ selected processing has facilitated approximately 42 HSCTs in combination of TCRαβ+/CD19 depletion at CHLA. The new approach to ex vivo processing utilizes negative depletion of cells thought to be responsible for the development of aGVHD, αβ TCR positive T-cells and includes simultaneous depletion of CD19+ B-cells. Since 2015, CHLA has conducted TCRαβ/CD19+ depleted HSCTs successfully on several protocols, including the ONC1401 KIR Study (IDE#16412).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 45
• Est. completion date: July 1, 2035
• Est. primary completion date: July 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 21 Years

Eligibility

Inclusion Criteria:

• Written informed consent (and written assent, if applicable) obtained prior to enrollment.
• Age < 21.
• Lansky Play-Performance Scale or Karnofsky Index score = 60%.
• Adequate organ function (within 4 weeks of initiation of preparative regimen) as evaluated per institutional guidelines. Adequate major organ system function as

demonstrated by:

• Renal: Creatinine clearance or GFR of = 60mL/min/1.73m2.
• Hepatic: total bilirubin < 2 mg/dL (unless due to Gilbert syndrome) and ALT/AST = 2.5 times the upper limit of normal.
• Cardiac: LVEF at rest = 50% or SF = 27% (by MUGA or ECHO).
• Pulmonary: DLCO, FEV1, and FVC = 50% of predicted corrected for hemoglobin. For patients < 7 years of age or those unable to perform PFTs: O2 Sat ? 92% on room air by pulse oximetry and on no supplemental O2 at rest.
• Available donor (matched/mismatched unrelated, mismatched related, related haploidentical) who is healthy and willing to donate peripheral blood stem cells.
• Patients that have been diagnosed with graft rejection/failure or relapse may be eligible to receive a second transplant pending patient status.

Exclusion Criteria:

• Patients with HIV or uncontrolled fungal, bacterial, or viral infections.
• Patients with active CNS leukemia or any other active site of extramedullary disease at the time of enrollment.
• Recipient with HLA antibody against donor.
• Patients that are pregnant, breastfeeding or unwilling to practice birth control during participation of the study.
• Any condition that, in the opinion of the Sponsor-Investigator, would compromise the safety of the participant, prevent study participation, or interfere with the evaluation of study endpoints.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Graft Vs Host Disease
• Graft-versus-host-disease
• Hematologic Malignancy
• Hematologic Neoplasms
• Leukemia
• Neoplasms
• Non-hematologic Malignancy
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Device:
• CliniMACS® device
CliniMACS TCR aß+/CD19+ cell depletion for related or unrelated haploidentical/mismatched/matched hematopoietic stem cell transplant patients and/or high risk GVHD patients.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Neena Kapoor, M.D.

References & Publications (15)

Abdelhakim H, Abdel-Azim H, Saad A. Role of alphabeta T Cell Depletion in Prevention of Graft versus Host Disease. Biomedicines. 2017 Jun 26;5(3):35. doi: 10.3390/biomedicines5030035. — View Citation

Arnold DE, MacMath D, Seif AE, Heimall JR, Wang Y, Monos D, Grupp SA, Bunin NJ. Immune Reconstitution Following TCRalphabeta/CD19-Depleted Hematopoietic Cell Transplantation for Hematologic Malignancy in Pediatric Patients. Transplant Cell Ther. 2021 Feb;27(2):169.e1-169.e9. doi: 10.1016/j.jtct.2020.10.006. Epub 2020 Dec 10. — View Citation

Bethge WA, Eyrich M, Mielke S, Meisel R, Niederwieser D, Schlegel PG, Schulz A, Greil J, Bunjes D, Brecht A, Kuball J, Schumm M, Vucinic V, Wiesneth M, Bonig H, Westinga K, Biedermann S, Holtkamp S, Karitzky S, Malchow M, Siewert C, Handgretinger R, Lang P. Results of a multicenter phase I/II trial of TCRalphabeta and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients. Bone Marrow Transplant. 2022 Mar;57(3):423-430. doi: 10.1038/s41409-021-01551-z. Epub 2021 Dec 24. — View Citation

Ciurea SO, Bayraktar UD. "No donor"? Consider a haploidentical transplant. Blood Rev. 2015 Mar;29(2):63-70. doi: 10.1016/j.blre.2014.09.009. Epub 2014 Sep 30. — View Citation

Food and Drug Administration, HHS. Current good tissue practice for human cell, tissue, and cellular and tissue-based product establishments; inspection and enforcement. Final rule. Fed Regist. 2004 Nov 24;69(226):68611-88. — View Citation

Food and Drug Administration, HHS. Eligibility determination for donors of human cells, tissues, and cellular and tissue-based products. Final rule. Fed Regist. 2004 May 25;69(101):29785-834. — View Citation

Fuchs EJ. Haploidentical transplantation for hematologic malignancies: where do we stand? Hematology Am Soc Hematol Educ Program. 2012;2012:230-6. doi: 10.1182/asheducation-2012.1.230. — View Citation

Giardino S, Bagnasco F, Falco M, Miano M, Pierri F, Risso M, Terranova P, Di Martino D, Massaccesi E, Ricci M, Chianucci B, Dell'Orso G, Sabatini F, Podesta M, Lanino E, Faraci M. Haploidentical Stem Cell Transplantation After TCR-alphabeta+ and CD19+ Cells Depletion In Children With Congenital Non-Malignant Disease. Transplant Cell Ther. 2022 Jul;28(7):394.e1-394.e9. doi: 10.1016/j.jtct.2022.04.002. Epub 2022 Apr 8. — View Citation

Gournay V, Dumas G, Lavillegrand JR, Hariri G, Urbina T, Baudel JL, Ait-Oufella H, Maury E, Brissot E, Legrand O, Malard F, Mohty M, Guidet B, Dulery R, Bige N. Outcome of allogeneic hematopoietic stem cell transplant recipients admitted to the intensive care unit with a focus on haploidentical graft and sequential conditioning regimen: results of a retrospective study. Ann Hematol. 2021 Nov;100(11):2787-2797. doi: 10.1007/s00277-021-04640-7. Epub 2021 Sep 3. — View Citation

Leung W, Campana D, Yang J, Pei D, Coustan-Smith E, Gan K, Rubnitz JE, Sandlund JT, Ribeiro RC, Srinivasan A, Hartford C, Triplett BM, Dallas M, Pillai A, Handgretinger R, Laver JH, Pui CH. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood. 2011 Jul 14;118(2):223-30. doi: 10.1182/blood-2011-01-333070. Epub 2011 May 25. — View Citation

Mitchell R, Cole T, Shaw PJ, Mechinaud F, O'Brien T, Fraser C. TCR alpha+ beta+ /CD19+ cell-depleted hematopoietic stem cell transplantation for pediatric patients. Pediatr Transplant. 2019 Sep;23(6):e13517. doi: 10.1111/petr.13517. Epub 2019 Jul 4. — View Citation

Oliansky DM, Camitta B, Gaynon P, Nieder ML, Parsons SK, Pulsipher MA, Dillon H, Ratko TA, Wall D, McCarthy PL Jr, Hahn T; American Society for Blood and Marrow Transplantation. Role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence-based review. Biol Blood Marrow Transplant. 2012 Apr;18(4):505-22. doi: 10.1016/j.bbmt.2011.12.585. Epub 2011 Dec 29. Erratum In: Biol Blood Marrow Transplant. 2012 Sep;18(9):1466. — View Citation

Oliansky DM, Rizzo JD, Aplan PD, Arceci RJ, Leone L, Ravindranath Y, Sanders JE, Smith FO 3rd, Wilmot F, McCarthy PL Jr, Hahn T. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol Blood Marrow Transplant. 2007 Jan;13(1):1-25. doi: 10.1016/j.bbmt.2006.10.024. — View Citation

Radestad E, Sundin M, Torlen J, Thunberg S, Onfelt B, Ljungman P, Watz E, Mattsson J, Uhlin M. Individualization of Hematopoietic Stem Cell Transplantation Using Alpha/Beta T-Cell Depletion. Front Immunol. 2019 Feb 11;10:189. doi: 10.3389/fimmu.2019.00189. eCollection 2019. — View Citation

Zeidan AM, Forde PM, Symons H, Chen A, Smith BD, Pratz K, Carraway H, Gladstone DE, Fuchs EJ, Luznik L, Jones RJ, Bolanos-Meade J. HLA-haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant. 2014 Mar;20(3):314-8. doi: 10.1016/j.bbmt.2013.11.020. Epub 2013 Dec 1. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of microbial contamination of the infused cells product leading to possible infection in the recipient (i.e., antibiotics needed for > 48 hours).	Assess the risk of microbial contamination in TCRaß+/CD19+ T-cell depleted products from the CliniMACS® device.	Day+30
Primary	Incidence of grade 3-4 acute and/or chronic GVHD at Day+100	Assess the cumulative incidence of severe GVHD following HSCT with TCRaß+/CD19+ T-cell depleted grafts, as determined by the presence of Grade III-IV aGVHD and/or cGVHD by Day+100 post-HSCT.	Day+100 post-HSCT
Secondary	Incidence of engraftment at Day+30.	Assess the efficacy of TCRaß+/CD19+ T-cell depleted HSCTs as measured by the engraftment of donor cells by Day+30 post-HSCT.	Day+30 post-HSCT
Secondary	Incidence of transplant-related mortality at 1-year post-HSCT.	Assess the efficacy of TCRaß+/CD19+ T-cell depleted HSCTs as measured by the incidence of transplant-related mortality at 1-year post-HSCT.	1-Year post-HSCT
Secondary	Incidence of T-cell reconstitution at Day+180 (CD4+ T-cell count > 200 and proliferation to PHA > 50% control).	Assess the immune reconstitution following TCRaß+/CD19+ T-cell depleted HSCTs as measured by the presence of expanded T-cell numbers and function at Day+180 post-HSCT(CD4+ T-cell count > 200 and proliferation to PHA > 50% control).	Day+180 post-HSCT