Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant for MonoMAC

NCT00923364 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 09009609-C-0096
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Stem cells are immature blood cells that grow in the bone marrow and produce all of the cells needed for normal blood and immunity. Stem cells can be taken from one person (donor) and given to another person (recipient) through allogeneic stem cell transplantation. Donor stem cells can then replace the recipients stem cells in the bone marrow, restoring normal blood production and immunity. Most allogeneic transplants now use stem cells collected from the donors blood in a process called peripheral blood stem cell transplantation.
• Monocytopenia and mycobacterial infection (MonoMAC) is an immunodeficiency disease that is characterized by a lack of monocytes, a type of white blood cell, and an increased risk of developing mycobacteria infections that may cause tuberculosis.
• Allogeneic stem cell transplantation has been used successfully to treat many kinds of immune diseases and cancers that develop in blood or immune system cells. Researchers have been studying a particular kind of stem cell transplantation that uses lower than usual doses of chemotherapy and particular combinations of drugs to improve the results of the procedure for patients with blood-related cancers and pre-cancerous conditions. Objectives:
• To determine the safety and efficacy of reduced-intensity hematopoietic stem cell transplants (a particular stem cell transplantation procedure) for treating MonoMAC. Eligibility:
• Patients 18-60 years of age who have MonoMAC and who have been matched with a suitable stem cell donor. Design:
• Donors and recipients will undergo separate procedures as part of this protocol.
• Donors:
• National Institutes of Health researchers will take the donor s medical history, perform a physical exam, take blood samples, and explain the procedure. Tests will be performed to check the donors heart, lung, kidney, and liver function.
• Donors will receive injections of a drug called filgrastim (G-CSF), which causes stem cells to travel from bone marrow into blood. The G-CSF shots will be given for 5 to 7 days before the collection procedure.
• Donors will undergo apheresis to collect white blood cells and stem cells directly from the blood, which can be done as an outpatient procedure. Researchers may consider the alternative of directly collecting bone marrow from the donor, which will require an overnight hospital stay.
• Recipients:
• Recipients will receive 3 days of pre-transplant chemotherapy and radiation therapy to prepare for the transplant. For 4 days before the transplant, recipients will receive the chemotherapy drug fludarabine, followed by a single dose of radiation therapy, and will also receive the drugs tacrolimus and sirolimus to prevent the donor cells from attacking the recipient s normal tissues.
• Recipients will then receive the transplant of donor stem cells and will continue to receive tacrolimus and sirolimus for 3 months after the transplant to prevent the donor cells from attacking the recipient s normal tissues. Recipients will be discharged from the hospital once their condition is stable.
• Recipients will visit the NCI clinic regularly for the first 5 months after the transplant, and then less often for at least 5 years. Recipients may receive additional donor immune cells (donor lymphocyte infusion) after the transplant if the study doctors believe they are needed.

Conditions

MDS; Immunodeficiency; GATA2

Keywords

GATA2; Transplant; Immunodeficiency; Myelodysplasia; MonoMAC

Outcome Measures

Primary Outcomes (2)

• Days to Neutrophil Engraftment

  Neutrophil engraftment is defined as a neutrophil count of \>0.5 x 10(9) cells/L for 3 consecutive days.

  30 days

• Days to Platelet Engraftment

  Platelet engraftment is defined as a platelet count of \>20 x 10(9) cells/L for 7 consecutive days without requiring a platelet transfusion.

  30 days

Secondary Outcomes (5)

• Percentage of Donor Cells at Last Follow Up in Patients With Mutations GATA Binding Protein 2 (GATA2)

  2 years

• Incidence of Acute and Chronic Graft-versus-host Disease (GVHD)

  2 years

• Overall Survival

  2 years

• Number of Participants With Disease Free Survival

  2 years

• Number of Participants With Serious and Non-serious Adverse Events

  Date treatment consent signed to date off study, approximately, 91 months

Study Arms (1)

Recipients and Healthy Related Donors

EXPERIMENTAL

Hematopoietic Stem Cell Transplant for MonoMAC: 10/10 Human Leukocyte Antigen (HLA) Matched Related Donor (MRD) or Unrelated Donor (URD) Transplant. 9/10 HLA Matched Related Donor or Unrelated Donor Transplant. Haploidentical Related Donor Transplant. Umbilical Cord Blood Transplant.

Drug: Cyclophosphamide (CTX, Cytoxan); Drug: Fludarabine(Fludara,Berlex Laboratories); Procedure: Total Body Irradiation (TBI); Procedure: Allogeneic Hematopoietic Stem Cell (HSC); Drug: Equine Anti-Thymocyte Globulin

Interventions

Cyclophosphamide (CTX, Cytoxan) DRUG

14.5 mg/kg intravenous (IV) (in the vein) infusion over 30 minutes once daily on days -6 and -5 (weight based dosing) or 50 mg/kg IV infusion over 2 hours on day -6 (weight based dosing) or 50/kg IV once daily x 2 doses on days +3 and +4

Also known as: Cytoxan

Recipients and Healthy Related Donors

Fludarabine(Fludara,Berlex Laboratories) DRUG

40 mg/m2 IV (in the vein) over 30 minutes (in the vein) once daily on Days -6, -5, -4, and -3 or 30 mg/m(2) IV over 30 minutes (in the vein) once daily on Days -6, -5, -4, -3, and -2

Also known as: Fludara

Recipients and Healthy Related Donors

Total Body Irradiation (TBI) PROCEDURE

200 centigray (cGy) on Day -1 or 300 cGy on Day -1 (for 9/10 URD and Haplo patients)

Also known as: TBI

Recipients and Healthy Related Donors

Allogeneic Hematopoietic Stem Cell (HSC) PROCEDURE

stem cell transplant

Recipients and Healthy Related Donors

Equine Anti-Thymocyte Globulin DRUG

30mg/kg IV (in the vein) once daily x 3 days on Days -6, -5, -4 (3 doses total)

Also known as: ATG

Recipients and Healthy Related Donors

Eligibility Criteria

• Age: 12 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patient age of 12-60 years
• GATA2 Mutation Syndrome
• Clinical history of at least two episodes of life-threatening infection with opportunistic organisms, one of which is a MAC infection.
• Mutation in the GATA2 gene performed by the CLIA certified laboratory of Dr. Steven Holland of the NIAID Institute of the NIH.
• Available 10/10 HLA-matched related or 8/8 matched unrelated donor, or 4/6 (or greater) matched UCB unit(s) with a total dose of greater than or equal to 3.5 times 10(7) TNC/kg.
• Patients may have evidence of MDS with one or more peripheral blood cytopenias and greater than 5% blasts but less than 10% blasts in the bone marrow in the absence of GCSF.
• Patients previously treated for acute myelogenous leukemia are eligible if they have less than or equal to 10% blasts in the bone marrow in the absence of G-CSF.
• Subjects 12-17 years of age are required to have MDS with chromosomal abnormalities in addition to mutation in the GATA2 gene for enrollment on this protocol.
• Left ventricular ejection fraction \> 50%, preferably by 2-D echo, or by MUGA, or shortening fraction \> 28% by ECHO, obtained within 28 days of enrollment.
• Pulmonary Function Tests: Adult patients: DLCO diffusion capacity and FEV1 greater than 10% of expected value obtained within 28 days of enrollment. Pediatric patients: DLCO corrected for hemoglobin and alveolar volume greater than or equal to 20% of predicted.
• Creatinine: Adult patients: less than or equal to 2.0 mg/dl and creatinine clearance greater than or equal to 30 ml/min; Pediatric patients: age-adjusted normal serum creatinine OR a creatinine clearance \> 60 mL/min/1.73m(2).
• Serum total bilirubin less than 2.5 mg/dl; ALT and AST less than or equal to 5 times upper limit of normal .
• Adequate central venous access potential.
• Written informed consent/assent obtained from patient/parent or legal guardian.
• Life expectancy of at least 3 months but less than 24 months.

You may not qualify if:

• HIV infection.
• Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For patients with a concomitant positive hepatitis B surface antigen, patients will require a hepatology consultation. The risk-benefit profile of transplant and hepatitis B will be discussed with the patient, and eligibility determined by the PI and the protocol chairperson.
• History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
• Active infection that is not responding to antimicrobial therapy.
• Active CNS involvement by malignancy (patients with known positive CSF cytology or parenchymal lesions visible by CT or MRI.
• Pregnant or lactating.
• Sexually active individuals capable of becoming pregnant who are unable or unwilling to use effective form(s) of contraception during time enrolled on study and for 1 year post-transplant. Effective forms of contraception include one or more of the following: intrauterine device (IUD), hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy, partners vasectomy, barrier methods, (condom, diaphragm, or cervical cap), or abstinence. The effects on breast-milk are also unknown and may be harmful to the infant; therefore, women should not breast feed during the interval from study entry to one year post-transplant. Males on the protocol must use an effective form of contraception at study entry, and for one year post-transplant. The effects of transplant, the radiation, and the medications used after transplant may be harmful to a fetus.
• Presence of active malignancy in another organ system other than the hematopoietic
• No available 10/10 HLA-matched related or 8/8 matched unrelated donor, or 4/6 (or greater) matched UCB unit(s) with a total dose of greater than or equal to 3.5 times 10(7) TNC/kg.
• Lack of mutation in GATA2 as demonstrated by the CLIA certified laboratory of Dr. Steven Holland in the NIAID.
• Related donor matched at HLA-A, B, C, DR, and DQ loci by high resolution typing (10/10 antigen/allele match) are acceptable donors.
• Matched related donors for pediatric recipients must be 18 years of age or older. If more than one matched related donor is available, we will select the oldest donor to further decrease the risk of potential disease transmission.
• Ability to give informed consent.
• Age 18-60 years.
• No history of life-threatening opportunistic infection.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (7)

• Anasetti C, Beatty PG, Storb R, Martin PJ, Mori M, Sanders JE, Thomas ED, Hansen JA. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol. 1990 Oct;29(2):79-91. doi: 10.1016/0198-8859(90)90071-v.

  PMID: 2249952 BACKGROUND

• Anderlini P, Korbling M, Dale D, Gratwohl A, Schmitz N, Stroncek D, Howe C, Leitman S, Horowitz M, Gluckman E, Rowley S, Przepiorka D, Champlin R. Allogeneic blood stem cell transplantation: considerations for donors. Blood. 1997 Aug 1;90(3):903-8.

  PMID: 9242518 BACKGROUND

• Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB, Hochberg EP, Wu CJ, Alyea EP, Soiffer RJ. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood. 2003 Sep 1;102(5):1601-5. doi: 10.1182/blood-2003-02-0489. Epub 2003 May 1.

  PMID: 12730113 BACKGROUND

• Cuellar-Rodriguez J, Gea-Banacloche J, Freeman AF, Hsu AP, Zerbe CS, Calvo KR, Wilder J, Kurlander R, Olivier KN, Holland SM, Hickstein DD. Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. Blood. 2011 Sep 29;118(13):3715-20. doi: 10.1182/blood-2011-06-365049. Epub 2011 Aug 3.

  PMID: 21816832 RESULT

• West RR, Hsu AP, Holland SM, Cuellar-Rodriguez J, Hickstein DD. Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation. Haematologica. 2014 Feb;99(2):276-81. doi: 10.3324/haematol.2013.090217. Epub 2013 Sep 27.

  PMID: 24077845 DERIVED

• Purisch SE, Shanis D, Zerbe C, Merideth M, Cuellar-Rodriguez J, Stratton P. Management of uterine bleeding during hematopoietic stem cell transplantation. Obstet Gynecol. 2013 Feb;121(2 Pt 2 Suppl 1):424-7. doi: 10.1097/aog.0b013e318270ecd3.

  PMID: 23344397 DERIVED

• Calvo KR, Vinh DC, Maric I, Wang W, Noel P, Stetler-Stevenson M, Arthur DC, Raffeld M, Dutra A, Pak E, Myung K, Hsu AP, Hickstein DD, Pittaluga S, Holland SM. Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications. Haematologica. 2011 Aug;96(8):1221-5. doi: 10.3324/haematol.2011.041152. Epub 2011 Apr 20.

  PMID: 21508125 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Immunologic Deficiency Syndromes; Anemia, Refractory, with Excess of Blasts; GATA2 Deficiency

Interventions

Cyclophosphamide; fludarabine phosphate; Whole-Body Irradiation; Antilymphocyte Serum

Condition Hierarchy (Ancestors)

Immune System Diseases; Anemia, Refractory; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; Bone Marrow Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Therapeutics; Investigative Techniques; Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures

Results Point of Contact

• Title: Dr. Dennis Hickstein
• Organization: National Cancer Institute

hicksted@mail.nih.gov

301-594-1718

Study Officials

• Dennis D Hickstein, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: May 7, 2009
• Primary Completion: June 12, 2014
• Study Completion: February 26, 2017
• Last Updated: March 12, 2020
• Results First Posted: November 30, 2017

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)