The primary aim of this clinical protocol is to evaluate whether allogeneic hematopoietic stem cell transplant (HSCT) reverses the hematological abnormalities in a recently described syndrome known as MonoMAC, which is characterized by: 1) onset in late adolescence or early adulthood;2) clinical history of opportunistic infection, frequently with mycobacterium avium complex (MAC);3) a distinct peripheral blood leukocyte subset pattern with the presence of T-lymphocytes but a severe deficiency of B-lymphocytes, natural killer (NK) cells, and the lack of monocytes;4) dominant inheritance;and 5) frequent progression to myelodysplastic syndrome (MDS). We propose to evaluate whether allogeneic hematopoietic stem cell transplantation (HSCT) can reconstitute normal hematopoiesis in MonoMAC, and reverse the hematological abnormalities in myelodysplastic syndrome (MDS) if MDS is present at the time of transplant. While allogeneic HSCT is the conventional curative treatment for immunodeficiency and MDS, patients with MonoMAC, because of an intact T-cell population and co-existing infection, represent a profile not generally encountered in the setting of allogeneic HSCT. The biological questions with MonoMAC center around whether the individual leukocyte compartments that are lost in MonoMAC (B-lymphocytes, natural killer cells, and monocytes) will be constituted with HSCT, and whether the residual recipient T-lymphocytes will represent an impediment to engraftment. We will also evaluate whether we achieve sufficient donor chimerism to reverse the myelodysplastic syndrome.
Our specific aims are: 1) To determine whether allogeneic HSCT reconstitutes normal hematopoiesis and reverses the MonoMAC flow cytometry phenotype in patients with MonoMAC by day +100;2) To determine whether HSCT demonstrates potential as a pre-emptive anti-leukemia strategy in this patient population;3) To characterize the engraftment kinetics of specific leukocyte subsets (monocytes, B-lymphocytes, and natural killer cells) deficient in MonoMAC, as well as reconstitution of T-cells that are depleted in the course of therapy, and the kinetics and extent of reversal of the abnormalities in MDS;4) To determine the safety of this therapeutic HSCT approach including transplant-related toxicity, the incidence of acute and chronic graft-versus-host disease (GVHD), immune reconstitution, overall survival, and disease-free survival. The primary end-points are to determine whether allogeneic HSCT reconstitutes normal hematopoiesis and reverses the MonoMAC flow cytometry phenotype in patients with MonoMAC by day +100, and to determine whether HSCT demonstrates potential as a pre-emptive anti-leukemia strategy in this patient population. We have now transplanted 15 patients with this syndrome with excellent results.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010870-06
Application #
8763254
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$393,515
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
West, Robert R; Hsu, Amy P; Holland, Steven M et al. (2014) Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation. Haematologica 99:276-81
Grossman, Jennifer; Cuellar-Rodriguez, Jennifer; Gea-Banacloche, Juan et al. (2014) Nonmyeloablative allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. Biol Blood Marrow Transplant 20:1940-8
Hsu, Amy P; Johnson, Kirby D; Falcone, E Liana et al. (2013) GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood 121:3830-7, S1-7
Bhanushali, Minal J; Kranick, Sarah M; Freeman, Alexandra F et al. (2013) Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation. Neurology 80:1494-500