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Severe aplastic anemia is a rare and serious form of bone marrow failure related to an immune-mediated mechanism that results in severe pancytopenia and high risk for infections and bleeding. Patients with matched sibling donors for transplantation have a 80-90% chance of survival; however, a response rate with just immunosuppression for those patients lacking suitable HLA-matched related siblings is only 60%. With immunosuppression, only 1/3 of patients are cured, 1/3 are dependent on long term immunosuppression, and the other 1/3 relapse or develop a clonal disorder. Recent studies have shown that using a haploidentical donor for transplantation has good response rates and significantly lower rates of acute and chronic GVHD.
Mismatched haploidentical donors will be identified for patients with severe aplastic anemia. These patients will undergo a preparative regimen of Fludarabine/Cyclophosphamide/TBI followed by haploidentical bone marrow transplantation. Post-transplant Cyclophosphamide will be administered on Days 3 & 4. Immunosuppression with Tacrolimus and MMF will begin on Day +5; MMF will be discontinued on Day +35 while Tacrolimus continues until Day +180. Investigators hypothesize that haploidentical transplantation with the above-mentioned preparative regimen will have a <30% graft failure rate. The one-sided exact Binomial test at 5% significance level will be used to test this hypothesis. The size of 20 patients provides the power of 92.5% for confirming the 30-day graft failure rate <30%.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Flu/Cy/TBI | Experimental | Fludarabine, Cyclophosphamide, TBI followed by bone marrow transplantation. Post-transplant Cyclophosphamide will be on Days 3 & 4. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fludarabine | Drug | 30 mg/m2 IV QD x 5 days (Days -6 to -2) |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Demonstrate sustained engraftment after T-cell replete HLA-mismatched haploidentical bone marrow transplantation by collecting chimerism tests monthly following transplant | Hypothesis is that following preparative regimen and bone marrow transplantation, the 30-day graft failure rate will be <30%. | 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Determine the incidence of regimen-related mortality at 100 days post transplantation by recording treatment-related adverse events | 2 years | |
| Determine the incidence of grade 2-4 and 3-4 acute graft versus host disease at 100 days post transplantation by assessing signs and symptoms of GVHD throughout post-transplant course |
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Inclusion Criteria:
Peripheral Blood (must fulfill 2 of 3):
Bone Marrow (must be either):
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Melhem Solh, MD | Contact | 404-255-1930 | msolh@bmtga.com | |
| Stacey Brown | Contact | 404-851-8238 | stacey.brown@northside.com |
| Name | Affiliation | Role |
|---|---|---|
| Melhem Solh, MD | Blood and Marrow Transplant Group of Georgia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Blood and Marrow Transplant Group of Georgia | Recruiting | Atlanta | Georgia | 30342 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20018919 | Background | Brodsky RA, Chen AR, Dorr D, Fuchs EJ, Huff CA, Luznik L, Smith BD, Matsui WH, Goodman SN, Ambinder RF, Jones RJ. High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. Blood. 2010 Mar 18;115(11):2136-41. doi: 10.1182/blood-2009-06-225375. Epub 2009 Dec 16. | |
| 24319167 | Result | Socie G. Allogeneic BM transplantation for the treatment of aplastic anemia: current results and expanding donor possibilities. Hematology Am Soc Hematol Educ Program. 2013;2013:82-6. doi: 10.1182/asheducation-2013.1.82. |
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| Cyclophosphamide |
| Drug |
14.5 mg/kg/day IV x 2 doses (Days -6 & -5) |
|
| Total Body Irradiation | Radiation | 300 cGy x1 dose (Day -1) |
|
|
| Rabbit ATG | Drug | 1.5 mg/kg/day x 3 days (Days -3 to -1) |
|
| Cyclophosphamide | Drug | Post-transplant: 50 mg/kg IV QD (Day +3 to +4) |
|
| 2 years |
| Determine incidence of chronic GVHD at 6 months and 1 year post transplantation by assessing signs and symptoms of GVHD throughout post-transplant course | 2 years |
| Estimate overall survival at 100 days and 1 year post transplantation by collecting survival information at those time points | 2 years |
| Northside Hospital | Recruiting | Atlanta | Georgia | 30342 | United States |
|
| 24319166 | Result | Young NS. Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology Am Soc Hematol Educ Program. 2013;2013(1):76-81. doi: 10.1182/asheducation-2013.1.76. |
| 22517900 | Result | Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012 Aug 9;120(6):1185-96. doi: 10.1182/blood-2011-12-274019. Epub 2012 Apr 19. |
| 26359881 | Result | Bashey A, Zhang X, Jackson K, Brown S, Ridgeway M, Solh M, Morris LE, Holland HK, Solomon SR. Comparison of Outcomes of Hematopoietic Cell Transplants from T-Replete Haploidentical Donors Using Post-Transplantation Cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 Allele-Matched Unrelated Donors and HLA-Identical Sibling Donors: A Multivariable Analysis Including Disease Risk Index. Biol Blood Marrow Transplant. 2016 Jan;22(1):125-33. doi: 10.1016/j.bbmt.2015.09.002. Epub 2015 Sep 7. |
| 25797174 | Result | Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A. Total Body Irradiation-Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling Donors. Biol Blood Marrow Transplant. 2015 Jul;21(7):1299-307. doi: 10.1016/j.bbmt.2015.03.003. Epub 2015 Mar 19. |
| 24842530 | Result | Bashey A, Solomon SR. T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor. Bone Marrow Transplant. 2014 Aug;49(8):999-1008. doi: 10.1038/bmt.2014.62. Epub 2014 May 19. |
| 2889870 | Result | Rozman C, Marin P, Nomdedeu B, Montserrat E. Criteria for severe aplastic anaemia. Lancet. 1987 Oct 24;2(8565):955-7. doi: 10.1016/s0140-6736(87)91432-2. |
| 22796534 | Result | Atta EH, de Sousa AM, Schirmer MR, Bouzas LF, Nucci M, Abdelhay E. Different outcomes between cyclophosphamide plus horse or rabbit antithymocyte globulin for HLA-identical sibling bone marrow transplant in severe aplastic anemia. Biol Blood Marrow Transplant. 2012 Dec;18(12):1876-82. doi: 10.1016/j.bbmt.2012.07.004. Epub 2012 Jul 11. |
| ID | Term |
|---|---|
| D000741 | Anemia, Aplastic |
| ID | Term |
|---|---|
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D000080983 | Bone Marrow Failure Disorders |
| D001855 | Bone Marrow Diseases |
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| ID | Term |
|---|---|
| C024352 | fludarabine |
| D003520 | Cyclophosphamide |
| D014916 | Whole-Body Irradiation |
| C512542 | thymoglobulin |
| ID | Term |
|---|---|
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D011878 | Radiotherapy |
| D013812 | Therapeutics |
| D008919 | Investigative Techniques |
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