Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVE:

I. To determine if this treatment can improve 2-year progression-free survival (PFS) in patients with high risk myelodysplastic syndrome (MDS) and in patients with acute myeloid leukemia (AML) >= 60 yrs age

SECONDARY OBJECTIVES:

I. To determine the safety and feasibility of using post-transplantation azacitidine.

II. To determine the ability to use pharmacokinetic-directed busulfan to achieve area under the curve (AUC) within 20% of target AUC in > 80% of patients.

III. To determine the rate of grade II-IV and III-IV acute graft-vs-host disease (GVHD).

IV. To determine the incidence of extensive chronic GVHD. V. To determine treatment-related mortality at 100 days and at 1 year. VI. To determine 5-year overall survival.

OUTLINE:

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor \[MSD\]) or -6 to -4 (matched unrelated donor \[MUD\]).

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).

CONSOLIDATION: Beginning on day 42, patients receive azacitidine subcutaneously (SC) or IV on days 1-5.

Treatment repeats every 4 weeks for 6 courses. Blood and bone marrow samples may be collected periodically for correlative and pharmacokinetic studies.

After completion of study treatment, patients are followed up every 6 months for 5 years.

• Allogeneic Hematopoietic Stem Cell Transplantation (Procedure), also known as Allogeneic, Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT, Stem Cell Transplantation, Allogeneic: Undergo allogeneic hematopoietic stem cell transplantation
• Anti-Thymocyte Globulin (Biological), also known as Antithymocyte Globulin, Antithymocyte Serum, ATG, ATS: Given IV
• Azacitidine (Drug), also known as 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, Onureg, U-18496, Vidaza: Given SC or IV
• Busulfan (Drug), also known as 1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508: Given IV
• Fludarabine Phosphate (Drug), also known as 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586: Given IV
• Laboratory Biomarker Analysis (Other): Correlative studies
• Methotrexate (Drug), also known as Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039: Given IV
• Pharmacological Study (Other): Correlative studies
• Tacrolimus (Drug), also known as FK 506, Fujimycin, Hecoria, Prograf, Protopic: Given PO or IV

Primary outcomes

• Progression-free Survival [Up to 5 years]: Progression-free survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are alive and progression free at 2 and 5 years from date of transplantation respectively. AML progression is defined as: * Reappearance of leukemia blast cells in peripheral blood and > 5% blasts in marrow * If no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow >= 1 week later with > 5% blasts * Development of extramedullary leukemia MDS progression is defined as * For patients with <5% bone marrow blasts: ≥50% increase in blasts to >5% blasts * For patients with 5-10% bone marrow blasts: ≥50% increase to >10% blasts * Any of the following: Reappearance of prior documented characteristic cytogenetic abnormality or refractory cytopenias with unequivocal evidence of dysplasia on bone marrow biopsy/aspirate

Secondary outcomes

• Overall Survival (OS) [Up to 5 years]: Overall survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are still alive 2 and 5 years after date of transplantation respectively. Estimated using the Kaplan-Meier product limit estimator.
• 100-day Mortality [Up to 100 days post-treatment]: The number of death reported within the first 100 days after transplant.

Sex: All, ages: 18 Years to 74 Years

Inclusion Criteria:

* Meets one of the following sets of criteria:

  * Myelodysplastic syndromes (MDS):

    * Disease with high-risk features (found either at diagnosis or before initiation of cytotoxic therapy), defined as one of the following:

      * International prognostic scoring system (IPSS) risk >= intermediate-2
      * Refractory anemia with excess blasts by French-American-British (FAB) classification
      * High-risk cytogenetics (either complex or -7)
    * Less than 10% bone marrow blasts as determined by bone marrow biopsy within the past 4 weeks (reduction in marrow blast percentage may be achieved with chemotherapy or other therapy)
    * Less than 75 years old
  * Acute myeloid leukemia (AML):

    * No FAB M3
    * No acute leukemia following blast transformation of prior chronic myelogenous leukemia or other myeloproliferative disease
    * Patients with preceding MDS or treatment-related AML are eligible
    * Prior central nervous system (CNS) involvement is allowed provided the disease is in remission at transplantation
    * Morphologic complete remission (leukemia-free state) is defined as meeting all of the following criteria:

      * Bone marrow blasts < 5% (as determined by bone marrow within the past 4 weeks), but without requirement for normal peripheral blood counts
      * No extramedullary leukemia
      * No blasts in peripheral blood
    * Achieved complete remission (CR) after no more than 2 courses of induction chemotherapy

      * Patients treated with azacitidine or decitabine who achieve a leukemia-free state are eligible (may have required up to 4 courses of therapy to reach this status)
    * Age 60 to 74 years
* Donors must meet the following criteria:

  * One of the following:

    * HLA-identical sibling (6/6) by serologic typing for class (A, B) and low-resolution molecular typing for class II (DRB1)
    * Matched unrelated donor (8/8) by high-resolution molecular typing at HLA-A, -B, -C, and DRB1
  * No syngeneic donors
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Calculated creatinine clearance ≥ 40 mL/min
* Bilirubin < 2 mg/dL OR bilirubin 2-3 mg/dL provided direct bilirubin is normal
* Aspartate aminotransferase (AST) < 3 times upper limit of normal
* Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease
* Left ventricle ejection fraction (LVEF) >= 30% by echocardiogram (ECHO) or multigated acquisition (MUGA)
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No uncontrolled diabetes mellitus or active serious infections
* No known hypersensitivity to E. coli-derived products, azacitidine, or mannitol
* No human immunodeficiency virus (HIV) infection or active hepatitis B or C
* Prior azacitidine or decitabine allowed

  * No patients who progressed from MDS to AML during treatment with azacitidine or decitabine
* At least 4 weeks since prior deoxyribonucleic acid (DNA)-hypomethylating chemotherapy, radiotherapy, and/or surgery
* No more than 2 courses of consolidation therapy before transplantation (for patients with AML)

  * Any consolidation regimen that does not require transplantation can be used
  * No more than 6 months from documentation of morphologic CR to transplantation

Participant flow

Outcome results

• Progression-free Survival (Primary), Number, percentage of patients: Treatment (Chemotherapy and Transplant) 41.2 (33.9 to 49.9)
• Overall Survival (OS) (Secondary), Number, percentage of patients: Treatment (Chemotherapy and Transplant) 45.7 (34.9 to 59.9)
• 100-day Mortality (Secondary), Count of participants, Participants: Treatment (Chemotherapy and Transplant) 10

Adverse events

Serious adverse events by term

117 more terms not shown.

Other adverse events by term

211 more terms not shown.

• Results publication: Vij R, Le-Rademacher J, Laumann K, Hars V, Owzar K, Shore T, Vasu S, Cashen A, Isola L, Shea T, DeMagalhaes-Silverman M, Hurd D, Meehan K, Beardell F, Devine S. A Phase II Multicenter Study of the Addition of Azacitidine to Reduced-Intensity Conditioning Allogeneic Transplant for High-Risk Myelodysplasia (and Older Patients with Acute Myeloid Leukemia): Results of CALGB 100801 (Alliance). Biol Blood Marrow Transplant. 2019 Oct;25(10):1984-1992. doi: 10.1016/j.bbmt.2019.06.007. Epub 2019 Jun 15. PMID 31212080

• Ravi Vij, Principal investigator, Alliance for Clinical Trials in Oncology

NIH grants: U10CA180821, U10CA031946