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PRO#0118: A Phase I Study of Decitabin in Combination With Fludarabin and Busulfan as a Reduced Intensity Conditioning Regimen for the Treatment of Myeloid Malignancies

Phase 1
45 Years
80 Years
Open (Enrolling)
Acute Myeloid Leukemia, Myelodysplastic Syndrome

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Trial Information

PRO#0118: A Phase I Study of Decitabin in Combination With Fludarabin and Busulfan as a Reduced Intensity Conditioning Regimen for the Treatment of Myeloid Malignancies

Aberrant DNA methylation patterns are commonly found in malignant cells. Hypermethylation
of gene promotes sequences in cancer cells resulting in transcriptional silencing of tumor
suppressor genes and contributing to malignant transformation. Hypomethylating agents have
been explored for the treatment of cancers such as acute myelogenous leukemia and
myelodysplastic syndrome. In vitro inhibition of methylation using azanucleosides results
in differentiation of transformed myeloid cells. In vivo these agents induce DNA
methylation of malignant myeloid cells. The most potent DNA methylating agent currently
available, decitabine, is effective in patients with myelodysplastic syndrome (MDS) and
acute myelogenous leukemia (AML). About 30% of patients with MDS and an abnormal karyotype
will have normalization of their karyotype after receiving the drug.

The myelodysplastic syndromes are a heterogeneous group of clonal hematologic disorders
characterized by bone marrow failure and proliferation of myeloblastic leukemia cells.
Patients with MDS develop cytopenias as a result of ineffective hematopoiesis. These
cytopenias are believed to be a result of an increase in apoptosis resulting in an increase
in futile cell cycling. In addition, the apparently mature and differentiated hematopoietic
cells in patients with MDS are functionally impaired. Granulocytes have decreased
myeloperoxidase activity and platelets have impaired function. Therapy for MDS includes
supportive care geared mostly to transfusional support. Allogeneic transplantation has been
shown to offer the possibility of long-term remission and remains the only curative option
for patients with MDS. The development of reduced intensity conditioning regimens expanded
the scope of allogeneic transplantation for older patients with MDS. A very large
retrospective analysis by the European Blood and Marrow Transplantation Group compared the
outcome of 836 patients with MDS treated with either a reduced-intensity conditioning
regimen or a conventional regimen before allogeneic transplantation. The 3-year
probabilities of progression-free and overall survival were similar in both groups, with a
3-year relapse rate being significantly higher in the reduced-conditioning group, offset by
a significantly reduced probability of non-relapse mortality. This demonstrates the
importance of the preparative regimen in preventing relapse in this setting.

Acute myeloid leukemia accounts for over 9,000 deaths yearly in the United States. The WHO
classification of AML incorporates and interrelated morphology, cytogenetics, molecular
genetics and immunologic markers in an attempt to construct a classification that is
clinically and prognostically valid. Under this classification the requisite blast
percentage in the marrow is > 20%. Hematopoietic stem cell transplantation is an
established therapeutic modality in patients with AML. An alloreactive immunotherapeutic
effect of donor cells has been demonstrated.

No other established therapy applied during complete remission offers as strong an
anti-leukemic effect. Transplant-related morbidity and mortality, however, remain obstacles
in the successful application of this treatment. More recently, reduced-intensity
conditioning has been applied as a therapy for AML. Reduced-intensity conditioning, which
includes potent immunosuppressive agents in addition to anti-leukemic agents, effectively
permits engraftment of donor hematopoietic stem cells. Several studies have demonstrated
that the morbidity and mortality are less with these regimens compared to myeloablative
conditioning. While the reduced intensity of the conditioning regimen has resulted in
reduced non-relapse mortality in patients with AML, some studies have suggested a
concomitant increase in relapse as a consequence of lowering the intensity of the cytotoxic
agents. New conditioning regimen that may increase the anti-leukemic effect while
maintaining the reduced-intensity regimen toxicity profile are therefore, needed.

Decitabine is a deoxycytidine analog that rapidly enters into cells by a nucleoside-specific
transport mechanism. It is then phosphorylated by deoxycytidine kinase and converted to the
active triphosphate form, 5AZA-dCTP, a substrate for DNA polymerase alpha. 5AZA-dCTP is
incorporated into DNA and inhibits DNA methylation as inactivating DNA methyltransferase.
Decitabine is s-phase specific. A recent study randomized 170 patients with MDS to receive
either decitabine or best supportive care. Patients who were treated with decitabine
achieved a significantly higher overall response rate (17%) including complete responses
(9%), compared with supportive care (0%). Responses were durable and were associated with
transfusion independence. Patients treated with decitabine had a trend toward a longer
median time to acute myelogenous leukemia (AML) progression or death compared with patients
who received supportive care alone. Responses in AML have also been demonstrated with 14%
complete responses and 8% partial responses in one study . Decitabine has been used in
combination with cyclophosphamide and busulfan as preparative regimen in patients with AML.
This regimen was associated with a high response rate, with 40% of patients with AML being
still in remission more than three years after transplantation. The total dose of
decitabine ranged from 400 mg/m2 to 800 mg/m2. No decitabine dose-limiting toxicity was
documented. The combination of fludarabine and busulfan has been well established as a
transplant regimen and is associated with a reduced regimen-related toxicity. The
combination of fludarabine and busulfan is the current standard of care for AML patients
undergoing allogeneic transplantation at HUMC. In this study the investigators will be using
the combination of reduced-intensity fludarabine and busulfan along with decitabine 300

Inclusion Criteria:

- Diagnosis of acute myelogenous leukemia or myelodysplastic syndrome being considered
for transplantation.

- Age 45 to 80 years or < 45 with co-morbidity including: disease not in remission

- No uncontrolled infections.

- Patients shall have a 6/6 HLA-compatible related donor or an 8/8 -HLA-compatible
unrelated donor.

- KPS 70-100%

- Creatinine < 1.6 X ULN (unless age < 45 yrs)

- Serum Bilirubin < 2.5 X ULN

- Capable of giving informed consent and have signed the informed consent form.

- Cardiac EF > 50% or cardiac clearance

- Pulmonary DLCO > 50% or pulmonary clearance

Exclusion Criteria:

- Untreated CNS leukemia

- Active hepatitis or other untreated infections

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To assess the effect of decitabine in combination with fludarabine and busulfan prior to allogeneic stem cell transplantation on the rate of primary graft rejection

Outcome Description:

Graft failure defined by the presence of <10% donor lymphoid cells on peripheral blood analysis performed on post transplant day 84(+/- 10 days) in patients who have not relapsed will be measured.

Outcome Time Frame:

up to 1 year post transplantation

Safety Issue:


Principal Investigator

Michele Donato, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

John Theurer Cancer Center at Hackensack University Medical Center


United States: Institutional Review Board

Study ID:

Decitabine plus mini-FluBu



Start Date:

May 2009

Completion Date:

December 2013

Related Keywords:

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndrome (MDS)
  • Bone Marrow Transplant
  • Stem Cell Transplant
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia



Hackensack University Medical Center - John Theurer Cancer Center Hackensack, New Jersey  07601