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A Phase II Trial of Reduced Intensity Allogeneic Stem Cell Transplantation With Fludarabine, Melphalan and Low Dose Total Body Irradiation


Phase 2
3 Years
75 Years
Open (Enrolling)
Both
Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Grade III Lymphomatoid Granulomatosis, Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Aplastic Anemia, Burkitt Lymphoma, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Childhood Chronic Myelogenous Leukemia, Childhood Diffuse Large Cell Lymphoma, Childhood Grade III Lymphomatoid Granulomatosis, Childhood Immunoblastic Large Cell Lymphoma, Childhood Myelodysplastic Syndromes, Childhood Nasal Type Extranodal NK/T-cell Lymphoma, Chronic Myelomonocytic Leukemia, Chronic Phase Chronic Myelogenous Leukemia, Congenital Amegakaryocytic Thrombocytopenia, Diamond-Blackfan Anemia, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, Juvenile Myelomonocytic Leukemia, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Nodal Marginal Zone B-cell Lymphoma, Paroxysmal Nocturnal Hemoglobinuria, Peripheral T-cell Lymphoma, Polycythemia Vera, Post-transplant Lymphoproliferative Disorder, Previously Treated Myelodysplastic Syndromes, Primary Myelofibrosis, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Recurrent Childhood Anaplastic Large Cell Lymphoma, Recurrent Childhood Grade III Lymphomatoid Granulomatosis, Recurrent Childhood Large Cell Lymphoma, Recurrent Childhood Lymphoblastic Lymphoma, Recurrent Childhood Small Noncleaved Cell Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Recurrent/Refractory Childhood Hodgkin Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Hairy Cell Leukemia, Refractory Multiple Myeloma, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Secondary Myelofibrosis, Severe Combined Immunodeficiency, Severe Congenital Neutropenia, Shwachman-Diamond Syndrome, Splenic Marginal Zone Lymphoma, T-cell Large Granular Lymphocyte Leukemia, Waldenstrom Macroglobulinemia, Wiskott-Aldrich Syndrome

Thank you

Trial Information

A Phase II Trial of Reduced Intensity Allogeneic Stem Cell Transplantation With Fludarabine, Melphalan and Low Dose Total Body Irradiation


PRIMARY OBJECTIVES:

I. To determine the transplant related mortality (TRM) of this reduced-intensity
transplantation (RIT) combination, fludarabine (fludarabine phosphate), melphalan, and TBI
in a patient population usually not eligible for a full a myeloablative allogeneic
hematopoietic stem cell transplantation (HSCT).

SECONDARY OBJECTIVES:

I. To evaluate clinical response, progression free survival (PFS) at one year, engraftment
rate, and graft-versus-host disease (GvHD) incidence with the proposed RIT regimen across a
variety of hematological conditions.

II. Correlative studies will include chimerism analysis by molecular analysis and evaluation
of immune reconstitution by cytomegalovirus (CMV) dextramer analysis using flow cytometry.

OUTLINE: PREPARATIVE REGIMEN:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -2
and melphalan IV over 30 minutes on day -2. Patients undergo low-dose TBI twice daily (BID)
on day -1.

TRANSPLANTATION:

Patients undergo allogeneic PBSCT on day 0.

GvHD PROPHYLAXIS:

Patients receive tacrolimus IV or orally (PO) BID on days -1 to 100 with taper over 4-6
months, MMF PO or IV every 6-8 hours on days -1 to 60, and methotrexate IV over 15-30
minutes on days 1, 3, and 6. After completion of study treatment, patients are followed up
periodically.


Inclusion Criteria:



- Diagnosis of a histology documented hematologic malignancy or marrow disorder

BONE MARROW FAILURE DISORDERS:

- Acquired bone marrow failure disorders include aplastic anemia, paroxysmal nocturnal
hemoglobinuria (PNH) * Primary allogeneic HSCT is appropriate for selected patients
with severe aplastic anemia; however, patients with aplastic anemia must have failed
at least one cycle of standard immunosuppressive therapy with calcineurin inhibitor
plus anti-thymocyte globulin (ATG) if a fully matched donor is available * Patients
with PNH should not be eligible for a myeloablative HSCT

- Hereditary bone marrow failure disorders include Diamond-Blackfan Anemia,
Shwachman-Diamond Syndrome, Kostmann Syndrome, congenital Amegakaryocytic
Thrombocytopenia; Fanconi Anemia or related chromosomal breakage syndrome,
Dyskeratosis Congenital are excluded from this study die to their poor
deoxyribonucleic acid (DNA) repair capacity * Fanconi anemia or related chromosomal
breakage syndrome: positive chromosome breakage analysis using diepoxybutane (DEB) or
mitomycin C if applicable * Dyskeratosis Congenita: diagnosis is supported by using
either telomerase RNA component (TERC) gene mutation in autosomal dominant
Dyskeratosis Congenita or X-linked DKC1 gene mutation

- Other non-malignant hematologic or immunologic disorders that require transplantation
* Quantitative or qualitative congenital platelet disorders (including but not
limited to congenital amegakaryocytopenia, absent-radii syndrome, Glanzmann's
thrombasthenia) * Quantitative or qualitative congenital neutrophil disorders
(including but not limited to chronic granulomatous disease, congenital neutropenia)
*Congenital primary immunodeficiency syndrome, Wiskott-Aldrich syndrome, CD40 ligand
deficiency, T-cell deficiencies)

ACUTE LEUKEMIAS:

- Subjects must be ineligible for or unable to receive a conventional myeloablative
transplantation

- Resistant or recurrent disease after at least one standard combination chemotherapy
OR first remission patients at high risk of relapse * Acute myeloid leukemia (AML)

- antecedent myelodysplastic syndrome, secondary AML, high risk cytogenetic
abnormalities or normal cytogenetics with high-risk molecular mutations (e.g.,
fms-like tyrosine kinase3-internal tandem duplication [Flt3-ITD] mutation) * Acute
lymphocytic leukemia (ALL)

- high or standard risk ALL

CHRONIC MYELOID LEUKEMIA (CML):

- Chronic phase (intolerant or unresponsive to imatinib and/or other tyrosine kinase
inhibitors), second chronic phase or accelerated phase who are ineligible for
conventional myeloablative transplantation

MYELOPROLIFERATIVE AND MYELODYSPLASTIC SYNDROME (MDS):

- Myelofibrosis (with/without splenectomy) with intermediate to high risk features

- Advanced polycythemia vera nor responding to standard therapy

- MDS with lower International Prognostic Scoring System (IPSS) score of intermediate
(Int)-2 or higher

- MDS with lower IPSS score Int-1 or less with severe clinical features such as severe
neutropenia or thrombocytopenia or high risk chromosome abnormalities such as
monosomy 7

- Secondary MDS with any IPSS scores

- Chronic myelomonocytic leukemia

LYMPHOPROLIFERATIVE DISEASE:

- Chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin lymphoma (NHL) (recurrent
or persistent) fludarabine refractory or with less than 6 months duration or complete
remission (CR) between courses of conventional therapy

- Multiple myeloma (progressive disease after autologous stem cell transplant, tandem
allogeneic transplant after prior autologous stem cell transplant)

- Waldenstrom's macroglobulinemia (failed one standard regimen)

- High grade NHL and diffuse large B-cell lymphoma (DLBCL)

- Not eligible for conventional myeloablative HSCT OR failed autologous HSCT

- First remission lymphoblastic lymphoma, or small, non-cleaved cell lymphoma or mantle
cell lymphoma

HODGKIN LYMPHOMA:

- Received and failed front-line therapy

- Failed or were not eligible for autologous transplantation DONOR: Permissible human
leukocyte antigen (HLA) matching: related donors

- single antigen mismatch at HLA A, B, or DRB1; unrelated donors

- a single antigen mismatch at HLA A, B, or C, +/- additional single allele level
mismatch at A, B, V or DRB1

- Minimum goal for peripheral blood stem cells (PBSC) dose is 2 x 10^6 CD34+ cells/kg
of recipient weight; minimum goal for the marrow dose is 1 x 10^8 nucleated cells/kg
of recipient weight

- No serious uncontrolled psychiatric illness

- No concomitant active malignancy that would be expected to require chemotherapy
within 3 years of transplant (other than non-melanoma skin cancer)

- Non-pregnant and non-nursing woman; (women or men with reproductive potential should
agree to use an effective means of birth control)

- Patients who have failed a prior autologous or allogeneic transplant are eligible;
however, at least 90 days must have elapsed between the start of this reduced
intensity conditioning regimen and the last transplant if patient had a prior
autologous or myeloablative allogeneic bone marrow transplant (BMT)

- At least 2 weeks since prior chemotherapy, radiation treatment and/or surgery

- Informed consent

DONOR: Compatibility at the four most informative HLA loci:

A, B, C and DRB1 are important for reducing the risk of GVHD and successful transplant
outcomes; the A, B, C and DRB1 loci comprise 8 possible alleles (a haplotype being
inherited from each parent); one additional locus, HLA-DQ, is also typed to ascertain
haplotypes and assist in the search for a compatible donor; however mismatching at DQ has
not been shown to be associated with adverse outcomes; high resolution molecular typing
(at the allele level) is now the standard of care for unrelated donor searches and allows
greater refinement of the search strategy

DONOR: Matched related donor:

a single antigen mismatch at A, B, or the DR transplant from a family member is associated
with a higher risk of GVHD but similar overall survival when compared to full identity at
these 3 regions; related donor/recipient pairs must be matched at 5 of 6 HLA antigens (A,
B, DRB1)

DONOR: Unrelated Donor:

When evaluating patients for unrelated donor transplant, the higher degree of matching,
the lower risk of GvHD; the A, B, C, DRB1 and DQB1 loci, comprising 10 possible antigen
(with alleles), will be typed for all unrelated transplants; given the higher risk of TRM
in mismatched transplants, RIT is often the best way to mitigate the risk; data from the
National Marrow Donor Program makes it possible to estimate the risk of donor-recipient
HLA mismatch at the allele or antigen level; the higher risk from HLA-mismatching must be
balanced against the clinical urgency and the patient's risk by the transplant team; at
this time, antigen level mismatches at DQB1 do not affect outcomes and will not be used
for matching purposes for donor selection; thus, the matching required will be at the HLA
A, B, C and DRB1 (8 loci); for this protocol, a single antigen mismatch at the HLA A, B,
C, with or without additional single allele level mismatch may participate in this
protocol for voluntary unrelated donors (blood or marrow) DONOR: Donor must be healthy and
have non-reactive test results for all infectious disease assays as required by state and
federal regulations; donors who screen seropositive for hepatitis an/or syphilis must be
cleared by infectious disease consultation DONOR: Donor must have no uncontrolled
cardiopulmonary, renal, endocrine, hepatic or psychiatric disease to render donation
unsafe DONOR: The donor (or parent in minor) must give informed consent for peripheral
blood stem cell collection or bone marrow collection DONOR: Syngeneic donors are not
eligible DONOR: Donors who have poor peripheral venous access, may require central venous
line placement for stem cell apheresis

Exclusion Criteria:

- Uncontrolled central nervous system (CNS) disease (for hematologic malignancies)

- Karnofsky (adult) or Lansky (for =< 16 years) performance status < 50%

- Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% predicted, corrected
for hemoglobin and/or alveolar ventilation

- Left ventricular ejection fraction < 40% - Bilirubin >= 3 X upper limit of
normal

- Liver alkaline phosphatase >= 3 x upper limit of normal

- Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvate
transaminase (SGPT) >= 3 x upper limit of normal

- Child's class B and C liver failure

- Calculated creatinine clearance < 40 cc/min by the modified Cockroft-Gault formula
for adults or the Schwartz formula for pediatrics

- Patients who have received maximally allowed doses (given in 2 Gy fractionations, or
equivalent) of previous radiation therapy to various organs as follows: *
Mediastinum: adult -40, pediatric (=<18 yrs) - 21 * Heart: adult 36, pediatric - 26
* Whole lung(s): adult - 12, pediatric - 10 * Small bowel: adult - 46, pediatric - 40
* Kidneys: adult - 12, pediatric - 10 * Whole liver: adult - 20, pediatric - 20 *
Spinal cord: adult - 36, pediatric - 36 * Whole Brain: adult 30, pediatric - 30

- Patients who previously have received a higher than allowed dose of radiation to a
small lung, liver, and brain volume, will be evaluated by the radiation oncologist to
determine if the patient is eligible for study

- Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or
other condition which, in the opinion of treating physician, would make this protocol
unreasonably hazardous for the patient

- Human immunodeficiency virus (HIV) positive

- Patients who in the opinion of the treating physician are unlikely to comply with the
restrictions of allogeneic stem cell transplantation based on formal psychosocial
screening

- Female of childbearing potential with a positive pregnancy test

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

transplant related mortality (TRM) for patients undergoing RIT with co-morbidities or who are otherwise not eligible or unable to receive a myeloablative allogeneic HSCT

Outcome Description:

An exact 95% confidence interval will be provided.

Outcome Time Frame:

In the first 100 days from day 0 of transplant

Safety Issue:

Yes

Principal Investigator

Hong Liu

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute

Authority:

United States: Institutional Review Board

Study ID:

I 177110

NCT ID:

NCT01529827

Start Date:

February 2012

Completion Date:

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Adult Acute Lymphoblastic Leukemia in Remission
  • Adult Acute Myeloid Leukemia in Remission
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Grade III Lymphomatoid Granulomatosis
  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Aplastic Anemia
  • Burkitt Lymphoma
  • Childhood Acute Lymphoblastic Leukemia in Remission
  • Childhood Acute Myeloid Leukemia in Remission
  • Childhood Chronic Myelogenous Leukemia
  • Childhood Diffuse Large Cell Lymphoma
  • Childhood Grade III Lymphomatoid Granulomatosis
  • Childhood Immunoblastic Large Cell Lymphoma
  • Childhood Myelodysplastic Syndromes
  • Childhood Nasal Type Extranodal NK/T-cell Lymphoma
  • Chronic Myelomonocytic Leukemia
  • Chronic Phase Chronic Myelogenous Leukemia
  • Congenital Amegakaryocytic Thrombocytopenia
  • Diamond-Blackfan Anemia
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Hepatosplenic T-cell Lymphoma
  • Juvenile Myelomonocytic Leukemia
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Nodal Marginal Zone B-cell Lymphoma
  • Paroxysmal Nocturnal Hemoglobinuria
  • Peripheral T-cell Lymphoma
  • Polycythemia Vera
  • Post-transplant Lymphoproliferative Disorder
  • Previously Treated Myelodysplastic Syndromes
  • Primary Myelofibrosis
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Recurrent Childhood Anaplastic Large Cell Lymphoma
  • Recurrent Childhood Grade III Lymphomatoid Granulomatosis
  • Recurrent Childhood Large Cell Lymphoma
  • Recurrent Childhood Lymphoblastic Lymphoma
  • Recurrent Childhood Small Noncleaved Cell Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Recurrent Small Lymphocytic Lymphoma
  • Recurrent/Refractory Childhood Hodgkin Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Hairy Cell Leukemia
  • Refractory Multiple Myeloma
  • Secondary Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Secondary Myelofibrosis
  • Severe Combined Immunodeficiency
  • Severe Congenital Neutropenia
  • Shwachman-Diamond Syndrome
  • Splenic Marginal Zone Lymphoma
  • T-cell Large Granular Lymphocyte Leukemia
  • Waldenström Macroglobulinemia
  • Wiskott-Aldrich Syndrome
  • Congenital Abnormalities
  • Primary Myelofibrosis
  • Anemia
  • Anemia, Aplastic
  • Burkitt Lymphoma
  • Neoplasms
  • Hemoglobinuria
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Immunologic Deficiency Syndromes
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myeloid, Chronic-Phase
  • Leukemia, Myelomonocytic, Chronic
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Lymphoproliferative Disorders
  • Waldenstrom Macroglobulinemia
  • Hemoglobinuria, Paroxysmal
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Mycoses
  • Mycosis Fungoides
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute
  • Myeloproliferative Disorders
  • Neutropenia
  • Polycythemia
  • Polycythemia Vera
  • Sezary Syndrome
  • Thrombocytopenia
  • Wiskott-Aldrich Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, T-Cell, Peripheral
  • Severe Combined Immunodeficiency
  • Lymphoma, Large-Cell, Anaplastic
  • Lymphoma, B-Cell, Marginal Zone
  • Bone Marrow Diseases
  • Lipomatosis
  • Exocrine Pancreatic Insufficiency
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell
  • Leukemia, Myelomonocytic, Juvenile
  • Hematologic Neoplasms
  • Anemia, Diamond-Blackfan
  • Myelodysplastic-Myeloproliferative Diseases
  • Leukemia, Large Granular Lymphocytic

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263