A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies

Sidney Kimmel Cancer Center at Thomas Jefferson University

Status and phase: Completed; Phase 2

Conditions: Recurrent Adult Hodgkin Lymphoma; Polycythemia Vera; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Refractory Multiple Myeloma; T-cell Large Granular Lymphocyte Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Chronic Neutrophilic Leukemia; Splenic Marginal Zone Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Chronic Eosinophilic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Adult Acute Myeloid Leukemia in Remission; Previously Treated Myelodysplastic Syndromes; Recurrent Marginal Zone Lymphoma; Childhood Myelodysplastic Syndromes; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Grade 1 Follicular Lymphoma; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Refractory Anemia With Ringed Sideroblasts; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Aplastic Anemia; Refractory Anemia; Essential Thrombocythemia; Adult Acute Myeloid Leukemia With Del(5q); Chronic Myelomonocytic Leukemia; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Waldenström Macroglobulinemia; Mastocytosis; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Recurrent Small Lymphocytic Lymphoma; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Recurrent Grade 2 Follicular Lymphoma; Adult Acute Lymphoblastic Leukemia in Remission; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Secondary Myelodysplastic Syndromes; Childhood Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Nodal Marginal Zone B-cell Lymphoma; Primary Myelofibrosis; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Adult Acute Myeloid Leukemia; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Refractory Hairy Cell Leukemia

Treatments: Biological: Donor Lymphocyte Infusion (DLI); Drug: Busulfan; Procedure: Peripheral blood stem cell transplantation (PBSCT); Radiation: Total Body Irradiation (TBI); Drug: Fludarabine; Device: Allogeneic hematopoietic stem cell transplantation; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: Cyclophosphamide (CY)

Study type: Interventional

Funder types: Other

Identifiers

NCT01384513

11D.247

2011-31 (Other Identifier)

Details and patient eligibility

About

The purpose of this research study is to compare the survival rates of patients with better risk disease undergoing hematopoietic stem cell transplant (HSCT) to the survival rates reported in the medical literature of similar patients undergoing reduced intensity HSCT from matched related donors.

Full description

PRIMARY OBJECTIVES:

I. To compare the overall survival (OS) rate at 2 years post treatment using the Jefferson 2 step reduced intensity conditioning (RIC) approach in patients with haploidentical family donors with hematological malignancies in morphological or radiographic remission or with chemosensitive, indolent diseases to historical OS rates in similar populations after RIC matched donor HSCT as reported in the literature.

SECONDARY OBJECTIVES:

I. To compare the treatment-related mortality (TRM) rate at 2 years for patients treated on this study to the historical TRM rates of patients undergoing RIC matched-sibling HSCT as reported in the literature.

II. To compare the 2 year relapse rates and relapse related mortality of patients with myeloid diseases to that of patients with lymphoid diseases who are treated on this Thomas Jefferson University (TJU) RIC 2 step approach.

III. To determine the incidence and severity of graft-versus-host disease (GVHD) in patients undergoing treated on the TJU RIC 2 step approach.

IV. To evaluate engraftment rates and lymphoid reconstitution in patients treated on the TJU RIC 2 step approach.

V. To evaluate the incidence of TRM at 100 days in patients treated on the TJU RIC 2 step approach.

OUTLINE:

REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 60 minutes on days -11 to -8 and bulsufan IV over 3 hours on days -10 to -9. Patients undergo total body irradiation (TBI) on day -6. Patients also receive cyclophosphamide IV over 2 hours on days -3 and -2.

TRANSPLANTATION: Patients undergo donor lymphocyte infusion (DLI) on day -6 and cluster of differentiation (CD)-34+ allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0.

GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV or orally (PO) with taper beginning on day 42. Patients also receive mycophenolate mofetil IV twice daily (BID) on days -1 to 28.

After completion of study treatment, patients are followed up periodically for 2 years.

Enrollment: 40 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Any patient with hematologic or oncologic diagnosis in which allogeneic HSCT is thought to be beneficial, and in whom front-line therapy has already been applied. Patients treated on this protocol will be without morphological evidence of disease (complete remission or "CR"), or if the patient has evidence of disease, the patient must have had at least a good partial response (PR) to the most recent therapy and the disease must be chemoresponsive.

2. Patients treated on this study will have:

   • Acute leukemia in 1st or 2nd CR
   • MDS (myelodysplastic syndrome), specific subtypes of RA (refractory anemia) or RARS (refractory anemia with ringed sideroblasts) subtypes.
   • Hodgkin or Indolent Non-Hodgkin's lymphoma with chemosensitive disease
   • Myeloma without morphological evidence of disease, or a deep PR to the most recent therapy
   • Myeloproliferative disorders with at least a PR to current therapy
   • Aplastic Anemia
   • A hematological or oncological disease (not listed) that meets the criteria reviewed above (in CR or with a good PR).

3. Patients must have a related donor who is HLA mismatched at 2, 3, or 4 antigens at the HLA-A; B; C; DR loci in the GVHD direction. (Patients with related donors who are HLA identical or are a 1-antigen mismatch may be treated on this therapeutic approach, but will have their outcomes will not be part of the statistical aims of the study (see Summary section).

4. Patients must adequate organ function:

   • LVEF (Left ventricular end diastolic function) of >50%
   • DLCO (Diffusing Capacity of the Lung for Carbon Monoxide ) ≥50% of predicted corrected for hemoglobin
   • Adequate liver function as defined by a serum bilirubin <1.8, AST or ALT < 2.5X upper limit of normal
   • Creatinine Clearance of ≥ 60 mL/min

5. Performance status ≥ 80% (TJU Karnofsky) for patients ≥ 60 years old or ≥70% for patients < 60 years old.

6. HCT-CI Score ≤ 4 points for patients ≥ 60 years old or ≤ 5 points for patients < 60 years old.

7. Patients must be willing to use contraception if they have childbearing potential

8. Able to give informed consent

Exclusion criteria

1. Performance status < 80% (TJU Karnofsky) for patients ≥ 60 years old or <70% for patients < 60.
2. Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) Score > 4 points for patients ≥ 60 years old or > 5 points for patients < 60.
3. HIV positive
4. Active involvement of the central nervous system with malignancy
5. Inability to obtain informed consent
6. Pregnancy
7. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
8. Patients who have received alemtuzumab within 8 weeks of the transplant admission, or who have recently received horse or rabbit anti-thymocyte globulin and have an anti-thymocyte globulin level of > 2 ugm/ml
9. Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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40 participants in 1 patient group

Treatment (Allogeneic PBSCT)

Experimental group

Description:

REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 60 minutes on days -11 to -8 and busulfan IV over 3 hours on days -10 to -9. Patients undergo TBI on day -6. Patients also receive cyclophosphamide IV over 2 hours on days -3 and -2. TRANSPLANTATION: Patients undergo DLI on day -6 and CD-34+ allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV or PO with taper beginning on day 42. Patients also receive mycophenolate mofetil IV BID on days -1 to 28.

Treatment:

Drug: Cyclophosphamide (CY)

Drug: Mycophenolate mofetil

Drug: Tacrolimus

Device: Allogeneic hematopoietic stem cell transplantation

Drug: Fludarabine

Procedure: Peripheral blood stem cell transplantation (PBSCT)

Radiation: Total Body Irradiation (TBI)

Drug: Busulfan

Biological: Donor Lymphocyte Infusion (DLI)