Back to results

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

Primary Purpose

Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Fludarabine

Busulfan

Total Body Irradiation (TBI)

Donor Lymphocyte Infusion (DLI)

Cyclophosphamide (CY)

Tacrolimus

Mycophenolate mofetil

Allogeneic hematopoietic stem cell transplantation

Peripheral blood stem cell transplantation (PBSCT)

About this trial

This is an interventional treatment trial for Adult Acute Lymphoblastic Leukemia in Remission focused on measuring Allogeneic HSCT, Hematopoietic stem cell transplantation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.
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).
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).
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
Performance status ≥ 80% (TJU Karnofsky) for patients ≥ 60 years old or ≥70% for patients < 60 years old.
HCT-CI Score ≤ 4 points for patients ≥ 60 years old or ≤ 5 points for patients < 60 years old.
Patients must be willing to use contraception if they have childbearing potential
Able to give informed consent

Exclusion Criteria:

Performance status < 80% (TJU Karnofsky) for patients ≥ 60 years old or <70% for patients < 60.
Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) Score > 4 points for patients ≥ 60 years old or > 5 points for patients < 60.
HIV positive
Active involvement of the central nervous system with malignancy
Inability to obtain informed consent
Pregnancy
Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
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
Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol

Sites / Locations

Thomas Jefferson University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (Allogeneic PBSCT)

Arm 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.

Outcomes

Primary Outcome Measures

Overall Survival (OS) in patients with haploidentical family donors with hematological malignancies in morphological or radiographic remission or with chemosensitive, indolent diseases

The primary null hypothesis is that 2 year OS rate is at most 35%. This hypothesis will be rejected if the 95% confidence interval for year OS rate computed from the estimated Kaplan-Meier survival curves will be entirely above 0.35.

Secondary Outcome Measures

Treatment Related Mortality (TRM)

To compare the treatment related mortality rate (TRM) for patients treated on this study to the historical TRM rates of patients undergoing reduced intensity conditioning (RIC) matched-sibling hematopoietic stem cell transplant (HSCT) as reported in the literature

Incidence and severity of GVHD, graded according to standard criteria

The estimates of incidence rates will be presented with corresponding 95% confidence intervals using the exact method

Relapse Rate

Evaluated by estimating Kaplan-Meier survival curves. From these curves, the 95% confidence interval for 2 year rates will be computed.

Engraftment Rates

The estimates of incidence rates will be presented with corresponding 95% confidence intervals using the exact method.

Incidence of Treatment Related Mortality (TRM)

The estimates of incidence rates will be presented with corresponding 95% confidence intervals using the exact method.

Relapse Related Mortality

Evaluated by estimating Kaplan-Meier survival curves. From these curves, the 95% confidence interval for 2 year rates will be computed.

Lymphoid Reconstitution

To evaluate lymphoid reconstitution in patients treated on the Two Step approach

Full Information

NCT ID

NCT01384513

First Posted

June 27, 2011

Last Updated

November 16, 2022

Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University

1. Study Identification

Unique Protocol Identification Number

NCT01384513

Brief Title

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

Official Title

A Two Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Completed

Study Start Date

August 4, 2011 (Actual)

Primary Completion Date

November 13, 2020 (Actual)

Study Completion Date

November 16, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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 Nasal Type Extranodal NK/T-cell Lymphoma, Aplastic Anemia, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Childhood Myelodysplastic Syndromes, Chronic Eosinophilic Leukemia, Chronic Myelomonocytic Leukemia, Chronic Neutrophilic Leukemia, Essential Thrombocythemia, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Juvenile Myelomonocytic Leukemia, Mastocytosis, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Nodal Marginal Zone B-cell Lymphoma, Polycythemia Vera, Previously Treated Myelodysplastic Syndromes, Primary Myelofibrosis, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Recurrent/Refractory Childhood Hodgkin Lymphoma, Refractory Anemia, Refractory Anemia With Ringed Sideroblasts, Refractory Hairy Cell Leukemia, Refractory Multiple Myeloma, Secondary Myelodysplastic Syndromes, Splenic Marginal Zone Lymphoma, T-cell Large Granular Lymphocyte Leukemia, Waldenström Macroglobulinemia

Keywords

Allogeneic HSCT, Hematopoietic stem cell transplantation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

40 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (Allogeneic PBSCT)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

fludarabine phosphate, Fludara

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Busulfan

Other Intervention Name(s)

Myleran, Busulfex IV

Intervention Description

Given IV

Intervention Type

Radiation

Intervention Name(s)

Total Body Irradiation (TBI)

Other Intervention Name(s)

radiotherapy

Intervention Description

2 Gy administered as part of the conditioning regimen

Intervention Type

Biological

Intervention Name(s)

Donor Lymphocyte Infusion (DLI)

Other Intervention Name(s)

buffy coat fusion

Intervention Description

Undergo DLI

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide (CY)

Other Intervention Name(s)

Endoxan, Cytoxan, Neosar, Procytox, Revimmune, cytophosphane

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Other Intervention Name(s)

FK-506, Fujimycin

Intervention Description

Given IV or PO

Intervention Type

Drug

Intervention Name(s)

Mycophenolate mofetil

Other Intervention Name(s)

MMF, CellCept

Intervention Description

Given IV

Intervention Type

Device

Intervention Name(s)

Allogeneic hematopoietic stem cell transplantation

Other Intervention Name(s)

CliniMACS

Intervention Description

Undergo CD34+ allogeneic PBSCT

Intervention Type

Procedure

Intervention Name(s)

Peripheral blood stem cell transplantation (PBSCT)

Other Intervention Name(s)

PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell

Intervention Description

Undergo CD34+ allogeneic PBSCT

Primary Outcome Measure Information:

Title

Overall Survival (OS) in patients with haploidentical family donors with hematological malignancies in morphological or radiographic remission or with chemosensitive, indolent diseases

Description

Time Frame

At 2 years

Secondary Outcome Measure Information:

Title

Treatment Related Mortality (TRM)

Description

Time Frame

At 2 years

Title

Incidence and severity of GVHD, graded according to standard criteria

Description

The estimates of incidence rates will be presented with corresponding 95% confidence intervals using the exact method

Time Frame

Assessed up to 2 years

Title

Relapse Rate

Description

Evaluated by estimating Kaplan-Meier survival curves. From these curves, the 95% confidence interval for 2 year rates will be computed.

Time Frame

At 2 years

Title

Engraftment Rates

Description

The estimates of incidence rates will be presented with corresponding 95% confidence intervals using the exact method.

Time Frame

Assessed up to 2 years

Title

Incidence of Treatment Related Mortality (TRM)

Description

The estimates of incidence rates will be presented with corresponding 95% confidence intervals using the exact method.

Time Frame

At 100 days

Title

Relapse Related Mortality

Description

Evaluated by estimating Kaplan-Meier survival curves. From these curves, the 95% confidence interval for 2 year rates will be computed.

Time Frame

At 2 years

Title

Lymphoid Reconstitution

Description

To evaluate lymphoid reconstitution in patients treated on the Two Step approach

Time Frame

100 days post-transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. 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). 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). 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 Performance status ≥ 80% (TJU Karnofsky) for patients ≥ 60 years old or ≥70% for patients < 60 years old. HCT-CI Score ≤ 4 points for patients ≥ 60 years old or ≤ 5 points for patients < 60 years old. Patients must be willing to use contraception if they have childbearing potential Able to give informed consent Exclusion Criteria: Performance status < 80% (TJU Karnofsky) for patients ≥ 60 years old or <70% for patients < 60. Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) Score > 4 points for patients ≥ 60 years old or > 5 points for patients < 60. HIV positive Active involvement of the central nervous system with malignancy Inability to obtain informed consent Pregnancy Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder 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 Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Dolores Grosso, DNP, CRNP

Organizational Affiliation

Sidney Kimmel Cancer Center at Thomas Jefferson University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Neal Flomenberg, MD

Organizational Affiliation

Sidney Kimmel Cancer Center at Thomas Jefferson University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Thomas Jefferson University

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19107

Country

United States

12. IPD Sharing Statement

Links:

URL

http://www.JeffersonHospital.org

Description

Thomas Jefferson University Hospitals

Learn more about this trial

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

We'll reach out to this number within 24 hrs