Myelofibrosis
Conditions
Keywords
Myelofibrosis, Myeloproliferative disease, Stem Cell Transplant, Allogeneic Transplant, Conditioning Regimen, Reduced Intensity Regimen, Fludarabine, Melphalan, ATG
Brief summary
Stem cell transplantation is used to treat may types of diseases. There a 2 types of transplants, conventional (very intense) and reduced intensity-non-myeloablative, also called mini-transplants. This study proposes to use a conditioning regimen for allogeneic transplantation along with a reduced intensity transplant. Conditioning regiment is the name for the combination of chemotherapy drugs that is given to patients before receiving a transplantation of donor stem cells. It is hoped that the regimen designed for this study proves to be less toxic and has an equal or better anticancer effect than the regimens that are normally used. The regimen being used is a combination of two chemotherapy drugs, fludarabine and melphalan. This regimen has been studied in recipients of matched sibling transplants and in recipients of alternative donor stem cells in other hematologic malignancies. Those subjects, who receive stem cells from an unrelated donor, will also receive and additional drug called ATG or anti thymocyte globulin. ATG suppresses the immune system, thus reducing the chances for the recipient rejecting the transplant (graft). The purpose of this study is to observe if reduced intensity transplants can be used to allow engraftment or take of the donor's bone marrow. Studies conducted in the past show this type of transplant is much less toxic than traditional bone marrow transplants. Reduced intensity transplants may be better tolerated by patients who may experience serious side effects from standard (very intense) stem cell transplant. The study has been recently amended to follow all subjects for survival.
Detailed description
This study is designed as a single arm Phase II clinical trial in patients with myelofibrosis who are eligible for transplantation from a related donor or from an unrelated donor source. Patients will be accrued into two separate strata defined by donor type. Each of the two strata will be analyzed separately. Patients will be followed yearly from time of enrollment into the study to assess clinical response and overall, progression and event free survival, as well as incidence and degree of acute and chronic GVHD. We will estimate cumulative survival and transplant related mortality in patients enrolled in each of the two strata.
Interventions
DRUGFludarabine, Melphalan +/- ATG
Conditioning regimen for Allogenic Stem Cell Transplant: Related Donor Fludarabine days -6 to -2 (30mg/m2 IVPB over 30 minutes daily) Melphalan days -3 to -2 (70mg/m2 IVPB over 30 minutes daily) Unrelated Donor Fludarabine days -6 to -2 (30mg/m2 IVPB over 30 minutes daily) Melphalan days -3 to -2 (70mg/m2 IVPB over 30 minutes daily) ATG (Thymoglobulin®) days -3 to -1 (0.5 mg/kg IV on day -3 \[given over 6 hours\], and 2 mg/kg on days -2 and -1 \[given over 4 hours\])
Sponsors
National Institutes of Health (NIH)
Myeloproliferative Disorders-Research Consortium
National Cancer Institute (NCI)
John Mascarenhas
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients with the following disease: Idiopathic myelofibrosis, or spent PV-, or ET-related myelofibrosis in chronic phase (\<20% blast cells in the bone marrow) with Lille score \>1 at any time, or platelet \<100K. * Age 18-65 years. * ECOG performance status \< 3. * Life expectancy \>3 months. * Adequate cardiac function, normal LVEF ≥ 45% by MUGA or echocardiogram and adequate pulmonary function DLCO ≥ 50% of predicted. * Serum creatinine \< 1.1 x the upper limit of normal (ULN) or Creatinine Clearance \>50 ml/min. * Serum bilirubin \< 2.0 mg/dl, SGPT \<2.5 x upper limit of normal * No evidence of chronic active hepatitis or cirrhosis * HIV-negative * Patient is not pregnant * Patient or guardian able to sign informed consent. * Patients with \>20% myeloblasts in the blood or marrow, extramedullary blast cell proliferation or large foci of blasts in bone marrow biopsy specimens are not eligible. * Pretransplant splenectomy: MMM patients with variable degrees of splenomegaly, or splenectomized, are eligible to be enrolled. Any decision of having a patient splenectomized prior to transplant will be made in each center prior to enrolling the patient in the study. * Patients should be off treatment with investigational for at least 4 weeks and have recovered from all toxicities.
Exclusion criteria
* Pregnancy * HIV positive * \> 20% myeloblasts in the peripheral blood or bone marrow * LVEF \< 45% * DLCO \< 50% of predicted * ECOG performance status ≥ 3 * Chronic active hepatitis or cirrhosis * Chronic renal insufficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Endpoint is Progression-free Survival. | 2 years | Number of participants alive at 2 years who are progression-free |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Outcomes | 180 days | assessed according to the IWG Criteria |
| Overall Survival | 73 months | The number of patients alive at last follow-up. |
| Absolute Neutrophil Count (ANC) | 2 years | Patients with ANC ≥0.5 × 10\^9/L |
| PLT | 2 years | Patients with PLT ≥20 × 109/L |
| Transplant-related Mortality | 2 years | Transplant-related Mortality including Graft-versus-host disease (GVHD) |
Countries
Canada, Italy, Sweden, United States
Participant flow
Recruitment details
Patients were recruited from 2007 to 2011 at 11 centers affiliated with the Myeloproliferative Disorders Research Consortium (MPD-RC)
Participants by arm
| Arm | Count |
|---|---|
| Sibling Donor Patients received a stem cell transplant from sibling | 32 |
| Unrelated Donor Patients received a stem cell transplant from an unrelated donor | 34 |
| Total | 66 |
Baseline characteristics
| Characteristic | Unrelated Donor | Sibling Donor | Total |
|---|---|---|---|
| Age, Continuous | 56 years | 55 years | 55 years |
| Bone Marrow Fibrosis Grade 1 | 2 participants | 0 participants | 2 participants |
| Bone Marrow Fibrosis Grade 2 | 6 participants | 2 participants | 8 participants |
| Bone Marrow Fibrosis Grade 3 | 23 participants | 18 participants | 41 participants |
| Bone Marrow Fibrosis Unknown | 3 participants | 12 participants | 15 participants |
| Diagnosis ET-MF | 4 participants | 15 participants | 19 participants |
| Diagnosis PMF | 25 participants | 14 participants | 39 participants |
| Diagnosis PV-MF | 5 participants | 3 participants | 8 participants |
| HLA match Full HLA matched | 25 participants | 30 participants | 55 participants |
| HLA match HLA 1 Ag mismatched, no allele mismatched | 4 participants | 2 participants | 6 participants |
| HLA match HLA Ag matched, 1 0r 2 alleles mismatched | 5 participants | 0 participants | 5 participants |
| JAK-2V617F Negative | 16 participants | 17 participants | 33 participants |
| JAK-2V617F Positive | 18 participants | 12 participants | 30 participants |
| JAK-2V617F Unknown | 0 participants | 3 participants | 3 participants |
| Karyotype Complex abnormality | 0 participants | 5 participants | 5 participants |
| Karyotype Normal | 14 participants | 14 participants | 28 participants |
| Karyotype One abnormality | 9 participants | 7 participants | 16 participants |
| Karyotype Unknown | 11 participants | 6 participants | 17 participants |
| Lille score 0 | 0 participants | 3 participants | 3 participants |
| Lille score 1 | 23 participants | 20 participants | 43 participants |
| Lille score 2 | 11 participants | 9 participants | 20 participants |
| Patient: donor gender Female:Female | 7 participants | 6 participants | 13 participants |
| Patient: donor gender Female:Male | 13 participants | 9 participants | 22 participants |
| Patient: donor gender Male:Female | 6 participants | 10 participants | 16 participants |
| Patient: donor gender Male:Male | 8 participants | 7 participants | 15 participants |
| Sex: Female, Male Female | 15 Participants | 13 Participants | 28 Participants |
| Sex: Female, Male Male | 19 Participants | 19 Participants | 38 Participants |
| Splenomegaly No | 1 participants | 3 participants | 4 participants |
| Splenomegaly Splenectomy | 5 participants | 5 participants | 10 participants |
| Splenomegaly Yes | 28 participants | 24 participants | 52 participants |
| Stem cell source Bone Marrow | 3 participants | 6 participants | 9 participants |
| Stem cell source Peripheral blood | 31 participants | 26 participants | 57 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 8 / 32 | 23 / 34 |
Outcome results
Primary
The Primary Endpoint is Progression-free Survival.
Number of participants alive at 2 years who are progression-free
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sibling Donor | The Primary Endpoint is Progression-free Survival. | 24 participants |
| Unrelated Donor | The Primary Endpoint is Progression-free Survival. | 11 participants |
Secondary
Absolute Neutrophil Count (ANC)
Patients with ANC ≥0.5 × 10\^9/L
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sibling Donor | Absolute Neutrophil Count (ANC) | yes | 31 participants |
| Sibling Donor | Absolute Neutrophil Count (ANC) | no | 1 participants |
| Unrelated Donor | Absolute Neutrophil Count (ANC) | yes | 26 participants |
| Unrelated Donor | Absolute Neutrophil Count (ANC) | no | 8 participants |
Secondary
Overall Survival
The number of patients alive at last follow-up.
Time frame: 73 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sibling Donor | Overall Survival | 25 participants |
| Unrelated Donor | Overall Survival | 11 participants |
Secondary
PLT
Patients with PLT ≥20 × 109/L
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sibling Donor | PLT | yes | 28 participants |
| Sibling Donor | PLT | no | 4 participants |
| Unrelated Donor | PLT | yes | 20 participants |
| Unrelated Donor | PLT | no | 14 participants |
Secondary
Response Outcomes
assessed according to the IWG Criteria
Time frame: 180 days
Population: Clinical responses were assessed according to the IWG-MRT 2006 criteria in 46 patients (29 sibling and 17 unrelated transplants) who survived at least 180 days.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sibling Donor | Response Outcomes | progressive disease | 0 participants |
| Sibling Donor | Response Outcomes | clinical complete response | 7 participants |
| Sibling Donor | Response Outcomes | clinical partial response | 8 participants |
| Sibling Donor | Response Outcomes | clinical improvement | 11 participants |
| Sibling Donor | Response Outcomes | stable disease | 2 participants |
| Unrelated Donor | Response Outcomes | stable disease | 4 participants |
| Unrelated Donor | Response Outcomes | clinical improvement | 5 participants |
| Unrelated Donor | Response Outcomes | clinical complete response | 6 participants |
| Unrelated Donor | Response Outcomes | progressive disease | 1 participants |
| Unrelated Donor | Response Outcomes | clinical partial response | 1 participants |
Secondary
Transplant-related Mortality
Transplant-related Mortality including Graft-versus-host disease (GVHD)
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sibling Donor | Transplant-related Mortality | yes | 3 participants |
| Sibling Donor | Transplant-related Mortality | no | 29 participants |
| Unrelated Donor | Transplant-related Mortality | yes | 20 participants |
| Unrelated Donor | Transplant-related Mortality | no | 14 participants |