Allogeneic Stem Cell Transplantation for Myelofibrosis and Myelodysplastic Syndrome

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00475020
• Collaborator: (none)
• Enrollment: 63
• Location: 1
• Arm: 1
• Actual Duration (Months): 141
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if using a combination of fludarabine, busulfan, and antithymocyte globulin (ATG) can help to control myelofibrosis or myelodysplastic syndrome in patients receiving a bone marrow or blood stem cell transplant. The safety of these drugs will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis	Drug: Busulfan; Drug: Fludarabine; Drug: Thymoglobulin (ATG)	Phase 2

Detailed Description

Busulfan is a chemotherapy drug that kills cancer cells by binding to DNA, and is commonly used in stem cell transplants. Fludarabine is a drug that has anti-leukemia and immunosuppressive effects. ATG helps to reduce the risk of transplant rejection and to prevent graft versus host disease.

You will receive fludarabine by vein over 1 hour on Days -5 to -2. You will receive busulfan by vein over 3 hours on Day -5 to -2 immediately after completing fludarabine. If you have an unrelated or a mismatched donor, you will receive ATG by vein over 6 hours on Days -3 to -1 to prevent graft versus host disease and to help engraftment.

You will first receive a low-level "test" dose of busulfan, and blood samples (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK) tests. This may be done as an outpatient prior to inpatient admission. PK tests measure the level of the study drug in the blood over different time points. This information will be used to decide the next dose needed to reach the target blood level that matches your body size.

About 11 total samples of blood will be drawn for PK testing after the test dose and before the first high-dose busulfan treatment. A heparin lock will be placed in your vein to lower the number of needle sticks needed for these draws. If it is not possible for these blood level tests to be performed for technical or scheduling reasons or for any other reason, you will receive the standard fixed busulfan dose without the "test dose."

You will receive the donor bone marrow or blood stem cells by vein over about 1 hour on Day 0.

Two (2) days before the stem cell infusion on Day -2, tacrolimus will be started as a non-stop infusion by vein and will be changed to oral tablets before you leave the hospital. You will continue to take tacrolimus by mouth, for at least 4 months.

Four (4) doses of Methotrexate will be give as a short infusion Day 1, Day 3, Day 6 and Day 11 after stem cell infusion. Both these are given to decrease the risk of getting graft-vs-host disease (GvHD). Further immunosuppressive therapy with methylprednisolone (a steroid) or other drugs may also be used to treat GvHD if it occurs.

You will have 3 teaspoonfuls of blood drawn for routine tests every day while you are in the hospital and at least 2 times a week for the first 100 days after transplant. You may need frequent blood transfusions and may have to be admitted to the hospital to receive antibiotics if you get a fever. Three (3) teaspoonful of blood and a bone marrow aspirate and biopsy will be taken 1 month, 3 months, 6 months, 12 months, 18 months, and 24 months after the transplant to check the response to the treatment. After the first 2 years, your disease status will be followed by a yearly phone call or letter from you or your regular doctor to the study doctor.

Tests and/or procedures may be performed before the scheduled time, if your doctor thinks it is needed.

You will be taken off the study if your disease gets worse or if further treatment is not in your best interest.

This is an investigational study. All the drugs to be used in this study are FDA approved and commercially available. About 110 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Allogeneic Stem Cell Transplantation for Myelofibrosis and Myelodysplastic Syndrome Using Reduced Intensity Busulfan and Fludarabine Conditioning
• Actual Study Start Date: Jan 4, 2006
• Actual Primary Completion Date: Oct 4, 2017
• Actual Study Completion Date: Oct 4, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Fludarabine + Busulfan + Thymoglobulin Fludarabine 40 mg/m^2 by vein daily over 1 hour x 4 days. Busulfan test dose = 32 mg/m^2 by vein x 1 day; 100 mg/m^2 by vein daily over 3 hours x 4 days. Thymoglobulin 2.5 mg/kg by vein over 6 hours x 3 days if there is an unrelated or a mismatched donor.

Drug: Busulfan; Test dose = 32 mg/m^2 by vein x 1 day; 100 mg/m^2 by vein daily over 3 hours x 4 days; Other Names: Busulfex Myleran ; Drug: Fludarabine; 40 mg/m^2 by vein daily over 1 hour x 4 days; Other Names: Fludarabine Phosphate ; Drug: Thymoglobulin (ATG); 2.5 mg/kg by vein over 6 hours x 3 days if there is an unrelated or a mismatched donor; Other Names: Antithymocyte Globulin Thymoglobulin ATG

Outcome Measures

Primary Outcome Measures

1. Rate of Non-relapse Mortality at 100 Days Post-transplant [Non-relapse mortality at 100 days post-transplant]

   To evaluate the safety of Fludarabine/Busulfan as conditioned regimen for allogeneic stem cell transplantation in patients with myelofibrosis/myelodysplastic syndrome at 100 days post-transplant

Secondary Outcome Measures

1. Efficacy of This Therapy 3 Years Post-transplant [Up to 3 years post-transplant]

   Efficacy Assessed as Number of Participants with Overall Survival, Leukemia Progression, Primary Graft Failure and Complete Hematological Response. Primary graft failure is defined as failure to achieve an ANC >/= 0.5 x 10 (9)/L for 3 consecutive days and evidence of donor chimerism by Day +28. Complete hematological response is defined by hemoglobin >/= 120 g/L; or achievement of transfusion independence, with stable Hb > 110 g/L, for RBC transfusion-dependent participants; Spleen not palpable; platelet count 150 x 10 (9)/L; White blood cell 4 x 10 (9)/L to 10 x 10(9)/L.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients with Idiopathic Myelofibrosis or Myelofibrosis secondary to Polycythemia Vera or Essential Thrombocythemia or Myelodysplastic syndrome with or without fibrosis.

2. Patients 75 years or younger

3. Patients must have an HLA matched or at least a 9/10 antigen (A, B, C, DQ or DR) matched related or unrelated donor.

4. Patients must have a Zubrod PS 2 or less.

5. Creatinine < 1.6 mg/dl

6. Ejection fraction >/= 40%, unless cleared by cardiology

7. Serum direct bilirubin < 2 mg/dl (unless due to Gilbert's syndrome), serum glutamate pyruvate transaminase (SGPT) </= 4 x normal values

8. Forced expiratory volume at one second (FEV1), forced vital capacity (FVC), or diffusing capacity of lung for carbon monoxide (DLCO) >/= 40% of expected.

9. Negative Beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization.

Exclusion Criteria:

1. Uncontrolled life-threatening infections

2. HIV positive

3. Patients with Active viral hepatitis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Uday Popat, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 9, 2012

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00475020
• Other Study ID Numbers: 2005-0726; NCI-2012-01477
• First Posted: May 17, 2007
• Last Update Posted: May 21, 2019
• Last Verified: May 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Idiopathic Myelofibrosis; Myelofibrosis; Essential Thrombocythemia; Polycythemia Vera; Busulfan; Antithymocyte Globulin; ATG; Fludarabine; Thymoglobulin
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Primary Myelofibrosis; Vidarabine; Fludarabine; Fludarabine phosphate; Busulfan; Thymoglobulin; Antilymphocyte Serum

Study Results

Participant Flow

Arm/Group Title	Participants With Myelofibrosis and Myelodysplastic Syndrome
Arm/Group Description	Allogeneic stem cell transplantation (SCT) with preparative regimen of fludarabine and busulfan in myelofibrosis and myelodysplastic syndrome
Period Title: Overall Study
STARTED	63
COMPLETED	58
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Participants With Myelofibrosis and Myelodysplastic Syndrome
Arm/Group Description	Allogeneic stem cell transplantation (SCT) with preparative regimen of fludarabine and busulfan in myelofibrosis and myelodysplastic syndrome
Overall Participants	58
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	45 77.6%
>=65 years	13 22.4%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Sex: Female, Male (Count of Participants)
Female	26 44.8%
Male	32 55.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 1.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 6.9%
White	53 91.4%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	58 100%

Outcome Measures

1. Primary Outcome

Title	Rate of Non-relapse Mortality at 100 Days Post-transplant
Description	To evaluate the safety of Fludarabine/Busulfan as conditioned regimen for allogeneic stem cell transplantation in patients with myelofibrosis/myelodysplastic syndrome at 100 days post-transplant
Time Frame	Non-relapse mortality at 100 days post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Participants With Myelofibrosis and Myelodysplastic Syndrome
Arm/Group Description	Allogeneic stem cell transplantation (SCT) with preparative regimen of fludarabine and busulfan in myelofibrosis and myelodysplastic syndrome
Measure Participants	58
Infections	1 1.7%
Organ Failures	2 3.4%
Sudden death: likely due to ischemic cardiac event	1 1.7%

2. Secondary Outcome

Title	Efficacy of This Therapy 3 Years Post-transplant
Description	Efficacy Assessed as Number of Participants with Overall Survival, Leukemia Progression, Primary Graft Failure and Complete Hematological Response. Primary graft failure is defined as failure to achieve an ANC >/= 0.5 x 10 (9)/L for 3 consecutive days and evidence of donor chimerism by Day +28. Complete hematological response is defined by hemoglobin >/= 120 g/L; or achievement of transfusion independence, with stable Hb > 110 g/L, for RBC transfusion-dependent participants; Spleen not palpable; platelet count 150 x 10 (9)/L; White blood cell 4 x 10 (9)/L to 10 x 10(9)/L.
Time Frame	Up to 3 years post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Participants With Myelofibrosis and Myelodysplastic Syndrome
Arm/Group Description	Allogeneic stem cell transplantation (SCT) with preparative regimen of fludarabine and busulfan in myelofibrosis and myelodysplastic syndrome
Measure Participants	58
Overall survival at 3 years	25 43.1%
Leukemia progression	27 46.6%
Primary graft failures	0 0%
Complete hematological remission	44 75.9%

Adverse Events

Time Frame	January 2006 to May 2012
Arm/Group Title	Participants With Myelofibrosis and Myelodysplastic Syndrome
Arm/Group Description	Allogeneic stem cell transplantation (SCT) with preparative regimen of fludarabine and busulfan in myelofibrosis and myelodysplastic syndrome
All Cause Mortality
	Participants With Myelofibrosis and Myelodysplastic Syndrome
	Affected / at Risk (%)	# Events
Total	8/58 (13.8%)
Serious Adverse Events
	Participants With Myelofibrosis and Myelodysplastic Syndrome
	Affected / at Risk (%)	# Events
Total	18/58 (31%)
Blood and lymphatic system disorders
Liver GvHD	1/58 (1.7%)
Secondary graft failure	6/58 (10.3%)
Hemolytic anemia	1/58 (1.7%)
Thrombocytopenia	3/58 (5.2%)
Gastrointestinal disorders
GI GvHD	2/58 (3.4%)
Hepatobiliary disorders
Veno-occlusive disease	2/58 (3.4%)
Elevated transminitis	6/58 (10.3%)
Infections and infestations
Infectious pneumonia	3/58 (5.2%)
Septic shock	1/58 (1.7%)
Renal and urinary disorders
Renal failure	2/58 (3.4%)
Skin and subcutaneous tissue disorders
Skin GvHD	1/58 (1.7%)
Other (Not Including Serious) Adverse Events
	Participants With Myelofibrosis and Myelodysplastic Syndrome
	Affected / at Risk (%)	# Events
Total	58/58 (100%)
Blood and lymphatic system disorders
Poor graft function	1/58 (1.7%)
ABO incompatibility	1/58 (1.7%)
Cardiac disorders
Hypertension	3/58 (5.2%)
Gastrointestinal disorders
GI GvHD	6/58 (10.3%)
Mucositis	43/58 (74.1%)
Upper GI GvHD	11/58 (19%)
Diarrhea	11/58 (19%)
Nausea	51/58 (87.9%)
General disorders
Headaches	5/58 (8.6%)
Hepatobiliary disorders
Liver GvHD	5/58 (8.6%)
Veno-occlusive disease	1/58 (1.7%)
Ascites	2/58 (3.4%)
Elevated transminitis	20/58 (34.5%)
Infections and infestations
Infections	34/58 (58.6%)
Infectious pneumonia	9/58 (15.5%)
BK virus associated hemorrhagic cystitis	5/58 (8.6%)
Investigations
ATG induced fevers	24/58 (41.4%)
Fluid overload	22/58 (37.9%)
Neutropenic fevers	14/58 (24.1%)
Cytokine release syndrome	2/58 (3.4%)
Fevers	4/58 (6.9%)
Nervous system disorders
Altered mental status changes	3/58 (5.2%)
Renal and urinary disorders
Renal insufficiency	8/58 (13.8%)
Hemorrhagic cystits	2/58 (3.4%)
Respiratory, thoracic and mediastinal disorders
ATG induced shortness of breath	2/58 (3.4%)
Skin and subcutaneous tissue disorders
Skin GvHD	14/58 (24.1%)
Cellulitis	2/58 (3.4%)
ATG induced skin rash	1/58 (1.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.