Study of Fludarabine Based Conditioning for Allogeneic Stem Cell Transplantation for Myelofibrosis

• Sponsor: John Mascarenhas (Other)
• Overall Status: Completed
• CT.gov ID: NCT00572897
• Collaborator: National Institutes of Health (NIH) (NIH), Myeloproliferative Disorders-Research Consortium (Other), National Cancer Institute (NCI) (NIH)
• Enrollment: 66
• Locations: 12
• Arm: 1
• Duration (Months): 94.5
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis	Drug: Fludarabine, Melphalan +/- ATG	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 66 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Study of Fludarabine Based Conditioning for Allogeneic Stem Cell Transplantation for Myelofibrosis
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Jun 15, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Fludarabine, Melphalan +/- ATG Fludarabine, Melphalan +/- ATG

Drug: Fludarabine, 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])

Outcome Measures

Primary Outcome Measures

1. The Primary Endpoint is Progression-free Survival. [2 years]

   Number of participants alive at 2 years who are progression-free

Secondary Outcome Measures

1. Response Outcomes [180 days]

   assessed according to the IWG Criteria

2. Overall Survival [73 months]

   The number of patients alive at last follow-up.

3. Absolute Neutrophil Count (ANC) [2 years]

   Patients with ANC ≥0.5 × 10^9/L

4. PLT [2 years]

   Patients with PLT ≥20 × 109/L

5. Transplant-related Mortality [2 years]

   Transplant-related Mortality including Graft-versus-host disease (GVHD)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Illinois at Chicago	Chicago	Illinois	United States	60612
2	Johns Hopkins	Baltimore	Maryland	United States	21205
3	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
4	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
5	Weill Cornell Medical College	New York	New York	United States	10065
6	Ohio State Univesity	Columbus	Ohio	United States	43210
7	University of Utah	Salt Lake City	Utah	United States	84132
8	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G2M9
9	University of Florence	Florence	IL	Italy	60302
10	Ospedali Riuniti di Bergamo	Bergamo		Italy	24128
11	University of San Martino	San Martino		Italy
12	Regionala etikprovningsnamnden Goteborg	Goteborg		Sweden	60302

Sponsors and Collaborators

• John Mascarenhas
• National Institutes of Health (NIH)
• Myeloproliferative Disorders-Research Consortium
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: John Mascarenhas, MD, Icahn School of Medicine at Mount Sinai
• Study Chair: Giovanni Barosi, MD, Myeloproliferative Disorders-Research Consortium
• Study Chair: Damiano Rondelli, MD, Myeloproliferative Disorders-Research Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: John Mascarenhas, Assistant Professor, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT00572897
• Other Study ID Numbers: GCO 07-0548-00101; P01CA108671-01A2; MPD-RC 101
• First Posted: Dec 13, 2007
• Last Update Posted: May 15, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by John Mascarenhas, Assistant Professor, Icahn School of Medicine at Mount Sinai: Myelofibrosis; Myeloproliferative disease; Stem Cell Transplant; Allogeneic Transplant; Conditioning Regimen; Reduced Intensity Regimen; Fludarabine; Melphalan; ATG
• Additional relevant MeSH terms: Primary Myelofibrosis; Fludarabine; Melphalan

Study Results

Participant Flow

Recruitment Details	Patients were recruited from 2007 to 2011 at 11 centers affiliated with the Myeloproliferative Disorders Research Consortium (MPD-RC)

Arm/Group Title	Sibling Donor	Unrelated Donor
Arm/Group Description	Patients received a stem cell transplant from sibling	Patients received a stem cell transplant from an unrelated donor
Period Title: Overall Study
STARTED	32	34
COMPLETED	32	34
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Sibling Donor	Unrelated Donor	Total
Arm/Group Description	Patients received a stem cell transplant from sibling	Patients received a stem cell transplant from an unrelated donor	Total of all reporting groups
Overall Participants	32	34	66
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55	56	55
Sex: Female, Male (Count of Participants)
Female	13 40.6%	15 44.1%	28 42.4%
Male	19 59.4%	19 55.9%	38 57.6%
Diagnosis (participants) [Number]
PMF	14 43.8%	25 73.5%	39 59.1%
PV-MF	3 9.4%	5 14.7%	8 12.1%
ET-MF	15 46.9%	4 11.8%	19 28.8%
Lille score (participants) [Number]
0	3 9.4%	0 0%	3 4.5%
1	20 62.5%	23 67.6%	43 65.2%
2	9 28.1%	11 32.4%	20 30.3%
Patient: donor gender (participants) [Number]
Female:Female	6 18.8%	7 20.6%	13 19.7%
Male:Male	7 21.9%	8 23.5%	15 22.7%
Male:Female	10 31.3%	6 17.6%	16 24.2%
Female:Male	9 28.1%	13 38.2%	22 33.3%
JAK-2V617F (participants) [Number]
Positive	12 37.5%	18 52.9%	30 45.5%
Negative	17 53.1%	16 47.1%	33 50%
Unknown	3 9.4%	0 0%	3 4.5%
Bone Marrow Fibrosis (participants) [Number]
Grade 1	0 0%	2 5.9%	2 3%
Grade 2	2 6.3%	6 17.6%	8 12.1%
Grade 3	18 56.3%	23 67.6%	41 62.1%
Unknown	12 37.5%	3 8.8%	15 22.7%
Splenomegaly (participants) [Number]
Yes	24 75%	28 82.4%	52 78.8%
No	3 9.4%	1 2.9%	4 6.1%
Splenectomy	5 15.6%	5 14.7%	10 15.2%
Karyotype (participants) [Number]
Normal	14 43.8%	14 41.2%	28 42.4%
One abnormality	7 21.9%	9 26.5%	16 24.2%
Complex abnormality	5 15.6%	0 0%	5 7.6%
Unknown	6 18.8%	11 32.4%	17 25.8%
Stem cell source (participants) [Number]
Peripheral blood	26 81.3%	31 91.2%	57 86.4%
Bone Marrow	6 18.8%	3 8.8%	9 13.6%
HLA match (participants) [Number]
Full HLA matched	30 93.8%	25 73.5%	55 83.3%
HLA 1 Ag mismatched, no allele mismatched	2 6.3%	4 11.8%	6 9.1%
HLA Ag matched, 1 0r 2 alleles mismatched	0 0%	5 14.7%	5 7.6%

Outcome Measures

1. Primary Outcome

Title	The Primary Endpoint is Progression-free Survival.
Description	Number of participants alive at 2 years who are progression-free
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sibling Donor	Unrelated Donor
Arm/Group Description	Patients received a stem cell transplant from sibling	Patients received a stem cell transplant from an unrelated donor
Measure Participants	32	34
Number [participants]	24 75%	11 32.4%

2. Secondary Outcome

Title	Response Outcomes
Description	assessed according to the IWG Criteria
Time Frame	180 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Sibling Donor	Unrelated Donor
Arm/Group Description	Patients received a stem cell transplant from sibling	Patients received a stem cell transplant from an unrelated donor
Measure Participants	29	17
clinical complete response	7 21.9%	6 17.6%
clinical partial response	8 25%	1 2.9%
clinical improvement	11 34.4%	5 14.7%
stable disease	2 6.3%	4 11.8%
progressive disease	0 0%	1 2.9%

3. Secondary Outcome

Title	Overall Survival
Description	The number of patients alive at last follow-up.
Time Frame	73 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sibling Donor	Unrelated Donor
Arm/Group Description	Patients received a stem cell transplant from sibling	Patients received a stem cell transplant from an unrelated donor
Measure Participants	32	34
Number [participants]	25 78.1%	11 32.4%

4. Secondary Outcome

Title	Absolute Neutrophil Count (ANC)
Description	Patients with ANC ≥0.5 × 10^9/L
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sibling Donor	Unrelated Donor
Arm/Group Description	Patients received a stem cell transplant from sibling	Patients received a stem cell transplant from an unrelated donor
Measure Participants	32	34
yes	31 96.9%	26 76.5%
no	1 3.1%	8 23.5%

5. Secondary Outcome

Title	PLT
Description	Patients with PLT ≥20 × 109/L
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sibling Donor	Unrelated Donor
Arm/Group Description	Patients received a stem cell transplant from sibling	Patients received a stem cell transplant from an unrelated donor
Measure Participants	32	34
yes	28 87.5%	20 58.8%
no	4 12.5%	14 41.2%

6. Secondary Outcome

Title	Transplant-related Mortality
Description	Transplant-related Mortality including Graft-versus-host disease (GVHD)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sibling Donor	Unrelated Donor
Arm/Group Description	Patients received a stem cell transplant from sibling	Patients received a stem cell transplant from an unrelated donor
Measure Participants	32	34
yes	3 9.4%	20 58.8%
no	29 90.6%	14 41.2%

Adverse Events

Adverse Event Reporting Description	all adverse events reported under serious adverse events. other non-serious adverse events were not separated out.
Arm/Group Title	Sibling Donor		Unrelated Donor
Arm/Group Description	Patients received a stem cell transplant from sibling		Patients received a stem cell transplant from an unrelated donor
All Cause Mortality
	Sibling Donor		Unrelated Donor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sibling Donor		Unrelated Donor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/32 (25%)		23/34 (67.6%)
Blood and lymphatic system disorders
Death	1/32 (3.1%)	1	3/34 (8.8%)	3
Death	1/32 (3.1%)	1	3/34 (8.8%)	3
Cardiac disorders
Death	1/32 (3.1%)	1	0/34 (0%)	0
Immune system disorders
Death	3/32 (9.4%)	3	5/34 (14.7%)	5
Infections and infestations
Death	0/32 (0%)	0	1/34 (2.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Death	1/32 (3.1%)	1	0/34 (0%)	0
Renal and urinary disorders
Death	0/32 (0%)	0	2/34 (5.9%)	2
Respiratory, thoracic and mediastinal disorders
Death	1/32 (3.1%)	1	2/34 (5.9%)	2
Surgical and medical procedures
Death	0/32 (0%)	0	20/34 (58.8%)	20
Death	0/32 (0%)	0	1/34 (2.9%)	1
Vascular disorders
Death	0/32 (0%)	0	1/34 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Sibling Donor		Unrelated Donor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.