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

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.

Study Overview

• Status: Completed
• Conditions: Myelofibrosis
• Intervention / Treatment: Drug: Fludarabine, Melphalan +/- ATG

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 Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G2M9
      • Princess Margaret Hospital
• Italy
  • Bergamo, Italy, 24128
    • Ospedali Riuniti di Bergamo
  • San Martino, Italy
    • University of San Martino
  • IL
    • Florence, IL, Italy, 60302
      • University of Florence
• Sweden
  • Goteborg, Sweden, 60302
    • Regionala etikprovningsnamnden Goteborg
• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State Univesity
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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])

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Outcomes	assessed according to the IWG Criteria	180 days
Overall Survival	The number of patients alive at last follow-up.	73 months
Absolute Neutrophil Count (ANC)	Patients with ANC ≥0.5 × 10^9/L	2 years
PLT	Patients with PLT ≥20 × 109/L	2 years
Transplant-related Mortality	Transplant-related Mortality including Graft-versus-host disease (GVHD)	2 years

Collaborators and Investigators

• Sponsor: John Mascarenhas
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH); Myeloproliferative Disorders-Research Consortium
• Investigators: Study Chair: Giovanni Barosi, MD, Myeloproliferative Disorders-Research Consortium; Study Chair: Damiano Rondelli, MD, Myeloproliferative Disorders-Research Consortium

Publications and helpful links

General Publications

• Rondelli D, Goldberg JD, Isola L, Price LS, Shore TB, Boyer M, Bacigalupo A, Rambaldi A, Scarano M, Klisovic RB, Gupta V, Andreasson B, Mascarenhas J, Wetzler M, Vannucchi AM, Prchal JT, Najfeld V, Orazi A, Weinberg RS, Miller C, Barosi G, Silverman LR, Prosperini G, Marchioli R, Hoffman R. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood. 2014 Aug 14;124(7):1183-91. doi: 10.1182/blood-2014-04-572545. Epub 2014 Jun 24.

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): June 15, 2015

Study Registration Dates

• First Submitted: December 11, 2007
• First Submitted That Met QC Criteria: December 12, 2007
• First Posted (Estimate): December 13, 2007

Study Record Updates

• Last Update Posted (Actual): May 15, 2017
• Last Update Submitted That Met QC Criteria: April 7, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Myelofibrosis; Melphalan; Fludarabine; Stem Cell Transplant; ATG; Myeloproliferative disease; Conditioning Regimen; Allogeneic Transplant; Reduced Intensity Regimen
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Primary Myelofibrosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Melphalan; Fludarabine
• Other Study ID Numbers: GCO 07-0548-00101; P01CA108671-01A2 (U.S. NIH Grant/Contract); MPD-RC 101 (Other Identifier: Myeloproliferative Disorders-Research Consortium)