Combination Chemotherapy, Total Body Irradiation, and Donor Blood Stem Cell Transplant in Treating Patients with Primary or Secondary Myelofibrosis

Status: Active

Description

This early phase I trial studies the side effects of combination chemotherapy, total body irradiation, and donor blood stem cell transplant in treating patients with primary or secondary myelofibrosis. Drugs used in chemotherapy, such as melphalan, fludarabine phosphate, cyclophosphamide, tacrolimus, mycophenolate mofetil, and filgrastim work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving combination chemotherapy and total body irradiation before a donor blood stem cell transplant helps to stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Eligibility Criteria

Inclusion Criteria

  • Diagnosis of primary or secondary myelofibrosis with transplant indication by Dynamic International Prognostic Scoring System (DIPSS)-plus (> intermediate -1)
  • Age 18-70; patients >= age 50 must have an comorbidity score (hematopoietic cell transplant-comorbidity index [HCT-CI]) =< 4 (Sorror). The principal investigator is the final arbiter for comorbidity;
  • Patients can be in chronic phase (CP) with bone marrow (BM) blast count =< 10% or after progression to acute myeloid leukemia (AML) and achieved =< 5% BM blasts (morphologic complete remission [CR] prior to transplant);
  • Lack of a human leukocyte antigen (HLA) matched donor or need to proceed fast to transplantation when a patient does not have an immediately available matched unrelated donor (typed by high-resolution in the registry);
  • Performance status >= 70% (Karnofsky); patients > 50 years should have adequate cognitive function; any concerns regarding cognitive function should be addressed by a geriatrician/neurologist;
  • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 5X upper limit of normal (UNL);
  • Bilirubin =< 5X UNL;
  • Creatinine clearance > 50mls/min (calculated with Cockcroft-Gault formula);
  • Left ventricular ejection fraction (LVEF) >= 50%;
  • Corrected diffusion capacity of the lung for carbon monoxide (DLCOc) >= 50%;
  • Prior treatment with JAK2 inhibitor therapy is not excluded. Patients on a JAK2 inhibitor may continue through conditioning until day -3 then tapered at the discretion of the investigator.

Exclusion Criteria

  • Evidence of portal hypertension with varices, ascites, or hepatic encephalopathy;
  • > 10% bone marrow blasts at transplant if no history of AML and > 5% if had previous progression to AML;
  • Human immunodeficiency virus (HIV) positive; active hepatitis B or C;
  • Patients with active infections. The principal investigator (PI) is the final arbiter of the eligibility;
  • Liver cirrhosis;
  • Prior central nervous system (CNS) involvement by tumor cells;
  • Severe pulmonary hypertension (PHT) (on echo or right side cardiac catheterization);
  • History of another primary malignancy that has not been in remission for at least 3 years (the following are exempt from the 3-year limit: non-melanoma skin cancer, fully excised melanoma in situ [stage 0], curatively treated localized prostate cancer, and cervical or breast carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou [PAP] smear);
  • Positive 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;
  • Noncompliance - inability or unwillingness to comply with medical recommendations regarding therapy or follow-up, including smoking tobacco. Smoking cessation is a standard teaching practice prior to admission for all patients undergoing stem cell transplant. Any patient who refuses to stop smoking prior to transplant will not be eligible for this study.

Locations & Contacts

Texas

Houston
M D Anderson Cancer Center
Status: Active
Contact: Stefan Octavian Ciurea
Phone: 713-792-8750

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. To evaluate the safety and tolerability of reduced-intensity (FM) haploidentical hematopoietic cell transplantation (Haplo-HCT) followed by post-transplant cyclophosphamide (PTCy) in patients with advanced myelofibrosis (MF), as assessed by the evaluation of toxicities, including type, frequency, severity, attribution, time course and duration.

SECONDARY OBJECTIVES:

I. To summarize and evaluate hematologic (neutrophil and platelet) recovery.

II. To estimate graft failure-free survival (GFS) at 100-days post-transplant.

III. To estimate overall survival (OS), progression-free survival (PFS) and cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100-days, 1-year, and 2-year post transplant.

IV. To estimate the cumulative incidence of acute graft-versus-host disease (GvHD), grade II-IV, at 100-days post-transplant (per Keystone Consensus modification of the Glucksberg criteria).

V. To estimate the cumulative incidence of chronic GvHD at 1-year and 2-year post transplant (per National Institute of Health [NIH] Consensus Criteria).

VI. To characterize the severity and extent of acute and chronic GvHD.

OUTLINE:

Patients receive melphalan intravenously (IV) over 30 minutes on days -5, fludarabine phosphate IV over 1 hour on days -5 to -2. Patients undergo total body irradiation (TBI) on day -1 and hematopoietic stem cell transplant (HCT) on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously for approximately 2 weeks, then orally (PO) for 6 months followed by a taper, mycophenolate mofetil PO thrice daily (TID) until day 100, and filgrastim subcutaneously (SC) daily from day 7 until continued until absolute neutrophil count (ANC) > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up at 1, 3, 6, 9, 12 and 24 months.

Trial Phase & Type

Trial Phase

No phase specified

Trial Type

Treatment

Lead Organization

Lead Organization
M D Anderson Cancer Center

Principal Investigator
Stefan Octavian Ciurea

Trial IDs

Primary ID 2017-0375
Secondary IDs NCI-2018-00910
Clinicaltrials.gov ID NCT03426969