Cytosine Arabinoside and Mitoxantrone for Patients With Juvenile Myelomonocytic Leukemia Receiving Repeat Stem Cell Transplantation

Cytosine Arabinoside and Mitoxantrone for Patients With Juvenile Myelomonocytic Leukemia Receiving Repeat Stem Cell Transplantation

Sponsors

Lead sponsor: Masonic Cancer Center, University of Minnesota

Source Masonic Cancer Center, University of Minnesota
Brief Summary

RATIONALE: Giving chemotherapy drugs, such as cytarabine and mitoxantrone, before a donor stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When certain 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine, methotrexate, and methylprednisolone before or after transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects and best way to give high-dose cytarabine together with mitoxantrone in treating patients with juvenile myelomonocytic leukemia undergoing a second donor stem cell transplant.

Detailed Description

OBJECTIVES:

Primary

- To determine the incidence of 1-year disease-free survival in patients with juvenile myelomonocytic leukemia and who is undergoing a repeat stem cell transplantation.

Secondary

- To evaluate the incidence of regimen-related toxicity.

- To evaluate the incidence of acute and chronic graft-versus-host-disease.

- To evaluate the incidence of relapse.

OUTLINE:

- Preparative cytoreductive therapy: Patients receive high-dose cytarabine IV over 2 hours on days -9 to -4 and mitoxantrone hydrochloride IV over 30 minutes on days -9 to -7.

- Allogeneic hematopoietic stem cell transplantation (HSCT): Patients undergo HSCT on day 0. Patients undergoing umbilical cord blood transplantation receive methylprednisolone (as graft failure prophylaxis) IV twice daily on days 5 to 19 followed by a taper every other day thereafter until day 25.

- Graft-versus-host-disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours every 8-12 hours or orally twice daily beginning on day -3 and continuing until day 50, followed by a taper to day 90, in the absence of GVHD. Patients undergoing nongenotypically identical bone marrow transplantation also receive methotrexate IV on day 1 beginning 24 hours after completion of stem cell infusion and on days 3, 6, and 11.

- Post-transplantation isotretinoin therapy: Patients receive oral isotretinoin once daily beginning on day 60 and continuing until 1 year after HSCT.

Patients undergo bone marrow sample collection on day 21, day 60, day 100, at 6 months, and at 1 year for chimerism studies. Patients also undergo blood sample collection periodically to monitor peripheral blood counts for immune reconstitution.

After completion of study treatment, patients are followed on day 21, day 100, at 6 months, and at 1 year.

Overall Status Terminated
Start Date June 1999
Completion Date June 2010
Primary Completion Date June 2010
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Disease-free Survival 1 year
Secondary Outcome
Measure Time Frame
Patients With Regimen-Related Toxicity Up to 30 Days Post Study Treatment
Patients With Graft-Versus-Host-Disease Up to 30 Days Post Study Treatment
Patients Who Relapsed 1 Year
Enrollment 1
Condition
Intervention

Intervention type: Drug

Intervention name: cyclosporine

Description: Patients will receive CSA therapy beginning on day -3, with a taper commencing on day +60 (unless GVHD) and ending on day +90. For patients >40 kg with normal renal function (creatinine <1.3 mg/dL), the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours. For children <40 kg, the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours.

Arm group label: Cytarabine + Mitoxantrone

Other name: CSA

Intervention type: Drug

Intervention name: cytarabine

Description: 3000 mg/m^2 intravenously (IV) over 2 hours x 2 (i.e. total 6000 mg/m^2/day) on days -9 through -4.

Arm group label: Cytarabine + Mitoxantrone

Other name: Ara-C

Intervention type: Drug

Intervention name: filgrastim

Description: Patients with absolute neutrophil count (ANC) <0.2 x 10^8/L on day 21 may receive G-CSF at 5 mcg/kg/day. G-CSF will be continued until ANC ≥2.5 x 10^8/L for two consecutive days. As the malignant cell population of JMML is known to be hypersensitive to GM-CSF, this cytokine will not be given to these patients.

Arm group label: Cytarabine + Mitoxantrone

Other name: G-CSF

Intervention type: Drug

Intervention name: methotrexate

Description: MTX will be administered to recipients of non-genotypically identical BMT. MTX will be administered at a dose of 15 mg/m^2 (based on adjusted ideal body weight) intravenously (IV) on day +1 and at a dose of 10 mg/m^2 IV on days +3, +6, and +11.

Arm group label: Cytarabine + Mitoxantrone

Other name: MTX

Intervention type: Drug

Intervention name: methylprednisolone

Description: Recipients of UCB will receive methylprednisolone 2 mg/kg/day from day +5 to +19 at a dose of 1 mg/kg twice a day (bid) with a 10% taper every week thereafter.

Arm group label: Cytarabine + Mitoxantrone

Other name: Medrol

Intervention type: Drug

Intervention name: mitoxantrone hydrochloride

Description: 10 mg/m^2 over 30 minutes intravenously (IV) on days -9 through -7.

Arm group label: Cytarabine + Mitoxantrone

Other name: Mitoxantrone

Intervention type: Procedure

Intervention name: allogeneic bone marrow transplantation

Description: Donor marrow will be collected in the usual sterile manner with a collection goal of 2.0 >10^8/kg recipient weight. Infused on Day 0.

Arm group label: Cytarabine + Mitoxantrone

Intervention type: Procedure

Intervention name: umbilical cord blood transplantation

Description: Umbilical cord blood (UCB) will be cryopreserved prior to transplantation. Cord blood units will be selected for transplantation according to current University of Minnesota Department of Blood and Marrow Transplantation Guidelines.

Arm group label: Cytarabine + Mitoxantrone

Intervention type: Drug

Intervention name: Cis-Retinoic acid

Description: Post-Transplant Cis-Retinoic Acid (CRA) Therapy - CRA will be given at a dosage of 100 mg/m^2/day by mouth in a single daily dose starting on day +60 and continuing until 1 year after transplant.

Arm group label: Cytarabine + Mitoxantrone

Other name: isotretinoin

Eligibility

Criteria:

Inclusion Criteria:

- Patients age 0-18 with juvenile myelomonocytic leukemia (JMML) who have relapsed or have residual disease after allogeneic HCT. Residual disease is defined as failure to eradicate original disease without prior documentation of remission. Relapse is defined as reappearance of i) leukocytosis with absolute monocytosis >1 x 10^8/L, ii) presence of immature myeloid cells in the peripheral circulation in two consecutive bone marrow specimens taken at least one month apart, or iii) presence of clonal cytogenetic abnormality. The diagnosis of relapse will be supported by the return of an abnormal cytogenetic marker (if present at diagnosis) or the presence of host cells by RFLP or other method.

- Patients should be at least 6 months from first hematopoietic cell transplant (HCT) if clinically stable. (If JMML is rapidly progressive, second HCT may be performed earlier).

- Adequate major organ function including:

- Cardiac: ejection fraction ≥45%

- Pulmonary: FEV >50%, DLCO >50%

- Renal: creatinine clearance ≥40 mL/min

- Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites)

- Karnofsky performance status ≥70% or Lansky score ≥50%

- Written informed consent.

Exclusion Criteria:

- Active uncontrolled infection within one week of HCT.

Gender: All

Minimum age: N/A

Maximum age: 18 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Margaret L. MacMillan, MD Principal Investigator Masonic Cancer Center, University of Minnesota
Location
facility
Masonic Cancer Center at University of Minnesota
Location Countries

United States

Verification Date

December 2017

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Arm group label: Cytarabine + Mitoxantrone

Arm group type: Experimental

Description: This is a phase I-II study designed to evaluate the efficacy of the administration of high dose cytosine arabinoside and mitoxantrone followed by HCT in patients with JMML who have residual disease or have relapsed after initial HCT.

Study Design Info

Allocation: Non-Randomized

Intervention model: Single Group Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov