The Role of Ruxolitinib in Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Neoplasm

March 18, 2020 updated by: Seoul National University Hospital

Concomitant Ruxolitinib Induction and Maintenance With Cytarabine Based Chemotherapy in Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Neoplasm

This trial aimed to investigate the therapeutic efficacy of ruxolitinib in combination with cytotoxic chemotherapy for post-myeloproliferative neoplasm secondary acute myeloid leukemia.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Acute myeloid leukemia (AML) is an uncommon, but often deadly complication of myeloproliferative neoplasms (MPN). Post-MPN AML is aggressive and resistant to conventional treatment with median survival of 3-5 months. Although allogeneic stem cell transplantation (alloSCT) have some prospective of promise in these patient, most of them are ineligible for alloSCT because of advanced age at diagnosis, comorbidities and scarcity of a compatible donor. Therefore, there is an urgent need for new therapeutic strategy for post-MPN AML.

Cytogenetic and/or molecular abnormalities associated with poor prognosis are quite common in patients with post-MPN AML. Although these findings likely contribute to the aggressive natural history and resistance to standard therapies, the genetic complexity of post-MPN AML may ultimately permit targeted therapy. Among these abnormalities, Janus kinase 2 (JAK2) has come to the fore recently. JAK2 V617F mutation, which is a hallmark of MPN, has been reported to be carried in approximately 35-50% of patients with post-MPN AML. We believe that this mutation be the most oncogenic driver in post-MPN AML.

In fact, BCR/ABL(+) acute leukemia (either blast crisis of CML or Ph+ ALL) is a similar disease model of the post-MPN AML. The clinical outcome of these disease has improved dramatically with ABL tyrosine kinase inhibitors (TKIs), such as imatinib, and nilotinib. It is a standard practice to give ABL TKI along with cytotoxic chemotherapy to BCR/ABL(+) acute leukemia. On the other hand, in BCR/ABL(+) acute leukemia, it is well known that single agent ABL TKI is not sufficient to control disease.

Likewise, ruxolitinib, which is a targeted agent for JAK2, have a great possibility to show efficacy for post-MPN AML when combined with cytotoxic agents. In a previous investigational study of ruxolitinib for refractory/relapsed leukemias, 2 of 3 AML patients evolving from MPN achieved complete remission with two cycles of ruxolitinib. In fact, many clinical trials are ongoing to investigate the therapeutic efficacy of ruxolitinib in post-MPN AML as a single agent.

However, considering a lesson from BCR/ABL(+) acute leukemia, ruxolitinib as a single agent may not be enough to cure these patients with post-MPN AML. Hence, for patients who are fit for intensive chemotherapy, it would easily conjectured that ruxolitinib in combination with cytotoxic chemotherapy would be better for these patients. Therefore, combination of ruxolitinib and cytotoxic chemotherapy would be an optimal treatment for post-MPN AML. From an epidemiologic perspective, it is true that post-MPN AML develops in elderly patients frequently. However, patients who fit for intensive chemotherapy are also encountered in the clinic for post-MPN AML not infrequently, justifying this study design. NCCN guideline also recommend intensive induction treatment for patients > 60 years when there performance and comorbidity allows intensive treatment.

In this study, the therapeutic efficacy of ruxolitinib in combination with cytotoxic chemotherapy for post-MPN AML will be investigated. Unlike other clinical trials induction and consolidation treatment should include cytotoxic chemotherapeutic agents in addition to ruxolitinib.

Study Type

Interventional

Enrollment (Anticipated)

17

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Youngil Koh, Dr.
  • Phone Number: +82-2-2072-3079
  • Email: go01@snu.ac.kr

Study Contact Backup

Study Locations

  • Korea, Republic of
      • Seongnam, Korea, Republic of, 13620
        • Recruiting
        • Seoul National University Bundang Hospital
        • Contact:
      • Seoul, Korea, Republic of, 03080
        • Recruiting
        • Seoul National University Hospital
        • Contact:
        • Principal Investigator:
          • Youngil Koh, MD
        • Sub-Investigator:
          • Sung soo Yoon, MD, PhD
        • Sub-Investigator:
          • In ho Kim, MD
        • Sub-Investigator:
          • Ryul Kim, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Cytologically confirmed AML following MPN
  • ECOG performance status 2 or better
  • Adequate physical condition that could tolerate cytotoxic induction chemotherapy judged by investigator
  • Age 18 years or older
  • Adequate cardiac function
  • Adequate hepatic, and renal function
  • Serum creatinine ≤ 2.5 mg/dl
  • ALT (SGOT) and/or AST (SGPT) equal to or than 1.5 x upper limit of normal
  • Life expectancy of ≥ 3 months
  • Signed and dated informed consent of document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment
  • For women of childbearing age, it should be confirmed that they are not pregnant and that they should be contraception during the study period and for up to 4 weeks after the end of the study
  • Male should agree to the barrier method during the study period and up to four weeks after the end of the study

Exclusion Criteria:

  • Diagnosis of any serious secondary malignancy within the last 2 years, except for adequately treated basal cell or squamous cell carcinoma of skin, or in situ carcinoma of cervix uteri
  • Pregnancy or breast feeding
  • Other severe acute or chronic medical or psychiatric condition
  • Prior treatment with ruxolitinib
  • Patients who received other chemotherapy within 2 weeks of the study enrollment
  • Patients participating in other clinical studies at the time of registration

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental arm
Drug: Ruxolitinib

Induction chemotherapy include combination of cytarabine (200mg/m2) and idarubicin (12mg/m2). Both 7+3 and 5+2 regimen is allowed according to age and performance status (PS) as follows;

  • If Age < 55 years and ECOG PS < 2 : 7+3 regimen
  • If Age ≥ 55 years or ECOG PS = 2 : 5+2 regimen

Ruxolitinib is administered for 14 days during induction/consolidation phase. After complete remission after induction, ruxolitinib is administered for the first 14 days during consolidation chemotherapy. Maximum 3 cycles of consolidation is recommended. In case of allogeneic stem cell transplantation (alloSCT), ruxolitinib is discontinued at the time of transplantation. After completion of consolidation, 2 years of ruxolitinib maintenance is planned. The follow-up period is from the time of enrollment until 24 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
complete remission rate
Time Frame: After 12 months from induction chemotherapy
After 12 months from induction chemotherapy
complete remission with incompletre recovery rate
Time Frame: After 12 months from induction chemotherapy
After 12 months from induction chemotherapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 3, 6, 12, 24 months after induction chemotherapy
from the date of transplantation to death from any cause
3, 6, 12, 24 months after induction chemotherapy
Progression-free survival
Time Frame: 3, 6, 12, 24 months after induction chemotherapy
from the date of transplantation to the date of disease progression or death from any cause
3, 6, 12, 24 months after induction chemotherapy
Toxicity profile
Time Frame: 3, 6, 12, 24 months after induction chemotherapy
according to CTCAE version 4.03
3, 6, 12, 24 months after induction chemotherapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Seoul National University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 17, 2018

Primary Completion (Anticipated)

April 30, 2022

Study Completion (Anticipated)

August 31, 2024

Study Registration Dates

First Submitted

May 24, 2018

First Submitted That Met QC Criteria

June 14, 2018

First Posted (Actual)

June 15, 2018

Study Record Updates

Last Update Posted (Actual)

March 19, 2020

Last Update Submitted That Met QC Criteria

March 18, 2020

Last Verified

March 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-1803-145-934

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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