Assessment Of Gh-Igf-1 Axis In Children With Chronic Myelogenous Leukemia (CML) In Remission

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by Postgraduate Institute of Medical Education and Research
Sponsor:
Information provided by (Responsible Party):
dr anuradha aggarwal, Postgraduate Institute of Medical Education and Research
ClinicalTrials.gov Identifier:
NCT01901666
First received: June 29, 2013
Last updated: July 12, 2013
Last verified: July 2013
  Purpose

CML is a myeloproliferative disorder defined by the presence of the Philadelphia chromosome, which arises from the reciprocal translocation of genes on chromosomes 9 and 22.It is rare in childhood and accounts for 2-3% of all leukemias in childhood.

BCR-ABL gene on Philadelphia chromosome results in a 210kd fused BCR-ABL protein with constitutive tyrosine kinase activity, and subsequent activation of cytoplasmic and nuclear signal transduction pathways including STAT, RAS, JUN, MYC, and phosphatidylinositol-3 kinase. The ultimate result of such activation is the myeloid proliferation and differentiation and suppressed apoptosis.

Children present with a higher WBC count, otherwise presentation is nearly identical to adults. Current treatment include tyrosine kinase inhibitors (TKI) and allogeneic stem cell transplant (SCT).Imatinibmesylate inhibits the tyrosine kinase (TK) activity of BCR-ABL1 and several related TKs, including c-kit and the platelet-derived growth factor receptor (PDGFR). Development of tyrosine kinase inhibitor (TKI) therapy has revolutionizedtreatment of CML. Imatinib or second generation TKIs (dasatinib or nilotinib) have become standard front-line therapy forchildren and adults with CML and are also important componentsof therapy for Ph+ acute lymphoblastic leukemia (ALL).

TKIs are administered orally and cause a number of side effects including fatigue, hypertension, rash, impaired wound healing, myelosuppression, and diarrhea . The overall toxicity of TKIs, while less life-threatening than conventional cytotoxic chemotherapy, nevertheless is common, and may require dose reduction.Recently, proposed endocrine-related side effects of these agents include alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, glucose metabolism and adrenal function.

Growth impairment is one of the major adverse effect of long-term imatinib treatment in children with CML. Multiple case reports have demonstrated growth retardation in children onimatinib.Imatinibmesylate inhibits the TK activity of BCR-ABL1 and several related TKs, including c-kit and theplatelet-derived growth factor receptor (PDGFR). It isthe inhibition of TK activity at the non-BCR-ABL sites that couldbe the likely cause for the adverse effect on growth. Severalstudies in adults have suggested that inhibition of c-kit,c-fms, and PDGF receptors results in modulation of bone metabolism. Other reports are focusing on disturbance of the growth hormone (GH) axis as a mechanism for growth impairment. Receptor and non receptor TK is expressed at multiple levels in GH-IGF-1 axis including GHRH-R, GH-R and IGF-1R. Inhibition of TKs with TKI, at any one of these level, might result in growth impairment.

Various studies are available to show that Imainib therapy may cause short stature in children on prolonged treatment but exact mechanism by which this occurs is still not clear. Further, no treatment modality has been tried so far, for short stature in these children.

So, the purpose of this study is to study GH-IGF1 axis in these children and to administer GH therapy to GH deficienct children in remission.


Condition Intervention Phase
Chronic Myelogenous Leukemia
Short Stature
Drug: Growth Hormone
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: ASSESSMENT OF GH-IGF1 AXIS AND TO STUDY RESPONSE TO GH THERAPY IN CHILDREN WITH CML IN REMISSION HAVING GH DEFICIENCY

Resource links provided by NLM:


Further study details as provided by Postgraduate Institute of Medical Education and Research:

Primary Outcome Measures:
  • To know whether patients of CML who are faltering on growth after imatinib therapy are GH deficient or having GH resistance by performing GH provocation tests and IGF-1 generation test. [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    Growth impairment is one of the major adverse effect of long-term imatinib treatment in children with CML. Receptor and non receptor TK is expressed at multiple levels in GH-IGF-1 axis including GHRH-R, GH-R and IGF-1R. Inhibition of TKs with TKI, at any one of these level, might result in growth impairment.Various studies are available to show that Imainib therapy may cause short stature in children on prolonged treatment but exact mechanism by which this occurs is still not clear.So, the purpose of this study is to study GH-IGF1 axis in these children


Secondary Outcome Measures:
  • To administer growth hormone therapy to children with CML on Imatinib in remission having GH deficiency and to measure IGF-1 levels, gain in height and height velocity on GH therapy. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Disturbance of the growth hormone (GH) axis has been shown as one of the mechanism for growth impairment. But, no treatment modality has been tried so far for short stature in these children. So, one of the outcome measure will be to study gain in height after administeration of GH therapy to these GH deficient children.


Estimated Enrollment: 20
Study Start Date: January 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Growth hormone deficient group
0.3mg/kg/week GH in seven divided doses will be given subcutaneously for one year.
Drug: Growth Hormone

All GH deficient patients with bone age <14 years will be treated with GH therapy for one year.Serum IGF-1 will be measured 4weekly and GH dose will be titrated till S.IGF-1 is in mid-normal range and then after every 3 months.

Growth parameters will be assessed after every 3 months.Serum T4, TSH will be done after every 3 months. Patients will be monitored for any side effects of GH therapy

Other Name: Recombinant human growth hormone

  Show Detailed Description

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

CML patients on Imatinib therapy for more than 6 months and in remission will be included in the study if there is

  1. severe short stature (height SDS <-3 SD)
  2. severe growth deceleration (height velocity <-2 SD over 12 months)
  3. Height <-2 SD and height velocity <-1.0 SD over 12 months
  4. Height <-1.5 SD and height velocity <-1.5 SD over 2 years

Exclusion Criteria:

  1. Patients with coexisting systemic illness(e.g. kidney disease, liver disease, celiac disease).
  2. Patients of CML not receiving Imatinib therapy as prescribed (poor compliance).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01901666

Contacts
Contact: ANIL BHANSALI, MBBS, MD,DM 9316977995 anilbhansaliendocrine@rediffmail.com

Locations
India
Postgraduate Institute of Medical Education and Research Recruiting
Chandigarh, UT, India, 160012
Contact: anil bhansali, MBBS,MD,DM    9316977995    anilbhansaliendocrine@rediffmail.com   
Sponsors and Collaborators
Postgraduate Institute of Medical Education and Research
  More Information

No publications provided

Responsible Party: dr anuradha aggarwal, senior resident, Postgraduate Institute of Medical Education and Research
ClinicalTrials.gov Identifier: NCT01901666     History of Changes
Other Study ID Numbers: GH-IGF-1 AXIS AND CML
Study First Received: June 29, 2013
Last Updated: July 12, 2013
Health Authority: India: Indian Council of Medical Research

Keywords provided by Postgraduate Institute of Medical Education and Research:
growth hormone, Chronic Myelogenous Leukemia, Imatinib,serum IGF-1

Additional relevant MeSH terms:
Dwarfism
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Genetic Diseases, Inborn
Endocrine System Diseases
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 24, 2014