Assessment Of Gh-Igf-1 Axis In Children With Chronic Myelogenous Leukemia (CML) In Remission
Assessment Of Gh-Igf-1 Axis In Children With Chronic Myelogenous Leukemia (CML) In Remission
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.
AIMS AND OBJECTIVES:

 -  To study GH-IGF1 axis in children with CML having short stature following Imatinib
 therapy.

 -  To administer growth hormone therapy to children with CML on Imatinib in remission
 having GH deficiency.

 STUDY DESIGN: It is an interventional, non-randomized study. STUDY GROUP: one NUMBER OF
 PATIENTS: 20

 ELIGIBILITY CRITERIA:

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

 -  Severe short stature (height SDS <-3 SD)

 -  Severe growth deceleration (height velocity SDS <-2 SD over 12 months)

 -  Height <-2 SD and height velocity <-1.0 SD over 12 months

 -  Height <-1.5 SD and height velocity <-1.5 SD over 2 years

 EXCLUSION CRITERIA:

 -  Patients with coexisting systemic illness (e.g. kidney disease, liver disease, celiac
 disease)

 -  Patients of CML not receiving Imatinib therapy as prescribed. (e.g. poor compliance)

 MATERIALS AND METHODS:

 Once eligibility criteria are confirmed, after having written informed consent, following
 parameters will be assessed:

 -  Chronological age

 -  Height

 -  Height for age

 -  Height SDS

 -  Target height

 -  Body proportion

 -  Weight

 -  Weight for age

 Following investigations will be done in all patients:

 -  Complete blood count with peripheral smear.

 -  Liver function tests

 -  Renal function tests

 -  Calcium, phosphate, ALP, albumin.

 -  Fasting Blood glucose

 -  Thyroid function tests (T4, and TSH)

 -  Serum Cortisol

 -  Serum Prolactin

 -  Serum Follicular stimulating hormone (FSH) and Luteinizing hormone (LH)

 -  Serum Testosterone

 -  Serum Estrogen

 -  Serum IgA anti-tTG antibodies

 -  Serum IGF-1.

 -  Serum IGFBP-3.

 -  X-Ray of left hand and wrist

 -  MRI Brain focussing pituitary hypothalamic region. Two dynamic growth hormone
 provocation,GHRH + Arginine andGlucagon tests will be performed in all patients having
 no other cause for short stature.Minimum gap of one week will be kept between the two
 GHstimulationtests.Priming will be done prior to each GH stimulation test. IGF-1
 generation test will be performed in all patients.Minimum gap of one week will be kept
 betweenGH stimulation and IGF-1 generation test.

 X-ray of left hand and wrist for bone age and sexual maturity rating (SMR) by Tanners scale
 will be performed for all patients. All GH deficient patients with bone age <14 years will be
 treated with GH therapy for one year. 0.3mg/kg/week GH in seven divided doses will be given
 subcutaneously. 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.

 Patients will be monitored for any side effects of GH therapy Growth parameters, Serum T4,
 TSH and complete blood count will be assessed after every 3 months.Cytogenetic and molecular
 remission will be assessed before and after completion of GH therapy.
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).