Chronic Myelogenous Leukemia Clinical Trial
Official title:
ASSESSMENT OF GH-IGF1 AXIS AND TO STUDY RESPONSE TO GH THERAPY IN CHILDREN WITH CML IN REMISSION HAVING GH DEFICIENCY
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.
;
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
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