A Vascular Necrosis of the Femoral Head Is It an Initial Presentation of CML or Consequences of Therapies (Interferon alpha and Tyrosine Kinase Inhibitors)
Authors: Yassin Mohamed A. , Al-Dewik Nader I , Nashwan Abdulqadir , Soliman Ashraf Tawfiq 
Published: November 2019

Avascular necrosis of the femoral head is not specific disease. It occurs as a complication or secondary to various causes. These conditions probably lead to impaired blood supply to the femoral head. The diagnosis of AVNFH is based on clinical findings and supported by specific radiological manifestations. AVNFH occurs as a complication traumatic and non-traumatic disorders. Most cases of AVNFH are non-traumatic and occur secondary to excessive corticosteroid use and alcohol abuse.Other causes include coagulopathies, hemoglobinopathies (sickle cell disease), chronic liver disease ,gout, idiopathic hyperlipidemia, metabolic bone disorders, pregnancy, radiation, chemotherapy, smoking, systemic lupus erythematosus and vasculitis syndromes. Intravascular coagulation appears to be the central event associated with nontraumatic AVNFH , Coagulation may occur secondary to extravascular compression (marrow fat enlargement), vessel wall injury (chemotherapy, radiation), or a thromboembolic event (fat emboli). Magnetic resonance imaging MRI considered the preferred method for diagnosis of occult AVN, since it is more sensitive than bone scan or plain films. Due to the high incidence of bilateral AVN, MRI may pick up AVN in opposite asymptomatic hip. MRI has 90-100% sensitivity for symptomatic disease

AVNFH can be presenting Manifestation for patient with CML as illustrated in table 1 Table 1.Chronic Myeloid Leukemia Presenting with Avascular Necrosis of Femur HeadPatientAgeGendersiteNoteYearReference124MaleRt Femoral HeadLeukocytecount 96,800/mm3, Platelets count 684,000/mm3, and Hemoglobin 10.4 g/dL.2005Moon JY, et al. (7)215FemaleRt Femoral HeadLeucocyte count of 290 X 109/L,Plateletcount 250 x 109/L, Hemoglobin 10.8 g/dl2003Gupta D, et al.(8)317MaleRt Femoral HeadUnknown1984Gibson J, et al.(9)49FemaleLt Femoral HeadLeukocytecount 359,000/mm3, Platelets count 809,000/mm31988Salimi Z, et al.(10)517MaleRt Femoral HeadUnknown1996Leone J, et al.(11)612FemaleRt Femoral HeadUnknown2013Leone J, et al.(12)Or can be consequence of therapy with interferon as illustrated in table 2or TKI as illustrated in table 3

Table 2. PATIENTS TREATED WITH INTERFERON-a Summary of Patients with Chronic Myeloid Leukemia and Associated AVNFH Patient Patient (yrs) Gender Interval from CML dx to development of AVNFH Platelet and WBC counts at time of AVNFH dx IFNa dose Other Rx Comment 1 22 Male 18 Platelets, 61-140x109/L; WBC, 2.5-3.5 x 109/L 5MU/q.o.d. to 2 MU 2x/week HU pegylated IFN, steroids x 1 week, anegrelide 2 45 Female 54 Platelets, 120-210 x 109/L; WBC, 15 x 109/L Varied from 10 MU/day to 5 MU/day HU, busulfan, ara-C (3 mos) 3 46 Female 6 Platelets, 160-220 x 109/L; WBC, 8.4-18 x 109/L 10 MU/day with concurrent ATRA and ara-C HU 4 17 Male Presenting symptom and symptoms recurred 1 month after starting IFNa and ara-c Platelets, 895 x 109/L; WBC, 167 x 109/L Unknown HU HU cytoreductiona/w clinical and radiographic improvement of AVNFH 5 25 Female 4 yrs Platelets, 1200 x 109/L;WBC 49 x 109/L Unknown HU ANFH developed when CML entered accelerated phase after 4 yrs of IFNa therapy

Table 3. PATIENTS TREATED WITH TYROSINE KINASE INHIBITORS (TKIs) Summary of Patients with Chronic Myeloid Leukemia and Associated AVNFH Patient Patient (yrs) Gender Interval from CML dx to development of AVN Platelet and WBC counts at time of AVN dx TKI dose Other Rx Comment 1 12 Male 8 yrs WBC 5600/mm3 Start dose 400mg/d; escalated to 600mg/d to achieve complete cytogenetic response Dx as CML (chronic phase in 2005; started on imatinib 400mg (340mg/m2) after 20 months dose escalated to 600mg/day (continued for 1 yr) Nataraj V et al 2 34 female 3 year WBC 6000/ mm3 Failed Imatinib 400mg Then shifted to Dasatinib 100 mg Developed AVNFH18 months after Dastinib in (CHR, CCR, MMR)yassin et al

Conclusion

From the above mentioned review of literature; 6 patients with CML presented with AVNFH as the initial presentation prior any therapy; five in the era of interferon and two in era with TKIs; one with Imatinib and the other with Dasatinib treatment. Two issues to be considered; either the condition is rare or there is under-reporting of this side effect. Observational studies with proper reporting are required to accurately measure the incidence of this complication which could significantly affect patients' safety and quality of life.

Disclosures

Al-Dewik: Qatar National Research Fund (QNRF): Other: sponsorship.