Nilotinib induced avascular necrosis of femoral head in an adult chronic myeloid leukemia patient

Abstract

We report a rare case of avascular necrosis of femoral head (AVNFH) in an adult chronic myeloid leukemia − chronic phase (CML-CP) patient during due course of therapy with second line Tyrosine Kinase Inhibitor (TKI), Nilotinib. A high index of clinical suspicion should be kept in any symptomatic CML patient on TKI’s.

1. Introduction

Nilotinib is a tyrosine kinase inhibitor approved for the treatment of adult patients with newly diagnosed CML-CP and for patients with Imatinib-resistant or Imatinib-intolerant CML-CP or accelerated phase (AP). AVNFH occurs due to traumatic as well as non-traumatic causes. AVNFH has been rarely reported in CML with only few case reports available in the literature.^{1, 2, 3, 4, 5, 6} AVNFH developing during TKI therapy is even more rare; there are only 2 cases reported − one each with Imatinib⁷ and Dasatinib,⁸ respectively. We report the first case of Nilotinib causing AVNFH in a CML-CP patient, along with a literature review of incidence of AVNFH in CML.

2. Case report

A 47-year-old male diagnosed as CML in chronic phase in 2008, was initially started on Imatinib 400 mg/day, which was later increased to 600 mg/day. Since Feb 2015 due to a progressive rise of BCR ABL transcript ratio, Imatinib resistance mutational analysis was done which revealed direct binding site F317L kinase domain mutation. He was thus switched to Nilotinib. After 9 months of Nilotinib therapy, he presented with 15 days history of dull aching pain in left side of hip with radiation along the medial aspect of left thigh. There was no history of fall or trauma. Clinical examination was unremarkable. Hemogram & peripheral smear were normal and suggestive of complete hematological remission. He had a negative ANA and sickling test. His lipid profile also was normal. BCR- ABL transcript ratio was 16% by qPCR (IS). Radiological evaluation by X-ray hip was suggestive of AVNFH in the left side (Fig. 1A), which was further confirmed by contrast Magnetic Resonance Imaging (Fig. 1B–D). He is presently planned for a total hip replacement.

Fig 1.

(A) Plain X Ray showing left femoral head with geographical appearance with mixed sclerotic and lucent areas, representing AVN related changes (B) MRI T1WI showing irregular articular surface of left femoral head with marked flattening and deformation. Left femoral head sub articular region shows ‘crescent sign’ (C) T2WI Left hip joint space is markedly reduced with sub articular sclerotic changes in acetabulum (D) T1WI showing signal intensity changes suggestive of edema, noted in acetabulum, head and neck of femur.

3. Discussion

Incidence of AVNFH in CML is not known because of the very few reports and absence of prospective studies addressing this issue. AVNFH has been described at the time of presentation as well as during Interferon (INF) α therapy in CML. 6 cases of AVNFH has been reported at the time of presentation (Table 1)^{1, 2, 3, 4, 5} and 4 cases during the course of interferon therapy,⁶ in CML. The mechanism proposed was due to leukocytosis and/or thrombocytosis causing microcirculatory occlusion or synergistic interaction between CML and INF α therapy leading to inhibition of angiogenesis. Interestingly there are no reports of AVNFH with INF α therapy for other indications.^{6, 9} In the TKI era, Nataraj et al. have reported a pediatric case of AVNFH associated with Imatinib in 2014.⁷ Similarly a single case report of Dasatinib associated AVNFH was reported by Yassin et al. in 2015,⁸ with authors concluding that the scarcity of reports may be due to either the rarity of the condition or under reporting of cases.

Table 1.

Literature review of reported cases of AVNFH in CML cases.

CML presenting with AVNFH
No.	Age/Sex	PARAMETERS	YEAR	REFERENCE
1	17/M	Unknown	1984	Gibson et al.2
2	9/F	TLC–359 × 109/L	1988	Salimi et al.3
		Plt- 809 × 109/L
3	17/M	Unknown	1996	Leone, et al.4
4	15/F	Hb-10.8 g/dL	2003	Gupta et al.1
		TLC–290 × 109/L
		Plt- 250 × 109/L
5	24/M	Hb-10.4	2005	Moon et al.10
		TLC-96.8 × 109/L
		Plt- 684 × 109/L
6	12/F	Unknown	2014	Kumar et al.5

AVNFH on INF α therapy for CML
No.	Age/Sex	PARAMETERS	Duration Of Rx with INF α (months)	REFERENCE
1	22/M	TLC − 2.5–3.5 × 109/L	18	Kozuch et al.6
		Plt − 61–140 × 109/L
2	45/F	TLC − 15 × 109/L	54
		Plt − 120–210 × 109/L
3	46/F	TLC − 8.4–18 × 109/L	6
		Plt − 160–220 × 109/L
4	17/M	TLC − 167 × 109/L	1
		Plt − 895 × 109/L
5	25/F	TLC − 49 × 109/L	48
		Plt − 1200 × 109/L

AVNFH on TKI therapy
No.	Age/Sex	PARAMETERS	Interval from diagnosis	REFERENCE
1	12/M	TLC − 5.6 × 109/L	8 years	Nataraj et al.7
			Imatinib × 8 years
			Dose escalated to 600 mg/day for 1 year
2	34/F	Hb − 13 g/dL	3 years	Yassin et al.8
		TLC − 6 × 109/L	Dasatinib x 18 months- (in CHR, CCR, MMR)
		Plt−235 × 109/dL
3	47/M	Hb − 12.5 g/dL	7 years	Present case, 2017
		TLC − 5 × 109/L	Nilotinib x 9 months
		Plt − 335 × 109/dL	Not in MMR

4. Conclusion

To the best of our ability we could not find any cases of AVNFH reported with Nilotinib. Our patient did not have any other cause attributable. Further he had normal WBC and platelet counts and was in hematological remission at the time of presentation. So AVNFH should be thought of in any symptomatic CML patient on TKI’s.

Conflict of interest

The authors have none to declare.