The effectiveness of tyrosine kinase inhibitor for chronic myeloid leukemia in tuberous sclerosis. A case report and review of literature

Abstract

The relationship between chronic myelogenous leukemia (CML) and tuberous sclerosis (TS) is unusual and uncommon. Here, we report a 24‐year‐old woman diagnosed with TS and later identified with CML, as the second case reported with such coexistence, treated with Nilotinib. This article proposes a hypothesis to explain the association. Therefore, we propose Nilotinib for the treatment of patients with such coexisting diseases. Further studies are warranted to reveal the dynamics between these conditions.

1. INTRODUCTION

The association of chronic myelogenous leukemia (CML) with tuberous sclerosis (TS) is extraordinary and rare. As the number of cases reported in the literature is scarce, we are reporting the second case of CML associated with TS.

Similar to the previous case, first‐line therapy with Imatinib failed, and a second line was utilized. Nilotinib was the treatment of choice in our case of a 24‐year‐old patient diagnosed with TS who was found to have CML.

Additionally, there has not yet been any established pathogenetic link between the two conditions, and this paper discusses a postulation to explain the association.

CML and TS both involve tyrosine kinase proteins implicated in their pathogenesis. We hypothesize that treating CML will impact the manifestations of TS. By obtaining radiographic imaging of several renal angiomyolipoma and brain tubers before and 6 months after completion of treatment, we aim to objectively demonstrate the efficacy of the TKI on these neoplasms.

1.1. Case presentation

A 24‐year‐old Palestinian lady who is a known case of tuberous sclerosis presented with multiple hypomelanotic macules and radiological findings on MRI of renal angiomyolipoma and bilateral cerebral and periventricular tubers. A lobulated lesion of abnormal signal intensity was demonstrated on radiographs involving the anterior horn, anterior body of the left lateral ventricle, the left caudothalamic groove, and the foramen of Monro. A genetic study showed a pathogenic mutation in the TSC2 gene (c.1119 + 2 T > G), confirming the diagnosis of tuberous sclerosis.

Later, she developed chronic myeloid leukemia in 2018. As upfront therapy, treatment was started with the tyrosine kinase inhibitor (TKI) Imatinib 400 milligrams daily. At 3 months, hematological remission was achieved but not molecular PCR as per European criteria. Therefore, she was shifted to second‐line treatment with Nilotinib 400 milligrams twice a day. Hematological toxicity emerged as a side effect of Nilotinib. Thus, 2 weeks of “drug holiday” were granted, and she was rechallenged with Nilotinib at the same dose and frequency. She redeveloped hematological toxicity again. As a result, the two‐week drug holiday was repeated, and she was restarted on Nilotinib 300 milligrams twice a day with good tolerance. She achieved both hematological and molecular remission after 3 months of therapy. A follow‐up brain and abdominal MRI was taken 6 months after the treatment and after achieving a hematological and molecular response. An MRI of the brain and abdomen showed no change or increase in the masses' size and number. Figure 1 (A, B, C, and D), Figure 2 (A, B, C, and D), The patient was asymptomatic and denied any loss of consciousness, convulsions, headaches, or behavioral changes.

FIGURE 1.

MRI of the brain 6 months after the treatment (A)‐Axial T1 fat‐suppressed image (B)‐Axial T2‐weighted image (C)‐Axial T1 post‐contrast image (D)‐Coronal T2‐weighted image‐Scattered subependymal tubers (A)‐A lobulated lesion 2.5 × 1.1 cm involving anterior horn, anterior body of left lateral ventricle, left caudothalamic groove and left foramen of Monro arrow (D).It shows low T1 signal (A), heterogeneously bright T2 signal (B and D) and heterogenous enhancement (C). Radiological diagnosis: SEGA (subependymal giant cell astrocytoma). There was no change in the size of the lesions compared with the previous MRI.

FIGURE 2.

Figure 2: MRI of the abdomen 6 months after the treatment (A)‐Axial T1‐weighted image (B)‐Axial T1‐fat suppression (C)‐Axial opposed phased image (D)‐ Axial post‐contrast T1 fat‐suppressed image Bilateral fat containing renal masses (angiomyolipoma) showing areas of bright T1 signal (A), drop of signal on fat suppressed image (B), opposed phased image (C) and in homogeneous post contrast enhancement (D). Compared with the previous MRI, there was no change in the size of the masses.

2. DISCUSSION

Tuberous sclerosis (TS) is a disorder of cell differentiation and growth. Although the condition is inherited in an autosomal‐dominant mode, the clinical phenotypes are variable in presentation. This neurocutaneous disorder can be found across all age groups, ethnicities, and genders. ¹ , ² Two gene mutations are described in the scientific literature that cause tuberous sclerosis, namely TSC1 (found on chromosome 9q34) and TSC2 (located on chromosome 16p13). The TSC2 mutation variant is estimated to account for 90% of all clinical cases of TS. However, both genetic types may produce the same clinical phenotype. This is postulated for multiple reasons, such as variable expressivity and somatic mosaicism. ¹ , ²

Platelet‐derived growth factor receptors (PDGFR) are transmembrane receptor tyrosine kinases (RTKs) that play an essential role in cell survival, growth, and proliferation via activation of intracellular cascades such as the PI3K/Akt (PKB)/mammalian target of rapamycin (PI3K/Akt [PKB]/mTOR) pathway. ³ , ⁴ Activated Akt will act in response to regulate and inhibit tuberous sclerosis complex (TSC1/TSC2). ³ , ⁵ The TSC1 gene is responsible for producing a hamartin protein, whereas TSC2 makes tuberin. Together, TSC1 and TSC2 form the TSC protein complex. ⁵

The composite protein, the TSC protein complex, acts as a tumor suppressor complex and governs multiple cellular pathways, including negative regulation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). ³ , ⁴ , ⁵ mTORC1 is a serine/threonine kinase involved in many functions, such as promoting cell growth and differentiation and inhibiting autophagy. Ras homolog enriched in the brain (Rheb) is a GTPase protein that mediates function between the TSC1/TSC2 complex and mTORC1. Specifically, while Rheb is bound to GTP, the complex above dephosphorylates it to form Rheb‐GDP, downregulating the activation of mTORC1, thereby inactivating it. In the TSC1/TSC2 mutations, loss of function in either gene results in increased Rheb‐GTP and mTORC1 activation. ⁶ In turn, the increased activity of mTORC1 is thought to be responsible for the cellular pathophysiology of TS and the increased tumors. ⁴ , ⁵ , ⁶

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder resulting from hematopoietic stem cells with a “gain of function” mutation due to the fusion gene BCR‐ABL1. ⁷ This is attributed to the reciprocal translocation of genes located on chromosome 9 and chromosome 22, or t (9;22) (q34;q11) [also known as the Philadelphia chromosome], which causes the production of an “always on” tyrosine kinase, leading to uncontrolled cell division. ⁸

The BCR‐ABL1 fusion protein affects multiple signaling pathways and can cause lymphoid and myeloid hematopoietic cell lines to proliferate unchecked by their usual dependency on cytokine signaling. BCR‐ABL1 leads to leukemogenesis through kinase‐dependent and kinase‐independent signaling pathways. However, the tyrosine kinase activity of ABL1 is a critical factor required for the tumorigenic potential of the BCR‐ABL1 protein. Multiple intracellular signaling pathways are dependent on the phosphorylation of tyrosine. Since BCR‐ABL1 is constitutively active and phosphorylates cellular proteins, many pathways are affected. ⁸

CML and TS both involve tyrosine kinase‐dependent pathways that are affected, which play a fundamental role in their respective pathogenesis. ⁴ , ⁵ , ⁸ Therefore, we hypothesize that due to this commonality, there is a possible association of CML with TS. Consequently, tyrosine kinase inhibitors, usually used as a treatment for CML, may show some benefit in TS. So far, one reported case of CML associated with TS has been reported. ⁹ According to the paper published by Koluman et al., the patient was diagnosed with TS and had seizures. She developed CML and was treated initially with Imatinib. However, the patient failed to achieve a complete response. Therefore, the patient was challenged with Dasatinib, which resulted in a hematological and molecular response. However, as measured by seizure frequency, the patient's clinical symptoms of TS were not altered. ⁹

TS is associated with multiple neoplasms, such as brain hamartomas, subependymal giant cell tumors, renal angiomyolipoma, angiofibroma, and rhabdomyomas. ² We are reporting the second case of CML associated with TS. However, more studies are needed to demonstrate a vital link between the two (CML and TS). Similarities were noted in the case reported here compared to previously published literature. Imatinib was used as first‐line therapy in both, but this failed to induce complete remission. This may suggest that a novel approach is needed to treat these cases of CML associated with TS.

Our report has confirmed the diagnosis of TS with genetic testing and was found to have a pathogenic mutation in the TSC2 gene. A pelvic and head MRI revealed renal angiomyolipoma and bilateral cerebral and periventricular tubers. Using Nilotinib as a second‐line treatment resulted in a complete hematological and molecular response. Both CML and TS involve tyrosine kinase in their pathogenesis. Therefore, it is hypothesized that treating CML will impact the course of illness of TS. To quantitatively measure this postulation, repeated imaging was obtained before and after initiating TKI therapy. In the post‐treatment imaging studies, there was no change in brain and renal mass sizes and numbers.

In the paper published by Koluman et al. (2009), the use of Dasatinib failed to reduce the frequency of seizures, which was the primary outcome measure. ⁹ Dasatinib is a nonspecific tyrosine kinase inhibitor (TKI), ¹⁰ as opposed to Nilotinib, a selective TKI that inhibits BCR‐ABL tyrosine kinase, c‐KIT, as well as platelet growth factor tyrosine kinase only. ¹¹ , ¹²

3. CONCLUSION

In summary, we reported a second case in the literature of TS associated with CML. Both diseases, TS and CML, share a common pathway in pathogenesis. CML in TS patients seems to respond better to the second‐generation TKI. We evaluated the effect of TKI on neoplasms found in TS patients. CML was treated with Nilotinib successfully. However, it did not show either worsening or reduction in the size and number of the neoplasms found in TS patients radiographically in MRI images at six‐month intervals post‐treatment. As a result, we recommend starting with second‐generation TKI, such as Nilotinib, as the first choice for treating CML in TS. Further studies on larger scales are needed to clarify the possible mutual effects of TKI on CML and TS.

AUTHOR CONTRIBUTIONS

Abdulrahman Al‐Abdulmalek: Writing – original draft; writing – review and editing. Reem Al‐Suliman: Investigation; writing – review and editing. Mohammad Abu‐Tineh: Writing – original draft; writing – review and editing. Mustafa Ali: Investigation. Mohamed A Yassin: Conceptualization; writing – review and editing.

FUNDING INFORMATION

This Article will be funded by Qatar national library if accepted, “the funders has no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript”.

CONFLICT OF INTEREST STATEMENT

The Authors have nothing to disclose.

ETHICS STATEMENT

This work was approved by Medical Research Center (MRC) Qatar before submission, referral number: MRC‐04‐22‐400.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Al‐Abdulmalek A, Al‐Suliman R, Abu‐Tineh M, Ali M, Yassin MA. The effectiveness of tyrosine kinase inhibitor for chronic myeloid leukemia in tuberous sclerosis. A case report and review of literature. Clin Case Rep. 2023;11:e7087. doi: 10.1002/ccr3.7087

DATA AVAILABILITY STATEMENT

The data used to support the findings of this study are included within the article.