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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 3  |  Page : 760-764

Effects of tyrosine kinase inhibitors for controlling Ph+ clone and additional clonal abnormalities in a chronic myeloid leukemia


1 MGM Center for Genetic Research and Diagnosis, MGM New Bombay Hospital; MGM Center for Genetic Research and Diagnosis, MGM Institute of Health Sciences, Navi Mumbai, Maharashtra, India
2 MGM Center for Genetic Research and Diagnosis, MGM New Bombay Hospital, Navi Mumbai, Maharashtra, India
3 Clinical Hematology Services, Kolkata, Park Nursing Home, Kolkata, India
4 MGM Center for Genetic Research and Diagnosis, MGM Institute of Health Sciences, Navi Mumbai, Maharashtra, India

Date of Submission04-Dec-2020
Date of Decision31-Aug-2021
Date of Acceptance25-Oct-2021
Date of Web Publication25-Jul-2022

Correspondence Address:
Bani Bandana Ganguly
MGM Center for Genetic Research and Diagnosis, MGM New Bombay Hospital, Sector 3, Vashi, Navi Mumbai - 400 703, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1755_20

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 > Abstract 


Purpose: The chronic myeloid leukemia (CML) is characterized by the presence of t(9;22)(q34;q11) that results in chimerization of BCR and ABL genes on the rearranged chromosome 22 or Philadelphia chromosome (Ph). Imatinib has been established as the first line of therapy for CML; in case of Imatinib failure or resistance, other second or third generation tyrosine kinase inhibitors (TKIs) are considered. However, acquisition of additional clonal abnormalities (ACAs) interferes in management of CML. We described a complex scenario of cytogenetic remission, relapse, response to TKIs and behavior of ACAs in a case of CML.
Materials and Methods: Conventional G-banding and FISH cytogenetics, and quantitative PCR studies were conducted in the bone marrow for diagnosis and follow up (FU) of the changes of BCR-ABL gene and ACAs at different time intervals.
Results: Ph− chromosome disappeared within 6 months of Imatinib therapy, and re-appeared within a year. Subsequent change of TKI to dasatinib eliminated the Ph+ clone, but established an ACA with trisomy 8 (+8). Further change to Nilotinib, eliminated +8 clone, but re-emergence of Ph+ clone occurred with an ACA with monosomy 7 (−7). Reinstate of Dasatinib eliminated Ph+ and −7 clones, but with gradual reappearance of Ph+ and +8 clones. The patient discontinued FU, though participated in a long term examination.
Conclusion: The complexity of ACAs and Ph+ clones needs frequent monitoring with changes of TKI and technologies.

Keywords: Additional clonal abnormalities, chronic myeloid leukemia, Philadelphia chromosome, tyrosine kinase inhibitors


How to cite this article:
Ganguly BB, Mandal S, Banerjee D, Kadam NN. Effects of tyrosine kinase inhibitors for controlling Ph+ clone and additional clonal abnormalities in a chronic myeloid leukemia. J Can Res Ther 2022;18:760-4

How to cite this URL:
Ganguly BB, Mandal S, Banerjee D, Kadam NN. Effects of tyrosine kinase inhibitors for controlling Ph+ clone and additional clonal abnormalities in a chronic myeloid leukemia. J Can Res Ther [serial online] 2022 [cited 2022 Aug 10];18:760-4. Available from: https://www.cancerjournal.net/text.asp?2022/18/3/760/351811




 > Introduction Top


Chronic myeloid leukemia (CML) is characterized by the reciprocal translocation between chromosomes 9(q34) and 22(q11), which results in the formation of a chimeric BCR-ABL oncogene on the derivative chromosome 22 called the Philadelphia chromosome (Ph 1).[1],[2] The BCR-ABL gene encodes BCR-ABL protein, which has constitutive tyrosine kinase activity in the hematopoietic stem cells.[3] The BCR-ABL protein kinase increases tyrosine kinase through binding to adenosine tri-phosphate (ATP) in signal transduction, and thus, tyrosine kinase inhibitors (TKIs) were targeted for controlling the overexpression of BCR-ABL kinase and clinical management of CML. The TKIs block the binding of ATP and prevents phosphorylation rendering Philadelphia-positive (Ph+) cells either have a selective growth disadvantage or undergo apoptotic cell death.[4],[5] The clinical manifestation of the BCR-ABL gene attributes to uncontrolled proliferation of myelogenous cells resulting in significant increase in white blood cells, and hepato- and splenomegaly as prominent clinical manifestations.

The action of TKIs against the aberrant BCR-ABL kinase renders 5- to 8-year overall survival (OS) in ~85% of the patients with an acceptable quality of life.[6] Imatinib was the first TKI introduced into the clinics for treatment of CML in 2003, and has been considered as the first line of therapy for its striking ability to block cell proliferation by inhibiting the tyrosine kinase activity of BCR-ABL.[6],[7] It confers a durable and complete cytogenetic response in the early (chronic) phase (CP) of CML; however, it fails to achieve response in 25-30% of CP-CML patients owing to primary or acquired resistance, and/or due to intolerance, causing relapse in ~15% patients after achieving initial response.[8] There are more TKIs such as Dasatinib, Nilotinib, Bosutinib, Ponatinib, etc., which are considered for treatment when Imatinib fails due to resistance or intolerance.[9]

Although the TKIs have revolutionized the clinical management of CML by changing its fate from fatal to a manageable condition, treatment failure has become an increasingly important concern for which the reason has not been fully elucidated. The acquisition of missense point mutations in the BCR-ABL kinase domain, complex chromosomal rearrangements, additional clonal aberrations (ACAs) and inherent genetic makeup could underlie the TKI resistance or intolerance, and interfere in durability of remission resulting in relapse of the disease.[9] Hence, follow up (FU) screening of mutational events and chromosomal rearrangements should be considered at shorter intervals for patients who are nonresponder or have developed resistance to TKI therapy. However, severe cytopenia, and availability of testing facility and associated financial burden might not support the clinicians and/or patients to look forward such extensive genetic screening to exclude or mitigate the blockers of TKI response.

The present report has described a complex situation with ACAs and transient remission and relapse with Ph− chromosome in a CML patient, which directed changing of TKI from Imatinib to Dasatinib to Nilotinib to Imatinib to Dasatinib, and finally, the patient had lost interest in FU.


 > Materials and Methods Top


A 48-year-old man having complaints of low degree fever for 5–6 months, progressive weight loss, and anemia was presented with hepato-splenomegaly (both nontender and firm) and suspected as a case of CML. Conventional cytogenetics and fluorescence in situ hybridization (FISH) studies were conducted in his bone marrow following the standard techniques. A total of 25 G-banded metaphases were karyotyped as per ISCN 2016 and 200 interphase cells were screened for BCR-ABL hybridization.[3] Quantitative polymerase chain reaction (PCR) studies were outsourced from a reliable institution. On the basis of the result, he was subjected to Imatinib as the first line of therapy. He was followed up for cytogenetic studies for ten times and quantitative PCR study was outsourced for two FU.

Patient's consent and ethical approval were obtained for this publication.


 > Results Top


The first cytogenetic and FISH results revealed presence of Ph in 100% cells with a 46,XY,t(9;22)(q34;q11)[25]karyotype [Figure 1]a. The first FU cytogenetics was conducted after 6 months in bone marrow following FISH technique and that revealed Ph-negative (Ph−) condition in 100% cells. He was afebrile and advised to continue Imatinib. At the time of 2nd FU after another 6 months of 1st FU and 1 year from the initiation of Imatinib-therapy, his only discomfort was mild fever; however, FISH-cytogenetics in bone marrow revealed Ph+ status in 93% cells. He discontinued Imatinib after ~18 months. Quantification of BCR-ABL transcripts by PCR-technique showed Ph+ for 2 years indicating failure of Imatinib response or resistance to Imatinib. Thus, his TKI was changed to Dasatinib. Following Dasatinib treatment after 6 months, 3rd FU study by conventional cytogenetics in bone marrow has revealed Ph− condition in 100% cells. The result indicated satisfactory outcome with Dasatinib therapy; however, acquisition of trisomy 8 (+8) was detected in 50% of the cells examined with 47,XY,+8[10]/46,XY[10] pattern [Figure 1]b. The additional clonal abnormality (ACA) was occurred in Ph− cells and in absence of Ph+ clone. He remained symptomatic with complaints of fever and cytopenia. Subsequently, his treatment was switched to Nilotinib from 12 months of Dasatinib treatment. After 6 months of Nilotinib therapy, his 4th FU following conventional cytogenetics in bone marrow revealed Ph− and +8 conditions in 100% and 15% cells respectively; however, the quantitative PCR revealed BCR/ABL ratio as 0.15. His hemogram showed hemoglobin 13.4, total count 4400, and platelet 150,000 of standard units. He continued with Nilotinib. The 5th FU study after 5 months i.e., 11 months following Nilotinib as TKI by G-banding cytogenetics had presented Ph+ in 8% cells with complete disappearance of +8 clone. The 6th FU examination after another 6 months appeared 100% Ph− by FISH study, while BCR/ABL ratio was 0. He continued Nilotinib treatment. His 7th FU study after 6 months by conventional cytogenetics had confirmed 100% remission status with Ph− cells; however, acquisition of another ACA was detected with monosomy 7 (−7) in 50% cells with 45,XY,-7[10]/46,XY[10] pattern [Figure 1]c. The ACA with − 7 was present in Ph− cells and in 100% Ph − condition. At that point, Nilotinib was discontinued after nearly 18 months of treatment, and Dasatinib reinstated [Figure 2]. The 8th FU surveillance appeared Ph- by G-banding cytogenetics after ~13 months, but with a BCR/ABL ratio of 0.00073 on PCR; however, the ACA with −7 increased to 100% cells. After a year (9th FU), the Ph+ clone was detected in 8% cells, while −7 was reduced to 92% in all Ph− cells. At the next (10th) FU at 1 year of interval, the conventional cytogenetics revealed expansion of Ph+ clone to 88%, and complete disappearance of the −7 clone; however, trisomy 8 re-appeared and was detected in all Ph− cells (12%) of the 50 cells studied.
Figure 1: Chromosomal alterations (arrowed) detected in bone marrow: (a) The reciprocal translocation between 9(q34) and 22(q11); (b) trisomy 8 in Ph− cells; (c) monosomy 7 in Ph− cells

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Figure 2: Cycle of treatment with tyrosine kinase inhibitors and appearance/disappearance of aberrations

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Altogether, the bone marrow conventional cytogenetic studies were monoclonal only for the first two studies, including the primary diagnosis and the remaining were bi-clonal, which included +8, −7 and/or Ph−/Ph + cells [Figure 3]. The FISH studies considering probes only for BCR and ABL genes could not detect presence or absence of +8 and/or −7.
Figure 3: Frequency of Ph+/− cells and additional clonal abnormality detected against tyrosine kinase inhibitors at different duration of treatment (Rx)

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 > Discussion Top


CML is a unique hematologic cancer where the disease in a clinical stage is presumably caused by a single molecular abnormality, and thus, helped in development of targeted drugs. In general, most of the CML patients are diagnosed in CP; however, the disease inexorably progresses to accelerated phase (AP) and culminates in blast crisis (BC) in absence of therapeutic intervention. Besides presence of BCR-ABL oncogene, acquisition of diverse additional mutations, particularly in the kinase domain, ACAs and amplification of the BCR-ABL oncogene have been implicated with disease progression and poor therapeutic outcome.[10],[11] ACAs are reported in 7% CP-CML, which may increase to 40%–70% in BC.[12] Over 70 different amino acid substitutions have been identified in 40%–90% TKI-resistant patients, of which over 15-20 mutations (T315I, Y253F/H, E255K/V, M351T, G250E, F359C/V, H396R/P, M244V, E355G, F317L, M237I, Q252H/R, D276G, L248V, F486S, etc.) in the kinase domain have been attributed to ~85% of clinical manifestation of resistance.[7],[13],[14] Also, phosphorylation of tyrosine residues in SH3-SH2 regions of the BCR-ABL by HCK, LYN and FYN kinases of the SRC-family may confer disease progression and imatinib resistance.[15] Co-occurrence of mutations containing T315I renders resistance at high magnitude to Imatinib, Nilotinib, and Dasatinib. Such diversified genetic instability favors the aberrant cells of CML to acquire a more aggressive malignant character resulting in lowering of OS.

Among the ACAs in CML, trisomy 8, i (17q) and an extra Ph-chromosome are commonly reported.[16; Ganguly et al. unpublished] ACA as monosomy 7 is relatively infrequent in CML. The present case was a CP-CML, who achieved cytogenetic remission in 6 months following Imatinib therapy. However, he relapsed within next 6 months, and thus, switched to Dasatinib. He again achieved cytogenetic remission, but acquired trisomy 8 following Dasatinib treatment. He further switched to Nilotinib; however, the disease relapsed with re-occurrence of Ph+ clone and acquired −7 clone as another ACA, and the treatment re-started with Dasatinib. Ph+ clone was controlled with elimination of −7, but Ph+ clone gradually re-occurred with+8 as ACA. Such a complex scenario with horse-trading like transient disappearance/re-appearance of Ph+ clone and ACAs created a puzzling situation for the clinician as well as the patient, and the patient discontinued FU. ACAs and other sub-clonal rearrangements are reported to prevent TKIs from binding, or favoring conformational changes leading to reduced TKI-sensitivity, and thus, interfere in treatment-outcome.[2],[10],[17],[18],[19],[20]

Screening of ACAs has apparently not gained attraction because the primary concern of treatment governs presence or disappearance of Ph+ clone, though concurrent ACAs were reported in approximately 30% AP and 80%–90% BC-CML.[6],[21] CML patients are generally monitored by FISH or quantitative PCR technique, which does not detect ACAs and thus, ACAs remain overtly underestimated. ACAs in CML are highly heterogeneous with varying clinical and prognostic implications;[11] therefore, European LeukemiaNet (ELN) had classified the ACAs as “major route” (trisomy 8, extra Ph, i (17q) and trisomy 19) and “minor route” (abnormalities with less common ACAs).[22],[23],[24],[25] Also, ACAs were proposed for stratification of CML for monitoring treatment outcome, survival and disease progression, such as Group 1 (trisomy 8, -Y and extra Ph− chromosome), and Group 2 (i (17q),-7/del7q and rearrangements of 3q26.2) for “good” and “poor” prognosis respectively, irrespective of the phase of origin.[16]

Mechanistically, the action of TKIs could vary due mainly to the difference in their structure. Imatinib binds to the catalytic site of the ABL causing inhibition of auto-phosphorylation and cell proliferation, and stabilizes the inactive form of the kinase in the A-loop in a closed DFG-out conformation and the P-loop of the ATP binding site in a distorted conformation.[26],[27] Thus, it prevents binding of ATP and activation of the kinase. Whereas, Dasatinib, a thiazole carboxamide, binds the open DFG-in conformation of the ABL, exerts inhibitory action via the ABL:ATP-binding site, and thus, the mutations in the ATP-binding region and P-loop reduced sensitivity of the ABL kinase to Dasatinib in vitro.[28] It is less affected by mutations in the A-loop.[29] And Nilotinib has Imatinib-derived structure, and it binds to the inactive form of the ABL tyrosine kinase with folding of P-loop over the ATP-binding site. Thus, the activation loop blocks the substrate binding site, disrupts the ATP-binding site, and inhibits the catalytic activity of the tyrosine kinase enzyme.[30],[31] Its methyl-imidazole ring fits in deeper hydrophobic pocket that is generated while the ABL kinase is in its inactive DFG-out form. It is powerful to inhibit imatinib-resistant mutations of BCR-ABL, except T315I,[32] and to reduce emergence of BCR-ABL mutations in treated CML patients.[33] However, the present case had re-emergence of Ph+ clone following 6 months of Nilotinib treatment, which was controlled with reinstate of Dasatinib therapy. The mechanism could not be understood in the present case with the investigational techniques employed. The mutations altering the hydrophobic pocket of Nilotinib might confer considerable resistance to it.[29] The DASISION study revealed that the patients with mutations had poor outcome, high rates of discontinuation (82% Dasatinib; 78% Imatinib), transformation (24% and 17%) and death (35% and 22%).[34] A serial follow-up study demonstrated MMR in 72.5% patients without ACA versus 36% patients with ACA, wherein the patients with ACA had lower survival.[35] Nevertheless, the TKIs don't work uniformly in every individual or develop resistance due mainly to the differences in heterogeneous mutations of kinase domain and acquisition of ACAs. Therefore, combination therapy of TKI and interferon was recommended.[12]

The present report has raised several concerns: Why did so early relapse occur following Imatinib therapy; when Nilotinib controls Dasatinib-induced +8 clone, why did Ph+ clone re-emerged; with Nilitinib transient reappearance/disappearance of Ph+ clone, what caused onset of -7 clone; when reinstate of Dasatinib controlled −7 clone, why did it induce +8 clone and why it couldn't control Ph+ clone as it did earlier; what should be the next course of treatment regiment, if the patient comes back for FU; and so on. A possible combination therapy and screening of the spectrum of mutations may extract the underlying mechanism of causing a complex scenario in CML, and also help in recognizing newer inhibitors as potential targeted drugs.[36]


 > Conclusion Top


The present report on transient appearance of Ph-chromosome and ACAs and complexity of the situation in response to TKIs suggests the importance of follow-up at frequent intervals and the employment of technological interventions for tracking down the Ph-clone and ACAs. Notably, exploration of the amino acid substitutions or kinase domain mutations, T315I in particular, would have deciphered the underlying mechanism and association of Ph+ clone and ACAs, exclusively in Ph- cells. However, the financial and psychological factors have to be taken into consideration with a view to benefiting the patient for management of the disease condition.

Acknowledgements

The authors wish to acknowledge the patient for his participation in series of follow up studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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