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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 108-111

Eradication of prior-to-treatment compound BCR-ABL mutations by interferon-alpha in chronic myeloid leukemia: Long-term follow-up studies and review of literature


1 Department of Zoology, Hematology, Oncology and Pharmaco-Genetic Engineering Sciences Group, Health Sciences Research Laboratories, Lahore, Pakistan; Molecular Genetics/Hematology & Oncology Section, Clinical Laboratory Sciences Program/Department, CoAMS-A, King Saud Bin Abdulaziz University for Health Sciences/KAIMRC, King Abdulaziz Medical City, National Guard Health Affairs, Al-Ahsa, Saudi Arabia; Department aNext-Generation Medical Biotechnology Division, Universaity of Sialkot, Sialkot, Pakistan
2 Department of Zoology, Hematology, Oncology and Pharmaco-Genetic Engineering Sciences Group, Health Sciences Research Laboratories, Lahore, Pakistan
3 Department aNext-Generation Medical Biotechnology Division, Universaity of Sialkot, Sialkot, Pakistan
4 Hematology/Oncology Division, Department of Medicine, KKUH and College of Medicine, King Saud University, Riyadh, Saudi Arabia
5 Department of Zoology, University of the Punjab, Lahore, Pakistan
6 Faculty of Applied Medical, Saudi Arabia
7 Allied Hospital, Faisalabad, Pakistan
8 Department of Zoology, Hematology, Oncology and Pharmaco-Genetic Engineering Sciences Group, Health Sciences Research Laboratories, Lahore; Department aNext-Generation Medical Biotechnology Division, Universaity of Sialkot, Sialkot, Pakistan
9 Department of Medicine, Asian Medical Institute, Kartik, Kyrgyzstan
10 Khyber Teaching Hospital and Hayatabad Medical Complex, Peshawar, Pakistan
11 Molecular Genetics/Hematology & Oncology Section, Clinical Laboratory Sciences Program/Department, CoAMS-A, King Saud Bin Abdulaziz University for Health Sciences/KAIMRC, King Abdulaziz Medical City, National Guard Health Affairs, Al-Ahsa, Saudi Arabia

Date of Submission13-Feb-2020
Date of Decision01-Mar-2020
Date of Acceptance13-Mar-2020
Date of Web Publication16-Sep-2020

Correspondence Address:
Dr. Zafar Iqbal
CoAMS-A, King Saud Bin Abdulaziz University for Health Sciences/KAIMRC, King Abdulaziz Medical City, National Guard Health Affairs, Al-Ahsa

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_13_20

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  Abstract 

BACKGROUND: Although tyrosine kinase inhibitors (TKIs) are the gold standard in clinical management of chronic myeloid leukemia, it is not feasible to use these drugs in at least some cases when patients are resistance to all available TKIs due to compound BCR-ABL mutations, due to patient safety profile or due to the nonavailability of drugs in developing countries on account of cost or logistic issues. We reported earlier that interferon alpha can eradicate compound BCR-ABL mutations and induce stable responses. Here, we report a follow-up of this study.
PATIENTS AND METHODS: Some chronic myeloid leukemia (CML) patients did not get TKIs directly because of very high cost of imatinib and were given interferon alpha (experimental group) until the provision of imatinib free of cost through GLIVEC® International Patient Assistance Program while the other groups of patients (control group) were directly given imatinib. A very sensitive allele-specific polymerase chain reaction was employed to detect BCR-ABL compound mutations before treatment and confirmation of mutations was carried out using reliable molecular assays. Mutations were reinvestigated at all important time points during the long-term follow-up studies.
RESULTS: The use of interferon-alpha for 6 months prior to TKIs eradicated compound BCR-ABL mutations (Phe311Val/Met351Thr and Thr315Ile/Phe311Val/Met351Thr) and provided deep molecular responses without any progression or mortality in CML patients (experimental group) as compared with patients who did not use interferon and was directly given TKIs (control group).
CONCLUSIONS: Interferon alpha can eradicate highly resistant BCR-ABL mutations and lead to durable deep molecular responses to TKIs in CML. Therefore, interferon-alpha is recommended for CML patients with compound mutations resistant to TKIs, specifically in those scenarios where some TKIs are not available or not safe to use for CML patients. Our long-term follow-up study is well supported by recently published literature.

Keywords: Chronic myeloid leukemia, compound BCR-ABL mutations, interferon, pan-tyrosine kinase inhibitor resistance, ponatinib resistance


How to cite this article:
Iqbal Z, Akhtar T, Khalid AM, Aleem A, Mahmood A, Akram AM, Rasool M, Shah IH, Bhalli A, Khalid M, Iqbal M, Jameel A, Al-Anazi N. Eradication of prior-to-treatment compound BCR-ABL mutations by interferon-alpha in chronic myeloid leukemia: Long-term follow-up studies and review of literature. J Appl Hematol 2020;11:108-11

How to cite this URL:
Iqbal Z, Akhtar T, Khalid AM, Aleem A, Mahmood A, Akram AM, Rasool M, Shah IH, Bhalli A, Khalid M, Iqbal M, Jameel A, Al-Anazi N. Eradication of prior-to-treatment compound BCR-ABL mutations by interferon-alpha in chronic myeloid leukemia: Long-term follow-up studies and review of literature. J Appl Hematol [serial online] 2020 [cited 2020 Sep 20];11:108-11. Available from: http://www.jahjournal.org/text.asp?2020/11/3/108/295114


  Introduction Top


In recent years, compound BCR-ABL mutations have posed new challenges by causing resistance to all FDA-approved tyrosine kinase inhibitors (TKIs) which are standard-of-care chronic myeloid leukemia (CML) and other BCR-ABL hematological malignancies.[1] Many studies have shown that BCR-ABL mutations may exist before TKI treatment and lead to resistance due to selective pressure of drug.[2],[3] Therefore, the detection of compound BCR-ABL mutations before the initiation of TKI-based therapy and their eradication prior to the start of treatment is mandatory to manage the resistance to these highly efficient anti-leukemic drugs and to induce stable and long-term treatment responses.[4] Therefore, finding a drug which kills such mutations can be a milestone in managing resistance to targeted therapies and optimizing their role as curative therapies.[2] Our earlier studies (in 2008) showed that interferon-alpha prior to imatinib can eradicate the preexisting compound BCR-ABL mutations and lead to stable molecular response in CML treated with standard-dose imatinib.[5] Here, we report a long-term follow-up of this study.


  Patients and Methods Top


Clinically diagnosed chronic-phase Philadelphia chromosome-positive CML patients were enrolled in this study. The male-to-female ratio was 2.2:1 and the median age was 38 years (range: 12–67). Patients were recruited from Allied Hospital, Faisalabad; Pakistan Institute of Medical Sciences, Islamabad; Khyber Teaching Hospital, Peshawar; Hayatabad Medical Complex, Peshawar; and Institute of Radiotherapy and Nuclear Medicine, Peshawar, Pakistan. During the initial phase of the study, some patients could not receive imatinib directly because of very high cost of imatinib and were given interferon alpha until the provision of imatinib free of cost through GLIVEC® International Patient Assistance Program (GIPAP). This constituted our experimental group. The control group of the patients could be directly given imatinib as either they could afford the cost of imatinib or enrolled later when imatinib was available through GIPAP clinic. Informed consent was received from all study participants from all participating clinical centers and the study was approved by the institutional review boards of all participating departments/institutes.

Prior-to-treatment compound BCR-ABL mutations were detected in all patients by a very sensitive and validated allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) assay as described earlier.[6],[7] Compound BCR-ABL mutations were confirmed as described using validated Sanger sequencing of BCR-ABL,[7] and all treatment response criteria were adopted from the European LeukemiaNet guidelines as described in our previous study.[7] Reinvestigations of BCR-ABL mutations were carried out at important time points during treatment with imatinib (400 mg/day), that is, at day 0, every 6 months during the first 30 months and then yearly and specifically at the time of drug resistance. Group 1 patients with pretreatment mutations received recommended doses of subcutaneous interferon-alpha for 6 months before imatinib monotherapy due to financial constraints. Group 2 patients (n = 30) with preexisting mutations received imatinib from day 0 and were included in the study for comparison. Treatment was monitored by studying hematological parameters, by cytogenetics and Real Time Quantitative PCR (RTQ-PCR) per the European LeukemiaNet guidelines detailed in our previous studies.[7]


  Results Top


In Group 1 (experimental group), pretreatment BCR-ABL mutations Phe311Val and Met351Thr were detected in the first patient while mutations Thr315Ile, Phe311Val, and Met351Thr in the second patient [Figure 1]. We could not detect these mutations after 6 months of interferon treatment. Both patients got partial cytogenetic responses, but persistent BCR-ABL. Therefore, interferon therapy was replaced by imatinib after 6 months after the provision of drug from an NGO (through GIPAP). Both patients showed complete hematologic, cytogenetic, and molecular responses and BCR-ABL negativity by nested RT-PCR at month 18, month 30, and then yearly during 16-year follow-up. No BCR-ABL mutations were detected and there was no progression to advanced phase CML.
Figure 1: (a-d). Detection of BCR-ABL mutations by allele-specific oligonucleotide-polymerase chain reaction and DNA sequencing[7].(-ve control = Negative control; bp = Base pair; PEM = Preexisting BCR-ABL mutations; C = Cytosine; T = Thymine; A = Adenine; G = Guanine). HL60 cell line was used as a negative control in allele-specific oligonucleotide-polymerase chain reaction and sequencing while KCL 22 was used as positive control in RT-PCR and DNA sequencing)

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All other CML patients, with preexisting BCR-ABL mutations but no before imatinib interferon therapy (Group 2 patients or control group), remained BCR-ABL positive and persisted with same preexisting BCR-ABL KD mutations during the first 30-month follow-up of imatinib treatment. During the follow-up studies of Group 2 patients, 10 out of these 30 (33.3%) CML patients progressed to advanced phase CML and switched to nilotinib. Out of these ten patients, two patients progressed to blast crisis and died. The remaining twenty patients showed major molecular response. Therefore, it is inferred that short-term interferon prior to imatinib therapy could effectively eradicate preexisting BCR-ABL mutations and lead to long-term stable molecular responses.


  Discussion Top


This study endorses our earlier studies that the use of interferon before the start of imatinib (and possibly other TKIs) can eliminate preexisting compound BCR-ABL gene domain mutations and lead to stable molecular responses.[5] It also establishes the utility of interferon alpha in inducing long-term deep molecular response to imatinib. Recently, Polivkova et al. have shown that interferon alpha can lead to eradication of compound BCR-ABL mutations and deep molecular responses in high-risk CML patients.[8] Similarly, Zu et al. have reported that interferon alpha can be good choice if substitute TKIs are not available for drug switching and resistance is manifested against TKIs.[9] This may be very useful in case of highly resistant compound BCR-ABL mutations where all FDA-approved TKIs become ineffective. In 2018, switch from nilotinib to interferon alpha was used as a clinical strategy to successfully stimulate ovaries to preserve pregnancy in a CML patient which also led to 3-year deep molecular responses.[10] Zeng et al. have reported the effectiveness of interferon-alpha in eradicating highly resistant T315I BCR-ABL mutation.[11] Very recently, a clinical trial has been carried out where forty CML patients with posttransplant molecular relapses treated with interferon only 12.6% relapses at 4.5 years in comparison to 42% relapse at 4.5 years in the control group.[12] They also reported benefit of short-term interferon for CML patients with molecular relapses based on the observation that during a median follow-up of 15.6 years, treatment-free survival of posttransplant CML patients was 75%.[12] These findings are supported by Henden et al. who utilized pegylated interferon alpha to invoke graft-versus-leukemia effect in a group of patients relapsing after stem cell transplantation.[13] Therefore, based on our long-term follow-up study and recently published literature, we recommend at least short-term use of interferon alpha for CML patients with compound mutations resistant to TKIs, specifically ponatinib-resistant mutations[8],[12],[13],[14],[15] and in those scenarios where some TKIs such as ponatinib for multi-TKI-resistant T315I BCR-ABL mutation are not available in developing countries like Pakistan. It could also be treat to opt for those TKI-resistant CML cases in which some TKIs are not safe to be used (e.g., ponatinib not safe to use in patients with cardiovascular complications)[16] unless some novel treatment strategies are discovered to treat BCR-ABL-positive leukemias resistant to all FDA-approved TKIs.[17]

Acknowledgments

We acknowledge the help and collaboration of Professor Moustapha Kassem working at the Department of Endocrinology, Molecular Endocrinology Laboratory, Department of Endocrinology, Odense University Hospital and University of Southern Denmark, and visiting professor at Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia. Help and collaboration of Professor Sai-Juan Chen and Prof Zhu Chen, Directors Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, China, for giving us an opportunity of training in leukemia stem cell characterization, BCR-ABL mutation detection, and functional characterization of leukemia genes. This work was partially supported by the College of Medicine Research Center, Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia. Research funding provided by Higher Education Commission Pakistan is also acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Parker WT, Yeung DT, Yeoman AL, Altamura HK, Jamison BA, Field CR, et al. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib. Blood 2016;127:1870-80.  Back to cited text no. 1
    
2.
Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL). Blood 2007;110:727-34.  Back to cited text no. 2
    
3.
Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Laï JL, Philippe N, Facon T, et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 2002;100:1014-8.  Back to cited text no. 3
    
4.
Naqvi K, Cortes JE, Luthra R, O'Brien S, Wierda W, Borthakur G, et al. Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR-ABL kinase domain mutations. Int J Hematol 2018;107:689-95.  Back to cited text no. 4
    
5.
Iqbal Z, Baig SM, Aziz Z, Shah IH, Khalid M, Iqbal M, et al. Interferon prior to imatinib therapy eradicates pre-existing BCR-ABL ATP-binding domain mutations conferring natural imatinib resistance and leads to more sustained/durable molecular response in chronic myeloid leukaemia. Ann Oncol 2008;19 (Suppl 3):Iii41-2.  Back to cited text no. 5
    
6.
Kang HY, Hwang JY, Kim SH, Goh HG, Kim M, Kim DW. Comparison of allele specific oligonucleotide-polymerase chain reaction and direct sequencing for high throughput screening of ABL kinase domain mutations in chronic myeloid leukemia resistant to imatinib. Haematologica 2006;91:659-62.  Back to cited text no. 6
    
7.
Iqbal Z, Aleem A, Iqbal M, Naqvi MI, Gill A, Taj AS, et al. Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: Implications in the post-imatinib era. PLoS One 2013;8:e55717.  Back to cited text no. 7
    
8.
Polivkova V, Rohon P, Klamova H, Cerna O, Divoka M, Curik N, et al. Interferon-α revisited: individualized treatment management eased the selective pressure of tyrosine kinase inhibitors on BCR-ABL1 mutations resulting in a molecular response in high-risk CML patients. PLoS One 2016;11:e0155959.  Back to cited text no. 8
    
9.
Zu YL, Zhang YL, Zhou J, Zhao HF, Gui RR, Li Z, et al. The efficacy analysis of interferon combined with imatinib in chronic myelogenous leukemia patients with ABL kinase domain mutations. Zhonghua Nei Ke Za Zhi 2016;55:794-6.  Back to cited text no. 9
    
10.
Gazdaru S, Perey L, Rosselet A, Mathevet P, Chalandon Y, Vulliemoz N. Successful ovarian stimulation for fertility preservation in a patient with chronic myeloid leukemia: Switch from nilotinib to interferon-α. Oncologist 2018;23:719-21.  Back to cited text no. 10
    
11.
Zeng Y, Zhang J, Li X, Zhang L, Liu J. Interferon-α based individualized treatment of a high risk chronic myelogenous leukemia patient harboring T315I mutation. Clin Lab 2018;64:1061-4.  Back to cited text no. 11
    
12.
Bezerra ED, Flowers ME, Onstad LE, Chielens D, Radich J, Higano CS. A phase 2 study of alpha interferon for molecularly measurable residual disease in chronic myeloid leukemia after allogeneic hematopoietic cell transplantation. Leuk Lymphoma 2019;60:2754-61.  Back to cited text no. 12
    
13.
Henden AS, Varelias A, Leach J, Sturgeon E, Avery J, Kelly J, et al. Pegylated interferon-2α invokes graft-versus-leukemia effects in patients relapsing after allogeneic stem cell transplantation. Blood Adv 2019;3:3013-9.  Back to cited text no. 13
    
14.
Eide CA, Zabriskie MS, Savage Stevens SL, Antelope O, Vellore NA, Than H, et al. Combining the allosteric inhibitor asciminib with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 mutants. Cancer Cell 2019;36:431-4300000.  Back to cited text no. 14
    
15.
Zhang H, He X, Ni D, Mou L, Chen X, Lu S. How does the novel T315L mutation of breakpoint cluster region-abelson (BCR-ABL) kinase confer resistance to ponatinib: A comparative molecular dynamics simulation study. J Biomol Struct Dyn 2020;38:89-100.  Back to cited text no. 15
    
16.
Chan O, Talati C, Isenalumhe L, Shams S, Nodzon L, Fradley M, et al. Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia. Blood Adv 2020;4:530-8.  Back to cited text no. 16
    
17.
Massimino M, Tirrò E, Stella S, Pennisi MS, Vitale SR, Puma A, et al. Targeting BCL-2 as a therapeutic strategy for primary p210BCR-ABL1-positive B-ALL Cells. In Vivo 2020;34:511-6.  Back to cited text no. 17
    


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