Jamal: Hypocalcemia with imatinib treatment in chronic myeloid leukemia patients

Introduction

Imatinib mesylate is a tyrosine kinase inhibitor targeted to BCR-ABL, PDGFR, and KIT mutations. It plays a pivotal role in treatment of chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumours (GISTs), and has dramatically changed the clinical management of these tumour types.1, 2, 3, 4

The adverse effects of imatinib are mostly mild and manageable.

Various side effects are as follows:

  1. Anemia

  2. Oedema

  3. Fatigue

  4. Nausea

  5. Diarrhoea

  6. Cramps

  7. Rash

  8. Myalgia

  9. Arthralgia

  10. Granulocytopenia

Musculoskeletal effects of imatinib are reported in 25% of GIST patients and 20–40% of CML patients, including arthralgia, myalgia, and muscle cramps, but are rarely dose-limiting.2, 5, 6, 7, 8

The pathophysiology of these effects is uncertain. Various pathophysiological mechanisms proposed are :

  1. Firstly, although KIT is expressed on renal tubular cells, their functions there are unknown. Imatinib could therefore be exerting a direct effect on renal tubular KIT receptors, resulting in relative hypocalcaemia.

  2. Secondly, imatinib is a member of a family of protein tyrosine kinase inhibitors which can induce marked changes in cell excitability and ion homeostasis. Indeed, imatinib blocks low voltage-activated T-type calcium channels in human embryonic kidney cells.9 Thus imatinib could have a nonspecific effect on calcium homeostatsis that is not KIT receptor-mediated.

  3. Thirdly imatinib might be causing nonspecific inhibition of calcium channels in tubule which might be leading to hypocalcemia.

Musculoskeletal complaints are a common side effect of imatinib and are manifested as muscle cramps and bone pain. The muscle cramps occur mainly in the hands, feet, calves, and thighs. The pattern, frequency, and severity of cramps are usually constant over time, and they may resemble titanic contractions. Some patients relate cramps to exertion or describe night time occurrence. Bone pain and arthralgias have been reported by 20% to 40% of patients. Their onset tends to be in the first month of therapy, and they frequently abate after a few months. The symptoms most frequently affect the femurs, tibias, hips, and knees. Bone or joint pain can be severe and disabling and may be strikingly asymmetric. In some cases, imaging studies were done but failed to detect abnormalities.

Various electrolyte imbalances common in imatinib treatment

  1. Hypophophatemia: This is the most common electrolyte imbalance associated with imatinib. The clinical manifestations of mild hypophosphatemia include myalgias, weakness, anorexia. Chronic severe depletion may be manifested by pain in muscles and bones.

  2. Hypocalcemia: This is the second most common abnormality which was detected in patients onimatinib, hypocalcemia increases excitation of nerve and muscle cells, primarily affecting the neuromuscular and cardiovascular systems. Extensive spasm of skeletal muscle causes cramps and tetany.9

  3. Hypokalemia: Described only in case reports in patients who are on imatinib, this is also a possible cause of myalgia and muscle spasms but does not cause arthralgia /bony pains.

The treatment which has been advised by NCCN and other literature evidence states that calcium supplementation is an important treatment aspect in the management of musculoskeletal pain along with fluids supplementation.10, 11

Conclusion

Myalgia and musculoskeletal is the one of the common nonhematological side effect in patients of chronic myeloid leukemia who are initiated on imatinib. This side effect must be efficiently taken care of inorder to increase the compliance of patients for better outcome.

Conflict of Interest

None.

References

1 

H Joensuu C Fletcher S Dimitrijevic S Silberman P Roberts G Demetri Management of malignant gastrointestinal stromal tumoursLancet Oncol200231165564

2 

MW Deininger SG O’brien JM Ford BJ Druker Practical management of patients with chronic myeloid leukemia receiving imatinibJ Clin Oncol2003218163747

3 

SG O’brien F Guilhot RA Larson Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemiaNew Engl J Med2003348119941004

4 

JY Blay S Bonvalot P Casali Consensus meeting for the management of gastrointestinal stromal tumorsAnn Oncol200516456678

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GD Demetri MV Mehren CD Blanke Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumorsNew Engl J Med2002347747280

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J Verweij PG Casali J Zalcberg Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trialLancet2004364112734

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M Debiec-Rychter H Dumez I Judson B Wasag J Verweij M Brown Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma GroupEur J Cancer200440568995

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M Talpaz RT Silver BJ Druker JM Goldman C Gambacorti-Passerini F Guilhot Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 studyBlood2002996192837

9 

D Marin S Marktel M Bua L Armstrong JM Goldman JF Apperley The use of imatinib (STI571) in chronic myelod leukemia: some practical considerationsHaematologica200287997988

10 

M Cataldi A Gaudino V Lariccia M Russo S Amoroso G Renzo Imatinib-mesylate blocks recombinant T-type calcium channels expressed in human embryonic kidney-293 cells by a protein tyrosine kinaseindependent mechanismJ Pharmacol Exp Ther200430912081510.1124/jpet.103.061184

11 

JY Blay P Berthaud D Perol I Ray-Coquard B Bui FDAC Braud Continuous vs intermittent imatinib treatment in advanced GIST after one year: a prospective randomized trial of the French Sarcoma GroupProc Am Soc Clin Oncol200422149006



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Article History

Received : 28-06-2021

Accepted : 06-07-2021

Available online : 23-11-2021


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https://doi.org/10.18231/j.ijpo.2021.089


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