Users Online: 606
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
BRAINTEASER
Year : 2014  |  Volume : 3  |  Issue : 1  |  Page : 92

Chronic myeloid leukemia: When the going gets tough


1 Department of Hematology, Kingston Hospital NHS Foundation Trust, United Kingdom
2 Department of Histopathology, Kingston Hospital NHS Foundation Trust, United Kingdom

Date of Web Publication5-Feb-2014

Correspondence Address:
Lucy A Pickard
Department of Hematology, Kingston Hospital NHS Foundation Trust
United Kingdom
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-330X.126574

Rights and Permissions

How to cite this article:
Pickard LA, Knee G, Jayakar V. Chronic myeloid leukemia: When the going gets tough. South Asian J Cancer 2014;3:92

How to cite this URL:
Pickard LA, Knee G, Jayakar V. Chronic myeloid leukemia: When the going gets tough. South Asian J Cancer [serial online] 2014 [cited 2019 Aug 18];3:92. Available from: http://journal.sajc.org/text.asp?2014/3/1/92/126574

A 57-year-old man previously fit and well, presented to the Hematology Department with a 3-month history of night sweats and a 2-week history of bruising. Examination revealed no palpable lymphadenopathy; his spleen was palpable 2 cm below the costal margin. Full blood count showed hemoglobin of 89 g/L, platelet count of 116 × 10 9 /L and white cell count of 187 × 10 9 /L differential; neutrophils 168 × 10 9 /L, lymphocytes 3.7 × 10 9 /L, basophils 3.7 × 10 9 /L, monocytes 7.4 × 10 9 /L and eosinophils 3.7 × 10 9 /L. The bone marrow aspirate and trephine was markedly hyper cellular with marked myeloid hyperplasia and a blast count of 3%. Cytogenetics showed the patient had the BCR-ABL mutation with a p210 break point.

The patient was diagnosed with chronic phase chronic myeloid leukemia (CML). The Sokal score was 0.73 (low risk) and the patient was commenced on hydroxycarbamide initially and then on imatinib 400 mg once daily after the BCR-ABL results. Hematological remission was achieved after 4 weeks.

The patient was given 4 weekly follow-up appointments, but failed to attend his next appointment due to relocation to a different county. The patient presented 6 weeks later with extreme lethargy and abdominal pain. Clinical examination revealed cervical lymphadenopathy and marked splenomegaly (palpable 8 cm below costal margin). Blood film and repeat bone marrow aspirate confirmed blast crisis with transformation to B-acute lymphocytic leukemia [Figure 1]. Cytogenetic analysis confirmed the presence of the T315I mutation. The patient was commenced on hydroxycarbamide and transferred to a specialist center for further treatment.
Figure 1: Bone marrow aspirate showing plentiful lymphoid blasts (black arrow) on a background of myeloid hyperplasia with eosinophilia (green arrow)

Click here to view



  Question Top


Which of the following is the most appropriate management strategy for the patient at this stage?

  1. Increase dose of imatinib
  2. Start chemotherapy (fludarabine, cytarabine, granulocyte colony-stimulating factor idarubicin [FLAG IDA]) and consider for stem cell transplant
  3. Start chemotherapy (FLAG IDA) only
  4. Start ponatinib only
  5. Start dasatinib and chemotherapy (FLAG IDA)



  Answer Top


B: Start chemotherapy (FLAG IDA) and consider for stem cell transplant.

The T315I mutation occurs in approximately 15% of imatinib-resistant patients and may be more frequently detected in patients with advanced CML and Philadelphia chromosome positive acute lymphoblastic leukemia. [1] The T315I mutation results in a threonine to isoleucine change at amino acid position 315 in the deoxyribonucleic acid coding sequence for an adenosine triphosphate (ATP) binding pocket of the BCR-ABL gene. [2] This changes the structure of the ATP pocket, eliminating a crucial hydrogen bond required for high affinity binding with first and second line tyrosine kinase inhibitors (imatinib, nilotinib and dasatanib). Ponatinib is a potent BCR-ABL inhibitor with activity against the T315I mutation. [3]

Though we used ponatinib for this patient, please note that on October 31, 2013, the Food and Drug Administration (FDA) asked the manufacturer of the leukemia chemotherapy drug ponatinib hydrochloride to suspend marketing and sales of this drug because of the risk of life-threatening blood clots and severe narrowing of blood vessels. Our patient was treated with the drug 7 weeks before this FDA alert. We discontinued the drug after this alert. Our patient did not have any adverse toxicity secondary to ponatinib.

Currently, one would use FLAG IDA and gear toward an allogenic stem cell transplant (Option B).

Treatment for this patient should involve reduction of the clone of leukemia with chemotherapy. The patient is young and should be considered for allogenic bone marrow transplantation. It is the only established curative modality and remains the ultimate salvage therapy for patients with imatinib-resistant CML.

 
  References Top

1.Hiwase DK, Yeung DT, White DL. Optimizing the selection of kinase inhibitors for chronic myeloid leukemia patients. Expert Rev Hematol 2011;4:285-99.  Back to cited text no. 1
[PUBMED]    
2.Soverini S, Iacobucci I, Baccarani M, Martinelli G. Targeted therapy and the T315I mutation in Philadelphia-positive leukemias. Haematologica 2007;92:437-9.  Back to cited text no. 2
[PUBMED]    
3.Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012;367:2075-88.  Back to cited text no. 3
[PUBMED]    


    Figures

  [Figure 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Question
Question
Answer
References
Article Figures

 Article Access Statistics
    Viewed1057    
    Printed23    
    Emailed0    
    PDF Downloaded193    
    Comments [Add]    

Recommend this journal