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  Table of Contents    
LETTER TO EDITOR  
Year : 2016  |  Volume : 59  |  Issue : 2  |  Page : 259-260
Biphenotypic extramedullary blast crisis with MLL gene rearrangement in a case of chronic myeloid leukemia following Dasatinib therapy: An unusual case


Department of Hematology, B L Kapur Super Speciality Hospital, New Delhi, India

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Date of Web Publication9-May-2016
 

How to cite this article:
Juneja R, Dhamija G, Dadu T, Handoo A. Biphenotypic extramedullary blast crisis with MLL gene rearrangement in a case of chronic myeloid leukemia following Dasatinib therapy: An unusual case. Indian J Pathol Microbiol 2016;59:259-60

How to cite this URL:
Juneja R, Dhamija G, Dadu T, Handoo A. Biphenotypic extramedullary blast crisis with MLL gene rearrangement in a case of chronic myeloid leukemia following Dasatinib therapy: An unusual case. Indian J Pathol Microbiol [serial online] 2016 [cited 2019 Dec 12];59:259-60. Available from: http://www.ijpmonline.org/text.asp?2016/59/2/259/182031


Editor,

Chronic myeloid leukemia (CML) is the most common myeloproliferative neoplasm. It originates from abnormal pluripotent stem cell, and its hallmark is Philadelphia (Ph) chromosome or BCR-ABL fusion gene.[1] Though the majority of the cases present in the chronic phase of the disease, 5–10% of the cases present in accelerated phase or blast crisis at diagnosis. Bone marrow, peripheral blood, liver, and spleen are common sites of involvement by this leukemia in the chronic phase; however, during blast crisis, blast can infiltrate skin, lymph node, soft tissue, and central nervous system (CNS). Although CML is very responsive to the tyrosine kinase inhibitors (TKI), with response rates in the chronic phase of >90%, response rates for patients with CML in accelerated phase and blast crisis are lower. Imatinib was a boon for CML patients; however, due to poor blood-brain barrier (BBB) permeability, it could not reduce the risk of CNS relapse.

Second generation TKI such as Dasatinib has better CNS penetration. This report presents a case of CML in myeloid blast crisis, which attained complete molecular response (CMR) with Dasatinib therapy, and later developed isolated CNS relapse with biphenotypic blast and MLL gene rearrangement.

A 68-year-old diabetic male patient presented with fever and weakness. On examination, splenomegaly was noted. Hemogram revealed Hb 9.4 g/dl, platelet count 58 × 109/l, and leukocyte count 119 × 109/l. Peripheral smear showed 25% blast with basophilia, eosinophilia, and shift to left in granulocytic cells. Bone marrow examination showed 54% blast cells and few myeloid precursors along with eosinophilic prominence [Figure 1]a. Flow cytometric immunophenotype of bone marrow revealed ~41% myeloid blast expressing CD34, CD38, human leukocyte antigen (HLA)-DR, CD117, CD13, CD 33, cMPO, and aberrant CD19. Blasts were negative for CD 79a. Karyotyping of bone marrow revealed 46 XY, t(9;22)(q34;q11.2) in all 20 metaphase analyzed [Figure 1]b. Qualitative polymerase chain reaction (PCR) was positive for BCR-ABL major type (p210). Hence, patient was diagnosed as a case of CML in myeloid blast crisis. The patient received induction regime followed by consolidation therapy. Dasatinib was also added. He achieved CMR in 4 months as confirmed by quantitative RT-PCR and was maintained on Dasatinib therapy. Considering the age of the patient, transplant was not an option. The patient was on regular follow-up and was asymptomatic for 19 months.
Figure 1: (a) Giemsa stained bone marrow aspirate smear (at presentation) showing blast crisis in chronic myeloid leukemia (×400). (b) Conventional karyotyping done with Giemsa banding technique (at presentation) revealed Philadelphia chromosome. 46 XY, t(9;22)(q34;q11.2)

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In December 2014, the patient presented with headache, vertigo, and vomiting. Hemogram was within normal limits; bone marrow was morphologically in remission and was negative for minimal residual disease. Lumbar puncture was done, and cerebrospinal fluid (CSF) showed leukocyte count of 0.625 × 109/l with 95% blasts [Figure 2]a. Flow cytometric immunophenotyping of CSF revealed blasts expressing CD34, CD38, HLA-DR, CD13, CD 33, CD117, cMPO, CD19, and cCD79a. Repeat Karyotyping at this time showed 46 XY t(6;11)(q27;q23) in 8 of 20 metaphase analyzed, [Figure 2]b suggesting MLL gene rearrangement, as secondary cytogenetic abnormality. Hence, he was diagnosed to have isolated CNS relapse with biphenotypic blasts. The patient was then treated with intrathecal methotrexate, cytosine arabinoside, and hydrocortisone and radiation therapy. The patient has been asymptomatic for the past 4 months.
Figure 2: (a) Giemsa stained cerebrospinal fluid cytospin smear (At relapse) showing 95% blast (×200) (b) Conventional karyotyping done with Giemsa banding technique (at relapse) revealed MLL gene rearrangement. 46 XY, t(6;11)(q27;q23)

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Extramedullary blast crisis commonly present in the lymph node, skin, spleen, and bone. CNS involvement is rare and when seen is more common with CML in lymphoid/biphenotypic blast crisis at presentation than with myeloid blast crisis.[2] Against this, our case, which was CML in blast crisis with myeloid phenotype at diagnosis, still relapsed in CNS with biphenotypic blasts. To our knowledge, this is the 2nd case of isolated CNS relapse with biphenotypic blast after Dasatinib therapy.[3]

Additional cytogenetic abnormalities such as extra Ph chromosome, trisomy 8, and i(17q) are usually noted with the progression of the disease.[1] Our patient presented with CML in myeloid blast crisis with t(9; 22)(q34;q11.2) and no additional cytogenetic abnormality. At the time of relapse, Karyotype revealed cytogenetic evolution to MLL gene rearrangement in the form of t(6;11)(q27;q23). To the best of our knowledge, this is first case report with MLL gene rearrangement at isolated CNS relapse in follow-up case of CML.

Imatinib has poor BBB permeability and leaves CNS as susceptible site for relapse.[4],[5] Second generation TKI (Dasatinib) has good BBB permeability and attains better therapeutic levels in CSF. Our patient received Dasatinib after initial therapy for blast crisis, however, he relapsed. There are only rare case reports where patient developed isolated CNS relapse after Dasatinib therapy. These can be explained by the development of Dasatinib resistant clone or cytogenetic evolution to t(6;11).

This case points toward the possibility of isolated CNS relapse in CML despite Dasatinib therapy and the need for defining risk factors for isolated CNS relapse in CML and guidelines to monitor such patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Swerdlow SH, Elias CE, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.  Back to cited text no. 1
    
2.
Leis JF, Stepan DE, Curtin PT, Ford JM, Peng B, Schubach S, et al. Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma 2004;45:695-8.  Back to cited text no. 2
    
3.
Matsuda M, Morita Y, Shimada T, Miyatake J, Hirase C, Tanaka M, et al. Extramedullary blast crisis derived from 2 different clones in the central nervous system and neck during complete cytogenetic remission of chronic myelogenous leukemia treated with imatinib mesylate. Int J Hematol 2005;81:307-9.  Back to cited text no. 3
    
4.
Petzer AL, Gunsilius E, Hayes M, Stockhammer G, Duba HC, Schneller F, et al. Low concentrations of STI571 in the cerebrospinal fluid: A case report. Br J Haematol 2002;117:623-5.  Back to cited text no. 4
    
5.
Aftimos P, Nasr F. Isolated CNS lymphoid blast crisis in a patient with imatinib-resistant chronic myelogenous leukemia: Case report and review of the literature. Leuk Res 2009;33:e178-80.  Back to cited text no. 5
    

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Correspondence Address:
Richa Juneja
1/45 1st Floor, Old Rajinder Nagar, New Delhi - 110 060
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.182031

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