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  Table of Contents    
CASE REPORT  
Year : 2021  |  Volume : 64  |  Issue : 1  |  Page : 189-191
Isolated CNS relapse in FLT 3 mutation positive CMML post allogeneic stem cell transplant: Report of a rare case


1 Department of Pathology, AFMC, Pune, Maharashtra, India
2 Department of Hematology, Command Hospital, Central Command, Lucknow, Uttar Pradesh, India
3 Department of Hematology, Command Hospital, Southern Command, Pune, Maharashtra, India

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Date of Submission07-Apr-2020
Date of Decision13-Jun-2020
Date of Acceptance23-Jun-2020
Date of Web Publication8-Jan-2021
 

   Abstract 


Chronic myelomonocytic leukemia is a clonal chronic hematopoietic disorder that has been classified under the category of Myelodysplastic syndrome/Myeloproliferative neoplasms (MDS/MPN). CMML has high chances of transforming to acute leukemia, however isolated CNS relapse in CMML has never been reported in literature. We report an extremely rare case of a 47 yearold female diagnosed to have CMML- 2 in remission, who developed an isolated central nervous system relapse after matched related allogeneic hematopoietic stem cell transplantation. To our knowledge this is the first report of isolated CNS relapse in CMML post allogeneic stem cell transplant.

Keywords: Chronic myelomonocytic leukemia, isolated CNS relapse , post allogeneic stem cell transplant

How to cite this article:
Mutreja D, Verma S, Venkatesan S, Sharma S, Das S. Isolated CNS relapse in FLT 3 mutation positive CMML post allogeneic stem cell transplant: Report of a rare case. Indian J Pathol Microbiol 2021;64:189-91

How to cite this URL:
Mutreja D, Verma S, Venkatesan S, Sharma S, Das S. Isolated CNS relapse in FLT 3 mutation positive CMML post allogeneic stem cell transplant: Report of a rare case. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Jan 28];64:189-91. Available from: https://www.ijpmonline.org/text.asp?2021/64/1/189/306508





   Introduction Top


Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder. It has been classified under the category of Myelodysplastic syndrome/Myeloproliferative neoplasms (MDS/MPN) in 2016 by WHO due to overlapping features of both.[1],[2] It is characterized by persistent monocytosis, dysplasia in cell lines and blasts less than 20%.[3]

CMML has high chances of transforming to acute leukemia,[3] however isolated CNS relapse of leukemia in CMML has never been reported in literature. We report an extremely rare case of a 47?year-old female diagnosed to have CMML- 2 in remission, who developed an isolated central nervous system relapse after definitive therapy in form of matched related allogeneic hematopoietic stem cell transplantation.


   Case Presentation Top


A 47-year-old female, housewife by occupation, known to have sensorineural hearing loss for 8 years and diabetes mellitus for one year, presented with weight loss of 8-10 kgs, easy fatigability and loss of appetite of three months duration. On examination, she was febrile (T-100° F), with pallor and generalized lymphadenopathy involving cervical, axillary and inguinal regions. Abdominal examination showed enlarged liver 3 cm below costal margin. Imaging studies revealed FDG avid multiple cervical, axillary, internal mammary, mediastinal, hilar, retroperitoneal, abdominal and pelvic lymph nodes along with hepatomegaly, (liver span 21 cm) and mild splenomegaly (spleen 12 cms). She was evaluated and admitted with a clinical diagnosis of lymphoma.

Hemogram showed severe anemia (hemoglobin 5.4 g/dL) with total leucocyte count (TLC) of 23,000/uL with differential count of neutrophils 63%, lymphocytes 13% monocytes 10%, blasts 6%, myelocytes 2% and metamyelocytes 6% [Figure 1]a and [Figure 1]b. Bone marrow (BM) was hypercellular with myeloid preponderance and 7% blasts. Dyspeptic features were noted in all cell lines [Figure 1]c and [Figure 1]d. Lymph node biopsy showed effaced architecture with extramedullary hematopoiesis. There was no evidence of lymphoma infiltration, increase in blasts or immature cells [Figure 1]e and [Figure 1]f. Grade 1 reticulin fibrosis was present. Karyotyping study of 25 metaphases showed normal female karyotype. Flow cytometry immunophenotyping of bone marrow aspirate was not done. Serum LDH levels were persistently high (varying from 1000 to 1400 IU/L)). Molecular studies for BCR-ABL, JAK2, CALR and MPL mutations were negative.
Figure 1: (a) Blasts and Monocytes on PBS; (b) Occasional blasts showing Auer rods; (c and d) Bone marrow aspirate showing dyserythropoiesis and dysmegakaryopoiesis (MGG 1000×); (e) Hypercellular bone marrow biopsy with myeloid preponderance; (H and E 100×); (f) Extramedullary hematopoiesis in lymph node (H and E 400×)

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Patient was presumptively diagnosed to have myelodysplastic/myeloproliferative neoplasms – unclassifiable and managed with hydroxyurea. However, she continued to have raised TLC with persistent absolute and relative monocytosis during follow up. At three months of follow up, she was opined as a case of CMML-2 in view of persistent monocytosis and BM blasts of 12% with Auer rods. Next generation sequencing revealed FLT3 and N RAS gene mutations. CMML specific prognostic score incorporating molecular data was 4 (high risk). Patient was administered two cycles of Azacitidine, following which she achieved hematological remission (BM blasts -3%). Thereafter, she was taken up for definitive therapy in the form of matched allogeneic SCT with sibling (brother) as donor. Myeloablative Flu-Bu conditioning regime was followed with PBSC infusion (CD34 dose of 5.5 × 106/kg). Cyclosporin – Methotrexate was used for GVHD prophylaxis. Post-transplant course was uneventful with 99.6% donor chimerism at D + 30 and D + 90. Mild chronic graft versus host disease was found at D + 150 and was managed with oral steroids.

Six months post-transplant, the patient presented with acute onset quadriparesis and bulbar symptoms. Nerve conduction test and MRI brain and spine were normal studies. Cerebrospinal fluid (CSF) showed leukocytosis 630/μl with positivity for blasts [Figure 2]a and [Figure 2]b. Her blood counts were normal with no blasts in the peripheral blood or marrow. Flow cytometry of CSF sample confirmed CNS involvement by myelomonocytic leukemia (56% cells with low SSC and moderate CD45 positivity, co-expressing HLA-DR, CD38, CD64, CD117, CD33, CD13 and cyMPO) [Figure 2c-f]. CSF cultures were sterile.
Figure 2: (a and b) Serial CSF: Positive for blasts (c.f) Flow cytometry plots showing dual positive blasts for myelomonocytic markers

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The patient was managed with 8 bi-weekly injections of intrathecal triple therapy with cytosar, dexamethasone, methotrexate. Subsequent CSF studies showed reduction in total counts and blast percentage. She was given cranial radiotherapy, following which her CSF is normal. She is planned for donor lymphocyte infusion.


   Discussion Top


Our patient fulfilled all diagnostic criteria for CMML.[1],[3] She had persistent monocytosis in the peripheral blood. Mutation studies for BCR-ABL1, other myeloproliferative neoplasms were negative. Other hematological neoplasm that may have monocytosis were ruled out and blast count were consistently <20% in peripheral blood and BM smears for >3 months. Dysplasia in all hematopoietic cell lines was present. Based on the above findings and presence of auer rods in blasts, she was diagnosed to have CMML- 2 with high risk score of 4 as per CPSS-Mol risk group.

CNS involvement post-transplant is less commonly described in cases of acute myeloid leukemia (AML) and described only in few reports in chronic myeloid leukemia.[4],[5] Risk factors for CNS relapse in AML include prominent monocytic component, FLT3 mutation, high LDH, hyperleucocytosis, and CD56 expression among others.[1],[2],[3],[4],[5],[6],[7] Our patient fulfilled many of these risk factors. Extensive literature search revealed only a single case report in CMML with CNS disease at presentation,[7] and did not reveal any cases of CNS relapse in CMML.

Extramedullary hematopoiesis, also seen in this patient, although rare, has been reported in CMML in case reports earlier.[8],[9]

The occurrence and prognostic implications of FLT3 in CMML have not been studied much in literature.[10],[11] Akin to FLT 3 in AML, this mutation did impart a poorer prognosis in this case.

Management of CMML cases depends on whether the case is low risk or high risk. These cases are managed with hydroxyurea, hypomethylating agents, but the definitive therapy remains allogeneic stem cell transplant.[1],[2],[3],[4] To our knowledge this is the first case of isolated CNS relapse in CMML post allogeneic SCT.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2018 update on diagnosis, risk stratification and management. Am J Hematol 2018;93:824-40.  Back to cited text no. 1
    
2.
Padron E, Komrokji R, List AF. The clinical management of chronic myelomonocytic leukemia. Clin Adv Hematol Oncol 2014;12:172-8.  Back to cited text no. 2
    
3.
Valent P, Orazi A, Savona MR, Patnaik MM, Onida F, Van De Loosdrecht AA, et al. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica 2019;104:1935-49.  Back to cited text no. 3
    
4.
Alakel N, Stölzel F, Mohr B, Kramer M, Oelschlägel U, Röllig C, et al. Symptomatic central nervous system involvement in adult patients with acute myeloid leukemia. Cancer Manag Res 2017;9:97-102.  Back to cited text no. 4
    
5.
Fuchs M, Reinhöfer M, Ragoschke-Schumm A, Sayer HG, Böer K, Witte OW, et al. Isolated central nervous system relapse of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation. BMC Blood Disord 2012;12:2-5.  Back to cited text no. 5
    
6.
Xie N, Zhou J, Zhang Y, Yu F, Song Y. Extramedullary relapse of leukemia after allogeneic hematopoietic stem cell transplantation: A retrospective study. Medicine (Baltimore) 2019;98:e15584.  Back to cited text no. 6
    
7.
Hannon M, Wilde L, Nwaoduah N, Kasner M. Chronic myelomonocytic leukemia with central nervous system involvement. Leuk Lymphoma 2018;59:2267-8.  Back to cited text no. 7
    
8.
Bowen JM, Perry AM, Quist E, Akhtari M. Extramedullary hematopoiesis in a sentinel lymph node as an early sign of chronic myelomonocytic leukemia. Case Rep Pathol 2015;2015:594970.  Back to cited text no. 8
    
9.
Hunter AE, Russell NH, Ellis I. Extramedullary haemopoiesis as a cause of mediastinal lymphadenopathy in chronic myelomonocytic leukaemia. Clin Lab Haematol 1990;12:465-9.  Back to cited text no. 9
    
10.
Daver N, Strati P, Jabbour E, Kadia T, Luthra R, Wang S, et al. FLT3 mutations in myelodysplastic syndrome and chronic myelomonocytic leukemia. Am J Hematol 2013;88:56-9.  Back to cited text no. 10
    
11.
Lin P, Jones D, Medeiros LJ, Chen W, Vega-Vazquez F, Luthra R. Activating FLT3 mutations are detectable in chronic and blast phase of chronic myeloproliferative disorders other than chronic myeloid leukemia. Am J Clin Pathol 2006;126:530-3.  Back to cited text no. 11
    

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Correspondence Address:
Deepti Mutreja
Department of Pathology, Armed Forces Medical College, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_344_20

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