Juvenile Myelomonocytic Leukemia – Experience from a Tertiary Care Hospital in Eastern India

  1. Kaustav Ghosh ,
  2. Subham Bhattacharya ,
  3. Shipla Roy ,
  4. Prakas Kumar Mandal ,
  5. Abhishek Sharma ,
  6. Shuvraneel Baul ,
  7. Sandeep Saha ,
  8. Rajib De ,
  9. Tuphan Kanti Dolai

Vol 9 No 1 (2024)

DOI 10.31557/apjcc.2024.9.1.161-164

Abstract

Background: Juvenile myelomonocytic leukemia (JMML), previously known as juvenile chronic myeloid leukaemia, is a rare, unique, and aggressive myeloproliferative neoplasm of early childhood. Making a diagnosis of JMML is challenging because of the overlapping clinical and haematological features with other myeloproliferative neoplasms (MPN). However, some unique features like monocytosis, the absence of BCR-ABL translocation, and the presence of specific mutations (PTPN-11, K-RAS, N-RAS, CBL, or NF1) clinch the correct diagnosis.
Methods: A prospective analysis of six JMML patients with variable clinical features treated with injection azacytidine as frontline therapy during the study period of 2 years.
Results: The median age was 4.5 years with male:female ratio 2:4. Pallor and splenomegaly were the most common presenting signs. Four patients (66.67%) achieved complete remission (CR), two patients (33.33%) had partial remission (PR), and one patient (16.67%) had progressive disease (PD). The overall survival rate was 66.67% (four out of six), and the mortality rate was 33.33%.
Conclusion: Azacitidine is an effective treatment option as upfront therapy for JMML, especially in resource poor developing countries.

Introduction

JMML is a rare haematological neoplasm accounting for 2–3% of all childhood malignancies and characterised by excessive proliferation of myeloid and monocytic lineages [1]. Males are more affected than females, and the median age of presentation is 2 years, with >90% having mutations in the RAS signalling pathway [2]. Close differentials include other MPNs, herpes virus infection, leukocyte adhesion defects, hemophagocytic lymphohistiocytosis, infantile malignant osteopetrosis, and wiskott-aldrich syndrome [3]. Diagnosis is made by WHO criteria fulfilling all the four major clinical/ haematological criteria (peripheral blood monocyte count ≥1x109/L, blast percentage in peripheral blood and bone marrow <20%, splenomegaly, and absence of philadelphia chromosome (BCR/ABL rearrangement), with either one genetic finding (somatic mutation in PTPN11 or K-RAS or N-RAS or RRAS, germline NF1 mutation and loss of heterozygosity of NF1 or clinical diagnosis of neurofibromatosis type 1, germline CBL mutation and loss of heterozygosity of CBL) [4].

Materials and Methods

This was a prospective analysis of six cases diagnosed as JMML as per the WHO criteria [4], over a study period of two years from March 2021 to February 2023 in the Department of Haematology at Nil Ratan Sircar Medical College and Hospital, Kolkata, India.

In all the cases, morphological evaluation in peripheral blood smears and bone marrow aspiration with biopsy smears was done. Reverse transcriptase Polymerase chain reaction (RT-PCR) for BCR-ABL qualitative assay from peripheral blood proved negative in all the cases, and conventional cytogenetics was done from bone marrow sample. Next-generation sequencing (NGS) was done from peripheral blood only in selected cases due to financial reasons.

All diagnosed JMML patients were included in the study, and those who proceeded with hematopoietic stem cell transplant (HSCT) were excluded from the study. All patients received injection azacytidine @ 75mg/m2/day intravenously daily for seven days per month as frontline therapy [5]. The Centre for International Blood and Marrow Transplant Research (CIBMTR) guidelines were followed for the determination of JMML response criteria [6].

Results

A total of eight JMML cases were screened during the study period, out of which two proceeded with HSCT and were excluded from the study. Hence, a total of six patients were included in the present study.

All six patients characteristics are summarised in Table 1.

Table 1. JMML Patient Characteristics (n=6).

  Case 1 Case 2 Case 3 Case 4 Case 5 Case 6
Age (years)/Sex 5/ Female 8/Female 6/ Male 5/Female 1/Female 4/Male
Presentation Fever, Pallor, Orbital mas Pallor, Epistaxis Pallor, abdominal fullness Fever, Pallor Pallor, Multiple petechiael spots Fever, Pallor
Clinical findings Spleen 4cm Cervical LAP Liver 2cm Spleen 6cm Liver 10cm Spleen 14 cm Cervical and axillary LAP Spleen 2cm Liver 2cm Spleen 2cm Cervical LAP Spleen 4cm
TLC (x 109/l) 78.72 54.56 39.92 124.56 61.24 28.77
Absolute monocyte count ((x 109/l) 16.45 9.92 6.32 24.47 12.34 4.56
Myeloid/eyrthroid precursors in PB Yes Yes Yes Yes Yes Yes
Hb (g/dl) 5 7.8 4 7.5 5.8 9.2
Platelet (x 109/l) 12 38 5 9 45 39
Blasts % (PB/BM) 05-Feb 04-Jan 08-Feb 10-Mar 05-Mar 03-Feb
Dysplastic lineage Dysgranulopoeisis Dysmegakaryopoeisis Dysgranulopoeisis Dysgranulopoeisis Dysgranulopoeisis Dysmegakaryopoeisis Dysgranulopoeisis Dysgranulopoeisis
Cytogenetics Trisomy 8 Normal Trisomy 8 Monosomy 7 Trisomy 8 Normal
Molecular profile NRAS+ NRAS+ NA NA NA CBL+
Chemotherapy cycle 1st cycle azacitidine 2nd cycle vincristine+ cytarabine + etoposide 2nd cycle azacitidine 2 cycles azacitidine 1st cycle azacitidine 13 cycles azacitidine/ 13 months 5 cycles azacitidine/ 5 months
Outcome / Follow up Dead Alive/ 2 months Lost to follow up/ 3 months Dead Alive Alive
Response PD PR CR PR CR CR

The median age was 4.5 years, and the male: female ratio was 2:4.

Fever (50%) and pallor (100%) were the most common presenting complaints, and one patient presented with right eye proptosis (16.67%) (Figure 1).

Figure 1. Clinical and Haematological Features in JMML Patients. 1. A) Case 1 presening as right eye proptosis. 1. B) Peripheral smear from Case 3 patient showing myeloid precursors (PM-Promyelocytes, MY-Myelocytes) along with dysmyelopoeisis in the from of dysplastic neutrophil (DN) and monocytosis (M).

Splenomegaly (100%) was the most common sign, which was present in all the patients. Hepatomegaly and lymphadenopathy (LAP) were present in three out of six patients (50%).

The median total leukocyte count (TLC) was 57.9 x 109/l (range 28.77–95.79), and the median absolute monocyte count was 11.13 x 109/l (range 4.56–24.47). Anaemia (100%) and thrombocytopenia (100%) were present in all the cases. Dysgranulopoeisis (100%) in bone marrow examination was evident in all six patients, and dysmegakryopoeisis was present in two out of six patients (33.34%).

In the cytogenetic studies, two patients had trisomy 8 (33.33%), and one patient had monosomy 7 (16.67%). NGS could be done on three patients, out of whom two (33.33%) had mutations in the NRAS gene and one (16.67%) had mutation in the CBL gene.

Azacitidine was given to all the patients. Case 1 was unresponsive to azacitidine; hence, a salvage chemotherapy cycle was given with vincristine, cytarabine, and etoposide, during which the patient succumbed to death. Four patients (66.67%) achieved complete remission (CR), two patients (33.33%) had partial remission (PR), and one patient (16.67%) had progressive disease (PD). The overall survival rate was 66.67% (four out of six), and the mortality rate was 33.33%. The mean duration of follow-up was 2.5 months (range 1–13). One patient lost follow-up after three cycles, and three alive patients are currently on their second, fifth, and 13th cycles, respectively.

Discussion

JMML is a lethal clonal myeloproliferative disorder characterised by the uncontrolled proliferation of myeloid and monocytic cell lineages due to mutations in the RAS signalling pathways. The median age in our study was 4.5 years (range 1–9 years) with female predominance, which was comparable to the study done by Saha et al [7], where the median age was 5 years with the majority being female. However, study done by Subramanian et al [8] showed male predominance in their JMML case series. Common clinical findings include symptoms and signs of anaemia, thrombocytopenia, and hepatosplenomegaly, as seen in our study, which was comparable to the studies done by Ghariani et al [9]. Ocular involvement as seen in case 1, is a rare finding in JMML, and only a few cases have been described in the literature regarding the same [10,11].

Although the median TLC count reported in a large cohort of patients was 33x1x109/L (range 5-259x109/L) [12], we found both TLC and absolute monocyte count on the higher side. Peripheral smear and bone marrow examination showed monocytosis, left shift, along with dysmyelopoeisis and dysmegakaryopoeisis, which was consistent with the literature [13]. Trisomy 8 was the most common cytogenetic abnormality seen in our study, which was comparable to the triology case series done by Azma et al [14]. Genetic study is of utmost importance in JMML, as wait and watch is the policy in the case of mutations in the CBL gene and a few cases of NRAS gene mutations. Although PTPN11 is the most common mutation seen in JMML (35% cases) [2], in the present study, out of four patients in whom genetic testing was successful, there were 50% cases with the NRAS mutation.

We used azacitidine (a DNAmethyltransferase-inhibiting azanucleoside assumed to reverse epigenetic dysregulation in malignant cells) as a frontline therapy in all the cases. Although the overall survival rate in JMML is poor, with 5-year survival rates being 50% even after allogenic HSCT [2], our results using azacitidine as a frontline therapy are promising, with an overall survival rate of 66.66%. Complete remission (CR) was observed in 50% of the cases, which was similar to the study done by Stenger et al [5] in which CR was observed in nine out of 18 patients (50%).

In conclusion, JMML is a rare, unique, and aggressive disease with clinical and hematological overlap with other myeloproliferative neoplasms. An accurate diagnosis is important for early treatment initiation. Azacitidine is an effective treatment option, especially in resource poor developing countries.

Declaration of patient consent

-The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References


  1. Introduction to a review series: the 2016 revision of the WHO classification of tumors of hematopoietic and lymphoid tissues Cazzola M. Blood.2016;127(20). CrossRef
  2. How I treat juvenile myelomonocytic leukemia Locatelli F, Niemeyer CM . Blood.2015;125(7). CrossRef
  3. Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia Yoshimi A, Kamachi Y, Imai K, Watanabe N, Nakadate H, Kanazawa T, Ozono S, et al . Pediatric Blood & Cancer.2013;60(5). CrossRef
  4. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data Arber DA , Orazi A, Hasserjian RP , Borowitz MJ , Calvo KR , Kvasnicka H, Wang SA , et al . Blood.2022;140(11). CrossRef
  5. Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial Niemeyer CM , Flotho C, Lipka DB , Starý J, Rössig Cl, Baruchel A, Klingebiel T, et al . Blood Advances.2021;5(14). CrossRef
  6. Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia Niemeyer CM , Loh ML , Cseh A, Cooper T, Dvorak CC , Chan R, Xicoy B, et al . Haematologica.2015;100(1). CrossRef
  7. A case series of clinical and hematological profile of juvenile myelomonocytic leukemia Saha A, Rai V, Kakoty S, Sawhney J, Kourav TPS . Pediatric Hematology Oncology Journal.2022;7(4). CrossRef
  8. Juvenile myelomonocytic leukemia: A case series of a rare hematological disease Subramanian KS , Jinkala SR , Kar R, Basu D, Dubashi B. Indian Journal of Cancer.2020;57(1). CrossRef
  9. Leucémie myélomonocytaire juvénile : à propos de trois cas Ghariani I, Jmili-Braham N, Haifa R, Achour B, Youssef Y, Sendi H, Bakir L, Kortas M. Archives de Pédiatrie.2016;23. CrossRef
  10. Juvenile myelomonocytic leukaemia case study Jeong Min H. Australian Journal of Medical Science.2023;44(1):27-31.
  11. Juvenile myelomonocytic leukemia: a surprising cause of peri-orbital tumor and squint Lee AC , Leo SW . Annals of Hematology.2019;98(5). CrossRef
  12. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Niemeyer CM , Arico M, Basso G, Biondi A, Cantu Rajnoldi A, Creutzig U, Haas O, et al . Blood.1997;89(10).
  13. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia Loh ML , Sakai DS , Flotho C, Kang M, Fliegauf M, Archambeault S, Mullighan CG , et al . Blood.2009;114(9). CrossRef
  14. Juvenile myelomonocytic leukaemia: a case series Azma RZ , Zarina AL , Hamidah A, Jamal R, Sharifah NA , Ainoon O, Hamidah NH . The Malaysian Journal of Pathology.2009;31(2).

Copyright

© Asian Pacific Journal of Cancer Care , 2024

Author Details

Kaustav Ghosh
Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

Subham Bhattacharya
Nilratan sircar medical college and hospital, Kolkata, West Bengal, India.
drsubham@rediffmail.com

Shipla Roy
<p>&nbsp;</p> <p>&nbsp;</p>
Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

Prakas Kumar Mandal
Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

Abhishek Sharma
Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

Shuvraneel Baul
<p>engal</p>
Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

Sandeep Saha
Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

Rajib De
Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

Tuphan Kanti Dolai
Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

How to Cite

Ghosh, K., Bhattacharya, S., Roy, S., Mandal, P., Sharma, A., Baul, S., Saha, S., De, R., & Dolai, T. (2024). Juvenile Myelomonocytic Leukemia – Experience from a Tertiary Care Hospital in Eastern India. Asian Pacific Journal of Cancer Care, 9(1), 161-164. https://doi.org/10.31557/apjcc.2024.9.1.161-164
  • Abstract viewed - 321 times
  • PDF (FULL TEXT) downloaded - 70 times
  • XML downloaded - 0 times