From remission to a new battle: Therapy-related juvenile myelomonocytic leukemia after B-cell acute lymphoblastic leukemia

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer, accounting for approximately 25% of all childhood malignancies.^[1-3] Children diagnosed with ALL typically present with symptoms related to bone marrow failure, including anemia, thrombocytopenia, and leukopenia.^[3] Treatment for B-ALL involves intensive chemotherapy, with a maintenance phase to consolidate remission.^[1] Although remission rates are high, complications such as therapy-related secondary malignancies, including juvenile myelomonocytic leukemia (JMML), can occur. JMML is a rare, aggressive myeloproliferative disorder characterized by monocytosis, splenomegaly, and myeloid blasts, often associated with mutations in the RAS signaling pathway.^[1,4] This report presents a rare case of therapy-related JMML occurring after treatment for B-cell ALL.

CASE REPORT

A 3-year-old female was diagnosed with standard-risk pre-B-cell ALL in January 2020. She was treated according to the UK ALL 2019 protocol^[5] and completed chemotherapy in August 2022.

This protocol includes, induction phase: Combination of vincristine, dexamethasone, polyethylene glycol (PEG)-asparaginase, and intrathecal methotrexate.

Consolidation phase: High-dose methotrexate with leucovorin rescue, cytarabine, and continued asparaginase.

Interim maintenance and delayed intensification: Alternating regimens to eradicate minimal residual disease (MRD), including cyclophosphamide, cytarabine, 6-mercaptopurine (6-MP), and vincristine.

Maintenance therapy: Daily oral 6-MP, weekly methotrexate, and monthly vincristine with dexamethasone pulses for approximately 2 years.

Initial cytogenetics revealed hyperdiploidy (gains of chromosomes 4, 9, 10, 17, 21, and 22). During treatment, complications included a single intensive care unit admission for pneumonia and prolonged cytopenias, likely related to 6-MP therapy.

Despite achieving negative MRD status, the patient experienced recurrent pneumonia episodes 4- and 6-month post-treatment, requiring IV antibiotics and oxygen therapy. Ten months after completing treatment, she developed splenomegaly without fever or other significant symptoms. Virological investigations (Ebstein Barr Virus [EBV], Parvovirus, Cytomegalovirus [CMV]) were negative, and ferritin levels were elevated (420 ng/mL), suggesting ongoing inflammation. Complete blood count revealed bicytopenia (hemoglobin: 7.3 g/dL, platelets: 25,000/µL) and white blood cell (WBC) count of 9,250/µL with notable monocytosis (15%). Peripheral blood smear showed left-shifted myeloid maturation and blasts. Flow-cytometric examination was asked on peripheral blood for B-cell MRD ruled out abnormal B-lymphoblasts but identified 0.9% abnormal myeloid blasts with aberrant expression of CD10 [Figure 1].

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Figure 1:

(a) Flowcytometric Immunophenotypic analysis (B-Acute lymphoblastic leukemia minimal residual disease [MRD]) on peripheral blood revealed no abnormal lymphoblasts, however, revealed abnormal myeloid blasts (Red colour) with moderate CD34, heterogeneous CD10 but negative for CD38. (b) Flowcytometric immunophenotypic analysis (acute myeloid leukemia MRD) was performed on peripheral blood, confirms abnormal myeloid blasts (Red colour) with moderate CD34, moderate CD33, heterogeneous CD117, Human leucocyte antigen-DR (HLADR), dim to negative CD13, and negative for CD38.

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Given persistent splenomegaly and peripheral monocytosis with abnormal myeloid blasts, bone marrow aspiration was performed. The marrow was normocellular with 2% blasts/hematogones. High-sensitivity flow cytometry for B-ALL MRD revealed no residual disease but detected abnormal myeloid blasts with an early stem cell phenotype with dim to negative CD10 expression similar as that of peripheral blood blasts. A high-sensitivity MRD assay for acute myeloid leukemia (AML) was conducted due to the presence of abnormal myeloid blasts in the B-MRD assay, revealing 6.4% abnormal myeloid blasts expressing moderate CD34, moderate CD33, heterogeneous CD117, heterogeneous CD36, heterogeneous Human leucocyte antigen-DR (HLADR), dim CD45, dim to negative CD10, dim to negative CD13, and negative for CD14, CD38, and CD64. Cytogenetic analysis revealed monosomy 7 (7q22.1q36.3) by fluorescent in situ hybridization, a known abnormality in myeloid neoplasms.

Next-generation sequencing (NGS) identified heterozygous mutations in SETBP1, sons of sevenless homolog1 (SOS1), and mutations in NF1, SH2B3, and IKZF1, which are associated with RAS pathway activation and therapy-related myeloid neoplasms. The SOS1 mutation suggested a potential connection to Noonan syndrome, although the patient did not meet full clinical criteria.

The patient was diagnosed with therapy-related JMML, characterized by peripheral monocytosis, splenomegaly, peripheral blasts <2%, and a molecular signature involving RAS pathway mutations. The NF1 mutation suggested a genetic predisposition to myeloproliferative disease.

DISCUSSION

JMML is an aggressive myeloproliferative disorder primarily affecting young children. It is characterized by monocytosis, splenomegaly, and a heterogeneous population of myelomonocytic cells. The disease is closely associated with genetic alterations in the RAS signaling pathway, with mutations in protein tyrosine phosphastase, nonreceptor type 11 (PTPN11), neuroblastoma RAS viral oncogene homolog (NRAS), kirstein rat sarcomA viral oncogene homolog (KRAS), NF1, and casitas b -lineage lymphoma (CBL) being commonly observed. The risk of developing secondary malignancies such as JMML is particularly high in patients treated with alkylating agents and topoisomerase inhibitors.

Therapy-related JMML is an exceedingly rare but serious complication, especially following treatment for ALL. While there are limited global statistics due to its rarity, studies have documented isolated cases of secondary JMML post-ALL therapy. A review by Inaba et al.^[6] suggests that therapy-related myeloid neoplasms (t-MNs) occur in approximately 1–2% of pediatric ALL survivors, though most are AML or MDS, not JMML. A retrospective study from a tertiary care center in India reported an incidence of t-AML/MDS among pediatric leukemia/lymphoma patients of 0.45% and not JMML, highlighting its exceptional rarity.^[7] A case series and literature review identified only a few cases, emphasizing its rarity and the need for further research.^[8]

Risk factors implicated in secondary JMML include cytotoxic chemotherapy agents: especially alkylating agents (cyclophosphamide and busulfan) and topoisomerase II inhibitors (etoposide).^[9,10] Genetic susceptibility: Germ line or somatic mutations in NF1, PTPN11, or CBL – often affecting the RAS-MAPK pathway.^[11,12] Monosomy 7 and chromosomal aberrations found in approximately 25–30% of JMML cases and are associated with poorer outcomes.^[13,14]

In this patient, NGS revealed NF1, SH2B3, SETBP1, and IKZF1 mutations, confirming the diagnosis of therapy-related JMML, likely triggered by chemotherapy for B-ALL. The presence of monosomy 7 and RAS pathway mutations suggested a high-risk JMML, with poor prognosis despite HSCT.^[15,16]

Although the development of therapy-related JMML cannot be fully predicted, following strategies in ALL treatment protocols may mitigate the risk:

• Risk-adapted therapy: Avoid overtreatment in standard-risk patients to limit exposure to genotoxic agents.

• Pharmacogenomic screening: Germ line mutation screening for genes associated with JMML (PTPN11, NF1, CBL, KRAS, and NRAS) in patients with a suggestive family history or dysmorphic features. Identification of patients with the above germ line mutations could guide the use of less leukemogenic agents.

• Monitoring of prolonged cytopenias: Close observation of patients with delayed marrow recovery and in patients with known predispositions to RASopathies or chromosomal abnormalities (e.g., Noonan syndrome) can help detect early signs of evolving myeloid neoplasia.

• Avoidance of high-risk drug combinations: Minimizing cumulative doses of alkylating agents and topoisomerase inhibitors, especially in patients with known predisposition.

• Post-treatment surveillance: Regular follow-up with complete blood counts and clinical examinations can facilitate early identification of secondary neoplasms. Proper and meticulous screening of myeloid blasts during routine B ALL MRD assessment for any asynchronous myeloid blast maturation or any abnormal antigen expression.

CONCLUSION

This case report underscores the rare occurrence of therapy-related JMML following treatment for B-cell ALL. The presence of monocytosis, monosomy 7, and RAS pathway mutations led to the diagnosis of secondary JMML. Despite intensive chemotherapy and HSCT, the prognosis remained poor due to rapid disease relapse and multi-organ involvement. JMML should be considered in the differential diagnosis of children with a history of ALL who develop unexplained monocytosis and splenomegaly after completing therapy.