Favorable outcome in TCF3::HLF-positive pediatric B-cell acute lymphoblastic leukemia without classic metabolic complications: A case report

Abstract

The t(17;19)(q22;p13) translocation, generating the TCF3::HLF fusion oncogene, occurs in < 1% of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and is associated with extreme chemotherapy resistance, frequent metabolic complications including hypercalcemia and disseminated intravascular coagulation (DIC), both of which have been reported with variable frequencies across published cohorts depending on the underlying TCF3::HLF fusion subtype, together with an extremely poor long-term prognosis. A 3-year-old girl with TCF3::HLF-positive BCP-ALL presented with fever, lethargy, and pancytopenia, but notably lacked hypercalcemia and overt disseminated intravascular coagulation (DIC). Cytogenetic analysis additionally revealed a high hyperdiploid karyotype (52–58 chromosomes) and duplication of 1q. She was treated with a high-risk Children’s Oncology Group (COG) protocol (prednisone, vincristine, daunorubicin, PEG-asparaginase), achieving a day-8 blast count < 1000/µL and complete remission with an exceptionally low flow-cytometric MRD of less than 0.01%. She underwent myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related donor and remains in complete remission(CR) more than 2 years post-transplantation. This case suggests that TCF3::HLF-positive ALL encompasses a clinical spectrum rather than a uniformly fatal disease. The absence of classic metabolic complications and the co-occurrence of high hyperdiploidy might delineate a subgroup with a better response to intensive chemotherapy and early HSCT. Larger studies integrating detailed molecular characterization are required to substantiate this hypothesis and guide risk-adapted therapy.

Introduction

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood leukemia. Although contemporary risk-adapted therapy achieves 5-year event-free survival approaching 90%, certain rare cytogenetic subtypes remain therapeutically challenging [1]. Among more than 30 recognized molecular subtypes, the t(17;19)(q22;p13.3) translocation producing the TCF3::HLF fusion oncogene occurs in < 1% of pediatric BCP-ALL and has historically been associated with profound chemotherapy resistance and poor long-term survival. TCF3::HLF-positive B-ALL is also characterized by distinctive clinical manifestations, including hypercalcemia and disseminated intravascular coagulation (DIC), although the reported frequencies of these features vary substantially according to the underlying molecular subtype rather than representing universal characteristics of the disease [2–4].

It is now clear that TCF3-rearranged leukemias are biologically heterogeneous. The partner gene, the specific TCF3 exon involved in the breakpoint, and co-occurring genetic alterations all influence the clinical phenotype and treatment susceptibility [4, 5]. For instance, hypercalcemia and coagulopathy have been linked to distinct molecular subgroups defined by the exon breakpoint [6, 7]. A deeper understanding of this heterogeneity is essential to move beyond the conventional view of a uniformly dismal prognosis. Given the rarity of this leukemia, meticulous reporting of cases with comprehensive molecular annotation and long-term follow-up remains critical. Here, we describe a child with TCF3::HLF-positive BCP-ALL whose atypical presentation and exceptionally favorable outcome challenge traditional assumptions and highlight the clinical spectrum of this entity.

Case presentation

A previously healthy 3-year-old girl, born to consanguineous parents, presented with a one-week history of nocturnal fever and progressive lethargy. Physical examination revealed pallor without organomegaly or lymphadenopathy. Initial laboratory evaluation showed pancytopenia: WBC = 3.3 × 10⁹/L (6% neutrophils, 94% lymphocytes), Hb = 5.1 g/dL, and Plt = 31 × 10⁹/L. Notably, serum calcium was normal (9.2 mg/dL), and there was no laboratory evidence of overt DIC: PT = 15 s, INR = 1.04, aPTT = 30 s, fibrinogen 260 mg/dL (normal 200–400), although D-dimer was mildly elevated at 720 µg/L (normal < 500). Renal and liver functions test were normal.

Bone marrow aspiration demonstrated > 90% lymphoblasts of B-cell lineage on flow cytometry. Reverse-transcription polymerase chain reaction (RT-PCR) confirmed the TCF3::HLF fusion.

Conventional G-banding cytogenetic analysis of 20 metaphases demonstrated a hyperdiploid clone with 52–58 chromosomes. Fourteen metaphases showed gains of chromosomes 4, 6, 9, 10, 13, 14, 15, 17, 18, and two additional copies of chromosome 21. A subclone carrying dup(1)(q21q24) was identified in seven metaphases, whereas six metaphases demonstrated a normal female karyotype (46,XX). The final karyotype was:

The patient was enrolled on a high-risk COG-based protocol. Induction therapy consisted of prednisone 60 mg/m²/day for 28 days, vincristine 1.5 mg/m² weekly (days 1, 8, 15, 22), daunorubicin 25 mg/m² weekly (same days), and a single dose of PEG-asparaginase 2500 IU/m² on day 4, together with intrathecal cytarabine (day 0) and methotrexate (day 8). A peripheral blood blast count of < 1000/µL on day 8 indicated a good early response. End-induction minimal residual disease (MRD) assessed by Next-generation flow cytometry(NGF) was 0.0006% (6 × 10⁻⁶); but next-generation sequencing-based MRD was not available.

Given the high-risk diagnosis, the patient proceeded to myeloablative conditioning with busulfan and cyclophosphamide followed by allogeneic HSCT from her fully HLA-matched father in first complete remission. At over two years post-transplant, she remains in sustained complete remission(CR) with no significant transplant-related complications and age-appropriate development. A comparison of her clinical features with classic TCF3::HLF-positive ALL and published literature reports is provided in Table 1.

Table 1.

Comparison of Present Case with Published Literature Reports of TCF3::HLF-Positive ALL [4, 6–9]

Parameter	Published literature	Present Case
Hypercalcemia at presentation	Reported in approximately 60–90% of published cohorts, predominantly in Type 2 disease*	Absent
Coagulopathy/DIC	Reported variably (approximately 40–80%), predominantly in Type 1 disease*	Absent (D-dimer mildly elevated)
Additional cytogenetics	Usually isolated t(17;19)	High hyperdiploidy + dup(1q)
Response to induction chemotherapy	Generally poor; complete remission rates vary substantially across published cohorts	CR with low MRD
Early relapse (< 2 years)	Frequently reported despite initial remission	None (> 2 years)
Long-term survival	Historically poor despite intensive therapy	Currently disease-free

*Hypercalcemia is predominantly observed in Type 2 (TCF3 exon 12–HLF exon 4) disease, whereas overt coagulopathy and DIC are more commonly associated with Type 1 (TCF3 exon 13–HLF exon 4) rearrangements [6, 10]

Discussion

This case illustrates that a favorable outcome is attainable in TCF3::HLF-positive BCP-ALL and underscores the biological heterogeneity concealed within this high-risk label. Two features are particularly instructive: the complete absence of classic metabolic complications (hypercalcemia and DIC) and the presence of a high hyperdiploid karyotype, a well-established favorable prognostic marker in childhood ALL that is almost never reported concurrently with TCF3::HLF.

Hypercalcemia and disseminated intravascular coagulation(DIC) are well-recognized manifestations of TCF3::HLF-positive ALL; however, neither represents a universal feature of this leukemia. Their reported frequencies vary substantially across published cohorts because these clinical manifestations correlate closely with the underlying fusion subtype. Hypercalcemia is predominantly associated with Type 2 (TCF3 exon 12–HLF exon 4) rearrangements, whereas overt coagulopathy and DIC are more frequently observed in Type 1 (TCF3 exon 13–HLF exon 4) disease. Since molecular breakpoint characterization was unavailable in our patient, direct genotype–phenotype correlation could not be established. Nevertheless, the absence of both hypercalcemia and overt DIC further illustrates the biological heterogeneity of TCF3::HLF-positive ALL [4, 6, 10, 11].

Our patient lacked both, exhibiting only a trivial D-dimer elevation without clinical coagulopathy. This supports recent evidence that the clinical presentation is dictated by the underlying molecular anatomy of the translocation—the TCF3 exon involved and the partner gene—rather than by the fusion per se [5, 12]. Unfortunately, the exon breakpoint was not available in our case, but the atypical phenotype strongly suggests a distinct molecular variant.

Equally important is the co-existence of high hyperdiploidy (52–58 chromosomes) and dup(1q). High hyperdiploidy is a hallmark of standard-risk ALL with excellent outcomes, while TCF3::HLF positivity confers extreme high risk. Although causality cannot be established from a single case, the coexistence of high hyperdiploidy, favorable trisomies (including chromosomes 4 and 10), and dup(1)(q21q24) may have modified the biological behavior of this otherwise highly aggressive leukemia and potentially contributed to the favorable early treatment response observed in our patient.

Indeed, the patient achieved a deep remission (MRD 0.0006% by NGF) after a standard COG high-risk induction, Although complete remission rates reported for TCF3::HLF-positive ALL vary across published cohorts, favorable early treatment responses remain uncommon, making the deep molecular remission achieved by our patient particularly noteworthy. The day-8 blast count of < 1000/µL further confirmed early chemoresponsiveness [2, 6, 8–10].

Allogeneic HSCT in first remission remains the cornerstone of curative therapy for this subtype. Our patient received a myeloablative busulfan/cyclophosphamide conditioning regimen followed by a matched related donor transplant, a strategy that likely consolidated the deep remission and prevented the early relapse observed in ~ 70% of cases [6, 8].

Given the historically poor response of TCF3::HLF -positive ALL to conventional chemotherapy, novel immunotherapeutic agents including Blinatumomab, Aurora A kinase inhibitors (Alisertib) and chimeric antigen receptor T-cell therapy(CAR-T), demonstrated efficacy in inducing remission and serving as a bridge to transplantation in refractory or relapsed cases. A recent update on a European cohort reported that four out of nine patients with TCF3::HLF -positive ALL remained in molecular remission after treatment with blinatumomab followed by HSCT [7, 12–14].

Despite these groundbreaking advances, our case suggests that in biologically more favorable variants; where classic metabolic complications are absent and a high hyperdiploid karyotype co-exists, long-term disease control can still be achieved through early risk stratification, an intensive chemotherapy backbone, and timely allogeneic transplantation in first complete remission. This duality underscores a critical principle that treatment strategy must be adapted to the molecular anatomy of the leukemia, matching the intensity of the approach with the underlying biological risk [10, 12, 15].

Study limitations and research implications

This report has several limitations. First, the TCF3 exon breakpoint could not be ascertained, and comprehensive next-generation sequencing was not performed, precluding a full depiction of cooperating mutations. Second, the single-case nature inherently restricts generalizability, and longer follow-up is needed to confirm durable cure.

Nevertheless, the findings support the proposal that TCF3::HLF-positive ALL represents a clinical spectrum. Prospective collection of cases with uniform molecular annotation and minimal residual disease monitoring is necessary to validate whether the absence of metabolic complications and the presence of favorable cytogenetic features can identify patients who may be cured with current intensive approaches, potentially sparing some from unnecessary treatment-related toxicity.

Furthermore, because molecular breakpoint characterization was unavailable, correlation between the patient’s clinical phenotype and the specific TCF3::HLF fusion subtype could not be established.

Conclusion

This case challenges the paradigm of universally poor outcomes in TCF3::HLF-positive ALL. The absence of hypercalcemia and coagulopathy, together with a favorable early response to chemotherapy and long-term remission after allogeneic HSCT, suggests that a subgroup of patients with distinct molecular features may have a more tractable disease. Larger collaborative studies with detailed genomic characterization are required to refine risk stratification and personalize therapy for these rare types of leukemia.

Authors’ contributions

GHM conceived and supervised the study and was responsible for patient management and treatment decisions. KH collected the clinical data, reviewed the literature, and drafted the initial version of the manuscript. EA contributed to data acquisition, literature review, and manuscript revision. All authors critically reviewed the manuscript for important intellectual content, approved the final version, and agree to be accountable for all aspects of the work.

Funding

This research received no external funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Written informed consent for participation was obtained from the patient’s legal guardian.

Consent to publish

Written informed consent for publication of this case report and any accompanying informations was obtained from the patient’s legal guardian.

Competing interests

The authors declare no competing interests.