Philadelphia chromosome-positive T-cell acute lymphoblastic leukemia: a case report

Abstract

Philadelphia chromosome-positive (Ph+) T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive type of acute leukemia. The Philadelphia chromosome is the hallmark of chronic myeloid leukemia (CML). The differentiation between Ph+ T-ALL and T-cell lymphoblastic crisis of CML may be problematic in some cases. Here, we report a rare case of de novo Ph+ T-ALL that presented a diagnostic challenge. The overall clinical, immunophenotypic, cytogenetic, and xenotransplantation results suggest a diagnosis of Ph+ T-ALL. The patient was treated with induction chemotherapy including imatinib followed by haploidentical stem cell transplantation and achieved complete remission.

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) comprises 15% to 25% of acute lymphoblastic leukemia (ALL) cases in children and adults.^1,2 The Philadelphia chromosome t(9;22)(q34;q11), which generates the BCR-ABL1 translocation, is a defining cytogenetic abnormality in chronic myeloid leukemia (CML) ³ . It is also present in a subset of B-cell acute lymphoblastic leukemia (B-ALL) cases, but rarely in T-ALL.^4,5 There is evidence that BCR-ABL1+ T-ALL arises from an early lymphoid progenitor cell. ⁵ BCR-ABL1+ T-ALL has an unfavorable prognosis with an approximately 50% 5-year overall survival (OS) rate, while relapsed T-ALL cases have a less than 7% 5-year OS rate.^6–9 Here, we present a challenging case of de novo BCR-ABL1+ acute leukemia in which a final diagnosis of BCR-ABL+ T-ALL was reached that was supported by xenotransplantation data.

Case presentation

A 27-year-old man without a significant past medical history presented to the Emergency Department (ED) with worsening left upper quadrant abdominal pain. In the ED, it was noted that he had leukocytosis (21 k/μL) and thrombocytopenia (17 k/μL). A CT scan showed pericardial/pleural effusion, ascites, splenomegaly, and a mediastinal mass (4 × 3 cm). Peripheral blood smear showed blasts (Figure 1a). Flow cytometry analysis of his peripheral blood detected approximately 60% of blasts with expression of CD34, CD19 (dim), CD33, and CD7 (bright) (Figure 1b), which led to an initial diagnosis of acute myeloid leukemia (AML) versus mixed phenotypic acute leukemia (MPAL), pending peripheral blood chromosome/fluorescent in situ hybridization (FISH) analysis along with myeloid next-generation sequencing (NGS) studies.

Figure 1.

(a) Peripheral blood smear (50×). (b) Flow cytometry analysis of peripheral blood. (c) Hematoxylin and eosin (H&E)-stained sections of bone marrow biopsy (10×, insert 50×). (d–j), Immunohistochemical staining results (50×): (d) CD34, (e) CD7, (f) CD3, (g) CD79a, (h) TdT, (i) MPO, and (j) PAX5. Note that CD79a can be positive in T-cell acute lymphoblastic leukemia (T-ALL) according to the World Health Organization (WHO) blue book. (k) Fluorescent in situ hybridization (FISH) results for BCR-ABL1 (break-apart probe). (l) Donor cell engraftment (left) and lineage (CD3+ T cells, CD19+ B cells, and CD33+ myeloid cells) commitment (middle and right) and (m) The expression of human CD7 in donor cells.

Subsequent bone marrow biopsy showed that the marrow space was replaced by sheets of medium-sized blasts (Figure 1c), which were diffusely positive for CD34 and CD7, weakly positive for cytoplasmic CD3 and CD79a in a subset of blasts, and negative for terminal deoxynucleotidyl transferase (TdT), myeloperoxidase (MPO), paired box gene 5 (PAX5), lysozyme, CD2, CD4, CD5, and CD8 (Figure 1d–j and data not shown). Karyotype analysis showed 47, XY, t(9;22)(q34;q11.2), and +19, and FISH confirmed BCR-ABL1 translocation (Figure 1k). Molecular analysis detected a p210 BCR-ABL1 fusion transcript by reverse transcription-polymerase chain reaction (RT-PCR). Myeloid NGS studies using a 30 gene hotspot panel detected a Wilms tumor 1 (WT1) mutation (variant allele frequency (VAF) of 26%). Note that all the ancillary studies (flow cytometry, cytogenetics, and molecular) were performed on peripheral blood. From these results, BCR-ABL1+ acute leukemia was diagnosed with T-cell lymphoblastic leukemia with aberrant expression of CD33 and CD19 favored. In addition, the mononuclear cells from the leftover peripheral blood were transplanted into busulfan-conditioned (25 mg/kg, intraperitoneal injection) NOD scid gamma-SGM3 (NSGS) mice through the tail vein to determine the lineage commitment of these leukemia blasts. As shown in Figure 1l and 1m, donor-derived cells were mainly CD3 (surface)⁺ CD7⁺ T cells two months post transplantation compared with CD33⁺ myeloid and CD19⁺ B cells, suggesting the leukemic blasts became more differentiated in NSGS recipient mice and supported the diagnosis of T-ALL.

The patient consented to treatment and was initially treated with Hyper-CVAD (cyclophosphamide, vincristine sulfate, Adriamycin, dexamethasone) and dasatinib, then switched to the pediatric AALL1631 protocol, ¹⁰ including imatinib, cyclophosphamide, 6-mercaptopurine, and cytarabine. This was followed by haploidentical stem cell transplantation. Currently, the patient is stable with no major issues. This case was reported according to the CARE guidelines. ¹¹ All patient details were de-identified.

Discussion

Here, we report a challenging BCR-ABL1+ acute leukemia case with negative or weak expression of lineage markers, as seen by both flow cytometry analysis and immunohistochemical staining. The negative expression of myeloid-defining marker MPO makes a diagnosis of AML unlikely. The low to negative expression of B cell markers CD19, CD79a, PAX5, and CD10 also rules out B-ALL. The young age of the patient, mediastinal mass, expression of immature marker CD34, weak positive expression of cytoplasmic CD3, and strong positive expression of CD7 led us to favor a diagnosis of T-ALL, recognizing that weak cytoplasmic expression of CD3 is not sufficient to define the T-cell lineage. However, the xenotransplantation results and that donor-derived T cells with cell surface expression of CD3 outcompete myeloid and B cell lineages support the blasts belonging to a T-cell lineage.

The main differential diagnoses in this case included MPAL and acute undifferentiated leukemia. WHO 2017 defining criteria ¹² for myeloid and B lineage marker expression were not met, excluding a diagnosis of MPAL. Although acute undifferentiated leukemia can show no specific marker expression for either lymphoid or myeloid lineage, similar to our case, the presence of the BCR-ABL1 translocation made the diagnosis problematic. BCR-ABL1+ acute leukemia with T-cell differentiation usually suggests either CML in T lymphoblastic crisis or de novo BCR-ABL1+ T-ALL. ¹³ The incidence of each is rare, with T lymphoblastic crisis occurring in roughly 1.3% of blast crisis CML cases, and less than 5% of BCR-ABL1+ ALL are of T lineage.^4,14 The p210 form of the BCR-ABL1 translocation in this case does raise the possibility of T-cell lymphoblastic crisis of CML. However, the patient had no prior history of CML and no BCR-ABL1 transcript was detected in the repeated bone marrow cells post-chemotherapy and before haploidentical stem cell transplantation. These findings suggest that BCR-ABL1 was not present in the myeloid lineage, essentially ruling out the possibility of pre-existing CML.

Although BCR-ABL1+ T-ALL is very rare, aggressive, and has a high rate of relapse and short-term complete remission,^15,16 our patient responded well to Hyper-CVAD and stem cell transplantation. The current case indicates that a comprehensive workup is required to achieve a correct diagnosis, which is essential for providing the most appropriate treatment plan to the patient.