B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA IN A CHILD WITH ATAXIA TELANGIECTASIA

Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterized by chromosomal instability or a DNA repair defect with a birth frequency of 1 in 3,000,000 [[1], [2]]. It is clinically characterized by, progressive cerebellar ataxia, recurrent sino-pulmonary infections, oculo-cutaneous telangiectasia, growth retardation, hypogonadism, and variable immune deficiencies[1].

A-T patients are at an increased risk of developing malignancies. Lymphoid neoplasms occur most commonly; other associated malignancies are tumors of the gastro-intestinal tract, brain, ovaries, uterus, and skin [2]. T-cell acute lymphoblastic leukemia (T-ALL) is most frequent hematological malignancy and is associated with poor prognostic features [[3], [4]]. We describe an 11-year-old male with A-T who developed CALLA positive (early pre-B-cell) ALL.

The boy was referred to our hospital for evaluation of increased leukocyte count, which was incidentally detected on routine evaluation for minor chest trauma that he had sustained 4 days earlier. A detailed clinical history of the patient revealed recurrent respiratory tract infections since 3 months of age, abnormal eye movements, abnormal gait since 3 years of age, and growth retardation. There was no history of fever, significant weight loss, bleeding from any site, or jaundice. On general physical examination his height was 120 cm, weight 23 kg, and head circumference 50 cm. There was pallor, and generalized lymphadenopathy and telangiectasia were present on both bulbar conjunctiva and ears. Patient had high arched palate, dry skin with icthsysiform changes, and clinodactly of left little finger. Central nervous system examination showed normal higher mental functions and no cranial nerve palsies, and cerebellar signs including horizontal nystagmus, ataxic gait, and speech were present. Fundus and cardiovascular examination were normal. Respiratory system examination showed a dull percussion note and reduced breath sounds on left infraxillary and infrascapular region. Abdomen was soft, the liver was enlarged 3 cm below costal margin, and spleen was 1 cm palpable below costal margin.

Laboratory investigations showed Hb 7.5 g/dL, total leukocyte count 30.4 × 10⁹/L, and platelet count 130 × 10⁹/L (differential leukocyte count was polymorph 32%, lymphocyte 34%, monocyte 1%, eosinophil 1%, myelocyte 3%, metamyelocyte 4%, lymphoid blast cells 25%). Peripheral smear showed normocytic normochromic red cells, lymphoid blast cells 25%, and adequate platelet counts. A bone marrow biopsy with immunophenotype studies was performed. The bone marrow imprint smear showed hypercellular marrow replaced with lymphoid blast cells (L-2 morphology). On cytochemical staining of the peripheral blood and bone marrow imprint smears the blasts were negative for Sudan black, nonspecific esterase, acid phosphatase. On immunophenotyping the blasts were positive for HLA-DR, CD10, and CD19 and negative for CD1, CD2, CD3, CD4, CD5, CD7, CD8, CD 33, CD13, CD14, and CD15, cytoplasmic myeloperoxidase, and cytoplasmic and surface immunoglobulins.

Biochemical tests for liver and renal functions were normal. The serum α-fetoprotein (AFP) level was raised (7.5 mg/mL; normal 0–3 mg/mL). Serum IgG level was 1748 mg/dL (normal 564–1765 mg/dL), serum IgA was reduced (50 mg/dL; normal 85–385 mg/dL) and serum IgM 579 mg/dl (normal 53–375 mg/dL). Serum LDH was found to be increased 4479 u/L (normal 240–480 u/L). Pleural fluid was hemorrhagic and cytopathological examination revealed lymphocytes and mesothelial cells only. The pleural fluid LDH level was 1568 u/L and the ADA level was 67.6 u/L (normal 6.0–19.7 u/L). Cytopathological examination of cerebrospinal fluid was negative for malignant cells. Skiagram of chest showed hilar adenopathy with left pleural effusion. Radiographs of hands showed clinodactly of left little finger. Cytogenetic studies was not performed in the patient.

A diagnosis of ataxia telangiectasia with B-cell acute lymphoblastic leukemia was made. The patient was started on induction chemotherapy (vincristine, doxorubicin, prednisolone, and l-asparginase). After receiving the first dose, the patient developed marked leukopenia (TLC 1.65 × 10⁹/L) with absolute neutrophil count of 0.5 × 10⁹/L and the platelet count was 60 × 10⁹/L. The family refused for further chemotherapy and patient was discharged on request.

DISCUSSION

A-T is a progressive multisystem disease and is regarded as a chromosomal instability disorder or disorder of DNA repair mechanism. The genetic defect (ATM gene) has been localized to chromosome 11q 22–23. ATM is a member of the phosphatidylinositol 3 (PI-3) kinase families of genes that sense double-strand breakage in DNA and activates the cycle checkpoint controls at G1/S border, S phase, and G2/M. ATM plays an important role in preventing the progress of cells harboring damaged DNA through the cell cycle and is fundamental to the genomic stability. Mutations of ATM gene in the PI-3 kinase domain increase genetic instability and are the possible mechanism of carcinogenesis in these patients [5].

A-T patients are at a 70-to 200-fold increased risk of developing hematological malignancies compared to general population [2]. Approximately 10–15% of all A-T homozygotes developed malignancy in childhood. Hematological malignancies are the most common (70–80% of all neoplasms) and leukemia constitutes 25% of all malignancies. Both T-and B-cell lymphoid malignancies occur and there is a 4-to 5-fold increased predisposition for T-cell malignancy compared to B-cell malignancy. Loss of heterozygosity of the ATM gene and ATM protein deficiency has been observed in patients with ALL, B-chronic lymphocytic leukemia, T-prolymphocytic leukemia, and NHL. It is postulated that the ATM is required for the normal rearrangement of the T-cell receptor alpha/delta locus and its mutation is associated with development of lymphoid neoplasm [5].

Taylor et al. [3], in a series of 78 A-T patients, found 17 (13%) cases of hematological malignancies over a period of 15 years in the United Kingdom. Eleven of the 17 (64.7%) had T-cell neoplasm. Most (82.4%) of these patients were below the age of 15 years. Similarly, in another large study of 412 A-T patients, 75 (18%) had lymphoid neoplasm. Non-Hodgkin lymphoma was the most frequent, 48 (64%); followed by acute leukemia, 11 (15%); Hodgkin disease, 10 (13%); and CLL, 3 (4%). Occurrence of different solid tumors in association with lymphoid malignancies in A-T patients was also observed [4]. T-cell acute lymphoblastic leukemia is more frequent than B-cell ALL. These patients have a high proportion of unfavorable prognostic features, which include older age (mean age 9 years), male predominance, high total leukocyte count, and occasional mediastinal mass at presentation [6].

Chemotherapy in A-T patients with lymphoid malignancies is still a subject of great debate. Some authors have used standard-dose chemotherapy, while others have used reduced-dose chemotherapy in which dose intensity and total cumulative dose were reduced because of fear that A-T patients have more side effects with standard dose [[6], [7]]. Sandoval and Shift [4] have observed that median survival was significantly better in patients receiving standard-dose chemotherapy (12 months) compared to reduced-dose chemotherapy (5 months). A-T patients are at increased risk of developing adverse effects of chemotherapy. Bleomycin should be used with caution in A-T patients because many of these patients already have chronic lung diseases due to recurrent infections. A-T patients have been found to have increased sensitivity to neurotoxic effects of chemotherapy and irradiation. These patients are at higher risk of developing infections because of immunodeficient state and immunosuppression secondary to chemotherapy.

Although overall prognosis of ALL in A-T is guarded, few prolonged remissions have been reported [4].