Gelatinous transformation of bone marrow following the use of dasatinib in a patient with philadelphia chromosome-positive acute lymphoblastic leukemia

Abstract

Gelatinous transformation of bone marrow (GTBM) is a rare disorder characterized by loss of adipose and hematopoietic tissues, and deposition of extracellular gelatinous mucopolysaccharides, particularly hyaluronic acid.1,2 The common causes of gelatinous transformation of bone marrow are anorexia nervosa, acquired immunodeficiency syndrome, alcoholism, carcinomas, leukemias, lymphomas and chemotherapeutic agents.1–5 Imatinib has been reported to cause gelatinous transformation of bone marrow in patients with chronic myeloid leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).6–8 We report here a case of Ph+ ALL who was treated with dasatinib, following which he developed gelatinous transformation of bone marrow. An 18-years-old male was admitted with the complaints of generalized weakness and fever for one month duration. On examination he had pallor with cervical lymphadenopathy and hepatosplenomegaly. Hemogram revealed hemoglobin 5.5 g/dl, total leukocyte count 130×109/l, platelet count 40×109/l with peripheral blood smear showing 85% blasts, morphologically lymphoid. Bone marrow examination confirmed the replacement of marrow by lymphoid blasts. On immunophenotyping the blasts were positive for CD34, HLA-DR, CD19, CD20 and cCD79a. Qualitative polymerase chain reaction (PCR) for BCR-ABL was positive. Cerebrospinal fluid examination also revealed the presence of blasts. His viral studies were negative for HBsAg, anti-HCV and HIV. He was started on supportive treatment with intravenous fluids, allopurinol and BFM-95 induction chemotherapy (prednisolone 60 mg/m2 from day 1 and vincristine 1.5 mg/m2 and daunorubicin 30 mg/m2 from day 8) alongwith dasatinib 50 mg twice daily from day 1. Intrathecal chemotherapy included methotrexate 12.5 mg twice weekly. Patient developed pancytopenia with febrile neutropenia on day 10 and was started on intravenous antibiotics as per institutional policy. Blood and urine cultures were negative for bacteria and fungi. Computed tomography of chest was normal. He was continued on supportive treatment. Peripheral blood smear on day 8 did not show any blasts. Because of persistent fever, amphotericin (1 mg/kg) was added along-with granulocyte-colony stimulating factor (G-CSF). Fever continued and patient had persistent cytopenias (total leukocyte count 0.2×109/l, absolute neutrophil count 0.05×109/l and platelet count 10×109/l). Bone marrow examination was repeated on day 32 and it showed serous degeneration of marrow with increased extracellular matrix, loss of fat cells and gelatinous transformation, confirmed with Alcian blue staining (Fig. 1). The overall cellularity of the bone marrow was 5–10%. Fig. 1 Photomicrograph of the bone marrow trephine biopsy showing gelatinous transformation. Alcian blue pH 2.5; 400×. Normally, gelatinous material is not found in the bone marrow and therefore, its presence signifies a pathological event. Chemotherapeutic drugs, including melphalan and imatinib, have been implicated in the causation of GTBM.6–10 There is usually complete recovery of marrow following initial gelatinous transformation in the patients receiving chemotherapy for acute leukemia,1 but our case showed no marrow recovery. Moreover, GTBM associated with chemotherapy is characterized by absence of fat atrophy and is often transient.1 Our patient had evidence of fat atrophy along-with gelatinous transformation. GTBM may respond to hematopoietic growth factors 9 but our patient did not have any response to G-CSF and succumbed to febrile neutropenia. The mechanism leading to the gelatinous transformation may involve inhibition of tyrosine kinase activity by tyrosine kinase inhibitors (TKI) leading to blockage of downstream signal pathways, affecting extracellular matrix deposition, adipocyte differentiation and angiogenesis.10–13 Moreover, the catabolic processes in leukemia may also lead to the production of hyaluronic acid by leukemic cells.1,5 Dasatinib, a more potent second generation TKI, has been used for treatment of chronic myeloid leukemia as well as Ph+ ALL. It can cause cytopenias but gelatinous transformation is an unusual event. Though our patient also received prednisolone, vincristine, daunorubicin and asparaginase as a part of induction therapy for ALL alongwith dasatinib, we conclude that the gelatinous transformation and non-recovery of marrow probably was due to dasatinib, analogous to that caused by imatinib as reported in previous studies.6,7,10 Pancytopenia can develop following treatment with TKIs 5,7,9,14 and bone marrow examination may be required for definitive diagnosis.