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Bone marrow with gelatinous transformation associated with residual disease in imatinib mesylate-treated chronic myelogenous leukaemia (CML)
CORRESPONDENCE
Bone marrow with gelatinous transformation associated with residual disease in imatinib mesylate-treated chronic myelogenous leukaemia (CML) Sir, With the advent of imatinib as a first line agent for chronic myelogenous leukaemia (CML), several studies have described morphological changes in marrows of imatinib-treated patients.1–3 Even so, only a handful of studies have reported the occurrence of serous atrophy (SA)/gelatinous transformation (GT) in imatinib-treated CML patients.4,5 In the reported cases, patients were on imatinib therapy for 12–24 months with bone marrow demonstrating a major molecular response.4,5 Unlike these previous cases, we report herein a patient in whom serous atrophy occurred earlier with concurrent cytogenetic evidence of residual CML. Our patient was a 67-year-old man who was treated with imatinib (400 mg/day) for 4 months after a diagnosis of BCRABL1 positive CML. During routine follow up, the patient was found to have pancytopenia with haemoglobin of 10.1 g/dL, white blood cell count 2.5 K/mL and platelets 33 K/mL. A bone marrow aspirate and biopsy along with flow cytometry and cytogenetics study was performed. The bone marrow core biopsy was markedly hypocellular (5–10% cellular) with markedly decreased haematopoietic cells involving all three cell lines associated with atrophic adipocytes (Fig. 1A). In addition, there was deposition of an extracellular gelatinous substance amidst atrophic adipocytes (Fig. 1B). This material stained positive with alcian blue stain at pH 2.5 (Fig. 1C) consistent with SA/GT. Conventional karyotype showed presence of Philadelphia chromosome in all 20 cells examined. Considering the potential risk associated with pancytopenia, imatinib was promptly discontinued and replaced with nilotinib. Although this led to restitution of marrow cellularity in two subsequent marrows, the patient continued to have residual disease by either
59
RT-PCR or FISH until 8 months after diagnosis without evidence of acceleration or transformation. A small proportion of CML patients have been reported to develop severely hypoplastic marrows following imatinib therapy.1–3 Notably, two of three chronic phase CML patients with severe hypoplasia (cellularity<20%) in the study by Hasserjian et al.3 showed residual disease by cytogenetics, while in the study of five CML patients by Srinivas and coworkers,6 both patients with chronic phase CML showed markedly hypoplastic marrows with evidence of residual disease by molecular studies.6 However, neither of these studies reported evidence of SA/GT in their cases. Specifically, only two prior studies have reported the occurrence of SA/GT in the setting of imatinib-treated CML,4,5 including two5 and one4 case(s) respectively of chronic phase CML; all three patients reportedly achieved a major molecular remission after imatinib therapy and showed hypocellular marrows with evidence of SA/GT at 12/22 and 11 months after initial diagnosis.4,5 In contrast, our case is notable for the earlier onset of SA/GT with concurrent residual disease. Presumably, these morphological changes most likely stem from the effects of imatinib on extracellular matrix components, consequent to perturbations in the TGF-b and/or PDGF pathways. Regardless of the causal role of imatinib for pancytopenia or the implication for treatment response/disease outcome, an awareness and early recognition of this phenomenon is important so that appropriate therapeutic changes (e.g., discontinuation of imatinib therapy or use of another tyrosine kinase inhibitor) can be effected to avoid morbidity associated with cytopenias. Conflicts of interest and sources of funding: None to declare. Beenu Thakral* Bryce Higa{ Girish Venkataraman{ Milind M. Velankar{ *Department of Pathology, North Shore University Health System, Evanston, IL, and {Department of Pathology, Loyola University Medical Center, Maywood, IL, USA Contact Dr G. Venkataraman. E-mail: [email protected] 1. Braziel RM, Launder TM, Druker BJ, et al. Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months’ experience. Blood 2002; 100: 435–41. 2. Frater JL, Tallman MS, Variakojis D, et al. Chronic myeloid leukemia following therapy with imatinib mesylate (Gleevec). Bone marrow histopathology and correlation with genetic status. Am J Clin Pathol 2003; 119: 833–41. 3. Hasserjian RP, Boecklin F, Parker S, et al. ST1571 (imatinib mesylate) reduces bone marrow cellularity and normalizes morphologic features irrespective of cytogenetic response. Am J Clin Pathol 2002; 117: 360–7. 4. Hong FS, Mitchell CA, Zantomio D. Gelatinous transformation of the bone marrow as a late morphological change in imatinib mesylate treated chronic myeloid leukaemia. Pathology 2010; 42: 84–5. 5. Ram R, Gafter-Gvili A, Okon E, Pazgal I, Shpilberg O, Raanani P. Gelatinous transformation of bone marrow in chronic myeloid leukemia during treatment with imatinib mesylate: a disease or a drug effect? Acta Haematol 2008; 119: 104–7. 6. Srinivas U, Pillai LS, Kumar R, Pati HP, Saxena R. Bone marrow aplasia–a rare complication of imatinib therapy in CML patients. Am J Hematol 2007; 82: 314–6.
Fig. 1 (A,B) Serous atrophy of bone marrow after four months of imatinib mesylate therapy. (C) Alcian blue stain (pH 2.5) highlighting serous atrophy of bone marrow.
DOI: 10.1097/PAT.0b013e32834e42df
Copyright © Royal College of Pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
Bone marrow with gelatinous transformation associated with residual disease in imatinib mesylate-treated chronic myelogenous leukaemia (CML) Sir, With the advent of imatinib as a first line agent for chronic myelogenous leukaemia (CML), several studies have described morphological changes in marrows of imatinib-treated patients.1–3 Even so, only a handful of studies have reported the occurrence of serous atrophy (SA)/gelatinous transformation (GT) in imatinib-treated CML patients.4,5 In the reported cases, patients were on imatinib therapy for 12–24 months with bone marrow demonstrating a major molecular response.4,5 Unlike these previous cases, we report herein a patient in whom serous atrophy occurred earlier with concurrent cytogenetic evidence of residual CML. Our patient was a 67-year-old man who was treated with imatinib (400 mg/day) for 4 months after a diagnosis of BCRABL1 positive CML. During routine follow up, the patient was found to have pancytopenia with haemoglobin of 10.1 g/dL, white blood cell count 2.5 K/mL and platelets 33 K/mL. A bone marrow aspirate and biopsy along with flow cytometry and cytogenetics study was performed. The bone marrow core biopsy was markedly hypocellular (5–10% cellular) with markedly decreased haematopoietic cells involving all three cell lines associated with atrophic adipocytes (Fig. 1A). In addition, there was deposition of an extracellular gelatinous substance amidst atrophic adipocytes (Fig. 1B). This material stained positive with alcian blue stain at pH 2.5 (Fig. 1C) consistent with SA/GT. Conventional karyotype showed presence of Philadelphia chromosome in all 20 cells examined. Considering the potential risk associated with pancytopenia, imatinib was promptly discontinued and replaced with nilotinib. Although this led to restitution of marrow cellularity in two subsequent marrows, the patient continued to have residual disease by either
59
RT-PCR or FISH until 8 months after diagnosis without evidence of acceleration or transformation. A small proportion of CML patients have been reported to develop severely hypoplastic marrows following imatinib therapy.1–3 Notably, two of three chronic phase CML patients with severe hypoplasia (cellularity<20%) in the study by Hasserjian et al.3 showed residual disease by cytogenetics, while in the study of five CML patients by Srinivas and coworkers,6 both patients with chronic phase CML showed markedly hypoplastic marrows with evidence of residual disease by molecular studies.6 However, neither of these studies reported evidence of SA/GT in their cases. Specifically, only two prior studies have reported the occurrence of SA/GT in the setting of imatinib-treated CML,4,5 including two5 and one4 case(s) respectively of chronic phase CML; all three patients reportedly achieved a major molecular remission after imatinib therapy and showed hypocellular marrows with evidence of SA/GT at 12/22 and 11 months after initial diagnosis.4,5 In contrast, our case is notable for the earlier onset of SA/GT with concurrent residual disease. Presumably, these morphological changes most likely stem from the effects of imatinib on extracellular matrix components, consequent to perturbations in the TGF-b and/or PDGF pathways. Regardless of the causal role of imatinib for pancytopenia or the implication for treatment response/disease outcome, an awareness and early recognition of this phenomenon is important so that appropriate therapeutic changes (e.g., discontinuation of imatinib therapy or use of another tyrosine kinase inhibitor) can be effected to avoid morbidity associated with cytopenias. Conflicts of interest and sources of funding: None to declare. Beenu Thakral* Bryce Higa{ Girish Venkataraman{ Milind M. Velankar{ *Department of Pathology, North Shore University Health System, Evanston, IL, and {Department of Pathology, Loyola University Medical Center, Maywood, IL, USA Contact Dr G. Venkataraman. E-mail: [email protected] 1. Braziel RM, Launder TM, Druker BJ, et al. Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months’ experience. Blood 2002; 100: 435–41. 2. Frater JL, Tallman MS, Variakojis D, et al. Chronic myeloid leukemia following therapy with imatinib mesylate (Gleevec). Bone marrow histopathology and correlation with genetic status. Am J Clin Pathol 2003; 119: 833–41. 3. Hasserjian RP, Boecklin F, Parker S, et al. ST1571 (imatinib mesylate) reduces bone marrow cellularity and normalizes morphologic features irrespective of cytogenetic response. Am J Clin Pathol 2002; 117: 360–7. 4. Hong FS, Mitchell CA, Zantomio D. Gelatinous transformation of the bone marrow as a late morphological change in imatinib mesylate treated chronic myeloid leukaemia. Pathology 2010; 42: 84–5. 5. Ram R, Gafter-Gvili A, Okon E, Pazgal I, Shpilberg O, Raanani P. Gelatinous transformation of bone marrow in chronic myeloid leukemia during treatment with imatinib mesylate: a disease or a drug effect? Acta Haematol 2008; 119: 104–7. 6. Srinivas U, Pillai LS, Kumar R, Pati HP, Saxena R. Bone marrow aplasia–a rare complication of imatinib therapy in CML patients. Am J Hematol 2007; 82: 314–6.
Fig. 1 (A,B) Serous atrophy of bone marrow after four months of imatinib mesylate therapy. (C) Alcian blue stain (pH 2.5) highlighting serous atrophy of bone marrow.
DOI: 10.1097/PAT.0b013e32834e42df
Copyright © Royal College of Pathologists of Australasia. Unauthorized reproduction of this article is prohibited.