From www.bloodjournal.org by guest on September 11, 2016. For personal use only. BLOOD, 7 NOVEMBER 2013 x VOLUME 122, NUMBER 19
CORRESPONDENCE
3387
7. Walsh KM, Chokkalingam AP, Hsu LI, et al. Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children [published online ahead of print April 25, 2013]. Leukemia.
9. Boyle AP, Hong EL, Hariharan M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9): 1790-1797.
8. Zhang H, Nestor CE, Zhao S, et al. Profiling of human CD4(1) T-cell subsets identifies the TH2-specific noncoding RNA GATA3-AS1. J Allergy Clin Immunol. 2013;132(4):1005-1008.
© 2013 by The American Society of Hematology
To the editor: Imatinib therapy in a patient with suspected chronic neutrophilic leukemia and FIP1L1-PDGFRA rearrangement A 54-year-old man with no significant past medical history presented with skin rash. Complete blood count showed a white blood cell count of 64 3 109/L (63% neutrophils, 2% eosinophils), hemoglobin 14 g/dL, and platelet count 166 3 109/L. Bone marrow evaluation showed a hypercellular marrow with marked granulocytic hyperplasia (Figure 1). There was no increase in marrow eosinophils or fibrosis. No dysplasia was identified. Conventional cytogenetics showed constitutional inv(9). Testing for BCR-ABL rearrangement and JAK2V617F mutation was negative. The patient was diagnosed with chronic neutrophilic leukemia (CNL) and treatment with hydroxyurea was initiated. Subsequently, array comparative genomic hybridization demonstrated monoallelic interstitial deletion of chromosome 4q12. This was confirmed by interphase fluorescence in situ hybridization (FISH) analysis using a probe set that detects loss of CHIC2 (surrogate marker of the fusion of the factor interacting with PAP [Fip1]-like 1 [FIP1L1] gene to the platelet derived growth factor receptor-a [PDGFRA] gene) and by reverse-transcription polymerase chain reaction. The diagnosis was revised to myeloproliferative neoplasm with FIP1L1-PDGFRA fusion Imatinib (100 mg daily) was prescribed. Hydroxyurea was discontinued. The white blood cell count normalized within 2 weeks and follow-up testing for FIP1L1PDGFRA fusion by FISH at 3 months was negative. The patient
Figure 1. Bone marrow morphology and CHIC2 FISH. The bone marrow biopsy (left panel) demonstrated hypercellularity and marked predominance of maturing neutrophilic granulocytes. Megakaryocytes were decreased, and no features of myelofibrosis or myelodysplasia were present. Notably, eosinophils and blasts were rare. By fluorescence in situ hybridization (right panel) using a tricolor probe set (Abbott Molecular), normal cells had two intact tricolor (green/orange/aqua) fusion signals whereas abnormal cells (90% in this sample) with monoallelic loss of CHIC2 (orange pseudocolor) had one green/aqua fusion signal.
continues to be treated with imatinib 100 mg daily for .1 year with no recurrence of skin rash or leukocytosis. Imatinib is approved for treatment of patients with FIP1L1PDGFRA fusion-positive myeloid neoplasms.1 These patients typically present with peripheral blood eosinophilia. Cools et al2 described this entity as an interstitial deletion of chromosome 4q12 that leads to the juxtaposition of the FIP1L1 gene to the PDGFRA gene. The resultant fusion product, FIP1L1-PDGFRA, results in constitutive activation of the tyrosine kinase PDGFRA and is amenable to therapy with imatinib. Baccarani et al3 reported achievement of complete hematologic response with imatinib in all patients with FIP1L1PDGFRA fusion and the responses were durable.4 Our patient presented with characteristic diagnostic features of patients with CNL (neutrophilic leukocytosis, hypercellular bone marrow with granulocytic hyperplasia, and absence of dysplasia).5 Although the patient did not present with eosinophilia, FIP1L1PDGFRA fusion was tested because of the presence of skin rash and, remarkably, the test was positive. To the best of our knowledge, this is the first case of a FIP1L1-PDGFRA fusion without eosinophilia that responded to tyrosine kinase inhibitor therapy. There is a recent report of FIP1L1-PDGFRA fusion without eosinophilia in a patient with monoclonal gammopathy; however, the response to imatinib was not reported.6 Imatinib response in a patient with CNL has also been reported previously; however, the molecular mechanism for the response was not elucidated.7 The diagnosis could easily have been missed in our patient because he did not present with eosinophilia. Establishing the correct diagnosis significantly altered the treatment management because FIP1L1-PDGFRA fusion is extremely sensitive to imatinib. The 2008 World Health Organization classification lists “myeloid neoplasms associated with PDGFRA rearrangement” under “myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA,” indicative of a strong emphasis on the presence of eosinophilia.8 This is a report of a single patient, but because of the enormous therapeutic implications, we recommend that evaluation for FIP1L1-PDGFRA fusion should be considered for all patients with nonclassical myeloproliferative neoplasms. We evaluated 7 additional CNL patients who had stored samples for FIP1L1-PDGFRA fusion by FISH; however, all were negative. Recently, activating CSF3R mutations were identified in majority of patients with CNL.9,10 It is possible that CNL patients without CSF3R mutations (17% to 41% of cases) likely have alternate molecular pathogenic lesions leading to constitutive activation of other tyrosine kinases such as PDGFRA. Nitin Jain Department of Leukemia, MD Anderson Cancer Center, Houston, TX Joseph D. Khoury Department of Hematopathology, MD Anderson Cancer Center, Houston, TX
From www.bloodjournal.org by guest on September 11, 2016. For personal use only. 3388
CORRESPONDENCE
Naveen Pemmaraju Department of Leukemia, MD Anderson Cancer Center, Houston, TX Praveen Kollipara Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN Hagop Kantarjian Department of Leukemia, MD Anderson Cancer Center, Houston, TX Srdan Verstovsek Department of Leukemia, MD Anderson Cancer Center, Houston, TX Contribution: N.J., J.D.K., N.P., P.K., H.K., and S.V. collected data, analyzed data, and wrote the paper. Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Srdan Verstovsek, Department of Leukemia, Clinical Research Center for Myeloproliferative Neoplasms, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX; e-mail: sverstov@ mdanderson.org.
References 1. Tefferi A, Gotlib J, Pardanani A. Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc. 2010;85(2):158-164.
BLOOD, 7 NOVEMBER 2013 x VOLUME 122, NUMBER 19
2. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201-1214. 3. Baccarani M, Cilloni D, Rondoni M, et al. The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study. Haematologica. 2007;92(9): 1173-1179. 4. Pardanani A, D’Souza A, Knudson RA, Hanson CA, Ketterling RP, Tefferi A. Long-term follow-up of FIP1L1-PDGFRA-mutated patients with eosinophilia: survival and clinical outcome. Leukemia. 2012;26(11):2439-2441. 5. Elliott MA. Chronic neutrophilic leukemia and chronic myelomonocytic leukemia: WHO defined. Best Pract Res Clin Haematol. 2006;19(3):571-593. 6. Rudzki Z, Giles L, Cross NC, Lumley M. Myeloid neoplasm with rearrangement of PDGFRA, but with no significant eosinophilia: should we broaden the World Health Organization definition of the entity? Br J Haematol. 2012;156(5):558. 7. Choi IK, Kim BS, Lee KA, et al. Efficacy of imatinib mesylate (STI571) in chronic neutrophilic leukemia with t(15;19): case report. Am J Hematol. 2004;77(4): 366-369. 8. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22(1):14-22. 9. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368(19): 1781-1790. 10. Pardanani A, Lasho TL, Laborde RR, et al. CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. Leukemia. 2013;27(9): 1870-1873.
© 2013 by The American Society of Hematology
To the editor: Spontaneous coronary artery dissection during hematopoietic stem cell infusion Spontaneous coronary artery dissection (SCAD) is a rare event.1 Known risk factors include female gender, peripartum status, hypertension, cocaine, smoking, heavy exercise, collagen vascular
Figure 1. Coronary angiogram. Right anterior oblique cranial projection outlining the typical angiographic appearance of coronary artery dissection of the mid segment of the left anterior descending artery (arrow). Furthermore, it reveals an abrupt cutoff of the distal left anterior descending artery consistent with thrombotic occlusion (arrowhead).
disease,2,3 and cardiac catheterization.4,5 Clinical presentation may be indistinguishable from ST segment elevation myocardial infarction.6 To our knowledge, SCAD has not been described as an adverse event in relation to stem cell infusion. Here, we report on a 61-year-old white female without any known history of coronary artery disease, who underwent a nonmyeloablative (Fludarabine and TBI 400 cGy)-matched unrelated donor bone marrow transplant for a purine analog refractory chronic lymphocytic leukemia. Her pre-transplant echocardiogram was normal, demonstrating an ejection fraction (EF) of 68% without any regional wall motion abnormalities. Due to donor preference, a bone marrow harvest was obtained. The patient started complaining of intermittent chest pain and shoulder pain during the bone marrow infusion. Peak systolic and diastolic blood pressures were 168 and 106 mm Hg, heart rate of 220 beats per minute. An electrocardiogram remained unchanged and nondiagnostic in the presence of a known left bundle branch block. Troponin T serum concentration was elevated at 1.8 ng/mL (normal ,0.01). A stat echocardiogram demonstrated akinesis of the apex and midventricular wall, and an EF of 27% suggestive of an acute coronary syndrome. A coronary angiogram demonstrated a dissection of the mid left anterior descending artery with thrombus formation and thrombotic occlusion of the distal left anterior descending artery (Figure 1). No coronary intervention was pursued but an intra-aortic balloon was placed for coronary perfusion support. She eventually had an uneventful recovery and continues to do well 3 months after her transplant with improvement in her EF (50% with improvement in wall motion abnormalities).
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2013 122: 3387-3388 doi:10.1182/blood-2013-07-516500
Imatinib therapy in a patient with suspected chronic neutrophilic leukemia and FIP1L1-PDGFRA rearrangement Nitin Jain, Joseph D. Khoury, Naveen Pemmaraju, Praveen Kollipara, Hagop Kantarjian and Srdan Verstovsek
Updated information and services can be found at: http://www.bloodjournal.org/content/122/19/3387.full.html Articles on similar topics can be found in the following Blood collections Myeloid Neoplasia (1538 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
CORRESPONDENCE
3387
7. Walsh KM, Chokkalingam AP, Hsu LI, et al. Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children [published online ahead of print April 25, 2013]. Leukemia.
9. Boyle AP, Hong EL, Hariharan M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9): 1790-1797.
8. Zhang H, Nestor CE, Zhao S, et al. Profiling of human CD4(1) T-cell subsets identifies the TH2-specific noncoding RNA GATA3-AS1. J Allergy Clin Immunol. 2013;132(4):1005-1008.
© 2013 by The American Society of Hematology
To the editor: Imatinib therapy in a patient with suspected chronic neutrophilic leukemia and FIP1L1-PDGFRA rearrangement A 54-year-old man with no significant past medical history presented with skin rash. Complete blood count showed a white blood cell count of 64 3 109/L (63% neutrophils, 2% eosinophils), hemoglobin 14 g/dL, and platelet count 166 3 109/L. Bone marrow evaluation showed a hypercellular marrow with marked granulocytic hyperplasia (Figure 1). There was no increase in marrow eosinophils or fibrosis. No dysplasia was identified. Conventional cytogenetics showed constitutional inv(9). Testing for BCR-ABL rearrangement and JAK2V617F mutation was negative. The patient was diagnosed with chronic neutrophilic leukemia (CNL) and treatment with hydroxyurea was initiated. Subsequently, array comparative genomic hybridization demonstrated monoallelic interstitial deletion of chromosome 4q12. This was confirmed by interphase fluorescence in situ hybridization (FISH) analysis using a probe set that detects loss of CHIC2 (surrogate marker of the fusion of the factor interacting with PAP [Fip1]-like 1 [FIP1L1] gene to the platelet derived growth factor receptor-a [PDGFRA] gene) and by reverse-transcription polymerase chain reaction. The diagnosis was revised to myeloproliferative neoplasm with FIP1L1-PDGFRA fusion Imatinib (100 mg daily) was prescribed. Hydroxyurea was discontinued. The white blood cell count normalized within 2 weeks and follow-up testing for FIP1L1PDGFRA fusion by FISH at 3 months was negative. The patient
Figure 1. Bone marrow morphology and CHIC2 FISH. The bone marrow biopsy (left panel) demonstrated hypercellularity and marked predominance of maturing neutrophilic granulocytes. Megakaryocytes were decreased, and no features of myelofibrosis or myelodysplasia were present. Notably, eosinophils and blasts were rare. By fluorescence in situ hybridization (right panel) using a tricolor probe set (Abbott Molecular), normal cells had two intact tricolor (green/orange/aqua) fusion signals whereas abnormal cells (90% in this sample) with monoallelic loss of CHIC2 (orange pseudocolor) had one green/aqua fusion signal.
continues to be treated with imatinib 100 mg daily for .1 year with no recurrence of skin rash or leukocytosis. Imatinib is approved for treatment of patients with FIP1L1PDGFRA fusion-positive myeloid neoplasms.1 These patients typically present with peripheral blood eosinophilia. Cools et al2 described this entity as an interstitial deletion of chromosome 4q12 that leads to the juxtaposition of the FIP1L1 gene to the PDGFRA gene. The resultant fusion product, FIP1L1-PDGFRA, results in constitutive activation of the tyrosine kinase PDGFRA and is amenable to therapy with imatinib. Baccarani et al3 reported achievement of complete hematologic response with imatinib in all patients with FIP1L1PDGFRA fusion and the responses were durable.4 Our patient presented with characteristic diagnostic features of patients with CNL (neutrophilic leukocytosis, hypercellular bone marrow with granulocytic hyperplasia, and absence of dysplasia).5 Although the patient did not present with eosinophilia, FIP1L1PDGFRA fusion was tested because of the presence of skin rash and, remarkably, the test was positive. To the best of our knowledge, this is the first case of a FIP1L1-PDGFRA fusion without eosinophilia that responded to tyrosine kinase inhibitor therapy. There is a recent report of FIP1L1-PDGFRA fusion without eosinophilia in a patient with monoclonal gammopathy; however, the response to imatinib was not reported.6 Imatinib response in a patient with CNL has also been reported previously; however, the molecular mechanism for the response was not elucidated.7 The diagnosis could easily have been missed in our patient because he did not present with eosinophilia. Establishing the correct diagnosis significantly altered the treatment management because FIP1L1-PDGFRA fusion is extremely sensitive to imatinib. The 2008 World Health Organization classification lists “myeloid neoplasms associated with PDGFRA rearrangement” under “myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA,” indicative of a strong emphasis on the presence of eosinophilia.8 This is a report of a single patient, but because of the enormous therapeutic implications, we recommend that evaluation for FIP1L1-PDGFRA fusion should be considered for all patients with nonclassical myeloproliferative neoplasms. We evaluated 7 additional CNL patients who had stored samples for FIP1L1-PDGFRA fusion by FISH; however, all were negative. Recently, activating CSF3R mutations were identified in majority of patients with CNL.9,10 It is possible that CNL patients without CSF3R mutations (17% to 41% of cases) likely have alternate molecular pathogenic lesions leading to constitutive activation of other tyrosine kinases such as PDGFRA. Nitin Jain Department of Leukemia, MD Anderson Cancer Center, Houston, TX Joseph D. Khoury Department of Hematopathology, MD Anderson Cancer Center, Houston, TX
From www.bloodjournal.org by guest on September 11, 2016. For personal use only. 3388
CORRESPONDENCE
Naveen Pemmaraju Department of Leukemia, MD Anderson Cancer Center, Houston, TX Praveen Kollipara Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN Hagop Kantarjian Department of Leukemia, MD Anderson Cancer Center, Houston, TX Srdan Verstovsek Department of Leukemia, MD Anderson Cancer Center, Houston, TX Contribution: N.J., J.D.K., N.P., P.K., H.K., and S.V. collected data, analyzed data, and wrote the paper. Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Srdan Verstovsek, Department of Leukemia, Clinical Research Center for Myeloproliferative Neoplasms, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX; e-mail: sverstov@ mdanderson.org.
References 1. Tefferi A, Gotlib J, Pardanani A. Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc. 2010;85(2):158-164.
BLOOD, 7 NOVEMBER 2013 x VOLUME 122, NUMBER 19
2. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201-1214. 3. Baccarani M, Cilloni D, Rondoni M, et al. The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study. Haematologica. 2007;92(9): 1173-1179. 4. Pardanani A, D’Souza A, Knudson RA, Hanson CA, Ketterling RP, Tefferi A. Long-term follow-up of FIP1L1-PDGFRA-mutated patients with eosinophilia: survival and clinical outcome. Leukemia. 2012;26(11):2439-2441. 5. Elliott MA. Chronic neutrophilic leukemia and chronic myelomonocytic leukemia: WHO defined. Best Pract Res Clin Haematol. 2006;19(3):571-593. 6. Rudzki Z, Giles L, Cross NC, Lumley M. Myeloid neoplasm with rearrangement of PDGFRA, but with no significant eosinophilia: should we broaden the World Health Organization definition of the entity? Br J Haematol. 2012;156(5):558. 7. Choi IK, Kim BS, Lee KA, et al. Efficacy of imatinib mesylate (STI571) in chronic neutrophilic leukemia with t(15;19): case report. Am J Hematol. 2004;77(4): 366-369. 8. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22(1):14-22. 9. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368(19): 1781-1790. 10. Pardanani A, Lasho TL, Laborde RR, et al. CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. Leukemia. 2013;27(9): 1870-1873.
© 2013 by The American Society of Hematology
To the editor: Spontaneous coronary artery dissection during hematopoietic stem cell infusion Spontaneous coronary artery dissection (SCAD) is a rare event.1 Known risk factors include female gender, peripartum status, hypertension, cocaine, smoking, heavy exercise, collagen vascular
Figure 1. Coronary angiogram. Right anterior oblique cranial projection outlining the typical angiographic appearance of coronary artery dissection of the mid segment of the left anterior descending artery (arrow). Furthermore, it reveals an abrupt cutoff of the distal left anterior descending artery consistent with thrombotic occlusion (arrowhead).
disease,2,3 and cardiac catheterization.4,5 Clinical presentation may be indistinguishable from ST segment elevation myocardial infarction.6 To our knowledge, SCAD has not been described as an adverse event in relation to stem cell infusion. Here, we report on a 61-year-old white female without any known history of coronary artery disease, who underwent a nonmyeloablative (Fludarabine and TBI 400 cGy)-matched unrelated donor bone marrow transplant for a purine analog refractory chronic lymphocytic leukemia. Her pre-transplant echocardiogram was normal, demonstrating an ejection fraction (EF) of 68% without any regional wall motion abnormalities. Due to donor preference, a bone marrow harvest was obtained. The patient started complaining of intermittent chest pain and shoulder pain during the bone marrow infusion. Peak systolic and diastolic blood pressures were 168 and 106 mm Hg, heart rate of 220 beats per minute. An electrocardiogram remained unchanged and nondiagnostic in the presence of a known left bundle branch block. Troponin T serum concentration was elevated at 1.8 ng/mL (normal ,0.01). A stat echocardiogram demonstrated akinesis of the apex and midventricular wall, and an EF of 27% suggestive of an acute coronary syndrome. A coronary angiogram demonstrated a dissection of the mid left anterior descending artery with thrombus formation and thrombotic occlusion of the distal left anterior descending artery (Figure 1). No coronary intervention was pursued but an intra-aortic balloon was placed for coronary perfusion support. She eventually had an uneventful recovery and continues to do well 3 months after her transplant with improvement in her EF (50% with improvement in wall motion abnormalities).
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2013 122: 3387-3388 doi:10.1182/blood-2013-07-516500
Imatinib therapy in a patient with suspected chronic neutrophilic leukemia and FIP1L1-PDGFRA rearrangement Nitin Jain, Joseph D. Khoury, Naveen Pemmaraju, Praveen Kollipara, Hagop Kantarjian and Srdan Verstovsek
Updated information and services can be found at: http://www.bloodjournal.org/content/122/19/3387.full.html Articles on similar topics can be found in the following Blood collections Myeloid Neoplasia (1538 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
