An Unusual Presentation of Chronic Myelogenous Leukemia: A Review of Isolated Central Nervous System Relapse

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1 745 An Unusual Presentation of Chronic Myelogenous Leukemia: A Review of Isolated Central Nervous System Relapse Scott M. Lindhorst, MD a,b ; Richard D. Lopez, MD a ; and Ronald D. Sanders, MD c Abstract Many effective therapeutic options are available for patients with chronic myelogenous leukemia (CML). Imatinib, a first-generation tyrosine kinase inhibitor (TKI), is one of several options for patients who present with CML, whether in chronic phase, accelerated phase, or blast crisis. Although CML is very responsive to the selective TKIs, with response rates in chronic phase of greater than 90%, unusual presentations have been documented. Response rates for patients with CML in accelerated phase and blast crisis are notably lower to both first- and second-generation TKIs. This report presents a recent case of a young woman with newly diagnosed CML who presented with an accelerated phase isolated central nervous system (CNS) relapse after standard imatinib therapy, who initially experienced a complete hematologic response. Further treatment options, and monitoring of disease response, are discussed. Aggressive strategies, such as intrathecal chemotherapy, change in tyrosine kinase inhibitor to one with increased CNS penetration, and consideration of allogenic stem cell transplantation, are potential therapeutic modalities. Prophylaxis of the CNS in patients deemed at risk is an area requiring further study. (JNCCN 2013;11: ) NCCN: Continuing Education Accreditation Statement This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center`s Commission on Accreditation. This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity. All clinicians completing this activity will be issued a certificate of participation. To participate in this journal activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the post-test with a 70% minimum passing score and complete the evaluation at node/24439; and 4) view/print certificate. Release date: July 12, 2013; Expiration date: July 12, 2014 Learning Objectives Upon completion of this activity, participants will be able to: Compare and contrast response rates to TKI therapy for patients who present with CML in chronic phase, accelerated phase, or blast crisis Discuss treatment strategies and monitoring of response to isolated CNS disease in patients with CML From the a Division of Hematology & Oncology, The University of Alabama at Birmingham Medical Center and Comprehensive Cancer Center, Birmingham, Alabama; b The Preston Robert Tisch Brain Tumor Center at Duke University Medical Center, Durham, North Carolina; and c Department of Pathology, The University of Alabama at Birmingham Medical Center and Comprehensive Cancer Center, Birmingham, Alabama. Submitted June 4, 2012; accepted for publication April 4, The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Correspondence: Scott M. Lindhorst, MD, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Trent Drive, 0317E Baker House, DUMC Box 3624, Durham, NC scott.lindhorst@duke.edu EDITOR Kerrin M. Green, MA, Assistant Managing Editor, JNCCN Journal of the National Comprehensive Cancer Network Ms. Green has disclosed that she has no relevant financial relationships. AUTHORS Deborah J. Moonan, RN, BSN, Manager, Supporter Outreach Ms. Moonan has disclosed the following relationship with commercial interests: AstraZeneca: Stockholder/Former Employee. Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations Ms. Gregory has disclosed that she has no relevant financial relationships.

2 746 Lindhorst et al Many effective therapeutic options are available for patients with chronic myelogenous leukemia (CML). The disease is a clonal myeloproliferative neoplasm characterized by a reciprocal rearrangement and fusion of the BCR and ABL genes. The driving factor for disease progression is the fusion gene product, the BCR/ABL tyrosine kinase. 1 Imatinib, a firstgeneration tyrosine kinase inhibitor (TKI), is one of several options for patients who present with CML, whether in chronic phase, accelerated phase, or blast crisis. 2 Although CML is very responsive to the selective TKIs, with response rates in chronic phase of greater than 90%, 3 unusual presentations have been documented. 4 Increased efficacy of TKI therapies in chronic phase CML has resulted in higher levels of molecular response compared with more advanced disease. Patients with newly diagnosed CML are noted to experience a 40% to 70% rate of major molecular response (BCR/ABL transcript level <0.1%). 5 The more potent second-generation TKIs (ie, nilotinib and dasatinib) produce higher molecular response rates than imatinib. Response rates to TKI therapy are notably lower for accelerated phase CML, with major molecular response rates reported at 20% to 30%, and less than 10% in blast phase CML. 6 This report presents a recent case of a young woman with newly diagnosed CML who presented with an isolated central nervous system (CNS) relapse after standard imatinib therapy with good response. Further treatment options, and monitoring of disease response, are discussed. A 24-year-old otherwise healthy Caucasian woman presented with several weeks of progressive fatigue, bruising, and eventually the development of fevers. She had no prior medical problems and took no medications. Physical examination revealed only moderate splenomegaly, measuring 14 cm. On initial laboratory evaluation, she was found to have a WBC count of 385,000/mm 3, a hemoglobin level of 8.2 g/dl, hematocrit 24%, and a platelet count of 1.23 million/mm 3. Differential revealed 25% neutrophils, 3% bands, 10% lymphocytes, 0% monocytes, 7% eosinophils, 1% basophils, 7% metamyelocytes, 24% myelocytes, 15% blasts, and 8% promyelocytes. Her lactate dehydrogenase level was 1938 U/L. A bone marrow biopsy revealed accelerated phase CML. Additional studies included flow cytometry, which was consistent with an increase in myeloid blasts, with approximately 5% of total cells CD34 +, CD117 +, CD13 low, CD33 +, CD15, CD64, CD2, CD56, and HLA-DR variable. Peripheral blood flow cytometry revealed an increased population of myeloid blasts, with approximately 3.6% of the cells staining positive for CD34, CD117, and CD7. Bone marrow PCR for the BCR/ABL1 fusion transcript revealed a ratio of compared with the internal control transcript (ABL). Chromosome analysis of bone marrow revealed 46,XX,t(9;22)(q34;q11.2) in 15 of 15 unstimulated bone marrow cells. Fluorescence in situ hybridization (FISH) analysis using the LSI BCR/ABL1 fusion probe (Abbott Laboratories; Abbott Park, Illinois) revealed that 97% of cells in the bone marrow contained the gene fusion. Based on the high white count presentation, the patient was admitted to an outside hospital where cytoreduction consisting of hydroxyurea and imatinib at 800 mg/d was initiated. Similar major molecular response rates at 1 year have been reported with imatinib at doses of both 800 and 400 mg/d; however, rates of major molecular response and complete cytogenetic response have been reported to occur earlier with the 800-mg/d dose. The clinical significance of earlier responses on high-dose imatinib has not been definitively established. 7 The patient tolerated initial cytoreduction with excellent response in counts. Based on initial response to therapy, consideration of upfront allogeneic hematopoietic stem cell transplantation was deferred. The patient was discharged and followed up as an outpatient, where imatinib was decreased to 400 mg/d. Hydroxyurea was discontinued soon after discharge. Over the next several months, the patient underwent regular follow-up. At 1 month from diagnosis, an excellent response was noted, with WBC counts decreasing to 1600/mm 3 with no left-shifted forms and no blasts. A complete hematologic response was obtained by 2 months from diagnosis, with a WBC count of 2600/mm 3, hemoglobin level of 12 g/dl, and a platelet count of 224,000/mm 3. The differential failed to show a left shift or any immature forms in peripheral blood. However, 3 months after initiation of therapy, despite a hematologic response, the patient began to develop fatigue. At this time, the patient presented to

3 747 CNS Relapse in CML the emergency department for new headache evaluation. A CT scan of the head was normal. However, because of worsening symptoms, the patient was admitted to the hematology inpatient service for more definitive evaluation and diagnostics. An MRI of the brain showed increased signal intensity in the periventricular area of the third ventricle on T2 imaging, although artifact could not be ruled out. A diagnostic lumbar puncture revealed the presence of CML. The WBC count in the cerebrospinal fluid (CSF) was 468 cells/mm 3. The cytology report described this finding as consistent with CML blast crisis. Flow cytometry performed on the cytospin specimen was found to be entirely consistent with immature blasts in the CSF, which were of myeloid lineage. FISH analysis also revealed that 100% of cells in the CSF contained the BCR/ABL fusion. Cytogenetic results were also consistent with CML (Figure 1). Treatment was initiated, consisting of therapeutic lumbar puncture with intrathecal cytarabine and hydrocortisone. The patient tolerated this well with fairly immediate resolution of symptoms. Also, given the patient s CML involvement of the CNS, the patient was changed from imatinib to dasatinib, because it was reasoned that the dasatinib would have better CNS penetration. Figure 1 Cytospin preparation of the cerebrospinal fluid showing blasts (top left and bottom center; Wright-Giemsa stain, original magnification x100). As part of the patient s restaging, a bone marrow biopsy with aspirate was performed, which was morphologically described as showing no evidence of disease. Flow cytometry likewise showed no evidence of disease. FISH analysis of the bone marrow failed to show any BCR/ABL fusion. Karyotype analysis revealed that 1 of 20 cells was 46,XY,t(9;22), Philadelphia chromosome positive (Ph + ), despite negative FISH results noted earlier. Peripheral blood PCR for the BCR/ABL fusion transcript revealed a ratio of 0.02 compared with an internal ABL control transcript. Mutational analysis of the TKI domain was performed on the bone marrow and failed to show any significant or known mutations of the TKI-binding domain. One week later, the patient received intrathecal methotrexate and hydrocortisone. CSF from this procedure revealed that the WBC count in the CSF had decreased from more than 460 to 99 white blood cells, although 39% of these still were blasts. The patient was subsequently discharged after placement of a Holter-Rickham shunt. The patient subsequently received scheduled intrathecal chemotherapy, primarily with liposomal cytarabine (Table 1). Based on subsequent clearing of the CSF with initial intrathecal liposomal cytarabine, the patient was scheduled to receive monthly liposomal cytarabine for a year as part of her ongoing therapy. The patient was thereafter maintained on 140 mg/d of dasatinib. She tolerated dasatinib well with the exception of a presentation to the emergency room complaining of new-onset chest pain and shortness of breath, which resolved with ibuprofen. Evaluation did not show fluid retention in the form of edema, pleural effusion, or pericardial effusion. Subsequently, the patient was referred to the bone marrow transplant program to discuss whether an allogeneic transplantation under these circumstances would be a reasonable option compared with long-duration therapy using intrathecal therapy, plus or minus whole-brain radiation, for her unusual CNS involvement with CML. The patient s care plan included once-monthly intrathecal cytarabine for 1 year. The patient was referred for allogeneic stem cell transplant from an unrelated donor 10 months after diagnosis. The preparative regimen included total body irradiation along with etoposide and antithymocyte globulin, with tacrolimus and methotrexate for graft-versushost disease prophylaxis. Plans were made to reinitiate TKI therapy 100 days after stem cell transplant.

4 748 Lindhorst et al Table 1 Representative Response to Intrathecal Therapy as Measured in the Cerebrospinal Fluid While on Dasatinib Days of Therapy Intrathecal Chemotherapy WBC/mcL Blood (BCR/ABL-to- ABL Ratio) 1 Cytarabine Methotrexate Liposomal cytarabine Liposomal cytarabine 8 (CSF negative by FISH for BCR/ABL) Liposomal cytarabine Liposomal cytarabine Liposomal cytarabine 4 (CSF negative by flow for BCR/ABL) Abbreviations: CSF, cerebrospinal fluid; FISH, fluorescence in situ hybridization Bone (BCR/ABL to- ABL Ratio) Discussion Despite achieving an initial hematologic response to imatinib at the 3 month milestone, this patient was found to have significant CNS disease at that time, consistent with CNS relapse. She was then treated with intrathecal chemotherapy using liposomal cytarabine, a therapy shown to provide good local disease control, specifically in patients previously on imatinib. 8 The imatinib was changed to dasatinib, a second-generation TKI with demonstrated efficacy, 9,10 based on dasatinib s superior CNS penetration. 11 CNS involvement is not typical for CML, although it has been well described. 12 Seeding of the CNS by leukemia cells is seen more often with high WBC counts at presentation. 13 In this patient, any leukemia cells present in the CNS could have eluded initial imatinib therapy because of the relatively poor CNS penetration of imatinib itself. 14 CML in blast crisis has been shown to have a propensity for CNS involvement. 15 Although also seen in Ph + acute lymphoblastic leukemia, an isolated CNS presentation of CML in chronic phase while on adequate TKI therapy has been less well described. 16 Standard therapies for CNS leukemia often result in significant toxicities and nonsustained responses. These interventions include high-dose systemic therapy, either with methotrexate or cytarabine; intrathecal chemotherapy with the same agents; and radiation to the craniospinal axis. 8 With the advent of TKIs, with imatinib as the prototype for BCR/ABL tyrosine kinase inhibition, efforts have been made to incorporate them into the treatment strategies of patients with Ph + leukemia with CNS disease. 17 CNS relapses have been documented in approximately 20% of patients with CML in blast crisis or Ph + ALL already treated with imatinib. 17,18 As in this patient, these cases often showed complete responses in the bone marrow and peripheral blood before relapse. This finding bolsters the case for the CNS as a sanctuary site for CML on treatment with imatinib. 19,20 Imatinib has been shown to produce a complete cytogenetic response in approximately 90% of patients in chronic phase CML, 3 and is currently included in the NCCN Guidelines for CML along with the second-generation TKIs as an option for first-line therapy 21 (to view the most recent version of these guidelines, visit NCCN.org). Porkka et al 11 showed the inability of imatinib to prevent CNS relapses, resulting from poor drug penetration across the blood brain barrier. Using a preclinical mouse model, treatment with imatinib and the second-generation TKI dasatinib was compared in intracranial Ph + leukemia. In this experiment, imatinib failed to inhibit intracranial tumor growth, whereas treatment with dasatinib induced clinically meaningful responses and resulted in increased survival. CNS disease showed both stabilization and regression on dasatinib. These results translated into a small human trial of 11 patients with Ph + ALL or blast crisis CML with CNS involvement. On diagnosis of CSF disease, treatment was initiated with oral dasatinib at 140 mg or 70 mg twice daily, with dose escalation in patients showing lack of response. A lumbar puncture was performed every 1 to 4 weeks to assess patient response via quantitative PCR analysis of the BCR/ABL transcript. All evaluated patients showed

5 749 CNS Relapse in CML a response. In addition, dasatinib was shown to have significantly greater CNS penetration than imatinib, as noted by pharmacokinetic measurement and plasma and CSF. 11 Conclusions The possibility of isolated CNS disease in patients with CML previously treated with imatinib should be considered. This may be more important in patients who initially present with hyperleukocytosis, particularly those in blast crisis. As in this patient, isolated CNS relapse may present even in those who have shown a complete hematologic and at least a major cytogenetic response to imatinib therapy. This patient was noted to be in blast crisis, with blasts of myeloid lineage present in the CNS. Aggressive strategies, such as intrathecal chemotherapy, change of TKI to one with increased CNS penetration, and consideration of allogenic stem cell transplantation, are potential therapeutic modalities. CNS prophylaxis in patients deemed at-risk requires further study. References 1. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med 1999;341: O Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med 2003;349: Deininger M, O Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib [abstract]. Blood 2009;114:Abstract Rajappa S, Uppin SG, Raghunadharao D, et al. Isolated central nervous system blast crisis in chronic myeloid leukemia. Hematol Oncol 2004;22: Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011;12: Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012;119: Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 2010;28: Aichberger KJ, Herndlhofer S, Agis H, et al. Liposomal cytarabine for treatment of myeloid central nervous system relapse in chronic myeloid leukaemia occurring during imatinib therapy. Eur J Clin Invest 2007;37: Kantarjian H, Shah N, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010;362: Taylor MJ, Scuffham PA. Pharmacoeconomic benefits of dasatinib in the treatment of imatinib-resistant patients with chronic myelogenous leukemia. Expert Rev Pharmacoecon Outcomes Res 2009;9: Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 2008;112: Radhika N, Minakshi M, Rajesh M, et al. Central nervous system blast crisis in chronic myeloid leukemia on imatinib mesylate therapy: report of two cases. Indian J Hematol Blood Transfus 2011;1: Altintas A, Cil T, Kilinc I, et al. Central nervous system blastic crisis in chronic myeloid leukemia on imatinib mesylate therapy: a case report. J Neurooncol 2007;84: Isobe Y, Sugimoto K, Masuda A, et al. Central nervous system is a sanctuary site for chronic myelogenous leukaemia treated with imatinib mesylate. Intern Med J 2009;30: Kim HJ, Jung CW, Kim K, et al. Isolated blast crisis in CNS in a patient with chronic myelogenous leukemia maintaining major cytogenetic response after imatinib. J Clin Oncol 2006;24: Rytting ME, Weirda WG. Central nervous system relapse in two patients with chronic myelogenous leukemia in myeloid blastic phase on imatinib mesylate therapy. Leuk Lymphoma 2004;45: Aftimos P, Nasr F. Isolated CNS lymphoid blast crisis in a patient with imatinib-resistant chronic myelogenous leukemia: case report and review of the literature. Leuk Res 2009;33:e Pavlu J, Czepulkowski B, Kaczmarski R, Jan-Mohamed R. Early blastic transformation with CNS infiltration in a patient with chronic myeloid leukaemia treated with imatinib. Lancet Oncol 2005;6: Breccia M, Santopietro M, Cannella L, et al. Isolated central nervous system relapse after nine years of complete molecular remission in a lymphoid blast crisis of chronic myeloid leukemia treated with imatinib. Leuk Res 2011;35;e Bujassoum S, Rifkind J, Lipton JH. Isolated central nervous system relapse in lymphoid blast crisis chronic myeloid leukemia and acute lymphoblastic leukemia in patients on imatinib therapy. Leuk Lymphoma 2004;45: O Brien S, Abboud CN, Akhtari M, et al. NCCN Clinical Practice Guidelines in Oncology for chronic myelogenous leukemia. Version Available at NCCN.org. Accessed June 24, 2013.

6 750 Lindhorst et al Instructions for Completion choice questions. Credit cannot be obtained for tests completed on paper. You must be a registered user on NCCN.org. If you are not registered on NCCN.org, click on New Member? Sign up here link on the left hand side of the Web site to register. Only one answer is correct for each question. Once you successfully answer all posttest questions you will be able to view and/or print your certificate. Software requirements: Internet. PostTest Questions 1. CNS relapses have been documented in approximately % of patients with CML in blast crisis or Ph + ALL already treated with imatinib. a. 30% b. 20% c. 10% d. 5% 2. Dasatinib is more active than imatinib for the treatment of isolated CNS disease in patients with CML. To participate in this journal activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 70% minimum passing score and complete the evaluation at node/24439; and 4) view/print certificate. After reading the article, you should be able to answer the following multiplea. True b. False 3. For patients in blast crisis with blasts of myeloid lineage present in the CNS who have had previous response to imatinib therapy, which of the following are potential therapeutic options? a. Intrathecal chemotherapy b. Switch to a TKI with increased CNS penetration c. Radiation therapy to the craniospinal axis d. all of the above