CNS Relapse in Acute Promyeloctyic Leukemia

VOLUME 28 ⅐ NUMBER 24 ⅐ AUGUST 20 2010

JOURNAL OF CLINICAL ONCOLOGY DIAGNOSIS IN ONCOLOGY

eral blood stem-cell transplantation (SCT) for consolidation, with CNS Relapse in Acute Promyeloctyic high-dose busulfan and cyclophosphamide conditioning.6,7 Five Leukemia months after SCT, the patient presented with 1 week of right-sided headache worse with neck flexion, 3 days of intermittent visual loss in A 42-year-old female was diagnosed with acute promyelocytic her right eye, and paresthesias of the right leg. Magnetic resonance leukemia (APL) with a translocation of chromosomes 15 and 17 image revealed diffuse leptomeningeal enhancement. Figure 1 shows involving the PML and RARA genes. On presentation she met criteria an axial T1-weighted, gadolinium-enhanced image demonstrating ϫ 9 for low-risk disease on the basis of platelet count (50 10 /L) and regions of leptomeningeal enhancement (arrows). Cerebrospinal ϫ 9 1 WBC count (0.8 10 /L). The patient achieved a complete molecu- fluid (CSF) analysis revealed blast cells that were CD33 and CD13 lar remission after induction chemotherapy with all-trans-retinoic positive and HLA-DR negative, and RT-PCR confirmed the presence acid (ATRA) and idarubicin (AIDA) and underwent consolidation of PML-RARA transcripts. Figure 2 shows a diffuse infiltrate of myelo- chemotherapy per the risk-adapted Spanish Cooperative Group for blasts and promyelocytes within the CSF (Fig 2A). On high-power Hematological Malignancies Treatment (PETHEMA) regimen, on view (Fig 2B), several abnormal promyelocytes are noted, with intense 2 completion of which she remained in molecular remission. She azurophilic granules, bilobed nuclei, and dispersed chromatin. Auer subsequently received maintenance therapy with oral ATRA, 6- rods, single as well as multiple, are present. Bone marrow analysis mercaptopurine, and methotrexate per the Cancer and Leukemia Group B C9710 protocol.3 Two weeks after completion of maintenance therapy, the patient had a bone marrow examination that dem- onstrated molecular relapse, on the basis of a positive bone marrow reverse transcriptase polymerase chain reaction (RT-PCR) for PML- A RARA that was confirmed on repeat study 4 weeks later. Peripheral blood counts, bone marrow morphology, and cytogenetics were normal. The patient reachieved molecular remission after two 30-day cycles of arsenic trioxide (ATO)4,5 and underwent autologous periph-

Fig 1. Fig 2.

Downloaded from ascopubs.org by University of Queensland on January 30, 2017 from 130.102.082.157 Copyright © 2017 American Society of Clinical Oncology. All rights reserved. Housman et al revealed the presence of systemic relapse, as evidenced by bone mar- favorable clinical predictors at presentation, most notably a low WBC row with 28% blasts that were CD33 and CD13 positive and HLA-DR count. The presence of the same FLT3 ITD clone at diagnosis and at negative, with cytogenetics showing t(15;17). An FLT3 internal tan- relapse suggests that this mutation cooperated with PML-RARA in dem duplication (ITD) mutation was also identified in the bone mar- leukemia initiation and re-emergence. The absence of leukocytosis row, with 29% variant allele detectable at relapse (11% variant allele makes it difficult to attribute the CNS relapse to the FLT3 ITD or to the was present in the patient’s original diagnostic marrow sample). The absence of AraC in her initial therapy, and suggests that there are patient was treated with twice-weekly intrathecal methotrexate and additional as yet unidentified biologic factors that affect disease course cytarabine until her CSF cleared. She also completed 12 fractions (total and prognosis in APL. Finally, this report emphasizes the efficacy of of 24 Gy) whole-brain radiation therapy. Her systemic disease was ATO in APL therapy. successfully treated with two 30-day cycles of ATRA plus ATO (ATRA beginning on day 10) that sent her into a third molecular remission.8,9 Elizabeth Housman In view of the patient’s recent autologous SCT, it was felt that a second Boston University School of Medicine, Boston, MA fully myeloablative transplant would incur an unacceptably high risk 10 Priscilla Chang, Steven W. Lane, and Russell Blinder of veno-occlusive disease of the liver, thus the patient received a Brigham and Women’s Hospital, Boston, MA matched unrelated-donor nonmyeloablative allogeneic SCT.11 She is currently 6 months post transplantation and has had an uncompli- Ilene Galinsky, Santosh Kesari, Vincent T. Ho, cated course to date, with bone marrow assessment at 6 months Richard M. Stone, and Ann Mullally demonstrating 99% donor chimerism and sustained complete molec- Dana Farber Cancer Institute, Harvard Medical School, Boston, MA ular remission. There are a number of interesting and informative aspects to this AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST case. First, the patient suffered two relapses within 3 years despite The author(s) indicated no potential conflicts of interest. presenting initially with low-risk disease as defined by a platelet count more than 40 ϫ 109/L and WBC count less than 10 ϫ 109/L.1 Patients REFERENCES with low-risk APL treated on the PETHEMA protocol have a cumu- 1. Sanz MA, Lo Coco F, Martín G, et al: Definition of relapse risk and role of 2 nonanthracycline drugs for consolidation in patients with acute promyelocytic lative incidence of relapse of just 6.4% within 6 years. Notably, this leukemia: A joint study of the PETHEMA and GIMEMA cooperative groups. patient had an FLT3 ITD mutation present at diagnosis and at relapse. Blood 96:1247-1253, 2000 FLT3 encodes a membrane-bound receptor tyrosine kinase that has a 2. Sanz MA, Martín G, Gonzalez M, et al: Risk-adapted treatment of acute critical role in normal hematopoiesis and is mutated in up to 45% of promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochem- 12 otherapy: A multicenter study by the PETHEMA group. Blood 103:1237-1243, patients with APL. FLT3 mutations are associated with leukocytosis 2004 at presentation in APL but have not been independently correlated 3. Powell BL: Effect of consolidation with arsenic trioxide (As2O3) on with response to treatment or with survival.13,14 Second, the patient event-free survival (EFS) and overall survival (OS) among patients with newly had striking leptomeningeal disease in her second relapse (first mor- diagnosed acute promyelocytic leukemia (APL): North American Intergroup Protocol C9710. J Clin Oncol 25:1s, 2007 (suppl; abstr 2) phological relapse). Extramedullary relapse in APL is infrequent, oc- 4. Soignet SL, Maslak P, Wang ZG, et al: Complete remission after treatment curring in less than 5% of APL cases and largely predominates in the of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339:1341- CNS.15,16 It has been reported to be almost always associated with 1348, 1998 marrow relapse (as in our patient) and carries a poor prognosis.15 5. Soignet SL, Frankel SR, Douer D, et al: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19:3852- Extramedullary relapse has been shown to occur more frequently in 3860, 2001 9 patients with increased WBC count (Ͼ 10 ϫ 10 /L), in younger 6. Thomas X, Dombret H, Cordonnier C, et al: Treatment of relapsing acute patients (age Ͻ 45 years), and in those with the bcr3 PML-RARA promyelocytic leukemia by all-trans retinoic acid therapy followed by timed isoform, although only high WBC count remained significant on sequential chemotherapy and stem cell transplantation. APL Study Group. Acute 15 promyelocytic leukemia Leukemia 14:1006-1013, 2000 multivariate analysis. The German AML Cooperative Group has 7. Meloni G, Diverio D, Vignetti M, et al: Autologous bone marrow transplan- shown that high-dose AraC given as part of induction obviates the less tation for acute promyelocytic leukemia in second remission: Prognostic rele- favorable prognosis seen in APL patients with high WBC count,17 vance of pretransplant minimal residual disease assessment by reverse- presumably as a result of CNS penetration by AraC. ATO appears to transcription polymerase chain reaction of the PML/RAR alpha fusion gene. Blood 90:1321-1325, 1997 cross the blood-brain barrier to some extent, with one recent study 8. Shen ZX, Shi ZZ, Fang J, et al: All-trans retinoic acid/As2O3 combination demonstrating ATO CSF levels to be approximately 18% of ATO yields a high quality remission and survival in newly diagnosed acute promyelo- plasma levels.18 Finally, it is notable that the patient was able to achieve cytic leukemia. Proc Natl Acad SciUSA101:5328-5335, 2004 a molecular remission with ATO therapy at each relapse. ATO is an 9. Ravandi F, Estey E, Jones D, et al: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab extremely active agent in APL therapy with CR rates of approximately ozogamicin. J Clin Oncol 27:504-510, 2009 5 85% in relapsed patients. The Shanghai group recently reported an 10. Ho VT, Revta C, Richardson PG: Hepatic veno-occlusive disease after overall survival of 92% at 5 years in newly diagnosed patients treated hematopoietic stem cell transplantation: Update on defibrotide and other current with ATRA/ATO, with WBC count at diagnosis, FLT3 mutational investigational therapies. Bone Marrow Transplant 41:229-237, 2008 19 11. Kharfan-Dabaja MA, Abou Mourad YR, Fernandez HF, et al: Hematopoietic status, and PML-RARA isoform having no impact on prognosis. cell transplantation in acute promyelocytic leukemia: A comprehensive review. These results have led to the use of ATRA-ATO as first-line treatment Biol Blood Marrow Transplant 13:997-1004, 2007 for older patients with APL9 and to the prediction that ATRA-ATO 12. Lo-Coco F, Ammatuna E: The biology of acute promyelocytic leukemia and will become standard therapy for all patients in the future.20 In sum- its impact on diagnosis and treatment. Hematology Am Soc Hematol Educ Program 156-61, 514, 2006 mary, this report highlights the case of a young woman with APL who 13. Noguera NI, Breccia M, Divona M, et al: Alterations of the FLT3 gene in had a very aggressive course that included a CNS relapse, despite acute promyelocytic leukemia: Association with diagnostic characteristics and

Downloaded from ascopubs.org by University of Queensland on January 30, 2017 from 130.102.082.157 Copyright © 2017 American Society of Clinical Oncology. All rights reserved. Diagnosis in Oncology analysis of clinical outcome in patients treated with the Italian AIDA protocol. in patients with newly diagnosed acute promyelocytic leukemia. German AML Leukemia 16:2185-2189, 2002 Cooperative Group. Leukemia 14:1362-1370, 2000 14. Gale RE, Hills R, Pizzey AR, et al: Relationship between FLT3 mutation 18. Au WY, Tam S, Fong BM, et al: Determinants of cerebrospinal ﬂuid arsenic status, biologic characteristics, and response to targeted therapy in acute concentration in patients with acute promyelocytic leukemia on oral arsenic promyelocytic leukemia. Blood 106:3768-3776, 2005 trioxide therapy. Blood 112:3587-3590, 2008 15. de Botton S, Sanz MA, Chevret S, et al: Extramedullary relapse in acute 19. Hu J, Liu YF, Wu CF, et al: Long-term efﬁcacy and safety of all-trans promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelo- Leukemia 20:35-41, 2006 cytic leukemia. Proc Natl Acad SciUSA106:3342-3347, 2009 16. Specchia G, Lo Coco F, Vignetti M, et al: Extramedullary involvement at 20. Tallman MS, Altman JK: How I treat acute promyelocytic leukemia. Blood relapse in acute promyelocytic leukemia patients treated or not with all-trans 114:5126-5135, 2009 retinoic acid: A report by the Gruppo Italiano Malattie Ematologiche dell’Adulto. J Clin Oncol 19:4023-4028, 2001 17. Lengfelder E, Reichert A, Schoch C, et al: Double induction strategy DOI: 10.1200/JCO.2009.27.1577; published online ahead of print at including high dose cytarabine in combination with all-trans retinoic acid: Effects www.jco.org on June 7, 2010

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Acknowledgment We thank Stefan Frohling, MD, for his insightful discussion of this case.