For Relapsed Early T-Cell Precursor ALL

Home , Nelarabine

LETTER TO THE EDITOR Durable remission with salvage decitabine and donor lymphocyte infusion (DLI) for relapsed early T-cell precursor ALL

Bone Marrow Transplantation (2017) 52, 1583–1584; doi:10.1038/ expressing CD5, CD7 with cytoplasmic CD3 and aberrant bmt.2017.191; published online 11 September 2017 expression of myeloid antigens CD13, CD33 and CD117 without myeloperoxidase expression. FISH showed normal male karyotype, 46-XY. He was treated per MRC UKALL XII/ECOG E2993 protocol7 T-cell ALL (T-ALL) comprises ~ 25% of ALL diagnoses in adults,1 with intrathecal methotrexate prophylaxis. After achieving CR, he and remains an aggressive leukemia. T-ALL is a heterogenous continued treatment with four cycles of multiagent consolidation disease classified according to different stages and surface chemotherapy followed by maintenance therapy per protocol. markers expressed during T-cell development. Early T-cell He remained in CR until early 2005 when his leukemia relapsed precursor (ETP) ALL is defined by early intrathymic developmental with 29% blasts in the bone marrow that demonstrated a similar arrest in T-cells. With the adaptation of pediatric-inspired T-cell phenotype with aberrant expression of myeloid antigens. He multiagent chemotherapy regimens, the outcome in adult T-ALL underwent reinduction with cytarabine and mitoxantrone fol- has improved.2 Nevertheless, compared to the non-ETP-ALL type, lowed by high-dose cytarabine consolidation, which resulted in ETP-ALL has a 10-year overall survival of only 19%.3 A purine achievement of a second CR. Then, at the age of 62, he proceeded nucleoside antimetabolite, nelarabine, has been approved for the to a peripheral blood unrelated HLA-matched allo-HSCT with TBI treatment of patients with T-ALL and T-cell lymphoblastic and high-dose melphalan myeloablative conditioning. He toler- lymphoma whose disease has not responded to or has relapsed ated his transplant well without development of graft versus host following treatment with at least two chemotherapy regimens.4 disease (GvHD). In 2006, ~ 1 year after allo-HSCT, his disease Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has relapsed for the second time with the same original phenotype. been adopted with curative intent for treatment of patients with He underwent another salvage treatment with cytarabine and ALL in the first or second CR,5 who can tolerate this treatment mitoxantrone, and achieved his third CR with full count recovery modality. For elderly or medically unfit patients with persistent and 100% donor chimerism. Remarkably he remained in CR for ALL, clinical trials and other salvage therapy are the only ~ 10 years, despite never having received additional donor cells. treatment options. Unfortunately, in 2016 he developed pancytopenia and was Here we report, the first case to our knowledge, of ETP-ALL in an found to have peripheral blasts once again. Bone marrow aspirate adult patient that relapsed after conventional induction che- and biopsy confirmed his third relapse of ETP-ALL with a similar motherapy, an allo-HSCT and nelarabine, but subsequently phenotype to that at diagnosis, with coexpression of myeloid responded to the combination of a DNA methyltransferase antigens CD117, CD13 and CD33 without expression of myeloper- inhibitor, 5-aza-2ʹ-deoxycytidine (decitabine)6 with donor lympho- oxidase, CD11c or lysozyme. Approximately 83% of cells showed a cyte infusions (DLI), and has remained in CR for 9 months hyperdiploid karyotype. He was next treated with nelarabine (Figure 1). 1500 mg/m2 IV on days 1, 3 and 5 repeated every 21 days, and A 73-year-old Caucasian man was diagnosed with T-ALL without achieved CR after 4 cycles of nelarabine. Unfortunately, he central nervous system involvement in 2003 at the age of 60. The developed a severe sensory neuropathy of his bilateral lower original bone marrow biopsy and aspirate showed 420% blasts extremities with profound disturbance in the large fiber/dorsal

CR CR CR CR CR (x2 years) (x1 years) (x10 years) (x4 months) (x9 months & remains in CR)

T-ALL T-ALL relapse T-ALL relapse T-ALL relapse T-ALL relapse (2003) (2005) (2006) (2016) (2016)

MRC UKALL Cytarabine & Cytarabine Nelarabine DLI Decitabine XII/ECOG Mitoxantrone & & E2993 protocol followed by Mitoxantrone DLI MUD-HSCT (HD melaphalan and TBI)

Figure 1. Timeline of disease course with response and treatment plan. CR = complete remission; DLI = donor lymphocyte infusion; HD = high dose; MUD-HSCT = matched unrelated donor-hematopoietic stem cell transplantation; T-ALL = T-acute lymphoblastic leukemia; TBI = total body irradiation. A full color version of this figure is available at the Bone Marrow Transplantation journal online. Letter to the Editor 1584 column function attributed to nelarabine, which required perma- In conclusion, using decitabine, as a single agent or preferably nent discontinuation. After cessation of nelarabine, he developed in combination with DLI, for treatment of refractory or relapsed new onset atrial fibrillation which required prolonged hospitaliza- ETP-ALL following allogeneic SCT warrants further investigation in tion during which time he developed pancytopenia in the prospective clinical trials. absence of confirmed relapsed disease. He received low dose (1 × 106 CD3+ cells/kg body weight) DLI with the intent of prolonging his remission and improving his counts. Unfortunately, CONFLICT OF INTEREST one month after this DLI, the leukemia relapsed for the The authors declare no conflict of interest. fourth time. Taking into account his poor performance status, the resistance F El Chaer1,2, N Holtzman1,2, E Binder1,2, NC Porter3, ZN Singh4, of the T-lymphoblasts to conventional cytotoxic chemotherapeu- M Koka4, AP Rapoport1,2 and A Emadi1,2 tics, and the unavailability of suitable clinical trials, decitabine was 1University of Maryland Greenebaum Comprehensive Cancer Center, chosen for the next line of treatment in conjunction with Baltimore, MD, USA; escalating doses of DLI. Decitabine can upregulate the expression 2Department of Medicine, University of Maryland School of Medicine, of cell surface markers including aberrant myeloid antigens and Baltimore, MD, USA; may epigenetically downregulate LYL1 and BCL2 genes in ETP-ALL 3Department of Neurology, University of Maryland School of cells. Further, decitabine has well known and tolerable adverse Medicine, Baltimore, MD, USA and event profile.8,9 The patient was treated with 10 days of IV 4Department of Pathology, University of Maryland School of decitabine at a dose of 20 mg/m2/day repeated every 28 days.9 Medicine, Baltimore, MD, USA After completing two cycles of decitabine, the patient recovered E-mail: [email protected] his platelet counts without evidence of circulating blasts, although he remained neutropenic. A bone marrow aspirate and biopsy showed no morphologic or immunophenotypic evidence of REFERENCES involvement by ETP-ALL indicating achievement of CR with 1 Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med 2004; incomplete count recovery (CRi) and 100% donor DNA chimerism 350: 1535–1548. by STR analysis. The patient received a third cycle of decitabine 2 Stock W, Luger SM, Advani AS, Geyer S, Harvey RC, Mullighan CG et al. Favorable outcomes for older adolescents and young adults (AYA) with acute lymphoblastic with similar dosing but for a shorter, 5-day duration. A few days 124 after completing this third cycle, a higher dose (1.0 × 107 CD3+ leukemia (ALL): early results of U.S. intergroup trial C10403. Blood 2014; : 796. 3 Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D et al. Early mononuclear cells/kg body weight) DLI was administered. He 7 + T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leu- received a third DLI (2.8 × 10 CD3 mononuclear cells/kg body kaemia. Lancet Oncol 2009; 10:147–156. weight) after his 4th cycle of decitabine and a fourth DLI with 4 DeAngelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT et al. Nelarabine 3.34 × 107 CD3+ mononuclear cells/kg body weight shortly after induces complete remissions in adults with relapsed or refractory T-lineage acute his 6th and final cycle of decitabine. At 9 months of follow-up after lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia starting decitabine treatment and 2 months after his sixth (and Group B study 19801. Blood 2007; 109: 5136–5142. final) cycle of decitabine, the patient remained in CR with 100% 5 Bakr M, Rasheed W, Mohamed SY, Al-Mohareb F, Chaudhri N, Al-Sharif F et al. donor chimerism in the myeloid, lymphoid and NK cell compart- Allogeneic hematopoietic stem cell transplantation in adolescent and adult fi patients with high-risk T cell acute lymphoblastic leukemia. Biol Blood Marrow ments of the peripheral blood and had signi cant improvement in Transplant 2012; 18: 1897–1904. his peripheral neuropathy and performance status. At last follow- 6 Reddy H, Duffy A, Holtzman NG, Emadi A. The role of β-elimination for the clinical up he did develop evidence of GvHD with lichenoid changes in activity of hypomethylating agents and cyclophosphamide analogues. American the oral cavity and elevated transaminases and bilirubin which Journal of Cancer Therapy and Pharmacology 2016; 3:1–8. was confirmed by biopsy to be due to liver GvHD. He was treated 7 Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM et al. Induction with prednisone. therapy for adults with acute lymphoblastic leukemia: results of more than 1500 Here, we report that decitabine in combination with DLI patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; 106 – appears to be an effective option for relapsed T-ALL after multiple : 3760 3767. lines of therapy, including allo-HSCT. Epigenetic modulation has 8 McCormack MP, Shields BJ, Jackson JT, Nasa C, Shi W, Slater NJ et al. Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL. Blood 2013; 122: been a successful approach for treatment of hematologic 2093–2103. malignancies. Decitabine is currently approved for treatment of 9 Bhatnagar B, Duong VH, Gourdin TS, Tidwell ML, Chen C, Ning Y et al. Ten-day myelodysplastic syndrome in the United States, and of acute decitabine as initial therapy for newly diagnosed patients with acute myeloid myeloid leukemia in Europe. Use of decitabine in a refractory case leukemia unfit for intensive chemotherapy. Leuk Lymphoma 2014; 55: 1533–1537. of childhood B-ALL has been reported with achievement of CR in a 10 Yánez L, Bermúdez A, Richard C, Bureo E, Iriondo A. Successful induction therapy heavily pretreated patient.10 However, to our knowledge, its with decitabine in refractory childhood acute lymphoblastic leukemia. Leukemia successful use in T-ALL has not been reported yet. The 2009; 23: 1342–1343. combination of decitabine with vorinostat, a histone deacetylase 11 Burke MJ, Lamba JK, Pounds S, Cao X, Ghodke-Puranik Y, Lindgren BR et al. A therapeutic trial of decitabine and vorinostat in combination with che- inhibitor, showed encouraging results in the treatment of patients 11 motherapy for relapsed/refractory acute lymphoblastic leukemia. Am J Hematol with relapsed and refractory ALL, as well. 2014; 89: 889–895. Emerging data highlight the essential role of aberrant DNA 12 Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D et al. The genetic 12,13 hypermethylation in leukemogenesis of T-ALL as well as in basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012; 481: development of relapsed T-ALL.14 Furthermore, inhibition of DNA 157–163. methyltransferase with a 5-aza-nucleoside, such as decitabine or 13 Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ et al. An azacitidine, could result in DNA hypomethylation culminating in epigenetic mechanism of resistance to targeted therapy in T cell acute lympho- 46 – augmentation of the immune system response against T-lymphoblastic leukemia. Nat Genet 2014; : 364 370. blasts by re- and over-expression of putative myeloid and 14 Hogan LE, Meyer JA, Yang J, Wang J, Wong N, Yang W et al. Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic lymphoid tumor antigens. Such an increase in immunogenicity strategies. Blood 2011; 118: 5218–5226. can manifest as graft-versus-leukemia post-DLI. In addition, 15 Lu BY, Thanawala SU, Zochowski KC, Burke MJ, Carroll WL, Bhatla T. Decitabine decitabine may deliver an antileukemic effect by significant enhances chemosensitivity of early T-cell precursor-acute lymphoblastic leukemia 15 downregulation of LYL1 and BCL2 genes in ETP-ALL. cell lines and patient-derived samples. Leuk Lymphoma 2016; 57:1938–1941.