Early T‐cell precursor lymphoblastic leukaemia: response to FLAG ‐ IDA and high‐dose cytarabine with sorafenib after initial refractoriness

Early T-cell precursor lymphoblastic leukaemia (ETP-ALL), accounting for 5–16% of T-cell acute lymphoblastic leukaemia (T-ALL) cases, has been proposed as a provisional entity in the recent World Health Organization classification and is associated with higher treatment refractoriness and worse overall survival than T-ALL (Arber et al, 2016). The diagnosis is based on immunophenotypic features (CD7, CD8 , CD1a , CD5 /low with myeloid/stem cell marker expression) and the gene expression pattern resembles an immature haematopoietic progenitor or leukaemic stem cell. NOTCH1 and FBXW7 mutations are less frequent than in T-ALL (Zhang et al, 2012). As the cell origin of ETP-ALL has been related to a common myeloid precursor, some studies suggest better responses with acute myeloid leukaemia (AML)type regimens (Patrick et al, 2014; Conter et al, 2016). Furthermore, targeted therapies, such as FLT3 or JAK inhibitors need to be explored in ETP-ALL, given the high frequency of mutations activating these pathways (Neumann et al, 2012; Maude et al, 2015). Herein we report four consecutive patients with ETP-ALL diagnosed at our centre over a 10year period, focusing on the salvage therapy received after being refractory to standard chemotherapy (Table I). Patient 1, a 31-year-old man, presented with a mediastinal mass and a white blood cell (WBC) count of 14 9 10/l (86% blasts, fulfilling ETP-ALL criteria), without central nervous system (CNS) involvement. The patient was enrolled in the Programa Espa~ nol de Tratamientos en Hematolog ıa (PETHEMA) high-risk adult ALL (LAL-AR) 2003 regimen (4week induction therapy with vincristine, daunorubicin 45 mg/ m, prednisone and L-asparaginase 10 000 iu/m). However, at day +14, bone marrow (BM) showed 95% blasts; therefore the induction regimen was changed to mitoxantrone (12 mg/ m 9 3 doses) and high-dose cytarabine (HDAC, 2 g/ m 9 2), which reduced blasts to 23% at the end of induction. Salvage therapy with FLAG-IDA (fludarabine 25 mg/m 9 4 daily, cytarabine 2 g/m, idarubicin 10 mg/m 9 3 doses) was administered and the patient achieved complete response (CR), without detectable minimal residual disease (MRD) by flow cytometry. The patient received a myeloablative allogeneic haematopoietic cell transplantation (alloHCT) with unrelated cord blood, but died from a toxoplasmic encephalitis, 4 months after transplant while in MRD-negative CR. Patient 2 was a 34-year-old man who presented with pancytopenia. WBC count was 3 9 10/l (70% blasts), fulfilling ETP-ALL criteria, and the patient started PETHEMA LALAR-2011 induction regimen (same scheme as PETHEMA LAL-AR-2003). BM evaluation on Day 14 showed 78% blasts, leading to modification of induction therapy with FLAG-IDA, which achieved a MRD-negative CR at Day +28. A myeloablative alloHCT from a haploidentical family donor was performed but the patient died from an infectious pneumonia after 6 months while in MRD-negative CR. Patient 3, a 39-year-old man, presented with a mediastinal mass and presence of 0 6% leukaemic cells, fulfilling ETP-ALL criteria, in the BM aspirate. Mutations in NOTCH1, FBXW7, PTEN, KRAS and NRAS were excluded. The patient started protocol PETHEMA LAL-AR-2011, with a reduction of the mediastinal mass but persistence of 0 06% blasts at Day +28. Therapy was changed to FLAG-IDA, resulting in a MRD-negative CR after one course. Following a myeloablative alloHCT from a human leucocyte antigen (HLA)-identical related donor, the patient has maintained a MRD-negative CR for 15 months. Patient 4 was a 33-year-old man who presented with pancytopenia. WBC count was 3 5 9 10/l (80% blasts, fulfilling ETP-ALL criteria). Molecular tests demonstrated the presence of a FLT3 internal tandem duplication (FLT3-ITD), with a FLT3-ITD/FLT3 wild type (wt) ratio of 0 08, a RUNX1 mutation and absence of mutations in NOTCH1, FBXW7, PTEN, KRAS and NRAS. The CNS was also involved, and the patient was started on the PETHEMA LAL-AR-2011 protocol and triple intrathecal chemotherapy. BM assessment at Day +14 showed 95% blasts and FLAG-IDA was initiated. After one cycle, a 2% ETP-ALL cell population persisted in BM, together with a FLT3-ITD/FLT3wt ratio of 0 03. Subsequently, an additional course of HDAC combined with the FLT3 inhibitor sorafenib (400 mg po bid) was given from day +8. The patient achieved MRD-negative status after 30 days, and sorafenib was maintained until a myeloablative HLA-matched sibling donor alloHCT was performed. Following transplant, sorafenib was reintroduced and the patient remains in MRD-negative CR at 6 months from alloHCT. These cases confirm the high rate of refractoriness to standard therapy reported previously (Coustan-Smith et al, 2009; Bond et al, 2017; Jain et al, 2017). Nevertheless, 3 patients achieved MRD-negative status with FLAG-IDA, whereas one required additional HDAC treatment with sorafenib. Interestingly, all patients maintained MRD-negative CR after transplantation, although two died due to a non-disease related cause and follow-up in the remaining patients is short. The optimal induction regimen for ETP-ALL has not yet been Correspondence