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The detection of recurrent chromosomal rearrangements in B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is critical for patient management decisions. We present a newly diagnosed case of B-ALL in a young adult with a cryptic KMT2A/AFF1 fusion that was unappreciable by conventional chromosome and fluorescence in situ hybridization (FISH) KMT2A break-apart probe studies. To further characterize this abnormality, a next-generation sequencing strategy, mate-pair sequencing (MPseq) was performed and characterized a cryptic, insertional rearrangement that created KMT2A/AFF1 gene fusion. This case highlights the superior precision and resolution capabilities of NGS when compared to traditional cytogenetic methodologies, including conventional chromosome and FISH studies.

To the editor: Peripheral T-cell lymphomas (PTCLs) represent a group of rare hematological cancers of mature T-cell or natural killer cell origin accounting for 10% to 15% of all lymphomas.[1][1] Although many patients have poor outcomes, some achieve long-term survival.[2][2],[3][3] Thus

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is usually diagnosed based on the presence of immature lymphoid marker terminal deoxynucleotidyl transferase (TdT), and T-cell specific markers, specifically CD3, by immunohistochemistry (IHC) staining on bone marrow and/or extramedullary tissue. We present a novel, TdT and CD3 negative, aggressive early T-cell precursor LBL (ETP-LBL) initially misdiagnosed as a high grade B-cell lymphoma due to expression of CD79a and the erroneous detection of BCL2/IGH fusion. The patient was eventually evaluated using molecular diagnostic techniques, including fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) assays that demonstrated PICALM-MLLT10 fusion and a NOTCH1 mutation in the absence of BCL2/IGH fusion. The use of NGS, specifically mate-pair sequencing (MPseq), subsequently confirmed an in-frame PICALM-MLLT10 fusion. Our retrospective analysis showed that PICALM-MLLT10 fusion has no association with CD3/TdT negativity, as 6/49 T-ALL/LBL cases from Mayo Clinic database (01/1998-09/2018), including this case, were noted to have PICALM-MLLT10 fusion; however, none of the other cases were associated with CD3/TdT negativity. We emphasize the importance of a comprehensive hematopathologic evaluation including multiple molecular studies for the appropriate interrogation and classification of a difficult acute leukemia diagnosis, and to prevent potential diagnostic errors of clinical significance.

Introduction: Recent results from two independent patient series have shown that chromosomal rearrangements of DUSP22 (DUSP22r+) and TP63 (TP63r+) can predict outcome in ALK-negative anaplastic large cell lymphoma (ALK-ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) with morphologic features resembling ALK-ALCL (Parilla-Castellar E, Blood 2014; Pedersen MB, Blood 2017). While DUSP22r+ is predictive for excellent survival similar to that of ALK+ALCL after CHOP/CHOP-like therapy, the rarely occurring TP63r+ is associated with an aggressive clinical behavior and poor outcome. The largest subgroup, i.e. patients with neither ALK nor DUSP22 nor TP63 rearrangements (triple negative), show a 5 year (yr) overall survival (OS) intermediate between that of ALK-/DUSP22r+ and ALK-/TP63r+ patients. The aim of the present study was to assess the impact of upfront high-dose therapy with autologous stem cell transplant (HDT/ASCT) on outcome in adult ALCL and PTCL-NOS patients according to their ALK, DUSP22 and TP63 status. The survival results from the two published series were pooled with those of a Nordic Lymphoma Group trial, the NLG-T-01 (d'Amore et al, JCO 2012), where patients were treated with 1st line CHOEP/CHOP followed, in chemosensitive cases, by upfront HDT/ASCT. Methods: Fluorescence in situ hybridization was performed on sections of previously constructed tissue microarrays using break-apart probes for the DUSP22-IRF4 and TP63 loci and a dual-fusion probe for TBL1XR1/TP63 fusion [inv(3)(q26q28)]. Evaluation of DUSP22 and TP63 rearrangements was performed in a blinded fashion without knowledge of PTCL subtype, clinical course, or outcome. Three independent patient cohorts were included: (i) one from Mayo Clinic consisting of 31 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 25; TP63r+: 6); (ii) one from Denmark consisting of 93 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 90; TP63r+: 3); and one from the NLG-T-01 trial consisting of 46 ALK-ALCL and PTCL-NOS (triple negative: 37; TP63r+: 1; DUSP22r+: 8), leading to a total study population of 170 patients. ALK+ ALCL was not included in the analysis, since no patients with this histology entered the NLG-T-01 trial. Association of genetic subtype with OS was assessed using Kaplan-Meier curves and Cox proportional models for hazard rate ratios (HR). Significant differences were defined as P Results: The eight DUSP22r+ patients (7 ALK-ALCL and 1 PTCL-NOS) from NLG-T-01 had a 5-yr OS of 83%, (95%CI 27-97), similar to that reported for DUSP22r+ in the Mayo and Danish cohorts (90% and 80%, respectively). No lymphoma-related events were observed in this subset. The only event was a septic death due to HDT-induced cytopenias in a patient who was in complete remission (CR). Among the 162 patients with DUSP22r-, ALK-ALCL and PTCL-NOS, those consolidated with HDT/ASCT (n=47) had a significantly better outcome (5-yr OS: 45%) than those treated with induction chemotherapy alone (5-yr OS: 30%) (n=115) (P=0.01). The patients in the HDT/ASCT group were younger (P Conclusion: In ALK-ALCL and PTCL-NOS patients from the NLG-T-01 trial, DUSP22r+ was associated with a very good outcome, similar to that seen in DUSP22r+ patients who had not undergone upfront autologous transplant. This observation supports the impression that upfront HDT/ASCT may not be of benefit in these patients. TP63r+ predicted poor outcome in non-transplanted patients. The impact of HDT/ASCT in the TP63r+ setting could not be adequately evaluated, since only one patient from the NLG-T-01 trial cohort was found to be TP63r+. Notably, this patient was the only survivor of the TP63r+ subset. For DUSP22r-, ALK-ALCL and PTCL-NOS patients taken as one group, those who received upfront HDT/ASCT had a superior survival compared to their age- and IPI-matched non-transplanted counterparts. Disclosures Ellin: ROCHE: Consultancy, Research Funding; CTI: Consultancy. Mannisto: Roche: Honoraria, Other: Travel expence; Takeda: Honoraria, Other: Travel expence; Amgen: Other: Travel expence; Novartis: Other: Travel expence; Celgene: Other: Travel expence; Gilead: Other: Travel expence; Pfizer: Honoraria; SOBI: Honoraria. Cerhan: Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering . Toldbod: Takeda Pharma: Honoraria.