UBTF::ATXN7L3 gene fusion defines novel B cell precursor ALL subtype with CDX2 expression and need for intensified treatment

Genomic aberrations—gene fusions in the majority of cases—and corresponding transcriptional regulations define an increasingly complex landscape of molecular subtypes in B cell precursor acute lymphoblastic leukemia (BCP-ALL) [1]. Up to 15% of patients cannot be allocated to established subtypes, suggesting the presence of unrecognized drivers—especially in adult patients who have been less studied so far

General condition and comorbidity of long-term survivors of adult acute lymphoblastic leukemia

Cure rates in adult acute lymphoblastic leukemia (ALL) improved using pediatric-based chemotherapy and stem cell transplantation (SCT). However, limited data on the health condition of cured adults are available whereas pediatric data cannot be transferred. The GMALL analyzed the health status in survivors of adult ALL retrospectively. Physicians answered a questionnaire on general condition (Eastern Cooperative Oncology Group [ECOG] status) and comorbidity or syndrome occurrence observed after treatment. Five hundred and thirty-eight patients with a median age of 29 (range, 15-64) years at diagnosis were analyzed, median follow-up was 7 (range, 3-24) years. Thirty-one percent had received SCT. ECOG status was 0-1 in 94%, 34% had not developed significant comorbidities. Most frequent comorbidities involved the neurologic system (27%), endocrine system (20%), skin (18%), graft-versus-host-disease (15%), cardiac system (13%), fatigue (13%). SCT impacted ECOG status and comorbidity occurrence significantly. ECOG 0-1 was observed in 86% of SCT and 98% of non-SCT patients (P<0.0001); comorbidity was observed in 87% and 57% respectively (P<0.0001). Our analysis elucidates the spectrum of comorbidities in cured adult ALL patients, with higher risk for transplanted patients, providing stimulations for the design of adequate aftercare programs. Overall, a large proportion of non-SCT patients achieved unrestricted general condition. The data provide a reference for new patient-centered endpoints in future trials

Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with B-Precursor Adult Lymphoblastic Leukemia (ALL): Results of the Ongoing GMALL Bold Trial

Abstract Older patients (pts) with newly diagnosed ALL are ineligible for unmodified pediatric-based therapies. Even with age-adapted, dose-reduced regimens early death rates (ED) are considerable and overall survival (OS) poor. Thus, 412 pts treated according to the GMALL Elderly Protocol showed a CR rate of 75%, with 16% early death (ED) and the 3 years (yrs) OS was only 30%. Therefore, the GMALL study group developed a trial to evaluate Blinatumomab (Blina), a CD19 directed bi-specific T-cell engager, in sequence with chemotherapy in this patient population with high medical need (NCT 03480438). Blina replaces several cycles of chemotherapy being part of the standard GMALL protocol for older pts. Pts aged 56 - 76 yrs with CD19-positive, Ph-neg B-precursor ALL are eligible. The primary endpoint is complete hematologic remission (CR) after induction i.e. one dose-reduced cycle chemotherapy induction (IP1) and one cycle Blina (Blina 1), and the key secondary endpoint is molecular response (table 1). The efficacy population includes pts treated with IP1 and Blina 1 or ED. The trial is ongoing and scheduled to recruit 50 pts. After a 5-d prephase with dexamethasone (dexa) and cyclophosphamide (cyclo) pts receive dexa (10 mg/m 2 d 7-8 and 14-17), vincristine (2 mg d 7 and 14) and idarubicin (10 mg d 7 and 15) together with i.th. triple prophylaxis (d 6 and d 20) and G-CSF as IP1. Rituximab is given to pts with CD20+ ALL. Thereafter, pts with CR, CRu or PR receive Blina 1 (28 µg/d, 28 d). Pts with failure to IP1 are treated with IP2 (cytarabine, cyclo) followed by Blina 1. A dose step after one week (9µg/d to 28µg/d) is scheduled in all pts starting Blina while not in CR/CRu. Consolidation treatment consists of alternating cycles of intermediate-dose methotrexate/ PEG-asparaginase, intermediate-dose cytarabine and reinduction and 3 further cycles of Blina. This is followed by a standard maintenance (6-MP/MTX) up to a total treatment duration of 2 yrs. Pts receive up to 9 doses of i.th. triple combination. MRD is measured in bone marrow in the central reference laboratory in Kiel with quantitative IG/TR PCR according to EuroMRD standards after IP1, Blina 1, consolidation 1 and 2 and thereafter approximately every 2-3 months. 34 pts with a median age of 65 (56-76) yrs were included from 13 centers in Germany. 7 pts were older than 70 yrs (21%). 7 pts (26%) had pro-B-ALL (N=2 KMT2A rearranged) and 25 pts c-/pre-B-ALL. 47% of the pts had comorbidities according to the Charlson Score; most frequent were diabetes (18%) myocardial infarction (12%), chronic pulmonary disorder (12%). In one pt study treatment was terminated in CR due to subdural hemorrhage in IP1 considered as contraindication for Blina 1. 33 pts were evaluable for IP1: 76% achieved CR/CRu, 9% PR (N=3) 3 pts had treatment failure (9%) and 2 pts (6%) died due to infections. 29% (N=9) had a molecular response (17% MolCR) (table 1). 1/3 pts with failure after IP1 had a CR after IP2. 29 pts were evaluable for the primary endpoint after Blina 1. 24 were in hematologic CR (83%), 3 had failure (10%) and 2 experienced ED (7%; both during IP1 as mentioned above; no additional ED). 82% of the CR pts (N=19) had a molecular response (69% MolCR). 8 / 9 pts with pro-B-ALL had a CR after Blina 1 (89%) and the molecular response rate was 62% (37% MolCR). The median follow-up is 363 (26-1001) days. Survival probability for the efficacy population (N=29) after 1 yr was 84% (figure 1) and 86% for the total population. The 1y OS was 89% for c/pre-B-ALL and 75% for pro-B-ALL. OS was 100% at 1 yr for pts aged 55-65 yrs and 66% for those older than 65 yrs. 2 pts were transplanted in CR1. 2 pts relapsed, both pro-B-ALL, 1 pt developed a secondary malignancy (Colonic Ca) and 2 pts died in CR (1 HLH, 1 arterial disease). Disease Free Survival was 89% at 1 yr. Blinatumomab was well tolerated. No death occurred during Blina 1. The pt with HLH died after consolidation I but correlation to prior Blina is possible. Overall tolerability and efficacy of the regimen was promising with a high cytologic and molecular response rate and low mortality for this age group. Dose-reduced chemo induction intended for leukemia debulking was effective but was also associated with two cases of ED. Age and subtype appeared to have an impact on the outcome with poorer results for older pts and those with pro-B-ALL. Confirmation of the results in a larger, potentially randomized trial and with longer follow-up is warranted. Figure 1 Figure 1. Disclosures Goekbuget: Incyte: Other: Research funding for Institution; Amgen: Consultancy, Other: Invited talks for company sponsored symposia (with honoraria); Research funding for institution; Astra Zeneca: Other: Invited talk for company sponsored symposia (with honor); Gilead/Kite: Consultancy; Novartis: Consultancy, Other: Research funding for Institution; Pfizer: Consultancy, Other: Research funding for institution; Jazz Pharmaceuticals: Other: Research funding for institution; Cellestia: Consultancy; Erytech: Consultancy; Morphosys: Consultancy; Servier: Consultancy, Other; Abbvie: Other. Topp: Macrogeniecs: Research Funding; Amgen: Consultancy, Research Funding; Regeneron: Consultancy, Research Funding; Gilead: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Universitatklinikum Wurzburg: Current Employment. Schwartz: Novartis: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Basilea: Other: Travel grants; MSD Sharp &amp; Dohme: Membership on an entity's Board of Directors or advisory committees; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; Morphosys: Research Funding; Gilead: Other: Travel grants, Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Hertenstein: Novartis: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; BMS: Honoraria. Vucinic: Gilead: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring; MSD: Honoraria; Janssen: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Viardot: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment. OffLabel Disclosure: Blinatumomab in newly diagnosed ALL </jats:sec

Long-Term Clinical and Molecular Remissions in Patients with Mantle Cell Lymphoma (MCL) Following High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)

Background:Long-term clinical and molecular remissions in patients with MCL following HDT and ASCT have been evaluated in only a few studies. Results are especially limited for remission duration over 5 years. So the curability of this disease remains an open question. Patients and methods:Altogether 61 patients with MCL were treated in our institution with ASCT from 1998 to April 2019 (50 1st-line ASCT, ten 2nd-line ASCT, one 3rd-line ASCT). The data were collected retrospectively in 29 and prospectively in 32 patients who participated in two clinical trials: the 1st-line therapy trials of the German Low Grade Lymphoma Study Group (GLSG, principal investigator W. Hiddemann [Dreyling M, Blood 2005] and the European Mantle Cell Lymphoma Network [Hermine O, Lancet 2016], respectively. The diagnosis was regularly approved by the reference pathology of the GLSG (W.K.). The induction therapy before 1st-line ASCT consisted of 6 courses CHOP (n=11), mostly combined with rituximab and followed by Dexa-BEAM, and 6 alternating courses of R-CHOP and R-DHAP (n=39), respectively. For the salvage treatment patients usually received three to four courses of the DHAP protocol or the ESHAP protocol, since 2001 also combined with rituximab.Stem cell apheresis was carried out in the Blood Transfusion Service following these protocols in remission. High-dose protocols: 1) total body irradiation with cyclophosphamide or melphalan and cytarabin (n=32) or 2) BEAM (n=29). Patients with partial remission after ASCT received a radiotherapy (RT) with 30-36 Gy in the field of persisting lymphoma, if possible (n=4). Since 09/2016 patients received a maintenance therapy with rituximab after ASCT (every 2 months, planned for 3 years, n=14). Further details are described in an earlier publication of our first 36 patients (Metzner B, Ann Hematol 2013). Response assessment was performed by careful clinical examination and by ultrasound, chest x-ray and partly CT at regular 3 - 12 monthly time points. In the case of long-term remission (≥ 5 years; n = 18), peripheral blood was regularly tested twice a year for minimal residual disease (MRD) by quantitative t(11;14) or allel specific IGH RQ-PCR and/or IGH-consensus PCR.Calculations were done using IBM SPSS Statistics Version 25. Data were analysed as of 01 July 2019. Results:With a median follow-up of 5 years (range 0.1-20) 10-year overall survival, progression-free survival (PFS) and freedom from progression (FFP) after 1st-line ASCT were 54%, 46% and 52%, respectively, after 2nd-line ASCT 42%, 20%and 20%, with a significant difference for PFS (p=0.045) and FFP (p=0.014) between 1st-line and 2nd-line cohort.Further prognostic factors (like sex, age, MIPI, bone marrow involvement, remission grade at ASCT: CR vs. PR, type of HDT: TBI vs. BEAM…) seemed to be without relevance (considering the small subgroups). Only one clinical relapse occurred after 5 years following ASCT in 1stor 2ndremission, respectively (one patient 6 years after 1st-line ASCT and another patient 7 years after 2nd-line ASCT and subsequent radiotherapy). So far, 18 patients experienced long-term remissions of at least 5 years (median 9 years, from 5 to 16 years). Fifteen of 17 tested patients were MRD negative at last follow-up, the two MRD positive patients (positive at a low level below the quantitative measuring range) had no clinical signs of relapse at last follow-up. None of these 18 patients had received rituximab maintenance therapy. None showed clinical criteria of "smoldering mantle cell lymphoma" at induction therapy. Treatment-related mortality at 100 days after ASCT was 1.6% (pneumonitis following TBI). One patient developed a secondary invasive malignancy in remission after ASCT (acute myeloid leukemia 4 years following TBI). Conclusion: Sustained long-term clinical and molecular remissions up to 16 years can be achieved following ASCT (without rituximab maintenance therapy), indicating the potential curative impact of 1st-line ASCT in MCL. The 2nd-line ASCT was obviously less effective. Disclosures Dreyling: Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Acerta: Other: scientific advisory board; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. </jats:sec

UBTF::ATXN7L3 gene fusion defines novel B cell precursor ALL subtype with CDX2 expression and need for intensified treatment

We performed transcriptome sequencing (RNA-Seq) on n = 568 adult BCP-ALL patients prospectively treated according to pediatric-based protocols of the German Multicenter Acute Lymphoblastic Leukemia (GMALL) study group including risk stratification based on minimal residual disease (MRD) and treatment intensification for high-risk patients. To define molecular subtypes, we used our previous integrative analyses [1] to train a machine learning classifier to predict subtype allocation from gene expression profiles of subsequently sequenced samples. Feature selection (LASSO) was used to identify the most informative genes. Underlying genomic aberrations were analyzed (whole-genome sequencing (WGS), whole-exome sequencing (WES); SNP-arrays) to confirm subtype allocation in selected cases. With this approach, we were able to allocate n = 535/568 (94%) samples to 15 previously established [1] molecular subtypes (Fig. 1A–D), with confirmation of corresponding genomic alterations in 91% of analyzed cases (Fig. 1D). Unsupervised gene expression analysis of previously unassigned samples revealed a distinct patient subset (n = 12; Supplementary Fig. S1A) defined by a novel in-frame gene fusion of upstream binding transcription factor (UBTF) and ataxin-7-like protein 3 (ATXN7L3) occurring exclusively in this patient cluster (n = 12/12 vs. n = 0/556 in remaining cohort, p < 1E−10; Fig. 1D). Comparison of gene expression profiles revealed that UBTF::ATXN7L3 rearranged cases in our cohort match to a recently described BCP-ALL subtype, which so far was identified by increased expression of the homeobox transcription factor CDX2 (‘CDX2 high’ ALL) [2] (Supplementary Fig. S1B). UBTF::ATXN7L3 represents an 11.3 kbp in-frame read-through between UBTF exon 17/21 and a 5′ UTR splice site of ATXN7L3, with the same sanger sequencing confirmed break point in all samples (Fig. 2A, Supplementary Methods). WGS of 3 samples revealed a 10.08 kb genomic deletion involving UBTF 3′ exons (18-21) and most of the intergenic region between UBTF and ATXN7L3 as underlying mechanism (Fig. 2A, Supplementary Fig. S2). Break-point-specific PCR and Sanger sequencing confirmed presence of the deletion in n = 11/11 UBTF::ATXN7L3 patients with available material (Supplementary Fig. S3). The same ATXN7L3 transcript breakpoint has previously been identified in a patient with diffuse large B cell lymphoma (GPATCH8::ATXN7L3) [3], suggesting a shared driver function in different B-lymphoid malignancies. Both fusion partners were highly expressed across the entire cohort without significant differences in the novel subtype (Supplementary Fig. S4), suggesting either gain-of-function or a dominant-negative effect of the gene fusion