Philadelphia-like acute lymphoblastic leukemia is associated with minimal residual disease persistence and poor outcome. First report of the minimal residual disease-oriented GIMEMA LAL1913

Early recognition of Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) cases could impact on the management and outcome of this subset of B-lineage ALL. In order to assess the prognostic value of the Ph-like status in a pediatric-inspired, minimal residual disease (MRD)driven trial, we screened 88 B-lineage ALL cases negative for major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2Ar) enrolled in the GIMEMA LAL1913 front-line protocol for adult BCR/ABL1-negative ALL. The screening - performed using the “BCR/ABL1-like predictor” - identified 28 Ph-like cases (31.8%), characterized by CRLF2 overexpression (35.7%), JAK/STAT pathway mutations (33.3%), IKZF1 (63.6%), BTG1 (50%) and EBF1 (27.3%) deletions, and rearrangements targeting tyrosine kinases or CRLF2 (40%). The correlation with outcome highlighted that: i) the complete remission rate was significantly lower in Ph-like compared to non-Ph-like cases (74.1% vs. 91.5%, P=0.044); ii) at time point 2, decisional for transplant allocation, 52.9% of Ph-like cases versus 20% of non-Ph-like were MRD-positive (P=0.025); iii) the Ph-like profile was the only parameter associated with a higher risk of being MRD-positive at time point 2 (P=0.014); iv) at 24 months, Ph-like patients had a significantly inferior event-free and disease-free survival compared to non-Ph-like patients (33.5% vs. 66.2%, P=0.005 and 45.5% vs. 72.3%, P=0.062, respectively). This study documents that Ph-like patients have a lower complete remission rate, event-free survival and disease-free survival, as well as a greater MRD persistence also in a pediatric-oriented and MRD-driven adult ALL protocol, thus reinforcing that the early recognition of Ph-like ALL patients at diagnosis is crucial to refine risk-stratification and to optimize therapeutic strategies

Incidence, treatment and outcome of central nervous system relapse in adult acute lymphoblastic leukaemia patients treated front-line with paediatric-inspired regimens: A retrospective multicentre Campus ALL study

Within the Campus ALL network we analyzed the incidence, characteristics, treatment and outcome of a central nervous system (CNS) relapse in 1035 consecutive adult acute lymphoblastic leukemia (ALL) patients treated frontline with pediatric-inspired protocols between 2009 and 2020. Seventy-one patients (6.8%) experienced a CNS recurrence, more frequently in T- (28/278; 10%) than in B-ALL (43/757; 5.7%) (p = 0.017). An early CNS relapse—< 12 months from diagnosis—was observed in 41 patients. In multivariate analysis, risk factors for early CNS relapse included T-cell phenotype (p = <0.001), hyperleucocytosis >100 × 109/L (p<0.001) and male gender (p = 0.015). Treatment was heterogeneous, including chemotherapy, radiotherapy, intrathecal therapy and novel agents. A complete remission (CR) was obtained in 39 patients (55%) with no differences among strategies. After CR, 26 patients underwent an allogenic transplant, with a significant overall survival benefit compared to non-transplanted patients (p = 0.012). After a median observation of 8 months from CNS relapse, 23 patients (32%) were alive. In multivariate analysis, the time to CNS relapse was the strongest predictor of a lower 2-year post-relapse survival (p<0.001). In conclusion, in adult ALL the outcome after a CNS relapse remains very poor. Effective CNS prophylaxis remains the best approach and allogenic transplant should be pursued when possible

Philadelphia-like acute lymphoblastic leukemia is associated with minimal residual disease persistence and poor outcome. First report of the minimale residual disease-oriented GIMEMA LAL1913

Early recognition of Ph-like acute lymphoblastic leukemia cases could impact on the management and outcome of this subset of B-lineage ALL. To assess the prognostic value of the Ph-like status in a pediatric-inspired, minimal residual disease (MRD)-driven trial, we screened 88 B-lineage ALL cases negative for the major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2Ar) enrolled in the GIMEMA LAL1913 front-line protocol for adult BCR/ABL1-negative ALL. The screening - performed using the “BCR/ABL1-like predictor” - identified 28 Ph-like cases (31.8%), characterized by CRLF2 overexpression (35.7%), JAK/STAT pathway mutations (33.3%), IKZF1 (63.6%), BTG1 (50%) and EBF1 (27.3%) deletions, and rearrangements targeting tyrosine kinases or CRLF2 (40%). The correlation with outcome highlighted that: i) the complete remission (CR) rate was significantly lower in Ph-like compared to non-Ph-like cases (74.1% vs 91.5%, p=0.044); ii) at time point 2 (TP2), decisional for transplant allocation, 52.9% of Ph-like cases vs 20% of non-Phlike were MRD-positive (p=0.025); iii) the Ph-like profile was the only parameter associated with a higher risk of being MRD-positive at TP2 (p=0.014); iv) at 24 months, Ph-like patients had a significantly inferior event-free and disease-free survival compared to non-Ph-like patients (33.5% vs 66.2%, p=0.005 and 45.5% vs 72.3%, p=0.062, respectively). This study documents that Ph-like patients have a lower CR rate, EFS and DFS, as well as a greater MRD persistence also in a pediatric-oriented and MRD-driven adult ALL protocol, thus reinforcing that the early recognition of Ph-like ALL patients at diagnosis is crucial to refine risk-stratification and to optimize therapeutic strategies

Does MRD have a role in the management of iNHL ?

Among indolent non- Hodgkin lymphomas (iNHLs), the analy sis of measur able / minimal residual disease (MRD) has been exten sively applied to fol lic u lar lym phoma (FL). Treatment com bi na tions have deeply changed over the years, as well as the tech niques to mea sure MRD, which is cur rently eval u ated only in the set ting of clin i cal tri als. Here, we dis cuss the evidence on the role of molec u lar mon i tor ing in the man age ment of FL. Mature data sup port the quan ti fi ca tion of molec u lar tumor bur den at diag no sis as a tool to strat ify patients in risk categories and of MRD eval u a tion at the end of treat ment to pre dict pro gres sion - free sur vival and over all sur vival. Moreover, MRD deserves fur ther stud ies as a tool to refi ne the clinical/ metabolic response and to modulate treatment intensity / duration. Patients with a higher relapse probability can be identifi ed, but the rele vance of continuous molecular follow - up should be clarifi ed by kinetic models of MRD analy sis. Being the BCL2 / heavy chain immu no glob u lin gene hybrid rearrangement detect able in about 50 % to 60 % of advanced FL and in 30% of positron emission tomography / computed tomography - staged localized FL, technical advancements such as next - gener ation sequencing/ tar get locus amplifi cation may allow broadening the FL population carrying a molecular marker. Droplet dig i tal poly mer ase chain reac tion can bet ter quan tify MRD at low lev els, and novel sources of DNA, such as cell - free DNA, may rep re sent a non in va sive tool to mon i tor MRD. Finally, MRD in other iNHLs, such as lymphoplasmacytic lymphoma/ Waldenstr öm macroglobulinemia and mar ginal zone lymphoma, is beginning to be explored

Digital droplet PCR for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia by Immunoglobulin/T-cell receptor and BCR::ABL1 gene analysis. Preliminary comparative results.

Background. BCR::ABL1 transcript and immunoglobulin/T-cell receptor clonal gene rearrangements (IG/TR) can be used as biomarkers for minimal residual disease (MRD) monitoring in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). There is a growing interest in evaluating MRD using a “double-hit strategy”, especially in the adult setting, where data are lacking. Real-time quantitative polymerase chain reaction (RQ-PCR) is the gold standard for MRD monitoring. It has, however, intrinsic issues that digital droplet PCR (ddPCR) may overcome. Aims. To carry out a parallel MRD monitoring at early time points (TPs) in adult Ph+ ALL patients by both molecular targets and, for BCR::ABL1, by both RQ-PCR and ddPCR to determine the concordance between the MRD values. Materials and methods. Samples were obtained from 28 adults with newly diagnosed Ph+ ALL, enrolled in the ongoing phase III GIMEMA ALL2820 clinical trial (NCT04722848). At diagnosis, all patients underwent IG/TR marker screening. MRD monitoring was performed by RQ-PCR and ddPCR for BCR::ABL1 quantification and by ddPCR for IG/TR. MRD results were considered discordant in case of a difference greater than one log10 or in case of a positivity/negativity. Results. The comparison between MRD values obtained by RQ-PCR and ddPCR using the BCR::ABL1 transcript showed an excellent degree of correlation (R2=0.996). Concerning IG/TR, a marker was identified in 20/28 patients, whereas 8/28 (29%) were no marker (NM). Moreover, in 4 patients (20%) it was not possible to design a sensitive allele-specific oligonucleotide (ASO) (NA). Sixteen samples were evaluated using both biomarkers by ddPCR. Overall, 7/16 (44%) samples were concordant by both targets, having either highly positive (2/7) or negative (5/7) MRD values, while 9/16 (56%) were discordant. Among these, 2/9 were MRD-positive by both targets but outside the concordance range, in 7/9 IG/TR MRD monitoring was negative, while BCR::ABL1 MRD monitoring was positive (range 10-3-10-1). In the 12 NM and NA patients, BCR::ABL1 ddPCR analysis revealed a quantifiable MRD in 8 cases (range 10-2-10-1), 1 proved positive not-quantifiable (PNQ), 2 were MRD-negative and 1 was not evaluable. Finally, in the NM subset, there were no differences in the type of fusion proteins (p190/p210) and enrichment of additional genetic lesions (Fig. 1), while the median WBC count at diagnosis was lower than in the other cases (6.27 x 109/l for NM vs 16.37 x 109/l for patients with IG/TR markers). Conclusions. BCR::ABL1 ddPCR is a sensitive tool for MRD monitoring, at least comparable to RQ-PCR. At variance, at least at early TPs, the degree of concordance between BCR::ABL1 transcript and IG/TR is suboptimal. Noteworthy, although IG/TR is the most widely used biomarker in children, the rate of NM in adult Ph+ ALL is high, suggesting that the BCR::ABL1 transcript remains the most sensitive target. Cohort expansion and clinical correlations are ongoing

High rate of MRD-responses in young and fit patients with IGHV mutated chronic lymphocytic leukemia treated with front-line fludarabine, cyclophosphamide, and intensified dose of ofatumumab (FCO2)

Nessun

NUP98/11p15 translocations affect CD34+cells in myeloid and T lymphoid leukemias

We assessed lineage involvement by NUP98 translocations in myelodysplastic syndromes (MDS), acute myeloid leukaemia (AML), and T-cell acute lymphoblastic leukaemia (T-ALL). Single cell analysis by FICTION (Fluorescence Immunophenotype and Interphase Cytogenetics as a Tool for Investigation of Neoplasms) showed that, despite diverse partners, i.e. NSD1, DDX10, RAP1GDS1, and LNP1, NUP98 translocations always affected a CD34+/CD133+ hematopoietic precursor. Interestingly the abnormal clone included myelomonocytes, erythroid cells, B- and T-lymphocytes in MDS/AML and only CD7+/CD3+ cells in T-ALL. The NUP98-RAP1GDS1 affected different hematopoietic lineages in AML and T-ALL. Additional specific genomic events, were identified, namely FLT3 and CEBPA mutations in MDS/AML, and NOTCH1 mutations and MYB duplication in T-ALL. (C) 2015 Elsevier Ltd. All rights reserved