T cell function is crucial for the success of several novel immunotherapeutic strategies for the treatment of acute myeloid leukemia (AML). However, changes in phenotype and function of T cells have been described in various hematologic malignancies, mimicking T cell exhaustion known from chronic viral infections. Detailed knowledge about phenotype and function of T cells in AML patients at different stages of the disease is indispensable for optimal development and application of immunotherapeutic strategies for this disease.

Alkylphosphocholines represent a new class of cytostatic drugs with a novel mode of action. Erufosine (ErPC3), the first compound of this class that can be administered intravenously, has recently been shown to be active against human tumor and leukemic cell lines.

The revised World Health Organization classification of 2016 for myeloid neoplasms and acute leukemia added a section of myeloid neoplasms with germline predisposition. The main objective of our study was to evaluate the frequency of hematologic and solid malignancies in the family history of patients with acute myeloid leukemia (AML) by using a systemic pedigree interview. The family history was taken of 50 patients between 24 and 80 years.

Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti-CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab-relapsed/refractory FL.

Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial.

Alterations of RUNX1 in acute myeloid leukemia (AML) are associated with either a more favorable outcome in the case of the RUNX1/RUNX1T1 fusion or unfavorable prognosis in the case of point mutations. In this project we aimed to identify genes responsible for the observed differences in outcome that are common to both RUNX1 alterations. Analyzing four AML gene expression data sets (n = 1514), a total of 80 patients with RUNX1/RUNX1T1 and 156 patients with point mutations in RUNX1 were compared. Using the statistical tool of mediation analysis we identified the genes CD109, HOPX, and KIAA0125 as candidates for mediator genes. In an analysis of an independent validation cohort, KIAA0125 again showed a significant influence with respect to the impact of the RUNX1/RUNX1T1 fusion. While there were no significant results for the other two genes in this smaller validation cohort, the observed relations linked with mediation effects (i.e., those between alterations, gene expression and survival) were almost without exception as strong as in the main analysis. Our analysis demonstrates that mediation analysis is a powerful tool in the identification of regulative networks in AML subgroups and could be further used to characterize the influence of genetic alterations.

We evaluated early disease progression and its impact on overall survival (OS) in previously untreated follicular lymphoma patients in GALLIUM (clinicaltrials.gov identifier: 01332968), and investigated the effect on early disease progression of the two randomization arms: obinutuzumab-based versus rituximab-based immunochemotherapy. Cause-specific Cox regression was used to estimate the effect of treatment on the risk of disease progression or death due to disease progression within 24 months of randomization and to analyze OS in patients with or without disease progression after 24 months. Mortality in both groups was analyzed 6, 12, and 18 months post randomization (median follow up, 41 months). Fewer early disease progression events occurred in obinutuzumab (57 out of 601) versus rituximab (98 out of 601) immunochemotherapy patients, with an average risk reduction of 46.0% (95%CI: 25.0-61.1%; cumulative incidence rate 10.1% vs 17.4%). At a median post-progression follow up of 22.6 months, risk of mortality increased markedly following a progression event [HR of time-varying progression status, 25.5 (95%CI: 16.2-40.3)]. Mortality risk was higher the earlier patients progressed within the first 24 months. Age-adjusted HR for OS after 24 months in surviving patients with disease progression versus those without was 12.2 (95%CI: 5.6-26.5). Post-progression survival was similar by treatment arm. In conclusion, obinutuzumab plus chemotherapy was associated with a marked reduction in the rate of early disease progression events relative to rituximab plus chemotherapy. Early disease progression in patients with follicular lymphoma was associated with poor prognosis, with mortality risk higher after earlier progression. Survival post progression did not seem to be influenced by treatment arm.

Standard treatment for higher risk myelodysplastic syndromes, chronic myelomonocytic leukemia and low blast acute myeloid leukemia is azacitidine. In single arm studies, adding lenalidomide had been suggested to improve outcomes. The ALLG MDS4 phase II trial randomized such patients to standard azacitidine or combination azacitidine (75mg/m2/d days 1 to 5) with lenalidomide (10mg days 1-21 of 28-day cycle from cycle 3) to assess clinical benefit (alive without progressive disease) at 12 months. A total of 160 patients were enrolled; median age 70.7 years (range 42.5-87.2), 31.3% female with 14% chronic myelomonocytic leukemia, 12% acute myeloid leukemia and 74% myelodysplastic syndromes. Adverse events were similar in both arms. There was excellent delivery of protocol therapy (median azacitidine cycles 11 both arms) with few dose reductions, delays or early cessations. At median follow up 33.1 months (range 0.7-59.5), the rate of clinical benefit at 12 months was 65% azacitidine arm and 54% lenalidomide+azacitidine arm (P=0.2). There was no difference in clinical benefit between each arm according to WHO diagnostic subgroup or IPSS-R. Overall response rate was 57% in azacitidine arm and 69% in lenalidomide+azacitidine (P=0.14). There was no difference in progression- free or overall survival between the arms (each P>0.12). Although the combination of lenalidomide and azacitidine was tolerable, there was no improvement in clinical benefit, response rates or overall survival in higher risk myelodysplastic syndrome, chronic myelomonocytic leukemia or low blast acute myeloid leukemia patients compared to treatment with azacitidine alone. This trial was registered at www.anzc-tr.org.au as ACTRN12610000271000.

A diverse intratumoral T-cell receptor (TCR) repertoire is associated with improved survival in diffuse large B-cell lymphoma (DLBCL) treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy. We explored the impact of intratumoral TCR repertoire on interim PET (iPET) done after four cycles of R-CHOP, the relationships between intratumoral and circulating repertoire, and the phenotypes of expanded clonotypes.

Achievement of complete remission signifies a crucial milestone in the therapy of acute myeloid leukemia (AML) while refractory disease is associated with dismal outcomes. Hence, accurately identifying patients at risk is essential to tailor treatment concepts individually to disease biology. We used nine machine learning (ML) models to predict complete remission and 2-year overall survival in a large multicenter cohort of 1,383 AML patients who received intensive induction therapy. Clinical, laboratory, cytogenetic and molecular genetic data were incorporated and our results were validated on an external multicenter cohort. Our ML models autonomously selected predictive features including established markers of favorable or adverse risk as well as identifying markers of so-far controversial relevance. De novo AML, extramedullary AML, double-mutated CEBPA, mutations of CEBPA-bZIP, NPM1, FLT3-ITD, ASXL1, RUNX1, SF3B1, IKZF1, TP53, and U2AF1, t(8;21), inv(16)/t(16;16), del(5)/del(5q), del(17)/del(17p), normal or complex karyotypes, age and hemoglobin concentration at initial diagnosis were statistically significant markers predictive of complete remission, while t(8;21), del(5)/del(5q), inv(16)/t(16;16), del(17)/del(17p), double-mutated CEBPA, CEBPA-bZIP, NPM1, FLT3-ITD, DNMT3A, SF3B1, U2AF1, and TP53 mutations, age, white blood cell count, peripheral blast count, serum lactate dehydrogenase level and hemoglobin concentration at initial diagnosis as well as extramedullary manifestations were predictive for 2-year overall survival. For prediction of complete remission and 2-year overall survival areas under the receiver operating characteristic curves ranged between 0.77-0.86 and between 0.63-0.74, respectively in our test set, and between 0.71-0.80 and 0.65-0.75 in the external validation cohort. We demonstrated the feasibility of ML for risk stratification in AML as a model disease for hematologic neoplasms, using a scalable and reusable ML framework. Our study illustrates the clinical applicability of ML as a decision support system in hematology.

Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis.

Mutations in BTK, PLCG2, and BCL2 have been reported in patients with progressive disease (PD) on continuous single-agent BTK or BCL2 inhibitor treatment. We tested for these mutations in samples from patients with PD after completion of first-line treatment with fixed-duration ibrutinib plus venetoclax for chronic lymphocytic leukemia (CLL) in the phase II CAPTIVATE study.

Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m2/day x7 days (n = 240) or conventional care regimens (CCR; n = 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51-0.99]; P = 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31-46% reduced risk of death vs CCR. The most frequent gene mutations were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140, 15%; R172, 8%]), and TP53 (21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with TP53 or NRAS mutations and azacitidine-treated patients with FLT3 or TET2 mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.

Compared with World Health Organization-defined acute myeloid leukaemia (AML) not otherwise specified, patients with AML with myelodysplasia-related changes (AML-MRC) are generally older and more likely to have poor-risk cytogenetics, leading to poor response and prognosis. More than one-half of all older (≥65 years) patients in the phase 3 AZA-AML-001 trial had newly diagnosed AML-MRC.

In acute myeloid leukemia (AML), internal tandem duplications (ITDs) of FLT3 are frequent mutations associated with unfavorable prognosis. At diagnosis, the FLT3-ITD status is routinely assessed by fragment analysis, providing information about the length but not the position and sequence of the ITD. To overcome this limitation, we performed cDNA-based high-throughput amplicon sequencing (HTAS) in 250 FLT3-ITD positive AML patients, treated on German AML Cooperative Group (AMLCG) trials. FLT3-ITD status determined by routine diagnostics was confirmed by HTAS in 242 out of 250 patients (97%). The total number of ITDs detected by HTAS was higher than in routine diagnostics (n = 312 vs. n = 274). In particular, HTAS detected a higher number of ITDs per patient compared to fragment analysis, indicating higher sensitivity for subclonal ITDs. Patients with more than one ITD according to HTAS had a significantly shorter overall and relapse free survival. There was a close correlation between FLT3-ITD mRNA levels in fragment analysis and variant allele frequency in HTAS. However, the abundance of long ITDs (≥75nt) was underestimated by HTAS, as the size of the ITD affected the mappability of the corresponding sequence reads. In summary, this study demonstrates that HTAS is a feasible approach for FLT3-ITD detection in AML patients, delivering length, position, sequence and mutational burden of this alteration in a single assay with high sensitivity. Our findings provide insights into the clonal architecture of FLT3-ITD positive AML and have clinical implications.

We describe laboratory-confirmed influenza A pandemic (H1N1) 2009 in 17 hospitalized recipients of a hematopoietic stem cell transplant (HSCT) (8 allogeneic) and in 15 patients with malignancy treated at 6 Australian tertiary centers during winter 2009. Ten (31.3%) patients were admitted to intensive care, and 9 of them were HSCT recipients. All recipients of allogeneic HSCT with infection <100 days posttransplantation or severe graft-versus-host disease were admitted to an intensive care unit. In-hospital mortality rate was 21.9% (7/32). The H275Y neuraminidase mutation, which confers oseltamivir resistance developed in 4 of 7 patients with PCR positive for influenza after > or = 4 days of oseltamivir therapy. Three of these 4 patients were critically ill. Oseltamivir resistance in 4 (13.3%) of 30 patients who were administered oseltamivir highlights the need for ongoing surveillance of such resistance and further research on optimal antiviral therapy in the immunocompromised.

Target genes of the protooncogene c-myc are implicated in cell cycle and growth control, yet the linkage of both is still unexplored. Here, we show that the products of the nucleolar target genes Pes1 and Bop1 form a stable complex with a novel member, WDR12 (PeBoW complex). Endogenous WDR12, a WD40 repeat protein, is crucial for processing of the 32S precursor ribosomal RNA (rRNA) and cell proliferation. Further, a conditionally expressed dominant-negative mutant of WDR12 also blocks rRNA processing and induces a reversible cell cycle arrest. Mutant WDR12 triggers accumulation of p53 in a p19ARF-independent manner in proliferating cells but not in quiescent cells. Interestingly, a potential homologous complex of Pes1-Bop1-WDR12 in yeast (Nop7p-Erb1p-Ytm1p) is involved in the control of ribosome biogenesis and S phase entry. In conclusion, the integrity of the PeBoW complex is required for ribosome biogenesis and cell proliferation in mammalian cells.

Innovative post-remission therapies are needed to eliminate residual AML cells. DC vaccination is a promising strategy to induce anti-leukaemic immune responses.

Although the genomic and immune microenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I cases were analyzed and compared with 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T cells (P = .02) and STAT6 mutations (false discovery rate [FDR] <0.001) were more frequent in stage I FL. In contrast, programmed cell death protein 1-positive T cells, CD68+/CD163+ macrophages (P < .001), BCL2 translocation (BCL2trl+) (P < .0001), and KMT2D (FDR = 0.003) and CREBBP (FDR = 0.04) mutations were found more frequently in stage III/IV FL. Using clustering, we identified 3 clusters within stage I, and 2 clusters within stage III/IV. The BLC2trl+ stage I cluster was comparable to the BCL2trl+ cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) and STAT6 (64%) mutations, without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%) with fewer CREBBP (45%) and STAT6 (9%) mutations. The other BCL2trl- stage I cluster was relatively heterogeneous with more copy number aberrations and linker histone mutations. This exploratory study shows that stage I FL is genetically heterogeneous with different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven, whereas BCL2trl- stage III/IV appears to be more BCL6trl driven.

The Phase Ib GERSHWIN study (NCT01680991) assessed the pharmacokinetic (PK) profile of obinutuzumab following multiple intravenous (i.v.) doses to Chinese patients with B-cell lymphomas, and compared findings with previous obinutuzumab PK studies in mainly Caucasian (non-Chinese) patients.