Adjunctive Volasertib in Patients With Acute Myeloid Leukemia not Eligible for Standard Induction Therapy : A Randomized, Phase 3 Trial

In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1-10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized >= 5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95-2.89]; P = 0.071). At final analysis (>= 574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8-1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections.Peer reviewe

Adjunctive volasertib in patients with acute myeloid leukemia not eligible for standard induction therapy: a randomized, phase 3 trial

In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1–10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized ≥5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95–2.89]; P = 0.071). At final analysis (≥574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8–1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections

RUNX1 mutations in acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by a great cytogenetic and molecular genetic diversity. Past years research has shed more light on the molecular background of the disease and identified new mutations and pathways, for example NPM1 and FLT3 mutations that allowed a more precise prognostic stratification beyond cytogenetics and opened the way to targeted therapies. This study aimed to characterize the role of RUNX1 mutations in AML focusing on the distribution of RUNX1 mutations among different WHO categories of AML, identifying cytogenetic and molecular markers associated with RUNX1 mutations and evaluating their clinical impact. To this aim, a total of 2439 adult AML patients enrolled treatment trials of the German-Austrian Study Group (AMLSG) were analyzed for RUNX1 mutations using Sanger sequencing. Overall, 280 RUNX1 mutations were detected in 245 (10 %) of 2439 AML patients. The majority of mutations clustered in exon 4 (n=81, 28.9 %) and exon 8 (n=63, 22.5 %). Approximately half of the RUNX1 mutations (49.6 %) were located in the Runt homology domain (RHD) and 40 % in the transactivation domain (TAD). Frameshift mutations prevailed in the TAD and missense mutation in the RHD. Regarding clinical characteristics, compared to patients with RUNX1 wildtype patients, RUNX1 mutated patients presented with more advanced age (59.2 years vs 53.6 years), had more immature FAB morphology (FAB M0) and secondary AML evolving from myelodysplastic syndrome. In the current category of “AML with recurrent genetic abnormalities” of the WHO 2008 Classification, RUNX1 mutations were largely mutually exclusive of all recurrent genetic abnormalities. We identified a significant association between RUNX1 mutation and abnormalities of chromosome 7 (-7/7q-) and trisomy 13. Molecular markers significantly associated with RUNX1 mutations were mutations in the epigenetic modifiers ASXL1, IDH2 and KMT2A. Among combined genotypes, the RUNX1mut/ASXL1mut genotype conferred a particularly poor prognosis. A significant finding was the high rate of resistant disease after double induction (41 %) for the RUNX1 mutated patients. In univariable analysis, RUNX1 mutations were a negative prognostic factor for all survival endpoints, whereas in multivariable analysis only event-free survival retained significance. For young patients eligible for allogeneic hematopoietic cell transplantation, a benefit in terms of prolonged relapse-free survival was found suggesting that allogeneic transplantation may be a therapeutic option for selected patients with RUNX1 mutations. The results of the present study identified RUNX1 as one of the most frequently mutated genes in AML. AML with RUNX1 mutations have distinct clinical and biological characteristics and may be considered as a genetic lesion defining a novel disease entity

Ruxolitinib is effective in the treatment of a patient with refractory T‐ALL

Abstract T‐cell acute lymphoblastic leukemia (T‐ALL) is a rare, aggressive T‐cell malignancy. Chemotherapy alone cures only 25‐45% of the cases, thus, novel treatment agents and strategies are urgently needed. We assessed the efficacy of ruxolitinib in a patient with a cutaneous relapse after allogeneic blood cell transplantation of a refractory T‐ALL with a Janus kinase 3 (JAK3) mutation. In this case report, we were able to show the potential benefit of the JAK inhibitor ruxolitinib in JAK3‐mutated refractory T‐ALL and emphasize the importance of integrating molecular markers in current treatment decision making for patients with T‐ALL

Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling

Parathyroid carcinoma (PC) is an ultra‐rare malignancy with a high risk of recurrence after surgery. Tumour‐directed systemic treatments for PC are not established. We used whole‐genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (a) immune checkpoint inhibition with pembrolizumab based on high tumour mutational burden and a single‐base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like) overactivation; (b) multi‐receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 (Fibroblast Growth Factor Receptor 1) and RET (Ret Proto‐Oncogene) and, (c) later in the course of the disease, PARP (Poly(ADP‐Ribose) Polymerase) inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome‐wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra‐rare cancers based on insight into disease biology

Protein phosphatase 4 regulatory subunit 2 (PPP4R2) is recurrently deleted in acute myeloid leukemia and required for efficient DNA double strand break repair

We have previously identified a recurrent deletion at chromosomal band 3p14.1-p13 in patients with acute myeloid leukemia (AML). Among eight protein-coding genes, this microdeletion affects the protein phosphatase 4 regulatory subunit 2 (PPP4R2), which plays an important role in DNA damage response (DDR). Investigation of mRNA expression during murine myelopoiesis determined that Ppp4r2 is higher expressed in more primitive hematopoietic cells. PPP4R2 expression in primary AML samples compared to healthy bone marrow was significantly lower, particularly in patients with 3p microdeletion or complex karyotype. To identify a functional role of PPP4R2 in hematopoiesis and leukemia, we genetically inactivated Ppp4r2 by RNAi in murine hematopoietic stem and progenitor cells and murine myeloid leukemia. Furthermore, we ectopically expressed PPP4R2 in a deficient human myeloid leukemic cell line. While PPP4R2 is involved in DDR of both hematopoietic and leukemic cells, our findings indicate that PPP4R2 deficiency impairs de-phosphorylation of phosphorylated key DDR proteins KRAB-domain associated protein 1 (pKAP1), histone variant H2AX (γH2AX), tumor protein P53 (pP53), and replication protein A2 (pRPA2). Potential impact of affected DNA repair processes in primary AML cases with regard to differential PPP4R2 expression or 3p microdeletion is also supported by our results obtained by gene expression profiling and whole exome sequencing. Impaired DDR and increased DNA damage by PPP4R2 suppression is one possible mechanism by which the 3p microdeletion may contribute to the pathogenesis of AML. Further studies are warranted to determine the potential benefit of inefficient DNA repair upon PPP4R2 deletion to the development of therapeutic agents