CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase.

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

NPM1-mutated myeloid neoplasms are a unique entity not defined by bone marrow blast percentage.

INTRODUCTION: NPM1-mutated (NPM1mut) myeloid neoplasms (MNs) with <20% bone marrow (BM) blasts (NPM1mut MNs<20) are uncommon, and their classification remains inconsistent. METHODS: The clinicopathologic features of 54 patients with NPM1mut MNs <20 were evaluated and compared with wild-type NPM1 MNs <20 and NPM1mut MNs≥20, respectively. RESULTS: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p = .023) and FLT3 (70% vs 11%, p < .001) frequency in patients with ≥20% BM blasts. Thirty-three (61%) patients with NPM1mut MNs <20 received low-intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p = .006) and median overall survival (mOS) (not reached vs 30.4 months, p = .06) were observed with IC compared to LIC. Young patients (age <60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p = .025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for <10%, 10%-19%, and ≥20% blasts, p = .700) regardless of treatment modality (LIC: p = .900; IC: p = .360). Twenty-three patients (43%) with NPM1mut MNs <20 had marrow blast progression to ≥20%. CONCLUSIONS: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage.

Fifth Edition of the World Health Classification of Tumors of the Hematopoietic and Lymphoid Tissue: Myeloid Neoplasms.

In this manuscript, we review myeloid neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors (WHO-HEM5), focusing on changes from the revised fourth edition (WHO-HEM4R). Disease types and subtypes have expanded compared with WHO-HEM4R, mainly because of the expansion in genomic knowledge of these diseases. The revised classification is based on a multidisciplinary approach including input from a large body of pathologists, clinicians, and geneticists. The revised classification follows a hierarchical structure allowing usage of family (class)-level definitions where the defining diagnostic criteria are partially met or a complete investigational workup has not been possible. Overall, the WHO-HEM5 revisions to the classification of myeloid neoplasms include major updates and revisions with increased emphasis on genetic and molecular drivers of disease. The most notable changes have been applied to the sections of acute myeloid leukemia and myelodysplastic neoplasms (previously referred to as myelodysplastic syndrome) with incorporation of novel, disease-defining genetic changes. In this review we focus on highlighting the updates in the classification of myeloid neoplasms, providing a comparison with WHO-HEM4R, and offering guidance on how the new classification can be applied to the diagnosis of myeloid neoplasms in routine practice.

TP53 copy number and protein expression inform mutation status across risk categories in acute myeloid leukemia.

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as copy neutral loss of heterozygosity in 5/32 (15.6%) AML patients who had intact TP53 CN. Importantly, we demonstrate that mutant p53 protein expression patterns by immunohistochemistry evaluated using digital image-assisted analysis provide a robust readout that integrates TP53 mutation and allelic states in patients with AML. Expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of comutations in TP53-mutant AML shows a muted landscape encompassing primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provide a rationale to refine risk stratification of patients with AML on the basis of integrated molecular and protein-level TP53 analyses.

Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms.

There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.

ASXL1/TET2 genotype-based risk stratification outperforms ASXL1 mutational impact and is independent of mutant variant allele fractions in chronic myelomonocytic leukemia.

Not available.

A framework for the clinical implementation of optical genome mapping in hematologic malignancies.

Optical Genome Mapping (OGM) is rapidly emerging as an exciting cytogenomic technology both for research and clinical purposes. In the last 2 years alone, multiple studies have demonstrated that OGM not only matches the diagnostic scope of conventional standard of care cytogenomic clinical testing but it also adds significant new information in certain cases. Since OGM consolidates the diagnostic benefits of multiple costly and laborious tests (e.g., karyotyping, fluorescence in situ hybridization, and chromosomal microarrays) in a single cost-effective assay, many clinical laboratories have started to consider utilizing OGM. In 2021, an international working group of early adopters of OGM who are experienced with routine clinical cytogenomic testing in patients with hematological neoplasms formed a consortium (International Consortium for OGM in Hematologic Malignancies, henceforth "the Consortium") to create a consensus framework for implementation of OGM in a clinical setting. The focus of the Consortium is to provide guidance for laboratories implementing OGM in three specific areas: validation, quality control and analysis and interpretation of variants. Since OGM is a complex technology with many variables, we felt that by consolidating our collective experience, we could provide a practical and useful tool for uniform implementation of OGM in hematologic malignancies with the ultimate goal of achieving globally accepted standards.

A retrospective study of cladribine and low-dose cytarabine-based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia.

BACKGROUND: Patients with higher risk chronic myelomonocytic leukemia (CMML) have limited therapeutic options beyond hydroxyurea and hypomethylating agents (HMAs). Regimens based on a backbone of cladribine (CLAD), low-dose cytarabine (LDAC), and an HMA are effective low-intensity therapies for acute myeloid leukemia (AML). METHODS: The authors conducted a retrospective chart review to evaluate the efficacy of CLAD/LDAC/HMA in CMML and secondary acute myeloid leukemia (sAML) arising from CMML. Responses were evaluated according to the 2006 International Working Group criteria for CMML and the 2017 European LeukemiaNet criteria for AML. The overall survival (OS), leukemia-free survival (LFS), and duration of response were evaluated with the Kaplan-Meier method. Patients were stratified on the basis of prior HMA exposure. RESULTS: The authors identified 21 patients with CMML (eight with HMA-naive CMML and 13 with HMA-failure CMML) and 33 patients with sAML (11 with HMA-naive sAML and 22 with HMA-failure sAML) treated with CLAD/LDAC/HMA-based regimens. The CMML cohort was enriched for high-risk features (proliferative type, elevated blasts, and RAS/MAPK mutations). The overall response rate was 33% in CMML (50% in HMA-naive CMML and 23% in HMA-failure CMML) and 48% in sAML (82% in HMA-naive sAML and 32% in HMA-failure sAML). The median OS was 14.4, 8.8, 42.9, and 2.9 months for HMA-naive CMML, HMA-failure CMML, HMA-naive sAML, and HMA-failure sAML, respectively. The median LFS was 14.4 and 3.9 months for HMA-naive CMML and HMA-failure CMML, respectively. CONCLUSIONS: CLAD/LDAC/HMA-based regimens are effective in a subset of patients with higher risk CMML and sAML arising from CMML who have not previously experienced HMA failure. These findings must be confirmed in prospective studies.

Phenotypic subtypes of leukaemic transformation in chronic myelomonocytic leukaemia.

Chronic myelomonocytic leukaemia (CMML) is a haematological disorder with high risk of transformation to acute myeloid leukaemia (AML). To characterize the phenotypic and genomic patterns of CMML progression, we evaluated a cohort of 189 patients with AML evolving from CMML. We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo-AML, 53%), immature myeloid (My-AML, 43%) or erythroid (Ery-AML, 2%). Mo-AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by SRSF2, TET2 and RAS pathway mutation co-dominance and were more likely to evolve from SRSF2-TET2 co-mutant CMML through emergence/expansion of RAS pathway mutant clones. Conversely, My-AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency of CD14, CD64 and CD56 expression) were less likely to exhibit SRSF2-TET2 co-mutations or RAS pathway mutations and had higher frequency of CEBPA mutations. Ery-AML was defined by complex karyotypes and TP53 mutations. A trend towards improved OS and EFS with hypomethylating agent-venetoclax combination was observed in My-AML, but not Mo-AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype-specific therapeutics.

Genome Mapping Nomenclature.

Background Genome Mapping Technologies (optical and electronic) uses ultra high-molecular weight DNA to detect structural variation and has an application in constitutional genetic disorders, haematological neoplasms and solid tumours. Genome mapping can detect balanced and unbalanced structural variation, copy number changes and haplotypes. The technique is analogous to chromosomal microarray analysis although genome mapping has the added benefit of being able to detect and ascertain the nature of more abnormalities than array, karyotyping or FISH. Key Messages This paper describes a specific nomenclature for genome mapping that can be used by diagnostic and research centres to accurately report their findings. An international nomenclature is essential for patient results to be understood by different healthcare providers as well as clear communication in publications and consistency in databases. Summary Genome mapping can detect aneuploidy, balanced and unbalanced structural variation as well as copy number changes. The Standing Committee for the International System for Human Cytogenomic Nomenclature (ISCN), recognised there was a need for a specific nomenclature for genome mapping that encompasses the range of abnormalities detected by this technique. This paper explains the general principles of the nomenclature as well as giving specific ISCN examples for the different types of numerical and structural rearrangements.

ROS1 Alterations as a Potential Driver of Gliomas in Infant, Pediatric, and Adult Patients.

Gliomas harboring oncogenic ROS1 alterations are uncommon and primarily described in infants. Our goal was to characterize the clinicopathological features and molecular signatures of the full spectrum of ROS1 fusion-positive gliomas across all age groups. Through a retrospective multi-institutional collaboration, we report a collection of unpublished ROS1 fusion gliomas along with the characterization and meta-analysis of new and published cases. A cohort of 32 new and 58 published cases was divided into the following 3 age groups: 19 infants, 40 pediatric patients, and 31 adults with gliomas. Tumors in infants and adults showed uniformly high-grade morphology; however, tumors in pediatric patients exhibited diverse histologic features. The GOPC::ROS1 fusion was prevalent (61/79, 77%) across all age groups, and 10 other partner genes were identified. Adult tumors showed recurrent genomic alterations characteristic of IDH wild-type glioblastoma, including the +7/-10/CDKN2A deletion; amplification of CDK4, MDM2, and PDGFRA genes; and mutations involving TERTp, TP53, PIK3R1, PIK3CA, PTEN, and NF1 genes. Infant tumors showed few genomic alterations, whereas pediatric tumors showed moderate genomic complexity. The outcomes were significantly poorer in adult patients. Although not statistically significant, tumors in infant and pediatric patients with high-grade histology and in hemispheric locations appeared more aggressive than tumors with lower grade histology or those in nonhemispheric locations. In conclusion, this study is the largest to date to characterize the clinicopathological and molecular signatures of ROS1 fusion-positive gliomas from infant, pediatric, and adult patients. We conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or codriver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy.

Characteristics and clinical outcomes of patients with acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2).

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has a very poor prognosis. Determinants of clinical outcomes and optimal treatment remain uncertain. We retrospectively reviewed 108 cases of AML with inv(3)/t(3;3) and evaluated clinicopathological characteristics and clinical outcomes: 53 newly diagnosed (ND) AML and 55 relapsed/refractory (R/R) AML. Median age was 55 years. White blood cell (WBC) count ≥20x109/L and platelet count ≥140x109/L was observed in 25% and 32% of ND patients, respectively. Anomalies involving chromosome 7 were identified in 56% of patients. The most frequently mutated genes were SF3B1, PTPN11, NRAS, KRAS and ASXL1. In ND patients, the composite complete remission (CRc) rate was 46% overall; 46% with high-intensity treatments and 47% with lowintensity treatments. The 30-day mortality was 14% and 0%, with high- and low-intensity treatment, respectively. In R/R patients, the CRc rate was 14%. Venetoclax based-regimens were associated with a CRc rate of 33%. The 3-year overall survival (OS) was 8.8% and 7.1% in ND and R/R patients, respectively. The 3-year cumulative incidence of relapse was 81.7% overall. Older age, high WBC, high peripheral blast count, secondary AML and KRAS, ASXL1, DNMT3A mutations were associated with worse OS in univariable analyses. The 5-year OS rates were 44% and 6% with or without hematopoietic stem cell transplantation in CR1, respectively. AML with inv(3)/t(3;3) is associated with low CR rates, very high risk of relapse and dismal long-term survival. Intensive chemotherapy and hy pomethylating agents provide similar rates of remission and patients achieving CR benefit from hematopoietic stem cell transplantation in first CR.

The outcomes of patients with chronic myeloid leukemia treated with third-line BCR::ABL1 tyrosine kinase inhibitors.

The BCR::ABL1 tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with chronic myeloid leukemia (CML). After failing second-generation TKI (2G-TKI), the optimal third-line therapy in chronic phase CML (CML-CP) is not well established. We analyzed 354 patients with CML-CP treated with a third-line BCR::ABL1 TKI at our institution, and in the PACE and OPTIC trials, and evaluated the outcome after alternate 2G-TKIs or ponatinib. We performed a propensity score matching analysis to compare outcomes and multivariate analysis to identify variables associated with survival. One hundred seventy-three (49%) patients received 2G-TKIs and 181 (51%) ponatinib. Patients in the ponatinib group had more cardiovascular risk factors (34% versus 19%) and higher disease burden (BCR::ABL1 transcript levels >1%, 165/175 [94%] versus 75/135 [55%]; p < .001) compared with the 2G-TKI group. Among the 173 evaluable patients treated with ponatinib, 89 (52%) achieved 2 + -log reduction of baseline transcripts (20% 2-log reduction and 32% 3 + -log reduction). Among the 128 evaluable patients treated with 2G-TKIs, 44 (34%) achieved 2 + -log reduction of baseline transcripts (13% 2-log reduction and 21% 3 + -log reduction). With a median follow-up of 46 months, the 3-year progression-free survival was 59% (60% before matching) with 2G-TKI and 83% (81% before matching) with ponatinib (p < .001). The 3-year survival was 83% (81% before matching) with 2G-TKI and 87% (89% before matching) with ponatinib (p = .03). By multivariate analysis, third-line therapy with ponatinib was the only independent factor associated with better survival (p = .003). In conclusion, ponatinib is an optimal treatment for patients with CML-CP failing two prior TKIs.

Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation treated in the pre- and post-ponatinib era.

Patients with chronic myeloid leukemia (CML) and T315I mutation generally have a poor prognosis. Their outcome in the post-ponatinib era remains unclear. We reviewed patients with CML in chronic (CP) or accelerated phase (AP) who developed a T315I mutation between March 15, 2004, and July 26, 2022. Patients were divided into CP, AP, or blastic phase (BP) at the time of mutation detection. Overall survival (OS) was defined from the time of mutation detection to the date of death or last follow-up. We identified a total of 107 patients: 54 (51%) in CP, 14 (13%) in AP, and 39 (36%) in BP. One hundred and two patients received subsequent therapy after the T315I mutation was detected. At a median follow-up of 75 months (95% CI, 41-110), the median OS was 49 months (95% CI, 26-73) and the 5-year OS rate was 44%. Patients who were in CML-CP at the time of mutation detection had better survival compared with those in AP or BP, with a median OS of 132, 31, and 6 months, and 5-year OS rates of 70%, 37%, and 10%, respectively (p < .001). Patients with CML-CP treated with ponatinib and/or asciminib had a 5-year OS of 77% compared with 50% in those who received other treatments (chemotherapy, second-generation tyrosine kinase inhibitors, homoharringtonine, and investigational drugs) (p = .14). In summary, patients with CML-CP at the time of T315I mutation detection may have a relatively indolent disease course with a long-term OS of 70%. Treatment with third-generation tyrosine kinase inhibitors seemed to improve survival in patients with CML-CP.

Performance of IPSS-M in patients with myelodysplastic syndrome after hypomethylating agent failure.

Evaluation of IPSS-M and exploratory prognostic model for MDS at the time of HMA failure.

Ultrasensitive NGS MRD assessment in Ph+ ALL: Prognostic impact and correlation with RT-PCR for BCR::ABL1.

Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, RT-PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay (sensitivity of 10-6 ) and its correlation with RT-PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT-PCR and NGS, and 31% of patients who achieved NGS MRD negativity were PCR+ at the same timepoint. Among eight patients with long-term detectable BCR::ABL1 by PCR, six were PCR+/NGS-. These patients generally had stable PCR levels that persisted despite therapeutic interventions, and none subsequently relapsed; in contrast, patients who were PCR+/NGS+ had more variable PCR values that responded to therapeutic intervention. In a separate cohort of prospectively collected clinical samples, 11 of 65 patients (17%) with Ph+ ALL who achieved NGS MRD negativity had detectable BCR::ABL1 by PCR, and none of these patients relapsed. Relapse-free survival and overall survival were similar in patients who were PCR+/NGS- and PCR-/NGS-, suggesting that PCR for BCR::ABL1 did not provide additional prognostic information in patients who achieved NGS MRD negativity. NGS-based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low-level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.

Phase II study of cladribine, idarubicin, and ara-C (CLIA) with or without sorafenib as initial therapy for patients with acute myeloid leukemia.

The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival.

Diagnostic work-up of hematological malignancies with underlying germline predisposition disorders (GPD).

Hematological malignancies with underlying germline predisposition disorders have been recognized by the World Health Organization 5th edition and International Consensus Classification (ICC) classification systems. The list of genes and the associated phenotypes are expanding and involve both pediatric and adult populations. While the clinical presentation and underlying molecular pathogenesis are relatively well described, the knowledge regarding the bone marrow morphologic features, the landscape of somatic aberrations associated with progression to hematological malignancies is limited. These pose challenges in the diagnosis of low-grade myelodysplastic syndrome (MDS) to hematopathologists which carries direct implication for various aspects of clinical management of the patient, donor selection for transplantation, and family members. Here in, we provide a focused review on the diagnostic work-up of hematological malignancies with underlying germline predisposition disorders with emphasis on the spectrum of hematological malignancies associated with each entity, and characteristic bone marrow morphologic, somatic cytogenetic and molecular alterations at the time of diagnosis of hematological malignancies. We also review the key clinical, morphologic, and molecular features, that should initiate screening for these entities.

Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial.

BACKGROUND: Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma. METHODS: We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m2 weekly for the first 4 weeks and then on day 1 of cycles 3-12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate-cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate-cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620. FINDINGS: 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related. INTERPRETATION: Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma. FUNDING: Pharmacyclics, Janssen.

Ibrutinib and Venetoclax for First-Line Treatment of CLL.

BACKGROUND: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. METHODS: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10-4). RESULTS: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. CONCLUSIONS: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).