Showing papers in "Hematological Oncology in 2019"
TL;DR: This review will discuss the grading and management of the two most common toxicities, cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS), observed acutely after this therapy.
Abstract: Chimeric antigen receptor (CAR) T-cell therapy has the potential to revolutionize the management of B-cell lymphomas and possibly other cancers. Two anti-CD19 CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for the management of relapsed/refractory large B-cell lymphoma after two lines of systemic therapy. Additional trials are ongoing to evaluate these and other CAR T products at earlier stages of the disease course as well as in other lymphomas. While the potential to induce durable remissions with a single CAR T-cell infusion even in patients who are chemorefractory has generated much enthusiasm in the field, practitioners need to familiarize themselves with the unique toxicities associated with these therapies. This review will discuss the grading and management of the two most common toxicities, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), observed acutely after this therapy. In addition, late toxicities including prolonged cytopenias and on-target off-tumor effects will be reviewed.
199 citations
TL;DR: The current diagnostic criteria, risk stratification, and approach to treatment of multiple myeloma, including treatment approach for both newly diagnosed and relapsed disease are discussed.
Abstract: The treatment of myeloma is rapidly evolving. This article reviews the current diagnostic criteria, risk stratification, and approach to treatment of multiple myeloma. Treatment approach for both newly diagnosed and relapsed disease are discussed.
126 citations
TL;DR: This review will highlight landmark trials for anti‐CD19 CAR T cells and first‐in‐human trials of novel CARs, as well as discuss promising innovative CAR designs that are still undergoing preclinical development.
Abstract: Chimeric antigen receptor (CAR) T-cell therapy has dramatically shifted the landscape of treatment for lymphoid malignancies, especially diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). However, there continue to be significant limitations of this therapy, such as incomplete or nonsustained responses and severe toxicities in a subset of patients. Furthermore, expanding the role of CAR T-cell therapy to new disease types is an important next step. In this review, we will highlight landmark trials for anti-CD19 CAR T cells and first-in-human trials of novel CARs, as well as discuss promising innovative CAR designs that are still undergoing preclinical development. Lastly, we will discuss toxicity and mechanisms of CAR T-cell resistance and failure, as well as potential future treatment approaches to these common issues.
108 citations
TL;DR: DLBCL patients with mutations in relapse-enriched genes, specifically hotspot deletions, may have power as biomarkers to identify patients at a high risk of relapse and could inform on the mechanism of acquired resistance to components of R-CHOP.
Abstract: tions are associated with treatment resistance in other cancers, the functional effect of this deletion has not been characterized. Conclusions: DLBCL patients with mutations in relapse-enriched genes are at a higher risk of treatment failure. Mutations in these genes, specifically hotspot deletions, may have power as biomarkers to identify patients at a high risk of relapse and could inform on the mechanism of acquired resistance to components of R-CHOP.
81 citations
TL;DR: Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib.
Abstract: The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), including the new kinase inhibitor idelalisib, has changed the therapeutic landscape of these diseases However, the use of idelalisib is associated with a peculiar profile of side effects, which require an optimization of the current approach to prophylaxis and supportive treatment Moving from the recognition that the abovementioned issue represents an unmet need in CLL and FL, a multidisciplinary panel of experts was convened to produce a consensus document aiming to provide practical recommendations for the management of the side effects during idelalisib therapy for CLL and FL The present publication represents a consensus document from a series of meetings held during 2017 The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process and explored 4 domains, ie, diarrhea/colitis, transaminitis, pneumonitis, and infectious complications Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib
55 citations
TL;DR: The histological and genetic spectrum of lymphomatoid papulosis has been expanded and prognostic subtypes were delineated for some entities and subtypes of CL such as folliculotropic mycosis fungoides and marginal zone lymphoma.
Abstract: Primary cutaneous lymphomas (CL) are the second most common form of extranodal lymphomas. Cutaneous T-cell lymphomas represent the majority. They are classified according to the WHO classification 2017 and the updated WHO-EORTC 2018 published in the fourth edition of the WHO classification for Skin Tumors monograph. Primary cutaneous acral CD8+ T-cell lymphoma and EBV-positive mucocutaneous ulcer have been listed as new provisional entities. Moreover, the histological and genetic spectrum of lymphomatoid papulosis has been expanded. Recently, prognostic subtypes were delineated for some entities and subtypes of CL such as folliculotropic mycosis fungoides and marginal zone lymphoma. Since CL show overlapping histological features, clinico-pathological correlation is of outmost importance for the diagnosis. Recent studies revealed new biomarkers and genetic alterations underlying the pathogenesis of CL. Moreover, targeted therapies have widened the treatment options particularly for aggressive lymphomas.
53 citations
TL;DR: Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate‐based chemotherapy may improve progression‐free survival in immunocompetent patients with newly diagnosed PCNSL.
Abstract: The CD-20 antibody rituximab is a standard component of treatment of non-Hodgkin B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system, also called primary central nervous system lymphoma (PCNSL), is a DLBCL confined to the central nervous system. There has been debate whether intravenous rituximab accumulates sufficiently in the central nervous system to exert an effect. In this systematic review, we assess the benefits and harms of rituximab in the treatment of immunocompetent patients with PCNSL. By searching MEDLINE, CENTRAL, and ClincialTrials.gov up to March 2019, we identified randomized controlled trials (RCTs) investigating the effect of rituximab in patients with PCNSL. We extracted study characteristics and results, assessed risk of bias, performed trial-level random-effects meta-analyses, and graded the certainty of evidence. The protocol was registered with PROSPERO (CRD42019121965). Main outcomes were overall survival (time to death), progression-free survival (time to progression or death), quality of life, grades 3 and 4 toxicity, and treatment-related mortality. We included two RCTs with a total of 343 participants. Overall survival was not statistically significantly improved (HR 0.76; 95% CI, 0.52-1.12; low certainty), with 187 fewer to 39 more deaths after 2 years in 1000 treated patients. Low certainty of evidence indicated that rituximab improved progression-free survival (HR 0.65; 95% CI, 0.45-0.95), which translated into 137 fewer progressions or deaths after 2 years in 1000 treated patients (231 to 18 fewer). None of the RCTs provided data on quality of life. We found no evidence that rituximab increased grades 3 and 4 toxicity or treatment-related mortality (RR 0.53; 95% CI, 0.20-1.37; low certainty). Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate-based chemotherapy may improve progression-free survival in immunocompetent patients with newly diagnosed PCNSL, the pooled effect estimates did not show evidence for improvement of overall survival.
47 citations
University of Cagliari1, University of Rome Tor Vergata2, University of Naples Federico II3, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico4, University of Bari5, University of Bologna6, University of Pisa7, Casa Sollievo della Sofferenza8, University of Verona9, University of Florence10, University of Padua11, University of Sassari12, Sapienza University of Rome13
TL;DR: Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels, and patients' AOEs were identified.
Abstract: Arterial occlusive events (AOEs) represent emerging complications in chronic myeloid leukemia (CML) patients treated with ponatinib. We identified 85 consecutive CML adult patients who were treated with ponatinib in 17 Italian centers. Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 60-month cumulative incidence rate of AOEs excluding hypertension was 25.7%. Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28 months (range, 3-69 months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P < 0.001). Patients aged ≥60 years showed a significantly higher incidence rate of AOEs (51.5% vs 16.9%, P = 0.008). In multivariate analysis, no association was found between AOEs and positive history of CV disease, age, dose of ponatinib, previous exposure to nilotinib, and comorbidities. Only the SCORE risk was confirmed as a significant predictive factor (P = 0.01; HR = 10.9; 95% C.I. = 1.7-67.8). Patients aged ≥60 years who were treated with aspirin had a lower incidence rate of AOEs (33.3% vs 61.8%). Among the 14 reported AOEs, 78.6% of them showed grade 3 to 4 toxicity. This real-life study confirmed the increased incidence of AOEs in CML patients treated with ponatinib, with high to very high SCORE risk. We suggest that patients aged ≥60 years who were treated with ponatinib should undergo prophylaxis with 100 mg/day of aspirin. Our findings emphasize personalized prevention strategies based on CV risk factors.
46 citations
TL;DR: Evidence of TLS via radiological imaging and electrocardiogram findings has been a limited way to evaluate TLS, indicating the need for further research in this area.
Abstract: Tumor lysis syndrome (TLS) is an oncologic emergency from the intracellular release of material in lysing malignant cells. The earlier it is treated, the less likely it is to be harmful to an individual and spread through the body. Common complications of TLS include arrhythmias, which are caused by hypocalcemia or hyperkalemia, renal failures due to hyperuricemia or hyperphosphatemia, and seizures. Furthermore, the risk to develop TLS varies widely based on several factors including factors that are related to disease, the patient, and the treatment of the patient. Laboratory data can be used to gauge the severity of TLS based on patient serum levels for specific markers. On the contrary, evidence of TLS via radiological imaging and electrocardiogram findings has been a limited way to evaluate TLS, indicating the need for further research in this area. Common trends of treatment have also been seen in the past several years, evident by case studies seen in the following literature review.
43 citations
TL;DR: Primary central nervous system lymphoma is a rare subtype of non‐Hodgkin lymphoma that is confined to the brain, leptomeninges, or the eye and is associated with a relatively poor prognosis compared to other extranodal diffuse large B‐cell lymphomas.
Abstract: Primary central nervous system lymphoma is a rare subtype of non-Hodgkin lymphoma that is confined to the brain, leptomeninges, or the eye and is associated with a relatively poor prognosis compared to other extranodal diffuse large B-cell lymphomas. However, methotrexate-based induction chemotherapy followed by consolidative chemotherapy or high-dose therapy and autologous stem cell transplantation is associated with improved survival and reduced neurotoxicity. Aberrant activation of B-cell receptor signaling and activation of nuclear factor kappa beta is a frequent genetic alteration and offers opportunities for targeted therapies in this lymphoma subtype.
43 citations
TL;DR: Recent updates on the evolution of frontline therapies for DLBCL are summarized and next‐generation sequencing has unveiled the remarkable complexity ofDLBCL and identified potential molecular targets for tailored therapies.
Abstract: Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with the standard immunochemotherapy R-CHOP, one-third of them relapses with a dismal outcome in most cases. In the recent years, remarkable advances have been achieved based on the discovery of molecular genetics in DLBCL. In addition to the major cell-of-origin designations of germinal center B-cell and activated B-cell subtypes, next-generation sequencing has unveiled the remarkable complexity of DLBCL and identified potential molecular targets for tailored therapies. Despite these findings, the current standard of care for DLBCL patients is still R-CHOP, and optimization of frontline therapy remains an important goal. In this review, we summarize recent updates on the evolution of frontline therapies for DLBCL.
TL;DR: Machine learning analysis pointed out miR‐29c‐5p expression as the best discriminator between childhood T‐ and B‐ALL, which is involved in calcium signaling, critical for B‐cell lymphocyte fate.
Abstract: MicroRNAs (miRNAs) play a critical role on biological and cellular processes; the search for functional markers may be of importance for differential diagnosis, prognosis, and development of new therapeutic regimens. In this context, we evaluated the bone marrow miRNA profile of Brazilian children exhibiting T- or B-cell acute lymphoblastic leukemia (T-ALL or B-ALL), using massive parallel sequencing, using the HiSeq 2500 platform (Illumina). The differential expression analysis was conducted considering a leave-one-out approach and FDR ≤ 0.05. Machine learning algorithms were applied to search for the disease subset biomarkers. Target prediction, functional enrichment, and classification of biological categories were also performed. Sixteen miRNAs were differentially expressed between T- and B-ALL, of which 10 (miR-708-5p, miR-497-5p, miR-151a-5p, miR-151b, miR-371b-5p, miR-455-5p, miR-195-5p, miR-1266-5p, miR-574-5p, and miR-425-5p) were downregulated and six (miR-450b-5p, miR-450a-5p, miR-542-5p, miR-424-5p, miR-629-5p, and miR-29c-5p) were upregulated in childhood T-ALL. These miRNAs may be used for distinguishing childhood lymphoblastic leukemia subtypes, since it provided the clear separation of patients in these two distinct groups. Six relevant biological pathways were identified according to their role in leukemia, namely, viral carcinogenesis, cell cycle, and B-cell receptor signaling pathways for induced miRNAs and TGF-beta signaling, apoptosis, and NF-kappa B signaling for the repressed miRNAs, of which several miRNA gene targets participate in cell differentiation and hematopoiesis processes. Machine learning analysis pointed out miR-29c-5p expression as the best discriminator between childhood T- and B-ALL, which is involved in calcium signaling, critical for B-cell lymphocyte fate. Further studies are needed to assure the role of the 16 miRNAs and miR-29c-5p on acute lymphoblastic leukemia subtypes and on disease prognosis.
TL;DR: This study shows that serum exosomal microRNAs can be used independently as novel serum biomarkers for MM.
Abstract: Accumulating studies have focused on circulating microRNAs, which might be potential biomarkers for different malignancies. The aim of this study was to investigate the potential of serum exosomal microRNAs to be novel serum biomarkers for smouldering myeloma (SMM) or even multiple myeloma (MM). The levels of serum exosomal microRNAs and serum circulating microRNAs were measured in healthy individuals and patients with SMM (n = 20) or MM (n = 20). Serum exosomal microRNAs and serum circulating microRNAs were extracted from serum, and the expression levels of selected microRNAs were quantified by real-time polymerase chain reaction (PCR). The levels of serum exosome-derived miR-20a-5p, miR-103a-3p, and miR-4505 were significantly different among patients with MM, patients with SMM, and healthy individuals, while there were differences in the levels of let-7c-5p, miR-185-5p, and miR-4741 in patients with MM relative to those in SMM patients or healthy controls. Additionally, a significant correlation was rarely found between the levels of serum and exosomal microRNAs. This study shows that serum exosomal microRNAs can be used independently as novel serum biomarkers for MM.
TL;DR: In this article, a phase I study to treat 10 pediatric B-cell acute lymphatic leukemia (R/R B-ALL) patients using a CD19-targeted second generation CAR with a 4-1BB intracellular costimulatory domain was conducted.
Abstract: Ninety percent of relapse/refractory B-cell acute lymphatic leukemia (R/R B-ALL) patients can achieve complete remission (CR) after CD19-targeting chimeric antigen receptor T (CAR-T) cell therapy. However, around 50% of them relapse in 1 year. Persistent CAR-T cell engraftment is considered as the key to remain durable remission. Here, we initiated a phase I study to treat 10 pediatric B-ALL patients using a CD19-targeted second generation CAR with a 4-1BB intracellular costimulatory domain. All patients received a standard fludarabine and cyclophosphamide (FC) preconditioning regiment, followed by a CAR-T infusion with a median number of 0.5 (0.3-1.58) × 106 CAR+ T cells/kg. The pretreatment tumor burdens were high with a median bone marrow (BM) blasts percentage of 59.2% (7.31%-86.2%), excluding one patient only with brain infiltration of leukemia cells (0% BM blasts). The initial CR rate was 80% (n = 8/10). Four patients (40%) experienced serious (grade > 2) cytokine release syndrome (CRS) and three patients (30%) with obvious neurotoxicity. Monthly assessments of CD19+ minimal residual disease (MRD) and CAR-T engraftment demonstrated the anti-CD19 activity of long-term engrafted CAR-T cell clones in one patient for more than 2 years.
TL;DR: A 61% rate of PET avidity in biopsy‐confirmed MALT lymphoma was found, and it was correlated with tumor size and Ki‐67 score, and PET/CT parameters were not related to survival.
Abstract: Mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent lymphoma with good prognosis and variable fluorine-18 fluorodeoxyglucose (18 F-FDG) avidity. Many possible prognostic factors have been investigated with controversial results, but the possible prognostic role of 18 F-FDG positron emission tomography/computed tomography (PET/CT) remains unclear. Our aim was to evaluate the prognostic impact of qualitative and semiquantitative baseline PET/CT parameters on outcome of MALT lymphoma. We retrospectively enrolled 161 patients with histologically confirmed MALT lymphoma who underwent 18 F-FDG PET/CT before any treatment. PET images were qualitatively and semiquantitatively analyzed by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS) times. Cox regression models were performed to determine the relation between PET/CT features and OS and PFS. Ninety-eight patients had positive 18 F-FDG PET/CT showing 18 F-FDG uptake (mean SUVbw, 10.1; SUVlbm, 7.2; SUVbsa, 2.7; MTV, 88.8; and TLG, 526); the remaining 63 were not 18 F-FDG avid. 18 F-FDG avidity was significantly correlated with tumor size and Ki-67 score. Relapse/progression of disease occurred in 47 patients with an average time of 40.2 months; death occurred in 12 patients with an average of 59 months. At a median follow-up of 62 months, median PFS and OS were 52 and 62 months, respectively. Advanced tumor stage and extragastric site were demonstrated to be independent prognostic factors for PFS, while only tumor stage for OS. Instead, PET/CT parameters were not related to survival, despite positive correlation at univariate analysis between MTV and TLG with PFS and positive PET/CT with PFS and OS. In conclusion, a 61% rate of PET avidity in biopsy-confirmed MALT lymphoma was found, and it was correlated with tumor size and Ki-67 score. Only tumor stage and localization were independently correlated with PFS and OS.
TL;DR: The ROBUST study did not meet the primary endpoint of PFS for R-CHOP vs placebo/R-CHop in previously untreated patients with ABC-DLBCL, although a positive trend favoring R- CHOP has been observed in advanced stage and higher risk patients.
Abstract: cebo/R-CHOP21 for 6 cycles, with 2 additional, optional doses of rituximab per local practice. The primary endpoint was progressionfree survival (PFS) assessed by independent central radiology per 2014 NHL IWG criteria, and defined as time from randomization to PD or death from any cause. Results: A total of 570 ABC-DLBCL patients met eligibility criteria and were enrolled in ROBUST (n = 285 per arm). Baseline demographics were similar between arms, with a median age for all patients of 65 y (52% ≥ 65 y), 42% IPI 2 score/58% IPI ≥ 3 score, 88% stage III/IV disease, and 34% bulky disease. The primary endpoint of PFS was not met with an HR = 0.85 (95% CI, 0.63-1.14) and P = 0.29; median PFS was not reached for either arm (Figure). Positive PFS trends favoring R-CHOP over placebo/R-CHOP were observed with disease stage III/IV (HR = 0.81 [95% CI, 0.60-1.10]) and IPI score ≥ 3 (HR = 0.74 [95% CI, 0.53-1.05]). Median EFS was not reached for either arm (HR = 1.04; 95% CI, 0.80-1.34; P = 0.73). At a median follow-up of 27.1 mo (range, 0-47) for survivors, 2-y OS was 79% for R-CHOP and 80% for placebo/R-CHOP (medians not reached). ORR was 91% for both arms, with 69% vs 65% CR for R-CHOP vs placebo/R-CHOP, respectively. 74% R-CHOP and 84% placebo/R-CHOP patients completed 6 cycles of treatment; AEs (mainly neutropenia) were the most common reason for treatment discontinuation. The most common grade 3/4 AEs (≥ 10%) for R-CHOP vs placebo/R-CHOP were neutropenia (60% vs 48%), anemia (22% vs 14%), thrombocytopenia (17% vs 11%), leukopenia (14% vs 15%), febrile neutropenia (14% vs 9%), and lymphopenia (11% vs 8%). Conclusions: Overall, the ROBUST study did not meet the primary endpoint of PFS for R-CHOP vs placebo/R-CHOP in previously untreated patients with ABC-DLBCL, although a positive trend favoring R-CHOP has been observed in advanced stage and higher risk patients. The safety profile of R-CHOP was consistent with those of individual medicines, and no new safety signals were identified with the combination.
TL;DR: It is suggested that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors.
Abstract: Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death-1 (PD-1) on total CD4+ (P < .01), total CD8+ (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on total CD4+ (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C-X-C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death-ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal β2-macroglobulin (β2-MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA-4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal β2-MG, normal LDH, IGHV-mutated and wild-type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.
TL;DR: The addition of lenalidomide to R-CHOP (R2CHOP) in this phase II study improved PFS in newly diagnosed DLBCL.
Abstract: RCHOP, HR 0.67 (95% CI 0.441.03), p (one-sided) =0.03 (Figure). The 2-year overall survival was 87% and 80%, respectively. Based on COO, PFS HR for R2CHOP was: 0.68 for ABC, p=0.15, 0.86 for GCB, 0.83 for Unclassified and 0.61 for unknown cases. Conclusion: The addition of lenalidomide to R-CHOP (R2CHOP) in this phase II study improved PFS in newly diagnosed DLBCL.
TL;DR: Daratumumab is a very effective and safe treatment option in AL patients with relapsed/refractory disease and high disease burden at diagnosis, and leads to rapid disease control and improvement of organ function.
Abstract: Daratumumab, an anti-CD38 antibody, is effective in AL amyloidosis with low tumor burden. Data of daratumumab treatment in patients with AL amyloidosis but high tumor burden (≥10% bone marrow plasma cells) are limited. We report retrospective data of 10 consecutive patients with high tumor burden treated with daratumumab for relapsed/refractory AL amyloidosis. The median age at diagnosis was 62.3 years; all patients had cardiac involvement, and six (60%) patients had renal involvement. Median bone marrow plasma cell infiltration was 15% (range 10%-40%), and the median difference between involved and noninvolved free light-chains (dFLC) was 446 mg/L (range 102-1392 mg/L). Patients had a median of three prior lines of therapy, including bortezomib in all patients and lenalidomide in seven (70%) patients. The median time to first hematological response was 14 days (range 7-28 days), and the median time to best hematological response was 64 days (range 7-301 days). The hematological overall response was 90%, with high-quality response (≥ very good partial remission [VGPR]) in 70% of the patients. Fifty percent of the patients had a cardiac response after a median of 3.8 months (range 0.7-9.1). Infusion-related adverse events ≤ grade 2 occurred in seven (70%) patients and grade 3 adverse events in one patient. After a median follow-up time of 10 months, eight (80%) patients continued to receive daratumumab. We conclude that daratumumab is a very effective and safe treatment option in AL patients with relapsed/refractory disease and high disease burden at diagnosis. Daratumumab leads to rapid disease control and improvement of organ function.
TL;DR: The findings demonstrate that the expression status of i-tRF-GlyGCC could serve as potential indicator of unfavorable prognosis in this hematological malignancy, as its prognostic significance is independent of other established prognostic factors in CLL.
Abstract: tRNA-derived fragments (tRFs) are 16-28 nucleotide fragments, which occur by specific cleavage of tRNA molecules. i-tRF-GlyGCC is an internal tRF, originating from the tRNAs bearing the Glycine anticodon \"GCC\". Other tRFs generated from tRNAGlyGCC have proved to be associated with various cancer types. Chronic lymphocytic leukemia (CLL) is a type of leukemia during which CD5+ B lymphocytes accumulate in marrow and lymphoid tissues and is characterized by differential clinical features among patients. In this original study, we verified the existence of this tRF experimentally, and examined, for the first time, the putative utility of this molecule as a prognostic biomarker in CLL, by developing an innovative tRF quantification method, based on the SYBR chemistry. Total RNA was extracted from peripheral blood mononuclear cells (PBMCs) collected from 91 CLL patients and 43 non-leukemic blood donors. In vitro polyadenylation and reverse transcription using an oligo-dT-adapter were carried out and quantitative expression analysis of i-tRF-GlyGCC was performed by an in-house-developed real-time quantitative PCR assay. Advanced biostatistical analysis followed, to assess our results. As revealed by Kaplan-Meier survival analysis, elevated levels of i-tRF-GlyGCC were associated with poor overall survival of CLL patients (p<0.001). Univariate bootstrap Cox regression analysis confirmed these results, by demonstrating a higher hazard ratio (HR) of 3.40 (95% CI=1.6-7.18, p=0.001) for patients overexpressing for i-tRF-GlyGCC, compared to patients with lower expression levels. Multivariate bootstrap Cox regression analysis revealed that the prognostic value of this tRF is independent of clinical stage, IGHV mutational status and CD38 expression (Binet or Rai stage: p<0.001. risk group, p=0.001; bootstrapping p=0.003 and p=0.004 respectively). Our findings demonstrate that the expression status of i-tRF-GlyGCC could serve as potential indicator of unfavorable prognosis in this hematological malignancy, as its prognostic significance is independent of other established prognostic factors in CLL.
TL;DR: Novel targeted and immunotherapy approaches, including chimeric antigen receptor T‐cell therapy, are currently being studied in clinical trials with promising early results.
Abstract: Although the majority of patients with Hodgkin lymphoma are cured with initial therapy, 10% to 15% of patients with early stage disease and 15% to 30% of patients with advanced disease have primary refractory or relapsed lymphoma. For younger patients whose disease is sensitive to second-line therapy, more than half of patients will experience long-term disease control with high-dose chemotherapy/autologous stem cell rescue (ASCT). For those patients who are chemotherapy refractory, relapse after, or are ineligible for ASCT, brentuximab vedotin, and checkpoint, inhibitors are highly active, although the majority of patients will ultimately experience recurrent lymphoma. Allogeneic transplant is curative in a subset of patients but may be associated with significant toxicity. Novel targeted and immunotherapy approaches, including chimeric antigen receptor T-cell therapy, are currently being studied in clinical trials with promising early results.
TL;DR: The results indicated that LINP1 promotes the malignant phenotype of AML cells and stimulates glucose metabolism, which can be regarded as a potential prognostic marker and therapeutic target for AML.
Abstract: LncRNAs play critical roles in various pathophysiological and biological processes, such as protein translation, RNA splicing, and epigenetic modification. Indeed, abundant evidences demonstrated that lncRNA act as competing endogenous RNAs (ceRNAs) to participate in tumorigenesis. However, little is known about the underlying function of lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1) in pediatric and adolescent acute myeloid leukemia (AML). The expression of LINP1 was examined in AML patient samples by qRT-PCR. Cell proliferation was examined by CCK-8 and Edu assays. β-Galactosidase senescence assay, mGlucose uptake assay, lactate production assay, and Gene Ontology (GO) analysis were performed for functional analysis. We found that LINP1 was significantly overexpressed in AML patients at diagnosis, whereas downregulated after complete remission (CR). Furthermore, knockdown of LINP1 expression remarkably suppressed glucose uptake and AML cell maintenance. Mechanistically, LINP1 was found to inhibit the glucose metabolism by suppressing the expression of HNF4a. Both LINP1 and HNF4a knockdown reduced the expression levels of AMPK phosphorylation and WNT5A, indicating for the first time that LINP1 strengthened the HNF4a-AMPK/WNT5A signaling pathway involved in cell glucose metabolism modulation and AML cell survival. Taken together, our results indicated that LINP1 promotes the malignant phenotype of AML cells and stimulates glucose metabolism, which can be regarded as a potential prognostic marker and therapeutic target for AML.
TL;DR: The updated safety and effectiveness data in the phase 1 trial of patients treated with MCL treated with BTK and ZanUBRUTINIB are presented, which shows improvements over the previous phase.
Abstract: UPDATED SAFETY AND EFFICACY DATA IN THE PHASE 1 TRIAL OF PATIENTS WITH MANTLE CELL LYMPHOMA (MCL) TREATED WITH BRUTON TYROSINE KINASE (BTK) INHIBITOR ZANUBRUTINIB (BGB-3111) C.S. Tam | M. Wang | D. Simpson | S. Opat | G. Cull | J. Munoz | T.J. Phillips | W. Kim | S. Atwal | R. Wei | J. Huang | R. Elstrom | J. Trotman Department of Haematology, Peter MacCallum Cancer Centre, St. Vincent’s Hospital, University of Melbourne, Melbourne, Victoria, Australia; Department of Lymphoma & Myeloma, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, United States; Waitemata DHB Haematology Service, North Shore Hospital, Auckland, New Zealand; Clinical Haematology, Monash Health, Monash University, Clayton, Victoria, Australia; Department of Haematology, Sir Charles Gairdner Hospital, University of Western Australia, Perth, WA, Australia; Hematology-Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, United States; Michigan Medicine Hematology Clinic, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Research and Development Center, BeiGene (Beijing) Co., Ltd, Beijing, China; BeiGene USA, Inc., San Mateo, United States; Department of Haematology, Concord Repatriation Hospital, The University of Sydney, Concord, NSW, Australia
TL;DR: The role of 18‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography with computed tomography (CT) (PET/CT) as a diagnostic and prognostic tool in newly diagnosed marginal zone lymphoma (MZL) patients is evaluated.
Abstract: We evaluated the role of 18-fluoro-2-deoxy-d-glucose positron emission tomography ([18F] FDG-PET) with computed tomography (CT) (PET/CT) as a diagnostic and prognostic tool in newly diagnosed marginal zone lymphoma (MZL) patients. This is a retrospective cohort study of patients with newly diagnosed MZL, treated with immunotherapy, chemotherapy regimens, surgery, or Helicobacter pylori eradication between 2008 and 2016 in a single tertiary center. Only patients who had a pretreatment PET/CT (P-PET/CT) were included. P-PET/CT, interim (I-PET/CT), and end-of-treatment PET/CT (E-PET/CT) studies were reviewed. P-PET/CT results were reported using two methods of evaluation, qualitative and semi quantitative: visual assessment (VAS) and maximal standardized uptake value (SUVmax), and I-PET and E-PET results were reported by Deauville 5-point score (DS) evaluation as well. Avidity of PET/CT was defined as abnormal uptake in any of these methods. The primary outcome was the prognostic role of P-PET/CT, I-PET/CT, and E-PET/CT on progression-free survival (PFS) and overall survival (OS). Data of 196 patients with MZL were identified, 110 of which had P-PET/CT and were included in this analysis. Median age was 67 years (range 18-93). The median follow-up period was 63 months (range 3-278). The median OS and PFS for the whole cohort were 63 (interquartile range 39-85) and 60 (interquartile range 37-76) months, respectively. The avidity of PET at baseline for the whole cohort was 70% (77/110 patients), for MALT lymphoma, 62.5% (40/64 patients), for NMZL, 76.4% (13/17 patients), and for SMZL, 82.7% (24/29 patients). When adjusted for IPI, sex, and comorbidities, positive E-PET/CT was associated with reduced PFS with a hazard ratio (HR) of 3.4 (95% CI, 1.27-9.14, P = 0.02). Positive E-PET/CT did not correlate with OS. However, there were only three events. P-PET/CT was not predictive of PFS or OS. Our study demonstrates that above 70% of MZL are FDG avid. Positive E-PET/CT is a strong prognostic factor for PFS.
TL;DR: The use and value of a lenalidomide/bortezomib/dexamethasone regimen for the treatment of three patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), a disease that lacks a consensus treatment, are described.
Abstract: We describe the use and value of a lenalidomide/bortezomib/dexamethasone regimen for the treatment of three patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN, a disease that lacks a consensus treatment). After five cycles of chemotherapy, we observed two complete responses and one clinical remission. Together with the encouraging literature data on the effects of lenalidomide and bortezomib on BPDCN cells, our results might prompt further investigations of this regimen's value in BPDCN.
TL;DR: Investigation of venetoclax exposure‐efficacy and exposure‐safety relationships and its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetClax in combination with low intensity therapies support the use of venEToclax 400 mg QD in conjunction with an HMA and 600 mgQD in combinations with LDAC to safely maximize the probability of response.
Abstract: The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.
TL;DR: Consultant Advisory Role: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche.
Abstract: neration: Speakers' Bureau: Roche, Abbvie, Janssen, Gilead, Novartis, Celgene. Kreuzer, K: Consultant Advisory Role: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche; Honoraria: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche; Research Funding: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche; Other Remuneration: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche. Tandon, M: Employment Leadership Position: Roche. Humphrey, K: Employment Leadership Position: Roche; Stock Ownership: Roche. Jiang, Y: Employment Leadership Position: Genentech; Stock Ownership: Genentech. Schary, W: Employment Leadership Position: Abbvie; Stock Ownership: Abbvie. Porro Lurà, M: Employment Leadership Position: F. Hoffmann La Roche Ltd; Stock Ownership: Yes. Fischer, K: Other Remuneration: Roche (Travel, Accommodations). Hallek, M: Consultant Advisory Role: Roche, Abbvie; Honoraria: Roche, Abbvie, Gilead, Janssen, Celgene, Boehringer Ingelheim; Research Funding: Roche, Abbvie; Other Remuneration: Speakers' Bureau: Roche, Abbvie. Stilgenbauer, S: Research Funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Other Remuneration: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis (Personal Fees).
TL;DR: In particular, vemurafenib plus rituximab is emerging as a short, safe, chemotherapy‐free regimen able to induce deep complete remissions in most HCL patients refractory to, or relapsed multiple times, after chemo(immuno)therapy.
Abstract: Hairy cell leukemia (HCL) responds initially very well to chemotherapy with purine analogues. However, up to 50% of patients relapse, often multiple times, and become progressively less sensitive to these myelotoxic and immune-suppressive drugs. At progression, viable therapeutic strategies include addition of rituximab to purine analogues, and treatment with the anti-CD22 immunotoxin moxetumomab pasudotox, which has been recently approved by the FDA in HCL patients after at least two prior therapies. Identification of the BRAF-V600E kinase mutation as the genetic cause of HCL has opened the way, in the relapsed/refractory experimental setting, to targeted and non-myelotoxic effective strategies that are based on inhibition of BRAF with vemurafenib, co-inhibition of BRAF and its target MEK with dabrafenib and trametinib, and BRAF inhibition with vemurafenib combined with anti-CD20 immunotherapy. In particular, vemurafenib plus rituximab is emerging as a short, safe, chemotherapy-free regimen able to induce deep complete remissions in most HCL patients refractory to, or relapsed multiple times, after chemo(immuno)therapy.
TL;DR: PET-based staging, PFS24 may not be a robust surrogate endpoint for OS, but improved outcomes in PET-staged patients with early progression may be associated with identification and exclusion of patients with transformed disease at time of therapy.
Abstract: PET-based staging, PFS24 may not be a robust surrogate endpoint for OS. The improved outcomes in PET-staged patients with early progression may be associated with identification and exclusion of patients with transformed disease at time of therapy. Patients with early progression are at risk for early death. In contrast, patients with early progression and no evidence of transformation have an extended OS, suggesting aggressive upfront therapies may not be warranted in these patients.