Publications by authors named "Brian T Hill"

107 Publications

Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies.

Cell Death Dis 2021 Nov 8;12(11):1061. Epub 2021 Nov 8.

Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.

Aberrant microRNA (miR) expression plays an important role in pathogenesis of different types of cancers, including B-cell lymphoid malignancies and in the development of chemo-sensitivity or -resistance in chronic lymphocytic leukemia (CLL) as well as diffuse large B-cell lymphoma (DLBCL). Ibrutinib is a first-in class, oral, covalent Bruton's tyrosine kinase (BTK) inhibitor (BTKi) that has shown impressive clinical activity, yet many ibrutinib-treated patients relapse or develop resistance over time. We have reported that acquired resistance to ibrutinib is associated with downregulation of tumor suppressor protein PTEN and activation of the PI3K/AKT pathway. Yet how PTEN mediates chemoresistance in B-cell malignancies is not clear. We now show that the BTKi ibrutinib and a second-generation compound, acalabrutinib downregulate miRNAs located in the 14q32 miRNA cluster region, including miR-494, miR-495, and miR-543. BTKi-resistant CLL and DLBCL cells had striking overexpression of miR-494, miR-495, miR-543, and reduced PTEN expression, indicating further regulation of the PI3K/AKT/mTOR pathway in acquired BTKi resistance. Additionally, unlike ibrutinib-sensitive CLL patient samples, those with resistance to ibrutinib treatment, demonstrated upregulation of 14q32 cluster miRNAs, including miR-494, miR-495, and miR-543 and decreased pten mRNA expression. Luciferase reporter gene assay showed that miR-494 directly targeted and suppressed PTEN expression by recognizing two conserved binding sites in the PTEN 3'-UTR, and subsequently activated AKT. Importantly, overexpression of a miR-494 mimic abrogated both PTEN mRNA and protein levels, further indicating regulation of apoptosis by PTEN/AKT/mTOR. Conversely, overexpression of a miR-494 inhibitor in BTKi-resistant cells restored PTEN mRNA and protein levels, thereby sensitizing cells to BTKi-induced apoptosis. Inhibition of miR-494 and miR-495 sensitized cells by cooperative targeting of pten, with additional miRNAs in the 14q32 cluster that target pten able to contribute to its regulation. Therefore, targeting 14q32 cluster miRNAs may have therapeutic value in acquired BTK-resistant patients via regulation of the PTEN/AKT/mTOR signaling axis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-021-04353-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575967PMC
November 2021

Effect of time to relapse on overall survival in patients with mantle cell lymphoma following autologous haematopoietic cell transplantation.

Br J Haematol 2021 Dec 28;195(5):757-763. Epub 2021 Sep 28.

Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.

In young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front-line setting. Recently, time-to-event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post-autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six-month [hazard ratio (HR) = 7·68], 12-month (HR = 6·68), and 18-month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non-relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high-risk group with inferior post-relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up-front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627449PMC
December 2021

The impact of socioeconomic disparities on the use of upfront autologous stem cell transplantation for mantle cell lymphoma.

Leuk Lymphoma 2021 Sep 15:1-9. Epub 2021 Sep 15.

Taussig Cancer Institute, Department of Medical Oncology and Hematology, Cleveland Clinic, Cleveland, OH, USA.

Using the National Cancer Database, we identified 10,290 patients with newly diagnosed mantle cell lymphoma (MCL) treated with chemotherapy with or without upfront autologous stem cell transplantation (ASCT). Only 17% of patients underwent ASCT. Patients who underwent ASCT were younger and more likely to have lower comorbidity scores, private insurance, higher income and education, and treatment received at an academic facility. On multivariable analysis, age, comorbidity index, insurance type, the transition of care, facility type, distance to facility, and diagnosis year were predictive for ASCT use. ASCT use was associated with improved 5-year overall survival in younger (82% vs. 64%,  < .001) and older (70% vs. 40%,  < .001) patients, which was retained in the matched propensity score and 12-month analyses. Female gender, the diagnosis year ≥2009, private insurance, higher income, and education were associated with superior survival, whereas Black race and higher comorbidities predicted inferior survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2021.1978085DOI Listing
September 2021

Early Relapse Identifies MCL patients with Inferior Survival after Intensive or Less Intensive Frontline Therapy.

Blood Adv 2021 Sep 13. Epub 2021 Sep 13.

Medical College of Wisconsin, Milwaukee, Wisconsin, United States.

While an expanding array of effective treatments has resulted in recent improvement in survival for patients with mantle cell lymphoma (MCL), outcomes remain heterogeneous and identification of prognostic factors remains a priority. We assessed the prognostic impact of time to progression of disease (POD) after first-line therapy among 455 patients with relapsed MCL. Patients were categorized by duration of first remission as PRF/POD6, defined as progressive disease during induction or POD within six months of diagnosis (n=65, 14%), POD6-24, defined as POD between six and 24 months from diagnosis (n=153, 34%), and POD>24 defined as POD beyond 24 months from diagnosis (n=237, 53%). Median overall survival from POD (OS2) was 1.3 [95% CI 0.9-2.4] years for PRF/POD6 patients, 3 [95% CI 2-6.8] years for POD6-24, and 8 [95% CI 6.2-NR] years among POD>24 patients. Median OS2 was inferior in patients with early POD (defined as PRF/POD6 or POD6-24) following both intensive and less intensive frontline treatment. The prognostic performance of time to POD was replicated in an independent cohort of 245 patients with relapsed MCL, with median OS2 of 0.3 [95% CI 0.1-0.5] years for PRF/POD6, 0.8 [95% CI 0.6-0.9] years for POD6-24, and 2.4 [95% CI 2.1-2.7] years for POD>24. Early POD is associated with inferior OS2 in patients with relapsed MCL, identifying a high-risk population for future prospective studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004765DOI Listing
September 2021

American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation Clinical Practice Recommendations for Transplantation and Cellular Therapies in Mantle Cell Lymphoma.

Transplant Cell Ther 2021 09;27(9):720-728

Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447221PMC
September 2021

Multicenter analysis of geriatric fitness and real-world outcomes in older patients with classical Hodgkin lymphoma.

Blood Adv 2021 09;5(18):3623-3632

Division of Hematology/Oncology, University of Virginia, Charlottesville, VA.

We performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 years with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had Eastern Cooperative Oncology Group performance status (PS) 0-2, and 12% had documented loss of ≥1 activity of daily living (ADL). Medical comorbidities were assessed by the Cumulative Illness Rating Scale-Geriatric (CIRS-G), where n = 44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; hazard ratio [HR] 2.13, P = .007) and overall survival (OS; HR 2.52, P = .02). Most patients (n = 203, 83%) received conventional chemotherapy regimens, including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P = .0007) and OS (HR 0.31, P = .0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, P = .63; OS HR 0.73, P = .55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28% vs 12%, P = .016) or documented geriatric syndrome (28% vs 13%, P = .02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, P = .02) and higher mortality from causes other than disease or treatment with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004645DOI Listing
September 2021

ASTCT, CIBMTR, and EBMT clinical practice recommendations for transplant and cellular therapies in mantle cell lymphoma.

Bone Marrow Transplant 2021 Aug 20. Epub 2021 Aug 20.

Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.

Autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities for mantle cell lymphoma (MCL). Recently, chimeric antigen receptor (CAR) T-cell therapy received approval for MCL; however, its exact place and sequence in relation to HCT is unclear. The ASTCT, CIBMTR, and the EBMT, jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-, allo-HCT, and CAR T-cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated; in the first-line setting auto-HCT consolidation represents standard-of-care in eligible patients, whereas there is no clear role of allo-HCT or CAR T-cell therapy, outside of a clinical trial. In the R/R setting, the preferential option is CAR T-cell therapy especially in MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T-cell therapy has failed or is not feasible. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-021-01288-9DOI Listing
August 2021

Multi-center analysis of practice patterns and outcomes of younger and older patients with mantle cell lymphoma in the rituximab era.

Am J Hematol 2021 11 10;96(11):1374-1384. Epub 2021 Aug 10.

Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.

Clinical outcomes and predictors of survival in patients with newly diagnosed mantle cell lymphoma (MCL) treated in the rituximab era (2000-2015) at 12 US academic centers were assessed to identify determinants of survival across age groups. Objectives were to characterize and compare practice patterns, outcomes and prognostic factors for survival in younger patients (age < 65) and older patients (age ≥ 65 years). Among 1162 patients included, 697 were younger and 465 were older. In younger patients, 2-year progression free survival (PFS) and overall survival (OS) rates were 79% and 92% respectively; blastoid histology, ECOG ≥ 2, and lack of maintenance rituximab (MR) remained statistically relevant to poor OS on univariate analysis (UVA) and multivariate analysis (MVA). In older patients, 2-year PFS and OS rates were 67% and 86% respectively; lack of maintenance rituximab remained significantly associated with inferior PFS and OS on UVA and MVA (p < 0.001). Two-year PFS rates were 79%, and 67% and 2-year OS rates were 92% and 86% for ages < 65 and ≥ 65 respectively (p < 0.001). First-line high-dose cytarabine exposure and/or MR lessened the negative impact of age on survival. Taken collectively, survival outcomes for older patients remain inferior to those of younger patients in the rituximab era. However, maintenance rituximab and potentially high-dose cytarabine-based induction can mitigate the negative impact of age on survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.26306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511300PMC
November 2021

The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Three-Factor Comorbidity Model.

Clin Cancer Res 2021 Sep 24;27(17):4814-4824. Epub 2021 Jun 24.

Knight Cancer Institute, Portland, Oregon.

Purpose: Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied.

Experimental Design: We conducted a retrospective analysis from 10 academic centers to ascertain the relative importance of comorbidities assessed by the cumulative illness rating scale (CIRS). The influence of specific comorbidities on event-free survival (EFS) was assessed in this derivation dataset using random survival forests to construct a CLL-specific comorbidity index (CLL-CI). Cox models were then fit to this dataset and to a single-center, independent validation dataset.

Results: The derivation and validation sets comprised 570 patients (59% receiving Bruton tyrosine kinase inhibitor, BTKi) and 167 patients (50% receiving BTKi), respectively. Of the 14 CIRS organ systems, three had a strong and stable influence on EFS: any vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity. These were combined to create the CLL-CI score, which was categorized into 3 risk groups. In the derivation dataset, the median EFS values were 58, 33, and 20 months in the low, intermediate, and high-risk groups, correspondingly. Two-year overall survival (OS) rates were 96%, 91%, and 82%. In the validation dataset, median EFS values were 81, 40, and 23 months (two-year OS rates 97%/92%/88%), correspondingly. Adjusting for prognostic factors, CLL-CI was significantly associated with EFS in patients treated with either chemo-immunotherapy or with BTKi in each of our 2 datasets.

Conclusions: The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-3993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416936PMC
September 2021

Intensive induction regimens after deferring initial therapy for mantle cell lymphoma are not associated with improved survival.

Eur J Haematol 2021 Sep 17;107(3):301-310. Epub 2021 Jun 17.

Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, US.

Introduction: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy.

Methods: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high-dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non-intensive (n = 131).

Results: There was no difference in progression-free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non-intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model.

Conclusions: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338766PMC
September 2021

Late Effects after Chimeric Antigen Receptor T cell Therapy for Lymphoid Malignancies.

Transplant Cell Ther 2021 03 21;27(3):222-229. Epub 2020 Dec 21.

Taussig Cancer Center, Cleveland Clinic, Cleveland, OH.

Chimeric Antigen Receptor T-cell [CAR T] therapy has changed the treatment landscape of relapsed/refractory lymphoid malignancies. With an expanding pool of post CAR T-cell therapy survivors, prevention and management of late toxicities is emerging as an important component of survivorship care. This review summarizes the current state of evidence on late toxicities after CAR T-cell therapy in lymphoid malignancies. Late effects that are well described in clinical trials and observational studies include hypogammaglobulinemia, prolonged cytopenias, late infections, neurologic and neuropsychiatric effects, immune-related late effects, and subsequent malignancies. Hypogammaglobulinemia is the most common late effect in the setting of CD19-directed CAR T-cell therapy, which necessitates immunoglobulin replacement. Common determinants of late toxicities are age, underlying tumor type, prior therapy, CAR construct, and acute toxicities. Among currently approved indications, the incidence of hypogammaglobulinemia and prolonged cytopenia is higher in patients with acute lymphoblastic leukemia compared to aggressive non-Hodgkin lymphoma. Patient-reported physical and mental quality of life in long-term survivors is comparable to general population, albeit, with limited data thus far. This review provides an overview of the incidence, known risk-factors, and strategies for prevention and management of late toxicities in this population. Further research is needed to characterize the trajectory of late effects from population-based registries and long-term follow-up of ongoing clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078596PMC
March 2021

Brexucabtagene autoleucel for the treatment of relapsed/refractory mantle cell lymphoma.

Expert Opin Biol Ther 2021 04 11;21(4):435-441. Epub 2021 Mar 11.

Lymphoid Malignancies Program, Staff Physician, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland, OH, USA.

: The therapeutic options for mantle cell lymphoma (MCL) include traditional chemo-immunotherapy for newly diagnosed cases, and targeted treatments including the bruton tyrosine kinase inhibitors in the relapsed/refractory (R/R) disease setting. The advent of commercially available chimeric antigen receptor (CAR) T-cell therapy in the last three years has dramatically improved the outcomes of patients with R/R large B-cell lymphoma.: This review is an in-depth evaluation and appraisal of brexucabtagene autoleucel (brexu-cel), the first anti-CD19 CAR T-cell therapy to be approved for patients with R/R MCL, after the results of a Phase II (ZUMA-2) trial.: In the absence of head-to-head comparison studies with Btk inhibitors, up-front use of brexu-cel in patients with high-risk MCL and poor prognostic features may be advantageous, possibly even before exposure to Btk inhibitor, and further study of this approach is warranted. While data on long-term outcomes of CAR T-cell therapy in MCL patients are needed, brexu-cel has shown remarkable clinical activity and its regulatory approval has immediate practice-changing implications in this highly aggressive malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14712598.2021.1889510DOI Listing
April 2021

Health-related quality of life and utility outcomes with selinexor in relapsed/refractory diffuse large B-cell lymphoma.

Future Oncol 2021 Apr 2;17(11):1295-1310. Epub 2021 Feb 2.

Department of Haematology, Somogy County Kaposi Mór Hospital, Kaposvár, 7400, Hungary.

Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Functional Assessment of Cancer Therapy (FACT) - Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Treatment responders maintained higher FACT - Lymphoma (p ≤ 0.05), FACT - General (p < 0.05) and EuroQoL five-dimensions five-levels index scores (p < 0.001) beginning in cycle 3. The estimated difference in health state utilities for treatment response and progressive disease was both statistically significant and clinically meaningful (mean difference: 0.07; p = 0.001). In patients with relapsed/refractory diffuse large B-cell lymphoma, objective response to selinexor was associated with HRQoL maintenance, reduction in disease-related HRQoL decrements and higher health utilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0946DOI Listing
April 2021

Late occurrence of progressive multifocal leukoencephalopathy after anti-CD19 chimeric antigen receptor T-cell therapy.

Eur J Haematol 2021 Apr 2;106(4):584-588. Epub 2021 Feb 2.

Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

Progressive multifocal leukoencephalopathy (PML) is a life-threatening infection of the central nervous system in immunocompromised patients, with an established predilection in non-Hodgkin's lymphoma and stem cell transplant recipients. In the era of chimeric antigen receptor T-cell therapy (CAR T-cell), the occurrence of new-onset neurological symptoms and encephalopathy in this patient population can be attributed to a variety of factors, including therapy-related neurotoxicity or disease progression. PML has not been implicated as a common cause of encephalopathy in CAR T-cell therapy recipients, and the identification of such rare infections is important to guide prognosis and treatment decisions. We hereby report the first case of late occurrence of PML, over one year after CAR T-cell therapy, for a patient with relapsed large B-cell lymphoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13583DOI Listing
April 2021

Polatuzumab Vedotin for Relapsed/Refractory Aggressive B-cell Lymphoma: A Multicenter Post-marketing Analysis.

Clin Lymphoma Myeloma Leuk 2021 03 18;21(3):170-175. Epub 2020 Dec 18.

Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Introduction: Polatuzumab vedotin is approved therapy in the United States for relapsed/refractory diffuse large B-cell lymphoma in combination with bendamustine and rituximab (Pola+BR). However, the safety and efficacy of Pola+BR outside of a clinical trial setting is unknown.

Patients And Methods: We analyzed use of pola-based therapy at 5 centers in the United States, including dose, response rates, progression-free survival (PFS), survival, and toxicity.

Results: Sixty-nine patients with aggressive B-cell lymphoma, including 66 with diffuse large B-cell lymphoma/high-grade B-cell lymphoma and 84% refractory to prior therapy, were treated. Responses occurred in of 50%, including 24% complete response. Median duration of response was 5.1 months, PFS was 2.0 months, and survival was 5.3 months, at 4 months median follow-up. Inferior PFS was associated with prior refractory disease (median, 57 days vs. not reached; P = .003) and lack of response to Pola+BR (PFS, 27 days vs. 152 days; P < .001). Discontinuation owing to planned cellular therapy was seen in 36% and owing to toxicity occurred in 12%; unplanned hospitalizations occurred in 36%.

Conclusions: We conclude that commercial Pola is applied to highly refractory lymphomas at our centers, often with intent to bridge to subsequent therapy. Although some clinical benefit was observed, efficacy was inferior to clinical trial data, especially among those with refractory disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.12.013DOI Listing
March 2021

Outcomes and factors impacting use of axicabtagene ciloleucel in patients with relapsed or refractory large B-cell lymphoma: results from an intention-to-treat analysis.

Leuk Lymphoma 2021 06 29;62(6):1344-1352. Epub 2020 Dec 29.

Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

Data on real-world outcomes of axicabtagene ciloleucel (axi-cel) therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL) are limited. In this intent to treat (ITT) analysis, we reviewed records of 38 consecutive patients with R/R LBCL for whom axi-cel was intended. Twenty-seven (71%) patients received axi-cel and 11 (29%) did not. Patients in the non-axi-cel group had a higher hematopoietic cell transplantation comorbidity index (HCT-CI) (median 4 vs. 2,  = .04). Median overall survival for the ITT, axi-cel and non-axi-cel group was 10 (95% CI, 3.7 to 13), 13 (95% CI, 7.7 to N.R.) and 1 (95% CI, 0.4 to 3.7) month(s) respectively. Factors limiting axi-cel use were disease progression, sepsis, manufacturing failure and socioeconomic barrier in 6 (55%), 3 (27%), 1 (9%) and 1 (9%) patient(s) respectively. Additional strategies are needed to ensure all LBCL patients for whom chimeric antigen receptor (CAR) T-cell therapy is prescribed can receive this treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1864349DOI Listing
June 2021

Survival following relapse after allogeneic hematopoietic cell transplantation for acute leukemia and myelodysplastic syndromes in the contemporary era.

Hematol Oncol Stem Cell Ther 2020 Dec 5. Epub 2020 Dec 5.

Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Objective/background: Relapse is the most common cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). No standard of care exists, and a wide range of treatments are used for post-alloHCT relapse. In the recent era, several novel therapies including targeted agents are available for acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).

Methods: We reviewed outcomes after alloHCT relapse, with or without use of these newer agents for ALL, AML, and MDS. In total, 115 adults with relapsed or refractory ALL (n = 17), AML (n = 67), and MDS (n = 31) at median 5 (range, 1-64) months after their first alloHCT in 2010-2018 were included.

Results: Median follow-up was 19 (range, 6-80) months after relapse from alloHCT. Targeted agents were given to 29 (25%) patients. In multivariable analysis, use of targeted agent at any time point after relapse was not associated with survival. Matched unrelated (vs. matched sibling; hazard ratio [HR] 1.70; p = .027) or haploidentical donor grafts (vs. matched sibling; HR 2.69; p = .003), presence of grade II-IV acute graft-versus-host disease before relapse (HR 2.46; p < .001), and less than 12 months from HCT to relapse (<6 vs. > 12 months; HR 6.34; p < .001; 6-12 vs. > 12 months; HR 3.16; p = .005) were adverse prognostic factors for post-relapse survival.

Conclusion: Outcomes after alloHCT relapse remain poor regardless of the novel agent use. Innovative treatment strategies are needed to improve outcomes after relapse post-alloHCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hemonc.2020.11.006DOI Listing
December 2020

Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance.

Cell Death Dis 2020 11 2;11(11):941. Epub 2020 Nov 2.

Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.

Defects in apoptosis can promote tumorigenesis and impair responses of malignant B cells to chemotherapeutics. Members of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins are key regulators of the intrinsic, mitochondrial apoptotic pathway. Overexpression of antiapoptotic BCL-2 family proteins is associated with treatment resistance and poor prognosis. Thus, inhibition of BCL-2 family proteins is a rational therapeutic option for malignancies that are dependent on antiapoptotic BCL-2 family proteins. Venetoclax (ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor that represents the first approved agent of this class and is currently widely used in the treatment of chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML). Despite impressive clinical activity, venetoclax monotherapy for a prolonged duration can lead to drug resistance or loss of dependence on the targeted protein. In this review, we provide an overview of the mechanism of action of BCL-2 inhibition and the role of this approach in the current treatment paradigm of B-cell malignancies. We summarize the drivers of de novo and acquired resistance to venetoclax that are closely associated with complex clonal shifts, interplay of expression and interactions of BCL-2 family members, transcriptional regulators, and metabolic modulators. We also examine how tumors initially resistant to venetoclax become responsive to it following prior therapies. Here, we summarize preclinical data providing a rationale for efficacious combination strategies of venetoclax to overcome therapeutic resistance by a targeted approach directed against alternative antiapoptotic BCL-2 family proteins (MCL-1, BCL-xL), compensatory prosurvival pathways, epigenetic modifiers, and dysregulated cellular metabolism/energetics for durable clinical remissions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-020-03144-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608616PMC
November 2020

Efficacy of bendamustine and rituximab in unfit patients with previously untreated chronic lymphocytic leukemia. Indirect comparison with ibrutinib in a real-world setting. A GIMEMA-ERIC and US study.

Cancer Med 2020 11 24;9(22):8468-8479. Epub 2020 Sep 24.

Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Limited information is available on the efficacy of front-line bendamustine and rituximab (BR) in chronic lymphocytic leukemia (CLL) with reduced renal function or coexisting conditions. We therefore analyzed a cohort of real-world patients and performed a matched adjusted indirect comparison with a cohort of patients treated with ibrutinib. One hundred and fifty-seven patients with creatinine clearance (CrCl) <70 mL/min and/or CIRS score >6 were treated with BR. The median age was 72 years; 69% of patients had ≥2 comorbidities and the median CrCl was 59.8 mL/min. 17.6% of patients carried TP53 disruption. The median progression-free survival (PFS) was 45 months; TP53 disruption was associated with a shorter PFS (P = 0.05). The overall survival (OS) at 12, 24, and 36 months was 96.2%, 90.1%, and 79.5%, respectively. TP53 disruption was associated with an increased risk of death (P = 0.01). Data on 162 patients ≥65 years treated with ibrutinib were analyzed and compared with 165 patients ≥65 years treated with BR. Factors predicting for a longer PFS at multivariable analysis in the total patient population treated with BR and ibrutinib were age (HR 1.06, 95% CI 1.02-1.10, P < 0.01) and treatment with ibrutinib (HR 0.55, 95% CI 0.33-0.93, P = 0.03). In a post hoc analysis of patients in advanced stage, a significant PFS advantage was observed in patient who had received ibrutinib (P = 0.03), who showed a trend for OS advantage (P = 0.08). We arrived at the following conclusions: (a) BR is a relatively effective first-line regimen in a real-world population of unfit patients without TP53 disruption, (b) ibrutinib provided longer disease control than BR in patients with advanced disease stage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666748PMC
November 2020

The Impact of Age on Survival in CLL Patients Receiving Ibrutinib as Initial Therapy.

Blood Lymphat Cancer 2020 24;10:1-5. Epub 2020 Aug 24.

Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Introduction: Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.

Methods: Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices.

Results: Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients >65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3).

Conclusion: These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/BLCTT.S262592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473982PMC
August 2020

Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium.

J Clin Oncol 2020 09 13;38(27):3119-3128. Epub 2020 May 13.

Moffitt Cancer Center, Tampa, FL.

Purpose: Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication.

Patients And Methods: Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification.

Results: Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis.

Conclusion: The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499611PMC
September 2020

KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma.

N Engl J Med 2020 04;382(14):1331-1342

From the University of Texas M.D. Anderson Cancer Center, Houston (M.W.), and Texas Oncology, Dallas (H.H.); Banner M.D. Anderson Cancer Center, Gilbert, AZ (J.M.); John Theurer Cancer Center, Hackensack, NJ (A.G.); Moffitt Cancer Center, Tampa (F.L.L.), and the University of Miami, Miami (A.B.) - both in Florida; Dana-Farber Cancer Institute, Boston (C.A.J.); Cleveland Clinic Foundation, Cleveland (B.T.H.), and the Ohio State University Comprehensive Cancer Center, Columbus (S.J.); David Geffen School of Medicine at UCLA, Los Angeles (J.M.T.), Stanford University School of Medicine, Stanford (D.B.M.), and Kite, a Gilead company, Santa Monica (W.P., L.Z., J.M.R., R.K.J., A.V.R.) - all in California; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (I.W.F.); Colorado Blood Cancer Institute, Denver (P.A.M.); Swedish Cancer Institute, Seattle (J.M.P.); the Academic Medical Center, University of Amsterdam, Amsterdam, for the Lunenburg Lymphoma Phase I/II Consortium (M.-J.K.); Centre Hospitalier Universitaire (CHU) Bordeaux, Service d'Hematologie et Therapie Cellulaire, Bordeaux (N.M.), and CHU Rennes, INSERM French Blood Establishment, Rennes (R.H.) - both in France; Fox Chase Cancer Center, Philadelphia (H.F.); Universitätsklinikum Würzburg, Würzburg, Germany (M.S.T.); and the University of Rochester Medical Center, Rochester, NY (P.M.R.).

Background: Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma.

Methods: In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×10 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.

Results: A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.

Conclusions: KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1914347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731441PMC
April 2020

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

Clin Cancer Res 2020 07 20;26(14):3589-3596. Epub 2020 Mar 20.

Division of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida.

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.

Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].

Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve ( = 130), and 81% were idelalisib naïve ( = 263). ORR to BTKi was 84% ( = 44) in BTKi-naïve patients versus 54% ( = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-3815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588795PMC
July 2020

Large granular lymphocytic leukaemia after solid organ and haematopoietic stem cell transplantation.

Br J Haematol 2020 04 20;189(2):318-322. Epub 2020 Jan 20.

Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

T-cell large granular lymphocytic leukaemia (T-LGLL) is a chronic clonal lymphoproliferative disorder of cytotoxic T lymphocytes which commonly occurs in older patients and is often associated with autoimmune diseases. Among 246 patients with T-LGLL seen at our institution over the last 10 years, we encountered 15 cases following solid organ or haematopoietic stem cell transplantation. Here, we studied the clinical characterization of these cases and compared them to de novo T-LGLL. This experience represented a clear picture of the intricate nature of the disease manifestation and the complexities of several immune mechanisms triggering the clonal expansion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370478PMC
April 2020

Outcomes of patients with limited-stage aggressive large B-cell lymphoma with high-risk cytogenetics.

Blood Adv 2020 01;4(2):253-262

Roswell Park Comprehensive Cancer Center, Buffalo, NY.

There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988401PMC
January 2020

Resistance to BTK inhibition by ibrutinib can be overcome by preventing FOXO3a nuclear export and PI3K/AKT activation in B-cell lymphoid malignancies.

Cell Death Dis 2019 12 4;10(12):924. Epub 2019 Dec 4.

Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.

Chronic activation of the Bruton's tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling is a hallmark of many B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). Ibrutinib, an FDA approved, orally administered BTK inhibitor, has demonstrated high response rates, however, complete responses are infrequent and acquired resistance to BTK inhibition can emerge. In this study, we generated ibrutinib-resistant (IB-R) cell lines by chronic exposure of CLL and activated B-cell (ABC)-DLBCL cells to ibrutinib in order to investigate the mechanism of acquired resistance to ibrutinib. IB-R cell lines demonstrated downregulation of FOXO3a and PTEN levels and activation of AKT, with their levels being low in the nuclei of resistant cells in comparison to the sensitive counterparts. Inhibition of PI3K and AKT using idelalisib and MK2206, respectively increased ibrutinib-induced apoptosis in IB-R cells by downregulation of pAKT and restoring FOXO3a levels, demonstrating the importance of these cell survival factors for ibrutinib-resistance. Notably, the exportin 1 inhibitor, selinexor synergized with ibrutinib in IB-R cells and restored nuclear abundance of FOXO3a and PTEN, suggesting that nuclear accumulation of FOXO3a and PTEN facilitates increase in ibrutinib-induced apoptosis in IB-R cells. These data demonstrate that reactivation of FOXO3a nuclear function enhances the efficacy of ibrutinib and overcomes acquired resistance to ibrutinib. Together, these findings reveal a novel mechanism that confers ibrutinib resistance via aberrant nuclear/cytoplasmic subcellular localization of FOXO3a and could be exploited by rational therapeutic combination regimens for effectively treating lymphoid malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-019-2158-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892912PMC
December 2019

Chemo-immunotherapy for Older Patients with Chronic Lymphocytic Leukemia - Passé Yet?

Hemasphere 2019 08 7;3(4):e275. Epub 2019 Aug 7.

Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HS9.0000000000000275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745924PMC
August 2019

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

Br J Haematol 2020 03 4;188(6):918-923. Epub 2019 Nov 4.

Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528953PMC
March 2020
-->