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2.
Transplant Cell Ther ; 2024 May 16.
Article in English | MEDLINE | ID: mdl-38762057

ABSTRACT

Genetically modified cell therapies (GMCT), particularly immune effector cells (IEC) such as chimeric receptor antigen (CAR) T cells, have shown promise in curing cancer and rare diseases after a single treatment course. Following close behind CAR T approvals are GMCT based on hematopoietic stem cells, such as products developed for hemoglobinopathies and other disorders. Academically sponsored GMCT products, often developed in academic centers without industry involvement, face challenges in sustaining access after completion of early phase studies when there is no commercial partner invested in completing registration trials for marketing applications. The American Society for Transplantation and Cellular Therapy (ASTCT) formed a task force named ACT To Sustain (Adoptive Cell Therapy to Sustain) to address the "valley of death" of academic GMCT products. This paper presents the task force's findings and considerations regarding financial sustainability of academically sponsored GMCT products in the absence of commercial development. We outline case scenarios illustrating barriers to maintaining access to promising GMCT developed by academic centers. The paper also delves into the current state of GMCT development, commercialization, and reimbursement, citing examples of abandoned products, cost estimates associated with GMCT manufacturing and real-world use of cost recovery. We propose potential solutions to address the financial, regulatory, and logistical challenges associated with sustaining access to academically sponsored GMCT products and to ensure that products with promising results do not languish in a "valley of death" due to financial or implementational barriers. The suggestions include aligning US Food and Drug Administration (FDA) designations with benefit coverage, allowing for cost recovery of certain products as a covered benefit, and engaging with regulators and policy makers to discuss alternative pathways for academic centers to provide access. We stress the importance of sustainable access to GMCT and call for collaborative efforts to develop regulatory pathways that support access to academically sponsored GMCT products.

3.
JACC CardioOncol ; 6(2): 251-263, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38774001

ABSTRACT

Background: The use of an artificial intelligence electrocardiography (AI-ECG) algorithm has demonstrated its reliability in predicting the risk of atrial fibrillation (AF) within the general population. Objectives: This study aimed to determine the effectiveness of the AI-ECG score in identifying patients with chronic lymphocytic leukemia (CLL) who are at high risk of developing AF. Methods: We estimated the probability of AF based on AI-ECG among patients with CLL extracted from the Mayo Clinic CLL database. Additionally, we computed the Mayo Clinic CLL AF risk score and determined its ability to predict AF. Results: Among 754 newly diagnosed patients with CLL, 71.4% were male (median age = 69 years). The median baseline AI-ECG score was 0.02 (range = 0-0.93), with a value ≥0.1 indicating high risk. Over a median follow-up of 5.8 years, the estimated 10-year cumulative risk of AF was 26.1%. Patients with an AI-ECG score of ≥0.1 had a significantly higher risk of AF (HR: 3.9; 95% CI: 2.6-5.7; P < 0.001). This heightened risk remained significant (HR: 2.5; 95% CI: 1.6-3.9; P < 0.001) even after adjusting for the Mayo CLL AF risk score, heart failure, chronic kidney disease, and CLL therapy. In a second cohort of CLL patients treated with a Bruton tyrosine kinase inhibitor (n = 220), a pretreatment AI-ECG score ≥0.1 showed a nonsignificant increase in the risk of AF (HR: 1.7; 95% CI: 0.8-3.6; P = 0.19). Conclusions: An AI-ECG algorithm, in conjunction with the Mayo CLL AF risk score, can predict the risk of AF in patients with newly diagnosed CLL. Additional studies are needed to determine the role of AI-ECG in predicting AF risk in CLL patients treated with a Bruton tyrosine kinase inhibitor.

4.
Nat Biomed Eng ; 8(4): 443-460, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38561490

ABSTRACT

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.


Subject(s)
Graft vs Host Disease , Immunosuppression Therapy , Mesenchymal Stem Cells , Receptors, Chimeric Antigen , Animals , Mesenchymal Stem Cells/immunology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Mice , Immunosuppression Therapy/methods , Receptors, Chimeric Antigen/metabolism , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/genetics , Graft vs Host Disease/immunology , Humans , Mesenchymal Stem Cell Transplantation/methods , T-Lymphocytes/immunology , Cadherins/metabolism , Mice, Inbred C57BL , Cytokines/metabolism
5.
Blood Adv ; 8(10): 2342-2350, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38537065

ABSTRACT

ABSTRACT: Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and 52%/38%, respectively. The median progression-free and overall survival estimates for the same treatment groups were 4.9/14.3 months, 14.9 months/not reached, and 3.3/9 months, respectively. CLL with del(17p) was associated with a lower complete response rate in the total cohort (odds ratio [OR] 0.15; 95% confidence interval [CI] 0.04-0.6; p=0.01) and venetoclax-naïve subgroup (OR 0.13; 95%CI 0.02-0.66; p=0.01). TP53 mutated CLL was associated with a lower complete response rate (OR 0.15; 95%CI 0.03-0.74; p=0.02) and shorter progression-free survival (hazard ratio 3.1; 95%CI 1.21-7.95; p=0.02) only in venetoclax-naïve subgroup. No other clinical or baseline characteristics, including prior venetoclax treatment for CLL, showed statistically significant association with outcomes. Grade 3-4 neutropenia and thrombocytopenia events were most frequent with intensive chemoimmunotherapy + venetoclax; grade 3-4 infection rates were similar across treatment groups. In this difficult-to-treat RT patient population, venetoclax-based combination regimens achieved high response rates, with durable remission and survival observed in a subset of patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Lymphocytic, Chronic, B-Cell , Sulfonamides , Humans , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Sulfonamides/therapeutic use , Sulfonamides/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Aged , Female , Male , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged, 80 and over , Retrospective Studies , Adult , Treatment Outcome , Cyclophosphamide/therapeutic use , Cyclophosphamide/administration & dosage , Rituximab/therapeutic use , Rituximab/administration & dosage , Doxorubicin/therapeutic use , Doxorubicin/administration & dosage , Vincristine/therapeutic use
6.
JAMA Oncol ; 10(4): 532-535, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38386311

ABSTRACT

This case-control study examines the incidence and risks of myeloid neoplasms in adults treated for B-cell lymphoproliferative disorders or multiple myeloma.


Subject(s)
Multiple Myeloma , Neoplasms , Receptors, Chimeric Antigen , Humans , Immunotherapy, Adoptive , T-Lymphocytes , Cell- and Tissue-Based Therapy , Multiple Myeloma/therapy , Receptors, Antigen, T-Cell
7.
Blood ; 143(3): 258-271, 2024 Jan 18.
Article in English | MEDLINE | ID: mdl-37879074

ABSTRACT

ABSTRACT: In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.


Subject(s)
Antibodies, Monoclonal, Humanized , Immunotherapy , Therapeutic Index , Antigens, CD19 , Immunotherapy, Adoptive/methods
9.
Surgery ; 175(1): 199-206, 2024 01.
Article in English | MEDLINE | ID: mdl-37919223

ABSTRACT

BACKGROUND: Of the half a million cases of thyroid cancer diagnosed annually, 95% are differentiated thyroid cancers. Although clinical guidelines recommend surgical resection followed by radioactive iodine ablation, loss of sodium-iodine symporter expression causes up to 20% of differentiated thyroid cancers to become radioactive iodine refractory. For patients with radioactive iodine refractory disease, there is an urgent need for new diagnostic and therapeutic approaches. We evaluated the thyroid-stimulating hormone receptor as a potential target for imaging of differentiated thyroid cancer. METHODS: We immunostained tissue microarrays containing 52 Hurthle cell carcinomas to confirm thyroid-stimulating hormone receptor expression. We radiolabeled chelator deferoxamine conjugated to recombinant human thyroid-stimulating hormone analog superagonist TR1402 with 89Zr (t1/2 = 78.4 h, ß+ =22.7%) to produce [89Zr]Zr-TR1402. We performed in vitro uptake assays in high-thyroid-stimulating hormone receptor and low-thyroid-stimulating hormone receptor-expressing THJ529T and FTC133 thyroid cancer cell lines. We performed in vivo positron emission tomography/computed tomography and biodistribution studies in male athymic nude mice bearing thyroid-stimulating hormone receptor-positive THJ529T tumors. RESULTS: Immunohistochemical analysis revealed 62% of patients (27 primary and 5 recurrent) were thyroid-stimulating hormone receptor membranous immunostain positive. In vitro uptake of 1nM [89Zr]Zr-TR1402 was 38 ± 17% bound/mg in thyroid-stimulating hormone receptor-positive THJ529T thyroid cancer cell lines compared to 3.2 ± 0.5 in the low-expressing cell line (P < .01), with a similar difference seen in FTC133 cell lines (P < .0001). In vivo and biodistribution studies showed uptake of [89Zr]Zr-TR1402 in thyroid-stimulating hormone receptor-expressing tumors, with a mean percentage of injected dose/g of 1.9 ± 0.4 at 3 days post-injection. CONCLUSION: Our observation of thyroid-stimulating hormone receptor expression in tissue microarrays and [89Zr]Zr-TR1402 accumulation in thyroid-stimulating hormone receptor-positive thyroid cancer cells and tumors suggests thyroid-stimulating hormone receptor is a promising target for imaging of differentiated thyroid cancer.


Subject(s)
Adenoma, Oxyphilic , Iodine , Receptors, Thyrotropin , Thyroid Neoplasms , Animals , Humans , Male , Mice , Cell Line, Tumor , Iodine Radioisotopes , Mice, Nude , Positron-Emission Tomography/methods , Receptors, Thyrotropin/metabolism , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/pathology , Thyrotropin , Tissue Distribution , Adenoma, Oxyphilic/diagnostic imaging , Adenoma, Oxyphilic/pathology
10.
Leukemia ; 37(10): 1953-1962, 2023 10.
Article in English | MEDLINE | ID: mdl-37626090

ABSTRACT

Chimeric antigen receptor T (CAR-T) cell therapy has drawn increasing attention over the last few decades given its remarkable effectiveness and breakthroughs in treating B cell hematological malignancies. Even though CAR-T cell therapy has outstanding clinical successes, most treated patients still relapse after infusion. CARs are derived from the T cell receptor (TCR) complex and co-stimulatory molecules associated with T cell activation; however, the similarities and differences between CARs and endogenous TCRs regarding their sensitivity, signaling pathway, killing mechanisms, and performance are still not fully understood. In this review, we discuss the parallel comparisons between CARs and TCRs from various aspects and how these current findings might provide novel insights and contribute to improvement of CAR-T cell therapy efficacy.


Subject(s)
Receptors, Chimeric Antigen , T-Lymphocytes , Humans , Receptors, Chimeric Antigen/metabolism , Neoplasm Recurrence, Local/metabolism , Receptors, Antigen, T-Cell , Immunotherapy, Adoptive
12.
Cancer Immunol Res ; 11(9): 1222-1236, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37378662

ABSTRACT

The receptor tyrosine kinase AXL is a member of the TYRO3, AXL, and proto-oncogene tyrosine-protein kinase MER family and plays pleiotropic roles in cancer progression. AXL is expressed in immunosuppressive cells, which contributes to decreased efficacy of immunotherapy. Therefore, we hypothesized that AXL inhibition could serve as a strategy to overcome resistance to chimeric antigen receptor T (CAR T)-cell therapy. To test this, we determined the impact of AXL inhibition on CD19-targeted CAR T (CART19)-cell functions. Our results demonstrate that T cells and CAR T cells express high levels of AXL. Specifically, higher levels of AXL on activated Th2 CAR T cells and M2-polarized macrophages were observed. AXL inhibition with small molecules or via genetic disruption in T cells demonstrated selective inhibition of Th2 CAR T cells, reduction of Th2 cytokines, reversal of CAR T-cell inhibition, and promotion of CAR T-cell effector functions. AXL inhibition is a novel strategy to enhance CAR T-cell functions through two independent, but complementary, mechanisms: targeting Th2 cells and reversing myeloid-induced CAR T-cell inhibition through selective targeting of M2-polarized macrophages.


Subject(s)
Neoplasms , Receptors, Chimeric Antigen , Humans , Axl Receptor Tyrosine Kinase , Proto-Oncogene Proteins , Receptor Protein-Tyrosine Kinases/genetics
13.
Lancet ; 402(10402): 641-654, 2023 08 19.
Article in English | MEDLINE | ID: mdl-37295445

ABSTRACT

BACKGROUND: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. FINDINGS: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). INTERPRETATION: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Aged , Female , Humans , Male , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Remission Induction , Sulfonamides/therapeutic use
14.
J Vis Exp ; (192)2023 02 10.
Article in English | MEDLINE | ID: mdl-36847405

ABSTRACT

Chimeric antigen receptor T (CART) cell therapy has emerged as a powerful tool for the treatment of multiple types of CD19+ malignancies, which has led to the recent FDA approval of several CD19-targeted CART (CART19) cell therapies. However, CART cell therapy is associated with a unique set of toxicities that carry their own morbidity and mortality. This includes cytokine release syndrome (CRS) and neuroinflammation (NI). The use of preclinical mouse models has been crucial in the research and development of CART technology for assessing both CART efficacy and CART toxicity. The available preclinical models to test this adoptive cellular immunotherapy include syngeneic, xenograft, transgenic, and humanized mouse models. There is no single model that seamlessly mirrors the human immune system, and each model has strengths and weaknesses. This methods paper aims to describe a patient-derived xenograft model using leukemic blasts from patients with acute lymphoblastic leukemia as a strategy to assess CART19-associated toxicities, CRS, and NI. This model has been shown to recapitulate CART19-associated toxicities as well as therapeutic efficacy as seen in the clinic.


Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Receptors, Chimeric Antigen , Humans , Animals , Mice , T-Lymphocytes , Receptors, Antigen, T-Cell/genetics , Heterografts , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Immunotherapy, Adoptive/methods
15.
Curr Hematol Malig Rep ; 18(2): 9-18, 2023 04.
Article in English | MEDLINE | ID: mdl-36763238

ABSTRACT

PURPOSE OF REVIEW: Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, the remarkable efficacy of therapy is not without significant safety concerns. Herein, we will review the unique and potentially life-threatening toxicities associated with CAR-T cell therapy and their association with treatment efficacy. RECENT FINDINGS: Currently, CAR-T cell therapy is approved for the treatment of B cell relapsed or refractory leukemia and lymphoma, and most recently, multiple myeloma (MM). In these different diseases, it has led to excellent complete and overall response rates depending on the patient population and therapy. Despite promising efficacy, CAR-T cell therapy is associated with significant side effects; the two most notable toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The treatment of CAR-T-induced toxicity is supportive; however, as higher-grade adverse events occur, toxicity-directed therapy with tocilizumab, an IL-6 receptor antibody, and steroids is standard practice. Overall, a careful risk-benefit balance exists between the efficacy and toxicities of therapies. The challenge lies in the underlying pathophysiology of CAR-T-related toxicity which relies upon the activation of CAR-T cells. Some degree of toxicity is expected to achieve an effective response to therapy, and certain aspects of treatment are also associated with toxicity. As progress is made in the investigation and approval of new CARs, novel toxicity-directed therapies and toxicity-limited constructs will be the focus of attention.


Subject(s)
Multiple Myeloma , Receptors, Chimeric Antigen , Humans , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/therapeutic use , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Multiple Myeloma/therapy , Multiple Myeloma/etiology , Cell- and Tissue-Based Therapy
17.
Transplant Cell Ther ; 29(3): 183.e1-183.e6, 2023 03.
Article in English | MEDLINE | ID: mdl-36584940

ABSTRACT

Hematopoietic stem cell transplantations (HSCT) are intensive and potentially curative modalities available for a variety of hematological diseases. Although alloHSCTs are typically performed in an inpatient setting, there has been increasing interest in moving them to the outpatient setting. AlloHSCTs are associated with a median length of hospital stay of 30 days. AlloHSCTs in the inpatient setting may increase patient exposure to nosocomial infections, drug-resistant organisms, rapid deconditioning with time spent in hospital beds, and loss of muscle mass. In this study, we aim to share outcomes of 856 consecutive alloHSCTs done in our institute over the past 2 decades. This is a single-center retrospective chart review encompassing 856 patients who underwent outpatient alloHSCTs between 2000 and 2017. Reduced-intensity conditioning, stem cell infusion, and much of the immediate follow-up in the early alloHSCT period was performed on an outpatient basis with daily evaluation, laboratory assessment, and intervention as needed. Rate of non-routine hospital admission was our primary outcome of interest. We also looked at various secondary outcomes, including causes of admission, median length of stay, and in-hospital mortality rate. Data analysis was performed using STATA statistical software Version 15. Descriptive statistics were used to summarize baseline demographic data and outcomes. Logistic regression modeling was used to identify predictors of hospital admission. We observed that about one third of our cohort never required admission to the hospital throughout the first 100 days after HSCT. Among those admitted, 6.6% experienced a direct admission to the intensive care unit, and the overall in hospital mortality was low at 5%. Furthermore, the median length of stay was noted to be decreased at 6 days compared to a median reported 30 days in existing literature. Overall, we observed favorable safety profile and outcomes with outpatient management of HSCTs.


Subject(s)
Hematopoietic Stem Cell Transplantation , Outpatients , Humans , Retrospective Studies , Treatment Outcome , Hospitalization
18.
Blood Cancer J ; 12(9): 124, 2022 09 01.
Article in English | MEDLINE | ID: mdl-36050317

ABSTRACT

Patients with chronic lymphocytic leukemia (CLL) with disease progression on ibrutinib have worse outcomes compared to patients stopping ibrutinib due to toxicity. A better understanding of expected outcomes in these patients is necessary to establish a benchmark for evaluating novel agents currently available and in development. We evaluated outcomes of 144 patients with CLL treated at Mayo Clinic with 2018 iwCLL disease progression on ibrutinib. The median overall survival (OS) for the entire cohort was 25.5 months; it was 29.8 months and 8.3 months among patients with CLL progression (n = 104) and Richter transformation (n = 38), respectively. Longer OS was observed among patients with CLL progression who had received ibrutinib in the frontline compared to relapsed/refractory setting (not reached versus 28.5 months; p = 0.04), but was similar amongst patients treated with 1, 2, or ≥3 prior lines (18.5, 30.9, and 26.0 months, respectively, p = 0.24). Among patients with CLL disease progression on ibrutinib, OS was significantly longer when next-line treatment was chimeric antigen receptor T-cell therapy (median not reached) or venetoclax-based treatment (median 29.8 months) compared to other approved treatments, such as chemoimmunotherapy, phosphoinositide 3'-kinase inhibitors, and anti-CD20 monoclonal antibodies (9.1 months; p = 0.03). These findings suggest an unmet need for this growing patient population.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Adenine/analogs & derivatives , Disease Progression , Humans , Piperidines , Pyrazoles/adverse effects , Pyrimidines
20.
Br J Haematol ; 199(2): 239-244, 2022 10.
Article in English | MEDLINE | ID: mdl-35841338

ABSTRACT

Patients with chronic lymphocytic leukaemia (CLL) disease progression on ibrutinib or after sequential ibrutinib and venetoclax-based treatments (double-refractory) have poor outcomes. In this retrospective study, we analysed outcomes with combined ibrutinib and venetoclax treatment in these groups of patients. The median treatment-free and overall survival for 22 patients with prior progression on ibrutinib (venetoclax-naïve) were 23.7 and 47.1 months respectively. In 11 patients with double-refractory CLL, the median treatment-free and overall survival were 11.2 and 27.0 months respectively. The combination of ibrutinib and venetoclax may help bridge the current gap in options for patients with disease refractory to the most commonly used novel agents.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Adenine/analogs & derivatives , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Piperidines , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Retrospective Studies , Sulfonamides
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