Literature Scan
Anti-CD19 CAR T-Cell Therapy Results in Sustained Molecular Remissions in Patients With Ibrutinib-Refractory CLL
Patients with chronic lymphocytic leukemia ( CLL ) with complex cytogenetics who relapse after treatment with ibrutinib have few treatment options and a short expected survival . According to results from a phase I / II feasibility and safety study published in the Journal of Clinical Oncology , treatment with anti-CD19 chimeric antigen receptor ( CAR ) T-cell therapy , combined with lymphodepletion chemotherapy , could be effective in these patients .
The 24 patients included in the study ( median age = 61 years ; range = 40-73 years ) achieved an overall response rate ( ORR ) of 71 percent ( n = 17 ) four weeks after CAR T-cell infusion , and “ a high rate of elimination of CLL from marrow and lymph node response after CAR T-cell therapy ,” lead author Cameron J . Turtle , PhD , of the Clinical Research Division at the Fred Hutchinson Cancer Research Center in Seattle , Washington , and co-authors reported .
The study included patients with CLL who had relapsed disease following treatment with an anti-CD20 antibody and fludarabine or bendamustine . They also received prior ibrutinib for a median duration of 13 months ( range = 0.75-39 months ). Nineteen patients experienced disease progression while receiving ibrutinib , and three were considered ibrutinib intolerant . The median number of previous therapies was five ( range = 3-9 therapies ).
All patients had high-risk disease , and 96 percent had high-risk cytogenetics . Nine of the 19 patients whose disease progressed after ibrutinib were found to have mutations associated with ibrutinib resistance , including BTK ( n = 7 ) and PLCG2 ( n = 2 ). Ibrutinib was discontinued prior to lymphodepletion with cyclophosphamide and fludarabine .
The study used a 3 + 3 design to determine the maximum tolerated dose ( MTD ) of CAR T cells : 2x10 5 cells / kg ( n = 4 ), 2x10 6 cells / kg ( n = 19 ), or 2x10 7 cells / kg ( n = 1 ).
The most common safety events in this patient population were cytokine release syndrome ( CRS ) and neurotoxicity – side effects commonly associated with CAR T-cell therapies . Twenty patients ( 83 %) experienced CRS , mostly grade 1 / 2 ( n = 18 ), and eight patients ( 33 %) reported neurotoxicity , mostly grade 3 ( n = 5 ). All patients who had neurotoxicity also experienced CRS . Two patients were admitted to the intensive care unit , and one patient
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died from neurotoxicity after receiving the 2x10 6 cells / kg dose . Neurotoxicity was reversible in all other patients .
The median duration of all-cause hospitalization was nine days ( range = 0-49 days ).
The investigators selected 2x10 6 cells / kg as the maximum dose for subsequent patients with CLL , given the grade 4 CRS and grade 3 neurotoxicity at higher dose levels in this study and previous reports of excessive
IMPORTANT SAFETY INFORMATION
Contraindication : History of hypersensitivity to BOSULIF . Reactions have included anaphylaxis . Anaphylactic shock occurred in less than 0.2 % of treated patients in clinical trials .
Gastrointestinal Toxicity : Diarrhea , nausea , vomiting , and abdominal pain can occur . In the clinical trial , median time to onset for diarrhea was 2 days , median duration was 2 days , and median number of episodes per patient was 3 ( range 1-268 ). Monitor and manage patients using standards of care , including antidiarrheals , antiemetics , and / or fluid replacement . Withhold , dose reduce , or discontinue BOSULIF as necessary .
Myelosuppression : Thrombocytopenia , anemia , and neutropenia can occur . Perform complete blood counts weekly for the first month and then monthly or as clinically indicated . Withhold , dose reduce , or discontinue BOSULIF as necessary .
Hepatic Toxicity : Twenty percent of patients experienced an increase in either ALT or AST . Liver enzyme elevation usually occurs early in treatment . The median time to onset of increased ALT and AST was 35 and 33 days , respectively , and the median duration for each was 21 days . Perform hepatic enzyme tests at least monthly for the first 3 months and as clinically indicated . In patients with transaminase elevations , toxicity with the 2x10 7 cells / kg dose in patients with acute lymphocytic leukemia and non-Hodgkin lymphoma .
The percentage of leukemic B cells in the bone marrow prior to therapy was
BOSULIF ® ( bosutinib ) is indicated for the treatment of adult patients with chronic , accelerated , or blast phase Philadelphia chromosome – positive ( Ph +) chronic myelogenous leukemia ( CML ) with resistance or intolerance to prior therapy . In the treatment of adult patients with Ph + CML with resistance or intolerance to prior therapy
Everyone has a distinct profile
Consider your patient . Consider BOSULIF ® .
( bosutinib )
Bosutinib ( BOSULIF ®) is recommended by the NCCN ( National Comprehensive Cancer Network ®) Clinical Practice Guidelines in Oncology ( NCCN Guidelines ®) as a treatment option for patients with CML in need of 2nd- or later-line TKI therapy . 1
Study design : BOSULIF 500 mg once daily was studied in a Phase 1 / 2 , open-label , multicenter clinical trial ( N = 546 ) in patients with CP CML in second line ( after imatinib ) ( n = 284 ) and in third line ( after imatinib followed by dasatinib or nilotinib ) ( n = 119 ); also in patients with AP ( n = 79 ) or BP ( n = 64 ) CML . The long-term analysis was based on a minimum of 60 months of follow-up for patients with CP CML treated with one prior TKI ( imatinib ) and a minimum of 48 months of follow-up for patients with CP CML treated with imatinib and at least one additional TKI .
AP = accelerated phase ; BP = blast phase ; CP = chronic phase ; TKI = tyrosine kinase inhibitor .
monitor liver enzymes more frequently . One case consistent with drug-induced liver injury occurred in a trial of BOSULIF in combination with letrozole . Withhold , dose reduce , or discontinue BOSULIF as necessary . In patients with mild , moderate , or severe hepatic impairment , the recommended starting dose is 200 mg daily .
Renal Toxicity : An on-treatment decline in estimated glomerular filtration rate has occurred in patients treated with BOSULIF . Monitor renal function at baseline and during therapy , with particular attention to patients with preexisting renal impairment or risk factors for renal dysfunction . Consider dose adjustment in patients with baseline and treatment emergent renal impairment . The recommended starting doses for patients with severe renal impairment ( CrCL < 30 mL / min ) or moderate renal impairment ( CrCL 30-50 mL / min ) are 300 mg and 400 mg daily , respectively .
Fluid Retention : Fluid retention can occur and may cause pericardial effusion , pleural effusion , pulmonary edema , and / or peripheral edema . In the clinical trial , Grade 3 / 4 fluid retention was reported in 26 patients ( 5 %). Monitor and manage patients using standards of care . Interrupt , dose reduce , or discontinue BOSULIF as necessary .
Embryofetal Toxicity : BOSULIF can cause fetal harm when administered to a pregnant woman . Women of childbearing potential should be advised of