Idelalisib treatment is associated with improved cytopenias in patients with relapsed/refractory inhl and CLL Susan M O Brien, Andrew J Davies, Ian W Flinn, Ajay K Gopal, Thomas J Kipps, Gilles A Salles, Terry Newcomb, Christopher C Waldapfel, Zhihai Zhang, Stephan Stilgenbauer ASH Annual Meeting Abstracts 215:1747
Background Bone marrow leukemia/lymphoma cell infiltrates are thought to be associated with cytopenia, resulting in impaired hematopoiesis 1 Idelalisib is a selective first-in-class oral PI3Kδ inhibitor In preclinical studies, idelalisib selectively targeted malignant B-cells with minimal toxicity to non-malignant B-cells and other hematopoietic cell types 2 Idelalisib demonstrated clinical activity with acceptable safety in registrational trials in CLL 3 and inhl 4 In the U.S., idelalisib is indicated in combination with rituximab for relapsed CLL, and as monotherapy in relapsed FL and SLL 5 In a phase II study of idelalisib plus rituximab in patients with treatment-naïve CLL/SLL, hematologic responses were observed in neutrophils, red blood cells, and platelets in patients with baseline cytopenia, despite grade 3 treatment-emergent neutropenia in 28% of patients 6 1. Zent CS, et al. Best Pract Res Clin Haematol 21;23:47 59. 2. Herman SE, et al. Blood 21;116:278 88. 3. Furman RR, et al. N Engl J Med 214;37:997 17. 4. Gopal AK, et al. N Engl J Med 214;37:18 18. 5. Zydelig (idelalisib) tablets prescribing information. Gilead Sciences, Inc., Foster City, CA. Revised July 214. 6. O Brien SM, et al. Blood 215;[Epub ahead of print]. CLL = chronic lymphocytic leukemia; FL = follicular lymphoma; inhl = indolent non-hodgkin lymphoma; PI3K = phosphatidylinositol 3-kinase; SLL = small lymphocytic lymphoma
Objectives Evaluate hemogram changes in patients with R/R CLL or inhl treated with idelalisib in two registrational studies 1,2 Describe trends in hematologic parameters over time during idelalisib treatment in patients with or without baseline cytopenias 1. Furman RR, et al. N Engl J Med 214;37:997 17. 2. Gopal AK, et al. N Engl J Med 214;37:18 18. CLL = chronic lymphocytic leukemia; inhl = indolent non-hodgkin lymphoma; R/R = relapsed/refractory
Study Design Post hoc analyses were performed on two trials: A phase III, multicentre, randomized, double-blind, placebo-controlled trial in 22 frail patients with R/R CLL (study 312-116; NCT1539512) 1 ; and A phase II, multicentre, single-group, open-label trial (study 11-9; NCT1282424) in 125 patients with R/R inhl 2 Patients with CLL received continuous idelalisib at a dose of 15 mg bid or placebo, plus eight doses of rituximab Patients with inhl received idelalisib at a dose of 15 mg bid, with an option for dose reductions to 1 mg or 75 mg Idelalisib treatment continued until disease progression, unacceptable toxicity, or death 1. Furman RR, et al. N Engl J Med 214;37:997 17. 2. Gopal AK, et al. N Engl J Med 214;37:18 18. Bid = twice daily; CLL = chronic lymphocytic leukemia; inhl = indolent non-hodgkin lymphoma; R/R = relapsed/refractory
Inclusion Criteria CLL study: patients with relapsed CLL who could not receive cytotoxic agents because of severe neutropenia or thrombocytopenia, with an estimated CrCl of <6 ml/min, or a CIRS score of >6 for coexisting illnesses unrelated to CLL inhl study: patients aged 18 years with inhl refractory to both rituximab and an alkylating agent, with an ECOG performance status of 2, an ANC 1. 1 9 /L, and a platelet count 5 1 9 /L Trial inclusion criteria allowed enrolment of patients with baseline cytopenias of any grade (CLL) or grade >3 (inhl) ANC = absolute neutrophil count; CLL = chronic lymphocytic leukemia CIRS = Cumulative Illness Rating Scale; CrCl = creatinine clearance; ECOG = Eastern Cooperative Oncology Group; inhl = indolent non-hodgkin lymphoma
Data Analyses Data cutoffs were October 15, 214 (CLL) and June 11, 214 (inhl) In the inhl study, patients with progressive disease at the first assessment (n = 1) were excluded from analyses to avoid confounding by underlying uncontrolled disease Baseline hemograms were summarized by severity using CTCAE (version 4.) and categorized as normal (no cytopenia) or abnormal (any grade of cytopenia) for ANC, Hgb, and platelets 1 Changes from baseline in Hgb, ANC, and platelet count were determined in patients who achieved stable disease or better Change from baseline in supportive care utilization was assessed by use of blood product transfusions, hematopoietic growth factors, and immunosuppressant therapies Treatment-emergent de novo autoimmune cytopenias and/or worsening of pre-existing autoimmune cytopenias were summarized All data were analyzed using descriptive statistics 1. U.S. Department of Health and Human Services. CTCAE. Version 4. (Published: May 28, 29). V4.3 (Published: June 14, 21) NIH Publication No. 9-541. 21. ANC = absolute neutrophil count; CLL = chronic lymphocytic leukemia; CTCAE = Common Terminology Criteria for Adverse Events; Hgb = hemoglobin; inhl = indolent non-hodgkin lymphoma
Patient Disposition The studies included 345 patients (CLL, n = 22; inhl = 125); the safety analysis set comprised 333 patients (CLL, n = 28; inhl, n = 125) For patients with CLL receiving idelalisib (n = 11), baseline cytopenias (grade 1) included anemia (75.5%), thrombocytopenia (61.8%), and neutropenia (33.6%) For patients with inhl receiving idelalisib (n = 115), baseline cytopenias (grade 1) included anemia (49.6%), thrombocytopenia (35.7%), and neutropenia (24.3%) CLL = chronic lymphocytic leukemia; inhl = indolent non-hodgkin lymphoma
Baseline Characteristics CLL* Idelalisib + R (n = 11) Placebo + R (n = 11) Median age, years (range) 71 (48 9) 71 (47 92) Rai stage at screening, n (%) I or II III or IV 34 (3.9) 7 (63.6) 1 (.9) 3 (27.3) 71 (64.5) Median number of prior regimens (range) 3 (1 12) 3 (1 1) Previous treatment, % Rituximab Cyclophosphamide Fludarabine Bendamustine Chlorambucil Median duration of exposure, months (range) 8.1 (.3 19.5) 4.6 (.1 14.6) 92 66 57 6 31 89 7 64 55 23 * There were no significant differences between the two groups at baseline. Percentages may not total the overall number in the category because of rounding. In the Rai staging system, stage denotes low-risk disease, stage I or II denotes intermediate risk, and stage III or IV denotes high risk. Did not include exposure to idelalisib in patients randomized to placebo who crossed over to idelalisib after progression of disease. CLL = chronic lymphocytic leukemia; R = rituximab
Baseline Characteristics inhl Idelalisib (n = 125) Median age, years (range) 64 (33 87) Disease burden, % Stage III or IV Elevated LDH Bulky disease* Median number of prior regimens (range) 4 (2 12) Previous treatment, % Rituximab Alkylating agent Combination rituximab/alkylating agent Bendamustine Anthracycline Purine analog Autologous stem-cell transplantation Median duration of exposure, months (range) 6.6 (.6 35.4) 89 3 26 1 1 91 65 64 34 11 * Defined as 1 node with 1 dimension of 7 cm. inhl = indolent non-hodgkin lymphoma; LDH = lactate dehydrogenase
Pre-existing Autoimmune Cytopenias at Baseline (Any Grade) n (%) CLL Idelalisib + R (n = 11) CLL Placebo + R (n = 11) inhl Idelalisib (n = 115) Any pre-existing autoimmune cytopenia 7 (6.4) 18 (16.4) Pre-existing AIHA 3 (2.7)* 8 (7.3) Pre-existing ITP 5 (4.6)* 17 (17.5) Pre-existing AIN 1 (.9) As of the data cutoff, no patient experienced treatment-emergent de novo and/or worsening of pre-existing autoimmune cytopenias * Included one patient with pre-existing AIHA and ITP. Included one patient with pre-existing AIN and ITP. Included six patients with pre-existing AIHA and ITP. AIHA = autoimmune hemolytic anemia; AIN = autoimmune neutropenia; CLL = chronic lymphocytic leukemia; inhl = indolent non-hodgkin lymphoma; ITP = immune thrombocytopenia; R = rituximab
Hemogram Changes: Hgb in Patients With and Without Baseline Anemia* In patients with a normal hemogram at baseline, median hematologic laboratory values remained unchanged over time
Hemogram Changes: Platelet Count in Patients With and Without Baseline Thrombocytopenia* In patients with a normal hemogram at baseline, median hematologic laboratory values remained unchanged over time
Hemogram Changes: ANC in Patients With and Without Baseline Neutropenia* In patients with a normal hemogram at baseline, median hematologic laboratory values remained unchanged over time
Hemogram Changes During Treatment Parameter Baseline Hgb CLL Idelalisib + R (n = 11) CLL Placebo + R (n = 18) inhl Idelalisib (n = 115)* Median Hgb (Q1, Q3), g/l 13. (88., 11.) 12. (87., 11.) 17. (97., 113.) Anemia, n (%) 83 (75.5) 79 (73.1) 57 (49.6) Change from baseline in Hgb n = 82 n = 76 n = 57 Median best change (Q1, Q3), g/l 125.5 (115., 137.) 113. (99.5, 123.) 128 (12, 137) Median best change (Q1, Q3), % 23.5 (13.5, 41.1) 12.6 (4., 2.7) 19.8 (11., 3.1) Median time to best change from baseline (Q1, Q3), months Baseline platelets 5.6 (2.3, 8.2) 2.3 (1., 3.7) 2.8 (1.4, 4.6) Median platelet count (Q1, Q3), x 1 9 /L 67 (48., 11.) 54 (26., 88.) 95 (77., 111.) Thrombocytopenia, n (%) 68 (61.8) 66 (61.1) 41 (35.7) Change from baseline in platelets n = 66 n = 61 n = 41 Median best change (Q1, Q3), x 1 9 /L 145 (18., 196.) 96 (4., 143.) 159 (119., 29.) Median best change (Q1, Q3), % 119 (61.4, 219.5) 48 (18.5, 14.8) 64 (33., 131.7) Median time to best change from baseline (Q1, Q3), months 4.6 (2.3, 6.9) 1.8 (.5, 3.7) 2.5 (1., 9.7) * Patients with progressive disease at the first evaluation were excluded from this analysis to avoid confounding by underlying uncontrolled disease. CLL = chronic lymphocytic leukemia; Hgb = hemoglobin; inhl = indolent non-hodgkin lymphoma; Q = quartile; R = rituximab
Hemogram Changes During Treatment (cont d) Parameter Baseline ANC CLL Idelalisib + R (n = 11) CLL Placebo + R (n = 18) inhl Idelalisib (n = 115)* Median ANC (Q1, Q3), x 1 9 /L 1. (.9, 1.6) 1.1 (.6, 1.6) 1.4 (1., 1.6) Neutropenia, n (%) 37 (33.6) 39 (36.1) 28 (24.3) Change from baseline in ANC n = 36 n = 35 n = 28 Median best change (Q1, Q3), x 1 9 /L 3.2 (2.1, 4.5) 2.3 (1.1, 3.2) 3.6 (2.7, 5.8) Median best change (Q1, Q3), % 168.9 (97.8, 35.6) 86.5 (2., 196.6) 24.7 (77.1, 34.9) Median time to best change from baseline (Q1, Q3), months 2.1 (1., 3.8) 1.4 (1., 2.8) 5.5 (2.6, 9.7) * Patients with progressive disease at the first evaluation were excluded from this analysis to avoid confounding by underlying uncontrolled disease. ANC = absolute neutrophil count; CLL = chronic lymphocytic leukemia; inhl = indolent non-hodgkin lymphoma; Q = quartile; R = rituximab
Hemogram Changes During Treatment (cont d) Anemia and thrombocytopenia were improved in patients with baseline cytopenia while they were on treatment with idelalisib For patients with CLL, the magnitude of improvement appeared larger for patients in the idelalisib arm compared to the placebo arm; median peak values of Hgb and platelets were observed within six months of idelalisib initiation In patients with baseline neutropenia, ANC remained stable over time in patients with CLL and increased in patients with inhl In patients with inhl, median peak values for Hgb and platelets were observed within three months of idelalisib initiation ANC = absolute neutrophil count; CLL = chronic lymphocytic leukemia; Hgb = hemoglobin; inhl = indolent non-hodgkin lymphoma
Supportive Care Utilization at Any Point During Study* n (%) CLL Idelalisib + R Normal Baseline Baseline Cytopenia CLL Placebo + R Normal Baseline Baseline Cytopenia Normal Baseline inhl Idelalisib Baseline Cytopenia Anemia, n 27 83 29 79 58 57 RBC transfusion Steroid use for AIHA ESA use Other 3 (11.1) 34 (41.) 3 (3.6) 2 (2.4) 2 (2.4) 1 (3.4) 36 (45.6) 6 (7.6) 1 (1.3) 3 (3.8) 1 (1.7) 1 (1.8) 1 (26.3) 6 (1.5) 1 (1.8) Thrombocytopenia, n 42 68 42 66 74 41 Platelet transfusion Steroid use for ITP IVIG use for ITP TPO 1 (2.4) 13 (19.1) 2 (2.9) 1 (1.5) 1 (1.5) 1 (2.4) 1 (2.4) 24 (36.4) 4 (6.1) 2 (2.7) Neutropenia, n 73 37 69 39 87 28 3 (7.3) G-CSF use** 18 (24.7) 13 (35.1) 5 (7.2) 17 (43.6) 9 (1.3) 14 (5.) * Included 3 days prior to treatment. ESA included epoietin alfa, epoietin beta, and darbopoietin alfa. Included rituximab and IVIG in the inhl study; included cyclosporine and danazol in the CLL study. Search terms for TPO included eltrombopag and romiplostim. ** Search terms for G-CSF included G-CSF, filgrastim, pegfilgrastim, and lenograstim. AIHA = autoimmune hemolytic anemia; CLL = chronic lymphocytic leukemia; ESA = erythropoiesis stimulating agent; G-CSF = granulocyte colony-stimulating factor; inhl = indolent non-hodgkin lymphoma; ITP = immune thrombocytopenia; IVIG = intravenous immunoglobulin; R = rituximab; RBC = red blood cell; TPO = thrombopoietin receptor agonist
Supportive Care Utilization Over Time in Patients with Baseline Anemia, Thrombocytopenia, and Neutropenia Over time, in patients with baseline cytopenia, there was an overall reduction in supportive care utilization for: (A) Anemia (B) Thrombocytopenia (C) Neutropenia
Summary and Conclusion In patients with R/R CLL or inhl and baseline cytopenia from two registrational clinical trials, idelalisib treatment was associated with improvements in Hgb and platelet counts and a reduction in supportive care utilization that occurred early in the course of treatment In patients with baseline neutropenia, no trend of deterioration was found, and the utilization of G-CSF decreased over time while on treatment with idelalisib Pre-existing cytopenias, including those due to advanced disease, myelosuppression from previous chemotherapy, autoimmune hemolytic anemia, and immune thrombocytopenia, do not preclude treatment with idelalisib CLL = chronic lymphocytic leukemia; G-CSF = granulocyte colony-stimulating factor; Hgb = hemoglobin; inhl = indolent non-hodgkin lymphoma; R/R = relapsed/refractory