Chaffee, Kari Rabe

Abstract Introduction: The Food and Drug Administration (FDA) approved ibrutinib in February 2014 based on results from a pivotal phase 2 clinical trial that enrolled 85 patients with relapsed/refractory CLL. A subsequent phase 3 trial confirmed the superior progression-free survival (PFS) and overall survival (OS) of ibrutinib compared to ofatumumab in 391 CLL patients. However, there is no information on the efficacy and safety of ibrutinib in CLL patients treated outside the context of clinical trials. Additionally, it is unclear if the reasons for discontinuation of ibrutinib differ in routine clinical practice from those described in patients treated on clinical trials. We conducted a retrospective study to evaluate these aspects in a large cohort of CLL patients treated with ibrutinib off-protocol. Methods: After IRB approval, CLL patients seen at Mayo Clinic, Rochester, MN, and treated with commercial ibrutinib from November 2013 through July 2015 were evaluated. The baseline characteristics, time to therapy discontinuation, reasons for discontinuation and survival following discontinuation were abstracted. Results: One hundred thirty-five patients with CLL were treated during the study interval; 124 received ibrutinib for relapsed/refractory CLL and 11 received ibrutinib for treatment-naïve CLL with TP53 disruption (either del17p on FISH or TP53 mutation). Patients with relapsed/refractory CLL (n=124) Patients were high-risk, with a median of 3 prior therapies (range, 1-15), 81% had unmutated IGHV, and 38% had either del11q or del17p on FISH testing. After a median follow-up of 6.4 months, 101 remain on ibrutinib therapy. The estimated proportion of patients continuing ibrutinib at 6 months was 84% (95% CI: 77-92%) and at 12 months was 70% (95% CI: 59-83%). Of the 23 who discontinued ibrutinib therapy, 8 discontinued for progressive disease (2 progressive CLL; 6 Richter's transformation). The remaining 15 discontinued therapy for reasons other than progression, including: infection (n=3), bleeding (n=3), diarrhea (n=1), atrial fibrillation (n=1), rash (n=1), immune thrombocytopenia (n=1), renal dysfunction (n=1), severe edema (n=1), MDS (n=1) and physician preference (n=2). Table 1 shows the reasons for discontinuation of ibrutinib in patients treated on clinical trials (Maddocks, JAMA Oncology, 2015) compared to the current cohort of patients. The estimated cumulative incidence of discontinuation of ibrutinib therapy due to CLL progression/Richter's transformation at 6 and 12 months was 9% (95% CI: 4-17%) and 12% (95% CI: 5-23%), respectively. The estimated cumulative incidence of ibrutinib discontinuation due to reasons other than progression at 6 and 12 months was 10% (95% CI: 5-17%) and 22% (12-34%), respectively (Figure). The median survival after discontinuation of ibrutinib for patients who had CLL progression was 3.5 months, not reached in patients who developed Richter's transformation and not reached in those patients who discontinued ibrutinib due to reasons other than progression. Patients with treatment-naïve CLL (n=11) All patients had evidence of TP53 disruption (9 had del17p, 3 had TP53 mutation, and 1 had both). After a median follow-up of 2.8 months, no patient has had progression of CLL, and 2 patients have discontinued ibrutinib therapy for reasons other than CLL progression (atrial fibrillation, n=2). The estimated proportion of patients continuing ibrutinib at 6-months was 71% (95% CI: 45-100%). All 11 are still alive, and no patient has undergone allogeneic stem cell transplantation. Conclusion: This is the first study that describes the outcomes of a large cohort of CLL patients treated with ibrutinib outside the context of clinical trials. Patients treated in routine practice appear more likely to discontinue ibrutinib for reasons other than progression of disease, compared to those participating in clinical trials. Our results confirm the poor survival of CLL patients who progress on ibrutinib. Table 1. Comparative analysis of reasons for discontinuation of ibrutinib in patients with relapsed/refractory CLL: Characteristic Current Study (%) Maddocks (JAMA Oncology 2015) (%) No. of patients 124 308 Median follow-up (months) 6.4 20 Reasons for Discontinuation Progression of disease CLL 2 (2) 13 (4) Richter's transformation 6 (5) 15 (5) Non-progression of disease Infection 3 (2) 28 (9) Other 12 (10) 17 (5) Figure 1. Figure 1. Disclosures Ding: Merek: Research Funding. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Tolero Pharm: Research Funding. Shanafelt:Cephalon: Research Funding; Celgene: Research Funding; Glaxo-Smith_Kline: Research Funding; Polyphenon E Int'l: Research Funding; Hospira: Research Funding; Janssen: Research Funding; Pharmactckucs: Research Funding; Genentech: Research Funding.

Abstract Background: PRCA is characterized by severe normochromic normocytic anemia, reticulocytopenia, and markedly reduced bone marrow erythroid precursors with intact leukocytic and megakaryocytic lineages. There is limited information about the prevalence and outcomes of PRCA in CLL, with the vast majority of information derived from case reports and small series comprising <10 patients. Here, we describe the clinical features, therapy, and outcomes of CLL patients with PRCA seen at our institution. Methods: The Mayo Clinic CLL Database includes all patients with a diagnosis of CLL evaluated at Mayo Clinic Rochester, MN between January 1995 and December 2014. We identified patients diagnosed with PRCA per the following diagnostic criteria: those who presented with normocytic anemia, had decreased erythroid precursors on bone marrow examination, and reticulocytopenia that could not be explained by any other cause besides PRCA. The baseline demographics, clinical characteristics, therapy, and outcomes were abstracted from the electronic medical records. We generated descriptive statistics and calculated overall survival (OS) from diagnosis date (PRCA, autoimmune cytopenia [AID], or CLL) to last known alive or death date. OS was plotted using Kaplan Meier curves and compared between groups using log-rank statistic. The Mayo Clinic IRB approved this study. Results: Of the 3945 CLL patients seen during the study interval, we identified 30 patients who met the diagnostic criteria of PRCA as described in the Methods section. The baseline characteristics, etiology and therapy for PRCA are shown in Table 1. The median time to PRCA from CLL diagnosis was 4.5 years (range-0.1-14 years). Of the 13 patients with IGHV results available, 12 (92%) were IGHV unmutated. Twenty-one (70%) were male and their median age at PRCA diagnosis was 67 years (range 40-81 years). Parvovirus testing was positive in 6 of 24 (25%) patients who were tested; 3 of these patients were treated with IVIG, 2 were treated with prednisone and IVIg, and 1 was treated with prednisone and rituximab. Eight patients (27%) had both PRCA and autoimmune hemolytic anemia (AIHA), and 1 patient (3%) had concomitant PRCA and immune thrombocytopenia (ITP). Of the 27 patients for whom we have treatment data, 10 required only one treatment regimen and 17 required 2-6 treatment regimens, with two patients requiring splenectomy for concomitant AIHA. The median survival of CLL patients after a diagnosis of PRCA was 4.6 years (Figure 1). There was no difference in survival between PRCA cases with and without parvovirus (p=0.92). Compared to newly diagnosed CLL Rai stage III/IV patients, there was no difference in OS (p=0.53). There was no statistically significant difference in survival from an AID cytopenia diagnosis when comparing PRCA, ITP, AIHA, and Evans syndrome (Figure 1; median 5 years for PRCA and 6 years for other groups; p=0.17). Conclusion: PRCA is a rare complication in CLL, occurring in <1% CLL patients seen at our institution over the past 20 years. Parvovirus was the etiologic factor in ~25% of patients and did not influence outcomes. There appears to be no significant difference in outcomes of PRCA patients compared to patients with other AID in CLL. Table 1. Patient Characteristics Characteristic N [range] or (%) Number of patients 30 Males 21 (70) IGHV status* · Unmutated · Mutated 12 (92) 1 (8) FISH results at CLL diagnosis* · 17p- · 11q- · Trisomy 12 · 13q- · Negative 0 (0) 1 (10) 3 (30) 3 (30) 3 (30) At PRCA Diagnosis Median age 67 [40 - 81] Median hemoglobin (gm/dL)* [normal range 12-15.5 gm/dL] 8.2 [3.5 - 10.8] Median absolute reticulocyte count (x 109/L)* [normal range: 38 - 113 x 109/L] 3.5 [0.0 - 25.3] Patients treated for CLL prior to PRCA diagnosis 25 (83) Etiology of PRCA Parvovirus (n = 24) 6 (25) Therapy-related: · Fludarabine · Alemtuzumab/rituximab · Pentostatin/cyclophosphamide/rituximab 3 (10) 1 (3) 1 (3) Autoimmune (neither therapy nor parvovirus related) 19 (63) Initial Therapy of Non-Parvovirus Related PRCA Steroids alone 2 (8) Steroids and Rituximab 3 (13) Steroids in combination with: · IVIG, Chlorambucil · Cyclosporine · Rituximab, IVIg · IVIg, splenectomy 1 (4) 2 (8) 1 (4) 1 (4) Monoclonal Ab alone · Alemtuzumab · Rituximab 1 (4) 4 (17) Cyclosporine 1 (4) Cyclophosphamide 2 (8) RCP (Rituxan, Cyclophosphamide, and prednisone) 2 (8) IVIg 1 (4) Not available 3 (13) *Not available for all patients Figure 1. Figure 1. Disclosures Ding: Merck: Research Funding. Kay:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Tolero Pharma: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Shanafelt:Cephalon: Research Funding; Hospira: Research Funding; Glaxo-Smith-Kline: Research Funding; Genentech: Research Funding; Jannsen: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding; Pharmacyclics: Research Funding.

Abstract Background: It is well established that the incidence of skin cancers in patients with CLL are significantly elevated compared to age- and sex- matched controls. However, little is known about the characteristics of CLL patients who develop skin cancer. Herein, we evaluate the associations of CLL clinical and prognostic characteristics, along with UV radiation exposure, with risk of first skin cancer following CLL diagnosis. Methods: Newly diagnosed CLL patients from Minnesota, Iowa, and Wisconsin were enrolled in the Mayo Clinic case-control study from 2002-2015 and systematically followed in the Iowa/Mayo Lymphoma SPORE. Clinical and prognostic CLL data were obtained from the Mayo Clinic CLL database, and skin cancer clinical data were abstracted from medical records using a standard protocol. The CLL international prognostic index (CLL-IPI) was computed using a weighted average of five independent CLL prognostic factors (IGHV mutational status, serum b2-microglobulin, Rai stage, age, and FISH 17p deletion/TP53 status). Self-reported history of midday sun exposure at various ages (birth to age 12; 13 to 21 years; 22 to 40 years, and 41+ years) was obtained from a risk factor questionnaire. For each age, we asked the extent of mid-day sun as: practically no exposure (under 3 hours per week), little exposure (4-7 hours per week), moderate exposure (8 to 14 hours per week) and extensive exposure (15+ hours per week). Midday sun exposure was modeled as an ordinal covariate. To evaluate associations with risk of skin cancer following CLL diagnosis, we calculated time from date of CLL diagnosis to date of first skin cancer, death, or last known follow-up. We used Cox regression analysis to estimate hazard ratios (HRs) and 95% CIs. CLL treatment was considered a time-dependent covariate. Results: Among 846 CLL patients enrolled, the median age at diagnosis was 63 years (range 28-91), 68% were male, 7% had Rai stage III-IV at diagnosis. Based on the CLL-IPI, 42% were categorized as low risk, 33% as intermediate risk, and 25% as high or very-high risk. 109 CLL cases (13%) had one or more reported skin cancers at or prior to CLL diagnosis. Melanoma was observed in 19 (2%) cases and non-melanoma was in 90 (11%) cases. At a median follow-up of 7 years from CLL diagnosis, 165 patients (20%) had one or more skin cancers after CLL diagnosis. Among these patients, 49 had skin cancer before CLL diagnosis. The most frequent skin cancer was squamous cell carcinoma (59%), followed by basal cell (31%), melanoma (5%), and Merkel cell (1%). 552 (65%) of the 846 patients returned a questionnaire. Significant associations of clinical and prognostic characteristics with risk of first skin cancer were observed for age (HR=1.35 per 10 year increase, 95% CI=1.17-1.56, P<0.001), male sex (HR=1.38, 95% CI 0.98-1.96, p=0.07), prior history of skin cancer (HR=4.19, 95% CI=2.98-5.88, P<0.001), and CLL-IPI (HR=1.26, 95% CI= 1.03-1.54, P=0.026, after adjusting for age, sex, and prior skin cancer). Of note, the risk of first skin cancer in those CLL patients categorized as very high via CLL-IPI had 2.28 fold risk (95% CI 1.02-5.11). Midday sun exposures for each of the ages considered showed no evidence of association with risk of first skin cancer (all P>0.05). 50 CLL patients were treated prior to first skin cancer following CLL diagnosis; we observed no evidence of association between treatment and risk of first skin cancer (HR=1.44, 95% CI= 0.93-1.92, P=0.12). Conclusion: CLL patients who are at an increased risk of skin cancer following CLL diagnosis are those who either have had a prior history of skin cancer or a more aggressive CLL disease at diagnosis, according to CLL IPI. Routine skin cancer screening is currently recommended for CLL patients. Our data suggest that more frequent screening would be particularly important among patients with aggressive CLL and who have a prior history of skin cancer. Unexpectedly, we found no evidence of association of skin cancer risk with UV radiation following CLL diagnosis or with CLL treatment. Further investigation is needed to determine whether other factors increase the risk of skin cancer following CLL diagnosis. Disclosures Shanafelt: Genentech: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding.