Preliminary Results of a Phase II Open-Label, Randomized Study of the BH3 Mimetic Protein Navitoclax (ABT-263) with or without Rituximab for Treatment of Previously Untreated B-Cell Chronic Lymphocytic Leukemia

Abstract Abstract 190 Introduction: Overexpression of Bcl-2 in Chronic Lymphocytic Leukemia (CLL) is associated with enhanced CLL-cell resistance to spontaneous or chemotherapy-induced apoptosis. The BH3 mimetic protein navitoclax (ABT-263) specifically inhibits Bcl-2, and related proteins Bcl-xL and Bcl-w, and can induce apoptosis of CLL cells in vitro. Phase I evaluation in relapsed/refractory CLL patients demonstrated 35% overall response rate (Roberts, 2012). Dose-limiting thrombocytopenia due to Bcl-xL inhibition was mitigated using a lead-in dosing schedule to allow the bone marrow to achieve a compensatory increase in platelets prior to dose escalation to the MTD of 250 mg. Based on the promising single-agent data, a Phase II trial randomized trial compared the safety, pharmacokinetics, and biologic activity of treatment with navitoclax and rituximab (RTX) versus RTX alone. Methods: Patients with CLL who required initial treatment according to iwCLL criteria (Hallek et al, 2008) were stratified by Binet stage and high-risk cytogenetic features (17p deletion and/or 11q deletion), and randomized 1:1:1 to receive RTX weekly for 8 wks (375 mg/m2 wk 1, 500 mg/m2 wks 2–8) (Arm A), or RTX for 8 wks plus navitoclax daily for 12 wks (250 mg/day following a 7–14 day lead-in period of 100 mg/day) (Arm B), or RTX for 8 wks plus navitoclax daily as in Arm B, but continued treatment with navitoclax until disease progression, relapse, or unacceptable toxicity (Arm C). Arm A to Arm B crossover was permitted. Response rate was assessed by iwCLL CLL response criteria at week 12, and every 12 weeks during follow-up. The study was stopped after the last patient had completed ≥ 12 weeks of treatment and week-12 response assessment. Results: Baseline characteristics and prognostic factors for the 118 randomized patients were generally balanced among the three treatment arms. Median age was 63 years (range 38–94), and 55% were Binet stage B+C. Median baseline lymphocyte count was 53,000 mm3 (range 7,000–552,000/mm3). FISH analyses identified higher than expected rates of deletion of 11q or 17p in the CLL cells of 32% or 28% of patients, respectively. Median time on study was 32 weeks overall (24 wks for Arm A, 33 wks Arm B, and 44 wks Arm C). AEs of Grade 3–4 that were more common (> 5% greater) in a navitoclax-treated arm compared with the RTX arm included thrombocytopenia, neutropenia, leukopenia, anemia, GI symptoms (diarrhea, abdominal pain), chills, fatigue, ALT/AST/bilirubin elevations, and infusion-related reactions (to RTX). Thrombocytopenia, neutropenia, and hepatic enzyme elevations were generally reversible when navitoclax was stopped and/or dose-reduced; however, 12 patients (15%) discontinued navitoclax due to laboratory abnormalities (9 due to ALT elevations). Neutropenia responded to growth factors. One serious event of epistaxis occurred related to the thrombocytopenia. Two deaths occurred on study, one on the RTX-only arm due to a pulmonary embolus and one on Arm B due to hypotension and dyspnea related to a severe RTX infusion reaction. Investigator-assessed objective response (CR and PR) rate was 35% for Arm A, 55% for Arm B (p=0.19 vs A), and 70% for Arm C (p=0.0034 vs A). All responses were PRs except for 2 CRs in Arm C. All responses were confirmed by CT (and BM for CR) ≥ 8 wks after clinical response assessment. While the presence of 17p deletion appeared to result in a lower response rate to RTX alone (Arm A, ORR 18%, 2/11 pts), it did not appear to affect the response to ABT-263 and RTX (Arm B, ORR 73%, 8/11 pts); Arm C, ORR 50%, 5/10 pts. Limited PFS results appeared consistent with the responses by arm, with a longer PFS associated with the longer duration of ABT-263 treatment on Arm C; however, the magnitude of PFS differences could not be precisely quantified due to the limited follow-up and patient number. Preliminary pharmacokinetic analysis did not detect any drug interaction between navitoclax and RTX. Conclusions: Navitoclax in combination with RTX weekly × 8 was generally well-tolerated as initial therapy for CLL patients and demonstrated greater clinical activity than treatment with RTX alone as well as responses in patients with 17p deletion. The preliminary results of this study indicate that a BH3-mimetic inhibitor of Bcl-2 could be highly effective when used in combination with RTX for treatment of patients with CLL. Disclosures: Eradat: Genentech: Research Funding. Off Label Use: BH3 Mimetic Protein Navitoclax (ABT-263). Catalono:Genentech: Consultancy. Kipps:Genentech: Research Funding. Zheng:Genentech: Employment. Yalamanchili:Genentech: Employment. Sahasranaman:Genentech: Employment. Hurst:Genentech: Employment. Ho:Genentech: Employment.

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Risk Factors Associated with Richter's Transformation in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-112442 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1697-1697 ◽

Cited By ~ 1

Author(s):

Yasmin Ben-Dali ◽

Mariam Hussein Hleuhel ◽

Michael Asger Andersen ◽

Christian Brieghel ◽

Erik Clasen-Linde ◽

...

Keyword(s):

Risk Factors ◽

Chronic Lymphocytic Leukemia ◽

Incidence Rate ◽

Cumulative Incidence ◽

Research Funding ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Increased Risk ◽

Binet Stage

Abstract Background Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Roughly, 2-10 % of patients with CLL develop RT most often as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL). Aim This study aimed to assess the incidence rate and risk factors for RT for patients with CLL in a nationwide cohort. Furthermore, we want to assess prognostic risk factors for patients with RT. Methods All patients diagnosed with CLL in Denmark between 2008 and 2016 were included in this study. Clinical data was retrieved from the Danish National CLL Registry (DCLLR), whereas all histologically verified DLBCL, HL and/or transformation diagnoses for patients with CLL were retrieved from the Danish National Pathology Registry. Patients were followed from date of CLL diagnosis until date of RT, death or end of follow-up, whichever came first. The time to RT was estimated as cumulative incidence considering death as a competing risk. Stepwise Cox analysis with backward elimination was applied to identify independent risk factors for RT in patients with CLL. Results A total of 3771 CLL patients were identified, and followed for 14165 person-years. With a median follow-up of 4.3 (IQR (2.4;6.6)) years, 120 (3%) CLL patients had a transformation diagnosis, of which 4 patients were excluded due to misdiagnosis. DLBCL accounted for 78/116 (67%) cases, HL for 15/116 (13%) cases and one patient presented with both DLBCL and HL. In the remaining 22/116 (19%) cases the subtype of the transformation was either unspecified or unclassified RT. The median time to RT was 3.4 (IQR (1.8;5.7)) years from CLL diagnosis and the median overall survival (OS) after development of RT was 4.9 (IQR (0.7;8.4)) years. The cumulative incidence of RT, calculated by Aalen-Johansen estimator, at 5 and 8 years post-CLL diagnosis were 3.3% and 7.9% respectively (Figure 1). The annual crude incidence rate of RT was approximately 0.7% per year for all CLL patients. In all, 918 (24%) patients received CLL-related treatment, of whom 59 (6.4%) patients developed RT, resulting in a cumulative incidence of RT of 7% after 5 years and 11% after 8 years. At the time of CLL diagnosis, patients treated for CLL prior to RT diagnosis had a worse median OS (1.49 years) compared to RT patients who were untreated for CLL (6.16 years). In the univariate analysis, RT was significantly associated with male gender, advanced Binet stage (B or C), unmutated IGHV status (CLL-U), elevated beta-2-microglobulin (>3.5 mg/L) and elevated lactate dehydrogenase (>205 U/L). Of cytogenic aberration, deletion 13q (del(13q)) had a protective effect on the risk of RT, whereas deletion 11q (del(11q)) and deletion 17p (del(17p)) increased the risk. In the multivariable model, advanced Binet stage (HR 2.86 (1.82;4.51), p<0.001), del(17p) ((HR 3.74 (2.12;6.61), p<0.001) and CLL-U ((HR 2.30 (1.46;3.63), p<0.001) showed an independent correlation with development of RT. ZAP70 and CD38 were excluded from statistical analyses due to incomplete data and high inter-laboratory variation. Among RT patients, CLL-U, trisomy 12 and del(17p) at CLL diagnosis as well as ECOG Performance Status (PS) (i.e. PS≥1) at time of RT diagnosis correlated with poor OS in univariate analysis. Both del(17p) and PS≥1 were independently associated with an increased risk of death in a multivariable analysis (HR 2.9, (1.1;7.7), p=0.04 and HR 3.0, (1.0;3.1), p=0.05, respectively). Conclusions To the best of our knowledge, we here report the largest study on RT assessing nationwide data of consecutive patients diagnosed with CLL. The incidence of RT in this unselected population was 3.3% after 5 years while the median OS for patients from time of RT was 4.9 years. Advanced Binet stage, del(17p) and CLL-U were significantly and independently associated with an increased risk of RT. Del(17p) at CLL diagnosis and PS≥1 at RT diagnosis were significant predictors for death for patients with RT. For patients diagnosed with RT prior to any CLL treatment, a less severe disease course with a median OS of 6.16 years was demonstrated. Contrary, the median OS for patients receiving prior CLL treatment was 1.49 years. Thus, assessment of different treatment options for patients developing RT based on whether they have received prior CLL treatment or not is warranted. Figure 1. Figure 1. Disclosures Ben-Dali: Rigshospitalet: Research Funding. Hleuhel:Rigshospitalet: Research Funding. Brieghel:Arvid Nilson's Fund: Research Funding; Rigshospitalet, Denmark: Research Funding. Niemann:Danish Cancer Society: Research Funding; Novo Nordisk Foundation: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy.

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Results of a Phase II of Low-Dose Fludarabine and Cyclophosphamide Combined with Standard Dose Rituximab (FCR-LITE) in Elderly, Untreated Patients with Chronic Lymphocytic Leukemia (CLL): The Israeli CLL Study Group Experience

Blood ◽

10.1182/blood-2018-99-111681 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5566-5566

Author(s):

Tamar Tadmor ◽

Yair Herishanu ◽

Andrei Braester ◽

Osnat Bairey ◽

Ariel Aviv ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Elderly Patients ◽

Phase Ii ◽

Research Funding ◽

Low Dose ◽

Lymphocytic Leukemia ◽

Novel Agents ◽

Categorical Variables ◽

Positive Direct

Abstract Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. Despite the development of novel agents and new monoclonal antibodies, FCR still remains the combination chemoimmunotherapy of choice for fit patients with CLL, yielding the longest durations of remission. When this study was first started, no established chemo-immunotherapy regimen was unanimously regarded as standard therapy for less fit elderly patients with CLL; this category of patients had clearly been underrepresented in clinical trials utilizing chemo - or chemo-immunotherapy. Patients and Methods We conducted a single arm, phase II trial to assess the efficacy and toxicity of low dose fludarabine and cyclophosphamide in combination with a regular dose of rituximab (FCR-LITE) in elderly patients with therapy naïve CLL. Our intention was to deliver 6 courses of Fludarabine which was given intravenously (IV) at 12.5 mg/m2/day together with IV cyclophosphamide 150 mg/m2/day for 3 consecutive days. IV rituximab was administered on day 0 of cycle 1 at a dose of 375 mg/m2, and at 500 mg/m2 on day 1 of cycles 2-6. Categorical variables were compared in patients with and without CR using chi-square test or Fisher's exact test and continuous variables were also compared using Mann Whitney test. Duration of follow-up was recorded using reverse censoring method. Kaplan Meier curve was used to establish PFS during clinical follow-up. All statistical tests were two sided. P<0.05 was considered as statistically significant. Results Forty patients treated with FCR-LITE were included in the efficacy analysis. The median age of the entire cohort was 72.7 years (range, 65.0 to 85.0), and 69% were male. The mean number of treatment cycles was 5.1 (range 1-6). The overall response rate was 67.5% (95% CI, 50.9%-81.4%); 17 patients (42.5%) achieved CR and 10 (25.0%) PR. Median PFS was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period. Reduced cumulative doses of FCR and fewer courses of treatment were both associated with lower CR rate. Hematological toxicities were the most common side effects encountered; grade-3/4 neutropenia occurred in twenty (47.6%) patients, only six (14.3%) developed neutropenic fever. Positive direct antiglobulin test (DAT), was seen in 11 patients but none of them developed autoimmune hemolytic anemia (AIHA) during treatment; two patients (4.8%) progressed to Richter's transformation and two (4.8%) had second malignancies (lung and metastatic colon carcinoma). Conclusion FCR-LITE is effective and safe for treating elderly patients with therapy-naïve CLL. It has the advantage of being both time and cost effective. In an era of novel agents, it can still be considered as suitable frontline treatment for fit elderly patients with CLL. This research was supported by roche pharmaceuticals Table. Table. Disclosures Tadmor: ABBVIE: Consultancy; ROCHE: Research Funding; NOVARTIS: Consultancy; JNJ: Consultancy; PFIEZER: Consultancy. Herishanu:JNJ: Consultancy; ABBVIE: Consultancy; ROCHE: Research Funding. Bairey:ROCHE: Research Funding; AbbVie: Consultancy; Jansen: Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Rahimi-Levene:ABBVIE: Consultancy. Fineman:ABBVIE: Consultancy; JNJ: Consultancy. Ruchlemer:JNJ: Consultancy; ABBVIE: Consultancy. Shvidel:JNJ: Consultancy; ROCHE: Consultancy, Research Funding; ABBVIE: Consultancy, Research Funding. Polliack:ABBVIE: Consultancy; ROCHE: Research Funding.

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Rituximab Plus Chlorambucil In Patients with CD20-Positive B-Cell Chronic Lymphocytic Leukemia (CLL): Final Response Analysis of An Open-Label Phase II Study

Blood ◽

10.1182/blood.v116.21.697.697 ◽

2010 ◽

Vol 116 (21) ◽

pp. 697-697 ◽

Cited By ~ 15

Author(s):

Peter Hillmen ◽

John G. Gribben ◽

George A. Follows ◽

Donald Milligan ◽

Hazem A. Sayala ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Phase Ii Study ◽

Lymphocytic Leukemia ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Off Label

Abstract Abstract 697 Introduction: Despite the increasing use of combination therapy with rituximab, fludarabine and cyclophosphamide (R-FC) for chronic lymphocytic leukemia (CLL), a significant proportion of patients (pts) are not suitable or eligible for such intensive chemotherapy due to co-morbidity and/or age. In those pts considered unfit for R-FC, chlorambucil (Chl) remains a widely used first-line therapy. However, overall responses rates with Chl are relatively modest with very few complete remissions and therefore more effective treatment options are required for this patient group. In this multi-centre Phase II study we evaluate the feasibility of adding R to Chl and assess response rate compared to single agent Chl. Methods: One hundred previously untreated CLL pts requiring therapy according to iwCLL criteria received R (day 1; 375 mg/m2 i.v. cycle 1, 500 mg/m2 cycles 2–6) plus Chl (days 1–7; 10mg/m2/day p.o.) every 28 days for 6 cycles. A further 6 cycles of Chl alone was permitted in pts with continuing clinical response at 6 cycles. Efficacy data were compared to matched historic data from the UK LRF CLL4 trial, which treated pts between 1999 and 2004 with Chl-monotherapy at the same dose as used in this study. Each patient of this study was matched to 2 pts treated with Chl in the LRF CLL4 study according to Binet Stage (B or C), VH Mutation (mutated or unmutated), 11q FISH (deleted or not) and age. It should be noted that the CLL4 data was from 1999–2005, while the Chl-R responses were from 2008. Over this time, any improvements in patient response may be due to better care, improved knowledge, different concomitant medications, etc, rather than treatment used. In addition the median age of patients in LRF CLL4 was significantly lower than those treated with Chl-R (66.5 compared with 70 yrs). Results: A total of 100 pts from 12 centres, who had completed the treatment were included in this analysis; median age was 70 years (range 43–86) and 65% were male. To date, 88 pts remain alive and 12 pts have died. Ninety-two pts (92%) had reported an AE by the end of treatment. The most common AEs were: nausea (47 pts), neutropenia (39 pts), lymphopenia (38 pts), fatigue (26 pts), pyrexia (26 pts), leukopenia (21 pts), diarrhoea (20 pts), vomiting (19 pts), anaemia (18 pts) and thrombocytopenia (18 pts). Most AEs reported were Grade 1–2; Grade 3–4 neutropenia occurred in 39% of pts. Infusion-related reactions occurred in 7 pts. Overall, 37% of pts reported a total of 53 serious AEs (SAEs). The most common SAEs were febrile neutropenia (5 pts) and neutropenic sepsis (4 pts). Overall response rate (ORR) on an intent-to-treat analysis was 82% (95% CI, 73.1–89.0), with 9 pts achieving a complete response (CR), 58 pts showing partial response (PR), 15 pts showing nodular PR (nPR) and 11 pts with stable disease (SD). Median PFS to date is 23.5 months. ORR in this study was 16% higher than in the matched subset of Chl pts from the CLL4 study (95% CI, 6.0–26.0%), suggesting improved responses for Chl-R compared with Chl-alone. Conclusions: With a median age of 70 years, the population in this study was noticeably older than that of pts in CLL4 and other large trials in CLL. This study represents a more typical CLL patient population, as often seen in the clinic. These data confirm that in previously untreated CLL pts who are unable to tolerate a more intensive chemotherapy regimen, the combination of R and Chl is an efficacious therapy with an acceptable tolerability profile resulting in a better ORR than Chl monotherapy. Further evaluation of R-Chl in a randomized Phase III study is warranted. Disclosures: Hillmen: F.Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glaxo Smith Kline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is used broadly in this indication at some specific lines of therapy/chemotherapy combinations may be off label in some countries. Dearden:Roche Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kennedy:Roche Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pettitt:Glaxo Smith Kline: Research Funding. Rawstron:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BD Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Honoraria. Pocock:F.Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Blood ◽

10.1182/blood.v128.22.2048.2048 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2048-2048 ◽

Cited By ~ 2

Author(s):

Carlos I. Amaya-Chanaga ◽

Michael Y. Choi ◽

Natalie Nguyen ◽

Elizabeth DeVore ◽

Colin MacCarthy ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Research Funding ◽

Response Rate ◽

Single Agent ◽

Response Assessment ◽

Lymphocytic Leukemia ◽

Multiparameter Flow Cytometry ◽

Phase Ib ◽

Overall Response ◽

Grade 3

Abstract Standard treatment for patients (pts) with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (a first-in-class BTK inhibitor) has shown to be effective in previously untreated (PU) pts including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The response rate could be higher in pts receiving ibrutinib (overall response of 71% and complete response of 13%) but the mobilization of lymphocytes, which is typically asymptomatic, decreases the response rate due to lack of complete fulfillment of iwCLL criteria. Ibrutinib-induced lymphocytosis could be ameliorated by using mAbs like rituximab or obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, and consequently increased the overall response rate. However, there are no data available assessing the combination of ibrutinib and G in the elderly population (> 65 years old) or in those pts < 65 years old where chemotherapy based agents are not indicated. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibrutinib in combination with G for therapy of PU pts with CLL. The study will enroll 32 PU pts with CLL. Pts receive G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibrutinib 420mg po. qd for up to 3 years. All pts receive prophylactic medications (acyclovir, allopurinol and low dose glucocorticoids). Pts will undergo response assessment two months after completion of the study treatment by iwCLL criteria, and will be followed for survival during 3 years until initiation of new treatment for CLL, disease progression, consent withdrawal or death, whichever occurs first. Here we present a preliminary analysis of safety / tolerability with the first 9 pts treated with this regimen. The median age of the pts was 63 years ± 8.6. 78% of the pts had a CIRS > 6, 44% had a Rai stage III-IV and 33% had an ECOG performance >2. The median baseline absolute lymphocyte count (ALC) was 96.6 ± 20.2 x103/mm3. Pts showed the following cytogenetic abnormalities: del(13q) in 67%, trisomy 12 in 22% and del(11q) in 11%. None of these pts showed del(17p). Most adverse events (AEs) were grade 1-2 (94%) without development of dose-limiting toxicities. Only one pt (11%) had a grade 1 G-infusion-related reaction (IRR). We did not observe grade 3-4 IRR. We observed neutropenia (all grades: 33%, grade 3-4: 22%), thrombocytopenia (all grades: 78%, grade 3-4: 11%) and anemia (all grades: 44%). 78% of the pts had a decrease in ALC during the first cycle of treatment and two pts had persistent lymphocytosis up to cycle three. There were no cases of febrile neutropenia. Two pts (22%) had grade 1-2 bleeding (one pt with asymptomatic lower gastrointestinal bleeding and the second pt with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. One pt (11%) developed community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2). Two pts were evaluable for response assessment by iwCLL criteria. One pt achieved a complete remission with MRDpositivein the bone marrow by multiparameter flow cytometry and the other pt had a partial response due to small residual lymph nodes > 1.5 cm. Overall, Ibrutinib-G combination has been well tolerated. All 9 pts have had favorable clinical and hematological responses. We observed a resolution of the lymphocytosis in 78% of the pts during the first cycle of treatment. We did not observe unexpected AEs with this regimen allowing all 9 pts to continue in the study. The most important finding thus far has been the very low rate of IRR, only one pt (11% - grade 1), and the absence of grade 3-4 IRR, suggesting that ibrutinib can strongly mitigate the incidence and severity of IRR with G. Pt enrollment continues and updated information will be presented at the meeting. Disclosures Hilger-Rolfe: Pharmacyclics: Employment; AbbVie: Employment. Kipps:AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

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Lenalidomide and Rituximab Maintenance Therapy after Front-Line Induction Chemoimmunotherapy in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Blood ◽

10.1182/blood-2019-124489 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5470-5470

Author(s):

Julie E Chang ◽

Vaishalee P. Kenkre ◽

Christopher D. Fletcher ◽

Aric C. Hall ◽

Natalie Scott Callander ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Maintenance Therapy ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Second Malignancies ◽

Front Line ◽

First Line ◽

11Q Deletion ◽

Line Chemotherapy

Introduction: Chronic lymphocytic leukemia (CLL) is incurable with standard therapy. With first-line chemotherapy, some patients (pts) may achieve durable remissions of many months/years. Lenalidomide (LEN) has improved progression-free survival (PFS) when given as maintenance (MNT) therapy after front-line chemotherapy (CALGB10404, CLLM1). The combination of LEN + rituximab (LR) has activity in relapsed CLL, hypothesizing benefit as MNT therapy after first-line chemotherapy. Methods: Adult pts ≥18 years with previously untreated CLL received induction bendamustine (B) 90 mg/m2 IV days 1 & 2 and rituximab (R) IV day 1 (375 mg/m2 cycle 1, then 500 mg/m2 cycles 2-6) for 6 treatment cycles (as few as 4 cycles allowed). MNT therapy with LR was initiated within 12 weeks after cycle 6, day 1 of BR. Criteria to start LR MNT included: neutrophils ≥1000/microliter (uL), platelets ≥75 K/uL, and creatinine clearance ≥40 mL/min. LEN was administered in 28-day cycles for 24 cycles, initially 5-10 mg daily continuous dosing, later modified to 5-10 mg on days 1-21 of each 28-day cycle in 6/2018 due to neutropenia and second malignancy risk. LEN was reduced to 5 mg every other day for toxicities at 5 mg/day. R 375 mg/m2 IV was given every odd cycle (total of 12 doses). Patients discontinuing LEN for any reason were allowed to continue R MNT per protocol. The primary endpoint is PFS with LR MNT therapy, calculated from the first day of MNT therapy until progressive disease (PD), death, or start of a new therapy. Secondary endpoints are response rate and overall survival. Results: Thirty-four pts have enrolled beginning 11/2013, with follow-up through 6/2019. Median age is 64 years, with 8 pts ≥70 years; 8 women and 26 men. CLL FISH panel is available on all pts: 14 with 13q (as sole abnormality), 9 with 11q deletion, 6 with trisomy 12, 4 with normal FISH panel and 1 with 17p deletion. Heavy chain mutation analysis is available on 11 pts: 8 unmutated, 2 mutated, 1 indeterminate. Thirty-one pts completed 4 (n=2) or 6 cycles of induction BR; 3 pts are receiving induction BR. Twenty-four pts have received MNT LR; 7 did not receive LR for reasons of PD during induction (n=2), infection (n=1), pt preference (n=2), renal insufficiency (n=1), and new carcinoma (n=1). MNT LR was completed in 7 pts; 9 pts are still receiving LR. Fourteen subjects have discontinued protocol therapy, 3 during induction due to PD (n=2) and infection (n=1), and 8 during MNT. Toxicities that led to discontinuation of LR were recurrent infections in 7 pts, including 2 events of PJP pneumonia; 4 pts had recurrent neutropenia with infections; 1 pt had neutropenia without infections. Response is assessable in 31 patients using the International Working Group Consensus Criteria. Best responses to treatment were: partial response 65% (22/34), complete response (CR)/unconfirmed CR 24% (8/34). The median number of MNT cycles received is 16. The dose intensity of LEN across total cycles received (n=278): 5 mg every other day (52.5%), 5 mg/day (43.9%), and 10 mg/day (3.6%). The most common reason for dose reduction or dose holding was neutropenia. Most common Gr 3/4 toxicities (reported as events Gr3/Gr4) during MNT therapy were: neutropenia (20/20), leukopenia (19/4), febrile neutropenia (3/1), and infections (11/-). The majority of Gr3 infections were pneumonia/respiratory (n=5). One event of disseminated herpes zoster occurred. Second malignancies during MNT included: basal cell CA (n=1), squamous cell carcinoma (n=5), and colon cancer (n=1). No unexpected second malignancies were observed in pts receiving LR. Two-year PFS (defined from day 1 of MNT therapy) is 90% (95% confidence interval [CI] 0.78-1), and the median follow-up for 24 patient who started maintenance therapy is 1.79 years (95% CI 1.53-2.7). There have been no deaths. Conclusion: The combination of LR is effective in sustaining remissions after a BR induction in previously untreated CLL, but with frequent neutropenia and infections even at low doses of LEN. Most patients discontinuing MNT did so due to neutropenia and/or infections. A shorter planned interval of MNT LR (i.e., 6-12 months) may confer similar benefit to extended dosing that is more tolerable. Pts at high risk for short remissions after front-line chemotherapy (e.g., unmutated heavy chain status, 11q deletion and/or failure to achieve minimal residual disease after induction) may be the populations for which LR MNT therapy is most appropriate. Disclosures Chang: Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Lenalidomide administered as maintenance therapy for first treatment of CLL/SLL.

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Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2020-143473 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Paula A. Lengerke Diaz ◽

Michael Y. Choi ◽

Eider F. Moreno Cortes ◽

Jose V. Forero ◽

Juliana Velez-Lujan ◽

...

Keyword(s):

Bone Marrow ◽

Side Effects ◽

Chronic Lymphocytic Leukemia ◽

Disease Progression ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Combination Regimen ◽

Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (>5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as <10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

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Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Final Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Blood ◽

10.1182/blood-2019-123630 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3491-3491 ◽

Cited By ~ 1

Author(s):

Alexey Danilov ◽

Habte A Yimer ◽

Michael Boxer ◽

John M Burke ◽

Sunil Babu ◽

...

Keyword(s):

Quality Of Life ◽

Health Status ◽

Chronic Lymphocytic Leukemia ◽

Global Health ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Future Health ◽

Equity Ownership

Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

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The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽

10.1182/blood.v114.22.1661.1661 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1661-1661 ◽

Cited By ~ 6

Author(s):

Brad S Kahl ◽

Hailun Li ◽

Mitchell R Smith ◽

Randy D. Gascoyne ◽

Elisabeth Paietta ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Complete Response Rate ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Complete Response ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

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Heritable Predisposition To Richter Syndrome In Patients With Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v122.21.2867.2867 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2867-2867 ◽

Cited By ~ 3

Author(s):

Sameer A. Parikh ◽

Susan L Slager ◽

Kari G. Rabe ◽

Neil E. Kay ◽

James R Cerhan ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Research Funding ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Chromosome 18 ◽

Richter Syndrome ◽

Increased Risk ◽

Translocation Breakpoints

Abstract Background Approximately 2-8% patients with chronic lymphocytic leukemia (CLL) will transform to diffuse large B-cell lymphoma (DLBCL, Richter syndrome [RS]). Clinical characteristics and molecular markers at the time of CLL diagnosis are associated with the risk of RS; however, there are no data regarding germline genetic variations and the risk of RS. Genomewide association studies (GWAS) have shown several single-nucleotide polymorphisms (SNPs) that are associated with a higher risk of familial CLL. It is not known whether any of these polymorphisms also predispose to RS. Methods Since 2002, all consecutive patients with newly diagnosed (<9 months diagnosis) CLL at Mayo Clinic were offered enrollment into a prospective genetic epidemiology study. Patients completed extensive epidemiologic questionnaires and baseline clinical, laboratory, and biologic data were abstracted using a standard protocol. Genotyping of germline tissue at diagnosis was performed using an Illumina iSelect panel and Affymetrix 6.0 SNP chip. All patients were prospectively and longitudinally followed at defined time-points with systematic collection of data on treatments, second cancers, and RS. All patients with biopsy-proven DLBCL during follow-up were considered to have undergone transformation into RS. Time to RS was calculated from CLL diagnosis date until RS or until last follow-up date for those with no RS. SNPs were modeled in two ways: ordinal and dominant. Cox regression was used to estimate hazard ratio (HR) for individual SNPs with time to transformation. Results Thirteen of the GWAS-discovered SNPs associated with risk of developing CLL were available and genotyped on 620 CLL patients. Median age at diagnosis of CLL was 62 years (range 27-88), and 428 (69%) were male. Three hundred and ten (51%) patients were low (0) Rai stage, 271 (45%) were intermediate (I-II) Rai stage, and 22 (4%) were advanced (III-IV) Rai stage. The immunoglobulin heavy chain gene was unmutated in 189 (40%) patients; 157 (32%) patients expressed ZAP-70, 163 (29%) expressed CD38 and 104 (31%) expressed CD49d. Fluorescence in-situ hybridization (FISH) revealed that 210 (41%) patients had del13q, 90 (18%) patients had trisomy 12, 37 (7%) had del11q, 23 (5%) had del17p and 141 (28%) had no detectable FISH abnormalities. As of last follow-up, 239 (39%) patients received therapy for CLL. After a median follow-up of 5.9 years (range 0-11), 15 (2.4%) patients developed biopsy-proven RS. The median time to RS in these 15 patients was 4.5 years (range 1.0-8.7 years). The ordinal HR for the 13 SNPs tested, their corresponding genes, and p-values are shown in Table 1. Germline polymorphisms in a single SNP, rs4987852, encoding for BCL2 (chromosome 18), was significantly associated with an increased risk of RS (ordinal HR=3.9; 95% CI=1.6-9.8; p-value=0.004). This allele was present in 48/605 (8%) non-transformed CLL patients compared to 4/15 (27%) of patients with RS. Time to RS according to the Kaplan-Meier analysis for rs4987852 is shown in Figure 1. This SNP is located in a region in which t(14;18) translocation breakpoints commonly occur in follicular lymphoma and overexpression of BCL2 leads to an increased incidence of B-cell lymphomas in mice. Conclusion Our results suggest that inherited genetic polymorphisms predispose CLL patients to develop RS. Specifically, SNP (rs4987852) present on the BCL2 gene on chromosome 18 in CLL is associated with an increased risk of transformation to RS. These observations require replication in other CLL cohorts. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

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Renal Disease In Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.5302.5302 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5302-5302 ◽

Cited By ~ 4

Author(s):

Tait D Shanafelt ◽

Kari G. Rabe ◽

Curtis A Hanson ◽

Timothy G. Call ◽

Susan Schwager ◽

...

Keyword(s):

Renal Function ◽

Chronic Lymphocytic Leukemia ◽

Renal Insufficiency ◽

Serum Creatinine ◽

Research Funding ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Disease Course ◽

To Receive

Abstract Background Chronic lymphocytic leukemia (CLL) can effect renal function in a variety of ways including direct infiltration of the kidney, ureteral obstruction by lymphadenopathy, and treatment related tumor lysis syndrome (uric acid nephropathy). Rarely, CLL has also been reported to be associated with light chain nephropathy, renal amyloidosis, membranoproliferative glomerulonephritis (MPGN), granulomatous interstitial nephritis (GIN), and minimal change disease (MCD). Nearly all the data on the effects of CLL on renal function is at the case report level. We systematically evaluated the prevalence of renal insufficiency at diagnosis as well the incidence of acquired renal insufficiency during follow-up in a large cohort of patients with newly diagnosed CLL to more accurately define the effects of CLL on the kidney and its impact on clinical outcomes. Methods Between January 1995 -February 2013, previously untreated CLL patients seen in the Division of Hematology at Mayo Clinic at diagnosis (<12 months) and who had baseline assessment of serum creatinine were included in this analysis. Patients with serum creatinine (Cr) ≥1.5 mg/dL at baseline were classified as having renal insufficiency at diagnosis. Patients who initially had baseline creatinine <1.5 mg/dL but who developed a Cr≥1.5 mg/dL during the course of their disease were considered to have acquired renal insufficiency. Results Existing renal insufficiency at the time of CLL diagnosis: Of 2047 patients who met the eligibility criteria, 153 (7.5%) patients had renal insufficiency (Cr≥1.5 mg/dL) at the time of CLL diagnosis including 15 (0.7%) with a Cr≥3 mg/dL. Renal insufficiency was also more common among men (9.3% vs. 3.9%; p<0.00001), those with advanced stage disease (Rai 0=7.0%; Rai I-II=6.4%, Rai III-IV=20.2%; p<0.0001), and CD49d positive patients (6.8% vs. 3.8%; p<0.038). Patients with renal insufficiency at diagnosis were also older (median age 72.2 vs. 63.9; p<0.0001). No difference in the prevalence of renal insufficiency at diagnosis was observed based on cytogenetic abnormalities detected by FISH or CD38, ZAP-70 or IGHV gene mutation status. Although renal insufficiency at diagnosis was strongly associated with OS on univariate analysis (p<0.001), no association was observed between renal insufficiency and TTT or OS on multi-variate analysis adjusting for age, sex, and Rai stage. Acquired renal insufficiency during CLL disease course: Among the 1894 patients with normal renal function at diagnosis, 304 (16.1%) acquired renal insufficiency (Cr≥1.5 mg/dL) during the course of their CLL disease course including 43 (2.3%) with peak Cr≥3 mg/dL. In addition to age (older) and male sex, a number of CLL disease characteristics were associated with a higher likelihood of acquired renal insufficiency including: IGHV UM (OR=2.0; p=0.0001), unfavorable FISH (del17p- or 11q-; OR=2.0; p=0.001), and being CD49d+ (OR=1.8; p=0.002), ZAP-70+ (OR=1.6; p=0.004), or CD38+ (OR=1.4; p=0.0.032),. Shorter TTT (p<0.001) and OS (P<0.001) was observed among patients with initially normal creatinine who acquired renal insufficiency (Figure 1A and 1B). On MV analysis adjusting for age, sex, and stage at diagnosis, acquired renal insufficiency remained an independent predictor of TTT (OR=1.77; p=0.001) and OS (OR=2.67; p<0.001). Renal insufficiency and therapy selection After median follow-up of 4.5 years (range 0-18.0), 620 of 2047 (30.3%) patients have progressed to require treatment. Patients with renal insufficiency prior to treatment were less likely to receive purine nucleoside analogue based therapy and more likely to receive single agent alkylator based treatment. Conclusions Approximately 1 in every 13 patients (7.5%) with CLL has renal insufficiency at the time of diagnosis and an additional 16.1% acquire renal insufficiency during the course of the disease. The risk of developing renal insufficiency is associated with a variety of CLL B-cell characteristics and is associated with TTT and OS. Data on causes of acquired renal insufficiency is being abstracted and will be presented at the meeting. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Off Label Use: MK2206 in a phase 1 trial of CLL.

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