scholarly journals Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort

Haematologica ◽  
2018 ◽  
Vol 104 (5) ◽  
pp. e208-e210 ◽  
Author(s):  
Maria Winqvist ◽  
Per-Ola Andersson ◽  
Anna Asklid ◽  
Karin Karlsson ◽  
Claes Karlsson ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Real World ◽  
Lymphocytic Leukemia ◽  
Compassionate Use

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

Blood ◽  
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.

scholarly journals Trends in the risk of second primary malignancies among survivors of chronic lymphocytic leukemia

2019 ◽  
Vol 9 (10) ◽  
Author(s):  
Vivek Kumar ◽  
Sikander Ailawadhi ◽  
Leyla Bojanini ◽  
Aditya Mehta ◽  
Suman Biswas ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hematological Malignancies ◽  
Lymphocytic Leukemia ◽  
Second Primary ◽  
Standardized Incidence Ratio ◽  
Improved Outcomes ◽  
History Of ◽  
Second Primary Malignancies

Abstract With improving survivorship in chronic lymphocytic leukemia (CLL), the risk of second primary malignancies (SPMs) has not been systematically addressed. Differences in risk for SPMs among CLL survivors from the Surveillance, Epidemiology, and End Results (SEER) database (1973–2015) were compared to risk of individual malignancies expected in the general population. In ~270,000 person-year follow-up, 6487 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI:1.17–1.23). The higher risk was for both solid (SIR 1.15; 95% CI:1.12–1.18) and hematological malignancies (SIR 1.61; 95% CI:1.5–1.73). The highest risk for SPMs was noted between 2 and 5 months after CLL diagnosis (SIR 1.57; 95% CI:1.41–1.74) and for CLL patients between 50- and 79-years-old. There was a significant increase in SPMs in years 2003–2015 (SIR 1.36; 95% CI:1.3–1.42) as compared to 1973–1982 (SIR 1.19; 95% CI:1.12–1.26). The risk of SPMs was higher in CLL patients who had received prior chemotherapy (SIR 1.38 95% CI:1.31–1.44) as compared to those untreated/treatment status unknown (SIR 1.16, 95% CI:1.13–1.19, p < 0.001). In a multivariate analysis, the hazard of developing SPMs was higher among men, post-chemotherapy, recent years of diagnosis, advanced age, and non-Whites. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL.

scholarly journals How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia

Blood ◽  
2019 ◽  
Vol 133 (12) ◽  
pp. 1298-1307 ◽  
Author(s):  
Deborah M. Stephens ◽  
John C. Byrd
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Real World ◽  
Lymphocytic Leukemia ◽  
Targeted Therapeutics ◽  
Therapeutic Approaches ◽  
Therapeutic Alternatives

Abstract Chronic lymphocytic leukemia (CLL) therapy has changed dramatically with the introduction of several targeted therapeutics. Ibrutinib was the first approved for use in 2014 and now is used for initial and salvage therapy of CLL patients. With its widespread use in clinical practice, ibrutinib’s common and uncommon adverse events reported less frequently in earlier clinical trials have been experienced more frequently in real-world practice. In particular, atrial fibrillation, bleeding, infections, and arthralgias have been reported. The management of ibrutinib’s adverse events often cannot be generalized but must be individualized to the patient and their long-term risk of additional complications. When ibrutinib was initially developed, there were limited therapeutic alternatives for CLL, which often resulted in treating through the adverse events. At the present time, there are several effective alternative agents available, so transition to an alternative CLL directed therapy may be considered. Given the continued expansion of ibrutinib across many therapeutic areas, investigation of the pathogenesis of adverse events with this agent and also clinical trials examining therapeutic approaches for complications arising during therapy are needed. Herein, we provide strategies we use in real-world CLL clinical practice to address common adverse events associated with ibrutinib.

Demographics, Treatment Patterns, Safety, and Real-World Effectiveness in Patients ≥70 Years of Age with Chronic Lymphocytic Leukemia Receiving Bendamustine with or without Rituximab,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3914-3914
Author(s):  
Kathryn S. Kolibaba ◽  
Avani D. Joshi ◽  
James A. Sterchele ◽  
Michael Forsyth ◽  
Erin Alwon ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
Real World ◽  
Progressive Disease ◽  
Lymphocytic Leukemia ◽  
Social Security Administration ◽  
Grade 3

Abstract Abstract 3914 Background Bendamustine is a unique, well-established alkylating agent with multifaceted actions leading to cancer cell death in several hematologic malignancies. In a phase 3 trial in treatment-naïve patients with chronic lymphocytic leukemia (CLL), rates of response and progression-free survival (PFS) were significantly superior to those for chlorambucil [Knauf WU et al. J Clin Oncol 2009;27:4378–84]. In vitro studies have found that the cytotoxic activity of bendamustine against CLL-derived cell lines is synergized by rituximab, an anti-CD20 monoclonal antibody [Demidem A et al. Cancer Biother Radiopharm 1997;12:177–86]. Older patients may demonstrate lower tolerance to chemoimmunotherapy [Foon KA & Hallek MJ. Leukemia 2010;24:500–11], and published clinical data on bendamustine-rituximab in CLL are scarce. Thus, this retrospective study sought to characterize a population of adults ≥70 years old with CLL receiving bendamustine with or without rituximab, describe patterns of care, assess data on real-world effectiveness outside of the controlled environment of clinical trials [Waldthaler C et al. Wien Klin Wochenschr 2011;123:269–275], and assess safety. Methods Records were extracted from US Oncology iKnowMed (iKM) record databases for all outpatients ≥70 years old with CLL (but no other tumor) and more than 1 visit recorded (but not enrolled in clinical trials) who received bendamustine between March 2008 and May 2010. Patients were classified as treatment-naïve or relapsed (including ≥ second-line therapy). To ascertain mortality, the iKM data were supplemented with vital-status data from the Social Security Administration Death Index. The overall response rate (ORR) included complete response (CR), nodal partial response (nPR), and partial response (PR). PFS was time from first bendamustine dose to progressive disease (change in line of therapy), relapse, or death from any cause. Data from patients who did not die, or had no progression and were lost to follow-up were censored. Results Among 91 patients, the mean (SD) initial age at beginning of first therapy was 77.4 (5.6) years, age at diagnosis was 70.3 (6.5) years, and 63.7% were male. Of the 16 (17.6%) treatment-naïve patients, 10 had received bendamustine monotherapy and 6 received bendamustine-rituximab. Of the 75 (82.4%) relapsed patients, 20 had received bendamustine monotherapy and 55 received bendamustine-rituximab. The observed ORR for treatment-naïve patients was 56.3% (n=9; 18.8% CR, 37.5% PR, and 0 nPR); 6.3% had progressive disease. For relapsed patients, the ORR was 58.7% (n=44; 13.3% CR, 44.0% PR, and 1.3% nPR); 24.0% had progressive disease. Among patients with data, median PFS for 16 treatment-naïve patients has not been reached (median follow-up 15.1 months); for 73 relapsed patients, PFS was 18.4 months. Kaplan-Meier estimates for PFS over time for each group are shown in the Figure. No unexpected toxicities were seen. The overall rate of blood/bone marrow toxicities (all grades) was 40.7%; grade 3/4 rates were 18.8% for treatment-naïve patients and 25.3% for relapsed patients. Other grade 3/4 adverse events (AEs) included upper respiratory infection and abdominal pain in the relapsed group as well as rash and sepsis in both groups (n=1 each). The most frequent nonhematologic AEs (≥5%, any grade) were fatigue (33.0%), weight loss (11.0%), infection (9.9%; herpes zoster [n=2]; cryptococcal sepsis, Klebsiella sepsis, and pneumonia [n=1 each]), gastrointestinal (8.8%), fever (8.8%), pulmonary (6.6%), and rash (5.5%). o = data censored. Conclusions In this retrospective chart review of patients ≥70 years old with CLL, bendamustine, either alone or with rituximab, provided meaningful response rates and was generally well tolerated. The length of PFS of both treatment-naïve and relapsed patients was clinically meaningful. This research was sponsored by and conducted in collaboration with Cephalon, Inc., Frazer, PA. Disclosures: Sterchele: Cephalon, Inc.: Employment. Beygi:Cephalon, Inc.: Employment. Kennealey:Cephalon, Inc.: Employment.

scholarly journals Other Cancers in Long-Term Survivors of Chronic Lymphocytic Leukemia: Incidence and Prognostic Relevance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3323-3323 ◽  
Author(s):  
Lorenzo Falchi ◽  
Michael Keating ◽  
Susan Lerner ◽  
Xuemei Wang ◽  
Kplola Y Elhor Gbito ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Observation Time ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Prognostic Impact ◽  
Long Term Survivors

Abstract Introduction. The clinical course of chronic lymphocytic leukemia (CLL) is mostly indolent. About one third of the patients are managed with lifelong watch-and-wait (WW) and those who receive therapy often achieve a durable remission. As a result, the majority of patients with CLL will live with their disease for long periods of time, and be exposed to several complications, including the occurrence of other cancers (OC). Patients with CLL may have an increased incidence in OC. Published reports indicate an incidence of 3-27%, mostly in treated patients, however, very little is known on OC in patients with CLL not requiring therapy. Furthermore, observation time in published studies is limited to <5 years, and the incidence of OC in patients followed for longer than 10 years is unknown. We, therefore, studied the incidence and prognostic impact of OC in treatment-naïve patients with CLL followed for ≥10 years. Methods. We reviewed our database and identified all patients with CLL untreated at the time of referral. We selected long-term survivors (LTS), defined as patients with a follow-up ≥10 years, and analyzed the incidence and prognostic impact of OC in this population. Non-melanoma skin cancers were excluded since these were diagnosed and treated promptly in virtually all cases and felt not to have prognostic impact. Standardized incidence ratios (SIR) were calculated for OC occurring after the diagnosis of CLL that were reportable to the Surveillance, Epidemiology and End Results program.The estimated overall survival (OS) according to the presence of OC was plotted considering OC as a time-dependent covariate. Results. We identified 797 LTS of CLL seen at our institution between 1957 and 2003. Median age was 56 years (24-88). 57% of patients were males. Median follow-up for the entire population is 154 months (120-485). We recorded 383 OC in 286 (36%) patients. 76/286 (26%) patients had >1 OC (62 had 2 OC, 10 had 3, 2 had 4, 1 had 5 and 1 had 6).The firstOC preceded or was diagnosed concomitantly with CLL in 100 patients (35%), while in the remaining 186 (65%) it occurred later during the course of the disease. 570 patients (71%) required treatment for CLL. Median time to treatment was 18 months (0-454). In treated patients, the cumulative frequency of OC was 205/570 (36%) and in WW patients 81/227 (36%). The SIR for all OC was 1.2 (p = .034). Males and patients younger than 60 years had a significantly higher incidence of OC (SIR 1.31 and 1.27, respectively). Among OC types, secondary leukemia, melanoma and head and neck cancers had the highest observed-to-expected ratio. Surprisingly, lung, digestive tract, and bladder cancer had a lower-than-expected incidence (table). 474 patients (59%) are alive. 222/570 (39%) treated patients and 101/227 (44%) WW patients have died. The median OS was longer in patients without OC (279 months) vs. those with OC (189 months). Independent predictors of shorter survival in multivariate analysis included higher creatinine, the presence of OC, and older age. Discussion. This is the first study to address the incidence of OC in LTS of CLL, including WW patients. In our population, the frequency of OC is similar in treated and WW patients. Although the incidence of OC in LTS of CLL is higher compared to matched general population, the incidence of lung, digestive and bladder cancer is lower than expected. Reasons of this finding remain to be identified.The occurrence of OC is an independent predictor of shorter survival, thus constituting a relevant competing risk of mortality in LTS of CLL. Variable Observed Expected Person-years SIR (O/E) 95% CI for O/E P -value Overall 148 123.34 10956 1.20 1.01 – 1.40 0.034 Male 96 73.4 5885 1.31 1.06 – 1.58 0.013 Female 52 49.93 5071 1.04 0.78 – 1.36 0.67 Age ≥60 years 60 54.33 3416 1.10 0.84 – 1.42 0.44 Age <60 years 88 69.02 7540 1.27 1.02 – 1.57 0.027 OC type Prostate 28 25.92 11809 1.08 0.72 – 1.56 0.64 Lung 20 29.08 11942 0.69 0.42 – 1.06 0.04 Breast 19 18.60 11855 1.02 0.62 – 1.59 0.96 Melanoma 16 4.23 11926 3.78 2.16 – 6.14 0.00 Leukemia 15 4.27 12009 3.51 1.96 – 5.79 0.00 Non-Hodgkin lymphoma 6 6.38 11996 0.94 0.34 – 2.05 1.00 Digestive 16 40.4 11937 0.40 0.23 – 0.64 0.00 Colon 8 19.42 11972 0.41 0.18 – 0.81 0.006 Pancreas 2 4.83 12024 0.41 0.05 – 1.49 0.18 Rectal 3 8.69 12011 0.34 0.07 – 1.00 0.05 Bladder 3 11.18 11993 0.27 0.05 – 0.78 0.009 Multiple Myeloma 2 1.98 12012 1.01 0.12 – 3.64 1.00 Lip 3 0.02 12015 150 31.00 – 438.5 0.00 Salivary gland 2 0.03 12026 66.66 8.00 – 240.06 0.00 Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document