Outcome of Second Line Treatment in Patients with Chronic Lymphocytic Leukemia Did Not Improve 2002-2013: A Population-Based Study from a Well-Defined Geographic Region

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4166-4166
Author(s):  
Anna Asklid ◽  
Agnes Mattsson ◽  
Einar Björgvinsson ◽  
Maria Winqvist ◽  
Sandra Eketorp Sylvan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
Second Line ◽  
Phase 2 ◽  
Line Therapy ◽  
Time Period ◽  
Grade 3

Abstract Background: Treatment of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) remains challenging. Major progress has been achieved with new agents such as ibrutinib and idelalisib. However relapses still occur with these agents or the treatment has to be withdrawn (Byrd et al, Blood 2015). Several new drugs have been or are currently tested in pivotal, non-controlled phase 2 trials on R/R CLL patients, with the majority of patients on 2nd line therapy following chemoimmunotherapy. Thus, reliable and matching historical data are required for comparison. We have previously reported on the outcome of heavily pretreated refractory patients (Eketorp Sylvan et al, Leuk Lymphoma 2014). The aim of the this study was to specifically investigate the outcome of 2nd line treatment prior to the access of small molecule-based treatment options, in consecutive patients from a well-defined geographical region, where almost complete follow-up exists and external referrals are minimal. Methods: Patients diagnosed with CLL were identified from the Cancer Registry in Stockholm (Nov 2002- Dec 2013) and patient files were reviewed individually to identify R/R patients. Efficacy and toxicity of 2nd line and later salvage therapies were recorded as well as long term follow-up. Patients were also grouped into treated in the early (Nov 2002-2007) and late time period (2008-2013) and compared regarding outcome. A multivariate cox proportional hazards model was perform to explore risk factors for outcome. Results: Chart review of 979 patients identified 148 consecutive, non-referred patients with R/R CLL undergoing various types of 2nd line salvage therapy. Median age was 73 years and 53% had Binet stage C. Del17p testing was available in 46% of patients of which 20.6% had del17p. Most frequently initiated treatments in 2nd line were chlorambucil (27.7%), FC (23.6%) and FCR (13.5%). The overall response rate (ORR) was 48.6% (3.4% CR). Median overall-survival (OS) from start of second line therapy was 37.9 months. Shorter OS was significantly associated with ECOG higher than 0, male sex, and age > 80 years. There was no difference in OS, PFS or ORR between those treated in the first vs the second time period of this study, despite that 2nd line use of chlorambucil decreased from 39% to 23% and use of FCR or BR increased from 0% to 26% from 2002-2007 to 2008-2013. However, median duration of response was significantly longer during the later time period (20.9 vs 10.3 months, p=0.035). During treatment, 50.7% of patients were hospitalized and 32.4% of patients experienced grade III-IV infections. Other AEs ≥ grade 3 occurred in 10.1% and 7.4% had bleeding events. Grade 3/4 hematological toxicity, according to IWCLL-criteria, occurred in 0.7%/0.7% (Hb), 11.5%/8.8% (platelets) and 16.9%/36.5% (neutrophils). Toxicity was similar in both time periods. Conclusion: Our study describes the outcome of 2nd line treatment in R/R CLL in consecutive patients from a geographically well defined region with almost complete follow-up and without influence on the results from external referrals. Almost no improvement was observed in the outcome of 2nd line treatment during the 10 year period. Such real-world results may be used for comparison with data obtained in non-controlled phase 2 trials on new orphan drugs. Keywords: Chronic lymphocytic leukemia, Relapsed, Refractory, Clinical outcome Disclosures Asklid: Janssen Cilag: Research Funding. Mattsson:Janssen Cilag: Research Funding. Björgvinsson:Janssen Cilag: Research Funding. Winqvist:Janssen Cilag: Research Funding. Eketorp Sylvan:Janssen Cilag: Research Funding. Søltoft:Janssen Cilag: Employment. Repits:Janssen Cilag: Employment. Diels:Janssen: Employment. Österborg:Janssen Cilag: Research Funding. Hansson:Jansse Cilag: Research Funding.

Long-Term Follow-up of a Phase 2 Study of Single Agent Lenalidomide in Previously Untreated, Symptomatic Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 718-718
Author(s):  
Christine Chen ◽  
Harminder Paul ◽  
Trina Wang ◽  
Lisa W Le ◽  
Vishal Kukreti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 718 Introduction: In a previously reported phase 2 study of single agent lenalidomide in 25 untreated CLL patients (pts), we reported an overall response rate (ORR) of 56% (14 pts), 40% SD (10 pts) and no CR at a median follow-up of 20.7 months (Chen et al. JCO 2010;29:1175). Although an amended protocol with conservative lenalidomide dosing was used to mitigate tumor lysis and severe myelosuppression observed in the first 2 accrued pts, we continued to observe frequent toxicities of grade 3–4 neutropenia (72%) and tumor flare (TF 88%). We now report long-term efficacy and toxicity from this study at a median follow-up of 47 months (mos). Methods: Patients were eligible if previously untreated and symptomatic (cytopenias, symptomatic adenopathy/organomegaly, constitutional symptoms, lymphocyte doubling count <12 mos). The amended starting dose for lenalidomide was 2.5mg daily on days 1–21 of a 28 day cycle, with slow monthly dose escalations (2.5mg cycle 1, 5mg cycle 2, 10mg cycle 3 and if required for response, further 5mg increments to a maximum of 25mg daily were allowed). Results: Longterm toxicities: Hematologic toxicities were common: grade 3–4 neutropenia (76%), thrombocytopenia (28%), anemia (20%). With longer term use, neutropenia tended to recur (12% of all cycles) and 10 pts required GCSF support (5 routinely during each cycle). Most common non-hematologic toxicities (all grades) were TF (88%), fatigue (76%), rash (60%), muscle cramping (40%), diarrhea (40%). All non-hematologic toxicities were mild (grade 1–2), except for 1 pt each with grade 3 rash and diarrhea. Although TF was most common during cycle 1, repeat flare symptoms upon resuming lenalidomide after the 7 day rest period of each cycle were noted in 16% of all 898 cycles administered, and as late as at cycle 28. Infections were mild (most respiratory, skin) with only 2 grade 3 events (disseminated zoster, S.pneumoniae bacteremia). Other malignancies: 2 pts developed transformed large cell lymphoma 7 and 18 mos after study discontinuation, 1 pt developed squamous cell carcinoma of skin at cycle 51, and 1 pt developed recurrence of remote non-small cell lung cancer at cycle 34. Dose modifications/discontinuation: The median highest dose achieved for all 25 pts was 15 mg (range 2.5–25 mgs); 8 pts were able to escalate to the maximal 25mg dose. Ten pts (40%) required dose reductions for grade 3 cytopenias [neutropenia (2), thrombocytopenia (2), both (2)], febrile neutropenia (2), and diarrhea (2). Of all 25 pts, the median duration on therapy was 31.1 mos (range 28 days – 60.6 mos). Twelve pts (52%) currently remain on study, receiving a median of 59 cycles of therapy (range 48–66). Causes of discontinuation for 13 pts included: treatment-related toxicity (8), lack of response/progressive disease (4), and recurrence of remote lung cancer (1). Toxicities leading to discontinuation included: prolonged cytopenias (3), recurrent infections (1), atrial fibrillation (1), disseminated herpes zoster (1), persistent grade 2 diarrhea (1), and grade 3 skin rash (1). Efficacy: With extended median follow-up from 20.7 to 47 mos, the ORR improved from 56% (14 pts) to 72% (18 pts), with 3 pts in PR upgrading to CR, and 1 SD to PR. Although the median time to response was 7.7 mos, responses occurred as quickly as 1.8 mos to as late as 27.0 mos of therapy. For the 3 CR pts, prolonged therapy with an additional 14.9, 28.3 and 40.6 mos beyond the time of first response was required to achieve CR. To date, 7 pts have progressed with 3-year PFS 68.8% (95% CI:52–91%) and OS 85.3% (95% CI:71.1–100%). Correlatives: Cereblon (CRBN), recently identified as a direct protein target of lenalidomide, was evaluated by gene expression profiling and Western blot and found to be uniformly expressed in all 19 evaluable day 1 pt samples regardless of lenalidomide response. Thus, baseline CRBN expression does not appear to be a useful predictive biomarker of response in this population. The mechanism by which CRBN is linked to response is reported by Trudel et al, ASH 2012. Conclusions: Long-term followup of this study demonstrates that when using low doses of single agent lenalidomide in CLL, prolonged therapy is feasible and may be required for the achievement of durable, high quality responses. Maximal daily doses of 25mg can be reached and may also be needed for optimal response, though recurrent myelosuppression remains limiting. Disclosures: Chen: Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Lundbeck: Consultancy; Janssen: Consultancy, Research Funding. Off Label Use: Lenalidomide is not approved for use in chronic lymphocytic leukemia. Kukreti:Roche: Honoraria; Celgene: Honoraria; Janssen Ortho: Honoraria. Trudel:Celgene: Honoraria, Research Funding, Speakers Bureau.

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 (&gt;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 &lt;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.

A Phase Ib/II Study of Combined Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2051-2051 ◽  
Author(s):  
Januario E. Castro ◽  
Michael Y. Choi ◽  
Carlos I. Amaya-Chanaga ◽  
Natalie Nguyen ◽  
Colin MacCarthy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Free Survival ◽  
Phase Ib ◽  
High Dose Methylprednisolone ◽  
Grade 3

Abstract High-dose methylprednisolone (HDMP) and rituximab (R) is an effective non-myelosuppressive treatment regimen for patients (pts) with chronic lymphocytic leukemia (CLL). Also, this combination has shown activity even in pts who have adverse leukemia-cytogenetics, such as del17p. Phase III studies have demonstrated that CLL pts treated with chlorambucil and obinutuzumab-Gazyva (G), another anti-CD20 mAb, had a superior outcome than comparable pts treated with R-chlorambucil. We hypothesized that G-HDMP is well-tolerated and effective in the treatment of pts with CLL. Accordingly, we initiated an open-label phase Ib/II clinical study. A total of 40 pts were enrolled in two cohorts of 20 pts each (previously untreated (PU) and relapsed/refractory (RR) CLL) and treated with HDMP 1 g/m2on Day 1-3 of cycles 1-4 (28 days/cycle) and G administered based on FDA dosing recommendations for 6 cycles. The pts had a median age of 67 years + 9.1 in the RR cohort and 63 years + 8.3 in the PU cohort. The median baseline absolute lymphocyte count was 30.7 + 7.3 x1,000/mm3 for pts in the RR cohort and 47.6 + 19.7 x1,000/mm3for pts in the PU cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 30% RR vs. 0% PU, del(13q) in 60% RR vs. 70% PU, del(11q) in 20% RR vs. 35% PU, and trisomy 12 in 15% RR vs. 20% PU. Most AEs were grade 1-2 (RR=87%; PU=93%) without development of dose-limiting toxicities. Only two pts needed therapy discontinuation. One pt due to pulmonary embolism and the second pt due to asymptomatic gastrointestinal bleeding that required blood transfusion and resolved spontaneously. Grade 1-2 G-infusion-related reactions (IRR) were observed in 40% and 80% of pts in the RR and PU cohorts, respectively. Grade 3-4 IRR were observed in 10% of pts in the PU cohort only. We observed cytopenias (neutropenia grade 3-4: RR=55%, PU=40%; thrombocytopenia grade 3-4: RR=35%, PU=20%; and anemia grade 3-4: RR=0%, PU=0%). There were no cases of febrile neutropenia. Two pts (10%) in the RR cohort and one pt (5%) in the PU cohort developed infection grade 1-2 that was treated with oral antibiotics but did not require study treatment discontinuation. The most frequent non-hematological adverse events (AEs) were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). There were no treatment related deaths in either cohort. The response assessment was performed in all 40 pts by iwCLL criteria. The ORR was 100% in the PU cohort and 95% in the RR cohort. 70% of the pts in the PU cohort and 85% of the pts in the RR cohort achieved a PR. CR was observed in 30% and 10% of the pts in the PU and RR cohorts, respectively. One pt (5%) in the RR cohort and four pts (20%) in the PU cohort achieved MRDneg status (<0.01% CLL in the bone marrow by multiparameter flow cytometry). Only one pt in the RR cohort achieved SD. At a median follow-up of 12.2 months, the RR cohort had a median Progression Free Survival (PFS) of 13.6 months and median Treatment Free Survival (TFS) of 14.7 months; the median Overall Survival (OS) has not been reached. In the PU cohort, the median PFS, TFS and OS have not been reached. One pt from the RR cohort and one pt from the PU cohort died during the follow-up period due to disease progression. G-HDMP was well tolerated and all 40 pts showed hematological and clinical responses during the study treatment without development of unexpected AEs. In both cohorts, most of IRR were grade 1-2 and severe IRR (grade 3-4) were much less compared with previously published data (G-chlorambucil / CLL-11 study). Compared to pts in the CLL-11 study, cytopenias appeared to be more frequent, however, the rate of infection and need for IV antibiotics or hospitalizations was lower. Of note, the eligibility criteria allowed pts with severe cytopenias and transfusion requirement to participate in our study. Response in PU pts were higher in terms of ORR, CR and CR-MRDnegativecompared with the data from the CLL-11 study and suggests a possible synergistic activity between G and HDMP. Overall, G-HDMP was well tolerated in the PU and RR CLL pts with a lower rate of IRR making this regimen more manageable in the outpatient setting. Responses were higher than previously reported in PU pts. Responses in RR pts appear to be comparable to our previous studies using R-HDMP. Our data supports G-HDMP as an alternative combination regimen for the treatment of CLL pts. Disclosures Kipps: Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 233-233 ◽  
Author(s):  
Susan M. O'Brien ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
Ian W. Flinn ◽  
Jan Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Over Time

Abstract Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton's tyrosine kinase inhibitor, is approved by the US FDA for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including pts with del17p. The phase 1b/2 PCYC-1102 trial showed single-agent efficacy and tolerability in treatment-naïve (TN; O'Brien, Lancet Oncol 2014) and relapsed/refractory (R/R) CLL/SLL (Byrd, N Engl J Med 2013). We report efficacy and safety results of the longest follow-up to date for ibr-treated pts. Methods: Pts received 420 or 840 mg ibr QD until disease progression (PD) or unacceptable toxicity. Overall response rate (ORR) including partial response (PR) with lymphocytosis (PR-L) was assessed using updated iwCLL criteria. Responses were assessed by risk groups: unmutated IGVH, complex karyotype (CK; ≥3 unrelated chromosomal abnormalities by stimulated cytogenetics assessed by a reference lab), and in hierarchical order for del17p, then del11q. In the long-term extension study PCYC-1103, grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation were collected. Results: Median age of the 132 pts with CLL/SLL (31 TN, 101 R/R) was 68 y (range, 37-84) with 43% ≥70 y. Baseline CK was observed in 41/112 (37%) of pts. Among R/R pts, 34 (34%) had del17p, 35 (35%) del11q, and 79 (78%) unmutated IGVH. R/R pts had a median of 4 prior therapies (range, 1-12). Median time on study was 46 m (range, 0-67) for all-treated pts, 60 m (range, 0-67.4) for TN pts, and 39 m (range, 0-67) for R/R pts. The ORR (per investigator) was 86% (complete response [CR], 14%) for all-treated pts (TN: 84% [CR, 29%], R/R: 86% [CR, 10%]). Median progression-free survival (PFS) was not reached (NR) for TN and 52 m for R/R pts with 60 m estimated PFS rates of 92% and 43%, respectively (Figure 1). In R/R pts, median PFS was 55 m (95% confidence intervals [CI], 31-not estimable [NE]) for pts with del11q, 26 m (95% CI,18-37) for pts with del17p, and NR (95% CI, 40-NE) for pts without del17p, del11q, trisomy 12, or del13q. Median PFS was 33 m (95% CI, 22-NE) and NR for pts with and without CK, and 43 m (95% CI, 32-NE) and 63 m (95% CI, 7-NE) for pts with unmutated and mutated IGVH, respectively(Figure 2). Among R/R pts, median PFS was 63 m (95% CI, 37-NE) for pts with 1-2 prior regimens (n=27, 3 pts with 1 prior therapy) and 59 m (95% CI, 22-NE) and 39 m (95% CI, 26-NE) for pts with 3 and ≥4 prior regimens, respectively. Median duration of response was NR for TN pts and 45 m for R/R pts. Pts estimated to be alive at 60 m were: TN, 92%; all R/R, 57%; R/R del17p, 32%; R/R del 11q, 61%; R/R unmutated IGVH, 55%. Among all treated pts, onset of grade ≥3 treatment-emergent AEs was highest in the first year and decreased during subsequent years. With about 5 years of follow-up, the most frequent grade ≥3 AEs were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). Study treatment was discontinued due to AEs in 27 pts (20%) and disease progression in 34 pts (26%). Of all treated pts, 38% remain on ibr treatment on study including 65% of TN pts and 30% of R/R pts. Conclusions: Single-agent ibrutinib continues to show durable responses in pts with TN or R/R CLL/SLL including those with del17p, del11q, or unmutated IGVH. With extended treatment, CRs were observed in 29% of TN and 10% of R/R pts, having evolved over time. Ibrutinib provided better PFS outcomes if administered earlier in therapy than in the third-line or beyond. Those without CK experienced more favorable PFS and OS than those with CK. Ibrutinib was well tolerated with the onset of AEs decreasing over time, allowing for extended dosing for 65% of TN and 30% of R/R pts who continue treatment. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Coutre:Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Burger:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses. Sharman:Gilead: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Wierda:Abbvie: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luan:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Chu:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership.

Comparative Safety Analysis of Currently Approved Anti-CD20 Monoclonal Antibodies for First Line Treatment of Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5587-5587
Author(s):  
Mkaya Mwamburi ◽  
Vasudha Bal ◽  
Teresa Cascella ◽  
Anshul Shah ◽  
Merena Nanavaty ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Safety Profile ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
Phase 2 ◽  
First Line ◽  
Grade 3 ◽  
Anti Cd20 ◽  
Cost Implications ◽  
First Line Treatment

Abstract Introduction: Treatment of CLL has advanced tremendously in the past decade with significant extension of life expectancy in patients diagnosed with the disease. Three anti-CD20 monoclonal antibody (mAB) combinations approved for previously untreated chronic lymphocytic leukemia (CLL) patients are obinutuzumab-chlorambucil (OBI-CHL), ofatumumab-chlorambucil (OFA-CHL), and rituximab-chlorambucil (RTX-CHL), have comparable efficacy but varying safety profiles in pivotal trials. Grade 3-4 adverse events (AEs), including infusion-related reactions (IRRs), neutropenia, thrombocytopenia, anemia, and infections differ by each mAB. Grade 3-4 AEs, defined as requiring hospitalization or life-threatening, result in reductions in patient quality of life (QoL) and bear cost implications. We sought to compare the safety of the IV-administered anti-CD20 mABs in the first-line treatment of CLL and to evaluate the respective QoL and economic implications of these AEs. Methods: A systematic literature review was conducted in PubMed, Embase, and Cochrane library for the time period of 2010-2016 and in conference proceedings of ASH, the American Society of Clinical Oncology (ASCO), and the European Hematology Association (EHA) for 2014-2016. Search was limited to clinical trials conducted on humans and published in English language. The IRRs were compared directly as CHL is administered orally. A Bayesian network meta-analyses (NMA) was conducted with data from phase 3 trials using SAS® (v9.3) to compare grade 3-4 neutropenia, thrombocytopenia, anemia, and infections associated with the three anti-CD20 mABs. A pooled analysis of data from phase 2 trials and cohort studies was conducted using MedCalc® version 16.2.1. Analyses were also conducted to estimate the potential impact of the AEs of respective anti-CD20 mABs on QoL and cost of care based on the NMA results and previously published estimates of utilities associated with CR (0.780), PR (0.790), SD/PD (0.760); disutilities associated with IRR (-0.11), neutropenia (-0.09), thrombocytopenia (-0.05), anemia (-0.09), and infections (-0.20); and costs associated with episodes of IRR ($4,482), neutropenia ($5,406), thrombocytopenia ($12,621), anemia ($8,894), and infections ($7,163) in CLL. Results: Of the 86 studies screened, 10 studies were included. Direct comparison showed that the rate of IRRs in OBI-CHL, OFA-CHL, and RTX-CHL were 21%, 10%, and 4%, respectively. Risks for neutropenia were lower for OFA-CHL compared to OBI-CHL (OR = 0.74; 95% CI: 0.12-4.59) and similar to RTX-CHL (1.08; 0.20-5.82); for thrombocytopenia were lower for OFA-CHL compared to OBI-CHL (0.16; 0.02-1.33) and to RTX-CHL (0.49; 0.06-4.15); for anemia were lower for OFA-CHL compared to OBI-CHL (0.80; 0.21-3.06) and similar to RTX-CHL (1.08; 0.24-4.64); and for infections OFA-CHL, OBI-CHL (1.00; 0.15-6.74) and RTX-CHL (0.86; 0.15-4.43) were similar. The pooled analyses of AEs observed in phase 2 / cohort studies revealed similar trends when assessed. The mean pre-progression QoL utilities associated with OBI-CHL, OFA-CHL, and RTX-CHL weighted by rates of AEs, utilities associated with respective response rates to treatments, and disutilities of the respective AEs were 0.772, 0.761, and 0.748 respectively. The total cost of treating AEs per 1,000 patients on OFA-CHL, OBI-CHL and RTX-CHL were $3.9M, $8.0M and $4.2M, respectively. Conclusion: The safety profile was most desirable for OFA-CHL, followed by RTX-CHL and OBI-CHL. Though RTX-CHL had the lowest rate of grade 3-4 IRR, OFA-CHL had the better grade 3-4 hematologic safety profile compared to OBI-CHL and RTX-CHL. As efficacy of CLL treatments has improved substantially, safety of treatments is increasingly important particularly on the impact of QoL. In addition, in the cost-conscious payer environment, selecting drugs with a better safety profile and lower cost implications is vital. Our findings demonstrate that better safety profile is associated with less impact on QoL and lower costs. We found that for every 1,000 patients covered by a payer, safety alone can save an excess of $4M based on regimen choice. Fewer incidences of AEs also results in better adherence and reduction in treatment interruption or discontinuation. Safety with the QoL and cost implications should be taken into consideration to maximize the overall benefits of the treatment to CLL patients. Disclosures Mwamburi: Novartis Pharmaceuticals: Consultancy. Bal:Novartis Pharmaceuticals: Employment. Cascella:Novartis Oncology: Employment. Shah:Novartis Pharmaceuticals: Consultancy. Nanavaty:Novartis Pharmaceuticals: Consultancy. Gala:Novartis Pharmaceuticals: Consultancy.

scholarly journals Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 327-327 ◽  
Author(s):  
Susan O'Brien ◽  
Jeffrey A. Jones ◽  
Steven Coutre ◽  
Anthony R. Mato ◽  
Peter Hillmen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

scholarly journals Results of a Phase 2 Study of MEDI-551 and Bendamustine Vs Rituximab and Bendamustine in Relapsed or Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4472-4472
Author(s):  
Douglas Gladstone ◽  
Marc Andre ◽  
Jan Zaucha ◽  
Sarit Assouline ◽  
Naresh Bellam ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Micro Rna ◽  
Lymphocytic Leukemia ◽  
Stock Ownership ◽  
Clinical Activity ◽  
Phase 2 ◽  
Mirna Signature ◽  
Grade 3 ◽  
All Treatment

Abstract Background: In patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), novel therapies are needed to prolong disease control. MEDI-551, an afucoslylated, affinity-optimized, anti-CD19 antibody, functions by antibody-dependent cellular cytotoxicity, with a 30% monotherapy response rate in CLL. A phase 2 randomized, open-label study (NCT01466153) is evaluating the clinical activity, efficacy, and safety of combination therapy with MEDI-551 + bendamustine compared with rituximab + bendamustine in R/R CLL patients. Methods: Patients were initially randomized to receive bendamustine 70 mg/m2 intravenously (IV) on days 1, 2 with either MEDI-551 2 or 4 mg/kg on days 2, 8 of cycle 1 (on day 1 of subsequent cycles) or rituximab 375 mg/m2 IV on day 1 of cycle 1 (then 500 mg/m2 IV on day 2 of subsequent cycles), for up to six 28-day cycles. The 4-mg/kg dose of MEDI-551 was selected for the final efficacy analysis against rituximab. Safety assessments included adverse events (AEs) and laboratory parameters. Disease response was determined using 2008 International Working Group criteria. Exploratory objectives included micro RNA (miRNA) expression levels before and after treatment. Results: As of March 2014, the safety population comprised 147 patients across all treatment arms. The median age was 66 years (range 41–81), with 11% of patients with deletion (del) (17p), 20% with del (11q), 30% with del (13q), 12% with trisomy 12, and 39% with unmutated immunoglobulin heavy chains (IgVH). The median number of treatment cycles was 4 (range 1–6). Treatment-related AEs observed in ≥20% of patients included nausea, infusion-related reactions (IRRs), nausea, fatigue, pyrexia, neutropenia, and cough in the MEDI-551 arm vs nausea, fatigue, constipation, asthenia, pyrexia, and neutropenia in the rituximab arm. Grade 3/4 treatment-related AEs are listed in the table. Table. Treatment-Related Grade 3/4 AEs (≥5% of patients in any treatment group) Parameter, n (%) MEDI-551 + Bendamustine Rituximab + Bendamustine 2 mg/kg (n=32) 4 mg/kg (n=56) (n=59) Patients reporting ≥1 event 20 (63) 25 (45) 29 (49) Neutropenia 8 (25) 9 (16) 20 (34) IRR* 6 (19) 4 (7) 1 (2) Thrombocytopenia 2 (6) 1 (2) 5 (9) Lymphopenia 2 (6) 1 (2) 4 (7) Anemia 1 (3) 0 3 (5) Fatigue 0 0 3 (5) *Note: After 42 patients were enrolled in the study (all treatment groups), corticosteroid prophylaxis was recommended before patients receiving the initial dose of MEDI-551. Discontinuation of study treatment because of AEs occurred in 26% of patients receiving MEDI-551/bendamustine (including neutropenia, thrombocytopenia, bradycardia, abdominal pain, asthenia, fatigue, cytokine release syndrome, hypersensitivity, pneumonia, infusion-related reactions, elevated liver function tests, dehydration, hyponatremia, headache, depression, epistaxis, hypoxia, rash, and hypotension) and in 20% of those receiving rituximab/bendamustine (including febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, cardiac failure, uveitis, small intestine obstruction, upper gastrointestinal hemorrhage, asthenia, fatigue, and systemic inflammatory response syndrome). No treatment-related deaths occurred in any treatment arm. Clinical activity was observed in both the MEDI-551 and rituximab arms, and a biomarker has been identified that may predict for MEDI-551 responders. Expression of a miRNA signature is specifically elevated in NHL patient samples. Low pretreatment levels of this miRNA signature in whole blood may predict for responders to MEDI-551. Three-fold lower levels (P<.0001) in pretreatment samples from MEDI-551 responders vs nonresponders were noted, but no differences in miRNA signature expression were noted between responders and nonresponders in the rituximab arm. Conclusions: Data show evidence of clinical activity in R/R CLL patients, with comparable safety observed between the MEDI-551 and rituximab arms. Expression level of a miRNA signature is able to predict for those more likely to respond to MEDI-551, with MEDI-551 responders having low pretreatment miRNA signature expression. Disclosures Gladstone: MedImmune: Research Funding. Andre:MedImmune: Research Funding. Zaucha:MedImmune: Research Funding. Assouline:MedImmune: Research Funding. Bellam:Genentech: Research Funding; Janssen: Research Funding; MedImmune: Research Funding; Facet: Research Funding. Cascavilla:MedImmune: Research Funding. Jourdan:MedImmune: Research Funding; Roche: Research Funding. Panwalkar:MedImmune: Research Funding. Patti:MedImmune: Research Funding. Zaja:MedImmune: Research Funding. Goswami:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Elgeioushi:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Streicher:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Bao:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Spaner:MedImmune: Research Funding.

scholarly journals An Open-Label, Phase Ib Study of Duvelisib (IPI-145) in Combination with Bendamustine, Rituximab or Bendamustine/Rituximab in Select Subjects with Lymphoma or Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4422-4422 ◽  
Author(s):  
Ian Flinn ◽  
Manish R. Patel ◽  
Michael B Maris ◽  
Jeffrey Matous ◽  
Mohamad Cherry ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Treatment Delay ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Grade 3

Abstract Background: Duvelisib is a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) being developed as a potential therapeutic in hematologic malignancies including B and T cell lymphoma and chronic lymphocytic leukemia (CLL). In a phase I study of single agent duvelisib (D), ORR of 52% was seen in pts with indolent non-Hodgkin’s lymphoma (iNHL) and 47% in CLL. Bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with either bendamustine or rituximab alone or in combination with each other may improve response rates and the durability of remission. The goal of this Phase 1b, open-label, three-arm, non-randomized, dose escalating, safety and tolerability trial is to characterize the safety, maximum tolerated dose (MTD) and preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL. Methods: Pts had relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID up to 12 cycles. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib were explored, 25, 50, and 75 mg PO BID. DLTs were defined as: febrile neutropenia, G4 neutropenia ≥7 days, G4 thrombocytopenia ≥ 7 days or G3 thrombocytopenia with bleeding, Grade 4 AST/ALT, Grade 2 hyperbilirubinemia ≥7 days, ≥ Grade 3 non-hematologic toxicity ≥7 days (excluding alopecia), Treatment delay of ≥7 days due to unresolved toxicity that prevents re-dosing, hepatocellular injury (defined as ALT>2 x ULN and (ALT/ULN)/(ALP/ULN) >5) and bilirubin >2 x ULN or jaundice ± alkaline phosphatase <2 x ULN. Patients were evaluated for response every 3 cycles according to specific criteria for their disease. Results: Between August 2013 and May 2014, 32 pts, median age 66 years (44-78) were enrolled to the study, 12 NHL pts on the dose escalation portion and 20 pts on dose expansion (13 CLL, 7 NHL). Patients had a median of 4 prior therapies (1-11). In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB) in which a higher dose of bendamustine is used 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days). Dose escalation continues in this arm as the MTD has not reached. Patients on the dose expansion portion of the study are receiving duvelisib at 25 mg BID due to emerging data of duvelisib monotherapy showing no advantage in doses greater than 25 mg BID in these histologies. The AE profile is consistent with the toxicities of the single agents. The most common AEs > grade 3 were neutropenia (28% overall; [Arm 1 (DR), 27%]; [Arm 2 (DBR), 38%]), and rash (16% overall; [Arm 1, 14%]; [Arm 2, 25%]). Grade 3 or higher AST/ALT increases were seen in 2 out of 12 patients on Arm 1, 2 out of 8 patients on Arm 2 and no patients on Arm 3. There have been 2 deaths (cardiac arrest and pneumonia), both on Arm 1. Twenty one pts were evaluable for response with an ORR of 81% (10% CR, 71% PR, 14% SD and 5% PD). With a median follow up of 4.0 months, time to event analyses are immature. However, Kaplan-Meier estimate of PFS at 3 months is 87%. PK analysis is consistent with the monotherapy Phase I trial of duvelisib. Conclusions: Initial early analysis of duvelisib administered in combination with bendamustine and rituximab suggests these combinations to be generally well-tolerated with encouraging. Further follow-up is required to better characterize response rates and durability of remissions. Disclosures Flinn: Infinity Pharmaceuticals: Research Funding. Matous:Infinity Pharmaceuticals: Research Funding.

Second-Line Therapies After Treatment with Fludarabine, Cyclophosphamide, and Rituximab (FCR) or Fludarabine and Cyclophosphamid Alone (FC) for Chronic Lymphocytic Leukemia (CLL) within the CLL8-Protocol of the German CLL Study Group (GCLLSG)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2863-2863 ◽  
Author(s):  
Paula Cramer ◽  
Anna-Maria Fink ◽  
Raymonde Busch ◽  
Barbara Eichhorst ◽  
Clemens-Martin Wendtner ◽  
...  
Keyword(s):  
Research Funding ◽  
Rating Scale ◽  
Single Agent ◽  
Progression Free Survival ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
Second Line ◽  
Free Survival ◽  
Line Therapy

Abstract Abstract 2863 Introduction: The CLL8-trial is the first study that has shown not only an increase in complete remission rates and progression-free survival, but also an improved overall survival (OS) in physically fit, treatment-naúve CLL-patients (pts) with FCR-chemoimmunotherapy in comparison to FC alone [Hallek et al., Lancet 2010]. Despite this remarkable progress, CLL remains an incurable disease and virtually all pts will eventually relapse. So far, little is known about the efficacy of 2nd-line therapies of these pts. Patients and Methods: Between July 2003 and March 2006 817 pts in good physical fitness as defined by a cumulative illness rating scale (CIRS) score of ≤6 and creatinine clearance 70 ml/min were randomized within the trial and received 6 courses FC (n=409; F: 25mg/m2 i.v. d1–3 and C: 250 mg/m2 i.v. d1–3; q 28 days) without or with rituximab (n=408; 375 mg/m2 i.v. d0 cycle 1, 500 mg/m2 d1 of all subsequent cycles; q 28 days) for 1st-line treatment. Results: As of March 2009, 65% of the patients who had received FCR were free of progression compared to 45% of those who were treated with FC (p<0, 0001) [Hallek et al, Lancet, 2010]. Until July 2010, 232 pts were treated for relapsed CLL, among them 91 of 408 (22%) initially treated with FCR and 141 of 409 (35%) initially treated with FC. In 2nd-line treatment after FCR and FC, the drugs most frequently used either alone or in combination were rituximab (R, 52% of all 2nd-line therapies), fludarabine (F) and bendamustine (B) (21% each), as well as alemtuzumab (A, 12%). The combination of cyclophosphamide, doxorubicin, vincristine, prednisolone and rituximab (CHOP-R) was the most common treatment (35 pts, 15% of all 2nd-line therapies), applied mainly in cases with a relapse ≤24 months after FC/FCR, whereas FCR or BR were administered predominantly in case of relapse >24months (32 and 27 pts, 14% and 12%). Other prevalent 2nd-line therapies were single agent A (20 pts) or B (17 pts), CHOP and FC (11 pts respectively), chlorambucil (9 pts) as well as R monotherapy (7 pts). 9 pts underwent stem cell transplantations. Second-line therapies with FC+/−R and B+/−R were found to be more effective with regard to treatment-free survival (TFS, time to 2nd relapse) and OS when compared to A or CHOP-R and CHOP-like chemotherapies. However, the outcome of 2nd-line therapies seemed to be influenced by the 1st-line treatment. In pts initially treated with FC, FCR was found to be the most effective 2nd-line therapy (TFS: 23 months, OS: not reached), whereas in pts initially treated with FCR, a substitution of the chemotherapeutic agents FC by B seemed justified, as TFS was superior after 2nd-line treatment with B+/−R (16 and 18 months respectively) when compared to FC+/−R (11 and 8 months). Furthermore, in pts who had received FCR for 1st-line treatment, chemotherapy with FC or B was found to be at least equally or even more effective in prolonging OS than FCR or BR (OS calculated from beginning of 2nd-line therapy: FC: not reached, B: 45, FCR: 19, and BR 18 months). Conclusion: Second-line treatments of pts with a relapse after FC or FCR were found to be surprisingly heterogeneous even though the patient collective examined is comparatively homogenous due to the inclusion/exclusion criteria of a clinical trial. As the majority of CLL8-patients is still in remission and has not yet received a 2nd-line treatment, the therapies captured in this analysis are predominantly 2nd-line therapies for earlier relapses. Therefore and because of the short follow-up time, the results ought to be considered as preliminary and descriptive trends. The worse outcome of CHOP-like regimen and A-based therapies in comparison to more established CLL-therapies such as FC+/−R and B+/−R might be related to the fact, that these therapies were administered more often in case of an early relapse after FC/FCR, which is known to be related to other poor prognostic factors [Fink et al, ASH 2010]. Nevertheless, the observation of favorable TFS and OS times after 2nd-line treatment with FC+/−R and B+/−R supports the recommendation to repeat chemoimmunotherapy in case of a relapse >24 months after 1st-line treatment. Further analyses are needed to confirm the observation that chemotherapy (FC or B) without rituximab might be sufficient for for 2nd-line treatment after FCR. Disclosures: Cramer: Mundipharma: Travel Grants. Fink:F. Hoffmann La Roche:. Eichhorst:Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Wendtner:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Pflug:Hoffmann La Roche:. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria. Fischer:Hoffmann La Roche:.

Fludarabine, Cyclophosphamide and Rituximab (FCR) Related Prolonged Cytopenia Is Frequent and Adverse Factor Affecting Survival of Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1790-1790
Author(s):  
Petra Obrtlikova ◽  
Anna Jonasova ◽  
Magda Siskova ◽  
Eduard Cmunt ◽  
Adela Berkova ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Significant Difference

Abstract Abstract 1790 Background: The immunochemotherapy regimen composed of fludarabine, cyclophosphamide and rituximab (FCR) has emerged as highly effective frontline or second line therapy for chronic lymphocytic leukemia (CLL). This regimen may be however associated with prolonged cytopenia and the risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Aims and methods: In our retrospective single center analysis, we evaluated the efficacy and the toxicity of FC or FCR regimen in unselected population of CLL patients with treatment indication. The overall survival (OS) and progression free survival (PFS) was calculated for all patients as intent to treat analysis. The prolonged cytopenia was defined as cytopenia (grade 2–4 according to CTCAE v.4 ) developing during of after the last cycle of FC/FCR and persisting two or more months. Cytopenia was evaluated in patients with follow-up at least 6 months after this treatment. Patients were excluded from analysis of cytopenia if they underwent immediate other treatment (antibody maintenance, high dose therapy with autologous stem cell transplantation (ASCT) consolidation, or they received other therapy due to unsatisfactory response to FCR). Patients with missing laboratory data after FC(R) were also excluded. Kaplan Maier curves for PFS and OS were calculated and log rank test was used for survival comparison. Results: Altogether, 252 patients started the treatment with FC or FCR in the years 2000–2012 at our institution. There were 86 (34%) women and 166 (66%) men with a median age of 62 years (31–87) at the time of FC(R) therapy. 52 (21%) pts received FC regimen, including 40 pts treated in first line therapy and 12 pts in second line therapy. FCR therapy was administered in 200 pts (79%): 153 pts received FCR as first line therapy, 38 pts as second line therapy and 8 pts as third or fouth line therapy. The median number of FC cycles was 5 (1–8) with or without R. The estimated OS for the first line therapy was 87,5% in FCR group vs 80% at 3y in FC group (p ns) (Hallek,CLL8: 87% vs 83%) and PFS was 70% in FCR group vs 50% in FC group (p=0,004) with the median of follow-up 45 months. Altogether 184 pts fulfill the criteria for cytopenia analysis. The most frequent immediate subsequent therapy considered as exclusion for this analysis was ASCT consolidation (n 20). Out of 184 pts, 146 recieved FC(R) as 1st line treatment and 38 subsequent therapy. The prolonged cytopenia was observed in 54 pts (29%), 42 (29%) in 1st line group and 12 (32%) in subsequent line group. Median duration of cytopenia was 8 m (2–65), 29 out of 54 patients have had persistent cytopenia at the time of last follow up. The cumulative probability to develop cytopenia was 30.3% at 2y among all pts and 29.7% among first line FCR treated pts. There was no significant difference between FC and FCR treated pts. Eleven pts developed MDS/AML, 7 cases were observed in the followed group of 184 pts (with probability 6.1% at 6y), in all cases the cytopenia preceded the MDS onset, 6y probability to develop MDS was 25.2% for patients who develop prolonged cytopenia after FC(R). Moreover 2 MDS and 1 AML were observed among 20 pts treated with ASCT (6y probability 5.6%, 8y probability 22.5%). The OS probability from 1stcycle of FC(R) was significantly better for pts without cytopenia (75.5% vs 57.5% at 5y, p<0.005), nonsigificant trend was observed if only first line FCR pts were analyzed (88% vs 85%). The median survival for the MDS pts from the time of MDS dg was 6 months only. Conclusions: Although the FCR is the best available standard treatment option for CLL pts, it is associated with prolonged cytopenia in 30% of cases. These patients with prolonged cytopenia afte FC(R) have considerably high probability (25.2%) to develop MDS and they have worse OS compared to pts without cytopenia. Disclosures: No relevant conflicts of interest to declare.

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