Combination of Ofatumumab and Lenalidomide In Patients with Relapsed Chronic Lymphocytic Leukemia: Initial Results of a Phase II Trial

Abstract Abstract 2464 Frontline chemoimmunotherapies induce high response rates in patients with CLL. Once disease recurs, however, effective treatment options are limited and new therapeutic modalities and combinations are needed. Ofatumumab is a fully humanized anti-CD20 monoclonal antibody which produces an overall response rate (ORR) of 47%–58% in patients with fludarabine-refractory CLL (Wierda W. et al, 2010). Lenalidomide, an immunomodulatory agent, induces an ORR of 32–47% in patients with relapsed/refractory CLL, (Chanan-Khan A.A. et al. 2006; Ferrajoli A. et al. 2008). The rationale for combining ofatumumab and lenalidomide is based on their single agent efficacy, distinct and potentially complimentary mechanisms of action and non-overlapping toxicity profiles. Furthermore, the combination of lenalidomide and rituximab has shown significant activity in patients with relapsed disease (Ferrajoli et al. 2009). We, therefore, designed a phase II study to evaluate efficacy and tolerability of ofatumumab and lenalidomide given in combination in patients with relapsed CLL. Patients with active disease were eligible if they had received prior treatment with purine analog-based therapy, had an ECOG/WHO performance status of 0–2, adequate renal (creatinine clearance > 30ml/min) and hepatic function (total bilirubin < to 2 mg/dl and ALT < 2 × ULN). Patients with any neutrophil count were eligible, whereas patients with platelet counts < 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis were excluded from participation. In this trial ofatumumab is administered intravenously weekly for four consecutive weeks (300mg week 1, 1,000 mg week 2 and all subsequent doses), then monthly for months 2–6 and once every two months for months 7–24. Lenalidomide is given orally at the dose of 10 mg daily, starting on day 9 and continued daily. Allopurinol at the dose of 300mg daily is given during the first two weeks of treatment as tumor lysis prophylaxis. Treatment duration is 24 months, and responses are assessed after 3, 6, 12, 18 and 24 months of therapy. Thus far 26 of the 40 planned patients have been accrued to this study and we present an analysis of response and toxicity for the first 16 patients that have been on study for at least 3 months. The median age of the patients is 62 yrs (45–82). Eight patients (50%) had Rai stage III-IV disease. The median Beta-2M level was 4.4 mg/dL (2–6.1). The median number of prior treatments was 2 (1–8). Four patients (25%) were refractory to fludarabine and all pts had received prior rituximab. Nine patients (56%) had unmutated IGHV genes, 5 patients (31%) had chromosome 17p deletion and 3 patients (19%) had 11q deletion as detected by FISH analysis. Responses were evaluated according to the 2008 IWCLL criteria: 10 of the 16 evaluable patients achieved a response [2 CR (13%), 8 PR (50%)] for an ORR of 63%. Four patients with stable disease are continuing on treatment. One patient discontinued therapy and did not return for response assessment and another patient progressed. All patients are alive. The most common grade 3–4 treatment related adverse events observed were: neutropenia (8 pts, 50%) and anemia (2 pts, 13%). One patient (6%) developed grade 2 superficial vein thrombosis. Lenalidomide-associated tumor flare reaction was limited to grade 1 in 2 patients (13%) while a grade 3 infusion reaction was observed in 1 patient (6%) during the first ofatumumab administration. Three grade 3 infectious episodes occurred: 2 cases of pneumonia and 1 case of parotiditis. None of the patients received routine antibiotic prophylaxis. The median daily dose of lenalidomide tolerated was 5 mg/day (2.5–10 mg). In conclusion, our initial analysis indicates that the combination of ofatumumab and lenalidomide is therapeutically active in patients with relapsed CLL. This treatment is well tolerated. Neutropenia is the most common toxicity observed. Enrollment is ongoing, and updated results will be provided. Disclosures: Off Label Use: Ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia. O'Brien: GlaxoSmithKline: Consultancy. Wierda: GlaxoSmithKline: Honoraria, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Estrov: Celgene Corporation: Consultancy. Keating: Celgene Corporation: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria. Ferrajoli: Celgene Corporation: Research Funding; GlaxoSmithKline: Research Funding.

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Combination Therapy with Ofatumumab and Lenalidomide in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): Results of a Phase II Trial

Blood ◽

10.1182/blood.v118.21.1788.1788 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1788-1788 ◽

Cited By ~ 5

Author(s):

Alessandra Ferrajoli ◽

Susan O'Brien ◽

William G. Wierda ◽

Stefan Faderl ◽

Xavier Badoux ◽

...

Keyword(s):

Pulmonary Embolism ◽

Phase Ii ◽

Research Funding ◽

Thrombotic Event ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Combination Regimen ◽

Treatment Indications ◽

Superficial Vein Thrombosis ◽

Grade 3

Abstract Abstract 1788 Patients with relapsed CLL have limited effective treatment options, and new therapies are needed. We report the results of a phase II study which investigated the efficacy and tolerability of a combination regimen with ofatumumab and lenalidomide in patients (pts) with relapsed CLL. These agents were evaluated as a combination regimen for pts with relapsed CLL based on their documented single-agent efficacy, distinct and potentially complimentary mechanisms of action and non-overlapping toxicities. Furthermore, the combination of rituximab and lenalidomide was active in relapsed CLL (Badoux et al. 2010). Pts with symptomatic disease who met treatment indications were eligible. Other inclusion criteria required prior treatment with purine analogs, an ECOG PS score of 0–2, and adequate organ function (creatinine clearance > 30ml/min, total bilirubin < to 2 mg/dl, ALT < 2 × ULN). Pts with any neutrophil count were eligible. Pts were excluded for platelets < 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis. Pts received ofatumumab IV weekly for four weeks (300mg week 1; 1,000 mg weeks 2 to 4), monthly during months 2–6, and every other month during months 7–24. Lenalidomide 10 mg PO daily was started on day 9 and continued daily for a maximum of 24 months. Allopurinol 300mg PO daily was given during the first two weeks of cycle 1. No pts received antibiotic or DVT prophylaxis. The use of growth factors was according to standard guidelines. Responses were assessed after 3, 6, 12, 18 and 24 months. Between January 2010 and January 2011, 36 pts were enrolled and 34 pts are evaluable (one pt withdrew consent prior to treatment and one was excluded because of concomitant MDS). The median age of the pts was 62 yrs (34–82). Twenty pts (59%) had Rai III-IV disease. The median beta-2M level at start of therapy was 4.4 mg/dL (1.7-16.5). The median number of prior treatments was 2 (1–8). All pts had received prior chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR). Twelve pts (35%) were fludarabine-refractory. Twenty-two pts (65%) had unmutated IgHV genes, 9 (26%) del(17p) and 4 (12%) del(11q). Responses were evaluated according to the 2008 NCI-WG criteria: 5 pts (15%) achieved CR (including 1 CRi) and 17 pts (50%) PR, for an ORR of 65%. Of the 5 CR pts, 1 was MRD-negative by flow cytometry. Two of the PR pts achieved marrow CR and only had persistent lymphadenopathy. Of the 22 responders, 13 are continuing on therapy with ongoing response (median time on therapy 14 months, range 8–20 months). Despite ongoing response, 7 pts discontinued therapy due to: transition to HSCT (3 pts; after 3, 6 and 6 months, respectively), pulmonary embolism (1 pt; after 4 months), recurrent zoster infection (1 pt; after 17 months of therapy) and physician choice (2 pts; after 9 and 16 months of therapy). Two pts discontinued therapy because of loss of response after 12 and 18 months of treatment, respectively. Thirty-one pts (91%) are alive. There have been no deaths on therapy. Three deaths occurred after discontinuation of therapy due to refractory disease (1), following HSCT (1) and due to progressive disease and adenocarcinoma of the lung (1). The most common grade 3–4 treatment-related hematological adverse events included neutropenia (15 pts, 44%), thrombocytopenia (3 pts, 9%) and anemia (1 pt, 3%). Thrombotic events occurred in 2 pts (6%). One pt experienced grade 3 pulmonary embolism and another patient grade 2 superficial vein thrombosis. In both cases with thrombotic event, ESAs were concomitantly administered. One pt (3%) experience a grade 3 infusion reaction during the first ofatumumab administration. Eight grade 3 infectious episodes occurred: pneumonia (3), neutropenic fever (2), parotitis (1), LE cellulitis (1) and CNS toxoplasmosis based on radiological findings (1). Intermittent grade 1–2 diarrhea was reported by 8 pts (24%). Grade 1–2 lenalidomide-associated tumor flare reaction was seen in 8 pts (24%). The median tolerated daily dose of lenalidomide was 5 mg/day (2.5-10 mg). In conclusion, the combination of ofatumumab and lenalidomide is well tolerated. Neutropenia was the most common toxicity. This combination induced responses in 65% of pts with relapsed CLL, all of whom had received prior chemoimmunotherapy. Responses are durable and ongoing in some pts. Disclosures: Ferrajoli: GlaxoSmithKline: Research Funding; Celgene: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Celgene: Consultancy. Wierda:GlaxoSmithKline: Research Funding.

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Dasatinib Has Activity in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL/SLL), a Phase II Trial

Blood ◽

10.1182/blood.v112.11.3162.3162 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3162-3162 ◽

Cited By ~ 1

Author(s):

Philip C. Amrein ◽

Eyal Attar ◽

Tak Takvorian ◽

Ephraim Hochberg ◽

Karen K. Ballen ◽

...

Keyword(s):

Bone Marrow ◽

Phase Ii ◽

Performance Status ◽

Lymphocytic Leukemia ◽

Ct Scans ◽

Fish Analysis ◽

Ecog Performance Status ◽

Bone Marrow Biopsies ◽

Lyn Kinase ◽

Grade 3

Abstract Background: Preclinical studies have shown that CLL cells overexpress lyn kinase protein, and in vitro inhibition of lyn kinase leads to apoptosis of the CLL cells (Contri, J Clin Invest 2005). Because dasatinib has been shown to inhibit lyn kinase in CML cells at concentrations easily achievable in patients, we undertook this phase II study in patients with previously treated CLL/SLL. Methods: Patients were required to be over 18 years of age, have a diagnosis of CLL/SLL by flow cytometry or immunohistochemistry, and have failed either 1 course of treatment with a fludarabine-containing regimen or 2 non-fludarabine containing regimens. The starting dose of dasatinib was 140 mg daily by mouth. This dose could be reduced to 100 mg or 80 mg daily for toxicity. At baseline all patients had bone marrow biopsies and CT scans, and these were repeated at 2 months. Sequential blood and bone marrow samples were tested for lyn kinase activity. Results: Among the 15 patients enrolled there were 10 male and 5 female subjects with a median age of 59 years (40–78 years). ECOG performance status was 0 in 9 subjects, 1 in 3, and 2 in 3 subjects. All patients had previously received fludarabine, and 5 patients required treatment within 6 months of their last regimen. The median number of prior treatments was 3 (range: 1 to 7). By cytogenetic/FISH analysis there were 5 patients with del(17p) and 6 patients with del(11q). All patients required treatment by NCI–WG criteria. The major toxicity encountered was myelosuppression: grade 3 + 4 neutropenia in 10 subjects, grade 3 + 4 thrombocytopenia in 4 subjects. Gastrointestinal toxicity was minor with only 1 subject experiencing grade 3 diarrhea. Other toxicities: 1 patient had a grade 2 pleural effusion, 1 patient had a transient serum K=9.9 (likely an artifact of high white count and without clinical sequelae), and 1 patient had a transiently prolonged QTc of 516 ms. There were no fatal events, and all toxicities were reversible. The median duration on study was 10 weeks, but 5 responding or stable patients have remained on treatment for over 9 months. Partial responses (PR) by NCI-WG criteria were achieved in 2 of the 15 patients (13% with 90% CI 2%–36%). An additional 2 patients would have qualified for PR (lasting >2 months) except for myelosuppression. Among the remaining 11 patients, 6 had nodal responses (2 CR and 4 PR) by physical exam (PE) without a 50% reduction in lymphocytosis. CT scans confirmed nodal responses in 3 of the 10 patients with nodal responses by PE. The relationship between clinical response and lyn kinase, bcl-2, and mcl-1 expression will be presented at the meeting. Conclusions: Dasatinib has modest activity in CLL, and combinations with standard agents, perhaps in an intermittent schedule, should be considered in subsequent trials.

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

Blood ◽

10.1182/blood.v128.22.233.233 ◽

2016 ◽

Vol 128 (22) ◽

pp. 233-233 ◽

Cited By ~ 53

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.

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The Combination of Lenalidomide and Rituximab Induces Complete and Partial Responses In Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v116.21.1395.1395 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1395-1395 ◽

Cited By ~ 3

Author(s):

Alessandra Ferrajoli ◽

Xavier Badoux ◽

Susan O'Brien ◽

William G. Wierda ◽

Stefan Faderl ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Research Funding ◽

Single Agent ◽

Tumor Lysis Syndrome ◽

Cell Activity ◽

Lymphocytic Leukemia ◽

Cytotoxic T Cell ◽

Tumor Lysis ◽

Significant Difference ◽

Grade 3

Abstract Abstract 1395 Lenalidomide is an immunomodulatory drug with single-agent activity in untreated and relapsed patients (pts) with chronic lymphocytic leukemia (CLL). Lenalidomide may potentiate the activity of rituximab through enhancement of NK and cytotoxic T-cell activity and antibody-dependent cytotoxicity. As lenalidomide is active as single-agent in relapsed/refractory CLL, we designed a trial to evaluate the combination of lenalidomide and rituximab in pts with previously treated CLL. Between 09/2008 and 10/2009, 59 pts with relapsed or treatment-refractory CLL were enrolled in this Phase II trial. Pts were eligible if they had relapsed disease requiring treatment and had received prior fludarabine-based therapy. Pts were required to have adequate performance status (WHO <3) and adequate renal and liver function (serum Cr or bilirubin <2mg/dl). Pts with an unrelated malignancy or with HIV, hepatitis B or C infection were excluded. Rituximab 375 mg/m2 was given intravenously weekly × 4 from Day 1 in Cycle 1 then every 4 weeks during cycles 3 – 12. Oral lenalidomide 10 mg/day was started on Day 9 of cycle 1 on a continuous dosing schedule. Cycles were 28 days with intention to continue therapy for 12 cycles or longer if the patient experienced a clinical response. Dose reductions were made following grade 3 or 4 lenalidomide-related toxicity. Allopurinol 300mg daily was prescribed during the first 2 weeks as tumor lysis prophylaxis. Response evaluation was performed with after cycles 3, 6 and every 6 cycles thereafter using 2008 IWCLL response assessment guidelines. Toxicity was graded according to CTC-v3.0 criteria. All 59 pts are evaluable for response and clinical outcome. Patient pre-treatment characteristics are shown in Table 1. All pts had prior rituximab therapy and 52 (88%) pts had prior chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR). The overall response rate was 64% with 5 complete responses (CR, 8%), 3 CR with incomplete hematological recovery (CRi, 5%), 7 nodular partial remissions (nPR, 12%) and 23 PR (39%). Most response (32/38, 84%) occurred by 3 cycles of therapy, but the majority of CR/CRi (7 of 8, 88%) occurred after 6 cycles of therapy. At a median follow-up of 14 months, the estimated treatment failure rate was 42% and estimated overall survival (OS) was 90%. There was no significant difference in responses or TTF for pts with deletion 17p when compared to other FISH subgroups. Two deaths occurred while on study therapy, one due to ischemic stroke and one to infectious exacerbation of chronic obstructive pulmonary disease. Six deaths occurred after progression of disease during subsequent therapies. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 40 (68%), 13 (22%) and 6 (10%) pts, respectively. Grade 3/4 infections occurred in 18 pts (31%), mostly lower respiratory tract. Seventy-three % of pts required a dose reduction of lenalidomide with a median tolerated daily dose of 5mg (2.5mg – 10mg). One patient experienced a grade 3 tumor lysis syndrome and 22 pts had grade 1–2 tumor flare reactions. In conclusion, combination therapy with lenalidomide and rituximab induces both complete and partial responses as salvage therapy in CLL. The addition of rituximab to lenalidomide appears to improve responses relative to single agent lenalidomide (Ferrajoli 2008, Chanan-Khan 2006) despite all pts having received prior rituximab-based therapies. This treatment was well tolerated with the most common toxicity being myelosuppression. Disclosures: Ferrajoli: Celgene: Research Funding; Genentech: Research Funding. Off Label Use: The use of lenalidomide in the treatment of chronic lymphocytic leukemia. O'Brien:Celgene: Consultancy; Genentech BioOncology: Consultancy. Wierda:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Advisory Board, Consultancy, Speakers Bureau. Estrov:Celgene: Consultancy. Keating:Celgene: Consultancy; Genentech: Consultancy.

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Final Analysis From the International Trial of Single-Agent Ofatumumab In Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v116.21.921.921 ◽

2010 ◽

Vol 116 (21) ◽

pp. 921-921 ◽

Cited By ~ 7

Author(s):

William G. Wierda ◽

Thomas J. Kipps ◽

Jiri Mayer ◽

Tadeusz Robak ◽

Martin JS Dyer ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Primary Endpoint ◽

Interim Analysis ◽

Research Funding ◽

Single Agent ◽

Early Death ◽

Progression Free Survival ◽

Final Analysis ◽

Lymphocytic Leukemia ◽

Grade 3

Abstract Abstract 921 Background: Patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab (FA-ref) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (BF-ref) have poor prognosis with salvage regimens (Tam et al. Leuk Lymphoma 2007). Ofatumumab, a human CD20 monoclonal antibody, was recently approved by the US FDA and EMEA for treatment of CLL refractory to fludarabine and alemtuzumab based on the interim analysis of the pivotal international clinical trial, which included data from 138 patients with FA-ref and BF-ref CLL. At the interim analysis, the overall response rate (ORR; primary endpoint) with single-agent ofatumumab was 58% (99% CI: 40, 74) in the FA-ref group and 47% (99% CI: 32, 62) in the BF-ref group (Wierda et al. J Clin Oncol 2010). Here, we report the final result for the primary endpoint in 206 patients with FA-ref or BF-ref CLL enrolled in this study. Methods: Patients with FA-ref or BF-ref CLL received 8 weekly doses of ofatumumab followed by 4 monthly doses (dose 1, 300 mg; doses 2–12, 2000 mg). Premedication included acetaminophen, antihistamine and glucocorticoid. The primary endpoint (ORR, 1996 NCI-WG criteria) was evaluated over the 24-week treatment period by an Independent Endpoint Review Committee (IRC). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS) and safety. Results: Baseline characteristics are summarized in the Table; 89% and 50% of patients completed 8 and 12 ofatumumab doses, respectively. The ORR (95% CI) by IRC evaluation was 51% (40, 61) for the FA-ref group and 44% (35, 64) for the BF-ref group. Two patients in the BF-ref group achieved complete remission (Table). Results for time-to-event analyses are shown in the Table. Infusion-related AEs occurred in 63% of patients, which primarily occurred during doses 1 and 2, and diminished with subsequent doses. Infusion-related reactions were grade 1–2 events in 95% of patients; no fatal reactions were reported. The most common (≥5% of all patients) grade ≥3 adverse events (AEs) that occurred from start of treatment until 30 days after the last infusion were infections (24%), neutropenia (12%) and anemia (5%). The most common grade ≥3 infection was pneumonia (8% of patients). Fatal infections occurred in 8% of patients (13% in FA-ref; 5% in BF-ref groups). Grade 3–4 thrombocytopenia occurred in 8 patients (4%), febrile neutropenia in 4 patients (2%) and autoimmune hemolytic anemia in 2 patients (1%). Early death (within 8 weeks from start of treatment) occurred in 5 patients (5%) in the FA-ref group (infections, n=5) and 4 patients (4%) in the BF-ref group (infections, n=2; myocardial infarction, n=1; pulmonary edema, n=1). Conclusions: These final results from the pivotal trial clearly demonstrate the efficacy and safety of ofatumumab monotherapy in this heavily pretreated patient population with FA-ref and BF-ref CLL. Additional data analyses are ongoing, and efficacy outcomes for patient subgroups will be presented. Disclosures: Wierda: GlaxoSmithKline: Honoraria, Research Funding. Kipps:GlaxoSmithKline: Research Funding. Mayer:GlaxoSmithKline: Consultancy, Research Funding. Robak:GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Furman:GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Cartron:GlaxoSmithKline: Honoraria; Roche: Honoraria. Padmanabhan:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chan:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Gorczyca:GlaxoSmithKline: Employment. Davis:GlaxoSmithKline: Employment. Losic:Genmab A/S: Employment, Equity Ownership. Lisby:Genmab A/S: Employment. Österborg:GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck KGaA: Research Funding.

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

Blood ◽

10.1182/blood.v120.21.718.718 ◽

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.

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Increasing Karyotypic Complexity Predicts Outcomes in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

Blood ◽

10.1182/blood-2020-136714 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 2-3

Author(s):

Daniel Goldstein ◽

Kyle A. Beckwith ◽

Cecelia Miller ◽

Ying Huang ◽

Lynne V. Abruzzo ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Retrospective Analysis ◽

Research Funding ◽

Performance Status ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Complex Karyotype ◽

Ecog Performance Status ◽

Cytogenetic Abnormalities ◽

Mutational Status

Introduction: Our group and others have previously shown that the presence of complex karyotype (>/= 3 cytogenetic abnormalities) is an important prognostic factor in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL) patients treated with ibrutinib (Woyach JCO 2017, Thompson Cancer 2015, Maddocks JAMA Oncology 2015). It has been shown recently that increasing karyotypic complexity is a prognostic marker (Baliakis Blood 2019), but whether this is relevant for patients treated with novel therapies is unclear. Here, we aimed to determine whether the degree of karyotypic complexity beyond the dichotomy of complex versus not is a prognostic variable for patients with CLL treated with ibrutinib. Methods: We conducted a retrospective analysis of all patients with CLL treated with ibrutinib as a single agent or in combination with a monoclonal anti-CD20 antibody (MOAB) from 2010 through 2019 at The Ohio State University. We included patients with both treatment-naïve (TN) and RR disease. To determine karyotype, cells were stimulated with mitogen cocktail (PWM/PMA/CpG-ODN) and analyzed according to standard laboratory procedures. FISH using probes for D13S319, D12Z3, ATM, and TP53 were done according to manufacturer's recommendations. PCR was used to determine IGHV mutational status. Cytogenetic testing was included in the analysis if done <6 months before or within 60 days after ibrutinib initiation. All characteristics were measured at ibrutinib start. Multivariable Cox proportional hazards models were built to correlate karyotypic complexity (defined as a continuous variable with 1 unit increases) with progression free survival (PFS) and overall survival (OS), adjusted for age, RR status, ECOG performance status (PS), lactate dehydrogenase (LDH), white blood cell (WBC) count, hemoglobin (HgB), platelet (PLT) count, presence of del17p13 and IGHV mutational status. Multivariable models were fit in imputed datasets, and estimates were obtained from combining results from across 30 imputed datasets. Results: We analyzed 561 patients with a median age of 65 (range 26-91). 86% were treated with ibrutinib monotherapy, 22% were TN, and median number of prior therapies was 2 (range 0-13). 96% had an ECOG performance status (PS) of 0 or 1. Median LDH, WBC, HgB and PLT were 213 U/L, 23.2 K/uL, 11.2 g/dL, and 115 K/uL respectively. With available data, del13q14, trisomy 12, del11q22, and del17p13 was present in 50%, 22%, 30%, and 29% of patients respectively; 74% of patients were IGHV unmutated. 63 patients were excluded from cytogenetic analyses as the test was not done during the specified time window. Of the 458 evaluable, 50% had >3 cytogenetic abnormalities including 30% with >5 abnormalities. After a median follow up of 55.5 months, for the entire cohort estimated median PFS was 61.6 months (95% CI 56.1-69.5), and estimated median OS was 95.4 months (95% CI 86.3-not reached). On univariable analysis, older age, RR status, higher ECOG PS and LDH, lower HgB and PLT, presence of del17p13 and increasing karyotypic complexity were found to be statistically significant predictors of worse PFS and OS. To illustrate the relationship between increasing karyotypic complexity and clinical outcome, Kaplan-Meier plots are provided grouping pts with 0-2, 3-4, and 5 or higher aberrations (Figure 1). Accounting for statistically and clinically important factors on multivariate analysis (MVA, Table 1), increasing karyotypic complexity continued to be a statistically significant predictor of both PFS (p=0.01, HR 1.08 (95% CI 1.02-1.15)) and OS (p=0.001, HR 1.14 (95% CI 1.05-1.23)). Del17p13 did not retain statistical significance independently of karyotypic complexity on MVA. The interaction effect between prior treatment status and karyotypic complexity term was not significant for OS (p=0.89) and PFS (p=0.46), suggesting the prognostic effect of karyotypic complexity is similar across TN and RR cohorts. Conclusions: In this single center retrospective analysis, we found that increasing karyotypic complexity predicts inferior survival for patients with CLL treated with ibrutinib. This highlights that it is not only important to dichotomize presence of complex karyotype as >3 abnormalities, but to describe the number of karyotypic abnormalities in subsequent studies. Disclosures Bond: Seattle Genetics: Honoraria. Byrd:Acerta Pharma: Research Funding; Trillium: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Janssen: Consultancy; Leukemia and Lymphoma Society: Other; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Vincera: Research Funding; Syndax: Research Funding. Rogers:AstraZeneca: Other: Travel; Abbvie, Acerta, AstraZeneca, Pharmacyclics: Consultancy; Abbvie, Genetech, Janssen: Research Funding. Woyach:Pharmacyclics: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; Loxo: Research Funding; Verastem: Research Funding.

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A Phase II Study of Dasatinib in Relapsed and Refractory Chronic Lymphocytic Leukemia (CLL/SLL).

Blood ◽

10.1182/blood.v110.11.3126.3126 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3126-3126 ◽

Cited By ~ 7

Author(s):

Philip C. Amrein ◽

Eyal C. Attar ◽

Tak Takvorian ◽

Ephraim P. Hochberg ◽

Karen Ballen ◽

...

Keyword(s):

Bone Marrow ◽

Phase Ii ◽

Phase Ii Study ◽

Performance Status ◽

Lymphocytic Leukemia ◽

Electrolyte Imbalance ◽

Fish Analysis ◽

Bone Marrow Biopsies ◽

Lyn Kinase ◽

Grade 3

Preclinical studies have shown that proliferation and survival of CLL cells are associated with overexpression of the Lyn kinase protein, and in vitro inhibition of Lyn kinase leads to apoptosis of the CLL cells (Contri, J Clin Invest 2005). Because dasatinib inhibits Lyn kinase in CML cells at doses easily achievable in patients, we undertook this phase II study of dasatinib in patients with previously treated CLL/SLL. Patients were required to be over 18 years of age, have a diagnosis of CLL/SLL by flow cytometry/immunostains, and have failed at least 1 course of treatment with a fludarabine-containing regimen or at least 2 courses of non-fludarabine containing regimens. The starting dose of dasatinib was 140 mg daily by mouth. This dose could be reduced to 100 mg or 80 mg daily for toxicity. At baseline all patients had bone marrow biopsies and CT scans, and these were repeated at 2 months. Sequential blood and bone marrow samples were tested for Lyn kinase activity. The design of the study provided for 2 phases such that if 3 responses were seen among the first 15 patients, the trial would expand to enroll another 20 patients. Among the first 9 patients enrolled there were 4 male and 5 female subjects with a median age of 59 years (40–78 years). ECOG performance status was 0 in 4 subjects, 1 in 3, and 2 in 2 subjects. All patients had previously received fludarabine: 1 subject had 1 prior treatment, 3 had 2 prior treatments, 3 had 3 prior treatments, and 2 had 4 prior treatments. By cytogenetic/FISH analysis there were 2 patients with del(17p) and another 4 patients with del(11q). All patients required treatment by NCI Working Group criteria. The major toxicity encountered was myelosuppression: grade 3 + 4 neutropenia in 7 subjects, grade 3 + 4 thrombocytopenia in 5 subjects. Gastrointestinal toxicity was minor with only 1 subject experiencing grade 3 diarrhea. One subject developed a grade 2 pleural effusion. There was 1 patient with an electrolyte imbalance consisting of a transient serum K=6.8, and in 1 patient there was a transiently prolonged QTc of 516 ms. There were no fatal events, and all toxicities were reversible. The median duration of treatment on study was 9 weeks with a range of 4 to 23 weeks. The clinical response data of the first 15 patients will be presented along with the correlative studies of Lyn kinase inhibition by dasatinib.

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Retrospective Analysis of the Experience with Rituximab and Methylprednisone In Elderly Patients with CLL

Blood ◽

10.1182/blood.v116.21.4636.4636 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4636-4636

Author(s):

Xavier Badoux ◽

Ali M Al-Ameri ◽

Susan O'Brien ◽

William G. Wierda ◽

Jan A. Burger ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Partial Response ◽

Elderly Patients ◽

Research Funding ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Chromosome 17 ◽

High Dose ◽

Β2 Microglobulin ◽

Grade 3

Abstract Abstract 4636 Background: Single agent rituximab has limited activity in chronic lymphocytic at standard doses; however, the addition of rituximab to purine analogues, monoclonal antibodies or steroids has been shown to improve responses and response duration in patients with untreated and relapsed chronic lymphocytic leukemia (CLL). The combination of rituximab and high dose methylprednisone has shown activity in patients with untreated and fludarabine-refractory CLL (Castro 2008, Castro 2009); however, there is limited reported experience with this regimen in elderly patients. These data prompted us to review our center's experience with rituximab in combination with high dose methylprednisone in elderly patients with CLL. Patients and Methods: We retrospectively identified 24 patients 65 years or older with CLL who received rituximab and methylprednisone between July 2002 and April 2010 at MD Anderson Cancer Center. Six patients received this treatment as initial therapy and 18 patients as salvage treatment. Rituximab 375–750 mg/m2 and methylprednisone 500–2000 mg were administered i.v. weekly for 4 weeks. Three patients received further maintenance treatment with rituximab 375–750 mg/m2 and methylprednisone 500 mg/m2 every month or every 3 months until failure of response. Responses were assessed according to 2008 NCI-WG criteria. Estimated progression free survival and OS were analyzed from time of treatment to progression or death using Kaplan-Meier survival curves. Results: The median age was 71 (65 – 87) years and 17 of 24 (71%) had Rai stage III or IV disease. Two patients had concomitant autoimmune hemolytic anemia (AIHA), one patient had immune thrombocytopenic purpura and AIHA was the indication for therapy in one patient. Median β2-microglobulin was 7.7 (2.3 – 21) mg/l and 5 patients had chromosome 17 abnormalities. Previously treated patients had received a median of 3 (1 – 7) prior treatments and 6 (32%) pts were refractory to fludarabine. Responses were observed in 4 of 6 untreated patients (ORR 67%) and included 3 clinical complete responses unconfirmed by bone marrow biopsy (CRu, 50%) and 1 partial response. The estimated median PFS and OS in this group were 13 and 55 months, respectively. Among patients who received rituximab and methylprednisone as salvage therapy, 7 patients achieved a partial response (ORR 39%), 10 (50%) patients failed treatment, 1 patient (6%) received another therapy after 1 cycle for lack of response and 1 patient (6%) was lost to follow-up. In the salvage group, estimated median PFS and OS were 4 and 18 months, respectively. Four deaths occurred 3, 5, 11 and 12 months after rituximab and methylprednisone without further therapy; 3 patients had progressive CLL and the cause of death was unknown in 1 patient. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in 6 (33%), 3 (14%) and 1 (5%) of evaluable patients. Four patients (17%) experienced grade 3 or 4 infections (3 pneumonia and 1 colonic abscess), 5 patients experienced minor infections and 3 patients experienced viral reactivations (1 CMV, 1 HSV, 2 VZV). There were four grade 3 or 4 non-hematological adverse events including grade 4 gastrointestinal and pulmonary hemorrhage (1), colitis (1), steroid myopathy (1) and peripheral edema (1). All grade 3 or 4 complication occurred in salvage patients. Conclusions: Based on our experience, rituximab and methylprednisone therapy can be safely administered to older patients with CLL. As previously reported by Castro et al, higher response rates were seen in untreated patients, whereas responses were less frequent and shorter lasting in patients with relapsed disease, although this group had high risk disease based on β2-microglobulin levels. Additional studies are required to explore the benefit of this regimen in elderly patients with CLL. Disclosures: Off Label Use: Ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia. O'Brien:Celgene: Consultancy; Genentech BioOncology: Consultancy. Wierda:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Advisory Board, Consultancy, Speakers Bureau. Estrov:Celgene: Consultancy. Keating:Celgene: Consultancy; Genentech: Consultancy. Ferrajoli:Celgene: Research Funding; Genentech: Research Funding.

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Bendamustine + Rituximab (BR) Chemoimmunotherapy and Maintenance Lenalidomide in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): A Wisconsin Oncology Network (WON) Study

Blood ◽

10.1182/blood.v120.21.3647.3647 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3647-3647

Author(s):

Julie E. Chang ◽

Chong Zhang ◽

KyungMann Kim ◽

Rachel Kirby ◽

Lynn Volk ◽

...

Keyword(s):

Maintenance Therapy ◽

Stable Disease ◽

Research Funding ◽

Progressive Disease ◽

Single Agent ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Fish Analysis ◽

Minor Response ◽

Grade 3

Abstract Abstract 3647 Introduction: BR chemoimmunotherapy was shown to have an overall response rate (ORR) of 59%, a median progression-free survival (PFS) of 14.7 months, and an acceptable toxicity profile in R/R CLL (Fischer K, et al. J Clin Oncol 2011). Given the single-agent activity of lenalidomide in R/R CLL/SLL, we hypothesized that maintenance lenalidomide after BR induction could improve PFS. Methods: Thirty-four patients requiring therapy for R/R CLL/SLL were treated with bendamustine 90 mg/m2 IV on days 1 & 2 and rituximab 375 mg/m2 IV on day 1 every 28 days for a maximum of 6 cycles. Growth factor support was permitted. Patients achieving at least a minor response (objective improvement even if not meeting criteria for partial response) were eligible to proceed with 12 cycles of maintenance therapy with lenalidomide 5–10 mg/day orally given continuously in each 28-day cycle. Patients were eligible if they had histologically proven CLL/SLL and had received >1 but ≤5 prior cytotoxic chemotherapy regimens (retreatment with an identical regimen was not counted as a separate treatment). The primary endpoint was PFS. Results: Baseline characteristics include median age 67 (range 38–86), 25 men/9 women, 26 CLL/8 SLL, and median of 2 prior therapies (range 1–4). Cytogenetic profiling by FISH analysis was available in 22 patients (65%), with 11/22 demonstrating presence of 17p and/or 11q deletions. Twenty-five patients (74%) completed 6 cycles of induction BR. Two patients died from toxicities of pneumonia and heart failure during cycle 1; 7 patients received <6 cycles due to toxicities (n=4), progressive disease (n=2), and stable disease (n=1). Dose modifications were required in 14 (41%) patients, most commonly for neutropenia (12/14), thrombocytopenia (3/14), and weight loss/failure to thrive (3/14). Grade 3/4 toxicities were primarily hematologic, with neutropenia in 20 patients, anemia in 1, and thrombocytopenia in 7. Febrile neutropenia occurred in 4 patients. Infections with or without neutropenia were common; grade 2 infections in 16 patients, grade 3 in 7 patients. Grade 2 rash occurred in 4 patients. Eleven deaths have been observed, 7 events due to progressive disease (including 2 events of transformed lymphoma). Responses were evaluable in 31/34 patients. The ORR was 65%, with 6 complete (18%) and 16 partial (47%) responses. An additional 7 patients achieving stable disease were eligible to proceed to maintenance therapy. With a median follow up of 20.1 months, the median PFS and overall survival are 24.3 months and 27.9 months, respectively. Conclusions: In our multicenter trial for patients with R/R CLL/SLL, the BR induction produced an ORR that is comparable to historical observations (65% vs 59%). However, the median PFS is longer (24.3 vs 14.7 months), suggesting maintenance lenalidomide may be contributing to an improved response duration. Based upon these promising results, we have initiated a successor study in which patients will receive lenalidomide plus rituximab maintenance after a BR induction. Disclosures: Chang: Celgene: Research Funding; Genentech: Research Funding. Off Label Use: Lenalidomide as maintenance therapy for CLL after induction rituximab + bendamustine chemoimmunotherapy. Fenske:Spectrum Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kahl:Millennium: Consultancy, Research Funding; Roche: Consultancy; Genentech: Consultancy, Research Funding.

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