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Meeting Report
Highlights in the treatment of chronic lymphocytic leukemia from the 2014 meeting of the American Society of Hematology Expert Rev. Hematol. 8(3), 277–281 (2015)
Stefano Molica Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Viale Pio X – 88100 Catanzaro, Italy Tel.: +39 096 188 3001 Fax: +39 096 188 3221 [email protected]
Included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL) Annual Meeting of the American Society of Hematology (ASH) held from 6–9 December 2014 in San Francisco The latest Annual Meeting of the American Society of Hematology, held in San Francisco, included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL). MABTENANCE and PROLONG study suggest that either rituximab or ofatumumab improves progression-free survival in CLL. According to final analysis of CLL-10 trial, rituximab and bendamustine may have a role in the upfront treatment of fit elderly patients. Further insight into the use of ibrutinib, a first-in-class covalent Bruton’s tyrosine kinase-inhibitor that is currently approved for patients with relapsed/refractory CLL and with del(17p), was also presented. Idelalisib, a selective inhibitor of PI3K delta, demonstrated its activity with manageable toxicity in previously untreated patients ‡65 years with CLL or small lymphocytic lymphoma. Finally, a series Phase I/II studies of BCL-2 inhibitor (i.e., venetoclax, GDC-0199) used alone or in combination provide promising results in patients with relapsed/refractory CLL.
The American Society of Hematology (ASH) annual meeting includes physicians, scientists, administrators, medical students, graduate students, allied health professionals and exhibitors. This year’s meeting was held in San Francisco, CA, and presentations focused on multidisciplinary approaches to the management of benign and malignant hematologic diseases with emphasis on the use of emerging therapeutic agents. In the area of chronic lymphocytic leukemia (CLL), several clinical trials provided further support for the role of immunotherapy in managing patients with either newly diagnosed or relapsed/refractory CLL. Findings from the CLL11 study suggest that the association of obinutuzumab plus chlorambucil, which is informahealthcare.com
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going to become a new standard of care in elderly/unfit patients with previously untreated CLL, is also effective in patients who are refractory to single-agent chlorambucil [1,2]. In the analysis presented by Goede et al. [2], 30 patients enrolled in the CLL11 trial chlorambucil arm were crossed over to salvage therapy with obinutuzumab plus chlorambucil after developing progressive disease within 6 months of completing frontline treatment. Notably, most patients (93%) who crossed over to salvage therapy with obinutuzumab plus chlorambucil had failed to respond to frontline chlorambucil treatment. The overall response rate (ORR) was 87%, while 7% of patients achieved complete response (CR), 3% incomplete response and 77% partial
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Molica
response (PR). In addition, minimal residual disease (MRD) negativity in the bone marrow and/or peripheral blood was obtained in 23% of patients. The grade 3/4 toxicity observed consisted of neutropenia in 33% of patients, infusion-related reactions in 17%, infection in 13%, thrombocytopenia in 10% and anemia in 7%. Finally, median progression-free survival (PFS) was 17.2 months [2]. Authors pointed out that the association of obinutuzumab plus chlorambucil is active as salvage therapy in patients with chlorambucil-refractory CLL. However, results from the CLL11 trial provide a strong rationale for giving chemoimmunotherapy upfront rather than later in the treatment sequence in elderly/unfit CLL patients [2]. There have been some investigational studies of rituximab as maintenance therapy in CLL [3]. In these trials, which generally included a small number of patients, hematologic and immunologic toxicity was mild [3]. Recently, Abrisqueta et al. [4] report a Phase II clinical trial consisting of an initial treatment with rituximab, fludarabine, cyclophosphamide and mitoxantrone followed by rituximab maintenance every 3 months for 2 years. Maintenance with rituximab after rituximab, fludarabine, cyclophosphamide and mitoxantrone improved the quality of the response, particularly in patients who were MRD-positive, after initial treatment and prolonged PFS. At the 2014 ASH meeting, Greil et al. [5] presented interim analysis of an international, multicenter, Phase III study (MABTENANCE trial), which enrolled 263 patients who achieved at least a PR to any rituximab-containing chemoimmunotherapy induction regimen in the first- or second-line settings. Patients were randomly assigned to rituximab maintenance therapy every 3 months (n = 134) or observation (n = 129) for up to 24 months. The primary endpoint was PFS. After a median follow-up of 17.3 months, 85.1% of patients in the rituximab maintenance arm remained free from disease progression when compared with 75.5% of patients in the observation arm (p = 0.007). Serious infections were more common in the rituximab maintenance arm (15.7%) than in the observation arm (7.0%). Secondary malignancies were also more common following rituximab maintenance (4.5%) than observation (1.6%). Results of studies addressing the role of ofatumumab (OFA) or lenalidomide as maintenance therapy in CLL have also been presented at the meeting [6,7]. PROLONG is an open-label, twoarm randomized trial of OFA versus observation that enrolled 476 patients in remission after induction treatment for relapsed CLL. The median PFS was 28.6 months for patients assigned to receive OFA and 15.2 months for patients randomized to observation (hazard ratio [HR] = 0.48; p < 0.0001). After a median follow-up of 26.1 months for OFA arm and 24.0 months for the observation arm, no differences in overall survival (OS) were found (HR = 0.92, p = 0.74) [6]. The CLLM1 trial, is a Phase III, randomized, double-blinded, placebo-controlled study designed to investigate the efficacy and safety of lenalidomide maintenance therapy for HR CLL following first-line chemoimmunotherapy. Adverse events (AEs) reported were generally mild or moderate and reasons for discontinuation were mostly nonserious events, including skin reactions and fatigue [7]. 278
In conclusion, results of these interim analyses suggest that an anti-CD20 monoclonal antibody (i.e., rituximab or OFA) or lenalidomide as maintenance after first- or second-line induction chemoimmunotherapy are safe treatment strategies in CLL [5–7]. Notably, maintenance with either rituximab or OFA prolongs PFS in comparison with observation, although longer follow-up analyses are needed to better define the benefits of this approach in CLL [5,6]. What should be kept in mind is that current guidelines do not recommend maintenance or consolidation therapy outside of clinical trials [8]. Eichhorst et al. [9] presented the final analysis of CLL-10 trial. This Phase III study was designed to demonstrate the noninferiority of frontline bendamustine and rituximab (BR) compared with fludarabine, cyclophosphamide and rituximab (FCR) in patients with active CLL without del(17p) who were classified as medically fit (cumulative illness rating scale score £6, creatinine clearance ‡70 ml/min). Patients were randomly assigned to treatment with six courses of FCR (n = 284) or BR (n = 280). The primary endpoint was PFS. ORR was equivalent in each treatment group (95.4 vs 95.7%; p = 1.0); however, patients in the FCR group were significantly more likely than those treated with BR to achieve a CR (39.7 vs 30.8%; p = 0.034). The median PFS was 55.2 months in the FCR group compared with 41.7 months in the BR arm (p < 0.001). The PFS benefit of FCR compared with BR persisted in patients aged £65 years (53.6 vs 38.5 months; p < 0.001), whereas it was no longer observed among patients aged >65 years (median PFS not reached vs 48.5 months; p = 0.170). Although no differences in OS between the FCR and BR groups at 36 months (90.6 vs 92.2%; p = 0.897) could be found, toxicity profiles favored BR, particularly in older patients. FCR significantly increased the risk of neutropenia (84.2 vs 59.0%; p < 0.001), thrombocytopenia (21.5 vs 14.4%; p = 0.03) and infection (39.1 vs 26.8%; p < 0.001) compared with BR. Interestingly, a twofold risk of developing infections was observed in the FCR group in comparison with BR group for patients aged >65 years (47.7 vs 20.6%; p < 0.001). In summary, results of CLL-10 trial suggest that frontline treatment with BR failed to outperform the goldstandard regimen of FCR in medically fit patients with CLL [7]. However, the milder toxicity profile of BR suggests that this association may have a role in the upfront treatment of fit elderly patients and medically unfit patients with advanced CLL [10]. The assessment of MRD at the end of therapy is a clinically relevant issue in CLL. In a pooled analysis of two Phase III studies of the German CLL study group (GCLLSG; i.e., CLL8 trial: fludarabine and cyclophosphamide without [FC] or with rituximab [FCR] and CLL10 trial: FCR vs BR), which included 542 patients, Kovacs et al. analyzed MRD status. Results indicate that MRD negativity determined in the peripheral blood after the end of treatment is a potent predictor of treatment efficacy regardless of the clinical response assessment. In addition, the persistence of splenomegaly as sole abnormality post treatment in MRD-negative patients has no negative influence on PFS [11]. Current guidelines recommend evaluation of MRD only for patients included in clinical trials; however, Expert Rev. Hematol. 8(3), (2015)
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News from 2014 ASH meeting
results of this study underscore its potential importance also in the day-to-day practice. Three studies presented provide further insight into the use of ibrutinib, a first-in-class covalent inhibitor of Bruton’s tyrosine kinase (BTK), that is currently approved for patients with relapsed/refractory CLL and for those with CLL with del (17p) [12–14]. According to the primary analysis of the RESONATE trial, ibrutinib, compared with OFA, improved PFS and OS in patients with CLL who had received at least one prior therapy [15]. The updated analysis performed after a 16-month follow-up provides further evidence for the consistent activity of ibrutinib in patients with relapsed/refractory CLL, regardless of number of prior therapies or high-risk genetic abnormalities [12]. In another subanalysis from the RESONATE trial, Barrientos et al. [13] evaluated changes of patient well-being and quality of life following treatment with ibrutinib or OFA. In the ibrutinib arm, 69% of patients experienced constant improvement of cytopenias, compared with 43% of patients in the OFA arm (p < 0.0001). This was particularly true for platelet counts (72 vs 22%, respectively; p < 0.0001) and absolute neutrophil counts (64 vs 32%, respectively; p = 0.0047). Also findings of patientreported outcomes were in favor of treatment with ibrutinib. Clinically meaningful improvement in fatigue scores (59 vs 46%, respectively; p = 0.06) could be observed at week 24 in the ibrutinib arm in comparison with OFA arm. Interestingly, IgA levels increased in the ibrutinib group, with a mean increase of 41% at week 24 compared with baseline. In summary, according to the improvements in hematologic and immunologic function, as well as patient-reported outcomes, in comparison with OFA, ibrutinib impacts favorably the quality of life of patients with relapsed/refractory CLL [13]. Clinical outcome of patients with CLL bearing del(17p) is typically poor and median survival of less than 2 years in the relapsed/refractory setting [16]. RESONATE-17 is the largest prospective trial dedicated solely to the study of patients with CLL and small lymphocytic lymphoma (SLL) who have the del(17p) mutation. In RESONATE-17, 144 previously treated patients with del (17p) (137 with CLL, seven with SLL) received single-agent ibrutinib once daily until progression [14]. The primary endpoint of the open-label, single-arm, multicenter trial was ORR. Investigator-assessed ORR was 82.6%, whereas independent review committee-assessed ORR was 65%. After a median follow-up of 13 months, the median PFS as assessed by the investigator had not been reached. The most common grade 3 or 4 AEs in the RESONATE-17 trial were neutropenia (14%), anemia (8%), pneumonia (8%) and hypertension (8%). The most frequently reported AEs of any grade were diarrhea (36%), fatigue (30%), cough (24%) and arthralgia (22%). Atrial fibrillation of any grade was reported in 11 people (7.6%). Major hemorrhage was reported in seven people (4.9%). At the time of the data assessment, the median treatment duration was 11.1 months, and 70% of patients continued treatment with ibrutinib. In conclusion, patient PFS in the RESONATE17 trial compares favorably with that of informahealthcare.com
Meeting Report
treatment-naı¨ve del(17p) CLL patients receiving FCR or alemtuzumab. These results support ibrutinib as an effective therapy for patients with del(17p) CLL/SLL. It is unknown whether subpopulations of patients with del (17p) may have a different pattern of response to ibrutinib. Del (17p) is frequently associated with a complex metaphase karyotype, which has been associated with inferior outcomes in CLL; however, the prognostic significance of this finding in ibrutinibtreated patients is unknown [17]. According to results of MD Anderson Cancer Center group based on 100 patients treated for relapsed/refractory CLL with investigational ibrutinib-based regimens, it seems that the presence of complex metaphase karyotype (i.e., defined as ‡3 distinct chromosomal abnormalities) is independently associated with inferior event-free survival and OS, whereas the same does not apply for del(17p) [17]. The inferior outcomes of patients with complex metaphase karyotype make them ideal candidates for treatment-intensification strategies in the context of well-designed clinical trials. In addition to ibrutinib, new BTK-inhibitors are now under investigation in both CLL and non-Hodgkin lymphomas. ONO-4059 is a highly potent selective inhibitor of BTK tested in 25 CLL patients who were enrolled in the ongoing Phase I study ONO-4059POE001 [18]. Patients had a median age of 67 (range 40–79) years and had received a median number of four prior therapies [2–8], including a rituximab-containing therapy in 23 of 25. Best ORR according to International Workshop on CLL criteria (including modified PR with lymphocytosis) was observed in 84% patients. Eight dose-independent ONO-4059-related G3 or G4 hematological toxicities were reported in five patients, while six grade 3 ONO-4059-related nonhematological events were recorded. These results qualify ONO-4059 as a promising oral BTK inhibitor with a favorable safety profile along with promising efficacy [18]. Idelalisib, a first-in-class, oral, highly selective, inhibitor of PI3K delta, was recently approved in combination with rituximab for the treatment of relapsed CLL [19,20]. Idelalisib plus rituximab significantly increases response and survival compared with rituximab alone across all genetic and clinical subgroups in patients with relapsed CLL, according to updated findings from an ongoing Phase III trial. Sharman et al. [21] focused on patient subgroups with poor prognostic factors as defined by unmutated immunoglobulin heavy chain variable (IGHV) (84%); del(17p) and/or TP53 mutation (43%); and del(11q) (34%). According to the authors’ results, it seems that the PFS benefit with idelalisib plus rituximab versus placebo plus rituximab was maintained in patients with unmutated IGHV (NR vs 4.0 months); del(17p)/TP53 mutation (NR vs 4.0 months) and del11q (10.7 vs 6.9 months). Despite the crossover trial design, a significant improvement in OS with idelalisib versus placebo was consistent for patients with unmutated IGHV (NR vs 18.1 months; HR, 0.35; p = 0.0003) and in those with del(17p) or TP53 mutation (NR vs 14.8 months; HR: 0.31; p = 0.001). In summary, idelalisib plus rituximab demonstrated a substantial benefit across all patient subgroups, regardless of high-risk genetic markers, such as unmutated 279
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IGVH, del(17p), TP53 mutation and del(11q). A Phase II study reports the preliminary experience with idelalisib single agent in 37 previously untreated CLL patients older than 65 years [22]. With an 81% ORR, which included 33% PR and 48% PR with lymphocytosis, idelalisib demonstrated a substantial single agent activity in treatment-naı¨ve patients with CLL or SLL. In this preliminary analysis, the safety profile of idelalisib was manageable, although early lymphocytosis with monotherapy was more frequent in comparison with lymphocytosis seen in the earlier cohort treated with idelalisib plus weekly rituximab [19,22]. Duvelisib, also known as IPI-145, inhibits both the gamma and delta isoforms of PI3 kinase. O’Brien et al. [23] evaluated the safety, maximum tolerated dose, pharmacokinetics and clinical activity of duvelisib administered in 54 patients with relapsed/ refractory CLL. The best ORR by International Workshop on CLL criteria was 55% in 49 evaluable patients, including one CR and 26 PR. The ORR was similar irrespective of dose (52%, £25 mg two-times a day [n = 29]; 60%, 75 mg two-times a day [n = 20]), or the presence of TP53mut/del(17p) (48% [n = 23], including one CR) or unmutated IGHV (52%, n = 31). As authors concluded, these results support the development of randomized Phase III studies with duvelisib in patients with relapsed/refractory CLL. For patients treated with ibrutinib who have disease progression, various mechanisms of ibrutinib resistance have been described [24]. Since the mechanism of action of duvelisib differs from ibrutinib, duvelisib was evaluated in a subset of 13 patients (6 with CLL, seven with non-Hodgkin’s lymphoma) previously treated with ibrutinib who were enrolled in an ongoing Phase I study [25]. Following treatment, five patients experienced stable disease, while one patient achieved a PR. Authors stressed the activity of this PI3K inhibitor in patients previously treated with ibrutinib, although the small number of patients analyzed prevent from drawing firm conclusions [25]. Venetoclax is a BCL-2 inhibitor that currently has a registration study pending for patients with del(17p). The primary objectives of study presented by Roberts et al. [26] were safety of the combination of venetoclax and rituximab, determination of maximum tolerated dose, optimal dose and dosing schedule in patients with relapsed/refractory CLL. The ORR was 89% and roughly one-third of patients achieved a CR. Noteworthy,
2.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Society of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
References 1.
22% of patients with del(17p) achieved a CR and 56% a PR. The 46% MRD-negativity in the bone marrow highlights the impressive efficacy of venetoclax. In conclusion, efficacy and the depth of remissions obtained with venetoclax are relevant. Phase III studies are currently in progress comparing venetoclax plus rituximab with BR in patients with previously treated CLL [27]. Salles et al. [28] presented data from an ongoing Phase Ib study that is evaluating the maximum tolerated dose of GDC-0199, an orally available, selective BCL2 inhibitor, given in combination with BR, in relapsed/refractory or previously untreated patients with CLL. In this study, the most frequent AEs were hematological toxicities and generally manageable. Two patients had to discontinue BR (after one and three cycles) but were able to remain on GDC-0199. Dose escalation in relapsed/refractory patients is continuing to evaluate the optimal dose and schedule with the aim to enroll previously untreated patients in the near future. In a Phase Ib study, GDC-0199 was associated with obinutuzumab [29]. The data presented by Flinn et al. [29] suggest that the combination is safely administered at the doses given (GDC-0199 given at dose of 100 or 200 mg/day). Nine patients were at medium or high risk for tumor lysis syndrome; however, only one developed laboratory tumor lysis syndrome, which was transient and managed. In the experience of authors, a gradual dose ramp-up of GDC-0199 appear to reduce the incidence of tumor lysis syndrome. A GDC-0199 dose escalation in relapsed/refractory patients at 400 mg/day is planned. In conclusion, this year, significant data were presented at the annual ASH meeting in the field of CLL treatment. They appear to be particularly relevant because of the longer patient followup. What is emerging is that the management of CLL is undergoing profound changes. The challenge is now to find the best combination and sequence of treatments to get the long-term control of CLL without worsening the patient’s quality of life.
Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370: 1101-10
3.
Goede V, Engelke A, Fischer K, et al. Salvage therapy with obinutuzumab (GA101) plus chlorambucil (Clb) after treatment failure of Clb alone in patients with chronic lymphocytic leukemia (CLL) and comorbidities: results of the CLL11 Study [abstract 3327]. American
Del Poeta G, Del Principe MI, Buccisano F, et al. Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia. Cancer 2008; 112(1):119-28
4.
Abrisqueta P, Villamor N, Terol MJ, et al. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-
280
FCM) for chronic lymphocytic leukemia. Blood 2013;122(24):3951-9 5.
Greil R, Obrtlikova P, Smolej L, et al. Rituximab maintenance after chemoimmunotherapy induction in 1st and 2nd line improves progression free survival: planned interim analysis of the international randomized AGMT-CLL8/a Mabtenance trial [abstract 20]. American Society of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
6.
van Oers MHJ, Kuliczkowski K, Smolej L, et al. Ofatumumab (OFA) maintenance
Expert Rev. Hematol. 8(3), (2015)
News from 2014 ASH meeting
prolongs PFS in relapsed CLL: prolong study interim analysis result [abstract 21]. American Society of Hematology (ASH) Annual Meeting; December 6-9, 2014; San Francisco, CA
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 06/04/15 For personal use only.
7.
Eichhorst B, Bahlo J, Fink AM, et al. Good tolerance of lenalidomide maintenance therapy in patients with high risk profile chronic lymphocytic leukemia (CLL) after frontline chemoimmunotherapy: preliminary safety overview of the CLLM1 trial of the German CLL study group (GCLLSG) [abstract 4699]. American Society of Hematology (ASH) Annual Meeting; 6-9 December 2014; San Francisco, CA
8.
Robak T. Maintenance in CLL. Blood 2013;122(24):3854-5
9.
Eichhorst B, Fink AM, Busch R, et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) shows superior efficacy in comparison to bendamustine and rituximab (BR) in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia (CLL): Final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study) [abstract 19]. American Society of Hematology (ASH) Annual Meeting; 6-9 December 2014; San Francisco, CA
10.
11.
12.
13.
Cuneo A, Marchetti M, Barosi G, et al. Appropriate use of bendamustine in first-line therapy of chronic lymphocytic leukemia. Recommendations from SIE, SIES, GITMO Group. Leuk Res 2014; 38(11):1269-77 Kovacs G, Boettcher S, Bahlo J, et al. Value of minimal residual disease (MRD) negative status at response evaluation in chronic lymphocytic leukemia (CLL): combined analysis of two phase III studies of the German CLL study group (GCLLSG) [abstract 23]. American Society of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA Brown JR, Hillmen P, O’Brien S, et al. Updated efficacy including genetic and clinical subgroup analysis and overall safety in the phase 3 RESONATE trial of ibrutinib versus ofatumumab in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma [abstract 3331]. American Society of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA Barrientos JC, O’Brien S, Brown JR, et al. Hematologic and immunologic function and patient well-being for the phase III
informahealthcare.com
RESONATE study of ibrutinib vs ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma [abstract 4696]. American Society of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA 14.
15.
O’Brien S, Jones JA, Coutre S, et al. 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 [abstract 327]. American Society of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA Byrd JC, Brown JR, O’Brien S, et al. RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371(3):213-23
16.
Tam CS, Stilgenbauer S. Clinical dilemmas: how best to manage CLL patients with 17p Deletion and/or TP53 mutation? Leuk Lymphoma 2015;56(3):587-93
17.
Thompsonm PA, Wierda WG, Ferrajoli A, et al. Complex karyotype, rather than del (17p), is associated with inferior outcomes in relapsed or refractory CLL patients treated with ibrutinib-based regimens [abstract 22]. American Society of Hematology (ASH) Annual Meeting; 6– 9 December 2014; San Francisco, CA
18.
Fegan C, Bagshawe J, Salles G, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ONO-4059: promising single agent activity and well tolerated in patients with high risk chronic lymphocytic leukaemia (CLL) [abstract 3328]. American Society of Hematology (ASH) Annual Meeting; 6– 9 December 2014; San Francisco, CA
19.
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370:997-1007
20.
Coutre SE, Furman RR, Sharman JP, et al. Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. J Clin Oncol 2014;32:5s (Suppl; abstr 7012)
21.
Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a phase 3 study of idelalisib (Zydelig) plus rituximab for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors [abstract 330]. American Society of Hematology (ASH)
Meeting Report
Annual Meeting; 6–9 December 2014; San Francisco, CA 22.
Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib monotherapy in previously untreated patients ‡65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [abstract 1986]. AmericanSociety of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
23.
O’Brien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3K-d,g inhibitor, is clinically active in patients with relapsed/ refractory chronic lymphocytic leukemia [abstract 3334]. AmericanSociety of Hematology (ASH) Annual Meeting. 6– 9 December 2014; San Francisco, CA
24.
Komarova NL, Burger JA, Wodarz D. Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL). Proc Natl Acad Sci USA 2014;111(38):13906-11
25.
Porcu P, Flinn I, Kahl BS, et al. Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-Kinase-d,g inhibitor, in patients previously treated with ibrutinib [abstract 3335]. AmericanSociety of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
26.
Roberts AW, Ma S, Brander DM, et al. Determination of recommended phase 2 dose of ABT-199 (GDC-0199) combined with rituximab (R) in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) [abstract 325]. AmericanSociety of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
27.
Available from: www.mskcc.org/cancer-care/ trial/14-215
28.
Salles GA, Boyd TE, Morschhauser F, et al. Preliminary results of a phase 1b study (GO28440) combining GDC–0199 (ABT– 199) with bendamustine/rituximab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia [abstract 3337]. AmericanSociety of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
29.
Flinn I, Brunvand M, Dyer MJS, et al. Preliminary results of a phase 1b study (GP28331) combining GDC-0199 (ABT199) and obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia [abstract 4687]. AmericanSociety of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA
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Meeting Report
Highlights in the treatment of chronic lymphocytic leukemia from the 2014 meeting of the American Society of Hematology Expert Rev. Hematol. 8(3), 277–281 (2015)
Stefano Molica Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Viale Pio X – 88100 Catanzaro, Italy Tel.: +39 096 188 3001 Fax: +39 096 188 3221 [email protected]
Included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL) Annual Meeting of the American Society of Hematology (ASH) held from 6–9 December 2014 in San Francisco The latest Annual Meeting of the American Society of Hematology, held in San Francisco, included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL). MABTENANCE and PROLONG study suggest that either rituximab or ofatumumab improves progression-free survival in CLL. According to final analysis of CLL-10 trial, rituximab and bendamustine may have a role in the upfront treatment of fit elderly patients. Further insight into the use of ibrutinib, a first-in-class covalent Bruton’s tyrosine kinase-inhibitor that is currently approved for patients with relapsed/refractory CLL and with del(17p), was also presented. Idelalisib, a selective inhibitor of PI3K delta, demonstrated its activity with manageable toxicity in previously untreated patients ‡65 years with CLL or small lymphocytic lymphoma. Finally, a series Phase I/II studies of BCL-2 inhibitor (i.e., venetoclax, GDC-0199) used alone or in combination provide promising results in patients with relapsed/refractory CLL.
The American Society of Hematology (ASH) annual meeting includes physicians, scientists, administrators, medical students, graduate students, allied health professionals and exhibitors. This year’s meeting was held in San Francisco, CA, and presentations focused on multidisciplinary approaches to the management of benign and malignant hematologic diseases with emphasis on the use of emerging therapeutic agents. In the area of chronic lymphocytic leukemia (CLL), several clinical trials provided further support for the role of immunotherapy in managing patients with either newly diagnosed or relapsed/refractory CLL. Findings from the CLL11 study suggest that the association of obinutuzumab plus chlorambucil, which is informahealthcare.com
10.1586/17474086.2015.1029450
going to become a new standard of care in elderly/unfit patients with previously untreated CLL, is also effective in patients who are refractory to single-agent chlorambucil [1,2]. In the analysis presented by Goede et al. [2], 30 patients enrolled in the CLL11 trial chlorambucil arm were crossed over to salvage therapy with obinutuzumab plus chlorambucil after developing progressive disease within 6 months of completing frontline treatment. Notably, most patients (93%) who crossed over to salvage therapy with obinutuzumab plus chlorambucil had failed to respond to frontline chlorambucil treatment. The overall response rate (ORR) was 87%, while 7% of patients achieved complete response (CR), 3% incomplete response and 77% partial
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response (PR). In addition, minimal residual disease (MRD) negativity in the bone marrow and/or peripheral blood was obtained in 23% of patients. The grade 3/4 toxicity observed consisted of neutropenia in 33% of patients, infusion-related reactions in 17%, infection in 13%, thrombocytopenia in 10% and anemia in 7%. Finally, median progression-free survival (PFS) was 17.2 months [2]. Authors pointed out that the association of obinutuzumab plus chlorambucil is active as salvage therapy in patients with chlorambucil-refractory CLL. However, results from the CLL11 trial provide a strong rationale for giving chemoimmunotherapy upfront rather than later in the treatment sequence in elderly/unfit CLL patients [2]. There have been some investigational studies of rituximab as maintenance therapy in CLL [3]. In these trials, which generally included a small number of patients, hematologic and immunologic toxicity was mild [3]. Recently, Abrisqueta et al. [4] report a Phase II clinical trial consisting of an initial treatment with rituximab, fludarabine, cyclophosphamide and mitoxantrone followed by rituximab maintenance every 3 months for 2 years. Maintenance with rituximab after rituximab, fludarabine, cyclophosphamide and mitoxantrone improved the quality of the response, particularly in patients who were MRD-positive, after initial treatment and prolonged PFS. At the 2014 ASH meeting, Greil et al. [5] presented interim analysis of an international, multicenter, Phase III study (MABTENANCE trial), which enrolled 263 patients who achieved at least a PR to any rituximab-containing chemoimmunotherapy induction regimen in the first- or second-line settings. Patients were randomly assigned to rituximab maintenance therapy every 3 months (n = 134) or observation (n = 129) for up to 24 months. The primary endpoint was PFS. After a median follow-up of 17.3 months, 85.1% of patients in the rituximab maintenance arm remained free from disease progression when compared with 75.5% of patients in the observation arm (p = 0.007). Serious infections were more common in the rituximab maintenance arm (15.7%) than in the observation arm (7.0%). Secondary malignancies were also more common following rituximab maintenance (4.5%) than observation (1.6%). Results of studies addressing the role of ofatumumab (OFA) or lenalidomide as maintenance therapy in CLL have also been presented at the meeting [6,7]. PROLONG is an open-label, twoarm randomized trial of OFA versus observation that enrolled 476 patients in remission after induction treatment for relapsed CLL. The median PFS was 28.6 months for patients assigned to receive OFA and 15.2 months for patients randomized to observation (hazard ratio [HR] = 0.48; p < 0.0001). After a median follow-up of 26.1 months for OFA arm and 24.0 months for the observation arm, no differences in overall survival (OS) were found (HR = 0.92, p = 0.74) [6]. The CLLM1 trial, is a Phase III, randomized, double-blinded, placebo-controlled study designed to investigate the efficacy and safety of lenalidomide maintenance therapy for HR CLL following first-line chemoimmunotherapy. Adverse events (AEs) reported were generally mild or moderate and reasons for discontinuation were mostly nonserious events, including skin reactions and fatigue [7]. 278
In conclusion, results of these interim analyses suggest that an anti-CD20 monoclonal antibody (i.e., rituximab or OFA) or lenalidomide as maintenance after first- or second-line induction chemoimmunotherapy are safe treatment strategies in CLL [5–7]. Notably, maintenance with either rituximab or OFA prolongs PFS in comparison with observation, although longer follow-up analyses are needed to better define the benefits of this approach in CLL [5,6]. What should be kept in mind is that current guidelines do not recommend maintenance or consolidation therapy outside of clinical trials [8]. Eichhorst et al. [9] presented the final analysis of CLL-10 trial. This Phase III study was designed to demonstrate the noninferiority of frontline bendamustine and rituximab (BR) compared with fludarabine, cyclophosphamide and rituximab (FCR) in patients with active CLL without del(17p) who were classified as medically fit (cumulative illness rating scale score £6, creatinine clearance ‡70 ml/min). Patients were randomly assigned to treatment with six courses of FCR (n = 284) or BR (n = 280). The primary endpoint was PFS. ORR was equivalent in each treatment group (95.4 vs 95.7%; p = 1.0); however, patients in the FCR group were significantly more likely than those treated with BR to achieve a CR (39.7 vs 30.8%; p = 0.034). The median PFS was 55.2 months in the FCR group compared with 41.7 months in the BR arm (p < 0.001). The PFS benefit of FCR compared with BR persisted in patients aged £65 years (53.6 vs 38.5 months; p < 0.001), whereas it was no longer observed among patients aged >65 years (median PFS not reached vs 48.5 months; p = 0.170). Although no differences in OS between the FCR and BR groups at 36 months (90.6 vs 92.2%; p = 0.897) could be found, toxicity profiles favored BR, particularly in older patients. FCR significantly increased the risk of neutropenia (84.2 vs 59.0%; p < 0.001), thrombocytopenia (21.5 vs 14.4%; p = 0.03) and infection (39.1 vs 26.8%; p < 0.001) compared with BR. Interestingly, a twofold risk of developing infections was observed in the FCR group in comparison with BR group for patients aged >65 years (47.7 vs 20.6%; p < 0.001). In summary, results of CLL-10 trial suggest that frontline treatment with BR failed to outperform the goldstandard regimen of FCR in medically fit patients with CLL [7]. However, the milder toxicity profile of BR suggests that this association may have a role in the upfront treatment of fit elderly patients and medically unfit patients with advanced CLL [10]. The assessment of MRD at the end of therapy is a clinically relevant issue in CLL. In a pooled analysis of two Phase III studies of the German CLL study group (GCLLSG; i.e., CLL8 trial: fludarabine and cyclophosphamide without [FC] or with rituximab [FCR] and CLL10 trial: FCR vs BR), which included 542 patients, Kovacs et al. analyzed MRD status. Results indicate that MRD negativity determined in the peripheral blood after the end of treatment is a potent predictor of treatment efficacy regardless of the clinical response assessment. In addition, the persistence of splenomegaly as sole abnormality post treatment in MRD-negative patients has no negative influence on PFS [11]. Current guidelines recommend evaluation of MRD only for patients included in clinical trials; however, Expert Rev. Hematol. 8(3), (2015)
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News from 2014 ASH meeting
results of this study underscore its potential importance also in the day-to-day practice. Three studies presented provide further insight into the use of ibrutinib, a first-in-class covalent inhibitor of Bruton’s tyrosine kinase (BTK), that is currently approved for patients with relapsed/refractory CLL and for those with CLL with del (17p) [12–14]. According to the primary analysis of the RESONATE trial, ibrutinib, compared with OFA, improved PFS and OS in patients with CLL who had received at least one prior therapy [15]. The updated analysis performed after a 16-month follow-up provides further evidence for the consistent activity of ibrutinib in patients with relapsed/refractory CLL, regardless of number of prior therapies or high-risk genetic abnormalities [12]. In another subanalysis from the RESONATE trial, Barrientos et al. [13] evaluated changes of patient well-being and quality of life following treatment with ibrutinib or OFA. In the ibrutinib arm, 69% of patients experienced constant improvement of cytopenias, compared with 43% of patients in the OFA arm (p < 0.0001). This was particularly true for platelet counts (72 vs 22%, respectively; p < 0.0001) and absolute neutrophil counts (64 vs 32%, respectively; p = 0.0047). Also findings of patientreported outcomes were in favor of treatment with ibrutinib. Clinically meaningful improvement in fatigue scores (59 vs 46%, respectively; p = 0.06) could be observed at week 24 in the ibrutinib arm in comparison with OFA arm. Interestingly, IgA levels increased in the ibrutinib group, with a mean increase of 41% at week 24 compared with baseline. In summary, according to the improvements in hematologic and immunologic function, as well as patient-reported outcomes, in comparison with OFA, ibrutinib impacts favorably the quality of life of patients with relapsed/refractory CLL [13]. Clinical outcome of patients with CLL bearing del(17p) is typically poor and median survival of less than 2 years in the relapsed/refractory setting [16]. RESONATE-17 is the largest prospective trial dedicated solely to the study of patients with CLL and small lymphocytic lymphoma (SLL) who have the del(17p) mutation. In RESONATE-17, 144 previously treated patients with del (17p) (137 with CLL, seven with SLL) received single-agent ibrutinib once daily until progression [14]. The primary endpoint of the open-label, single-arm, multicenter trial was ORR. Investigator-assessed ORR was 82.6%, whereas independent review committee-assessed ORR was 65%. After a median follow-up of 13 months, the median PFS as assessed by the investigator had not been reached. The most common grade 3 or 4 AEs in the RESONATE-17 trial were neutropenia (14%), anemia (8%), pneumonia (8%) and hypertension (8%). The most frequently reported AEs of any grade were diarrhea (36%), fatigue (30%), cough (24%) and arthralgia (22%). Atrial fibrillation of any grade was reported in 11 people (7.6%). Major hemorrhage was reported in seven people (4.9%). At the time of the data assessment, the median treatment duration was 11.1 months, and 70% of patients continued treatment with ibrutinib. In conclusion, patient PFS in the RESONATE17 trial compares favorably with that of informahealthcare.com
Meeting Report
treatment-naı¨ve del(17p) CLL patients receiving FCR or alemtuzumab. These results support ibrutinib as an effective therapy for patients with del(17p) CLL/SLL. It is unknown whether subpopulations of patients with del (17p) may have a different pattern of response to ibrutinib. Del (17p) is frequently associated with a complex metaphase karyotype, which has been associated with inferior outcomes in CLL; however, the prognostic significance of this finding in ibrutinibtreated patients is unknown [17]. According to results of MD Anderson Cancer Center group based on 100 patients treated for relapsed/refractory CLL with investigational ibrutinib-based regimens, it seems that the presence of complex metaphase karyotype (i.e., defined as ‡3 distinct chromosomal abnormalities) is independently associated with inferior event-free survival and OS, whereas the same does not apply for del(17p) [17]. The inferior outcomes of patients with complex metaphase karyotype make them ideal candidates for treatment-intensification strategies in the context of well-designed clinical trials. In addition to ibrutinib, new BTK-inhibitors are now under investigation in both CLL and non-Hodgkin lymphomas. ONO-4059 is a highly potent selective inhibitor of BTK tested in 25 CLL patients who were enrolled in the ongoing Phase I study ONO-4059POE001 [18]. Patients had a median age of 67 (range 40–79) years and had received a median number of four prior therapies [2–8], including a rituximab-containing therapy in 23 of 25. Best ORR according to International Workshop on CLL criteria (including modified PR with lymphocytosis) was observed in 84% patients. Eight dose-independent ONO-4059-related G3 or G4 hematological toxicities were reported in five patients, while six grade 3 ONO-4059-related nonhematological events were recorded. These results qualify ONO-4059 as a promising oral BTK inhibitor with a favorable safety profile along with promising efficacy [18]. Idelalisib, a first-in-class, oral, highly selective, inhibitor of PI3K delta, was recently approved in combination with rituximab for the treatment of relapsed CLL [19,20]. Idelalisib plus rituximab significantly increases response and survival compared with rituximab alone across all genetic and clinical subgroups in patients with relapsed CLL, according to updated findings from an ongoing Phase III trial. Sharman et al. [21] focused on patient subgroups with poor prognostic factors as defined by unmutated immunoglobulin heavy chain variable (IGHV) (84%); del(17p) and/or TP53 mutation (43%); and del(11q) (34%). According to the authors’ results, it seems that the PFS benefit with idelalisib plus rituximab versus placebo plus rituximab was maintained in patients with unmutated IGHV (NR vs 4.0 months); del(17p)/TP53 mutation (NR vs 4.0 months) and del11q (10.7 vs 6.9 months). Despite the crossover trial design, a significant improvement in OS with idelalisib versus placebo was consistent for patients with unmutated IGHV (NR vs 18.1 months; HR, 0.35; p = 0.0003) and in those with del(17p) or TP53 mutation (NR vs 14.8 months; HR: 0.31; p = 0.001). In summary, idelalisib plus rituximab demonstrated a substantial benefit across all patient subgroups, regardless of high-risk genetic markers, such as unmutated 279
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IGVH, del(17p), TP53 mutation and del(11q). A Phase II study reports the preliminary experience with idelalisib single agent in 37 previously untreated CLL patients older than 65 years [22]. With an 81% ORR, which included 33% PR and 48% PR with lymphocytosis, idelalisib demonstrated a substantial single agent activity in treatment-naı¨ve patients with CLL or SLL. In this preliminary analysis, the safety profile of idelalisib was manageable, although early lymphocytosis with monotherapy was more frequent in comparison with lymphocytosis seen in the earlier cohort treated with idelalisib plus weekly rituximab [19,22]. Duvelisib, also known as IPI-145, inhibits both the gamma and delta isoforms of PI3 kinase. O’Brien et al. [23] evaluated the safety, maximum tolerated dose, pharmacokinetics and clinical activity of duvelisib administered in 54 patients with relapsed/ refractory CLL. The best ORR by International Workshop on CLL criteria was 55% in 49 evaluable patients, including one CR and 26 PR. The ORR was similar irrespective of dose (52%, £25 mg two-times a day [n = 29]; 60%, 75 mg two-times a day [n = 20]), or the presence of TP53mut/del(17p) (48% [n = 23], including one CR) or unmutated IGHV (52%, n = 31). As authors concluded, these results support the development of randomized Phase III studies with duvelisib in patients with relapsed/refractory CLL. For patients treated with ibrutinib who have disease progression, various mechanisms of ibrutinib resistance have been described [24]. Since the mechanism of action of duvelisib differs from ibrutinib, duvelisib was evaluated in a subset of 13 patients (6 with CLL, seven with non-Hodgkin’s lymphoma) previously treated with ibrutinib who were enrolled in an ongoing Phase I study [25]. Following treatment, five patients experienced stable disease, while one patient achieved a PR. Authors stressed the activity of this PI3K inhibitor in patients previously treated with ibrutinib, although the small number of patients analyzed prevent from drawing firm conclusions [25]. Venetoclax is a BCL-2 inhibitor that currently has a registration study pending for patients with del(17p). The primary objectives of study presented by Roberts et al. [26] were safety of the combination of venetoclax and rituximab, determination of maximum tolerated dose, optimal dose and dosing schedule in patients with relapsed/refractory CLL. The ORR was 89% and roughly one-third of patients achieved a CR. Noteworthy,
2.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Society of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
References 1.
22% of patients with del(17p) achieved a CR and 56% a PR. The 46% MRD-negativity in the bone marrow highlights the impressive efficacy of venetoclax. In conclusion, efficacy and the depth of remissions obtained with venetoclax are relevant. Phase III studies are currently in progress comparing venetoclax plus rituximab with BR in patients with previously treated CLL [27]. Salles et al. [28] presented data from an ongoing Phase Ib study that is evaluating the maximum tolerated dose of GDC-0199, an orally available, selective BCL2 inhibitor, given in combination with BR, in relapsed/refractory or previously untreated patients with CLL. In this study, the most frequent AEs were hematological toxicities and generally manageable. Two patients had to discontinue BR (after one and three cycles) but were able to remain on GDC-0199. Dose escalation in relapsed/refractory patients is continuing to evaluate the optimal dose and schedule with the aim to enroll previously untreated patients in the near future. In a Phase Ib study, GDC-0199 was associated with obinutuzumab [29]. The data presented by Flinn et al. [29] suggest that the combination is safely administered at the doses given (GDC-0199 given at dose of 100 or 200 mg/day). Nine patients were at medium or high risk for tumor lysis syndrome; however, only one developed laboratory tumor lysis syndrome, which was transient and managed. In the experience of authors, a gradual dose ramp-up of GDC-0199 appear to reduce the incidence of tumor lysis syndrome. A GDC-0199 dose escalation in relapsed/refractory patients at 400 mg/day is planned. In conclusion, this year, significant data were presented at the annual ASH meeting in the field of CLL treatment. They appear to be particularly relevant because of the longer patient followup. What is emerging is that the management of CLL is undergoing profound changes. The challenge is now to find the best combination and sequence of treatments to get the long-term control of CLL without worsening the patient’s quality of life.
Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370: 1101-10
3.
Goede V, Engelke A, Fischer K, et al. Salvage therapy with obinutuzumab (GA101) plus chlorambucil (Clb) after treatment failure of Clb alone in patients with chronic lymphocytic leukemia (CLL) and comorbidities: results of the CLL11 Study [abstract 3327]. American
Del Poeta G, Del Principe MI, Buccisano F, et al. Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia. Cancer 2008; 112(1):119-28
4.
Abrisqueta P, Villamor N, Terol MJ, et al. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-
280
FCM) for chronic lymphocytic leukemia. Blood 2013;122(24):3951-9 5.
Greil R, Obrtlikova P, Smolej L, et al. Rituximab maintenance after chemoimmunotherapy induction in 1st and 2nd line improves progression free survival: planned interim analysis of the international randomized AGMT-CLL8/a Mabtenance trial [abstract 20]. American Society of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
6.
van Oers MHJ, Kuliczkowski K, Smolej L, et al. Ofatumumab (OFA) maintenance
Expert Rev. Hematol. 8(3), (2015)
News from 2014 ASH meeting
prolongs PFS in relapsed CLL: prolong study interim analysis result [abstract 21]. American Society of Hematology (ASH) Annual Meeting; December 6-9, 2014; San Francisco, CA
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 06/04/15 For personal use only.
7.
Eichhorst B, Bahlo J, Fink AM, et al. Good tolerance of lenalidomide maintenance therapy in patients with high risk profile chronic lymphocytic leukemia (CLL) after frontline chemoimmunotherapy: preliminary safety overview of the CLLM1 trial of the German CLL study group (GCLLSG) [abstract 4699]. American Society of Hematology (ASH) Annual Meeting; 6-9 December 2014; San Francisco, CA
8.
Robak T. Maintenance in CLL. Blood 2013;122(24):3854-5
9.
Eichhorst B, Fink AM, Busch R, et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) shows superior efficacy in comparison to bendamustine and rituximab (BR) in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia (CLL): Final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study) [abstract 19]. American Society of Hematology (ASH) Annual Meeting; 6-9 December 2014; San Francisco, CA
10.
11.
12.
13.
Cuneo A, Marchetti M, Barosi G, et al. Appropriate use of bendamustine in first-line therapy of chronic lymphocytic leukemia. Recommendations from SIE, SIES, GITMO Group. Leuk Res 2014; 38(11):1269-77 Kovacs G, Boettcher S, Bahlo J, et al. Value of minimal residual disease (MRD) negative status at response evaluation in chronic lymphocytic leukemia (CLL): combined analysis of two phase III studies of the German CLL study group (GCLLSG) [abstract 23]. American Society of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA Brown JR, Hillmen P, O’Brien S, et al. Updated efficacy including genetic and clinical subgroup analysis and overall safety in the phase 3 RESONATE trial of ibrutinib versus ofatumumab in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma [abstract 3331]. American Society of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA Barrientos JC, O’Brien S, Brown JR, et al. Hematologic and immunologic function and patient well-being for the phase III
informahealthcare.com
RESONATE study of ibrutinib vs ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma [abstract 4696]. American Society of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA 14.
15.
O’Brien S, Jones JA, Coutre S, et al. 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 [abstract 327]. American Society of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA Byrd JC, Brown JR, O’Brien S, et al. RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371(3):213-23
16.
Tam CS, Stilgenbauer S. Clinical dilemmas: how best to manage CLL patients with 17p Deletion and/or TP53 mutation? Leuk Lymphoma 2015;56(3):587-93
17.
Thompsonm PA, Wierda WG, Ferrajoli A, et al. Complex karyotype, rather than del (17p), is associated with inferior outcomes in relapsed or refractory CLL patients treated with ibrutinib-based regimens [abstract 22]. American Society of Hematology (ASH) Annual Meeting; 6– 9 December 2014; San Francisco, CA
18.
Fegan C, Bagshawe J, Salles G, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ONO-4059: promising single agent activity and well tolerated in patients with high risk chronic lymphocytic leukaemia (CLL) [abstract 3328]. American Society of Hematology (ASH) Annual Meeting; 6– 9 December 2014; San Francisco, CA
19.
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370:997-1007
20.
Coutre SE, Furman RR, Sharman JP, et al. Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. J Clin Oncol 2014;32:5s (Suppl; abstr 7012)
21.
Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a phase 3 study of idelalisib (Zydelig) plus rituximab for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors [abstract 330]. American Society of Hematology (ASH)
Meeting Report
Annual Meeting; 6–9 December 2014; San Francisco, CA 22.
Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib monotherapy in previously untreated patients ‡65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [abstract 1986]. AmericanSociety of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
23.
O’Brien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3K-d,g inhibitor, is clinically active in patients with relapsed/ refractory chronic lymphocytic leukemia [abstract 3334]. AmericanSociety of Hematology (ASH) Annual Meeting. 6– 9 December 2014; San Francisco, CA
24.
Komarova NL, Burger JA, Wodarz D. Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL). Proc Natl Acad Sci USA 2014;111(38):13906-11
25.
Porcu P, Flinn I, Kahl BS, et al. Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-Kinase-d,g inhibitor, in patients previously treated with ibrutinib [abstract 3335]. AmericanSociety of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
26.
Roberts AW, Ma S, Brander DM, et al. Determination of recommended phase 2 dose of ABT-199 (GDC-0199) combined with rituximab (R) in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) [abstract 325]. AmericanSociety of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
27.
Available from: www.mskcc.org/cancer-care/ trial/14-215
28.
Salles GA, Boyd TE, Morschhauser F, et al. Preliminary results of a phase 1b study (GO28440) combining GDC–0199 (ABT– 199) with bendamustine/rituximab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia [abstract 3337]. AmericanSociety of Hematology (ASH) Annual Meeting; 6–9 December 2014; San Francisco, CA
29.
Flinn I, Brunvand M, Dyer MJS, et al. Preliminary results of a phase 1b study (GP28331) combining GDC-0199 (ABT199) and obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia [abstract 4687]. AmericanSociety of Hematology (ASH) Annual Meeting. 6–9 December 2014; San Francisco, CA
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