ResourcesClinical Vignettes Series: Hematologic Malignancies
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The Clinical Vignettes series is a collection of online clinical case presentations, which focus on an interesting or challenging patient encounter, with the goal of reviewing the treatment decision-making process for the practicing community-based oncologist/hematologist. This series will focus on mantle cell lymphoma (MCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL).
PER Pulse™ Recap
Two PER Pulse™ Recaps presenting clinical case presentations focusing on mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) in the frontline and relapsed/refractory setting.
PER Pulse™ Recap
Medical Writer: Kathleen Wildasin, MA
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PER Pulse™ Recap: Mantle Cell Lymphoma
The following PER Pulse™ Recap summarizes data from clinical trials investigating new treatment options for patients with mantle cell lymphoma (MCL) in the frontline and relapsed/refractory setting.
Frontline Therapy in MCL
Nonanthracycline-containing regimens have been investigated in the treatment of MCL with the goal of reducing toxicity in elderly patients who cannot tolerate intensive approaches. In a phase III European trial in 560 newly diagnosed patients with MCL (age ≥66 years or between the ages of 60-65 years if not eligible for high-dose therapy), investigators compared rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) versus rituximab plus fludarabine and cyclophosphamide (R-FC) as frontline therapy; the primary endpoint was complete response (CR).1 A second randomization was conducted to assess maintenance therapy with rituximab versus interferon alfa; the primary endpoint was duration of remission (DOR). CR in patients receiving R-CHOP versus R-FC was similar (34% and 40%, respectively; P = .10), but the 4-year overall survival (OS) rate was higher in the former than latter group (62% vs 47%, respectively; P = .005); the proportion of patients with grade 3/4 adverse events (AEs) was generally lower in patients treated with R-CHOP than R-FC. Median DOR with maintenance rituximab versus interferon alfa was 75 and 27 months, respectively (P < .001); toxicities were low in both maintenance therapy arms, but grade 3/4 neutropenia was higher with interferon alfa than rituximab (36% vs 24%, respectively).
Two noninferiority trials recently investigated the use of bendamustine plus rituximab (BR) as frontline therapy in patients with non-Hodgkin lymphoma (NHL), including MCL:
In a European trial comparing frontline BR with R-CHOP in 514 assessable patients (94 [18%] of whom had MCL), a statistically significant difference was observed in the primary endpoint of progression-free survival (PFS), favoring BR over R-CHOP.2 At median follow-up of 45 months, median PFS was 69.5 versus. 31.2 months in the BR and R-CHOP arms, respectively (HR = 0.58; P = .0001). Furthermore, a PFS benefit was observed for BR in patients aged >60 years (HR = 0.62; P = .002) and ≤60 years (HR = 0.52; P = .002).2
- In the international BRIGHT trial comparing frontline BR to either R-CHOP or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) in 447 patients (74 [17%] of whom had MCL), the primary endpoint of CR achieved with BR was noninferior to that achieved with R-CHOP/R-CVP. In patients with MCL, BR demonstrated superiority over R-CHOP/R-CVP in terms of CR (50% vs 27%, respectively; P = .018).3
Newly Approved Agents in Relapsed/Refractory MCL
Lenalidomide was approved by the US Food and Drug Administration (FDA) in June 2013 for patients with relapsed/refractory MCL who had received two previous therapies, one of which included bortezomib. FDA approval was based on the results of a phase II trial in 134 patients with MCL whose disease had relapsed or was refractory to bortezomib, and who had also received therapy with an anthracycline or mitoxantrone, cyclophosphamide, or rituximab; the primary study endpoints were overall response rate (ORR) and DOR.4 ORR was 28% (7.5% CR/unconfirmed complete response), and median DOR was 16.6 months. Median PFS and OS were 4.0 and 19.0 months, respectively. The main grade 3/4 AEs were hematologic; grade 3 diarrhea was observed in 6% of patients.
Ibrutinib, a small-molecule inhibitor of Bruton’s tyrosine kinase, received accelerated approval from the FDA in November 2013 for the treatment of patients with MCL who had received ≥1 prior therapy. FDA approval was based on a phase II trial of single-agent ibrutinib in 111 patients (48 [43%] of whom had received prior bortezomib) with relapsed/refractory MCL; the primary endpoint was ORR.5 In the overall study group, ORR was 68%, with similar results observed in patients with and without prior bortezomib therapy. Median PFS was 13.9 months, and OS had not been reached at the time of reporting. The main grade 3/4 AEs were neutropenia (16%) and thrombocytopenia (11%); grade 3 diarrhea was reported in 6% of patients.
Investigational Agents in Relapsed/Refractory MCL
Two investigational agents--the BCL-2 inhibitor ABT-199 and the phosphatidylinositol 3-kinase delta inhibitor idelalisib--have shown promise in the relapsed/refractory MCL setting:
In a phase I study, ORR in patients treated with single-agent ABT-199 was 100% (all partial responses); grade ≥3 tumor lysis syndrome occurred in 12.5% of patients with MCL, and grade 3/4 neutropenia occurred in 13% of all patients with any type of NHL.6
In a phase I study, ORR in patients treated with single-agent idelalisib was 40% (CR, 7.5%), and median PFS was 3.7 months; grade ≥3 AEs included diarrhea (17.5%), pneumonia (12.5%), and elevated alanine aminotransferase or aspartate aminotransferase (20%).7
- In a phase II study investigating the effectiveness of idelalisib in combination with either everolimus, bortezomib, or BR, the ORR was 39%, 46%, and 100%, respectively; grade ≥3 AEs included acute renal failure with idelalisib plus everolimus (17%), diarrhea with idelalisib plus bortezomib (18%), and not reached with idelalisib plus BR.8
- Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520-531.
- Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203-1210.
- Flinn IW, van der Jagt R, Kahl BS, et al. Open-label, randomized, noninferiority study of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of advanced indolent NHL or MCL: the BRIGHT study [published online ahead of print March 3, 2014]. Blood. 2014. doi:10.1182/blood-2013-11-531327.
- Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol. 2013;31:3688-3695.
- Wang ML, Rule S, Martin P. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369 507-516.
- Davids MS, Seymour JF, Gerecitano JF, et al. Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL). Presented at: the 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract 8520.
- Spurgeon SE, Wagner-Johnston ND, Furman RR, et al. Final results of a phase I study of idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase P110δ (PI3Kδ), in patients with relapsed or refractory mantle cell lymphoma (MCL). Presented at: the 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract 8519.
Wagner-Johnston ND, De Vos S, Leonard J, et al. Preliminary results of PI3Kδ inhibitor idelalisib (GS-1101) treatment in combination with everolimus, bortezomib, or bendamustine/rituximab in patients with previously treated mantle cell lymphoma (MCL). Presented at: the 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract 8501.
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PER Pulse™ Recap: Chronic Lymphocytic Leukemia
The following PER Pulse™ Recap summarizes data from clinical trials investigating new treatment options for patients with chronic lymphocytic leukemia (CLL) in the frontline and relapsed/refractory setting.
New Frontline Treatment Options for Elderly or Comorbid Patients with CLL
Elderly or comorbid patients with CLL may not be able to tolerate intense fludarabine-based treatment regimens, thus chlorambucil-based therapy remains a standard of care.1 Two next-generation CD20 monoclonal antibodies—obinutuzumab and ofatumumab—have recently been approved by the US Food and Drug Administration (FDA) in combination with chlorambucil for the frontline treatment of CLL.
Obinutuzumab plus Chlorambucil: The CLL11 Study
Obinutuzumab in combination with chlorambucil was approved by the FDA in November 2013 for the frontline treatment of CLL based on the results of the CLL11 study.2,3 In the 3-arm CLL11 study, 781 previously untreated elderly (median age, 73 years) patients with CLL who had substantial comorbidities (median score on the Cumulative Illness Rating Scale, 8) were randomized to receive obinutuzumab plus chlorambucil, rituximab plus chlorambucil, or single-agent chlorambucil; the primary endpoint was progression-free survival (PFS).
Median PFS in the obinutuzumab-plus-chlorambucil, rituximab-plus-chlorambucil, and single-agent chlorambucil arms was 26.7, 16.3, and 11.1 months, respectively; the overall response rate (ORR) was 77%, 66%, and 31%, respectively.
The rate of certain grade ≥3 adverse events (AEs; infusion reactions, thrombocytopenia, and neutropenia) was higher in patients receiving obinutuzumab than rituximab, whereas the rate of febrile neutropenia and infections was similar in the two treatment arms.
Ofatumumab plus Chlorambucil: The COMPLEMENT-1 Study
Ofatumumab in combination with chlorambucil was approved by the FDA in April 2014 for the frontline treatment of patients with CLL who are not candidates for fludarabine regimens based on the results of the COMPLEMENT-1 study.4 In the 2-arm COMPLEMENT-1 study, 447 previously untreated elderly patients with CLL who had a median of three comorbidities and for whom fludarabine was not appropriate were randomized to receive either ofatumumab plus chlorambucil or single-agent chlorambucil; the primary endpoint was PFS.
Median PFS in the ofatumumab-plus-chlorambucil versus single-agent-chlorambucil arms was 22.4 and 13.1 months, respectively (hazard ratio [HR] = 0.57; P < .001). ORR was 82% (complete response [CR], 14%) in patients receiving ofatumumab plus chlorambucil and 69% (CR, 1%) in those receiving single-agent chlorambucil (P < .001).
The rate of grade ≥3 infusion reactions and neutropenia was higher in the ofatumumab-plus-chlorambucil arm than in the single-agent-chlorambucil arm, whereas the rate of grade ≥3 thrombocytopenia and infections was lower in the former than latter arm.
Inhibitors of B-Cell Signaling: A New Class of Agents for CLL Therapy
Bruton’s tyrosine kinase (BTK) and phosphatidylinositol 3-kinase delta (PI3K-delta) are the targets of several new agents in development.5,6 In particular, the BTK inhibitor ibrutinib has been approved by the FDA for use in both mantle cell lymphoma and CLL, and a New Drug Application has been filed for the PI3K-delta inhibitor idelalisib for use in CLL.
Ibrutinib in Pretreated CLL: Phase Ib/II Data
A phase Ib/II trial in 85 patients with relapsed/refractory CLL or small lymphocytic lymphoma investigated the use of single-agent ibrutinib dosed at 420 mg/day and 840 mg/day; the primary endpoint was safety.7 Data from a subset of patients receiving 420 mg/day were used for the FDA application.
ORR was 71% in both dosing cohorts (ie, all patients) and 68% in patients with a 17p deletion.
Most AEs were grade 1/2. The main grade 3/4 AEs were neutropenia (15%), fever (5%), fatigue (4%), and diarrhea (2%).
In February 2014, the FDA granted accelerated approval to ibrutinib for the treatment of patients with CLL who have received at least one prior therapy.
Idelalisib plus Rituximab in Relapsed CLL: Phase III Data
A phase III trial in 220 patients with relapsed CLL who could not receive cytotoxic therapy investigated the use of idelalisib plus rituximab versus placebo plus rituximab; the primary endpoint was PFS.8
ORR was significantly higher in patients receiving idelalisib plus rituximab than placebo plus rituximab (81% vs 13%, respectively; P < .001). Median PFS at the time of reporting had not been reached in the idelalisib-plus-rituximab arm and was 5.5 months in the placebo-plus-rituximab arm (HR = 0.15; P < .001); the HR for PFS was 0.14 in 57 patients with the 17p deletion. AEs were predominantly grade 1/2. Grade ≥3 neutropenia occurred in 34% of the patients in the idelalisib-plus-rituximab arm and 22% in those in the placebo-plus-rituximab arm. Other grade ≥3 AEs with higher rates in the idelalisib-plus-rituximab arm than in the placebo-plus-rituximab arm included diarrhea (4% vs 0%, respectively) and pyrexia (3% vs 1%, respectively).
Based on these data, idelalisib was granted Breakthrough Therapy designation for relapsed CLL. In December 2013, a New Drug Application for idelalisib was filed with the FDA.
Investigational Agents in Relapsed/Refractory CLL
Three investigational agents—IPI-145, ABT-199, and CC-292—have shown promise in the relapsed/refractory CLL setting:
In a phase III study, ORR in patients treated with single-agent IPI-145, an inhibitor of PI3K-delta and PI3K-gamma, was 47%; grade ≥3 AEs included neutropenia (30%) and diarrhea (6%).9
In a phase III study, ORR in patients treated with single-agent ABT-199, an inhibitor of BCL-2, was 84% (CR, 23%); grade ≥3 AEs included neutropenia (36%) and tumor lysis syndrome (9%).10
- In a phase I study, ORR in patients treated with single-agent CC-292, an inhibitor of BTK, was 40%; the only grade ≥3 AE was neutropenia (21%).11
- Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;114:3382-3391.
- Owen C, Stewart DA. Obinutuzumab for the treatment of lymphoproliferative disorders. Expert Opin Biol Ther. 2012;12:343-351.
- Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101-1110.
- Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study COMPLEMENT 1 (OMB110911). Presented at: the 2013 Annual Meeting of the American Society of Hematology; December 7-10, 2013; New Orleans, LA. Abstract 528.
- Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117:6287-6296.
- Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117:591-594.
- Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.
- Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007.
- Flinn I, Patel M, Kahl BS, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-delta, gamma, in patients with chronic lymphocytic leukemia. Presented at: the 2013 Annual Meeting of the American Society of Hematology; December 7-10, 2013; New Orleans, LA. Abstract 677.
- Seymour JF, Davids MS, Pagel JM, et al. Bcl-2 inhibitor ABT-199 (GDC-0199) monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Presented at: the 2013 Annual Meeting of the American Society of Hematology; December 7-10, 2013; New Orleans, LA. Abstract 872.
- Brown JR, Harb WA, Hill BT, et al. Phase 1 study of single agent CC-292, a highly selective Bruton’s tyrosine kinase (BTK) inhibitor, in relapsed/refractory chronic lymphocytic leukemia (CLL). Presented at: the 2013 Annual Meeting of the American Society of Hematology; December 7-10, 2013; New Orleans, LA. Abstract 1630.
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