CLINICAL REVIEW Obinutuzumab
CLINICAL REVIEW
Role of obinutuzumab in the treatment of chronic lymphocytic leukemia Gary W. Jean and Jill M. Comeau
C
hronic lymphocytic leukemia (CLL), the most common hematologic malignancy in the western hemisphere, will account for an estimated 14,620 new cancer diagnoses and 4,650 cancer deaths in the United States in 2015.1 It is mostly a disease of older men (median age at diagnosis, 71 years) and is more common in Caucasians than in African Americans.2 CLL is defined as a clonal proliferation of small, mature, CD5-positive B cells in the peripheral blood of at least 5,000 cells/mL. These cancerous cells can also be found in the bone marrow, the lymph nodes, and the spleen.3,4 If patients have these malignant B cells only in the lymph nodes or the spleen (or both), with less than 5,000 cells/ mL in the blood, small lymphocytic leukemia (SLL) is diagnosed. The 5-year relative survival rate from the time of diagnosis is 83.5%.2 CLL is thought to progress from monoclonal B-cell lymphocytosis, which has been found in 12% of otherwise healthy adults greater than 40 years of age, occurring at a rate of 1.1% per year.5,6 Progression to leukemia is enhanced by multiple complex chromosomal
Purpose. The pharmacology, pharmacokinetics, safety and efficacy, and place in therapy of obinutuzumab in the treatment of chronic lymphocytic leukemia (CLL) are reviewed. Summary. Obinutuzumab, a fully humanized monoclonal antibody that targets the CD20 receptor on mature B cells, was recently approved for use in combination with chlorambucil in patients with previously untreated CLL. In a Phase III clinical trial including 671 patients with CLL and significant comorbidities, patients who received obinutuzumab–chlorambucil combination therapy had longer median progression-free survival than those who received rituximab plus chlorambucil (26.7 months versus 15.2 months, p < 0.001) or chlorambucil alone (11.1 months, p < 0.001). Overall survival was also improved with the use of obinutuzumab– chlorambucil versus chlorambucil alone
aberrations, including deletions in micro-RNA genes, which prevent apoptosis in the malignant B cells.7 Initial chromosomal abnormalities in CLL include deletions on chromosome 13q. This abnormality occurs in 55% of patients with newly diagnosed CLL and is associated with a favorable prognosis. Other
Gary W. Jean, Pharm.D., BCOP, is Assistant Professor of Pharmacy Practice, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo. Jill M. Comeau, Pharm.D., BCOP, is Assistant Professor of Clinical Sciences, University of Louisiana at Monroe School of Pharmacy, and Gratis Assistant Professor of Internal Medicine, Feist-Weiller Cancer Center and Inpatient Bone Marrow Transplant Unit, LSU Health–Shreveport, Shreveport, LA.
(hazard ratio for death, 0.41, p = 0.002) and similar to survival with the use of rituximab plus chlorambucil. The main type of adverse effect reported in association with obinutuzumab use is infusion-related reactions (IRRs), which occurred in 66% of patients in the Phase III trial, with 20% of reactions categorized as grade 3 or 4; IRR risk can be reduced with appropriate dosing, premedication, patient monitoring, and immediate treatment of IRRs. Ongoing clinical trials are evaluating the effects of obinutuzumab in patients with newly diagnosed and relapsed or treatmentrefractory CLL. Conclusion. In patients who are elderly or who have multiple comorbidities, the use of obinutuzumab, a CD20 monoclonal antibody, in combination with chlorambucil is an efficacious regimen for treatment-naive patients with symptomatic CLL. Am J Health-Syst Pharm. 2015; 72:933-42
mutations found later in the course of the disease include deletions of chromosomes 11q (18% of patients) and 17p (7% of patients). Patients with these mutations have a worse prognosis.8 The survival of CLL cells is dependent on a supply of proteins from other cells, including dendritic cells, T cells, and macrophages.9
Address correspondence to Dr. Comeau ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/0601-0933. DOI 10.2146/ajhp140282
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Current treatment for CLL involves a combination of chemotherapy, immunotherapy, monoclonal antibody therapy, and targeted therapy.10 For patients with early-stage asymptomatic disease, observation is recommended. Patients with symptoms such as fevers, night sweats, weight loss, severe fatigue, end organ damage, progressive bulky disease, anemia, and thrombocytopenia should receive treatment immediately. The choice of therapy depends on the patient’s age, comorbidities, performance status, cancer staging and prognosis, and cytogenetic abnormalities. In patients who are otherwise healthy, multidrug chemotherapy in combination with immunotherapy is recommended; for those who are frail or have multiple comorbidities, single-agent chemotherapy, single-agent immunotherapy, or a combination of these therapies are recommended. Due to the overall demographics of patients with CLL, this article focuses on the treatment of older individuals. The first monoclonal antibody approved by the Food and Drug Administration (FDA) for use in B-cell non-Hodgkin’s lymphoma (NHL) was rituximab (in 1998).11 Rituximab causes apoptosis of CD20-positive cells through both antibody-dependent cell-mediated cytotoxicity (ADCC) and direct cell death (DCD).12 In patients with CLL, rituximab has been studied as a single agent and in combination with one or more chemotherapeutic agents.10 In a Phase II trial, patients with relapsed or refractory CLL or SLL who received single-agent rituximab had an objective response rate (ORR) of 51%, with a median progression-free survival (PFS) of 18.6 months.13 This PFS duration was much lower than that reported with single-agent rituximab in clinical trials involving patients with follicular lymphoma (FL), in which the PFS was around 36–40 months. 14,15 Rituximab has been shown to increase the likelihood of 934
promising outcomes in CLL when it is combined with other cytotoxic agents. For example, in 28 patients (median age, 65 years) diagnosed with fludarabine-refractory CLL who received rituximab combined with high-dose methylprednisolone, an ORR of 96% was achieved, with 32% of patients obtaining a complete response (CR); the median PFS was 30.5 months.16 When rituximab was used in combination with fludarabine, patients with previously untreated CLL had an ORR of 84%, a median PFS of 42 months, and a median overall survival (OS) of 85 months.17 In 2010, FDA approved rituximab for patients with CLL who are beginning chemotherapy for the first time and for patients with a diagnosis of relapsed or refractory CLL.18 The next CD20 monoclonal antibody developed for use in CLL was ofatumumab, a recombinant fully human anti-CD20 monoclonal antibody that has higher DCD activity in vitro than rituximab.19 The increase in DCD activity is due to ofatumumab’s higher affinity for the CD20 epitote. Ofatumumab was originally approved in 2009 for the treatment of CLL in patients who are refractory to other forms of chemotherapy.18 In an interim analysis of data on 138 treatmentexperienced patients with CLL, the ORR observed with single-agent ofatumumab was 58%, the median PFS was 5.7 months, and the median OS was 13.7 months.20 In April 2014, the FDA-approved labeling of ofa tumumab was amended to include an indication for use in treatmentnaive patients with CLL who cannot tolerate traditional fludarabinebased chemotherapy. 21 That approval was based on the results of a Phase III trial conducted by Hillmen et al.22 in which 447 patients were randomly assigned to receive ofatumumab and chlorambucil or chlorambucil alone. The ORR was 82% in the combination therapy group
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and 69% in the chlorambucil monotherapy group, with median PFS durations of 22.4 and 13.1 months, respectively. The median OS endpoint had not been reached in either group at the time of publication of the study results. Obinutuzumab (formerly known as GA101), the most recently approved CD20 monoclonal antibody, was approved on November 1, 2013, for use along with chlorambucil in treatment-naive patients with CLL.23 Currently, National Comprehensive Cancer Network (NCCN) guidelines recommend the use of obinutuzumab in combination with chlorambucil in treatment-naive patients with CLL regardless of age, comorbidities, and chromosomal abnormalities; this is a category 2A recommendation (i.e., it is based on low-level evidence, but there was uniform consensus among NCCN panel members regarding the intervention’s appropriateness).10 The objective of this article is to review the efficacy, safety, and place in therapy of obinutuzumab in the treatment of CLL. A PubMed literature search covering the period January 1947–April 2014 was conducted using the following terms: obinutuzumab, GA101, and chronic lymphocytic leukemia. Abstracts from the American Society of Hematology (December 2004– April 2014) and the American Society of Clinical Oncology (January 1983– April 2014), as well as the ClinicalTrials.gov website, were reviewed for information about completed and ongoing clinical trials. The articles included in this review were peer reviewed and written in the English language; clinical trials that did not include patients with either CLL or SLL were excluded. In total, three Phase I studies, one Phase II trial, and one Phase III trial were included in this analysis. Pharmacology Obinutuzumab (Gazyva, Genentech, South San Francisco, CA) is a third-
CLINICAL REVIEW Obinutuzumab
generation humanized, glycoengineered, type II anti-CD20 monoclonal antibody of the immunoglobulin G1 subclass.24,25 Type II antibodies such as tositumumab and obinutuzumab exert their activity on cells via ADCC, DCD, and strong homotypic aggregation of lymphoma cells.26,27 The mechanism of action of obinutuzumab is centered around ADCC, DCD induction, and (to a lesser extent) homotypic aggregation of cells.24,28-30 Specifically, data from early in vitro research indicated that obinutuzumab has unique characteristics that accentuate its ADCC. During the antibody humanization process, specific variants at the elbow hinge region were selected to provide superior type II binding.29 Furthermore, the Fc portion of the antibody was glycoengineered in order to increase binding affinity for Fc-g receptors. It was identified that the Fc-γIIIa receptor (also known as CD16) on natural killer cells and macrophages interacts to a greater extent with the Fc portion of obinutuzumab than it does with rituximab. It is this interaction of lymphoma cells and natural killer cells and macrophages that is responsible for the increased ADCC of obinutuzumab relative to rituximab.24,28-30 In addition to its ADCC, obinutuzumab expresses its antitumor effect through DCD induction. 30,31 Interestingly, the ability of obinutuzumab to induce DCD is dependent on the extent of homotypic adhesion between tumor cells after binding of monoclonal antibody. It has been demonstrated through analysis of in vitro data that obinutuzumab induces actin-dependent lysosomal cytoskeletal reorganization, which ultimately results in nonapoptotic programmed cell death. In conjunction with lysosomal membrane permeabilization, homotypic adhesion is dependent on the actin reorganization of the cytoskeleton.30 The ultimate result of DCD is likely dependent on the generation of reactive
oxygen species, a process that occurs downstream from actin cytoskeletal reorganization and lysosomal membrane permeabilization and is mediated by nicotinamide adenine dinucleotide phosphate oxidase.30,32 Pharmacokinetics Obinutuzumab is usually administered via i.v. infusion at a dose of 1000 mg; however, the dosage recommended in the prescribing information is fractionated and administered over two days in the first cycle of treatment (100 mg on day 1 and 900 mg on day 2).25 In general, obinutuzumab exhibits linear pharmacokinetics.33 Data from Phase I trials showed that serum obinutuzumab concentrations were dose dependent and were more likely to stay elevated with continued dosing.25,33,34 Based on a population pharmacokinetic analysis, the drug’s mean volume of distribution at steady state is approximately 3.8 L.25 The mean terminal clearance of the drug is 0.09 L/day, with a mean half-life of 28.4 days. It should be noted that although both volume of distribution and steady-state clearance increase with the weight of the individual, weight-based dosage adjustments are not warranted.25,33 The pharmacokinetic properties of the drug are not altered in patients with a creatinine clearance of ≥30 mL/ min, but obinutuzumab has not been evaluated in patients with a creatinine clearance of 25 × 109 cells/L or a high tumor burden are at risk for tumor lysis syndrome; prophylaxis should start 12–24 hours before the first obinutuzumab infusion and include hydration and allopurinol. There are no specific dosing recommendations for obinutuzumab in patients who have impaired renal function, a creatinine clearance of 65 years of age), the use of fludarabine monotherapy was associated with an improved ORR and a higher rate of complete remission relative to chlorambucil monotherapy but no relative advantage in terms of PFS or OS.43 A post hoc analysis of data from the four CALGB (Cancer and Leukemia Group B) clinical trials of fludarabine versus chlorambucil for treatment-naive patients with CLL did not show a relative benefit in PFS or OS with the use of fludarabine in patients 70 years of age or older. In another study, the addition of rituximab therapy to fludarabine therapy was associated with improvements in PFS and OS relative to single-agent therapy with either drug, regardless of patient age, reinforcing the importance of CD20-targeted therapy.44 In patients less than 70 years of age, fludarabine-based regimens remain a viable option.10,44 Based on currently available data, obinutuzumab plus chlorambucil is the only combination shown to confer an OS benefit relative to single-agent chlorambucil therapy in patients who are elderly or have multiple comorbidities. Also, in the trial of Goede et al.,39 patients who received obinutuzumab with chlor ambucil had quality-of-life scores comparable to those of patients who received chlorambucil monotherapy. Ongoing Phase III clinical trials are comparing the outcomes of treatment with obinutuzumab alone or in combination with fludarabine and cyclophosphamide, bendamustine, or chlorambucil in treatment-naive patients with CLL and patients with relapsed or refractory CLL. Obinutuzumab is also being used in combination with bendamustine or lenalidomide in patients with relapsed or refractory CLL in separate Phase II trials.45
Conclusion In patients who are elderly or who have multiple comorbidities, the use of obinutuzumab, a CD20 monoclonal antibody, in combination with chlorambucil is an efficacious regimen for treatment-naive patients with symptomatic CLL. References 1. American Cancer Society. Leukemia— chronic lymphocytic. www.cancer. org/acs/groups/cid/documents/ webcontent/003111-pdf.pdf (accessed 2015 Feb 3). 2. Howlader N, Noone AM, Krapcho M et al., for the National Cancer Institute. SEER cancer statistics review (CSR) 1975– 2011 (April 2014). http://seer.cancer.gov/ csr/1975_2011/ (accessed 2015 Feb 3). 3. Hallek M, Cheson BD, Catovsky D et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report for the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute– working group 1996 guidelines. Blood. 2008; 111:5446-56. 4. Zenz T, Mertens D, Kuppers R et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer. 2010; 10:37-50. 5. Nieto WG, Almeida J, Romero A. Increased frequency (12%) of circulating chronic lymphocytic leukemia-like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach. Blood. 2009; 114:33-7. 6. Shanafelt TD, Kay NE, Rabe KG. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol. 2009; 27:3959-63. 7. Calin GA, Dumitru CD, Shimizu M et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002; 99:15524-9. 8. Dohner H, Stilgenbauer S, Benner A et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343:1910-6. 9. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009; 114:3367-75. 10. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: non-Hodgkin’s lymphoma, v. 2.2014. www.nccn.org (accessed 2014 Apr 15). 11. Hagemeister F. Rituximab for the treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs. 2010; 70:261-72.
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12. Rituxan (rituximab) package insert. South San Francisco, CA: Genentech; 2013 Sep. 13. Hainsworth JD, Litchy S, Barton JH et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a Phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003; 21:1746-51. 14. Ghielmini M, Hsu Schmitz S, Cogliatti SB et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004; 103:4416-23. 15. Hainsworth JD, Litchy S, Burris HA et al. Rituximab as first-line and maintenance therapy for patients with indolent nonHodgkin’s lymphoma. J Clin Oncol. 2002; 20:4261-7. 16. Castro JE, James DF, Sandoval-Sus JD et al. Rituximab in combination with highdose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009; 23:1779-89. 17. Woyach JA, Ruppert AS, Heerema NA et al. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol. 2011; 29:1349-55. 18. Food and Drug Administration. FDA approves Rituxan to treat chronic lymphocytic leukemia. News and events. www.fda.gov/newsevents/newsroom/ pressannouncements/ucm201069.htm (accessed 2014 Apr 17). 19. Teeling JL, Mackus WJ, Wiegman LJ et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006; 177:362-71. 20. Wierda WG, Kipps TJ, Mayer J et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010; 28:1749-55. 21. Food and Drug Administration. Approved drugs: ofatumumab. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm393823.htm (accessed 2014 Apr 17). 22. 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). Blood. 2013; 122:528. Abstract.
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23. Food and Drug Administration. Approved drugs: Gazyva (obinutuzu mab). www.fda.gov/Drugs/Information OnDrugs/ApprovedDrugs/ucm373263. htm (accessed 2014 Apr 17). 24. Dalle S, Reslan L, Besseyre de Horts T et al. Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101. Mol Cancer Ther. 2011; 10:178-85. 25. Gazyva (obinutuzumab) package insert. South San Francisco, CA: Genentech; 2013 Nov. 26. Klein C, Lammens A, Schafer W et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs. 2013; 5:22-3. 27. Van Merrten T, Hagenbeek A. CD20targeted therapy: the next generation of antibodies. Semin Hematol. 2010; 47:199-210. 28. Pievani A, Belussi C, Klein C et al. Enhanced killing of human B-cell lymphoma targets by combined use of cytokine-induced killer cell (CIK) cultures and anti-CD20 antibodies. Blood. 2011; 117:510-8. 29. Patz M, Isaeva P, Forcob N et al. Comparison of the in vitro effects of the antiCD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haemotol. 2011; 152:295-306. 30. Alduaij W, Ivanov A, Honeychurch J et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosomemediated cell death in B-cell malignancies. Blood. 2011; 28:4519-29. 31. Bologna L, Gotti E, Manganini M et al. Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab. J Immuol. 2011; 186: 3762-9. 32. Honeychurch J, Alduaij W, Azizyan M et al. Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is mediated through a novel reactive oxygen species-dependent pathway. Blood. 2012; 119:3523-33. 33. Ogura M, Tobinai K, Hatake K et al. Phase I study of obinutuzumab (GA101) in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Cancer Sci. 2013; 104:105-10. 34. Salles G, Morschhauser F, Lamy T et al. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab
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35.
36.
37.
38.
39.
40. 41.
42.
43.
44.
45.
(GA101) in B-cell lymphoma patients. Blood. 2012; 119:5126-32. Sehn LH, Assouline SE, Stewart DA et al. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20positive B-cell malignancies. Blood. 2012; 119:5118-25. Abstract. Salles GA, Morschhauser F, Solal-Celingy P et al. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013; 31:2920-6. Morschhauser FA, Cartron G, Thieblemont C et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013; 31:2912-9. Radford J, Davies A, Cartron G et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood. 2013; 122:1137-43. 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. Red Book Online [online database]. Greenwood Village, CO: Truven Health Analytics; 2014 (accessed 2014 Feb 23). Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood. 2013; 122:3723-34. Knauf WU, Lissitchkov T, Aldaoud A et al. Benamustine in the treatment of chronic lymphocytic leukemia—consistent superiority over chlorambucil in elderly patients and across clinically defined risk groups. Blood. 2009; 114:2367. 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; 114:3382-91. Woyach JA, Ruppert AS, Rai K et al. Impact of age on outcomes after initial therapy with chemotherapy and different chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia: results of sequential cancer and leukemia group B studies. J Clin Oncol. 2013; 31:440-7. Clinicaltrials.gov. Search results: obinutuzumab CLL. www.clinicaltrials.gov/ ct2/results?term=CLL+obinutuzumab& Search=Search (accessed 2014 Apr 21).
CLINICAL REVIEW
Role of obinutuzumab in the treatment of chronic lymphocytic leukemia Gary W. Jean and Jill M. Comeau
C
hronic lymphocytic leukemia (CLL), the most common hematologic malignancy in the western hemisphere, will account for an estimated 14,620 new cancer diagnoses and 4,650 cancer deaths in the United States in 2015.1 It is mostly a disease of older men (median age at diagnosis, 71 years) and is more common in Caucasians than in African Americans.2 CLL is defined as a clonal proliferation of small, mature, CD5-positive B cells in the peripheral blood of at least 5,000 cells/mL. These cancerous cells can also be found in the bone marrow, the lymph nodes, and the spleen.3,4 If patients have these malignant B cells only in the lymph nodes or the spleen (or both), with less than 5,000 cells/ mL in the blood, small lymphocytic leukemia (SLL) is diagnosed. The 5-year relative survival rate from the time of diagnosis is 83.5%.2 CLL is thought to progress from monoclonal B-cell lymphocytosis, which has been found in 12% of otherwise healthy adults greater than 40 years of age, occurring at a rate of 1.1% per year.5,6 Progression to leukemia is enhanced by multiple complex chromosomal
Purpose. The pharmacology, pharmacokinetics, safety and efficacy, and place in therapy of obinutuzumab in the treatment of chronic lymphocytic leukemia (CLL) are reviewed. Summary. Obinutuzumab, a fully humanized monoclonal antibody that targets the CD20 receptor on mature B cells, was recently approved for use in combination with chlorambucil in patients with previously untreated CLL. In a Phase III clinical trial including 671 patients with CLL and significant comorbidities, patients who received obinutuzumab–chlorambucil combination therapy had longer median progression-free survival than those who received rituximab plus chlorambucil (26.7 months versus 15.2 months, p < 0.001) or chlorambucil alone (11.1 months, p < 0.001). Overall survival was also improved with the use of obinutuzumab– chlorambucil versus chlorambucil alone
aberrations, including deletions in micro-RNA genes, which prevent apoptosis in the malignant B cells.7 Initial chromosomal abnormalities in CLL include deletions on chromosome 13q. This abnormality occurs in 55% of patients with newly diagnosed CLL and is associated with a favorable prognosis. Other
Gary W. Jean, Pharm.D., BCOP, is Assistant Professor of Pharmacy Practice, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo. Jill M. Comeau, Pharm.D., BCOP, is Assistant Professor of Clinical Sciences, University of Louisiana at Monroe School of Pharmacy, and Gratis Assistant Professor of Internal Medicine, Feist-Weiller Cancer Center and Inpatient Bone Marrow Transplant Unit, LSU Health–Shreveport, Shreveport, LA.
(hazard ratio for death, 0.41, p = 0.002) and similar to survival with the use of rituximab plus chlorambucil. The main type of adverse effect reported in association with obinutuzumab use is infusion-related reactions (IRRs), which occurred in 66% of patients in the Phase III trial, with 20% of reactions categorized as grade 3 or 4; IRR risk can be reduced with appropriate dosing, premedication, patient monitoring, and immediate treatment of IRRs. Ongoing clinical trials are evaluating the effects of obinutuzumab in patients with newly diagnosed and relapsed or treatmentrefractory CLL. Conclusion. In patients who are elderly or who have multiple comorbidities, the use of obinutuzumab, a CD20 monoclonal antibody, in combination with chlorambucil is an efficacious regimen for treatment-naive patients with symptomatic CLL. Am J Health-Syst Pharm. 2015; 72:933-42
mutations found later in the course of the disease include deletions of chromosomes 11q (18% of patients) and 17p (7% of patients). Patients with these mutations have a worse prognosis.8 The survival of CLL cells is dependent on a supply of proteins from other cells, including dendritic cells, T cells, and macrophages.9
Address correspondence to Dr. Comeau ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/0601-0933. DOI 10.2146/ajhp140282
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Current treatment for CLL involves a combination of chemotherapy, immunotherapy, monoclonal antibody therapy, and targeted therapy.10 For patients with early-stage asymptomatic disease, observation is recommended. Patients with symptoms such as fevers, night sweats, weight loss, severe fatigue, end organ damage, progressive bulky disease, anemia, and thrombocytopenia should receive treatment immediately. The choice of therapy depends on the patient’s age, comorbidities, performance status, cancer staging and prognosis, and cytogenetic abnormalities. In patients who are otherwise healthy, multidrug chemotherapy in combination with immunotherapy is recommended; for those who are frail or have multiple comorbidities, single-agent chemotherapy, single-agent immunotherapy, or a combination of these therapies are recommended. Due to the overall demographics of patients with CLL, this article focuses on the treatment of older individuals. The first monoclonal antibody approved by the Food and Drug Administration (FDA) for use in B-cell non-Hodgkin’s lymphoma (NHL) was rituximab (in 1998).11 Rituximab causes apoptosis of CD20-positive cells through both antibody-dependent cell-mediated cytotoxicity (ADCC) and direct cell death (DCD).12 In patients with CLL, rituximab has been studied as a single agent and in combination with one or more chemotherapeutic agents.10 In a Phase II trial, patients with relapsed or refractory CLL or SLL who received single-agent rituximab had an objective response rate (ORR) of 51%, with a median progression-free survival (PFS) of 18.6 months.13 This PFS duration was much lower than that reported with single-agent rituximab in clinical trials involving patients with follicular lymphoma (FL), in which the PFS was around 36–40 months. 14,15 Rituximab has been shown to increase the likelihood of 934
promising outcomes in CLL when it is combined with other cytotoxic agents. For example, in 28 patients (median age, 65 years) diagnosed with fludarabine-refractory CLL who received rituximab combined with high-dose methylprednisolone, an ORR of 96% was achieved, with 32% of patients obtaining a complete response (CR); the median PFS was 30.5 months.16 When rituximab was used in combination with fludarabine, patients with previously untreated CLL had an ORR of 84%, a median PFS of 42 months, and a median overall survival (OS) of 85 months.17 In 2010, FDA approved rituximab for patients with CLL who are beginning chemotherapy for the first time and for patients with a diagnosis of relapsed or refractory CLL.18 The next CD20 monoclonal antibody developed for use in CLL was ofatumumab, a recombinant fully human anti-CD20 monoclonal antibody that has higher DCD activity in vitro than rituximab.19 The increase in DCD activity is due to ofatumumab’s higher affinity for the CD20 epitote. Ofatumumab was originally approved in 2009 for the treatment of CLL in patients who are refractory to other forms of chemotherapy.18 In an interim analysis of data on 138 treatmentexperienced patients with CLL, the ORR observed with single-agent ofatumumab was 58%, the median PFS was 5.7 months, and the median OS was 13.7 months.20 In April 2014, the FDA-approved labeling of ofa tumumab was amended to include an indication for use in treatmentnaive patients with CLL who cannot tolerate traditional fludarabinebased chemotherapy. 21 That approval was based on the results of a Phase III trial conducted by Hillmen et al.22 in which 447 patients were randomly assigned to receive ofatumumab and chlorambucil or chlorambucil alone. The ORR was 82% in the combination therapy group
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and 69% in the chlorambucil monotherapy group, with median PFS durations of 22.4 and 13.1 months, respectively. The median OS endpoint had not been reached in either group at the time of publication of the study results. Obinutuzumab (formerly known as GA101), the most recently approved CD20 monoclonal antibody, was approved on November 1, 2013, for use along with chlorambucil in treatment-naive patients with CLL.23 Currently, National Comprehensive Cancer Network (NCCN) guidelines recommend the use of obinutuzumab in combination with chlorambucil in treatment-naive patients with CLL regardless of age, comorbidities, and chromosomal abnormalities; this is a category 2A recommendation (i.e., it is based on low-level evidence, but there was uniform consensus among NCCN panel members regarding the intervention’s appropriateness).10 The objective of this article is to review the efficacy, safety, and place in therapy of obinutuzumab in the treatment of CLL. A PubMed literature search covering the period January 1947–April 2014 was conducted using the following terms: obinutuzumab, GA101, and chronic lymphocytic leukemia. Abstracts from the American Society of Hematology (December 2004– April 2014) and the American Society of Clinical Oncology (January 1983– April 2014), as well as the ClinicalTrials.gov website, were reviewed for information about completed and ongoing clinical trials. The articles included in this review were peer reviewed and written in the English language; clinical trials that did not include patients with either CLL or SLL were excluded. In total, three Phase I studies, one Phase II trial, and one Phase III trial were included in this analysis. Pharmacology Obinutuzumab (Gazyva, Genentech, South San Francisco, CA) is a third-
CLINICAL REVIEW Obinutuzumab
generation humanized, glycoengineered, type II anti-CD20 monoclonal antibody of the immunoglobulin G1 subclass.24,25 Type II antibodies such as tositumumab and obinutuzumab exert their activity on cells via ADCC, DCD, and strong homotypic aggregation of lymphoma cells.26,27 The mechanism of action of obinutuzumab is centered around ADCC, DCD induction, and (to a lesser extent) homotypic aggregation of cells.24,28-30 Specifically, data from early in vitro research indicated that obinutuzumab has unique characteristics that accentuate its ADCC. During the antibody humanization process, specific variants at the elbow hinge region were selected to provide superior type II binding.29 Furthermore, the Fc portion of the antibody was glycoengineered in order to increase binding affinity for Fc-g receptors. It was identified that the Fc-γIIIa receptor (also known as CD16) on natural killer cells and macrophages interacts to a greater extent with the Fc portion of obinutuzumab than it does with rituximab. It is this interaction of lymphoma cells and natural killer cells and macrophages that is responsible for the increased ADCC of obinutuzumab relative to rituximab.24,28-30 In addition to its ADCC, obinutuzumab expresses its antitumor effect through DCD induction. 30,31 Interestingly, the ability of obinutuzumab to induce DCD is dependent on the extent of homotypic adhesion between tumor cells after binding of monoclonal antibody. It has been demonstrated through analysis of in vitro data that obinutuzumab induces actin-dependent lysosomal cytoskeletal reorganization, which ultimately results in nonapoptotic programmed cell death. In conjunction with lysosomal membrane permeabilization, homotypic adhesion is dependent on the actin reorganization of the cytoskeleton.30 The ultimate result of DCD is likely dependent on the generation of reactive
oxygen species, a process that occurs downstream from actin cytoskeletal reorganization and lysosomal membrane permeabilization and is mediated by nicotinamide adenine dinucleotide phosphate oxidase.30,32 Pharmacokinetics Obinutuzumab is usually administered via i.v. infusion at a dose of 1000 mg; however, the dosage recommended in the prescribing information is fractionated and administered over two days in the first cycle of treatment (100 mg on day 1 and 900 mg on day 2).25 In general, obinutuzumab exhibits linear pharmacokinetics.33 Data from Phase I trials showed that serum obinutuzumab concentrations were dose dependent and were more likely to stay elevated with continued dosing.25,33,34 Based on a population pharmacokinetic analysis, the drug’s mean volume of distribution at steady state is approximately 3.8 L.25 The mean terminal clearance of the drug is 0.09 L/day, with a mean half-life of 28.4 days. It should be noted that although both volume of distribution and steady-state clearance increase with the weight of the individual, weight-based dosage adjustments are not warranted.25,33 The pharmacokinetic properties of the drug are not altered in patients with a creatinine clearance of ≥30 mL/ min, but obinutuzumab has not been evaluated in patients with a creatinine clearance of 25 × 109 cells/L or a high tumor burden are at risk for tumor lysis syndrome; prophylaxis should start 12–24 hours before the first obinutuzumab infusion and include hydration and allopurinol. There are no specific dosing recommendations for obinutuzumab in patients who have impaired renal function, a creatinine clearance of 65 years of age), the use of fludarabine monotherapy was associated with an improved ORR and a higher rate of complete remission relative to chlorambucil monotherapy but no relative advantage in terms of PFS or OS.43 A post hoc analysis of data from the four CALGB (Cancer and Leukemia Group B) clinical trials of fludarabine versus chlorambucil for treatment-naive patients with CLL did not show a relative benefit in PFS or OS with the use of fludarabine in patients 70 years of age or older. In another study, the addition of rituximab therapy to fludarabine therapy was associated with improvements in PFS and OS relative to single-agent therapy with either drug, regardless of patient age, reinforcing the importance of CD20-targeted therapy.44 In patients less than 70 years of age, fludarabine-based regimens remain a viable option.10,44 Based on currently available data, obinutuzumab plus chlorambucil is the only combination shown to confer an OS benefit relative to single-agent chlorambucil therapy in patients who are elderly or have multiple comorbidities. Also, in the trial of Goede et al.,39 patients who received obinutuzumab with chlor ambucil had quality-of-life scores comparable to those of patients who received chlorambucil monotherapy. Ongoing Phase III clinical trials are comparing the outcomes of treatment with obinutuzumab alone or in combination with fludarabine and cyclophosphamide, bendamustine, or chlorambucil in treatment-naive patients with CLL and patients with relapsed or refractory CLL. Obinutuzumab is also being used in combination with bendamustine or lenalidomide in patients with relapsed or refractory CLL in separate Phase II trials.45
Conclusion In patients who are elderly or who have multiple comorbidities, the use of obinutuzumab, a CD20 monoclonal antibody, in combination with chlorambucil is an efficacious regimen for treatment-naive patients with symptomatic CLL. References 1. American Cancer Society. Leukemia— chronic lymphocytic. www.cancer. org/acs/groups/cid/documents/ webcontent/003111-pdf.pdf (accessed 2015 Feb 3). 2. Howlader N, Noone AM, Krapcho M et al., for the National Cancer Institute. SEER cancer statistics review (CSR) 1975– 2011 (April 2014). http://seer.cancer.gov/ csr/1975_2011/ (accessed 2015 Feb 3). 3. Hallek M, Cheson BD, Catovsky D et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report for the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute– working group 1996 guidelines. Blood. 2008; 111:5446-56. 4. Zenz T, Mertens D, Kuppers R et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer. 2010; 10:37-50. 5. Nieto WG, Almeida J, Romero A. Increased frequency (12%) of circulating chronic lymphocytic leukemia-like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach. Blood. 2009; 114:33-7. 6. Shanafelt TD, Kay NE, Rabe KG. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol. 2009; 27:3959-63. 7. Calin GA, Dumitru CD, Shimizu M et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002; 99:15524-9. 8. Dohner H, Stilgenbauer S, Benner A et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343:1910-6. 9. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009; 114:3367-75. 10. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: non-Hodgkin’s lymphoma, v. 2.2014. www.nccn.org (accessed 2014 Apr 15). 11. Hagemeister F. Rituximab for the treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs. 2010; 70:261-72.
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