General Description

Figure 1. Properties of Rituximab

Rituximab is a chimeric mouse/human monoclonal antibody (mAb) therapy with binding specificity to CD20. It was the first therapeutic antibody approved for oncology patients and was the top-selling oncology drug for nearly a decade with sales reaching $8.58 billion in 2016. Since its initial approval in 1997, it has improved outcomes in all B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia.

History of Rituximab

Rituximab was created by Ronald Levy for the express purpose of targeting malignant B cells. In 1982, it was made public that his first mAb cancer patient was successfully treated with the mAb, which rapidly lead to the creation of the pharmaceutical company IDEC. Maloney et al. reported the first phase I clinical trials of rituximab, initially named IDEC-C2B8, in 1994, after it had proved effective at killing CD20 expressing cells in vitro and in the blood and lymph of macaques. Fifteen patients with relapsed NHL were given one of five dosage ranges from 10 to 500 mg/m², and six of those patients experienced tumor regression. In 1997, results from a phase I/II trial of 20 patients receiving 125, 250, or 375 mg/m² of rituximab weekly for 4 weeks were published. This study was the basis for FDA approval of rituximab as well as the now standard 375 mg/m² dosage that was used for phase II trials. One year later, McLaughlin et al. reported equally impressive benefits of rituximab treatment for patients with relapsed indolent lymphoma, with half of the 166 patients responding to the same four-dose regimen.^1,2,3

Clinical Impact of Rituximab in B-CeLL NHL Treatment

Despite the incomplete details on the biological role of CD20, targeting it with rituximab has proven effective for treating a subset of patients in nearly all forms of B-cell NHL. It is frequently given as an initial treatment, either in combination with traditional chemotherapeutics or as a monotherapy. It is also given as maintenance therapy, although benefits of maintenance rituximab (MR) are still unclear for many NHLs. It is rare for B-cell NHLs to be CD20-negative at initial diagnosis, representing only 1–2% of all B-cell lymphomas. However, it is more common among B-cell NHL that have relapsed following rituximab treatment, suggesting a selective process toward increased resistance. The following section contains current standards of care for the various lymphoma subtypes with historical context from select clinical trials. Current trials and the remaining questions still surrounding the immunotherapy for each specific cancer are also highlighted.⁴

Burkitt Lymphoma (BL)

The largest prospective study to date, published in 2014, which spanned from 2002 to 2011 and included 363 patients ranging from 16 to 85 years old demonstrated that the combination immunotherapy was efficacious and feasible, and while the CR rate was not significantly higher than comparable studies without rituximab, OS and PFS were substantially improved. Several retrospective studies have attempted to determine rituximab benefits for these patients but were unable to achieve significance. However, a recent meta-analysis concluded that there was a significant increase in overall survival when rituximab was given with various chemotherapy regimens compared with chemotherapy alone. Also, a 2016 single-arm randomized phase III trial comparing short-intensive chemotherapy alone (n = 66) or the same treatment in combination with rituximab (n = 70) on BL patients over 18 years of age found that inclusion of rituximab indeed improved 3 years EFS (75 vs. 62%).^5,6,7

Mantle Cell Lymphoma (MCL)

Rituximab maintenance has demonstrated an OS benefit in a phase III randomized MCL clinical trial, which has not been shown in other lymphoma subtypes. The study compared MR (n = 120) after autologous stem cell to observation only (n = 120) and found a 4-year PFS of 83 and 61%, respectively. The MR group also had a significantly increased OS. Interestingly, retreatment with rituximab when molecular relapse occurs has also proven a successful strategy to regain molecular remission status, and likely to prolong clinical remission time. This could provide a strategy for more cost-effective maintenance of remission in MCL.^8,9,10

Chronic Lymphocytic Leukemia (CLL)

In CLL patients who are young and fit and lack deletion of 17p or TP53, current treatment guidelines recommend chemotherapy, commonly fludarabine, cyclophosphamide in combination with rituximab (FCR) as initial treatment based on the proven effectiveness of rituximab from several clinical trials. A recent Canadian study confirmed the tangible benefits in CLL by evaluating patients treated in the pre- and post-rituximab era. The currently ongoing FLAIR phase III trial includes 754 CLL patients given either the current standard of care FCR, ibrutinib plus rituximab, ibrutinib plus venetoclax, or ibrutinib alone, potentially eliminating the need for more harmful chemotherapeutics in favor of more targeted therapeutics as the new standard of care. This study should also assess the benefit of the addition of rituximab to small molecule targeted therapies (in this case ibrutinib), which has been relatively understudied.^11,12

Shorfalls of Rituximab

Although rituximab as a monotherapy, or in combination with chemotherapeutics, has greatly improved the prognosis of all B-cell NHL, there are still many cases in which it fails. In the case of DLBCL, 30–50% of patients are not cured by R-CHOP, with about 20% being initially refractory and another 30% relapsing after CR. The majority of indolent NHLs will eventually relapse and are incurable. This high rate of failure has spurred on the search for improved methods of treating refractory or relapsed patients, emphasizing the need for new biomarkers that identify those who will, and those who will not, be effectively treated by rituximab-based regimens.^13,14

A relatively recent development in rituximab therapy was the FDA approval of a subcutaneous formulation of the mAb which combines it with recombinant human hyaluronidase. Recombinant human hyaluronidase is used to increase the dispersion and absorption of molecules and thus allow very small, highly concentrated volumes to be injected subcutaneously while retaining efficacy. In 2014 a randomized phase III study, SABRINA, evaluated the pharmacokinetics (PK) and safety of subcutaneous rituximab in FL. The study compared 48 patients who received subcutaneous rituximab to 54 who received intravenous rituximab and found that subcutaneous delivery was non-inferior. The subcutaneous delivery was also preferred by nearly all patients, and the benefits include less time in the clinic with anticipated reduced workloads for clinical staff, lower health-care cost, and increased accessibility of rituximab therapy. Following the 2014 study, similar trials have found subcutaneous rituximab to be non-inferior in treating CLL and DLBCL as well. The subcutaneous formulation was approved by the FDA in 2017 to treat FL, DLBCL, and CLL.^15,16

Mechanism of Rituximab Response

Figure 2.Rituximab-mediated cell killing of CD20 expressing B-cells.

The binding of rituximab to CD20 facilitates cell death in four main ways, three of which rely on recruiting effector mechanisms from the patient’s own immune system. Because of this reliance on the human immune system (HIS) to mediate antitumor effects, the exact in vivo mechanisms remain challenging to study. Based on a combination of in vivo, ex vivo, and in vitro work, we know that rituximab-mediated killing occurs by triggered cell death via binding of rituximab to CD20, CDC, ADCC, and antibodydependent phagocytosis (ADP). One major barrier to fully understanding the mechanisms of the immune system in immunotherapies is the lack of an ideal animal model. Because rituximab is targeted against human CD20, it can be evaluated in immunocompromised mice xenografted with human lymphoma, but these mice do not possess human immune cells or human complement proteins. Much work is being done to better model human NK cells in mice to provide more biologically relevant animal models, mainly through the development of HIS mice. One major issue is achieving normal NK cell development in a murine body. Recent findings suggest knocking in human SIRPA and IL15 to replace the wild-type copies in HIS mice resulted in normal tissue distribution circulation of NK cells. Furthermore, the NK cells in these HIS mice can facilitate ADCC, providing a crucial next step toward research tools for understanding the role of rituximab-mediated ADCC in vivo. Still, the complexities of rituximab response are further complicated by potential competition and synergy between all other immune effector responses, including direct cell killing.^17,18

References

1.Maloney DG, Grillo-López AJ, Bodkin DJ, White CA, Liles TM, Royston I, et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol (1997) 15:3266–74.

2.Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, GrilloLopez A, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood (1994) 84:2457–66.

3.McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol (1998) 16:2825–33.

4.Katchi T, Liu D. Diagnosis and treatment of CD20 negative B cell lymphomas. Biomark Res (2017) 16:1–5.

5.Hoelzer D, Walewski J, D?hner H, Viardot A, Hiddemann W, Spiekermann K, et al. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood (2014) 124:3870–9.

6.Nie M, Wang Y, Bi XW, Xia Y, Sun P, Liu PP, et al. Effect of rituximab on adult Burkitt's lymphoma: a systematic review and meta-analysis. Ann Hematol (2016) 95:19–26.

7.Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet (2016) 387:2402–11.

8.Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med (2017) 377:1250–60.

9.Ladetto M, Magni M, Pagliano G, De Marco F, Drandi D, Ricca I, et al. Rituximab induces effective clearance of minimal residual disease in molecular relapses of mantle cell lymphoma. Biol Blood Marrow Transplant (2006) 12:1270–6.

10.Kolstad A, Pedersen LB, Eskelund CW, Husby S, Gr?nb?k K, Jerkeman M, et al. Molecular monitoring after autologous stem cell transplantation and preemptive rituximab treatment of molecular relapse; results from the nordic mantle cell lymphoma studies (MCL2 and MCL3) with median follow-up of 8.5 years. Biol Blood Marrow Transplant (2017) 23:428–35.

11.Collett L, Howard DR, Munir T, McParland L, Oughton JB, Rawstron AC, et al. Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial. Trials (2017) 18:387.

12.Lee LJ, Toze CL, Huang SJT, Gillan TL, Connors JM, Sehn LH, et al. Improved survival outcomes with the addition of rituximab to initial therapy for chronic lymphocytic leukemia: a comparative effectiveness analysis in the province of British Columbia, Canada. Leuk Lymphoma (2017):1–8.

13.Coiffier B, Sarkozy C. Diffuse large B-cell lymphoma: R-CHOP failure—what to do? Hematology Am Soc Hematol Educ Program (2016) 2016:366–78.

14.Nowakowski GS, Blum KA, Kahl BS, Friedberg JW, Baizer L, Little RF, et al. Beyond RCHOP: a blueprint for diffuse large B cell lymphoma research. J Natl Cancer Inst (2016) 108:1–8.

15.Davies A, Berge C, Boehnke A, Dadabhoy A, Lugtenburg P, Rule S, et al. Subcutaneous rituximab for the treatment of B-cell hematologic malignancies: a review of the scientific rationale and clinical development. Adv Ther (2017) 34:2210–31.

16.Davies A, Merli F, Mihaljevic B, Siritanaratkul N, Solal-Céligny P, Barrett M, et al. Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol (2014) 15:343–52.

17.Fargier E, Ranchon F, Huot L, Guerre P, Safar V, Dony A, et al. SMABcare study: subcutaneous monoclonal antibody in cancer care: cost-consequence analysis of subcutaneous rituximab in patients with follicular lymphoma. Ann Hematol (2017) 97:1–9.

18.Lopez-Lastra S, Di Santo JP. Modeling natural killer cell targeted immunotherapies. Front Immunol (2017) 8:370.

References

1.Maloney DG, Grillo-López AJ, Bodkin DJ, White CA, Liles TM, Royston I, et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol (1997) 15:3266–74.

2.Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, GrilloLopez A, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood (1994) 84:2457–66.

3.McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol (1998) 16:2825–33.

4.Katchi T, Liu D. Diagnosis and treatment of CD20 negative B cell lymphomas. Biomark Res (2017) 16:1–5. 

5.Hoelzer D, Walewski J, D?hner H, Viardot A, Hiddemann W, Spiekermann K, et al. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood (2014) 124:3870–9.

6.Nie M, Wang Y, Bi XW, Xia Y, Sun P, Liu PP, et al. Effect of rituximab on adult Burkitt's lymphoma: a systematic review and meta-analysis. Ann Hematol (2016) 95:19–26.

7.Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet (2016) 387:2402–11.

8.Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med (2017) 377:1250–60.

9.Ladetto M, Magni M, Pagliano G, De Marco F, Drandi D, Ricca I, et al. Rituximab induces effective clearance of minimal residual disease in molecular relapses of mantle cell lymphoma. Biol Blood Marrow Transplant (2006) 12:1270–6.

10.Kolstad A, Pedersen LB, Eskelund CW, Husby S, Gr?nb?k K, Jerkeman M, et al. Molecular monitoring after autologous stem cell transplantation and preemptive rituximab treatment of molecular relapse; results from the nordic mantle cell lymphoma studies (MCL2 and MCL3) with median follow-up of 8.5 years. Biol Blood Marrow Transplant (2017) 23:428–35.

11.Collett L, Howard DR, Munir T, McParland L, Oughton JB, Rawstron AC, et al. Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial. Trials (2017) 18:387.

12.Lee LJ, Toze CL, Huang SJT, Gillan TL, Connors JM, Sehn LH, et al. Improved survival outcomes with the addition of rituximab to initial therapy for chronic lymphocytic leukemia: a comparative effectiveness analysis in the province of British Columbia, Canada. Leuk Lymphoma (2017):1–8.

13.Coiffier B, Sarkozy C. Diffuse large B-cell lymphoma: R-CHOP failure—what to do? Hematology Am Soc Hematol Educ Program (2016) 2016:366–78.

14.Nowakowski GS, Blum KA, Kahl BS, Friedberg JW, Baizer L, Little RF, et al. Beyond RCHOP: a blueprint for diffuse large B cell lymphoma research. J Natl Cancer Inst (2016) 108:1–8.

15.Davies A, Berge C, Boehnke A, Dadabhoy A, Lugtenburg P, Rule S, et al. Subcutaneous rituximab for the treatment of B-cell hematologic malignancies: a review of the scientific rationale and clinical development. Adv Ther (2017) 34:2210–31.