The non-Hodgkin’s lymphomas (NHL) are the most common haematological malignancies in adults, with approximately 85% of NHL of B cell origin expressing the specific B cell marker CD20. CD20 is a transmembrane protein of undefined function1 and its expression is B cell maturation-regulated. The prototype therapeutic anti-CD20 antibody (Ab) is rituximab (RTX), a chimeric Ab composed of a human IgG1 heavy-chain constant region and murine Ig variable region that is specific for CD20. The first therapeutic monoclonal Ab (mAb) to receive U.S. Food and Drug Administration (FDA) approval in 1997, RTX has been routinely used for treatment of almost all types of B cell NHL, whether indolent or aggressive. Addition of RTX to standard chemotherapy substantially enhances response to therapy and improves overall outcomes, which makes RTX therapy the most noticeable advance in lymphoma treatment over the past decades. Despite this remarkable success, major challenges remain: a) a significant percentage of patients with aggressive NHL are refractory to RTX-containing regimens;2 b) the long-term survival of patients with aggressive lymphomas is still limited (with 10-year progression-free survival approximately 35% in high-risk patients;3,4 c) most indolent lymphomas remain incurable;5 and d) RTX relies heavily on chemotherapy to achieve optimal therapeutic outcome, but chemotherapy is often associated with toxic adverse effects, which may compromise RTX activity and antitumour immunity, as discussed below.6 Continuous efforts have been made in an attempt to generate new anti-CD20 Ab with efficacy superior to RTX, but the new Ab do not seem to be fundamentally improving therapeutic outcome yet. The main reason for this appears to be that all anti-CD20 Ab are not directly cytotoxic to lymphoma cells but rely primarily on indirect effector mechanisms to attack lymphoma cells. In settings where the indirect effector mechanisms are absent, consumed, or compromised, such as in patients receiving toxic chemotherapy, the activity of anti-CD20 Ab can be disrupted.
Making anti-CD20 Ab directly cytotoxic to lymphoma cells may circumvent the dependence on indirect mechanisms and fundamentally enhance and sustain Ab activity. In this article, the mechanisms of RTX action and resistance, the features of newer generations of anti-CD20 mAb, and the therapeutic advantages of directly cytotoxic antibodies are reviewed.7
MECHANISMS OF RITUXIMAB ACTION AND RESISTANCE
The mechanism of RTX action is the subject of active study. While controversies remain, all the data demonstrate that RTX targets lymphoma cells through multiple mechanisms. Despite the multiple activities, the therapeutic capacity of RTX as a monotherapy appears rather limited.8 The reason for this appears to be, as discussed below, that RTX targets lymphoma cells mostly via indirect mechanisms that could readily be compromised by various situations, including chemotherapy.
RTX can activate the complement system by binding C1q to the Fc region of the Ab, generating a membrane attack complex to disrupt the plasma membrane and kill target cells. Components of the activated complement system can also act as opsonins by binding receptors on phagocytes and natural killer (NK) cells to activate Ab-dependent cell-mediated cytotoxicity (ADCC). While in vitro experiments have demonstrated complement-dependent cytotoxicity (CDC) in RTX activity,9,10 controversies remain whether in vivo CDC is required, sufficient, or unnecessary to mediate therapeutic effects of RTX.11,12 In patients with chronic lymphocytic leukaemia (CLL), RTX infusion results in rapid and profound depletion of complement components,13 suggesting that complement depletion may contribute to observed RTX treatment failure.14 Alternatively, CDC does not appear to be similarly active in follicular NHL, which is nodal, as opposed to CLL, which is predominantly bone marrow and peripheral blood-based. Genetic polymorphisms in the gene coding for C1q have been linked to variations in RTX efficacy,15 and Ab-resistant cells surviving RTX therapy have been reported to express high levels of complement-regulatory proteins (mCRP), which inhibit complement action.16-18 Therefore, the activity of RTX-induced CDC varies depending on patients, lymphoma type, and treatment duration, and can be compromised under various circumstances. CD20 downregulation is also reported as a mechanism of acquired RTX resistance. The primary mechanism for CD20 downregulation is believed to result from the shaving or stripping of CD20 from the cell surface by macrophages.18 This phenomenon is particularly relevant during the binding of RTX to CD20, and it does not eliminate lymphoma cells because of absence or exhaustion of the host effector mechanisms such as CDC and ADCC. Making RTX directly cytotoxic might overcome this resistance mechanism.
Antibody-Dependent Cellular Cytotoxicity
RTX can also activate ADCC attack on CD20+ cells through Fcγ receptor-bearing effector cells, such as NK cells, granulocytes, and macrophages. Activation of ADCC by RTX has been established by in vitro experiments.19 In murine models, depletion of normal B cells by RTX was reported to be dependent on FcγRI and FcγRIII; B cell depletion did not occur in FcγR-deficient mice, supporting an in vivo role for ADCC.12 In humans, single nucleotide polymorphisms (SNP) in FCGR3A (low affinity immunoglobulin gamma Fc region receptor III-A) with substitution of either a valine (V) or phenylalanine (F) residue at position 158 of the FCγRIIIa receptor can substantially impact ADCC. Cells bearing Fc receptor homozygous for V (158V/V) have a higher in vitro affinity for IgG1 compared to cells with the 158V/F or 158F/F receptor,20 showing higher response rates to RTX in NHL patients with the 158V/V receptor as compared to patients with 158V/F or 158F/F receptor.21-23 The polymorphisms have no prognostic significance in patients treated with chemotherapy alone,24 suggesting ADCC as an effector mechanism for anti-CD20 therapy. However, studies have not found an impact of the FCGR3A genotype on outcomes in B cell CLL treated with RTX,25 suggesting that the clinical contribution of ADCC depends on the characteristics of the underlying malignant cells.
In addition to genetic variations and lymphoma types, other conditions affect ADCC. For instance, activated complement components, such as C3b, inhibit NK cell-mediated ADCC.26 A common mechanism to disrupt ADCC is chemotherapy, which causes cytopenia with loss of effector cells of both myeloid and lymphoid lineages, including NK cells, granulocytes, macrophages, and T cells. Given that the FcγR-bearing cells are required for ADCC, loss of these effector cells in patients with cytopenia can be expected to halt RTX-mediated ADCC.
Induction of Apoptosis
RTX has very limited, if any, capacity to directly kill target cells in culture.7 While studies have reported induction of a degree of apoptosis to some malignant B cell lines in culture, this often requires plate-coated RTX or the presence of a second Ab crosslink Ab or FcγR to crosslink with RTX.27-29 Even with plate-immobilised RTX, the most vigorous form of crosslinking, the extent of cell death is limited, especially with cells of aggressive lymphomas, e.g., diffuse large B cell lymphoma (DLBCL) line SU-DHL-4.29 While studies have reported CLL cell apoptosis in patients receiving RTX treatment, it is unclear whether indirect mechanisms are involved in the induction of apoptosis.30 Discrepancies also remain regarding the mechanism of RTX- induced apoptosis. Some studies have suggested a central role of caspase in the induction of apoptosis,30 while others have shown caspase-independent apoptosis.31-33
It is noteworthy that while brief exposure to RTX downregulates B cell lymphoma (BCL)-2 expression, sensitising cells to apoptosis and chemotherapy,34 prolonged RTX exposure inhibits expression of the pro-apoptotic BCL-2 family proteins BAX and BAK, leading to resistance not only to apoptosis but also to multiple antineoplastic agents.35,36 RTX is typically administered over a number of weeks in the induction therapy, followed by multiple cycles of therapy every 8 weeks for up to 12 doses. While the intensive therapy protocol might play an important role in improving the response and durability of RTX treatment, it may also contribute to induction of resistance, as indicated in the long-term follow-up studies.3
In vitro experiments have shown that RTX facilitates the uptake and cross-presentation of apoptotic Daudi cell antigen to cytotoxic T lymphocytes (CTL).37 Whether RTX therapy similarly promotes antigen presentation and activation of specific CTL in vivo in patients remains to be established. It is unclear whether antitumour immunity in patients is generally compromised as a result of the intensive chemotherapy administered along with RTX. Antitumour immunity is now known to play a critical role in the prognosis of cancers, including lymphomas.38-40
The Adverse Impact of Chemotherapy on Rituximab Activity
Despite the proposed multiple antilymphoma mechanisms of RTX, the therapeutic capacity of RTX as a monotherapy appears limited.8 Patients treated with RTX alone showed very low response rates, especially for aggressive lymphoma, which is often fatal in months if untreated effectively. As a result, RTX has generally been used as adjuvant therapy in combination with chemotherapy consisting of multiple toxic chemotherapeutic agents for optimal therapeutic outcome, such as in CHOP (cyclophosphamide, doxorubicin [hydroxydaunomycin], vincristine [Oncovin®, Cellpharm GmbH, Hanover, Germany], and prednisolone), the most commonly used regimen.8 While intensive CHOP substantially increases response rate to RTX, it is often associated with toxic side effects, including life-threatening cytopenia.41 Cytopenia not only predisposes patients to high infection risk but can also disrupt RTX activity. For instance, ADCC might be compromised due to lack of effector cells. Induction of apoptosis might be impaired due to loss of FcγR-bearing cells that are required for RTX crosslinking. Lymphopenia can also seriously weaken immune activation function of RTX because of T cell deficiency.6 Lymphopenia could have significant long-term adverse sequela because T cell recovery could be very slow, especially in adult patients, due to thymic involution.42 A number of studies have demonstrated close relationships between lymphopenia and high incidence of relapse of lymphomas, including DLBCL,6,43 implicating the role of antitumour immunity in preventing recurrence. Therefore, implementation of toxic chemotherapy to RTX therapy might not only compromise RTX’s original activity but also the antitumour immunity of the hosts, predisposing patients to delayed lymphoma relapse. Novel strategies are needed to improve RTX efficacy in the absence of toxic chemotherapy.
THE NEWER GENERATIONS OF ANTI-CD20 ANTIBODIES
There are several new-generation anti-CD20 mAb engineered to provide advantages over RTX, including ofatumumab, ocrelizumab, veltuzumab, ocaratuzumab, and ublituximab. These mAb induce potent CDC but relatively weak ADCC, similar to RTX, and are categorised as type 1 Ab. Ibritumomab tiuxetan and obinutuzumab (OBZ) are regarded as type 2 Ab because of stronger ADCC relative to CDC. Compartmentalisation and redistribution of CD20 into lipid rafts is believed to be the mechanism behind Type 1 Ab induction of intensive strong Fc clustering and complement activation.44 The Type 2 Ab do not redistribute CD20 into lipid rafts.
Ofatumumab is at the most advanced stage of clinical development. Ofatumumab binds to a unique CD20 epitope, giving rise to a slow off-rate and a high capacity for complement activation. Ofatumumab-induced CDC in RTX-resistant CLL cells and lymphoma cell lines that express high levels of complement defence proteins and/or low levels of CD20.45 In clinical trials, ofatumumab showed improved response rates and progression-free survival, but benefits are still limited. For treatment of follicular and DLBCL, chemotherapy is still required.46,47 If enhancing CDC does not improve anti-CD20 mAb efficacy and RTX resistance is largely dictated by a failure of immune effector cell function, it would seem unlikely that these novel mAb will result in substantial improvements over RTX.
OBZ has a glycoengineered Fc region that includes nonfucosylated oligosaccharides that interact with FcR, particularly FcRIIIa, which enhances ADCC.48 It has features of a Type 2 anti-CD20 mAb in evoking nonapoptotic programmed cell death in addition to not having a strong ability to translocate CD20 into lipid rafts for complement activation.49 Studies reported superior tumour growth inhibition compared with RTX in lymphoma xenograft models,50 and greater B cell depletion than RTX in nonhuman primates and hCD20 transgenic mice. OBZ is approved for CLL and follicular lymphoma. Despite reports of potent capacity to induce strong ADCC and nonapoptotic programmed cell death, OBZ relies on chemotherapy for optimal outcome. While OBZ-based immunochemotherapy and maintenance therapy resulted in longer progression-free survival than RTX-based therapy in follicular lymphoma, the improvement appeared limited.51 The dependence on chemotherapy might compromise OBZ- mediated ADCC. If enhancing ADCC does not improve anti-CD20 mAb efficacy because of chemotherapy-induced failure of effector cells, the importance of having cytotoxic anti-CD20 Ab capable of eliminating lymphoma cells in the absence of chemotherapy will be heightened.
Radioisotope-Labelled Anti-CD20 Antibodies
Radioisotope-labelled anti-CD20 Ab had the potential to be good examples of directly cytotoxic anti-CD20 Ab. Two such Ab have been produced: 90Y-labelled ibritumomab tiuxetan and 131I-labelled tositumomab.52,53 Both Ab were FDA-approved for the treatment of relapsed or refractory follicular lymphoma or transformed B cell NHL. These Ab were highly effective even when used as monotherapy during the treatment of lymphomas refractory to salvage immunochemotherapy at relapse, demonstrating the unmatched potency of cytotoxic anti-CD20 Ab. However, neither Ab is in clinical application because of serious radiation-derived side effects, including bone marrow suppression, severe and prolonged cytopenia, and the sequelae of cytopenia.54,55 Tositumomab and I131 tositumomab were discontinued by the manufacturer in February 2014 and are no longer available.
OTHER ANTI-CD20 MODIFICATION APPROACHES
Other anti-CD20 modifications have been comprehensively reviewed in recent literature.56 Bispecific Ab, such as anti-CD20/CD3 or anti-CD20/NKGD2L, act through nonspecific activation of conventional or gamma/delta T cells initiating an attack on lymphoma cells. Toxin-combined anti-CD20 can directly attack,57 but because of utilisation of only one CD20-specific single-chain, the avidity of the bispecific Ab for CD20 might be substantially diminished. Various approaches have been taken to generate hypervalent anti-CD20 Ab without using second crosslinking Ab, FcγR, or plate immobilisation. Tetravalent anti-CD20 Ab are generated by genetic engineering.58 The dock-and-lock method has been used to produce hexavalent anti-CD20 antibodies.59 More recently, a two-step method using pretargeting component (anti-CD20 Fab’ conjugated with an oligonucleotide-1) and a subsequent crosslinking component (N-[2-hydroxypropyl] methacrylamide [HPMA] grafted with multiple complementary oligonucleotide-2) has also been reported to generate multivalent anti-CD20 Ab.60 All these different forms of hypervalent anti-CD20 Ab demonstrate enhanced direct antilymphoma activity in culture in the absence of cross-linking antibodies as compared to the native Ab counterparts, which is manifested as enhanced antiproliferative and apoptosis-inducing activity. However, direct cytotoxicity is not reported. In animal experiments using severe combined immunodeficiency mice, both the dock-and-lock and two-step pretargeting components generated multivalent anti-CD20 Ab and inhibited lymphoma progression in the absence of chemotherapy.
ANTIBODY–GRAPHENE OXIDE COMPLEX
More recent studies have reported drastic enhancement of RTX as well anti-Her2 Ab trastuzumab activity by non-covalently associating Ab with nanomaterial graphene oxide (GO).7,61
Noncovalent Binding Between Rituximab and Graphene Oxide Generates Stable Rituximab/ Graphene Oxide Complex with Marked High Avidity for CD20
GO is the thinnest nanomaterial available. Composed of a single-atom-thick nanosheet, GO has recently attracted intense interest within research investigating drug delivery. GO is nontoxic at low concentrations, but can cause oxidative stress, rupture of liposomes, disrupt the integrity of bacterial cell membranes, and kill cancer stem cells at high concentrations. When mixed in low salt solution, RTX and GO form a stable complex at 37°C, which no longer dissociates in physiological solutions such as phosphate-buffered saline and serum.7 Despite the fact that the RTX forms a complex with GO through a stochastic process, the random interaction between the two does not interfere with RTX reactivity with CD20. The RTX/GO complex demonstrated substantially enhanced CD20-binding capacity as compared to free RTX. While the mechanism behind the substantial increase in binding capacity is not yet fully understood, the data suggest that RTX interacts with GO through the Fc region with the Fab region uninterrupted, and the multivalent nature of RTX/GO gives rise to high avidity.7
Rituximab/Graphene Oxide Complex is Directly Cytotoxic to Malignant B Cells
When Raji cells, which are known to be resistant to apoptosis, were cultured with RTX/GO they underwent rapid cell death, determined by trypan blue and microscopic cell counting, Cell Count Kit, LIVE/DEAD stain, and electron microscopy. Annexin V staining of RTX/GO-killed cells did not detect significant staining, and DNA electrophoresis did not identify apoptotic DNA fragmentation, indicating nonapoptotic cell death (necroptosis, as determined in unpublished experiments). In line with these findings, the pan-caspase inhibitor Z-VAD-FMK could not rescue RTX/GO-treated cells. In contrast, RTX/GO-killed cells show rapid loss of plasma membrane integrity.7 Complement is not required for RTX/GO- mediated cytotoxicity, indicating RTX/GO directly kills lymphoma cells. Similarly, potent cytotoxicity was also demonstrated on other CD20+ cells, including Daudi (Burkitt lymphoma), SUDHL-4 and SUDHL-8/9 (DLBCL), primary lymphoma cells from a patient with CLL, as well as primary B lymphocytes from healthy donors. When the capacity of RTX/GO to activate complement was examined, RTX/GO had much weaker activity to activate complement as compared to free RTX. As complement activation is believed to be responsible for infusion-related side effects,62 the weak complement activation function of RTX/GO might be beneficial. Therefore, association of RTX with GO confers potent, direct cytotoxicity to CD20+ lymphoma cells, which is not observed for any of the previously reported anti-CD20 Ab formulations.
The Mechanism of Rituximab/Graphene Oxide Complex-Mediated Cytotoxicity
It remains incompletely understood how RTX/GO kills target cells. The results show that the highest valence of RTX in RTX/GO gives rise to the strongest cytotoxicity.7 As CD20 crosslinking causes CD20 capping, and reorganisation of the actin network is required for capping,63 the actin polymerisation inhibitor, latrunculin B (LatB), was tested in a RTX/GO-cytotoxicity assay. LatB completely abrogated RTX/GO-induced cell death, indicating that the actin network is involved in the cytotoxicity.7 Anti-major histocompatibility complex Class I (HLA-A/B/C) and Class II (HLA-DR) mAb W6/32 and L243 were also used to generate mAb/GO complexes. HLA-DR is a lipid raft-associated protein whereas HLA-A/B/C are located outside of lipid rafts.64 W6/32/GO induced limited Raji cell death; on the other hand, L243/GO killed the target cells as extensively as RTX/GO.7 These results suggest that lipid raft-associated proteins are involved in RTX/GO-mediated activity. Given the previous report that the actin network plays a role in controlling location and function of lipid raft proteins, the protective activity of LatB might result from interruption of relocation of lipid-raft proteins. Calcium (Ca) influx is required for RTX/GO-mediated killing as Ca2+ chelator alleviates the cytotoxicity. RTX/GO also induces strong reactive oxygen species in the target cells and blocking reactive oxygen species production prevents the cell death (unpublished data). All the results indicate that potent cytotoxicity of RTX/GO results from a combined action of CD20-crosslinking-induced intracellular activity and biological activity of GO.
Rituximab/Graphene Oxide Complex Rapidly Eliminates Established Burkitt Lymphoma in Vivo
The therapeutic potential of RTX/GO in vivo was studied in immunodeficient NODragkoγko (NRG) mice that were intravenously transplanted (Burkitt lymphoma) with Raji cells. As NRG mice are deficient in T, B, and NK cells along with a defective complement system and macrophage activity,65 they constitute an ideal animal model for the evaluation of RTX/GO therapeutic activity in the absence of host effector mechanisms such as CDC and ADCC. To determine whether RTX/GO could eliminate established lymphoma, the treatment was not initiated until the 8th day of Raji cell transplantation, when extensive lymphoma infiltrates were identified in the bone marrow and liver.7 The mice were treated intravenously every 2–3 days for a total of four treatments. When analysed 3 days after the last treatment, extensive lymphoma infiltrates were identified in the bone marrow of the PBS, GO, and RTX-treated animals, but not in RTX/GO-treated mice. The Raji cell counts in the bone marrow of GO and RTX-treated mice were similar to that of PBS-treated mice. Infiltrating lymphoma was identified in all the PBS, GO, and RTX-treated mice but not in any of the RTX/GO-treated mice. No pathological abnormalities nor any evidence of morbidity was identified in the RTX/GO- treated mice.7 The in vivo results demonstrate that RTX/GO has the capacity to diffuse out of the blood circulation, penetrate through the tissue to reach target cells, and rapidly eliminate established lymphomas in the absence of host effector mechanisms.
DISCUSSION AND CONCLUSION
The findings with RTX/GO demonstrate a new strategy to substantially improve therapeutic activity of RTX. While CD20-crosslinking-induced cell death has been reported to be apoptotic, RTX/GO kills by necroptosis. Necroptosis might provide a therapeutic advantage because faulty apoptotic pathways often contribute to therapy resistance. The serum half-life of RTX/GO may be shortened compared to that of free RTX, according to previous reports;66,67 however, an extended serum half-life may not be necessary for the RTX/GO therapeutic effect, as RTX/GO appears to eliminate lymphoma rapidly. Elimination of established lymphoma in the NRG hosts is unique to RTX/GO therapy. The results suggest effectiveness of RTX/GO therapy in patients with compromised host effector mechanisms. More importantly, the independence on toxic chemo-agents of RTX/GO therapy implicates protection of the host immune cells that are critical in antitumour immunity and maintenance of durable remission. Clearly, much is yet to be understood regarding RTX/GO, including the mechanism of cytotoxicity, pharmacological kinetics, side effects, and clinical efficacy. In a more recent study, GO-associated anti-HER2 Ab complex, trastuzumab/GO, demonstrated the ability to directly kill HER2lo cancer cells,61 similar to RTX/GO. Therefore, the data taken together indicate that noncovalent association of antitumour Ab with GO might constitute a highly effective methodology to enhance efficacy.
The direct effects of rituximab include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and the indirect effects include structural changes, apoptosis, and sensitization of cancer cells to chemotherapy.Does rituximab cause complement dependent cytotoxicity? ›
Rituximab contains a human IgG1 Fc portion capable of activating immune effector mechanisms in man and rodents, including activation of the complement system and complement-dependent cytotoxicity (CDC) next to antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis mediated by either Fc—or complement receptors ...What is the therapeutic class of rituximab? ›
Rituximab injection products are in a class of medications called monoclonal antibodies. They treat the various types of NHL and CLL by killing cancer cells.Why is rituximab given before chemotherapy? ›
RITUXAN (rituximab) is a type of antibody therapy that can be used alone or with chemotherapy. They work in different ways to find and attack the cells where cancer starts. RITUXAN targets and attaches to the CD20 protein found on the surface of blood cells with cancer and some healthy blood cells.How toxic is rituximab? ›
Rituximab has been involved in several cases of diffuse interstitial pneumonia. Two literature reviews of 45  and 126  cases are available. The overall mortality rate is around 15%. Lung toxicity occurred mostly in the setting of non-Hodgkin lymphoma (93% cases) with an estimated frequency of 0.01–0.03% cases.Is immunotherapy considered cytotoxic? ›
A cytotoxic immunotherapy strategy creates such a tumor vaccine in situ. Immunogenic tumor cell death provides tumor antigen targets for the adaptive immune response and stimulates innate immunity.What is the most common reason for discontinuing rituximab? ›
Overall, 31.2% of patients stopped rituximab, with the largest reason for discontinuing being primary inefficacy (42.1%). Comparison of Kaplan–Meier curves showed that rituximab drug survival was lower in seronegative patients and in patients who had previously failed at least one biologic DMARD (bDMARD).What are two strategies used to prevent infusion reaction with rituximab? ›
Rituximab is a widely used anti-cancer treatment with a high incidence of hypersensitivity reaction (HSR). Strategies to reduce the incidence of HSR include premedications and slow titration.How does complement dependent cytotoxicity work? ›
Complement-dependent cytotoxicity (CDC) is an immune response in which target cells are lysed through activation and recruitment of the complement cascade to the targeted cell surface.How do you know if rituximab is working? ›
Rituximab works by lowering the number of these B-cells, to reduce inflammation, pain, swelling and joint damage. If rituximab works for you, you'll probably notice an improvement in your symptoms 8-16 weeks after you start treatment.
RITUXAN® (rituximab) is a prescription medicine used to treat: Adults with Non-Hodgkin's Lymphoma (NHL): alone or with other chemotherapy medicines. Children 6 months of age and older with mature B-cell Non-Hodgkin's Lymphoma (NHL) and mature B-cell acute leukemia (B-AL): in combination with chemotherapy medicines.What does rituximab do to your immune system? ›
Rituximab suppresses the immune system. Therefore, serious fungal, bacterial and new or reactivated viral infections (for example, hepatitis B or C, shingles) can occur during or after treatment. Generally, rituximab is avoided in the presence of active, significant infections.How many Rituxan treatments can a person have? ›
Administer RITUXAN as a single-agent every 8 weeks for 12 doses. Following completion of 6-8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses.What are the long term side effects of rituximab? ›
- heart problems, such as heart attack or ventricular fibrillation (a type of abnormal heart rhythm)
- blockage or tearing of your intestines.
- kidney failure or other serious kidney problems.
- serious infections, such as shingles.
- reactivation of the hepatitis B virus*
Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. Renal Toxicity: Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with Non– Hodgkin's Lymphoma (NHL).What is the most important toxicity with rituximab? ›
The most frequent adverse event of rituximab is infusion-related toxicity, e.g. cytokine-release syndrome that occurs usually during the first infusion. However, there is scarce data on feasibility and tolerability of rituximab infusions in CLL outside clinical trials.Who should avoid rituximab? ›
- Painful sores or ulcers on your skin, lips, or in your mouth.
- Peeling skin.
This medicine may cause heart and heart rhythm problems (eg, heart attack, arrhythmia, cardiogenic shock). Check with your doctor if you have chest pain or discomfort, pain or discomfort in the arms, jaw, back, or neck, dizziness, fainting, fast, slow, or irregular heartbeat, cool, sweaty skin, or trouble breathing.What does it mean if a medicine is classified as cytotoxic? ›
Cytotoxic drugs (sometimes known as antineoplastics) describe a group of medicines that contain chemicals which are toxic to cells, preventing their replication or growth, and so are used to treat cancer.Does cytotoxic mean chemo? ›
Chemotherapy uses anti-cancer (cytotoxic) drugs to destroy cancer cells. Cytotoxic means toxic to cells. Most chemotherapy drugs are carried in the blood. This means they can reach cancer cells anywhere in the body.
(SY-toh-TOK-sik ... sel) A type of immune cell that can kill certain cells, including foreign cells, cancer cells, and cells infected with a virus. Cytotoxic T cells can be separated from other blood cells, grown in the laboratory, and then given to a patient to kill cancer cells.How many years can you take Rituxan? ›
The majority of patients with RA treated with rituximab remain on treatment after four years. The three most common reasons for rituximab discontinuation in RA were ineffectiveness, death and adverse events. Rituximab is well tolerated when used as a first or second line biologic DMARD for RA.What is the most common side effect of Rituxan? ›
The most common side effects during treatment with Rituxan are: infusion-related reactions. infections (may include fever, chills) body aches.Is there an alternative to rituximab? ›
Ofatumumab is a feasible alternative anti-CD20 therapy in patients intolerant of rituximab.Why is Tylenol given before Rituxan? ›
Medications commonly used before RITUXAN infusions include antihistamines and acetaminophen. Severe reactions typically occur during the first RITUXAN infusion. Taking the suggested medication before treatment may reduce the chance of having a severe infusion-related reaction.Why is Benadryl given with Rituxan? ›
Before rituximab is infused, you will likely be treated with medications that reduce the likelihood of an allergic reaction. This includes Tylenol (acetaminophen) and Benadryl (diphenhydramine) and sometimes steroid medications.Why give Tylenol for Rituxan? ›
Your child will be given acetaminophen (Tylenol® or another brand) and diphenhydramine (Benadryl®) before the dose of rituximab to help avoid the flu-like symptoms and decrease the chance of allergic reactions.What happens when complement is activated? ›
Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules.What are the three major outcomes effects of the complement system? ›
At the basic level the broad functions of the complement system can be split into three areas: (1) the activation of inflammation; (2) the opsonization (labeling) of pathogens and cells for clearance/destruction; (3) the direct killing of target cells/microbes by lysis.How do you perform a cytotoxicity assay? ›
Testing involves extracting devices in a cell culture media and then exposing the extract fluid to mouse fibroblast cells (L929). The cells are allowed to grow in the extract fluid for a specified amount of time before the cells are evaluated using either qualitative or quantitative methods.
After rituximab, patients should avoid 'live' vaccines such as oral polio, rubella (German measles), BCG, measles, oral typhoid, yellow fever and the nasal flu vaccine. This includes any 'live' vaccines needed for travel abroad.What is the success rate of rituximab? ›
A key clinical study known as the REFLEX Trial showed that at 6 months: In another study, 54% of people who received a second course of Rituxan plus MTX saw an additional 6 months of improvement compared to 45% of people who received placebo + MTX.How long does it take for rituximab to destroy B cells? ›
Treatment with rituximab results in complete B cell-depletion within 72 h. Recovery of B cell counts usually starts only 6-9 months after the completion of therapy, and normal levels are obtained after 9-12 months (5).What is the difference between Rituxan and rituximab? ›
Official answer. Truxima (rituximab-abbs) is a biosimilar to Rituxan (rituximab). Truxima is indicated for the treatment of non-Hodgkin's lymphoma, while Rituxan is indicated for the expanded treatment of non-Hodgkin's lymphoma, plus several other medical conditions.Is rituximab a high risk medication? ›
Taking sex, age, medical conditions, and other factors into account, the study determined that the risk of death for the cancer patients taking rituximab was more than double and the risk for patients with a rheumatologic condition was nearly three-quarters higher compared with medically similar people in the study.What autoimmune diseases does rituximab treat? ›
It was originally used to treat lymphoma but is increasingly used for the treatment of autoimmune diseases. Rituximab was found to be effective in randomised controlled trials for rheumatoid arthritis, granulomatosis with polyangiitis and other antineutrophil cytoplasmic antibody-associated vasculitides.Is rituximab cytotoxic? ›
The direct effects of rituximab include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and the indirect effects include structural changes, apoptosis, and sensitization of cancer cells to chemotherapy.Does Rituxan cause memory loss? ›
This can occur several months after the infusion and is usually transient. It may cause no problems but increases the risk of serious infections. It is treatable if needed. may cause memory problems, confusion, sight loss and difficulty walking.What is the black box warning for Rituxan? ›
WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) See full prescribing information for complete boxed warning. occur; approximately 80% of fatal reactions occurred with first infusion.Are immunosuppressants cytotoxic? ›
Cytotoxic drugs prevent cell division or cause cell death. 1 They act predominantly on rapidly dividing cells such as T lymphocytes, and are therefore immunosuppressive and anti-inflammatory.
Conjugated monoclonal antibodies are considered hazardous drugs because they are bound to cytotoxic substances or radioisotopes. However, naked mAbs don't meet the criteria to be tested as hazardous drugs.What type of monoclonal antibody is rituximab? ›
Rituximab, an anti-CD20 chimeric monoclonal antibody, was approved for the treatment of patients with relapsed/refractory low-grade B-cell non-Hodgkin lymphomas.Which of the drugs are cytotoxic chemotherapeutic agents? ›
Cytotoxic chemotherapy is the primary treatment option for metastatic angiosarcoma, although there is no convincing evidence to show survival benefit. The main drug groups used in CAS are paclitaxel, docetaxel, pegylated liposomal doxorubicin, and liposomal daunorubicin.How long does Rituxan suppress immune system? ›
The effects of rituximab usually last for between six and nine months. Rituximab suppresses the immune system. Therefore, serious fungal, bacterial and new or reactivated viral infections (for example, hepatitis B or C, shingles) can occur during or after treatment.What does it mean if a drug is cytotoxic? ›
Cytotoxic drugs (sometimes known as antineoplastics) describe a group of medicines that contain chemicals which are toxic to cells, preventing their replication or growth, and so are used to treat cancer. They can also be used to treat a number of other disorders such as rheumatoid arthritis and multiple sclerosis.What is the strongest immunosuppressant? ›
Cyclophosphamide (Baxter's Cytoxan) is probably the most potent immunosuppressive compound. In small doses, it is very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias, granulomatosis with polyangiitis, and other immune diseases.Is Rituxan a hazardous drug? ›
Reviewing the literature, CDC and NIOSH guidelines revealed that Rituximab is not considered a hazardous drug and has no adverse health effects through eye, skin, or mucous membrane contact (Genentech, 2011).What is the difference between cytotoxic and hazardous drugs? ›
Hazardous medications can cause toxicity or adverse effects to our health at low doses, and they include cytotoxic drugs. A cytotoxic drug can pose damaging action (e.g., carcinogenic, teratogenic, genotoxic, or mutagenic) on cells (including healthy cells) and includes most anti-cancer or chemo medication.Why are cytotoxic drugs hazardous? ›
Exposure to cytotoxic drugs has been reported to cause increased frequency of chromosome damage in exposed workers. They can cause acute skin, eye, and mucous membrane irritations, as well as nausea, headaches, and dizziness.What are the most common adverse effects of rituximab? ›
- Back pain.
- black, tarry stools.
- bloating or swelling of the face, arms, hands, lower legs, or feet.
- blood in the urine or stools.
- body aches or pain.
- burning or stinging of the skin.
- chest pain or tightness.
- difficulty with breathing.
Rituximab affects your immune system, which can make you more likely to pick up some infections. Tell your doctor or rheumatology nurse straight away if you develop any signs of infection. These include a sore throat or fever, or any other new symptoms that concern you.Why is rituximab so expensive? ›
Biological medicines are understandably expensive because of the research, development, and complex manufacturing processes involved. Such medicines also have extended patent protection over chemical pharmaceuticals in order to help drug companies recoup the extensive costs. Those costs are passed on to the patient.What is the most cytotoxic chemotherapy? ›
Anthracyclines. Anthracyclines are the most widely used type of cytotoxic agent. These drugs bind with DNA, preventing it from making copies of itself and therefore interfering with its reproduction. They are used in the treatment of bladder cancer, breast cancer, and many other types of cancer.What is the difference between chemotherapy and cytotoxic drugs? ›
Chemotherapy uses anti-cancer (cytotoxic) drugs to destroy cancer cells. Cytotoxic means toxic to cells. Most chemotherapy drugs are carried in the blood. This means they can reach cancer cells anywhere in the body.Is cytotoxic therapy the same as chemotherapy? ›
This type of cancer treatment works by keeping cancer cells from growing, dividing, and making more cells. Chemotherapy can be used as a treatment for many different cancers. Your doctor may refer to chemotherapy as standard chemotherapy, traditional chemotherapy, or cytotoxic chemotherapy.