RESUMEN

BACKGROUND: With the increasing use of daratumumab (DARA)-containing regimens for multiple myeloma (MM) patients in China, the standard infusion time of DARA is long, with the potential for infusion-related reactions (IRRs) and increased hospitalization and use of resources. Shortening the duration of DARA infusion helps to optimize the hospital stay and enhance the patient treatment experience. The current, commonly used 90-min rapid DARA infusion regimen may not be applicable to Chinese MM patients, and therefore, we explored a new 110-min rapid DARA infusion regimen aimed at reducing the treatment burden on patients to guarantee therapeutic safety. METHODS: MM inpatients treated with the DARA regimen were divided into two groups according to the number of times the DARA regimen was used: a standard infusion regimen for patients treated with the first two doses of DARA and a 110-min rapid infusion regimen for patients treated with more than two doses of DARA. Anti-allergy medications were routinely administered prior to the start of DARA infusion, patient consent, and authorization was obtained for all treatments, and statistical evaluation of the results was conducted via descriptive analyses, one-way ANOVA and chi-square tests. RESULTS: A total of 129 patients were included in this study: 68 in the standard infusion group, with 121 DARA infusions, and 129 in the rapid infusion group (patients who participated in the standard infusion subsequently participated in the rapid infusion), with 738 DARA infusions. The incidence of IRRs was 27.27% (36/121) in the standard infusion group and 1.35% (10/738) in the rapid infusion group, which were significantly different (p < 0.001). The incidence of IRRs after rapid infusion in other studies was <6%. The incidence of grade 1 IRRs in the rapid infusion group was 0.81% (6/738), the incidence of grade 2 IRRs was 0.54% (4/738), and there were no IRRs above grade 3; age, sex, and underlying disease had no effect on the choice of infusion method (p > 0.05). The mean infusion time after the occurrence of IRRs was also shorter in the rapid infusion group than in the standard infusion group (F = 24.781, p < 0.001). CONCLUSION: The 110-min rapid infusion DARA regimen is feasible and safe for use in Chinese MM patients.

Asunto(s)

RESUMEN

BACKGROUND: Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) involving the bone marrow (BM) with presence of IgM monoclonal protein, and comprises > 95% of all LPL cases. Rituximab-based regimens have been predominant in the management of WM. Infusion-related reactions (IRRs) are a primary concern with rituximab, although it is generally better tolerated with less toxicity than conventional anticancer agents. Here, we present an autopsy case of an elderly man who died suddenly after receiving the initial infusion of rituximab for WM/LPL. CASE PRESENTATION: An 84-year-old man was found dead in his bedroom. He had undergone the initial intravenous rituximab infusion for progressive anemia related to Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) approximately 15 h before death. Although the protocol for rituximab administration and additional medication was considered appropriate, he exhibited several symptoms consistent with infusion-related reactions (IRRs) during the infusion. Autopsy revealed monotonous proliferation of small-to-medium-sized lymphocytic cells in the bone marrow, consistent with the premortem diagnosis of WM/LPL. Additionally, immunoglobulin λ-light chain-derived amyloid (ALλ) deposition was identified in all organs other than the brain. Although ALλ deposition and LPL infiltration were found in the heart, they were not severe enough to cause severe functional impairment. Severe congestion and/or edema were observed in the lungs, liver, and brain. Although significant inflammatory cell infiltration was not found in any organs, laboratory tests revealed elevated serum levels of inflammatory cytokines, including interleukin-1ß, interleukin-6, tumor necrosis factor-α and the presence of IgM-λ monoclonal protein. CONCLUSION: Acute IRRs associated with the initial rituximab infusion were the major contributing factor to his sudden unexpected death. The autopsy findings of present case suggest the necessity for thorough monitoring of older patients with WM/LPL undergoing rituximab treatment, particularly when pronounced IRRs occur during the first administration, in addition to investigating complications of WM/LPL before infusion.

Asunto(s)

RESUMEN

T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE.

Asunto(s)

RESUMEN

This report documents the treatment of a 41-year-old male with sickle cell disease (SCD) and repeated stuttering priapism using crizanlizumab, which alleviated the priapism but induced a significant vaso-occlusive crisis during the second infusion. Encouragingly, no subsequent vaso-occlusive crises occurred. However, the potential for infusion-related adverse events warrants close supervision. Further research is necessary to explore its full benefits on priapism management.

RESUMEN

INTRODUCTION: Trastuzumab is a vital treatment option for human epidermal growth factor 2 positive breast cancer. Since 2017, there have been 5 trastuzumab biosimilars approved for use. Despite hypotheses of infusion-related reactions among intravenous trastuzumab, subcutaneous trastuzumab, and trastuzumab biosimilars, there is minimal available literature comparing these agents. This evaluation will compare the rate of infusion-related reactions among these agents, evaluate our institution's utilization, and compare acquisition costs to determine if there is a potential cost savings by utilizing specific agents as our formulary preferred medication. METHODS: We retrospectively analyzed medical records to identify the incidence of infusion-related reaction after administration of intravenous or subcutaneous trastuzumab or trastuzumab biosimilars. Additionally, we conducted a cost analysis to identify potential cost savings by switching to an alternative institutional preferred agent. Infusion chair time was calculated to identify chair time savings with subcutaneous administration. RESULTS: There were 183 patients included in this study. Seven patients (3.8%) experienced an infusion-related reaction. The most utilized agent within our cohort was intravenous trastuzumab. During our study period, 181 patients received intravenous infusions, which could allow for substantial infusion chair savings by switching to trastuzumab/hyaluronidase, the subcutaneous formulation. Beyond the chair time, direct drug cost savings were also identified when comparing the costs of each of the evaluated medications. CONCLUSION: Subcutaneous trastuzumab or trastuzumab biosimilars do not pose a greater risk of infusion-related reactions compared to intravenous trastuzumab and may offer more affordable treatment options for breast cancer patients who qualify for trastuzumab therapy.

RESUMEN

OBJECTIVE: This phase II clinical trial evaluated feasibility and tolerability of 90-minute rituximab infusion and a concentration of 4 mg/mL rituximab infusion in Japanese patients with previously untreated follicular lymphoma or diffuse large B-cell lymphoma. METHODS: Treatment was rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone. In cycle 1, rituximab at a dose of 375 mg/m2 (4 mg/mL) was administered at the standard infusion rate stipulated in the package insert. On confirmed tolerance of rituximab, patients received 90-minute infusion in second and subsequent cycles. The primary endpoint was incidence of grade 3 or higher infusion-related reactions during 90-minute rituximab infusion in cycle 2 of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone. RESULTS: All 32 patients (median age 61.5 years, 16 males, 24 with diffuse large B-cell lymphoma) completed the prescribed six or eight cycles of treatment. One patient withdrew consent after cycle 1, and another developed grade 2 erythema and continued receiving 4 mg/mL at the standard infusion rate for cycle 2. The remaining 30 patients received 90-minute rituximab infusion; 28 (93.3%) completed cycle 2 at the scheduled infusion rate and dosage. No grade 3 or higher infusion-related reactions were associated with a concentration of 4 mg/mL rituximab dose or 90-min rituximab infusion in cycle 2. The most common infusion-related reaction symptoms were pruritus, hypertension and oropharyngeal discomfort. During the study, toxicities and adverse events were as expected, with no new safety signals. CONCLUSION: High-concentration dosing (4 mg/mL) and 90-minute infusion of rituximab are feasible and tolerable in Japanese patients with previously untreated follicular lymphoma or diffuse large B-cell lymphoma. CLINICAL TRIAL NUMBER: JapicCTI-173 663.

Asunto(s)

RESUMEN

Rituximab, anti-CD20 monoclonal antibody, has broad clinical application. The aim of this study is to compare the safety and cost of the original reference rituximab (MabThera) and its biosimilar (Riximyo). This retrospective analysis of 262 patients receiving Riximyo in the Department of Hematology of Wroclaw Medical University in Poland from the period of 1 October 2020 to 21 June 2021 focused on infusion-related reactions (IRRs), which occurred in 4,96% of patients (N = 13). 109 patients (41,6%) had previously been treated with the reference drug and 2 IRRs were reported after switching therapy. During the study period, after biosimilar introduction, the cost of rituximab decreased by 41%. Rixmyo while maintaining similar safety profile is much more cost-effective.

Asunto(s)

RESUMEN

Monoclonal antibodies, such as PD-1 inhibitors, are increasingly used in various cancers. Acute low back pain as infusion-related reaction (IRR) to monoclonal antibodies is poorly described. We report a bicentric series of 10 cases of acute low back pain due to administration of monoclonal antibodies directed against PD-1/PD-L1 for skin cancer treatment in patients treated at University Hospital Heidelberg and University Medical Center Mainz (Germany). The management of IRR symptoms was immediate interruption of infusion and analgesia leading to quick improvement and complete symptom relief in all patients. Our findings suggest that the risk of developing low back pain as IRR is depending on the concentration of the administered drug. Low back pain as IRR can be managed by early interruption of infusion and by decreasing the infusion rate or concentration in following administrations.

RESUMEN

This retrospective study aimed to assess the characteristics and predictors of infusion-related reactions (IRRs) to rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL). The medical records of adult patients with B-NHL who received their first cycle of rituximab from August 2020 to August 2022 were reviewed. IRRs were defined as any signs experienced by patients during rituximab infusion and graded according to the Common Terminology Criteria for Adverse Events. During the study period, 334 patients were included; among them, 100 patients (30%) developed IRRs (mean age 54.7 (SD 13.2) years). Of the reported IRRs, 90% were grade II reactions, and 10% were grade III reactions. The multivariate analysis identified indolent lymphoma [OR 1.90, p = 0.025], no hydrocortisone as premedication [OR 3.03, p = 0.029], thrombocytopenia [OR 2.55, p = 0.009], and absolute lymphocyte count ≥ 2000 lymphocytes/microL [OR 1.74, p = 0.045] as independent predictors for IRRs.

RESUMEN

Rituximab is a widely used anti-CD20 monoclonal antibody with a high incidence of infusion-related reactions (IRRs) during administration. Reducing the incidence of IRRs remains problematic in hematological practices. In the present study, a novel strategy of a prednisone pretreatment regimen was designed similar to the combination of rituximab, cyclophosphamide, epirubicin, vincristine and prednisone (R-CHOP) with the aim of exploring the effect on the incidence of IRRs to rituximab in patients with diffuse large B-cell lymphoma (DLBCL). A prospective, randomized (1:1) and controlled study was conducted in three regional hospitals in two groups (n=44 for each group): i) A control group treated with standard R-CHOP-like regimen; and ii) a group receiving a prednisone-pretreatment, modified R-CHOP-like protocol for newly diagnosed patients with DLBCL. The primary endpoint was to assess the incidence of IRRs to rituximab, as well as the association of IRRs with the efficacy of treatment. The second endpoint involved clinical outcomes. The total incidence of IRRs to rituximab in the treatment group was significantly lower compared with that in the control group (15.9 vs. 43.2%; P=0.0051). The different grade incidence of IRRs was lower in the treatment group compared with that in the control group (P=0.0053). In total, 29.5% of patients (26/88) experienced >1 IRR episode. The incidence of IRRs in the pre-treatment group was decreased compared with that in the control group in the 1st cycle (15.9 vs. 43.2%; P=0.0051) and 2nd cycle (6.8 vs. 27.3%; P=0.0107). The overall response rate was similar between the two groups (P>0.05). Median progression-free survival and median overall survival time were not statistically distinct between the two groups (P=0.5244 and P=0.5778, respectively). Grade ≥III toxicities mainly included vomiting and nausea (<20%), leukopenia and granulocytopenia (<20%), and alopecia (<25%). No death events were reported. Apart from IRRs to rituximab, the incidence of other adverse events was similar in both groups. The novel prednisone-pretreatment R-CHOP-like protocol in the present study significantly decreased the total and different grade incidences of IRRs to rituximab among newly diagnosed patients with DLBCL. This clinical trial was retrospectively registered with the Chinese Clinical Trial Registry (registration number, ChiCTR2300070327; date of registration, 10 April 2023).

RESUMEN

Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha-mannosidase deficiency and accumulation of mannose-rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase, is the first enzyme replacement therapy for non-neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA-treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion-related reactions (IRRs). This pooled analysis evaluated data from 33 VA-treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment-emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment-emergent ADA-positive patients with relatively high titers (n = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well-managed; patients with lower titers (n = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA-positive and ADA-negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM.

RESUMEN

Biosimilars offer cost-effective and safe treatment options both for patients and healthcare systems. CT-P10 is the first biosimilar of rituximab approved in Europe for use in all indications of originator rituximab (oRTX). This study aimed to provide real-life data on treatment changes and adverse events in patients who received oRTX or CT-P10. We retrospectively reviewed treatment-related adverse events [infusion-related reactions (IRRs), infections, hypogammaglobulinemia] in patients treated with at least one dose of oRTX (MabThera®) or CT-P10 (Truxima®) between 2020 and 2021 and had at least 6 months follow-up after rituximab infusion in a rheumatology clinic. The switches between oRTX and CT-P10 were performed according to drug availability at the hospital pharmacy at the time of infusion according to the local hospital procedure. Physicians were not involved in the decision of biosimilar selection. A total of 128 patients (CT-P10, n = 64; oRTX, n = 64) were included. CT-P10 was switched in 52 (40.6%) patients who had previously used oRTX, and 48 (37.5%) patients remained on oRTX. We demonstrated no difference between patients treated with oRTX or CT-P10 in the rates of IRRs, in which all reactions were grade 1 and 2. Comparable rates of infections (p > 0.05) and the rate of hypogammaglobulinemia (p > 0.05) were found in both groups with no significant difference. CT-P10 provides a safe treatment alternative in patients who require rituximab therapy. The rational use of biosimilars can be supported by evolving evidence on interchangeability and switching in real-life settings, which will help clinicians in decision-making.

Asunto(s)

RESUMEN

Daratumumab, a CD38-directed monoclonal antibody indicated for multiple myeloma treatment in adult patients, is associated with a high incidence of infusion-related reactions (IRRs). Due to CD38 receptor presence in the lungs, many reactions present similarly to asthma or allergic rhinitis. Montelukast, a leukotriene receptor antagonist, has been hypothesized to reduce daratumumab IRRs due to its efficacy in treating allergic rhinitis and asthma and the presence of leukotriene receptors in the lungs. Recently published data reported daratumumab can be safely administered via rapid rate protocol that reduces infusion time from 195 min to 90 min after completion of two doses. This retrospective, observational cohort study examined 73 patients who received daratumumab in the outpatient setting between December 2015 and April 2020. Patients were included if they were 18 years or older, had an International Classification of Disease (ICD)-10 diagnosis code for multiple myeloma, and received daratumumab intravenously. The primary outcome was a comparison of IRRs between those who did and did not receive montelukast. Secondary outcomes included IRR symptoms, rescue medications utilized for IRRs, and rapid rate administration outcomes. Montelukast use was associated with a lower rate of IRRs (44.4% vs. 65.2%, p = 0.044). Pulmonary IRR symptoms were more common in those who did not receive montelukast. Rapid rate administration of daratumumab did not lead to any IRRs. Adding montelukast as a pre-medication for daratumumab infusions led to a reduction in IRRs, and rapid rate administration was found to be safe after completion of two full doses of daratumumab.

Asunto(s)

RESUMEN

Sickle cell disease is an autosomal recessive disorder characterized by the presence of sickle hemoglobin that leads to chronic hemolysis and vaso-occlusive crisis. After decades of limited therapy options, crizanlizumab is a humanized monoclonal antibody approved by the Food and Drug Administration (FDA) in 2019 for sickle cell-related pain crises for patients 16 years of age and above. Although rare, infusion-related reactions, including painful crises, occurred in 3% as per the package insert. However, the data on how to deal with such reactions and about further treatment outcomes are limited as most patients stopped crizanlizumab after the reaction. Herein, we report the good outcome of 13 doses of crizanlizumab in a 19-year-old female patient with sickle cell disease on hydroxyurea, despite experiencing a severe infusion-related painful crisis during the second infusion. Additional benefits of crizanlizumab, in this case, were preventing new episodes of acute chest syndrome, quitting chronic narcotics use, and a remarkable improvement in quality of life and overall performance.

RESUMEN

B cell-depleting therapies such as ocrelizumab (OCR) are highly effective in people with multiple sclerosis (MS). Especially at treatment start and initial infusion, infusion-related reactions (IRR) are a common adverse event. The relevance of acute changes of cell-depleting therapies on peripheral immune compartments and routine lab testing is important for clinical practice. We systematically analyzed routine blood parameters, detailed blood immunophenotyping and serum cytokine profiles in 45 MS patients starting on OCR. Blood samples were collected before and after corticosteroid premedication and directly after each OCR infusion of the first three ocrelizumab infusions. Blood B cells were rapidly depleted and accompanied only by a mild cytokine release at the first OCR infusion. Cytokine release was not significantly detectable from a third application in line with decreasing IRRs. B cell depletion was accompanied by short-lived changes in other immune cell populations in number, activation and cytokine secretion after each OCR infusion. Standard lab parameters did not show any clinically relevant changes. Our data demonstrate only mild changes during the first OCR infusion, which are not present any more during long-term treatment.

Asunto(s)

Asunto(s)

RESUMEN

Background: The anti-CD38 monoclonal antibody daratumumab is the backbone of most anti-multiple myeloma (MM) regimens. To mitigate the risk of infusion-related reactions (IRRs), intravenous daratumumab administration requires 7 hours for the first infusion and 3.5-4 hours thereafter, thus making daratumumab-containing regimens burdensome for patients and health care resources. Preliminary data suggest that a rapid (90-minute) infusion of daratumumab is safe and does not increase IRRs. The rapid schedule was adopted by our centers since 2019. Methods: We conducted an observational multi-center, real-life study to assess the safety of rapid daratumumab infusion protocol from the third administration in relapsed MM patients receiving daratumumab alone or in combination with lenalidomide-dexamethasone or bortezomib-dexamethasone. The primary endpoint was the safety of the rapid infusion protocol, particularly in terms of IRRs. Results: A total of 134 MM patients were enrolled. IRRs occurred in 7 (5%) patients and were mostly mild (6/7 of grade 1-2), with only 1 patient experiencing a grade 3 IRR. Due to the IRRs, 5 (3.7%) patients discontinued the rapid infusions and resumed daratumumab at the standard infusion rate, while 1 patient permanently discontinued daratumumab. In 4/7 patients (57%), IRRs occurred while resuming rapid daratumumab infusions after a temporary interruption (2-4 months). No other adverse event was considered related to the rapid infusion protocol. Conclusions: Our findings confirmed the safety of rapid daratumumab infusions starting from the third administration. In case of prolonged daratumumab interruption, it is advisable to resume infusions at the standard rate (3.5 hours) before switching to the rapid infusion.

RESUMEN

Daratumumab is an anti-CD38 monoclonal antibody approved for multiple myeloma. The initial infusion is administered over a median of 7.5 hours with subsequent infusions given over 3 to 4 hours. Studies show high incidence of infusion related reactions (IRRs) with the initial dose which decreases with subsequent infusions. Accelerated 90 minute daratumumab infusions following the second dose of standard administration are widely accepted in practice including at Beth Israel Deaconess Medical Center (BIDMC) despite limited data from small safety studies. The objective of this study is to evaluate the safety of accelerated daratumumab administration compared to standard administration. The primary outcome is the incidence of common terminology criteria for adverse events (CTCAE) version 5.0 grade 1 or higher for IRRs in accelerated and standard infusions. Secondary outcomes include non-IRR adverse events and amount of supportive care medications used pre- and post- and during accelerated and standard infusions. A total of seventy five patients received a daratumumab infusion between November 2015 and August 2019. There were a total of 420 daratumumab infusions evaluated, 317 (75.5%) were standard infusions of which 152 infusions were standard infusions that preceded an accelerated infusion. There were a total of 103 (24.5%) accelerated infusions. IRRs occurred in a total of 38 (9%) of the infusions with CTCAE grade 2 reactions occurring in total of 21 (5%) infusions and grade 1 occurring in 15 (3.6%) infusions. Overall accelerated daratumumab administration is safe and well tolerated when given following at least two standard infusions.

Asunto(s)

RESUMEN

The most common adverse reactions to rituximab are infusion-related reactions (IRR). We evaluated the efficacy of split dosing the first rituximab infusion over two days to reduce IRR incidence in patients with hematological cancer and a high lymphocyte count. This is a retrospective observational study conducted in two healthcare centers in Quebec, Canada. The study enrolled patients with white blood cell counts ≥25.0 × 109/L who received their first rituximab dose for hematological cancer between December 2007 and May 2020. One healthcare center used asymmetrical split dosing, while the other used symmetrical split dosing. A total of 183 treatment episodes were collected from 143 patients. Among patients who received a fractionated dosing schedule, 42% developed an IRR from the first rituximab infusion compared with 50% for the standard protocol (adjusted relative risk, 0.89; p = 0.540). No significant difference was observed in IRR severity between either groups. However, 24% of patients who received the asymmetrical protocol developed an IRR compared to 68% for the symmetrical protocol (adjusted relative risk, 0.32; p = 0.003). These results suggest that an asymmetrical split dosing could be effective in reducing the incidence of IRR and is preferable to a symmetrical one.

Asunto(s)

RESUMEN

Anti-CD20 antibody treatments, such as obinutuzumab, have been associated with infusion-related reactions (IRRs). In the phase 3 iLLUMINATE study of ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab in first-line chronic lymphocytic leukemia/small lymphocytic lymphoma, IRRs were substantially reduced with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab. We prospectively analyzed inflammatory cytokines to evaluate the impact of ibrutinib on circulating cytokine levels following obinutuzumab infusion. In iLLUMINATE, ibrutinib or chlorambucil was given approximately 30-120 min before the first obinutuzumab infusion. Cytokines evaluated were IFNγ, IL-6, IL-8, IL-10, IL-18, MCP-1, MIP-1α, MIP-1ß, and TNFα. Changes in peak cytokine levels from baseline (immediately before obinutuzumab) to post-obinutuzumab infusion were compared between arms and between patients with versus without IRRs using Wilcoxon rank sum test. Of 228 treated patients, 95 on ibrutinib-obinutuzumab (15 with IRRs, 80 without) and 88 on chlorambucil-obinutuzumab (45 with IRRs, 43 without) with cytokine data were included. Irrespective of IRR occurrence, median increase in cytokines was lower with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab for all cytokines (P < 0.01) except MIP-1ß. Across treatment arms, post-obinutuzumab median increase in all cytokines except MIP-1ß was greater in patients with versus without IRRs (P < 0.001). IL-6 and IL-8 elevations were associated with IRRs in both treatment arms. Among patients with IRRs, those receiving ibrutinib-obinutuzumab had lower post-obinutuzumab increases in IL-6, IL-8, IL-10, and MCP-1 (P < 0.04) than patients receiving chlorambucil-obinutuzumab. For patients in the ibrutinib-treatment arm, we observed a reduction in both the rate of clinically apparent IRRs and the levels of IRR-related cytokines and chemokines. This observation supports an immunomodulatory mechanism of action for ibrutinib. Clinical Trial Registration: NCT02264574.

Asunto(s)