Incidence Of Infusion-related Reactions Research Articles

Infusion-related reactions from immune checkpoint inhibitors: A proportional and network meta-analysis.

38 Background: Immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of patients with solid tumors. Infusion-related reactions (IRRs) to ICIs have been reported in up to 20%, but the incidence varies among ICIs. Therefore, we aimed to report and compare the incidence of IRRs to each ICI therapy. Methods: We searched PubMed/MEDLINE, Embase, and Web of Science to identify phase 3 randomized controlled trials (RCTs) evaluating ICIs (CTLA-4, PD-1, PD-L1, and LAG-3 inhibitors) in solid tumors. We performed a random-effects model network meta-analysis to compare the odds ratio (OR) of IRRs by using RCTs comparing dual ICIs, ICI monotherapy, and placebo/observation. For a proportional meta-analysis, treatment arms evaluating ICI monotherapy, or dual ICIs, were selected to pool the incidence of IRRs. Results: A total of 25,250 patients from 47 phase 3 RCTs were included in the analysis. A network meta-analysis of treatment-related IRRs included 10 RCTs and showed that avelumab (OR 70.2, 95% confidence interval [CI]: 4.32-1140) and atezolizumab (40.72, 2.47-671.4) had a significantly higher risk of treatment-related IRRs compared with placebo/observation. Network ranking revealed that avelumab, atezolizumab, and relatlimab plus nivolumab were the top three therapies with risk of treatment-related IRRs. Proportional meta-analyses revealed that the pooled incidence of treatment-related IRRs was 5.39% for PD-1 plus CTLA-4 inhibitors, 8.25% for PD-L1 (avelumab: 13.1%, non-avelumab: 1.93%), 1.97% for CTLA-4, and 1.95% for PD-1 inhibitors. Results of immune-related IRRs were relatively consistent with those of treatment-related IRRs (Table). Conclusions: Avelumab has the highest risk of IRRs followed by atezolizumab and dual ICIs. This comparative study provides insight into the incidence of IRRs with ICI regimens. These results are useful in assessing which systemic therapies are responsible for IRRs, particularly when ICIs are combined with other agents. [Table: see text]

Safety and feasibility analysis of rapid daratumumab infusion in Chinese patients with multiple myeloma.

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. 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. 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). The 110-min rapid infusion DARA regimen is feasible and safe for use in Chinese MM patients.

A phase II trial to evaluate the epithelial-to-mesenchymal (EMT) inhibitor sotevtamab combined with docetaxel in patients with metastatic non-small cell lung cancer following failure of primary chemoimmunotherapy.

8577 Background: Sotevtamab is an investigational humanized monoclonal antibody that binds to tumor associated secreted clusterin (TA-sCLU). TA-sCLU is a potent inducer of the epithelial-to-mesenchymal transition (EMT), a process known to contribute to tumor invasion, metastasis, chemoresistance and immune evasion. Sotevtamab abrogates the EMT-promoting activity of TA-sCLU by inhibiting its ability to be internalized in cancer cells. Methods: An open-label, single-arm, multi-center Phase II clinical study of sotevtamab administered in combination with docetaxel was performed in subjects with metastatic non-small cell lung cancer who had experienced progression following frontline immunochemotherapy. 35 subjects were enrolled from March 2021 to November 2022 and the study was completed in December 2023. Sotevtamab was administered at a dose of 12 mg/kg once weekly on Days 1, 8 and 15 combined with docetaxel at a dose of 75 mg/m2 once every 3 weeks on Day 1. One cycle of treatment consisted of 21 days. The primary objectives were to determine the objective response rate (ORR) and the safety and tolerability of the combination. Tumor biopsies were performed prior to study initiation and after two cycles of therapy for pharmacodynamicevaluation. Results: As per interim data obtained from a rolling database lock performed in February 2023, the mean subject age was 63 and 22 patients (63%) were female. Of the 35 subjects, 28 were diagnosed with adenocarcinoma, 6 with squamous cell carcinoma and 1 with adenosquamous carcinoma; 11 were ECOG 0, 22 ECOG 1 and 2 ECOG 2. Six subjects with adenocarcinoma had a partial response for an ORR of 17.1%. Stable disease (SD) was experienced in an additional 10 subjects (9 adenocarcinomas and one squamous cell carcinoma) for an SD rate of 28.6%. The observed responses were sustained with a median duration of over one year (405 days). The estimated one-year survival rate was 33.9%. The most frequent adverse events were fatigue, infusion related reaction (IRR), diarrhea, nausea and anemia. The incidence of IRR was significantly decreased following the implementation of a premedication protocol. Analysis of paired tumour biopsies revealed in certain patients that sotevtamab induced a strong intratumoral immune response with the formation of Tertiary Lymphoid Structures (TLS). Various pharmacodynamic evaluations are being performed to better define the profile of responding patients. Conclusions: This phase II study showed promising response and overall tumor control. Duration of response was particularly encouraging and relevant to further exploration. The sotevtamab and docetaxel combination may enhance immune-mediated anti-tumor response through induction of TLS. Data from the final database lock will be presented. Clinical trial information: NCT04364620 .

Impact of Premedication De-Escalation on Incidence of Infusion-Related Reactions With Daratumumab.

Daratumumab is an anti-CD38 monoclonal antibody used to treat multiple myeloma and light chain amyloidosis. Because daratumumab may cause reactions after intravenous or subcutaneous (SC) administration, the manufacturer labeling recommends administration of premedications before every dose. Given incidence of infusion reactions appears to be rare after cycle 1, in April 2022, the Mayo Clinic implemented a practice change in which premedications were omitted from all daratumumab order sets after completion of cycle 1. This study investigated the safety of this practice. A retrospective chart review at the Mayo Clinic reviewed eligible patients with multiple myeloma or amyloid light-chain (AL) amyloidosis who received their first dose of daratumumab within the 4 months preceding the date of implementation (preimplementation group) or no more than 4 months after (postimplementation group) the date of implementation on April 13, 2022. Data were collected only from the first eight once per week doses of daratumumab. The primary outcome was the incidence of infusion-related reactions. Data analyzed used descriptive statistics. Nearly all patients (95.9%) received daratumumab by SC route of administration. Of the 97 patients in the preimplementation group, >90% received premedications throughout cycles 1 and 2, and five patients (5.2%) experienced infusion reactions. Of 72 patients in the postimplementation group, <20% received premedications during cycle 2 and three patients (4.2%) experienced infusion reactions. All infusion reactions occurred within the first daratumumab cycle, indicating elimination of cycle 2 premedications did not cause any infusion reactions. No patient experienced more than one infusion reaction. Omission of premedications after cycle 1 of daratumumab did not increase the incidence of infusion. Premedications may safely be omitted after cycle 1 of daratumumab when administered by the SC route.

Infusion-related reactions with immune checkpoint inhibitors in genitourinary cancers: A systematic review and meta-analysis.

604 Background: Immune checkpoint inhibitors (ICIs) are widely used to treat genitourinary cancers, particularly urothelial carcinoma (UC) and renal cell carcinoma (RCC). Infusion-related reactions (IRRs) have been reported in up to 20% of all patients treated with ICIs. However, the risk of IRRs varies with the type of ICI and the accurate incidence in genitourinary cancers remains unclear. We undertook a systematic review and meta-analysis to determine the incidence of IRRs in patients with genitourinary cancers treated with ICIs. Methods: We performed a systematic search of PubMed/MEDLINE, Embase, and Web of Science to identify phase 3 randomized clinical trials (RCTs) evaluating ICIs (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], programmed cell death protein 1 [PD-1], and programmed death-ligand 1 [PD-L1] inhibitors) in patients with UC and RCC. The odds ratio [OR] of grade 1-5 and grade 3-5 IRRs was calculated and pooled by the random-effect model meta-analysis. Meta-analysis was performed based on study types as follows: 1) Studies with a design “ICI plus treatment A (including placebo/observation) vs. treatment A”, 2) Studies evaluating ICI monotherapy vs. chemotherapy in patients with UC, and 3) Studies assessing ICI plus vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) vs. sunitinib in patients with RCC. When IRRs were reported in studies evaluating oral VEGF-TKIs, IRRs were referred to as hypersensitivity or anaphylactic reactions, defined in each RCT. Results: We identified 12 RCTs with 10,001 participants for the meta-analysis, out of which one evaluated a CTLA-4 inhibitor while the others evaluated PD-1 or PD-L1 inhibitors. The addition of ICIs to other systemic therapies was associated with significantly higher rates of grade 1-5 IRRs (OR=2.90, 95% confidence interval [CI]: 1.16-7.29, p = 0.02) but not of grade 3-5 IRRs (OR=2.98, 95% CI: 0.64-13.74, p = 0.16). When compared to chemotherapy, PD-1 or PD-L1 inhibitor monotherapy was not associated with an increase in either grade 1-5 (OR=0.86, 95% CI: 0.25-2.95, p = 0.81) or grade 3-5 IRRs (OR=1.13, 95% CI: 0.07-18.19, p = 0.93) in patients with UC. When compared to sunitinib in patients with RCC, the combination of ICI plus VEGF-TKIs was not associated with an increase in either grade 1-5 (OR=5.43, 95% CI: 0.62-46.07, p = 0.13) or grade 3-5 IRRs (OR=3.49, 95% CI: 0.64-19.04, p = 0.15). Sensitivity analysis performed by removing studies evaluating avelumab did not alter the overall results (data will be presented). Conclusions: Compared to the previous standard of care without ICIs, therapies with ICIs were not associated with increased IRRs in genitourinary cancers. However, the addition of ICIs to other systemic therapies was associated with an increased incidence of IRRs. The latter merits further prospective evaluation and careful consideration while designing clinical trials.

The utility of H2 receptor antagonists in preventing infusion-related reactions to paclitaxel chemotherapy.

Paclitaxel has a risk of infusion-related reactions (IRRs) and despite no prospective evidence, is often given with premedication including a corticosteroid, H1 antagonist, and H2 antagonist (H2RA). Backorders impacted the supply of intravenous H2RAs at our center, and it was removed as routine premedication. The authors compared the incidence of IRR in patients treated without H2RA to patients receiving standard H2RA premedication. The authors reviewed outpatients starting paclitaxel at the Ottawa Hospital from December 2019 to October 2021. Two cohorts were created: patients treated without H2RA premedication (intervention), and those receiving standard H2RA (control). Demographics, treatment, and IRR information were collected retrospectively. Primary end point was rate of grade ≥2 IRRs during first two doses of paclitaxel. A total of 182 patients were treated without H2RA premedication, compared to 184 control patients treated during non-backorder periods. Baseline characteristics included: median age, 63 years; 86% female; and primary tumor 52% breast/24% gynecologic/10% gastric/esophageal/8% lung/6% other. There were no significant differences between cohorts in baseline characteristics. There was no difference in the rate of grade ≥2 IRR between cohorts; 12.1% (22 of 182; 95% confidence interval [CI], 7.7%-17.7%) for patients treated without H2RA, and 15.1% (28 of 185; 95% CI, 10.3%-21.1%) for control patients. The rate of grade ≥3 IRRs were also similar, 4.4% in intervention cohort versus 3.8% in control cohort. The removal of H2RAs from premedication for paclitaxel did not result in an increased incidence of IRRs. The use of H2RAs in preventing IRRs to paclitaxel should be re-evaluated.

Incidence of infusion related reactions of daratumumab-hyaluronidase-fihj: Pre-post intervention study of premedication omission.

6574 Background: Daratumumab-hyaluronidase-fihj subcutaneous (Dara-SQ) is utilized frequently in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Initially approved as an intravenous formulation, daratumumab (Dara-IV) showed significant infusion related reactions (IRRs), requiring premedication (acetaminophen, diphenhydramine, dexamethasone, and some add montelukast) prior to each dose. Dara-SQ was shown to be noninferior to Dara-IV with significantly fewer IRRs. Despite the reduced IRR risk, indefinite premedication is also recommended in the package insert for Dara-SQ. Given that IRRs are rare after the first dose of Dara-SQ and premedication extends the time for patients in an infusion center, we investigated whether premedication may be safely omitted after the first cycle. Methods: This pre-post interventional quality improvement study included all patients aged 18 years or older diagnosed with MM or amyloidosis that received at least one dose of Dara-SQ between July 1st, 2020 – December 31st, 2022. Omission of premedication (excluding dexamethasone) after four doses of Dara-SQ was introduced June 1st, 2022. The pre-interventional arm followed standard of care with premedication continued (Arm 1) and post-interventional arm included patients with premedication omitted after fourth dose (Arm 2). Patient demographics, prior therapy, Dara-IV exposure, and premedication usage were collected to evaluate the primary endpoint: incidence of IRR after premedication omission. Secondary analysis included any IRR prior to intervention, timing of reaction, reaction management, and post-reaction management. Results: A total of 102 patients (63 in Arm 1 and 39 in Arm 2) were included in the study, with a median age of 69 (38-86) years old; 52% African American and 54% male. IRR prior to fourth dose occurred in 1.6% (1/63) for Arm 1 vs. 5.1% (2/39) for Arm 2 [ p= 0.6], Dara-IV exposure was 52.4% (33/63) in Arm 1 vs. 10.2% (4/39) in Arm 2 [ p= 0.02], and indication was newly diagnosed MM in 21% (13/63) of Arm 1 vs. 41% (16/39) of Arm 2 [ p= 0.03]. For the primary objective, there were zero reactions in both arms. All three reactions prior to fourth dose occurred after the first dose of Dara-SQ, with a median time to reaction of 4.8 hours. These were all grade 2 per CTCAE v5.0, with all patients discharged home after reaction, and all patients received subsequent Dara-SQ without issues. For the two reactions prior to fourth dose in Arm 2, premedication was omitted after 6 doses in one patient and 8 doses in the other with no further issues on subsequent doses. Estimated therapy time saved was 194 hours, with an estimated savings of $145,500 thus far. Conclusions: IRRs to Dara-SQ occur early, are rare, and mild in course. Omitting premedication after a minimum of four Dara-SQ doses is safe and carries substantial time savings for patients and infusion centers.

A novel prednisone premedication protocol significantly decreases infusion‑related reactions of rituximab in newly diagnosed diffuse large B‑cell lymphoma.

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).

Obinutuzumab Can Be Administered as a 90-minute Short Duration Infusion in Patients With Previously Untreated Follicular Lymphoma: GAZELLE End of Induction Analysis.

Obinutuzumab Can Be Administered as a 90-minute Short Duration Infusion in Patients With Previously Untreated Follicular Lymphoma: GAZELLE End of Induction Analysis.

Safety and tolerability of a 90-minute rapid infusion of Sandoz biosimilar rituximab in B-cell lymphoproliferative disorders in a real-world setting.

Although rituximab is generally well-tolerated, infusion-related reactions (IRRs) are common with the initial dose when administered intravenously according to standard recommendations. To prevent IRRs, premedication and low-speed infusion rates have been recommended. Consequently, intravenous (i.v.) infusion of rituximab can become a labor-intensive process. Rapid i.v. rituximab infusion over 90 min has demonstrated a favorable safety profile for the second and subsequent infusions during the course of therapy. The aim of this study was to investigate the safety and tolerability of 90-min rapid infusion of Sandoz rituximab biosimilar (SDZ-RTX) for patients with CD20+ lymphoma or chronic lymphocytic leukemia (CLL). We retrospectively reviewed all patients with CD20+ lymphoma or CLL who received SDZ-RTX infusions in 90 min from July 2019 to July 2021 at seven Spanish hospitals. The primary end point was the incidence of IRRs. We identified 124 patients and 576 rapid administrations of SDZ-RTX, with an average of five rapid infusions per patient. Most rapid infusions of SDZ-RTX were in combination with CHOP/CHOP-like therapy (48.4%), followed by SDZ-RTX alone (15.1%), in combination with bendamustine (14.5%), or with other regimens (22%). The 90-min SDZ-RTX infusion schedule was well-tolerated with no grade 3/4 IRRs. The incidence of any grade IRR during the first rapid infusion was 1% (5 grade 1 IRRs and 1 grade 2 IRR). In conclusion, rapid 90-min i.v. administration of SDZ-RTX for the second and subsequent infusions during the course of therapy is well-tolerated in patients with CD20+ lymphoma or CLL.

S181: MODAKAFUSP ALFA (TAK-573): UPDATED CLINICAL, PHARMACOKINETIC (PK), AND IMMUNOGENICITY RESULTS FROM A PHASE 1/2 STUDY IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM)

Background: Modakafusp alfa (TAK-573) is a first-in-class immunocytokine designed to deliver attenuated interferon alpha-2b to CD38+ cells. In this phase 1/2 study (NCT03215030), the maximum tolerated dose of modakafusp alfa was defined as 3 mg/kg every 4 weeks (Q4W); preliminary data from 29 pts treated at 1.5 mg/kg Q4W (5 in dose escalation, 24 in dose expansion) showed single-agent, anti-myeloma activity with an overall response rate (ORR) of 38% after a median follow-up of 4.2 months (mos) (Vogl ASH 2021, #898). Aims: We present a clinical update on the efficacy and safety of modakafusp alfa 1.5 mg/kg Q4W after a median follow-up of 4.5 mos. We also present PK, immunogenicity, and dose-exposure-response data from the overall study. Methods: Eligible pts had received ≥3 prior lines of treatment. Pts received modakafusp alfa as a 1–4-hour IV infusion at 10 dose levels from 0.001–6 mg/kg at weekly (cycles 1–2 only; 0.001–0.75 mg/kg), every-2-week (0.2–0.3 mg/kg), every-3-week (Q3W; 0.4–0.75 mg/kg), or Q4W (0.75–6 mg/kg) dosing intervals; an expansion cohort was opened at 1.5 mg/kg Q4W after anti-myeloma activity was observed in 3/5 pts in the escalation cohort at that dose. Serum samples prepared from blood were used for PK and anti-modakafusp alfa antibody (ADA) assessments. Modakafusp alfa concentrations were determined via a validated enzyme-linked immunosorbent assay; ADA were detected using a validated bridging electrochemiluminescence assay. Results: As of Oct 2021, 30 pts had received modakafusp alfa 1.5 mg/kg Q4W. The median number of prior lines was 7 (range 3–16); 90% of pts were refractory to an anti-CD38 monoclonal antibody (mAb), while 37% were exposed to an anti-B-cell maturation agent (BCMA). Grade (G) 3–4 treatment-emergent adverse events (TEAEs) were reported in 25 pts (83%); the most frequent G3–4 TEAEs were neutropenia in 19 (63%), thrombocytopenia in 13 (43%), leukopenia in 12 (40%), anemia in 9 (30%), and decreased lymphocyte count in 9 (30%) pts. As reported previously, 1 pt in the 1.5 mg/kg Q4W cohort had a G3 bleeding event, while 3 pts had G3 infections. Among all pts, the ORR was 40% (complete response, 7%; very good partial response, 20%; partial response, 13%); among anti-CD38 mAb-refractory and anti BMCA-exposed pts, the ORR was 37% and 27%, respectively. Median progression-free survival was 6 mos and median duration of response had not been reached (Kaplan-Meier estimate, 91% at 6 mos). Based on pooled available data for the Q3W and Q4W cohorts (all doses) within the escalation and expansion phases, there was a strong trend for a dose-exposure-response relationship for ORR, with the apparent inflection point at 1.5 mg/kg Q4W dosing. No apparent relationship between dose-exposure-response and G3/4 thrombocytopenia or neutropenia was observed across all doses, whereas a correlation between dose-exposure-response and incidence of infusion-related reactions across the 0.4–6 mg/kg Q3W and Q4W dosing cohorts was found. There was an apparent non-linear (more than dose proportional) increase in exposure in the dose range of 0.1–3 mg/kg with a geometric mean terminal half-life of 13 hours in serum for modakafusp alfa 1.5 mg/kg. Based on the available data, 14% and 60% of pts were ADA positive at baseline and post-treatment, respectively. Summary/Conclusion: Modakafusp alfa has a novel mechanism of action and has shown encouraging activity with a manageable safety profile in pts with RRMM. Characterization of the potential clinical impact of immunogenicity is ongoing. The optimal dose for single-agent modakafusp alfa will be further investigated in a phase 2 study.

Abstract CT198: Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: Initial safety and pharmacokinetic results from the PALOMA study

Abstract Background: Amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, is approved for patients with advanced EGFR exon 20 insertion non-small cell lung cancer after progression on platinum-based chemotherapy. First-dose intravenous (IV) delivery leads to infusion-related reactions (IRR) among 66% of patients, resulting in dose interruptions and slower infusion restart rates (infusion duration ranges 2-4 hours) and necessitates splitting of the dose over 2 days (Park Ann Oncol 32[suppl_5]:S981). Subcutaneous (SC) administration of amivantamab, which could simplify and accelerate administration, is being investigated in an ongoing phase 1 study (PALOMA; NCT04606381). Preliminary safety (including IRR) and pharmacokinetics (PK) of SC formulations of amivantamab ± recombinant human hyaluronidase (rHuPH20) for enhanced absorption were evaluated. Methods: PALOMA is an ongoing phase 1 dose escalation study of amivantamab SC in patients with advanced solid tumors who may derive benefit from EGFR or MET-directed therapy. Eligible patients must have progressed after standard-of-care therapy for metastatic disease, be ineligible for, or have declined current standard therapies. The study objectives were to evaluate the feasibility of administration, safety, and PK of a low concentration formulation, 50 mg/mL of amivantamab ± rHuPH20 (Part 1) and a high concentration formulation, 160 mg/mL of amivantamab ± rHuPH20 (Part 2). Patients in Part 1 and Part 2 received the currently approved dosage of amivantamab, 1050 mg (1400 mg for bodyweight ≥80 kg) SC (weekly for the first 4 weeks and every other week thereafter). This study also evaluated administering the full dose of amivantamab on the first day. Results: The full safety, PK, bioavailability, and receptor occupancy data of patients enrolled in Part 1 (n=16) and Part 2 (n=17) will be presented. Compared to IV administration, initial SC experience demonstrates the co-formulation of high concentration amivantamab with rHuPH20 shortened the needed infusion time to less than 5 minutes, with initial bioavailability of approximately 65% of IV administration. Saturation of soluble free EGFR and MET was achieved after the first SC dose. The incidence of IRRs was 18.2%, with all events of grade 1-2 severity. The full amivantamab SC dose was safely given at first administration to 14 patients, potentially obviating the need for split dosing. Conclusions: Initial SC amivantamab ± rHuPH20 was well tolerated with improvements in time and ease of administration and associated with a meaningful reduction in IRRs, eliminating the need for split dosing compared with IV administration. Higher SC dose levels and alternative dosing schedules are being explored. Citation Format: Matthew G. Krebs, Melissa L. Johnson, Byoung Chul Cho, Se-Hoon Lee, Rachel Kudgus-Lokken, Donna Zemlickis, Anna Mitselos, Eileen Berkay, Joshua M. Bauml, Roland E. Knoblauch, Peter Hellemans, Anna Minchom. Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: Initial safety and pharmacokinetic results from the PALOMA study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT198.

244P The incidence of infusion related reactions with trastuzumab-emtansine

Ado-trastuzumab-emtansine (T-DM1) is licensed as palliative and adjuvant treatment for breast cancer. The recommendation is for post-infusion observation of 90 minutes following cycle 1, and 30 minutes for subsequent cycles, owing to the risk of hypersensitivity reactions. The need for observation has significant implications for oncology day unit capacity and patient time in hospital. This study aimed to evaluate the rate and severity of trastuzumab-emtansine infusion reactions in our cohort of patients, to determine if shorter observation times would be safe.

Abstract PD8-01: Phase 3 SOPHIA study of margetuximab (M) + chemotherapy (CTX) vs trastuzumab (T) + CTX in patients (pts) with HER2+ metastatic breast cancer (MBC) after prior anti-HER2 therapies: Final overall survival (OS) analysis

Abstract Background: CTX + dual HER2-targeting monoclonal antibodies (mAb) remains a standard of care for treatment (Tx) of both HER2+ early-stage and MBC. However, when the SOPHIA trial was launched, limited Tx options existed after progression on T, pertuzumab (P), and ado-trastuzumab emtansine. M, an Fc-engineered anti-HER2 mAb, targets the same epitope as T and exerts similar antiproliferative effects. M enhances CD16A-mediated ADCC compared to T. Furthermore, M treatment is associated with increased HER2-specific T- and B-cell responses and increased T-cell clonality compared to baseline. The phase 3 SOPHIA (NCT02492711) study demonstrated PFS benefit of M vs T, both + CTX, in HER2+ MBC pts. M improved PFS over T, with a 24% relative risk reduction (HR .76; 95% CI .59-.98; P=.033; median, 5.8 [95% CI 5.5-7.0] months (mo) vs 4.9 [95% CI 4.2-5.6] mo (Rugo HS, et al. JAMA Oncol 2021), resulting in FDA approval. Median OS after 270 mortality events (2nd interim analysis) was 21.6 mo with M vs 19.8 mo with T (HR .89; 95% CI .69-1.13; P=.33). Here we report final OS after 385 events, as well as updated safety.Methods: Pts with disease progression after ≥2 lines of anti-HER2 Tx, including P, and 1-3 lines of Tx for HER2+ MBC were randomized 1:1 to CTX + either M (15 mg/kg) or T (8 mg/kg loading dose, then 6 mg/kg), both given IV every 3 weeks. Randomization was stratified by number of metastatic sites (≤2, &amp;gt;2), lines of Tx for MBC (≤2, &amp;gt;2), and CTX choice (capecitabine, eribulin, gemcitabine, or vinorelbine). Sequential primary end points were central-blinded review of PFS and OS.Results: The intent-to-treat (ITT) population comprised 536 pts (M, 266; T, 270). At the median follow-up of 20.2 mo among all ITT pts, pts received a median of 7 cycles of M + CTX vs 6 cycles of T + CTX. Median OS after 385 events in the ITT population was 21.6 mo with M vs 21.9 mo with T (HR .95; 95% CI .77-1.17; P=.62; Table). Based on a prespecified, non-α-allocated exploratory analysis, a numerical OS advantage in favor of the M arm was observed in the subgroup of pts homozygous for the CD16A-158F low-affinity allele (median OS, 23.6 vs 19.2 mo; HR .72; 95% CI .52-1.00; nominal P=.05). In contrast, in the small subgroup of CD16A-158V homozygotes, median OS was longer for T vs M (31.1 mo vs 22.0 mo; HR 1.77; 95% CI 1.01-3.12; nominal P=.04). Grade ≥3 adverse events (AE) occurred in 146 pts (55.3%) receiving M vs 141 pts (53.0%) receiving T. Serious AEs were seen in 47 pts (17.8%) receiving M vs 51 pts (19.2%) receiving T. Incidence of infusion-related reactions was higher with M (36 [13.6%]) vs T (9 [3.4%]). Left ventricular dysfunction requiring delay or cessation of M/T administration occurred in 4 pts (1.5%) receiving M and in 7 pts (2.6%) receiving T. Conclusions: The median OS in the ITT population was not statistically different between the 2 arms. An exploratory analysis of CD16A genotyping indicates a numerical OS advantage in favor of M in F homozygous pts, along with a numerical OS advantage in favor of T in V homozygous pts. Safety of M + CTX was similar to previous reports and consistent with M FDA-approved label. Studies of M in HER2+ breast cancer pts with different CD16A allelic variants are warranted, including MARGOT, the neoadjuvant investigator-initiated study on the efficacy of M vs T in pts carrying F-allelic variants of CD16A. Median OSITT analysisPrespecified, non-α-allocated exploratory analysis (n=506)N=536CD16A-158F carriers (F/F and F/V)(n=437)CD16A-158F homozygotes (F/F)(n=192)CD16A-158F/V heterozygotes(n=245)CD16A-158V homozygotes (V/V)(n=69)aM + CTX, mo21.6 (n=266)23.3 (n=221)23.6 (n=102)21.3 (n=119)22.0 (n=37)T + CTX, mo21.9 (n=270)20.8 (n=216)19.2 (n=90)22.0 (n=126)31.1 (n=32)HR (95% CI)0.95 (0.77-1.17)0.86 (0.69-1.08)0.72 (0.52-1.00)0.96 (0.71-1.30)1.77 (1.01-3.12)P value0.620.19b0.05b0.78b0.04bAbbreviations: CTX, chemotherapy; HR, hazard ratio; ITT, intent to treat; M, margetuximab; mo, months; OS, overall survival; T, trastuzumab. Cutoff date: June 14, 2021. aThis subgroup was characterized by an imbalance in poor prognostic features. bNominal P value. Citation Format: Hope Rugo, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Antonino Musolino, Mark D. Pegram, Thomas Bachelot, Gail S. Wright, Cristina Saura, Santiago Escrivá-de-Romaní, Michelino De Laurentiis, Gary N. Schwartz, Timothy Pluard, Francesco Ricci, William Gwin, III, Christelle Levy, Ursa Brown-Glaberman, Jean-Marc Ferrero, Maaike de Boer, Sung-Bae Kim, Katarína Petráková, Denise A. Yardley, Orit Freedman, Erik H. Jakobsen, Einav Nili Gal-Yam, Rinat Yerushalmi, Peter A. Fasching, Emily Ashley, Shengyan Hong, Minori Rosales, William J. Gradishar. Phase 3 SOPHIA study of margetuximab (M) + chemotherapy (CTX) vs trastuzumab (T) + CTX in patients (pts) with HER2+ metastatic breast cancer (MBC) after prior anti-HER2 therapies: Final overall survival (OS) analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-01.

A novel rituximab administration protocol to minimize infusion-related adverse reactions in patients with B-cell lymphoma.

Background Infusion-related reactions (IRRs) during rituximab administration are occasionally severe and remain problematic in oncology practice. Aim To establish a safer, risk-stratified rituximab protocol for patients with B-cell lymphoma. Method We stratified patients into low-, moderate-, and high-risk groups according to the number of risk factors for IRRs, specifically, low-grade histology and bulky tumors (>10cm): Then, the administrating schedule of rituximab (375mg/m2, diluted in 1mg/mL concentration) was individualized. For the first rituximab cycle, the low- and moderate-risk groups underwent conventional infusion #1 (25-200mg/h, ~4.3h), and the high-risk group underwent long infusion (25-100mg/h, 6.8h). Patients in the low-, moderate-, and high-risk groups without IRRs in the first cycle underwent short infusion (100-400mg/h, 2.3h), conventional infusion #2 (100-200mg/h, 3.5h), and conventional infusion #1, respectively. Patients with IRRs in the first cycle received a second rituximab cycle with the same schedule as the first cycle. The procedure for the third cycle was at the attending physician's discretion. Results Among 81 patients, the overall incidence of IRRs was 28%. IRR incidences in the low- (n = 39), moderate- (n = 35), and high-risk groups (n = 7) were 31%, 20%, and 57%, respectively. All IRRs were grade ≤2. The overall conversion rate to short infusion in the third cycle was 54%, without any IRRs. Conclusions Our step-by-step rituximab protocol demonstrated a fewer incidence of severe IRRs among B-cell lymphoma patients receiving rituximab.

A Novel Protocol for Rituximab Administration with Reduced Incidence of Severe Infusion-Related Adverse Reactions in Patients with B-Cell Non-Hodgkin Lymphoma

Introduction: Rituximab is widely used as the standard treatment for most types of B-cell non-Hodgkin lymphomas (B-NHL). However, infusion-related reactions (IRRs), such as fever, chills, nausea, rashes, rigors, or hypotension, are a significant burden to patients and oncology practitioners. Thus, we developed a novel protocol on the rituximab administration to avoid severe IRRs during a short-time infusion in the outpatient chemotherapy center of Nihon University Itabashi Hospital.Methods: This observational study aimed to establish an effective dosing schedule for safely administering rituximab within a short time for patients with various B-NHL types. Rituximab was diluted to a concentration of 1 mg/mL and intravenously administered to patients at a dose of 375 mg/m 2. Before the rituximab administration, prophylactic premedications were given per guidelines. We stratified patients into low (n = 0), moderate (n = 1), or high risk (n = 2) groups according to the observed number of risk factors for IRRs identified in our previous study, i.e., indolent histology and presence of bulky disease (>10cm) (Hayama et al. 2017, PMID: 28144804). In the low- and moderate-risk groups, the infusion rate of rituximab was set at 25 mg/h (first 1h), 100 mg/h (next 1h), and a maximum of 200 mg/h thereafter (conventional infusion #1, approx. 4.3h). In the high-risk group, the infusion rate of rituximab was set at 25 mg/h (first 1h) and a maximum of 100 mg/h thereafter (long infusion, approx. 6.8h). The second infusion of rituximab was dependent on the occurrence of IRRs in the first cycle. If a patient in the low-risk group did not have IRRs in the first cycle, the infusion rate of rituximab in the second cycle was then started at 100 mg/h for the first 30min and increased by 100 mg/h every 30min to a maximum of 400 mg/h thereafter (short infusion, approx. 2.3h). Also, for a patient in the moderate-risk group without any grade of IRRs in the first cycle, the infusion rates of second rituximab was set at 100 mg/h (first 1h) and a maximum of 200 mg/h thereafter (conventional infusion #2, approx. 3.5h). Finally, a patient in the high-risk group without IRRs in the first cycle received the second rituximab as per the conventional infusion #1. If patients experienced any grades of IRR in the first cycle, the next rituximab was administered on the same schedule as the first cycle. The infusion procedure for the third cycle was at the discretion of attending physicians (Figure). The primary endpoint was the incidence of IRRs during the first and second doses of rituximab in each risk group. The secondary endpoints were; overall incidence of IRRs in the first and second doses of rituximab; infusion rates of rituximab at the IRRs; conversion rate of the short infusion at the third cycle in each group; overall conversion rate of the short infusion at the third cycle.Results: A total of 81 B-NHL patients treated with rituximab in 2018 and 2019 at Nihon University Itabashi Hospital was evaluated. The incidence of IRRs during the first and second cycles in each risk group was 31%, 20%, and 57% in the low- (n = 39), moderate- (n = 35), and high-risk (n = 7) groups, respectively, with no significant difference among the three risk groups (p = 0.1407). The overall incidence of IRRs was 28% without grade 3 or higher severity. The IRRs occurred most frequently at the infusion rate of 100 mg/h (n = 16). Conversion rates to the short infusion at the third cycle of rituximab were 82%, 29%, and 29%, in the low-, moderate-, and high-risk groups, respectively, with a significant imbalance between the groups (p <0.0001). The overall conversion rate of the short infusion in the third cycle was 54%, without any grades of IRRs (Table).Conclusions: Our step-by-step infusion protocol of rituximab provided a safe and comfortable drug administration for both patients and oncology practitioners. In addition, the protocol can reduce unexpected, severe adverse reactions to rituximab that typically require hospital admission and medical expenses (UMIN-CTR, UMIN000032309). [Display omitted] DisclosuresMiura: Chugai: Honoraria; Kyowa Kirin: Honoraria. Hatta: Pfizer Japan Inc.: Honoraria; Novartis KK: Honoraria; Bristol-Myers Squibb: Honoraria; Otsuka Pharmaceutical.: Honoraria.

Impact of Split Dosing the First Rituximab Infusion in Patients with High Lymphocyte Count.

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.

Infusion-related reaction to ramucirumab plus FOLFIRI in patients with advanced colorectal cancer.

An infusion-related reaction (IRR) is a well-known adverse event related to monoclonal antibodies, and antihistamine premedication is recommended to prevent IRRs. Ramucirumab plus FOLFIRI therapy is the standard second-line treatment for metastatic colorectal cancer (CRC). Ramucirumab is a fully human antibody, suggesting that the incidence of IRRs is lower, however, the current recommendation for the proper use of ramucirumab is antihistamine premedication, but the incidence and severity of ramucirumab-induced IRR without antihistamine premedication have not been elucidated. A retrospective study to evaluate the incidence of ramucirumab-induced IRRs in unresectable CRC patients treated by ramucirumab plus FOLFIRI therapy. If the incidence of IRR without antihistamine premedication was not higher than that of cetuximab in a previous report (5.7%), planning a prospective study was considered. A total of 147 patients with unresectable CRC who had been treated by ramucirumab plus FOLFIRI therapy were identified. Of them, 106 (72%) patients received intravenous antihistamine premedication. An IRR occurred in 2 patients (1.4%), 1 grade 2 and 1 grade 3. They received antihistamine and steroid premedication. On the other hand, IRRs were not observed in 41 patients without antihistamine premedication, and the incidence of IRRs was significantly lower compared with the previous report of cetuximab (p < 0.001). The incidence of ramucirumab-induced IRRs without antihistamine premedication is low. Not using antihistamine premedication can decrease medical costs. These findings warrant further investigation in large-scale cohorts to clarify the incidence and severity of ramucirumab-induced IRRs and further clarify the proper use of ramucirumab.

Evaluation of the Safety and Tolerability of Rapid Infusion of Biosimilar Rituximab Truxima® — the University College London Hospitals (UCLH) Experience

▪Rituximab is a chimeric anti-CD20 monoclonal antibody approved in the EU (MabThera®; Roche) and US (Rituxan®; Genentech) to treat non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL).In April 2017 the first biosimilar rituximab (Truxima®; NAPP) was approved in the UK for all indications of the reference biologic. Its adoption is expected to deliver a significant reduction in treatment costs.Administration of rituximab is associated with infusion-related reactions (IRRs). The incidence of IRRs is greatest with the first infusion and decreases significantly with subsequent infusions.To reduce the risk of IRRs, manufacturers recommend that the first dose is gradually increased every 30 minutes in 50mg/hour increments to a maximum of 400mg/hour. For subsequent infusions gradually increase every 30 minutes in 100mg/hour increments to a maximum of 400mg/hour, known as standard subsequent rate infusion. This means a typical rituximab infusion can take 4-6 hours.If the first infusion is well-tolerated, it is now widespread practice to administer subsequent MabThera® doses as a rapid infusion over 90 minutes, whereby 20% of the dose is given over the first 30 minutes, with the remaining 80% over the following 60 minutes (Sehn et al, Blood 2007).Reverting to slower infusion rates with the introduction of biosimilar rituximab could adversely impact daycare unit capacity, nursing resource, appointment length, and patient satisfaction.AimThe aim of our study was to assess the safety of rapid infusion of Truxima® by reviewing infusion related adverse events in patients 1) switching from MabThera® 2) with previous exposure to MabThera® but last dose received over 6 months ago and 3) rituximab naïve patients.MethodIn May 2017 all patients were switched from MabThera® to Truxima® at UCLH, London. Truxima® doses given between 22nd May and 26th July 2017 were identified from the electronic prescribing system (Chemocare®). Infusion-related reactions were noted from nursing infusion records and graded using Common Terminology Criteria for Adverse Events version 4.03.Patients who had been receiving MabThera® as a rapid infusion continued at this rate with Truxima®. Those patients who had received only one prior dose of MabThera® at the standard first dose infusion rate received their first Truxima® dose as a rapid infusion.Patients who had not received MabThera® for over 6 months or were MabThera® naïve, received their first Truxima® dose at the standard first dose infusion rate. If well-tolerated, subsequent doses were given as a rapid infusion.All patients received premedication with paracetamol (acetaminophen) and antihistamine.ResultsTable 1 shows the patient characteristics, MabThera® and Truxima® infusion rates and infusion-related reactions.DiscussionThe results showed that rapid infusion of Truxima® was well-tolerated in all three groups of patients. Additionally, patients switching from MabThera® safely received their first Truxima® dose as a rapid infusion. One patient switching from MabThera® developed tachycardia during their first Truxima® dose at rapid infusion rate; however this patient was able to receive subsequent Truxima® doses with additional glucocorticoid pre-medication without IRRs.Grade 2 or 3 IRRs were observed with 8 first rate infusions (12%) and 4 of the patients have received further Truxima® doses so far. These patients received their next dose at standard subsequent infusion rate with glucocorticoid pre-medication without incident, and 2 of the patients have had further doses as a rapid infusion without an IRR. Updated results will be presented at the ASH meeting 2017.ConclusionThis study is the first reported post-marketing experience of rapid infusion of biosimilar rituximab and showed that patients can be safely switched from MabThera® to Truxima® without reverting to slower infusion rates. In addition patients who tolerated their first infusion rate of Truxima® were able to tolerate a rapid infusion rate with subsequent doses.These findings will facilitate the introduction of Truxima® at centres prescribing rituximab without adversely impacting resource utilisation or patient experience. [Display omitted] DisclosuresCheesman:Roche: Consultancy; Novartis: Consultancy; Napp: Consultancy; Amgen: Consultancy. Ardeshna:ADC Therapeutics: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses. Townsend:Roche: Consultancy.

Brentuximab Vedotin Plus Bendamustine Is an Effective Salvage Regimen for Pediatric Patients with Relapsed Hodgkin Lymphoma

Background :Pediatric patients with relapsed/refractory Hodgkin Lymphoma have superior outcomes when achieving a complete remission prior to autologous stem cell transplant (ASCT). Optimal salvage regimens need to be identified as current approaches result in complete responses (CR) in approximately 25-35% of patients. The combination of brentuximab vedotin and bendamustine is highly active in adult patients with relapsed/refractory Hodgkin Lymphoma, but has not been evaluated in the pediatric population. We report our preliminary experience regarding the safety and efficacy of brentuximab vedotin and bendamustine prior to stem cell transplant (SCT) in pediatric patients treated for relapsed Hodgkin lymphoma at a single center.Methods:We performed a retrospective review of pediatric patients with relapsed Hodgkin lymphoma treated with brentuximab vedotin and bendamustine between April 2016 to July 2017. Patients received an infusion of 1.8mg/kg of brentuximab vedotin on Day 1 with bendamustine 90mg/m2 on Days 1 and 2 of 3-week cycles. Response assessment was performed and repeated following 2-3 cycles of therapy. Patients went on to SCT after achieving a CR or best response at the discretion of the treating physicians. Patients resumed post-transplant treatment with brentuximab vedotin as monotherapy for up to 16 doses.Results:Five patients (1 female, 4 males) with a median age of 16.5 years at the time of relapse (range, 12.2 -17.9 years) were treated with the combination of brentuximab/bendamustine. Four patients were in first relapse and 1 was treated in second relapse nine months following a prior ASCT. Patients received a median of 5 cycles of therapy (range 2-5 cycles), with 2 patients receiving an additional cycle of brentuximab monotherapy prior to proceeding to SCT. The main toxicity observed was infusion-related reactions, with 2 patients experiencing anaphylaxis. These individuals were able to continue planned therapy following desensitization against brentuximab. All patients were in complete remission by PET prior to SCT. Four patients underwent successful stem cell mobilization and collection. The individual treated following second relapse received an allogeneic transplant from a matched unrelated donor. All patients are alive with no evidence of disease a median of 11.3 months since beginning salvage therapy (range 1.2-15 months). Four patients are a median of 6.5 months (range 4-11 months) post-SCT and continue on brentuximab monotherapy, with 1 individual currently awaiting ASCT.Conclusions :Combination therapy with brentuximab vedotin and bendamustine was highly active in pediatric patients with relapsed Hodgkin lymphoma and would compare favorably with currently accepted salvage regimens. Incidence of infusion-related reactions can be minimized through the use of adequate premedication. These results support further evaluation of this regimen in the context of a multicenter prospective clinical trial. DisclosuresCurran:Novartis: Consultancy; Juno Therapeutics: Research Funding. Kernan:Gentium: Other: NAK received grants from Gentium during the conduct of the study, and her research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA008748; the content is solely the responsibility of the author .