Resolution Of Peripheral Neuropathy Research Articles

Seven-year overall survival analysis from ECHELON-1 study of A+AVD versus ABVD in patients with previously untreated stage III/IV classical Hodgkin lymphoma.

7053 Background: In ECHELON-1 (NCT01712490), 6-year follow-up (FU) analyses demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) with A+AVD (brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), with a comparable safety profile. Here, we report data at 7-year median FU. Methods: Analyses of OS and PFS per investigator were conducted in the intent-to-treat (ITT) population (data cut-off March 11, 2023). Patients (pts) were randomized 1:1 to receive ≤6 cycles of A+AVD (n=664) or ABVD (n=670) on days 1 and 15, every 28 days. PET scan after cycle 2 (PET2) evaluation was mandatory. Long-term safety outcomes in the safety population included resolution or improvement of peripheral neuropathy (PN), second malignancies, and pregnancies. Results: At median FU of 89.3 months (95% CI 87.0–90.2), 7-year OS rates were 93.5% (95% CI 91.1–95.2) with A+AVD and 88.8% (95% CI 85.8–91.1) with ABVD; OS favored A+AVD over ABVD (HR 0.62; 95% CI 0.42–0.90; p=0.011). Subgroup analyses showed consistent OS benefit for A+AVD, including in the age <40 years and Stage IV disease subgroups (Table). 7-year PFS rates with A+AVD vs ABVD were 82.3% (95% CI 79.1–85.0) vs 74.5% (95% CI 70.8–77.7; HR 0.68 [95% CI 0.53–0.86]; p=0.001). PN improved/resolved in most pts at last FU (A+AVD: 86%; ABVD: 87%). Median (range) time to complete resolution of PN (A+AVD vs ABVD) was 16 (0–373) vs 10 (0–343) weeks; median (range) time to improvement was 42 (2–182) vs 19 (15–142) weeks. PN was ongoing in 28% (4% grade ≥3) of A+AVD and 20% (1% grade ≥3) of ABVD pts. Second malignancies were reported in 5% of A+AVD and 6% of ABVD pts. Pts and their partners reported 84/92 livebirths/pregnancies with A+AVD and 59/73 with ABVD; no stillbirths were recorded. Conclusions: At 7-year median FU, pts with stage III/IV cHL who received A+AVD showed a sustained PFS and OS benefit vs ABVD, with PFS rates indicating potential curability. The safety profile in pts treated with A+AVD showed no new safety signals at 7 years. Clinical trial information: NCT01712490 . [Table: see text]

Brentuximab vedotin plus AVD for Hodgkin lymphoma: incidence and management of peripheral neuropathy in a multisite cohort

AbstractBrentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is increasingly used for frontline treatment of stage III/IV classical Hodgkin lymphoma (cHL). Peripheral neuropathy (PN) was the most common and treatment-limiting side effect seen in clinical trials but has not been studied in a nontrial setting, in which clinicians may have different strategies for managing it. We conducted a multisite retrospective study to characterize PN in patients who received BV + AVD for newly diagnosed cHL. One hundred fifty-three patients from 10 US institutions were eligible. Thirty-four patients (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage, performance status, and comorbidities. PN was reported by 80% of patients during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of patients because of PN leading to BV discontinuation in 23%, dose reduction in 17%, and temporary hold in 4%. With a median follow-up of 24 months, PN resolution was documented in 36% and improvement in 33% at the last follow-up. Two-year progression-free survival (PFS) for the advanced-stage patients was 82.7% (95% confidence interval [CI], 0.76-0.90) and overall survival was 97.4% (95% CI, 0.94-1.00). Patients who discontinued BV because of PN did not have inferior PFS. In the nontrial setting, BV + AVD was associated with a high incidence of PN. In our cohort, which includes patients who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable.

Incidence and Resolution of Eribulin-Induced Peripheral Neuropathy (IRENE) in Locally Advanced or Metastatic Breast Cancer: Prospective Cohort Study.

Eribulin, a halichondrin-class microtubule dynamics inhibitor, is a preferred treatment option for patients with advanced breast cancer who have been pretreated with an anthracycline and a taxane. Peripheral neuropathy (PN) is a common side effect of chemotherapies for breast cancer and other tumors. The Incidence and Resolution of Eribulin-Induced Peripheral Neuropathy (IRENE) noninterventional postauthorization safety study assessed the incidence and severity of PN in patients with breast cancer treated with eribulin. IRENE is an ongoing observational, single-arm, prospective, multicenter, cohort study. Adult patients (≥18 years of age) with locally advanced or metastatic breast cancer and disease progression after 1-2 prior chemotherapeutic regimen(s) for advanced disease were treated with eribulin. Patients with eribulin-induced PN (new-onset PN or worsening of preexisting PN) were monitored until death or resolution of PN. Primary endpoints included the incidence, severity, and time to resolution of eribulin-induced PN. Secondary endpoints included time to disease progression and safety. In this interim analysis (data cutoff date: July 1, 2019), 67 (32.4%) patients experienced any grade eribulin-induced PN, and 12 (5.8%) patients experienced grade ≥3 eribulin-induced PN. Median time to resolution of eribulin-induced PN was not reached. Median time to disease progression was 4.6 months (95% CI, 4.0-6.5). Treatment-emergent adverse events (TEAEs) occurred in 195 (93.8%) patients and serious TEAEs occurred in 107 (51.4%) patients. The rates of any grade and grade ≥3 eribulin-induced PN observed in this real-world study were consistent with those observed in phase III randomized clinical trials. No new safety findings were observed.

Brentuximab vedotin + AVD for newly diagnosed classic Hodgkin lymphoma (cHL): Incidence and management of peripheral neuropathy in a multi-institution cohort.

7542 Background: Brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is the new standard of care for newly diagnosed stage III/IV cHL. In the pivotal ECHELON-1 trial, peripheral neuropathy (PN) was the most common toxicity, seen in 67% of patients (pts) and leading to discontinuation of BV in 6.6%. However, PN from BV+AVD in cHL has not been studied in a non-trial setting, where clinicians may have different strategies for managing it. Methods: We conducted a multi-site, retrospective study to characterize PN in pts who were planned to receive 6 cycles of BV+AVD for newly diagnosed cHL before 9/2022. Data was obtained from medical records and PN was graded retrospectively using CTCAE v5.0 criteria. Multivariable logistic regression was used to assess factors associated with PN. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan Meier method. A Cox proportional hazards model was used to test the effect of discontinuation on PFS. Results: 153 pts from 10 US institutions were eligible. Median age was 35 years (range 18-76) with 22% of pts over 60 years old. Thirty-four pts (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage (8% stage I/II), performance status (3% ECOG 3+), preexisting PN (6%), or other comorbidities including HIV and other malignancies (10%). Of advanced stage pts, 41% had IPS 4-7. Median no. BV+AVD cycles was 6 (range 1-6). PN was reported by 80% of pts during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of pts due to PN leading to BV discontinuation in 23% with median no. of doses omitted of 4 (range 1-10), dose reduction in 17% and temporary dose hold in 4%. Vinblastine was modified in 17% of pts due to PN including discontinuation or temporary hold in 10% and dose-reduction in 7%; in 35% of pts with vinblastine modification, BV was continued. None of the factors assessed (age, sex, baseline PN, diabetes mellitus) predicted development of any grade PN. However, higher initial dose of BV in mg (based on weight) was associated with increased risk of grade 2+ PN (OR 1.03, 95% CI 1.01-1.05, p = 0.002). With median follow up of 24 months (range 0.33-87), PN resolution was documented in 36% and improvement in 33% at last follow up. Ongoing G2+ PN was present in 13% of pts at last follow up. 2-year PFS for the advanced stage patients was 82.7% (95% CI 0.76-0.90) and OS was 97.4% (95% CI 0.944-1). Discontinuation of BV due to neuropathy did not affect PFS (HR 1.1, 95% CI 0.45-2.5). Conclusions: In the non-trial setting, BV+AVD was associated with a high incidence of PN. In our cohort, which includes pts who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable; discontinuation of BV was not associated with inferior PFS.

The Effect of Schwann Cells/Schwann Cell-Like Cells on Cell Therapy for Peripheral Neuropathy

Peripheral neuropathy is a common neurological issue that leads to sensory and motor disorders. Over time, the treatment for peripheral neuropathy has primarily focused on medications for specific symptoms and surgical techniques. Despite the different advantages of these treatments, functional recovery remains less than ideal. Schwann cells, as the primary glial cells in the peripheral nervous system, play crucial roles in physiological and pathological conditions by maintaining nerve structure and functions and secreting various signaling molecules and neurotrophic factors to support both axonal growth and myelination. In addition, stem cells, including mesenchymal stromal cells, skin precursor cells and neural stem cells, have the potential to differentiate into Schwann-like cells to perform similar functions as Schwann cells. Therefore, accumulating evidence indicates that Schwann cell transplantation plays a crucial role in the resolution of peripheral neuropathy. In this review, we summarize the literature regarding the use of Schwann cell/Schwann cell-like cell transplantation for different peripheral neuropathies and the potential role of promoting nerve repair and functional recovery. Finally, we discuss the limitations and challenges of Schwann cell/Schwann cell-like cell transplantation in future clinical applications. Together, these studies provide insights into the effect of Schwann cells/Schwann cell-like cells on cell therapy and uncover prospective therapeutic strategies for peripheral neuropathy.

Five-Year Survival Results: Frontline Brentuximab Vedotin in Combination with CHP in Patients with CD30-Expressing Peripheral T-Cell Lymphomas

Five-Year Survival Results: Frontline Brentuximab Vedotin in Combination with CHP in Patients with CD30-Expressing Peripheral T-Cell Lymphomas

Polatuzumab Vedotin Plus Bendamustine with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Updated Results of a Phase Ib/II Randomized Study

Polatuzumab Vedotin Plus Bendamustine with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Updated Results of a Phase Ib/II Randomized Study

LBA4 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

LBA4 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

Resolution of Peripheral Neuropathy (PN) in Patients Who Received A+AVD or ABVD in the Phase 3 ECHELON-1 Trial

Resolution of Peripheral Neuropathy (PN) in Patients Who Received A+AVD or ABVD in the Phase 3 ECHELON-1 Trial

Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 Alcanza Study

Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 Alcanza Study

Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up

Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up

Peripheral neuropathy (PN) in patients (pts) with metastatic breast cancer treated with eribulin: Resolution and association with efficacy.

147 Background: PN is a known adverse effect of various antimicrotubule agents, including eribulin. We report here the incidence and resolution of PN in breast cancer pts treated with eribulin in completed phase 2 and 3 studies, and the efficacy of eribulin in pts with PN in the phase 3 EMBRACE and 301 studies. Methods: In EMBRACE, women had received 2-5 lines of chemotherapy for advanced disease. In this ≥ 3rd-line setting, pts randomized to eribulin mesylate received it at 1.4 mg/m2 iv, days 1 and 8 every 21 days. The dosing schedule was the same in study 301, which involved pts who had received 0-2 prior chemotherapies for advanced disease. Overall survival (OS) and progression-free survival (PFS) were analyzed by stratified log-rank test. Data from EMBRACE and 301 were pooled with data from 2 phase 2 studies to assess time to improvement (a decrease of ≥ 1 grade) and resolution (decrease in grade to 0, 1 or baseline) of grade 3 or 4 PN. Results: In the pooled safety analysis, 7.7% (116/1503) of pts treated with eribulin had grade 3 or 4 PN; 63.8% of these experienced improvement in PN and 50% had resolution. Median time to improvement was 2.1 weeks and to resolution was 7.7 weeks. Characteristics were similar in pts with or without PN in EMBRACE and 301. Those with PN had longer exposure to eribulin vs pts without PN (median exposure [months], study 301: 4.9 vs 3.2; EMBRACE: 4.8 vs 2.9). OS and PFS were significantly longer in pts with PN (Table). Conclusions: Pts who had a favourable therapeutic response to eribulin, received a longer course of treatment and thus had a greater risk of PN. Severity of PN improved in most pts within a short period. Regarding PN, the risk–benefit ratio for eribulin supports treatment. Clinical trial information: NCT00337103, NCT00388726. [Table: see text]

Bortezomib- and Thalidomide-Induced Peripheral Neuropathy (PN) in Multiple Myeloma (MM): Clinical and Molecular Analysis of 474 Patients Treated with Thalidomide-Dexamethasone (TD) or Bortezomib-TD (VTD)

Abstract 1821 Introduction: PN is an important complication of MM and its incidence has been further increased after the introduction of the novel agents thalidomide and bortezomib. In a phase 3 trial comparing TD with VTD as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation for previously untreated MM patients, the VTD arm was significantly superior over TD in terms of improved rates of complete or near-complete response (CR/nCR) (the primary study endpoint) and progression free survival (PFS). Toxicity of VTD and TD regimens, including PN, was a secondary study endpoint. Methods: We performed a subanalysis of the study to assess the frequency, reversibility, risk factors and molecular markers associated with treatment-emergent PN. PN was graded by use of National Cancer Institute9s Common Toxicity Criteria (NCI CTCAE) version 3.0. Since grade 1 PN could be misinterpreted and does not interfere with the daily activities, only patients who developed PN of at least grade 2 were evaluated. A total of 474 patients (of whom, 236 randomized to the VTD arm and 238 to TD) were stratified according to the development or not of grade ≥2 neurological adverse events (NAEs). Gene expression profiles (GEP) of pre-treatment CD138+ bone marrow plasma cells (BMPCs) were analyzed in a subset of 127 VTD-treated patients for whom biological samples taken at diagnosis were adequate for genomic analysis. GEP experiments were performed using the Affymetrix HG-U133 Plus 2.0 platform and class comparison of groups of array was done with one-way ANOVA Partek Genomic Suite (version 6.4). Results: Occurrence of PN throughout the entire treatment program was significantly higher in the VTD arm compared with TD. In particular, the rate of grade ≥2 PN was 35% vs 10% (p Conclusions: Although VTD incorporated into double ASCT was associated with a higher incidence of grade ≥2 PN compared with TD, the probability of complete resolution or improvement to at least grade 1 was comparable in both VTD- and TD-treated groups. Importantly, NAEs did not adversely affect the rate of CR/nCR, and TTP and PFS. No relationship between development of PN and both patient demographics and disease characteristics was observed. Conversely, GEP analysis of BMPCs from patients with VTD-induced PN showed the significant deregulated expression of genes involved in the nervous system function. Disclosures: Off Label Use: Bortezomib and Thalidomide as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation in newly diagnosed multiple myeloma. Tosi:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol-Mayers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria. Cavo:Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Post-Approval Safety Study (PASS) of Lenalidomide Compared with Other Treatments In Patients with Relapsed or Refractory Multiple Myeloma: Evaluation of Peripheral Neuropathy In the First 1,011 Patients

AbstractAbstract 1939 Aim and Background:Lenalidomide plus dexamethasone was EMEA approved in 2007 for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Subsequently, an observational patient cohort study was implemented to characterize the safety profile of lenalidomide in clinical practice, and to place the incidence of adverse events (AEs) into context with those occurring in patients with MM receiving other treatments second line or later. A secondary objective of the study was to assess the evolution or resolution of peripheral neuropathy (PN) in patients taking lenalidomide, who had pre-existing PN at baseline. Methods:Data were collected prospectively from 1,011 patients with MM, in 177 institutions in 15 European countries. Patients had received at least one prior therapy and were commencing a new treatment with prescribed medication in accordance with normal clinical practice at the time of enrollment. No additional treatments or investigations outside of normal clinical practice were required. PN status was assessed by physicians according to their normal clinical practice. PN was recorded at baseline and, if present, the status was subsequently recorded at all following data collection points until the patient discontinued study treatment. For those patients who did not have PN at baseline, any new occurrence of PN was documented as an AE. Data cutoff for this analysis was May 4, 2010. Results:Of the 1,011 patients who entered the study, 658 patients started lenalidomide-, 207 bortezomib-, and 53 thalidomide-based therapies; 43 patients commenced other therapies and 50 had missing data. Median Kaplan-Meier estimated treatment duration was 6.4 months for lenalidomide, 3.8 for bortezomib, and 4.8 for thalidomide. Baseline PN was reported in 39% (254/658) of patients in the lenalidomide cohort: 22% (144/658) were reported to be due to previous bortezomib and 18% (118/658) were due to previous thalidomide. In the bortezomib cohort 21% (43/207) had baseline peripheral neuropathy: 3% (6/207) were reported due to previous bortezomib and 13% (27/207) due to previous thalidomide. Baseline PN due to prior vincristine use was low (2% of patients), and non-drug induced PN was between 4–6% in the three cohorts overall. Observed PN in the lenalidomide cohort was 42% (89/213) at baseline and 29% (62/213) at 4 months, compared with 26% at baseline (16/61) and 23% (14/61) at 4 months in the bortezomib cohort. There was no change over the 4 month period in the thalidomide cohort (16% 3/19). Treatment discontinuations due to AEs were highest in the thalidomide cohort (24.5%), and similar in the lenalidomide (14.1%) and bortezomib (15.5%) cohorts. However, patient discontinuations due to PN were six times higher in the bortezomib (4.8%) cohort compared with the lenalidomide cohort (0.8%). The incidence of drug-related PN and grade 3* or 4** drug-related PN was four times lower in the lenalidomide cohort compared with the bortezomib cohort. Conclusion:In this unselected group of patients taken from normal clinical practice and treated with lenalidomide-, bortezomib-, or thalidomide-based therapies, lenalidomide demonstrated a low incidence of drug-related PN. A high proportion of patients commencing treatment with lenalidomide had baseline PN due to their previous anti-myeloma therapy. Preliminary data on these patients at 4 months of treatment indicated a trend towards improvement of PN in patients receiving lenalidomide. Discontinuations due to PN were low in the lenalidomide cohort compared with the bortezomib cohort. Disclosures:Delforge:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Ortho-Biotech: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Hajek:Celgene Corporation: Honoraria; Janssen-Cilag: Honoraria; Merck, Sharp, and Dohme: Honoraria. Lokhorst:Celgene Corporation: Speakers Bureau. Collins:Celgene Corporation: Employment. Rosettani:Celgene Corporation: Employment. Brandenburg:Celgene Corporation: Employment.

Clinical characteristics and treatment outcome of disease-related peripheral neuropathy in Waldenstrom's macroglobulinemia (WM).

8114 Background: Peripheral neuropathy (PN) is a debilitating morbidity in WM, whose natural history and treatment outcome is largely unknown. Methods: We examined the incidence, characteristics, and treatment outcome of disease related PN in 900 WM patients. Results: 199 (22.1%) patients had disease related PN with a higher incidence in sporadic vs. familial WM (23.5% vs. 15.6%; p=0.02). PN patients had lower serum IgM (p=0.02), B2M (p=0.02), and BM disease burden (p=0.001). Among 122 PN patients evaluated for neuropathic antibodies, 24.5%, 1.64%, and 0.81% were positive for MAG, GM1, and sulfatide antibodies, respectively. Patients with neuropathic antibodies had lower serum IgM (p=0.0002) and BM disease burden (p=0.001) vs. non-PN patients. 13/61 (21.3%) patients examined for amyloid were positive, and only 1 had a neuropathic antibody. The median time to treatment for all PN patients was 9 months. Among non-amyloid related PN patients who received PP or IVIG as their first intervention, 29/42 (69%) and 1/8 (12.5%) reported symptomatic improvement, respectively. 151 PN patients received frontline CTX which consisted of an oral alkylator, nucleoside analogue or rituximab; or rituximab combination with a nucleoside analogue, cyclophosphamide, thalidomide or bortezomib. Of these, 71 (47%) and 8 (5.3%) had improvement or complete resolution of PN following CTX, respectively. Symptomatic improvement was more likely with non-amyloid related PN (48.5% vs. 15.4%; p=0.045); in patients who achieved a major response, i.e. ≥50% reduction in serum IgM (79% vs. 35.5%; p<0.0001); those who received earlier therapy, i.e. ≤24 months (57.3% vs. 42.5%; p=0.06); and those who received rituximab combination vs. any monotherapy (59.3% vs. 37.0%; p=0.007; p=0.06 vs. rituximab alone). Conclusions: PN is a common morbidity, particularly among sporadic WM patients. PP for non-amyloid related PN is an effective interim intervention. Improvements in symptomatic neuropathy occur in half of PN patients following CTX, and are more likely to occur in WM patients with non- amyloid related PN, those who receive earlier therapy, combination therapy with rituximab, and who achieve a major response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biogen Idec, Celgene, Genentech, Millennium Biogen Idec, Celgene, Genentech, Millennium Celgene, Millennium

A prospective characterization of the resolution of ixabepilone induced peripheral neuropathy: data from a large registrational program in patients with metastatic breast cancer.

Abstract Abstract #6140 Background:&amp;#x2028; Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts whose tumors were resistant to (study 046, JCO, 2007) or pretreated with anthracycline (A) and taxanes (T) (study 048). In 048, ixa + C, compared to C alone, demonstrated significant increases in PFS (HR 0.79 [0.69-0.90]) and ORR (43% vs 29%). A trend toward increased OS was seen both in 048 (HR 0.90 [0.78-1.03]) and in 046 (HR 0.90 [0.77-1.05]), which did not reach statistical significance. Similar to taxanes, dose-limiting peripheral neuropathy (PN) is a side effect associated with ixa treatment. Here we present the incidence rates, management of ixa-induced PN from 3 registrational studies in pts with MBC and an analysis of resolution time. Also, data on potential risk factors for PN are presented.&amp;#x2028; Methods:&amp;#x2028; Incidence of PN is summarized from a 2000 pt program from 3 multi-center clinical trials. In this program, almost 1100 pts with MBC received ixa either as a monotherapy (40 mg/m2 IV over 3h Q3w, N=126) in a phase II study, or in combination with C (1000 mg/m2 PO BID x14d Q3w) in 2 large phase III studies (N = 369 and N = 595). PN was evaluated every 4 weeks after completion of treatment until toxicity was resolved. Resolution of PN was defined as the time from onset of worst grade to baseline or grade 1. A Cox regression analysis was also performed on a dataset of 945 pts with different tumor types across multiple studies, receiving ixa as a monotherapy or in combination with C, to identify the potential risk factors for grade 3/4 PN.&amp;#x2028; Results:&amp;#x2028; Incidence rates of grade 3/4 PN and resolution time observed in 1 phase III study (046) and the phase II (081) have been published before (081: JCO, 25; 3407). Here we present the data from the final confirmatory phase III study (048).&amp;#x2028; &amp;#x2028; PN was effectively managed with dose reduction. After dose reduction, symptoms improved or did not worsen in the majority of pts, and a median of 2-3 additional treatment cycles were delivered. Pts with diabetes were at a higher risk of grade 3/4 PN (HR: 1.67 [1.00-2.78], p-value = 0.049).&amp;#x2028; Conclusions:&amp;#x2028; Incidence of ixa-associated PN was similar to that observed in trials of other T based regiments. Ixa-induced PN has a predictable median time to resolution of 5-6 weeks over 3 large studies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6140.

Frequency, Characteristics, and Reversibility of Peripheral Neuropathy (PN) in the APEX Trial.

Introduction: Bortezomib (Bz, VELCADE) is a proteasome inhibitor proven safe and effective for patients (pts) with relapsed and/or refractory multiple myeloma (MM). Pts in SUMMIT (NEJM 2003; 348:2609) and CREST (BJH 2004; 127:165) underwent rigorous testing (neurologic evaluations, FACT/GOG-Ntx questionnaires, nerve conduction studies) to determine the incidence, characteristics and reversibility of PN. In these phase 2 trials, the PN rate was 31–41% (grade [G] ≥ 3 in 11–12%). Specific dose modification (DM) guidelines for PN were not incorporated into the phase 2 trials but were developed for subsequent studies. The objective of this report was to evaluate the frequency, characteristics and reversibility of PN in an updated analysis of the randomized phase 3 APEX trial (NEJM 2005; 352:2487), in which specific DM guidelines for PN were implemented.Methods: Pts with relapsed MM were randomized to Bz 1.3 mg/m2 IV on d 1, 4, 8, 11 q3wk for 8 cycles then 3 cycles on d 1, 8, 15, 22 q5wk, or dexamethasone (Dex) 40 mg PO on d 1–4, 9–12, 17–20 q5wk for 4 cycles, then 5 cycles on d 1–4 q4wk. Pts with G ≥ 2 PN were excluded. Data were collected on incidence, severity and reversibility of PN.Results: Of 331 pts safety evaluable enrolled on Bz, 120 (36%) developed PN, including 30 (9%) with G ≥ 3. PN was classified as sensory or not specified in the vast majority of cases; motor neuropathies were rare. Of 91 pts with G ≥ 2 PN, 68 had DM, including 37 with doses reduced, held or schedule modification and 31 with Bz discontinuation (DC); 23 pts not following DM protocol. The majority (58 pts; 64%) of the 91 pts improved (9%) or had complete resolution (55%) of symptoms. Of 37 pts with DM without Bz DC, the majority (26 pts; 70%) had improvement, all with complete resolution of PN to baseline, with a median time to resolution of 78 d. Of 31 pts requiring Bz DC, 2 (6%) improved and 17 (55%) had complete resolution of PN with a median time to improvement/resolution of 121 d. Of 23 pts who did not follow the DM protocol, 12 (52%) had complete resolution with a median time to resolution of 106 d. The rates of PN (any G, G ≥ 3) were similar regardless of pt age or number/type of prior therapies (Table). The median TTP of 91 pts with G ≥ 2 PN, 68 pts with DM, and the Bz arm overall were 6.2, 6.9 and 6.2 months, respectively.Conclusion: The overall rate of PN in APEX was similar to that of SUMMIT and CREST, but the rate of G ≥ 3 PN was lower, perhaps because of specific DM guidelines. PN was reversible in the majority of pts, and DM did not compromise efficacy. Pt age or number/type of prior therapies did not appear to affect the rate or severity of PN.PNBz SubgroupAny G*, %G ≥3, %ge; 65 y359< 65 y379> 1 prior therapy36101 prior therapy378Steroids387Alkylating agent357Anthracycline397Vinca alkaloid388Thalidomide448Transplantation377*Bz related