Baseline Peripheral Neuropathy Research Articles

Cryocompression to Reduce Peripheral Neuropathy in Gynecologic Cancer: A Randomized Controlled Trial.

To investigate the efficacy of cryocompression therapy to prevent chemotherapy-induced peripheral neuropathy. This single-institution, randomized, self-controlled trial of cryocompression enrolled gynecologic cancer patients planned for five to six cycles neurotoxic chemotherapy. Exclusion criteria were prior neurotoxic chemotherapy or baseline peripheral neuropathy. Participants were randomized to cryocompression on dominant versus non-dominant hand and foot (treatment), with no intervention on the opposite side (control). Compression socks and gloves and ice bags were applied 15 minutes before, during, and 15 minutes after infusion. Primary outcome measures included the PNQ (Patient Neurotoxicity Questionnaire) and the Semmes-Weinstein monofilament test; secondary outcomes included the FACT/GOG-NTX (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity) and patient acceptability and tolerability. Sixty patients completing the study were necessary to detect a 70% reduction in the odds of PNQ grade C or higher peripheral sensory neuropathy with 80% power. Ninety-one patients were enrolled from January 2021 to October 2022; 69 were eligible for final analysis. Of the 91 patients, 64.8% were White, 30.8% were Black, and 1.1% were Hispanic or Latina. With successive cycles, more patients had sensory PNQ grade C or higher neuropathy on the control side compared with the cryocompression side. Cryocompression decreased the odds of sensory neuropathy (PNQ grade C or higher) by 46% at final visit (odds ratio 0.54, 95% CI 0.31-0.94; P =.03). There was no difference in tactile sensitivity based on the monofilament test between sides at the final visit. At the final visit, average FACT/GOG-NTX-11 (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity 11 Item Version) scores were significantly lower on the cryocompression than the control side (estimate -0.97, 95% CI -1.89 to -0.06; P =.04), as were FACT/GOG-NTX-4 (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity 4 Item Version) scores (estimate -0.35, 95% CI -0.64 to -0.05; P =.02). More than 85% of patients assessed the intervention as acceptable and tolerable. Cryocompression therapy reduces subjective chemotherapy-induced peripheral sensory neuropathy in patients who are receiving paclitaxel or cisplatin for gynecologic cancer. ClinicalTrials.gov , NCT04563130.

Association of enfortumab vedotin (EV) toxicity with baseline parameters and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC).

e16585 Background: EV is an antibody-drug conjugate approved for the treatment of mUC. Toxicities of special interest with EV are neuropathy, rash, and hyperglycemia. While it has been reported that EV-related skin toxicity may be associated with better responses to EV, the relationship of EV-related adverse events (AEs) with clinical outcomes is still unclear. The aim of this study is to investigate the association of EV-related toxicity and clinical outcomes among pts with mUC. Methods: We retrospectively reviewed demographic, clinical and laboratory data from pts with mUC who were treated with > 1 dose of EV at Dana-Farber Cancer Institute. AEs were graded per the CTCAE V5.0. A multivariable Cox regression analysis was performed to analyze overall survival (OS) and the occurrence of AEs while accounting for age, sex, and baseline peripheral neuropathy (BPN). A landmark analysis was performed to evaluate the association of toxicity occurrence and clinical outcomes, accounting for guarantee-time bias. Results: Our cohort included 54 pts with a median age of 72 years, of which 72.2% (n = 39) were male. Median follow-up was 18.6 months. Neuropathy was the most common AE occurring in 66.7% (n = 36) pts with 7.4% (n = 4) grade 3-4. Skin toxicity occurred in 57.4% (n = 31) pts with 3.7% (n = 2) grade 3-4. There were no recorded grade 5 AEs. Worse baseline Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was associated with the development of more AEs (HR = 2.8; 95% CI = 1.2-6.3; p = 0.01). Decreased baseline hemoglobin (Hb) was associated with more EV-related neuropathy (1/HR = 1.25; 95% CI = 1.1-1.4; p = 0.01) and higher neuropathy grade (1/HR = 1.7; 95% CI = 1.1-2.5; p = 0.01). Moreover, pts who have previously received immune checkpoint inhibitors (ICI) were more likely to develop EV-related rash (HR = 5.4; 95% CI = 1.1-26.2; p = 0.03; Table 1). Overall, 30 deaths were observed, and median OS was 13.3 months (95% CI = 9.5-NA). A landmark analysis at 2 weeks of therapy (marking the final infusion of the 1st cycle of EV therapy) showed that in 16 pts who developed early skin toxicity, OS was improved vs. 38 pts who did not develop early skin toxicity (HR = 0.4; 95% CI = 0.2-0.9; p = 0.04). Conclusions: To our knowledge, this is the first study to investigate the association of EV-related AEs and clinical outcomes of pts with mUC using a landmark analysis. ECOG-PS and baseline Hb may be predictors of EV-related AEs. The incidence of early skin toxicity may be associated with improved OS. [Table: see text]

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.

Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility. The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75years) to receive oral co-micronised fenofibrate 200mg (n=4895) or placebo (n=4900) daily for a median of 5years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures. Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p=0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p=0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p=0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p=0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p=0∙04). Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.

Patterns of Neuropathy in ALL Patients Treated with Vincristine Based Regimens with and without Tyrosine Kinase Inhibitors

Introduction: Acute lymphoblastic leukemia (ALL) is the most common acute leukemia in pediatric patients, but accounts for only 20% of acute leukemia diagnoses in adults. Vincristine (VCR) is a cornerstone chemotherapy agent in the management of ALL, but is known to cause high rates of chemotherapy induced peripheral neuropathy (CIPN). Tyrosine kinase inhibitors (TKIs) are routinely incorporated into the treatment of Philadelphia chromosome positive (Ph+) ALL, and have been shown to have potential neuroprotective effects in the prevention of CIPN. Pre-clinical work using animal models has suggested the attenuation of VCR CIPN with the TKI nilotinib. Based on these pre-clinical results, we sought to evaluate whether TKIs had a protective effect on the development of CIPN in patients with ALL treated with VCR containing regimens. Methods: We performed a retrospective study on adult ALL patients who were treated with VCR-based regimens from 1/1/11 to 12/31/20 at the Ohio State University James Cancer Hospital. Demographics including age, gender, race/ethnicity, relationship status, and drug and alcohol use were collected. Clinical information was also collected including performance status, height/weight, subtype of ALL and date of diagnosis, chemotherapy regimen, comorbidities, falls, date of last follow-up, and information on CIPN. Descriptive statistics were generated on all patients, stratified by those who received a TKI and those who did not. Chi-squared tests were performed to assess for an association between presence and severity of CIPN and TKI use and to evaluate other significant factors associated with the development of CIPN. Given that the majority of TKI patients received hyper-CVAD (cyclophosphamide, VCR, doxorubicin hydrochloride, and dexamethasone), a sub-analysis was performed for all patients treated with hyper-CVAD. Results: A total of 220 patients were included in the analysis, with a summary of key patient characteristics shown in Table 1. Median age at diagnosis was 42 (range 17-80) and 57.7% of patients were male. The majority of patients had B-cell ALL (75%), with 18.6% T-cell ALL and 6.4% other. The most common treatment regimen was hyper-CVAD (50.5%), followed by the CALGB 10403 (Stock Blood 2019) regimen (29.5%). Approximately one quarter (26.8%) of patients received TKIs, with the large majority (96.6%) receiving dasatinib and 1.7% receiving either nilotinib or ponatinib. The presence of baseline peripheral neuropathy and lower body mass index (BMI) were the only statistically significant variables between the no CIPN group (grp) and the CIPN grp (P=0.0092, 0.0359). Median BMI was 30 (range 18.9-54.7) in the no CIPN grp as compared to 27.2 (range 17.2-52.9) in the CIPN grp. Cumulative dosing and total doses of VCR was not significant between the no CIPN and CIPN grps (P=0.2675, 0.0630). When comparing those patients who received TKI (TKI grp) to those who did not (no TKI grp), there was a trend toward lower rates of CIPN in the TKI as compared to the no TKI grp at 71.2% compared to 81.4%, but no significant difference was seen (P=0.1027, Table 2). In the sub-analysis of patients who received hyper-CVAD (n=111), 66% of pts in the TKI grp developed CIPN as compared to 71.9% in the no TKI grp, with no significant difference seen (P=0.504, Table 2). For both the entire cohort and hyper-CVAD sub-analysis, there was no significant difference in max dose reduction, holds or cessation due to neuropathy, or grade at worst seen between the grps (Table 2). For both analyses, the no TKI grp also received significantly higher cumulative doses and total doses of VCR (Table 2). Conclusions: Overall, we found no significant differences in the development of neuropathy in patients with ALL treated with VCR-based regimens with or without TKI, despite higher doses of VCR utilized in patients treated without TKIs. However, the majority of our patients received dasatinib rather than nilotinib, which has been the focus of recent pre-clinical studies. Our findings may suggest a potential mechanistic difference in the effects of dasatanib and nilotinib on the neuronal transport of VCR. While our findings should be confirmed in a larger analysis, they suggest that dasatinib lacks a protective effect against neuropathy for ALL patients treated with VCR-based regimens. Based on promising preclinical data, future studies should focus on the impact of nilotinib for neuroprotection in the prevention of CIPN. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Baseline peripheral neuropathy was associated with age and a prognostic factor in newly diagnosed multiple myeloma patients

Multiple myeloma (MM) is an incurable plasma cell hematological malignancy. Bortezomib has become the primary drug in the treatment of patients with MM. However, its negative effects, especially peripheral neuropathy (PN), affect the patients’ life quality and treatment continuity. However, there are few studies on baseline PN of MM, and little is known of the impact of baseline PN on the prognosis of MM patients. Therefore, we reviewed the clinical data of newly diagnosed MM patients in our center, explored the influencing factors of baseline PN, and evaluated PN’s influence on the prognosis of MM patients undergoing induction therapy with bortezomib. According to the inclusion and exclusion criteria, 155 MM patients were eligible for the retrospective study. The multivariate regression analysis, generalized additive fitting smooth curve, the receiver operating characteristic curve (ROC) and K-M curve were conducted in this study. We found that baseline PN in patients with MM was age-related; MM patients with baseline PN have more severe bortezomib induced PN (BiPN) during the four courses of induction therapy with bortezomib as the primary regimen and worse PN outcome after induction therapy. Additionally, the progression-free survival (PFS) and overall survival (OS) of MM patients with baseline PN were worse than those of the MM patients without baseline PN.

POLARGO: Randomized Phase III Study of Polatuzumab Vedotin Plus Rituximab, Gemcitabine, and Oxaliplatin in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

POLARGO: Randomized Phase III Study of Polatuzumab Vedotin Plus Rituximab, Gemcitabine, and Oxaliplatin in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Fitness, a UK Myeloma Research Alliance (UK-MRA) Frailty-Adjusted Therapy Study, Supports the Feasibility of Recruiting Frail Newly Diagnosed Myeloma Patients to Large Clinical Trials

Fitness, a UK Myeloma Research Alliance (UK-MRA) Frailty-Adjusted Therapy Study, Supports the Feasibility of Recruiting Frail Newly Diagnosed Myeloma Patients to Large Clinical Trials

Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE

In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n= 743) or trastuzumab (n= 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR)= 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR= 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

POLARGO: A Randomized Phase III Study Evaluating Polatuzumab Vedotin Plus Rituximab, Gemcitabine, and Oxaliplatin in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Who Had Received One or More Previous Therapies

POLARGO: A Randomized Phase III Study Evaluating Polatuzumab Vedotin Plus Rituximab, Gemcitabine, and Oxaliplatin in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Who Had Received One or More Previous Therapies

Patient and Physician Preferences for First-Line Treatment of Classical Hodgkin Lymphoma in the United States

▪Introduction: The standard of care for previously untreated classical Hodgkin lymphoma (HL) in the United States has been combination chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or with radiotherapy depending on clinical characteristics. Other treatment programs exist, including intensified chemotherapy regimens, and substitution of brentuximab vedotin for bleomycin recently received FDA approval as first-line therapy for advance stage HL. The objective of this study was to understand how specific treatment attributes impact preferences among patients and physicians for choice of first-line treatment of HL.Methods: An online survey including a discrete choice experiment (DCE) was administered both to oncologists who manage patients with HL and to patients diagnosed within HL within the last two years in the United States. Participants were identified via online research panels. The attributes and levels of the hypothetical treatments presented in the DCE were informed by targeted literature review and physician and patient interviews. For physicians, six attributes were included: two-year overall survival (OS); two-year progression free survival (PFS); risk of side effects requiring hospitalization; risk of peripheral neuropathy (PN); risk of pulmonary toxicity; and patient out-of-pocket cost. The patient DCE included four attributes: OS, PFS, risk of PN and risk of pulmonary toxicity. DCE scenarios were developed using a d-efficient design. Participants reviewed 10 scenarios, and selected their preference between two hypothetical treatments. Patients considered themselves when selecting their preference; physicians considered four different advanced HL patient profiles that differed in age (30 or 65 years), smoking status, and the presence of baseline PN. The DCE data were analyzed using a mixed logit model (MXL). The relative importance of each attribute was calculated by determining the differences between the maximum and minimum coefficients of each attribute. These were then normalized and presented as percentages.Results: A total of 200 physicians and 141 patients were included in the analysis. Physicians had a mean of 15 years' experience and 71% practiced in a community setting. Patients had a median age of 35 years (range 19 to 69), 60% were male, and 34% were diagnosed with advanced stage HL. In the DCE, the most important attributes to both patients and physicians were OS and PFS. Based on the coefficients from the MXL model, a 1% increase in OS was more important to both groups than a 1% increase in PFS. The coefficients and level ranges for each attribute were used to calculate preference weights (see methods). Based on preference weights, PFS was the most important attribute for patients, followed by OS, risk of pulmonary toxicity, and risk of PN (Table 1). Compared to male patients, there was a trend for female patients to have a lower preference for a 1% decrease in risk of progression (p=0.077). Patients above the median age of 35 years had a significant preference (p=0.048) for a lower risk of pulmonary toxicity, and a trend for a higher preference for a 1% increase in OS (p=0.059) was observed. OS was also marginally more important to patients diagnosed with advanced stage HL versus those diagnosed in earlier stages. For physicians, preferences for treatment attributes differed based on the patient profile presented. PFS outweighed OS for a healthy 35 year-old patient (Table 2), whereas OS had a higher relative preference weight for a 35 year old smoker and older patients. For smokers, physicians ranked pulmonary toxicity as the most important attribute. Among older patients, side effects requiring hospitalization were more important to physicians' preferences than both OS and PFS. There were no major differences in preferences between academic and community oncologists.Conclusion: Patients are willing to accept treatments with worse short and long-term side effects in exchange for improved OS or PFS. Physicians' treatment preferences are patient-specific, with age and comorbidities impacting both the relative weight of OS and PFS attributes and the importance of pulmonary toxicity and short-term side effects. These results underscore the importance of assessing and sharing patient and physician preferences in creating a treatment plan for the management of newly diagnosed Hodgkin lymphoma. DisclosuresFeliciano:Seattle Genetics: Employment, Equity Ownership. Mueller:ICON plc: Employment. Korol:ICON plc: Employment. He:ICON plc: Employment. Matasar:Seattle Genetics: Honoraria.

Outcomes of Patients With Familial Transthyretin Amyloidosis After Liver Transplantation.

Familial transthyretin amyloidosis is a disease caused by misfolded transthyretin aggregates that can impair multiple organ systems. Liver transplantation is the first-line treatment for familial transthyretin amyloidosis. Our objective is to study outcomes and survival among patients with familial transthyretin amyloidosis after transplantation. All patients undergoing orthotopic liver transplant for familial transthyretin amyloidosis at Mayo Clinic between 1997 and 2012 were reviewed. Baseline clinical characteristics, organs transplanted, and posttransplant clinical course were assessed. Of the 40 patients, 7 patients had the V30M mutation and 33 had other mutations. Nineteen patients received liver only, 19 liver and heart, and 2 combined liver, heart, and kidney transplants. The 5-year overall survival was 85% for those receiving multiple organ transplant and 52% for those receiving liver transplant only ( P = .057). There was no difference in overall survival based on mutation (V30M vs other mutations), but survival was confounded by varied disease involvement and organs transplanted. Those who had early death (≤24 months from liver transplant) had a higher incidence of baseline peripheral neuropathy, autonomic neuropathy, lower modified BMI, and higher alkaline phosphatase. Outcomes of orthotopic liver transplant in familial transthyretin amyloidosis are variable due to heterogeneity in mutations and patient status at the time of transplant. Familial transthyretin amyloidosis can progress, despite liver transplantation. Patients receiving combined liver, heart/kidney transplant demonstrated improved survival compared to liver transplant alone.

Safety of BTZ retreatment for patients with low-grade peripheral neuropathy during the initial treatment

Neuropathy is an important complication that may limit treatment options for patients with multiple myeloma. Previous studies have focused on treatment efficacy and have shown that retreatment with bortezomib (BTZ) is an effective treatment option. The goal of this study was to focus on the clinical manifestations of peripheral neuropathy (PN) and to retrospectively compare the incidence and severity of PN between the initial BTZ regimen and upon retreatment. Furthermore, this study evaluated how certain factors affect BIPN, which will help determine what conditions should be considered prior to retreatment. Charts were reviewed from 93 patients who were retreated with a BTZ-containing regimen after previously being treated with this drug. Among the patients who developed PN, most patients in the study had low-grade neuropathy during the initial BTZ treatment (n=52, 68%). The results showed no evidence of cumulative toxicity, and there was no significant difference in the incidence and severity of PN upon retreatment. Factors such as the presence of baseline PN, number of prior treatments, dose of BTZ, and comorbidities did not increase the severity of PN upon retreatment. The lapse of time between the two regimens also did not affect the severity of PN. The results suggest that retreatment with BTZ may be a feasible option, without additional risks of PN, for MM patients even with peripheral neuropathy during their initial treatment with this drug.

Clinical Risk Factors for Peripheral Neuropathy in Patients Treated with Subcutaneous or Intravenous Bortezomib for Newly Diagnosed Multiple Myeloma

Clinical Risk Factors for Peripheral Neuropathy in Patients Treated with Subcutaneous or Intravenous Bortezomib for Newly Diagnosed Multiple Myeloma

Bortezomib-induced peripheral neuropathy in multiple myeloma patients

To describe the side effects of bortezomib in treatment of multiple myeloma (MM), especially the incidence of peripheral neuropathy (PN). Information of 107 patients with MM who were treated with bortezomib in the First Affiliated Hospital of Zhejiang University from 2009 to 2014, were collected and analyzed retrospectively, to analyze the occurrence of adverse events during the treatment, especially the incidences of PN in each cycle and in different patients. A total of 40 (37%) patients suffered from PN, among which 13 patients were grade 3 PN and no patients reported grade 4 PN. Other common treatment-related side effects were thrombocytopenia, gastrointestinal reactions, fatigue, lung infection, herpes zoster in turn. In 44 MM patients treated strictly with bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11) of each 3-week cycle, 20(45%) patients suffered from PN, of which 6 (14%) patients got grade 3 PN. In other 63 patients who received bortezomib less than 1.3 mg/m(2), 20 (32%) patients got PN and 7(11%) patients were grade 3 PN. There was no significant difference in the incidence of PN between the two groups of MM patients mentioned above (P=0.149), as well as the incidence of grade 3 PN (P=0.694). Univariate and multivariate analyse revealed that gender, age, a history of hypertensive disease, diabetes or hepatitis B virus infection, baseline PN symptoms and a history of neurotoxicity drug therapy were all not risk factors for PN (all P>0.05). The reduction of bortezomib do not decrease the incidence of PN in bortezomib treatment of MM. Age, a history of diabetes and baseline PN symptoms are not risk factors for PN in bortezomib treatment of MM.

A Phase 2 Study of High-Dose Melphalan Plus Bortezomib (Mel/Vel) Conditioning Followed By Autologous Hematopoietic Cell Transplantation in Myeloma

Background:High-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) remains the integral component of multiple myeloma (MM) therapy in the era of novel agents. We published our prior study with the use of high-dose melphalan + bortezomib (Mel/Vel) conditioning regimen for tandem transplants in refractory MM patients (Nishihori, et al. Br J Haematol 2012). We designed a phase 2 trial using MelVel conditioning followed by autologous HCT in patients with newly diagnosed chemosensitive MM (NCT 00948922).Methods:Sixty seven newly diagnosed MM patients who achieved ≥ partial response (PR) to induction therapy with ≤grade 1 peripheral neuropathy (PN) were enrolled from 12/2009 to 06/2014. Patients received high-dose melphalan at 100 mg/m2 IV for 2 days, immediately followed by 1 dose of bortezomib at 1.3 mg/m2 (Mel/Vel conditioning). Maintenance therapy was not prescribed by design. The protocol later was modified to include maintenance bortezomib subcutaneously (started at 3 months after HCT) at 1.3 mg/m2 weekly x4, every 8 weeks, for a total of 6 cycles. Progression-free and overall survival (PFS and OS) estimates were calculated using Kaplan-Meier method.Results:A total of 67 patients received autologous HCT. The median age was 58 (25 - 73) years with the following disease characteristics: Durie-Salmon stage, 3A (72%) and 3B (10%); IgG (55%), IgA (21%), IgD (1%), and light chain (22%). High-risk cytogenetics/FISH were seen in 28% of patients. The median beta-2 microglobulin was 3.3 (range, 1.3 – 34.8). Induction regimens were bortezomib-based in 39%, lenalidomide-based in 19% and, both bortezomib and lenalidomide in 42%. Median time from initiation of induction to HCT was 204 days (range, 101 - 664). Responses prior to HCT were stringent CR (sCR) 21%, CR 12%, very good partial response (VGPR) 34%, and PR 33%. Neutrophil engraftment was achieved after a median of 11 days (range, 10 – 14) and platelet engraftment occurred after a median of 15 days (range, 11 – 22). Median CD34 cell dose was 3.8 x 106/kg (range, 2 – 20.08). Responses at 3 months after HCT (in 64 evaluable patients) were sCR 47%, CR 14%, VGPR 20%, PR 16% and progressive disease 3%. Bortezomib maintenance was prescribed to 31 patients (46%). Prevalence of grade 1 PN before (n=67) and at 3 months (n=64) after HCT were 37% and 38%, respectively. Two patients withdrew consent to initiate maintenance and 1 patient was unable to initiate maintenance due to grade 1 PN (baseline PN of 0). At the time of review, a median number of maintenance delivered was 4 (range, 1-6) and only one patient required dose reduction. The 2-year PFS and OS estimates are 62% (95% CI 0.47 – 0.75) and 90% (95% CI 0.80 – 0.97) with a median follow-up of 21 months (range, 2 – 54). The 1-year PFS estimates were 85% (95% CI 0.65 – 0.97) for bortezomib maintenance vs. 81% (95% CI 0.66 – 0.92) for no maintenance (p=0.6). There were no significant differences in PFS or OS stratified by cytogenetic/FISH risk status. There was no transplant related mortality.Conclusions:The combination of bortezomib and high-dose melphalan (Mel/Vel) as conditioning regimen for autologous HCT is well tolerated and appears to improve responses after HCT. Weekly x4 post HCT bortezomib maintenance given every 8 weeks appears to be well tolerated and is a promising strategy for eligible patients. Longer follow up is required to assess the benefit of post HCT maintenance strategy. DisclosuresBaz:Millennium: Research Funding. Alsina:Millennium: Consultancy, Research Funding.

Phase I/II study of weekly LOC-paclitaxel (LOC-pac) injection in patients (pts) with metastatic melanoma (MM).

9053 Background: LOC-paclitaxel (LOC-pac) is a covalent conjugate of paclitaxel linked to an omega-6 fatty acid designed to enhance uptake of paclitaxel into tumors leading to higher intra-cellular drug concentrations and potentially enhance anti-tumor activity of paclitaxel. This is a first in human, phase I, open label, dose-escalating clinical study of LOC-pac administered weekly in patients (pts) with metastatic melanoma (MM). Methods: Adult MM pts who were refractory to prior systemic therapy or were ineligible for other therapy of higher priority with normal organ function and ECOG PS 0-2 were eligible for this trial. Patients with baseline peripheral neuropathy over grade 1, prior exposure to taxane chemotherapy, hypersensitivity to cremaphor or with serious concurrent medical conditions were excluded. LOC-pac was given intravenously over 1 hour on days 1, 8, 15, 22 and 29 every 42 days. LOC-pac dosing was escalated from 100mg/m2 to 1000mg/m2 after safety of the prior dose level was confirmed in co...

Abstract P4-12-09: Results from a phase 2a study of trastuzumab emtansine, paclitaxel, and pertuzumab in patients with HER2-positive metastatic breast cancer

Abstract Introduction The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the antitumor properties of trastuzumab (H) with the cytotoxic agent DM1 via a stable linker. T-DM1 prolonged PFS and OS vs standard therapy in a phase 3 study of patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with H and a taxane. Preclinical data suggest synergy when T-DM1 is combined with paclitaxel (T) or pertuzumab (P). In the phase 1b study TDM4652g, the maximum tolerated doses of T-DM1 + T ± P were defined. Here we present results from the phase 2a expansion, which further explored feasibility and safety. Methods TDM4652g is a phase 1b/2a open-label study of pts with HER2-positive locally advanced or MBC. Pts had no prior T-DM1 or P, no baseline peripheral neuropathy (PN; phase 2a only), and had LVEF ≥50%. Pts in phase 2a were randomized to T-DM1 3.6 mg/kg q3w + T 80 mg/m2 qw ± P 840 mg loading dose [LD], then 420 mg q3w. The primary objective, feasibility, was assessed by the percent of evaluable pts receiving ≥12 doses of T within 15 weeks of cycle 1, day 1, and those receiving 12 consecutive weeks of T. Results Forty-four pts were enrolled (T-DM1 + T, n = 22; T-DM1 + T + P, n = 22); the data snapshot date was May 23, 2013. Median age was 52.5 years (range, 35–81); median number of prior agents for MBC was 6 (range, 0–12). 43 (98%) pts had previously received H, and 36 (82%) pts had received taxane therapy. Median dose intensities were T-DM1, 94% (range 54–105); T, 50% (range 9–100) and P, 100% (range 67–100). 2 pts were not evaluable for feasibility (progressive disease [PD] before receiving 12 doses of T). 21/42 (50%) pts received ≥12 doses of T within 15 weeks; 6/42 (14%) pts received 12 consecutive doses by week 12, and 33/42 (79%) pts received ≥8 doses within 12 weeks. Grade 3/4 adverse events (AEs) were reported for 18 (82%) and 17 (77%) pts in the T-DM1 + T and T-DM1 + T + P groups, respectively (see Table for AEs and best responses). Ten pts discontinued early due to PD (n = 6), PD-related death (n = 2), AEs (n = 1), or withdrawal from the study (n = 1). 21 pts discontinued T due to AEs, most commonly PN (n = 12). Grade 3/4 AEs occurring in >1 patientAE, n (%)All patients (N = 44)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw (n = 22)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw + P 840 mg LD, 420 mg q3w (n = 22)Neutropenia10 (23)6 (27)4 (18)Peripheral neuropathy9 (20)3 (14)6 (27)Fatigue6 (14)3 (14)3 (14)Thrombocytopenia6 (14)5 (23)1 (5)Anemia3 (7)2 (9)1 (5)Abdominal pain2 (5)2 (9)0Decreased hemoglobin2 (5)1 (5)1 (5)Muscosal inflammation2 (5)1 (5)1 (5)Muscular weakness2 (5)02 (9)Nausea2 (5)1 (5)1 (5)Best response,* n (%)CR2 (5)1 (5)1 (5)CR confirmed1 (2)1 (5)0PR27 (61)13 (59)14 (64)PR confirmed8 (18)3 (14)5 (23)SD10 (23)6 (27)4 (18)PD3 (7)1 (5)2 (9)*At any time point with responses ordered CR>PR>SD>PD. Conclusions Overall, 50% of pts received ≥12 doses of T within 15 weeks. Adding P to the combination of T-DM1 + T did not appear to increase the incidence of grade 3/4 AEs. Data support further investigation of T-DM1 + T ± P in larger studies in early breast cancer. Final data from all phase 2a patients will be available for the full report. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-09.

Clinical Profile Of Single-Agent Modified-Release Oprozomib Tablets In Patients (Pts) With Hematologic Malignancies: Updated Results From a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study

Clinical Profile Of Single-Agent Modified-Release Oprozomib Tablets In Patients (Pts) With Hematologic Malignancies: Updated Results From a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study

Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies

Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities.