Ruxolitinib Therapy Improves Renal Function in Patients with Primary Myelofibrosis

Abstract Introduction. Renal dysfunction is commonly observed in patients with primary myelofibrosis (PMF), but its etiology remains largely unknown. Recent evidence suggests that in many cases it may be a direct consequence of PMF, rather than simply reflecting individual aging. Glomerulopathy, in fact, can be observed in PMF, presenting with mesangial proliferation and hypercellularity, likely as a consequence of abnormal cytokine expression, and case reports show that the use of ruxolitinib may improve its outcome. Methods. We performed a retrospective analysis of 100 patients with previously untreated PMF, receiving frontline treatment with single agent ruxolitinib at our institution between 07/2004 and 11/2013. Creatinine clearance (CrCl) values were calculated by Cockcroft-Gault equation at baseline and serially during treatment. Renal improvement was defined as best percentage change in CrCl during treatment as compared to baseline value. A group of 105 patients with PMF, receiving frontline treatment with a non-ruxolitinib-based therapy on protocol during the same time range, and matched by age, sex and CrCl, was used as control. Results. Baseline characteristics of 100 patients with previously untreated PMF receiving frontline ruxolitinib are shown in the Table. Eighty-one (81%) patients in the ruxolitinib group had an increase in CrCl while on treatment (as compared to baseline) vs 61 (58%) in the control group (p<0.001). A renal improvement (RI) ≥ 10% was achieved in 73 (73%) patients in the ruxolitinib group and 52 (50%) patients in the control group (p=0.01), after a median time of 11 and 7 months, respectively (p=0.32)(Figure). A RI ≥ 25% was achieved in a small population sample (33% and 23%, respectively). The association between baseline patient characteristics and achievement of a RI ≥ 10% was evaluated among all patients. On univariate analysis (UVA), factors associated with a RI ≥ 10% were non-Caucasian race (99% vs 88%, p=0.006), elevated baseline serum creatinine (1 mg/dL vs 0.9 mg/dL, p=0.05), low baseline CrCl (66 ml/min vs 78 mL/min, p<0.001) and use of a JAKi (58% vs 34%, p=0.001). On multivariate analysis (MVA), use of a JAKi maintained its independent association with a RI ≥ 10% (odd ratio 3, 95% confidence interval [CI] 1.6-5.5, p <0.001). After a median follow-up of 41 months (range, 1-159 months), all patients failed frontline treatment, and median failure-free survival (FFS) was 14 months (range, 1-117 months). Factors associated with prolonged FFS on UVA were intermediate-1 DIPSS plus score as compared to intermediate-2 and high score (53 months vs 24 months and 6 months, p<0.001), use of ruxolitinib (39 months vs 6 months, p<0.001) and achievement of a RI ≥ 10% (24 months vs 8 months, p=0.01). Achievement of a RI ≥ 10% maintained its independent association with prolonged FFS on MVA (hazard ratio 1.4, 95% CI 1.1-2, p=0.02). Discussion This is the first study showing that the use of ruxolitinib is associated with improved renal function in patients with PMF. Similarly to what is done in other hematological malignancies, routine kidney biopsies in patients with PMF and unexplained renal dysfunction may shed light on its etiology and help assess the efficacy on ruxolitinib for the treatment of PMF-related glomerulopathy. Figure. Figure. Disclosures Verstovsek: Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Safety of Deferasirox (Exjade®) in Myelodysplastic Syndromes (MDS) and Non-MDS Patients with Transfusional Iron Overload: A Pooled Analysis Focusing On Renal Function.

Blood ◽

10.1182/blood.v114.22.1768.1768 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1768-1768 ◽

Cited By ~ 6

Author(s):

Mathias Schmid ◽

M. Domenica Cappellini ◽

John B. Porter ◽

Peter L. Greenberg ◽

Tomasz Lawniczek ◽

...

Keyword(s):

Renal Function ◽

Abdominal Pain ◽

Renal Dysfunction ◽

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Pooled Analysis ◽

Advanced Age ◽

Advisory Committees ◽

Starting Dose

Abstract Abstract 1768 Poster Board I-794 Background Assessment of the safety profile, in particular renal function, of the oral iron chelator deferasirox (Exjade®) is of particular relevance in MDS patients (pts), given their advanced age and associated decline in renal function. This 1-yr pooled analysis characterizes the safety profile of deferasirox in a large population of MDS and non-MDS pts (β-thalassemia [β-thal] and other anemias [sickle cell, Diamond-Blackfan, aplastic and other]), with emphasis on renal function. Methods Analysis is based on 1-yr pooled data from iron-overloaded pts who were enrolled in five open-label deferasirox studies: US02 and US03 (single-arm (SA), Low/Int 1 MDS pts, starting dose 20 mg/kg/day); 2409 (SA, pts with transfusional hemosiderosis, starting dose 20 mg/kg/day); 107 (randomized trial in β-thal pts, dosing 5–40 mg/kg/day) and 108 (SA, pts with chronic anemias, dosing 5–40 mg/kg/day). Datasets pooled: baseline (BL) characteristics, dosing, transfusion, adverse events (AEs) and laboratory data. Results 1798 pts were assessed (951 β-thal; 584 MDS, 263 other). MDS pts were older (median age 71 yrs) compared with those with β-thal (25 yrs) and other anemias (38 yrs). Mean actual dose of deferasirox (mg/kg/day): β-thal pts 23.5; MDS pts 20.3; other 19.9. Mean transfusional iron intake (mg/kg/day): 0.34, 0.32 and 0.23 in β-thal, MDS and other anemias, respectively. At 1 yr, 88%, 53% and 69% of β-thal, MDS and other pts remained in the study, respectively. Most frequent reasons for discontinuation: AEs (n=42 [4%] β-thal; n=115 [20%] MDS; n=34 [13%] other anemias). Frequency of drug-related AEs was similar for MDS (68%) and other anemias (63%) compared with 49% for β-thal. Most common drug-related AEs in β-thal, MDS and others, respectively, were: diarrhea (11%; 37%; 23%), nausea (7%; 15%; 20%), vomiting (3%; 8%; 8%); rash (11%; 8%; 6%); abdominal pain (6%; 7%; 8%) and upper abdominal pain (4%; 5%; 8%). 64 deaths occurred (none assessed as related to deferasirox by the investigator); 4 (primarily cardiac), 47 (primarily infections, hemorrhages, progression to AML, cardiac events) and 13 (primarily infections) in the β-thal, MDS and other pts, respectively. BL versus last available creatinine clearance (CrCl) were analyzed graphically for MDS pts with/without investigator-reported renal dysfunction AEs (Figure). CrCl for the majority of β-thal and non-MDS pts was >60 mL/min at BL (not shown), while in the MDS group, as expected, there were more pts with CrCl <60 mL/min and reported renal dysfunction AEs (Fig. A). To evaluate pts with BL CrCl <60 mL/min, an expanded view was created (Fig. B). A greater proportion of MDS pts with renal AEs was reported in the 20–<30 mL/min (43%) and 30–<40 mL/min category (30%), versus the 40–<50 mL/min (13%) and 50–<60 mL/min categories (7%). Exploratory logistic regression modeling confirmed odds of reporting a renal dysfunction AE were 4 and 22 times for pts with CrCl 40–<60 mL/min and <40 mL/min, respectively, compared to pts with CrCl ≥60 mL/min. Pts with BL CrCl <40 mL/min (n=6) were >70 yrs with primarily pre-existing chronic renal insufficiency, diabetes, hypertension and congestive heart failure. Pts with BL CrCl 40–60 mL/min had fewer pre-existing conditions, but still had reported renal dysfunction AEs. In about half of cases with BL CrCl <60 mL/min, reported renal dysfunction AEs were not associated with a clinically significant increase in SCr and corresponding CrCl decline, consistent with investigators' discretion in reporting. Conclusions This comprehensive assessment of MDS and non-MDS pts with transfusional iron overload confirmed the known safety profile of deferasirox; with the most frequent drug-related AEs reported as gastrointestinal events. The findings were also consistent with the clinical features of MDS such as advanced age and co-morbidities. Pts with BL CrCl <40 mL/min were more likely to report renal dysfunction AEs and less likely to be able to compensate for additional stresses on their existing decreased renal function, given their pre-existing co-morbidities and advanced age. Deferasirox may be used in pts with BL CrCl 40–<60 mL/min with close monitoring, and should not be used in pts with BL CrCl <40 mL/min. Disclosures Cappellini: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Greenberg:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lawniczek:Novartis Pharma AG: Employment. Glaser:Novartis Pharma AG: Employment. Dong:Novartis Pharmaceuticals: Employment. Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials.

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Nephrotoxicity and its prevention by catechin in ferric nitrilotriacetate promoted oxidative stress in rats

Human & Experimental Toxicology ◽

10.1191/0960327104ht427oa ◽

2004 ◽

Vol 23 (3) ◽

pp. 137-143 ◽

Cited By ~ 6

Author(s):

Kanwaljit Chopra ◽

Devinder Singh ◽

Vikas Chander

Keyword(s):

Oxidative Stress ◽

Renal Function ◽

Renal Dysfunction ◽

Thiobarbituric Acid ◽

Control Group ◽

Morphological Alterations ◽

Group Iii ◽

Ferric Nitrilotriacetate ◽

Group I ◽

Rats And Mice

Intraperitoneal injection of ferric nitrilotriacetate (Fe-NTA) to rats and mice results in iron-induced free radical injury and cancer in kidneys. This study was designed to investigate the effect of catechin, a bioflavonoid with antioxidant potential, on Fe-NTA-induced nephrotoxicity in rats. Four groups were employed in the present study. Group I served as control group, Group II animals received Fe-NTA (8 mg iron/kg body weight i.p.), Group III animals were given 40 mg/kg catechin p.o. twice a day for 4 days and on the 5th day Fe-NTA was challenged, and Group IV animals received catechin alone for 4 days. Renal function was assessed by measuring plasma creatinine and blood urea nitrogen. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, glutathione reductase and superoxide dismutase. One hour after a single intraperitoneal (i.p.) injection of Fe-NTA (8 mg iron/kg), a marked deterioration of renal architecture, renal function and severe oxidative stress was observed. Pretreatment of animals with catechin markedly attenuated renal dysfunction, reduced elevated thiobarbituric acid reacting substances (TBARS), restored the depleted renal antioxidant enzymes and normalized the renal morphological alterations. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of catechin on Fe-NTA-induced nephrotoxicity in rats.

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Prediction of renal dysfunction in patients with obstructive icterus

Medicinski pregled ◽

10.2298/mpns1110503r ◽

2011 ◽

Vol 64 (9-10) ◽

pp. 503-506 ◽

Cited By ~ 1

Author(s):

Suzana Raicevic-Sibinovic ◽

Aleksandar Nagorni ◽

Vesna Brzacki ◽

Mirjana Radisavljevic

Keyword(s):

Renal Function ◽

Renal Dysfunction ◽

Concentration Index ◽

Surgical Intervention ◽

Urine Osmolality ◽

Sodium Concentration ◽

Control Group ◽

Osmotic Concentration ◽

Creatinine Concentration ◽

Urinary Osmolality

Introduction. Renal dysfunction is one of complications in patients with obstructive icterus. It is important to recognize it early and take adequate measure to prevent its occurrence. One third of the patients with obstructive icterus have deterioration of renal function before surgical intervention. The aim of the research was to assess the renal dysfunction markers in patients with obstructive icterus. The following factors were examined: diuresis, urinary sodium concentration, sodium excretory fraction, urine osmolality, osmotic concentration index, creatinine concentration index and renal index of lesion. Material and methods. The study included 85 patients with obstructive icterus (50 patients before surgical intervention and 35 after surgical intervention) and 30 patients without icterus as a control group. The patients with normal renal function before the development of the disease were included. Results. Malignant etiology was present in 39 patients and benign in 46 patients of the examined group. The evaluation parameters of renal function were examined in all of the patients. Creatinine concentration index led to the greatest change in the coefficient value of an internal consistency, showing that it was the best renal function marker in the examined group of patients with icterus. The next one was the urinary osmolality, since its exclusion would lead to a decrease in the value of Cronbach ? coefficient to 0.06. Icterus and surgical intervention show statistically significant effects to change in the value of the markers of laboratory differentiation of renal function, observed as an entire set. Discussion and conclusion. The examination showed that the concentration clearances of creatinine and urine osmolality are the parameters which point to the probability of renal dysfunction occurrence in obstructive icterus.

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Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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Management of Secondary Prevention in Venous Thromboembolism: Use of Reduced Doses of Rivaroxaban and Apixaban in Extended Therapy

Blood ◽

10.1182/blood-2020-141908 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-17

Author(s):

Desiree Campoy ◽

Katia Flores ◽

Gonzalo Artaza ◽

César A Velasquez ◽

Tania Canals ◽

...

Keyword(s):

Venous Thromboembolism ◽

Secondary Prevention ◽

Board Of Directors ◽

Dose Reduction ◽

Standard Dose ◽

Control Group ◽

Advisory Committees ◽

The Mean ◽

D Dimer

BACKGROUND After a standard anticoagulation period (3-6 months), the risk of venous thromboembolism recurrence (RVTER) needs to be considered. Such risk is higher in unprovoked events and patients with persistent risk factor. The increase of D-dimer (DD) levels during the therapy seems to be strongly associated to RVTER. The use of rivaroxaban 10 mg/day and apixaban 2.5mg/12h as an extended therapy (ET) after the standard anticoagulation period has been proven to be an effective strategy to prevent recurrence without increasing bleeding events. AIM To assess the effectiveness and safety of reduced doses of rivaroxaban and apixaban as ET in patients with RVTER and to compare their DD levels with those of a control group on anticoagulant therapy at a standard dose. METHODS From April 2016 to June 2020, we included patients with venous thromboembolism (VTE) who received ET with rivaroxaban and apixaban with/at reduced doses. Dose reduction was performed following the clinical algorithm of our unit (Fig. 1). The DD values were determined using HemosIl D-Dimer HS-500 and the cut-off value was established at 500 µg/L DD levels were compared with a control group of 235 patients with VTE who received ET with standard doses of anticoagulation. DD levels were measured at the time of diagnosis (D1), initiation of treatment (D2) and 3 months after treatment (D3). RESULTS From a total of 116 patients (65.5% women), 77.6% (n=90) received rivaroxaban 10 mg/24h and 22.4% received apixaban 2.5 mg/12h as an ET. The mean duration of the initial anticoagulant therapy was 12 +/- 8.8 months. The mean DD value prior to the ET was 388 µg/L. In this group, 63.8% (n=74) was an unprovoked VTE and 17.2% (20) had hereditary thrombophilia. The mean of follow-up time was 6.9 +/- 8.3 months. No recurrences of VTE were observed during the follow-up and only one major bleeding event was reported in a high-bleeding risk patient. We observed a progressive decrease of DD levels from the VTE diagnosis to the last visit, with D1, D2, and D3 values of 987 µg/L ± 324, 388 µg/L ± 134, and 288 µg/L ± 98, respectively. There were no differences in d-dimer concentrations between patients with reduce doses of rivaroxaban or apixaban and the control group with standard doses (D1: 85.6% vs 81%, p =0.22; D2: 10.2% vs 8.0%, p =0.14; and D3: 9.1% vs 9.5%, p =0.18). CONCLUSIONS Our data indicated that an ET strategy with reduced doses of rivaroxaban or apixaban is effective and safe. We did not observe significant differences in DD levels at follow-up compared to the control group receiving a standard dose of anticoagulation. Further studies are needed in order to select and standardize dose reduction criteria in secondary prevention. Figure 1 Disclosures Campoy: boehringer ingelheim: Consultancy; Daiichi Sankyo: Speakers Bureau. Sierra:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Olivera:Daiichi Sankyo: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BAYER: Consultancy.

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Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-124727 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3816-3816 ◽

Cited By ~ 2

Author(s):

Ryan J. Daley ◽

Sridevi Rajeeve ◽

Charlene C. Kabel ◽

Jeremy J. Pappacena ◽

Sarah E. Stump ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Hypersensitivity Reactions ◽

Newly Diagnosed ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Frontline Treatment

Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a >10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p<0.001) compared to those regimens that included PEG-ASP during induction (pediatric/pediatric-inspired regimens) (Table 2). Younger age (40-59 vs. ≥60 years) was associated with a greater risk of hypertriglyceridemia (p<0.001) and higher PEG-ASP dose (≥2000 vs. <2000 units/m2) was associated with a greater risk of hypertriglyceridemia and hypofibrinogenemia (p=0.002 and p=0.025, respectively). Thirty-eight pts (63%) received all intended doses of PEG-ASP. Six pts stopped PEG-ASP to proceed to allogeneic hematopoietic stem cell transplantation (5 in CR1, 1 in CR2), and 7 pts stopped for hypersensitivity reactions. Hepatotoxicity was the only ASP-related toxicity that led to PEG-ASP discontinuation occurring in 5 pts (hyperbilirubinemia, N=4; transaminitis, N=1). The total number of intended doses of PEG-ASP based on regimens used was 186, and 112 were administered. Conclusion: PEG-ASP was incorporated into the treatment of 60 adult ALL pts age ≥40, with manageable toxicity. Seven pts discontinued PEG-ASP due to hypersensitivity reactions and 5 discontinued due to hepatotoxicity, but other reported toxicities did not lead to PEG-ASP discontinuation and the majority of the pts completed all intended doses of PEG-ASP. This study suggests that with careful monitoring, PEG-ASP can safely be administered in adults ≥40 years of age. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Tallman:UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Takeda: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy.

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Treating Acute Leukemia during the COVID-19 Pandemic: A Multicenter Latin American Registry

Blood ◽

10.1182/blood-2020-139018 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Roberta Demichelis ◽

Martha Alvarado ◽

Jule F Vasquez ◽

Nancy Delgado ◽

Cynthia Gómez ◽

...

Keyword(s):

High Risk ◽

Maintenance Therapy ◽

Acute Leukemia ◽

Board Of Directors ◽

Latin American ◽

Refractory Disease ◽

Newly Diagnosed ◽

Advisory Committees ◽

Factors Associated ◽

Latin American Countries

Introduction The COVID-19 pandemic has affected the entire world. Health systems have been affected in such a way that patients with diseases other than COVID-19 have suffered serious consequences. In Latin America, the disease has emerged in a fragile system with more disparities, making our patients more vulnerable. Acute leukemia patients have a high risk of severe COVID-19 disease. Various expert recommendations have emerged with the aim of minimizing the risk of COVID-19 without affecting leukemia-related outcomes. However, multiple logistical issues tangentially associated with the pandemic have also appeared, potentially limiting the quality of management of these patients. The objective of this study was to register treatment modifications associated with the COVID-19 pandemic and its short-term consequences in Latin American countries. Methods We included patients older than 14 years, from 14 centers of 4 Latin American countries (Mexico, Peru, Guatemala and Panama), with the diagnosis of acute leukemia, who were on active treatment since the first case of COVID-19 was documented in each country. We documented their baseline characteristics and followed the patients prospectively until July 15, were data-cutoff for this pre-planned analysis was performed. The primary outcome was the incidence of COVID-19 disease and its complications. Secondary outcomes included treatment and consult modifications, and cause of death during the study period. Logistic regression was performed to determine factors associated with COVID-19 and all-cause mortality. Results We recorded the information of 635 patients: 58.1% Ph-negative ALL, 25.7% AML, 9% APL and 7.2% Ph+ALL. The median age was 35 years (14-90 years); 58.8% were consideredf high-risk patients. The majority were on CR (68.3%) receiving consolidation or maintenance therapy, while 14.5% were newly diagnosed and 17.2% with relapsed/refractory disease. The majority (91.8%) were treated in centers that were also receiving COVID-19 patients, 40.2% in centers were patients could not be electively hospitalized for leukemia treatment because of the COVID-19 pandemic. The COVID-pandemic led to treatment-modifications in 40.8% of the cases. Reasons for modifications were associated with logistical issues (22.4%), medical decisions (15.1%) or patient choice (3.3%). The most frequent modification was chemotherapy delay (17.3%) followed by regimen modification (13.4%) and dose-reductions (10.1%). (Figure 1) 83 patients (13.1%) developed COVID-19 disease, the majority mild-moderate disease (54.2%), 27.7% severe disease and 18.1% critically ill; 27.7% required mechanical ventilation and 37.7% died from COVID-19 disease, representing 4.9% of the entire cohort. We identify as risk factors for COVID-19 disease the presence of active leukemia (newly diagnosed or relapsed) (OR 3.46 [95% CI: 2.16-5.5], p<0.001), high-risk leukemia (OR 1.63 [95% CI: 1.54-4.52], p<0.001) and being treated in a center were elective hospitalization was possible (OR 2.17 [95% CI 1.29-3.67], p=0.004). Treatment modifications, appointment prolongations or the use of virtual consultation were not associated with a reduction in the risk of COVID-19. On the other hand, 16.7% of patients died during period analyzed due to leukemia (57.5%), COVID-19 (29.2%) or treatment related-mortality (13.2%). Independent factors associated with mortality were AML vs. ALL (OR 1.89 [95% CI: 1.12-3.18], p=0.016), relapsed-refractory disease (OR 8.34 [95% CI: 4.83-14.41], p<0.001), induction/consolidation vs. maintenance therapy (OR 2.20 [95% CI: 1.25-3.18], p<0.001) and the use of virtual consultation (OR 0.35 [95% CI: 0.13-0.94] p=0.037). (Table 1) Discussion/Conclusions The COVID-19 pandemic led to significant modifications in the standard of care treatment of patients with acute leukemia. The incidence of COVID-19 disease in acute leukemia patients was considerable and more than a third of the patients with acute leukemia and COVID-19 disease died. Despite a short-follow up, 16.7% of the patients died and leukemia-related deaths were the most frequent. In low- and middle-income countries with fragile health systems, the collateral damage for patients with acute leukemia may be just as important as the direct consequences of COVID-19. Disclosures Alvarado: Roche: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Alexion: Speakers Bureau. De la Peña-Celaya:Amgen: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau. Perez:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Gomez-Almaguer:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-136370 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Brian T. Hill ◽

Deepa Jagadeesh ◽

Alex V. Mejia Garcia ◽

Robert M. Dean ◽

Omer N. Koc ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Proteasome Inhibitors ◽

Marginal Zone Lymphoma ◽

Aggressive Lymphoma ◽

Advisory Committees ◽

Frontline Treatment

INTRODUCTION: Lenalidomide and Rituximab (R2) is an effective frontline treatment regimen for patients (pts) with indolent B-cell lymphoma including follicular lymphoma (FL). Recent phase III data from the RELEVANCE trial comparing R2 to traditional chemoimmunotherapy showed that this regimen is generally well-tolerated and has favorable clinical efficacy [61% overall response, 53% CR rate, 77% 3-year progression free survival (PFS) (Morschhauser, et al)]. Proteasome inhibitors such as bortezomib disrupt NF-KB signaling and have shown clinical activity in indolent NHL. Although randomized trials have failed to demonstrate clinical benefit of adding bortezomib to standard chemoimmunotherapy regimen bendamustine + rituximab (BR) for frontline treatment of FL, the addition of proteasome inhibitors to lenalidomide is a mainstay of treatment for plasma cell neoplasms due to synergistic antitumor effect. The oral proteasome inhibitor ixazomib has less potential for dose-limiting neuropathy than bortezomib, making it an attractive option to incorporate into the R2 regimen. We sought to investigate the safety and efficacy of the addition of ixazomib to R2 for FL and indolent B-cell NHL through a phase I clinical trial of this combination for patients with high risk disease. METHODS: Adult (age ≥ 18) pts with untreated FL or other indolent lymphoma, adequate organ function and performance status were enrolled. To be enrolled, FL patients were required to have stage 2, 3 or 4 disease, with high tumor burden by GELF criteria and/or FLIPI score of 3-5. During 3 x 3 dose escalation, ixazomib was given at a dose of 2 mg (n=3), 3 mg (n=3) or 4 mg (n=12) PO on days 1, 8, and 15 with lenalidomide 20 mg PO on days 1-21 every 28 days. Rituximab was administered at standard dosing on days 1,8,15,21 for cycle 1, once every 28 days for cycles 2-6 and then once every 2 months for cycles 7-12. Treatment was continued for 12 cycles and no maintenance therapy was specified per protocol. All pts received low dose aspirin for venous thromboembolism prophylaxis and acyclovir for prevention of VZV reactivation. Response assessments by CT were performed after cycle 3 and 6 and by PET/CT at the end-of-treatment (cycle 12). RESULTS: 20 pts were enrolled and 18 were eligible for treatment [15 FL (14 grade 1-2, 1 grade 3A), 2 splenic marginal zone lymphoma and 1 nodal marginal zone lymphoma].The median age of treated pts was 61 (range 40-83) years old. 55% of patients were female. Stage at diagnosis was II (n =2), III (n = 4) and IV (n = 12). For FL pts, FLIPI scores at enrollment were low (n=2), intermediate (n = 5) and high risk (n=8) and FLIPI-2 scores were low (n=3), intermediate (n = 2) and high risk (n=10). There were no dose limiting toxicities during 3 x 3 dose escalation. Grade (G) 1/2 and G3/4 treatment-related hematologic adverse events (AEs) included neutropenia (6%, 28%), thrombocytopenia (16.7%, 5.6%) and anemia (16.7%, 0%). The most common treatment-related AEs included nausea/vomiting (44% G1, 11% G2), diarrhea, (50% G1, 22% G2, 5% G3), rash (33% G1, 6% G2, 11%G3), peripheral neuropathy (22% G1, 6% G2), myalgia/arthralgia (17% G1, 17% G2), and infection (33% G2, 17% G3). There was one pulmonary embolism and no cases of febrile neutropenia. As of June, 2020, median follow-up among living pts was 21 months. 4 pts discontinued treatment due to disease progression; 2 with transformation to aggressive lymphoma. Of the transformed cases, one subject died on study due to progression disease and one developed CNS disease on study treatment but proceeded to autologous stem cell transplant. The best overall response rate was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. 18-month Kaplan-Meier estimates of PFS and overall survival were 71% and 94%, respectively (Figure). CONCLUSION: R2 can safely be combined with at the target dose of 4 mg of ixazomib for treatment-naïve indolent NHL patients. Non-hematologic AEs were generally consistent with known toxicity of each component of therapy. CR rate and PFS were was similar to the outcomes reported in the RELEVANCE trial despite enrolling high risk patient. R2 may serve as backbone for future studies of novel treatment combinations for high risk FL after thorough evaluation for occult transformation to aggressive lymphoma. Disclosures Hill: Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jagadeesh:MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Smith:Takeda: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Ixazomib is off-label for treatment of NHL

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Are Racial Disparities in Acute Myeloid Leukemia (AML) Clinical Trial Enrollment Associated with Comorbidities and/or Organ Dysfunction?

Blood ◽

10.1182/blood-2019-129096 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 381-381

Author(s):

Abby Statler ◽

Brian P. Hobbs ◽

Tomas Radivoyevitch ◽

Sudipto Mukherjee ◽

Kimberly Bell ◽

...

Keyword(s):

Renal Function ◽

Racial Disparities ◽

Board Of Directors ◽

Organ Dysfunction ◽

Research Funding ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Eligibility Criteria ◽

Advisory Committees ◽

Laboratory Values

Background: Minority patient (pt) populations are underrepresented in clinical trials and the proportion of such pts accrued to cancer studies has decreased, specifically among African Americans (AA) (Kwiatkowski et al. Cancer 2013). If minority pt populations have higher rates of comorbidities, restrictive eligibility criteria may contribute to systematic exclusion from studies. To explore the validity of this potential bias within AML pts, we characterized the comorbidity profile and compared outcomes between AA and white pts with AML. Methods: Adult (≥18 years) AML pts who received chemotherapy at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic/renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Organ dysfunction was defined as ≥ grade 1 per the Common Terminology for Adverse Events. Fisher's exact and Welch's t-tests were performed to compare baseline characteristics. Multivariable logistic and Cox regression analyses were used to identify prognostic factors for response status per International Working Group criteria, and overall survival (OS). Kaplan-Meier method and log-rank test were used to estimate and evaluate OS, respectively. Results: Of 1,040 AML pts included, 939 (90.3%) identified as white and 101 (9.7%) as AA. Age, AML etiology, and AML risk were balanced between the two groups. Insurance coverage was different by race: AAs were more likely than whites to have Medicaid (11.9% vs. 5.1%), and less likely to have private insurance (16.8% vs. 34.6%), P<.001. Pts were treated with the following: 868 (83.5%) with intensive, cytarabine-based, and 172 (16.5%) with non-intensive (low-dose cytarabine or hypomethylating agents) regimens. AA pts were just as likely as whites to receive intensive therapy (P=.68) (Table 1). AA pts presented with similar frequencies of both overall and specific comorbidities. Liver function laboratory values (AST/ALT/bilirubin) and cardiac test results (QTc/LVEF) at baseline were also similar; however, a greater proportion of AAs presented with renal dysfunction when compared to whites, as measured by creatinine (48.5% vs. 36.5%, P=.01) or creatinine clearance by Cockcroft-Gault (CrCl; 55.4% vs. 47.3%, P=.01; Table 2). With a median follow-up of 12.73 months (IQR: 4.59-43.05), the OS for the cohort was 14.75 months (range: 0.03-189.25). Median OS did not differ by race (AA vs. whites: 13.7 vs. 14.9 months, P=.89). Overall, the complete response (CR) rate was 44.2%, which also did not differ by race: (AA vs. whites: 37.6% vs. 44.9%, P=.19). When adjusting for other known predictors, in a multivariable analysis, there was no difference in OS between AAs and whites (HR=1.20, P=.16); additionally, there was no association between comorbidities/organ dysfunction and OS, with the exception of liver comorbidities (HR=2.03, P=.002) and bilirubin (>1.5 x ULN vs. normal: HR= 1.69, P=.01). Clinically insignificant creatinine (>ULN - 1.5 x ULN vs. normal: HR= 0.99, P=.97) and CrCl (84-60 ml/min vs. normal: HR=0.96, P=.69) abnormalities were not independently associated with OS. Subgroup analyses by race revealed similar results for AAs, although, there were no differences in OS based upon bilirubin. With the exception of liver comorbidities (OR= 0.17, P=.01), our analysis failed to identify significant evidence of association between response and comorbidities/organ dysfunction (similar results within the AA subgroup). Although AA were less likely to achieve a CR (AA vs. whites: OR=0.56, P=.05), there was no association between response and creatinine/CrCl abnormalities, regardless of severity. Conclusions: Within this cohort, renal function eligibility criteria may be an important barrier to enrollment, specifically within the AA population. Since there is no association between clinically insignificant renal laboratory values and OS or response, the liberalization of such criterion may be justified. Future trials that broaden the renal function eligibility criterion have the potential to accrue more diverse pt populations, which may reduce recruitment racial disparities and improve the generalizability of the trials' results. Disclosures Hobbs: Amgen: Research Funding; SimulStat Inc.: Consultancy. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Gerds:CTI Biopharma: Consultancy, Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; Imago Biosciences: Research Funding. Nazha:Daiichi Sankyo: Consultancy; Incyte: Speakers Bureau; Jazz Pharmacutical: Research Funding; Abbvie: Consultancy; Tolero, Karyopharma: Honoraria; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.

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A Randomized Phase 2 Trial of Bortezomib–Dexamethasone Versus Bortezomib–Dexamethasone with Added Cyclophosphamide or Lenalidomide in Multiple Myeloma Patients Achieving Stable Disease After Four Cycles of Bortezomib–Dexamethasone Administered as Second-Line Treatment.

Blood ◽

10.1182/blood.v114.22.4937.4937 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4937-4937

Author(s):

Meletios A. Dimopoulos ◽

Huw Roddie ◽

Meral Beksac ◽

Lotfi Benboubker ◽

Romualdas Jurgutis ◽

...

Keyword(s):

Renal Function ◽

Board Of Directors ◽

Research Funding ◽

Safety Data ◽

Phase 2 ◽

Advisory Committees ◽

Ortho Biotech ◽

Function Group ◽

Grade 3 ◽

Renal Function Group

Abstract Abstract 4937 Bortezomib (Velcade®) plus dexamethasone (Vel/Dex) is known to be effective and well tolerated in patients with multiple myeloma (MM). As demonstrated in the frontline setting, the addition to Vel/Dex of cyclophosphamide (VCD) or lenalidomide (Revlimid®; VRD) may lead to improved efficacy, but may be associated with increased toxicities; however, few studies have prospectively assessed Vel/Dex as second-line therapy. This randomized, open-label, parallel-group, phase 2 study in patients who have relapsed after or are refractory to primary MM therapy is designed to evaluate the safety and efficacy of an additional 4 cycles of Vel/Dex, VCD, or VDR in patients achieving stable disease (SD) after 4 cycles of Vel/Dex. Bortezomib-naïve patients aged ≥18 years, with measurable MM, KPS ≥60, life expectancy ≥6 months, adequate hematologic and hepatic function, and without grade ≥2 peripheral neuropathy (PN) received 4 3-week cycles of Vel/Dex (Vel 1.3 mg/m2 IV on days 1, 4, 8, and 11, and Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12). Patients then received a further 4 cycles of therapy as follows: patients achieving at least a partial response (PR) received Vel/Dex; patients with SD underwent central randomization to receive Vel/Dex, VCD, or VRD; patients with progressive disease (PD) discontinued treatment. Here we report efficacy and renal function improvement in patients who had the opportunity to complete the initial 4 cycles of Vel/Dex as of April 2009, and safety data for patients who received at least 1 dose of study drug. Response was assessed by IMWG uniform response criteria based on measurement of serum and urine M-protein prior to treatment on day 1 of each cycle, at end of treatment, and monthly thereafter. Renal function as defined by calculated glomerular filtration rate (GFR; Cockcroft–Gault formula) was assessed prior to treatment on day 1 of cycles 1–5. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 122 patients have been enrolled; by data cut-off (July 21 2009), 24 (20%) had not completed a single treatment cycle and are excluded from the safety population (N=98). Eighteen had received <4 cycles at data cut-off. Of the remaining 80 who were eligible for response, 63 had completed 4 cycles, 6 discontinued prior to completing 4 cycles (due to PD in 3 patients, death in 1, drug-related AEs in 2), 9 were not under treatment at data cut-off, and 2 had died. Their median age was 62 years (range 34–86), 55% were male, 21.3% had KPS ≤70; median time from prior therapy was 18.6 months. Response rate in the efficacy population was 41/80 (51%) after 4 cycles, including 8% CR. Median times to first and best response were 37 and 57 days, respectively. Patient renal function (by GFR) at baseline, median improvement in GFR, and responses achieved by the 10 patients in whom GFR improved by at least one renal function group are shown in the Table. Among the 98 patients who received at least one treatment dose, mean cumulative doses of bortezomib and dexamethasone were 14.6 mg/m2 (4.9, 4.5, 4.4, and 4.3 mg/m2 in cycles 1–4) and 478 mg (151.8, 145.6, 145.4, and 144.0 mg for cycles 1–4), respectively. Most patients (90%) reported AEs, including 39% with grade 3/4 AEs and 23% with serious AEs, within the first 4 cycles. The most common grade 3/4 AEs included thrombocytopenia (13%), anemia (7%), and pneumonia (6%). AEs resulting in dose reductions/treatment stop were seen in 21%/10% of patients. Incidence of sensory PN and PN was 29% (3% grade 3/4); most PN events were reversible, with 68% resolving within a median 53 days. Updated efficacy and safety data for the first 4 cycles of Vel/Dex for all patients enrolled by July 31 will be presented. Table: Improvement in renal function (as measured by GFR)* Renal function group at baseline, n† <15 mL/min 3 15–<30 mL/min 6 30–<60 mL/min 33 ≥60 mL/min 36 Median GFR (median improvement from previous cycle), mL/min At baseline 58.3 After cycle 1 64.4 (4.8) After cycle 2 68.9 (2.9) After cycle 3 68.6 (9.9) After cycle 4 73.5 (9.4) Renal improvement by at least 1 grade, n (response achieved) 10 <15 to 15–<30 mL/min 1 (1 CR) 15–<30 to 30–<60 mL/min 1 (1 PR) 30–<60 to ≥60 mL/min 8 (2 CR, 1 VGPR, 3 PR, 2 SD) * 1 patient only had a baseline GFR measurement and was not included in the renal analysis † 1 patient had no baseline GFR measurement Disclosures Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Beksac:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Langer:Celgene: Consultancy; Ortho Biotech: Consultancy. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees.

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