Growth Differentiation Factor-15 (GDF-15) Is a New Biomarker with Independent Prognostic Significance for Survival and Renal Outcomes in Different Cohorts of Patients with Light Chain (AL) Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 648-648 ◽  
Author(s):  
Efstathios Kastritis ◽  
Giampaolo Merlini ◽  
Ioannis Papassotiriou ◽  
Paolo Milani ◽  
Evangelos Terpos ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Value ◽  
Prognostic Significance ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Growth Differentiation Factor 15 ◽  
Renal Outcomes ◽  
Independent Prognostic Significance ◽  
Stage 1

Abstract Growth differentiation factor-15 (GDF-15), a member of TGF-beta family, is involved in several pathological conditions, which include inflammation, cancer, cardiovascular, pulmonary and renal diseases. Serum GDF-15 levels add prognostic information to conventional prognostic factors, such as NT-proBNP and troponins, in cardiovascular disorders and also have shown to be associated with renal damage and risk of end stage renal disease in patients with diabetes. Based on the above data, we evaluated the prognostic value of GDF-15 levels in patients with AL amyloidosis and showed that in a cohort of 77 patients GDF-15 was associated with early death, shorter survival and progression to dialysis, independently of the cardiac biomarkers and renal stage. In order to validate the prognostic value of serum levels of GDF-15, we evaluated GDF-15 in two independent cohorts of patients treated in two different centers (Pavia Amyloidosis Center and Department of Clinical Therapeutics, Athens). Circulating levels of GDF-15 were measured by a novel pre-commercial immunoassay (Roche Diagnostics) in stored serum. The Pavia cohort included 202 and the Athens cohort included 107 patients with AL amyloidosis. Standard criteria were used for the diagnosis, evaluation of organ involvement and cardiobiomarker-based risk stratification. Renal staging was based on the system proposed by Palladini et al, based on baseline proteinuria >5 gr/day and eGFR <50 ml/min. Median age and involved FC (iFLC) levels were similar between the two cohorts but there were differences in other baseline characteristics including heart involvement (77% vs 62% for Pavia vs Athens, p=0.007), Mayo stage (15%, 43% & 42% for stage 1, 2 & 3 in Pavia cohort, vs 26%, 43% & 31% in Athens cohort, p=0.04, but stage 3B was similar, 22% vs 24%). Also there were differences in peripheral nerve involvement (11% in Pavia vs 25% in Athens cohort, p=0.001). Renal involvement (67% vs 72%, p=0.415), median eGFR and renal stage distribution were similar between the two cohorts (p=0.544). Median follow up for the Pavia cohort was 18 months and for the Athens cohort was 45 months (p<0.001). Survival at 2 years was 59% for Pavia and 56% for Athens cohort. Median GDF-15 levels was 3027 pg/ml in Pavia (range 624 to >100000 pg/ml) and 3854 pg/ml (range 626-71475 pg/ml) in Athens cohort (p=0.09); the upper quartile of GDF-15 levels however was ≥5658 pg/ml for the Pavia and ≥7553 pg/ml for Athens cohort, while 90% and 94% of patients in the two cohorts had GDF-15 levels >1200 pg/ml (the upper limit of normal for individuals without cardiovascular disease). We then evaluated the prognostic significance of GDF-15 levels in the two cohorts by applying the previously identified cutoff of 7575 pg/ml. GDF-15 above cutoff was associated with significantly shorter survival both in Pavia (17 months vs not reached, p=0.003) and in Athens cohort (13 vs 47 months, p=0.03) (Figure 1). A multivariate model that included Mayo stage, separately for each cohort was applied. In both cohorts GDF-15 retained independent prognostic significance over Mayo stage, having a hazard ratio (HR) of 1.9 (95% CI 1.2-3.3, p=0.01) in Pavia cohort (the respective HRs for Mayo stage -2 vs -1 was 2.1 and for stage -3 vs stage -1 was 4); in Athens cohort HR for GDF-15 was 1.8 (95% CI 1.2-3.6, p=0.03) and the respective HRs for Mayo stage -2 vs -1 was 5.3 and for stage 3- vs stage -1 was 6.8. We then evaluated the prognostic significance regarding renal outcomes (dialysis): GDF-15 >4000 pg/ml was associated with a HR of 6 (95% CI 2015.6, p=0.001) in Athens cohort (progression to dialysis within 2 years in 7% vs 47%); however, very few events have occurred in Pavia cohort and analysis was inconclusive. Although renal stage discriminated 3 groups in univariate analysis (p=0.03), in multivariate analysis, GDF-15 >4000 pg/ml outperformed renal stage and was the only independent prognostic factor for dialysis risk. In conclusion, our study validated and confirmed in two independent cohorts, with differences in their characteristics, the prognostic value of GDF-15, which emerges as a novel biomarker with prognostic implications for different outcomes in patients with AL amyloidosis. Importantly, GDF-15 emerges also as new biomarkers for renal outcomes in patients with AL amyloidosis. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kastritis: Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria. Merlini:Takeda and Janssen-Cilag: Honoraria. Terpos:Genesis: Consultancy, Honoraria, Other: Travel expenses; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Palladini:Prothena: Honoraria.

Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL-Amyloidosis with Tolerable Neurotoxicity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 746-746 ◽  
Author(s):  
Jeffrey A Zonder ◽  
Vaishali Sanchorawala ◽  
Rachel M. Snyder ◽  
Jeffrey Matous ◽  
Howard Terebelo ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Adjustment ◽  
Response Rate ◽  
Al Amyloidosis ◽  
Two Stage ◽  
Advisory Committees ◽  
Subsequent Dose ◽  
Stage 1

Abstract Abstract 746 Introduction: Primary systemic amyloidosis (AL) is a monoclonal plasma cell disorder associated with progressive organ dysfunction and short survival. Standard therapy for patients (pts) not eligible for autologous stem cell transplant (ASCT) is melphalan (Mel; M) + dexamethasone (Dex; D). With non-ASCT therapy, the median overall survival (OS) of high-risk AL pts remains < 1 yr. After the VISTA study showed the addition of bortezomib (Bz) to Mel + Prednisone improved response rate, complete response rate, response duration, and OS in pts with myeloma, we designed this study to determine if adding Bz to MD improves outcomes in AL. Key eligibility criteria: ECOG PS ≤ 3, Cr ≤ 5 mg/dL, T.Bili ≤ 2.5 x IULN, ALT/AST ≤ 3 x IULN, ANC ≥ 1.0 K/mm3, PLT ≥ 80 K/mm3, peripheral neuropathy (PN) ≤ Gr 2 (≤ 1 if painful), no lower limit for LVEF. Study design: Two-stage Phase II study. Stage I: 16 pts with biopsy-proven AL or light chain deposition disease (LCDD). 1° endpoint: complete hematologic responses (cHR). If ≥5 cHRs observed, then 2nd stage with 17 more pts to be opened. The study has a 90% power to detect a true cHR rate of 50%. 2° endpoints include overall HR (cHR + Partial Responses (PR)), organ response (OrR), and OS. Treatment: M (9 mg/m2 PO days 1-4; 6 mg/m2 if Cr > 2.5 mg/dL), Bz (1.3 mg/m2 IV days 1, 8, 15, 22; 1.0 mg/m2 if pt has PN at baseline) and D (40 mg PO/IV days of & days after Bz; 20 mg if ≥ 70 yrs, peripheral edema, or CHF) in 4-6 wk cycles, max of 20 cycles. PN was assessed serially with the FACT/GOG-Ntx survey. Results: To date, 23 pts have been enrolled: 21 with AL; 2 with LCDD. Med age 64 (range: 47-76). Med # prior Rx: 1 (range: 0-2; 7 with ≥1 prior ASCT). Med # organs involved: 4 (range 1-6; 8 pts with ≥ 3). PS 0-1/2-3: 18/1. Response data for the 16 pts comprising stage 1 of this two-stage study are reported here; accrual of all 33 pts is expected to be complete by ASH, and results will be updated. One pt who was not response-evaluable (RE) for HR is included in toxicity data (n=17). Med # cycles MD-Bz: 4+ (range: 2-12+; 9 pts still on treatment). 15 of 16 pts had heme responses: 6 cHRs & 9 PRs. Ten RE pts had OrR (2 cardiac, 3 renal, 6 nerve, 1 lung; total >10 because some pts improved in > 1 organ). Nerve symptom improvement occurred exclusively in pts with cHR. Two pts had progressive disease (PD). Two pts died (4.5 and 9 mos from enrollment, from pneumonia and PD, respectively). Despite baseline dose adjustment for co-morbidities, 12 pts needed subsequent dose-reduction of ≥ 1 of the study meds during therapy (10 Bz, for thrombocytopenia and/or PN in almost all cases). Five pts developed neutropenia (Gr 3-4: 1), 15 pts developed thrombocytopenia (Gr 3-4: 11). Nine pts developed peripheral neuropathy (Gr 3: 2). Other grade 3-4 non-hematologic AEs seen in ≥ 2 pts included edema (5), syncope (3), SVT (2), dehydration (2), fatigue (2), and renal failure (2). One pt developed reversible cardiomyopathy (cycle 8) attributed to Bz. Calculated sensory/dysfunction (S/D) composite scores based on patient responses from the FACT/GOG-Ntx survey improved in 7 of 14 pts between cycles 1 and 4, were stable in 4 pts and worsened in only 3. On average, the S/D score accounted for 43% of each pt's total Ntx score at baseline, whereas it only accounted for 39% of the score after 4 cycles, and 45% after 8 cycles, indicating progressive disability from Bz-related PN was uncommon. As results of nerve conduction studies did not correlate well with reported symptoms or FACT/GOG-Ntx scores in stage 1 of the study, mandatory EMGs were discontinued in stage 2. Conclusions: MD-Bz shows promising activity in the treatment of AL, with 94% of pts in the first stage of this trial achieving HR (38% cHR) and evidence of OrR observed in 63%. Toxicity is manageable, but meds often require baseline or subsequent dose adjustment. A randomized study of MD +/- Bz in AL is planned. Disclosures: Zonder: Cephalon: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Millennium: Consultancy, Research Funding, Speaking CME Only, No PromotionalTalks; Celgene: Speaking CME only; no Promotional Talks. Off Label Use: Bortezomib is being used in the treatment of AL amyloidosis in this trial; it is currently approved for use as treatment of multiple myeloma.. Matous:Celgene: Honoraria, Speakers Bureau; Cephalon: Speakers Bureau. Janakiraman:Millennium: Honoraria, Research Funding. Mapara:Resolyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Membership on an entity's Board of Directors or advisory committees, My Wife: Suzanne Lentzsch, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, My wife: Suzanne Lentzsch, Research Funding; Sentium: Stocks. Gasparetto:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Prognostic Restaging at the Time of 2nd-Line Therapy in Patients with AL Amyloidosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5594-5594
Author(s):  
Yi L. Hwa ◽  
Morie A. Gertz ◽  
Shaji K. Kumar ◽  
Martha Q. Lacy ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Mayo Clinic ◽  
Initial Treatment ◽  
Research Funding ◽  
Prognostic Value ◽  
Staging System ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Line Therapy ◽  
Staging Systems

Abstract Background: It is well known that the staging stratification at diagnosis predicts survival in immunoglobulin light chain (AL) amyloidosis, but there is a paucity of literature delineating the prognostic value of these systems at the time of 2nd-line therapy. Methods: We conducted a retrospective study to evaluate the prognostic value of AL staging among 563 patients with staging data, who initiated a 2nd-line therapy between 2000 and 2015. Both the Revised Mayo 2012 staging system and the European revision of the Mayo 2004 staging system were used. Results: The median time from initial treatment to 2nd-line therapy was 11.6 months. Median follow-up from institution of 2nd-line therapy was 54.1 months. The 1st-line therapy for patients was autologous stem cell transplant (ASCT) in 216 (38%) patients; and 2) non-ASCT therapies in 347 patients. Both staging systems were prognostic with a risk ratio of 9.4 (95%CI: 6.0, 15.1; p<0.0001) between stage IIIb and I, and of 12.2(8.1, 18.5; p<0.0001) between IV and I. At the time of 2nd-line therapy the staging systems' predictive values were independent of what the patients' 1st-line therapies had been despite the fact that the median time from initial treatment to 2nd-line therapy was 19.4 months in ASCT group and 8.0 months in non-ASCT group. Among the patients receiving 2nd-line therapy after ASCT, the 5-year overall survival (OS) from 2nd-line therapy for those with ≤ stage II versus >stage II was 65% and 31% (Mayo 2004) and 70% and 23% (Mayo 2012). The respective numbers for patients relapsing from a non-ASCT therapy were 57% and 26% (Mayo 2004) and 60% and 23% (Mayo 2012). Conclusions: This study indicates that the Mayo staging systems work well at the time of instituting 2nd-line therapy and is independent of whether 1st-line therapy was ASCT based. Figure. Figure. Disclosures Gertz: annexon: Consultancy; Medscape: Consultancy; Apellis: Consultancy; celgene: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; Research to Practice: Consultancy; Teva: Consultancy; janssen: Consultancy; Alnylam: Honoraria. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

HOVON 104; Results of First 25 Patients from a Multicenter, Multinational, Prospective Phase II Study of Bortezomib Based Induction Treatment Followed By Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Al Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4628-4628 ◽  
Author(s):  
Monique Minnema ◽  
Kazem Nasserinejad ◽  
Bouke Hazenberg ◽  
Ute Hegenbart ◽  
Lucien Noens ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
De Novo ◽  
Performance Status ◽  
Induction Treatment ◽  
Al Amyloidosis ◽  
Exclusion Criteria ◽  
Advisory Committees ◽  
Stage 1

Abstract Introduction Bortezomib (B) has been reported to be very effective in AL amyloidosis with overall response rates (ORR) varying between 50-80%. However, no prospective data have been published from multicenter studies on B treatment in de novo patients. Previously, we have demonstrated the positive long term effect of induction therapy followed by high dose melphalan (HDM) and autologous stem cell transplantation (SCT). We therefore investigated the efficacy and safety of B-Dexamethasone (BD) induction treatment followed by HDM + SCT to improve the complete response rate (CR) in de novo AL amyloidosis patients. This report is on the first 25 patients. Methods The HOVON 104 trial was performed in the Netherlands, Belgium and Germany from Jan 2012 to April 2016 and started with a randomized phase III design of BD versus dexamethasone (D) induction treatment followed by HDM + SCT. Due to slow accrual the D arm closed after including 7 patients. Patients with biopsy proven AL amyloidosis, aged between 18-70 years, with detectable M-protein and/or level of involved FLC > 50 mg/L, WHO performance status 0-2, NYHA stage 1-2 and ejection fraction > 45% were included. Major exclusion criteria were symptomatic orthostatic hypotension, NT proBNP level > 5000 pg/ml, Troponin T> 0.06 ug/l, Bilirubin > 2x ULN, eGFR < 30 ml/min, CTCAE grade peripheral sensory neuropathy > grade 2 or > grade 1 with pain. Inclusion and exclusion criteria were installed both at entry and before stem cell mobilization (SCM). B was given subcutaneously 1.3 mg/m2 twice a week for 2 weeks in a 21-day cycle, D 20 mg orally on each B and the following day. HDM dosage was 200 mg/m2. Hematological responses were defined according to consensus criteria with the addition of very good partial response (VGPR), defined as the difference between involved and uninvolved FLC (dFLC) < 40 mg/L. Cardiac, renal and liver response and progression criteria were defined according to consensus criteria with addition of NT proBNP. The primary endpoint was the proportion of patients with CR at 6 months after SCT. To demonstrate improvement from 30 to 50% with 80% power, 44 eligible patients were needed and 50 patients were registered. Results Median age was 60 years (range 26-70) and 68% were male. WHO performance status (PS) was 0-1 in 88% of patients and NYHA stage 1 in 52% and 2 in 44% of patients. Mayo cardiac risk score (2004) was I (28%), II (32%), III (36%). Organ involvement was 88% renal, 76% heart, 20% liver, 12% neurological, 4% gastrointestinal and 72% of patients had 2 or more organs involved. Bone marrow plasmacells were > 10% in 11 patients. Six of the 25 (24%) patients could not proceed to SCM. One patient due to low PS, one because of B related toxicity, two due to amyloidosis related complications and two patients died, both amyloidosis related. Of these 19 patients, 2 went subsequently off protocol because of ineligibility for HDM and one due to hematological progression. Sixteen out of 25 patients (64%) received HDM + SCT which was performed without any treatment related mortality (TRM). In total 29 SAEs were reported in 18 patients. The ORR after induction was 72% and ≥ VGPR in 56% of patients. The ORR in the 16 patients at 6 months after SCT was 75% and ≥ VGPR 63%. Median time to first response was 1 month. Intention to treat analysis demonstrated that the primary endpoint was met in 6 (24%) patients. Organ responses after induction were 9/22 renal and 3/19 heart, and at 6 months after SCT 9/14 renal and 5/13 heart. The first two BD cycles were given as planned in most patients, 80 and 70%, respectively, but doses were reduced and delayed thereafter for B in half of patients, mostly because of neurotoxicity. Mean cumulative dosage of B was 80% of planned. Also D was reduced in almost half of patients due to toxicity. The most common AEs during induction are shown in Table 1. Conclusions Analysis of 25 patients demonstrates that with BD treatment the dropout rate before HDM is 36% which is comparable to previous induction treatments. We therefore conclude that BD, given twice weekly, despite good efficacy, cannot prevent early amyloidosis related toxicity. The SCT procedure was without TRM. The hematological response rate is comparable to previously reported and renal response are 41% after BD and 64% at 6 months after SCT. Trial registration www.trialregister.nl ( NTR 3220), EudraCT 2010-021445-42 , supported by the Dutch Cancer Society (UU 2010-4884 ) and by an unrestricted grant from Janssen-Cilag Disclosures Minnema: Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Hazenberg:GSK: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Hegenbart:Jansen Cilag: Honoraria, Other: financial support of conference participation. Ypma:Advisory Board Sanofi (Plerixafor): Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Broijl:Celgene: Honoraria; Jansen Cilag: Honoraria; Amgen: Honoraria. Sonneveld:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Schoenland:Jansen: Honoraria, Other: financial support of conference participation, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) As a Biomarker of Renal Outcomes in AL Amyloidosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Efstathios Kastritis ◽  
Ioannis Papassotiriou ◽  
Foteini Theodorakakou ◽  
Alexandra Margeli ◽  
Anastasia Barzteliotou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Renal Outcomes ◽  
Hematologic Response ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Renal Progression ◽  
Plasminogen Activator Receptor

Introduction: Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) is the circulating form of a glycosyl-phosphatidylinositol-anchored three-domain membrane protein. suPAR is expressed on a variety of cells, including immunologically active cells, endothelial cells, and renal podocytes. Both the circulating and membrane-bound forms are directly involved in the regulation of cell adhesion and migration through binding of integrins. Elevated suPAR levels have been associated with poor outcomes in various conditions. suPAR has been implicated in the pathogenesis of kidney disease, specifically Focal Segmental Glomerulosclerosis and Diabetic Nephropathy, through interference with podocyte migration and apoptosis. Elevated plasma suPAR levels were associated with incident Chronic Kidney Disease (CKD) and a more rapid decline in the eGFR in persons with normal kidney function at baseline, and with acute kidney injury in various clinical and experimental contexts. suPAR was a strong and independent predictor of mortality in patients with Chronic Heart Failure (CHF), in a recent study. In patients with AL amyloidosis renal involvement is very common and is associated with a high risk of progression to End Stage Renal Disease (ESRD). Evaluation of renal response is challenging and prognostication is based mainly in serum creatinine and proteinuria; limited data exist about new renal biomarkers. Thus, we evaluated suPAR, as a potential new biomarker for renal outcomes in patients with AL amyloidosis treated with contemporary therapies. Methods: we measured serum suPAR levels in 136 patients with AL amyloidosis, before start of therapy and at 6 months in 98 of them. Serum suPAR levels were determined using a standard commercial enzyme-linked immunosorbent assay (suPARnostic Standard kit; ViroGates A/S, Birkerød, Denmark). Results: The median age was 65, 56% were males, 72% had renal, 71% heart, and 17% liver involvement; Mayo stage disposition was 15%, 56% and 29% and renal stage disposition 39%, 44% and 17%, respectively; 82% received bortezomib-based therapy. Median baseline suPAR levels were 6.6 ng/mL (range 2.7-29.0 ng/mL), which is significantly higher than in other studies in non-amyloidosis patients with CKD or CAD/CHF (median 3.04-3.7 ng/ml). We observed a weak negative correlation of suPAR levels with eGFR, but there was no correlation with proteinuria or serum albumin levels in patients with AL amyloidosis and was not associated with renal stage (as defined by eGFR&lt;50 ml/min and proteinuria &gt;5 gr/d). suPAR levels were higher in patients with heart involvement and were associated with NT-proBNP (p=0.003), hs-TnT (p&lt;0.001) and Mayo stage. suPAR levels were higher among those with liver involvement and strongly correlated with alkaline phosphatase levels (p&lt;0.001). There was also a positive correlation with involved Free Light Chain (iFLC). At 6 months suPAR levels were 6.1 ng/mL and in pairwise comparison this reduction was marginally significant (p=0.039); however, this reduction was independent of baseline level and of hematologic response. Baseline suPAR levels were associated with higher probability of eGFR decline (p=0.008) and with renal progression per consensus criteria (p=0.02), at 6 months. Furthermore, suPAR levels at 6 months were strongly associated with the probability of progression to dialysis (2% vs 20% at 2 years and 2% vs 38% at 4 years, p&lt;0.001), independently of renal stage, of renal progression by standard criteria at 6 months, and of the depth of hematologic response (no response vs PR vs VGPR/CR) (figure 1). A reduction of suPAR levels at 6 months compared to baseline was also associated with lower probability of progression to ESRD requiring dialysis, independently of baseline eGFR, baseline renal stage and hematologic response. Conclusion: in patients with AL amyloidosis suPAR levels are prognostic of renal outcomes, especially with progression to ESRD requiring dialysis. Most importantly, suPAR levels and their changes were independently associated with renal progression and progression to dialysis either when measured before start of therapy or at 6 months, independent of baseline renal stage, renal progression by the Palladini criteria and even of the quality of hematologic response. Further evaluation in larger cohorts is required to evaluate suPAR as a biomarker for renal outcomes in AL amyloidosis. Figure 1 Disclosures Kastritis: Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou:Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:Sanofi: Honoraria; Janssen: Honoraria, Research Funding; Genesis Pharma SA: Honoraria, Other, Research Funding; Celgene: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other, Research Funding; Amgen: Honoraria, Research Funding. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees.

scholarly journals Primary Treatment of Light Chain (AL) Amyloidosis with Bortezomib, Lenalidomide and Dexamethasone (VRD)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3248-3248
Author(s):  
Eftathios Kastritis ◽  
Ioanna Dialoupi ◽  
Maria Gavriatopoulou ◽  
Maria Roussou ◽  
Nikolaos Kanellias ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Primary Treatment ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Travel Grant ◽  
Stage 1

Abstract The aim of therapy in AL amyloidosis is to rapidly eliminate the production of toxic, amyloidogenic light chains by targeting the plasma cell clone. Especially for patients with advanced cardiac involvement, a rapid hematologic response may be critical, while, the depth of response is important in order to maximize the probability of organ response. Bortezomib with the addition of dexamethasone with either cyclophosphamide (CyBorD) or melphalan (BMDex) remain the most commonly used primary treatment. In myeloma multiple (MM) patients the combinations of bortezomib with an IMiD [thalidomide (VTD) or lenalidomide (VRD)] are very effective and widely used in newly diagnosed patients. In AL amyloidosis the tumor clone is usually of low burden without adverse prognostic features ; thus, the VRD regimen should be particularly effective. However, IMiDs have unique toxicity in patients with AL and their tolerability is poorer than in MM patients and lower doses of IMiDs are commonly used in AL patients. Here we report our experience with a VRD light regimen as primary therapy in consecutive patients with AL amyloidosis. From March 2017, 30 consecutive patients (28 evaluable at the day of this report) treated at the Department of Clinical Therapeutics, Athens, Greece, received bortezomib 1.3 mg/m2 on days 1, 8 & 15, with lenalidomide (starting at 5 to 15 mg, according to age, cardiac and renal function) on days 1-21 and dexamethasone 20 mg weekly, every 28 days for 8 cycles (VRD regimen). Standard and updated criteria for organ involvement and response evaluation and for hematologic response were used. A rigorous assessment following standard institutional protocol for efficacy and toxicity was followed. Among the 30 patients, 71% were males, median age was 65 years (range 46-84); 75% had cardiac involvement, median NTproBNP was 3649 pg/ml (81- >30000) and per Mayo stage 14%, 54% , 14% and 18% were stage 1, 2, 3A and 3B respectively; 54% had renal involvement with a median eGFR of 59 ml/min/1.73 m2 (range 10-133), renal stage distribution was 13%, 53% and 33% (stages 1, 2 & 3) and no patient required dialysis at the time of initiation of VRD. So far 14 patients have completed the planned 8 cycles, 7 died prior to completion of planned therapy, 1 discontinued per physician's decision and 8 are still on therapy. The starting dose of lenalidomide was 5 mg in 26 (86%), 10 mg in 2 (7%) and 15 mg in 2 (7%) patients. After the first cycle of VRD, 32% patients achieved a VGPR and 29% a PR; after 3 months 76% of evaluable patients (N=17) had a VGPR and 24% a PR, while after 6 cycles ≥VGPR and PR rates (N=15 evaluable) were 94% and 6% respectively. Overall, on intent to treat, the best hematologic response was CR in 24%, VGPR in 48% and PR in 16%, for an ORR of 88% and ≥VGPR of 72%. Median follow up is 10 months and 6 and 12 month survival is 73% (100%, 85% and 71% for stage 1, 2 & 3A patients respectively, but only 20% for stage 3B). At 6 month landmark, organ responses were documented in 21% of patients (20% renal and 15% cardiac), but the follow up is still short. Hematologic toxicity was mild (≥Gr3 neutropenia: 4%, anemia: 7%, thrombocytopenia: 7%). Among non hematologic toxicities rash was common (Gr2: 29%, Gr3: 11%, Gr4: 4%); median time to development of rash was 118 days, in 2 patients lenalidomide was discontinued due to rash and in the rest it was continued with the addition of anti-histamines, low dose steroids with or without dose reductions of lenalidomide. Other common AEs included infections (≥Gr3: 11%), constipation (≥Gr3: 11%), neuropathy (Gr2: 18%). Thromboprophylaxis with aspirin was given in 46%, LMWH in 25%, NOACs in 14% and coumadin in 15%. A thromboembolic event (pulmonary embolism) occurred in only one patient with heavy nephrotic syndrome who was receiving LMWH prophylaxis. In total, 43% of patients required lenalidomide dose reduction, 28% discontinued lenalidomide before therapy completion, while, 29% required bortezomib dose reduction and 11% discontinued bortezomib before cycle 8. We conclude that VRD with weekly bortezomib and low dose lenalidomide is a very effective and rapidly acting regimen that can induce deep hematologic responses within 3 months of therapy with toxicity that is manageable with appropriate interventions and thromboprophylaxis. Disclosures Kastritis: Prothena: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Genesis Pahrma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos:Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1884-1884 ◽  
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

scholarly journals Long-Term Outcomes and Organ Responses with Daratumumab Therapy in Previously Treated Patients with AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1828-1828
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
Erik Eckhert ◽  
Stanley Schrier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Renal Response ◽  
Cardiac Responses ◽  
Previously Treated

Introduction: AL amyloidosis involves deposition of abnormally folded light chains into a wide range of tissues causing end-organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously relapsed/refractory disease. However, data on long-term outcomes to daratumumab, including organ responses, are lacking. Here we present the largest retrospective study to date on patients with previously treated AL amyloidosis treated with daratumumab. Methods: We conducted a retrospective analysis of relapsed/refractory AL amyloidosis patients treated at Stanford University from January 2016 to January 2019. Patients treated with daratumumab, either as monotherapy with dexamethasone (DMT) or in combination with other plasma-cell directed therapies (DCT) were included. Hematologic and organ responses were assessed by consensus guidelines. Hematologic responses were based on the maximal change in the difference between involved and uninvolved free light chains (dFLC). For cardiac response, a >30% and >300 pg/mL decrease in NT-proBNP for patients with initial baseline NT-proBNP ≥650 pg/mL was considered a response. A graded cardiac response metric was also explored with partial response (PR) representing 30-59% reduction, very good partial response (VGPR) ≥60% reduction, and complete response (CR) NT-proBNP <450 pg/mL as previously reported. For renal response, a >30% decrease (by at least 0.5 g/day) in 24-hour urine protein without worsening in creatinine or creatinine clearance by more than 25% in patients with at least 0.5 g/day pretreatment was considered a response. A graded renal response metric was also explored with PR representing 30-59% reduction in proteinuria, VGPR ≥60%, and CR ≤ 200 mg per 24-hour period. Survival data was analyzed using the Kaplan-Meier method. All time-to-event outcomes, including survival and organ responses, were determined from initiation of daratumumab. Results: Eighty-four patients were identified with baseline characteristics at start of daratumumab shown in Table 1. Median duration of follow-up was 16 months. Two-year overall survival (OS) was 83% and median OS was not reached. Median time-to-next-treatment or death was 31 months. Sixty-seven out of 80 evaluable patients (84%) achieved a hematologic response, with 47 patients (59%) achieving a VGPR or better (Figure 1). Sixty-eight patients (81%) had cardiac involvement, and among the 34 evaluable patients, 18 (53%) of evaluable patients achieved a cardiac response with a median response time of 2 months among responders. In terms of a graded cardiac response, 6 patients (18%) were able to achieve cardiac CR, 5 patients (15%) cardiac VGPR, and 7 patients (21%) PR (Figure 2). The median NT-proBNP percent reduction was 64.5% (IQR: 48.3 - 81.1%) and the median absolute reduction was 2395 pg/mL (IQR 1279.5 - 4089.5 pg/mL). Cardiac responses were associated with an improvement in OS (p<0.001, Figure 3), with landmark analysis for cardiac responses at 6-month trending towards statistical significance (100% vs. 51% at 30 months, p=0.052). Fifty-three patients (63%) had renal involvement, and among the 26 evaluable patients, 12 patients (46%) achieved a renal response with a median initial response time of 6 months among responders. Using graded response, 1 patient (4%) achieved renal CR, 7 patients (27%) renal VGPR, 4 patients (15%) renal PR, and 14 patients had no response, worsening creatinine, or were subsequently started on hemodialysis (54%) (Figure 4). The median percent reduction in proteinuria was 74.1% (IQR: 49.2 - 83.1%) and the median absolute reduction in proteinuria was 3.1 g/24 hours (IQR 2.1 - 4.9 g) among responders. There were no significant differences in OS between renal responders and non-responders. Conclusion: Daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve durable hematologic responses as well as improvements in organ function. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke: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; Janssen: 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; Takeda: 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; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. OffLabel Disclosure: Daratumumab in AL amyloidosis

Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 814-814 ◽  
Author(s):  
Paul G. Richardson ◽  
Melissa Alsina ◽  
Donna M. Weber ◽  
Steven E. Coutre ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Treatment Phase ◽  
Employment Equity ◽  
Advisory Committees ◽  
Overall Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Stage 1

Abstract Abstract 814FN2 Background: Patients with refractory multiple myeloma (MM) have limited treatment options and an extremely poor prognosis. A recent study of patients who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive an immunomodulatory drug (IMiD, thalidomide or lenalidomide) demonstrated a median event-free survival of only 5 months (Kumar S et al, Leukemia, 2011). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Preclinical studies have demonstrated synergistic anti-myeloma activity of the combination of panobinostat and bortezomib through dual inhibition of the aggresome and proteasome pathways. In a phase I study (B2207) of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib, clinical responses (≥ minimal response [MR]) were observed in 65% of patients, including in patients with bortezomib-refractory disease. PANORAMA 2 seeks to expand upon these preliminary results and seeks to determine whether panobinostat can sensitize resistant patients to a bortezomib-containing therapeutic regimen. Methods: PANORAMA 2 is a single arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with bortezomib-refractory MM. Patients with relapsed and bortezomib-refractory MM (≥ 2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last bortezomib-based therapy) are treated in 2 phases. Treatment phase 1 consists of 8 three-week cycles of oral panobinostat (20 mg days 1, 3, 5, 8, 10, 12) + intravenous bortezomib (1.3 mg/m2 days 1, 4, 8, 11) + oral dexamethasone (20 mg on day of and after bortezomib). Patients demonstrating clinical benefit (≥ stable disease) can proceed to treatment phase 2, consisting of 4 six-week cycles of panobinostat (20 mg TIW 2 weeks on 1 week off, and repeat) + bortezomib (1.3 mg/m2 days 1, 8, 22, 29) + dexamethasone (20 mg on day of and after bortezomib). The primary endpoint is overall response (≥ partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first 8 cycles of treatment phase 1. A Simon 2-stage design is used to test the primary endpoint where ≥ 4 responses (≥ PR) in 24 patients are needed in stage 1 in order to proceed to stage 2, where ≥ 9 responses in all patients (N = 47) are required to reject the null hypothesis (overall response rate ≤ 10%). Results: A sufficient number of responses ≥ PR were observed in stage 1 to allow for enrollment to continue to stage 2. As of 15 July 2011, 53 patients with bortezomib-refractory MM were enrolled. Safety and demographic data were available for 48 patients. The median age was 61 (41–88) years. Patients were heavily pretreated, with a median of 4 (2–14) prior regimens, and most patients (69%) received prior autologous stem cell transplant. Efficacy data were available for 44 patients. At the time of this analysis, 9 patients achieved ≥ PR (2 near CR [nCR] and 7 PR) as best overall response, and an additional 7 patients achieved an MR. Responders exhibited a long duration on therapy, and, to date, 8 patients have proceeded to treatment phase 2. The 2 patients with nCR have received ≥ 10 cycles of treatment (duration of therapy 190 and 253 days). Four patients who achieved PR have received ≥ 9 cycles (duration of therapy 155–225 days). Updated response data will be presented. Common adverse events (AEs) of any grade included, fatigue (52%), diarrhea (41%), thrombocytopenia (38%), nausea (38%), and anemia (21%). Gastrointestinal AEs were generally mild, with a relatively low incidence of grade 3/4 events. Grade 3/4 AEs were generally hematologic in nature, with grade 3/4 thrombocytopenia, anemia, and neutropenia reported in 38%, 12%, and 10% of patients, respectively. Other common nonhematologic grade 3/4 AEs included fatigue (10%) and pneumonia (10%). Of note, to date, a relatively low rate of peripheral neuropathy (17%) has been observed. No grade 3/4 peripheral neuropathy has been observed. Conclusions: The combination of panobinostat and bortezomib is a promising treatment for patients with bortezomib-refractory MM. These data, along with forthcoming data from the phase III study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM (PANORAMA 1), will further define the potential role of panobinostat in the treatment of patients with MM. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: 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; BMS: Membership on an entity's Board of Directors or advisory committees. Alsina:Novartis: Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding; Onyx: Research Funding; Millennium: Consultancy, Research Funding. Weber:Millennium: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Gasparetto:Millennium: Speakers Bureau. Warsi:Novartis: Employment, Equity Ownership. Ondovik:Novartis: Employment, Equity Ownership. Mukhopadhyay:Novartis: Employment, Equity Ownership. Snodgrass:Novartis: Employment, Equity Ownership.

Head-To-Head Comparison Of Obinutuzumab (GA101) Plus Chlorambucil (Clb) Versus Rituximab Plus Clb In Patients With Chronic Lymphocytic Leukemia (CLL) and Co-Existing Medical Conditions (Comorbidities): Final Stage 2 Results Of The CLL11 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 6-6 ◽  
Author(s):  
Valentin Goede ◽  
Kirsten Fischer ◽  
Raymonde Busch ◽  
Anja Engelke ◽  
Barbara Eichhorst ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Final Stage ◽  
Research Funding ◽  
Observation Time ◽  
Lymphocytic Leukemia ◽  
Type Ii ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Stage 1

Abstract Introduction CLL11 is a large randomized phase 3 trial investigating first-line chemoimmunotherapy in CLL patients with comorbidities, i.e. patients typically treated in daily practice. Here, we present: (i) The final stage 2 analysis with efficacy and safety results of the head-to-head comparison between GA101 plus Clb (GClb) and rituximab plus Clb (RClb); at the pre-planned interim analysis, the primary endpoint was met early and the results were released by the independent data monitoring board. (ii) An update on the stage I analysis (GClb vs. Clb and RClb vs. Clb comparisons) with longer observation time; the final stage 1 analysis recently showed that GClb or RClb has superior efficacy to chemotherapy with Clb alone. Methods Treatment-naïve CLL patients with a Cumulative Illness Rating Scale (CIRS) total score >6 and/or an estimated creatinine clearance (CrCl) <70 mL/min were eligible. Patients received Clb alone (0.5 mg/kg po d1, d15 q28 days, 6 cycles), GClb (100 mg iv d1, 900 mg d2, 1000 mg d8, d15 of cycle 1, 1000 mg d1 cycles 2-6), or RClb (375 mg/m2 iv d1 cycle 1, 500 mg/m2 d1 cycles 2-6). Primary endpoint was investigator-assessed progression-free survival (PFS). Response rates, minimal residual disease (MRD), and overall survival (OS) were key secondary efficacy endpoints. Results Final results of the stage 2 analysis: Median observation time was 19 months. The GClb and RClb treatment arms were well balanced for baseline characteristics. Median age, CIRS score, and CrCl at baseline were 73 years, 8, and 63 mL/min respectively. Key efficacy and safety results are shown in the table. The PFS benefit of GClb over RClb was supported by all pre-planned subgroup analyses (including the cytogenetic subgroups 17p-, 11q-, 12+, 13q-). The number of patients with MRD negative blood samples at end-of-treatment was more than 10-fold higher with GClb compared with RClb (63/214 [29.4%] vs. 6/243 [2.5%]). Grade 3-4 infusion-related reactions with GClb occurred at first infusion only. Updated results of the stage 1 analysis: Median observation time was 23 months. Confirming the primary stage 1 results, GClb or RClb compared with Clb alone was associated with statistically significant and clinically meaningful improvement in PFS (GClb vs. Clb: HR 0.18, CI 0.13-0.24, p<.0001, RClb vs. Clb: HR 0.44, CI 0.34-0.57, p<.0001). The updated median PFS in GClb, RClb and Clb were 26.7, 16.3 and 11.1 months, respectively. Updated OS analysis demonstrated a benefit of GClb over Clb (HR 0.41, CI 0.23-0.74, p=0.002). OS analysis for RClb over Clb showed HR 0.66, CI 0.39-1.11, p=0.113. At the data cut-off, 9%, 15%, and 20% of the patients in the GClb, RClb, and Clb arms, respectively, had died. OS medians were not reached. Conclusions GA101, a novel, glycoengineered, type II CD20 antibody, in combination with Clb (GClb regimen) demonstrated statistically significant and clinically meaningful prolongation of PFS, and higher complete response rate and MRD negativity rate compared with RClb in previously untreated CLL patients with comorbidities. Infusion-related reactions and neutropenia were more common with GClb without an increase in infections. Furthermore, GClb vs. Clb alone demonstrated a prolongation of OS. Overall, GClb is superior to RClb and a highly active treatment in this typical CLL patient population. Disclosures: Goede: Mundipharma: Honoraria; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin’s Lymphoma and other hematologic indications. Fischer:Mundipharma: Travel grants, Travel grants Other; F. Hoffmann-La Roche: Travel grants Other. Engelke:F. Hoffmann-La Roche: Travel grants Other. Eichhorst:Mundipharma: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy; F. Hoffman-La Roche: Honoraria, Research Funding. Wendtner:F. Hoffmann-La Roche: Consultancy, Research Funding. Dilhuydy:F. Hoffmann-La Roche: Consultancy. Opat:F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Alexion Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Owen:F. Hoffmann-La Roche: Honoraria. Kreuzer:F. Hoffmann-La Roche: Consultancy, Honoraria. Langerak:F. Hoffmann-La Roche: Research Funding. Ritgen:F. Hoffmann-La Roche: Research Funding. Stilgenbauer:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding. Asikanius:F. Hoffmann-La Roche: Employment. Humphrey:F. Hoffmann-La Roche: Employment. Wenger:F. Hoffmann-La Roche: Employment, Ownership interests (including stock options) in a start-up company, the stock of which is not publicly traded Other. Hallek:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

Growth Differentiation Factor-15 in Patients with Light Chain (AL) Amyloidosis Has Independent Prognostic Significance and Adds Prognostic Information Related to Risk of Early Death and Renal Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 306-306 ◽  
Author(s):  
Efstathios Kastritis ◽  
Ioannis Papassotiriou ◽  
Evangelos Terpos ◽  
Athanassios Akalestos ◽  
Erasmia Psimenou ◽  
...  
Keyword(s):  
High Risk ◽  
Prognostic Significance ◽  
Early Death ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
Prognostic Information ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Hematological Response ◽  
Independent Prognostic Significance

Abstract Growth differentiation factor-15 (GDF-15) is a member of the TGF-beta family, which is involved in several pathological conditions, including inflammation, cancer, cardiovascular, pulmonary and renal diseases. GDF-15 has prognostic value in patients with cardiovascular disorders and adds prognostic information to conventional prognostic factors, such as NT-proBNP and high-sensitivity troponin (hs-TnT). Cardiac involvement is the most important determinant of prognosis in patients with AL amyloidosis and cardiac biomarkers have major prognostic importance in AL. The aim of the study was to explore the value of GDF-15 in patients with AL amyloidosis. We measured the circulating levels of GDF-15, NT-proBNP and hs-TnT in 77 patients with newly diagnosed AL amyloidosis, before and 3 months post frontline treatment. GDF-15 was measured by a novel pre-commercial immunoassay (Roche Diagnostics). Patients' median age was 68 years; most patients had cardiac (61%) or renal involvement (74%); 61% had NT-proBNP >1284 pg/ml and 46% had hsTnT>54 ng/ml. Median eGFR was 57 ml/min/1.73m2, 52% had eGFR <60 ml/min/1.73m2, while 12% required dialysis at the time of treatment initiation. All patients received primary therapy with bortezomib- (49%) or lenalidomide-based regimens (51%). Median levels of GDF-15 were 3594 pg/ml (range 626-71,475pg/ml); 95% of patients with AL had GDF-15 levels >1200 pg/ml (the upper limit of normal for individuals without cardiovascular disease). GDF-15 correlated with NT-proBNP (r=0.538, p<0.001), hs-TnT (r=0.447, p=0.02) and eGFR (r=-0.570, p<0.001). Patients with GDF-15 levels within the upper quartile (>7575 pg/ml) had a very poor outcome (median overall survival (OS) 3 months) compared to patients with GDF-15 levels below the upper quartile (p=0.01; see the Figure). Among other cardiac markers, hs-TnT >54 ng/ml (12 vs >48 months, p=0.001) and NT-proBNP >1284 pg/ml (11 vs >48 months, p<0.001) were also associated with shorter OS. Higher cut-off levels for NT-proBNP and hs-TnT did not discriminate patients at high risk for early death more accurately. In a multiple logistic regression model which included GDF-15, NT-proBNP and hs-TnT, only GDF-15 in the upper quartile (HR: 8.427, 95% CI 1.73-41.1, p=0.008) was independently predictive of early death at 3 months. Similar results were obtained when these biomarkers were treated as continuous variables. Regarding OS, GDF-15 had independent prognostic significance in a multivariate model that included both NT-proBNP and hs-TnT. We also evaluated changes in the levels of GDF-15, NT-proBNP and hs-TnT in patients who received lenalidomide after 3 months of treatment. In these patients NT-proBNP often increases without obvious deterioration of cardiac function, thus complicating the assessment of cardiac response early, during the course of therapy. GDF-15 levels did not change significantly either in patients with hematological response (p=0.998) or those without hematological response (p=0.774). However, NT-proBNP levels increased substantially both in those with hematological response (p=0.05) and in those without hematological responses (p=0.013). Similarly, hs-TnT levels increased in non-responders (p=0.006) and did not change in patients with hematological response (p=0.251). As GDF-15 reflects heart and renal defects, we further evaluated whether GDF-15 could be associated with the risk of progression to ESRD and need for dialysis. Using ROC analysis, GDF-15 >median was identified to better discriminate patients which had a shorter time to dialysis (29 months vs not reached, p=0.001, see the Figure; with 38% vs. 8% progressing to ESRD, respectively). eGFR< 60 ml/min/m2 was also a strong predictor of ESRD (p=0.004). However, in multivariate analysis which included GDF-15 >median, eGFR <60 ml/min/m2 and proteinuria >5 g/day, only GDF-15 was independently associated with a higher risk of ESRD requiring dialysis (HR: 4.25, 95% CI 1.01-18, p=0.045). In conclusion, GDF-15 is a novel biomarker with prognostic implications for different outcomes in patients with AL; it is associated with a high risk of early death, with OS and also with renal outcome. More importantly GDF-15 adds prognostic information independent of the traditional cardiac biomarkers and thus, its measurement in larger series of patients is recommended. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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