Abstract: Although survival in AL patients is related in part to the number of marrow clonal plasma cells (PC) (1, 2), staging for AL patients is based on end-organ damage without a clear role for cytogenetic aberrations in clonal PC. Recently several groups have described potential roles for gain 1q and t(11;14) as prognostic markers in AL, and possibly as predictive of response to therapy (3-5). In multiple myeloma, del 17p is a cytogenetic aberration present in about 10% at diagnosis and its prognostic impact depends on the percentage of clonal PC with del 17p (6). The relevance of del 17p in AL is undefined. We report our initial analysis of the outcomes and survival of the first multinational retrospective study of AL patients with del 17p as a feature of their clonal plasma cell disease and include preliminary findings from an age-based case-control analysis. AL patients with del 17p were identified and their clinical characteristics and outcomes summarized. Methods for determining the presence of del 17p were reviewed. We compared the overall survival (OS) of patients in whom del 17p was identified in 〈 or ≥ 50% of clonal cells, and evaluated the impact of bortezomib-based therapy and cardiac stage on OS in newly diagnosed and relapsed patients. These cases were then matched for age (± 5 years) with a control cohort from the Amyloidosis Treatment and Research Center in Pavia, IT, representing a subset of patients reported previously (7). Differences between cases and controls for OS were evaluated by Kaplan-Meier with statistical significance by the log-rank test. P 〈 0.05 was the threshold for significance. Thirty-four AL patients with del 17p in clonal cells were identified, 30 at diagnosis and 4 at relapse. Thirty-one cases had del 17p assessed on CD138-selected marrow cells and 3 on marrow mononuclear cells; for the latter, the percentage of marrow PC was used to estimate the del 17p fraction. Commercially available methods were used at all centers. Median age was 66 years and males constituted 53% of cases. Cardiac involvement was present in 72% of cases, 41% of whom had stage III involvement. Ninety-four percent had free light-chain (FLC) clones of lambda isotype with a median difference between involved and uninvolved FLC (dFLC) of 249mg/L and a median percentage of marrow PC of 18%. In all 34 cases the median percentage of clonal PC with del 17p by FISH was 42% (range 2-93%) while in newly diagnosed AL patients it was 37%. Eighty-three percent of cases had del 17p in combination with other cytogenetic abnormalities including t(11;14) in 36% and gain 1q in 18%. Among the newly diagnosed cases, 32% had ≥ 50% of clonal cells with del 17p and had a median OS of 23.5 months while those with 〈 50% survived a median of 33 months (P = 0.12). Seventy-three percent of patients responded to initial therapy and 32% had ≥ VGPR. Twenty-three percent had a cardiac response to initial therapy. There was no difference in OS between patients who had bortezomib-based therapy and those who did not, and no difference between the OS of cardiac stage 1/2 and stage 3 patients. One patient with 37% del 17p and a complex karyotype at baseline progressed at relapse to both advanced AL cardiac involvement and plasma cell leukemia with over 90% del 17p containing PC, suggesting that del 17p may confer risk in AL as in MM under certain circumstances. In the preliminary case-control analysis, OS was no different between cases and controls (Fig 1, P = 0.32). Recent data indicate that the more common cytogenetic abnormalities in AL, namely t(11;14) and gain 1q, are associated with differences in response to melphalan or bortezomib. In this series of AL cases with del 17p, we find suggestive evidence that high levels of clonal cells with del 17p may confer a poorer prognosis than already exists as a consequence of the tropism of AL light chains for the heart. We are seeking more cases for inclusion in this series and conducting both a multivariate analysis and a detailed case-control comparison which may shed light on this issue. References (1) Comenzo et al. Blood 2001;98(3):714-20. (2) Warsame et al. Blood Cancer Journal 2015;5, e-310, e-pub 1 May 2015 (3) Bochtler et al. Amyloid. 2014 Mar;21(1):9-17. (4) Bochtler et al. J Clin Oncol. 2015 Apr 20;33(12):1371-8. (5) Zhou et al. Clin Lymphoma Myeloma Leuk 2012;12(1):49-58. (6) An et al. Clin Cancer Res; 21(9); 2148-56. (7) Palladini et al. Blood 2015, e-pub 18 May 2015 Figure 1. Figure 1. Disclosures Hegenbart: Janssen: Honoraria. Landau:Prothena: Consultancy, Honoraria; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Janssen: Consultancy; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Avet-Loiseau:onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Hansen:Celgene GmbH: Honoraria. Schönland:Janssen, Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Comenzo:Janssen: Research Funding; Prothena: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Research Funding; Karyopharm: Research Funding.

Abstract: The treatment of newly diagnosed patients with AL has dramatically improved with the use of the first-in-class proteasome inhibitor bortezomib in initial therapy (Kastritis et al., Haematologica, 2007). Overall hematologic response rates of 62% have been reported in a large series with 43% of patients achieving very good partial (VGPR) or complete responses (CR), i.e. 〉 VGPR (Palladini et al., Blood, 2015). In fact, bortezomib-based therapy is now commonly used as front-line treatment in lieu of transplant or as cytoreduction prior to ASCT. However, patients who have suboptimal hematologic responses such as partial or no response (PR, NR) to bortezomib-based therapy are likely to have inferior overall survival (Palladini et al., JCO, 2012). The clinical efficacy of risk-adapted melphalan (MEL) and autologous stem cell transplantation (ASCT) as a second-line option for such patients has not been formally studied. We report on 12 patients, 8 men and 4 women with a median age of 58 (range, 53-70) with suboptimal responses to initial therapy who were referred for and underwent ASCT after a median of 4 cycles of bortezomib-based therapy (range, 2-8). Eight patients had NR with median involved FLC values at diagnosis and post initial therapy/pre-SCT of 180 (74-648) and 265mg/L (116-410) respectively while 4 had PR with medians of 1401 (250-9750) and 94mg/L (43-1620); in neither case were comparisons significant by paired t-test. Seven patients had 2 organs involved and 5 had one. Eight patients had cardiac involvement, seven stage 2 and one stage 3. Six patients had renal involvement, one stage 1, four stage 2, and one stage 3. Two had GI involvement. All patients were mobilized successfully with filgrastim and plerixafor as previously described (Kaul et al., BMT, 2014). A median of 9.8 x 106 CD34+ cells/kg (range, 5.4-23.3) were collected. All patients received melphalan at doses of 200 mg/m2 (4 patients, 33%), 140 mg/m2 (7 patients, 58%), and 100 mg/m2 (1 patient, 8%). A median of 6.6 x 106 CD34 cells/kg (4.5-14.0) were infused. All patients engrafted and all had their post-SCT hematologic responses assessed. There was one treatment-related death at 2 months post-SCT in a 70 year old woman who had stage 2 cardiac and stage 2 renal disease, received MEL 100 mg/m2 and had improved her hematologic response status from NR to PR. Overall post-SCT, 75% of patients achieved 〉 VGPR including 42% who achieved CR (n=5). Eight patients have received consolidation with bortezomib and/or lenalidomide based regimens, with four patients achieving CR. Two patients are about to start consolidation. With a median follow-up of 27 months (1-42), two renal and four cardiac responses have been achieved. Median overall survival post-SCT has not been reached (Figure). In conclusion, risk-adapted melphalan and ASCT is a safe, feasible, timely and effective second-line therapy for patients with AL who have suboptimal responses to bortezomib-based initial therapy. Figure Figure. Disclosures Comenzo: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Karyopharm: Research Funding.

Abstract: Cardiac stage and depth of hematologic remission are major predictors of survival for AL amyloidosis patients (Wechalekar et al., Blood, 2013; Dispenzieri et al., JCO, 2004; Palladini et al., JCO, 2012). Renal staging in AL amyloidosis (AL) has been studied in the context of renal survival (Palladini et al., Blood 2014). Influences on survival for renal patients have yet to be fully defined. We performed a retrospective study of all AL patients with renal involvement diagnosed at our center between 7/1/08 and 6/30/15. In this cohort of consecutive patients (n=80) median age was 63 (IQR 55-70) and 56% were men. Eighty-eight percent had lambda plasma cell disease and median involved FLC was 140mg/L (69-485). Thirty-nine percent were renal stage 1, 44% stage 2, and 16% stage 3. Median 24-hour proteinuria and serum creatinine were 6.23 g (3.47-10.70) and 1.03 mg/dL (0.80-1.80) respectively, and median eGFR was 72 mL/min (41-90). Fifty-eight percent had cardiac involvement, of whom 11% were cardiac stage 1, 54% stage 2, and 34% stage 3, while 18% had GI and 9% peripheral nerve involvement. As first-line therapy, 70% received bortezomib-based regimens and 25% melphalan-based autologous stem cell transplant. By intention-to-treat, at 6 months after beginning therapy, 54% of patients had a hematologic response of PR or better, and renal and cardiac responses occurred in 13% and 14% of patients respectively, while renal progression occurred in 6%. Median overall survival (OS) for this cohort (n=80) was 67 months. Those with cardiac involvement (n=45) had a median OS of 41 months and, while median OS was not reached for cardiac stage ≤ 2, it was 31 months for those who were stage 3 (P 〈 0.05) (Figure). Median OS was also not reached for patients achieving hematologic response ≥ VGPR with a median follow-up of 19 months. In conclusion, for AL patients with renal involvement, both cardiac stage and depth of hematologic response are important contributors to overall survival. Furthermore, as this real world intention-to-treat analysis demonstrates, there is a continuing need for better therapies for both the hematologic disease and the organ damage associated with AL. Figure. Figure. Disclosures Oliver: Prothena Biosciences, Inc.: Employment, Equity Ownership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Comenzo:Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Karyopharm: Research Funding; Janssen: Consultancy, Research Funding.

Abstract: Chronic extensive, severe graft-versus-host-disease (GVHD) is a major cause of morbidity and mortality following an allogeneic hematopoietic stem cell transplant (HSCT). Patients with progressive chronic GVHD (cGVHD) following standard treatments have limited options. Patients with extensive refractory cGVHD have a decreased performance status (PS) and an increased non-relapsed mortality. Extensive sclerodermatous cGVHD responds poorly to standard treatments. Colchicine is a well-known anti-inflammatory drug that has been used in the treatment of many inflammatory disorders (1). We report a series of 8 patients with extensive cGVHD who were refractory to multiple lines of therapy and then were treated with colchicine. All patients had improvements in ECOG PS, skin GVHD and/or oral GVHD after starting colchicine. All patients were able to decrease their immunosuppressive therapies (IST) after starting colchicine. We retrospectively examined 8 patients with refractory extensive cGVHD, treated with colchicine (0.6 mg QD or BID). IST for cGVHD was defined by the following: steroids, extracorporeal photopheresis (ECP), imatinib, mycophenolate mofetil (MMF), tacrolimus, bortezomib, montelukast, cyclophosphamide (Cy), pentostatin, and rituximab. National Institutes of Health 2014 cGVHD consensus criteria (2) were used to grade the cGVHD prior to colchicine and at the time of best response after colchicine was started. Baseline patient characteristics are listed in Table 1. Conditioning regimen for allogeneic HSCT consisted of PPT (ECP, pentostatin, TBI) (4/8), busulfan/Cy (2/8), Cy-TLI (1/8), or Cy/TBI (1/8). GVHD prophylaxis involved CSA/MTX (7/8), tacrolimus/MTX (1/8) and ATG in addition to CSA/MTX (1/8). Median number of organs involved in cGVHD was 4.5 (range 2-5). All patients had extensive cGVHD with skin (8/8), oral (8/8), eye (8/8), GI (7/8), lung (6/8), liver (2/8), and/or genital (2/8) involvement. Median number of failed IST was 3.5 (range 1-6). Patients failed steroids (7/8), ECP (6/8), MMF (5/8), imatinib (3/8), cyclophosphamide (2/8) and bortezomib (1/8). Median number of IST immediately before colchicine was 2.5 (range 1-6). Most patients required twice daily dosing of colchicine (5/8). Median follow-up since beginning colchicine was 11 weeks (range 3-67 weeks). At best response with colchicine, all patients had clinical improvement of chronic GVHD (Figure 1). Patients with extensive cGVHD of the skin, including all patients with extensive sclerodermatous changes, responded to the addition of colchicine, and had steroid and MMF doses lowered, and/or were stopped on IST. Median number of IST fell to 2 (range 0-5). Four patients had a reduction in the number of IST. One patient was taken off 4 IST (ECP, imatinib, Cy and MMF). Another patient was able to stop ECP. Five patients had a reduction in prednisone with median reduction of 5mg (range 5-40 mg), while 2 had reductions in the total daily dose of MMF. Adverse events were uncommon and included 2 patients with grade 1-2 diarrhea. The most severe adverse event was grade 2 diarrhea in one patient that led to eventual discontinuation of colchicine. No hematologic toxicity was observed. The rest (7/8) continued on colchicine therapy. In conclusion, patients with extensive cGVHD involving the skin and mouth, refractory to multiple lines of IST, experienced clinical improvement on colchicine. Toxicity was limited to mild GI side effects. These observations need to be validated in a prospective clinical trial. References (1) Slobodnick et al. Am J Med. 2015 May;128(5):461-70. (2) Jagasia et al. Biol Blood Marrow Transplant. 2015 Mar;21(3):389-401.e1. Epub 2014 Dec 18. Table 1. Baseline Characteristics Variable Frequency (%) Age, median (range), yr 57 (30-65) Donor/recipient gender Sex-mismatched female/male 1 (13%) Sex-matched 7 (88%) Race White/Caucasian 7 (88%) Disease category Acute myeloid leukemia 4 (50%) Myelofibrosis 2 (25%) Aplastic anemia 1 (13%) Lymphoblastic lymphoma 1 (13%) Remission status at transplantation CR 8 (100%) Graft source BM 1 (13%) PBSC 7 (88%) Donor type Matched sibling 4 (50%) Matched unrelated 3 (38%) Mismatched 1 (13%) GVHD type Progressive 3 (38%) Overlap syndrome 2 (25%) De novo 3 (38%) Figure 1. Figure 1. Disclosures Off Label Use: Colchicine will be discussed as treatment for GVHD. Comenzo:Karyopharm: Research Funding; Prothena: Research Funding; Takeda Millennium: Research Funding; Janssen: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Roberts:Millenium: Speakers Bureau. Miller:Biogen Idec: Consultancy; AbbVie: Speakers Bureau; Millennium: Speakers Bureau; Onynx: Speakers Bureau.