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  • 1
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 643-643
    Abstract: Background: Mortality in patients with AL Amyloidosis remains high due to progressive organ damage from amyloid deposition. Current therapies eliminate the plasma cell clone that produces amyloidogenic light chains. However, there are no approved therapies that directly target amyloid deposits, a major culprit of progressive multi-organ dysfunction. To address this, a murine (Mu) amyloid fibril-reactive monoclonal antibody (mAb) 11-1F4 was developed that binds to a conformational epitope present on human light-chain amyloid fibrils and initiates cell-mediated phagocytosis. In vivo testing of the Mu mAb and later its chimeric (Ch) form in mice with induced human AL amyloidomas resulted in rapid amyloidolysis without any evidence of toxicity [Hrncic 2000; Solomon 2003]. Subsequent evaluation of an I-124 labeled Mu mAb confirmed that it specifically bound to amyloid-laden organs as evidenced by PET/CT imaging [Wall 2010] . Because of these favorable results, GMP-grade amyloid fibril-reactive Ch IgG1 mAb 11-1F4 was produced by NCI's Biological Resource Branch for a phase 1a/b trial. An analysis of Phase 1a was presented at the American Society of Hematology's 2015 annual meeting. Here we report data from the phase 1a/b trial. Methods: Patients with relapsed or refractory AL Amyloidosis were enrolled in this open-label, dose-escalation phase 1a/b study of Ch IgG1 mAb 11-1F4 (NCT02245867). The primary objective was to determine safety and tolerability of the antibody when given as a single intravenous infusion (phase 1a) or as a series of weekly infusions for 4 weeks (phase 1b). Secondary objectives included pharmacokinetics and efficacy as evidenced by organ response. For both phase 1a and 1b, a dose-escalation "up and down" design was used where sequential doses of 0.5, 5, 10, 50, 100, 250 and 500 mg/m2 were administered to successive patients. Assessment of organ response was based on the International Society of Amyloidosis' revised consensus criteria [Pallidini 2012] and the clinically validated renal staging and response criteria [Pallidini 2014] . Results: As of July 15th, 2016, 8 (2 κ and 6 λ) patients completed phase 1a and 11 (4 κ and 7 λ) patients commenced treatment in phase 1b. Median age was 67 years (range: 34 - 77) and median number of organs involved was 2 (range: 1 - 4) with heart and kidney being the most common. All patients received prior anti-plasma cell systemic treatment and achieved at least partial hematologic response. All patients tolerated the given dose of mAb 11-1F4. The maximum tolerated dose (MTD) was 500mg/m2 for phase 1a and 1b. There were no grade 4 or 5 adverse events (AEs) related to the drug. In phase 1a, one patient at dose level 4 developed a grade 2 rash 4 days after infusion. Skin biopsy revealed a so far undiagnosed cutaneous amyloidosis and immunohistochemical staining showed the mAb surrounding amyloid fibrils with an accompanying neutrophilic infiltrate. The same patient and another patient developed a similar rash during treatment in phase 1b suggesting mAb 11-1F4 binding. Although the primary objective of the trial was to evaluate safety, 63% of patients (5 of 8) with measurable disease burden demonstrated organ response after one infusion of mAb 11-1F4 in phase 1a. In phase 1b, 83% of patients (5 of 6 who completed follow up) showed organ response. At the time of presentation, we will report a complete analysis of the phase 1a and 1b clinical trial. Conclusions: Treatment with mAb 11-1F4 is well tolerated and safe without grade 4 or 5 AEs or dose limiting toxicity up to an MTD of 500mg/m2. Clinical efficacy data shows early and sustained organ response when the mAb is administered as a single infusion or as a weekly infusion for 4 weeks. Based on these very encouraging results, a phase 2 SWOG trial for patients with newly diagnosed AL Amyloidosis will be launched. Overall, we posit that amyloid fibril-specific 11-1F4 mAb represents a novel and promising adjunct to the treatment of AL Amyloidosis by safely promoting amyloid resolution and subsequent improvement in organ function. This may result in improved outcomes for patients with this devastating disease. Disclosures Wall: Prothena Inc: Patents & Royalties. Lentzsch:Celgene: Consultancy, Honoraria; BMS: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 121, No. 2 ( 2013-01-10), p. 385-391
    Abstract: The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non–type A (n = 26; 13%) patients. At diagnosis, non–type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P 〈 .001) and less often trisomy 22 (P = .02). No patient with non–type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non–type A and type A patients with wild-type KIT were similar. We also derived a fusion-type–associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed—among others—an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non–type A patients. We conclude that non–type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2514-2514
    Abstract: Abstract 2514 Approximately 8% of de novo AML pts have inv(16)(p13q22) or t(16;16)(p13;q22) [inv(16)] and this cytogenetic group is associated with high complete remission (CR) rates and a relatively favorable outcome after cytarabine/daunorubicin (ara-c/dnr)-based induction and high-dose ara-c (HiDAC) consolidation therapy. However, ∼40% of these pts still relapse. The molecular mechanisms that impact on the prognosis of inv(16) pts remain to be fully elucidated. We and oth ers reported that presence of the mutated KIT (mutKIT) gene is associated with worse outcome, but other contributing factors may play a role. Molecularly, inv(16) results in disruption of the MYH11 gene at 16p13 and CBFB gene at 16q22, creating a CBFB-MYH11 fusion gene. Since the genomic breakpoints within CBFB and MYH11 are variable and the fusion transcripts depend on the exons fused, at least 11 different sized CBFB-MYH11 fusion transcript variants have been found. The frequency of each fusion varies, with ∼85% being type A and ∼5% each types D and E; types B, C, and F-K were reported in single cases (hereafter we refer to non-type A fusions as “rare”). To our knowledge, only one study (Schnittger et al. Leukemia 2007;21:725) has examined the biological and clinical significance of rare CBFB-MYH11 fusions in AML. Fusion type was not found to be prognostic, but the cohort included pts with therapy-related and secondary AML. Thus, further studies are warranted. Accordingly, we analyzed 149 de novo CBFB-MYH11 positive AML pts aged 〈 60 years (y; median, 40 y; range 18–59) receiving ara-c/dnr-based induction and HiDAC consolidation therapy (Cancer and Leukemia Group B protocols 9621, 19808, 10503). Among 149 pts, 129 (87%) had type A fusion, 17 (11%) type E, 2 (1%) type D, and 1 ( 〈 1%) type I. Pts with rare fusions had lower white blood cell counts (P=.02; median, 18.9 v 27.5 ×109/L), less often skin infiltration (P=.04; 0% v 18%) and tended to have FAB subtype M4Eo less often than the type A fusion pts (P=.13; 67% v 85%). Eighteen rare and 100 type A fusion pts had at least 1.7 y follow-up and thus could be analyzed for outcome. No significant differences in CR rates (P=1.00; 94% v 92%), cumulative incidence of relapse (CIR; P=.16; 5 y rates, 30% v 47%) or overall survival (OS; P=.30; 5 y rates, 78% v 60%) were found between rare and type A fusion pts. However, a trend toward longer event-free survival (EFS) was observed for rare fusion pts compared with type A pts (P=.07; 5 y rates, 66% v 42%; Figure). In an analysis of secondary cytogenetic abnormalities (abns) we found trisomies 8, 13 and 21 were more frequent in rare fusion pts than in type A pts (P=.03; P=.07; P 〈 .001, respectively). Of the rare fusion pts, 44% had at least one of +8, +13 or +21 compared to only 11% of the type A pts. No rare fusion transcript pt harbored +22, which was present in 24 (19%) pts with type A fusion (P=.05; Table]. Strikingly, no rare fusion pt had mutKIT compared with 29% of type A fusion pts (P=.01). Given that +22 has been associated with improved and mutKIT with worse outcome, we also assessed the impact of fusion transcript type by restricting our analysis first to pts with no +22, then to pts without mutKIT, and finally excluding both +22 and mutKIT. No significant differences in CR rates, CIR, OS or EFS were observed between the two groups. We conclude that the type of fusion transcript does not appear to affect significantly the prognosis of inv(16) pts, although a favorable trend for pts with the rare transcript exists. Type A and rare fusion pts differ with regard to distribution of accompanying genetic or cytogenetic alterations, such as KIT mutation or +22, which did not occur in any of the rare fusion pts. Further studies are required to elucidate if the rare fusion transcripts themselves created the necessary biologic conditions that exclude the concurrent presence of the genome aberrations.Table.Secondary abns in pts with rare v type A fusionsAbn type*Rare fusion (n=20†) No. pts (%)Type A fusion (n=129) No. pts (%)P‡None [sole inv(16)] 8 (44)81 (63).20+220 (0)24 (19).05+85 (28)11 (9).03+215 (28)2 (2) 〈 .001+132 (11)2 (2).07At least one +8 or +13 or +218 (44)14 (11).001del(7q)/add(7q)0 (0)7 (5).60Other2 (11)11 (9).66*Pts may have multiple secondary abns.†2 unknown.‡Fisher's exact test. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2602-2602
    Abstract: Abstract 2602 Poster Board II-578 One of the major revisions in the 2008 WHO classification of “AML and Related Precursor Neoplasms” is the use of certain cytogenetic abnormalities (abns) as a criterion for inclusion in the “AML with myelodysplasia-related changes” category. These abns include 9 specific reciprocal translocations, 8 unbalanced abns, and complex karyotypes (CK), ie, ≥3 unrelated abns. The clinical features and outcome of patients (pts) with these abns require further study to confirm the appropriateness of their inclusion in this WHO category. Therefore, we evaluated 2,724 consecutive untreated adults meeting criteria for possible inclusion in this WHO category (ie, non-therapy-related AML and not part of the first WHO AML category) in the CALGB cytogenetics database; 516 (19%) pts harbored ≥1 myelodysplasia-related abn and/or CK, and had outcome data available. Their median age was 62 years (y; range, 15–88 y). The 9 reciprocal translocations were very rare, with t(3;5)(q25;q34) found in 6 pts, t(3;21)(q26.2;q22.1) in 2, t(1;3)(p36.3;q21.1) and t(2;11)(p21;q23) in 1 pt each and the remaining 5 translocations not detected. Their rarity precluded further analyses. With the exception of idic(X)(q13), found in 2 pts, the remaining 7 unbalanced abns were more common (Table). Importantly, the abns were not mutually exclusive, ie, ≥2 different abns could co-exist in the same karyotype and/or be part of a CK. Among 453 pts with ≥1 specific unbalanced abn (Table), 62% had CK; the highest % of CK, 89–95%, were seen in the i(17q) or t(17p), −13 or del(13q) and −5 or del(5q) groups and the lowest, only 24%, in del(9q) pts. As a group, non-CK pts had a higher complete remission (CR) rate (P=.002) and longer overall survival (OS; P 〈 .001) than CK pts. This was also the case for OS for most specific abns (Table). Notably, within the non-CK −7 or del(7q) group, −7 pts had worse outcome than del(7q) pts (CR rates, P=.09; OS, P=.002), suggesting that the −7 or 7q- category is not uniform prognostically. Strikingly, pts with del(9q) were younger than pts with other specific myelodysplasia-related unbalanced abns [median age of del(9q) v median age of all others combined, 42 v 63 y, P 〈 .001], and their outcome was better [del(9q) v all others combined: CR rates, 90% v 43%, P 〈 .001; OS, P 〈 .001, 3-y rates, 31% vs. 8%, Figure]. Among 342 pts with CK, those with ≥1 specific myelodysplasia-related unbalanced abn (n=281) had shorter OS than pts without any such abn (n=61; P 〈 .001; 3-y rate, 2% v 20%). We conclude that 1) for most specific myelodysplasia-related unbalanced abns, CK pts do worse than non-CK pts; 2) the presence of specific abns adversely impacts on outcome of CK pts; 3) −7 or 7q- category is not uniform prognostically; 4) del(9q) pts are younger, much less often have CK and their outcome is better than outcome of pts with other unbalanced myelodysplasia-related abns. Consequently, pts with del(9q) appear biologically and clinically different, and their inclusion in the WHO “AML with myelodysplasia-related changes” category should be reconsidered. Future molecular genetic analyses should help characterize each of the cytogenetic subsets within this WHO category further, and might become useful for guiding treatment. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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