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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 8511-8511
    Abstract: 8511 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells in vitro. It has shown synergistic activity with bortezomib (V) and dexamethasone (d). Combination of the CD38 monoclonal antibody daratumumab (D) with Ven is hypothesized to further increase anti-myeloma activity based on dual mechanisms of pro-apoptotic effects on tumor cells and enhanced immune stimulation. Methods: This ongoing Phase 1/2, nonrandomized, multicenter study (NCT03314181) is evaluating safety, efficacy and pharmacokinetics (PK) of VenDd +/- V in patients (pts) with relapsed/refractory MM. In Part 1, pts with t(11;14) who received ≥1 prior line of therapy (PI and an immunomodulatory drug) were treated with VenDd [Ven QD + D 16 mg/kg IV + d 40 mg weekly]. In Part 2, pts irrespective of t(11;14) status, non-refractory to PIs and who received 1–3 prior lines of therapy were treated with VenDVd [Ven QD + D 16 mg/kg IV + V (1.3 mg/m 2 ) + d (20 mg)]. A randomized, open-label expansion (Part 3) will further evaluate and compare safety and efficacy of VenDd (400 or 800 mg Ven dose levels) with control DVd in pts with t(11;14). Results: As of Dec 05, 2019, 48 pts were enrolled. Part 1 included 24 pts with t(11;14), median age 63 (range 51–76). Part 2 included 24 pts, median age 65 (range 41–80) of which 6 (25%) had t(11;14). Frequent adverse events (AEs; VenDd/VenDVd) were fatigue (71%/25%), diarrhea (58%/46%), nausea (46%/50%), insomnia (33%/50%), upper respiratory tract infection (33%/21%), cough (42%/9%), and dyspnea (25%/25%). Frequent Grade ≥ 3 AEs in pts on VenDd were neutropenia (17%), hypertension (12%), fatigue and hyperglycemia (8% each), and in pts on VenDVd were insomnia (21%), diarrhea and thrombocytopenia (8% each). Nine pts had infection-related Grade ≥ 3 AEs (5 VenDd, 4 VenDVd). Eighteen pts had a serious AE (11 VenDd, 7 VenDVd) with pyrexia (n = 3) being most common. One pt on VenDVd died of progressive disease. PK analyses showed that addition of D and V did not impact Ven exposure. Median follow-up time (VenDd/VenDVd) was 10 and 9 months. Overall response rate in VenDd/VenDVd was 96%/92% and 96%/79% had ≥ very good partial response rate. Median progression free survival and duration of response were not reached. Conclusions: Pts treated with VenDd +/- V continue to demonstrate a tolerable safety profile with encouraging efficacy, notably among pts with t(11;14) treated with VenDd. Safety, efficacy, PK, and cytogenetics analyses will be updated for presentation. Clinical trial information: NCT03314181 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 2
    Online Resource
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    Mark Allen Group ; 2010
    In:  British Journal of Hospital Medicine Vol. 71, No. 2 ( 2010-02), p. 70-75
    In: British Journal of Hospital Medicine, Mark Allen Group, Vol. 71, No. 2 ( 2010-02), p. 70-75
    Abstract: Amyloidosis is a heterogeneous group of diseases characterized by normally soluble proteins deposited extracellularly in an abnormally folded, insoluble fibrillar form. This can lead to organ impairment and premature death. This article discusses the pathogenesis, classification system and means of diagnosis of the amyloid diseases.
    Type of Medium: Online Resource
    ISSN: 1750-8460 , 1759-7390
    Language: English
    Publisher: Mark Allen Group
    Publication Date: 2010
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3975-3975
    Abstract: Abstract 3975 Background: Elderly patients with AL amyloidosis present a unique therapeutic challenge. Both the disease itself and other co-morbidities contribute to organ dysfunction, potentially limiting treatment options. Despite this, durable responses can be achieved leading to both improvements in quality and longevity of life. Here we present our experience with patients 〉 75 years (yrs) enrolled in the UK-wide ALchemy study. Patients and Methods: ALchemy was designed to collect comprehensive treatment, outcome and toxicity data in newly diagnosed patients attending the National Amyloidosis Centre in the UK. Analysis of prospectively collected data revealed 46 pts 〉 75 yrs who were enrolled in the study beginning in 2009. 8 patients still alive at last assessment but having 〈 3m follow-up were excluded. Haematologic response was defined as per the 2005 consensus criteria. The dFLC response (difference between the involved and uninvolved free light chain) was defined as the percent difference in the dFLC at the start of therapy and at response assessment and was considered assessable if the baseline dFLC was 〉 50mg/L. A dFLC between 50–90% defined a partial response (PR) and a dFLC of 〉 90% defined a very good partial response (VGPR). The analysis was performed on an intention-to-treat basis and patients who died prior to response assessment were defined as non-responders. Overall survival (OS) was calculated by the Kaplan-Meier method and calculated from diagnosis until death or last follow-up. Results: The final cohort comprised 38 patients. Median age was 78.0 years. Median follow-up was 8.7 months (m). 37 patients had complete information for Mayo staging and 37% were stage III. 3 patients did not receive therapy. 20 patients received CTD as first line therapy, 4 received Mel/Dex, 4 received MPT, 1 received CVD, 3 received CD, 1 received RCD and 2 received CVP-R given baseline IgM secreting clonal B-cell lymphoproliferative disorders. 46% received less than 4 cycles of the planned upfront therapy. Overall response rate (RR) was 68% (11% attained a CR). 65% attained a partial dFLC response and 22% attained a VGPR. 9 patients received second line therapy. 5 were treated for relapsed disease, none of whom bettered their previous haematologic response but 2 patients attained a VGPR. Of the 4 patients who were treated for sub-optimal response none bettered their previous response. A correlation between receiving at least 3 cycles of therapy and attaining a CR or VGPR was observed (correlation coefficient 0.23, P = 0.09 and 0.42, P = 0.009 respectively). Median OS for the entire cohort was 10.7m. 45% died within one year of diagnosis. Median OS for Mayo stage III patients was 6.2 months. Attaining a VGPR by dFLC criteria correlated with a statistically significant improvement in OS compared with patients who did not achieve this milestone (median not reached vs 9.8m respectively; P = 0.016). A similar trend in OS was seen in patients who attained a CR but this did not reach statistical significance (median not reached vs 9.8m respectively; P = 0.192). Discussion: Treatment of elderly patients with AL amyloidosis remains a challenge. From our analysis despite receiving standard of care, median OS is 〈 1 year. However, based on this study appropriate treatment resulted in both attainment of CRs and VGPRs. Both endpoints are important treatment milestones previously shown to correlate with improved survival, and this is further corroborated here. Median OS was not reached in patients achieving either a CR or VGPR. Unfortunately, CR and VGPR rates remain 〈 25% in this population and it appeared that at least one factor is the inability to complete 3 cycles of treatment. Further study examining this distinct group of patients is warranted with the aim to develop therapeutic regimens balancing both effectiveness and tolerability. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 4
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4074-4074
    Abstract: Abstract 4074 AL amyloidosis is caused deposition of monoclonal immunoglobulin light chain and is associated with IgM-paraproteinemia in 5% of cases – mostly due to underlying Waldenstrom's macroglobulinaemia. The standard treatments for AL amyloidosis are typically regimes derived from multiple myeloma and are inappropriate in this group of patients. Response to alkylating agents is poor and there is no agreed standard treatment. We describe here the treatment and outcome of 297 patients with IgM-related AL amyloidosis, with particular focus on the impact of outcomes when treated with regimes developed specifically for Waldenstrom's macroglobulinaemia. 267 consecutive IgM patients with AL amyloidosis were identified form the databases of amyloidosis groups based in London, UK, Pavia, Italy and Limonges/Tolouse/Paris, France- evaluated between 1988 and 2011. 64% of patients had underlying lymphoma mainly of lymphoplasmocytic subtype; lymph node amyloid was present in 18%. Commonest organ involved was the kidney (64%) followed by heart (42%). Serum free light chain ratio was abnormal in 163 (72%) patients with baseline difference between uninvolved and uninvolved FLC (dFLC) 〉 50 mg/L in 124 (54%) cases. 135 patients required therapy, of whom 124 were evaluable for frontline regimen: chlorambucil/melphalan in 57, rituximab-containing regime 60 (23%) (R-CVP, FCR, RCD, R-Bortz, R-CHOP, others), purine analogs in 44 (17%), bortezomib containing 24 (8%), R-CHOP and R-CD in 18 (7%) and 20 (8%). 9 (3%) had high dose melphalan followed by autograft. The haematological response rate on an intention to treat basis was 28% (41% for evaluable patients) with only 2% VGPR or better. Median time to next treatment was 10 months with a better outcome for frontline HDM, CHOP/CVP and FCR (median 49, 16 and 13mo, respectively) with 50% responders. Median OS was 48 months. Presenting dFLC 〉 180mg/L was predictive of poorer outcomes - median survival 48 months for patients with dFLC 〈 180mg/L vs. 21 months for dFLC 〉 180mg/L. The Mayo cardiac stage at presentation was strongly predictive of outcomes with median survival of stage 1 – 74 months, stage 2 24 months and stage 3 – 10 months. Although complete response rates were low, there was a significant survival advantage for patients achieving at least a partial response with estimated 3 year survival of 78% for responders vs. 55% for non-responders (figure 1).: There was a survival advantage for patients receiving HDMel, bortezomib combination (median OS not reached) and FCR (78mo) compared to (R)CHOP/CVP or FC regimens (median OS 42 and 31mo). In summary, the overall treatment responses in patients with IgM associated AL amyloidosis are poor. Presenting free light chains and cardiac biomarkers are prognostic factors in patients with IgM associated AL amyloidosis. Patients with IgM related AL amyloidosis should be treated with appropriately tailored regimens for the underlying lymphoproliferative disorder to achieve at least PR. Exposure at some stage to bortezomib, FCR or HDM appears to be associated with better survival. Figure 1: Overall survival stratified by degree of haematological response Figure 1:. Overall survival stratified by degree of haematological response Disclosures: Roussel: janssen: Honoraria; celgene: Honoraria. Wechalekar:Janssen-Cilag: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 745-745
    Abstract: Abstract 745 The treatment of AL amyloidosis has evolved rapidly over the last few years. The role of autologous stem cell transplantation is controversial and oral combination chemotherapy is often the treatment of first choice. The optimal induction regime is not uniformly agreed upon although some consider oral Mel-Dex as the current “standard of care”. We report our large experience with both Mel-Dex and CTD as upfront treatment for AL amyloidosis in a comparative retrospective study and compare these findings with those of our smaller prospective randomized trial (UKATT), also to be presented as this meeting, using the same treatment regimens (Gillmore et al). Patients treated with Mel-Dex and CTD as first-line treatment between 2002–2009 were identified from the database of the UK National Amyloidosis Centre, London. Organ involvement and responses were assessed according to international consensus criteria (Gertz et al, 2005). The results are summarised below. Our CTD experience has previously been reported at this Congress (Gibbs et al, 2008). A total of 58 patients received Mel-Dex and 122 patients received CTD as upfront therapy. The baseline characteristics of the two groups were not significantly different in terms of median number of organs involved (by both consensus criteria and 123I labelled serum amyloid P component (SAP) scintigraphy), cardiac involvement, creatinine clearances (CrCl) 〈 30ml/min, and NT-ProBNP levels. The Mel-Dex group was an older population, and there was a trend that their CrCl was lower at diagnosis. The median number of cycles administered for both treatments was 5 (range 1–15). More patients presenting with neurological involvement were treated with Mel-Dex. The clonal response rates between the two regimens were not significantly different. The median time to best serum free light chain response (FLC) response for CTD was 2 months (range 1–5 months) versus 3 months for Mel-Dex (range 1–7). At 12 months, organ responses were observed in 44/113 (39%) patients treated with CTD compared to 12/56 (21%) patients treated with Mel-Dex (p = 0.03). Most Mel-Dex responses were renal. The median follow-up is 19 months and the median time to clonal progression was not reached in either group. There was no significant difference in the estimated overall survival at 3 years. Toxicity of any grade was reported by 76% of Mel-Dex patients and 84% of CTD patients (p=0.30). The commonest severe toxicity in both groups was fluid retention. In conclusion, this is the largest comparative series of oral Mel-Dex and CTD in AL amyloidosis. Both regimes are not significantly different in terms of complete (CR) and overall response (OR) rates, toxicity, time to clonal progression or overall survival. There is a suggestion that time to best FLC responses with Mel-Dex is slower than CTD (3 vs 2 months). These results concur with the results of our prospective UKATT trial. Mel-Dex has the disadvantages of being a stem cell toxic regimen, requiring dose adjustment in renal failure. CTD is a reasonable alternative to Mel-Dex in the treatment of AL amyloidosis and a large international randomized prospective trial should be considered. Patient Characteristics at DiagnosisMel-DexCTDp-valueNumber of patients58122Median age (years)7264 〈 0.0001 Males (%)7146Lambda FLC excess (%)7175Abnormal SAP scintigraphy (%)9185Median number organs involved22Median NT Pro-BNP (pmol/L)1241740.84 Median Creatinine (umol/L)9392Median CrCl (ml/min)59730.07 CrCl 〈 30ml/min1415Organs Involved (% patients)Kidney8677Cardiac4748Nervous System3316Liver1018Gastrointestinal107Soft Tissue3119Treatment ResponsesFLC CR, n (%)14/45 (31%)36/96 (38%)FLC PR, n (%)20/45 (44%)40/96 (42%)Overall CR10/56 (18%)28/117 (24%)0.48 Overall PR28/56 (50%)46/117 (39%)Overall Response38/56 (68%)74/117 (63%)0.67 Organ responses12/56 (21%)44/113 (39%)0.03 Renal organ responses11/50 (22%)35/96 (36%)0.11 Median time to FLC PR (months)21Median time to best FLC response (months)32Toxicity, any grade44/58 (76%)102/122 (84%)0.30 Overall survival at 3 years44/57 (77%)90/122 (74%)NS Disclosures: Off Label Use: Off-label use of thalidomide.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 6
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3978-3978
    Abstract: Abstract 3978 Background: Bortezomib alone and in combination with other agents has shown great promise in the treatment of AL amyloidosis in various preliminary open studies. Here we present our experience at the UK National Amyloidosis Centre with CVD in both the upfront and relapsed setting. Patients and Methods: The primary cohort comprises 37 patients referred to the National Amyloidosis Centre in London from 2006–2010. 27 patients had cardiac involvement by 2005 consensus criteria. 29 had renal involvement, 10 had liver involvement and 26 had other organs involved. Complete information for staging by the Mayo clinic criteria was available in 34 patients, and 47% were stage III based on values obtained prior to the initiation of CVD (23% of upfront patients and 62% of relapsed patients). The recommended CVD regimen was as follows: bortezomib 1.0 mg/m2 IV days 1, 4, 8, 11 (increase to 1.3 mg/m2 if well tolerated) cyclophosphamide 350 mg/m2 po days 1, 8, 15 dexamethasone 20 mg po days 1, 4, 8, 11 (increase to 40 mg if well tolerated) with an aim to deliver 6 cycles of treatment. Dose modifications were at the discretion of the treating haematologist. We aimed to assess response at 6 months (m). Haematologic and organ responses were defined as per the 2005 consensus criteria. The dFLC response (difference between the involved and uninvolved free light chain) was defined as the percent difference in the dFLC at the start of therapy and at response assessment and was considered assessable if the baseline dFLC was 〉 50mg/L. A dFLC of 50–90% defined a partial response, and a dFLC of 〉 90% defined a VGPR. Progression free survival (PFS) was calculated by the Kaplan-Meier method and calculated from the start of CVD until relapse, death or last follow-up. Statistical analysis was performed using SPSS version 19. Approval for analysis and publication was obtained from the institutional review board at the University College London, and written consent was obtained from all patients. Results: Median follow-up was 13.3m. Median time to assessment was 5.9m. Median number of cycles given was 4.9. All 37 patients were assessable by haematologic response criteria, 29 of whom were assessable for dFLC response. Overall hematologic response rate (RR) was 78.4% (CR = 35.1%). A VGPR was attained 48.3% of patients with an overall dFLC RR of 79.3%. 14 patients were treated with CVD upfront with a RR of 85.7% (CR = 64.3%, VGPR = 66.7%). 23 patients were treated in the relapse setting and the RR was 73.9% (CR = 17.4%, VGPR = 35.3%). Clonal response is detailed in table 1. 26 patients were assessable for a BNP response based on a pre-treatment NT-proBNP 〉 660 ng/L. BNP responses were seen in 8 patients (31%), stable disease in 14 (54%) and progression in 4 (15%). Of the entire cohort only one death was reported and there were no treatment related mortalities. The time to maximal response was 3.8m (3.0m and 3.8m in patients treated upfront and at relapse respectively). Median PFS has not been reached. The estimated 2-year PFS was 55.6% for the entire cohort, 69.6% for patients treated upfront and 43.8% for those treated at relapse. Attaining a CR correlated with a significant improvement in progression free survival compared with those who had not (median PFS not reached vs. 23.1m respectively, P = 0.029; figure 1A). Attaining a VGPR also correlated with an improved PFS compared with those who had not (median PFS not reached vs. 13.2m respectively, P = 0.003; figure 1B). Conclusion: This retrospective series lends further support to the use of bortezomib containing regimens in the treatment of AL amyloidosis. CVD is a safe and effective treatment option supporting similar findings in other small retrospective series, particularly when used in the upfront setting. This is, to our knowledge, the first series reporting PFS with this regimen. In addition, it confirms the importance of achieving a CR for improved survival outcomes and further validates the dFLC response as an important treatment endpoint. CVD is an attractive treatment combination for patients with AL amyloidosis many of whom are transplant ineligible due to advanced disease. Larger phase III studies are warranted and are underway. Disclosures: Wechalekar: Jansen Cilag: Honoraria.
    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
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  • 7
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 988-988
    Abstract: Abstract 988 The treatment of patients with systemic AL amyloidosis remains challenging. Cyclical combination chemotherapy is used in majority of patients but a report that I.V. melphalan-dexamethasone may not overcome the poor prognosis for cardiac amyloidosis (Deitrich S et al, Blood, 116, 2010) has fuelled the controversy about best front line treatment. We report outcomes of 428 patients treated with oral cyclophosphamide thalidomide dexamethasone (CTD), oral melphalan dexamethasone (M-dex), bortezomib dexamethasone with or without an alkylator (BD), cyclophosphamide-lenalidomide-dexamethasone (CLD) or stem cell transplant (ASCT) as first line treatment for systemic AL amyloidosis assessed at three large European amyloid centres in London (UK), Pavia (Italy) and Athens (Greece) between 2003–2010. Patients with a full baseline data set were included in the study. Clonal and organ responses were defined according to the international amyloidosis consensus statement (Gertz et al 2005) and responses were assessed at 6 months or at the end of treatment. dFLC (difference between involved and uninvolved free light chain (FLC)) was used to assess the absolute FLC change after treatment. 204 (48%) received M-dex, 155 (36%) received CTD, 13 (3%) received ASCT, 28 (7%) received BD and 25 (6%) received CLD. The median number of cycles received was 5 for all regimens. 257 (60%) had cardiac involvement, 325 (76%) had renal and 59 (14%) had liver involvement. Cardiac involvement by regime was: BD 75%, CLD 68%, M-dex 65%, CTD 45% and ASCT 23%. 30 (7%) died within six months of diagnosis. The median number of organ involved was 2 (range 1–5) with ECOG performance status ≥2 in 123 (28%). 98 (23%) patients achieved a complete response (CR), 175 (41%) achieved a partial response (PR) and 125 (29%) did not respond to treatment. A haematological CR/PR was seen, respectively, in 22%/41% treated with CTD, 26%/44% with M-dex, 23%/46% with ASCT, 39%/42% with BD and 4%/44% with CLD. There was significantly greater reduction in dFLC after BD (median reduction 91% over starting value) compared to CTD (median 81%; p = 0.006), M-Dex (median 83%; p = 0.004) and CLD (median 72%; p = 0.03). There was no significant difference in the median dFLC reduction between patients treated with CTD and M-Dex. 100/325 (30%) had a renal organ response, 17/59 (29%) had a hepatic response and 24/257 (9%) had a cardiac response, and 61 (16%) had a cardiac response by NT-proBNP criteria. The organ and NT-proBNP responses respectively were highest in the cohort treated with BD (53% and 32%) followed by CTD (38% and 12%), ASCT (30%), M-dex (23% and 19%) and CLD (12% and nil). CTD achieved significantly better organ responses compared to M-dex (p=0.0024). At median follow up of 29 months, median overall survival (OS) for the whole cohort has not been reached with 2, 3 and 4 year estimated survival of 75%, 65% and 61%, respectively. When patients with cardiac involvement were considered, those achieving a CR have not reached median OS with an estimated 3 year survival of 89%, those with PR had an estimated median OS of 50 months and the non-responders had a median OS of 21 months. Detailed comparison by Mayo stage will be presented. There was no significant difference in the OS of patients treated with CTD or M-Dex (as compared directly or by centre). In summary, outcome of patients with AL amyloidosis across three major European centres appears comparable. BD treatment achieves significantly lower end of treatment dFLC values compared to CTD, M-dex, ASCT or CLD – which importantly translates into an organ response in over half of all patients receiving BD compared to a third of those treated with CTD and quarter of those with M-dex and further follow up may yet reveal survival differences. Organ responses appear significantly better with CTD compared to M-dex – possibly due to more rapid response to CTD since the end of treatment dFLC values are not significantly different - although this does not translate into a survival advantage. Depth of clonal response appears to be directly linked to improvement in survival of patients with cardiac amyloidosis (including in patients treated with CTD and M-dex) and organ response in general. This study supports the rational for doing urgent phase III studies confirming benefits of bortezomib combination chemotherapy for upfront treatment in AL amyloidosis and the benefit of rapid deep clonal responses in cardiac amyloidosis irrespective of the regimen. Disclosures: Off Label Use: Thalidomide, bortezomib, lenalidomide. Dimopoulos:Celgene: Honoraria; Othro Boitech: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 8
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3557-3557
    Abstract: Aim: Cardiac amyloidosis is a protein deposition disease that can be difficult to diagnose and has a poor prognosis if diagnosis or treatment are delayed. The two major subtypes are AL and transthyretin (ATTR). Both have vastly different treatments so confirming the correct amyloid subtype is crucial. A tissue biopsy is usually required for the diagnosis of amyloidosis and to distinguish between the subtypes. No blood test, echocardiography or cardiac MRI can reliably distinguish between AL and ATTR. With a cardiac biopsy, distinguishing AL from ATTR can be challenging with immunohistochemistry, and time consuming with mass spectrometry. Recently, Gillmore et al demonstrated bone scintigraphy with 99mTc-DPD tracer can reliably diagnose ATTR, avoiding endomyocardial biopsies to confirm the subtype in most cases. [1] 99mTc-HDP is a tracer similar to 99mTc-DPD and is more readily available in Australian and the USA. We sought to examine the use of 99mTcHDP bone scintigraphy in Australia and determine the accuracy of this tracer to diagnose cardiac amyloidosis and distinguish between the AL and ATTR subtypes. Methods: All patients with confirmed ATTR or AL who had 99mTcHDP bone scintigraphy were analysed. Results were correlated with histology, NT ProBNP, Troponin-T, free light chains, cardiac MRI and echocardiography. Grading was conducted with Perugini scoring.[1] Results: 25 patients with amyloidosis diagnosed by cardiac MRI and/or biopsy, had 99mTcHDP bone scintigraphy. 18 were confirmed ATTR, 7 AL. Two ATTR patients had hereditary disease (Thy60Ala and Gly109Lys), the remainder were wildtype. 17 (94%) patients with ATTR and 2 (29%) AL had positive scans. The negative ATTR patient had localized bladder disease only with a normal echocardiogram and cardiac biomarkers. All ATTR patients with positive scans had Perugini scores of 2 or 3, including the 2 patients with hereditary mutations, while the two positive AL only had scores of 1. All 11 patients with amyloid features on cardiac MRI had positive scans. Mean NTproBNP values for ATTR and AL were 530pmol/L and 1396pmol/L respectively. The two AL amyloidosis patients with positive bone scans had higher NTproBNP values. No ATTR patient had a detectable plasma cell dyscrasia. Conclusion: Bone scintigraphy with 99mTcHDP tracer is an easily accessible, rapid and non-invasive method of diagnosing cardiac amyloidosis. In our small series, all patients with Perugini scores 2 or 3 had ATTR, while those with negative or Perugini score 1 scan either had AL or no cardiac amyloidosis. There was a suggestion that AL patients with higher NTproBNP scores were more likely to have positive scans. This suggests that the 99mTcHDP tracer can be used like 99mTc-DPD to aid in the diagnosis of cardiac amyloidosis, and, as suggested by Gillmore et al, can confirm the ATTR subtype in those with no detectable plasma cell dyscrasia and Perugini score 2 or 3 scans, thus hastening accurate diagnosis and avoiding cardiac biopsies. Reference: Gillmore JD, Maurer MS, Falk RH, Merlini M, Damy T, Dispenzieri A, et al. Non-biopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12 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: 2016
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  • 9
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1863-1863
    Abstract: Abstract 1863 Poster Board I-888 The role of thalidomide maintenance has been the subject of much debate in the setting of multiple myeloma, however its use in AL amyloidosis has not been previously reported. We report our experience with thalidomide maintenance in patients who had previously received risk adapted cyclophosphamide, thalidomide and dexamethasone chemotherapy (CTD) for the treatment of AL amyloidosis, specifically examining its relationship to clonal response, time to clonal progression, overall survival and toxicity. All patients who achieved either a partial (PR) or complete response (CR) to CTD between 2002 – 2008 were identified from the database of the UK National Amyloidosis Centre, London and included in this study. Clonal and organ involvement and responses were assessed according to international consensus criteria for AL amyloidosis (Gertz et al, 2005). Progression-free (PFS) and overall survival (OS) was assessed by the method of Kaplan-Meier (KM) both for patients who did and did not receive thalidomide maintenance after a clonal response to CTD. PFS was defined as time to clonal progression after commencement of CTD. Thalidomide maintenance was defined as ongoing treatment with single agent thalidomide after CTD. The total number of patients achieving a clonal response to CTD was 108. Thalidomide maintenance was administered to 25 patients (23%), including 6 patients (24%) with symptomatic myeloma. Of these 25 patients, males accounted for 40%. The median age was 60 years (range 42–77). Median number of organs with AL amyloidosis involved was 2. Before thalidomide maintenance, 11 patients had achieved a CR with CTD (44%) and 14 had achieved a PR (56%). The median number of cycles of CTD administered before thalidomide maintenance was 4.5 (range 1 – 7). The median dose of thalidomide administered as maintenance treatment was 50mg daily (range 50mg alternate days to 200mg daily). The median length of maintenance was 10 months (range 1–70 months). Toxicity was the most common reason for cessation of maintenance treatment. After thalidomide maintenance, only 2/14 patients had an improvement in clonal response (14%). One patient had converted a near complete remission (nCR) to CR and another had converted a serum free light chain (FLC) PR to an FLC CR, but without a whole paraprotein response. Clonal progression was seen in 3/25 (12%) patients during thalidomide maintenance treatment, with another 7 patients relapsing after thalidomide was ceased (10 patients (40%) in total). Organ responses were seen in 3 patients - 2 cardiac and one liver - however these patients were already in a clonal CR after CTD treatment before thalidomide maintenance. 19 patients had stable organ involvement with AL amyloidosis. Organ disease progression was seen in 3 patients. Grade 2 or greater toxicity was reported in 18/25 patients (72%) with neuropathy the most common symptom, reported in 10/25 (40%) patients. All but one patient experienced new onset neuropathy after 10 months of thalidomide maintenance. The median follow-up of the thalidomide maintenance patients was 27 months (range 8–71 months). The median KM estimated OS was not reached for patients who either received CTD alone or with thalidomide maintenance. The median PFS was 33 months for patients treated with CTD alone, whereas this had not yet been reached for those treated with thalidomide maintenance (log rank p = 0.55). In conclusion, thalidomide maintenance after CTD in AL amyloidosis is associated with a high rate of additional toxicity (72%) with only minor improvements in clonal responses (14%) and no improvement in overall survival. There is a suggestion that thalidomide maintenance may delay clonal progression however. The optimal dose for thalidomide maintenance is unknown. While this study is small, we suggest that thalidomide should not be routinely used as maintenance therapy in AL amyloidosis. In selected patients who achieve a good clonal response to CTD and tolerate this chemotherapy well, there may be an argument for thalidomide maintenance if a prolongation in PFS is desired. Agents with less toxicity such as lenalidomide might be preferable and need to be further examined in the maintenance setting. Patients with CTD only Patients with CTD and thalidomide maintenance Number patients 83 25 Males 63% 40% CR at end of CTD 41% 44% Median PFS 33 months Not yet reached Further clonal response with thal maintenance NA 14% Grade 2 + toxicity with thal maintenance NA 72% Disclosures: Off Label Use: Off-label use of thalidomide.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    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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  • 10
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2869-2869
    Abstract: Abstract 2869 Poster Board II-845 Introduction: Risk adapted CTD, oral MD and high dose melphalan with autologous stem cell transplantation (SCT) (in selected cases) have emerged as important frontline treatments in AL amyloidosis. We report the interim results of a randomised prospective pilot study designed to estimate response rates and test feasibility of two randomisations using these treatments for patients with newly-diagnosed systemic AL amyloidosis. The final analysis is due in October 2009 and final full study results will be presented at the meeting. Patients and methods: The trial recruited for 14 months from January 2008 in the UK. Twenty four patients each were planned to enter a high intensity (SCT versus CTD) or a low intensity randomization (MD versus CTD) respectively, depending on suitability for SCT. Eligibility for the high-intensity arm was deliberately stringent in order to minimize risk of transplant-related mortality. Primary endpoints were haematologic response by free light chain assay (measured at each cycle with landmark assessments at 3 and 7 months), safety and recruitment rate. A myeloma quality of life (QOL) questionnaire was piloted in the absence of a disease-specific questionnaire for AL amyloidosis at baseline and 7 months post randomisation. Results: The high intensity arm was closed early due to lack of recruitment, mostly from clinical ineligibility and no further results from this arm are reported. The low intensity arm successfully recruited the required 24 patients (12 in each group). Median (range) age at randomization was 66 (42-85) years and stratification was by ECOG performance status which ranged from 0 to 3 (21%, 33%, 33% and 13% of patients respectively). 24 (100%) and 16 (67%) patients have response assessments (or are not evaluable) at 3 months and 7 months respectively at the time of submission. One patient in each arm died and one patient in the MD arm withdrew prior to the 3 month assessment. Overall haematological response rate at 3 months (at least a PR) was similar between the two arms; 9 (75.0% (95% Confidence Interval 43% to 95%)) in the CTD arm versus 8 (66.7% (95% CI 35% to 90%)) in the MD arm. At 3 months, CR was achieved in 7 (58.3% (95% CI 28% to 85%)) CTD and 3 (25.0% (95% CI 6% to 57%)) MD patients. Final response data at 7 months will be presented at the meeting. Median (range) time to achieve at least a PR from commencement of chemotherapy was 88 (34-218) and 95 (74-133) days in the CTD and MD groups respectively. To date, 17 of the 24 patients have reached their maximal clonal response (10 CTD, 7 MD patients), two patients died before achieving maximal response and one patient is not evaluable as they withdrew prior to the first response assessment. 4 patients could still achieve maximal response once 7 month follow up is completed. Of those currently evaluable for a maximal response, 8 (80%) CTD patients had CR versus 3 (43%) MD patients and 1 (1%) CTD patient had PR compared with 4 (57%) MD patients. There were no treatment-related deaths in either arm. Seventeen of 24 (71%) patients experienced grade ≥ 3 toxicities during chemotherapy (10 CTD patients (83%) versus 7 MD patients (58%)) though only 9 were classified as trial medication related SAEs (serious adverse events) which appeared to be similar in each arm - 5 CTD versus 4 MD. Lethargy (n=6), worsening congestive heart failure/fluid overload (n=5), infections (n=7) and pain (n=4) were the most common grade 3/4 toxicities, again with no noticeable differences between the treatment groups. The EORTC QLQ-MY20 myeloma QOL questionnaire appeared valid for use in AL amyloidosis patients and showed comparable QOL among both groups. Conclusions: Randomisation to SCT versus combination chemotherapy is not feasible using the current criteria in the UK. These interim results suggest that CTD may compare favourably with MD with possible higher early CR rates with CTD. There is a general perception that CTD has greater toxicity than MD but in this study there was no evidence of increased SAEs in either group and the QOL was comparable. Further comparison of CTD and MD is warranted in a large phase III randomized trial, but in order to be feasible would require international collaboration. Disclosures: Off Label Use: Off label use of thalidomide.
    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
    Library Location Call Number Volume/Issue/Year Availability
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