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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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    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. 120, No. 21 ( 2012-11-16), p. 2966-2966
    Abstract: Abstract 2966 Introduction: Poor survival in AL amyloidosis is largely driven by outcomes in patients with advanced cardiac disease. To date, the Mayo cardiac staging system is the most widely used tool to identify these high risk patients. For stage III patients few treatment options exist to modify the natural history of this disease with up to 50% dying within the first 6 months. Moreover, there are currently no studies comparing different regimens in the novel agent era specifically addressing this group. Here we present a matched comparison examining response and survival endpoints after upfront treatment in Mayo stage III patients using either Cyclophosphamide, Bortezomib and Dexamethasone (CVD) or Cyclophosphamide, Thalidomide and Dexamethasone (CTD), the current standard of care for this disease in the United Kingdom. Patients and Methods: The primary cohort comprises 78 patients (39 in each arm) referred to the National Amyloidosis Centre in London between 2008–2012. All patients had cardiac involvement by the 2005 consensus criteria and all were Mayo stage III. The CVD cohort reflects all patients seen at the NAC with Mayo stage III disease treated with this regimen upfront. Based on baseline NT-proBNP ( 〉 8000ng/L) and dFLC ( 〉 180mg/L) the patients were then matched with a recent cohort treated with CTD as first line therapy. The CVD and CTD regimens were recommended as previously described (1, 2). Dose modifications were at the discretion of the treating haematologist. Both conventional haematologic responses and dFLC responses were examined (3, 4). Overall survival (OS) was calculated by the Kaplan-Meier method and calculated from the start of treatment until death or last follow-up. To correct for the influence of early deaths on response rates a landmark analysis was performed in patients surviving at least 3 months from treatment (n=21 (CVD) and n=30 (CTD)). Results: In the intention-to-treat (ITT) cohort response rates are comparable although there was a trend to higher CR rates with the CVD regimen (table 1). On an ITT basis, there was no statistically significant difference in the 1-year OS (59.4% vs 46.2% for CVD and CTD respectively, p = 0.9, figure 1a). A high rate of early deaths is noted. 23.7% of CVD and 13.1% of CTD patients died within 6 weeks (p = 0.24). 36.8% of CVD and 23.7% of CTD patients died within 3 months (p = 0.22). In the landmark analysis upfront therapy with CVD correlated with an improved 1-year OS (94% vs 62.1%, p = 0.01, figure 1 b). This may be partly driven by the increased CR rate in the CVD cohort compared to those receiving CTD (47% vs 24% respectively, p = 0.03, table 1). Conclusion: Compared with CTD, treatment with CVD was not associated with a reduction in the high rate of early deaths often seen in patients with Mayo cardiac stage III disease. However, these data suggest that survival of patients treated with CVD upfront may be superior among those who remain alive after the first 3 months, consistent with the higher CR rates achieved. While it did not reach statistical significance the high rate of early deaths indicates that further optimisation and better supportive care strategies are required during the early stages of treatment especially with CVD. Ongoing phase III trials are currently underway to address these issues in a prospective manner. The ITT cohort is shown in (A) and the landmark cohort is shown in (B). Solid and dashed lines reflect CVD and CTD treated patients respectively. Disclosures: 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
    detail.hit.zdb_id: 1468538-3
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  • 7
    In: Journal of the American College of Cardiology, Elsevier BV, Vol. 59, No. 13 ( 2012-03), p. E1225-
    Type of Medium: Online Resource
    ISSN: 0735-1097
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
    detail.hit.zdb_id: 1468327-1
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  • 8
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2796-2796
    Abstract: Abstract 2796 Poster Board II-772 Background: Risk stratification for patients with AL amyloidosis remains difficult. The Mayo staging system (Dispenzieri et al JCO 2004), based on cardiac biomarkers, is a widely accepted staging method. The Mayo staging cohort was diagnosed over a 21 year period during which the treatment for AL amyloidosis has completely changed. It also does not take into account the underlying clonal disease biology which is emerging as an independent prognostic factor. We propose a new staging for AL amyloidosis incorporating serum free light chains into the Mayo staging system using a much more uniformly treated cohort of patients. Methods: 212 patients with systemic AL amyloidosis attending the UK National Amyloidosis Centre between Jan 2001 and March 2008 with complete data sets (or stored sampled for retrospective testing) for FLC, NT-ProBNP and cardiac Troponin-T prior to any treatment were identified from the database. Patients with overt symptomatic myeloma were excluded from the analysis. Results: Median age was 64 years (range 26-88), male: female ratio was 1.3:1. Median serum creatinine was 149 μmol/L (37-1079), and 24 hour proteinuria 3.9g ( 〈 0.1- 20g) with renal involvement being the commonest followed by cardiac. The FLC ratio was abnormal in 180 (85%) patients, with a lambda bias in 136 (64%) cases and a kappa bias in 44 (21%). The concentration of the abnormal class of FLC (iFLC) exceeded 500mg/L in 71 (33%) cases. The median overall survival (OS) of the cohort was 1.8 years with no significant difference in OS for patients with either kappa or lambda as the abnormal component. The cut-off for NT-ProBNP and troponin-T were based on the Mayo staging system (35 pMol/L and 0.03 ng/ml respectively) and iFLC cut-off was selected as 500 mg/L. The median overall survival for patients with values above and below the cut-off were: troponin-T – 0.4 yrs vs. 4.7 yrs (p 〈 0.0001), NT-ProBNP – 1.2 yrs vs. median not reached (p 〈 0.0001) and FLC – 0.9 yrs vs. 3.2 yrs (p=0.02). All patients with a high troponin-T had high NT-ProBNP. For patients with high troponin-T, serum free light chain level at presentation did not significantly affect OS (0.34 vs. 0.48 yrs). When this group was excluded, serum free light chains further stratified patients with a normal or abnormal NT-ProBNP. For the group with normal NT-ProBNP, the median OS was not reached for patients with iFLC 〈 500 mg/L vs. 3.1 yrs for those with iFLC 〉 500mg/L; those with abnormal NT-ProBNP – median OS was 4.6 yrs vs. 1.2 yrs (p=0.015) respectively for low and high FLC. iFLC 〉 500 mg/L independently predicted for poorer OS in a multivariate model (p =0.016). A new staging system is proposed incorporating iFLC using the above mentioned cut-off values for NT-ProBNP, troponin-T and iFLC: Stage I - normal NT-ProBNP/troponin-T with low iFLC (median OS not reached); Stage II - high NT-ProBNP and low iFLC (median OS 4.6 yrs); Stage III - high iFLC (median OS 2 yrs); and Stage IV - abnormal troponin (median OS 0.4 yrs). At 18 months from diagnosis, 8% of stage I, 25% of stage II, 45% of stage III and 76% of stage IV patients had died. Stage IV patients were more likely to have not completed a full course of treatment (42%) compared to other groups (23% stage, 18% and 24% for the other three stages). 6% and 7% of stage I and II patients underwent an autologous stem cell transplant compared to none in the other stages. Conclusion: This new staging system for AL amyloidosis brings clonal markers in the stratification process. Patients with high troponin-T at presentation have a dismal outcome even with recent treatment advances which is unaffected by clonal parameters and need novel rapidly effective approach to treatment. In the other groups, the free light chains at presentation – a surrogate for the clonal burden – are prognostically important. This system offers better stratification of patients over the current system – it upstaged 14% Mayo stage I and 32% stage II patients. Adding the clonal markers may make this useful for addressing new questions in clinical trials. Given the low clonal burden in the good risk stage I patients, is the highest intensity treatment (i.e. ASCT) really needed and could they conceivably achieve the same outcome with less toxic short course treatment? This new staging system needs to be validated in independent patient groups and if validated should be adopted as a new amyloidosis staging system. Disclosures: Bradwell: The Binding Site: Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 9
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4355-4355
    Abstract: Introduction: The introduction of novel agentshas revolutionised the treatment of multiple myeloma, with improvements in survival of newly diagnosed and relapsed/refractory patients. However, despite these advances, the role for allogeneic haematopoietic stem cell transplantation (HSCT) in the treatment of these patients remains in question. Reduced-intensity conditioning (RIC) HSCT with Seattle regimen (30 mg/m2 fludarabine and 2 Gray total-body irradiation, TBI) for multiple myeloma has been reported to be an effective treatment with low upfront toxicity, and the potential for graft-versus-myeloma effect (Niederwieser D et al, Blood, 2003). Its use as part of tandem HSCT (autologous HSCT followed by RIC-HSCT) is associated with a treatment-related mortality (TRM) rate as low as 15% (Björkstrand B et al, J Clin Onc, 2011). However, data on survival following auto-HSCT/RIC-HSCT is inconsistent and no unifying consensus has been reached regarding the optimal timing of RIC-HSCT in the treatment algorithm. In this retrospective multi-centre study, we investigated the safety, tolerability and efficacy of RIC-HSCT in multiple myeloma patients in remission following previous auto-HSCT. Methods: A retrospective series was conducted for early-phase, high-risk myeloma patients who underwent RIC-HSCT following prior auto-HSCT in two tertiary transplant centres in Manchester in North West England, between November 2006 and July 2014. Results: Over the eight-year period, 42 myeloma patients (male n=29, female n=13) underwent Seattle-conditioned RIC-HSCT following prior auto-HSCT. 66.6% (n=28) were performed in tandem. Median age at RIC-HSCT was 52 years (range 41-65), and median β2-microglobulin at diagnosis was 3.1 mg/L (range 1.6-18.0). 16 patients had cytogenetics assessed at the time of diagnosis, of which loss of TP53 and translocation of chromosome 14 were most common. 37 patients (88.1%) had previously been exposed to immunomodulatory agents (IMiDs). 53.3% patients (n=24) were in first remission at RIC-HSCT, whilst 37.8% (n=17) were in second remission. 31.1% (n=14) of RIC-HSCTs were performed after second auto-HSCT following previous relapse and re-induction chemotherapy. 34 patients (55.9%) had achieved at least a very good partial response (VGPR) prior to RIC-HSCT. RIC-HSCT was performed a median of 20 months (range 10-89) from diagnosis. Two patients (4.8%) required re-transplantation for failed engraftment, but subsequently engrafted following in vivo T cell-depleting regimens. Mortality at early and interim time-points was low relative to registry and trial series, with TRM of 2.4% (n =1) and 9.5% (n=4) at day 100 and 365, respectively. 37 patients (82.2%) experienced chronic graft-versus-host disease (GVHD). Chronic skin GVHD was observed in 21 patients (grade 1-2: n=20; grade 3-4: n=1); chronic gastrointestinal GVHD in four patients (grade 1-2: n=1; grade 3-4: n=3); chronic hepatic GVHD in six patients (grade 1-2: n=4; grade 3-4: n=2); chronic oral GVHD in 17 patients (grade 1-2: n=17); and chronic ophthalmic GVHD in five patients (grade 1-2: n=5). There was an association between GVHD and enhanced disease control, as complete response rates increased from 26.5% to 51.5% by day 100 post-RIC-HSCT. However, 22 patients (48.9%) eventually relapsed with a median time to relapse of 6.5 months. 13 patients remain in CR one year post-RIC-HSCT. Relapse was treated with escalating donor lymphocyte infusions (DLI, n=13) or IMiDs (n=16). Response to lenalidomide at relapse was potentiated, despite the majority of patients having prior exposure to IMiDs. The median length of follow-up from diagnosis was 27 months (range 1-90). Median overall survival (OS) has not been reached; OS at two years was 69.2% (Figure 1). Conclusions: In this retrospective series we demonstrate the feasibility of Seattle-conditioned RIC-HSCT in multiple myeloma. We observed a very low early TRM of 9.5% and presence of allo-immune disease control (graft-versus-myeloma effect), thereby augmenting IMiD efficacy. Chronic GVHD was prevalent and relapse occurred in a significant proportion of patients, but salvage with DLI and IMiDs highlighted the efficacy of the graft-versus-myeloma effect elicited by RIC-HSCT. Figure 1. Survival outcomes after RIC-HSCT in myeloma. Median OS has not been reached, two-year OS was 69.2%. Figure 1. Survival outcomes after RIC-HSCT in myeloma. Median OS has not been reached, two-year OS was 69.2%. Disclosures Cavet: Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Speaker. Tholouli:Pfizer: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Gibbs:Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 10
    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
    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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