Efficacy of Bortezomib/Cyclophosphamide/Dexamethasone (VCD) Chemotherapy In Naive Patients with High Risk Cardiac Light Chain Amyloidosis (Mayo Clinic stage III)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5126-5126
Author(s):  
Arnaud Jaccard ◽  
Murielle Roussel ◽  
Anne Banos ◽  
David Lavergne ◽  
Jacques Ninet ◽  
...  
Keyword(s):  
High Risk ◽  
Mayo Clinic ◽  
Poor Prognosis ◽  
Cardiac Amyloidosis ◽  
Median Number ◽  
Stage Iii ◽  
Hematological Toxicity ◽  
Al Amyloidosis ◽  
Hematological Response

Abstract Abstract 5126 Purpose: Severe cardiac involvement is known to confer a poor prognosis in patients with AL amyloidosis. High-dose chemotherapy is not an option for these patients and melphalan/dexamethasone (M-Dex) therapy is not able to overcome this poor prognosis (Dietrich et al, 2010). Bortezomib (Bb) is known to induce rapid hematological response in amyloidosis and its association with cyclophosphamide and dexamethasone is proven to be highly active and effective in multiple myeloma. (Reeder, Leukemia 2009). We therefore proposed to use this regimen for patients with high-risk cardiac amyloidosis as defined by Mayo Clinic stage III, treated among the French network for amyloidosis. Patients and Method: We retrospectively evaluated 13 patients with systemic AL amyloidosis, classified as Mayo Clinic stage III cardiac amyloidosis based on their elevated cardiac biomarkers NT-proBNP and troponine-T values treated with VCD as first line treatment in 5 centres. To reduce toxicity in these frail patients Bb was administered once weekly with a usual dosage of 1.3 mg/m2 on days 1, 8, 15 and 22 in a 5 week schedule. Dexamethasone was given the day of Bb administration and the day after, 10 or 20 mg depending on patient age and performans status; cyclophosphamide, 300 mg/m2, max 500 mg, was given orally at days 1, 8 and 15. The new criteria defined at the international amyloidosis meeting in Roma in April 2010 were used to define the hematological response. Result: There were 7 women and 6 men, median age was 69 (55–81). Median NT-proBNP was 12325 ng/L (1036–66000) and median troponine-T was 0, 11 mg/mL (0.04–0.61). The median number of involved organ was 2 (1–5). Median difference between pathologic and normal FLC (dFLC) was 281 mg/L (82–2976). Height patients had a renal involvement. Median follow up of the entire cohort is 3.0 months (0–8), only 1 patients died, during ongoing VCD, probably from cardiac arrest. Median number of cycle was 3 (1–6). Height patients had a free light chain (FLC) measurement after 1 to 3 cycles (median 3) and all achieved an hematological response (4 CRs (50%), 3 PRs (37.5 %) and 1 VGPR (12.5 %) defined as a dFLC below 40 mg. The median dFLC of these 8 pts was 278 (137–3759) at diagnosis and 17.9 (0.6–298) at evaluation. We observed non-hematological toxicity in 5 patients, sepsis in 1, non fatal cardiac decompensation in 2, diarrhoea in 1 and bowel obstruction in 1. No neuropathy or hematological toxicity was observed. Therapy was stopped before the planned 6 – 8 cycles in 2 patients due to patient choice in 1 case and to clinician choice in 1 patient in CR. Therapy is still ongoing in 8 patients. Conclusion: The retrospective nature, small sample size and short follow-up limit this study (which should be updated for the meeting), but the impressive hematological response rate (CR-VGPR = 62.5%) obtained very rapidly, the low toxicity profile and the excellent OS with only 1 death in these very severe cohort of naive patients with Mayo stage III (median OS 3.5 months, Dispenzieri et al, 2004) already justify a prospective phase II trial using this regimen in Mayo stage III pts. Disclosures: Jaccard: Janssen: Honoraria, Research Funding.

Metronomic therapy for heavily pretreated relapsed/refractory multiple myeloma (RRMM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8041-8041
Author(s):  
Xenofon Papanikolaou ◽  
Jackie Szymonifka ◽  
Alan Mitchell ◽  
Jason Keller ◽  
Christoph Johann Heuck ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Model ◽  
Median Number ◽  
Outpatient Setting ◽  
Salvage Treatment ◽  
Hematological Toxicity ◽  
Toxicity Profile ◽  
Heavily Pretreated ◽  
Metronomic Therapy

8041 Background: RRMM represents a true challenge in MM therapy. Based on the effectiveness of metronomic therapy in solid tumors, we developed a treatment of metronomically scheduled therapy (MT) for RRMM (Hollmig, ASH 2004). We are now updating our experience with a median follow up of 25.6 months. Methods: We identified 187 patients treated with MT from 03/2004 to 11/2011. Results: The median age was 61 years (range 36-83); the median number of prior therapies was 14 (range 1-51). 79% of patients had prior HDT, 99% had a prior exposure to bortezomib, 98% to an IMiD, and 95% to their combination . The median number of completed MT cycles was 1 (range 1-5). 63% of patients had a response of MR or better (6% CR ,7% VGPR, 36% PR, 16% MR). The median overall (OS) and progression free (PFS) survivals were 11.3 and 3.7 months respectively. 91 of 187 patients had gene expression profiling (GEP) prior to initiation of MT, of which 53% were high risk according to the 70-gene (GEP70) risk model. OS was affected by elevated CRP (> 8mg/L, HR=1.71, p=0.009) and cytogenetic abnormalities within 6 months of initiation of MT (HR=2.45, p<0.001). For the 91 patients with GEP data available, OS was correlated with elevated CRP > 8mg/L (HR=2.11, p=0.009) and GEP70 high-risk (HR=2.65, p<0.001), which also showed a trend towards shorter PFS. Hematological toxicity grading was difficult as 69% of patients presented with grade >=3 thrombocytopenia within 90 days prior to starting MT. Grade 4 leucopenia , anemia thrombocytopenia due to MT occurred in 74%, 17%, 89% of patients respectively. Incidence of grade 4 neutropenic fever was 1%. Grade 4 or worse incidence of all non-hematological toxicities was below 9%. Most patients were treated in the outpatient setting (95%) and secondary admissions due to regimen toxicity occurred in 20%. Conclusions: MT is an effective salvage treatment in RRMM, with a high ORR and a favorable toxicity profile. [Table: see text]

Efficacy and Toxicity of Dose-Reduced Bortezomib/Dexamethasone Chemotherapy In Patients with High Risk Cardiac Light Chain Amyloidosis (Mayo Clinic stage III)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1960-1960 ◽  
Author(s):  
Stefan O Schonland ◽  
Tilmann Bochtler ◽  
Anthony D. Ho ◽  
Ute Hegenbart
Keyword(s):  
Light Chain ◽  
Mayo Clinic ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Early Death ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 1960 Purpose: Severe cardiac involvement is known to confer a poor prognosis in patients with light chain (AL-) amyloidosis. These patients do not qualify for high-dose chemotherapy regimens. In a recent analysis we could show that melphalan/dexamethasone therapy was not able to overcome this poor prognosis (Dietrich et al, 2010). Since bortezomib is known to rapidly lower the involved light chain levels (iFLC), it appears a promising alternative regimen. There is only one prospective phase I/II trial in AL amyloidosis using single agent bortezomib (Reece et al., 2009). However, patients with advanced cardiac amyloidosis had been excluded. We therefore assessed the feasibility of bortezomib/dexamethasone (Bd) in patients with high-risk cardiac amyloidosis as defined by Mayo Clinic stage III (median overall survival (OS) 3.5 months (mo), Dispenzieri et al, 2004). Patients and Method: We retrospectively evaluated 38 consecutive patients with systemic AL amyloidosis, who were classified as Mayo Clinic stage III cardiac amyloidosis based on their elevated cardiac biomarkers NT-proBNP, TNT and hsTNT values (patient characteristics table 1). 14 patients were untreated. For the sake of tolerability Bd was administered twice weekly with a reduced bortezomib dosage of 4 × 1.0 mg/m2 and dexamethasone 8 × 8 mg in a 3 week schedule. Result: Median observation of living patients is 5 mo after start of Bd. Median OS is 9 mo (Figure 1a). 18 patients died; among them 11 (29%) during ongoing bd. Median OS of the first line therapy group was 7 mo versus 13 mo in the relapsed group (p=0.056, Figure 1b). 21 patients achieved a hematological remission (HR) after a median of 3 cycles (64% out of 33 evaluable patients, 2 CRs and 19 PRs), whereas 3 patients died during the first Bd cycle and further 2 just started with Bd. Hematologic toxicity grade 3 or 4 according to NCI criteria was observed in 9 patients (24%) (toxicities are listed in table 1). Apart from the 11 early deaths we observed non-hematologic toxicity grade 3 in 8 patients and grade 4 in 6 patients. In 3 patients, the bortezomib dose had to be reduced due to toxicity. Therapy was stopped before the planned 6 – 8 cycles in 11 patients, in 4 cases due to toxicity, in 5 cases due to lacking HR and in 2 cases due to patient‘s choice. 9 patients completed their therapy regularly in HR while therapy is still ongoing in 5 patients. It is planned to update these data in November 2010. Discussion: The goal of this study was to assess whether patients with severe cardiac amyloidosis as defined by Mayo Clinic stage III benefit from Bd therapy. As already known from other studies, we observed a fast reduction of iFLC within 3 months from 203 to 81 mg/l (of evaluable patients) in median. Overall, HR rate was 64%, which is comparable to 71% previously reported by Kastritis et al, 2010. However, toxicity and early death rate were considerable. Main problem of the newly diagnosed patients was the severity of cardiac involvement (median NTpro BNP 11.346 ng/l) leading to a high early mortality. Main problem of the pretreated patients was the lower HR rate of 52% versus 83% of the newly diagnosed patients. Though we observed substantial toxicities in spite of the reduced Bd dosages, the rather poor OS does not appear to be largely due to toxicity. Conclusion: Dose-reduced Bd might be an important treatment option for patients with severe cardiac AL amyloidosis Mayo Clinic stage III because of its high efficacy. However, the toxicity is still significant. Inpatient care for the first cycle of Bd might lead to a reduction of the early death rate. Disclosures: No relevant conflicts of interest to declare.

A European Collaborative Study of Treatment Outcomes In 428 Patients with Systemic AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 988-988 ◽  
Author(s):  
Ashutosh D Wechalekar ◽  
Efstathios Kastritis ◽  
Giampaolo Merlini ◽  
Philip N Hawkins ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Median Number ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Line Treatment ◽  
End Of Treatment ◽  
Significant Difference ◽  
Organ Response

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.

scholarly journals Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naive patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III)

Haematologica ◽  
2014 ◽  
Vol 99 (9) ◽  
pp. 1479-1485 ◽  
Author(s):  
A. Jaccard ◽  
R. L. Comenzo ◽  
P. Hari ◽  
P. N. Hawkins ◽  
M. Roussel ◽  
...  
Keyword(s):  
High Risk ◽  
Mayo Clinic ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
Treatment Naïve

scholarly journals Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial

2020 ◽  
Vol 38 (33) ◽  
pp. 3925-3936 ◽  
Author(s):  
Alexander M. M. Eggermont ◽  
Christian U. Blank ◽  
Mario Mandala ◽  
Georgina V. Long ◽  
Victoria G. Atkinson ◽  
...  
Keyword(s):  
Lymph Node ◽  
High Risk ◽  
Phase Iii ◽  
Stage Iii ◽  
Recurrence Free Survival ◽  
Meaningful Improvement ◽  
Free Survival ◽  
Stage Iii Melanoma ◽  
The Impact

PURPOSE We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. PATIENTS AND METHODS A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)–positive tumors. RESULTS Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1–positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). CONCLUSION In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.

Excellent Immune Recovery Following the Intensive Chemotherapy CODOX-M/IVAC, An Effective Therapy for HIV-Associated Burkitt’s Lymphoma (BL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3612-3612
Author(s):  
Silvia Montoto ◽  
Jamie Wilson ◽  
Kate Shaw ◽  
Maureen Heath ◽  
Andy Wilson ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Stage Iii ◽  
Concomitant Treatment ◽  
Immune Recovery ◽  
Intensive Chemotherapy ◽  
End Of Treatment ◽  
High Risk Disease ◽  
Immunological Recovery

Abstract Background and aim: The outcome of patients with HIV-associated Burkitt’s lymphoma (HIV-BL) treated with infusional regimens remains poor, even in the highly active anti-retroviral (HAART) era. In contrast, promising results have been published in HIV-BL with the same intensive chemotherapies used in the non-HIV population. However, scarce data on immunological recovery following these regimens are available. The objective of this multicentre study was to analyse the outcome of patients with HIVBL treated with the intensive chemotherapy regimen CODOX-M/IVAC and HAART, with a particular emphasis on the analysis of immunological recovery after treatment. Patients and methods: 29 patients (22 male; median age: 38) from 3 UK centres consecutively treated with CODOX-M/IVAC from 2003 to 2008 were included in the study. CODOX-M/IVAC consisted of 2 alternating cycles of CODOX-M (cyclophosphamide 800mg/sqm day 1 and 200mg/sqm days 2–5, doxorubicin 40mg/sqm day 1, vincristine 1.5mg/sqm days 1 and 8, methotrexate 3g/sqm day 10) and IVAC (etoposide 60mg/sqm days 1–5, ifosfamide 1g/sqm days 1–5, cytarabine 1g/sqm bd days 1 and 2) for patients with high-risk disease and 3 cycles of CODOX-M for patients with low-risk disease. High-risk disease was defined by the presence of at least 2 of the following: stage III–IV, ECOG≥2, extranodal sites≥2 or high serum LDH. All patients received concomitant treatment with HAART (NRTI + NNRTI: 21; NRTI + PI: 8) and prophylactic antimicrobials as well as intrathecal prophylaxis and G-CSF as per protocol. Four patients received rituximab in combination with the chemotherapy. Lymphocyte subsets and plasma HIV-1 viral load (VL) were measured during chemotherapy and at 3-month intervals during follow-up. Results: HIV was diagnosed concomitantly with BL in 12 patients. The median CD4 count at BL diagnosis was 167/mm3 (range: 4–848), with CD4>200/mm3 in 41% of patients and VL being undetectable in 5 (18%) patients. Eight (28%) of the patients previously known to have HIV infection were on HAART before the diagnosis of BL. The majority of the patients (72%) had high-risk disease. Twenty patients (69%) were diagnosed in advanced stage (III–IV), with bone marrow (BM) involvement in 6 (21%) and central nervous system (CNS) infiltration in 5 (17%). The International Prognostic Index (IPI) was high (3–5) in 14 (48%) patients. Grade 3–4 non haematological toxicity was as follows: infection, 66% of the cycles; mucositis, 12%; and diarrhoea, 13%. Nine patients died during treatment, due to disease progression in 3 cases, toxicity in 5 (3 infections, 2 GI bleeding) and 1 patient died with a CNS lesion that was not biopsed. Response at the end of treatment amongst 23 assessable patients was as follows: complete response (CR)/CR uncertain (CRu): 16 patients (69%); partial response (PR): 4 (17%); progression: 3 patients (13%). After a median follow-up of 17 months (range: 9–67), 17 of 20 responding patients remain alive without disease progression, whilst 2 patients (1 CR, 1 PR) relapsed at 2 and 1 months after finishing treatment and died. One HAART non-compliant patient died in CR of HIV-related causes. Three patients in PR at the end of treatment survive without evidence of disease progression at 28, 37 and 51 months. Overall survival (OS) and disease-free survival (DFS) at 3 years were 49% and 70% respectively. Blood samples for immune recovery analyses were available for the majority of the patients during follow-up (81% 6 months after finishing chemotherapy, 86% at 12 and 24 months). VL was undetectable in 85% and CD4>200/mm3 in 53% of assessable patients 6 months after completing chemotherapy. Time (no. patients at risk) % CD4>200/mm 3 VL undetectable no./no. assessed % no./no. assessed % At BL diagnosis (29) 12/29 41 5/28 18 1 month after finishing chemotherapy (21) 5/17 29 10/15 67 6 months after finishing chemotherapy (16) 8/15 53 11/13 85 12 months after finishing chemotherapy (14) 9/12 75 10/12 83 Conclusions: This retrospective analysis demonstrates that the intensive regimen CODOX-M/IVAC is feasible and effective in HIV positive patients on HAART with BL. Immunological recovery after treatment, not previously reported after such intensive chemotherapy, is excellent. Whether concomitant treatment with rituximab will improve outcome warrants further study.

Adherence to Imatinib Mesylate Treatment: Two Years Follow up

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4267-4267 ◽  
Author(s):  
Carlos A. Doti ◽  
German R Stemmelin ◽  
Elena Beatriz Moiraghi ◽  
María Gabriela Flores ◽  
Juan Garcia ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Complete Information ◽  
Cytogenetic Response ◽  
Hematological Toxicity ◽  
Control Group ◽  
Hematological Response ◽  
Complete Hematological Response

Abstract Background: Since the introduction of Imatinib (IM), the treatment of chronic myeloid leukemia (CML) experienced its most important change. As this drug became the first line for the treatment of CML, we learned that under-dosing was associated with a delay in achieving cytogenetic response and the development of acquired resistance. Last year we presented a case-control study that analyzed how compliance affects the cytogenetic response to Imatinib. This is an update of that data. Materials and Methods: Twenty-four patients with newly diagnosed Ph (+) chronic phase CML (CP-CML) were included and followed for 24 months. Patients received 400mg of IM and were asked to note down all taken doses, and reasons for non-compliance. Follow up visits were scheduled every 28–30 days and prescriptions were filled in order to last for only 30 days. During each visit, the medication was counted and non-adherence reasons were determined. Adverse events were graded according to the CTC and modifications in the Imatinib dose were only allowed with related adverse events with a CTC score ≥3. As a control group, we matched each case with a Phi + CP-CML patient from our data base of the same sex and similar age as the case patient. All control patients had to have complete information about dosing and response. They all received initial treatment with IM 400mg; thereafter, dose was adjusted according to each physician’s criteria. Compliance was measured as: mg prescribed/mg taken during the study period. Results: Twenty-four patients, 14 males median age 56 yo (range: 24–83), were included in the study. Three were lost to follow up, leaving only twenty-one for analysis of compliance. At the end of the first year, all patients had complete hematological response. Compliance during these 12 months was 96.1, which is clearly superior to the 80% reported in the setting of clinical trials. All patients had a complete hematological response, 89.9 achieved a major cytogenetic response (MCyR) and 87.4 a complete cytogenetic response (CCyR), compared to 60 of the control group with a MCyR (p=0.027) and 57.8 a CCyR (p=0.025). During the second year, four patients lost CCyR, three responded to an increase in IM dose and one progressed to an accelerated phase and died. Compliance fell slightly during this period to 90.86% which was reflected in 81.66% CCyR, which was still statistically higher than the 54% of major responses in the control group (p=0.033). In both groups, none of the patients not achieving MCyR at 12 months achieved MCyR at 24 months. Hematological toxicity was more frequently observed within the first 6 months of treatment and after the increase in dosage. Severity and incidence of adverse events were similar in both groups, and were the main reasons for interruption or reduction of IM dose in the control group. The only additional difference besides compliance between the two groups was the average IM dose prescribed during the duration of the study (cases group: 430mg – control group: 330mg). Conclusions: Adherence to Imatinib is associated with an improvement in cytogenetic response that can be seen even at two years after the start of therapy. Since outcome and development of resistance seem to be associated with compliance to therapy, emphasis should be put on maintaining treatment at an adequate dose for as long as possible.

ALchemy - A Large Prospective ‘Real World' Study of Chemotherapy in AL Amyloidosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 992-992 ◽  
Author(s):  
Thirusha Lane ◽  
Lisa Rannigan ◽  
Darren Foard ◽  
Ashutosh Wechalekar ◽  
Simon Gibbs ◽  
...  
Keyword(s):  
Disease Severity ◽  
Real World ◽  
Poor Prognosis ◽  
Fluid Overload ◽  
Conflicts Of Interest ◽  
Unmet Need ◽  
Whole Body ◽  
Al Amyloidosis ◽  
First Line

Abstract Abstract 992 Background: There have been few prospective clinical trials in AL amyloidosis; existing prospective studies in this heterogeneous disease have been hampered by small patient numbers due to rarity of the condition, a lack of validated endpoints and high cost. More importantly, they have been subject to considerable bias due to almost complete exclusion of poor prognosis patients. Aims: The aims of this prospective observational study, was to include all patients with systemic AL amyloidosis regardless of age or disease severity, in order to convey a ‘real-world' picture of the disease, its response to myeloma-type chemotherapy regimens, associated toxicity and outcomes in terms of amyloidotic organ function, quality of life (QoL) and survival. Methods: All patients referred to the UK National Amyloidosis Centre (NAC) from 1st September 2009 were screened for participation in the AL chemotherapy study (ALchemy). Patients were eligible if they were newly diagnosed with systemic AL amyloidosis and in need of chemotherapy. At each NAC evaluation (baseline, after completion of 3 cycles of chemotherapy and 6, 12, 18 and 24 months) the underlying clonal disease was assessed by sFLC assay and serum and urine electrophoresis; amyloidotic organ dysfunction/response was assessed according to the international consensus criteria. At baseline patients underwent bone marrow examination, assessment of whole-body amyloid load by 123I-SAP scintigraphy, and completed a QoL questionnaire. Amyloid burden was monitored 6 monthly thereafter, and QoL after 3 cycles and yearly thereafter. Clonal disease assessments were undertaken monthly throughout the duration of the study and toxicity assessments during periods of chemotherapy. Patients received chemotherapy in local hematology centers and regimens and doses were at the discretion of treating physicians. Results: Two hundred and fifty patients were recruited in 2 years; 57% were male. Median age at presentation was 64 years (IQR 57 to 73). At baseline evaluation, which occurred a median of 1 month from diagnosis, 20% of patients had Mayo stage 1 disease, and 40% each had stage 2 and 3 disease. Renal (50%) and cardiac (31%) presentations predominated. At censor, 9 (4%) patients had died prior to starting chemotherapy and 217 (87%) patients had received at least one cycle and were thus considered ‘evaluable'. First-line treatment was with CTD in 168 (77%) cases, 89% of whom received dose attenuation. Nineteen (9%) patients received a melphalan- or bortezomib-based regimen first line. One third of those patients who commenced chemotherapy underwent a regimen change, usually (82%) to one containing bortezomib, either as monotherapy (9 patients) or in combination with dexamethasone and/or cyclophosphamide (47 patients). On an intention to treat basis, 20% patients died before reaching the 3 cycle timepoint and a further 9% were withdrawn or lost to follow up. Among the 154 remaining evaluable patients, the 3 cycle evaluation resulted in continuation of the same chemotherapy regimen in 42% cases, a switch of regimen in 21% cases, and cessation of chemotherapy altogether in 28% cases. At this timepoint, clonal CR, VGPR, PR and NR rates among evaluable patients were 35%, 9%, 30% and 26% respectively. Toxicity ≥grade 3 occurred in 49% of patients with a total of 359 episodes. The commonest severe toxicities were fluid overload (61%), lethargy (38%), infection (26%), hypotension (18%) and neuropathy (12%). Of 217 patients, 111 (51%) were admitted with a total of 148 hospitalizations, most commonly due to fluid overload or infection. After median follow-up of 7 months, 29% of patients had died. Mayo stage 3 disease, dominant cardiac presentation and inadequate clonal response after 3 cycles were independent risk factors for death. Achieving a dFLC response >65% after the first cycle of chemotherapy, appeared to overcome the poor prognosis associated with Mayo Stage 3 disease. Conclusion: ALchemy is fast becoming the largest prospective study in AL amyloidosis and has provided a wealth of information on treatment, toxicity and outcome in a real-world clinical setting. The inclusion of most patients, regardless of disease severity, indicates a persistently poor prognosis among a substantial proportion of patients who are ineligible for randomized controlled trials, and highlights the unmet need for improved diagnosis and treatment. Disclosures: No relevant conflicts of interest to declare.

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

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

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

A Phase II Add-on Study of Vorinostat (VOR) in Higher Risk Myelodysplastic Syndrome with Failure of Hypomethylating Agents (HMA): The GFM Azavor Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2900-2900
Author(s):  
Thomas Prebet ◽  
Jacques Delaunay ◽  
Eric Wattel ◽  
Thorsten Braun ◽  
Pascale Cony-Makhoul ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rate ◽  
Standard Of Care ◽  
Median Number ◽  
Current Standard ◽  
Stage Design ◽  
Early Evaluation ◽  
Positive Results

Abstract Background: Azacitidine (AZA) is the current standard of care for patients treated for higher risk MDS, but 40-50% patients do not respond and most responders eventually relapse. Median survival after AZA failure is only 5 months and no standard of care is defined for this population. Preclinical studies and positive results of phase I-II trials support a synergistic effect of the histone deacetylase (HDAC) vorinostat (VOR) and AZA in terms of response, although no survival advantage of the combination has as yet been demonstrated. We hypothesized that adding VOR to AZA in patients with primary or secondary AZA resistance could rescue response and prolong survival. Methods: inclusion criteria inGFM AZAVOR study (NCT 01748240) were: 1/IPSS int 2 or high risk MDS at the time of initiation of AZA 2/treatment with at least 6 cycles of AZA and either failure to achieve any response or loss of response (per IWG2006 criteria) 3/a maximum of 3 months between AZA failure and inclusion with no other treatment in between. Patients received VOR 300mg bid from day 3 to day 9 of each cycle. AZA was given at standard 75mg/m2/d day 1 to 7 or at the maximum previously tolerated dose in case of dose reduction. Patients were evaluated after 6 cycles and responding patients treated until progression. The trial used a two-stage design, and accrual was to be stopped if less than 3 responses were seen in the first 14 evaluable patients. Results 21 patients were included between march 2013 and September 2014. Nineteen patients were treated (1 patient died and 1 progressed before treatment). Median age was 72 years. All pts had higher risk MDS and had received a median of 6 cycles of AZA before entering the trial. The median number of AZA+ VOR cycles administered was 3 (range: 1-12). No unexpected SAEs were seen, and the most common AEs were infection, thrombocytopenia, GI toxicities, and fatigue. After 6 cycles of treatment, only 2 patients (11%) achieved response (1 erythroid hematological improvement, 1 partial remission), , which, per protocol, triggered the stop of accrual. At last follow-up, 18 patients were off study and one patient was still on treatment. Nine patients stopped treatment because of progression (42%), 4 stopped treatment for lack of response (21%), 2 stopped treatment because of intolerance (11%), 1 patient stopped at his request (5%), and 1 patient died of complications of cytopenias while on treatment (5%). Median overall survival was 13 months. Conclusion This is the first report of an add-on study in high risk MDS, a strategy that may be useful for the early evaluation of drugs for which synergy with AZA is expected. Our results show that the proposed regimen of AZA +VOR can be used safely. However, the observed response rate was not above the "background" response rate expected from AZA alone continuation in a comparable patient population, indicating that the addition of VOR cannot reverse resistance to AZA. Disclosures Prebet: CELGENE: Research Funding. Off Label Use: lenalidomide. Wattel:Janssen: Consultancy, Honoraria, Research Funding; PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.

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