scholarly journals Autologous Stem Cell Transplant (ASCT) Improves the Prognosis of AL Amyloidosis By Inducing a Higher Organ Response Rates and May be Preferred As First Line Treatment Both in AL and in AL Associated with Multiple Myeloma (MM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4634-4634
Author(s):  
Angelo Belotti ◽  
Rossella Ribolla ◽  
Claudia Crippa ◽  
Vincenza Orlando ◽  
Mariella D'Adda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Low Risk ◽  
Line Treatment ◽  
First Line ◽  
Risk Patients ◽  
Organ Response ◽  
Ecog Ps ◽  
First Line Treatment

Abstract Introduction: Immunoglobulin light chain amyloidosis (AL) may occur in association with a recognizable plasma cell (PC) clone diagnostic for multiple myeloma (MM) both with CRAB symptoms (AL-CRAB) and without them but with more than 10% marrow PCs (AL-PCMM). Prognosis of AL-CRAB and AL-PCMM was significantly poorer than AL in a large retrospective study by the Mayo Clinic (Kourelis et al, JCO 2013). Treatment with autologous stem cell transplantation (ASCT) improved the 5-y overall survival (OS) rates of all the three entities by approximately 40%. Therefore it is debated if patients with AL should receive more MM-oriented treatment including ASCT and if patients with AL-PCMM or AL-CRAB should receive the same treatment as MM patients. Aims: to contribute to this debate we analysed the outcome of patients with amyloidosis treated at our center according to their underlying disease: AL, AL-PMCC and AL-CRAB. Furthermore, we analysed the outcome according to the use of ASCT as part of first line treatment strategy. Methods: Of 53 patients newly diagnosed between Jan 1999 to June 2016 (median age 62 years), 19 (36%) were affected by AL, whereas 23 (43%) presented with AL-PCMM and 11 (21%) with AL-CRAB. Of 53 patients 18 (34%) underwent first line ASCT (21% of AL patients, 35% of AL-PCMM and 55% of AL-CRAB patients), upfront (6) or following induction chemotherapy (12). The 35 patients (66%) who didn't receive ASCT were treated with CyBorD regimen (21), melphalan-dexamethasone (8), VMP (4) or lenalidomide-dexamethasone (2). Risk groups were identified as follows: cTnI >0.1ng/ml and/or ECOG PS ³3: high risk; age ²65 years with normal cTnI levels, ECOG PS <3 and eGFR > 50ml/min: low risk. Intermediate risk patients were defined if not meeting criteria for high or low risk. Mayo Stage classification (Dispenzieri et al, JCO 2004) was also applied to stratify risk categories. MM diagnosis was made according to IMWG criteria. Haematological and organ response (OR), OS and event free survival (EFS: time to 2nd line therapy or death) were analysed. Results: the proportion of high risk patients was 37%, 44% and 18% in AL, AL-PCMM and AL-CRAB, respectively, whereas the proportion of Mayo stage III patients was 47%, 30% and 9% for each subgroup. Median dFLC was similar (150, 150 and 146, respectively), such as baseline NT-proBNP (1318, 1301 and 1396). No difference was observed in terms of haematologic and organ response between patients with AL only or with concomitant MM: overall response rate (ORR) and complete remission (CR) were 63% and 37% in AL only patients and 88% and 32% if concomitant MM was present, whereas organ response was 47% and 56%, respectively. Similar results were seen among high risk or Mayo Stage III patients between the two subgroups. Haematologic response was similar between patients receiving ASCT in first line treatment and patients who did not: ORR and CR rates were 89% and 44% in the ASCT group and 71% and 29% in the no ASCT group, respectively. However, OR was significantly higher in the ASCT group (83% vs 37%, p 0.0014). Toxicity was manageable in both groups. After a median follow up of 32 months no significant difference was seen overall between AL only and AL with concomitant MM in terms of EFS (65% vs 85% at 2 years, respectively; HR 1,46, 95% CI 0,64-3,35) and OS (71% vs 87% at 2 years, respectively; HR 2,28, 95% CI 0,75-6,95). ASCT significantly improved both EFS and OS, comparing patients receiving or not transplantation (EFS 87% vs 64% at 2 years, p 0,013; HR 0,41, 95% CI 0,21-0,83; OS 100% vs 71% at 2 years, p 0,005; HR 0,23, 95% CI 0,08-0,64, see Figure 1). Of note, in patients achieving OR, similar OS was observed regardless of having received ASCT or not. Our data confirm the survival advantage with ASCT reported by Kourelis et al. The better outcome observed in AL with concomitant MM may be due to the more frequent use of a transplant strategy in first line treatment for AL-MM at our institution. Conclusion: We confirm that selected patients with AL AL-PCMM and AL-CRAB may have a survival advantage when receiving ASCT. These results may be related to the higher OR rates obtained with ASCT and to the improvement in OS in patients achieving OR. As no difference in terms of treatment response were observed between different underlying diseases, our study also supports the use of conventional MM treatment therapies incorporating high doses of melphalan followed by ASCT also for patients with AL Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

NOTCH1, SF3B1 and BIRC3 Mutations in Chronic Lymphocytic Leukemia (CLL) Patients Requiring First-LINE Treatment: Correlation with Biological Parameters and Response to Treatment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1784-1784 ◽  
Author(s):  
Sabina Chiaretti ◽  
Marilisa Marinelli ◽  
Ilaria Del Giudice ◽  
Silvia Bonina ◽  
Sara Gabrielli ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Clinical Impact ◽  
Biological Parameters ◽  
Line Treatment ◽  
First Line ◽  
Cytogenetic Abnormalities ◽  
Risk Patients ◽  
Notch1 Mutations ◽  
First Line Treatment

Abstract Abstract 1784 Introduction: The introduction of whole exome sequencing has allowed to unravel novel molecular lesions in CLL. NOTCH1, SF3B1 and BIRC3 mutations are detected, according to the phases of disease, in 4–12%, 5–17% and 4–24% of patients, respectively. In retrospective studies, their presence has been shown to correlate with overall survival (OS) and treatment-free interval shortening. Aims: To define the incidence, correlation with known prognostic factors and clinical impact of NOTCH1, SF3B1 and BIRC3 mutations in CLL patients undergoing first-line treatment. Methods: We evaluated 162 CLL patients enrolled in the GIMEMA LLC0405 protocol (n=80) for patients aged <60 yrs and in the ML21445 protocol (n=82) for elderly patients (aged >65 yrs or 60–65 if not eligible for fludarabine-based programs). In the GIMEMA LLC0405 protocol, patients were stratified into low and high-risk: patients with del17p or with del11q plus an unmutated IGHV status and/or CD38 positivity and/or ZAP70 positivity were considered as high-risk (HR) and underwent Fludarabine plus Campath, followed by stem cell transplantation procedures, whereas low-risk patients received Fludarabine and Cyclophosphamide. The MLL21445 protocol consisted of 8 cycles of Chlorambucil and 6 of Rituximab induction treatment. NOTCH1 (exon 34), SF3B1 (exons 14 and 15) and BIRC3 (exons 2–9, including splicing sites) were screened by Sanger sequencing on either genomic DNA (gDNA) or whole genome amplified DNA (WGA) collected at the time of treatment. These studies were not part of the clinical protocols. Results: NOTCH1 mutations were detected at the time of treatment in 18 cases (22%) enrolled in the LLC0405 study. There was a significant association with high-risk stratification (p=0.036), namely with an IGHV unmutated status (p=0.0035), CD38 (p=0.03), +12 (p=0.034) and, partly, ZAP-70 expression (p=0.059). While the overall response rate (ORR) did not differ between NOTCH1 mutated vs wild-type (WT) cases (82% vs 77%, respectively), the complete response (CR) rate was significantly lower in NOTCH1 mutated patients (43% for WT vs 17% for NOTCH1 mutated cases; p=0.05). So far, no significant difference between mutated and WT patients has emerged in terms of OS and progression-free survival (PFS); this may be contributed by the fact that most NOTCH1 mutated cases were HR and were therefore treated more aggressively. SF3B1 mutations were recorded in 9 cases (11%); no significant associations were found with known biological parameters and, so far, with the ORR and CR rate. A single case harbored a BIRC3 mutation; this patient had an IGHV unmutated status, no FISH abnormalities and a concomitant SF3B1 mutation. In the ML21445 cohort, NOTCH1 mutations were found in 12 cases (15%), were associated with an unmutated IGHV status (p=0.047) and ZAP-70 expression (p=0.007), and did not impact on the ORR and CR rate. SF3B1 mutations were found in 11 cases (13%); no significant associations were found with known biological parameters and the ORR rate. Of interest, only 1/11 SF3B1 mutated patients achieved a CR. BIRC3 mutations were recorded in 3 patients (3.6%); of these, 2 were IGHV mutated, 1 had no cytogenetic abnormalities and 1 carried a del11q, while the third patient was IGHV unmutated status and had no cytogenetic abnormalities. No NOTCH1 and/or SF3B1 mutations were detected. Overall, NOTCH1, SF3B1 and BIRC3 mutations were largely mutually exclusive among each other and with TP53 lesions in the whole cohort. Conclusions: This study confirms the association of NOTCH1 mutations with unfavorable biologic markers and +12, while the presence of SF3B1 mutations was not coupled to poor prognostic markers in CLL patients requiring first-line treatment. Furthermore, it suggests that NOTCH1 mutations impact on the CR rate of young patients receiving Fluda-based regimens, while SF3B1 appears to impact on the CR rate of elderly patients treated with Chlorambucil and Rituximab. Given the small numbers of patients harboring BIRC3, it is at present difficult to draw any conclusion on the clinical impact of this mutation in the cohort of patients hereby analyzed. Disclosures: No relevant conflicts of interest to declare.

Percutaneous cholecystotomy as first line treatment for high-risk patients with biliary sepsis: our experience so far

2013 ◽  
Vol 68 ◽  
pp. S16
Author(s):  
Philip Borg ◽  
John M. Trotter ◽  
Heather Harris ◽  
Nick Everett ◽  
Krish Ravi ◽  
...  
Keyword(s):  
High Risk ◽  
Line Treatment ◽  
First Line ◽  
High Risk Patients ◽  
Biliary Sepsis ◽  
Risk Patients ◽  
First Line Treatment

Pattern of Relapse and Progression After Autologous Stem-Cell Transplantation As Upfront Treatment for Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3987-3987
Author(s):  
Carlos Fernández de Larrea ◽  
Raquel Jiménez ◽  
Laura Rosiñol ◽  
Eva Giné ◽  
Natalia Tovar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Line Treatment ◽  
First Line ◽  
Asymptomatic Relapse ◽  
First Line Treatment

Abstract Abstract 3987 Background: Autologous stem cell transplantation (ASCT) is the gold standard as first-line treatment in young patients with multiple myeloma (MM). Prognostic factors have been usually related to patient characteristic and disease stage. Few investigations on the pattern of relapse or progression after ASCT have been addressed. The differentiation of serological or asymptomatic progression versus clinical relapse requiring treatment is also an important issue. The aim of this study was to investigate the characteristics at the time of relapse or progression in patients with MM who received ASCT as part of a first-line treatment. Patients and Methods: Two-hundred and eleven patients underwent melphalan-based ASCT at our institution during the last 18 years. Of these, 170 patients (87M/83F; median age 56 years, range 25 to 70) who achieved at the least a minimal response (PR) after no more of two induction lines before ASCT are the basis of this study. Initial baseline demographics, clinical and laboratory data at relapse or progression, and information concerning treatment and follow up were collected. The M-protein heavy-chain isotype was IgG (57%), IgA (23%), light chain only (14%) and others (3.5%). Only 2.5% were oligosecretory MM. Extramedullary plasmacytomas (EMP) were observed in 37 out of 170 patients (22%) at diagnosis. The ISS stage was I (45.3%), II (26.5%), III (18.8%) and unknown (9.5%). 12.6% of the patients had a serum creatinine level ≥2 mg/dL and 16.2% had hypercalcemia. The median follow-up for alive patients was 3.9 years (range 4 months to 18 years). Response, relapse, and progression were defined according to European Blood and Marrow Transplantation (EBMT) criteria. Results: Median PFS was 3.3 years (CI 95% 2.7 to 3.9 years) and the median OS of 6.8 years (CI 95% 3.9 to 9.6 years). 47.7% of the patients achieved a complete remission (CR). As of December 2011, 93 patients (54.7%) had relapsed or progressed after ASCT. 37 out of the 93 patients (40%) had relapsed from CR, while the remaining 60% had progressed from PR. A serological or asymptomatic relapse/progression was as frequent as a symptomatic one (49.5% vs. 50.5%, respectively), the latter requiring immediate treatment in the median of a month. Patients with serological relapse/progression had a significantly longer OS than those requiring immediate treatment (p=0.002)(Figure). The main clinical reasons to start myeloma therapy were anemia (43%), new bone lytic lesions (36%), EMP (23.7%), bone pain (14.4%), renal insufficiency (12.2%) and/or hypercalcemia (9%). 22 of the 93 patients (24%) relapsed/progressing patients had EMP at the time of progression. In three of them, the extramedullary involvement was the only criteria of progression. The presence of EMP at diagnosis was significantly associated with extramedullary disease at relapse (p=0.001). In fact, 12 out of the 22 patients (54.5%) with EMP at relapse had also EMP at the time of diagnosis. Median time between serological relapse or progression and treatment was of only 5.6 months (range 0 to 5.6 years). However, in 12 out of 46 patients (26%) with serological relapse/progression, treatment was not initiated within first two years. Finally, time to next treatment was significantly longer in patients relapsing from CR (median 2.85 years; CI 95% 2.1 to 3.6) vs. those progressing from PR (median 1.65 years; CI 95% 1.1 to 2.2) (p=0.017). Conclusion: After ASCT, serological or asymptomatic relapse/progression is observed in about one half of the patients. The treatment-free interval in these patients is longer in patients relapsing from CR than in those progressing from PR. Patients with symptomatic relapse/progression have shorter OS. Extramedullary involvement is frequent, being the highest risk in patients with EMP at diagnosis. Finally, relapse/progression with extramedullary disease only is rare. Disclosures: No relevant conflicts of interest to declare.

Lenalidomide, Adriamycin and Dexamethasone (RAD) As An Induction Regimen In Newly Diagnosed Multiple Myeloma – Interim Results From a German Multicenter Phase II Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1987-1987 ◽  
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars O Muegge ◽  
Wolf Roesler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
First Line Treatment

Abstract Background Induction triplets utilizing at least one of the “novel drugs” and steroids with or without chemotherapy are considered current standard of care in newly diagnosed, symptomatic multiple myeloma (MM). Medically fit patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while use of allogeneic (allo) SCT remains a matter of debate. As we had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory MM, we evaluated this combination in first-line treatment. Methods The current phase II trial (DSMM XII) was designed to include a total of 190 pts up to 65 years of age with symptomatic MM. Four 4-week cycles of RAD (lenalidomide 25 mg/day, d 1-21; adriamycin 9 mg/m² as 24-hour infusion, d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) preceded stem cell chemomobilization. Low-molecular weight heparin for prophylaxis of venous thromboembolic events (VTE) was mandatory. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel200) or auto followed by allo SCT. Allo SCT (preparative regimen: treosulfan/fludarabine) was reserved for pts featuring at least one cytogenetic or serologic risk factor who had a matched sibling or unrelated donor available. Lenalidomide maintenance was administered for one year following both tandem auto and auto/allo SCT. This is the second pre-planned interim safety and efficacy analysis. Results Eighty-nine pts with a median age of 54 (range, 30-65) years, who were recruited between August 2009 and October 2010, are evaluable. Fifty pts (56.2%) had ISS stage II/III disease and in all except three, molecular cytogenetic analysis was performed. Incidences of chromosomal abnormalities were as follows: deletion of (del) 13q, 24.7%; translocation t(4;14), 12.4%; t(14;16), 3.4%; and del 17p, 5.6%. Treatment-related mortality with RAD induction was 0% while 61.8% of pts had treatment-emergent SAEs. Seventeen pts (19%) experienced neutropenia of grades 1 to 4. Incidences of severe (grades 3/4) and febrile neutropenia were 5.6 and 1%, respectively. Seven pts each (8%) had pneumonia and VTE, respectively. Post-RAD-induction CR/sCR and at least VGPR rates were 9% and 47.2%, respectively. All 78 pts with at least stable disease successfully mobilized stem cells. Overall response rate (at least partial response, PR) following first SCT on an intention-to-treat basis was 83%. Twelve pts each (13.5%) achieved centrally confirmed complete response (CR) or stringent (s)CR, respectively, and 54 pts (60.7%) had at least very good PR (VGPR). Conclusions This interim analysis shows RAD to be very well tolerated and effective in first line treatment of symptomatic MM. Mel200 further increased rates of deep response (at least VGPR) achieved by RAD induction. We are currently comparing this regimen to bortezomib, lenalidomide and dexamethasone (VRd) in a phase III trial. Disclosures: Knop: Celgene GmbH: Honoraria. Off Label Use: Lenalidomide and doxorubicin in newly diagnosed multiple myeloma. Engelhardt:MSD, Janssen-Cilag: Research Funding. Einsele:Celgene GmbH: Consultancy, Honoraria, Research Funding. Bargou:Celgene GmbH: Research Funding.

Third Autologous Salvage Transplant at Late Myeloma Relapse Is Associated with Favourable Overall Survival and Contributes to Improvement of Exhausted Bone Marrow Function

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3988-3988
Author(s):  
Susanne Strifler ◽  
Inken Hilgendorf ◽  
Martina Kleber ◽  
Christoph Röllig ◽  
Lars-Olof Mügge ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Novel Agents ◽  
The Novel ◽  
Line Treatment ◽  
Next Generation ◽  
First Line ◽  
Bone Marrow Function ◽  
First Line Treatment

Abstract Background High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has been the mainstay of first-line treatment in multiple myeloma for nearly two decades. As the majority of patients (pts.) will experience relapse, we continuously are in need of effective salvage strategies such as the era of the “novel agents” is offering. The “next generation” compounds such as pomalidomide or carfilzomib significantly improve prognosis. However, virtually all drug combinations need to be delivered continuously through (subsequent) disease progression, thereby contributing to exhaustion of bone marrow function. This in turn leads to compromised full-dose treatment, which would be necessary to conquer refractory disease. Given these challenges and considering a long interval since the initial exposure to melphalan (Mel) a further autotransplant seems reasonable. Whether a third autotransplant still is effective in patients who have initially received tandem ASCT and may overcome therapy-induced exhausted bone marrow function is unclear. Therefore, we assessed the outcomes of pts. receiving a third melphalan-based salvage ASCT (ASCT3). Methods We queried the databases of six German myeloma centres for cases that were offered a third autotransplant after uniform melphalan-based tandem ASCT as part of their first-line therapies. Results 55 pts. with a median age of 58 years at diagnosis (range, 36 – 72) and of 63 (range, 38 – 77) at ASCT3 were identified. ASCT3 was performed at a median of 63 (range, 14 – 355) months (mos.) from myeloma primary diagnosis and a median interval from initial tandem autotransplant of 51 (range, 5 – 131) mos. Median progression-free survival (PFS) from primary tandem transplant had been 23 mos. (range, 4 – 94). 45 pts. (82%) had either received bortezomib and/or lenalidomide, and 37 pts. both. Eleven pts. had been double refractory and 23 pts. at least had been refractory to one of the novel agents prior to their 3rd transplant. In 45 cases cytogenetic analysis had been available, of which 9.1% could be classified as ”high-risk” (17p13 del, t(4;14), t(14;16), amp1q21, del1p). At ASCT3, median administered Mel-dose had been 100mg/m2 (range, 30-200). 50 pts. received autografts, which had been harvested at first-line treatment while 5 pts. had successfully undergone additional stem cell mobilisation. Median number of re-infused CD34+ cells was 3.0 (range, 0.4 – 15.7) x 10exp6/kg body weight with all patients achieving stable engraftment. A remarkable improvement of platelet count (PLT) and haemoglobin (Hb) within 3 mos. of ASCT3 could be achieved. PLT improvement occurred in 53% and Hb improvement (when compared to pre-ASCT3 values) in 64% of pts. Beyond that, overall response rate (partial response (PR) or better) was 59% with 8 pts. (15%) achieving CR, 6 pts. (11%) VGPR and an additional 18 pts. (33%) PR, respectively. 23 pts. (42%) suffered from grade 3 non-hematologic toxicities and in one case a grade 4 toxicity was documented. Non-relapse mortality (NRM) within 3 mos. after ASCT3 was 5%. Median PFS after ASCT3 was 6 mos. for the whole group and 2 mos. for the group with “high risk” cytogenetics (p=0,06), respectively, whereas median OS (30 mos.) was identical. In case of double-refractory myeloma, PFS did not differ significantly (3 mos. vs. 7 mos., p=0.35) whereas there was a significant difference in median OS (12 mos. vs. 35 mos., p=0.002) in comparison with non-refractory pts., respectively. Conclusions Our analysis indicates that salvage ASCT at late relapse is feasible and associated with a 6 mos.’ additional PFS interval but also contributes to improved hematopoietic function. Pts. may thus tolerate further conventional lines of treatment what is suggested by an OS of 30 mos. In addition, ASCT offers a substantial treatment-free interval when compared to either “next generation” novel drug. In this series, unfavourable cytogenetics were associated with a trend for worse PFS but not OS outcomes, meanwhile being double refractory was linked with clearly inferior OS. Interestingly, median duration of storage of their autografts of 52 mos. (range, 1 – 154) did not impair engraftment after salvage transplant. Disclosures No relevant conflicts of interest to declare.

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