scholarly journals Impact of p53 Disruption on AML & HR-MDS Treatment out-Come. a Single Centre Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4465-4465
Author(s):  
Ezzat Elhassadi ◽  
Senthil Kumar ◽  
Laura McDonald ◽  
Fiona Lynott ◽  
Aisha Mohamed ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Cell Transplant ◽  
Intermediate Risk ◽  
Wild Type ◽  
P53 Expression ◽  
Male Predominance ◽  
Poor Risk ◽  
Blast Count ◽  
The Impact

Abstract Introduction: Acute myeloid leukaemia (AML) is a heterogeneous disorder that arises from clonal expansion of malignant hematopoietic precursor cells. Somatic mutations of the p53 gene have been reported in 5-10% of AML, with a higher incidence therapy-related disease and elderly patients. Alteration or loss of p53 is one of the most powerful independent indicators of poor outcome. Methods: This is a retrospective analysis of AML & high risk-Myelodysplastic syndrome (HR-MDS) patients treated over the study period (2006-2020). Informed consent was obtained. Initial presentation, treatment response, and survival were analysed. Percentage of p53 expression (a surrogate marker for TP53 mutations) by immunohistochemistry (IHC) (>30% cut-off) on BM trephines was analysed and its impact on treatment outcome was evaluated. Results: We identified 114 patients (AML=104 & HR-MDS=10), the median age was 70 years (Range 36-85) with male predominance (M=73 vs. F=41). The AML group included, 57 patients (50%) with Denovo AML and 47 patients (41%) with Secondary AML (MDS=27, MPN=12 / JAKII mutation =7, t-AML=8). The median age was 70 years (Range 36-85) and the median blast count was 70% (Range 25-95%). Cytogenetic analysis reports were available on 78 patients (75%)(Poor risk=40 vs. Intermediate risk=38). NPM1 (22 patients) and FLT3 mutations analysis (33 patients )were available and reported as positive in 4(18%) and 5(15%) patients respectively. The HR-MDS is defined by patients who fall into higher-risk group categories in the original or revised IPSS (N=10), the median age was 74 years (Range 63-83) with male predominance (M=7 vs. F=3). The median blast count was 15% (Range 11-18%). Cytogenetic risk prognostic subgroup results were available on 6 patients (60%), 2 patients (2%) had intermediate-risk and 4 patients (4%) had poor-risk. Ninety-nine patients (87%) were eligible for treatment, 48 patients (42%) were treated with intensive induction chemotherapy, and 51 patients (45%) received less intensive therapy (HMA / LD-Ara C). Five patients (4%) consolidated with allogeneic stem cell transplant (Allo-SCT) post-induction therapy. The remaining (15 patients) were on supportive care. Forty-one AML patients (36%) relapsed post CR1, 3 patients had Allo-SCT in CR2. Table 1 At the time of study analysis (31/01/2021), 25 patients (22%) are still alive including 23 patients (20%) with AML (Denovo AML=18 & Sec AML=5) and 2 patients (4%) with HR-MDS. The median age of the survival group was 69 years (Range 51-83). The whole study cohort median OS was 12 months. (Figure. 1) The median OS & PFS for AML patients were 15 & 13 months respectively. According to AML sub-type, t-AML associated with shortest median OS of 2.5 months (P.value 0.0190). (Figure. 2) The median OS was more favourable for intermediate-risk than the high-risk cytogenetic AML, 24 and 10 months respectively (P<00016).(Figure. 3) The HR-MDS group median OS was 22 months. One hundred and four patient's BM trephines (91%) were available and screened for p53 IHC expression (AML= 96 & HR-MDS =8). Eight samples (8%) showed p53 over-expression, all these samples with underlying AML diagnosis. The remaining 96 samples (92%) were negative for high p53 expression. The majority of p53 over-expressed AML harboured complex cytogenetics, 4 patients with Sec AML, 3 patients with Denovo AML, and 1 patient with t-AML. Most of the patients (5 patients) in this sub-set had a refractory disease to induction therapy, of whom 2 patients (25%) had Allo-SCT consolidation in CR2. Only one patient (12%) is still alive in this sub-group. The median OS & PFS in p53 wild-type AML cohort was 16 & 13 months respectively, which compared favourably to 12 & 8 months in those with p53 disruptions. The P. values were 0.134 & 0.193, respectively. The impact of the p53 alterations was more pronounced on the AML sub-group treated with intensive chemotherapy (42%), the median OS & PFS in wild-type p53 AML were 24 & 20 months, while in p53 disrupted cohort were 12 & 10 months respectively (P= 0.030)(95%CI of ratio 0.1755 to 1.425) & (P=0.049)( 95%CI of ratio 0.7015 to 5.702).(Figure.4) Conclusion: In this study we demonstrated the potential role for p53 expression by IHC, which is readily available in routine practice, in assessing AML prognosis. Our real-life data confirms the dismal prognosis of p53 alterations in this disease. Participation in clinical trials based on genetic risk stratification is warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Outcome in patients with refractory high-risk neuroblastoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10537-10537
Author(s):  
Amir Bari Siddiqui ◽  
Akosua Oppong ◽  
Cindy Yuan ◽  
Guimin Gao ◽  
Rochelle Bagatell ◽  
...  
Keyword(s):  
High Risk ◽  
Metastatic Disease ◽  
Induction Therapy ◽  
Tumor Biology ◽  
Induced Response ◽  
Cell Transplant ◽  
Refractory Disease ◽  
Disease Response ◽  
Post Induction ◽  
The Impact

10537 Background: Outcome for high-risk neuroblastoma (HRNBL) patients (pts) with refractory disease at end of induction (EOI) is poor. The impact of therapies such as I-131-MIBG or irinotecan/temozolomide/dinutuximab (I/T/DIN) prior to autologous stem cell transplant (ASCT) on outcome is unknown. Methods: A multi-center, retrospective study of HRNBL pts diagnosed between 2008-2018 with refractory disease at EOI was conducted. Demographics, tumor biology, treatment response, and outcomes were abstracted. 3-year (yr) EFS and OS from time of diagnosis were estimated by the Kaplan-Meier method. Results: 3-yr EFS and OS were 54% and 79% for the 136 pts analyzed. 91 pts received no additional therapy prior to ASCT (Cohort 1); 32 pts received post-induction therapy prior to ASCT (Cohort 2); and 13 pts did not undergo ASCT (Cohort 3). The prevalence of metastatic disease in Cohort 1, 2, and 3 was 65%, 97%, and 85%. 3-yr EFS and OS were not statistically different between Cohort 1 (3-yr EFS and OS; 62% and 81%) and Cohort 2 [3-yr EFS and OS; 49% (p = 0.48) and 82% (p = 0.19)]. Outcome for Cohort 3 pts was significantly worse than Cohort 1 [3-yr EFS: 15% vs. 62% (p < .001); and 3-yr OS: 48% vs. 81% (p = 0.003)] and Cohort 2 [3-yr EFS: 15% vs. 49% (p < .001); and 3-yr OS 48% vs. 82% (p = 0.035)]. For Cohort 2 pts with metastatic disease, post-induction therapy included I/T/DIN (n = 12), MIBG (n = 16), MIBG plus I/T/DIN (n = 1), and other (n = 2). Metastatic disease response was observed in 10/12 (83%) pts who received I/T/DIN and 9/16 (56%) who received MIBG. MIBG plus I/T/DIN (n = 1) or MIBG with chemotherapy (n = 1) also induced response. Among the 21 pts with metastatic disease response, 3-yr EFS and OS were 69% and 94%; significantly better than Cohort 2 patients who did not respond to post-induction therapy [3-yr EFS and OS: 11% (p = 0.016) and 66% (p = 0.2)]. 6 Cohort 2 pts achieved a complete response (CR) in metastatic sites following I/T/DIN (n = 5) or MIBG (n = 1), and all are alive without relapse with median follow-up of 3.4 years (range 2.7-8.1). The single Cohort 3 patient who achieved a metastatic CR with I/T/DIN and did not undergo ASCT remains disease-free 2.4 years from diagnosis. Conclusions: Patient characteristics differed in the 3 Cohorts, reflecting the influence of refractory disease on treatment decisions. For Cohort 2 pts, outcome was better for those with metastatic disease at EOI who responded to post-induction therapy compared to those who did not. Pts who achieved a metastatic CR of refractory disease had excellent survival. Prospective studies testing the efficacy of I/T/DIN in pts with refractory metastatic disease at EOI are warranted.

Prognostic Significance of FLT3 and NPM1 Mutations in Adults of Age 18–60 with De Novo Acute Myeloid Leukemia (AML) on SWOG S0106 Study: A Study by FHCRC and SWOG

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2520-2520 ◽  
Author(s):  
Era L. Pogosova-Agadjanyan ◽  
Kenneth J. Kopecky ◽  
Stephen Petersdorf ◽  
Harry Paul Erba ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Induction Therapy ◽  
De Novo ◽  
Risk Group ◽  
Risk Groups ◽  
Phase Iii ◽  
Intermediate Risk ◽  
Poor Risk ◽  
Flt3 Mutations ◽  
De Novo Aml ◽  
The Impact

Abstract Abstract 2520 INTRODUCTION. Age, cytogenetics, FLT3 and NPM1 mutations are the most significant prognostic factors (PFs) for adult AML treated with standard regimens, but the predictive significance of FLT3 and NPM1 with contemporary treatments is unknown. We examined the clinical significance of NPM1 and FLT3 mutations in adult de novo AML pts enrolled on SWOG study S0106. METHODS. S0106 was a randomized phase III clinical trial for pts of age 18–60 with de novo non-M3 AML, evaluating the effects of adding Gemtuzumab Ozogamicin (GO) to standard induction therapy (Cytosine Arabinoside and Daunomycin, AD), and of post-consolidation GO vs. no additional therapy (ASH, 2009, Abstract 790). Samples from 198 of the 600 eligible pts were evaluated. Analyses for nucleotide insertions in exon 12 of the NPM1 gene and internal tandem duplications (ITD) within exons 14–15 of FLT3 were performed using fragment analyses in diagnostic bone marrow (BM, N=190) and peripheral blood (PB, N=8) samples. Mutant/wild-type (WT) allelic ratios (AR) were computed for all mutations. Effects of mutations and other PFs on complete response (CR), resistant disease (RD), overall survival (OS) and relapse-free survival (RFS) were analyzed by logistic and Cox regression. P-values are 2-sided. RESULTS. Patient characteristics and outcomes are shown in Table 1. In univariate analyses, NPM1-Mut pts had significantly higher CR (81% vs. 58%, P=.0018) and lower RD (13% vs. 28%, P=.028) rates, better OS (64% vs. 47%, P=.045) and RFS (54% vs. 41%, P=.50). FLT3-ITD was not associated with CR or RD, but was associated with poorer OS (hazard ratio [HR] 2.28, P=.0011) and RFS (HR 2.74, P=.0009). FLT3-ITD length (range 18–366, median 46), FLT3 AR (range 0.18–8.2, median 0.98), and NPM1 AR (range 0.2–1.0, median 0.8) were not associated with CR, RD, or OS, but RFS tended to be lower with higher ITD length (P=.076). In multivariate analyses with other PFs, neither NPM1 nor FLT3 was associated with CR or RD rates, however the combined effects of FLT3 and NPM1 identified 3 mutation risk groups for OS (P=.0044, Fig 1A) and RFS (P=.0003, Fig 1B), since NPM1 did not significantly affect outcomes within the FLT3-ITD pts. These risk groups are FLT3-WT/NPM1-Mut (Good Risk: 3-yr OS 82%, RFS 69%), FLT3-WT/NPM1-WT (Intermediate Risk: OS 49%, RFS 43%), and FLT3-ITD (Poor Risk: OS 29%, RFS 14%). The impact of adding GO to induction therapy was examined within each risk group. In each risk group, CR rates were higher in the AD+GO arm, though not significantly so. Likewise, the RD rates were lower in the AD+GO arm, but this difference was significant only in the largest group: Intermediate Risk, FLT3-WT/NPM1-WT, 17% vs. 34% (P=.026). Treatment arm did not significantly affect OS and RFS in any mutation risk group. CONCLUSION. This study confirmed prognostic effects of FLT3 and NPM1 mutations in de novo AML pts treated with AD or AD+GO. Analyses of the joint impact of NPM1 and FLT3 mutations do not rule out the possibility that they act independently. With the small numbers of pts in the “good” and “poor” risk groups, there was no clear evidence that mutation status predicts clinical benefit from adding GO to therapy. We are evaluating additional samples and will update these results as data matures. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Impact of Preoperative Risk on the Association between Hypotension and Mortality after Cardiac Surgery: An Observational Study

2020 ◽  
Vol 9 (7) ◽  
pp. 2057
Author(s):  
Vanja Ristovic ◽  
Sophie de Roock ◽  
Thierry G. Mesana ◽  
Sean van Diepen ◽  
Louise Y. Sun
Keyword(s):  
Cardiac Surgery ◽  
Risk Factor ◽  
High Risk ◽  
Hospital Mortality ◽  
Risk Group ◽  
High Risk Group ◽  
Group Care ◽  
Intermediate Risk ◽  
Intraoperative Hypotension ◽  
The Impact

Background: Despite steady improvements in cardiac surgery-related outcomes, our understanding of the physiologic mechanisms leading to perioperative mortality remains incomplete. Intraoperative hypotension is an important risk factor for mortality after noncardiac surgery but remains relatively unexplored in the context of cardiac surgery. We examined whether the association between intraoperative hypotension and in-hospital mortality varied by patient and procedure characteristics, as defined by the validated Cardiac Anesthesia Risk Evaluation (CARE) mortality risk score. Methods: We conducted a retrospective cohort study of consecutive adult patients who underwent cardiac surgery requiring cardiopulmonary bypass (CPB) from November 2009–March 2015. Those who underwent off-pump, thoracic aorta, transplant and ventricular assist device procedures were excluded. The primary outcome was in-hospital mortality. Hypotension was categorized by mean arterial pressure (MAP) of <55 and between 55–64 mmHg before, during and after CPB. The relationship between hypotension and death was modeled using multivariable logistic regression in the intermediate and high-risk groups. Results: Among 6627 included patients, 131 (2%) died in-hospital. In-hospital mortality in patients with CARE scores of 1, 2, 3, 4 and 5 was 0 (0%), 7 (0.3%), 35 (1.3%), 41 (4.6%) and 48 (13.6%), respectively. In the intermediate-risk group (CARE = 3–4), MAP < 65 mmHg post-CPB was associated with increased odds of death in a dose-dependent fashion (adjusted OR 1.30, 95% CI 1.13–1.49, per 10 min exposure to MAP < 55 mmHg, p = 0.002; adjusted OR 1.18 [1.07–1.30] per 10 min exposure to MAP 55–64 mmHg, p = 0.001). We did not observe an association between hypotension and mortality in the high-risk group (CARE = 5). Conclusions: Post-CPB hypotension is a potentially modifiable risk factor for mortality in intermediate-risk patients. Our findings provide impetus for clinical trials to determine if hemodynamic goal-directed therapies could improve survival in these patients.

Targeting the Human Double Minute (HDM)-2 p53 Ubiquitin Ligase as a Strategy Against Non-Hodgkin Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1374-1374
Author(s):  
Richard J. Jones ◽  
Dajun Yang ◽  
Nathalie Bruey-Sedano ◽  
Robert Z. Orlowski
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Human Umbilical Cord ◽  
Wild Type ◽  
Inhibition Of Proliferation ◽  
P53 Expression ◽  
Non Hodgkin Lymphoma ◽  
Drug Concentrations ◽  
Chemotherapy Agents ◽  
The Impact

Abstract Background: The ubiquitin-proteasome pathway has been validated as a target for non-Hodgkin lymphoma (NHL) with the recent approval of bortezomib for mantle cell lymphoma (MCL). In addition to anti-tumor activity, however, proteasome inhibitors have pleiotropic effects, including activation of an anti-apoptotic heat shock protein response, and their use clinically is complicated by toxicities such as peripheral neuropathy. By targeting E3 ubiquitin ligases, which are involved in ubiquitination of only a small subset of cellular proteins, it may be possible to achieve more specific anti-tumor effects with a better therapeutic index. One such attractive target is HDM-2, which is responsible for ubiquitination of the p53 tumor suppressor. Methods: To evaluate the therapeutic potential of agents targeting HDM-2, we studied the impact of the small molecule MI-63, an inhibitor of the HDM-2-p53 interaction, in both p53 wild-type and -mutant cell line models. Results: Treatment of wild-type p53 MCL, NHL, and acute lymphocytic leukemia (ALL) cell lines with MI-63 induced a dose- and time-dependent inhibition of proliferation, with an IC50 in the 1.0–5.0 μM range. This was associated with G1/S cell cycle arrest, and apoptosis mediated by caspases-3, 8 and 9. MI-63 induced accumulation and phosphorylation of p53 at serine 15 and 37, and also enhanced HDM-2 levels. Multiple p53 target genes were induced, including p21Cip1 and p53-upregulated modulator of apoptosis (PUMA), resulting in cleavage of poly-ADP-ribose-polymerase (PARP). MI-63 also decreased the levels of the ribonucleotide reductase subunit R2, and caused a corresponding increase in the R2p53 subunit. MI-63 also decreased the levels of E2F. Cell lines expressing certain p53 mutants were sensitive to the effects of MI-63, resulting in apoptosis. Cells without p53 expression were less sensitive to MI-63, but at higher drug concentrations proliferation was still inhibited, indicating a possible impact on HDM-2-mediated but p53-independent cell death pathways. Primary human umbilical cord vein endothelial cell growth was also inhibited and cells failed to recover after extended exposure to MI-63, whereas primary PBMC’s were unaffected by MI-63. Combinations of MI-63 with the molecularly targeted chemotherapy agents bortezomib and rapamycin were synergistic, with mean CI values of 0.88 and 0.6 respectively. The conventional chemotherapy agents doxorubicin and cisplatin were less effective at inducing synergism, with mean CI values of 1.06 and 0.9 respectively. Pretreatment of cells with MI-63 followed by chemotherapy was antagonistic with all agents used, while treatment with a chemotherapeutic first followed by MI-63 was additive to synergistic, indicating a sequence-dependent interaction. Conclusions: Inhibition of the HDM-2-p53 interaction is a promising approach both by itself, and in combination with currently used chemotherapeutics, against lymphoid malignancies, providing a rationale for translation of such agents into the clinic.

Early Treatment Intensification in High Risk (HR)-AML Patients Using Allogeneic Hematopoietic Stem Cell Transplantion in a Randomized Multicenter Setting.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3018-3018
Author(s):  
Thomas Illmer ◽  
Markus A. Schaich ◽  
Christian Thiede ◽  
Uwe Platzbecker ◽  
Wandt Hannes ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Treatment Strategy ◽  
Search Strategy ◽  
Allogeneic Transplantation ◽  
Response To Therapy ◽  
Hematopoietic Stem ◽  
Fast Search ◽  
Blast Count

Abstract There are several biological markers that are now known to confer HR in AML patients as there are cytogenetic high risk aberrations, FLT3 length mutations with a high allelic ratio (AR) and the initial response to therapy as defined by more than 10% blasts in the “day 15” bone marrow blast count (d15). For most of those patients categorized as having HR-AML allogeneic transplantation comprises the only option of cure. Recently we reported (Platzbecker et al., Leukemia 2006) on a highly active transplantation strategy using reduced intensity conditioning that allowed for an upfront allogeneic transplantation in HR-AML patients as part of the induction treatment. In 2003 we started a multicenter randomized trial which investigates both the feasibility and efficacy of allogeneic stem cell transplantation as upfront intensification therapy in HR-AML patients. Here we report the feasibility of the approach. The study is being conducted in a classical 2×2 design with intensified treatment arms B and D that scheduled allogeneic transplantation in HR patients as part of the induction therapy (IT) during marrow aplasia achieved by DA (daunorubicin 60 mg/m2 - day 3–5; cytarabine 100 mg/m2 - day1–7). Intensified risk adapted therapy was compared to a “conventional” treatment strategy (arm A and C) which allows for allogeneic transplantation only in patients achieving remission after two induction courses (DA) with a complex aberrant karyotype or in patients with aberrant chromosome 7 and 5. We identified 109 patients with HR in the intensified treatment groups (B/D) where HR was defined by cytogenetic criteria (n=73); FLT3-AR (n=14) and d15 blast count (n=21). At the same time a fast search strategy was conducted and revealed donor availability (related or unrelated) in 92 patients (84.4%). Consequently, 46 out of 109 HR-AML patients assigned to the intensified treatment strategy (B/D) received allogeneic transplantation within the protocol (42.2%). In contrast, 8 out of 102 HR patients in the none-intensified treatment arms (A/C) were treated with allogeneic transplantation within the protocol (7.8%). Whereas 19 of 109 patients (17%) with an intensified treatment strategy (B/D) were transplanted after achieving remission, 27 of the 109 patients (25%) were treated with allogeneic transplantation during marrow aplasia after IT1 (n=9) or IT2 (n=18) respectively. Available donors were predominantly family donors for patients receiving transplant after IT1 (6/9) but were more often unrelated donors after IT2 (12/18). Allogeneic transplantation was performed in (B/D) HR-AML patients with a median time from diagnosis of the disease to transplantation of 54 days (range 29–204). In conclusion, early allogeneic transplantation is possible in 40–50% of HR-AML patients during the induction phase of therapy in a randomized AML trial. An early upfront transplantation strategy in aplasia is logistically challenging. However, the presented data show that given a fast search strategy at the time point of diagnosis about 25% of patient can be transplanted during the aplasia of induction therapy.

Revalidation of the Flipi Score in the Era of Immunotherapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4437-4437
Author(s):  
German Stemmelin ◽  
Carlos Doti ◽  
Claudia Shanley ◽  
Jose Ceresetto ◽  
Oscar Rabinovich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Univariate Analysis ◽  
Risk Groups ◽  
Marrow Transplant ◽  
Intermediate Risk ◽  
Significant Difference ◽  
The Difference ◽  
The One ◽  
The Impact

Abstract The FLIPI prognosis score for follicular lymphoma (FL) was developed based on cases diagnosed between 1985 and 1992, and treated with different schemes that did not include rituximab (R). In the present study, we report the evolution of all FL treated in a single institution through the last decade and analize whether FLIPI mantains its effectiveness to identify different risk groups within patients treated with the new therapeutic alternatives available. Material and Methods: We identified sixty two patients with diagnosis of grade I-II-IIIa FL. Patients characteristics: median age 57.5 yr (r, 30–80); 36 males; 63% stages III–IV, and 37% with bone marrow infiltration at the time of diagnosis. Thirty eight percent had a low risk by FLIPI, 34% had an intermediate risk and 27.4% had a high risk. In 19 pts (30.6%) the initial decision was “watch and wait” but 82% received a form of treatment at some point. R was used in 36 pts (58%) with some of the following regimes: chemotherapy (chemo) + R and/or R as consolidation therapy and/or R as monotherapy and/or R as maintenance therapy. Of all prescribed treatments (excluding R as monotherapy and/or maintenance treatment), 52.8% were chemo alone, 20.2% chemo + R, 21.3% radiotherapy and 5.6% received a bone marrow transplant. Results: we considered the analysis of overall survival (OS) the most appropiate approach, since most treatments were seeking the control of the FL, and not the complete remission or cure. The follow up median time was 53.2 months ± 34.8 1SD. The 5-yr OS for the 62 pts was 81.8% ± 11.3 CI 95%. The 5-yr OS for those with a low, intermediate and high risk FLIPI was 100% −5, 84.2% ± 21 and 52% ±26.2, respectively. The difference in 5-yr OS was statistically significant between low and high risk, intermediate and high risk, but failed to prove a significant difference between low and intermediate risk. Among the different risk factors tested in a univariate analysis only age ≥ < 60 yr old demonstrated a significant difference, 60.7% vs 90%, respectively. Conclusions: The 5-yr OS in our series is higher than the one described in the original FLIPI study (Blood2004; 104:1258–65) which was 81.8% vs 71% for the whole group; 90% vs 78.1% for pts <60 yr old; 60.7% vs 57.7% for ≥ 60 yr old; 100% vs 90.6% for low FLIPI and 84.2% vs 77.6% for intermediate FLIPI. The only group that failed to prove an improvement was the high risk FLIPI with 52% vs 52.5%. The impact of novel therapies was more evident in patients with a low or intermediate FLIPI and was even more evident in patients younger than 60 yr old. According to our results, FLIPI maintains its effectiveness in differentiating two risk groups, i.e., low-intermediate vs high. We believe that the OS curves will probably continue to improve as the treatments that are considered today as the most effective ones, were just included in our series in the last three years.

The Interaction of Response and FISH-Based Risk Stratification to Better Define Clinical Outcome in Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1823-1823
Author(s):  
Kevin D Boyd ◽  
Fiona M Ross ◽  
Mark T Drayson ◽  
Roger G Owen ◽  
Alex J Szubert ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Factor ◽  
Induction Therapy ◽  
Response Rates ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Important Prognostic Factor

Abstract Abstract 1823 Background: The achievement of a complete response (CR) is an important prognostic factor in myeloma. The international staging system (ISS) and tumor genetic lesions detected by FISH also impact survival. It is not known whether response rates are adversely affected by these factors, whether achieving CR overcomes the adverse prognosis associated with these factors, or if achievement of CR is more important in a specific biological subgroup. We have examined the importance of CR in the context of these other prognostic factors in the intensive arm of a phase III randomized trial, MRC Myeloma IX, in which all patients were planned to proceed to autologous stem cell transplant (ASCT) after induction. Patients and Methods: Patients were randomized to a conventional or thalidomide-based induction regimen followed by ASCT, with a second randomization to maintenance thalidomide versus no maintenance. Response was assessed after completion of induction therapy and 100 days post-ASCT. iFISH was performed on diagnostic bone marrow samples and genetic lesions associated with adverse progression free survival (PFS) were defined as t(4;14), t(14;16), t(14;20), +1q and 17p-. Results: To confirm that CR was prognostically important in the data set, patients with a CR at 100 days post-ASCT (N=355) were compared to non-CR (N=344) (comprising VGPR, PR and SD). CR was strongly associated with improved PFS (median 30.8 months vs 38.7 months, P<0.001) but was not associated with improved OS at median follow-up of 3.7 years. Response rates were assessed in the context of other prognostic factors. Interestingly, the presence of high risk FISH lesions was not associated with impaired CR rates following induction therapy (P=0.584) or following ASCT (P=0.314). Patients without adverse genetic lesions had a CR rate of 11.1% post-induction which improved to 48.3% post-ASCT. In comparison, patients with adverse FISH lesions had a 13.3% CR rate, rising to 44.9% post ASCT. Similarly, there was no correlation between ISS stage and response. The absence of adverse FISH lesions (hazard ratio (HR) 2.68 (1.94-3.70) P<0.001) and achievement of CR (HR 1.58 (1.15-2.17) P=0.005) were independently associated with improved PFS in multivariate analysis. The prognostic impact of achieving CR was assessed in various prognostic groups. CR was associated with improved PFS in patients with no adverse FISH lesions (N=179)(median PFS 58.4 vs 37.1 months, P=0.031), and in ISS I (N=182)(median PFS 51.2 vs 33.2 months, P=0.008). In patients with adverse FISH lesions, and in ISS II and III, there was a trend towards improved PFS with CR that was not significant. For patients achieving CR as their maximum response (N=398), in a multivariate analysis including the ISS, the presence of high risk FISH lesions was the most significant factor associated with impaired PFS and OS. Patients with more than 1 adverse FISH lesion were associated with an especially high risk of progression or death (PFS HR 6.63 (3.23-13.53) P<0.001; OS HR 5.35 (1.98-14.45) P=0.001). Conclusion: These data show that attainment of CR is an important prognostic factor associated with improved PFS in patients treated with ASCT, and this benefit was most significant in patients with favorable prognostic factors such as lack of adverse FISH lesions and ISS I. The presence of t(4;14), t(14;16), t(14;20), +1q or 17p- was also strongly associated with PFS, and the impaired outcome associated with these adverse genetic lesions was not overcome by achievement of CR, within the context of the therapies used in this trial. The presence of more than 1 adverse FISH lesion identified a patient group with an especially poor prognosis, despite achieving CR. However, CR rates within these high risk patients were similar to patients without adverse genetic features, showing that they were sensitive to chemotherapy, but progressed quickly after therapy was stopped. The implication of these data is that it may be possible to improve the poor outcome of this genetically-defined high risk group with an alternative treatment strategy aimed at maintaining these responses. Disclosures: Gregory: Celgene: Honoraria. Child:Celgene: Honoraria.

Reduced Intensity Transplant May Improve Survival in Patients Over the Age of 40, Especially If a Sibling Donor Is Used: Pooled Analysis of 2454 Patients and 407 Transplants in the UK NCRI AML15 and AML16 Trials

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 231-231
Author(s):  
Nigel H Russell ◽  
Robert K. Hills ◽  
Lars Kjeldsen ◽  
John L Yin ◽  
Charles Craddock ◽  
...  
Keyword(s):  
Older Patients ◽  
Risk Group ◽  
Pooled Analysis ◽  
Cell Transplant ◽  
Intermediate Risk ◽  
Sibling Donor ◽  
Risk Patients ◽  
The Uk ◽  
The Impact ◽  
Reduced Intensity

Abstract Abstract 231 Reduced Intensity conditioning (RIC) offers a feasible option for older patients to an allogeneic stem cell transplant and to potentially benefit from a graft vs leukaemia effect. However the relative clinical benefit in AML is less clear. Since our previous experience did not show an overall survival advantage from myeloablative transplant in patients >40 years we have examined the impact of RIC allograft in 1st CR on the outcome of patients aged 40–70 years treated within the UK NCRI AML15 (2002–2009) and AML16 (2006–2012) trials compared to chemotherapy. Methods: Both trials offered the option of RIC transplant in CR1 for patients who were not good risk. A total of 2454 patients between 40 to 70 years entered CR (AML15: 1580 and AML16: 874) of whom 407 received a RIC (292/1580 in AML15 and 115/874 in AML16). Matched sibling transplants were given in 229, and MUDs in 178. The cytogenetic risk groups were 258 intermediate, 59 adverse, 90 not known. Follow-up is complete to 1st January 2012. Comparisons of transplant versus not are carried out using Mantel-Byar analysis to allow for time to transplant, with patients censored at the time of non-RIC allo transplant. Data from the two trials were pooled and split by age. Results: The OS for the 255 patients <60 yrs. was significantly superior to no transplant (53% vs 41%, HR 0.79(0.66–0.96), p=0.02). There was clear benefit in the 164 intermediate risk group patients (59% vs 44%, HR 0.67 (0.53–0.86) p=0.0008) with less evidence for the 40 who had adverse risk (16% vs 10%, HR 0.89 (0.58–1.35) p=0.6). In 152 patients 60+ yrs. the overall benefit was not significantly superior (37% vs 24%, HR 0.85 (0.68–1.06), p=0.2), there was a non-significant trend for benefit in the 94 intermediate risk group patients (43% vs 26%, HR 0.73 (0.49–1.09), p=0.3), and clearer benefit in the 19 patients in the adverse group (16% vs 3%, HR 0.57 (0.36–0.91), p=0.01). Considering the types of transplant, in the <60 group the survival benefit was restricted to sibling RIC (Sibling 61%: MUD 35%: no transplant 41%), and in the 60+ group a similar trend of borderline significance was seen (Sibling 49%:MUD 28%: no transplant 24%). In analysis by cytogenetic group, with the exception of patients over 60 yrs with adverse karyotype, sibling allograft gave consistently better survival. Conclusion: This pooled analysis shows that RIC allo SCT in AML 1st CR improves the survival of older patients with AML aged <60 but possibly only if a sibling donor is used. There was less benefit (sibling or MUD) for adverse risk patients. For patients aged >60 years overall benefit was less clear but there was a similar trend for benefit in intermediate risk patients. However, given the lack of statistical heterogeneity, our data does not exclude a benefit for patients with adverse risk cytogenetics or for those undergoing SCT from an unrelated donor. This observation runs counter to what we observe in patients <40 yrs, where the benefit is limited to adverse risk patients. Disclosures: No relevant conflicts of interest to declare.

Conditioning Intensity In Middle Aged Patients With AML In CR1. No Advantage For Myeloablative Regimens Irrespective Of The Risk Group. An Observational Analysis By The Acute Leukemia Working Party Of The EBMT

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 542-542
Author(s):  
Jakob Passweg ◽  
Myriam Labopin ◽  
Jan J Cornelissen ◽  
Liisa Volin ◽  
Gérard Socié ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Intermediate Risk ◽  
Poor Risk ◽  
Conditioning Intensity ◽  
Good Risk ◽  
Related Mortality

Abstract Introduction In younger patients with AML achieving CR1 with intermediate or high risk disease allogeneic HSCT is the treatment of choice. Conditioning intensity is varied, reduced intensity (RIC) conditioning regimens are usually given to older patients, whereas young patients traditionally receive myeloablative regimens (MAC). In patients between the ages of 40-60 both types of regimens are used with little knowledge about factors that would lead physicians to prefer one over the other. Previous studies had shown that RIC regimens were associated with somewhat higher relapse risks but lower risks of transplant related mortality (TRM). We hypothesized that in low-intermediate risk disease based on cytogenetic classification RIC is superior to MAC whereas in high risk leukemia MAC is superior to RIC given higher antileukemic activity. Patients and Methods This study included 2974 of 5388 eligible patients with AML transplanted in CR1 in 2000-2011 based on the availability of cytogenetics to classify by risk status at diagnosis. Only sibling or unrelated donors and marrow or peripheral blood stem cell transplants were considered. Regimens were classified as MAC (n=1638) or RIC (n=1336) based on published criteria. Median follow-up of surviving patients was 46 and 41 months respectively. Groups differed by many variables. MAC recipients were significantly younger (37.6 vs 53.8 years), had a shorter interval from diagnosis to transplantation (143 vs 165 days), were more frequently male (53% vs 48%), had less frequently poor risk cytogenetics 19% vs 22%, received less frequently stem cells from an unrelated donor (20% vs 33%), and had more frequently marrow as a stem cell source (36% vs 7%). The Kaplan-Meier estimator, the cumulative incidence function and Cox proportional hazards regression models were used where appropriate. Results Table 1 shows similar overall (OS) and leukemia free survival (LFS) in both groups but a lower relapse incidence (RI) and a higher transplant related mortality incidence (TRM) in the MAC group. Acute grade II-IV GvHD was higher with MAC, incidence of chronic GvHD did not differ significantly. In univariate analysis overall survival was higher with RIC in cytogenetic good risk AML (55±5% vs 77±7% MAC vs RIC) but not in intermediate risk (61±1% vs 62±2%) or poor risk AML (42±3% vs 40±3%). Relapse incidence was lower with MAC in poor risk AML (36±3% vs 51±3%) and intermediate risk AML (21±1% vs 30±1%) but not in good risk AML (19±4% vs 13±5%). TRM was higher in MAC vs RIC in all three cytogenetic risk groups. Multivariate analysis confirmed a significant LFS and OS advantage of RIC in good risk but not in intermediate and poor risk leukemia. Conclusions In patients aged 40-60 MAC conditioning has no advantage over RIC conditioning in spite of RIC transplant recipients being generally in a poorer risk category. We confirm lower relapse rates but higher TRM risks with MAC compared to RIC. We fail to show superiority of MAC in patients with high risk cytogenetics but there appears to be an advantage for RIC over MAC in the small cohort of patients with good risk leukemia. Disclosures: Kuball: Miltenyi: GMP product development Other.

HCT.CI in Autologous Stem Cell Transplantation. Predicting Early and Late Transplant Related Mortality

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3449-3449 ◽  
Author(s):  
Mariano Berro ◽  
Maria M Rivas ◽  
Jorge Alberto Arbelbide ◽  
Ana Lisa Basquiera ◽  
Adriana Vitriu ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
High Risk ◽  
Hodgkin Lymphoma ◽  
Early Mortality ◽  
Cell Transplant ◽  
End Point ◽  
The Impact ◽  
Autologous Hsct ◽  
Related Mortality

Abstract Background. Hematopoietic Stem Cell Transplant Comorbidity Index (HCT.CI) score, described by Sorror, is a useful tool to assess the risk for Non Relapse Mortality (NRM) after Allogeneic HSCT. The impact of this score in Autologous HSCT is still to be confirmed. Aims. To determine the impact of HCT.Ci score in the morbidity and mortality after autologous HSCT, assessing the 100 day morbidity defined as orothraqueal intubation (OTI), dialysis or shock (defined as vasopressors need), 100 day mortality, early morbi-mortality (combined end-point by any of the previous end-point) and long term NRM. Materials and Methods. We retrospectively reviewed 1478 medical records of adult patients who received an autologous HSCT in our centre between October 2002 and April 2016. Median age was 49 years (range 16-74 years), 58% were male, prevalent diseases were Multiple Myeloma (48%), Non Hodgkin Lymphoma (27%) and Hodgkin Lymphoma (18%), 49% were in complete remission, 46% received one chemotherapy scheme before transplant, 41% two schemes and 12% three or more (heavily pre-treated). In respect to conditionings, melphalan was used in 48% of the cases, CBV in 25%, BEAM in 8% as well as BendaEAM. Seventy five percent received an infusion of stem cells CD34+≥3x10.6/kg. Regarding comorbidities, 58% had low risk (LR) HCT.CI (score 0), 32% intermediate risk (IR) (1-2) and 11% high risk (HR) (≥3). For univariate analysis we use Chi2 for dichotomic variables, Kaplan-Meier for Overall Survival (OS) and cumulative incidence for NRM; for multivariate analysis we used logistic regression for dichotomic and Cox regression for time dependant variables. Results. Median follow up was 1.9 years. Early mortality (day 100) was 2.8%, 5.6% required OTI, 4.8% required vassopresors and 2.2% dialysis, 1-3 years NRM and OS were 4.3-5.2% and 89-77% respectively. High risk HCT.Ci patients had a significant increase in 100 day mortality compared to IR and LR (7% vs.3% vs. 2% respectively, p=0.002), OTI (12% vs. 7% vs. 4%, p<0.001), dialysis (4.5% vs.2.6% vs. 1.5%, p=0.04), shock (10% vs.6.4% vs. 3%, p<0.001), early morbi-mortality (15% vs.9 % vs. 4.6%, p<0.001) and NRM (1-3 years 9.2-13% vs. 3.8-3.8% vs. 3.5-4.5%, p<0.001) (figure 1). After multivariate analysis these outcomes remain significant (showed as OR with 95% CI, IR and HR compared to LR): early mortality (1.8, 0.8-4.2 and 3.9, 1.6-9.7, p=0.003), OTI (2.1, 1.2-3.7, p<0.01 and 3.9, 2.0-7.5, p<0.001), dialysis (2.2, 0.8-5.5 and 4.1, 1.4-11.7, p<0.01), shock (2.7, 1.4-4.9, p=0.001 and 4.4, 2.1-8.9, p<0.001), early morbi-mortality (2.4, 1.4-4.0, p=0.001 and 4.2, 2.3-7.6, p<0.001) and NRM (1.3, 0.7-2.4 and 3.0, 1.5-5.7, p=0.001) (table 1). No significant impact was observed in OS. Other than comorbidities, significant impact was observed in early mortality (pre-transplant status, heavily pre-treated patients and BendaEAM conditioning), OTI (NHL, heavily pre-treated patients, BendaEAM conditioning), dialysis (pre-transplant status and BendaEAM conditioning), shock (NHL, heavily pre-treated patients and BendaEAM conditioning), morbi-mortality (NHL and BendaEAM conditioning) and NRM (male patients, NHL, pre-transplant status, heavily pre-treated patients and BendaEAM conditioning). Conclusions. We observed that HCT.CI had a significant impact on Autologous HSCT treatment related mortality basically due to early toxicity express as 100 day mortality and the three main morbidity outcomes as well as the combined end point. This observation should be confirmed in larger series. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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