Minimal Residual Disease (MRD) Re-Growth Kinetics Are An Independent Predictor for Progression Free Survival (PFS) in Chronic Lymphocytic Leukemia (CLL) and Are Related to Biologically Defined CLL-Subgroups– Results From the CLL8 Trial of the German CLL Study Group (GCLLSG)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1777-1777 ◽  
Author(s):  
Sebastian Boettcher ◽  
Matthias Ritgen ◽  
Kirsten Fischer ◽  
Stephan Stilgenbauer ◽  
Raymonde Busch ◽  
...  
Keyword(s):  
Thymidine Kinase ◽  
Growth Kinetics ◽  
Research Funding ◽  
Prognostic Significance ◽  
Mutational Status ◽  
Group 3 ◽  
Equity Ownership ◽  
Group 2 ◽  
Single Time Point ◽  
Group 1

Abstract Abstract 1777 MRD single time point assessments during therapy and at the end of treatment have been identified as independent predictors of PFS and overall survival in CLL patients (pts) by our group and others. However, it is currently unknown whether MRD kinetics during follow-up (FU) also have prognostic significance and whether kinetics show associations with CLL risk features. We therefore investigated MRD during treatment-free FU within the CLL8 trial of the GCLLSG (phase III, front-line RFC vs FC, Hallek et al., Lancet 2010) MRD kinetics were analyzed in 256 pts who had not progressed 1 year after completion of therapy and for whom at least 2 peripheral blood MRD assessments during the subsequent year were available. The slope of the common logarithm of MRD / time was calculated for 193 patients with at least 2 positive MRD measurements. Median MRD increase was 6.3fold during the observation period for the whole group (i.e. 0.80 log MRD unit increase / year). We compared groups of pts who (1) were always MRD negative (25% of all 256 pts), (2) had measurable disease with a slope below median (slow re-growth, 37% of pts), and (3) had measurable disease with a slope above median (fast re-growth, 39 %). The medians of the first measurable MRD levels during observation did not differ significantly between groups 2 (4.3 × 10−3) and 3 (1.7 × 10−3, p=.16). Pts with faster MRD re-growth kinetics (group 3) experienced a shorter median PFS (40 months) than pts with slower re-growth (group 2, 66 months), whereas median PFS has not been reached in pts who were always MRD negative (group 1, log-rank p= 3 × 10−14). Compared to group 1, group 2 and 3 pts carried increasingly higher risks of progression (HR 3.1 and 7.7, resp.). Pts showing a slow re-growth pattern (group 2) had a 2.5fold lower risk of clinical progression than pts with a greater MRD slope (group 3, p=5 × 10−6). The prognostic significance of MRD kinetics for PFS was also tested in Cox regression analysis together with clinical response, deletion 17p, IGHV mutational status, number of treatment cycles, treatment arm, thymidine kinase, beta2-microglobulin, pre-therapeutic WBC and MRD levels 1 year after completion of therapy. MRD kinetics (p=4×10−9), MRD levels (7×10−14), cycle number (8×10−5) and IGHV mutational status (1×10−3) remained independently significant for PFS in this multivariate analysis. We next correlated MRD slopes during the second year of FU and prognostic features in 204 pts (groups 2 and 3 plus 11 pts with early clinical relapse but measurable MRD slope during second FU year). Pts who required treatment within 2 years from diagnosis experienced a faster re-growth after therapy (.92/a) than pts with a longer treatment-free interval (.68, p=.04). The slope was significantly lower in pts with Binet A disease prior to therapy (.43/a) than in Binet B (.77/a, p =.03) and Binet C (.88/a, p=.02) pts. Pts carrying a chromosomal deletion (del) 13q as single abnormality had a significantly slower MRD re-growth pattern (.58/a) than those with del(11q) (1.0/a, p=.0004) or without cytogenetic abnormalities (1.1/a, p=.001), while the difference to pts with 12q+ (.71/a) was not significant. Pts with a mutated IGHV gene progressed slower (.54/a) than those with unmutated IGHV (.96/a, p=.0002). A thymidine kinase of at least 10 U/L was associated with a steeper MRD slope (.82/a) than lower levels (.61/a, p=.03). MRD slopes were not significantly associated with gender, WBC prior to therapy, beta2-microglobuline levels, presence of B-symptoms, or treatment arm. We demonstrate for the first time the independent prognostic significance of MRD kinetics during FU in CLL. MRD kinetics improve the prediction of PFS even when single time point MRD assessments during FU and other major risk features in CLL are additionally considered. MRD kinetics classify known CLL risk factors into two groups. IGHV, cytogenetics, thymidine kinase, stage, and time to treatment distinguish CLL subgroups with different re-growth kinetics, likely characterizing the relationship of proliferation to spontaneous apoptosis of the CLL clone itself. Other risk features did not show an association with kinetics in spite of proven significance in the CLL8 trial. Those features likely identify differences in responsiveness to therapy. We hypothesize that maintenance strategies will chance the course of the disease most effectively in patients who are responsive to therapy but relapse early due to fast CLL re-growth. Disclosures: Boettcher: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants. Ritgen:Hoffmann La Roche: Research Funding. Fischer:Hoffmann La Roche: Travel grants. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fingerle-Rowson:Hoffmann-La Roche: Employment. Fink:F. Hoffmann La Roche: Travel grants. Wenger:Hoffmann La Roche: Employment, Equity Ownership. Mendila:Hoffmann La Roche: Employment, Equity Ownership. Wendtner:Hoffmann-La Roche: Honoraria, Research Funding. Eichhorst:Hoffmann La Roche: Honoraria, Research Funding, Travel Grants. Hallek:Hoffmann-La Roche: Honoraria, Research Funding. Kneba:Hoffmann La Roche: Honoraria, Research Funding.

scholarly journals Emerging Real-World Midostaurin Treatment Patterns and Outcomes in FLT3-Mutated Acute Myeloid Leukemia at a Comprehensive Cancer Center

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4745-4745
Author(s):  
Connor Willis ◽  
Jyothi Menon ◽  
Sudhir Unni ◽  
Trang Au ◽  
Briana Ndife ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Research Funding ◽  
Treatment Patterns ◽  
Consolidation Therapy ◽  
Advisory Committees ◽  
Group 3 ◽  
Equity Ownership ◽  
Group 2 ◽  
Relapse Rates ◽  
Group 1

Abstract Introduction: Fms-like tyrosine kinase 3 (FLT3) gene mutation occurs in approximately 25-30% of acute myeloid leukemia (AML) cases and is associated with poor prognosis. Decreased overall survival is reported in FLT3-mutated vs. FLT3-wildtype. Midostaurin, a pan-targeted kinase inhibitor that inhibits activated FLT3 received FDA approval in April 2017 for adult patients with newly diagnosed FLT3-mutated AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. We report descriptive US clinical treatment patterns and outcomes in FLT3-mutated early midostaurin-users, historical FLT3-mutated patients prior to midostaurin approval, and historical FLT3-wildtype AML patients all treated with 7+3 induction therapy at an academic cancer specialty hospital to support the development of a larger database across several comprehensive cancer centers. Methods: This retrospective, observational study utilized ICD codes, tumor registry data, and pharmacy records from the Huntsman Cancer Institute (HCI) to identify AML patients treated with 7+3 induction chemotherapy from 2007 to July 2018. FLT3-mutated midostaurin-users treated with 7+3 induction including midostaurin from May 2017 to July 2018 comprise Group 1. Historical FLT3-mutated patients prior to midostaurin approval (non-users) and FLT3-wildtype patients comprise Groups 2 and 3, respectively. Complete response (CR), relapse rates, overall survival and treatment patterns were described. Results: A total of 105 patients met eligibility for inclusion in the study. Groups 1, 2, and 3 included five, 39 and 61 patients, respectively. Off-label midostaurin use in Group 1 after induction therapy was observed in one patient with post-consolidation monotherapy and salvage therapy in combination with ATRA (tretinoin) and CLAG (cladribine, cytarabine, and filgrastim). Following midostaurin approval, two FLT3-mutated patients received induction therapy without midostaurin due to enrollment in clinical trials that excluded midostaurin use for induction and consolidation therapy. These two patients were excluded from the study. Descriptive results of the comparative groups are summarized in Table 1. CR rate from induction therapy was 100% for Group 1, 90% for Group 2, and 77% for Group 3. The proportion of patients who received consolidation therapy was 60%, 74%, and 67%, and patients who maintained CR during consolidation therapy was 100%, 83%, and 49% for Groups 1, 2, and 3, respectively. Sixty-six percent of eligible Group 1 patients, 74% of Group 2 patients, and 54% of Group 3 patients received transplant. Median time from diagnosis to transplant was 81, 99, and 145 days for Groups 1, 2, and 3, respectively. The proportion of patients who received salvage therapy in Groups 1, 2, and 3 was 20%, 38%, and 56% respectively. Median follow-up was 6 months for Group 1, 14 months for Group 2, and 24 months for Group 3. After CR, 20% of Group 1, 49% of Group 2, and 59% of Group 3 relapsed. All Group 1 patients were alive at time of analysis while four Group 2, and eight Group 3 patients died during the study period. Discussion: Similar CR and relapse rates were observed between the comparative groups, although early use observations indicate improved response rates of induction therapy and consolidation therapy in a limited Group 1 sample. Patients in Group 1 and Group 2 underwent transplant earlier and more frequently than patients in Group 3, which may explain the higher relapse rate in Group 3. As this data resource is expanded across similar institutions, statistical comparisons of FLT3-mutated AML patients treated with and without midostaurin can be made. Sponsorship: Funding for this study was provided by Novartis Pharmaceuticals. Disclosures Unni: Novartis: Research Funding. Ndife:Novartis: Employment. Joseph:Novartis Pharmaceuticals Corporation: Employment; Amgen: Equity Ownership; Pfizer: Equity Ownership; Express Scripts: Equity Ownership. Bonifacio:Novartis: Employment. Stein:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Pfizer: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees. Kovacsovics:Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Brixner:BD: Consultancy; Abbott: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Millcreek Outcomes Group: Equity Ownership; University of Utah: Research Funding. Stenehjem:Novartis: Research Funding.

Prognosis Impact of Positive Minimal Residual Disease By Flow Cytometry Prior to Transplant According to the Cut-Off Threshold in Patients with Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Claudia Nunez-Torron ◽  
Fernando Martin Moro ◽  
Juan Marquet Palomanes ◽  
Miguel Piris-Villaespesa ◽  
Ernesto Roldan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Allogeneic Transplant ◽  
Group 3 ◽  
Baseline Characteristics ◽  
Group 2 ◽  
Minimal Residual ◽  
Group 1

Introduction: Patients with Acute Myeloid Leukemia (AML) and positive Minimal Residual Disease (MRD) prior to allogeneic transplant are currently considered to be a group at high risk of relapse. Multiparameter flow cytometry is a standard technique to measure MRD, and generally we use a 0.1% threshold for positivity. The clinical significance of those patients with an MRD levels >0% but <0.1% is uncertain and it is recommended to define the prognosis of this subgroup. Material and methods: We performed a single-center retrospective analysis of 88 patients transplanted between 2012 and 2020. All patients achieved complete remission (CR) with or without hemoperipheral recovery prior to allogeneic transplant. We have divided our cohort into three groups according to MRD state by flow cytometry: Group 1 patients with negative MRD, Group 2 patients with MRD level >0% but <0.1% and Group 3 patients with MRD ≥ 0.1%. The baseline characteristics of each group were compared using the Chi2 test. The survival analysis was performed through Kaplan-Meier method and the risk was calculated with Cox regression. The Overall Survival (OS) was defined as the time from transplantation to death and the Relapse-Free Survival (RFS) as the time from transplantation to either relapse or death. P<0.05 was defined as statistically significant difference. Results: The baseline characteristics of our cohort are reflected in Table 1. We did not find statistical significant differences except for the response to induction. The median follow-up of the entire cohort was 13.5 months (range 6-43.5). The 4-year RFS (4y-RFS) was 47% and the 4-year OS (4y-OS) 50%. The 4y-RFS was 52.5% in Group 1 vs 59% in Group 2 vs 30% in Group 3. The 4y-OS was 60% in Group 1 vs 60% in Group 2 vs 31% in Group 3 (Image 1). The Hazard Ratio (HR) for RFS and OS comparing Group 1 vs Group 2 was 0.9 [95% CI ((0.3-2.5)] and 1.1 [95% CI (0.4-3)] respectively. The HR for the RFS and OS comparing Group 1 vs 3 was 1.2 [95% CI (0.9-1.7)] and 1.2 [95% CI (0.8-1.6)]. We have stratified patients according to the European LeukemiaNet risk classification. In Group 1, the 4y-RFS was 79% in patients with Favorable Risk (FR) vs 55% in those with Intermediate Risk (IR) and 53% in patients with Adverse Risk (AR) [HR 1.2, 95% CI (0.6-2.3)] and the 4y-OS was 79% vs 54% vs 53% respectively [HR 1.3, 95% CI (0.6-2.5)]. In Group 2, the 4y-RFS was 100% in those with FR vs 83% in IR vs 33% in AR [HR 3.9, 95% CI (0.4-30)] and the 4y-OS was 100% vs 82% vs 36% respectively [HR 4, 95% CI (0.5-32%)]. In Group 3, the 4y-RFS in patients with FR was 82% vs 0% in IR vs 0% in AR [HR 2.1, 95% CI (1.1-4.1)] and the 4y-OS was 82% vs 0% vs 0% respectively [HR 1.6, 95% CI (0.8-3.3)] (Image 2). Conclusions: In our cohort, positive MRD >0.1% prior to transplant identified a group with worse RFS and OS compared to those with negative MRD or positive MRD level >0% but <0.1%. Positive MRD >0.1% is especially relevant in the IR and AR groups of the European LeukemiaNet risk classification. In the AR subgroup even any detectable level of positive MRD could identify patients with unfavorable post-transplant OS and RFS outcomes. We must establish post-transplant strategies in these patients to improve survival. Disclosures Garcia-Gutiérrez: Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding.

13q14 Chromosome Deletion Size and Number of Deleted Cells Influence Prognosis In Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3578-3578
Author(s):  
Francesca Maria Rossi ◽  
Davide Rossi ◽  
Clara Deambrogi ◽  
Francesco Bertoni ◽  
Michele Dal Bo ◽  
...  
Keyword(s):  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
Single Institution ◽  
Group 4 ◽  
Median Size ◽  
Mutational Status ◽  
Genome Wide ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Abstract 3578 Introduction: Chronic lymphocytic leukemia (CLL) patients bearing 13q14 deletion are known to experience a more favorable clinical course. Recent studies, focusing on patients with loss of 13q as the sole cytogenetic aberration at diagnosis (del13q-only cases), showed that the number of malignant cells carrying this genetic lesion correlates with a more aggressive clinical behavior. However, whether the size of the 13q deletion may also influence the clinical outcome remains to be elucidated. Patients and Methods: Probes for chromosome 13q (LSI-RB1, LSI-D13S319), 11q (LSI-ATM), 17p (LSI-p53) and chromosome 12 (CEP12) were utilized on nuclei collected at diagnosis from: i) a multi-institutional CLL cohort (342 del13q-only cases) and ii) a consecutive unselected single-institution cohort of 265 cases. RB1 deleted cases (delRB1) were defined as having at least 5% of deleted nuclei. Time to treatment (TTT) intervals, as well as Rai staging, IGHV mutational status, CD38 and ZAP70 expression, B2-microglobulin levels, all evaluated at diagnosis, were also available for all cases that entered the study. Genome wide DNA profile was performed in a pilot series of 90 CLL samples using Affymetrix GeneChip Human SNP6 arrays. Results: According to genome wide DNA analysis, delRB1 occurred in a proportion of del13q-only cases (36/90; 40%), always comprising the deleted region detected with the LSI-D13S319 probe (that covers the miR-15a/16-1 cluster and the DLEU2 gene) and characterized by a larger chromosome loss (median size 2.07 Mb vs. a median size of 0.86 Mb for the canonical del13S319). Maximally selected log-rank statistics identified the 70% of nuclei bearing del13S319 as the most appropriate cut-off value capable of separating del13q-only cases into two subgroups with different TTT distributions. Consistently, del13q-only cases with at least 70% of nuclei bearing del13S319 showed a significantly shorter TTT than del13q-only cases with less than 70% deleted nuclei (p=0.0001). Del13q-only cases were then divided in four subsets according to the percentage of nuclei bearing del13S319 with or without a concomitant delRB1: del13S319 <70% (group 1), 144 cases; del13S319 <70% + delRB1 (group 2), 95 cases; del13S319 >70% (group 3), 64 cases; del13S319 >70% + delRB1 (group 4), 39 cases. The median TTT of group 1 (not reached) was significantly longer than the median TTT of group 2 (92 months, p=0.012), group 3 (68 months, p<0.0001), and group 4 (82 months, p=0.0025; see Fig. 1A). Multivariate Cox proportional hazard analyses selected the presence of delRB1 (p=0.029), along with the IGHV mutational status (p<0.0001), as an independent negative prognosticator in the context of del13q-only cases with low/intermediate Rai risk (Rai stage of 0/I at diagnosis) and <70% of del13S319. Cases belonging to the consecutive unselected single-institution CLL cohort were divided into subsets according to the classification proposed by Döhner et al (NEJM, 2000). Notably, the presence of del13S319 in <70% of cells in the absence of delRB1 identified a patient subset with particularly stable and benign clinical course (group A in Fig. 1B, 48 cases; median TTT not reached). Conversely, patients characterized by del13S319 in <70% of cells but with a larger deletion, as determined by concomitant delRB1 (group B, 24 cases), or del13S319 in >70% of cells (with or without delRB1, group C, 25 cases) or a normal karyotype (group D, 75 cases) had shorter median TTT intervals (ranging from 105 to 129 months, p<0.01 in all the comparisons). Finally, patients affected by CLL bearing trisomy 12 (group E, 48 cases) and del11q or del17p (group F, 45 cases) experienced the worst clinical courses (p<0.0001). Conclusion: In the context of del13q-only cases, different clinical outcomes were associated to the percentage of 13q14 deleted cells, as well as to the size of the 13q14 deletion, as detected by the LSI-RB1 probe. Moreover, the presence of delRB1 emerged as a feature capable of refining the prognostic assessment in the context of CLL cases with <70% del13S319. The underlying genetic mechanisms correlated with the different clinical outcomes and associated with the size of the 13q deletion are presently under investigation. Disclosures: No relevant conflicts of interest to declare.

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2771-2771 ◽  
Author(s):  
Sikander Ailawadhi ◽  
Carole B. Miller ◽  
Anand P. Jillella ◽  
Nebu Koshy ◽  
Brian Tudor ◽  
...  
Keyword(s):  
Research Funding ◽  
Molecular Response ◽  
Employment Equity ◽  
Transcript Levels ◽  
Log Reduction ◽  
End Point ◽  
Day Range ◽  
Equity Ownership ◽  
Group 2 ◽  
Group 1

Abstract Abstract 2771 Background: NIL is a potent, highly selective Bcr-Abl kinase inhibitor approved for newly diagnosed adult pts with Philadelphia-chromosome positive (Ph+) CML-CP and in Ph+ CML-CP and accelerated-phase pts who are resistant or intolerant to IM. Achieving complete cytogenetic response (CCyR) and major molecular response (MMR, 3-log reduction of Bcr-Abl transcript level from the baseline mean) are favorable prognostic factors for CML. This multicenter, open-label study (ENABL) was designed to explore nilotinib Bcr-Abl effects in pts with CCyR but who have suboptimal molecular response to IM. Methods: This study evaluates change in Bcr-Abl trends in 2 groups of CML-CP pts (total n = 18) who achieved CCyR but have suboptimal molecular response to IM defined as: (Group 1) treated ≥ 1 year with IM, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) > 1-log increase in Bcr-Abl transcript levels from best response regardless of IM treatment duration. Pts are treated with NIL 300 mg twice daily for ≥ 1 year. RQ-PCR analysis is performed by a central lab at screening, then every 3 months (mos) for Group 1. Group 2 pts are monitored by RQ-PCR monthly for the first 3 mos, then every 3 mos. The 1° end point is change in Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR at 12 mos. The data cutoff date for this analysis was June 30, 2011. Results: Eighteen pts (Group 1, n = 17; Group 2, n = 1) have been treated with NIL for a median of 17 mos on study (range 3–34 mos). Thirteen pts have been treated for ≥ 6 mos and 10 for ≥ 12 mos. One pt was deemed ineligible due to lack of evidence of CCyR at baseline but is included in the analysis because there was at least 1 post-baseline evaluation performed. The remaining 17 pts had CCyR at baseline. Before enrollment, pts were treated with at least 400 mg once-daily IM; the mean dose of prior IM treatment was 487 mg/day (range 342–786 mg/day). Median duration of prior IM treatment was 3.4 yrs (range 1.3–10.2 yrs). Three pts had prior interferon treatment. All 18 pts were treated for ≥ 3 mos and had ≥ 1 post-baseline RQ-PCR result. Overall, 15 of 18 evaluable pts (83%) achieved MMR during treatment; 10 pts by 3 mos, 1 pt by 4.5 mos (measured at end of study), 1 pt by 6 mos, 2 pts by 9 mos, and 1 pt by 30 mos (Figure 1). The 3 pts who did not reach MMR at any point were only followed for up to 3 mos before discontinuing from the trial but showed a decreasing Bcr-Abl trend. Overall, pts achieved a median log reduction of PCR transcript levels of 3.1 (0.08% IS) at 3 mos; median 3.3-log reduction (0.05% IS) at 6 mos, and median 3.5-log reduction (0.035% IS) at 9 mos. Four pts had > 4-log (≤ 0.01% IS) reduction in Bcr-Abl; of these, 2 pts reached > 4.5-log (≤ 0.0032% IS) reduction in Bcr-Abl at least once during the study. Median Bcr-Abl transcript log reduction at 12 mos was 3.6 (0.025% IS, 1° end point) for 10 evaluable pts. All these pts reached MMR during NIL treatment; 9 pts by 12 mos, 1 pt after 30 mos. NIL was well tolerated and brief dose interruptions were sufficient to manage most adverse events (AEs). Seven of 18 pts were dose reduced for NIL-related AEs and re-escalated if the patient recovered from the AEs. Patients were permitted to dose escalate to 400 mg b.i.d. per physician's discretion if MMR was not achieved after 6 mos (n = 1). The Grade 3 AEs reported include 2 cases of rash and 1 case each of pneumonia, squamous cell carcinoma, bladder prolapse, uterine prolapse, bradycardia, hypertension, hyperbilirubinemia and hypophosphatemia. The rashes and bradycardia were suspected to be related to NIL. No Grade 4 AEs were reported. The median dose intensity was 600 mg/day (range 300–683 mg/day). Five pts were discontinued from the study (3 due to abnormal laboratory values, 1 due to an AE, and 1 due to protocol violation). No pts who experienced QTcF changes had differences > 33 msec from baseline. No QTcF prolongation > 500 msec was observed. Conclusions: NIL treatment results in high molecular response rates in CML-CP pts with suboptimal molecular responses to IM. Overall 83% of pts who switched to NIL achieved MMR, and the median Bcr-Abl log reduction for pts who reached 12 mos on study was 3.6 (0.025% IS). The IRIS study has shown that MMR rates increase with time in pts treated with IM (Hughes Blood 2010); however, this study appears to demonstrate that MMR is achieved relatively quickly in suboptimal molecular IM-treated pts when switched to NIL. Disclosures: Ailawadhi: Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Akard:Eisai: Speakers Bureau; Bristol Myers-Squibb: Speakers Bureau; Novartis: Speakers Bureau; Millenium: Speakers Bureau; Chemgenex: Consultancy. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lin:Novartis: Employment, Equity Ownership. Radich:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. DeAngelo:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy.

Use of Thymoglobulin for Graft Versus Host Disease Prophylaxis Does Not Increase the Incidence of Clostridium Difficile Infection in Recipients of Allogeneic Stem Cell Transplant Recipients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5447-5447
Author(s):  
Divaya Bhutani ◽  
Paul Naylor ◽  
Charles Jaiyeoba ◽  
Joseph P. Uberti ◽  
Voravit Ratanatharathorn ◽  
...  
Keyword(s):  
Research Funding ◽  
P Value ◽  
Transplant Recipients ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Group 3 ◽  
Equity Ownership ◽  
Baseline Characteristics ◽  
Group 2

Abstract Introduction: Clostridium difficile (C.diff) colitis (CDI) continues to be a common complication in recipients of allogeneic stem cell transplantation (AlloSCT). Multiple risk factors were associated with CDI in this patient population including prior CDI, antibiotic prophylaxis and therapy, acute graft versus host disease (aGVHD), etc. Our aim in this study was to evaluate the effect of thymoglobulin used in GVHD prophylaxis on the incidence of CDI in patients undergoing AlloSCT. Methods: We studied 3 consecutive cohorts of AlloSCT recipients. Group1- related donor AlloSCT without thymoglobulin (N=100, transplanted 3/2010-12/2013); group 2 - unrelated donor AlloSCT with thymoglobulin (N=110, transplanted 4/2012-12/2013); and group 3 - unrelated AlloSCT without thymoglobulin (N=100, transplanted 12/2009-12/2011). Majority of patients except three in group 3 were diagnosed with CDI with a PCR based test. Results: All 3 groups were similar with respect to the baseline characteristics (Table 1). The median follow up for the 3 groups was 2 years. At a median follow up of 2 years the incidence of CDI in the three groups were 19%, 26%, 28% respectively, p=0.2 (table 2). The incidence of CDI prior to aGVHD was similar in three groups (18/100, 25/110 and 19/100 in groups 1, 2 and 3 respectively). The incidence of CDI after development of aGVHD was higher in group 3 (1/100, 4/110 and 9/100 p=0.06 in groups 1, 2 and 3 respectively). The incidence of Grade II-IV aGVHD was significantly higher in group 3 (63%) as compared to groups 1 and 2 (49 and 41%) p=0.006 (Table 2). Similarly the incidence of any grade GI GVHD was higher in group 3 (44% Vs 23% and 24%) p=0.0009. The median time to development of aGVHD was similar in all three groups (28 days in groups 1, 31 days in group 2 and 26 days in group 2). Multivariable analysis revealed that none of the factors examined (age, sex, diagnosis, intensity of conditioning, type of transplant, use of thymoglobulin, acute GVHD) was related to development of CDI. Development of GI GVHD tended to increase the risk of subsequent CDI (40% vs 27%, p=0.06). Development of CDI did not increase the risk of development of subsequent GI GVHD (30% vs. 26%). Use of thymoglobulin improved two year overall survival in patients undergoing unrelated transplant (p=0.006). Conclusion: Thymoglobulin use did not affect the overall incidence of CDI in recipients of Allo-SCT. There is a trend towards increased incidence of late onset CDI in patients undergoing unrelated Allo-SCT and not recieving thymoglobulin probably because of higher incidence of GVHD and steroid use. There was no difference in the incidence of CDI in related vs. unrelated transplant recipients. Use of thymoglobulin improved survival in recipients of unrelated Allo-SCT. Table 1. Baseline Characteristics: Related (N=100) unrelated with Thymo (N=110) Allo unrelated without Thymo (N=100) P-value Age Median 54 58 52 NS Gender F 42 47 51 NS M 58 63 49 Race Caucasian 83 99 91 NS Other 17 11 9 Conditioning regimen Myeloablative 76 59 63 NS RIC 24 51 37 Diagnosis Leukemia 47 61 56 NS Lymphoma 30 21 20 MDS 12 20 11 Other 11 8 13 Source of stem cells BM 9 6 10 NS PBSC 91 104 90 HLA match 10/10 94 71 71 NS* 9/10 2 26 21 8/10 13 8 Haploidentical 4 GVHD** Prophylaxis Tac/MMF 97 100 Tac/MMF/Thymo 101 Tac/Sirolimus/Thymo 9 *No difference in HLA match between the groups 2 and 3. **Tac (Tacrolimus); MMF (Mycophenolate Mofetil); THYMO (Thymoglobulin). Table 2. Results: Groups 1. Related 2. Unrelated with Thymo 3. unrelated without Thymo P value Incidence of aGVHD II-IV 48% 41% 63% p=0.006 Incidence of GI GVHD 23% 23.6% 44% p=0.0009 Use of systemic steroids 38% 32% 61% p=0.0001 Overall Incidence of CDI 19/100 (19%) 29/110 (26%) 28/100 (28%) p=0.20 Incidence of CDI prior to GVHD 18/100 (18%) 25/110 (22%) 19/100 (19%) NS Incidence of CDI after onset of GVHD 1/100 (1%) 4/110 (3.6)% 9/100 (9%) p=0.06 Median Overall survival at 2 year f/u 68% 52% 46% p=0.0057 Disclosures Deol: Bristol meyer squibb: Research Funding. Lum:Karyopharm Therapeutics Inc: Equity Ownership; Transtarget.Inc: Equity Ownership. Revankar:Actelion, Merck, Gilead, Astellas: Research Funding; Dara biosciences: Consultancy. Chandrasekar:Merck, Glaxo, Chimerix,: Research Funding.

Prophylactic Use of a Combination of an Anticoagulant and Ursodeoxycholic Acid for Sinusoidal Obstruction Syndrome after Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5755-5755
Author(s):  
Hiroshi Okamura ◽  
Mitsutaka Nishimoto ◽  
Takahiko Nakane ◽  
Hideo Koh ◽  
Yasuhiro Nakashima ◽  
...  
Keyword(s):  
Risk Factors ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Adult Patients ◽  
Allogeneic Hsct ◽  
History Of ◽  
Group 3 ◽  
Group 2 ◽  
Prophylactic Use ◽  
Group 1

Abstract Introduction: Sinusoidal obstruction syndrome (SOS) is one of the potentially fatal complications of hematopoietic stem cell transplantation (HSCT). In particular, severe SOS frequently leads to multiple organ failure, and a worse prognosis. Thus, prophylaxis against development of SOS could contribute improved survival after HSCT. Previous reports demonstrated the effectiveness of the prophylactic use of ursodeoxycholic acid (UDCA) or certain anticoagulants, including unfractionated and low-molecular-weight heparin, for SOS. In two randomized controlled trials and two meta-analyses it was reported that UDCA, a hydrophilic bile acid, was an effective and safe drug for prophylaxis against SOS. The usefulness and feasibility of prophylactic use of anticoagulants after allogeneic HSCT are however still controversial. In addition, to our knowledge no study has evaluated the feasibility of usage of UDCA combined with an anticoagulant for SOS prevention after allogeneic HSCT in adult patients. To assess the efficacy and safety of use of UDCA combined with an anticoagulant as SOS prophylaxis, we performed a retrospective cohort study to examine the occurrences of SOS and hemorrhagic events in patients who underwent myeloablative allogeneic HSCT at our institution. We examined use of any anticoagulant together with simultaneous administration of UDCA, in comparison with UDCA alone for the prevention of SOS. Patients and methods: We reviewed the charts of consecutive adult patients in whom myeloablative allogeneic HSCT was performed at our hospital from November 1994 to May 2014, and who received either unfractionated heparin or dalteparin (low-molecular-weight heparin) with UDCA (group 1), danaparoid with UDCA (group 2), or UDCA only (group 3), used for prophylaxis against SOS. Results: A total of 280 patients (group 1: n=52; group 2: n=33; and group 3: n=195) were investigated. The proportions of patients with risk factors for SOS-including non-remission at the time of HSCT, a second or subsequent HSCT, high aspartate aminotransferase (AST) levels before HSCT, high ferritin levels before HSCT, a history of receiving gemtuzumab ozogamicin, and HLA disparity-were similar across the three groups. In group 1, a conditioning regimen containing busulfan was used less frequently (P = 0.002). SOS occurred in seven patients (13.7%) in group 1, five patients (15.2%) in group 2, and 28 patients (14.4%) in group 3, all meeting the Seattle criteria. None of the patients in group 1, two (6.1%) in group 2, and nine (4.6%) in group 3 had SOS diagnosed according to the Baltimore criteria. There was no significant difference in the incidence of SOS among the three groups. In addition, with regard to the cumulative incidence of severe SOS, no statistically significant difference was present among the three groups. The incidence of hemorrhagic events within 30 and 100 days following allogeneic HSCT was not significantly different across the three groups (30 days; 5.8%, 3.0%, 5.1%, P = 0.843, 100 days; 17.6%, 15.2%, 14.4%, P=0.843, respectively). Furthermore, the probabilities of OS and NRM until day 100 after allogeneic HSCT were similar among the three groups (P = 0.733 and P = 0.637, respectively). In a univariate model, a history of gemtuzumab ozogamicin treatment, high serum ferritin levels before HSCT, an HLA mismatched donor, and non-complete remission of disease at the time of allogeneic HSCT were found to be significant risk factors for SOS. Multivariate analysis revealed that a history of gemtuzumab ozogamicin therapy, a mismatched HLA donor, and non-complete remission of disease at the time of allogeneic HSCT were significant and independent risk factors for SOS. In the multivariate as well as univariate analyses, combined administration of UDCA and any anticoagulant for SOS prophylaxis did not have a significant effect on the incidence SOS, when compared to prophylaxis with UDCA alone. Conclusion: Our study results suggest that the combined use of UDCA and an anticoagulant for SOS prophylaxis after myeloablative allogeneic HSCT in adult patients was not beneficial. Establishment of an optimal strategy for prophylaxis against SOS after HSCT is still needed. Disclosures Nakane: Mundipharma KK: Research Funding. Koh:Pfizer: Consultancy, Honoraria. Hino:Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Speakers Bureau; Alexion: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding.

Prognostic significance of magnetic resonance imaging in the acute phase of cervical spine injury

1992 ◽  
Vol 76 (2) ◽  
pp. 218-223 ◽  
Author(s):  
Dale M. Schaefer ◽  
Adam E. Flanders ◽  
Jewell L. Osterholm ◽  
Bruce E. Northrup
Keyword(s):  
Cervical Spine ◽  
Mr Imaging ◽  
Prognostic Significance ◽  
Spinal Segment ◽  
Content Type ◽  
Group 3 ◽  
Group 2 ◽  
Fine Print ◽  
Group 1

✓ Fifty-seven patients with acute cervical spine injuries and associated major neurological deficit were examined within 2 weeks of injury by magnetic resonance (MR) imaging. All patients had abnormal scans, indicating intramedullary lesions. This study was undertaken to determine if the early MR imaging pattern had a prognostic relationship to the eventual neurological outcome. Three different MR imaging patterns were observed in these patients: 21 patients had patterns characteristic of intramedullary hematoma (Group 1); 17 had intramedullary edema over more than one spinal segment, but no hemorrhage (Group 2); and 19 had restricted zones of intramedullary edema involving one spinal segment or less (Group 3). The neurological state was determined using standard motor index scores at admission and at follow-up examination. Characteristically, the patients in Group 1 had admission motor scores significantly lower than the other two groups. At follow-up examination, the median percent motor recovery was 9% for Group 1, 41% for Group 2, and 72% for Group 3. These studies suggest that the MR imaging pattern observed in the acutely injured human spinal cord has a prognostic significance in the final outcome of the motor system. It is only when an accurate prognosis can be given at the outset that useful treatment data might be collected for homogeneous injury groups, and accurately based long-term planning made for the best patient care.

scholarly journals EZH2 Upregulation Is Associated with Unfavorable Prognosis in Diffuse Large B-Cell Lymphoma through Potential RUNX3 Downregulation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5301-5301
Author(s):  
Denise Peker ◽  
Samara Roman-Holba ◽  
Yuri Kwon ◽  
Jennifer Gordetsky ◽  
Amitkumar Mehta ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Rna Expression ◽  
Large B Cell Lymphoma ◽  
Group 3 ◽  
Group 2 ◽  
Large B Cell ◽  
Group 1

Abstract Introduction: The runt-related transcription factor 3 (RUNX3) is a downstream effector of the transforming growth factor-β (TGF-β) signaling pathway, and has critical roles in apoptosis, angiogenesis, cell migration and invasion. Putative tumor suppressor activity of RUNX3 has been presented extensively in the literature, particularly in solid epithelial tumors and recently in lymphoma with loss of expression favoring tumorigenesis and/or prognosis, but its role in diffuse large B-cell lymphoma (DLBCL) has not been studied. Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, has been shown to mediate silencing of RUNX3. RUNX3 downregulation due to EZH2 upregulation has been shown in various solid tumors. In the present study, we investigated the EZH2 and RUNX3 RNA expression status in DLBCL and its impact on clinical outcome. Methods: A retrospective chart review was performed and 169 cases of DLBCL treated with chemoimmunotherapy between 2003 and 2013 were included. Immunodeficiency- or EBV-associated and MYC+ LBCL were excluded. Archived formalin-fixed-paraffin-embedded tissue samples were retrieved and RNA was extracted using commercially available kits. We correlated the RNA expression levels for EZH2 and RUNX3 in various sites using quantitative real-time PCR (Taqman assay) and custom designed primers for each gene. Control samples included three benign lymph nodes free of a neoplastic process. Results: We identified 66 cases of DLBCL, including25 nodal DLBCL and 41 extranodal DLBCL, with sufficient RNA extracted. Extranodal locations included testis (n=12), orbit (n=6), primary central nervous system (n=5), bone (n=3), breast (n=2) and viscera (n=13). The median age was 64 years (range 29- 81 years) with a female to male ratio of 0.4 (F=20 and M=46). Median overall survival (OS) was 28 months (1-156 months). Immunophenotypic subtype based on cell-of-origin using Hans algorithm was available in 63 cases; 34 cases were germinal center B-cell (GCB) type while 29 were non-GCB type. Treatment data was available in 63 cases and all patients received R-CHOP as initial therapy except three patients who died shortly after diagnosis. Forty-four cases showed higher expression of EZH2 and RUNX3 when compared to normal lymph nodes (p < 0.05). Nineteen out of 44 cases showed increased EZH2 and decreased RUNX3 expression (Group 1) while EZH2 expression was lower than RUNX3 in the remaining cases (Group 2). The remaining 22 DLBCL cases did not show significant correlation for expression (Group 3). Overall survival was significantly low in Group 1 compared to Group 2 and Group 3 (p =0.030 and p=0.026, respectively). There was no difference for OS between Groups 2 and 3 (p>0.05) (Figure 1). Conclusions: Our results showed that decreased RUNX3 RNA expression is associated with EZH2 overexpression and poses an adverse prognostic factor in DLBCL. Larger studies are needed to establish the prognostic and therapeutic utility of EZH2 and/or RUNX3. Disclosures Mehta: Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Medimmune: Research Funding; Roche Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Forero:University of Alabama at Birmingham: Research Funding. Costa:Sanofi: Honoraria, Research Funding.

Clinical Significance of Homozygous D13S319 Deletion in B-Cell Chronic Lymphocytic Leukemia (B-CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2799-2799 ◽  
Author(s):  
Stephanie Fink ◽  
Susan Geyer ◽  
Tait Shanafelt ◽  
Stephanie Smoley ◽  
Sarah Paternoster ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Median Percentage ◽  
Time To Treatment ◽  
Treatment Status ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Background: In B-CLL, the observation of interphase cells with hemizygous D13S319 deletion at 13q14 (13q-x1) as a sole anomaly in blood is widely considered a favorable prognosis. The observation of cells with 11q-, +12 or 17p- has been associated with a relatively poor prognosis. Over the past 1.5 yrs, 16.2% (174/1,076) of patients (pts) referred for fluorescence in situ hybridization (FISH) testing for B-CLL in our clinical practice had a clone with homozygous D13S319 deletion (13q-x2), but the prognostic significance of this observation is poorly understood. Moreover, 39.3% (142/361) of pts with unfavorable FISH anomalies have 13q-x1 and/or 13q-x2 and the clinical significance of this observation is also unknown. Thus, we investigated pts with 13q- (with or without other chromosome anomalies) to establish the relative clinical significance of 13q- in B-CLL. Methods: We studied 333 pts with B-CLL sampled between 9/1999 and 6/2004 who had FISH performed on interphase nuclei from blood. The FISH probe set was designed to detect 6q-, 11q-, +12, 13q-, 17p-, and translocations involving IgH at 14q32. We classified pts into four groups: 13q-x1 only (group 1), 13q-x1 and 13q-x2 only (group 2), 13q-x2 only (group 3) and 13q-x1 and/or 13q-x2 plus other FISH anomalies (group 4). FISH groups were compared with gender, age, Rai stage, treatment status, time to treatment, CD38 and IgVH mutation. Results: Of the 333 pts, 171 (51.3%) had a 13q-: 71 were in group 1, 25 in group 2, 26 in group 3 and 49 in group 4. %CD38+ differed significantly across FISH groups; in pairwise analyses, the proportion of pts with >30% CD38+ was significantly greater for pts in group 4 vs. group 3 (p=0.0015) although no significant differences were observed for group 3 vs. group 1 or vs. group 2. Pts in group 3 were not significantly different from other FISH groups for Rai stage, IgVH mutation or gender. The median percentage of abnormal nuclei for pts with group 1 was 54.5% vs. 79.5% for pts in group 4 (p<0.0001). The median percent abnormal nuclei for pts in groups 3 and 2 was 72.5% and 68.5%, respectively. Median % abnormal nuclei for group 3 was not significantly different than the other FISH groups. Treatment status was available on 147 pts, where the proportion of pts who had treatment in each group was as follows: group 1, 15/66; group 2, 2/22; group 3, 4/21; and group 4, 9/38. Due to limited sample size and heavy censoring, any analysis on time to treatment is preliminary; however, these early analyses suggest group 4 pts have a lower median time to treatment (9 yrs) compared to groups 3 and 1 (12.3 and 13 yrs, respectively). Conclusions: This study has generated new information about the 13q- anomaly in B-CLL. First, known prognostic markers for B-CLL pts with 13q-x2 are not significantly different than for pts with 13q-x1 or 13q-x1/13q-x2. Second, 13q-x1 and/or 13q-x2 occurring with other unfavorable FISH anomalies have an unfavorable prognosis; i.e. potential benefits of 13q- are trumped when it is observed with unfavorable FISH anomalies. Thus, patients with any form of 13q- alone may have indolent disease while patients with 13q- and unfavorable FISH anomalies should be considered to be in a more aggressive phase.

Moderate Intensive Chemotherapy Including CNS-Prophylaxis with Liposomal Cytarabine Is Feasible and effective in Older Patients with Ph-Negative Acute Lymphoblastic Leukemia (ALL): Results of a Prospective Trial From the German Multicenter Study Group for Adult ALL (GMALL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1493-1493 ◽  
Author(s):  
Nicola Goekbuget ◽  
Joachim Beck ◽  
Monika Brueggemann ◽  
Thomas Burmeister ◽  
Eike C. Buss ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Research Funding ◽  
Prospective Trial ◽  
Bone Marrow Toxicity ◽  
Liposomal Cytarabine ◽  
Charlson Score ◽  
Cns Prophylaxis ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Abstract 1493 Few older ALL pts are entered into prospective trials and data on characteristics and outcome are scarce. The GMALL started a prospective trial in older ALL (>55 yrs) in 2003. In Ph-neg ALL a prephase (Dexa, Cyclo, MTX i.th.) was followed by induction I (Dexa, VCR, Idarubicin), induction II (Cyclo, AraC), alternating consolidation with IDMTX (d 1,15) ×3, VM26/AraC ×2, reinduction (VCR, Ida, Cyclo, AraC) and maintenance (MP, MTX) up to 2 yrs. In CD20+ ALL Rituximab ×8 was added. CNS-prophylaxis consisted of i.th. triple combination (MTX, AraC, Dexa) ×4 during induction, ×8 during consolidation/maintenance. The original protocol (group 1) was amended to optimize CNS prophylaxis and consolidation (group 2). I.th. therapy was then performed with liposomal cytarabine, 3x during induction, 3x during consolidation. IDMTX dose was increased from 500 to 1000 mg/m2 and native E.coli ASP (10.000 U/m2) was added on d2 and d16 of IDMTX. VM26/AraC was replaced by IDAraC (1000 mg/m2 d1,3,5). In a further amendment the original i.th. prophylaxis was reinserted until final analysis of liposomal AraC became available. Furthermore, after induction, one cycle with pegylated ASP (500 U/m2) (PEG-ASP) was scheduled to evaluate feasibility in older pts (group 3). Results of induction were compared for groups 1–3; outcome analysis was restricted to 1–2 due to still short follow-up for group 3. 268 pts with a median age of 67 (55–85) yrs treated in 94 hospitals were evaluable (180, 43 and 45 pts in groups 1, 2 and 3 resp.). 39% were aged 55–65 yrs, 51% 66–75 yrs and 10% above 75 yrs. 67% had c/pre-B-ALL, 18% pro-B-ALL and 15% T-ALL. WBC was >30/nL in 27%. Poor ECOG status (≥2) before (ECOGb) or after (ECOGa) onset of ALL was described in 7% or 38% resp. 78% had any comorbidity and 9% had a Charlson score (ChS) ≥3. No significant differences were detected between groups 1–3. Overall 76% (N=203) achieved CR after induction, 14% experienced early death (ED) and 10% did not achieve CR. In groups 1–3 CR rates were 72%, 86% and 82% resp. and ED rates 18%, 0% and 11% resp. (p=.03). CR rates were 84%, 74% and 52% in three age groups (p=.002) with ED rates of 7%, 14% and 37% resp. (p=.0004). Immunophenotype and WBC (<> 30.000) correlated with CR but not ED rate. ECOGb 0–1 vs ≥2 correlated with CR (82% vs 33%;p<.0001) and ED (7% vs 53%;p<.0001). Also ECOGa correlated with CR (85% vs 67%;p=.003) and ED (6% vs 19%;p=.003). CR and ED rates were not influenced by comorbidity itself but by ChS < vs ≥3: CR (78% vs 59%;p=.003) and ED (11% vs 33%;p=.0007). Multivariate analysis confirmed ECOGb, WBC and age for CR rate, and ECOGb, age and ChS for ED. Overall survival (OS) at 5 yrs was 23%; 33% at 2 yrs for group 1 and 52% for group 2 resp. (p=.01). Mortality in CR was 6% and 15% of the pts were withdrawn in CR. Probability of continuous complete remission (CCR) was 32% at 5 yrs, 42% and 43% at 2 yrs for group 1 and group 2 resp. (p=>.05). Age (42% vs 37% vs 8%;p=.0007), WBC (43% vs 15%;p<.0006), ECOGb (40% vs 14%;p=.0008) and ECOGa (42% vs 30%;p=.0023) were correlated with OS in contrast to comorbidity and ChS. Age, treatment group, WBC, ECOGb and ECOGa were confirmed in multivariate analysis. Pts younger than 75 yrs with ECOGb below 2 had an 86% CR rate with 10% ED and 36% OS at 3 yrs. WBC and MRD were significant prognostic factors for CCR. MRD results after consolidation I were available in 33 pts. CCR was 11% in molecular failure vs 68% in molecular CR. Preliminary results confirmed feasibility of PEG-ASP. With this age adapted regimen a favorable CR rate was achieved in a large patient group with a median age of 67 yrs. CR was increased (86%) and mortality was decreased (0%) significantly with liposomal cytarabine compared to triple i.th. prophylaxis during induction, since the latter probably induced more bone marrow toxicity. Reduced ED contributed considerably to improved OS. Moderate intensive consolidation was feasible and ASP, including PEG-ASP, was well tolerated. Age was correlated with outcome and 75 yrs appears to be the upper limit for this regimen. General condition was an additional highly relevant prognostic factor whereas comorbidity, measured by Charlson score was associated with ED but not with OS. These results encourage further treatment optimisation in older ALL pts, including those with comorbidities, based on comprehensive diagnostics, geriatric assessment, MRD evaluation, intensified consolidation, use of ASP, dose-reduced stem cell transplantation and integration of new, targeted drugs. Disclosures: Goekbuget: Medac: Consultancy, Research Funding, Speakers Bureau; Novartis: Research Funding; BMS: Research Funding; Genzyme: Research Funding; Mundipharma: Research Funding, Speakers Bureau; Glaxo: Research Funding, Speakers Bureau; Micromet/AMGEN: Consultancy; Sigma Tau: Consultancy. Off Label Use: Liposomal cytarabine in prophylaxsis of CNS relapse in ALL.

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