scholarly journals Prognostic Impact of Cytogenetic Abnormalities in Adult Patients with Philadelphia-Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL) Who Underwent Allogeneic Stem Cell Transplant (allo-SCT)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2024-2024
Author(s):  
Hiroaki Shimizu ◽  
Takayuki Saitoh ◽  
Shinichiro Okamoto ◽  
Yoshinobu Kanda ◽  
Heiwa Kanamori ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Complete Remission ◽  
Research Funding ◽  
Pharmaceutical Research ◽  
Patient Characteristics ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Cytogenetic Abnormalities ◽  
Significant Difference

Abstract Background: Cytogenetic abnormalities at diagnosis are recognized as a potent prognostic factor for acute leukemia patients. Among acute myeloid leukemia patients, the prognostic implications of cytogenetic abnormalities have been established for those treated with chemotherapy as well as those undergoing allo-SCT. In the context of Ph-negative ALLpatients, cytogenetic abnormalities at diagnosis clearly stratify the prognosis, whereas it has not been elucidated whether similar prognostic stratification is applicable to allo-SCT recipients. Objective: The aim of this retrospective study was to assess the prognostic impact of cytogenetic abnormalities in adult Ph-negative ALL patients who underwent allo-SCT. Patients and Methods: The study cohort included 373 adult Ph-negative ALL patients aged over 15 years who underwent allo-SCT for the first time between January 2001 and December 2012 at the 23 institutions participating in the Kanto Study Group for Cell Therapy (KSGCT). Patients' clinical data were collected from the KSGCT database. The Institutional Review Board of Gunma University approved the protocol of this study. Karyotypes considered high risk (HR) included t(4;11), t(8;14), low hypodiploidy, and complex (equal or more than five abnormalities), and all other karyotypes were designated standard risk (SR). On this basis, 308 patients (82.6%) were categorized as SR and 65 patients (17.4%) were categorized as HR at diagnosis. Of the 373 patients, 267 underwent allo-SCT in complete remission (CR) (224 in the SR group and 43 in HR group), and 106 in non-CR (84 in the SR group and 22 in HR group). For analysis, the study population was stratified based on disease status at the time of transplant. Almost all patients were conditioned with total body irradiation (TBI)-containing myeloablative conditioning (MAC) regimens prior to transplantation. Overall survival (OS) was defined as the interval from the date of transplantation to the date of death. Non-relapse mortality (NRM) was defined as any death in continuous complete remission (CR). The Fisher's exact test was used for comparison of binary variables. OS and RFS were estimated by the Kaplan-Meier method, and compared using the log-rank test. Cumulative incidences (CI) of relapse and NRM were compared using the stratified Gray test. P < 0.05 was considered as statistically significant. Results: [Patients in CR] No significant difference in patient characteristics and transplant procedures was observed between the SR and HR groups. The 5-year OS rates were similar between the SR and HR groups (60.5% vs. 74.1%, respectively; p = 0.225) (Figure 1). Similarly, there were no significant differences in the 5-year CI of relapse and NRM rates between the two groups (relapse: 26.3% vs. 24.8%, respectively; p = 0.498, NRM: 19.6% vs. 10.0%, respectively; p = 0.232). Multivariate analysis for OS identified MAC and TBI-containing regimens, not cytogenetic risk, as significant positive prognostic factors. [Patients in non-CR] No significant difference was observed between the SR and HR groups in terms of patient characteristics or transplant procedures, although there was a female predominance in the HR group. Patients in the SR group had a significantly superior 5-year OS rate compared to the HR group (15.4% vs. 4.5%, respectively; p = 0.022). There was no significant difference in the 5-year CI of relapse between the SR and HR groups (60.3% vs. 50.0%, respectively; p = 0.411), whereas the 5-year CI of NRM in the SR group was significantly lower than that in the HR group (24.8% vs. 45.5%, respectively; p = 0.024). Multivariate analysis revealed cytogenetic risk group as an independent prognostic factor. Conclusion: These findings suggest that adult Ph-negative ALL patients in remission with HR cytogenetic abnormalities have similar transplant outcomes to those in the SR group. Considering the reported equality of the CR rates between the two groups, allo-SCT at an early clinical phase is recommended for HR group patients, reminiscent of Ph-positive ALL patients in the pre-imatinib era. Current transplant procedures do not improve outcomes for patients who are not in remission, especially those with HR cytogenetic abnormalities. Disclosures Usuki: MSD: Other: personal fees, Research Funding; SymBio Pharmaceutical: Other: personal fees, Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Shionogi: Other: personal fees; Fujimoto Pharmaceutical: Research Funding; Bristol-Myers Squibb: Other; Takeda Pharmaceutical: Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; Sanofi: Other: personal fees, Research Funding; Shire: Research Funding; Kyowa Hakko Kirin: Other: personal fees, Research Funding; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Novartis: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Chugai Pharmaceutical: Other: personal fees; Fuji Film RI Pharma: Other: personal fees; Taiho Pharmaceutical: Other: personal fees, Research Funding; Astellas: Research Funding. Nakaseko:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Otsuka: Honoraria, Research Funding.

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.

scholarly journals Prognostic Impacts of Additional Cytogenetic Abnormalities Acquired at the First Relapse in Adult Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplant in Second Complete Remission

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3380-3380
Author(s):  
Hiroaki Shimizu ◽  
Junichi Mukae ◽  
Naoki Shingai ◽  
Takashi Toya ◽  
Yuho Najima ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Statistical Significance ◽  
Cell Transplant ◽  
Reduced Intensity Conditioning ◽  
Cytogenetic Abnormalities ◽  
Cytogenetic Changes ◽  
Conditioning Regimens ◽  
First Relapse

Abstract Background: Additional cytogenetic abnormalities (ACA), the most frequent form of cytogenetic changes, are considered as a result of genetic instability and clonal evolution of leukemia cells. Recently, we described that ACA at the first relapse was associated with the significantly lower second complete remission (CR2) rate and poor survival in adult acute myeloid leukemia (AML) patients (Hematol Oncol. 2018;36:252-257). However, the prognostic impact of ACA after allogeneic stem cell transplant (allo-SCT) has not been elucidated in adult AML patients. Patients and methods: Of the 145 adult AML patients who underwent the first allo-SCT in CR2 between 1997 and 2019, 98 patients whose cytogenetic abnormality data both at diagnosis and at the first relapse were available were included in this study. Cytogenetic changes between at diagnosis and the first relapse were classified into four groups: (1) no change, (2) ACA was acquired at the first relapse, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the first relapse, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the first relapse. In this study, groups 2 and 4 were defined as ACA acquisition. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p &lt; 0.20) in univariate analyses were subjected to multivariate analysis. The Cox and Fine-Gray proportional hazard model were used for multivariate analysis of prognostic and risk factors, respectively. Values of p &lt; 0.05 were considered to indicate statistical significance. Results: Of the 98 patients included in this study, 57 were male, and 41 were female. The median age at transplant was 45 years (range, 17-71 years). The median duration of CR1 was 12.4 months (range, 1.3-70.3 months) and cytogenetic risk groups were good, intermediate, and poor in 26 (27%), 70 (71%), and two patients (2%), respectively. Donor types were related, unrelated, and cord blood in 23 (24%), 59 (60%), and 16 patients (16%), respectively, and 86 (87%) and 61 patients (62%) were conditioned with myeloablative and total body irradiation-containing regimens, respectively. According to the definition described above, 20 patients (20%) acquired ACA at the first relapse. There was no significant difference in baseline characteristics and transplant procedures between patients with and without ACA acquisition. The OS rates were not significantly different between two groups (55% vs. 72% at three years after transplant; p = 0.28). The CI of relapse was significantly higher in patients with ACA acquisition than those without ACA acquisition (59% vs. 15%; p &lt; 0.01), while the CI of NRM were not significantly different between two groups (5% vs. 19%; p = 0.17). Multivariate analysis for OS revealed that age over 50 years (hazard ratio [HR] = 2.4; p &lt; 0.01), but not ACA acquisition, was identified as an independent prognostic factor. ACA acquisition (HR = 4.7; p &lt; 0.01) was extracted as an independent risk factor of relapse, while use of reduced intensity conditioning regimens (HR = 3.1; p = 0.03) and more than or equal to 1 of performance status at transplant (HR = 2.7; p = 0.04) showed independent risks of NRM. The similar OS rates between two groups might resulted from an offset of the lower relapse rate with the higher NRM rate in patients without ACA acquisition despite not reaching statistical significance. This increasing NRM rates in those without ACA acquisition was potentially associated with use of reduced intensity conditioning regimens in larger proportion (0% vs. 15%; p = 0.12). Conclusion: These findings suggested that ACA acquisition at the first relapse was associated with a higher risk of relapse even after allo-SCT in CR2 in adult AML patients. As AML cells with ACA acquisition was resistant to not only chemotherapy but also graft-versus-leukemia effect, innovative therapeutic strategy is warranted. Disclosures Handa: Janssen: Honoraria; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Chugai: Research Funding; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding.

scholarly journals Clinical Significance of Clonal Cytogenetic Heterogeneity (CCH) at Diagnosis in Adult Patients with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2820-2820
Author(s):  
Hiroaki Shimizu ◽  
Nahoko Hatsumi ◽  
Satoru Takada ◽  
Takuma Ishizaki ◽  
Akihiko Yokohama ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Statistical Significance ◽  
Prognostic Impact ◽  
Common Ancestry ◽  
Complex Karyotype ◽  
Abnormal Karyotype ◽  
Cytogenetic Abnormalities

Abstract Background:Although cytogenetic abnormalities at diagnosis are recognized as one of the most potent prognostic factors in acute leukemia patients, CCH acquisition at diagnosis, which are considered as a result of clonal evolution of leukemia cells, is not taken into account in prognostic classifications. Recent studies reported that CCH acquisition was observed in 24 - 32% of adult AML patients with abnormal karyotype, was more likely to occur in patients with older age and complex karyotype, and showed adverse prognostic impact. However, the clinical significance of CCH acquisition has not been investigated in adult ALL patients to date. Patients and methods: Of the 238 adult ALL patients diagnosed between 1990 and 2016, 120 patients with abnormal karyotype at diagnosis, who underwent intensive chemotherapy, were included in this study. CCH was defined as presence of two or more cytogenetically abnormal clones. A defined ancestral clonal evolution included either mother-daughter and/or branched patterns. In the mother-daughter pattern, a daughter clone showed all cytogenetic abnormalities of a mother clone plus additional abnormality(s), which define a distinct subclone. In a branch pattern, all subclones possessed common cytogenetic abnormalities suggesting presence of a common ancestry, but each subclone acquires unique additional abnormality(s), which define them as distinctive subclones. Both patterns of cytogenetic clonal evolution were sometimes seen in a patient. Composite karyotypes were applied to patients where a common ancestry could not be clearly determined because of too complicated cytogenetic findings. Fisher's exact test was used to compare binary variables. The logistic regression model was used for multivariate analysis of predisposing factors. Overall survival (OS) was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. Values of p < 0.05 were considered to indicate statistical significance. Results:Of the 120 patients included in this study, 64 patients were male, and 56 were female. The median age was 50 years (range, 16-79 years). Karyotypes at diagnosis were Philadelphia chromosome (Ph) in 56 patients, complex in 15, and t(8;14) in seven. According to the definition described above, 47 patients (39%) showed CCH at diagnosis, and two (4%) among them were categorized as composite karyotype. Of the 45 patients harboring a defined ancestral clonal evolution, numbers of subclones were two, three, and four in 32 patients (68%), 11 (24%), and 2 (4%), respectively. Mother-daughter pattern, branched pattern, and both were seen in 34 patients (76%), 5 (11%), and 6 (13%). In univariate analysis for predisposing factors of CCH acquisition, only younger age was significantly associated with CCH acquisition (48% in age <= 50 vs. 29% in age > 50; p = 0.04), but not karyotype. This statistical significance was confirmed with multivariate analysis (odds ratio = 0.44; p = 0.03). When investigating the prognostic impact of CCH acquisition, patients were divided into Ph-negative or Ph-positive ALL groups. In the 64 Ph-negative ALL patients, the CR rates were not significantly different between patients with or without CCH (78% vs. 78%, respectively; p = 1.00). The OS rates were similar between two groups (26% vs. 39% at five years, respectively; p = 0.56). Multivariate analysis for OS revealed that complex karyotype and t(8;14) were independent prognostic factors, but not CCH acquisition. Likewise, in the 56 Ph-positive ALL patients, CCH acquisition was not significantly associated with the CR rates (92% vs. 78%, respectively; p = 0.27), and the OS rates did not significantly differ between the two groups (34% vs. 40% at five years, respectively; p = 0.90). In multivariate analysis for OS, no independent prognostic factor was identified. Conclusion: Adult ALL patients with abnormal karyotype acquired CCH at diagnosis with a frequency comparable to that of AML patients. However, unlike AML patients, CCH acquisition was more frequently observed in younger population and did not show any prognostic impact in ALL patients. These findings suggested that biological backgrounds of CCH acquisition at diagnosis were possibly different between in patients with ALL and AML. So, to confirm these important findings, clinical studies with larger study subjects are warranted. Disclosures Handa: Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Outcomes of HMA and Venetoclax in Relapsed AML Post-Allogenic Hematopoietic Stem Cell Transplant

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Osama Diab ◽  
Haitham Abdelhakim ◽  
Joseph P. McGuirk ◽  
Tara Lin
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Complete Remission ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Pharmaceutical Research ◽  
Cell Transplant ◽  
Hematopoietic Stem

Background: There is no standard of care treatment for Acute Myeloid Leukemia (AML) in relapse post-allogeneic hematopoietic stem cell transplant (post-HSCT), with overall 5-year survival about 5-10%. Venetoclax (Ven) is a novel BCL2 inhibitor approved by the FDA for treatment of newly diagnosed AML in combination with hypomethylating agents (HMA) or low dose cytarabine for patients unfit for intensive induction. However, data in relapsed/refractory AML are limited, especially in the post-HSCT setting. In this retrospective study, we reviewed outcomes of patients with AML relapse post-HSCT who received Ven in combination with HMA in a single center. Methods: Charts of 17 patients who had AML relapse post-HSCT treated with combination of Ven and HMA between November 2018 - March 2020 at the University of Kansas Medical Center were reviewed. We utilized descriptive statistics for baseline characteristics and outcomes, and Kaplan-Meier log-rank test for calculating overall survival. Results Seventeen patients received Ven+HMA for AML relapse post-HSCT in our center. At the time of SCT, patients were in first complete remission (CR) (n=15); second CR (n=1) and primary failure induction (1). Median age was 62 at time of relapse (31-71) years, and 8 patients were female (47%). 9 patients (53%) had adverse risk AML (ELN 2017) 8 of them were in CR1 and 1 with primary induction failure. Common mutations included DNMT3a, ASLX-1, TET2 (3); TP53 (2); IDH1/2 (2); NPM1/FLT3 (1); NPM1/IDH2 (1); NPM1 (1 transplanted in CR2); FLT3 (1). 2/17 had received Ven+HMA prior to SCT; 4 patients received HMA alone prior to SCT. 11 patients (65%) were naïve to either Ven or HMA prior to relapse. Median time to relapse was 181 (44-851) days post-HSCT. 9 (53%) patients received Azacitidine+Ven and 8 (47%) received Decitabine+Ven. HMA+Ven was the first line of therapy post-HSCT relapse in 14 patients. 2 had donor lymphocyte infusion (DLI) after either MEC or dacogen but relapsed prior to Ven+HMA. 1 had IDH (2) inhibitor. Patients received median of 2 (1-10) cycles of HMA+Ven. Six (35%) patients achieved complete remission/complete remission with incomplete hematologic recovery (CR/CRi), and 2/6 patients had negative measurable residual disease by multiparameter flow cytometry. Median overall survival was 361 days from relapse (Figure 1). 3/14 patients received subsequent DLI with Ven+HMA. Disease progression was the most common cause of death in 8/9 of patients who died during the follow up period. Most common side effects included neutropenic fever (n=8, 47%) and acute graft versus host disease (aGVHD) (n=5, 30%). 2/5 developed new aGVHD on HMA+Ven with no prior history of aGVHD. However, aGVHD was mainly grade I-II and responsive to therapy. Discussion HMA+Venetoclax demonstrates potential activity in patients with AML relapse post-HSCT with a CR/CRi rate of 35%, comparable to other salvage therapies. There were no unexpected side effect in this high-risk population. Larger studies are needed to confirm efficacy and toxicity in this setting. Disclosures McGuirk: Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding. Lin:Aptevo: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; Jazz: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Astellas Pharma: Research Funding.

scholarly journals Clinical Significance of Additional Cytogenetic Abnormalities (ACA) Acquired at the First Relapse in Adult Acute Myeloid Leukemia (AML) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3673-3673
Author(s):  
Hiroaki Shimizu ◽  
Akihiko Yokohama ◽  
Nahoko Hatsumi ◽  
Satoru Takada ◽  
Takayuki Saitoh ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Clinical Significance ◽  
Induction Chemotherapy ◽  
Multiple Logistic Regression Analysis ◽  
Predisposing Factors ◽  
Prognostic Impact ◽  
Cytogenetic Abnormalities ◽  
Cytogenetic Changes ◽  
First Relapse

Abstract Background: Cytogenetic changes between the time of diagnosis and the first relapse are found in 30 to 60% of relapsed AML cases. ACA, the most frequent form of cytogenetic changes, are considered as a result of genetic instability and clonal evolution of AML cells. However, because the clinical significance of ACA has not been elucidated in adult AML patients, we conducted a large-scale retrospective study to address this unsolved issue. Patients and methods: Of the 375 adult patients diagnosed with AML between 1990 and 2010, 144 relapsed patients whose cytogenetic abnormality data both at diagnosis and at the first relapse were available were included in this study. All these patients underwent intensive chemotherapy. Patients with acute promyelocytic leukemia were excluded. Cytogenetic changes between the time of diagnosis and the first relapse were classified into four groups: (1) no change, (2) ACA was acquired at time of the first relapse, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the time of the first relapse, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the time of the first relapse. In this study, groups 2 and 4 were defined as those with ACA acquisition. Overall survival (OS) was defined as the interval from the date of the first relapse to the date of death. Fisher’s exact test was used to compare binary variables. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Multiple logistic regression analysis and the Cox proportional hazard model were used for multivariate analysis of predisposing factors and prognostic factors, respectively. Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 144 patients included in this study, 81 patients were male, and 63 were female. The median age was 53 years (range, 15–79 years). According to the definition described above regarding cytogenetic changes between the time of diagnosis and the first relapse, 83 (58%), 55 (38%), 2 (1%), and 4 (3%) patients were categorized into group 1, 2, 3, and 4, respectively; thus, 59 patients (41%) acquired ACA at the first relapse. With univariate analysis, t(8;21), complex karyotype, fewer than 12 months duration of the first remission, and relapse after allogeneic stem cell transplantation (allo-SCT) were extracted as statistically significant predisposing factors for ACA acquisition at the first relapse. Of these four factors, the first three were confirmed with multivariate analysis to be independent predisposing factors. Excluding four patients that directly proceeded to allo-SCT without re-induction chemotherapy, the 140 patients with ACA acquisition showed a significantly lower second remission rate compared with those without ACA acquisition (20.0% vs. 72.5%, respectively; p < 0.001). Furthermore, among all 144 patients, the 3-year OS rate after the first relapse in patients with ACA acquisition was significantly poorer than that in those without ACA acquisition (8.5% vs. 36.8%, respectively; p < 0.001). Multivariate analysis revealed that ACA acquisition was the strongest negative prognostic factor compared to all other reported factors (hazard ratio: 2.13, p < 0.001). Of the 59 patients with ACA acquisition (median age: 51, range; 15–79 years), 27 underwent allo-SCT after the first relapse. Eight patients were in remission at the time of transplant, and one directly proceeded to allo-SCT without re-induction chemotherapy. The 3-year OS rates after the first relapse were significantly different between patients undergoing allo-SCT after the first relapse and those treated only with chemotherapy (17.8% vs. 0%; p = 0.007). With multivariate analysis, undergoing allo-SCT after the first relapse was identified as an independent prognostic factor, in addition to the cytogenetic risk group at diagnosis. Conclusion: These findings suggested that ACA acquisition at the time of the first relapse was associated with chemo-refractive disease and poor prognosis. As ACA acquisition showed the most potent prognostic impact, treatment approaches for relapsed AML patients should be determined with consideration of this phenomenon. Clarification of the biological background of ACA acquisition may contribute to the development of novel therapeutic strategies and improved treatment outcomes in adult AML patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals NT-Probnp As Personalized Medicine Tool and New Biomarker Predicting Response to Chemotherapy and Survival in AML

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3435-3435
Author(s):  
Irene Graf ◽  
Georg Greiner ◽  
Rodrig Marculescu ◽  
Karoline V. Gleixner ◽  
Susanne Herndlhofer ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Complete Remission ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Independent Prognostic Factor ◽  
White Blood Count ◽  
Advisory Committees ◽  
The Impact

Abstract Acute myeloid leukemia (AML) is a hematologic neoplasm resulting from abnormal proliferation and accumulation of clonal myeloid precursor cells. The course and prognosis of AML vary depending on the type of AML, karyotype, and molecular abnormalities. In addition, patient-related factors and comorbidities are of prognostic relevance. Cardiac comorbidities are of particular importance as they influence treatment tolerability, early death (ED) and survival in patients receiving chemotherapy. Brain natriuretic peptide (NT-proBNP) is a well-established marker of cardiac function and often used to predict treatment tolerability and outcome. However, so far, little is known about the impact of NT-proBNP levels on the clinical course in patients with AML. We analyzed 312 AML patients (median age: 61 years; range 17-89 years; &lt;60 years: n=141, ≥60 years: n=171; f:m-ratio: 1:1.15; observation period: February 1998 - September 2020) treated with a daunorubicin (day 1-3) and ARA-C (day 1-7)-based induction therapy and consolidation with up to 4 cycles of intermediate-dose (2x1g/m² for 3 day) or high-dose (2x3g/m² for 3 days) ARA-C. In 199 patients (63.8%), elevated NT-proBNP levels were detected, and in 113 (36.2%), NT-proBNP levels were within normal range (0-125 pg/mL). In 20 patients (6.4%) NT-proBNP exceeded 2000 pg/mL. NT-proBNP levels differed significantly between patients aged &lt;60 years (median: 146.7 pg/mL; range: 0.5-15930 pg/mL) and patients ≥60 years (median: 226 pg/mL; range 1-19883 mg/dL; p=0.003). A weak correlation was observed between NT-proBNP levels and other clinical or laboratory parameters like age (R=0.183; p=0.001), lactate dehydrogenase (LDH; R=0.242; p&lt;0.001) and serum creatinine levels (R=0.256; p&lt;0.001). Applying the Charlson comorbidity index (CCI), patients without comorbidities (n=60) had the lowest median NT-proBNP levels followed by those with moderate (n=79), intermediate (n=95), and high-risk comorbidities (n=56) (139.3 pg/mL, 156.0 pg/mL, 199.5 pg/mL, and 307.7 pg/mL, respectively; p=0.028). The Eastern Cooperative Oncology Group (ECOG) performance status was available in 176 patients. Those with ECOG 1 had a significantly higher median NT-proBNP (225.1 pg/mL, range: 0.5-5369 pg/mL) compared to patients with ECOG 0 (133.6 pg/mL, range: 1-15930 pg/mL) (p=0.008). Following induction therapy, 219 patients (70.2%) achieved complete remission (CR), 63 (20.2%) had no remission (NR), and 30 (9.6%) died within 60 days after chemotherapy (ED). Median NT-proBNP levels differed significantly among CR, NR and ED patients, with 153.3, 225.9, and 735.5 pg/mL, respectively (p&lt;0.0001) (Figure 1). The difference in NT-proBNP levels among CR, NR and ED patients was significant in patients aged &lt;60 years and in those aged ≥60 years (p=0.004 and p=0.001, respectively). In multivariate analysis including NT-proBNP together with age, sex, the ELN-2009 classification, white blood count (WBC) and CCI, NT-proBNP remained an independent prognostic factor for treatment response (CR, NR, or ED; p&lt;0.001). In this analysis, age and the ELN-2009 classification were also independent prognostic markers (p=0.014 and p&lt;0.001 respectively). The median overall survival (OS) was 1.38 years (IQR 0.96-1.84) in the total cohort of patients. Significant differences in OS were observed when comparing patients with normal (&gt;125 pg/mL), moderately elevated (125-2000 pg/mL), and highly elevated NT-proBNP levels (p=0.0002). The median OS in these groups was 3.08 (IQR 0.8-16.5), 1.14 (IQR 0.5-4.8), and 0.34 (IQR 0.04-3.7) years, respectively (Figure 2). In multivariate analysis including NT-proBNP, age, ELN-2009 classification, WBC, sex, and CCI, NT-proBNP remained an independent predictive variable for OS (p=0.006). Significant differences were also observed when analyzing OS in patients &lt;60 years (p=0.012) but were not seen in those aged ≥60 years (p=0.203). Similar results were obtained for continuous complete remission (CCR) (median CCR of all patients: 1.6 years), where NT-proBNP was of prognostic significance in the cohort aged &lt;60 years (p=0.011) but not in patients aged ≥60 years. Together, NT-proBNP is a new emerging biomarker and independent prognostic factor indicating the risk of induction failure, ED and reduced survival in patients with AML. The predictive power of NT-proBNP is particularly strong in AML patients aged &lt;60 years. Figure 1 Figure 1. Disclosures Gleixner: Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria. Knoebl: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jaeger: Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hoermann: Novartis: Honoraria. Valent: Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; OAP Orphan Pharmaceuticals: Honoraria. Sperr: AbbVie, BMS-Celgene, Daiichi Sankyo, Deciphera, Incyte, Jazz, Novartis, Pfizer, StemLine, Thermo Fisher: Honoraria, Research Funding.

scholarly journals Does Presence of Persistent Molecular Mutations Matter in AML Patients Undergoing Allogeneic Stem Cell Transplant?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2172-2172 ◽  
Author(s):  
Sangmin Lee ◽  
Jingmei Hsu ◽  
Yassine Tahri ◽  
Zhengming Chen ◽  
Tsiporah B. Shore ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Mutation Testing ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Post Transplant

Abstract Introduction: Mutations at diagnosis in acute myeloid leukemia (AML) patients have prognostic implications. For AML patients undergoing allogeneic stem cell transplant (SCT), the prognostic impact of molecular mutations pre-transplant and immediately post-transplant are less well characterized. Here we examine the mutation status of AML patients at different time points in relation to allogeneic SCT and their implications in relapse and survival. Methods: AML patients who underwent allogeneic SCT after achieving complete remission with available molecular mutation testing at diagnosis, prior to transplant (within 4 weeks), and 28 days post-transplant were included in the analysis. Multivariable cox regression analysis was adjusted for age, gender, CIBMTR disease risk index (DRI), type of transplant, and genetic mutation. Backward selection method was used to select the best combination of genes that is associated with OS and relapse-free survival (RFS). Results: A total of 110 AML patients with molecular genetic data available from 2014 to2018 at Weill Cornell Medicine were included in the analysis. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (20-77). Twenty-three molecular mutations analyzed at baseline, pre-transplant, and at 28 days are listed in Table 2. With a median follow-up time of 31.6 month, the median overall survival for the cohort was 37.1 months. Eighty-one patients had molecular testing at diagnosis. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced RFS, but not OS on multivariate analysis. Seventy-seven patients had molecular testing prior to transplant and 27 patients had persistent mutations (Table 2). The presence of mutations in ETV6 and FLT3-ITD were independently associated with worse RFS ((HR 49.7, p=0.001, CI 5.0-528) & (HR 36.4, p<0.0001, CI 6.6-200)) and OS ((HR 38.31, p=0.0035, CI 3.31-443.37) & (HR 10.57, p=0.0038, CI 2.14-52.27)). The presence of NRAS mutations was associated with worse RFS (HR 105, p=0.0004, CI 8.1-1350), but not OS. Mutations in TP53 were associated with worse RFS (HR 70.97, p=0.0026 CI 4.44-1135) and OS on univariate (HR 9.82, p=0.0327, CI 1.21-79.82), but not on multivariate analysis. At 28 days post-transplant, only 9 of the 84 patients had persistent mutations. Persistence of FLT3-ITD conferred worse RFS and OS in both univariate ((HR 11.92, p=0.0218, CI 1.43-98.98) & (HR 25.16, p=0.0052, CI 2.62, 241.92)) and multivariate ((HR 18.13, p=0.0089, CI 2.07-158.86) & (HR 35.47, p=0.0028, CI 3.41-368.81)) analysis. Conclusions: Persistent presence of mutations in ETV6 and FLT3-ITD prior to stem cell transplant were associated with shorter RFS and OS independent of CIBMTR DRI. Persistent mutations in NRAS and CBL prior to stem cell transplant were associated with poor RFS and OS respectively. This analysis further supports association of adverse outcomes in AML patients with selected persistent mutations prior to stem cell transplant. Utility of serial mutation testing prior to transplant should be further investigated in prospective studies. Disclosures Lee: AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Ritchie:NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Desai:Argenx: Consultancy; Cellerant Inc: Consultancy. Roboz:Eisai: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Argenx: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy.

Cytogenetic Abnormalities Predict Clinical Outcome In Patients Diagnosed With Relapsed Acute Myeloid Leukemia (rAML): Single Center Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4955-4955
Author(s):  
Hassan Alkhateeb ◽  
Rhett P Ketterling ◽  
Niamh Keane ◽  
Mrinal M Patnaik ◽  
Animesh Pardanani ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Complete Remission ◽  
Clinical Outcome ◽  
Salvage Therapy ◽  
Prognostic Value ◽  
Clonal Evolution ◽  
Wilcoxon Test ◽  
Cell Transplant ◽  
Prognostic Role ◽  
Cytogenetic Abnormalities

Abstract Background Cytogenetic abnormalities have significant prognostic role in AML at the time of diagnosis. Several prognostic groupings have been recommended including the NCCN and European LeukemiaNet classification. It is still unknown whether cytogenetic abnormalities have any prognostic role at the time of relapse for predicting clinical outcome. In addition, clonal evolution (CE) has been seen in many AML cases, but its prognostic value remains to be identified. Aim To study cytogenetic abnormalities and clonal evolution impact on clinical outcome for patients diagnosed with rAML Method A retrospective, single institution study through chart review of all cases diagnosed with rAML at Mayo Clinic Rochester between 2003 to 2011 was performed. Pts who achieved complete remission and relapsed at our institution were included. Pts with PML-RARA and BCR-ABL rearrangements were excluded from this study. Pts with available cytogenetics data, both at presentation and relapse, were included. Response to treatment was defined as per international working group (IWG) criteria (Cheson JCO 2003). Appropriate IRB approval was obtained in accordance with Helsinki declaration. Comparison between groups’ medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier curves using JMP V9. Results Out of 192 pts, 74 pts matched our inclusion criteria. The median age at diagnosis is 60 years (range 18-81), 53% were males. At relapse, median white blood cell (WBC) was 3.2 x109, hemoglobin 10.4 g/dL, platelet 59 x109, peripheral blood (PB) blast 2% (range, 0-96), bone marrow (BM) blasts 23% (range, 1-95) and cellularity 60%. Relapse site was mainly in the BM (95%). Flt3 mutation was found in 12/43 (28%), while NPM1 mutation in 2/7 (29%). Upon treatment with salvage therapy, 27 (36%) pts achieved complete remission (CR) and 16 (22%) pts partial remission (PR) for a total overall response (OR) of 58%. Twenty one (28%) pts were able to proceed to allogeneic stem cell transplant (SCT) after achieving remission. Median overall survival (mOS) was 198 days. Pts had a longer mOS if they proceeded to SCT (386 days vs 121 days, p =0.0003). Cytogenetic analysis (CG) were diploid in 32 (43%) of 74 pts at relapse. Five pts had favorable cytogenetics (3 pts with t(8,21) and 2 pts with inv (16)). CG was divided into favorable, intermediate and poor prognosis as per NCCN classification in 5 (7%), 45 (61%), 24 (32%), respectively. As per European LeukemiaNet, there were 4 CG groups divided into: favorable, Intermediate-1, intermediate-2, and adverse in 5 (7%), 33 (45%), 12 (16%), 24 (32%), respectively. Upon comparison of CG at diagnosis and relapse; clonal evolution (a change in CG due to gain or loss of chromosomal abnormalities) was found in 42/74 (57%) of pts. CG reverted back to diploid in 8/42 (19%) or gained additional CG abnormalities at relapse in 32 (76%) pts. CR2 was achieved in 80% of favorable CG (NCCN grouping), 40% (intermediate), and 21% in poor risk (p=0.01). Using NCCN CG grouping mOS was: 435 days (favorable), 266 (intermediate), and 104 (poor) (p value = 0.01). However, using European LeukemiaNet grouping mOS was: 435 days (favorable), 174 (intermeidtae-1), 363 (intermediate-2), and 104 (poor) (p=0.004). CE did not affect mOS (p =0.7). On multivariate analysis, response to salvage therapy (p<0.0001), NCCN CG grouping (p =0.03), wbc (p=0.045), and PB blasts (p=0.01) were significant but not age, BM blast, platelet and CE. Conclusion CG were diploid in 43% of relapsed pts. CE (gain or loss of cytogenetic abnormalities) was seen in 57% of CG at relapse compared to diagnosis but did not affect mOS. NCCN (and not European LeukemiaNet) cytogenetic grouping did affect clinical outcome through both achieving second CR and mOS (both on univariate and multivariate analysis). Our results confirm the prognostic value of CG on relapse, and need to be confirmed by larger studies.  Disclosures: No relevant conflicts of interest to declare.

scholarly journals Increasing Lengths of First Complete Remission with 7+3 Induction Chemotherapy for Acute Myeloid Leukemia over the Past Four Decades: Analysis of SWOG Trial Data

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 291-291
Author(s):  
Megan Othus ◽  
Guillermo Garcia-Manero ◽  
John E. Godwin ◽  
James K. Weick ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Complete Remission ◽  
Research Funding ◽  
Patient Characteristics ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Logistic Regression Models ◽  
Data Safety ◽  
Monitoring Committee ◽  
Survival After Relapse ◽  
Over Time

Background: We have previously shown that the survival of patients with AML who fail to achieve complete remission (CR) with 7+3 has improved since the 1980s. However, although CR rates with 7+3 have improved over the last four decades, we have not previously evaluated how outcomes for patients who achieve a CR1 with 7+3 has changed over time. Here we evaluate if either length of first CR (CR1) after 7+3 or of survival after relapse from CR1 has changed over the last four decades. Patients and Methods:We analyzed 1247 patients randomized to 7+3 arms from 5 SWOG studies and restricted to patients age 65 or younger: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), S1203 (n=261). S8600 enrolled patients in the 1980s, S9031 and S9333 in the 1990s, S0106 in the 2000s, and S1203 in the 2010s. S9031 and S9333 were analyzed together. All 5 protocols gave 7+3 per existing standard, which changed over time. In S8600, S9031, and S9033 the ara-C and daunorubicin doses were 200mg/m2and 45mg/m2, in S0106 100mg/m2and 60mg/m2, and in S1203 200mg/m2and 90mg/m2. CR was defined morphologically. To account for censoring in the dataset, we used landmark analyses. To evaluate patterns in length of CR1, among patients achieving CR1 and alive at 2 and 3 years, we calculated the proportion of 2 (or 3) years spent in CR1. To evaluate survival after relapse, among patients who achieved CR1 but who relapsed in next 2 (or 3) years we calculated the proportion of patients alive at least 1 year after relapse. To account for changing patient characteristics over time, multivariate linear and logistic regression models were fit. Results:Overall survival has improved dramatically over the last 4 decades (Figure 1). Additionally, among patients who achieved CR1 and were alive 2 years later, the proportion of those 2 years spent in CR1 has significantly improved over the last 4 decades (Figure 2) from a median of 58% to a median of 96% (p&lt;0.001). This trend was maintained in multivariable modeling (Table 1) and similar trends were observed using a 3-year landmark time. Survival after relapse also improved over the 4 decades. Among patients who relapsed in the first 2 years after CR1, the proportion alive at least one year after relapse has significantly increased from 32% to 52% (Table 2, p&lt;0.0001). This pattern was maintained in multivariable modeling adjusting for patient prognostic factors (Table 3) and similar trends were observed using a 3-year landmark time. Conclusion:Both length of CR1 and survival after relapse have increased over the last four decades in patients age 65 or younger even after accounting for differences in patient characteristics. Possible explanations for the longer survival after relapse include higher 2ndCR rates, more frequent use of hematopoietic cell transplant in CR, or better supportive care. Regardless, the longer survival after relapse suggests analyses of event-free survival should complement those of overall survival when evaluating new treatments in AML. Acknowledgement:The authors wish to gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106. Disclosures Othus: Glycomimetics: Other: Data Safety and Monitoring Committee; Celgene: Other: Data Safety and Monitoring Committee. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding. Erba:Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding; Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy; Celgene, Incyte, Novartis: Speakers Bureau.

scholarly journals Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1884-1884 ◽  
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
David Iberri ◽  
Erik Eckhert ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Control Group ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Interval ◽  
Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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