scholarly journals Impact of Choice of Induction Regimen on Overall Survival and Post-Remission Survival Among Older Adults with Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2329-2329
Author(s):  
Kelli McCrum ◽  
Justin LaPorte ◽  
Asad Bashey ◽  
Scott R. Solomon ◽  
Lawrence E Morris ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Induction Regimen ◽  
Acute Myeloid

Abstract Older patients make up the majority of those diagnosed with acute myeloid leukemia (AML), however, many of these patients are not able to tolerate intense induction chemotherapy regimens. The use of lower intensity induction such as hypomethylating agents (HMA) with or without venetoclax or other targeted therapies has widened the scope of patients who are able to receive induction chemotherapy and move towards a hematopoietic stem cell transplant. Recent data from the Center of International Blood and Marrow Transplant research showed that patients aging >64 years accounted for 26% of all allogeneic transplantations in 2019 compared to only 9% in 2009. We have previously published a report showing that induction with FLAG +/- Idarubicin (FLAG+ IDA) results in better post remission survival than '7+3'induction (Solh et al, Leuk res 2020). In order to determine how induction chemotherapy affects post-remission outcomes among older patients with AML, 289 patients over the age of 55 year who received either FLAG±IDA, 7+3, or HMA based induction at a single institution were analyzed. Median follow up was 48 months. Patient and disease characteristics were as follows: Median age 64 (55,83) years, secondary AML (10%), abnormal cytogenetics (49%), and NCCN non-favorable risk (76%). Induction regimens included FLAG+/- Ida (n=208, 72%), 7+3 (n=60, 21%) and HMA based (n=21, 7%). A total of 248 patients (86%) achieved CR/Cri after induction with a median time from induction to CR of 28 days. Patients who received induction with FLAG±IDA reached a higher rate of CR after one cycle (92% vs 75% vs 62%) and had a shorter time to CR (27 vs 33vs 55 days) compared to '7+3' or HMA based therapy (p<0.001 for both). FLAG±IDA had better overall survival and DFS 3 years post-remission compared to '7+3' and HMA OS (50%, 45%, 22%, p=0.021) and DFS (45%, 37%, 8% p=0.01) respectively. A total of 133 patients received allogeneic transplantation. Transplant rate was similar between FLAG+/- IDA (n=100) and 7+3 (n=29) at 48% and was significantly better than HMA-based induction 19% (n=4) (p=0.03). Post-transplant survival and DFS was not significantly different between FLAG+/-Ida and 7+3, however both were better compared to HMA based induction with OS (54%, 44%, 25%) and DFS (51%, 44%, 25%) . On multivariate analysis on post remission survival and disease free survival, NCCN risk and age were both associated with OS ( high risk NCCN vs others HR 3.63, P<0.001; Age per 5 year increment HR 1.16, p=0.049) and NCCN risk was the only factor associated with worse DFS ( high vs others HR 2.4, p<0.0001). The choice of induction regimen did not significantly impact post-remission survival outcomes. In conclusion, Older patients with AML achieve higher rates of complete remission, shorter time to remission and better post-remission survival with FLAG+/-IDA than 7+3 or HMA-based induction. Disclosures Solh: BMS: Consultancy; Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; ADCT Therapeutics: Consultancy, Research Funding.

scholarly journals Combination of Sorafenib and 5-Azacytidine in Older Patients with Untreated Acute Myeloid Leukemia with FLT3-ITDmutation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1611-1611 ◽  
Author(s):  
Maro Ohanian ◽  
Guillermo Garcia-Manero ◽  
Elias J. Jabbour ◽  
Naval Daver ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Median Overall Survival ◽  
Cell Transplant ◽  
Overall Response ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background: The combination of 5-azacytidine (AZA) and sorafenib has been reported to be a safe and effective strategy in patients with relapsed and/or refractory FLT3-ITD mutated acute myeloid leukemia (AML). We hypothesized that combining sorafenib with AZA, may be used effectively in older patients with untreated AML whose leukemic cells harbor the mutation. Methods: Patients were eligible if they had untreated AML with a FLT3-ITD clone detectable by polymerase chain reaction (at least 10% mutation burden), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. The treatment regimen included AZA 75 mg/m2daily for 7 days combined with sorafenib 400 mg twice daily for 28 days. Cycles were repeated approximately every 4 to 5 weeks. Dose adjustments of both agents, and delay of AZA, based on toxicity were allowed. Results: Overall, 23 patients with untreated AML with a median age of 74 yrs (range, 61-86 yrs) were enrolled. They included 14 (61%) patients with normal cytogenetics, 2 (9%) with complex karyotype, 4 (17%) with other miscellaneous abnormalities, and 3 (13%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all patients with a median allelic ratio of 0.35 (range, 0.01-0.89). The overall response rate in 22 evaluable patients was (77%) including 7 (32%) with CR, 9 (41%) CRi/CRp, and 1 (5%) PR. Patients have received a median of 3 (range, 1-35) treatment cycles with the median number of cycles to response being 2 (range, 1-5) and the median time to achieve response, 1.9 months (range, 0.7-4.3 months). The median duration of CR/CRp/CRi is 14.5 months (range, 1.2-28.7 months). Two (9%) patients have proceeded to allogeneic stem cell transplant. With a median follow-up of 4.2 months (range, 0.9-61.4), 8 patients remain alive, 7 still in remission (CR/CRP/CRi). The median overall survival for the entire group is 8.8 months, and 9.2 months in the 17 responding patients (Figure 1). Treatment-related grade 3/4 adverse events included: grade 3 diarrhea (n=2), grade 3 pneumonitis (n=3), grade 4 sepsis (n=2), grade 3 infections (n=3). When patients treated with AZA + sorafenib (n=23) were compared to a matched cohort of historical patients older than 60 years who were treated with hypomethylator-based therapy without sorafenib (n=20), overall response rates (including CR, CRp, CRi, and PR) were statistically similar (77% vs.31%, respectively; p=0.6). The median overall survival for the two groups were 8.8 months and 9.4 months (p=0.67), respectively. The remission duration for the responding patients treated with AZA+sorafenib was significantly longer (16 months) than those on other hypomethylator-based regimens without sorafenib (3.8 months)(p=0.008) (Figure 2). Conclusions: The combination of AZA and Sorafenib is effective and well tolerated in older patients with untreated FLT3-ITD mutated AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Ariad: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Lack of Association of Mutations in IDH1, IDH2, DNMT3A with Outcome in Older Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents (± Histone Deacetylase Inhibitors).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2483-2483
Author(s):  
Farhad Ravandi ◽  
Keyur P. Patel ◽  
Rajyalakshmi Luthra ◽  
Sherry A. Pierce ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hypomethylating Agents ◽  
Idh Mutations ◽  
Acute Myeloid

Abstract Abstract 2483 Background: Mutations of several genes believed to be important in the methylation apparatus of the cell have been recently described in patients with acute myeloid leukemia (AML) but their presence has not been correlated with a worse or better outcome using hypomethylating agents. Methods: We evaluated the association of mutations in IDH1, IDH2, DNMT3A, and EZH2 with the outcome [complete response (CR) rate, event free survival (EFS) and overall survival (OS)] among patients older than 60 with AML (≥ 20% blasts) treated with hypomethylating agents as their first line of treatment. TET2 mutations were not evaluated due to lack of available material. Results: Among the 68 patients (median age 72 years; range, 60 – 83) with available data, 11 patients (16%) had IDH1 or IDH2 mutations (mutually exclusive) and 10 patients (15%) had DNMT3A mutations with 5 patients (7%) having both IDH and DNMT3A mutations. Cytogenetics was diploid in 19 (28%), abnormal chromosome 5/7 and/or complex in 27 (40%), trisomy 8 in 5 (7%), miscellaneous in 14 (21%), and insufficient in 3 (4%). Presence of IDH mutations was associated with a diploid karyotype and the presence of NPM1 mutations (p=.03 and p=.02, respectively) but not with FLT3- ITD or RAS mutations (present in 7 and 4 patients, respectively). DNMT3A mutations were not associated with any specific karyotype or with the presence of NPM1, FLT3-ITD, or RAS mutations. None of the 68 patients had EZH2 mutations. All patients were treated with hypomethylating agents [decitabine in 39 (57%) and 5-azacytidine in 29 (43%)] with 42 patients (62%) receiving concomitant histone deacetylase inhibitor therapy (SAHA or valproic acid). Overall, 17 patients (25%) achieved CR; the presence of IDH or DNMT3A mutations or both was not associated with achievement of CR. With a median duration of follow-up of 60 months, the median EFS is 3.3 months (range, 0.25 – 3.75 months) and the median overall survival is 6 months (range, 0.25 – 90.5 months). Presence of IDH mutations was not associated with an impact on EFS (p=.29) or OS (p=.14). Similarly, DNMT3A mutations were not associated with an effect on EFS (p=.21) or OS (p=.58). The presence of both IDH and DNMT3A mutations was also not associated with a better or worse response, EFS, or OS as compared with patients with neither mutation. Conclusion: We were not able to detect an association between presence of IDH1/2 and DNMT3A mutations and outcome in this elderly population of patients with AML treated with epigenetic modulators. Disclosures: Ravandi: Johnson and Johnson: Honoraria; Celgene: Research Funding. Off Label Use: Use of decitabine, 5-azacytidine, SAHA, and valproic acid in the treatment of older patients with AML. Garcia-Manero:Celgene: Research Funding. Cortes:Celgene: Research Funding; Eisai: Research Funding.

Impact Of The Early Intensification Of Induction Chemotherapy On Complete Remission and Survival Rates For De Novo Adult Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3402-3402
Author(s):  
Seung-Ah Yahng ◽  
Jae-Ho Yoon ◽  
Sung-Eun Lee ◽  
Seung-Hwan Shin ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Remission Induction ◽  
Advisory Committees ◽  
Induction Regimen ◽  
Acute Myeloid

Abstract Background The successful induction chemotherapy of acute myeloid leukemia (AML) depends on the ability to achieve complete remission (CR) and to maintain remission status as long as possible. Approach to improve the rate of CR includes the intensification of induction chemotherapy for AML. The primary goal of this study was to evaluate and compare the long-term outcomes between remission induction therapy with and without early intensification added to the standard 3+7 remission induction regimen. Methods A retrospective analysis was performed on de novo AML patients diagnosed and treated at Catholic Blood and Marrow Transplantation Center between January 2001 and December 2010. Six hundred forty-one adults of ages between 16 and 60 were included, all of whom received induction chemotherapy starting with 3 days of idarubicin and 7 days of cytarabine or behenoyl cytarabine (BHAC). Cases with t(9;22) and t(15;17) were excluded. Bone marrow (BM) aspiration study was assessed on day 7 of induction in all patients. Factors which were considered for early intensification of induction were the presence of ≥ 5% BM blasts, patient performance, and other high risk clinical characteristics, such as karyotype. Groups according to early intensification on days 8 to 10 of induction were as followings: no intensification (3+7), n=156; cytarabine or BHAC for 3 days (3+10), n=233; addition of idarubicin for 2 days to 3+10 regimen (5+10), n=252. After a median duration of 5.5 months (3.3-19.0) from diagnosis, 479 patients underwent stem cell transplantation (autologous [auto-SCT], n=144; allogeneic [allo-SCT], n=335). Conditioning regimen for auto-SCT consisted of fractionated total body irradiation (TBI), melphalan, and cytarabine, whereas 83% (n=278) of patients with allo-SCT received myeloablative conditioning, of which was mostly TBI-based regimen (92%). Donors were matched sibling (n=213), matched unrelated (n=63), mismatched unrelated (n=39), and haploidentical related (n=20). Results The median age at diagnosis was 39 years (16-60). Mean values of BM blast % on day 7 of induction was 3.5 in 3+7 group, 7.9 in 3+10, and 33.6 in 5+10 (p=<0.0001), while no significant difference in the proportion of adverse karyotype was shown (11.7% vs. 12.8%, p=0.804). After first induction (3+7, n=165; 3+10/5+10, n=465), the CR/CRi rate was significantly higher in 3+10/5+10 versus 3+7 (78.1% vs. 69.2%, p=0.023), while the rate for death in aplasia was lower (4.3% vs. 9.6%, p=0.013). After re-induction with various regimens, the CR/CRi rate was still significantly higher in intensified group (p=0.012). The relapse rates between the groups in 536 patients achieving CR (83.6%), however, was not significantly different (8.9% vs. 9.9%, p=0.737). SCT was performed at CR1 (n=459), CR2 (n=10), or relapsed/refractory status (n=10). Patients with auto-SCT mostly had better/intermediate cytogenetic risk (96%) at diagnosis, while 12% of allo-SCT had poor karyotype. After the median follow-up duration of 60.2 months (2.2-143.5), the median overall survival (OS) in all patients (n=641) was 65.6 months. The 5-year disease-free survival (DFS) of patients with auto- and allo-SCT was 58.4±4.2 and 64.9±2.7, respectively. Of 334 patients receiving allo-SCT, the 5-year DFS was significantly higher in patients achieving CR1 (n=299) after first induction therapy (p<0.0001), in whom 75% of them had early intensification. Other factors with significant impact on DFS after allo-SCT (n=334) were karyotype at diagnosis (p=0.032) and donor type (HLA-matched vs. HLA-mismatched sibling or unrelated, 58.1%±3.8 vs. 45.1±8.0, p=0.016). The significances were confirmed in multivariate analysis, which demonstrated that achieving CR1 after first induction regimen and its maintenance until SCT was the most powerful predictor for DFS after allo-SCT (67.1±2.9 vs. 34.6±7.8, p=<0.0001). When all patients were analyzed, according to induction intensification, a statistically significant benefit in 10-year OS was observed in 5+10 intensified group (44.8% vs. 52.9%, p=0.032). Conclusion Our results suggest possible benefit of examining day 7 BM aspiration for the strategy of early intensification of induction chemotherapy for adult AML patients and our intensification doses can be safely added with high efficacy in the achievement of CR1 compared to 3+7 standard regimen, and may have affected for better DFS after allo-SCT. Disclosures: Kim: BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

The FLAG Chemotherapy Regimen Is an Alternative to Anthracycline Based Therapy for the Treatment of Acute Myeloid Leukemia for Patients with Multiple Co-Morbidities or Preexisting Cardiac Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 961-961
Author(s):  
Lalit Saini ◽  
Robert Turner ◽  
Loree Larratt ◽  
Joseph Brandwein ◽  
Marlene Ann Hamilton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Cardiac Disease ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Advanced Age ◽  
Cell Transplant ◽  
Poor Risk ◽  
Significant Difference ◽  
Acute Myeloid

Abstract BACKGROUND: Anthracycline based treatment for acute myeloid leukemia (AML) can be associated with significant morbidity and mortality amongst older patients or those with significant co-morbidities. Furthermore, for patients with previous anthracycline exposure or preexisting cardiac disease anthracyclines pose an increased risk of cardiotoxicity. For such patients intensive treatment options are limited. The FLAG (fludarabine, cytarabine and filgrastim) regimen is a non-anthracycline based chemotherapy useful for relapsed/refractory AML and as initial therapy for “fit” eligible patients. We present our experience using FLAG as first line therapy in a cohort of newly diagnosed AML patients with advanced age, significant co-morbidities or preexisting cardiac disease. METHODS: A single institution retrospective chart review was undertaken of patients treated with FLAG as frontline therapy from 2004 – 2013 with follow-up until June 2014. All patients were considered ineligible for standard ‘3+7’ treatment by the attending physician. RESULTS: Over the study period 56 patients received FLAG. Due to patient refusal or induction complications bone marrow assessments to ascertain remission status were not performed in 10 patients – to minimize bias these patients were evaluated for toxicity and overall survival (OS) but excluded from complete remission (CR) and relapse free survival (RFS) analysis. Of the 56 patients, 68% were males. The median age was 69 (21 – 80) with 79% aged ≥ 60 and 43% aged ≥ 70. Fifty-five percent (31) of the patients had primary AML and cytogenetics were favorable in 5% (3), intermediate in 66% (37), poor-risk in 21% (12) and failed in 7% (4). Forty-six percent (26) were treated with FLAG due to preexisting cardiac disease and others due to advanced age (20%), poor performance status (16%), co-morbidities (16%) or previous anthracycline exposure (2%). The ages of patients treated with FLAG due to cardiac disease or other reasons was similar (63.5 years vs. 66.9 years, p=0.27). Amongst patients with cardiac disease a pre-chemotherapy cardiac evaluation revealed wall motion abnormalities in 39% and an ejection fraction (EF) ranging from 33% - 81% with a borderline (≤ 50-51%) EF in 46%. Febrile neutropenia was observed in 82% (46) of patients, 27% (15) required intensive care support and the induction mortality was 16% (9). Amongst patients evaluated for a CR (46/56), 48% (22/46) obtained a CR. Although a CR was seen in 100% (3/3), 46% (15/33) and 37% (3/8) of patients with favorable, intermediate and poor-risk cytogenetics respectively there was no statistically significant difference (p=0.22) between groups. A CR was obtained in two additional patients following a second course of FLAG for an overall CR rate of 52% (24/46). Of these 24 patients, 8 (33.3%) received no additional treatment while 16 (66.7%) received consolidative chemotherapy. Of 10 eligible patients, 4 proceeded to an allogeneic stem cell transplant (allo-SCT) including two with preexisting cardiac disease. Of patients not transplanted 50% (10/20) eventually relapsed. There was no difference in relapse rates for those receiving FLAG for age/co-morbidities vs. cardiac disease (60% vs. 40%, p= 0.66) or for patients age <60 vs. ≥ 60 (50% vs. 50%, p=1.0). The median RFS was 441 days with no difference between patients treated with FLAG for cardiac reasons vs. other reasons (p=0.33) or for patient’s age < 60 vs. ≥ 60 (p=0.66). The median OS for the 56 patients was 278 days with 1 and 2 year survivals of 44% and 22% respectively. The median OS for patient’s age < 60 was higher than those age ≥ 60 (1102 days vs. 218 days, p=0.009) but there was no difference in the OS between patients treated with FLAG for cardiac disease and those treated for other reasons (305 days vs. 254 days, p=0.202). The median survival of patients with favorable, intermediate and unfavorable risk cytogenetics was 523 days, 311 days and 87 days respectively but this was not statistically significant (p=0.25) likely due to limited patient numbers. Conclusions: The FLAG regimen is a non-anthracycline based regimen that may serve as an alternative to the standard ‘3+7’ induction for AML in older adults or those with significant co-morbidities including preexisting cardiac disease. It is associated with comparable remission rates and overall survival in older patients. In addition, it may allow some patients with preexisting cardiac disease to proceed to allo-SCT. Disclosures No relevant conflicts of interest to declare.

A Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in the Induction Chemotherapy for Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2535-2535 ◽  
Author(s):  
Je-Hwan Lee ◽  
Hawk Kim ◽  
Young-Don Joo ◽  
Won Sik Lee ◽  
Sung Hwa Bae ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
High Dose ◽  
Event Free Survival ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
Acute Myeloid

Abstract Introduction: We conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with acute myeloid leukemia (AML) and showed intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d x 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d x 3d) (Lee JH et al. Blood 2011;118:3832). As it is necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin, we performed another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin (ClinicalTrials.gov #NCT01145846). Here, we present final results of the study. Methods: Between May 2010 and March 2014, a total of 316 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study. Seventeen patients were removed from the study (change of diagnosis in 11, patient's refusal to be randomized in 3 and other in 3) and the remaining 299 patients were analyzed. After random assignments, 149 patients received idarubicin (AI, 12 mg/m2/d x 3d) and 150 patients received high-dose daunorubicin (AD, 90 mg/m2/d x 3d) in addition to cytarabine (200 mg/m2/d x 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d x 2d) or daunorubicin (AD, 45 mg/m2/d x 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 x 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 x 6d) plus etoposide (150 mg/m2 x 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion after one or two cycles of consolidation chemotherapy in most transplant cases. Results: CR was induced in 232 (77.6%) of 299 patients. Reasons for induction failure were resistant disease in 50, hypoplastic death in 5, and indeterminate cause in 12. As postremission therapy, 3 patients received no further treatment, 71 received consolidation chemotherapy without HCT, 137 underwent allogeneic HCT, and 21 underwent autologous HCT. The CR rates were not significantly different between two arms: 80.5% (120 of 149, AI) vs. 74.7% (112 of 150, AD) (P=0.224). With a median follow-up of 1046 days, overall survival probabilities at 4 years were 51.1% in AI vs. 54.7% in AD (P=0.756). The probabilities at 4 years for relapse-free survival were 63.5% in AI vs. 74.2% in AD (P=0.181) and those for event-free survival were 44.8% in AI vs. 50.7% in AD (P=0.738). Toxicity profiles were similar between two arms. Interestingly, overall and event-free survivals of 44 patients with FLT-ITD mutants (27 in AI and 17 in AD) were significantly different according to the induction regimens (AI vs AD; overall survival, 30.8% vs. 61.9%, P=0.030; event-free survival, 31.4% vs. 61.9%, P=0.025). Conclusions: The results of this phase 3 trial, which compared idarubicin (12 mg/m2/d x 3d) with high-dose daunorubicin (90 mg/m2/d x 3d), did not show significant differences between two arms in the outcomes of patients in terms of CR rates and overall, relapse-free or event-free survivals. In subset analysis, high-dose daunorubicin seems to be more effective than idarubicin in patients with FLT-ITD mutants. Disclosures Kim: Celgene: Research Funding; Alexion Pharmaceuticals: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding.

High Disease-Free and Overall Survival Rate Following Allogeneic Hematopoietic Stem Cell Transplantation for FLT3-Mutated Acute Myeloid Leukemia Even in Non-Remission Status

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2283-2283 ◽  
Author(s):  
Aya Nishida ◽  
Mitsuhiro Yuasa ◽  
Kosei Kageyama ◽  
Kazuya Ishiwata ◽  
Shinsuke Takagi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Poor Prognosis ◽  
Hematopoietic Stem ◽  
Remission Status ◽  
Disease Free ◽  
Acute Myeloid

Abstract [Background] FMS like tyrosine kinase 3 (FLT3) mutations occur in about 30% of patients with acute myeloid leukemia (AML). Patients with FLT3-mutated AML have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). So far, there is still limited data available on allo-HSCT for FLT3-mutated AML in non-remission status. [Objective and method] To assess the clinical features and outcome of allo-HSCT for FLT3-mutated AML, we retrospectively analyzed patients underwent first allo-HSCT for FLT3-mutated AML excluding acute promyelocytic leukemia (FAB M3) from January 2011 to March 2016. [Result] During the study period, 332 patients received first allo-HSCT for AML in our institute. One hundred and thirty-eight were tested for the presence of FLT3-mutation and 35 showed positive results and were subjected to the analysis. The median follow-up day of survivors was 602 (101-1867). The median age of the patients was 55 years (range, 21-72). Twenty-one patients had de novo AML, 12 had AML with myelodysplasia related changes, and 2 had therapy related AML. Eighteen had normal karyotype, 4 had complex, and 13 had others. Seven were in remission (5 in CR1, and 2 in CR2), and 28 were in non-remission (8 in primary induction failure, 13 in relapse 1, and 7 in chemo naïve status). Twenty-nine patients used unrelated cord blood, 2 did unrelated bone marrow, and 4 did related peripheral blood stem cell as grafts. All but 1 received myeloablative pretransplant conditionings. At 2 years after transplantation, overall survival (OS), disease free survival (DFS), relapse rate (RR), and non-relapse mortality (NRM) of whole studied population were 65.9%, 50.2%, 28.4%, and 21.4%, respectively. Among those in non-remission before transplantation, OS, DFS, RR, and NRM at 2 years post-transplant were 62.2% (Figure 1A), 49.9%(Figure 1B), 24.3%, and 25.8%, respectively. Only younger age (<55 years) was the factor associated with better OS with statistical significance in multivariate analysis. [Conclusion] Our data indicated that allo-HSCT could overcome the poor prognosis of FLT3-mutated AML even for those in non-remission status, despite the profound chemo-resistant character of FLT3-mutated AML. Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures Izutsu: Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding.

Clinical Implications of Acute Myeloid Leukemia Presenting as Granulocytic Sarcoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2155-2155
Author(s):  
Batia Ronit Avni ◽  
Deborah Rund ◽  
Moshe Levin ◽  
Sigal Grisaro ◽  
Dina Ben-Yehuda ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Medical Center ◽  
Granulocytic Sarcoma ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Abstract 2155 Introduction: Granulocytic sarcoma (GS), also known as chloroma, is described as an extramedullary tumor composed of immature myeloid cells. It has been reported to develop in 2–8% of patients with acute myeloid leukemia (AML) and can occur prior to, concomitantly with, or following the diagnosis of AML. Rarely patients present with GS as an isolated mass without evidence of AML (Byrd JC, J Clin Oncol. 1997). Due to the rarity of this disorder, large series of patients are seldom reported and the prognosis and optimal treatment of patients presenting with GS are not clear. Objectives: In this retrospective study we analyzed the presenting characteristics, treatments and overall survival of all patients presenting with isolated granulocytic sarcoma (GS) or GS with concomitant acute myeloid leukemia (AML) at presentation and compared them to all AML patients, treated at our institution during the same period. Methods: We identified cases who were diagnosed as having GS (with or without bone marrow involvement by AML) and cases of AML (without evidence GS at diagnosis) using ICD-9 codes in the hospitalization data base of the Hadassah Medical Center between 1990 and 2005. We excluded patients with GS at the time of relapse. All GS cases were biopsy-proven. Results: The study population consisted of 19 GS and 235 AML non-GS patients. The median age of these patients was 41 and 48 years, respectively. There was no statistically significant difference between the groups regarding gender, age, cytogenetic risk groups, rate of complete remission (CR), number of cycles of chemotherapy needed to achieve CR and rate of first relapse. Hematopoietic stem cell transplant (HSCT) (either autologous or allogeneic) was performed in 10 of 19 patients (52.6%) in the GS group and in 66 of 235 (28.1%) in the AML group (p=0.025). The overall survival in the GS group (median 16 months) was not significantly different (p= 0.60) from the AML group. The median time to death in subjects who had radiotherapy (6/19) was identical (median 21 months, p=0.79) to that of subjects who did not receive radiotherapy. Transplantation was associated with prolonged survival in both GS and AML groups (p=0.018 and p<0.0001 respectively). At the end of the follow up, 4 patients in the GS group who underwent HSCT were alive, compared to none in the group who did not undergo HSCT. Karyotype was found to be a prognostic factor in both the GS and AML groups (p=0.0034 and p<0.0001 respectively). In a multivariate analysis there was no statistically significant difference in the risk of death between subjects in the AML and the GS group; hazard ratio (HR) = 0.83, 95% CI (0.456-1.516), p=0.55, after controlling for age, karyotype and transplantation. As expected, in the model, age less than 47.5 years (HR=0.646 (p=0.0022)) and favorable and intermediate karyotype (HR=0.13 (p<0.0001) and HR=0.44 (p<0.0001) respectively, compared to unfavorable) were associated with a lower risk of death. Subjects who did not undergo transplantation had an increased risk of death compared with subjects who underwent the procedure (HR=1.88, p=0.0023) (Fig. 1). Conclusions: To the best of our knowledge this is the first retrospective series of GS patients with concomitant AML at diagnosis compared to all other AML patients in one medical center. The addition of radiotherapy as a treatment modality for GS patients did not appear to change survival. Patients with GS at diagnosis might benefit from upfront aggressive treatment with HSCT. Due to the rarity of this disorder and the remaining open questions, a prospective multi-center study is necessary to address these issues. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation for Therapy-Related Myelodysplastic Syndromes and Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2036-2036
Author(s):  
Leland Metheny ◽  
Wael Saber ◽  
Daniel J. Weisdorf ◽  
Marcos de Lima ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Allogeneic Hct ◽  
Autologous Transplant ◽  
Acute Myeloid

Patients who develop therapy-related myelodysplastic syndromes (t-MDSs) or acute myeloid leukemia (t-AML) following prior chemotherapy or an autologous hematopoietic cell transplant (HCT), have a poor prognosis. An earlier analysis of allogeneic HCT (n=868, 1990-2004) showed 5-year overall survival (OS) and disease free survival (DFS) were 22% and 21% (reference). Furthermore, older age, graft source other than a HLA-matched sibling or HLA well matched unrelated donor (URD), t-AML not in remission or advanced t-MDS, and poor risk cytogenetics were associated with worse outcomes. Modern supportive care and conditioning regimens including reduced intensity (RIC) regimens may have improved outcomes. Therefore we analyzed 1531 HCT for t-AML (n = 772) or t-MDS (n = 759) performed from 2000 to 2014. The median age at transplant was 52 (18-77) for t-AML and 59 (18-74) for t-MDS. Eleven percent of patient with t-AML and 24% of patient with t-MDS had a prior autologous transplant. A myeloablative regimen was used for conditioning in 61% of patients with t-AML and 49% of patients with t-MDS (Table 1). For t-AML, the 5-year non-relapse mortality (NRM) and relapse rates (RR) were 33% (95% confidence interval [CI], 30-36) and 43% (40-47), respectively. For t-MDS, the 5 year TRM and RR were 32% (29-36) and 46% (43-50), respectively. Five year DFS and OS were 24% (21-27) and 25% (22-28), respectively, for patients with t-AML. Five year DFS and OS were 21% (18-24) and 27% (23-31), respectively, for patients with t-MDS. In multivariate analysis, t-AML OS and DFS was worse for: previous autologous transplant, relapsed disease at HCT, intermediate or adverse cytogenetics, partially matched and cord blood grafts, and RIC. For t-MDS: age greater than 60, previous autologous transplant, very high IPSS score, and use of HLA-partially matched unrelated grafts. A significant minority of patients with t-AML and t-MDS can achieve long-term remission with allogeneic HCT, yet risks of both NRM and relapse are still excessive. Relapse is the major cause of treatment failure. Disclosures Metheny: Takeda: Speakers Bureau; Incyte: Speakers Bureau. Weisdorf:Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy. Kebriaei:Jazz: Consultancy; Amgen: Research Funding; Pfizer: Honoraria; Kite: Honoraria.

A Phase 1 Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Bortezomib for Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3595-3595 ◽  
Author(s):  
Anjali Advani ◽  
Paul Elson ◽  
Eric D. Hsi ◽  
Randall Davis ◽  
Matt Kalaycio ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 3595 The overexpression of proteasomes and constitutive activation of NF-KB in acute myeloid leukemia (AML) cells suggest that proteasome inhibitors (PI) such as Bortezomib (Bz) may be an effective therapy. PI or a decoy NF-KB oligonucleotide increases chemosensitivity to both anthracyclines and cytarabine. Thus, PI may improve the effectiveness of MEC (mitoxantrone, etoposide, cytarabine), a standard regimen for relapsed/refractory (R/R) AML. The primary objectives of this study were to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended Phase 2 dose of Bz in combination with MEC in patients (pts) with R/R AML. Secondary objectives included evaluating the preliminary activity of this combination and correlating CD74 antigen expression with response. CD74 may identify a subset of leukemias in which NF-KB is operative, with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446–54). Methods: All pts were treated at the Cleveland Clinic from August 2010-July 2012. This protocol was reviewed and approved by the institution's review board. Eligibility included: age 18–70 yrs, R/R AML, cardiac ejection fraction ≥ 45%. CD74 was assessed by flow cytometry using CD45 PE (BD Biosciences San Jose, CA) and CD74-Alexa 488 (AbD Serotec Raleigh, NC). All pts received MEC: mitoxantrone (6 mg/m2/d), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) Days 1–6. Bz was administered IV on Days 1, 4, 8, and 11 and was dose escalated using a standard 3 × 3 design. Dose levels (DL) were: −1 (0.40 mg/m2), 1 (0.70 mg/m2), 2 (1.00 mg/m2), 3 (1.30 mg/m2). One cycle of treatment was administered. Response was assessed by bone marrow aspirate/biopsy by Day 45, and CR was defined by IWG criteria (Cheson, 2006). Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLT included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting, alopecia, and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy (not related to leukemia); (4) Any grade 3 NHT > grade 2 by 45 days beyond the start of chemotherapy. The following were redefined as not being DLT: (1) anorexia requiring TPN; (2) fatigue requiring bed rest; (3) grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5-<10x ULN, 10.0–20.0 × ULN, and > 20 × ULN respectively. Results: Seventeen pts have enrolled; and 15 are evaluable for response. The median age was 54 years (range 33–69), 7 (47%) were male, and median baseline WBC 3.58 K/μL (range 0.96–76.53). The median time from initial diagnosis to enrollment was 7.1 months (range 1.4–84.9) and 2 pts had a history of an antecedent hematologic disorder. Nine pts (60%) were in first relapse, 2 (13%) in second relapse, and 4 (27%) refractory. One pt had received a prior allogeneic hematopoietic stem cell transplant; and 4 out of 15 pts (27%) had adverse cytogenetics at the time of relapse based on CALGB 8461 criteria. At DL 1, 1 DLT occurred (Grade 4 thrombocytopenia). No DLTs occurred at DL 2. Three pts were enrolled on DL 3, with one DLT occurring thus far (Grade 4 transaminases: likely related to leukemia). Only one pt had their Day 11 Bz held secondary to Grade 2 ileus (DL 1). Overall, 3 pts (all on DL 1) have died from blood stream infections. In addition to Grade 4 hematologic toxicity, the most commonly reported adverse events (AEs) have been gastrointestinal (GI). GI toxicities were the mostly commonly reported AEs attributable to Bz. Nine pts reported constipation and/or abdominal pain (7: Grade 1 or 2; 2: Grade 3). Six of the 15 evaluable pts (40%) have achieved a complete remission (CR) or CRp (complete remission without platelet recovery). Eight of the fifteen pts had CD74 expression testing, but only 6 of 8 were evaluable for response. The median CD74 expression was higher in refractory pts (35.9%) (range 14–87) than in responders (3.2%) (range 0.9–16). Conclusions: The MTD of MEC in combination with Bz will be reported at the meeting; but currently we are in the last DL (3) and the MTD has not been reached. The toxicities of the combination are similar to that of MEC, except potentially an increase in GI toxicities. We await the results of preliminary response in the expanded cohort of pts, once the MTD is achieved. Higher CD74 expression appears to correlate with refractory disease rather than response in this R/R AML cohort, but larger pt numbers are needed to confirm this. Disclosures: Advani: Millenium: Research Funding. Hsi:Millenium: Research Funding.

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