Novel Combination Drug Regimens Using Hypomethylating Agents in Treatment of Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

INTRODUCTION -The prognosis of acute myeloid leukemia (AML) in elderly population is inherently poor due to multiple factors including: frailty, medical co-morbidities and high treatment related morbidity with traditional induction chemotherapy and presence of adverse risk cytogenetics in 17-20% of patients. For patients who are not candidates for intensive chemotherapy, outcomes in terms of complete response/complete response with incomplete hematologic response (CR/CRi) and median overall survival (mOS) have been evaluated using hypomethylating agents(HMA) including azacytidine (AZA)(CR/CRi=18-27.8%, mOS=10.4-24.5 months) and decitabine (CR/CRi= 18-47%, mOS= 7-7.8 months). Recently, addition of venetoclax to HMA has shown to further improve CR/CRi (75%) and mOS (17.5 m). We conducted a systematic review of literature to identify recent studies that were published between 2015-2020 with an aim is to evaluate newer combination drug regimens (CDR) involving hypomethylating agents (AZA and decitabine) in treating elderly patients with newly diagnosed AML. METHODS- A comprehensive literature search was conducted in PubMed, Embase, and Cochrane databases. We included phase I/II studies that used CDR with HMA in elderly patients with newly diagnosed AML. RESULTS- Initial database search lead to 1120 studies. After exclusion (duplicates, case reports/series, relapsed/refractory AML) final analysis included 12 studies (n=655). Seven phase I/II with CDR using decitabine (n=500) were included in our review. Drugs used in combination included gemcitabine ozagamicin (n=40, CR/CRi =45%, mOS= 7 m), cladribine and low dose cytarabine (n=118, CR/CRi= 68%, mOS =13.8 m), vadastuximab talirine (n=53, CR/CRi=70%, mOS=11.3 m) and selinexor (n=5, CR/Cri= 80%) . In addition, three studies compared outcomes of CDR involving decitabine with all trans retinoic acid (ATRA)(n=93, ORR=21.9% vs 13.5%, p=0.06; mOS= 8.2 m vs 5.1 m, p=0.006) or talacotuzumab (CR/CRi= 15% vs 11%, p=0.44; mOS= 5.36 m vs 7.26 m, p=0.78) or bortezomib (CR/CRi= 39% vs 38%, p=0.91, mOS=9.3 m vs 8.9,p=0.18) to decitabine alone. In addition, cladribine and low dose cytarabine with decitabine in patients with adverse cytogenetics showed a decent CR/CRi of 50%, mOS= 10.5 months. In TP 53 positive mutations, CR/CRi was 40% and mOS was 5.4 months. Five phase I/II studies using CDR with AZA (n=155) were included in our review. Drugs included midostaurin (n= 88 , CR/CRi=25-29% mOS= 6-8 m) and pracinostat (n= 50, CR/CRi =46% mOS=19.1 m), In addition, two studies compared outcomes using CDR involving AZA with panobinostat (n=22, CR= 22.4 vs 30.8%, OS at 1 year = 60% vs 70%) or entinostat (n=18, ORR= 0% vs 16.6%, mOS=6 m vs 13 m) to AZA alone. None of the two comparative CDR studies using AZA showed superior outcome compared to AZA alone. CONCLUSIONS - Novel drug combinations involving decitabine including cladribine and low dose cytarabine, vadastuximab talarine showed superior CR/CRi and mOS compared to decitabine alone used in historic studies. In addition, CR/CRi were similar to HMA and venetoclax combination. In small number of patients, CDR with selinexor also showed superior CR/CRi compared to decitabine alone. CDR involving decitabine and ATRA showed superior mOS in direct comparison with decitabine alone. In addition, cladribine, low dose cytarabine and decitabine has shown promising outcomes in patients with adverse cytogenetics. Among CDR involving AZA only Proctinostat showed superior CR/CRi and mOS compared to historic studies with AZA alone. A recent phase III study though involving this CDR in comparison with decitabine was terminated early due to lack of efficacy on preliminary analysis. The above listed efficacious CDR involving decitabine in phase I/II studies need to be evaluated in large, randomized trials to assess for definitive benefit. If proven efficacious in larger studies, they could serve as additional first line CDR options in addition to HMA and venetoclax in treating elderly patients with newly diagnosed AML. Disclosures No relevant conflicts of interest to declare.

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GRASPA-AML 2012-01 study (NCT01810705): A multicenter, open, randomized phase 2b trial evaluating ERY001 (L-asparaginase encapsulated in red blood cells) plus low-dose cytarabine vs low-dose cytarabine alone, in treatment of newly diagnosed acute myeloid leukemia (AML) elderly patients, unfit for intensive chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.tps7099 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. TPS7099-TPS7099 ◽

Cited By ~ 1

Author(s):

Xavier G. Thomas ◽

Emmanuelle Tavernier Tardy ◽

Romain Guieze ◽

Patrice Chevallier ◽

Jean pierre Marolleau ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Red Blood Cells ◽

Blood Cells ◽

Myeloid Leukemia ◽

Low Dose ◽

Intensive Chemotherapy ◽

Newly Diagnosed ◽

Low Dose Cytarabine ◽

Acute Myeloid

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TREATMENT WITH LOW-DOSE CYTARABINE IN ELDERLY PATIENTS (AGE 70 YEARS OR OLDER) WITH ACUTE MYELOID LEUKEMIA: A SINGLE INSTITUTION EXPERIENCE

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2016.009 ◽

2016 ◽

Vol 8 ◽

pp. 2016009 ◽

Cited By ~ 7

Author(s):

Maël Heiblig ◽

Mohamed Elhamri ◽

Isabelle Tigaud ◽

Adriana Plesa ◽

Fiorenza Barraco ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Myeloid Leukemia ◽

Low Dose ◽

Intensive Chemotherapy ◽

Hypomethylating Agents ◽

Single Institution ◽

Low Dose Cytarabine ◽

Acute Myeloid ◽

Better Than

Objectives: Low-dose cytarabine (LD-AraC) is still regarded as the standard of care in elderly patients with acute myeloid leukemia (AML) ‘unfit’ for intensive chemotherapy. In this study, we compared the efficacy of LD-AraC, in patients ≥ 70 years old, with that of intensive chemotherapy, best supportive care (BSC), or hypomethylating agents in a single institution experience.Methods: Between 2000 and 2014, 60 patients received LD-AraC at 20 mg once or twice daily by subcutaneous injection for 10 consecutive days every 4-6 weeks. 85 patients were treated by intensive chemotherapy, 34 patients by hypomethylating agents, and 43 patients only by BSC.Results: Complete remission rate with LD-AraC was 7% versus 56% with intensive chemotherapy and 21% with hypomethylating agents. Median overall survival (OS) of patients treated with LD-AraC was 9.6 months with 3-year OS of 12%. Survival with LD-AraC was better than with BSC only (P = 0.001). Although not statistically significant, intensive chemotherapy and hypomethylating agents tended to be better than LD-AraC in terms of OS (median: 12.4 months and 16.1 months, respectively). There was no clear evidence that a beneficial effect of LD-AraC was restricted to any particular subtype of patients, except for cytogenetics.Conclusions: Despite a trend in favor of intensive chemotherapy and hypomethylating agents over LD-AraC, no real significant advantage could be demonstrated, while LD-AraC showed a significant advantage comparatively to BSC. This tends to confirm that LD-AraC can still represent a baseline against which new promising agents may be compared either alone or in combination.

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Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia

Oncotarget ◽

10.18632/oncotarget.3361 ◽

2015 ◽

Vol 6 (8) ◽

pp. 6448-6458 ◽

Cited By ~ 17

Author(s):

Jianyong Li ◽

Yaoyu Chen ◽

Yu Zhu ◽

Jianfeng Zhou ◽

Yanli Xu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Myeloid Leukemia ◽

Low Dose ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Low Dose Cytarabine ◽

Acute Myeloid

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Clofarabine Plus Low-Dose Cytarabine Induction Followed By Clofarabine Plus Low-Dose Cytarabine Alternating With Decitabine Consolidation In Acute Myeloid Leukemia Frontline Therapy For Older Patients

Blood ◽

10.1182/blood.v122.21.3948.3948 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3948-3948

Author(s):

Aziz Nazha ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

Xuelin Huang ◽

Xuemei Wang ◽

...

Keyword(s):

Elderly Patients ◽

Myeloid Leukemia ◽

Low Dose ◽

Single Agent ◽

Newly Diagnosed ◽

Free Survival ◽

Elevated Creatinine ◽

Prolonged Consolidation ◽

Low Dose Cytarabine

Abstract Background The outcome of elderly patients (pts) with acute myeloid leukemia (AML) treated with currently available therapies remains unsatisfactory. Clofarabine has single agent activity in AML. The combination of clofarabine with low-dose cytarabine produced higher response rates with a comparable safety profile compared with single-agent clofarabine. We previously reported a phase II study of clofarabine + low dose cytarabine followed by prolonged consolidation with clorarabine + low dose cytarabine alternating with decitabine in elderly patients with newly diagnosed AML (Faderl, Cancer 2012). The complete remission (CR) rate was 58%. With median follow up of 31.2 months, the median overall survival (OS) was 12.7 months, and the median relapse free survival was 14.1months. The combination was well tolerated with induction mortality of 3% (Early Death <28 Days), 7% at 8-weeks. Here we report the result with a larger patient population and longer follow up. Material and Methods Pts were eligible if they were >/= 60 years of age with newly diagnosed AML (based on World Health Organization [WHO] criteria) or high-risk myelodysplastic syndrome (MDS; >/=10% blasts or >/= intermediate-2 by the International Prognostic Scoring System) with Eastern Cooperative Oncology Group (ECOG) performance status of </= 2 and adequate organ function (serum total bilirubin </=2 mg/dL, alanine aminotransferase or aspartate aminotransferase </= 4 X the upper limit of normal, serum creatinine </= 2 mg/dL, and cardiac ejection fraction >40%). Induction therapy consisted of clofarabine 20 mg/m2 IV daily X 5 days (1-5) plus cytarabine 20 mg subcutaneously (SC) twice daily (BID) X10 days (1-10). All responses were defined as per IWG criteria (2003). Pts who did not achieve a CR could receive 1 re-induction cycle at the same dose after at least 28 days from C #1. Pts could receive up to 17 cycles of consolidation therapy. Consolidation was administered in blocks of 3 cycles where clofarabine 20 mg/m2 IV daily X 3 days (1-3) plus cytarabine 20 mg SC BID X 7 days (1-7) alternated with decitabine 20 mg/m2IV X5 days (1-5). Consolidation cycles were repeated every 4 to 7 weeks depending on hematopoietic recovery. Results Between 10/21/08 and 10/17/2011, a total of 118 patients were enrolled. The clinical characteristics are summarized in Table 1. The overall response rate (ORR) was 68% (71 [60%] CR, 9 [8%] CRp/CRi). Twenty two (19%) pts required re-induction, 16 (73%) achieved a response (12 achieved CR, 2 CRp, and 2 CRi). Median number of cycles received was 3 (range, 1-19). With median follow up of 31.2 months (range, 9.5-53.9), the median OS was 11.1 (range, 0.2-53.9), EFS 7.7 (range, 0.2-49.5), and relapse-free survival (RFS) 15.9 months (range, 0.3-48.3). The median OS among the responders was 21.1 months (range, 1.3-53.9). Four-week mortality was 3% and 8-week mortality 8%. Adverse events were predominantly grade 2 or less and included (>/= 10%): elevated liver enzymes (53%), elevated bilirubin (42%), diarrhea (19%), nausea (81%), rash (54%), hand and foot syndrome (10%), and elevated creatinine (10%). Grade 3 or more toxicities included: elevated creatinine (3%), rash (2%), vomiting (1%), and hand and foot syndrome (1%). No unexpected toxicities were observed. Conclusion Clofarabine plus low-dose cytarabine followed by prolonged consolidation alternating with decitabine is an active regimen with an ORR of 73% in older patients with newly diagnosed AML and high risk MDS. The regimen was well tolerated with low induction mortality. A randomized trail to compare this combination to best available therapy is needed to further asses the role of this combination in the treatment paradigm of elderly patients with AML. Disclosures: Off Label Use: Clofarabine and decitabine use in AML. Faderl:Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia

PLoS ONE ◽

10.1371/journal.pone.0164499 ◽

2016 ◽

Vol 11 (10) ◽

pp. e0164499 ◽

Cited By ~ 5

Author(s):

Christoph Schliemann ◽

Joachim Gerss ◽

Stefanie Wiebe ◽

Jan-Henrik Mikesch ◽

Nicola Knoblauch ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Phase I ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Low Dose ◽

Dose Escalation Study ◽

Low Dose Cytarabine ◽

Acute Myeloid

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Three Drug Regimens for Newly Diagnosed Multiple Myeloma Transplant-Ineligible Elderly Patients - a Systematic Review

Blood ◽

10.1182/blood-2019-132095 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5574-5574

Author(s):

Abdul Aziz Siddiqui ◽

Kazi Najamus-saqib Khan ◽

Arafat Ali Farooqui ◽

Muhammad Saad Farooqi ◽

Muhammad Junaid Tariq ◽

...

Keyword(s):

Multiple Myeloma ◽

Elderly Patients ◽

Phase Ii ◽

Low Dose ◽

Phase Ii Trial ◽

Alkylating Agents ◽

Phase Iii ◽

Newly Diagnosed ◽

Great Efficacy ◽

Drug Regimens

Introduction: Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT) tend to have comorbidities and/or advanced age that make this subset of patients difficult to manage with current drug regimens. Methods: A comprehensive literature search of PubMed, Embase, Clinicaltrials.gov and Web of Science was performed from inception and completed on 07/17/2019. Studies focusing on efficacy and tolerability of 3-drug regimens in patients with NDMM were included for the review. Results: Out of 3579 studies, a total of 10 (08 phase II and 03 phase III) clinical trials in last ten years (2010-2019) using 3-drug regimens in NDMM elderly pts (893M/807F) ineligible for ASCT (determined by investigators) were selected. A total of 1703/1740 NDMM pts were evaluated. Proteasome inhibitors (PIs) such as carfilzomib (C), bortezomib (V) and ixazomib (I) showed promising results in elderly transplant-ineligible NDMM pts. CLARION trial (phase III, n=955) compared two PIs (C and V) with melphalan (M) and prednisone. There was no statistically significant difference in progression-free survival (PFS) between two groups (median: 22.3 vs 22.1 months; HR: 0.91; 95% CI, 0.75-1.10, p = 0.159) as well as overall survival (OS) (HR: 1.08; 95% CI: 0.82-1.43). Difference in the least square means of the HR-QoL (Health related- quality of life) was 4.99 (p<.0001) favoring C-group. M may not be an ideal drug to combine with carfilzomib in this setting given more AEs.(Facon et al 2019). V as 3-drug regimen in combination with lenalidomide (L) in 242 pts achieved statistically significant prolonged PFS (median 43 mo) and OS (median 75 mo) with great efficacy and acceptable risk-benefit profile. (Durie et al 2017; phase III). Multinational phase II trial (n=70) by Dimopoulos et al (2019) evaluated I, with different fixed doses of cyclophosphamide (Cy). Median duration was 19 cycles, indicating the long-term tolerability of regimen. With favorable toxicity profile and maintained QoL scores, trial concluded that this therapy is tolerable in elderly transplant-ineligible NDMM pts. Tuchman et al (2017) in phase II trial (n=14) investigated (V-Cy-d) and achieved ORR of 64%, with ≥VGPR of 57%. Low dose V showed great efficacy with M yielding ORR of 86% and VGPR or better of 49% in phase II trial (n=101) that also evaluated Cy as 3-drug combination but results were more productive with M with longer PFS and OS which reduced when impact of frailty was examined on outcomes. Since toxicity was higher with M, trial suggested that 2-drug combination should be preferred in elderly frail patients. (Larocca et al 2015). Efficacy was quite promising when Bringhen et al (2014) trialed C with Cy-d; 87% OS and 76% PFS at 1 y in phase II trial (n=58) with much favorable safety profile. Monoclonal antibodies (mAb) such as elotuzumab (E) and pembrolizumab (Pe) are also tested in elderly. First study conducted on NDMM pts using humanized mAb; E, in phase II trial (n=40) by Takezako et al (2017) attained primary endpoint of the study (ORR) of (88%) and VGPR or better of 45% in Japanese pts with tolerable toxicities in elderly. No subjects on this study experienced severe peripheral neuropathy. KEYNOTE-185; a phase III multinational trial by Usmani et al (2019) evaluated Pe with Ld in 151 pts. FDA halted this study due to unfavorable benefit-risk profile; 19 deaths, 6 due to disease progression (PD), and 13 due to treatment-related AEs. Median PFS and median OS were not reached in either group. Immunomodulators such as L achieved one of the longest PFS reported in a trial of transplant ineligible patients (35 mo) by using LVd regimen in phase II multicenter trial (n=50). (O'Donnell et al 2018) Alkylating agents like bendamustine (ben) and M have been tested in different novel regimens. Decreasing intensity and increasing duration of ben resulted in better outcomes in phase II trial (n=59) by Berdeja et al (2016) and can be given as first line treatment. Ben yielded great results with low dose dexa as compared to high dose achieving 92% ORR. Original regimen was effective but relatively more toxic. Incidence of herpes and neuropathy decreased dramatically with the treatment modifications. Conclusion: Three-drug regimens having PIs, mABs, immunomodulators and alkylating agents have shown desirable results in NDMM transplant (ASCT)-ineligible elderly patients and are likely the emerging standard of care for NDMM. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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