Cladribine, Cytarabine, Granulocyte Colony Stimulating Factor ± Mitoxantrone (CLAG ± M) Is Highly Effective Therapy for Secondary and Relapsed/Refractory Acute Myeloid Leukemia
Authors: Przespolewski Amanda , Freyer Craig W. , Ji Wenyan , Cronin Tara L. , Thota Swapna , Griffiths Elizabeth A. , Thompson James E. , Elshoury Amro , Baron Jeffrey , Walsh Mark , Wang Eunice S. 
Published: November 2019

Background: Patients (pts) with secondary acute myeloid leukemia (s-AML) or relapsed/refractory (r/r) AML represent a high-risk populations with poor long-term outcomes following standard induction chemotherapy with 7+3. Until 2017, there was no standard regimen for these patients. CLAG ± M has been described in the literature to result in significant responses in r/r AML (Wierzbowska et al, Eur J Haematol 2008), and as front-line therapy for s-AML following azanucleoside failure (Jagal et al, Leuk Res 2014). Here we describe our institutional experience (RP) with CLAG±M as a standard induction/re-induction strategy for r/r and s-AML patients. We further compare our institutional data for s-AML patients treated on label with CPX-351 compared to CLAG±M.

Methods: Medical records were retrospectively reviewed to identify pts treated with CLAG±M for r/r or untreated s-AML. S-AML pts treated with CPX-351 as induction therapy following FDA approval for these indications were also identified as a comparator cohort. Treatment, demographics, disease-specific variables, and overall survival outcomes were collected under an institutional review board approved protocol.

Results: 60 pts with r/r (n=44; 73.3%) or s-AML (n=16; 26.7%) were treated with CLAG±M between 2003-18. 12 pts (19%) did not receive mitoxantrone. The median age of treated pts was 65 years (y;range 21 - 77) and 40 were male (63.5%). Cytogenetics were high-risk in 26 pts (41.3%) and intermediate risk in 37 pts(58.7%), 10 (15.9%) had 17p abnormalities. 41 (65.1%) pts had previously received hypomethylating (HMA) therapy. The overall response rate (ORR=CR+CRi+PR) was 81.7%; 41 pts achieved CR/CRi (68.3%), and 8 achieved PR (12.7%), 25 (39.7%) went on to allogenic stem cell transplant (AlloT). The most common adverse event (AE) was infection (58.7%, n=37). Thirty-day (d) mortality was 5%, and 60-d mortality was 14%. Median overall survival (OS) was 313 d (range 172 - 503), median progression-free survival (PFS) was 225 d (range 135 - 423). Similar response rates, OS and PFS were seen comparing pts with intermediate and high-risk cytogenetics, r/r and s-AML, and those with 17p abnormalities. The addition of mitoxantrone did not impact outcome (Table 1). Younger pts (&lt;60yo) had improved OS (613 vs. 141 d; p=0.007) and PFS (313 vs. 186 d; p=0.022) as compared to older (≥ 60yo) (Figure 1).

We then examined outcomes for the subset of s-AML (n=16) pts treated with CLAG±M and compared them with a cohort of s-AML pts treated at our institution with CPX-351 following it's FDA approval for this indication. Median age of CLAG-M cohort was 65.5y (range 24 - 77), most 75% (12), were male, 7 pts (43.8%) had high-risk and 9 (56.3%) intermediate-risk cytogenetics. 14 pts (87.5%) had prior HMA exposure. The ORR with CLAG+M was 81.3%; 8 pts (50%) achieved CR/CRi and 7 (43.8%) went on to AlloT. The most common AE was infection (43.8%, n=7). Thirty- and 60-d mortality were 0% and 12% respectively. The OS was 423 days (range 71 - not reached). When compared to s-AML pts treated with CPX-351 (n=22), the ORR following CLAG±M was significantly higher at 81.3% vs. 40.9% (p=0.02). However, no difference was noted in CR/CRi rate, OS (Figure 2), or transplant percentage. Of particular note 14 pts (87.5%) in the CLAG±M cohort compared to 3 (13.6%) in the CPX-351 cohort had received prior HMA (p=&lt;0.001), a notoriously challenging to treat population (Table 2).

Conclusions: Our institutional analysis suggests that CLAG+M results in a remarkably high ORR (81.7%) and excellent OS of 10.4 m in adult pts with r/r and s-AML. Responses were observed despite a cohort with higher risk features including prior HMA, high-risk cytogenetics, and 17p abnormalities. ORR were similar independent of age, but younger pts (&lt; 60yo) had better OS and PFS compared to older counterparts. Equivalent responses were seen irrespective of anthracycline inclusion. S-AML pts treated with CLAG±M had significantly higher ORR, but a similar OS compared with a sequential cohort of RP treated pts who received CPX-351. CLAG±M is active and tolerable with high response rates and excellent OS in r/r and s-AML pts with poor risk clinical features (prior HMA, p53 mutations, older age, high risk cytogenetics, inability to tolerate anthracycline therapy). Prospective clinical trials of this regimen compared with alternative regimens (CPX-351, venetoclax/HMA) are warranted.

Disclosures

Przespolewski: Jazz Pharmaceuticals: Other: PI on clinical trial. Thota:Incyte, Inc.: Speakers Bureau. Griffiths:Persimmune: Consultancy; Abbvie, Inc.: Consultancy, PI on a clinical trial; Novartis Inc.: Consultancy; Boston Scientific: Consultancy; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Celgene, Inc: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy; Boston Scientific: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Persimmune: Consultancy; New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial. Wang:Amgen: Other: Advisory role; Agios: Other: Advisory role; Daiichi: Other: Advisory role; Stemline: Other: Advisory role, Speakers Bureau; Pfizer: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; Jazz: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role.