CLAG±M (cladribine, cytarabine, granulocyte colony stimulating factor ± mitoxantrone) Results in High Response Rates in Older Patients with Secondary and Relapsed/Refractory Acute Myeloid Leukemia - a Single Institute Experience
Authors: Muppidi Monica Reddy , Freyer Craig W. , Ford Laurie Ann , Ontiveros Evelena P , Thompson James E. , Griffiths Elizabeth A. , Wang Eunice S. 
Published: October 2019

Introduction: Relapsed/refractory (r/r) and secondary acute myeloid leukemia (AML) are associated with poor outcomes and low survival rates, particularly in older individuals. Because there is no standard salvage regimen, the choice of therapy for patients (pts) is often based on institutional experience. The Polish Adult Leukemia group reported high anti-leukemic activity and acceptable toxicity with CLAG±M in r/r AML pts (Wierzbowska et al, Eur J Haematol 2008); however these patients were primarily younger individuals with a median age of 45 years. Jaglal et al (Leuk Res 2014) reported their single institute experience showing that CLAG-M was superior to historical 7+3 for induction of secondary AML pts after prior azanucleoside therapy. Based on these data, we have been utilizing CLAG±M as a standard induction/re-induction strategy for r/r and secondary AML pts at our institute since 2013.

Methods: Here we retrospectively reviewed the medical records of 45 consecutive adult pts with secondary or r/r AML who received CLAG±M chemotherapy at Roswell Park Cancer Institute from 2013 to the present. Disease characteristics, clinical response, toxicities, and overall survival were recorded for all patients.

Results: Median age was 66 (range 21-77) years. Twenty-six (58%) were male. Twenty-eight (62%) had received prior hypomethylating agents (HMA). Pts had a median of 1 prior AML therapies (range 0-5). Eight pts (18%) had no previous therapy for AML and of these all had secondary AML. The remainder (72%) had r/r AML. Median ECOG performance status was 1 (0-4). Initial WBC count was 1.86 (0.3-190) K/mcL with a mean of 9.53K/mcL. Median marrow blasts were 35% (0-95%). Two pts had extramedullary AML only.

Out of 42 evaluable pts, 12 (29%) had a complete remission (CR), 16 (38%) had a complete remission with incomplete count recovery (CRi), and 3 (7%) had a 50% reduction in marrow blast count (partial remission, PR). The CR/CRi rate was 67% with an overall response rate (CR/CRi/PR) of 74%. Median overall survival (OS) was 107 (17-548) days (Figure 1). Fourteen pts (31%) proceeded to allogeneic transplant (BMT). Treatment was overall well tolerated with no unexpected dose-limiting toxicities. The most common toxicity was neutropenic fever, which occurred in 36 pts (80%). Of note, 35 pts received CLAG+M while 10 pts (23%) received CLAG without mitoxantrone due to prior anthracycline exposure or cardiomyopathy. However ORR (78% vs 60%) and median OS (101 vs. 175 days, p=0.18) in CLAG+M vs. CLAG treated pts were not significantly different. There was no difference in response rates or median OS in patients who had/ had not received prior HMA or who had received several prior lines of therapy (0-2 vs. >2).

Two-thirds (30 of 45) of pts were ³ 60 years with a median ECOG of 1 (range 0-3). Despite higher percentages of secondary/therapy-related AML and prior HMA use in older pts, outcomes of CLAG+M were similar in both age groups (Table 1). ORR was 72% vs. 77% (p=NS) and median OS was 101 vs. 145 days (p=0.06) in older versus younger pts, respectively. Equal numbers of older and younger pts (33%) underwent subsequent BMT. In older pts receiving CLAG±M, there were no documented cases of neurotoxicity and no increased neutropenic complications.

Conclusions: CLAG±M resulted in high clinical responses and prolonged overall survival in pts with secondary and r/r AML with poor risk features, specifically older age (³60 years old) and multiple prior lines of therapy including previous HMA. Unlike other higher dose cytarabine-containing regimens, CLAG±M was well tolerated without significant neurotoxicity. Although larger prospective clinical trials are required to support these findings, overall our results support the use of CLAG±M as a valuable addition to the current armamentarium of salvage regimens for older fit AML patients.

Table 1. Outcomes of older ( ³ 60 yrs) vs. younger AML pts treated with CLAG±M Age ³ 60 yrs Age <60 yrs No. of patients N=30 N=15 Median age (yrs) 72 (60-77) 48 (21-59) Prior HM Agents (%) 22/30 (73%) 6/15 (40%) No. of prior therapies (Median) 1 (0-5) 2 (0-5) Secondary/ tAML (%) 18/3 (70%) 2/0 (13%) Complete remission (CR/CRi, %) 8/11 (66%) 4/5 (69%) Overall response rates (ORR) 21 (72%) 10 (77%) Median OS from CLAG±M (days, range, CI) 101 (32-409, 95% CI 90-158) 145 (17-548, 95% CI 103-295) Neutropenic fever (%) 21/30 (70%) 13/15 (87%) Post treatment BMT (%) 10 (33%) 5 (33%)

Figure 1. Survival of CLAG±M patients from treatment Figure 1. Survival of CLAG±M patients from treatment

Disclosures

Thompson: Kinex Pharmaceuticals: Research Funding. Griffiths:Celgene: Honoraria; Astex: Research Funding; Alexion Pharmaceuticals: Honoraria. Wang:Immunogen: Research Funding.