Introduction

Relapsed and Refractory (R/R) Acute Myelogenous Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) have poor outcomes. No uniform consensus has been made on a preferred treatment regimen for R/R AML & ALL. FLAG, comprised of fludarabine, cytarabine, granulocyte colony-stimulating factor (GCSF), with or without Idarubicin, is an induction and salvage chemotherapy regimen for these diseases. Studies reviewing FLAG-/+Ida are decades-old with small populations. CR rates in R/R-AML historically range from 52-63% and in R/R-ALL from 30-39%. Here, we retrospectively review the outcomes for R/R-AML/ALL patients recently treated with FLAG-/+Ida at the UC Davis Comprehensive Cancer Center (UCDCCC).

Methods

Adult patients (≥18 years) with R/R-AML and R/R-ALL who received FLAG or FLAG-Ida from January 1, 2012 to October 31, 2016 were eligible. Patient charts were generated from a pharmacy electronic medical record report and retrospectively reviewed. Baseline data included demographics, performance status, number of prior therapies, disease status, and pre-treatment peripheral blood and marrow biopsy data, including cytogenetic and molecular studies. Disease status was defined as "relapsed" if patients experienced recurrence of disease after previously obtaining CR with another chemotherapy regimen and "refractory" if they failed to obtain CR with another regimen prior to receiving FLAG. Primary outcomes were complete remission (CR) and overall survival (OS). Secondary outcomes included overall response rate [ORR: defined as number of patients achieving CR plus CR with incomplete count recovery (CRi)], disease-free survival (DFS), and adverse events.

Results

Of the 57 patients identified, 42 had AML, 14 had B-Cell ALL and 1 had T-Cell ALL. The median age was 51 (range 22-74). Twenty-two (38.5%) patients were relapsed, 31 (54.4%) refractory, and 4 (7%) relapsed and refractory. The median number of chemotherapy regimens prior to FLAG was 2, with range from 1 to 5. Seventy-seven percent of patients had an ECOG score of 0 to 1 at treatment initiation. For AML patients, 4 (9.5%) were European Leukemia Network (ELN) Favorable Risk, 20 (47.6%) were ELN Intermediate-1, 15 (35.7%) were ELN Intermediate-2, and 3 (7.1%) were ELN Adverse Risk. No patients with ALL were Philadelphia chromosome positive, 10 (66%) were older than age 35, and 5 (33%) had a WBC count higher than 30k at start of therapy. For AML, responses were CR in 20 (47.6%), CRi in 5 (11.9%), and partial response in 1 (2.4%). In ALL, responses were CR in 7 (46.7%) and no patients achieved CRi or PR. ORR (CR+CRi) was 59.5% for AML and 46.7% for ALL. Ten (23.8%) patients with AML received FLAG within 100 days prior to allogeneic hematopoietic stem cell transplant (HSCT; n=3) or donor lymphocyte infusion (DLI, n=7). Two (4.8%) AML patients received FLAG within 100 days after HSCT. Two (13.3%) patients with ALL received FLAG within 100 days prior to HSCT(n=1) or DLI (n=1). Median OS in AML was 10 months and Median DFS was 8.8 months. When censored for HSCT, Median OS and DFS in AML were both 7.8 months. Median OS and DFS in ALL were both 4.7 months, and censoring for HSCT did not change this duration. Patients experienced the following notable adverse events: febrile neutropenia 40 (70.2%), culture-positive bacteremia 14 (24.6%), pneumonia 3 (5.3%), colitis 6 (10.5%), port/line infection 1 (1.8%), hemorrhage/thrombus/DIC 5 (8.8%), and renal injury 3 (5.3%). Eight died within 30 days (14%) and 5 additional died within 60 days (8.8%) of treatment. Three died within 1 day of treatment, respectively from intracranial hemorrhage, blast crisis, and DIC. One died of STEMI on day 26. The remaining 9 early deaths were attributed to febrile neutropenia with septic shock. The most common primary cause of death over the course of treatment was refractory leukemia, 30 (52.6%).

Conclusion

Outcomes of FLAG +/- Ida in patients with R/R-AML and R/R-ALL at UCDCCC are similar to historical controls, confirming its role as a salvage regimen in these poor risk patients. As expected, adverse events were common in this population, and comparable to historical controls. Although supportive care advances, such as improved treatments for infection, have been developed since earlier publications of the FLAG regimen, our study suggests treatment outcomes remain similar. This further encourages the investigation of novel regimens for relapsed and refractory AML and ALL.

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Disclosures

Rosenberg: Amgen: Speakers Bureau. Jonas: Rigel: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding.

Topics:
acute lymphocytic leukemia, adverse event, allogeneic hematopoietic stem cell transplant, bacteremia, b-cell acute lymphocytic leukemia, blast phase, bone marrow biopsy, cancer care facilities, chemotherapy regimen, colitis

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2017 by The American Society of Hematology
2017
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