Targeting Systemic Inflammatory Response Syndrome As Initial Therapy and Oral Arsenic Based Consolidation Regimen for Acute Promyelocytic Leukemia

Early life-threatening complications are a hindrance towards the cure of acute promyelocytic leukemia (APL). Some patients could indicate symptoms in line with systemic inflammatory response syndrome (SIRS) at admission or along with induction therapy. Here we designed this multicenter, single-arm APL-SIRS prospective study and enrolled 140 patients to test the efficacy and safety of the early intervention through targeting SIRS as initial therapy.

The diagnostic of SIRS based on previous reported criteria. Other systematic manifestations include: weight gain (from capillary leak and soft tissue edema), respiratory distress, radiographic opacities, pleural or pericardial effusion, hypotension, renal failure, abnormal coagulation manifestation, and disseminated intravascular coagulation (DIC) may also be present. We stratified patients with SIRS based on the presence or absence of systematic symptoms, and tailored treatment accordingly. The risk groups were defined as (i) low-risk (LR): Patient diagnosed with SIRS but without systematic manifestations of SIRS or underlying diseases; (ii) medium-risk (MR): Patient diagnosed with SIRS with 1-2 of systematic presentations; (iii) high-risk (HR): Patients diagnosed with SIRS plus with ≥ 3 of the systematic presentations.

We used stratified glucocorticoid therapy in addition to ATRA, anthracycline, and ATO in induction. The consolidation regimen consisted of two additional cycles of ATRA and oral tetra-arsenic tetra-sulfide formula, Realgar-Indigo Naturalis Formula (RIF), followed by maintenance therapy with ATRA, oral methotrexate (MTX), and 6-mercaptopurine (6MP).

Our results indicated that increased SIRS risk levels are associated with higher WBC counts (P<0.0001). Strikingly, there is no mortality difference was observed between groups with WBC<4x10⁹/L, 4x10⁹/L≤WBC <12x10⁹/L, and WBC ≥ 12x10⁹/L (P>0.05). This result suggests that though elevated WBCs could reflect an ongoing inflammation cascade initiated by cytokine secretion, appropriate stratified glucocorticoid therapy in addition to standard induction therapy appear to mitigate any potential differences in outcome.

We monitored the levels of both pro-inflammatory (TNFα, IL-1β, IL2, IL-6, IL-8) and anti-inflammatory (IL-4, IL-10, IL-13) cytokines on day 1, 8, 15, 22, and 28 and evaluated their prognostic value in different SIRS risk groups. Interestingly, we see differences in cytokine expression level within different SIRS risk groups. However, following glucocorticoid treatment the increased cytokine levels decline by the end of induction, and differences in cytokine levels between groups disappeared. Further statistical analysis indicated there is no difference among different SIRS risk groups at the end of induction in both pro- and anti--inflammatory cytokine levels. We also found that the change of cytokine level happens prior to clinical symptom changes, which make it possible that cytokines may be a sensitive prognostic marker tailoring for APL treatment.

In total 126 cases attained CR and all survived throughout the follow-up period. The estimated 10 years overall survival for the whole cohort was 92.14±2.27%. There are 11 people died in SIRS-LR (2/44), -MR (3/44), -HR (6/50), respectively. The overall survival of SIRS-LR, -MR, and -HR group was 95.46±3.14%; 93.48±3.64%; and 88.00±4.60%. During follow up, 15 cases has events (SIRS-LR: 3/44, SIRS-MR: 5/46, SIRS-HR: 7/50) and all of them are in remission again after intervention. No patients received hematopoietic stem cell transplantation. The EFS for SIRS-LR, SIRS-MR, SIRS-HR are 88.64±4.79%, 82.61%±5.59%, 74.00±6.20%, respectively.

In short, early diagnosis and intervention of SIRS is likely a key to decreasing the early mortality of APL. The dynamic change of cytokine value could be potentially used as prognostic makers to detect early disease progression of APL.