Acute Graft Versus Host Disease increases due to chemotherapy induced immune stimulation in AML patients

Acute Graft versus Host Disease (aGvHD) is a chief cause of mortality and comorbidities post-transplantation. This condition can also limit the success of Allogenic Hematopoietic Stem Cell Transplantation (allo-HSCT) and increase the risk of relapse.  To prevent the occurrence of GvHD, a non-personalized prophylactic approach is currently employed in patients yet this therapeutic strategy has not had a high success rate in preventing GvHD in patients.

Chemotherapy phases prior to allo-HSCT is often complicated by infections, toxicities, and leukemic infiltration. These complications can induce immune stimulations by inducing tissue damage and immune activation.  However, it is still not unknown whether these inflammatory complications and the activation of the immune response increase the incidence of GvHD.

Lining Wang from the Saint Louis Hospital, Paris, France, and colleagues published an article ahead of print in Leukemia Research, in January 2017, where they carried out a retrospective study on 238 de novo Acute Myeloid Leukemia (AML) patients with favorable cytogenetics (median age = 47) transplanted at first remission and investigated the impact of immune stimulation prior to allo-HSCT on the incidence of aGvHD in these patients.

The key results of the study:

• During induction, grade ≥3 complications included skin (16.4%), gut (30.6%), and liver CTCAE (6.3%)
• No significant difference between GvHD prophylaxis and skin (P = 0.214), gut (P = 0.884), and liver (P = 0.331) complications
• Significant correlation between skin complications and skin aGvHD; P = 0.003, Overall Risk (OR; 95% CI) = 1.14
• Significant correlation between gut complications and stage 3–4 gut aGvHD; P = 0.013, OR (95% CI) = 1.09
• Significant correlation between prolonged febrile duration during chemotherapy and elevated incidence of grade 2–4 aGvHD ; P = 0.025, OR (95% CI) = 2.01
• Median Progression Free Survival (PFS), Overall Survival (OS) and GvHD-free Relapse Free Survival (GRFS) is 11.2, 12.4, and 8.3 months, respectively
• No significant correlation between survival and skin, gut, and liver complications
• Prolonged febrile duration significantly correlated with PFS (P = 0.03), OS (P = 0.03),  and had an impact on GRFS (P = 0.05)

Other significant results from this study demonstrated that cutaneous and digestive immune stimulations during induction increased the incidence of skin and gut aGVHD, respectively.

In summation this is the first study to demonstrate a correlation between inflammatory complications prior to allo-HSCT and aGVHD.

The authors concluded by stating that local immune stimulation during chemotherapy is significantly correlated with an increased incidence of aGvHD. The authors further suggested that personalized GvHD prophylactic strategies could improve the incidence of aGvHD, which in turn could improve the quality of life of transplanted patients.

Abstrac t

 60–70% of AML patients have an indication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) during their treatment. Graft versus host disease (GvHD), the major cause of mortality and comorbidities post-transplantation, develops by immunological mechanism and decides greatly prognosis and quality of life (QoL) of graft recipient. Current GvHD prophylaxis is not personalized. Infections, toxicities and leukemic infiltration complicate the first chemotherapy phases prior to allo-HSCT. They, to certain extent, induce local immune stimulation. Impact of immune stimulation of this period on incidence of GvHD has not been evaluated. We retrospectively studied 238 AML patients transplanted at first remission from 21 French centers in the ALFA-0702 protocol and found that cutaneous and digestive immune stimulation during induction increases the incidence of skin and gut aGVHD, respectively. Furthermore, prolonged febrile duration correlates with elevated incidence of grade II–IV aGvHD. Thus, we identified a group of patients with higher risk of aGvHD. The benefit of personalized GvHD prophylaxis should be explored in a prospective cohort to decrease incidence of aGvHD in these patients and improve their QoLs.