Page 174 - Haematologica-April 2018

W.R. Drobyski et al.
The importance of IL-6 in human GvHD is supported by studies which have shown that patients with elevated plasma levels of IL-6,9,10 as well as those with a recipient or donor IL-6 genotype which results in increased IL-6 pro- duction,11-14 have an increased incidence and severity of this disease. The Food and Drug Administration (FDA) approval of tocilizumab (Toc; Actemra), which is a humanized anti-IL-6 receptor antibody that blocks both the membrane and soluble forms of the receptor for the treatment of severe active rheumatoid arthritis,15,16 has allowed off-label use of this agent to determine whether blockade of IL-6 signaling attenuates GvHD. To that end, it was demonstrated that Toc induced clinical responses in patients with steroid refractory acute (a)GvHD that pri- marily involved the lower GI tract.17 Furthermore, the addition of Toc to standard immune suppression resulted in a low incidence of aGvHD in a patient population which was comprised primarily of myeloid maliganan- ices,18 providing evidence that inhibition of IL-6 might also be an effective approach for the prevention of GvHD. Notably, however, in the latter study myeloablative (MA) conditioning was carried out exclusively with total body irradiation (TBI) and cyclophosphamide (Cy), which is not a widely employed regimen for the treatment of myeloid malignancies. Since the intensity of the conditioning regi- men is known to affect the magnitude of inflammatory cytokine production,19 the relevance of these results to patients treated with alternative, more commonly utilized conditioning regimens is not clear. Furthermore, there was no corresponding demographically-matched control population against which to assess these results.
In the study herein, we sought to determine whether the addition of Toc to standard immune suppression was effective for the prevention of aGvHD in patients who received busulfan (Bu)-based conditioning regimens, with particular emphasis given to the lower GI tract given prior pre-clinical studies and the primacy of this organ in GvHD pathophysiology. To place our results in context, we inter- rogated the Center for International Blood and Marrow Transplant Research (CIBMTR) database to obtain a con- trol population that was matched for relevant demograph- ic and transplant characteristics. We also examined longi- tudinal immune reconstitution and inflammatory cytokine production as additional parameters by which to assess the effect of IL-6 inhibition in transplant recipients.
Methods
Patient population
Patients were eligible for this trial if they met the following cri- teria: age >18 years; a diagnosis of acute leukemia, chronic myel- ogenous leukemia, myeloproliferative disease, myelodysplasia with less than 5% of blasts in the bone marrow, or a diagnosis of chronic lymphocytic leukemia, non-Hodgkin lymphoma or Hodgkin lymphoma with chemosensitive disease; availability of a 10/10 matched sibling or 8/8 matched unrelated donor; ejection fraction at rest >45% for MA conditioning or >40% for reduced intensity conditioning (RIC); estimated creatinine clearance greater than 50 mL/minute; adjusted diffusing capacity for carbon monoxide (DLCO) ≥40% and forced expiratory volume in 1 sec- ond (FEV1) ≥50%; and total bilirubin < 1.5 x and alanine transam- inase (ALT)/ aspartate transaminase (AST) < 2.5x the upper nor- mal limit. Patients were excluded if they had had a prior allogene- ic HSCT, Karnofsky Performance Score <70%, uncontrolled bac- terial, viral or fungal infections at time of enrollment, prior intoler-
ance or allergy to Toc, use of rituximab, alemtuzumab, antithymo- cyte globulin (ATG) or other monoclonal antibody at time of con- ditioning regimen, or history of diverticulitis, Crohn’s disease, ulcerative colitis or a demyelinating disorder.
Control population
The control population was derived from cases reported to the CIBMTR.20 Eligibility criteria for the control cohort consisted of having received a first allogeneic transplant at an American center, excluding The Medical College of Wisconsin (MCW), and meeting the same eligibility as the study population, with the exception of receiving only tacrolimus (Tac)/ methotrexate (MTX) as GvHD prophylaxis. Controls were selected from the years 2010-2015. This selection process resulted in the screening of 1,442 patients to define an optimally-matched control cohort.
Conditioning regimens and GvHD prophylaxis
All patients received Bu as part of the preparative regimen. Patients receiving MA conditioning were treated with either Bu 3.2 mg/kg/day (days -7 to -4) and Cy 60 mg/kg/day (days -3 and - 2) or Bu 3.2 mg/kg/day (days 5- to -2) and fludarabine (Flu) 30 mg/m2/day (days -5 to -2). Bu dosing was modified after the fifth dose, if necessary, to achieve a targeted level of 900±100 ng/mL. RIC was with Flu 30 mg/m2/day (days -6 to -2) and Bu 3.2 mg/kg/day (days -5 and -4). Patients received either T-cell replete bone marrow or granulocyte colony factor-stimulated peripheral blood stem cell grafts. For GvHD prevention, Tac was adminis- tered intravenously at a dose of 0.03 mg/kg/day starting on day – 3 to maintain a level of 5-15 ng/mL. MTX was given at the doses of15mg/m2 IVonday+1,and10mg/m2 IVondays+3,+6and +11 after hematopoietic stem cell infusion. Toc was infused intra- venously at a dose of 8 mg/kg (maximum dose of 800 mg) once on day-1 approximately 24 hours prior to the hematopoietic stem cell infusion, as per Kennedy and colleagues.18
Study design
The primary objective of this study was to compare the proba- bility of grades II-IV aGvHD-free survival at day 180 post-trans- plant between recipients of Toc, Tac and MTX and a contempo- rary control population who received Tac/MTX-based GvHD pro- phylaxis. Pre-specified secondary objectives of the study were to compare chronic (c)GvHD, transplant related mortality (TRM), disease relapse or progression, disease-free survival (DFS) and overall survival (OS) between Toc/Tac/MTX and Tac/MTX CIBMTR controls. Online Supplementary Table S1 contains the def- inition of the events, censorings, and competing risks for all time- to-event outcomes. Additionally, secondary objectives included description of the incidence of grades ≥3 toxicities according to Common Terminology Criteria for Adverse Event (CTACAE) v4, neutrophil and platelet engraftment, characterization of infections, proportion of donor chimerism, extent of immune reconstitution, and production of proinflammatory cytokines among patients who received Toc/Tac/MTX. A population that consisted of patients who were otherwise eligible for the trial but did not receive Toc in addition to Tac/MTX for GvHD prophylaxis was employed as a control for the cytokine analysis. These patients were consented and enrolled on a separate study. Both protocols were approved by the Institutional Review Board at the MCW.
Outcome assessments
Neutrophil recovery was defined as the first of three consecu- tive days with an absolute neutrophil count (ANC)>500. Platelet engraftment was defined as the first day of a sustained platelet count above 20,000 without any platelet transfusions for the pre- ceding seven days. Five patients who received reduced intensity
718
haematologica | 2018; 103(4)