PROACTIVE: Prevention of Acute and Chronic GVHD Using TocIlizumab in Combination With Standard GVHD Prophylaxis After allogEneic Transplantation

We earlier hypothesized and demonstrated that tocilizumab could attenuate the incidence of
acute GVHD (aGVHD) after myeloablative conditioning (MAC) and reduced intensity conditioning
(RIC) Allogeneic hematopoietic cell transplantation (alloHCT), using matched sibling or
unrelated donor. In this study, we hypothesize that longer term interleukin 6 (IL-6)
inhibition through treatment with tocilizumab by repeated dosing would mediate a beneficial
effect not only on the risk of aGVHD, but also on chronic GVHD. This will be achieved by
administering an additional dose of tocilizumab at Day +100 post-alloHCT, besides the
pretransplant dose, as done in our previous clinical trial, thereby providing total
prophylaxis against both acute and chronic GVHD.

Inclusion Criteria:

1. Age ≥18 years.

2. Patients with any hematologic malignancy for which alloHCT is indicated. Patients with
acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) must be in
complete remission at the time of alloHCT(<5% blasts in the bone marrow, normal
maturation of all cellular components in the bone marrow and absence of extramedullary
disease).

3. Myeloablative conditioning (MAC) regimen, based on CIBMTR criteria.

4. T cell-replete peripheral blood graft.

5. Patients must have a matched related or unrelated donor (at least 6/6 match at HLA-A,
-B and -C for related donors and at least 8/8 match at HLA-A, -B, -C and -DRB1 for
unrelated donors).

6. Cardiac function: Left ventricular ejection fraction ≥45% for myeloablative
conditioning.

7. Estimated creatinine clearance ≥40 mL/minute (using the Cockcroft-Gault formula and
actual body weight).

8. Pulmonary function: DLCO ≥40% (adjusted for hemoglobin) and FEV1 ≥50%.

9. Liver function: total bilirubin <3 x upper limit of normal and ALT/AST <5 x upper
normal limit.

10. Signed informed consent: Voluntary written consent must be given before patient
registration and performance of any study related procedure not part of standard
medical care, with the understanding that consent may be withdrawn by the patient at
any time without prejudice to future medical care.

11. Female patient: A negative pregnancy test will be required for women of child bearing
potential. Breast-feeding or lactation is not permitted.

12. Planned posttransplant maintenance therapy is allowed.

Exclusion Criteria:

1. Prior allogeneic HCT.

2. Active CNS involvement with malignancy.

3. Patients receiving cord blood or haploidentical allograft.

4. Patients undergoing in vivo or ex vivo T cell-depleted alloHCT.

5. Karnofsky Performance Score <60%.

6. Patients with uncontrolled bacterial, viral or fungal infections (currently on
treatment and with progression of infectious disease or no clinical improvement) at
time of enrollment.

7. Active hepatitis B or C virus infection or known human immunodeficiency virus (HIV)
positive.

8. Prior intolerance or allergy to tocilizumab.

9. Use of rituximab, alemtuzumab, anti-thymocyte globulin (ATG) or other monoclonal
antibody planned as part of conditioning regimen for GVHD prophylaxis.

10. History of diverticulitis, Crohn's disease or ulcerative colitis.

11. History of demyelinating disorder.

12. Any current uncontrolled cardiovascular conditions, including uncontrolled ventricular
arrhythmias, NYHA class III or IV congestive heart failure, uncontrolled angina, or
electrocardiographic evidence of active ischemia or active conduction system
abnormalities.

13. Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.