Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Randomized Open-label Multi-center Study of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation
Brief Summary: Assess the efficacy and safety of ruxolitinib compared to Best Available Therapy (BAT) in patients with corticosteroid-refractory acute graft vs. host disease (aGvHD) after allogeneic stem cell transplantation.


Options:
A: Inclusion Criteria:

PATIENT

1. Diseases

   Hematological malignancies confirmed histologically and not rapidly progressing:
   * AML in CR (defined as ≤ 5% marrow blasts and absence of blasts in the peripheral blood);
   * MDS with ≤ 5% marrow blasts and absence of blasts in the peripheral blood;
   * CML in CP;
   * MPS not in blast crisis and not with extensive marrow fibrosis,
   * ALL in CR;
   * Multiple myeloma not rapidly progressing;
   * CLL;
   * Non-Hodgkin's lymphoma (aggressive NHL should have chemosensitive disease);
   * Hodgkin's disease with chemosensitive disease.
2. Clinical situations

   * Theoretical indication for a standard allo-transplant, but not feasible because:

     * Age \> 50 yrs;
     * Unacceptable end organ performance;
     * Patient's refusal.
   * Indication for a standard auto-transplant: perform mini-allotransplantation 2-6 months after standard autotransplant.
3. Other inclusion criteria

   * Male or female; fertile patients must use a reliable contraception method;
   * Age \< 75 yrs;
   * Informed consent given by patient or his/her guardian if of minor age.

DONOR

* Related to the recipient (sibling, parent or child) or unrelated;
* Male or female;
* Any age;
* 10 of 10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele matched;
* Weight \> 15 Kg (because of leukapheresis);
* Fulfills criteria for allogeneic PBSC donation according to standard procedures;
* Informed consent given by donor or his/her guardian if of minor age, as per donor center standard procedures.

Exclusion Criteria:

PATIENT

* Any condition not fulfilling inclusion criteria;
* HIV positive;
* Non-hematological malignancy(ies) (except non-melanoma skin cancer) \< 3 years before nonmyeloablative HCT.
* Life expectancy severely limited by disease other than malignancy;
* Administration of cytotoxic agent(s) for "cytoreduction" within three weeks prior to initiating the nonmyeloablative transplant conditioning (Exceptions are hydroxyurea and imatinib mesylate);
* CNS involvement with disease refractory to intrathecal chemotherapy.
* Terminal organ failure, except for renal failure (dialysis acceptable)
* Uncontrolled infection;
* Karnofsky Performance Score \<70%;
* Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment;
* Patient is a female who is pregnant or breastfeeding;
* Previous radiation therapy precluding the use of 2 Gy TBI or 8 Gy TLI;

DONOR

* Any condition not fulfilling inclusion criteria;
* Unable to undergo leukapheresis because of poor vein access or other reasons.
B: Inclusion Criteria:

* Standard-risk of recipients with hematological malignancies (including AML-CR1, ALL-CR1, CML-CP, MDS-RA, RARS,RCMD,RAEB-1); age from 40 to 60; having HLA-matched sibling donor; Eastern Cooperative Oncology Group (ECOG)≤1, ejection fraction (EF)≥50%; bilirubin≤35µmol/L; AST, and ALT lower than or equall to two-fold baseline;creatinie≤130µmol/L.

Exclusion Criteria:

* Active, uncontrolled infection; severe allergy to ATG, including shock or laryngeal edema; secondary stem cell transplant recipient; haplidentical recipients; matched unrelated donor recipients; non-myeloablative condioning regimen recipients; EF\<50%; bilirubin\>35µmol/L; AST, and ALT higher than two-fold baseline; creatinie\>130µmol/L.
C: Inclusion Criteria:

Participation of patients in simultaneous diagnostic and comprehensive therapeutical trials for certain entities is allowed.

* Patients 18-60 years of age;
* Patients suffering from one of the following diseases:

  * AML: 1st complete remission (CR1) or beyond 1st remission (CR2, CR3), in relapse, not in remission (primary refractory, induction failure);
  * ALL: 1st complete remission (CR1) or beyond 1st remission (CR2, CR3), in relapse, not in remission (primary refractory, induction failure);
  * MDS, if transplantation is medically indicated: RA (with poor risk factors as classified by the International Prognostic Scoring System of MDS), RARS, RAEB, RAEB-t, CMML;
  * CML: beyond 1st chronic phase (CP1): accelerated phase, blast crisis, chronic phase (CP2, CP3);
  * OMF, if transplantation is medically indicated: Osteomyelofibrosis;
* Patients designated to undergo allogeneic bone marrow transplantation or allogeneic peripheral blood stem cell transplantation;
* Patients with a HLA-A, -B (DNA-based, 2 digits), HLA-DRB1, -DQB1 (DNA-based 4 digits) matched (8 out of 8 alleles) unrelated donor; serological typing is not required
* Patients with a Karnofsky Performance Score (KPS): \> 60%;
* Patients who underwent all obligatory screening examinations (special examinations within the last 4 weeks);
* Patients who have given their written informed consent to participate in the study.

Exclusion Criteria:

* Patients with significant cardiac (e.g. ejection fraction \<50%), pulmonary (e.g. FEV1 \<50%), renal (e.g. creatinine \> 1.5 mg/dl), metabolic (e.g. bilirubin \> 2.0 mg/dl) and/or CNS disease, currently uncontrolled by treatment, which may interfere with the completion of the study;
* Patients with any bacterial, viral, or fungal infections not under adequate antimicrobial control;
* Patients who are known to have serum hepatitis or who are carriers of the Hepatitis B surface antigen (HBs-Ag), or Hepatitis C antibody, or who are known to have a positive result to the test of HIV antibodies;
* Patients with any additional concurrent or previous malignant disease;
* Patients with known hypersensitivity to rabbit immunoglobulin antibodies in past patient history or with known allergy to any substance chemically related to the study medication;
* Pregnant (β-HCG test) or lactating women;
* Patients who formerly underwent transplantation including previous autologous transplants;
* Patients who cannot communicate reliably with the investigator or who are not likely to cope with the requirements of the study.
D: Inclusion Criteria:

* Have undergone Allogeneic Stem Cell Transplanttaion (alloSCT) from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
* Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
* Confirmed diagnosis of steroid refractory aGvHD defined as patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day \[or equivalent prednisone dose 2.5 mg/kg/day\]), given alone or combined with calcineurin inhibitors (CNI) and either:

  * Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR
  * Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,OR
  * Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:
* Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day) , OR
* Failure to taper the methylprednisolone dose to \<0.5 mg/kg/day (or equivalent prednisone dose \<0.6 mg/kg/day) for a minimum 7 days.

Exclusion Criteria:

* Has received more than one systemic treatment for steroid refractory aGvHD.
* Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
* Evidence of uncontrolled viral infection including Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Human Herpes Virus-6 (HHV-6), Hepatitis Virus (HBV), or Hepatitis C Virus (HCV) based on assessment by the treating physician.
* Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.

Answer: D