Obinutuzumab Containing Conditioning Regimen for Patients With Poor Risk CLL or Richter's Transformation Requiring Allogeneic Stem Cell Transplantation
Obinutuzumab Containing Conditioning Regimen for Patients With Poor Risk CLL or Richter's Transformation Requiring Allogeneic Stem Cell Transplantation
The primary objective of the study is to evaluate the feasibility, efficacy and safety of an
 obinutuzumab containing conditioning regimen for poor risk CLL patients and patients with
 Richter's transformation requiring an allogeneic stem cell transplantation.
CLL is the most common haematological malignancy in the western world. Though in the majority
 it behaves like a chronic disease with minimal impact on life expectancy, in around 15-20% of
 the patients it takes a very aggressive course. Patients who experience a high grade
 transformation, i.e., Richter's transformation also have a poor prognosis. Despite the advent
 of new therapeutic agents like Bcl-2 and BTK inhibitors which are revolutionising the outlook
 for this particular patient cohort, allogeneic stem cell transplantation is the only
 currently available therapy with the potential to cure. The non relapse mortality associated
 with this treatment is a major deterrent for physicians and patients alike to opt this
 intervention. We propose a trial to study the use of a B-cell depleting agent, obinutuzumab
 to simultaneously reduce tumour bulk control and offer GvHD prophylaxis in the
 peri-transplant setting and thereby analyse its impact on non relapse morbidity and mortality
 as well as maximum minimum residual disease (MRD) eradication. All patients with poor risk
 CLL (current EBMT criteria) and Richter's transformation with the best possible response to
 available therapies will be considered for the trial. Due to the poor disease control
 associated with peri-transplant T-cell depletion, obinutuzumab will be used instead of T-cell
 depleting agents as GvHD prophylaxis.
Inclusion Criteria:

 1. Have documented CLL according to iwCLL criteria

 2. a) CLL requiring transplant according to the consensus statement 2014

 -  Non-response or early relapse within 24 months after purine analogue combination
 therapy or treatment of similar efficacy plus high risk CLL TP53
 deletion/mutation (del 17p-) and/or del 11 plus response to kinase inhibitors or
 other small molecules or

 -  Non-response or early relapse within 24 months after purine analogue combination
 therapy or treatment of similar efficacy and refractory to or non-tolerating
 kinase inhibitors or other small molecules or b) Transformation of CLL to
 aggressive NHL (Richter's transformation) The CLL patients should have at least
 one therapy with the newer targeted agents such as BCL-2 inhibitors or BCR
 targeting agents. Both poor risk CLL patients and patients with Richter's
 transformation should achieve the best possible response defined as disease
 sensitivity measured as CR, PR or SD prior to transplant with an available
 salvage therapy

 3. Availability of a suitable fully matched (10/10) sibling or unrelated donor

 4. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤
 1.

 5. Hematology values within the following limits unless cytopenia is caused by the
 underlying disease, i.e., no evidence of additional bone marrow dysfunction (e.g.
 myelodysplastic syndrome 2, hypoplastic bone marrow):

 -  Absolute neutrophil count ≥ 1.0 x 109/L

 -  Platelets ≥ 50 x 109/L and more than 7 days since last transfusion

 6. Adequate liver function as indicated by a total bilirubin AST, and ALT ≤1.5 the
 institutional ULN value, unless directly attributable to the patient's CLL

 7. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative,
 patients positive for anti-HBc may be included if PCR for HBV DNA is negative and
 HBV-DNA PCR is performed every month until 1 year after last dosage of obinutuzumab),
 negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to
 registration

 8. 18 years of age or older but not older then 70 years

 9. Able and willing to provide written informed consent and to comply with the study
 protocol procedures

 10. Patient agrees to inform other physicians about study participation

 Exclusion Criteria:

 1. Previous allogeneic stem cell transplant

 2. Known central nervous system (CNS) involvement

 3. Patients with a history of confirmed PML

 4. Clinically significant cardiac disease including unstable angina, acute myocardial
 infarction within six months prior to randomization, congestive heart failure (left
 ventricular ejection fraction < 50%).

 5. Organ dysfunction DLCO < 50%, TLC < 70%, FEV1 < 70% and or receiving supplementary
 oxygen, Inadequate renal function: Creatinine clearance < 50ml/min

 6. Patients with active non-controlled infectious disease under treatment (no decrease of
 CRP or PCT) including active viral infection and active fungal infections with
 radiological progression despite treatment with Ambisome or active Triazole for more
 than a month

 7. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
 antibodies. Known sensitivity or allergy to murine products

 8. Hypersensitivity to obinutuzumab or to any of the excipients such as for example
 Mannitol

 9. Hypersensitivity to Fludarabine or hypersensitivity to both Treosulphan and Busulphan
 or any of the excipients of the used products

 10. Hypersensitivity to both Ciclosporin A and calcineurin inhibitors or hypersensitivity
 to Mycophenolat-Mofetil or any of the excipients of the used products

 11. Uncontrolled haemolytic anemia

 12. Participation in another experimental drug trial (including chemotherapy, antibody
 treatment, kinase inhibitors, BCL2-antagonists or immunmodulatory agents) with start
 of the conditioning regimen/first obinutuzumab application.

 13. Pregnant women and nursing mothers (a negative pregnancy test is required for all
 women of childbearing potential within 14 days before start of treatment)

 14. Fertile men or women of childbearing potential unless:

 -  Surgically sterile or ≥ 2 years after the onset of menopause

 -  Willing to use two methods of reliable contraception including one highly
 effective (Pearl Index < 1) such as oral hormonal contraceptives, intrauterine
 device, sexual abstinence and one additional effective (barrier) while on study
 and maintained for up to 3 years after allogeneic transplantation or 18 months
 after the last dose of obinutuzumab therapy, whichever is longer

 15. Vaccination with a live vaccine a minimum of 28 days prior to randomization

 16. Prisoners or patients who are institutionalized by regulatory or court order or
 persons who are in dependence to the sponsor or an investigator