A phase II study evaluating the effect of the addition of lenalidomide to R-CHOP for patients with newly diagnosed MYC positive DLBCL and BCL-U.

* DLBCL or BCL-U, histologically confirmed according to the WHO classification 2008 with a MYC rearrangement as determined by FISH comprising:

- single hit (SH MYC+ lymphoma, not fulfilling the criteria for Burkitt Lymphoma ) or

- double hit lymphoma (DH) MYC+/BCL2+ or MYC+/BCL6+ or

- triple hit lymphoma (TH)MYC+/BCL2+/BCL6+

* Age ¡Ý 18 year

* No prior treatment except

- local radiation or short course (max 7 days) steroids (max 100 mg/day)

- 1 course of R-CHOP in case MYC positivity became evident during first cycle of treatment

* WHO performance status (PS) 0-3, status 4 only if disease related (see appendix C)

* Ann Arbor stage II-IV

* Measurable disease: on CT scan at least 1 lesions/node with a long axis of >1.5 cm and at least one positive lesion on 18F-FDG PET scan.

* Negative pregnancy test at study entry

* Patient is willing and able to adhere to the requirements of the lenalidomide
Pregnancy Prevention Risk Management Program

* Written informed consent

* Patient is capable of giving informed consent

* All histopathological diagnoses other than DLBCL or BCL-U according to the WHO classification 2008, like Burkitt lymphoma, irrespective of the presence of MYC rearrangement

* Known history of indolent lymphoma. If during screening localization of an indolent lymphoma in the bone marrow biopsy is diagnosed, the patient is eligible.

* Inadequate renal function or creatinine clearance < 30 mL/min (after rehydration). Creatinine clearance may be calculated by Cockcroft –Gault formula:

CrCl = (140 - age [in years]) x weight [kg] (x 0.85 for females)/(0.815 x serum creatinine [ìmol/L])

* Inadequate hepatic function: bilirubin > 3 times ULN (total) except patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin

* Inadequate hematological function: ANC < 1.0x109/L or platelets < 75x109 /L unless lymphoma related

* CNS localization of the lymphoma

* Female subject pregnant or breast-feeding

* History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma

* Active symptomatic ischemic heart disease, myocardial infarction, or congestive heart failure within the past year. If echo or MUGA is obtained the LVEF should exceed 40%

* Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, cancer, etc.) that would jeopardize the patient's ability to receive the regimen with reasonable safety

* HIV positivity

* Active Hepatitis B or C infection as defined by positive serology and transaminitis. Non-active Hepatitis B carriers may be included if protected with lamivudine (see 9.4 of protocol)

* Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D of protocol)

* Severe neurological or psychiatric disease

* Current participation in another clinical trial interfering with this trial

* Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

* Claustrophobia to the extent that PET-CT is impossible