Dose Dense Chemotherapy and Rituximab for Young High Risk Diffuse Large B-Cell Lymphoma Patients (CRY-04)
Dose Dense Chemotherapy and Rituximab for Young High Risk Diffuse Large B-Cell Lymphoma Patients (CRY-04)
The purpose is to test whether dose densified chemoimmunotherapy followed by central nervous
 system (CNS) prophylaxis for young high risk diffuse large B-cell lymphoma (DLBCL) patients
 is feasible and could improve time to treatment failure and reduce the risk of CNS relapses.
 Six courses of rituximab-cyclophosphamide-doxorubicin-etoposide-vincristine-prednison
 (R-CHOEP) given in two weeks intervals with the support of G-CSF is followed by one course of
 high dose methotrexate (HD-MTX) and high dose cytarabine (HD-Ara-C). The results will be
 compared to a historical Nordic study.
Pathology:

 Patients may be included on the bases of the histological diagnosis of the local pathologist.
 The specimen will be reviewed by a central pathologist in each country

 Treatment:

 All patients receive CHOEP-14 with rituximab x 6 with the support of G-CSF followed by high
 dose cytarabine i.v. and high dose methotrexate i.v.Intrathecal (i.t.) CNS prophylaxis in
 combination with chemotherapy is not to be given, but i.t. methotrexate may be given once
 after initial liquid sampling. Radiotherapy will be given at the discretion of the individual
 centres.

 Investigations before, during and after treatment:

 The disease status will be assessed prior to treatment start, after 3 cycles of CHOEP +
 rituximab and after completion of the treatment schedule. Positron Emission Tomography (PET)
 using F18 deoxyglucose may be performed after fulfillment of treatment. Persistent, suspected
 lymphoma tissue should whenever possible be confirmed with a biopsy, otherwise the patient
 will be regarded as PR and second line therapy will be considered (see schematic outline).

 Clinical and radiological (CT) assessment are performed at pretreatment and subsequently on
 sites initially involved, and bone marrow biopsy if initially involved

 -  After the 3rd course

 -  After the last course (within one month) of chemotherapy (biopsy if indicated)

 -  After radiotherapy (for patient given radiotherapy as part of the primary treatment)

 Clinical follow-up:

 -  4x per year during the first and second year of follow-up

 -  2x per year during the third, fourth and fifth year of follow-up

 Radiological investigations at follow up:

 -CT after 6, 12 and 24 months of sites initially involved. CT abdomen in all cases after 12
 and 24 months. X-ray of the thorax (if CT thorax is performed) after 6, 12 and 24 months
Inclusion Criteria:

 1. Age ≥ 18 - < 65 years.

 2. Histology verified according to the WHO classification and with CD20 positivity by
 immunhistochemistry or flow cytometry:

 -  Diffuse large B-cell lymphomas with subgroups except posttransplantation-,
 Burkitt-like- and primary CNS lymphomas and cases with leptomeningeal lymphoma
 involvement. Morphologically discordant lymphomas (most often follicular lymphoma
 and diffuse large cell B-cell lymphoma in different biopsy specimens, e.g.
 lymphatic gland and bone marrow) and transformed lymphomas are not to be
 included.

 -  Follicular lymphomas grade III The diagnosis made by the local pathologist of the
 participating centre will be accepted for registration

 3. Patients in at least stage II with age adjusted IPI score of 2 or 3:

 Stage III /IV and elevated LDH and/or WHO performance status 2 - 3 Stage II and
 elevated LDH and WHO performance status 2 - 3.

 4. Previously untreated.

 5. Performance status < 4 (Appendix 2).

 6. Written informed consent

 Exclusion Criteria:

 1. Severe cardiac disease: cardiac function grade 3-4 (Appendix 2) or Left Ventricular
 Ejection Fraction (LVEF) < 45% (based on MUGA scintigraphy or echo Doppler
 cardiography).

 2. Impaired liver, renal or other organ function not caused by lymphoma, which will
 interfere with the treatment schedule.

 3. Pregnancy.

 4. Men and women of reproductive potential not agreeing to use an acceptable method of
 birth control during treatment and for six months after completion of treatment.

 5. Patients with other severe medical problems and with an expected short survival for
 non-lymphoma reasons.

 6. Known HIV positivity.

 7. Present or previous cancer except basal cell carcinoma and cervical carcinoma in situ.

 8. Uncontrolled infectious disease.

 9. Psychiatric or mental disorder which make the patient unable to give an informed
 consent and/or adhere to the protocol.