Your staff oncologist contacts the pharmacy to speak with a board certified oncology pharmacist requesting the dose of rituximab [Rituxan®] when used in combination with CHOP for treatment of lymphoma. She presents her patient as follows:

43 year old active duty officer (male) who underwent a recent excisional biopsy from the right axilla for a suspicious lymph node. The patient describes an unexplained weight loss and night sweats over the previous 10 days. Quick pathology results suggest a tissue diagnosis of Diffuse Large Cell Lymphoma (DLCL). The oncologist has decided to use CHOP plus rituximab in this patient. The patient specific data appears below.

Locations of lymphadenopathy: both axilla, neck, submandibular, groin

Pertinent Labs: WBC 12,000, LDH 760, EBV panel (pending), CD20 typing (pending), Lytes (WNL), ESR 65, Albumin 3

Vital signs: Temp 101, HR 96, BP 115/60,

Appearance: healthy 43 yo male in good physical condition, weight 190 pounds, 5' 10" tall

What dose do you recommend? Is rituximab even indicated or appropriate in this patient?

** THANKS to Dr Phillip Hall, BCOP, FCCP, Board certified oncology pharmacist, Medical University of South Carolina, for his help with this Pearl as well as another "anonymous clinical contributor". **

Answer: Yes, rituximab IS appropriate in this patient. Based on a recent trial published in the New England Journal of Medicine (reference below), the rate of complete response (defined as the disappearance of all lesions and of radiological or biologic abnormalities observed at diagnosis and the absence of new lesions) was 76% with CHOP plus rituximab and 63% with CHOP alone (p=0.005) without a significant increase in toxicity. The doses used were:

Cyclophosphamide                750 mg/m2 (day 1)

Doxorubicin                         50 mg (day 1)

Vincristine                          1.4 mg/m2 to a max of 2mg/day (day 1)

Prednisone                         40mg/m2 po QD x five days

Rituximab                           375 mg/m2 (day 1)

Patients in both groups received 8 courses of chemo.

CHOP continues to be a very good regimen to treat lymphoma. While this 4-drug regimen has been around a long time, there doesn't appear to be a better core combination to use for this patient. CHOP is composed of Cytoxan (750mg/M2) Adriamycin (50mg/M2), Oncovin (1.4mg/M2, max 2mg), and Prednisone po (100mg/d) typically repeated every 21 days for 4-6 cycles. A recent trial published in the New England Journal of Medicine and presented at the American Society of Hematology (ASH) in 2000 shows CHOP plus rituximab is superior to CHOP alone.

Risk assessment and staging are very important before a prognosis or recommendation for more aggressive therapy can be given. CHOP alone results in a 5 year 73% survival in low risk patients, but a 5-year 26% survival in the high risk group.

Based on this patient's characteristics we can use the International Non-Hodgkins Lymphoma Prognostic Factors Project as a predictive model for DLCL.

The following five characteristics were deemed to be independently statistically significant for more advanced disease.

Negative prognostic factors

* Age greater than 60

* Tumor stage III or IV

* Number of extranodal sites involved > 1

* Patient Performance Status of 2, 3, or 4

* Lactate Dehydrogenase (LDH) greater than upper limit of normal

(These factors predict outcome if a patient has TWO negative prognostic factors, his chance of a CR (complete remission) of 55-67% and a 5 year overall survival of 43-51%.)

Our patient would have 2 or 3 of the characteristics based on the final workup for dissemination of the disease and would be classified as intermediate.

The range is low risk (0-1), low intermediate (2), high intermediate (3), and high risk (4 or 5)

Since this patient has multiple lymph node involvement above and below the diaphragm, he would be stage III which may include an extranodal organ or site (IIIE), spleen (IIIS) or both (IIISE). If the patient has diffuse or distant extranodal organ involvement in one or more locations, the stage will be IV.

By the time pelvic, chest, and neck CTs are performed and bone marrow biopsy is completed, this patient could be intermediate or high risk and will be stage III or IV. Either way, this patient has advanced disease and with a very aggressive, fast growing cancer. The clinical pharmacist recalls a study comparing CHOP to CHOP plus Rituximab which resulted in a statistically better survival without a higher incidence of adverse events.

Rituximab (Rituxan) is a murine derived chimeric monoclonal antibody which targets the CD20 antigen (+) cells that are one of three common antigens found on the lymphoma cell surface. The CD20 results are pending in this patient. If they are positive, adding Rituximab would be a wise addition. Other options currently being studied would be dose intensified CHOP regimens with growth factor support or a high dose chemotherapy regimen with bone marrow or stem cell transplantation.

References:

1. The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A Predictive Model for Aggressive Non-Hodgkin's Lymphoma. N Engl J Med 1993; 329: 987

2. Skarin AT, Dorfman DM: Non Hodgkins Lymphomas: Current Classification and Management. CA Cancer J Clin 1997; 47: 351-372

3. Vose JM, Link BK, Grossbard ML: Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated intermediate- or high-grade Non-Hodgkin's Lymphoma (NHL). Proc Am Soc Hematol. 1999; 94 (suppl 1): 89a.

4. Coiffer B et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B cell lymphoma, N Engl J Med 2002;346:235-42.