Diffuse large B cell lymphoma medical therapy

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3)Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2], Sowminya Arikapudi, M.B,B.S. [3]

Overview

The optimal therapy for diffuse large B cell lymphoma depends on the stage at diagnosis,age, IPI (International Prognostic Index) and aaIPI (Age adjusted International Prognostic index). The predominant therapy for diffuse large B cell lymphoma is chemotherapy. Adjunctive radiotherapy may be required. Inclusion in a clinical trial is recommended when available.

Medical Therapy

Chemotherapy

Main treatment of Choice for DLBCL. Chemotherapy is administered intravenously and people receiving chemotherapy commonly have a (peripherally inserted central catheter) in their arm near the elbow or a surgically implanted medical port. It is most effective when it is administered multiple times over a period of months (e.g. every 3 weeks, over 6 to 8 cycles). Different regimens of Chemotherapy with different durations/Cycles are used depending on the stage of disease, age of patient and prognsotic index. In general

• Patients with limited stage disease receive 3 cycles of therapy
• Patients with extensive disease 6 or 8 cycles of chemotherapy. In the United States, 6 cycles is the preferred approach rather than 8 cycles.

Radiation therapy

Radiation is often added in the treatment. It is used commonly after completing 3 cycles of treatment in limited stage disease. In extensive disease, after 6-8 cycles of chemotherapy, radiation can be used at the end of the treatment to areas of bulky involvement. Radiation therapy alone is not an effective treatment for this disease

Stem Cell Transplantation

High dose Chemotherapy coupled with stem cell transplantation is sometimes used to treat patients whose disease is refractory or relapsed following initial chemotherapy. Most common is Autologous stem cell transplant in which patients receive their own stem cells. Other option is Allogenic stem cell transplant in which patient will receive stem cells from a donor

Regimens of Chemotherapy

1) R-CHOP

• Standard treatment is CHOP-R, also referred to as R-CHOP, an improved form of CHOP with the addition of rituximab (Rituxan), which has increased the rates of complete responses for Diffuse large B cell lymphoma patients, particularly elderly patients.

R-CHOP is a combination of one monoclonal antibody, 3 chemotherapy drugs and one steroid:

• Rituximab (Rituxan)
• Cyclophosphamide (Cytoxan)
• Doxorubicin (Hydroxydaunorubicin)
• Vincristine (Oncovin)
• Prednisone

2) R-ACVBP

Alternate Intensive immmunochemotherapy that is preferred in patients with an age-adjusted IPI score of 1. However, its clinically significant toxic adverse effects have limited its use. It is a combination of:

• Rituximab
• Doxorubicin
• Cyclophosphamide
• Vindesine
• Bleomycin
• Prednisone

3) R-CHOEP

• Rituximab
• Cyclophosphamide
• Doxorubicin
• Vincristine
• etoposide
• Prednisolone

Limited-Stage Disease (stage I or II disease, non-bulky and localized) with Age Younger Than 60 Years and Low IPI ( 0 )

• This represents about 30% of patients
• Those patients often have low-risk clinical features and a favorable outcome
• Four Cycles of R-CHOP are enough
• Radiotherapy Consolidation treatment has no proven benefit in patients with non-bulky disease. It may cause late relapses and second cancers
  

Patients Who Are Not Candidate For Standard Therapy

• This represents about 20 to 25% of patients who are not candidates for the standard treatment such as R-CHOP
• The etiology is poor fitness due to advanced age, heart disease, or coexisting medical conditions
• A detailed geriatric assessment or simple functional testing can be helpful to recognize patients for whom a modified approach is required
• Patients with low functional status may benefit from dose-reduced regimens of R-CHOP, such as R-mini-CHOP
• To reduce the adverse effects, a short prephase of glucocorticoids, with or without vincristine can be useful for that purpose
• If there is a contraindication to anthracycline, replacement with gemcitabine or etoposide is an option
  

Central Nervous System Prophylaxis

• Central nervous system (CNS) recurrence occurs in 3 to 5% of patients, with median survival of less than 6 months
• Risk factors:
• CNS-IPI risk model including the five IPI risk factors in addition to renal or adrenal involvement, stratifies patients into risk categories, with 12% of patients having a high risk of CNS recurrence
• Double expression of MYC and BCL2
• ABC subtype
• Testicular involvement at the time of presentation
• The role of CNS prophylaxis is still controversial
• The use of prophylactic intrathecal chemotherapy is no longer recommended for DLBCL
  

Management of Refractory or Relapsed Cases

• Primary refractory disease (i.e., an incomplete response or a relapse within 6 months after therapy) occurs in about 10-15% of patients treated with R-CHOP
• Approximately 20-25% will develop a relapse after the initial response, often within the first 2 years
• Failure of frontline treatment indicates poor outcome with a median overall survival of about 6 months
• Patients with late relapses (more than 2 years after treatment) have better outcomes
  

non Bulky with aaPI Low-Intermediate risk ( 1 ) OR aaPI Low ( 0 ) with Bulky Disease

• Six Cycles of R-CHOP given every 21 days plus Radiotherapy is recommended along with chemotherapy in this group
• Alteranative treatment can include intensive immunochemotherapy with R-ACVBP( Dose intensive Rituximab, Doxorubicin, Cyclophosphamide, Vindesine, Bleomycin and Prednisone) with subsequent consolidation therapy and can improve survival. Radiotherapy is not recommended in this regimen.

Intermediate High risk or High Risk ( > or equal to 2 )

• No current standard therapy
• Inclusion in Clinical Trial is recommended
• Eight cycles of R-CHOP given every 21 days is most frequently used therapy
• Intensive treatment with R-ACVBP or R-CHOEP is also used sometimes

Age 60-80 years

• Detailed Geriatric assessment should be done to assess co-morbidities and functional decline to decide upon the treatment of choice
• Current Standard treatment is R-CHOP and include 8 Doses of Rituximab given every 21 days with 6-8 cycles of Combination Chemotherapy with CHOP
• Radiotherapy can improve outcome in patients in this age group with bulky disease

A new development is obtaining a PET scan after completing two cycles of chemotherapy, to help make further decisions after chemotherapy.

Age more than 80 years

• The elderly are usually unable to tolerate therapy well. Multiple lower intensity regimens have been attempted in this age group
• Attenuated Chemotherapy also known as R mini-CHOP is used and is associate with improved outcome in these patients
• In Patients with Cardiac Dysfunction, Doxorubicin can be replaced with other chemotherapeutic agents like Etoposide, Gemcitabine or Liposomal doxorubicin

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References

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