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
  

Transplantation-Eligible Patients

• Using high-dose chemotherapy in addition to autologous stem cell transplantation (ASCT) has been found to achieve the best chance of cure in cases of relapsed or refractory disease; however, advanced age and coexisting medical conditions prevent half of such patients from being candidates for transplantation
• In randomized trials, the most frequently used platinum-based salvage regimens are (rituximab with dexamethasone, high-dose cytarabine, and cisplatin [R-DHAP], rituximab with ifosfamide, carboplatin, and etoposide [R-ICE], and rituximab with gemcitabine, dexamethasone, and cisplatin [R-GDP]). These regimens have been found to be equally effective
• About half of patients have a response to initial salvage treatment and then undergo ASCT
• The overall cure rate is 25 to 35%

Transplantation-Ineligible Patient

• This includes patients with advanced age or coexisting medical conditions, those who are refractory to salvage therapy, and those with a relapse following ASCT
• Palliative therapy can be achieved by sequential single-agent chemotherapy or a multiagent regimen with an acceptable side effect profile

CAR T-Cell Therapy

• This is a gene-modified cellular treatment, that is considered a breakthrough in the treatment of refractory or relapsed DLBCL (who had at least two lines of systemic therapy)
• Initially, it included autologous T cells targeting CD19
• It is not appropriate for all patients due to its associated toxic effects
• The toxic effects include grade 3 to 4 cytokine release syndrome (in 2 to 22% of patients) and neurologic side effects (10 to 28% of patients)

Novel Therapies

• There is an increased demand for novel therapies for management of relapsed or refractory DLBCL
• Antibody–drug conjugates are used for selective delivery of cytotoxic agents to tumor cells using targeted antibodies
• The combination of polatuzumab vedotin with bendamustine–rituximab got regulatory approval based on a randomized phase 2 trial involving transplantation-ineligible patients. That combination has been found to improve the rates of metabolic response and overall survival, as compared with bendamustine–rituximab alone
• Another novel drug called selinexor, a selective inhibitor of the nuclear export protein XPO1, resulting in accumulation of tumor suppressor proteins in the nucleus, also got regulatory approval for patients with refractory or relapsed DLBCL who have received at least two lines of treatment, based on phase 2 trial that revealed a modest single-agent activity
• Also, tafasitamab, a humanized anti-CD19 monoclonal antibody, combined with lenalidomide were shown to be effective, so they received regulatory approval for transplantation-ineligible patients with DLBCL
• A macrophage immune checkpoint inhibitor called magrolimab block CD47, the “don’t eat me” molecule, has shown synergism with rituximab, augmenting macrophage cellular phagocytosis
• Bispecific antibodies are those antibodies that target the antigens on T cells and tumor cells resulting in cell-mediated cytotoxicity. they have shown efficacy in refractory and relapsed cases of DLBCL. For example, blinatumomab, that targets CD3 and CD19; however, the development of this agent is stopped due to its continuous infusion schedule and neurotoxicity
• Mosunetuzumab has been found to be effective in patients with refractory or relapsed DLBCL in an ongoing phase 1–1b study including patients with failed CAR T-cell therapy
• Several other agents are still under investigation
  
  

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References

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