Diffuse Large B-Cell Lymphoma Refractory

When diffuse large B-cell lymphoma stops responding to treatment or comes back after a period of improvement, patients face a challenging situation that requires specialized care and newer treatment approaches.

Table of contents

• What Is Relapsed and Refractory DLBCL
• Outcomes and Prognosis
• Treatment Options
• Stem Cell Transplantation
• CAR T-Cell Therapy
• Combination Chemotherapy Regimens

What Is Relapsed and Refractory DLBCL

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of cancer affecting a specific kind of white blood cell. While many patients can be cured with initial treatment, approximately 30 to 40 percent of people will experience problems after their first round of therapy^[4][6][7].

The term “relapsed” refers to disease that reappears or grows again after a period of remission, which means a time when the cancer could not be detected. The term “refractory” is used to describe when the lymphoma does not respond to treatment, meaning that the cancer cells continue to grow, or when the response to treatment does not last very long^[1].

Around 15 to 20 percent of patients have refractory disease, while 20 to 30 percent experience relapse after the first line of treatment^[6]. For the 30 to 40 percent of patients who relapse following initial treatment, the situation remains challenging, and outcomes are often poor given the aggressive nature of this disease^[4].

Outcomes and Prognosis

Before the development of newer therapies, patients with relapsed or refractory DLBCL had very poor survival rates. A large international study called SCHOLAR-1 examined 636 patients with refractory DLBCL and found that only 26 percent had an objective response to their next line of therapy, with just 7 percent achieving complete remission. The median overall survival was only 6.3 months, and the two-year overall survival rate was only 20 percent^[2][7][8].

Historically, over 80 percent of patients failed to respond sufficiently to second-line chemotherapy or were ineligible to receive autologous stem cell transplant (a procedure where patients receive their own stem cells), leaving only 20 percent of patients cured in the relapsed setting^[4][7].

Treatment remains challenging for these patients, and outcomes are often poor given the aggressive nature of this disease and the need to choose treatment in the context of the patient’s other medical conditions^[4][7].

Treatment Options

In recent years, several novel therapies have been approved that provide more effective options than conventional chemotherapy and that have manageable toxicity profiles^[6]. The advent of novel therapeutic options has added greater complexity in treatment selection and optimal sequencing^[4][7].

Key features impacting treatment selection include the timing of relapse, eligibility for curative options in the second-line setting, as well as considerations of mechanism of action and side effect profile^[4][7].

Stem Cell Transplantation

High-dose chemotherapy followed by stem cell transplantation can be used to treat patients with DLBCL whose disease is refractory or relapsed following initial chemotherapy^[1]. This approach has been the standard second-line treatment for relapsed and refractory DLBCL, but only about half of patients will be eligible for transplantation^[11].

The majority of patients undergoing stem cell transplantation will have an autologous transplant, where the patient receives his or her own stem cells that were collected prior to the procedure. Occasionally, a patient will undergo an allogeneic transplant, where the patient receives stem cells from a donor^[1].

For patients who achieve a complete response to chemotherapy, proceeding with high-dose chemotherapy followed by autologous stem cell transplant remains an option^[13].

CAR T-Cell Therapy

For some relapsed or refractory patients, a form of immunotherapy called chimeric antigen receptor (CAR) T-cell therapy may be a possible treatment option^[1]. This is a specialized treatment where a patient’s own immune cells are modified in a laboratory to better fight cancer.

In 2017, CAR T-cell therapy with axicabtagene ciloleucel for DLBCL patients who were either refractory to second-line chemotherapy or relapsed after autologous stem cell transplant demonstrated an overall response rate of 82 percent and complete response rate of 58 percent, with a five-year overall survival of 42.6 percent. This confirmed the curative potential of this cellular therapy^[4][7].

In 2021, CAR T-cell therapy with either axicabtagene ciloleucel or lisocabtagene maraleucel were approved for patients with primary refractory disease or disease relapsing within 12 months as an alternative and preferred second-line treatment option instead of autologous stem cell transplant^[4][7].

The approved CAR T-cell therapies include^[1]:

• axicabtagene ciloleucel (Yescarta)
• Lisocabtagene Maraleucel (liso-cel, Breyanzi)
• tisagenlecleucel (Kymriah)

CAR T-cell therapy has become a new standard treatment for patients with refractory or early relapsed DLBCL^[6].

Combination Chemotherapy Regimens

For relapsed or refractory patients, several combination chemotherapy regimens are available. These second-line regimens include^[1]:

• ifosfamide, carboplatin, and etoposide (ICE)
• dexamethasone, cisplatin, and cytarabine (DHAP)
• gemcitabine-based therapy
• bendamustine (Treanda) plus rituximab (Rituxan)
• lenalidomide (Revlimid) plus rituximab (Rituxan)
• polatuzumab vedotin-piiq (Polivy)
• selinexor (Xpovio)
• tafasitamab-cxix (Monjuvi)
• epcoritamab-bysp (Epkinly)
• glofitamab-gxbm (Columvi)

For those relapsed or refractory patients who have a subset of DLBCL called primary mediastinal large B-cell lymphoma (PMBCL), second-line regimens include pembrolizumab (Keytruda)^[1].

The combinations of polatuzumab vedotin with bendamustine and rituximab, and tafasitamab with lenalidomide are among the approved options for patients who are not candidates for transplant^[6].