RT that developed after venetoclax appears to bear similar molecular alterations involving TP53 disruption. Despite advances in understanding the genetic aberrations, much remains to be investigated in the immune evolution underlying RT. Clonality of the T-cell receptor repertoire decreased in patients with RT vs CLL, indicating that a diversification of the T-cell receptor repertoire occurs during CLL transformation to DLBCL, 42 possibly secondary to newly formed tumor antigens owing to the acquired mutations in the process of transformation.
In summary, it is reasonable to speculate that a unique tumor biology TP53 disruption, genomic instability, and BCR signaling alterations as well as a permissive tumor microenvironment increased PD-L1 expression and T-cell exhaustion both contribute to the development of RT in CLL patients treated with novel targeted therapies.
However, determination of a clonal relationship requires paired CLL and RT samples and complicated molecular analysis of immunoglobulin gene rearrangement, which are not readily available in routine clinical practice. Dr Rong He and colleagues at the Mayo Clinic suggested an alternative test to determine the clonal relationship. In multivariate analysis, TP53 disruption was identified as the only molecular marker that was prognostic, 27 possibly owing to its role in mediating chemoresistance.
Our group also confirmed that treatment-naive RT had a significantly better outcome in a large cohort of RT patients. Data in the novel agent era suggest that RT that develops in patients who received novel agent therapy for CLL has a poor prognosis, 10,16,22,39 likely owing to frequent adverse molecular features. A number of studies reported universally poor outcomes with RT that develops after use of ibrutinib, with a median survival of only 2 to 4 months.
RT that developed after ibrutinib or venetoclax frequently presents with bulky nodal or extranodal disease, similarly to highly aggressive B-cell lymphoma. Concurrent resistant CLL in bone marrow or blood is common. These clinical features highlight the difficulty in managing these RT cases. No randomized clinical trials have been conducted to investigate therapeutic approaches for RT. All available evidence regarding the treatment of RT comes from single-arm clinical trials with small patient numbers, or retrospective studies.
These data were thoroughly reviewed in a number of prior articles. These regimens were associated with severe hematologic toxicity, increased infection, and relatively high treatment mortality, however, resulting in a similar or even shorter survival. Given the short duration of response achieved with chemotherapy, autologous and allogeneic stem cell transplant have been explored with a goal to maintain durable remission.
A retrospective study by EBMT showed that a subset of patients benefited from transplant. Importantly, retrospective analyses of transplant are subject to selection biases because they enroll patients who achieved at least a partial remission PR with chemotherapy and are in good clinical condition, with a good performance status. Because treatment outcomes with chemotherapy have been disappointing and novel agents are emerging, new strategies to manage RT are being actively studied.
Preclinical studies suggest that exhausted T cells contribute to the immunodeficiency status in CLL. Five of the 9 RT patients had relapsed or refractory disease following prior RT-directed therapies before starting pembrolizumab. All 4 responses to pembrolizumab were observed in patients who developed RT after ibrutinib. The median OS for the RT cohort was approximately 11 months. PD-1 blockade appeared to be capable of inducing nodal response in RT patients, but did not induce bone marrow CLL response.
Therefore, a combination of PD-1 blockade and CLL targeted therapy is needed to effectively control both diseases. Although BTK inhibitor—naive patients were likely to respond to ibrutinib in these 2 combination trials, BTK inhibitor—exposed patients may have developed an immune-rich tumor microenvironment 42 that made them more susceptible to immune checkpoint inhibitors. This off-label use of nivolumab or pembrolizumab resulted in poor efficacy, with a median time to treatment failure of 1.
Given the poor outcome with chemotherapy in the majority of RT patients, novel targeted therapies are being investigated for use in this setting. A novel combination compound containing a new BTK inhibitor in combination with everolimus Afinitor, Novartis and pomalidomide Pomalyst, Celgene is currently in a phase 1 trial for CLL, RT, and other lymphomas, and early results seem promising. However, it is unclear how durable the response will be.
Given the lack of sufficient data, it is challenging to establish standard approaches to the management of DLBCL-RT in the era of novel agents. This process allows clinicians to classify the exact sub-type, grade, and stage of the specific lymphoma in question and, hence, consider the best possible treatment options. The current standard first-line treatment for this type of lymphoma is the immuno-chemotherapy using a combination of chemo drugs and a targeted anti-CD 20 monoclonal antibody.
If Hodgkin lymphoma is confirmed, the current first-line is combination chemotherapy alone. Rarely, CLL can also transform into Hodgkin lymphoma or another type of aggressive lymphoma. We do not know the exact cause of Richter transformation. One theory is that there are many cells in the bodies of patients with lymphoma that already have the aggressive behavior, but they are somewhat hidden behind the actual CLL cells.
Sometimes, these few aggressive cells become stronger and take over either the bone marrow, lymph nodes, or the whole body and become much more widespread, until they develop into a new type of lymphoma. What is the typical course of treatment for CLL patients who develop Richter transformation?
When CLL transforms to a higher-grade lymphoma, we usually put patients on aggressive therapy right away. Historically, we used to try to control the disease with either combination chemotherapy, chemoimmunotherapy such as R-CHOP the monoclonal antibody rituximab [Rituxan] added to combination chemotherapy [cyclophosphamide, doxorubicin, vincristine, prednisone] , or another aggressive regimen.
In my experience, if patients have already been treated with rituximab, a different monoclonal antibody called obinutuzumab Gazyva may yield better results when added to a combination chemotherapy regimen like EPOCH etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin or ICE ifosfamide, carboplatin, etoposide. There are some clinical trials now studying nonchemotherapeutic agents like monoclonal antibodies and combining them with targeted therapies like ibrutinib Imbruvica.
Although our combination chemotherapy approach is not ideal, it is often the best option for patients who are not eligible for a clinical trial. At first, we use several cycles of a combination chemoimmunotherapy to try to induce a remission. At that point, for patients who are eligible for allogeneic stem cell transplantation, we try a transplant to see if we can achieve a partial or even full remission. I tell newly diagnosed patients to live as healthy and as normal a lifestyle as possible, because often people do not need treatment for many years.
I also encourage patients to exercise, because that helps the immune system to fight. Lastly, I tell them not to trust all the information they read or hear. The stage shows whether the non-Hodgkin lymphoma NHL is in one area of your body localised or has spread to other areas.
There are 4 stages for NHL. Your treatment depends on the type, grade and stage of your non-Hodgkin lymphoma. Treatment might include chemotherapy, targeted drugs, steroids, radiotherapy and transplants. About Cancer generously supported by Dangoor Education since Questions about cancer? Call freephone 9 to 5 Monday to Friday or email us. Skip to main content. Read about NHL and what high grade means. Find out more about getting diagnosed. Go to the A to Z list of cancer drugs.
Read more about stem cells transplants. Read about radiotherapy.
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