Educational theme: High-risk patients with lymphoid malignancies

In patients with DLBCL who relapse after first-line therapy the chance of a central nervous system (CNS) relapse is prominent. In another subanalysis of the GOYA trial, summarized by the Lymphoma Hub here, the prognostic role of the cell of origin (COO) and of the CNS-International Prognostic Index (IPI) in predicting CNS relapse in high-risk DLBCL patients were examined. The study concluded that high CNS-IPI score and COO subtypes were independent risk factors for CNS relapse in DLBCL. Combining CNS-IPI score and COO improved identification of high-risk DLBCL patients. Patients with high-risk of CNS relapse should receive CNS prophylaxis.

Recently, evidence for another predictor of DLBCL outcomes following first-line treatment with R-CHOP was published by Chiche et al., and summarized by the Lymphoma Hub here. According to the study, patients with low levels of GAPDH respond poorly to R-CHOP and have a significantly lower overall survival.

As far as treatment is concerned, high-risk patients that fail first-line therapy with R-CHOP will undergo hematopoietic stem cell transplantation provided they meet the eligibility criteria. Many patients will still relapse following transplantation and have recently been presented with a new therapeutic strategy, chimeric antigen receptor T-cells (CAR-T). To date, two different CAR-T products have been approved by both the FDA and EMA for the treatment of high-risk patients with previously-treated DLBCL. Results so far indicate durable responses in approximately 40% of patients following CAR-T infusion. For more details on CAR-T in DLBCL please read the educational theme of our previous month here and watch our interview with Renier Brentjens on the latest advances in CAR-T therapy below.

Renier Brentjens | ICML 2019 | What are the latest advances in CAR T-cell therapy?

Follicular lymphoma (FL)

Although FL is considered as indolent NHL a significant proportion of patients present with more aggressive disease, have very poor chances of survival and are classified as high-risk if they relapse early (less than two years from treatment initiation). In the FL setting, the need for early prognostic markers that can successfully identify high-risk patients is crucial. Currently, prognostic markers are classified into two categories depending on the time of assessment; a) baseline assessment markers and b) post-induction markers. In the first category, TMTV is the main prognostic marker of high-risk FL, while the latter includes molecular response and metabolic response by PET/CT. The prognostic value of PET over CT in terms of patient responses in FL was reported in a subanalysis of the GALLIUM trial, summarized here. The study concluded that PET is more accurate than CT in evaluating the responses of FL patients treated with first-line immunochemotherapy and that it could be able to guide response-based FL therapies.

Despite the existence of these prognostic markers for high-risk FL, the key unanswered question is how to most effectively integrate these tools into treatment strategies, to guarantee good patient prognosis and early high-risk identification, as explained by Stefano Luminari in his interview with the Lymphoma Hub during ASCO 2018.

Stefano Luminari | ASCO 2018 | Overview of high-risk follicular lymphomas

An improved prognostic index for risk assessment in patients with FL was presented by Marek Trněný at the 2018 EHA meeting. Trying to improve upon the current FLIPI index the PRIMA-PI that stratifies patients into risk groups depending on their β2-microglobulin (b2M) levels, was developed by the Czech Lymphoma Study Group. According to the investigators, PRIMA-PI is a very easy and useful tool for progression-free survival (PFS) risk assessment with a similar stratification as FLIPI or FLIPI-2. The study outcomes showed that high-risk patients had significantly worse overall survival compared to low or intermediate risk. They also noted that high-risk PRIMA-PI patients have 2.6x higher risk of death, even among late progressors and this finding could influence treatment choices in those patients who relapse late. The results of this study have been summarized by the Lymphoma Hub here and in the interview below.

Marek Trněný | EHA 2018 | Was the PRIMA PI prognostic index feasible in a real-world cohort of FL patients?

Chronic lymphocytic leukemia (CLL)

CLL is considered as high-risk if one or more of the following criteria are met: a) disease refractory to purine analogs, b) relapsing disease within two years of chemoimmunotherapy, and c) existence of deletion and/or mutation of the TP53 gene.²

In an interview with Anthony Mato at the 2018 ASH meeting, he provided the Lymphoma Hub with an update on prognostic testing for risk assessment in patients with CLL. He mentioned that to date, the majority of the patients are not receiving the appropriate and recommended prognostic tests. He highlighted the importance of this testing for designing risk-guided therapies and identifying early patients with high-risk CLL, especially those developing resistance to venetoclax.

Anthony Mato | ASH 2018 | CLL treatment updates and prognostic testing

An additional phase II study published by Nitin Jain et al. evaluated the efficacy of venetoclax plus ibrutinib in previously untreated high-risk CLL patients. The results of this study were reported by the Lymphoma Hub here and showed that addition of venetoclax following ibrutinib monotherapy led to the conversion of partial responses into complete responses, and an increase in patients with undetectable bone marrow minimal residual disease.

Last but not least, CAR-T cell therapy in combination with ibrutinib is also under investigation for the treatment of relapsed/refractory CLL patients, who have previously failed ibrutinib therapy. The preliminary results of this pilot phase I-II trial are presented here. The study concluded that CD19 CAR T-cell infusion combined with ibrutinib leads to durable responses without cytokine release syndrome events higher than grade III and a 1-year overall survival of 80% in responders.

Based on these studies, venetoclax and CAR-T therapy with or without ibrutinib are emerging as a viable treatment option for high-risk patients with CLL.

The Lymphoma Hub will be covering all the latest updates on the treatment and management of high-risk patients over the next month, so make sure you follow us for the next update!