Novel agents for primary central nervous system lymphoma: evidence and perspectives

Illerhaus, Gerald; Schorb, Elisabeth; Kasenda, Benjamin

doi:10.1182/blood-2018-01-791558

Cited by 29 publications

(21 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…At 1 year, two patients remained in CR. 46 Similarly, in the RELY-30 trial, CD30 CAR T-cells were infused in patients after receiving the lymphodepleting combination of cyclophosphamide and fludarabine. Of eight patients, six (75%) had a CR lasting up to 6 months, while the other two patients progressed.…”

Section: Beyond Checkpoint: Other Novel Targetsmentioning

confidence: 99%

Immune targeting of the microenvironment in classical Hodgkin’s lymphoma: insights for the hematologist

Carreau

Diefenbach

2019

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

While up to 80% of patients with Hodgkin’s lymphoma (HL) are cured with first-line therapy, relapsed/refractory (R/R) disease remains a clinical challenge and is fatal for many young patients. HL is unique in that the tumor cells (Hodgkin Reed–Sternberg; HRS cells) are a small fraction (<1%) of the tumor bulk, with the remaining tumor composed of the cells of the tumor microenvironment (TME). The support and integrity of the TME is necessary for HRS cell growth and survival. Targeting the programmed death 1 pathway has shown exciting activity in relapsed HL and led to United States Food and Drug Administration approval of the checkpoint inhibitors, nivolumab and pembrolizumab, for R/R HL. Novel combinations with checkpoint blockade therapy (CBT), targeted approaches such as combinations of CBT with brentuximab vedotin or chemotherapy, chimeric antigen receptor T-cells, and the use of CBT to potentially sensitize to subsequent therapy are being investigated as treatment approaches. As understanding of the HL TME grows, hopefully this will increase the number of rational therapeutic targets.

show abstract

Section: Beyond Checkpoint: Other Novel Targetsmentioning

confidence: 99%

Immune targeting of the microenvironment in classical Hodgkin’s lymphoma: insights for the hematologist

Carreau

Diefenbach

2019

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

show abstract

“…Novel agents for PCNSL include BTK inhibitors, immunomodulatory agents, checkpoint inhibitors, m-TOR inhibitors, and PI3K inhibitors [20]. These novel agents offer the potential to improve outcomes in PCNSL, particularly in transplantation-ineligible patients [21]. Further data are needed to assess how to incorporate these agents into upfront treatment, particularly for older or unfit patients.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of Consecutively Diagnosed Primary Central Nervous System Lymphoma Patients Using the Alberta Lymphoma Clinical Practice Guideline Incorporating Thiotepa-Busulfan Conditioning for Transplantation-Eligible Patients

Sanders

Larouche

Shafey

et al. 2019

Biology of Blood and Marrow Transplantation

View full text Add to dashboard Cite

While no widely accepted standard treatment regimen exists for primary central nervous system lymphoma (PCNSL), growing evidence supports an approach that incorporates autologous stem cell transplantation (ASCT) as consolidative therapy when feasible. In November 2011, the Alberta Hematology Tumor Team established a new clinical practice guideline (CPG) for PCNSL involving high-dose methotrexate (HDMTX)/cytarabine-based induction followed by ASCT for eligible patients using a thiotepa and busulfan (TBu) conditioning regimen that omitted cyclophosphamide from the regimen that was used before 2011. This retrospective study analyzed all 64 patients with PCNSL diagnosed consecutively in 3 Canadian centers between November 2011 and December 2017 to evaluate adherence to the 2011 CPG and associated outcomes. Of the 64 patients with PCNSL, 38 were initiated on the transplantation-eligible protocol, of whom 30 underwent successful ASCT, and 26 were deemed transplantationineligible, of whom only 7 completed the transplantation-ineligible HDMTX-based protocol. For the transplantation-eligible and-ineligible cohorts, the projected 3-year overall survival (OS) rates were 83.8% and 14.3% and progression-free survival (PFS) rates were 78.1% and 0%, respectively. For the 30 patients who underwent TBu/ ASCT, the 3-year OS and PFS rates were 92.7% and 88.9%, respectively, with no treatment-related mortality or significant neurotoxicity. These real-world results highlight the efficacy and tolerability of TBu/ASCT consolidation for PCNSL in patients young and fit enough for an intensive treatment program, along with the significant need for improved therapies for older or less fit patients with PCNSL.

show abstract

“…PQR620 retains the ability of bimiralisib [44] to pass the blood-brain barrier [13]. This is relevant as PQR620 was active in ABC DLBCL cell lines, and the most common type, PCNSL, which is an aggressive type of extranodal lymphoma, for which PI3K/mTOR inhibitors are an area of clinical research [48]. Our data also show that PQ620 maintained the anti-tumor activity of bimiralisib reported in a canine DLBCL model [49], indicating that dogs with spontaneous lymphomas might represent an effective pre-clinical animal model to test this compound as well.…”

Section: Discussionmentioning

confidence: 99%

The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax

Tarantelli

Gaudio

Hillmann

et al. 2019

Cancers

View full text Add to dashboard Cite

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling cascade is an important therapeutic target for lymphomas. Rapamycin-derivates as allosteric mTOR complex 1 (TORC1) inhibitors have shown moderate preclinical and clinical anti-lymphoma activity. Here, we assessed the anti-tumor activity of PQR620, a novel brain penetrant dual TORC1/2 inhibitor, in 56 lymphoma cell lines. We observed anti-tumor activity across 56 lymphoma models with a median IC50 value of 250 nM after 72 h of exposure. PQR620 was largely cytostatic, but the combination with the BCL2 inhibitor venetoclax led to cytotoxicity. Both the single agent and the combination data were validated in xenograft models. The data support further evaluation of PQR620 as a single agent or in combination with venetoclax.

show abstract

Novel agents for primary central nervous system lymphoma: evidence and perspectives

Cited by 29 publications

References 69 publications

Immune targeting of the microenvironment in classical Hodgkin’s lymphoma: insights for the hematologist

Immune targeting of the microenvironment in classical Hodgkin’s lymphoma: insights for the hematologist

Outcomes of Consecutively Diagnosed Primary Central Nervous System Lymphoma Patients Using the Alberta Lymphoma Clinical Practice Guideline Incorporating Thiotepa-Busulfan Conditioning for Transplantation-Eligible Patients

The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax

Contact Info

Product

Resources

About