2018 June 28

A door opens for a possible new treatment for a drug resistant type of non-Hodgkin lymphoma in adults

Two research groups from the Josep Carrera Leukaemia Research Institute have collaborated on a complex study carried out by several large hospitals to find an effective treatment for high risk patients with diffuse large cell lymphoma (DLCL), the most common type of non-Hodgkin lymphoma in adults. 

In the study published in Haematologica samples from 52 untreated patients were analysed and the results checked against the progress of the disease in each one.  This type of prospective study, following how patients progress, is very important when looking for ways to predict how a disease will develop in an individual (prognosis) and also when looking for ways to personalize medicine by identifying early on how a patient will respond to different drugs.

Members of the Stem cells, mesenchymal cancer and development group, led by Dr Palbo Menendez and Dr Ramon Mangues and Dr Isolda Casanova, both of the Biomedical Research Institute at Sant Pau (IIB-Sant Pau) and the IJC contributed to this work.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in adults (30-40% of newly diagnosed cases).  Although new immune-chemotherapy treatments have improved survival, 60% of patients are not cured by the treatment and have a very poor prognosis indeed.

It is known that cells that have a receptor called CXCR4 are found in haematological tumours as diverse as B-cell acute lymphoblastic leukemia (B-ALL); acute myeloid lymphoma (AML); chronic lymphocytic leukemia (CLL) and multiple myeloma (MM).   The receptor helps cancer cells home in on sites in other tissues that produce a substance called CXLC12 and this in turn helps a blood vessels to form in tumours and promotes their growth as cells proliferate abnormally.  Various clinical trials are underway to use drugs that target these tumours by seeking out where CXCR4 and CXLC12 are interacting.

Previous studies have shown that CXCR4/CXCL12 found on tumour cells correlates with a bad prognosis for DLBCL patients.  In agreement with this, in this study CXCL12 in the tumour biopsies correlated with bone marrow involvement at the time of diagnosis and tumours with well-developed blood vessels.  Previous trials of standard chemotherapy combined with a drug that targeted the CXCR4/CXCL12 interaction were initially promising, but the drug AMD3100 was found to have serious side effects.   This study used a different less toxic drug, which was not only more effective on DLBCL cells but also reduced the cancer-producing effects of the oncogene MYC.  High levels of MYC in DLBCL patients is associated with shorter survival and CXCR4 is known to stabilize it in cancer cells.

In conclusion this study is important as it has identified a new potent drug that can be taken orally and has anti-tumour properties.  It also provides the first solid evidence that a dual approach might be effective in DLBCL patients.  This opens the door to new clinical trials in patients that have had no effective treatment on offer until now.

Reference

2018 Jun 28. pii: haematol.2017.180505. doi: 10.3324/haematol.2017.180505. [Epub ahead of print]

Funding

The Stem Cells, Mesenchymal Cancer and Development Group is supported by and has received funding from the European Research Council (ERC) (CoG-2014-646903; Spanish Ministry of Economy and Competiveness (SAF2016-4603 and RTC2016-4603-1), the Generalitat of Catalunya (SGR 330), the Instituto Carlos III (ISCIII/FEDER PI14-01191) and the Associación Española Contra el Cáncer (AECC-CI2015).

Pablo Menendez is an ICREA Research Professor at the IJC.