Clinical trials update from the ASH conference

Highlights from the annual American Society of Hematology (ASH) conference on Hodgkin lymphoma, high-grade non-Hodgkin lymphoma and chronic lymphocytic leukaemia (CLL). 

Man looking down microscope

The annual American Society of Hematology (ASH) conference took place in December 2019 in Orlando, Florida. Earlier this year, haematologists, oncologists and clinical nurse specialists met in London to discuss the implications of the research presented at ASH for clinical practice in the UK.

Highlights on:

Hodgkin lymphoma

High-grade non-Hodgkin lymphoma

Chronic lymphocytic leukaemia (CLL)

Hodgkin lymphoma

Dr Wendy Osborne, Consultant Haematologist at the Freeman Hospital in Newcastle upon Tyne, discussed some of the most interesting studies in Hodgkin lymphoma.

Early-stage, unfavourable Hodgkin lymphoma

There are many different treatment options for people with early-stage Hodgkin lymphoma who have a higher risk of relapse (unfavourable lymphoma). Data presented at ASH examined some of the different options – although individual factors such as patient preference and whether it is necessary to avoid radiotherapy also need to be considered.

  • Results after 8 years of follow-up of the HD14 study found that in people with early-stage, unfavourable Hodgkin lymphoma, two cycles of BEACOPPesc plus two cycles of ABVD (plus radiotherapy) provided better long-term lymphoma control than four cycles of ABVD (plus radiotherapy). Overall survival and the rate of development of second cancers was similar in both treatment groups. A PET-directed approach using four cycles of ABVD and radiotherapy and escalating people who have a positive PET scan after two cycles of ABVD also achieves a similar level of disease control to the HD14 approach.
  • Another study analysed the results of two trials in people with stage 2b unfavourable Hodgkin lymphoma who had a PET scan after two cycles of ABVD or BEACOPPesc to guide how many more cycles of treatment were necessary, or whether treatment should be switched to the alternative regimen (with or without radiotherapy). The analysis found that all PET-directed treatment groups had similar outcomes after 4 years. The main factors that predicted response to treatment were the amount of active lymphoma (the ‘total metabolic tumour volume’) at diagnosis, and whether the PET scan after two cycles of treatment was positive or negative.
  • The NIVAHL trial looked at substituting bleomcyin, the ‘B’ of ABVD, with nivolumab (a type of targeted therapy called a checkpoint inhibitor) in people with early-stage unfavourable Hodgkin lymphoma. Around 8 in 10 people had a complete response to treatment. Side effects were acceptable. This combination may have a role for people who are not able to tolerate full-dose chemotherapy.

Advanced Hodgkin lymphoma

An analysis presented at ASH found that BEACOPDac – where the procarbazine component of BEACOPPesc is replaced by dacarbazine – was as effective as BEACOPPesc in people with advanced Hodgkin lymphoma. People treated with BEACOPPDac needed fewer blood transfusions than those treated with BEACOPPesc, which suggests that dacarbazine might be less toxic than procarbazine. Further follow up on fertility data are awaited.

A Danish study into long-term toxicity of treatment for Hodgkin lymphoma examined fertility rates in young people (age 18 to 40 at diagnosis) who had been successfully treated for Hodgkin lymphoma. Most patients were treated with ABVD. Interestingly, after an average follow-up of around 10 years, fertility rates were higher in people who had been successfully treated for Hodgkin lymphoma than in people of the same age and sex who had not had Hodgkin lymphoma. These results are very reassuring for people who are diagnosed at a young age.

A phase 2 trial tested a new approach to Hodgkin lymphoma therapy: three cycles of pembrolizumab (a checkpoint inhibitor) followed by four to six cycles of AVD, depending on the stage of the lymphoma. Results were encouraging in people with advanced Hodgkin lymphoma, with high response rates and favourable tolerability. This could be an interesting treatment strategy that avoids radiotherapy and bleomycin, which can cause long-term effects.

In another phase 2 trial, people over 60 with advanced Hodgkin lymphoma who were not able to have standard chemotherapy were treated with nivolumab (another checkpoint inhibitor) plus brentuximab vedotin (an antibody–drug conjugate: a chemotherapy drug joined to an antibody that targets lymphoma cells). The combination was well tolerated with an encouraging response rate. It could be a suitable option for older people who may not be able to tolerate traditional chemotherapy.

Relapsed and refractory Hodgkin lymphoma

Two trials reported encouraging results for brentuximab vedotin–based approaches to relapsed or refractory Hodgkin lymphoma.

  • In a phase 1/2 trial , people with relapsed or refractory Hodgkin lymphoma were treated with a combination of brentuximab vedotin and ICE chemotherapy. Those who had a complete response to two cycles of treatment went on to have further cycles followed by a stem cell transplant using their own cells (autologous stem cell transplant). Almost 7 in 10 people had a complete response to treatment, which is similar to other chemotherapy regimens. The combination had an acceptable side effect profile.
  • Another phase 1/2 trial found that brentuximab vedotin plus nivolumab produced durable responses in people with relapsed or refractory Hodgkin lymphoma after an average of almost 2 years of follow-up.

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High-grade non-Hodgkin lymphoma

Dr Chris Fox, Consultant Haematologist at Nottingham University Hospitals, discussed the results of trials presented at the ASH conference that have the potential to change the management of some types of high-grade lymphoma.

Early-stage diffuse large B-cell lymphoma

A US study looked at how effective it is to use an interim PET scan (after 3 cycles of R-CHOP) to guide treatment choices in people with early-stage (stage 1 or 2) diffuse large B-cell lymphoma (DLBCL).

People in this trial had three cycles of R-CHOP followed by a PET scan. Those with a negative PET scan had one more cycle of R-CHOP but no radiotherapy. Those with a positive PET scan had radiotherapy and radioimmunotherapy (an antibody that delivers a small dose of radiation directly to lymphoma cells).

In this trial, almost 9 in 10 patients had a negative PET scan after three cycles of R-CHOP and did not have any radiation therapy. Outcomes of treatment were excellent in both the PET-positive and PET-negative groups.

These results suggest that it may be safe to omit radiotherapy for most people with low-risk early-stage DLBCL after a negative PET scan.

A large population-based analysis investigated long-term outcomes of a similar PET-directed approach to early-stage DLBCL. It found that people who had a positive PET scan and received radiotherapy in addition to R-CHOP had a slightly less favourable long-term outcome than those who had a negative PET scan and did not need radiotherapy. These people might need different treatment approaches.

Most patients with low risk, early-stage DLBCL are PET negative after three cycles of treatment and will have excellent outcomes with four cycles of R-CHOP without exposure to radiotherapy.
Dr Chris Fox, Consultant Haematologist, Nottingham

Extranodal NK/T-cell lymphoma

Extranodal NK/T-cell lymphoma (ENKTL) is a rare lymphoma that can be very aggressive. Advanced stage disease is often treated with a chemotherapy regimen known as SMILE. Although this is more effective than standard CHOP treatment, it has potentially serious side effects. A study in China found that a chemotherapy regimen called DDGP (cisplatin [DDP], dexamethasone, gemcitabine and pegasparaginase) produced better outcomes than SMILE in people with ENKTL who had not been treated before. It also caused significantly fewer toxic effects. This could be a promising treatment option for people newly diagnosed with advanced stage ENKTL.

Secondary central nervous system lymphoma

Secondary central nervous system (CNS) lymphoma is lymphoma that developed somewhere else in the body and spread to involve the brain or spinal cord. It is usually a type of DLBCL. It is often very difficult to treat.

The MARIETTA trial aimed to find out whether intensive chemotherapy with three cycles of MATRIX and three cycles of R-ICE, followed by high-dose chemotherapy and a stem cell transplant using the patient’s own stem cells (autologous SCT), might have the potential to improve outcomes in secondary CNS lymphoma.

The trial met its ‘primary endpoint’ – the key result that defines whether or not the treatment is considered effective. Outcomes in people who proceeded to autologous SCT after MATRIX–R-ICE seem to be more favourable than those in people who did not. Outcomes were better in people who had CNS lymphoma at the time they were diagnosed than in people who developed CNS lymphoma when DLBCL relapsed after previous treatment. People who did not respond to the MATRIX regimen did not benefit from R-ICE treatment.

The results suggest that MATRIX–R-ICE, followed by autologous SCT, could be a beneficial regimen for some people with this very difficult-to-treat type of lymphoma.

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Chronic lymphocytic leukaemia

Dr Piers Patten, Consultant Haematologist at King’s College Hospital in London, discussed advances in the treatment of chronic lymphocytic leukaemia (CLL).

First treatment for CLL

  • The ELEVATE TN trial compared acalabrutinib, with or without obinutuzumab, to chlorambucil plus obinutuzumab in people with CLL who had not been treated before. People who had acalabrutinib-based treatment had longer periods before their lymphoma got worse than people treated with chlorambucil plus obinutuzumab. Longer-term follow-up is underway.
  • The CAPTIVATE trial looked at using a combination of ibrutinib and venetoclax in people with CLL who had not been treated before. This combination of targeted drugs is an oral, once-daily, chemotherapy-free treatment. It resulted in high rates of undetectable minimal residual disease (no leukaemic cells detectable), which suggests it is likely to produce durable treatment responses.
  • Long-term follow-up of the ECOG1912 study showed that the combination of ibrutinib and rituximab continues to produce more favourable outcomes than FCR chemotherapy in younger people with CLL that has not been treated before, particularly in people who had a mutation in the IGHV gene.
  • Updated results from the CLL14 study showed that fixed-duration treatment with venetoclax plus obinutuzumab achieved high and durable rates of undetectable minimal residual disease in people with CLL and coexisting conditions who had not been treated before. This is another chemotherapy-free option. In this study, relapse was more likely in people without a mutation in the IGHV gene.
Recent trial results suggest that testing IGHV mutation status before treatment might help guide treatment decisions.
Dr Piers Patten, Consultant Haematologist at King’s College Hospital

Relapsed or refractory CLL

  • Four-year data from the MURANO  trial found that venetoclax plus rituximab had sustained benefits over bendamustine plus rituximab in people with relapsed or refractory CLL. Responses were durable after 2 years off treatment.
  • The TRANSCEND  study is a phase 1/2 trial of lisocabtagene maraleucel, a CAR T-cell therapy, in people with CLL who had relapsed after at least two previous treatments. Early results seem promising, with serious but manageable side effects. The study is still in progress.
The latest trial data suggests that chemo-immunotherapy no longer has a routine role in the treatment of people experiencing a first or second relapse of CLL, although it may be appropriate in some, more uncommon circumstances.
Dr Piers Patten, Consultant Haematologist at King’s College Hospital

With thanks to Dr Wendy Osborne, Dr Chris Fox and Dr Piers Patten for reviewing these updates. 

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18 May 2020