ISH/BSH 2016: Dr Craig Moskowitz (Memorial Sloan Kettering Cancer Center, NY, USA) and Professor David Linch (University College London Hospital) discuss the role of transplant in HL. Also included an associated article entitled ‘Allogeneic stem cell transplantation: still a role in CLL/lymphoma?’

Allogeneic stem cell transplantation: still a role in CLL/lymphoma?

by Christine Clark

Professor Peter Dreger, Heidelberg University Hospital, Germany.

The goal of allogeneic transplant therapy is to provide good graft versus CLL/lymphoma (GVL) activity, Professor Peter Dreger (Heidelberg University Hospital, Germany) told the audience.  In CLL this can be monitored by means of minimal residual disease (MRD) kinetics. This approach is not readily applicable to the other types of lymphoma but examination survival curves after allogeneic transplantation (alloSCT) shows that the different lymphoma subtypes exhibit a spectrum of GVL sensitivities. At one end follicular lymphoma (FL) is the most sensitive to GVL activity – less than 20% relapse after five years – and the majority (if they do not die from complications of treatment) remain in sustained remission after alloSCT. At the other end of scale is Hodgkin lymphoma (HL) with the highest frequency of relapse, and the other lymphomas fall in between.

The usual indication for an alloSCT is relapse after autologous stem cell transplant (autoSCT). In CLL only relapsed or refractory patients are now considered to be suitable transplant candidates.

Recent figures show that transplantation is decreasing for chronic lymphocytic leukaemia (CLL) mantle cell lymphoma (MCL) and FL whereas numbers are increasing for HL, T-cell lymphoma and large cell lymphoma. This is attributed to continual advances in transplant technology, particularly reduced intensity conditioning (RIC).  Transplantation is increasingly accessible to older patients – before 2000 only 20% of patients were aged over 50 years whereas now about 50% of patients are 50-70 years of age.

Haplo-transplantation, in which post-transplant cyclophosphamide is used to bring about selective, in-vivo T-cell depletion, is now growing faster than other forms of stem cell transplantation. Haplo-transplantation with post-transplant cyclophosphamide appears to be associated with a lower incidence of chronic GVH disease than allogeneic transplantation.

Some new drugs given before alloSCT might affect toxicity and/or disease control. An example is a case series of 19 HL patients who received PD-1 inhibitors four months prior to alloSCT but most remained refractory and all underwent RIC. There was little mortality and few relapses which prompted the authors to suggested a possible causal relationship between prior treatment with PD-1 inhibitors and the lower incidence of relapse. Further study will be needed to confirm this, said Professor Dreger.

Brentuximab vedotin (BV) probably does not interfere with toxicity and efficacy of later transplant, except that those in remission before transplant have a lower risk of post-transplant relapse. The same might be true for ibrutinib but data are still preliminary.

 

New drugs after transplant

In a small study 12 HL patients received nivolumab for post-transplant relapse with an intermediate outcome.  Most responded but 25% had severe graft versus host disease (GVHD); however it is too early to draw definite conclusions. When BV is used after transplant there is some extra efficacy without significant interference in toxicity of the transplant, especially induction of GVHD.

 

Do new drugs affect SCT indication?

Ibrutinib has a profound impact on relapsed and refractory CLL. One study showed that patients who received ibrutinib in addition to bendamustine and rituximab had much better disease control in the relapsed setting and overall survival was excellent. In view of this finding, patients with high-risk CLL should be treated with one of the novel agents and if they respond, and then either continue treatment or proceed to alloSCT, said Professor Dreger.

 

Patients who fail to respond to treatment (or lose response)

In a retrospective study, patients who had to discontinue ibrutinib or idelalisib due to drug toxicity or progressive disease were switched to the alternate kinase inhibitor (i.e. from ibrutinib or idelalisib or the other way round). The median remission duration (PFS) after the switch was seven months. In view of this finding the treatment algorithm is likely to be amended such that patients who lose the response to a new drug (or have none) are put on the transplant track. As they are a high-risk group, more co-morbidity and less well-matched donors may also be permitted, said Professor Dreger.

 

Transplant failures

There are now several published case series of CLL patients that show that when ibrutinib is given after transplant the overall survival (OS) and PFS is at least as good as in transplant naïve patients but it is only possible to eradicate disease in a few patients.

Relapsed MCL responds less well than CLL to ibrutinib with a median PFS of 15 months   and OS of 24 months. This is partly due to the poor outcomes of patients whose disease progresses under ibrutinib treatment or where the drug has to be discontinued due to toxicity.  “Ibrutinib is not the final solution for relapsed MCL but it might be useful in bridging to alloSCT in patients who relapse after autoSCT”, said Professor Dreger.

Drugs could also affect subsequent toxicity or relapse risk of transplant and could interfere with outcome by affecting GVL or GVHD after transplant if used in post-transplant setting. Clearly this depends on the type of graft and the disease in question.

 

Chimeric antigen receptor T-cells (CAR-T) – new cellular therapy

In some patients with CD9-positive malignancies who relapse after alloSCT there is a chance of inducing remission with CAR-T therapy. In contrast to autoSCT, B cells recover after several days and the CAR-T cells do not persist – so there could be synergy between alloSCT and CAR-T technology.  Comparing the pros and cons of CAR-T and alloSCT, Professor Dreger noted that there is robust evidence of efficacy for alloSCT and plenty of long-term data on toxicity and efficacy. The clinical product can be obtained independent of the disease and pre-treatment status of the patient, unlike CAR-T, where the presence of functional T-cells is necessary to obtain effector cells. However, there is always a 10-30% risk of non-relapse mortality (NRM) and the probability of GVHD and associated morbidity, which is not the case after CAR-T therapy.  There are no donor problems with CAR-T, because the patient is the source, but there are no long-term toxicity and efficacy data, availability is limited and the costs are high.

In summary Professor Dreger speculated on how the new technologies might affect transplant indications in the future. B-cell receptor inhibitor failure could be indication for transplantation in CLL. In HL, many patients might prefer to be treated with a checkpoint inhibitor prior to alloSCT. The same could apply to anaplastic large cell lymphoma, where brentuximab might also be used. In DLBCL, MCL and FL it is unlikely that the transplant indications will change in the near future.