Improving outcomes in rare lymphomas

“Rare lymphomas are not that rare”, said Martin Dreyling, introducing the symposium. In fact, so-called rare lymphomas account for about 50% of what is seen in clinical practice, he continued. Mantle cell lymphoma (MCL) accounts for approximately 6% of all non-Hodgkin’s lymphomas (NHLs),  marginal zone B-cell lymphomas (MZLs) 5% and Waldenström’s macroglobulinaemia (WM) 1–5%. Nevertheless, the rarity of these diseases makes phase III studies difficult and lengthy. However, there are data from many phase II trials that need interpretation. In addition, reimbursement barriers often impose restrictions on prescribing in this area.

Professor Dreyling reminded the audience that in Europe bendamustine is licensed for the treatment of indolent NHLs as monotherapy in patients who have progressed during or within six months following treatment with rituximab or a rituximab-containing regimen. However, in his practice in Germany it is regarded as a first-line treatment. Indeed, many of the treatments provided for the rarer lymphomas are off-label, he acknowledged.

WM was first described by Jan Gosta Waldenström in 1944 but another 70 years were to pass before the underlying aetiology was understood, according to Steve Treon (Director WM Program, Dana Farber Cancer Institute and Brigham and Women’s Hospital, Boston, USA)

About 3000 new cases are seen each year in USA and the median age at diagnosis is 62 years. There is a strong familial predisposition and almost 25% of patients have a first or second degree relative with the disease or a related lymphoma. About 20% of patients have an Ashkenazi Jewish background. Overall survival depends on symptomatic status at time of diagnosis.

This disease is found predominantly in the bone marrow and it is rare to see adenopathy or splenomegaly in WM patients. Often treatment is started because rising levels of IgM protein in the plasma cause hyperviscosity. High levels of IgM can also cause neuropathy, cryoglobulinaemia or cold agglutinaemia. It is important to remember that patients should only be treated when symptomatic, emphasised Dr Treon.

Consensus guidelines recommend treatment when haemoglobin falls below 10g/dl, the platelet count is less than 100,000mm3, there is symptomatic hyperviscosity (serum viscosity more than 4.0 centipoise), there is moderate-to-severe peripheral neuropathy, or because the patient is experiencing symptoms due to cryoglobulins, cold agglutinins, or other IgM- or paraprotein-related problems.

Rituximab has made a big impact on the management of WM. Polymorphisms at the Fc gamma RIIIa receptors influence the response to rituximab. The presence of one valine molecule at this site is associated with a better response. Care is needed when dosing rituximab because many patients experience a flare in IgM and this can cause a hyperviscosity crisis. Thus, at the Dana Farber Cancer Institute, if the IgM level is above 4000, rituximab is not used before plasmapheresis or not given with the chemotherapy.

Rituximab can be given alone over four or eight weeks and elicits an overall response rate of up to 45%. However, when used in combination with, for example, cyclophosphamide, nucleoside analogues, bortezomib or bendamustine, overall responses of between 70% and 90% are seen. Complete responses of 25–30% have been reported with bortezomib and bendamustine combinations. Progression-free survival (PFS) is closely correlated with complete response (CR) and very good partial response (VGPR) to initial treatment. Cyclophosphamide-based treatments are commonly used and with these ‘less is more’ – doxorubicin and vincristine can be omitted and patients still do well, noted Dr Treon. A 90% response rate and three-year remission can be achieved with treatment using a combination of rituximab, cyclophosphamide and dexamethasone. The use of nucleoside analogues should be avoided in WM patients because these patients are at high risk of transformation to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML). Moreover, they may be candidates for later stem-cell collection for autologous transplants and this could be compromised. Combination treatment with the immunomodulators thalidomide and lenalidomide has been used but thalidomide is associated with neuropathy and lenalidomide can cause an abrupt fall in haematocrit. Combination treatments using bortezomib and rituximab can achieve an overall response rate of up to 95% but 30% of patients with WM will experience grade III neuropathy, considerably worse than bortezomib treatment of multiple myeloma where grade III neuropathy is seen in only 10–12% of patients. One option here is to reduce bortezomib treatment from twice-weekly to once-weekly with a slightly higher dose. Promising results are now being reported with combinations including carfilzomib in place of bortezomib, he added.

Turning to bendamustine, Dr Treon explained that a well-known recent study that compared bendamustine–rituximab (B-R) with CHOP-R (cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab) included 44 patients with WM and provided valuable information. PFS at four years was 80% with B-R compared with 15% with CHOP-R. At the Dana Farber Cancer Institute, work has focused on patients with refractory disease and an overall response rate of 83% has been achieved with B-R. In addition, b-r has proved to be a useful treatment for bulky disease, said Dr Treon.

Maintenance treatment with rituximab was associated with a greatly improved PFS but with an increase in grade I infectious events, particularly sinus and bronchial infections.

Genome sequencing studies have identified an important mutation associated with WM. When tumour DNA was compared with patients’ DNA, one chromosome mutation was found in more than 90% of WM patients – the MYD88 L265 gene. This mutation was relatively rare in other lymphomas and absent in healthy individuals. MYD88 is an important signalling protein that is triggered by TOLL receptors and interleukin-1 receptors. Once activated, MYD88 dimerises and activates IRAK proteins that, in turn, activate NF-kappa-B signalling. Inhibition of MYD88 and IRAK 1 and 4 leads to apoptosis of WM cells. This could inform future research in this area and lead to better-targeted treatments, suggested Dr Treon.

Summarising, Dr Treon said that bendamustine, bortezomib, cyclophosphamide and thalidomide-based therapies in combination with rituximab are active, and can be tailored to treatment of the symptomatic WM patient. Maintenance therapy with rituximab is a reasonable option and associated with improved clinical outcomes. The use of nucleoside analogues should be carefully weighed. Gene sequencing studies have now revealed a somatic mutation in MYD88 in 91% of WM patients and this has allowed identification of a pathway that is amenable to drug (inhibitor) treatment and represents a novel target for future therapy.

Describing the management of MCL in the elderly, Professor Simon Rule (Consultant Haematologist and Honorary Professor, Peninsula Medical School, Plymouth, UK) said that the disease is diagnosed on the basis of cytogenetic investigations and clinical characteristics – most patients are 65 years or older. The Mantle Cell Lymphoma International Prognostic Index (MIPI) score is used to separate patients into high, intermediate and low risk categories and these correlate closely with the probability of overall survival. The MIPI is a prognostic index derived from performance status, age, lactate dehydrogenase (LDH) levels and leucocyte count, with age being the predominant factor.

In young patients the treatment of choice for MCL is a high-dose cytosine arabinoside (ara-C)-containing regimen but this is not suitable for elderly patients.

A review of more than 5000 cases showed that overall survival in MCL did not improve between 1992 and 2007. A recent UK randomised study showed that the addition of rituximab to oral fludarabine and oral cyclophosphamide led to a significant improvement in overall survival in newly diagnosed MCL patients. The patients were predominantly elderly, with high or intermediate risk MIPI scores. Age had a major impact on survival, with the under-70 years age group faring markedly better than the over-70s, commented Professor Rule.

Another study of MCL in elderly patients had compared R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone) with R-FC (rituximab with fludarabine and cyclophosphamide). After successful induction treatment, patients were randomised again to receive either rituximab or interferon as maintenance treatment. The results showed that R-CHOP was superior to R-FC. R-CHOP also has the advantage of being less toxic and that re-treatment is possible, he added. Rituximab was a more effective maintenance treatment and overall survival was better after R-CHOP induction treatment than after R-FC.

Rituximab as a single agent for MCL produces a response rate of 30–35%, in common with most drugs in this disease. An earlier study had shown that maintenance rituximab (after rituximab induction) had no effect on overall survival – a finding that confuses the picture, said Professor Rule.

Some new anti-CD-20 monoclonal antibodies appear promising because they are more active against MCL “in the test tube”. Ofatumumab is now being added to treatment combinations and GA101 (obinutuzumab) might also be a possible treatment.

In the landmark study of B-R vs CHOP-R (from the Study Group on Indolent Lymphomas (StiL), Germany), 18% of patients (45 in each arm) had MCL. Overall, PFS was better in patients over the age of 60 who received B-R and it was significantly better in patients with MCL. The side-effect profile of bendamustine is also much better – especially for females – because it does not cause hair loss, he said.

Although it is not a targeted drug, there are two publications concerning the use of chlorambucil and rituximab (chlorambucil-R) and this may be an effective treatment in the elderly.

Immunomodulators are active against MCL. Lenalidomide is superior to thalidomide and responses are improved a little by the addition of rituximab. A useful treatment regimen is rituximab and thalidomide given with PEPC (prednisolone, etoposide, procarbazine and cyclophosphamide) for elderly patients with recurrent MCL. This is a very effective combination that is very well tolerated – it can provide a durable PFS in some patients, said Professor Rule.

The two agents that are licensed for treatment of MCL are bortezomib (in the USA) and temsirolimus (in Europe). Neuropathy can be a problem with bortezomib and temsirolimus has to be given weekly by intravenous injection, commented Professor Rule. Weekly dosing of bortezomib and, possibly, switching to subcutaneous administration might reduce the frequency of neuropathy for this useful drug, he added.

One of the most exciting developments is the Bruton’s tyrosine kinase (Btk) inhibitor, PCI-32765 (ibrutinib). Btk is critical for lymphoma cell survival and proliferation. Response rates of up to 70% have been reported in early trials of ibrutinib. Professor Rule commented that it is rare to see such large and rapid responses, with patients often beginning to feel better the next day. Moreover, the common side-effects such as diarrhoea and fatigue appear to be minor and short lasting, and there are “virtually no” haematological side-effects, he said.

There is a range of treatments available and it is important to pick the regimen according to the fitness of the patients. In future, treatment with low-dose ara-C in elderly patients needs to be explored.

In summary, Professor Rule said that chemotherapy options for MCL were becoming clearer and that there was a host of new drugs on the way.

MZLs arise from the marginal tissue of B-cell follicles, which are found in the lymph nodes, spleen and mucosal lymphoid tissues, explained Antonio Salar (Associate Professor of Haematology, Hospital del Mar-IMAS, Barcelona, Spain). MZLs are currently categorised into three clinicopathological entities: nodal MZL, splenic MZL and extranodal MZL of the mucosa-associated lymphoid tissue (MALT lymphoma), he continued.

MALT lymphomas are the third most common type of NHL, comprising 7–10% of all NHL in Western populations. At least one third of MALT lymphomas arise in the stomach and it can be difficult to distinguish histologically between chronic gastritis and MALT lymphoma. It is also important to remember that MALT lymphomas can be multifocal. Patients often have a history of inflammatory disease and infections (such as Helicobacter pylori (H. pylori)) in lymphomas of the stomach) and auto-immune conditions can also play a role. Characteristic genetic changes have been described including translocations in the MALT1 gene.

The clinical features of MALT lymphomas are non-specific and relate to the primary site of disease. Only a few patients have raised LDH or immunoglobulins. The standard work-up includes a complete blood count, basic biochemical studies (including LDH and beta-2-microglobulin) and hepatitis B and C serology. Computed tomography scans of chest–abdomen–pelvis and bone marrow biopsy are performed. The role of positron emission tomography scanning is controversial at present, said Dr Salar. In addition, investigations based on the site of origin (for example, gastroscopy with biopsies, endoscopic ultrasound) are performed.

In general, the prognosis for patients with MALT lymphomas is good, with overall survival being measured in years rather than months. However, the optimal treatment still remains to be determined, said Dr Salar.

The eradication of H. pylori with antibiotics is the treatment of choice for localised H. pylori-positive gastric MALT lymphoma, leading to remission in more than three quarters of cases. The median time to remission is between two and six months, but can be longer. A number of factors have been identified that are associated with an inferior response to antibiotics. These include the absence of H. pylori and concomitant auto-immune disease. The most serious is the presence of certain genetic translocations (t(11;18) or t(1;14)) or the nuclear expression of bcl 10, which are associated with poor responses and rapid relapses.

Recent evidence suggests that eradication of Chlamydia psitttaci is associated with regression of ocular adnexa MALT lymphomas. In one phase II study, patients treated with doxycycline, 100mg twice daily for three weeks, resulted in chlamydia eradication in 48% of patients by 12 months. The overall response rate was 65% and was higher among those in which chlamydia was eradicated.

Surgery for gastric MALT lymphomas has been abandoned but it remains an option for both diagnosis and treatment of localised disease at some sites (for example, skin). Radiotherapy gives good control and a low relapse rate in gastric MALT lymphomas and is the preferred treatment in many centres especially for lymphomas of the ocular adnexa and skin. Treatment-related toxicities include cataract formation and xerophthalmia and therefore clinicians need to balance the benefits of good local clearance against the severity of side-effects.

Turning to chemotherapy, Dr Salar said that it is usually reserved for patients who have disseminated disease at the time of diagnosis or who have relapsed after antibiotics, surgery or radiotherapy. There is no consensus on initial treatment but the introduction of rituximab has changed practice.

Rituximab combined with oral or intravenous fludarabine gave very good results, with a high overall response rate. In one study, nine out 21 patients experienced grade 3–4 haematological side-effects and many of them required granulocyte colony stimulating factor rescue, acknowledged Dr Salar.

The combination of rituximab with chlorambucil is superior to chlorambucil alone, producing a CR of 78% compared with 65% and a significantly improved event-free survival (78% vs 50% at five years).

Bendamustine is an alkylating agent with part of its structure similar to purine analogues. In addition to the activation of traditional apoptosis pathways, bendamustine inhibits the mitotic checkpoint and also causes inefficient DNA repair; all these activities lead to mitotic catastrophe and tumour shrinkage. Moreover, in vitro, bendamustine has low stem cell toxicity whereas fludarabine does not, said Dr Salar. A phase II trial in Spain evaluated the effects of a combination of rituximab and bendamustine in patients with MALT lymphoma. After three cycles, the CR rate was 85% and after four cycles it was 97%, although only 15% of patients required more than four cycles. Overall, the combination had a favourable safety profile – grade 3–4 haematological toxicity was infrequent and neutropaenia occurred in 3% of the courses, said Dr Salar. In contrast, up to 40% of patients develop grade 3–4 neutropaenia with fludarabine, he noted.

Oral lenalidomide represents another treatment option. In one study, an overall response rate of 65% was achieved with an acceptable toxicity profile.

Bortezomib also has activity against MALT lymphomas but it has proved to be less effective than expected, and concerns about neuropathy and haematological toxicity limit its use.

Radio-immunotherapy using Y90 ibritumomab has been tried in MALT lymphomas of the ocular adnexa with excellent overall responses and very mild haematological toxicity.

Intralesional rituximab has also been used to treat indolent primary cutaneous B-cell lymphomas with an overall response rate of 94%. Again, adverse reactions were mild, said Dr Salar

In conclusion, Dr Salar said that eradication therapy remains the first option for localised gastric MALT lymphoma associated with H. pylori infection. Classical alkylating agents are effective for relapsed or disseminated MALT lymphomas in many sites, but resistance can be a problem with certain genetic translocations. Rituximab in combination with chlorambucil, fludarabine and bendamustine is highly effective and has a good safety profile, but in future novel agents or routes of administration might offer more effective treatment for relapsed or refractory disease.