FOR UK HEALTHCARE PROFESSIONALS ONLY
 

This feature has been funded by Janssen UK and written on the company’s behalf by M&F Health, based on interviews with Professor Christopher Fegan and Advanced Nurse Practitioner Karen Stanley. The views expressed here are their personal opinions.

A decade ago, non-specific chemotherapy dominated the management of chronic lymphocytic leukaemia (CLL). The availability of a new treatment for CLL back in 2010¹ ushered in a new era of treatments targeted at the specific survival pathways that subsequently drive malignant B-lymphocyte proliferation and survival. The subsequent introduction of oral targeted therapies marked the beginning of a revolution that has fundamentally changed CLL management.² The arrival of anti-CD20 monoclonal antibodies heralded a search for other differentially expressed survival pathways with the likewise surface marker, the B-Cell Receptor, coming to the fore.

“Oral, targeted therapies have markedly increased survival and quality of life for CLL patients,” says Professor Christopher Fegan, Honorary Consultant Haematologist, Cardiff University. Despite many CLL treatments being in the pharmacological vanguard, Professor Fegan and Karen Stanley, Advanced Nurse Practitioner at Guy’s and St Thomas’ NHS Foundation Trust, London both agree that the multidisciplinary team (MDT) remains the bedrock of care.

How important is precision medicine in MDT team discussions?
“In the UK CLL management is increasingly protocol driven based on NICE recommendations. Nevertheless, the MDT remains integral to care and discussion of patients at MDT meetings is part of best practice,” says Ms Stanley. “The MDT allows us to discuss ‘difficult’ cases as well as ratifying treatment of more typical CLL. The MDT discussions may include results of blood markers, symptoms, imaging and social circumstances. The size of the caseload still allows the MDT to discuss all CLL cases. I’m confident that the same applies across England. Even in smaller centres, the Cancer Nurse Specialist can meet the consultant and other colleagues to decide on management of each CLL patient. The days of a consultant alone deciding on treatment are gone.”

Professor Fegan says that discussions during MDT meetings tend to focus on clinical factors, such as age, co-morbidities, prior treatment and response, history (e.g. toxicity and any serious bleeds), cytogenetic and molecular abnormalities and lymph node size. New agents including some treatments targeting specific enzymes (Bruton’s tyrosine kinase and phosphatidylinositol-3-kinase delta respectively³) in the B-cell antigen receptor (BCR) pathway that drive proliferation and survival of malignant B-lymphocytes are often discussed, as well as anti-apoptotic protein B-cell lymphoma 2 inhibitors (BCL-2 inhibitors). With such an increase in therapeutic options, the MDT has a very important role in identifying the right treatment for the right patient at the right time.

“Typically, we decide between different treatments on clinical grounds but given the various choices available the patient’s preference also needs to be considered,” Professor Fegan remarks. “For example, some patients prefer to have minimal time off work so outpatient delivered only therapies may suit them better. Also, we know some treatments may not be suitable in patients with significant cardiovascular co-mobidities or may cause tumour lysis syndrome if there is a high white blood cell count and/or lymph node >5cm in size,^4,5,6 necessitating closer monitoring including more regular visits to hospital and blood tests or even occasionally overnight stay.”

Ms Stanley stresses the importance of engaging with the wider MDT to optimise CLL care. “Patients might ask nurses that administer their treatment infusions about their treatment, for instance,” she remarks. “We send detailed letters to our primary care colleagues and welcome phone calls to discuss treatment further if, for example, a GP or pharmacist are concerned about drug-drug interactions.”

What are some of the most contentious issues during MDT meetings?
“There is very little data about drug sequencing in CLL, so it can lead to considerable discussion during MDTs,” Professor Fegan says. “Therefore, the chosen sequence is often based on personal experience and familiarity rather than robust evidence. In the absence of meaningful studies, a consensus document from haematology professional bodies to guide management while the evidence base matures would be valuable.”

The growing number of therapeutic options for CLL currently in development will further complicate sequencing. The Notch signalling pathway, for instance, drives cell proliferation, differentiation and survival.^7,8,9 “Notch inhibitors could have a role in a subgroup of CLL patients,¹⁰” Professor Fegan speculates. “Bispecific antibodies, which binds a patient’s T cells to their CLL cells, seem promising.^11,12 There’s also considerable excitement about chimeric antigen receptor [CAR] T-cell therapy in CLL although to date the results do not appear as good as that seen in Diffuse Large B-cell Lymphoma or Acute Lymphoblastic Leukaemia.¹³ This is perhaps unsurprising as T-Cell function is impaired in CLL.¹⁴ So, I feel more data will be needed before CAR-T becomes an established treatment in CLL.”

How important are the patient’s views and expectations in the MDT discussions?
“The MDT certainly needs to consider patient’s views and expectations,” Professor Fegan says. “Patients are much better informed than they were a few years ago. This makes life a lot easier when the doctor and the patient agree. But the discussion can be more difficult and protracted if their information comes from an unreliable source. The MDT needs to take the time to explain why the suggested treatment is most suitable for that particular patient at that time. Whatever the treatment choice, it’s important to ensure that the patient is on board, which encourages adherence with all treatments but especially oral treatments. The consultation with the Clinical Nurse Specialist offers a safe space for patients to discuss their concerns, which we can feed back to the consultant and the MDT,” Ms Stanley adds.

Professor Fegan emphasises the importance of signposting to blood cancer patient groups. “Patient groups for people with CLL in the UK are excellent,” he remarks. “They can be an invaluable source of information and support for patients and their families.” “Professional training and education have become increasingly difficult in recent years,” Ms Stanley says. “The meetings, online courses and other training offered by pharmaceutical companies and organisations, such as Bloodwise and Leukaemia Care, are essential as training budgets and study days have been reduced.”

Is there a need to improve education about the genetic basis of CLL?
“With the availability of genetic testing and the knowledge of the number of genetic factors that potentially influences CLL treatment increases, the MDT will need additional education,” Professor Fegan says. “We have all seen the positive impact that the targeted agents can have in poor prognosis 17P deleted patients.^15,16

Guidelines that include genetic and molecular advances help the MDT keep pace with the rapid advances in genetics and molecular medicine relevant to CLL. “Haematology generally and CLL in particular are moving so rapidly. We’ve seen profound changes in management and our understanding of CLL since 2014. So, any education could become outdated very quickly especially with the wider availability of new tests such as next generation sequencing,” Professor Fegan warns.

How would you characterise the change in CLL care over the last few years?
“Chemoimmunotherapy remains the first-line treatment for all treatment naive non 17p deleted/mutated CLL patients in the UK. Nevertheless, the improvement produced by oral targeted treatments has been remarkable. Targeted treatments mean that CLL patients get their lives back,” says Professor Fegan. “Patients that would have a life expectancy of a few months only a few years ago, are now alive and in many instances well five years later.^17,18,19,20 Not only that, oral targeted treatments are generally well tolerated, so patients have a good quality of life.²⁰ They’re not just alive, they’re living better.”

“When I think back 10 or 15 years, it’s remarkable how far we’ve come in CLL treatment. Precision medicine helps preserve patients’ quality of life and offers the best chance of long-term survival,” Ms Stanley add.

“We can already see CLL moving towards being a chronic disease that needs monitoring, similar to diabetes; a disease that you die with, rather than from.” Professor Fegan says. “We’re not quite there yet. We need more therapeutic options and a better understanding of sequencing and drug resistance, for example. But targeted treatments make this a realistic prospect.”

“It’s a very exciting time to work in CLL. The number of options allow healthcare professionals to offer precision treatment that maintains CLL in remission, with manageable side-effects,” Ms Stanley concludes. “We can now treat patients that we would never have thought possible a few years ago. I look forward to discussing the next generation of drugs with the MDT. But precision medicine has already transformed the outlook for people with CLL.”

Date of preparation: February 2020
Job code: CP-134715

References

¹ Salles G, Barrett M, Foà R et al Rituximab in B-Cell hematologic malignancies: A review of 20 years of clinical experience Advances in Therapy 2017;34:2232-2273
² Koffman B and Schorr A The 21st century revolution in CLL: Why this matters to patients Best Practice & Research Clinical Haematology 2016;29:122-132
³ Hallek M, Shanafelt TD, and Eichhorst B Chronic lymphocytic leukaemia The Lancet 2018;391:1524-1537
⁴ EMC. MabThera 100 mg Concentrate for Solution for Infusion. Available at: https://www.medicines.org.uk/emc/product/3801/smpc. Last accessed February 2020.
⁵ EMC. Imbruvica 140 mg Hard Capsules. Available at: https://www.medicines.org.uk/emc/product/3414/smpc. Last accessed February 2020.
⁶ EMC. Venclyxto 10 mg film-coated tablets. Available at: https://www.medicines.org.uk/emc/product/2267/smpc. Last accessed February 2020.
⁷ Rosati E, Sabatini R, Rampino G, Tabilio A, Di Ianni M, Fettucciari K, Bartoli A, Coaccioli S, Screpanti I, Marconi P. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood. 2009 Jan 22;113(4):856-65.
⁸ Xu ZS, Zhang JS, Zhang JY, Wu SQ, Xiong DL, Chen HJ, Chen ZZ, Zhan R.Constitutive activation of NF-κB signaling by NOTCH1 mutations in chronic lymphocytic leukemia. Oncol Rep. 2015 Apr;33(4):1609-14.
⁹ Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia. Mangolini M, Götte F, Moore A, Ammon T, Oelsner M, Lutzny-Geier G, Klein-Hitpass L, Williamson JC, Lehner PJ, Dürig J, Möllmann M, Rásó-Barnett L, Hughes K, Santoro A, Méndez-Ferrer S, Oostendorp RAJ, Zimber-Strobl U, Peschel C, Hodson DJ, Schmidt-Supprian M, Ringshausen I.  Nat Commun. 2018 Sep 21;9(1):3839. doi: 10.1038/s41467-018-06069-5.
¹⁰ López-Guerra M, Xargay-Torrent S, Rosich L, Montraveta A, Roldán J, Matas-Céspedes A, Villamor N, Aymerich M, López-Otín C, Pérez-Galán P, Roué G, Campo E, Colomer D. The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells. Leukemia. 2015 Jan;29(1):96-106.
¹¹ Wong R, Pepper C, Brennan P, Nagorsen D, Man S, Fegan C Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells. Haematologica. 2013 Dec;98(12):1930-8. doi: 10.3324/haematol.2012.082248. Epub 2013 Jun 28.
¹² Robinson HR, Qi J, Cook EM, Nichols C, Dadashian EL, Underbayev C, Herman SEM, Saba NS, Keyvanfar K, Sun C, Ahn IE, Baskar S, Rader C, Wiestner A. A CD19/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib eraBlood. 2018 Aug 2;132(5):521-532.
¹³ Lemal R, Tournilhac O. State-of-the-art for CAR T-cell therapy for chronic lymphocytic leukemia in 2019. J Immunother Cancer. 2019 Aug 1;7(1):202.
¹⁴ Man S, Henley P. Chronic lymphocytic leukaemia: the role of T cells in a B cell disease. Br J Haematol. 2019 Jul;186(2):220-233.
¹⁵ Jones J, Mato A, Coutre S, Byrd JC, Furman RR, Hillmen P, Osterborg A, Tam C, Stilgenbauer S, Wierda WG, Heerema NA, Eckert K, Clow F, Zhou C, Chu AD, James DF, O'Brien SM. Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials. Br J Haematol. 2018 Aug;182(4):504-512.
¹⁶ O'Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, Österborg A, Siddiqi T, Thirman MJ, Furman RR, Ilhan O, Keating MJ, Call TG, Brown JR, Stevens-Brogan M, Li Y, Clow F, James DF, Chu AD, Hallek M, Stilgenbauer S. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016 Oct;17(10):1409-1418.
¹⁷ Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23.
¹⁸ Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Kipps TJ, Moreno C, Montillo M, Burger JA, Byrd JC, Hillmen P, Dai S, Szoke A, Dean JP, Woyach JA. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019 Dec;94(12):1353-1363.
¹⁹ Coutre SE, Byrd JC, Hillmen P, Barrientos JC, Barr PM, Devereux S, Robak T, Kipps TJ, Schuh A, Moreno C, Furman RR, Burger JA, O'Dwyer M, Ghia P, Valentino R, Chang S, Dean JP, James DF, O'Brien SM. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv. 2019 Jun 25;3(12):1799-1807.
²⁰ Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, Bairey O, Hillmen P, Coutre SE, Devereux S, Grosicki S, McCarthy H, Simpson D, Offner F, Moreno C, Dai S, Lal I, Dean JP, Kipps TJ. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2019 Oct 18. doi: 10.1038/s41375-019-0602-x