Chronic lymphocytic leukaemia (CLL) has traditionally been one of the most challenging leukaemias for clinicians to manage.¹ Treatment options have been evolving for decades, and never faster than right now.² To reflect upon the age of chemotherapy to chemo-immunotherapy and now targeted therapy, the limbic sat down with Professor John Seymour, Co-Director of the Division of Cancer Medicine, and Director of the Department of Haematology at the Peter MacCallum Cancer Centre, Melbourne to discuss where we’ve been and where we are headed with the management of patients with CLL.

Chemotherapy was symptom directed and palliative

For over half a century CLL has been treated with oral alkylating agents, primarily chlorambucil, or cyclophosphamide.^3,4 At best these agents are symptom directed and palliative, with little or no effect on the natural history of the disease.¹

As Prof. Seymour describes, “there is no evidence that these chemotherapy agents prolong survival whatsoever and almost never achieve complete remission, but they do give good relief from bulky or uncomfortable lymph nodes and diminish the symptom impact of the disease for patients.” Indeed, chlorambucil therapy has shown little effect on 10-year overall survival (OS), which occurs in less than 5% of patients.³ This, explains Prof. Seymour, “is because traditional chemotherapeutic agents lack selectivity and impact normal cells to a similar degree to the malignant clone.”

The complete mechanism of action of chlorambucil in CLL is still not known, but certainly involves DNA cross-linking and induction of apoptosis, but as noted by Prof. Seymour is not selective to B cells alone.⁵

For some, chemoimmunotherapy changed the course of disease

In the early 1990s the purine analogue fludarabine was discovered and showed improved response and progression-free survival (PFS) compared to alkylator-based therapy.⁴ While treatment intensification resulted in greater cellular immune suppression and myelosuppression, it did not greatly improve treatment outcomes (at least as measured by OS) in patients with high-risk genomic features such as unmutated immunoglobulin heavy chain variable region (IGHV) disease, del(17p13.1) and p53 mutations.⁴

Identifying therapies that circumvented or combatted these adverse prognostic factors was a high priority.⁴ Targeted monoclonal antibodies (mAbs), which can mediate cytotoxicity towards tumour cells through a range of direct and indirect mechanisms were of particular interest.⁴ The first target was CD20, a glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase.⁶

Shortly after, the synergy of fludarabine with cyclophosphamide and the anti-CD20 monoclonal antibody rituximab (FCR) was recognised.³ This became the first systemic therapy to prolong OS compared with alkylating agent monotherapy or supportive care.³

“First used at the turn of the century, chemoimmunotherapy was able to achieve complete remission in more than 50% of patients, and for the first time had altered the natural history of the disease, modestly increasing the OS of patients,” notes Prof. Seymour.

However, an increase in OS came at a cost, with “the side effects of treatment making it not broadly applicable to the average patient – who is someone in their 70s with other comorbid conditions.^6-8 So many patients with CLL were not able to benefit from that advancement,” explains Prof. Seymour.

Common adverse events during chemoimmunotherapy appear to be due to myelosuppression as well as immunosuppression, and the risk of secondary malignancies appears higher in patients treated with FCR than in the general population.⁹

Attempts to further increase the efficacy of the FCR regimen were made with the addition of anthracyclines, or the substitution of rituximab with other mAbs with alternative cellular targets such as CD52.³ However they were not clearly more efficacious, and an increase in toxicity, specifically opportunistic infections precluded the wider use of these regimens.¹⁰

For patients who are older (≥70 years of age) with significant comorbidities, the combination of chlorambucil with a third-generation fully humanised anti-CD20 monoclonal antibody (obinutuzumab) or bendamustine and rituximab are now established first-line treatment options.^6,11,12

Despite the advances in disease control and extended survival for patients, chemoimmunotherapy is still not generally considered to be a curative treatment, nor is it an ideal treatment option for all patients.¹³

While there are patients with favourable prognostic markers (mutated IGHV status), there remains subsets of patients with poor prognostic markers such as 17p (p53) deletion, who have a very brief duration of response even with chemoimmunotherapy.¹³ This meant alternative treatment options were needed to level the playing field for these patients.

Enter the age of targeted therapies and continuous treatment

Over the last decade, our understanding of the pathogenesis of CLL has led to the development of novel therapies with different, more specific targets than traditional chemotherapy.⁶ Specifically, the targeted therapies ‘target’ specific kinases in the B-cell receptor pathway such as the Bruton tyrosine kinase (BTK, e.g. ibrutinib) and phosphatidylinositol-3-kinase (PI3K, e.g. idelalisib).⁶ “What targeted therapies have in common is that their potency, as measured by the frequency, quality and durability of response are at least equivalent to chemoimmunotherapy.⁶ But because of the far greater selectivity, these generally have more favourable adverse event profiles than chemoimmunotherapy and can be used in a far greater proportion of patients. Therefore the public health impact is more substantial,¹⁴” explains Prof. Seymour.

Indeed these novel, small-molecule inhibitors have already changed the standard of care for patients with relapsed disease, demonstrating long-term disease control for up to 5 years for regimens containing either ibrutinib or 3 years with idelalisib.^9,13,15-18 They have improved the overall response rate (ORR), progression free survival (PFS) and OS in a majority of patients both in the treatment naïve and relapsed/refractory setting.¹⁷ In patients with del(17p) and/or p53 mutation in need of first line or relapsed treatment, ibrutinib is now considered the standard of care.⁹

Moving back towards time-limited treatment

According to Prof. Seymour targeted therapies are very promising, highly active and generally well tolerated.⁶

However, he said one disadvantage of targeted therapies like BTK inhibitors and PI3K inhibitors is that they are continuous suppressive therapies rather than a short pulse of therapy (like chemotherapy).^19,20

“So you have the prospect of a patient taking medication indefinitely. For a patient who is 85 years old, who may have other comorbid conditions this may be acceptable. But for younger patients who might be looking at being on medication for decades, this may be less acceptable to the patient.

We are also beginning to see the emergence of the disease developing mutations that bypass the activity of some of these agents raise concerns that continuous therapy may select more resistant clones,⁹” notes Prof. Seymour.

As Prof. Seymour explained, venetoclax is another novel, small-molecule inhibitor that targets BCL2, which is over-expressed in CLL due to a deletion of the micro-RNAs miR15a and miR16-1, which negatively regulate BCL2 expression.⁹

It is a BH3 mimetic which acts similarly to the BH3-only proteins which antagonises BCL2.⁹ In this way, it restores apoptosis in tumours directly.⁹ In clinical trials involving venetoclax, it has not only shown profound reductions in peripheral blood leukaemic lymphocyte count, target lymph-node lesion diameter and bone marrow infiltration, it has also been shown to induce minimal residual disease-negative complete response, which is generally not seen with PI3K and BTK inhibitors.¹⁷

“This depth and duration of response has opened up the paradigm of time-limited therapy, albeit in a small number of patients to date treated with venetoclax and rituximab and followed for up to 2 years off therapy without evidence of progression,²¹” says Prof. Seymour.

So how will clinicians decide which therapy to use, and when?

Despite the advances in therapy, the appropriate sequencing of therapy remains in question.¹³ Determining who will get which treatment will ultimately come down to the clinical stage of the disease, symptoms of the patients, fitness of the patient, genetic risk factors of the leukaemia and the treatment situation – or line of treatment.¹³

Prof. Seymour explained more specifically about how the targeted therapies could fit into already established treatment routines. “There are prognostic subgroups within CLL. The most adverse we can identify are those who have a low probability of responding to chemoimmunotherapy and a low probability of survival.

Specifically, those with a del(17p) who have loss of p53 function will probably be one group of patients in whom targeted therapies may be a frontline treatment option.⁹ In other patients, it will need to be worked out on a case-by-case basis, taking into consideration patient age, fitness and comorbidities.”

Another consideration notes Prof. Seymour is the risk of inducing p53 mutations with specific treatment regimens. “Using chemoimmunotherapy frontline may also select for p53 mutation, so this is another consideration for treatment order.²² In all, at a public-health level there will be consideration about the cost-benefit of treatment order which will take all of these factors into account.”

Upon reflection, Prof. Seymour has optimism about the future of CLL because of our increased understanding of the treatment options we have available. “With chemotherapy, it was a very crude and non-selective tool that was difficult to optimise because we didn’t understand its exact mechanism of action.

Looking forward, one of the major advantages of the targeted therapies is we have a very good understanding of how they work. This provides an advantage when it comes to designing rational combinations.⁹ Because we know they work, we might also be able to identify the mechanisms of resistance and target those preventatively.”

This article was sponsored by AbbVie, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of AbbVie Pty Ltd.

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