Frontline Treatment of the Young, Fit Patient with CLL: A Canadian Perspective

Round 1

Reviewer 1 Report

The paper talks about the frontline treatment of CLL in young and fit patients; a first part is more focused on therapeutic advances in last decades passing from chemotherapy-based options throught immunotherapy to ibrutinib-based therapy. A second part goes into details of Canadian landscape highlighting the pros and cons of FCR and ibrutinib. I think it is a well written paper and it deserves to be published, all parts are clear and I think it can help physicians in the decision-making and in the communication with patients to choose the best option available for them. See also, for the first part:  Tumor Suppressors in Chronic Lymphocytic Leukemia: From Lost Partners to Active Targets;  Cancers 2020, 12, 629; doi:10.3390/cancers12030629

Author Response

We thank the reviewer for their feedback and suggestion.

The following statement and references below are now included in lines 126-135, section 3 (First-Line Treatment Evolution in the Young, Fit Population) with the addition highlighted. Tumour suppressor inhibitors were not included in the list as these are investigational and we focused on clinically approved agents.

• “Furthermore, loss of function of tumour suppressor genes such as TP53, ataxia telangiectasia mutated (ATM), and other somatic gene mutations (ie, SF3B-1) or complex karyotypes lead to chemotherapy-resistance in in CLL [15,16]. A number of clinically approved agents have been developed to target these pathways and proteins, including acalabrutinib (BTK inhibitor), ibrutinib (BTK inhibitor), idelalisib (PI3Kδ inhibitor), obinutuzumab (anti-CD20 antibody), rituximab (anti-CD20 antibody), and venetoclax (BCL-2 inhibitor).”

Reviewer 2 Report

The Authors provide a well written and complete review regarding a Canadian perspective on therapeutic strategy for fit CLL patients.

I recommend the publication in present form

Author Response

We thank the reviewer for the positive comments.

Reviewer 3 Report

This is a nice overview of treatment options for young, fit patients diagnosed with CLL in Canada. The evidence base for the evolution of current strategies is well articulated. The paper is very well presented, clear and concise. (Very minor point: In Abstract, suggest replace comma after 'alone' with a full stop in line 8).

There are a few intriguing omissions, or absence of explanations, for non-residents in Canada, such as: why are there no cancer incidence data for Quebec; why was there a sudden rise in the incidence of CLL in Prince Edward Island in 2018; and why is the incidence of CLL in Nova Scotia and Newfoundland & Labrador apparently low? (I interpret the data as incidence per 100,000 population, so low population density is not the reason). The reader is left to speculate that the variations reflect less than rigorous data collection in those provinces with significantly lower incidences. If so, remedial action should be encouraged. If, however, the variations are true, reasons for these should be investigated.

However, these comments in no way diminish the merit of the paper which will be of interest not only to Canadian clinicians, but also to an international readership. It would have been interesting to learn how uniform is the decision to treat in Canada, and to hear of real-life data regarding outcomes. Hopefully the latter is being collected and will be offered for publication in the coming years as such data is a very useful adjunct to that from clinical trials.

Author Response

• We thank the reviewer for the positive comments.
• Thank you for the suggestion, the abstract (line 20) has been updated as suggested.
• Regarding the absence of cancer incidence data from Quebec, information from Statistics Canada indicate that:

"Although the Canadian Cancer Registry (CCR) strives to achieve national uniformity, reporting procedures and completeness still vary across the country. Specific issues follow:

1. Because Quebec relies primarily on hospital data (i.e., hospitalizations or day surgeries) for cancers diagnosed until the end of 2010, the number of cases of some cancers are underestimated particularly for prostate cancer and melanomas of the skin (source: Brisson J, Major D, Pelletier E. Evaluation of the completeness of the Fichier des tumeurs du Québec. Institut national de la santé publique du Québec; 2003).
2. Differences may exist between the content of the CCR and the provincial/territorial cancer registries because of incomplete updating of the CCR by the provinces and territories.
3. Nova Scotia has no death certificate only (DCO) cases reported in 2018 (around 85 cases were reported in 2017); Quebec has no DCO cases reported for 2010 (around 1370 cases reported in 2009); Manitoba has not reported DCO cases since 2013 (43 cases were reported in 2012); and Newfoundland and Labrador did not report DCO cases until 2006.”

• We thank the reviewer for noting the sudden rise in incidence of CLL in PEI in 2018. We have noted a typographical error in Figure 1 – the legend representing the years was in reverse order. The updated Figure 1 shows a sudden decrease in the incidence of CLL in PEI – while we might speculate as to the reason for this dramatic decrease from 2014 to 2015, it would be just that, speculation. The province is small geographically and is only 160,000 in population, thus a small change in patient care may have affected a large percentage of patients who were at risk. To fully understand this observation would likely move away from the scope of the present review.
  • We have updated Figure 1 in the manuscript and revised the description in section 2 (line 84-88), which now reads: “The proportion of the Canadian population with CLL that would be considered young and fit also varies by region [13], with incidence rates ranging from between 2 to 4 per 100,000 population in Manitoba, Nova Scotia, Saskatchewan, and British Columbia, to greater than 4 to 7 per 100,000 population in Alberta, Ontario, and New Brunswick (Figure 1).”
• Regarding the apparent low incidence of CLL in Nova Scotia and Newfoundland & Labrador:
  • There are many remote communities in these provinces, and it may be less common to have annual checkups with accompanying blood work, possibly leaving asymptomatic CLL undiagnosed. We speculate that the reciprocal explanation of PEI applies to Nova Scotia and Newfoundland, ie – these are large provinces geographically, and improvements in screening and diagnosis have not yet been taken up into the many remote communities. However, this is speculation only, and, as with the previous question, full understanding of this is outside the scope of the paper.
• We thank the reviewer for the suggestion and agree with commenting on the observation regarding the variations in incidence rates. We further speculate that the lower incidence of CLL in Atlantic Canada may be related to lower access to primary care and/or hematologists which may result in less referrals accepted for lymphocytosis, deferred cases, and/or are not reported to hematologic cancer registries.
  • We have added the following statement to line 88-91: “These data indicate potential disparities in registries capturing the incidence of cancers, such as CLL, across the provinces and territories of Canada. Ongoing advocacy is required to ensure that cancer incidence is captured by these databases accurately.”
• We thank the reviewer for the kind words and look forward to future RWE clinical studies examining important research questions such as this.

Reviewer 4 Report

What is the aim of the maniscript? to provide a picture of canadian clinicians attitude or to analize a challenging question: can we permantely leave chemoimmmunotherapy in CLL young fit patients after the advent of ibrutinib?

If the answer is the second one, i think that the goal of this review/expert point has not been reached by the authors, as no clear and practical considerations in the manuscript on the factors that should guide clinicians in their choice are provided.

In a biological low-risk setting, FCR showed to lead to extremely long (>10 years, Fischer, Rossi, Thompson) remissions rising the question if these patients may have been potentially "cured" from treatment. On the other side the risk of infections and second cancer is concrete.

Also, factors not in favour of ibrutinib are only mentioned: absence of complete remission, resistances, long-term treatment with some side effects potentially altering life quality, cardiovascular risk (and even if extremely rare, sudden cardiac events are described) and, not least, costs.

Authors define generally as "high risk" those cLL that should receive ibrutinib. For many clinicians the concept of high-risk can be limited to 17p/TP53. There is a general consensus that all patients with UNmutated IgHV or 11q- would benefit from ibrutinib instead of chemoimmuno. This must be make explicit and supported by long term analysis available (RESONATE2, PCYC1102..)

Authors should mention that the combination of venetoclax with obinutuzumab, despite approved for elderly and unfit patients could be potentially a time-limited chemofree option even for young-fit population. Similarly, ongoing studies with target agents combo  in young fit pts should be mentioned

Author Response

• We thank the reviewer for their comments and feedback.
• The goal of this manuscript is to provide treating clinicians with evidence-based and practical guidance on managing their young, fit patients with CLL.
• The considerations for treating with ibrutinib are included in Figure 6. The below paragraphs are also included in the manuscript:
  • Line 268-276: “Care must be taken in deciding to use BTK inhibitors in patients with moderate to severe bleeding disorders; concomitant use of anticoagulant/antiplatelet agents; prior Grade 3 or 4 atrial fibrillation; unstable cardiovascular disease such as hypertension or new ischemic heart disease; chronic skin conditions; and compliance with oral therapy. Other considerations of continuous therapy with an oral BTK inhibitor include the risk of skin cancer; the need for patients to see their oncologists or family physician at least every three months for vital sign measurements; the importance of interrupting BTK inhibitor therapy when surgery is planned; and the necessity of education for both patients and other health care professionals.”
  • Line 317-321: “Continuous oral BTKi therapy, on the other hand, may result in long term disease remission in certain patients with high-risk features [7,31,33], but, by its very nature, presents a low but real risk of mutations in the binding site which may give rise to a higher risk of treatment-resistant disease [9,22].”
• We have added the statement and references below to lines 212-216 in section 3 (First-Line Treatment Evolution in the Young, Fit Population) of the manuscript.
  • “The RESONATE-2 and PCYC-1102 clinical trials provide important long-term evidence for the safety and efficacy of ibrutinib in patients with CLL, including in those with high-risk features [32,33]. However, the studied populations were older and, as such, are out of scope for this review, which is focused on the young, fit patient. ”
• We revised the below statement in lines 322-324 in the conclusions section of the manuscript, including references to the venetoclax data.
  • “Finally, novel combinations, such as those that include BCL-2 inhibitors, present the possibility of durable response, in some patients, with time-limited therapy [47–49].”

Round 2

Reviewer 4 Report

No further coments