"The treatment landscape for patients with chronic lymphocytic leukemia (CLL) has changed considerably with the introduction of very effective oral targeted therapies (such as Bruton tyrosine kinase inhibitors and venetoclax) and next-generation anti-CD20 monoclonal antibodies (such as obinutuzumab). These agents lead to improved outcomes in patients with CLL, even among those with high-risk features, such as del17p13 or TP53 mutation and unmutated immunoglobulin heavy chain (IGHV) genes. Selecting the right treatment for the right patient requires consideration of disease characteristics and prior treatment sequence, as well as patient preferences and comorbidities. The CLL-International Prognostic Index (CLL-IPI) remains the best-validated tool in predicting the time to first therapy among previously untreated patients, which guides selection for early intervention efforts. This review summarizes our current approach to the management of CLL, right from the time of diagnosis through relapsed disease."
Things that stand out:
1. Only those patients who meet the 2018 iwCLL criteria for initiation of therapy should be offered treatment . In the Relapsed/Refractory setting, progressive disease often does not immediately equate to an indication for starting a treatment or changing the current treatment, until patients meet the 2018 iwCLL criteria for therapy.
2. A clinical trial should be considered for all patients who meet the 2018 iwCLL guidelines for the commencement of therapy, regardless of their risk classification and regardless of whether they are considering their first or subsequent therapy.
3. Venetoclax- and BTKi-based treatments are both excellent options for patients without a TP53 aberration and either is favoured over CIT in this setting, regardless of IGHV mutation status. (See healthunlocked.com/cllsuppo... for more information about how IGHV might influence treatment choice).
When a BTK inhibitor is selected, either acalabrutinib or zanubrutinib is preferred in most patients.
See the article for more details about each of these treatments, including guidance about when one might be more suitable than another for particular patients.
4. Continuous BTK inhibitor-based treatment in patients with TP53 disruption may provide superior PFS in the frontline setting.
5. Patient fitness is another important consideration. Very frail patients who score 'unfit' with a CIRS score of ≥ 6-8 and whose comorbidities preclude BTKi or venetoclax, might consider single-agent obinutuzumab in addition to those therapies already referenced above.
6. "MRD at the end of CLL therapy (and potentially also as a dynamic assessment) remains a powerful prognostic tool in the novel agent era, particularly with time-limited venetoclax-based approaches. Achieving uMRD with continuous BTKi treatment, in contrast, does not impact PFS."
7. "Patients with relapsed CLL should undergo a comprehensive assessment of their disease status, including bone marrow aspirate and biopsy and typically CT imaging (chest/abdomen/pelvis). A positron emission tomography (PET)/CT scan is preferred if there is suspicion for Richter transformation, and biopsy of lesions with a maximum standardized uptake value (SUVmax) ≥ 5 should be strongly considered (sensitivity 96%, specificity 21%, negative predictive value 86%, among patients experiencing disease progression on BTKi). TP53 mutation testing and CLL FISH panel should be repeated. Evaluating patients with relapsed CLL also requires the same considerations for medical comorbidities and frailty. The added calculus comes with review of prior treatment regimens and outcomes"
See the full article for details about the various treatment alternatives, depending on which frontline therapy a patient has already receivedand depending on whether the patient is changing therapy because of toxicity or disease progression.
8. "A disease flare phenomenon, characterized by rapidly progressive symptoms and adenopathy and rarely histopathologic evidence of Richter transformation, may occur during interruptions in BTKi treatment, but particularly after stopping the covalent BTKi until the next line of therapy is started. We recommend continuing the BTKi during the transition period to next-line therapy, particularly through venetoclax ramp-up until the target dose is reached ."
9. Cell therapy evaluation is recommended during remission on the second targeted agent.
The article discusses different cell therapies, including Allogeneic HSCT, CAR-T and CAR-NK therapies.
It also raises the need to consider any complications a patient might be experiencing, such as autoimmune cytopenias, which occur in ~5–10% of CLL patients, and other autoimmune complications.
"Richter transformation remains a feared complication of CLL in the novel agent era, retaining a poor prognosis." The article directs readers to recently published papers about Richter transformation of CLL.
CONCLUSION:
"Momentous gains in efficacy and tolerability of targeted therapies have continued to shape a dynamic treatment landscape, increasing the ability to individualize treatment to the goals and values of the patient. Pressing questions in the next phase of CLL research include how best to combine novel agents, the sequencing of these treatments, and administering time-limited treatments to achieve deep remissions that allow stopping therapy."
Hampel, P.J., Parikh, S.A. Chronic lymphocytic leukemia treatment algorithm 2022. Blood Cancer J. 12, 161 (2022). doi.org/10.1038/s41408-022-...
Note: not all of the therapies recommended in this algorithm are available to patients in all places. In some places, outside of a clinical trial, the only initial therapy available to patients without a TP53 mutation/17p deletion is chemo/chemoimmunotherapy. This makes the recommendation for all patients to consider a clinical trial, whatever their stage of CLL, all the more important.
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Only thing I wish is we could achieve longer periods of remissions with each line of targeted therapy. Seems like best case scenario right now with time limited treatment is 5 years.
We've really only been seeing data from trials for therapies based on combinations of targeted agents for a relatively short time, as the timeline in the image from a review article written by Jan A Burger, printed in the New England Journal of Medicine in 2020, shows.
It's also worth remembering the following statement that comes from a post from earlier this year which was about an article that looks back at what's been achieved in CLL in the past 10 years.
'Ten years ago, diagnosis of chronic lymphocytic leukemia (CLL) meant treatment with chemotherapy and, for most patients, a shorter life expectancy than before diagnosis. Today, those are no longer foregone conclusions.'
Thanks for a really nice and informative chart this morning. And a personal pick-me-up for me (since I never like winter, so any pick me ups I get are great!).
This chart reminds me how well I'm doing in Watch and Wait. Passed my median to treatment time with flying colors (when you start on the 1st row with 4 points and then get to add more, well, let's say it doesn't take that long, it seems, to pass the median time:). Now, on to hitting the "almost impossible time" for the chart, as I keep trying to make it 10 years from diagnosis to treatment (aka, the time it would take me to get my last to freshman year of college - every one I get in would be a help, but having them all not need me - priceless:).
I probably won't get there, but it's good to have hard-to-reach goals b/c you keep having to reach for them!
Go for it! I hope your CLL progresses at a slow rate but be heartened that there are some great treatment options available now and they're improving all the time.
1. This paper has an international focus, because it cites CLL-IPI and iwCLL, but was written by Mayo Clinic authors from Minneapolis, Minnesota. I think the paper heralds changes to come in both CLL-IPI and iwCLL.
2. The iwCLL criteria has not been updated in 4 years, and still has an overall assumption of chemotherapy risk built in.
3. CLL-IPI has not been updated since 2016. More people are being diagnosed earlier due to more blood testing, so TTFT (Time To First Treatment) is growing in the real world for some.
4. In the U.S., the NCCN Guidelines Evidence Blocks probably should guide U.S. hemo/oncos rather than this paper, but I think the paper takes that into account:
nccn.org/professionals/phys... (free access after registration, even for patients. It's 97 pages, and has a zillion references, and is very technical) It can be updated several times a year as new studies shed new light and new drugs are approved by the FDA.
5. The iwCLL criteria still seem to apply in some (many?) clinical studies in the U.S.
6. Don't use the CLL-IPI to assess yourself after diagnosis if some time has passed. It assumes "at diagnosis,. That fact is built into the CLL-IPI statistics, I believe. Even for newly diagnosed, the paper notes, "Given the rapid adoption of novel agents in the management of CLL, the CLL-IPI can no longer be used to predict OS; however, it is one of the most powerful tools in predicting time to first therapy (TTFT) in patients with previously untreated CLL." I would say that as more and more people are coincidentally diagnosed at younger and younger ages, even CLL-IPI TTFT is not that great.
7. There's really no good prognostics for people already in Watch and Wait that I've seen, until one actually starts treatment. Please correct me if I'm wrong! I've been in Watch and Wait for 12 years now, and have seen so many changes in diagnosis and treatment.
8. Based on anecdotes, I'm seeing signs of a trend in the U.S. to earlier treatment, despite the iwCLL. Constitutional symptoms and fitness can be the deciding factor, and are somewhat subjective. Driving this is that much has been learned about BTKi, BCL2 (Venetoclax), and CD20 adverse events, such as ramping up.
9. The section on Fitness refers to CIRS scores (Cumulative Illness Rating Scale), but some (many?) trials still use ECOG (Eastern Cooperative Oncology Group). They're roughly equivalent, and they're somewhat subjective.
10. I found this wording a bit odd: "Achieving uMRD with continuous BTKi treatment, in contrast, does not impact PFS [49]." That would seem to imply that uMRD with continuous BTKi is not good. It is. The paper referenced is titled, "Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib." So I think it's a typo, and should have said "Detectable MRD with continuous BTKi treatment, in contrast, does not impact PFS [49]," because the paper says, "In the IR arm, patients with detectable MRD did not have significantly worse PFScompared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10-1 than in those with MRD levels above this threshold."
CLL-IPI and TTFT:ncbi.nlm.nih.gov/pmc/articl...The chronic lymphocytic leukemia international prognostic index (CLL-IPI) predicts time to first treatment in early CLL: Independent Validation in a Prospective Cohort of Early Stage Patients
Fair comments, Seymour: thanks for taking the time to add them to the post.
After some discussion with AussieNeil , I'll also add the following:
As you've noted, the "iwCLL criteria still has an overall assumption of chemotherapy risk built in" which is understandable, given those guidelines are intended for international use and many countries are still using older chemotherapy treatments.
In some places, only patients with a 17p deletion can get access to targeted therapy in the frontline which leaves many who are IGHV unmutated looking at an FCR/BR treatment option as their first treatment.
Given that unmutated people are likely to need treatment before those who are mutated, that introduces a bias towards those patients needing a subsequent treatment earlier, due to selected sub-clones for 17p del and TP53, plus they have an increased risk of secondary blood cancers . . . which is going to influence your point 7. (As an aside, as someone who only spent three years in watch and wait, I'm very envious of your twelve. I wonder what treatment will look like in another twelve.)
The two things that really stood out to me when I read through this algorithm were:
a) the recommendation that all patients should consider a clinical trial when they require treatment and
b) the role of cellular therapy in the relapsed/refractory setting.
Also, as next-generation sequencing and the CLL mapping project (that's been discussed elsewhere) progress further, we'll probably see another shift in practice and, I suspect, we may see additional changes to the management, in particular, of those who are considered higher risk.
> The two things that really stood out to me when I read through this algorithm were:
> a) the recommendation that all patients should consider a clinical trial when they require treatment and
> b) the role of cellular therapy in the relapsed/refractory setting.
I think the clinical trial recommendation is because of early positive results for limited duration targeted therapy combinations, as well as pirtobrutinib. In addition, I think they're hinting that patients get better care during trials on average, as it forces additional testing, and tends not to automatically select older therapies still used by doctors with a bias toward what "used to work well." The word "well" is being redefined continuously.
Cellular therapy continues to get refined, but I really hope I never need it myself. People do need to understand that cellular therapy is still a last resort because of side effects. It's touted as a game changer - and it is - but the side effects seldom get mentioned in the popular press. Pirtobrutinib has done well in a trial for relapsed/refractory CLL, too.
I'm hoping to get into a limited duration, frontline, triple therapy with pirtobrutinib, venetoclax, and obinutuzumab at MDA:
Time-limited Triplet Combination of Pirtobrutinib, Venetoclax, and Obinutuzumab for Patients With Treatment-naïve Chronic Lymphocytic Leukemia (CLL) or Richter Transformation (RT)
I'm nervous about being disqualified at the last moment due to some odd requirement or committee/
Neither pirtobrutinib nor cellular therapy has a 100% success rate, but the percentages have looked better than older equivalents. Pirtobrutinib has dodged the C481S resistance mutation, but resistance can still build at other BTK locations, though it seems less quickly. The hype doesn't mention that very often, I think.
Clinical trials are important everywhere but they're especially important in places with more limited therapy offerings and that's probably something that the algorithm took into account, too.
Also, it's important for trial participants to be as diverse as possible. Exploring trial offerings for all patients who require treatment is an important step to help achieve that. Other measures would also need to be put in place to ensure greater patient diversity in clinical trials but, at least exploring what might be possible, is a good first step.
Waiting to see if you meet the criteria for inclusion in a trial is an anxious time. I hope you don't have to wait too long before you can start your trial of choice.
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