I was reading Bill188's post where he talked about taking V for 2 year plan. And there is discussion about the clonoseq test? Being a little confused I posted this reply to Bill1288 but decided to post for broader audience.
Good morning I'm a little confused reading this string. I completed my O+V treatment in July. 6 cycles of O and 12 months of Venclexta (400Mg dose daily) as prescribed by Moffitt Cancer Center/Florida Cancer Specialists and CB JONES Cancer Centers.
My last two Flow Cytometry Reports have shown no aberrant T-cell population or increased blasts detected, Also no B-cells detected.
I am having monthly blood tests for 6 months and then we will start expanding the cycle for tests if nothing indicates to the contrary,
Why do we need the clonoseq tests? Why are some people on 2 years of V?
I see my Hematologist in January and I want to understand better. Additional insight will be helpful.
Thank you
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Rico49
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You don't. It's able to detect 1 CLL cell in 1,000,000 B-cells. Normal testing is usually limited to finding 1 CLL cell in 10,000. The increased depth can serve to either reassure patients that the treatment was a success or worry them that are already with a few cells in a million on a countdown to progressing.
Why are some people on 2 years of V?
It's their second time around. Be assured your 12 cycles of V+O was the correct treatment.
Venetoclax + Rituximab (VenR) is for relapsed or refractory (R/R) CLL.
V+O is for treatment naive, first line treatment.
Two years of V+O is "off label". For R/R CLL US doctors are taking the 2 year duration of VenR and using it for V+O.
The GAIA/CLL13 trial for untreated CLL has shown that 12 cycles of V+O is very much better than 12 cycles of VenR. The hazard ratio (HR) at 4-years for unmutated IgHV is 0.65 and for mutated IgHV 0.4. V+O is more effective for unmutated IgHV.
There are 3 currently approved treatments for CLL that use Venetoclax in the US. These extracts are from the FDA label. The label fails to specify R/R or untreated.
The recommended dosage of VENCLEXTA is 400 mg once daily after completion of the 5-week ramp-up dosing schedule (see Table 1). Continue VENCLEXTA until disease progression or unacceptable toxicity.
In Combination with Rituximab
Start rituximab administration after the patient has completed the 5-week ramp-up dosing schedule for VENCLEXTA (see Table 1) and has received VENCLEXTA at the recommended dosage of 400 mg orally once daily for 7 days. Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, at a dose of 375 mg/m2 intravenously for Cycle 1 and 500 mg/m2 intravenously for Cycles 2-6. Continue VENCLEXTA 400 mg orally once daily for 24 months from Cycle 1 Day 1 of rituximab.
In Combination with Obinutuzumab
On Cycle 1 Day 22, start VENCLEXTA according to the 5-week ramp-up dosing schedule (see Table 1). After completing the ramp-up phase on Cycle 2 Day 28, continue VENCLEXTA at a dose of 400 mg orally once daily from Cycle 3 Day 1 until the last day of Cycle 12.
The current NCCN Clinical Guidelines (version 2025.1) for CLL (the guidelines for U.S. patients) now recommend venetoclax and obinutuzumab as a preferred for relapsed/refractory disease. VR is now listed under Other Recommended Regimens, but has Category 1 evidence. VO is Category 2A.
Page CAT-1:
"NCCN Categories of Evidence and Consensus
Category 1 Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that theintervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference
Preferred intervention Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended intervention Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances Other interventions that may be used for selected patient populations (defined with recommendation)."
• ncBTKi - Resistance or intolerance to prior cBTKi
> Pirtobrutinib
** Venetoclax ± anti-CD20 mAb (obinutuzumab preferred) is a treatment option for relapse after a period of remission"
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Page CSLL-D 4 OF 6
SUGGESTED TREATMENT REGIMENS
FOOTNOTES
"a See references for regimens on CSLL-D 5 of 6 and CSLL-D 6 of 6.
b Supportive Care for Patients with CLL/SLL (CSLL-C).
c Rituximab and hyaluronidase human injection for subcutaneous use may be used in patients who have received at least one full dose of a rituximab product by intravenous route.
d Re-challenge with the same mAb is not recommended in patients experiencing rare complications (eg, mucocutaneous reactions including paraneoplastic pemphigus,
Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis). It is unclear whether re-challenge with alternative anti-CD20 mAbs poses the same risk of recurrence.
e An FDA-approved biosimilar is an appropriate substitute for rituximab.
f Please refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: accessdata.fda.gov/scripts/....
g A baseline cardiovascular risk assessment should be considered prior to initiation of cBTKi. Awan F, et al. Blood Adv 2022;18:5516.
h Venetoclax: Recommended TLS Prophylaxis and Monitoring Based on Tumor Burden (CSLL-F).
i The panel consensus to list ibrutinib under "other recommended regimens" is based on the toxicity profile.
j Data from the CLL10 study confirmed the superiority of FCR over bendamustine + rituximab (BR) in younger patients. For patients >65 y, the outcome was similar for
both regimens with less myelosuppression and infection for BR. FCR was associated with improved PFS (with a plateau in PFS beyond 10-year follow-up) in patients
with mutated IGHV without del (17p)/TP53 mutation (Thompson P, et al. Blood 2016;127:303-309).
k AIHA should not preclude the use of combination therapy containing fludarabine; however, patients should be observed carefully and fludarabine should be avoided in those where a history of fludarabine-associated AIHA is suspected.
l Anti-CD20 mAbs include: obinutuzumab or rituximab.
m For patients aged ≥65 y or patients aged <65 y with significant comorbidities (CrCl <70 mL/min) dose is 70 mg/m2 in cycle 1 with escalation to 90 mg/m2 if tolerated.
n Not recommended for frail patients.
o Recommended only for patients aged ≥65 y or patients aged <65 y with significant comorbidities (creatinine clearance [CrCl] <70 mL/min).
p Acalabrutinib or zanubrutinib has not been shown to be effective for ibrutinib-refractory CLL with BTK C481S mutations. Patients with ibrutinib intolerance have been successfully treated with acalabrutinib or zanubrutinib without recurrence of symptoms.
q Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: fda.gov/media/145711/download. See also CAR T-Cell–Related Toxicities in the NCCN Guidelines for Management of Immunotherapy-Related Toxicities for the management of cytokine release syndrome (CRS) and neurologic toxicity management.
r Indicated for patients for whom rituximab monotherapy would be considered appropriate due to the presence of other comorbidities (reduced renal function as measured by CrCl <60 mL/min, or NCI CTCAE grade ≥3 neutropenia or grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents).
s Recommended only for patients aged <65 y without significant comorbidities.
t Lenalidomide can be given as continuous or intermittent dosing for patients with CLL. Growth factors and/or dose adjustment may be needed to address cytopenias, without necessitating holding treatment. See Andritsos L, et al. J Clin Oncol 2008;26:2519-2525; Wendtner C, et al. Leuk Lymphoma 2016;57:1291-1299.
u While alemtuzumab is no longer commercially available for CLL, it may be obtained for clinical use. Alemtuzumab is less effective for bulky (>5 cm) lymphadenopathy;
monitor for CMV reactivation. See Treatment and Viral Reactivation (CSLL-C 1 of 4)"
"Retreatment with venetoclax ± anti CD20 mAb (VenO is preferred) is an option for disease relapse after a period of remission (if previously used as first-line therapy), irrespective of del(17p)/TP53 mutation.[146]"
That reference 146 is recent, but sadly, it's paywalled.:
Real-world evidence of obinutuzumab and venetoclax in previously treated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma
Leuk Lymphoma. 2024 May;65(5):653-659.
"Abstract
Venetoclax-obinutuzumab (Ven-O) is frequently administered off-label in relapsed/refractory (r/r) CLL/SLL where venetoclax-rituximab is the approved regimen. We conducted this retrospective, real-world study to evaluate Ven-O in r/r CLL/SLL. Between 7/2019 and 6/2022, 40 patients with r/r CLL/SLL on Ven-O were included. The median age was 72, 28.2% had TP53 mutation and/or 17p deletion, median number of prior therapies was 1 (range, 1-6), and 55% had prior BTK inhibitor exposure. The overall response rate was 90% (complete response [CR] or CR with incomplete marrow recovery in 27.5% and partial response in 62.5%) of patients, and the 2-year progression-free survival was 81.2% (95% CI, 69.5-94.8). Therapy was well tolerated. No laboratory or clinical TLS occurred with venetoclax (Howard criteria). One (3%) patient experienced laboratory TLS with obinutuzumab initiation. In summary, this retrospective cohort study demonstrated that Ven-O achieves frequent, durable responses and can be safely administered in r/r CLL/SLL."
Despite it being off-label, NCCN recommendations usually carry considerable weight if insurance disputes the treatment.
It's not clear whether this was fixed duration or continuous therapy. The MURANO trial of VR in relapsed/refractory patients was a 2 year fixed duration or continuous therapy, I believe. I don't think V, VR, or VO would produce good results with just 1 year.
I would add that the AbbVie web site for Venclexta makes no statements that I could find about length of treatment in relapsed/refractory, with rituximab or with obinutuzumab. I think it's up to the doctor.
It's fairly well known now that continuous Venetoclax eventually builds drug resistant mutations after 2 years of therapy. I have not seen anything about 1 year of initial therapy plus 2 years of r/r therapy having more resistance yet. Other resistance mechanisms also occur that lead to relapse sooner in second line, but they're not easily testable, I think.
R/R therapy recommendations are the same as for initial treatment. There are studies underway to determine how uMRD testing at the 10-6 level correlate with depth of remission. Studies are looking at stopping treatment when one reaches uMRD at 10-6 as well as continuing treatment for varying periods of time once undetectable disease state is reached.
There 's some discussion as to "individualizing treatments" and exactly how this is to be done hasn't yet reached a consensus. The iwCLL Guidelines were last updated in 2018 and there has been a lot of knowledge gained since then.
I know in my case, I was technically uMRD (at 10-4) after a year. A second year was recommended to see if the disease could be tamped down even more, which in my case didn't. I was the one asking to stop treatment at 2 years. I was well aware that a severe disease flare would have me re-starting. My doc is heavy into research, I am pretty healthy besides the CLL, blood levels of various things are somewhat stable. So he likely was OK with me wanting to monkey a bit with treatment. Patients who are unstable, or have severe side effects or severe changes in other cell lines, may want a doc to do otherwise.
My understanding is that since the MURANO study ran treatment with V&O for 2 years, this is a solid reference point clinicians may use in treatment decisions. The original FDA comments stated that venetoclax was to be continued until disease progression or unacceptable toxicity. And this has changed since the 2016 recommendation.
There's a lot of new information and thus recommendations are changing, regarding most all our treatments. It costs a lot of money to change "official package inserts" in the US and a drug manufacturer may not always choose to do this.
Thank you . You have brought much more clarity. My hematologist told me that since I had such a terrific response with O+V that it would be considered again if I have a relapse. I hope I have plenty of time before I have to worrying about that. thank you again and good luck with you on your journey if you are on one also
Nobody needs MRD testing yet. It's prognostic only right now. At some point, it will become the standard way of defining a successful course of treatment instead of the current iwCLL 2018 guidelines. At some point beyond that, MRD testing will be used to signal re-treatment even before the current iwCLL 2018 guidelines. MRD testing is therefore a standard part of clinical trials to gather data to support changing the iwCLL guidelines.
What I like about ClonoSEQ is that I can see if my CLL is beginning to rebound way before it shows up in my lymphocyte count. I can also compare my MRD status with published trial results to get an idea of my possible length of remission.
Note that unlike flow cytometry MRD testing, ClonoSEQ requires a sample from before treatment to see the dominant clones to look for on later tests.
I'm with you. I'm a ClonoSEQ proponent and my insurance company wants to fight me. In my opinion, it's better to have data than not have data.
I did V&O, with 2 years of Venetoclax as my first-line treatment. I was doing ClonoSEQ tests every 6 months in those two years, went off of treatment, then did a ClonoSEQ one year after treatment.
At the end of treatment I was 28 cells / million. One year after treatment I'm 7500 cells / million—a huge jump. We'd have never known based on regular labs as everything else is in normal range, right down the middle. At this rate, it's safe to say I'll be back in treatment by the end of the year.
None of this would have been that predictable had I not demanded ClonoSEQ tests. I'm on the younger side of this group, trying to get married and start a family, and this information drastically affects planning. We basically need to try for our first kid now, as once I start the next treatment we won't know if I'll have another chance.
Both copies of 11q? Having a single deleted copy of 11q leads to a longer remission than if both are missing, because the complete lack of the ATM gene (which is on 11q) means it cannot repair DNA damage.
Which IGHV gene family? For example, M.D. Anderson's Molecular Diagnostics IGH Hypermutation Analysis report showed me as:
IGHV Gene IGHV1-69-IGHJ6
% Deviation from Germline Sequence 0
Each IGHV gene family has varying associations with longer or shorter remission.
=seymour=
References:
These are 2 recent studies of FiSH and IGHV mutation status and family and statistical outcomes. Bear in mind that for any statistic, you can be above or below for various reasons. Do not despair! I hope this is useful in documenting cases where people exceeded the averages.
I had a 172 gene NGS panel done at M. D. Anderson in August, 2022, which they call EndLymphoma Mutation Assay by NGS. Such panels are not standardized, and the actual genes they test, and the thoroughness may vary from lab to lab. MDA's panel is aimed at all lymphomas, and I suspect that's true in other labs, rather than doing a custom NGS panel for CLL/SLL/MBL.
There are 6 or 7 genes that are studied in particular for risk for more serious CLL - TP53, ATM, NOTCH1, SF3B1, MYD88, BIRC3, XPO1 . TP53 in particular is considered mandatory to sequence by NGS rather than FiSH by the NCCN Clinical Guidelines for CLL. So doctors may order that separately. But no guidelines exist for the other genes.
The big panels will turn up several kinds of results:
1. Common mutations in the above genes with fairly well known meaning - good or bad.
2. Mutations in other genes with less well known significance for CLL, but known significance for other lymphomas - which doesn't mean necessarily that you're at increased risk for that lymphoma.
3. Common variants seen in many people that are not risky
4. Variants of Unknown Significance - (VUS) - means what it says.
The results also have a numeric assessement of how frequently the mutation was seen in the blood sample - VAF - Variant Allele Frequency. Allele means roughly, "How the gene is spelled in DNA - the A, C, T, G nucleotide sequence." The higher the percentage, the more copies of the gene have that allele, and therefore the greater the effect.
In my case, they turned up the typical NOTCH1 mutation, c.7541_7542del, with a VAF of 22%. That means that some of the cells had a copy of the NOTCH1 gene with that mutation. (a deletion of 2 base pairs at locations 7541, and 7542 in NOTCH1, which made the DNA past that point shift over, and become gibberish - a frameshift mutation.)
I also had a BCL2 mutation, which they said did not affect anything in particular.
They have not repeated the panel after treatment. I imagine that's because they don't think it would add any insight so far. So the panel is a huge net they cast mostly to populate their research database.
Congratulations on completing treatment and having good numbers!!!!
You've asked some very great questions. As a physician and a veteran with CLL it has been a journey for me to grasp these concepts.
V + O for 1 year is recommended for previously untreated patients.
The 2 year protocol is recommended for individuals who have been treated and then relapsed, as was my case.
The next question pertains to something called detectable measurable disease. In other words, how much residual leukemia is present blood or marrow.
Flow cytometry can detect one CLL cell per anywhere between between 1 CLL cell per 5-10,000 white blood cells.
Clonal sequence can identify 1 CLL cell per 10,000, or 100,000, or 1 million white blood cells.
uMRD is undetectable measurable disease. A number often follows such as four, five, or six.
The higher the number the less leukemia that is still detectable either blood or bone marrow. uMRD6 means less than 1 in 1 million white blood cells have markers for CLL.
Bone marrow samples are generally a bit more accurate than blood.
Studies are being conducted to determine a correlation between uMRD status and overall survival duration (OS) or time to next treatment (TTNT). So far there is emerging evidence that the higher the degree of uMRD, the longer the duration of overall survival and time to next treatment.
While this is commonly used in clinical trial settings, it is not that available in a community setting.
Certain people, I know that are physicians, will do additional therapy beyond the original plan, to get a higher level of MRD status. Other physicians I know with CLL , don't want to know to that level. It's a sort of out of sight out of mind approach. I am learning that all of my research, goals and hard work to measure, and to achieve to achieve uMRD 6 have created a lot of frustration and stress for me as in my community setting, These things are either not available, or get sabotage by. Labs and insurance.
I learned that because we did not do the clonal sequence at the start of treatment, that the bone marrow biopsy at one year, and 18 months on VO could not be sent for clonal sequence because they had no pre-treatment samples to compare to.
In my case, the best level of detection in available labs was 1 in 10,000 or uMRD 4.
I wanted to finish treatment before two years because of my family situation and risk of infections. My spouse and certain children have not been supportive of protecting me.
So the one year point I was tested for MRD and had 4/10,000 CLL cells per WBC. my Docs thought that this was a really good result even though it wasn't the uMRD6 that I had hoped for. I was given the option to stop then.
As a quick backdrop, I received Chemo immunotherapy in 2018 called FCR. at that point, my doctor would not even do flow cytometry to see how deep my remission was because she said that it would not affect my treatments nor decision at the time. and looking back, although I was disappointed, I agree that knowing MRD status would not have changed anything for me. in fact, it may have made me a bit more anxious during the return to watch and wait
With current VO, I continued for about five months after the first bone marrow biopsy and obtained another again hoping for a clonal sequence test with MRD6. I was disappointed again that I could not do Clos sequence because there was not enough CLL in the previous Bone Marrow to compare to. However, this turned out to be irrelevant because now there were 8/10,000 CLL cells . Although this was within margin of error, it was obvious to both of my CLL docs that continuing for the full two years was not going to improve my MRD status, and stopping would alleviate the side effects and allow for earlier immune system recovery. I stopped treatment.
At times I thought of going to a center that does the research on this treatment to see what unpublished data they had on people in my situation and does perhaps reconsider continuation of treatment.
ultimately, after the FCR, the 15 Skin Cancer, that followed, the loneliness of Covid as my family abandoned me, and the side effects of the most recent treatment, I decided the best thing for me was to just take a break from it all.
For me having a break was more valuable than achieving a higher degree of MRD status, or trying to perfect my treatment success.
While I know that my treatment free interval will be shorter than hoped, I do know that there are so many more treatments available now and they do a great job, I am not concerned about that shorter treatment, free interval.
I am focusing on, feeling well, and enjoying life as much as possible.
In your situation it is unlikely that a lab will have specimens from pre-treatment that could be sent to clonal sequence so that you could be tested for uMRD 6. Fortunately, studies are showing excellent treatment free survival after one year of VO in cases like yours.
If and when relapse occurs and you are interested in clonal sequence you would need to get someone to send a specimen to clono sequence prior to starting treatment. Then at intervals during treatment, you could be retested to see where you're at, and that could perhaps influence important treatment decisions. By then, there will be much more research. Available to determine how useful clono sequence is.
I hope this helps you sort through your situation.
Thank you so much for this explanation. I liked " I am focusing , feeling well, and enjoying life as much as possible."
As I understand it I can't do this additional testing because no one took samples before we started treatment in 2023. I assume the sample would have been specific for this test. I had two bone marrow biopsies before starting treatment but this testing was never mentioned.
I've been a lucky man. This is my second battle with Cancer. I survived squamous cell carcinoma of the tonsil (7 nodes) in 1996 and now in remission with CLL. I was given cisplatin then and had too sign a release that the drug may lead to leukemia in 20 years. I t was 20 years to the month that i was diagnosed with CLL. Of course no one knows if it was the cisplatin but I tracked my blood for 20 years and told my family Dr the year I went in for my annual that my absolute lymphocytes were going to go over 5000 and they did. I was on watch and wait for 7 years.
Good luck to you and may you be blessed like I have been.
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