Real-world incidence and prevention of tumor lysis syndrome (TLS) in chronic lymphocytic leukemia (CLL) treated with venetoclax. From MSK

[AussieNeil]

A few members who have been recommended ventoclax/Venclexta treatment, have posted about their concerns of developing Tumor Lysis Syndrome (TLS). So hopefully the following report from Memorial Sloan Kettering (MSK), summarising 5 years of experience (2016 to 2020 inclusive), of "616 venetoclax escalations among 136 pts with CLL", will be reassuring. The abstract reports that "none developed clinical TLS."

As the venetoclax safety information states: venclexta.com/important-saf...

TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS.

You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA.

It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

The Venclexta physician information document, rxabbvie.com/pdf/venclexta.pdf states;

"The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. Splenomegaly may also increase the risk of TLS in patients with CLL/SLL.

Assess all patients for risk and provide appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA, follow dose modification guidance."

Section 2.4 of that document includes a section Risk Assessment and Prophylaxis for Tumor Lysis Syndrome.

Now to the abstract from the MSK report of 5 years of experience with venetoclax ramp-up for CLL patients, which also provides one center's experience of the percentage of patients requiring hospitalisation for proactive TLS monitoring, with my emphasis.

pubmed.ncbi.nlm.nih.gov/391...

Venetoclax is a BCL2 inhibitor used in chronic lymphocytic leukemia (CLL) which can cause tumor lysis syndrome (TLS). We aimed to determine the incidence of and risk factors for TLS among patients with CLL/small lymphocytic lymphoma (SLL) who received treatment with venetoclax at our institution from 1/1/2016 to 12/31/2020. We included 616 venetoclax escalations among 136 pts with CLL. 74 pts (54%) underwent escalation exclusively outpatient, 35 (26%) had at least one planned hospitalization and 27 (20%) were escalated exclusively inpatient. During venetoclax initiation, 86% of pts received allopurinol, 71% intravenous hydration, 18% phosphate binders, and 10% prophylactic rasburicase. Among the entire cohort, 7 pts (5.1%) developed laboratory TLS by modified Cairo Bishop criteria and none developed clinical TLS. Incidence of laboratory TLS was 15% for those escalated exclusively inpatient, 2.9% for those with any prophylactic hospitalization and 2.7% for those escalated exclusively outpatient. Those who developed TLS were more likely to have higher TLS risk, and no additional risk factors were identified. In this single institution retrospective cohort study, laboratory TLS was observed, though clinical TLS was not. Prophylactic measures, including use of IV hydration, may have contributed to low rates of observed TLS in the outpatient setting.

The attached graphic illustrates how the risk of TLS is determined and the recommended mitigation steps.

Neil

[SurfSurf]

Thank you AussieNeil for posting this—Dr. Geyer, one of the authors, is the Dr. who took care of me during my high risk TLS starting June 2023. “Lucky” to live close to MSK he allowed me to live at home during V ramp up, but this meant I was at the clinic 5 or more days a week vs 3 days a week in hospital. Only one Wednesday I almost had to be admitted. Was a long 5 weeks but am happy to report was uMRD at 6 months and off the V at 9 months (am on a fixed duration V+O trial). High risk TLS is “manageable” now!

Susan

[TeamDirtyBoots in reply to SurfSurf]

Yes, thank you AussieNeil for posting and as SurfSurf wrote, TLS is manageable now.

Doctors have much better understanding of who will likely be mostly affected by TLS, and they have learned more about how to prevent and how to treat TLS.

I was concerned about TLS when I started V+R in 2019. The change in letters itself shows its been awhile. My doctor at Stanford at the time (Dr. Coutre RIP) assured me that since I didn't have bulky lymph nodes I likely wouldn't have much in terms of TLS and he was right.

[Kwenda]

The recommendation states ;- "Splenomegaly ( enlarged spleen ) may also increase the risk of TLS in patients with CLL/SLL."..

Is not then a better choice to take say Acalabrutinib or any BTK drug for a few months FIRST to reduce the blood counts and spleen size a little, BEFORE going to the V & O.??

Are there any drug trials, or readers of this page, following this combination.?

[AussieNeil Partner Administrator in reply to Kwenda]

With combination therapies incorporating venetoclax, it's common to have a cycle of BTKi or anti-CD20 monoclonal antibody treatment (obinutuzumab or rituximab) before commencing the venetoclax ramp-up, to reduce the TLS risk.

Neil

[SeymourB in reply to Kwenda]

Kwenda -

I am reminded of the report that pretreatment with Ibrutinib (and probably other BTKi's) helps prevent Obinutuzumab/Gazyva infusion reactions:

ncbi.nlm.nih.gov/pmc/articl...

Ibrutinib reduces obinutuzumab infusion-related reactions in patients with chronic lymphocytic leukemia and is associated with changes in plasma cytokine levels

Haematologica. 2020 Jan; 105(1): e22–e25.

However hopeful this is, pretreatment with a BTKi doesn't seem to be an option outside of a clinical trial, at least not in the U.S.

Also, I should mention that Obinutuzumab as the initial drug in the O&V combo also carries a risk of TLS.

=seymour=

[LeoPa]

This risk is why they bring down the ALC with Obin before they start with the Venetoclax, right?

[AussieNeil Partner Administrator in reply to LeoPa]

Yes, that or another drug is the usual approach, as I mentioned above healthunlocked.com/cllsuppo...

[SeymourB]

AussieNeil -

We should note that the abstract mentions only the less serious laboratory TLS. Much more serious, and much less common is clinical TLS.

ncbi.nlm.nih.gov/books/NBK5...

StatPearls: Tumor Lysis Syndrome

Last Update: October 31, 2022.

=seymour=

[AussieNeil Partner Administrator in reply to SeymourB]

Yes, the abstract notes that "In this single institution retrospective cohort study, laboratory TLS was observed, though clinical TLS was not." So while some of the patient blood tests showed the biochemical disruption of TLS, it wasn't serious enough for any of them to become ill.

[elm1]

thanks for that. I just started the O infusions. In a couple of weeks I start V. I was a little spooked. So thanks for the reassurance

[Skyshark]

Two provinces in Canada and at least one NHS cancer alliance (Thames Valley Network) in UK now use a slower initial rate for infusion of Obinutuzumab with hourly escalation to normal rate for those considered to be at high risk of severe IRR. 6mg/hr > 12mg/hr > 25mg/hr, takes about 5 and a half hours instead of 4. This should reduce cases of early IRR that often occur in the first few minutes but obviously won't affect late reactions that may occur hours or even days after infusion.

V+O 80 patients, 1 case of laboratory TLS on day 3 of first dose of Obinutuzumab. Makes case for Venetoclax ramp-up as outpatient on V+O.

ash.confex.com/ash/2023/web...

V+I TLS risk reduction from CAPTIVATE FD trial, although similar small percentage of high risk remain, they and some medium risk were still considered to need hospitalisation.

pharmacyclicsmedinfo.com/do...

The lead in 3 doses of Obinutuzumab on V+O and 3 cycles of Ibrutinib on V+I both reduce the risk of TLS on Venetoclax ramp-up. V+O shows a greater percentage transition to low risk TLS. After de-bulking, patients should be re-staged for TLS risk before starting Venetoclax.

(I failed to de-bulk, V ramp-up was in hospital, reached unconfirmed CR by cycle 7 of V+O and CR at EOT cycle 12.)

I've not looked at TLS risks for Venetoclax monotherapy or R/R Ven+R, this is a bridge I've yet to cross and I'm hoping that ReVenGe trial delivers V+O as 2nd line in UK NHS before that, already available in US. When a patient taking BTKi drugs shows signs of progression the BHS guideline is to start the Venetoclax ramp-up while still on BTKi and then add the Rituximab. This will usually be at a low level of disease burden rather than waiting to reach iWILL guidelines for treatment.

TLS risk category, V+O C1D22, V+I after 3 cycles I.