Tumor Lysis Syndrome: What ( CLL ) Patients Need to Know (Leukemia and Lymphoma Society podcast)

[AussieNeil]

Many of us are aware of the risk of tumor lysis syndrome (TLS) when we commence treatment, particularly with venetoclax and that the purpose of the venetoclax ramp-up, is to reduce the risk of TLS occurring. TLS can also occur with other CLL treatments, especially when they are fast acting, rapidly killing CLL cells, such as can occur with obinutuzumab and rituximab. Having poor renal function and/or a large CLL tumour burden; such as an enlarged spleen, large lymph nodes, and/or a high lymphocyte count, also increases your risk.

Many may not be aware that three brave CLL patients lost their lives in an early phase venetoclax clinical trial, halting that trial until the FDA was satisfied that the trial could safely continue with the ramp up which was introduced to mitigate that risk. So now have the venetoclax/Venclexta prescribing information, which includes the legacy of a TLS assessment risk. The starting pack accordingly includes the 10, 20, 50, 100, 200, 400mg dose per week ramp-up packs. From the venetoclax prescribing information venclextahcp.com/cll/dosing...

Considerations for TLS with VENCLEXTA (venetoclax tablets)

- VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for tumor lysis syndrome (TLS) at initiation and during the ramp-up phase in all patients, and during reinitiation after dosage interruption (see dose modification and interruption information)

- Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase

- The risk of TLS is a continuum based on multiple factors, particularly reduced renal function (CLcr <80 mL/min) and tumor burden; splenomegaly may also increase the risk

- Consider all patient comorbidities before final determination of prophylaxis and monitoring schedule

- The risk of TLS may decrease as tumor size decreases

Further down in the venetoclax prescribing information, you'll find the Tumor Burden Assessment Tutorial

venclextahcp.com/cll/dosing...

For those interested in thorough detail about TLS and how it is treated, this is covered in this week's The Bloodline with LLS - A Podcast for Patients and Caregivers

Tumor Lysis Syndrome: What Patients Need to Know

In certain blood cancers, an urgent condition called tumor lysis syndrome (TLS) can develop. Dr. Tina Bhatnagar of the West Virginia University Cancer Institute joins us in this episode to explain why tumor lysis syndrome occurs and how it is treated. Although considered a medical emergency, Dr. Bhatnagar reviews how prevention and treatment can be successful in the treatment of TLS.

:

And what it essentially amounts to is a tumor breakdown. As cancer cells are dying off, either spontaneously or in response to chemotherapy, a number of electrolytes, including phosphate and uric acid end up in the bloodstream and can end up precipitating in the kidneys and ultimately causing a lot of organ dysfunction.

Primarily, we see it in the kidneys; but in it's most severe forms, it can cause neurologic issues like seizures or altered mental status, or it can also cause heart rhythm disturbances if left untreated. And so, it is something to be very aware of, and it has to be monitored aggressively because it's very treatable and something that can eventually lead to significant side effects and morbidity if it's left untreated.

thebloodline.org/TBL/142e140

The interview transcription is available here: thebloodline.org/TBL/wp-con...

Of note. the requirement to drink more fluid than you may be used to, prior to and throughout the venetoclax ramp-up phase is to help protect your kidneys. Just keep in mind that more is not necessarily better; drinking excessive amounts disrupts your sleep, which your body needs for repair/recovery during treatment. It's also possible to make yourself very ill if you overdose on water/fluids, when you can develop potentially fatal hyponatremia (too dilute blood sodium). mayoclinic.org/diseases-con... Again, from the venclexta dosing and administration information, with my emphasis:-

*1.5-2 L of water (~56 ounces) should be consumed every day starting at least 2 days before the first dose and throughout the ramp-up phase, especially the first day of each dose increase. Administer intravenous hydration for any patient who cannot tolerate oral hydration.

†Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA.

‡Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time.

§For patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent dose ramp-up.

Note that you don't need to continue with the high fluid intake after you have completed ramp-up. Also, while the dosing information doesn't specifically note this, all fluid intake, not just water should be counted in achieving the 1.5 to 2 litres. The slight diuretic effect of caffeine in tea, coffee and energy drinks, isn't considered to make any difference. Per this advice from Mayo Clinic "Water is the best liquid you can drink to stay hydrated. But caffeinated drinks can help meet your daily fluid needs." mayoclinic.org/healthy-life...

Given the importance of knowing about TLS, this is an unlocked post, so any replies can be read by people finding this post via Google, etc.

Neil

[JigFettler Volunteer]

Thanks Neil. This is important and just a bit scary.

During FCR I lost 7kg in the 1st week- I had massive lymphadenopathy - and my renal function dropped to 50% briefly.

Lymphnode mass and spleen vanished in 1st 10 days. That was a lot of tissue to dispose of.

TLS is quite scary, but medics know about it and can manage it. No excuse not to be on top of it. Drinking a lot was my part of the process.

Jig

[CLLerinOz Administrator]

Earlier this month, the British Medical Journal posted an online early view of an article about a study that looked at venetoclax ramp-up strategies for CLL in the UK.

The real-world retrospective study "evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp-up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS."

The authors note that:

"Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation may have manageable associated TLS risks, including in high risk cohorts".

However, they also noted that their observations "require confirmation in larger studies".

Additionally, they identify "common denominators of centres where outpatient ramp-up was feasible" and propose them as minimal standards to conduct outpatient venetoclax dose escalation:

"(i) dedicated CLL/haematology nurse specialists,

(ii) immediate availability of acute hospital admission beds and

(iii) relatively rapid laboratory turnaround time to manage 6 h blood results during working hours.

The authors appreciate these conditions might not be met in all CLL-treating centres, as suggested by the unexpectedly high proportion of low-risk patients escalated as inpatients, which was maintained up to 15% even in the final steps of the ramp-up phase.

"In our study population, only three patients received venetoclax-obinutuzumab, hence we cannot draw conclusions on the real-world TLS risk of these regimens."

" . . . high TSL [TLS] risk was the only variable associated independently with TLS events".

In this study, "venetoclax was most frequently following BTKi exposure and mostly in the third line or later setting."

"Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high-risk patients, four occurred at 20 mg dose and three at the 6-h time-point. Inpatient versus outpatient TLS rates within the high-risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis.

"The main limitations of our study were the low number of TLS events and the potential for selection bias in the inpatient/outpatient groups. Nonetheless, provided appropriate infrastructure and staffing levels permitting it, we provide evidence of relative safety of the outpatient escalation for venetoclax and validate the effectiveness of the venetoclax ramp-up scheme mitigating TLS risk in this context."

The full article is available here: Figueroa-Mora, R,  Rampotas, A,  Halperin, D,  Worth, T,  Vidler, J,  Melotti, D, et al.  Venetoclax ramp-up strategies for chronic lymphocytic leukaemia in the United Kingdom: a real world multicentre retrospective study. Br J Haematol.  2023; 00: 1– 6. doi.org/10.1111/bjh.18738

(my emphasis)

[spi3]

Ty for sharing and God blessed the 3 folks that led the way for venetoclax to be taken for so many of us

[JigFettler Volunteer in reply to spi3]

Absolutely agree. Well said!

Thinking of those, and so many others who spear head progress for us all.

I had FCR outwith a trial under the guise I did not want to switch consultant. I would have had to ... it was the FLAIR trial then in the UK.

Jig.

[SeymourB]

AussieNeil -

Really excellent interview, Neil!

I can assure folks that Venetoclax is not the only risky therapeutic for TLS. The ramp up has largely made TLS a thing of the past for Venetoclax, I think. But new combo therapies mayincrease the risk in susceptible people, I think.

I think it's important to stress who is at risk - large lymph nodes, large spleen, high ALC, high bone marrow concentration, high uric acid, and high creatinine or eGFR <60mL/min.

I suspect that Obinutuzumab/Rituximab along with almost any other therapeutic could trigger it in susceptible people.

I found a nice YouTube that explains TLS in more detail, but is not specific to CLL:

youtube.com/watch?v=yPLzcb9...(Not working as expected?)

Armando Hasudungan - Tumour Lysis Syndrome (Tumor Lysis Syndrome) - pathophysiology, diagnosis and treatment

Armando correctly distinguishes between Laboratory TLS and Clinical TLS

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

StatPearls, Tumor Lysis Syndrome

Adebayo Adeyinka; Khalid Bashir.

Last Update: October 31, 2022.

I had a case of Laboratory Tumor Lysis, in the opinion of the doctors at M.D.Anderson. My creatinine peaked at 1.41, but I had no seizures or arrhythmias. Uric Acid was 8.9 mg/dL the week before, for which they gave me Allopurinol. Calcium dropped below normal, and Potassium increased above normal, but not quite by the formula in the above article.

I'm still going through my test results and physician notes from the early days of my Pirtobrutinib, Obinutuzumab, Venetoclax trial. I think I had almost 2 dozen blood draws in 4 days while hospitalized for back in February. I did not start Venetoclax until a month later.

What triggered TLS for me was the initial Day 1 dose of Obinutuzumab (100ml) plus 200mg of Pirtobrutininb. I think that either one of those alone might not have triggered it. I never did do the Day 2 dose (900ml) of Obunutuzumab. I did 200mg of Pirtobrutinib daily.

The doctors at M.D. Anderson knew I was at risk for TLS, becuse I had at least one lymph node at 5cm, high ALC/WBC (ALC at one point > 124K), splenomegaly - those 3 together define "bulky disease" ,plus high uric acid, and high creatinine that started back in November, 2022. I was told that the high uric acid and creatinine was due to a spontaneous tumor lysis before treatment as my CLL got more aggressive. The dying cells overwhelmed my kidneys somewhat. I started on Allopurinol for the uric acid a week before treatment. I thought I was hydrating enough, but I wasn't counting actual ounces or liters until after I was hospitalized.

The evening after the infusion reaction to the initial dose of Obin, I had my first dose of Pirtobrutinib, and 24 hours later my ALC went from 88K on Feb 23 to 5K on the 24th in 24 hours and has stayed down since then. The addition of Venetoclax has brought it down further. It was most recently at 1K on May 2 (Cycle 3, Day 14).

My LDH went from 496 before treatment on Feb 14th to a peak of 1701 on Feb 23d, and has stayed normal since a week later.

The doctor's notes said:

"#. CLL (FISH: +12; IGHV-unmutated; NGS-NOTCH1, BCL2)

-Originally diagnosed at OSH in 2011 and remained on observation

-Developed left parotid gland swelling around 2021-->biopsied at outside 8/2022 and showed CLL without transformation

-Presented to MDA originally on 8/8/2022 to establish care

-Bmbx done 2/14/23 showed CLL, trisomy 12, unmutated IGHV

-Currently C1D3 of Pirtobrutinib+Obinutuzumab on protocol 2021-0578

-Held and skipped D2 dose of Obinutuzumab (900 mg) due to severe reaction for testing dose 100 mg obinu on 2/22, plus dramatically drop of WBC and PLT and TLS

-Per Dr. Jain (PI), ok to skip D2 dose, will continue D8 dose

-Follows Dr. Swaminathan outpatient 2/28/23, may readmit for D8 dose on 3/1

-Will follow local oncologist in Louisiana in interim

#. Fever/chills/Hypotension/Diarrhea/Nausea Secondary to Obintuzumab Infusion

-2/22/23 15 minutes after starting obintuzumab infusion patient became dizzy, diaphoretic, developed diarrhea, and blood pressure 84/57-->500 cc fluid bolus of normal saline given X1-->blood pressure recovered to 106/59, continue hydration @100cc/hr on 2/23

-Fever during obinutuzumab infusion and continue, last fever 2/24@0014

-2/23/23: Cultures NTD, CXR unremarkable

-2/23/23: start Zyvox/Cefepime, dc Zyvox 2/23, dc cefepime 2/24 (consider infusion reaction and not infection)

-Hold and skip D2 dose Obinutuzumab 900 mg dose on 2/23/23, and plan to resume D8 dose on 3/1/23

-Close monitor

#. TLS Secondary to CLL therapy, resolved

-Patient admitted 2/21/23 WBC: 85.4K starting on CLL treatment with Pirtobrutinib+Obintuzumab with risk for TLS

-Baseline creatine 1.2-1.3

-Cr trending up, Cr-1.4 on 2/23/23; K slightly elevated, Phos and uric acid WNL

-TLS lab WNL on 2/24/23

-S/p hydration @100 cc/hr, continue on scheduled allopurinol 300mg oral daily

-Avoid nephrotoxic medications and renally dose medications as necessary

-After discharge, encourage oral hydration."

The following week, they spread the Day 8 Obinutuzumab infusion across 2 days, and had me stay a few nights as an inpatient. But no further Obin reaction. I did the Day 15 infusion all in 1 dose as planned.

I've been on the full 400mg dose of Venetoclax in addition to the 200mg dose of Pirtobrutinib since April 26th. I also get Obinutuzumab infusions monthly. ALC has been slightly above normal a couple of times in March, peaking at 6.6K. But it's been < 3K for a month now. I get bi-weekly tests now till the end of Cycle 7.

I currently still aim for 2-3 liters of water per day - 68-101 oz. Even at 80oz, I had perceptibly high creatinine on a couple of draws during the Venetoclax rampup - 1.14 to 1.21 mg/dL (range 0.67-1.14mg/dL) that may have been due to high protein meals or something - I'm really not sure.

=seymour=

[starlifter]

You asked about my experience with rituximab and venetoclax I started with cyclofosfamide and that didnt go very well, i had a thrombosis then we switched to venetoclax with 6 months of rituximab it went very well that was 2 years ago , I am now back to stage 0 in complete remission , with no side effects during treatment which doesnt always happen and I feel excellent now off treatment and being followed up every six months , for me venetoclax and rituximab best thing every invented , thanks