Richter's and Novel Treatments/Combinations

[Jm954]

We've had a few members post about Richter's recently so I thought it might be time for a bit of an update on new treatments. In these reports there is not a lot of information about clonality and which mutations the patients have. Extensive pretesting for these variables as well as the clinical ones such as previous treatments etc should allow for a deep dive and more segmentation of Richter's diagnosis with better targeted treatment.

Richter Transformation (RT) of CLL remains one of the biggest challenges in the treatment and management with outcomes still very poor with a reported median OS is between 6 to 8 months. Conventional approaches with chemo- and chemoimmunotherapy have largely failed to improve response rates in RT patients. However, as the established treatment approach for de-novo Diffuse Large B Cell Lymphoma (DLBCL) is chemoimmunotherapy with a combination of Rituximab, Cyclophosphamid, Hydroxydaunorubicin, Vincristin and Prednisolon (R-CHOP), this has become the most commonly used regimen for lack of proven alternative strategies. Patients being fit enough for allogeneic transplantation are undergoing this procedure after induction with R-CHOP. However, the majority of patients are not suitable for transplantation and relapse quickly.

There clearly remains an urgent need to improve the therapy of RT by testing new compounds and combinations for treatment of this disease and there are several trials around the world using combinations of targeted treatments.

*

Tislelizumab is a humanized monoclonal IgG4 antibody against programmed death receptor-1 (PD-1) and now being tested in RT in a trial of Zanubrutinib Plus Tislelizumab. This trial, NCT04271956, from the German study group is recruiting currently around the world. Details here including inclusion and exclusion criteria clinicaltrials.gov/study/NC... ashpublications.org/blood/a...

*

This is an ASH report of the GIVeRS Phase-II Study to Evaluate the Efficacy and Safety of Obinutuzumab, Ibrutinib, and Venetoclax (GIVeRS) in Patients with Richter's Syndrome. Of note is that only 10% of participants in this trial had received any treatment for their CLL and many of the patients had already received a prior treatment for RT. Unfortunately, remissions were not long lasting but this tolerable combination may be a useful bridging treatment to get to SC transplant or CAR-T. ashpublications.org/blood/a...

*

In the UK, the STELLAR trial continues to recruit and offers the opportunity to have the addition of acalabrutinib to R-CHOP. There are no preliminary results as yet. cancerresearchuk.org/about-...

*

A retrospective, multicenter study of venetoclax-based treatment for patients with Richter transformation of chronic lymphocytic leukemia. In this study there is a lot of nuanced information but in summary, venetoclax-based combination regimens achieved higher CR rates than historical studies using chemotherapy, including a nearly 50% CR rate in the subgroup treated with R-CHOP + venetoclax. From the limited data available in this study, patients with prior venetoclax exposure for CLL had lower likelihood of achieving CR than those who were venetoclax naïve (13% vs 40%). Survival outcomes remained poor overall. ashpublications.org/bloodad...

*

This article reviews the current results for the treatment of Richter's with novel agents/chemo-immunotherapy. Unfortunately the results don't't offer any reason for huge optimism yet but new therapeutic developments, focusing on inhibitors of BTK, BCL2, the PD1-PDL1 axis, and T-cell–activating/engaging therapies have the potential to impact the natural RT disease course. These combinations must be tested in clinical trials to obtain the best information possible.

"Given the current treatment landscape, allo-HCT is one of the only options available for fit patients to achieve a long-lasting remission—a result often dependent on a deep treatment response prior to transplant. Perhaps the emergence of new combinations of treatments and development of novel targeted agents will not only allow for more efficacious bridging treatments for patients prior to allo-HCT, but also offer effective long-term disease control in patients who are transplant ineligible. Given historical poor OS seen with RT, we hope that the breadth of the trials currently available for patients with RT may bring exciting new treatment options for patients in clear need of improved therapies."

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

Jackie

[johnliston]

Kind of depressing

[mrsjsmith]

Thank you Jackie and agree it’s depressing reading.

Colette

[PennyLane2024]

It is important for everybody to know that Richter’s is RARE. According to huge study at Mayo Clinic, our chance of getting Richter’s in next five years is .7% for males and .3% for females. If you don’t have a complex karyotype and/or 17/53, 11, or 12, then your chances of getting Richter’s are minuscule.

ajmc.com/view/risk-of-richt...

[Jm954 Administrator in reply to PennyLane2024]

It is uncommon but not rare sadly even in untreated CLL.

Lots of figures splashed about here but these are the figures I have taken from that paper and it reports a 4.9% cumulative incidence at 10 years.

"Incidence of RT from time of diagnosis not statistically significantly different in the pre–novel agent and novel agent cohorts (HR, 1.6; 95% CI, 0.9-3.0, P = 0.13). And while there was a higher risk of RT after treatment for CLL/SLL prior to the novel agent era, the difference was not statistically significant (HR, 2.4; 95% CI, 0.9-6.1; P = 0.07)."

"The cumulative incidence rates for RT at 1, 5, and 10 years from CLL/SLL diagnosis were 0.6% (95% CI, 0.4-0.9%), 1.8% (95% CI, 1.3-2.3%), and 3.0% (95% CI, 2.4-3.8%), respectively. The 1-, 5-, and 10-year incidence rates for RT were 0.3% (95% CI, 0.1-0.8%), 3.3% (95% CI, 2.4-4.5%), and 4.9% (95% CI, 3.7-6.5%) among the 1382 patients who received therapy for CLL/SLL in the study period.

Not trying to scare anyone but it's good to be informed and aware.

[PennyLane2024 in reply to Jm954]

“In the novel agent era, 1366 patients diagnosed with CLL/SLL had 1- and 5-year RT incidence rates of 0.5% (95% CI, 0.2-1.1%) and 1.1% (95% CI: 0.6-2.2%), respectively.” The 10 year rate in the novel era is not available.

As far as I know, this study is the largest and most recent study of the risk of Richter’s in the novel era. Individuals can decide themselves if 1% is rare or not. I am going to believe it is rare because I need less anxiety in my life right now.

[Sushibruno in reply to PennyLane2024]

This is the most terrifying thing about cll to me is so so terrifying. My anxiety takes off I don’t think that I would be able to handle it!

[Big_Dee in reply to Jm954]

Hello Jm954

Whereas the information is somewhat depressing, it is very important to understand RT enough to know that early detection is of benefit to us. It is also important to know that aggressive CLL, bulky lymph nodes and high LDH are possible indicators of RT, so everyone does not panic. Thank you for this timely information.

[Jm954 Administrator in reply to Big_Dee]

I had exactly those features and positive PET when I relapsed and I was investigated for RT. Horrible time but thankfully 'only' aggressive and accelerated CLL on biopsy.

Decision to go to all transplant when we could was made by my Dr at that point.

[PennyLane2024]

Great study on who is at risk for Richters.

haematologica.org/article/v...

[Fowey2009]

Thank you for this Jackie, which is very comprehensive.

The information above refers to RT to DLBC Lymphoma. There is another RT to Hodgkin’s lymphoma which is even rarer, but much easier to treat with the chemo ADVB. Because it is so rare it took a long time before they diagnosed it in my husband. However once he received chemo he bounced back, and is now very well two years later (now on acalabrutinib).

Beryl

[Junebug20 in reply to Fowey2009]

Yes, apparently there are only 100 in the nation. My husband also had a transformation from CLL to Hodgkin’s lymphoma. Yes, my husband was near death until they finally figured it out. He gets his last chemo the end of the month and a pet scan on Sept 5. 🤞He is doing well, so we are hoping for a good report.

[Fowey2009 in reply to Junebug20]

How interesting, as we have a similar story. My husband was diagnosed with CLL in 2013 (aged 66) and had several treatments (including FCR and venetoclax) before becoming very unwell in 2022. It took some time for him to be admitted to hospital and he then spent 7 weeks there. I don't think anyone thought he would be coming home as he was so ill. However the minute they figured out that it was hodgkins and started him on chemo, he bounced back (first chemo was grim but OK after that).

Since then he has been on acalabrutinib (calquence) and all his bloods are in the normal range. Last week we went on holiday and walked miles including up mountains. In a few weeks time we are off to Europe for a 4 week trip.

Having had a close shave with death, we are making the most of him being so well.

I do hope your husband has such a good recovery.

(My husband is Trisomy 12 - that's about as much info as we got in the UK)

Beryl

#hodgkins #richters #CLL

[RedDevil74]

But with a median time to progression from CLL diagnosis of <5 years. Does this mean Richters is more of an early event? And due to the heterogeneous nature of CLL, is a crude percentage risk accurate?

[Jm954 Administrator in reply to RedDevil74]

Brilliant questions. There are some answers in the links that I posted

Some mutations definitely predispose to Richter's eg NOTCH1 and I'm sure there will be others that are not routinely tested for that we don't yet know about.

This link posted by  PennyLane2024 is an excellent summary

haematologica.org/article/v...

[Devonwife]

My husband was diagnosed with Richters in December 2021. He had been treated with Ibrutinib for the very rare, B-cell prolymphocytic leukemia (atypical CLL) for the previous two years. He chose not to accept R CHOP and instead was enrolled on the Pirtobrutinib (now marketed in the US as Jaypirca) trial which he has been on now for 2 years and 8 months. When we first read about Richters, the main message from online searches was that the survival rate was 'dismal' but online research now reveals an improving picture. Dr Toby Eyre in the attached video produced in November 2023, gives a realistic but more optimistic view on the current situation with new drugs having potential including nemtabrutinib, epcoritamab, glofitamab and mosunetuzumab. So not all gloom and doom and my husband is a walking testament to that.

vjhemonc.com/video/66jds15f...

[Newdawn Administrator in reply to Devonwife]

Your message is so important Devonwife because during this recent period where I was having investigations for a more aggressive transformation, I researched and sourced the people who had more optimistic journeys after a RT diagnosis. I observed a much improved picture even though it’s clearly a very challenging diagnosis nobody wants.

I do worry that RT has become the ‘hide behind the sofa’ condition and quite rightly it instills dread. We need to be aware of the risks and the challenge it presents but for anyone presently diagnosed or undergoing tests for RT, I’d urge more hope and possibility because I was amazed how many people were able to evidence much better outcomes. There’s so many factors to consider in each individual case. After hearing about median survival rates of under a year, I was stunned at how many cases I heard of people surviving years with RT/DLBCL essentially eliminated (even in the clonally related patients). Of course the CLL remained and much depends on what flavour of that was continuing to create mischief! 🙄

Newdawn

[Jm954 Administrator in reply to Devonwife]

Just brilliant, so important to hear this 🎉

[laurieq in reply to Devonwife]

Thank you for this. My husband with RT is also on Pirtobrutnib and doing well.

It is very depressing to hear all the adjectives and it makes me so anxious. I think it is so important for those of us involved with patients who are doing well to share the information that all is not "dismal". Thank you for sharing that message!

[RogerPinner]

Jackie, the most optimistic comment in your post may be "new therapeutic developments, focusing on inhibitors of BTK, BCL2, the PD1-PDL1 axis, and T-cell–activating/engaging therapies have the potential to impact the natural RT disease course. These combinations must be tested in clinical trials to obtain the best information possible". This presumably is what Devonwife is referring to in regard to her husband's positive response to Pirtobrutinib, and the Toby Eyre video.

Let's hope the trials proceed at pace.

Roger

[Katinlr]

Is CAR-T not one of the therapies with some amount of success?

[Jm954 Administrator in reply to Katinlr]

Less long term success than transplant but this may change in the future, still relatively new. Getting the T cells is part of the difficulty.

[Smakwater]

According to science the universe is 13.7 billion years old.

I just want a medicine to stop a headache and after that maybe treat Richter's reliably.

JM

[Analeese]

Wow! Very frightening since I have three out of the four markers mentioned plus notch one and a few more besides that.

[Skyshark]

This report has nice flowchart to treatment.

ascopubs.org/doi/10.1200/ED...

RT flowchart to treatment

[Skyshark in reply to Skyshark]

And a graphic of trials.

RT trials

[AussieNeil Partner Administrator]

This 'biggest challenge' is receiving international attention. From Italian CLL researchers;

Advances in the understanding of molecular genetics and therapy of Richter transformation in chronic lymphocytic leukemia

pubmed.ncbi.nlm.nih.gov/392...

During the last years, advances in the knowledge of the biological mechanisms underlying RT allowed to identify genetic and molecular lesions that can potentially be targeted by novel selective agents. Pathway and checkpoint inhibitors, bispecific antibodies and CAR T-cell therapy are currently under investigation and represent promising treatment options. This review summarizes current biological evidence and available data on novel therapeutic agents.

Unfortunately, currently paywalled.

Neil