Remembering Jacques-Louis Binet (1932–2024): A CLL Pioneer

 Until recently researching CLL was a dead end in a hematologist’s career, but Dr. Binet and Dr. Kanti Rai changed that with their staging of CLL.

Their staging began to organizing thinking around CLL and helps sort out the wide heterogeneity or differences seen in the outcomes of different CLL patients. CLL became more predictable, more sortable and therefore more accessible to researchers.

Below is a comparison of the two staging systems for chronic lymphocytic leukemia.  Remember that both systems were designed before the molecular/genomic era and remain in use today, especially for prognosis in untreated patients.

Timeline:

• 1975 – Rai staging (USA):
  Kanti Rai and colleagues published a staging system in Blood that stratified CLL based on lymphocytosis, lymphadenopathy, splenomegaly/hepatomegaly, anemia, and thrombocytopenia.
• 1981 – Binet staging (France/Europe):
  Jean-Louis Binet and colleagues published their simpler system in Cancer, focusing on the number of involved lymphoid areas and presence of *anemia or thrombocytopenia.

 

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Rai vs. Binet

System	Stage(s)	Criteria	Risk Grouping
Rai (1975)	Stage 0	Lymphocytosis only	Low
	Stage I	+ Lymphadenopathy	Intermediate
	Stage II	+ Splenomegaly and/or Hepatomegaly	Intermediate
	Stage III	+ Anemia (Hb < 11 g/dL)	High
	Stage IV	+ Thrombocytopenia (<100 ×10⁹/L)	High
Binet (1981)	Stage A	< 3 lymphoid areas involved, no anemia or thrombocytopenia	Early
	Stage B	≥ 3 lymphoid areas involved, no anemia or thrombocytopenia	Intermediate
	Stage C	Anemia and/or thrombocytopenia, regardless of nodal involvement	Advanced

The genius of their observation and their clinical relevance is what made these staging systems so useful to this very day.

Those were the days before flow cytometry and genetic testing, days when physicians had to rely solely on their diagnostic acumen to manage their patients. Days before “Test before Treat.”

Dr. Binet passed late last year at 92 years old. I had the pleasure of meeting him late in his life. Dr. Rai is still as sharp as ever in his mid 90s, but his impaired mobility limits his ability to practice medicine. He saw his last patient in august of 2025. I consulted him at Long Island Jewish early in my CLL journey and we stayed friends since. He was a wonderful doctor. The CLL community is diminished by his retirement.

An era is passing. Dr. Kipps shares this wonderful remembrance of Dr. Binet closing with the line: “With his passing, hematology is not widowed, but orphaned.”

My CLL Hangs on by a Thread: Stopping Epcoritamab

As I said before, August 2025 marks two full years that I’ve enjoyed the benefits from my trial of epcoritamab, a bispecific T -cell engaging monoclonal antibody for my CLL. But the last remains of my chronic lymphocytic leukemia (CLL) have remained stubbornly persistent for about a year and half. I have been in a complete remission (CR) with normal blood counts, normal physical exam, and all my lymph nodes shrunken back to normal size when imaged since February of 2024. That was only six months after starting the trial for my high risk (del 17p, TP53 mutated, del 11q, complex karyotype, unmutated IGVH, NOTCH1, and more) relapsed CLL. This rapid response was reinforced when my testing for measurable residual disease (MRD) by next generation sequencing (NGS), specifically clonoSEQ testing showed only one or less clonal CLL cells per million in my peripheral blood and about 45 cells per million in the bone marrow. It seemed I was destined for a uMRD^-6 remission.

But the rapid fall in tumor burden has not continued. A year and half later, my CLL MRD testing in my blood stream remains the same. So have my routine blood counts and scans. I am still in a complete remission with detected measurable residual disease by clonoSEQ at the level of less than one per million cells (dMRD^-6). What’s new now is that the results are still unchanged through the end of July 2025. Four sequences were measured: 

·      one stayed the same at undetectable,

·      one stayed the same at less than one,

·      two moved from one per million to less than one per million. 

So essentially stable.  As far as know, I am the only one in the trial who has achieved a CR without also reaching uMRD^-6.  So close, but not there

I am not sure what benefit continuing to flog my T-cells with the bispecific antibody to kill my cancer cells will do. 

I am also not sure what harm it might be doing. 

I do know that my good B lymphocytes are missing in action as they are directly targeted by epcoritamab. I know my T lymphocyte subsets are low and that the ones that I do have are likely exhausted (and therefore ineffective) by two years of being called into action to kill all my B- cells, cancerous or not.

Not surprisingly with no B-cells and iffy T-cell counts and activity, early data shows infections are the leading cause of death in my trial.

I also know that once I go off the trial, it may be hard to restart epcoritamab “off label” as no bispecific is yet approved in CLL should I need it again. 

Psychologically, epcoritamab has been my security blanket. I feel I am doing something by staying in the trial, but am I really? It was hard for me to stop my ibrutinib, but when I did, I did fine for years. 

My past experience with relapses helps predict the future. Once my CLL reached one per million cells in the blood after my CAR-T, I was staring at a new treatment choice in less than two years. That treatment was epcoritamab. Will it take off faster this time? The timing of when I need treatment must be near prefect, as I almost certainly will be looking to a clinical trial for knocking back my recurring clone. Will there be a degrader or a new BCl2 inhibitor or dual inhibitor or combo trial that I could use when I need it? 

Still most bispecifics, when used for other lymphomas, are taking for a fixed duration such as two years, not forever. 

I thought last month would have been when I stopped. But I stopped the cordyceps instead on Dr. Danilov’s advice with a plan to recheck my T-cells. Regardless, I will be surprised if I continue epcoritamab any longer. 

Despite a rough take off with cytokine release syndrome (CRS) and adverse events over the first rocky two months, it has bought me two great years of a deep remission, and a chance for a long glide off therapy. I am very grateful for the trial and to the team that has cared for me led by Dr. Danilov, trial nurse Alex and GenMab for their flexibility and diligence in making this possible. I hope, but am uncertain, that others with CLL will be able to enjoy similar benefits.

My CLL Immunity is Impaired in Both My B and T Cells

By August 2025, I’ll be two years on epcoritamab, effective against my CLL but also suppressing my normal T and B cells and increasing my infection risk.

Infections are the leading cause of death in chronic lymphocytic leukemia or CLL, accounting for between one-third and half of all mortality. Patients on treatment are often at even higher risk.

In the case of my trial of epcoritamab, of the four deaths recorded, three were from infection and one was from skin cancer that may well have been related to the immune suppression caused by both the CLL itself and the epcoritamab.

While I have so far dodged any infections or second cancers other than one basal cell carcinoma easily cured with a Mohs procedure, specialized method of surgically excising the cancer, I don’t plan to test my luck anymore.

What cinched my decision to stop the trial was the results of my T cell subsets blood test. I already knew that the bispecific antibody had for the most part wiped out all my all my B cells, the cancerous ones that had mutated to form my clonal CLL, but also all my healthy antibody producing B cells. Epcoritamab targets the surface marker CD20 found on all B lymphocytes, so no surprise there. In this way it is similar to other monoclonal antibodies used to treat CLL such as rituximab and obinutuzumab in that it depletes cells that are normal or cancerous. And while not having any antibody forming B cells is not ideal, it is rarely life threatening.

Low or no T cells is a whole different story. Think AIDS. Epcoritamab is a bispecific antibody. It works its magic by engaging my healthy T lymphocytes to kill the B lymphocytes, but in doing so, the T lymphocytes exhaust themselves and die.

My T cell counts are low. They weren’t six months ago. My helper CD4 T cell count is 350. Normal is >500. AIDS range in <200. My cytotoxic or CD8 killer T cell count is also low. Obviously, my total T cell count is low. It might be even lower now as the blood was drawn before I received another and likely last epcoritamab injection. And the T cell counts only address the quantity of cells. Their quality is almost certainly impaired. 

Time to quit. The risk benefit ratio has tilted in the wrong direction. The likelihood of getting much more benefit from one more shot in the belly is small, the chances of a long treatment free remission are already high if I stop now, and the future looks bright with the number of great new therapeutic options available when the time inevitably comes that I’ll need treatment again growing every year.

Definitely time to say thanks and move on. In a follow-up post here, I’ll talk more about the psychological impact of going off therapy. At least in my case, while it will be wonderful to not have to engage with my cancer so often through all the regular trial visits, there was some real reassurance in checking in monthly with my doctor and knowing all was going well. I will miss that.

Doing Great Two Years on CLL Epcoritamab Trial: Time to Stop?

 August 2025 marks two years on the epcoritamab trial for my CLL. Since Feb 2024, blood tests show zero to one cancer cell per million white blood cells.

Very good news, but the numbers really haven’t moved in about a year and a half. The chronic lymphocytic leukemia cell count is a little higher in the marrow. Although I have had almost no side effects from the subcutaneous shots every four weeks (after some very tough weeks at the start), and the trial doesn’t require me to stop, I am thinking it’s time to be grateful, declare victory or at least a prolonged ceasefire and quit the trial.

Epcoritamab has a done a great job of cleaning up my cancer. My MRI scans are all totally normal. My blood counts are all totally normal. I am uMRD^-4 but not uMRD^-6. That means I am enjoying a complete remission with detectable measurable disease by clonoSEQ using next generation sequencing (NGS). 

My absolute lymphocyte counts are low and stable. But they are not getting better. Or worse. Is my trial drug doing much good now? I don’t think so. And the bispecific antibody therapy is very immunosuppressive, so I’m betting it’s done all that it can and it’s time to move on.

Soon I will do a repeat clonoSEQ  for MRD testing in the blood and maybe in the marrow and then decide for sure.

Expect an uptick in my posting here on my blog where my public advocacy in CLL began Watch for more details and updates of my CLL journey, plus my thoughts and discussions with experts on CLL therapy as I move onto to the next phase of my almost two decade personal journey trying to outsmart CLL.

Stay strong. We are all in this together

Brian

Mike Peters of the Alarm Dies from CLL and Richter’s

“The fight against cancer is the same as standing up to injustice… it’s about not backing down.” Mike Peters

Mike Peters was a rockstar. lead singer for The Alarm, who didn’t try to hide his CLL or Richter’s Transformation, but rather proudly and boldly used his fame to raise money and awareness to fight cancer. He was recognized as a Member of the Order of The British Empire (MBE) for his charity work though his Love Hope Strength Foundation founded with his wife of 39 years, Jules.

He was also the most optimistic person I ever met. Kind, generous, funny and with a smile that could put the sun to shame. And rock and roll music was, well his rock and salvation.

Patty and I were lucky to visit with Mike and Jules in their small hometown in northern Wales when Mike was considering options for his relapsing Richter’s Transformation. We became fast friends because of our shared journey (CAR-T and later epcoritamab) and our passion to fight for our own lives and that of others facing cancer.

If you want to know more about Mike, The Alarm, his music, his wonderful family, his cancer  journey, and his charity work, watch the documentary: The Man in the Camo Jacket. 

There you’ll learn some of his musical history, including his sharing the stage with Bono, Springsteen and singing with Dylan ironically Knocking on Heaven’s Doors.

He was planning a fun raising and fundraising American tour to the last minute to replace the one canceled when he discovered an enlarged nodes when shaving that turned out to be Richter’s Transformation. His last email to me a few days before he passed was about meeting in California.

So what does this rockstar do when facing Richter’s? Write the first punk anthem dedicated to CAR-T therapy. I urge you to crank up the volume and listen to CHIMERA. The Mohawk was his answer to the chemo induced hair loss.

Mike and Jules, Brian and Patty in Dyserth, Wales, 2024.

Mike was actively touring in the UK during his harsh chemo treatments for his RT. He recorded a  new album, Transformation, including songs like OUTLIER that will be released in June. How many record covers feature diagnostic imaging of a CLL/ Richter’s patient? He sure embraced the battle, knew his enemy and with rock and roll gusto chose his battle weapons of LOVE, HOPE and STRENGTH. And music and family.

I will sure miss him. I feel lucky to have known him and have learned from him. His passing reminds me, us as if we needed reminding, that CLL is not a solved problem.

It also teaches lessons about how to live our lives and face our deaths.

I leave you with this final song from my friend Mike Peters: TOTALLY FREE

Rest in peace.

A Matching-Adjusted Indirect Comparison of Acalabrutinib vs. Zanubrutinib in Relapsed or Refractory CLL

The Bottom Line:

Acalabrutinib and zanubrutinib have similar excellent efficacy in relapsed or refractory chronic lymphocytic leukemia (CLL). However, acalabrutinib had a lower rate of serious hemorrhage, hypertension, and the need for dose reduction due to adverse events compared to zanubrutinib.

Who Performed the Research and Where Was it Presented:

Dr. Adam Kittai of Ohio State University led a group of international researchers who presented the result of the comparison between acalabrutinib and zanubrutinib at the American Society of Clinical Oncology (ASCO) annual meeting in 2023 in Chicago.

Background:

BTK Inhibitors (BTKi) have revolutionized the treatment of CLL. All three approved BTKi have similar impressive efficacy, so treatment choices are often guided by which drug is safer and better tolerated. Direct comparisons between acalabrutinib and zanubrutinib are lacking, so this research was an effort to start answering the questions about safety and tolerability.

Methods and Participants:

Matching-adjusted indirect comparison (MAIC) is a method to compare data from different trials. For this MAIC, individual patient data on acalabrutinib from the ASCEND trial were weighted to match zanubrutinib patient data from the ALPINE trial.

Weighted variable included:

• Sex
• ECOG, a measure of a patient’s ability to care for themself, daily activity, and physical ability (walking, working, etc.) developed by the Eastern Cooperative Oncology Group (ECOG),
• Bulky disease
• Prior chemoimmunotherapy
• del(11q) status
• del(17p) status
• TP53 without del(17p)
• IGHV status
• Region
• Age
• Prior lines of therapy
• Rai stage

Results:

• Progression-free survival (PFS) was similar for both drugs.
• There were similar risks for those on either drug development:
• Any grade ≥ 3 adverse events (AE). Grade 3 adverse events are serious and interfere with a person’s ability to do basic things such as eating or getting dressed without help. Grade 3 events may also require medical intervention. Grade 4 AE results in being hospitalized, and a Grade 5 event is “medical jargon” for the patient dying.
• Atrial fibrillation
• Grade ≥ 3 atrial fibrillation/atrial flutter
• Grade ≥ 3 hemorrhage
• An AE leading to discontinuation
• Those taking acalabrutinib had a lower risk than those taking zanubrutinib of having:
• A serious AE
• Any grade and ≥ 3-grade hypertension
• Any grade hemorrhage
• An AE leading to dose reduction

Conclusions:

Progression-free survival was similar for both drugs, but acalabrutinib led to fewer specific adverse events. However, MAIC is, at best, an imperfect way to compare therapies, and we really won’t know the validity of these results until we make a head-to-head comparison between the two drugs as has already been done by each medication with ibrutinib (both drugs caused CLL patients fewer problems than ibrutinib). There are, however, reasons to doubt that we will ever see a trial comparing acalabrutinib and zanubrutinib.

Links and Resources:

To read all the details of the ASCO abstract, please click on A Matching-Adjusted Indirect Comparison (MAIC) of The Efficacy and Safety of Acalabrutinib Versus Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia.

Stay strong. We are all in this together.

Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.

 

My personal decision to restart my CLL (chronic lymphocytic leukemia) treatment

I have good reasons to believe it is time to re-treat my CLL.

Before deciding on the best therapy choice to treat my CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma), I first needed to determine if it was the right time to start therapy.  

 

In most cases, the decision about when to treat CLL is usually just that: a decision. iwCLL has clear guidelines for when treatment is indicated, which we outline in this article: CLL: When to Watch and Wait and When to Start Treatment. I think these might be more helpful in outlining when therapy is not likely appropriate because none of the iwCLL indications are met. For example, someone might have a lymphocyte count that has reached 100,000 or even 500,000 and not need any therapy if they are feeling well and have no low blood counts. 

 

On the other hand, just because one's platelets have dropped below 100,000, which is an iwCLL indication to treat, that does not mean that one urgently has to start to knock back the CLL with medication, especially if the downward trend is slow with ups and downs. One might choose to wait and follow the trend. Or not. It’s a shared medical decision.

 

What about the opposite decision, namely starting sooner than iwCLL guidelines might suggest? 

 

That is what I am choosing.

 

Let me start by saying this is my personal decision, relevant to my circumstances, and likely not applicable to anyone else.

 

In brief, I was diagnosed with CLL in 2005, an aggressive variant, and within a year, I was in a world of trouble with single-digit platelets from a rare and, in my case, difficult-to-treat autoimmune complication (immune thrombocytopenic purpura or ITP) that resulted in multiple hospitalizations, an urgent splenectomy, and massive internal bleeding. ITP tried hard to kill me several times, came close, and I know how lucky I am to be alive. The ITP and the fear of it raging again drove my decision to get a first remission hematopoietic stem cell transplant (HSCT or bone marrow transplant) that quickly failed. My subsequent jump into two phase 1 clinical trials saved my life; the first was for PCI-32765, later to become the practice-changing therapy, ibrutinib, and then for JCAR-014. This CAR-T construct helps birth list-cel, a promising CAR-T cellular therapy already approved in other blood cancers but still experimental in CLL. Both gave me years of deep and wonderful remissions. My fear of recurrent ITP is my primary driver to treat it early again.

 

After beating the odds with a 5½ year remission with CAR-T, my CLL is demanding my attention again. But not in the usual way.

 

True, I have some symptoms that need attention. 

 

True, there are advantages to starting some therapies earlier when the disease burden is low. With some therapies, this can mean both higher efficacy and lower risk of adverse events when the cancer is being rapidly killed, especially early in the treatment.

 

True, some treatment options, especially those in trials, may have narrow windows of accessibility, and when a slot is available, it may force a quicker move than planned.

 

But the real impetus behind my decision to treat now is that I am not waiting for my blood counts to fall. I know that when my platelets fall, they fall off a cliff. In the past, my lymphocyte counts were only slightly elevated when my platelet count fell dangerously low. My other blood cell counts were all perfectly normal at the time. My ITP doesn't send a notice that it’s on its way.

 

Today my absolute lymphocyte count is only 3.8, barely above normal, and only about ¼ of those are monoclonal chronic lymphocytic leukemia cells. That is a very low number, but I know it’s been doubling every 2-3 months for a long time with no signs of slowing down because I have been following it closely with MRD(measurable residual disease) testing using NGS (next-generation sequencing) specifically Clonoseq since it was barely detectable at 1/1,000,000 cells.

 

I am not waiting. My CLL is coming back. It’s not if I’ll need therapy; it's when. With my CLL’s return, it carries the risk of reawakening my ITP. 

 

I am making a preemptive strike. In Julius Caesar, the play by Shakespeare, Brutus could have been talking about my ITP instead of his plot against Caesar “Think him as a serpent's egg, / Which, hatched, would as his kind, grow mischievous, / And kill him in the shell."  

 

I won't let my ITP hatch. I am treating early.

 

Your decision is likely to be different. Waiting and postponing therapy is often the very best option. Everyone's case is unique. The only universal is that nearly always the timing of when to start treatment for chronic lymphocytic leukemia should be a carefully considered shared medical decision between the patient and the healthcare provider.

 

Stay strong; we are all in this together.

 

Brian Koffman MDCM (retired) MS Ed