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ASH 2020: Dr. Arnon Nagler on Safety and Efficacy of CD19-CAR T Cells in Richter’s Transformation After Targeted Therapy for Chronic Lymphocytic Leukemia (CLL)

By Bkoffman

At the virtual ASH 2020 Annual Conference and Exposition,Dr. John Pagel of Swedish Hospitaland one of CLL Society’s directors interviewedDr. Arnon Nagler of Sheba Medical Center in Israel concerning using “in-house” CAR-T cells made locally at his medical center for Richter’s Transformation patients.

Richter’s Transformation (RT) is usually an aggressive transformation of chronic lymphocytic leukemia into a fast-moving lymphoma, usually clonally related, DLBCL (diffuse large B-cell lymphoma). RT is associated with a very poor response to most therapies and has a discouraging prognosis.

It remains one of the most pressing unmet needs in CLL patients.

That is why when the Israeli group showed that six of nine Richter’s patients responded to CAR-T therapy, their research was recognized for its importance and given a slot as one of the six oral CLL clinical presentations at ASH 2020.

Take Aways:

·  These were mostly heavily pretreated patients, all having progressed on ibrutinib and/or venetoclax

·  Del 17p/TP53 was found in 83% (five out of six) of those tested

·  Despite these poor markers and their aggressive disease, six of nine patients had complete remissions

·  Only two of these six progressed within a year, including one who went on to have a bone marrow transplant

·  One significant advantage of an “in-house” CAR-T is that the waiting time to manufacture the CAR-T is only ten days, so “bridging therapy” to keep the fast-moving Richter’s under control while waiting for the cells is less likely to be needed

·  No new problems or adverse events were noted in this Richter’s population. Just the usual three that are seen in most CAR-T treatments:

1.  Cytokine release syndrome (CRS): An acute systemic inflammatory syndrome characterized by fever, flu-like symptoms, and has the potential for low blood pressure and multiple organ dysfunction. It is usually of short duration, is now well understood, and can be safely managed in nearly all cases.

2.  Neurotoxicity: Might include headache, confusion, delirium, language disturbance, coma, seizures, and rarely acute brain swelling. It is usually mild and is almost always fully reversible.

3.  Low blood counts: May include anemia, low neutrophils, low platelets, and low lymphocytes. It can be persistent, but counts do recover over time.

Conclusions:

These results give us clear proof that CAR-T cellular therapy can work in Richter’s Transformation, and that is much-needed good news. The numbers are small, so larger studies will be needed, and I am sure will be done to confirm the promising findings.

But there remain many unanswered questions.

Can CAR-T be curative for some? For at least some patients, there is reason to be hopeful this might be the case.

Should it be used as a bridge to an allogeneic stem cell (bone marrow) transplant for RT patients to “consolidate” their response? We know the transplants (while high-risk and not perfect) still offer the best, most durable responses in Richter’s to those who are well enough to undergo the procedure.

Here is Dr. Pagel’s interview with Professor Nagler from ASH 2020: https://youtu.be/yFOWNR0x-u0

A transcript of the interview is being provided, as some of the interview is difficult to understand. We ask you to rely on the abstract linked below for study details, as we are not certain of the accuracy of every word in the transcript.

Here is the ASH abstract: Safety and Efficacy of CD19-CAR T Cells in Richter’s Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia

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