Addition of Venetoclax to Richter Syndrome Treatment Regimen Achieves Complete Remission at 3 Months Post alloSCT

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Although patients with Richter syndrome often experience poor outcomes, there are many new treatment strategies that have demonstrated a durable response.

Patients with Richter syndrome, an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), often experience poor outcomes, explained Tanya Siddiqi, MD, director of the Chronic Lymphocytic Leukemia Program at the Toni Stephenson Lymphoma Center and associate professor in the Division of Lymphoma at the City of Hope, during a presentation at the 64th American Society of Hematology (ASH) Annual Meeting and Exhibition in New Orleans, Louisiana. Siddiqi noted that complete remission (CR) rates for Richter syndrome are at approximately 20%, with long-term survival with chemoimmunotherapy (CIT) at less than 20%.1,2

“We all know that [Richter syndrome] has sort of become the bane of our existence in CLL,” Siddiqi said. “Unfortunately, it's one of the things we've had the most challenges dealing with, so I will start with a clinical case.”1

The case study Siddiqi presented was for a 73-year-old female patient with Richter syndrome who was originally diagnosed with CLL and was treated in 2011 with 6 cycles of fludarabine (Fludara; Pfizer), cyclophosphamide (Cytoxan; Amneal Pharmaceuticals), and rituximab (Rituxan, Genentech; FCR) CIT. Following this regimen, she achieved CR; however, in 2017, the CLL progressed.1,2

“Within 6 years [she] progressed,” Siddiqi said. “That time, there was more knowledge of our genomic evaluation, and it seems like she had unmutated [immunoglobulin heavy-chain variable region gene (IGHV)].”1

Since Richter syndrome presents as biologically heterogeneous and 80% of patients with CLL develop diffuse large B-cell lymphoma (DLBCL), the disease is clonally related to the CLL. However, Siddiqi noted that clonally unrelated cases are genetically and immunologically distinct with more favorable responses to CIT. These patients are best treated as de novo DLBCL.1,2

Further, Siddiqi explained that relatively favorable outcomes with CIT are also observed in patients who have never been previously treated for CLL and who lack TP53 mutation or deletion. However, for all other patients, treatment in a clinical trial is optimal.1,2

Following genomic evaluation of the patient at progression, Siddiqi explained it had become clear that the patient had unmutated IGHV with IGHV4-39-IGHJ5 (subset no. 8) utilization. Siddiqi noted that they proceeded to conduct a chromosomal analysis, which showed a diploid karyotype, with trisomy 12 identified in 34% of interphases by fluorescence in situ hybridization (FISH). Further, next generation sequencing revealed a NOTCH1 mutation.1,2

“She enrolled in a clinical trial with 2 years of fixed duration on ibrutinib [Imbruvica; Pharmacyclics and Janssen Biotech] plus venetoclax [Venclexta; Genentech USA] and achieved CR,” Siddiqi said. “Just a year later, she developed rapid nodal enlargement.”1

Specifically, the patient had nodal enlargement, splenomegaly, and constitutional symptoms. Siddiqi explained that they conducted a positron emission tomography/computed tomography (PET/CT) to assess the extent of the nodal enlargement. The PET/CT showed widespread nodal disease with a maximum standardized uptake value (SUV) of 10.9. A biopsy then confirmed the CLL had progressed to DLBCL.1,2 

Further, genotyping of the biopsy specimen demonstrated it was clonally related disease, with identical IGHV4-39-IGHJ5 utilization; no analyzable metaphases for karyotyping; trisomy 12 by FISH; NOTCH1 mutation; and no TP53 mutation. Additionally, an analysis of the untransformed CLL cells was conducted at progression, revealing trisomy 12 with a complex karyotype (46,XX,add (1(p36.1),-7,add(7)(q22),-10,+12,-14,+2mar).2

Siddiqi explained that the patient was then enrolled in a clinical trial (NCT03984448) with rituximab, cyclophosphamide, doxorubicin hydrochloride (Lipodox; Sun Pharmaceutical Industries), vincristine sulfate (Oncovin; Eli Lilly Company), prednisone (Rayos, Horizon Pharma; R-CHOP) plus venetoclax. During the first cycle, the patient poorly tolerated R-CHOP alone at standard doses, with grade 4 ileus and febrile neutropenia. However, subsequent cycles that added venetoclax without vincristine (Marqibo; CASI Pharmaceuticals) and with a dose reduction to 400 mg/m2 of cyclophosphamide and 25 mg/m2 of doxorubicin were well tolerated.1,2 

After cycle 3, the patient achieved CR on PET/CT, with undetectable minimal residual disease at a level lower than 10−6 in the bone marrow by next generation sequencing following cycle 6.2 The patient then proceeded to an allogeneic stem cell transplantation (alloSCT) from a matched unrelated donor. Siddiqi noted that as of today, the patient remains well and in CR 3 months post alloSCT.1,2

“I feel that as we are doing better and better for [patients with CLL] over the last so many years, our patients are generally living longer, which is great, but the natural evolution of CLL has been showing up as more and more Richter syndrome cases that we've seen,” Siddiqi said. “Today, there are many, many, many newer strategies that we can use.”

Reference

  1. Siddiqi T. Treatment of Richter's syndrome. Presented at: 64th American Society of Hematology (ASH) Annual Meeting and Exhibition in New Orleans, LA; December 11, 2022.
  2. Siddiqi T, Thompson PA. Treatment of Richter's syndrome. Hematology Am Soc Hematol Educ Program. 2022(1):329–336. doi:10.1182/hematology.2022000345
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