Sequential administration of immunochemotherapy and venetoclax after failure of BCR inhibitor treatment – interactive video case study
The treatment of chronic lymphocytic leukemia (CLL) is evolving. What was impossible years ago is now becoming a reality. From chemotherapy, through immunochemotherapy, to the use of molecules targeting apoptotic pathways of tumor cells, the prognosis for patients has markedly improved. However, the wide therapeutic spectrum also brings its own specifics and complications, and the correct sequencing of treatment lines and their selection for each individual is necessary, considering the nature of CLL, overall condition, and comorbidities.
History and Initial Examination
A 67-year-old retired woman, formerly a teacher, was admitted to the hospital in March 2017 with an anterior wall myocardial infarction (MI), affecting 3 coronary arteries, and a left ventricular ejection fraction (LVEF) of 40%. Partial revascularization of the coronary arteries was performed, with plans for continuation later. As a secondary finding, her blood count (BC) showed 320 × 109/l leukocytes (Leu), hemoglobin (Hb) 97 g/l, platelets (PLT) 220 × 109/l, and elevated lactate dehydrogenase (LDH) to 20 μkat/l. Clinically, generalized lymphadenomegaly (LAM) was apparent. Her personal history included arterial hypertension, dyslipidemia, cholecystolithiasis, osteoporosis, post thyroidectomy, and meningioma surgery. The overall performance status according to ECOG was 1 and the CIRS score > 6. Chronic lymphocytic leukemia was diagnosed, and prognostic markers included trisomy 12, unmutated IGHV, Rai III, and Binet C.
First Line of Therapy
Considering the treatment options available in 2017 for a 67-year-old patient with significant cardiac comorbidity and lymphocytosis, we chose to induce monotherapy with bendamustine for cytoreduction. Anti-CD20 antibody administration was planned after tumor mass and lymphocytosis reduction to avoid a hypothetical infusion reaction. After administering 120 mg of bendamustine, a systemic shock reaction with blood pressure drop and fever occurred, differentially diagnosing a cytokine reaction or sepsis. The condition stabilized with supportive antibiotic and infusion therapy, requiring vasopressors. A follow-up coronary angiography was performed a month later.
Lab results indicated active CLL even a month after treatment initiation, with BC showing 210 × 109/l Leu, Hb 100 g/l, highly elevated LDH 30 μkat/l, with no hemolysis signs. PET/CT and LU histology ruled out Richter’s transformation. From May 31 to September 12, 2017, immunochemotherapy 5× FCR Q-lite was initiated. The treatment was complicated by an MI relapse after the second cycle, with new coronary artery occlusions resolved by stenting. There was a favorable response to treatment lasting 5 months. On February 31, 2018, a disease relapse was noted.
Second Line of Therapy
Nine months after concluding the first-line treatment, the patient met criteria for restarting therapy (lymphocyte doubling time). Early relapse after first-line therapy led to the indication for ibrutinib on June 5, 2018. During disease progression, skin eruptions with infiltrate characteristics appeared, mainly on the limbs. Ibrutinib therapy was reduced to 140 mg/day due to co-medication with antiplatelets. CLL was well-controlled post-treatment, with normalization of BC and clinical symptoms remission. Complications included treated Lyme disease and severe bilateral COVID-19 pneumonia in December 2020, requiring hospitalization and oxygen therapy.
Despite good CLL control, a gradual mild rise in lymphocytes was observed, and on October 8, 2021, with ibrutinib treatment interrupted due to a skin “abscess” in the popliteal area, a fulminant CLL progression occurred with lymphocytosis 361 × 109/l, LDH 40 μkat/l, and skin eruptions. Massive lymphadenomegaly was absent, and no genetic progression of CLL (Tri 12, del 11q, p53 mutation negative) was found.
Third Line of Therapy
For active CLL with high proliferative activity, significant tumor burden, and ongoing antibiotic therapy for resolving skin infection, we chose cytoreduction with rituximab/cyclophosphamide/dexamethasone combination.
Therapeutic effect was relatively satisfactory but short-lived, and after a temporary drop in lymphocytes to 21.4 × 109/l on November 8, 2021, a rise to 37 × 109/l prompted the start of the “ramp-up” period of venetoclax treatment. Dose escalation was outpatient. The first week was reduced to 10 mg/day, followed by the standard regimen to a final 400 mg/day.
Subsequently, the BC normalized, and skin infiltrates vanished completely. Venetoclax medication was only paused for 7 days due to a mild COVID-19 infection in April 2022. With the patient experiencing full quality of life, remission of CLL with minimal residual disease (MRD) 4 × 10–4/l in peripheral blood was confirmed on May 3, 2022.
Conclusion
This case demonstrates the remarkable effect of ibrutinib even at a reduced dose over 40 months, with a good safety profile in chemo-refractory CLL. Subsequently, the advantageous use of cytoreductive immunochemotherapy R-CD followed by safe transition to venetoclax in outpatient care without adverse effects. Venetoclax treatment is effective even in highly aggressive relapsing/refractory CLL, achieving deep hematological response while maintaining very good quality of life in a fragile CLL patient.
MUDr. Peter Turcsányi, Ph.D.
Department of Hemato-Oncology, Faculty of Medicine, Palacký University, and University Hospital Olomouc
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