Case Series Suggests Venetoclax Plus Hypomethylating Agent Therapy Tolerable, Effective in Very Elderly AML Patients

Very elderly patients with acute myeloid leukemia have historically been limited to less intensive, less effective treatment regimens. A recent series of cases suggests age alone should not be a limiting factor for effective treatment.

Patients with acute myeloid leukemia (AML) are often elderly, making intensive chemotherapy an unfavorable option in many cases. Recent advances in the treatment landscape have led to improved management in those not considered fit for induction chemotherapy, and a selection of cases published in Case Reports in Hematology found that even patients above the age of 85 may be fit for and respond to treatment with venetoclax and a hypomethylating agent (HMA) for AML.

The median age of AML diagnosis is 67 to 68 years but treating the elderly population can be tricky due to potentially poor responses to typical regimens and intensive chemotherapy. These patients also tend to have more comorbidities, adverse genomic features, or drug-resistant disease phenotypes compared with younger patients.

Generally, older patients who are considered unfit for intensive therapy have instead received lower-intensity regimens of HMA monotherapy or low-dose cytarabine. Lower-intensity treatment strategies, however, do not typically elicit satisfactory responses. While they are safe, they lack effectiveness; but intensive chemotherapy has been linked to excess morbidity and mortality in elderly patients.

Venetoclax in combination with an HMA (decitabine or azacitidine) earned accelerated FDA approval in 2018 for patients ineligible for chemotherapy or for adults over 75 years old. Clinical trials showed the combination was safe, and there were good response rates in patients with AML. Compared with HMA monotherapy, venetoclax with an HMA led to increased overall survival, improved rates of remission, and has since been a go-to therapy combination for very elderly patients with AML.

“Information on using these regimens to manage older, ‘real-world’ patients, particularly those over 85 years of age, would be helpful to clinicians in clinical practice,” the case study authors noted. “There remains a paucity of data on how to best manage these extremely elderly AML patients with venetoclax plus HMAs.”

Three case studies involving patients over the age of 85 were included, and all patients received venetoclax with an HMA. The authors did not use any specific tools to assess these elderly patients’ fitness for AML therapy, although all 3 patients were not cognitively impaired, were ambulatory, and had family support and transportation to and from the center.

Patient 1, an 87-year-old male, had a significant number of circulating myeloblasts and a white blood cell count of 84,900 at hospital admission. He was started on venetoclax and azacitidine when his white blood cell count dipped below 35,000, achieved complete remission after a 21-day cycle, and went through 10 more cycles with manageable complications. His disease was stable for 6 months on azacitidine alone after combination therapy was stopped due to Sweet’s syndrome, then progressed with leukocytosis and circulating blasts. He responded to targeted therapy for a FLT3 ITD mutation he developed before passing away due to AML complications 25 months after initial diagnosis.

The second patient, a 92-year-old male, was found to be pancytopenic during a biopsy of a right lower lobe lung adenocarcinoma. Biopsied bone marrow was hypocellular and showed 43% myeloid blasts in clusters. After successful lung lesion radiation, the patient started a course of intravenous azacitidine and venetoclax. The treatment was well-tolerated, and he continued for 9 additional cycles of therapy — 5 with azacitidine monotherapy and 4 with 14 days of venetoclax in the 21-day cycle. His disease relapsed and he died 17 months post initial diagnosis.

Patient 3, an 85-year-old male, had myelodysplastic syndrome with multilineage dysplasia that transformed to AML after a year. Bone marrow biopsy showed transformation to AML with extensive bone marrow involvement. He began a regimen of decitabine with reduced-dose venetoclax due to drug-drug interaction concerns with other medications. After a 21-day cycle, blasts were reduced from 80% to 14%. He completed 4 further cycles — 2 with 14 days on venetoclax in each 21-day cycle, 1 on decitabine monotherapy, and a final cycle of combination therapy. He transitioned to hospice care 6 months after initial diagnosis.

All 3 patients were able to receive full therapeutic doses of the combination venetoclax plus HMA therapy. All patients also experienced bone marrow responses, and 2 of 3 successfully went through more than 10 therapy cycles total.

“We did modify subsequent cycles of venetoclax plus HMA to use venetoclax only for 14 days instead of 21 and occasionally omitted venetoclax cycles and treated with HMA alone, all in an effort to manage cytopenias and avoid significant complications such as neutropenic fevers while the patients were on active treatment,” the authors wrote. “Fungal prophylaxis and bacterial prophylaxis were used while the patients were neutropenic.”

In all 3 cases, patients maintained good quality of life and were motivated to receive treatment. Overall, the cases taken together suggest that age alone should not prevent patients from being treated for AML.

Reference

Lee AM, Goodman AM, Mangan JK. Age-adjusted schedules of venetoclax and hypomethylating agents to treat extremely elderly patients with acute myeloid leukemia. Case Rep Hematol. Published online April 26, 2022. doi:10.1155/2022/2802680