Advisory board comment
Treatment of elderly patients with acute leukemia is challenging. Currently, no consensus exists regarding optimal therapy in this patient population. The reasons for the poor outcomes in the older adults are both patient- and disease-related. Older patients constitute a heterogeneous population with various combinations of comorbidities, disabilities, general functioning, cognition, quality of life, and other geriatric syndromes. Regarding leukemia characteristics, the cytogenetic profile differs from that of younger patients with a greater incidence of unfavorable chromosomal abnormalities and a mutational profile that also appears significantly different. The superiority of active therapy over palliative treatment only is well established. However, quality of life remains an important concern for the older patient population. It seems therefore essential to tailor therapeutic approaches according to the patient’s condition and disease characteristics. In this setting, effective therapeutic options are urgently needed for these patients.
The Lancet Oncology recently published two papers reporting results from early phase trials combining standard therapeutic agents with either venetoclax (an oral anti-apoptotic B-cell lymphoma 2 protein [Bcl-2] inhibitor) or inotuzumab ozogamicin (an anti-CD22 antibody linked to the chemotherapeutic agent calicheamicin) in elderly patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), respectively [1,2]. Both of these therapeutic approaches have in common particularly attractive promising results that deserve some comments.
Hypomethylating agents (HMAs) currently represent the standard of care for the treatment of elderly AML patients unfit for intensive chemotherapy. The benefit of HMAs has been shown in large phase III studies. In the AZA-AML-001 trial, median overall survival (OS) was 10.4 months in the azacitidine arm, and the difference compared to control arm became significant when censoring patients at the start of the subsequent AML therapy (12.1 vs 6.9 months) . Similarly in the DACO-016 study, the decitabine cohort demonstrated higher complete remission (CR) rates than the control arm (17.8 vs 7.8%), and a significant difference in terms of median OS (7.7 vs 5 months) was demonstrated in an unplanned ad hoc analysis . However, these improvements remain limited, and various novel agents are currently under investigation in AML. Among them, venetoclax has shown some efficacy as a single-agent treatment and also in combination with low-dose cytarabine .
In The Lancet Oncology, DiNardo et al reported primary interesting data with the combination of venetoclax with an HMA . These results draw several comments. First, treatment was well tolerated with early mortality rates similar to those seen with HMAs in monotherapy.
Second, overall response rates (61%) were rapidly obtained and much higher than those observed with HMAs as single-agent. They also compared favorably to those achieved after intensive chemotherapy considering the fact that the study cohort consisted of older patients including many patients with high-risk features. Furthermore, some patients proceeded to allogeneic stem cell transplantation while in remission because of their improved clinical status. However, targeting leukemia stem cells remains the main goal of acute leukemia therapy. In the study by DiNardo et al, median OS was only 12.3 months suggesting an unexpectedly inadequate effect of venetoclax on leukemia initiating cells, which is surprising as Bcl-2 inhibition-induced reduction in oxidative phosphorylation should theoretically selectively eradicate quiescent leukemia stem cells that express high levels of Bcl-2.
Third, it appears that venetoclax is best used in combination with another agent. However, the best partner for treatment with venetoclax is still to be determined. Resistance to venetoclax can be mediated through anti-apoptotic proteins like Bcl-xL and MCL1. Recent data support further investigation of venetoclax in combination with various standard cytotoxic drugs and in combination with direct inhibitors of MCL1 . Finally, leukemia features also seem to be of importance. An increased sensitivity of AML with IDH mutations, MLL fusions, or HOX gene expression to Bcl-2 inhibition has been demonstrated [7–9]. Targeting of Bcl-2 might, therefore, be a promising option, especially in patients with specific or adverse AML features.
Standard chemotherapy for older adults with Philadelphia chromosome (Ph)-negative ALL is, at present, far from ideal. Unlike other age groups, there has been no significant improvement in outcomes for elderly ALL patients over the last 25 years. Prospective studies have shown CR rates ranging from 30% to up to 70%, but median survival times are generally less than one year, and only about 20% of patients are alive at 3 years . Here again, new therapeutic options are urgently needed. Combinations with novel targeted therapeutic agents are required and should profoundly affect medical hematology. Recent developments in B-cell monoclonal antibody therapy are particularly exciting and are worth considering in this age group. Advances in antibody engineering have yielded the creation of antibody–drug conjugates such as inotuzumab ozogamicin.
In a recent issue, The Lancet Oncology published promising results of a phase II trial combining inotuzumab ozogamicin with low-intensity chemotherapy in older Ph-negative ALL patients . These results appeared to be superior to the historical data with hyper-CVAD in a similar patient population . Although longer follow-up is still required to confirm primary outcomes and safety profiles, the use of inotuzumab ozogamicin in older ALL patients should enter common practice in the near future. However, much improvement is still needed in the treatment of this patient population.
In this setting, other targeted therapies are becoming available that also have the potential to change the standard of care. Rituximab has already been given to ALL patients with CD20-positive expression, and the sequential addition of immunotherapy with bispecific monoclonal antibodies such as blinatumomab may also be effective means of eliminating minimal residual disease with a potentially acceptable toxicity in older patients , although large-scale efficacy data are lacking.
Because the global population is aging, with an accompanying expected increase in the incidence of acute leukemia, there is an urgent need to improve outcomes in the older population. These two studies from The Lancet Oncology confirm that active treatments should be considered in elderly patients with acute leukemia, and that clinical trials should certainly be adapted to account for the specificities of this patient population. Intensive chemotherapy is toxic, poorly tolerated, and often disappointing. The use of targeted therapy in both studies demonstrated encouraging primary results. However, combinations were required to achieve results that could not be expected when only using single-agent therapy.
- DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018; 19: 216–228.
- Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol 2018; 19: 240–248.
- Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126: 291–299.
- Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012; 30: 2670–2677.
- Wei A, Strickland SA, Roboz GJ, et al. Safety and efficacy of venetoclax plus low-dose cytarabine in treatment-naive patients aged ≥65 years with acute myeloid leukemia. Blood 2016; 128 (issue22): 102.
- Teh TC, Nguyen NY, Moujalled DM, et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia 2018; 32: 303–312.
- Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 2015; 21: 178–184.
- Niu X, Wang G, Wang Y, et al. Acute myeloid leukemia cells harboring MLL fusion genes or with the acute promyelocytic leukemia phenotype are sensitive to the Bcl-2-selective inhibitor ABT-199. Leukemia 2014; 28: 1557–1560.
- Kontro M, Kumar A, Majumder MM, et al. HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia. Leukemia 2017; 31: 301–309.
- Marks DI. The challenges of managing older patients with acute lymphoblastic leukemia. Am Soc Clin Oncol Educ Book 2015; e343–e351.
- O’Brien S, Thomas DA, Ravandi F, et al. Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia. Cancer 2008; 113: 2097–2101.
- Kantarjian HM, Stein AS, Bargou RC, et al. Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute lymphoblastic leukemia: results from 2 phase 2 studies. Cancer 2016; 122: 2178–2185.