Investigation of intensive chemotherapy regimens has unfortunately resulted in a lack of improvement in outcomes for patients with acute lymphoblastic leukemia in the second of the bimodal peaks.
Adam S. DuVall, MD
Acute lymphoblastic leukemia (ALL) is predominantly a childhood disease, with approximately 75% of cases occurring in patients younger than 6 years, but the incidence is bimodal, with the second peak occurring after age 60.1 Over the past few decades, ALL has seen rapid treatment advances and improvement in outcomes.3 This has been accomplished through both large collaborative group studies and the rapid development of targeted therapies. Survival for children younger than 15 years has improved to greater than 90%, and ALL survival in adolescent young adults has improved to 70% to 80% through large collaborative group trials of different, intense combination chemotherapy regimens. However, these regimens are generally not tolerated by older adults because of an unacceptable level of treatment-related mortality (TRM).2,3 Investigation of intensive chemotherapy regimens has unfortunately resulted in a lack of improvement in outcomes in the second of the bimodal peaks. Patients who are over 60 years old still have a long-term survival of approximately 20% or less, necessitating the need for new treatment strategies.
Wendy Stock, MD
To review, the current standard of care for the treatment of older patients with ALL has changed little over the past few decades. Most TRM is related to the amount of myelosuppression and outcomes that are not significantly improved with the addition of growth factors (granulocyte colony-stimulating factor).4 Most discussions between clinicians and patients revolve around moderate versus intensive-based chemotherapy. The largest trial of moderate-intensity chemotherapy was performed using a consensus treatment protocol from the European Working Group for Adult ALL. This used a modified Berlin-Frankfurt Münster induction backbone divided into 2 courses, with 6 consolidation courses alternating between intermediate-dose methotrexate and asparaginase with high-dose cytarabine.5 Age remained an important prognostic factor, as complete response (CR) rates were 84%, 74%, and 52%, and early mortality rates were 7%, 14%, and 37% for age ranges 55 to 65, 66 to 75, and greater than 75 years, respectively.5 Similar results were demonstrated with a protocol by the Spanish group Programa Español de Tratamientos en Hematología.6 The largest experience with high-intensity chemotherapy comes from The University of Texas MD Anderson Cancer Center (MDACC), which primarily uses hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone with high-dose methotrexate and cytarabine (hyper- CVAD protocol) in ALL and followed by POMP as maintenance therapy. A high CR rate, 84%, was achieved by patients older than 60 years, but this was also associated with a high rate of early mortality, 10%.7
Rituximab (Rituxan) was the first targeted agent shown to be a feasible addition to chemotherapy backbones, and CD20 is expressed on approximately 40% of B-cell ALL.8 However, the addition of rituximab did not significantly improve outcomes in elderly patients or at least require further studies to elucidate the correct regimen.8,9 Likely, this is due to increased TRM associated with the addition of rituximab to combination chemotherapy. When added to hyper-CVAD, rituximab did result in high rates of CR of 88%, but TRM was increased mainly because of deaths following achievement of CR, which can be hypothesized to be due to the immunosuppressive effects of rituximab.8
Advances in targeted therapy without traditional chemotherapy have been made recently in the relapsed/refractory (R/R) setting of ALL in trials that have included older adults. The 2 most applicable agents are inotuzumab ozogamicin (Besponsa) and blinatumomab (Blincyto). Inotuzumab ozogamicin is a humanized monoclonal antibody that targets CD22 with subnanomolar affinity and is conjugated to calicheamicin, a cytotoxic antibiotic.10
The INO-VATE ALL trial (NCT01564784), a phase 3, trial between inotuzumab and standard-of-care chemotherapy, resulted in a CR rate of 81.4% in the inotuzumab group versus 25.0% for standard of care in those 55 years and older.10 Blinatumomab is a bispecific T-cell engager antibody that simultaneously binds the CD3 of cytotoxic T lymphocytes and the CD19 of B cells, which activates T cells to recognize and eliminate leukemic B-cell blasts.11
A phase 3 trial comparing blinatumomab with salvage chemotherapy confirmed a superior CR rate for blinatumomab of 34% versus 16% and a CR with full, partial, or incomplete hematologic recovery (CR/CRi) of 44% versus 25% favoring blinatumomab.11 This study did not report specifically on the older population, although patients up to 80 years of age participated in the study. However, pooled data from two phase 2 studies of blinatumomab in the R/R setting demonstrated safety and efficacy in an older population, 65 years and older, with a CR rate of 39% and CR/CRi rate of 56%.12 The toxicity profile in the older population showed higher rates of neurologic events, with grade 3 or higher events occurring in 28% of the elderly population versus 13% of those younger than 65 years.12 Blinatumomab has also been used in those with a CR who are still positive by minimal residual disease (MRD) testing. In a phase 2, single-arm study, patients—13% of whom were 65 years or older—received blinatumomab, with 80% achieving MRD-negative CR after 1 cycle of therapy.13 Most notably, grade 3/4 neurologic toxicities were seen at a lower rate of 13%, with 97% of these toxicities resolving completely, suggesting that a lower overall disease burden may decrease the incidence of therapy-limiting neurologic toxicity.13 This study led to FDA approval in the setting of persistent MRD positivity after CR.
Bringing Novel Therapies Up Front
The next logical effort is to bring these novel therapies into the up-front remission induction setting. MDACC reported on a phase 2 study of min–hyper-CVD with targeted agent inotuzumab.14 Mini–hyper-CVD reduces the doses of cyclophosphamide and dexamethasone to 50% and methotrexate to 25% of standard doses in hyper-CVAD while eliminating anthracyclines altogether and limiting intrathecal chemotherapy to 8 doses. The outcomes of the MDACC mini– hyper-CVD were very encouraging: a CR rate of 85% and an impressive CR/CRi rate of 97%.14 Overall survival was also better than reported in previous studies and was 66% at 2 years and 56% at 3 years.14 However, associated toxicity was significant. Twelve percent of patients died from adverse events, including 10% from sepsis and 2% from veno-occlusive disease, which is an established adverse effect of inotuzumab.14
Regarding moving blinatumomab into up-front therapy, the Southwest Oncology Group reported initial results from a phase 2 single-arm clinical trial of blinatumomab as induction therapy followed by POMP maintenance in an older population, over 65 years of age, with ALL.15 The overall response rate CR/CRi was 66%, and somewhat surprisingly, only 1 patient (3.4%) developed grade 3 cytokine release syndrome and 1 patient (3.4%) developed grade 3 neurotoxicity.15 Neither strategy has been tested against standard-of-care chemotherapy, although mini–hyper-CVD is listed as an option for up-front therapy in elderly patients in the National Comprehensive Cancer Network ALL clinical guidelines.16 Blinatumomab in combination with dasatinib (Sprycel), a TKI targeting the BCR-ABL protein of Ph+ ALL, has recently been used in a phase 2 study of adult patients up to 82 years of age with Ph+ ALL in the GIMEMA LAL2116 D-ALBA trial (NCT02744768). This chemotherapy-free regimen resulted in a 12-month survival of 94.2% and a molecular response rate of 80.0% after the fourth cycle of blinatumomab, potentially changing the treatment paradigm for Ph+ ALL.16
The final class of drugs that may have a role in the treatment of older patients with ALL is the small molecule inhibitors. In a phase 1 study, patients over 60 years of age with B-cell and T-cell ALL with untreated ALL or over 18 years of age with R/R ALL, a small molecule inhibitor targeting BCL2, venetoclax (Venclexta), was combined with mini–hyper-CVD.17 Reported preliminary results of 10 older patients with untreated ALL (7 with B-cell and 3 with T-cell ALL) resulted in a 90% MRD-negative CR rate with acceptable toxicities.17 Additionally, navitoclax, a BCL2, BCLxL, and BCLW inhibitor, was added to venetoclax in a phase 1 study of patients with R/R ALL or acute lymphoblastic lymphoma.18 In this very heavily pretreated population, 56% of patients achieved a CR/CRi, with 50% of these patients being MRD negative.18
This raises the final questions: What should the standard-of-care therapy be now, and what does the future hold for elderly patients with ALL? Upcoming head-to-head trials of combination chemotherapy (such as mini–hyper-CVD with inotuzumab or other combinations) versus moderate- to high-intensity chemotherapy will answer the question of what is the current standard of care? It is possible that in the future, the treatment of ALL in elderly patients will evolve to become completely chemotherapy-free.
One interesting treatment strategy would be to use inotuzumab to induce remission, potentially without chemotherapy, as CR rates in the R/R setting are high. Subsequently, using blinatumomab as consolidation and potentially as maintenance therapy would be a logical next step given its success and FDA approval in the MRD-positive space with a lower toxicity profile. The toxicity of these agents also does not overlap with inotuzumab affecting the liver most significantly and blinatumomab’s association with neurologic sequelae. In fact, a phase 2 trial of inotuzumab followed by blinatumomab in older adults with newly diagnosed disease is currently ongoing through the Alliance for Clinical Trials in Oncology.18 The addition of venetoclax and/or navitoclax to these regimens could also be considered. These trials will likely be initiated in the cooperative group setting over the next few years, and in combination with continued research and drug development, it is realistic to predict significant improvement in outcomes without additional toxic chemotherapy in the near future for the elderly population with ALL.
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