Novel approaches with highly active, minimally toxic agents are needed to improve upon traditional chemotherapy and possibly eliminate chemotherapy altogether in the treatment of patients with acute lymphoblastic leukemia.
Traditional cytotoxic chemotherapy-containing regimens have been the backbone of treatment for adults with acute lymphoblastic leukemia (ALL) for decades. Common complications of traditional chemotherapy can be fatal and include infection, bleeding, thrombosis, neuropathy, osteonecrosis, and the development of secondary cancers including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Compared with children with ALL, response and cure rates are substantially lower in adults. For patients over 60 years of age, traditional cytotoxic chemotherapy yields low cure rates, high treatment-related death rates, and poor long-term survival of less than 20%. For older adults, there has been minimal improvement in survival over the past 40 years despite marked improvement for adults under 60 years, adolescents, and children.1 For older patients, traditional chemotherapy approaches have largely failed.
Because the balance between efficacy and toxicity of chemotherapy has been reached for most adults with ALL, novel approaches with highly active, minimally toxic agents are needed to improve on traditional chemotherapy and possibly eliminate chemotherapy altogether.
Tyrosine kinase inhibitors (TKIs) for Philadelphia-chromosome positive (Ph+) ALL, the anti-CD22-calicheamicin antibody-drug conjugate inotuzumab ozogamicin (Besponsa) for relapsed/refractory (R/R) B-cell ALL, and the anti-CD3/CD19 bifunctional T-cell engaging antibody blinatumomab (Blincyto) for R/R B-cell ALL have transformed care. Inotuzumab ozogamicin and blinatumomab are both superior for remission rates and survival compared with traditional chemotherapy in phase 3 studies in R/R B-cell ALL.2,3 Inotuzumab ozogamicin yielded high complete response rates (81%) and minimal residual disease (MRD) negativity rates (78%) but with short median duration of remission (DOR;4.6months).2 Blinatumomab had a lower complete response (CR) rate than inotuzumab ozogamicin (44%) but a longer median DOR (7.3 months) and was found most effective in patients with low-burden disease in the marrow (lymphoblasts < 50%, CR rate 66%), suggesting that blinatumomab may be a highly effective agent in consolidation of remission in the frontline.3
There are multiple answers that are appropriate: Traditional chemotherapy alone (1) is ineffective in most patients with certain types of ALL (such as Ph+ ALL); (2) has a high treatment-related mortality with low cure rates in older patients; (3) requires extended, complicated, and toxic treatment for 3 to 4 years; (4) is often only a bridge to allogeneic hematopoietic cell transplantation (HCT), which has a high rate of treatment-related morbidity and mortality; and (5) has long-term morbidity independent of allogeneic HCT including osteonecrosis of the bone, neuropathy, neurocognitive changes, and secondary cancers. Novel targeted agents are more active than traditional chemotherapy in ALL and maximizing their use in the front line may yield similar or superior results, even when combined with reduced-dose or no chemotherapy. Adding new agents to traditional chemotherapy also may lead to inferior outcomes as targeted agent doses are frequently reduced for toxicity when given in combination with chemotherapy and the combinations can have high non-relapse mortality that may erase any benefit of increased efficacy from adding the novel agent.4
The Philadelphia (Ph) chromosome occurs from translocation of chromosomes 9 and 22, which generates a BCR-ABL1 oncogenic fusion protein with constitutive tyrosine kinase activity and is the genetic hallmark of chronic myeloid leukemia (CML) and Ph+ ALL. Historically a poor-risk disease, adults with Ph+ ALL had long-term survival rates of less than 20% with chemotherapy alone.5-7
The development and application of BCR-ABL1—targeted tyrosine kinases inhibitors (TKIs), such as imatinib mesylate (Gleevec), dasatinib (Sprycel), and ponatinib (Iclusig) in CML and Ph+ ALL has dramatically changed care and improved survival. An earlier study of imatinib with chemotherapy improved survival, principally by facilitating more patients proceeding to allogeneic HCT.7 Without allogeneic HCT most patients treated with imatinib relapsed due in large part to numerous different mutations in the BCR-ABL1 kinase domain (KD). Although encouraging benefits have been observed, resistance remains a challenge that is associated with TKI use.
Second-generation TKIs, such as dasatinib, overcome most TKI resistance by BCR-ABL1 KD mutation although they are ineffective against the T315I mutation seen in 70% to 75% of relapses in dasatinib-treated patients.8-10 The combination of second-generation TKIs with intensive chemotherapy appears to lead to superior outcomes to imatinib-based approaches. Investigators of SWOG 0805 (NCT00792948) evaluated dasatinib with hyper cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) in adults 60 years and younger with Ph+ ALL. Patients undergoing allogeneic HCT after dasatinib/hyper-CVAD induction had better survival than those receiving dasatinib and chemotherapy alone, supporting the use of allogeneic HCT in this population.11
Ponatinib, a TKI that overcomes resistance by most BCR-ABL1KD mutations including T315I, has been studied in combination with hyper-CVAD. The combination was highly active with a CR rate of 100%, complete molecular response (CMR) rate of 78%, and 3-year event-free survival (EFS) of 70%.12,13
The toxicities of these intensive approaches are typically prohibitive for use in older adults with Ph+ ALL, the population with the highest incidence of the disease. Given the high activity of BCR-ABL1–targeted TKIs in Ph+ ALL, approaches to reduce treatment-related mortality have been studied by reducing or eliminating chemotherapy. GRAAPH-2005 (NCT00327678) randomized patients to imatinib with hyper-CVAD or with minimal chemotherapy. The CR rate was higher with the minimal chemotherapy approach (98% vs 91%, P = .006) principally because of increase induction death with hyper-CVAD.14 Studies of chemotherapy-free induction with TKIs with corticosteroids showed that the approach yields CR rates of 95% to 100% with minimal or no induction death.
Investigators of the GIMEMA study LAL1205 (NCT00391989) evaluated dasatinib with prednisone followed by provider choice of post remission therapy. The regimen was well tolerated with a CR rate of 93%. Relapse occurred in 74%, 36%, 11% of patients receiving post-remission therapy with TKI only, TKI with chemotherapy, and allogeneic HCT, respectively.8 A subsequent GIMEMA study, the D-ALBA study (NCT02744768), evaluated dasatinib and blinatumomab for 5 cycles, then dasatinib maintenance as post remission therapy after dasatinib/corticosteroid induction. The CR rate was 98% with excellent 18-month overall survival (OS) and disease-free survival (DFS) of 95% and 88%, respectively.15 At last report with 27 months follow-up, there were 9 relapses among 63 patients (4 systemic, 4 CNS, 1 nodal).16 Confirmatory data are awaited from the ongoing US Intergroup SWOG 1318 study (NCT02143414), which has completed accrual.
The failing of dasatinib because of BCR-ABL1 T315I ALL is being addressed by treating older patients with ponatinib and corticosteroids alone. An early report showed a high CR rate (95%) and favorable molecular response rate (CMR rate 46%) with short follow-up.17 More recently, investigators at The University of Texas MD Anderson Cancer Center in Houston reported early outcomes of ponatinib with blinatumomab. In newly diagnosed patients, the CR rate was 100%, CMR rate was 87%, and estimated 1-year OS and DFS rates were both 100%.18 Although extremely promising, long-term follow up is needed for durability of responses and late toxicity.
The road to chemotherapy-free regimens in Ph-negative ALL is just being paved given the recent availability of highly effective targeted therapies. For Ph-negative ALL, inotuzumab ozogamicin and blinatumomab are being actively studied as part of traditional chemotherapy regimens in randomized studies in the front line (eg, A041501, NCT03150693; EA1910, NCT02003222). Given the impressive activity of these agents in R/R ALL, studies are also evaluating them in chemotherapy-free induction or as chemotherapy-free regimens.
SWOG 1318 evaluated blinatumomab as induction therapy followed by 6-mercaptopurine, vincristine, methotrexate, prednisone maintenance for older, transplant-ineligible patients. The regimen was very well tolerated with a CR rate of 66%, MRD negativity rate of 92%, and a 1-year DFS rate of 56%.19 Inotuzumab ozogamicin has demonstrated a 100% CR rate and MRD negativity rate of 74% as induction in German Multicenter Study Group on Adult Acute Lymphoblastic LeukemiaINITIAL-1trial (NCT03460522).20 Given the success of higher dose of blinatumomab observed in those with low burden disease, investigators of Alliance A041703 (NCT03739814) are studying induction with 2 cycles inotuzumab ozogamicin followed by consolidation with 4 to 5 cycles of blinatumomab in older patients with results expected in 2022.
Advancements in chemotherapy-free regimens are improving outcomes in Ph-positive ALL and hold promise in Ph-negative ALL. Clinical trials have been and remain essential to continuing the transformative progress that has occurred in adult ALL in the past 5 years. Because of the novelty of these approaches and short follow-up on existing studies, questions will need to be answered including the optimal CNS prophylaxis, need for and/or duration of maintenance, antigen levels conferring benefit, the benefit of adding novel agents including BH3 mimetics such as venetoclax (Venclexta) or navitoclax, antibodies such asdaratumumab (Darzalex), and checkpoint inhibitors, and mechanisms of resistance to inform future development of these therapies. It is hoped “chemo-free”approaches will set a new standard of care and form a backbone on which to build even more effective, highly tolerable, and convenient therapies with very high cure rates.