The rapid progress in research and therapy of acute lymphoblastic leukemia (ALL) questions the value of the traditional research methodologies. There are now multiple exciting and highly effective research modalities targeting CD19, CD20, CD22, and others. These include antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), chimeric antigen receptor (CAR)-T cellular therapies, BCL2/BCL-XL inhibitors (venetoclax, navitoclax), and menin inhibitors. Optimizing these in combination regimens could be done safely and expeditiously in well-designed and carefully monitored single-arm trials, rather than in large-scale randomized trials. This could shorten the time to the ultimate development of the most optimal ALL regimens that can then be tested in randomized trials and accelerate the broader access of these strategies to patients with ALL.
The cure rates in children with ALL are 80-90 percent with regimens delivered over 2.5-3 years, and that combine about 15 chemotherapy drugs in intensive treatments that include induction, intensifications, maintenance, and central nervous system (CNS) prophylaxis.1 This comes at the expense of significant longer-term side effects in adulthood. The same regimens applied in adult and older ALL result in cure rates of 20-60+ percent depending primarily on the age group. The reported cure rates with modern regimens are 60-70 percent in adolescent and young adults, 50-60 percent in patients 40-60 years old, and (until recently) 20-25 percent in patients 60 years and older.2,3
In Philadelphia chromosome (Ph)-positive ALL, the combination of BCR-ABL1 tyrosine kinase inhibitors (TKIs) with chemotherapy regimens improved the cure rates from less than 20 percent before 2000 to a range of 50-75 percent since, depending on the TKI used.4-8 While the Hyper-CVAD plus dasatinib regimen followed by allogeneic stem cell transplantation (SCT) in first CR is the standard of care today in the U.S., the concept is challenged by the better results of Hyper-CVAD plus ponatinib from single-arm trials, and more importantly, by the results of TKIs plus blinatumomab without or with minimal chemotherapy.7-10
Thus, reliance on recommendations and guidelines like the ones from the National Comprehensive Cancer Network (NCCN) may be challenged by recent strategies that show impressive results, even though they may be derived from single-arm or single-institution trials. This review will update some of the exciting therapeutic strategies in ALL, which we believe will radically change the therapeutic approach in non-childhood ALL soon.
Philadelphia Chromosome-Positive ALL
Before 2000, patients with Ph-positive ALL were treated with intensive chemotherapy followed by allogeneic SCT when possible. This resulted in 5-year survival rates of 10-30 percent.
In 2000, with the availability of imatinib, its combination with Hyper-CVAD chemotherapy produced a 5-year survival rate of 40 percent.4 Replacing imatinib with second-generation TKIs (dasatinib, nilotinib) in single-arm and randomized trials improved the results further.5,6 The combination of Hyper-CVAD plus dasatinib showed positive results in a single-institution trial, and later tested in a SWOG trial that confirmed its benefit.
The SWOG trial accrued 97 patients, and reported a CR rate of 88 percent and a 3-year survival rate of 69 percent. The outcome was better among patients who underwent allogeneic SCT in first CR.6
A randomized trial of dasatinib versus imatinib added to intensive chemotherapy in 189 children with Ph-positive ALL showed dasatinib to be superior. The 4-year survival rate was 88 percent with dasatinib versus 69 percent with imatinib (p=0.04). Dasatinib therapy was also associated with a significant decrease in the rate of systemic relapse (20% vs. 34%; p=0.01) and of CNS disease (2.7% vs. 8.4%; p=0.06).11
About 20-25 percent of failures on Hyper-CVAD plus TKIs were due to relapses with T315I-mutated disease.12 This led to investigating the combination of ponatinib (a third-generation TKI that is active against T315I mutations) and Hyper-CVAD in 2010.7
Also, as patients were living longer, CNS relapses were occurring in 10-15 percent of patients with eight intrathecal doses of CNS chemotherapy prophylaxis, leading to modifying the study to include 12 intrathecals.13
Because of the serious side effects of ponatinib 45 mg daily, the dose was reduced post induction to 30 mg in CR, then to 15 mg once a deep molecular response was achieved (BCR-ABL1 transcripts < 0.01%). Patients with persistent disease (PCR > 0.1% 3-6 months into CR) were offered allogeneic SCT.
Among 86 patients treated (median age 47 years; range 39-61 years), the CR rate was 100 percent, the MRD negativity rate by multi-color flow cytometry was 99 percent, the PCR-negativity rate was 84 percent, and the 6-year survival was 76 percent.8 The CNS relapse rate was 0 percent, and few patients (less than 20%) needed allogeneic SCT. The improved regimen with the most potent TKI transformed Ph-positive ALL from a very unfavorable ALL subset to a very favorable one.
Spanish investigators combined intensive chemotherapy and ponatinib but relied on allogeneic SCT in first CR as the curative strategy.14 Among 30 patients treated (median age 50 years; range 20-59 years), the CR rate was 100 percent, the complete molecular response rate was 68 percent, and the 2-year event-free survival rate was 91 percent.14 Twenty-eight of 30 patients (93%) underwent allogeneic SCT. A meta-analysis and a propensity-matched score analysis showed the superiority of ponatinib over other TKIs.15,16
European investigators explored early on TKIs with minimal chemotherapy in patients with Ph-positive ALL who were older or unfit for intensive chemotherapy. These resulted in generally low survival rates, 30-45 percent at 5 years, with still 30-70 percent of patients needing allogeneic SCT in first CR.12 A study of ponatinib and steroids in 42 patients (median age 69 years; range 27-85 years) produced a CR rate of 93 percent, a complete molecular response rate of 46 percent, and an estimated 2-year survival rate of 62 percent.17
Once blinatumomab and inotuzumab were shown to be superior to standard-of-care chemotherapy in refractory-relapsed Ph-positive ALL,18-20 investigations explored the combination of TKIs with blinatumomab. In one study, 63 patients (median age 54 years; range 24-82 years) received dasatinib 140 mg daily (with steroids during induction); blinatumomab was added 3 months into dasatinib therapy for 2-5 courses. The response rate was 100 percent; the complete molecular response rate was 41 percent. Fifteen patients had MRD increases (6 with T315I-mutated disease), which decreased with the addition of blinatumomab. Fifty percent of patients still underwent allogeneic SCT. There were 9 relapses so far, 4 systemic, 4 CNS, and 1 nodal. The estimated 2-year survival rate was 88 percent and event-free survival rate was 80 percent.9
At MD Anderson, we initiated a similar frontline approach combining ponatinib with blinatumomab, both starting in induction.10 Among the first 20 patients treated, complete molecular responses were documented very early on (85% overall, 58% at CR), and all patients achieved CR. The estimated 2-year survival rate was 93 percent.10,21
We believe that the current standards of care in Ph-positive ALL (chemotherapy-second generation TKIs-allogeneic SCT) will soon be replaced by new standards of care that incorporate ponatinib with blinatumomab and minimal chemotherapy. The CNS prophylaxis may need to be intensified since the new regimens omit high-dose systemic chemotherapy. Allogeneic SCT may still be needed in a minority of patients or may be replaced with immunotherapeutic modalities like CAR-T or other (e.g., allogeneic NK) cellular therapies.
ALL in Younger Patients
In the early 1980s, the U.S. investigators developed adult ALL regimens that shifted away from the principles of pediatric ALL regimen, and resembled more the strategies used in adult AML regimens: reduction of the intensity of the non-myelosuppressive drugs (steroids, vincristine, asparaginase); shorter maintenance therapy with POMP (6-mercaptopurine, vincristine, methotrexate, prednisone); early use of autologous and allogeneic SCT in first CR.
Retrospective studies comparing the pediatric-inspired regimens to the “modified” adult ALL regimens in adolescents and young adults (up to age 39) showed the superiority of the pediatric regimens. Prospective studies using pediatric-inspired regimens in patients up to the age of 40 years reported 5-year survival rates of 60-65 percent.22,23 Because of the inclusion of asparaginase induction in these regimens, the asparaginase-associated toxicities, more common with older age, limited their use in adult-older ALL.
The Hyper-CVAD regimen (hyper-fractionated cyclophosphamide, vincristine, adriamycin, dexamethasone alternating with methotrexate and cytarabine) is a pediatric-inspired regimen that kept the principles of pediatric regimens (intensive induction-consolidation-intensification-maintenance; intrathecal CNS prophylaxis), but relegated asparaginase to later courses as consolidation. With this and similar modern anti-ALL regimens that include rituximab, the CR rates are 90+ percent, but cure rates plateaued at 50-60 percent in patients up to 60 years old. These cannot be improved with further chemotherapy intensifications.24-30
The 30-40 percent difference in outcome between pediatric and adult ALL is largely because of four cytogenetic-molecular subsets that have different incidences and outcomes in pediatric versus adult ALL.31
The first two are the hyperdiploid karyotype and the ETV6-RUNX1 translocation, which have favorable prognoses and constitute about 50 percent of childhood ALL, but less than 10 percent of adult ALL. The other two are the Ph-positive ALL (25% of adult ALL, 5% of pediatric ALL; historically adverse, but not today) and the “Ph-like ALL” (15-25% of adult ALL, less than 10% of pediatric ALL; historically adverse, but perhaps not today with the new regimens combining chemotherapy and novel therapies targeting CD19 and CD22).
Ph-like ALL presents with a molecular profile similar to Ph-positive ALL, but without the characteristic Ph cytogenetic abnormality or the BCR-ABL1 fusion oncogene.2,3 Ph-like ALL is associated with cytokine receptor like factor 2 (CRLF2) overexpression in 80 percent of cases (half with JAK mutations; unfavorable and not responsive to JAK2 inhibitors; may be sensitive to the novel CD19 or CD22 targeted therapies and to the BCL2 inhibitor venetoclax). The other 20 percent have translocations involving ABL1 or others. The Ph-like ALL with ABL or PDGFR translocations are responsive to BCR-ABL1 TKIs.32-35
Since 2000s, there has been remarkable progress in the treatment and outcome of adult ALL because of several incorporated strategies: 1) the addition of BCR-ABL1 TKIs to chemotherapy regimens in Ph-positive ALL, and the more recent substitution of blinatumomab in place of intensive chemotherapy (discussed earlier);8-10 2) the addition of rituximab and other CD20 antibodies (e.g., ofatumumab) to chemotherapy in CD20-positive ALL;24-27,30 3) the discovery of the activity of the ADC inotuzumab ozogamicin targeting CD22 (conjugated to calicheamicin) and of the BiTE blinatumomab targeting CD19;36-40 4) the development of the CAR-T therapy in ALL salvage;41-43 and 5) the recognition of the adverse significance of MRD-positive disease in CR and implementation of modifying strategies (e.g., blinatumomab, inotuzumab, and other antibodies; CAR T cells; or combined targeted therapies plus chemotherapy modalities, including sequential allogeneic SCT).44,45
In 1992, the Hyper-CVAD regimen was developed.46 Because of the expression of CD20 on the surface of Burkitt and pre-B-ALL cells, rituximab was added to Hyper-CVAD in the two subtypes in 2000.24,25 This combination showed better results than the historical experience with Hyper-CVAD. Randomized trials in Burkitt disease and in pre-B adult ALL confirmed the benefit of adding rituximab.26,27 In 2012, rituximab was replaced with ofatumumab in the Hyper-CVAD regimen30 and did better.47 With Hyper-CVAD plus ofatumumab, the 4-survival rate was 68 percent. Among patients < 40 years old, the 4-year survival rate was 74 percent.30 These results may be further improved with the possible use of the novel potent CD20 BiTEs, which are showing impressive single-agent activity in lymphomas (CR rates 35-55% in refractory-relapsed lymphoma and 45 percent in frontline older lymphoma)48,49
The “great escape” from the therapeutic monotony in ALL happened around 2010 with the discovery of the powerful anti-ALL effects of CD19 and CD22 targeted therapies. Topp and the German investigators discovered the efficacy of blinatumomab.36 Inotuzumab was developed on an institutional IND at MD Anderson.37,38 Randomized trials in refractory-relapsed ALL confirmed the superiority of blinatumomab and inotuzumab over standard-of-care intensive chemotherapy.39,40 However, because of their costs and modest survival benefits, we do not consider them to offer a good “treatment value” as single agents in adult-older ALL (in contrast to the experience in childhood refractory-relapsed ALL).50,51
This led to a rapid transition to exploring them in combination with intensive chemotherapy, initially as the mini-Hyper-CVD-inotuzumab-blinatumomab regimen in both refractory-relapsed and frontline older ALL.52-56 In ALL Salvage 1, the mini-CVD-inotuzumab-blinatumomab regimen resulted in a CR rate of 91 percent and a 3-year survival rate >40 percent.53 In 2015, the experience was robust enough to explore the combination of Hyper-CVAD, first with blinatumomab, and later with the addition of inotuzumab in younger ALL. In the first 38 adult patients treated with Hyper-CVAD plus blinatumomab, the CR rate was 100 percent, the MRD negativity rate was 97 percent, and the estimated 3-year survival was 80 percent.57 If the data mature with similar results in a larger cohort of patients, this may open a new form of therapy in adult ALL.
Italian colleagues investigated a similar approach that added blinatumomab sequentially following 3 and 6 courses of chemotherapy. Among 149 patients treated (median age 49 years; range 10-65 years), the CR rate was 90 percent. MRD clearance was 73 percent post chemotherapy early consolidation and increased to 96 percent post course 1 of blinatumomab. Conversion to MRD-negative status post blinatumomab was noted in 20/23 patients (87%). The 12-month survival was 84 percent; the relapse rate was 11 percent.58
ALL in Older Patients
The treatment of older adults (generally defined as age ≥60 years and older) with Ph-negative ALL is challenging. This is highlighted by the fact that patients 60 years or older account for only 20 percent of ALL cases, but 50 percent of all ALL-related deaths.59,60 These patients historically have a long-term survival rate of 20 percent or less when treated with intensive chemotherapy, due to a higher incidence of adverse-risk cytogenetic and molecular features and poorer tolerance of conventional therapies, including high rates of induction mortality and death in CR.60-62
To improve on these results, blinatumomab and inotuzumab were combined with low-intensity mini Hyper-CVD chemotherapy in older frontline ALL. Among 70 newly diagnosed older patients (median age 68 years; range 60-81 years) treated, the CR rate was 98 percent, the flow-cytometry MRD negative rate was 96 percent, and the 3-year survival was 54 percent (compared with <25% historical survival with Hyper-CVAD).55,56
Stelljes and colleagues reported on 31 older patients (median age 65 years; range 56-80 years) treated with low-intensity chemotherapy (cyclophosphamide-vincristine-steroids prephase), followed by fractionated inotuzumab induction, followed by two consolidations with inotuzumab, five chemotherapy consolidation courses, and 1 year of 6-mercaptopurine/methotrexate. The CR/CRi rate was 100 percent, the MRD-negativity rate was 78 percent, and the 1-year survival rate was 87 percent.63
Novel Approaches of Interest
Researchers are developing better engineered CAR-Ts that target CD19, CD20, and CD22.64 Targeting can be in the form of dual-targeting CAR-Ts or as separate sequential CD19 and CD22 CAR-T infusions. Pan infused CD19 CAR-Ts in Course 1 and CD22 CAR-Ts in Course 2 in 20 patients (median age 6 years; range 1-15 years) with refractory-relapsed ALL and reported CR/CRi and MRD-negativity in 20/20 (100%). With a median follow-up of 27 months, the 2-year leukemia-free survival rate was 60 percent and overall survival rate was 81 percent.65 Yang and colleagues treated 10 patients with refractory-relapsed ALL with GC022F (autologous CD19xCD22 CAR T-cells; 24-hour manufacturing time) and reported 6/6 CR (MRD-negative in 5/6) with active ALL and MRD negativity in 3 of 4 patients with MRD-positive ALL. At the last follow-up, 50 percent were still in MRD-negative CR.66 Yang and colleagues used CD19-CD20 dual synthetic T-cell receptor and antigen receptor (STAR) T-cell therapy in 10 patients, reporting MRD-negative CR in 8/9 evaluable 2 weeks into therapy. Six of the 8 underwent later allogeneic SCT and 4 are still in CR.67 In addition to the exciting results with CD20 BiTEs in lymphoma, trispecific T-cell engagers (TriTEs) targeting CD20 and CD19 or CD22 (in addition to CD3) are being developed.68 Cellular therapy with allogeneic off-the-shelf products, repeated infusions, NK cells, and using such therapies in first CR to eradicate MRD or as consolidation therapy should be explored.
Next-generation sequencing techniques to detect MRD <10-6 may finesse the prediction of ALL relapse, direct changes in therapy, and adjust individual duration of therapy.
HAGOP KANTARJIAN, MD, is Professor and Chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, where he is also the Samsung Distinguished Leukemia Chair in Cancer Medicine. ELIAS JABBOUR, MD, is Professor of Medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.
Interested in More Articles on Leukemia?
Review the latest research and stay up-to-date on new treatments for leukemia. Sign up to be notified every time a new item is added. Explore the online collection at https://bit.ly/3AKJvNW.
Article References Online
You can explore all the references for this article online at https://bit.ly/3mikFB0