Evolving therapy of adult acute lymphoblastic leukemia: state-of-the-art treatment and future directions

The prognosis of R/R ALL has historically been dismal with complete remission (CR) rates of 20-40%, median overall survival (OS) of 6 months, and cure rates of < 10% even with intensive salvage chemotherapy and HSCT [17, 18]. However, recent years have witnessed the introduction of novel agents, which showed significant survival benefit against standard therapies and expanded the armamentarium of ALL. The details of these single-agent studies have been reviewed extensively [19‐21] and the data from pivotal trials are summarized in Table 1. We will therefore focus primarily on emerging therapies and the ways these novel agents are being explored in innovative combinations.

Adults older than 60 years of age account for 20% of ALL cases and 50% of all ALL-related deaths across all age groups [45]. This striking difference between incidence and disease-specific mortality highlights the poor outcome and high unmet need of this older population. Survival rates have been historically dismal; less than 20% across many study groups primarily due to a higher risk of adverse-risk biology and comorbidities that may preclude intensive curative modalities (Table 3) [45‐49]. Efforts made to modify intensive chemotherapy in order to decrease induction mortality and improve remission rates have resulted in sub-optimal success. For instance, in one retrospective study, despite dose reduction of cytarabine, the rates of induction mortality and death in CR in older patients treated with HCVAD regimen (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) were 10% and 35%, respectively [1, 46].

In the R/R setting, blinatumomab and InO have improved remission and survival rates irrespective of age (> 60 years and < 60 years) compared with standard salvage chemotherapies [12, 13]. Due to their acceptable toxicity profile and significant activity, there has been much interest in combining them with lower-intensity chemotherapy in the frontline setting in order to decrease toxicity and improve outcomes of older patients. For example, InO has been successfully combined with mini-HCVD with no induction mortality and with high clinical efficacy [50]. A similar combination of InO with lower intensity chemotherapy for older patients with Ph-negative B cell ALL is also being investigated in the EWALL-InO study (NCT03249870).

Similar to the R/R setting, the sequential combination of InO mini-HCVD followed by blinatumomab has been investigated in a phase 2 study in older untreated patients with promising results [31]. Among 64 patients treated with mini-HCVD and InO, with or without blinatumomab, the median age was 68 years (range 60–81 years) with 42% being older than 70 years. The CR rate was 98%, and the MRD negativity rate was 95%. The 3-year CR duration and OS rate were 76% and 54%, respectively. A propensity match score showed significant improvement compared to the historical 3-year OS rate of 32% with HCVAD in this older population (P = 0.007). Although no early death occurred in induction, the rate of death in remission was 33% and was significantly higher in those age ≥ 70 years compared to those age 60-69 years (50% versus 22%, respectively; P = 0.02). In order to mitigate the significant toxicity in this older population, the protocol has been amended to decrease the number of mini-HCVD plus InO cycles from four to two, and to replace POMP maintenance with blinatumomab monotherapy for patients ≥ 70 years of age.

The SWOG 1318 study evaluated chemotherapy-free induction and consolidation with blinatumomab (total of 4-5 cycles) followed by POMP maintenance (prednisone, vincristine, methotrexate, and 6-mercaptopurine). Thirty-one patients with a median age of 73 years (range 66-84) were treated. Early results showed no induction death, CR rate of 66% (among them 92% with negative MRD), and 1-year RFS and OS rates of 56% and 65%, respectively [32]. A planned phase 2 trial will investigate the combination of InO with blinatumomab in older untreated patients or R/R B cell ALL (NCT03739814).

In order to further improve outcomes of younger patients with newly diagnosed B cell ALL, a phase 2 trial is investigating the sequential use of HCVAD and blinatumomab with promising safety and efficacy [33]. The regimen consists of 4 cycles of HCVAD followed by 4 cycles of blinatumomab. Earlier incorporation of blinatumomab after 2 cycles of chemotherapy is allowed for patients at high risk for early relapse, particularly those with Ph-like ALL, complex karyotype, t(4;11), low-hypodiploidy/near triploidy, or persistent MRD. Four cycles of blinatumomab are also incorporated in the 12 cycles of POMP maintenance (each 3 cycles of POMP followed by 1 cycle of blinatumomab) for a total of 18 months of maintenance therapy. Among 27 patients treated (median age 27 years [range 18-57]), the CR and MRD negativity rates were 100% and 96%, respectively, with no induction death. One-third of patients underwent HSCT for high-risk features. With a median follow-up of 17 months, 93% are alive; one patient died after HSCT of a transplant-related complication, and one died of sepsis during re-induction after relapse. The 1-year RFS and OS rates were 76% and 89%, respectively. A randomized phase 3 trial is currently evaluating chemotherapy with or without blinatumomab for ALL in the frontline setting and may provide more definitive evidence about the benefit of early incorporation of blinatumomab (NCT02003222).

The TKI era in Ph-positive ALL started when the addition of imatinib to intensive chemotherapy improved CR rates to ~ 95% and long term OS rates to 40-50%, which compared very favorably to the historical long term OS of < 10-20% in the pre-TKI era [9, 10, 53, 72, 73]. Dasatinib is a second-generation TKI that was combined with HCVAD regimen in two phase 2 trials, showing improvement upon imatinib data, with a CR rate of 96%, CMR rate of 56% and 3-year DFS and OS rates of 60-62% and 64-69%, respectively [9, 54, 74]. A landmark analysis of the SWOG study of HCVAD plus dasatinib in younger adults with Ph-positive ALL showed benefit for HSCT in CR1 in terms of RFS (P = 0.038) and OS (P = 0.037); however, MRD data were not available so it is not clear whether any subgroup preferentially benefited from consolidative HSCT. Nilotinib plus chemotherapy has also been studied with similarly promising results (2-year OS rate: 72%) [55].

T315I mutations of the ABL1 kinase domain have been described in up to 75% of patients who relapse after treatment with first- or second-generation TKIs [58, 74]. This has led to interest in using ponatinib, a third-generation TKI with high potency and activity against this common resistance mutation [58, 74, 75]. The addition of ponatinib to HCVAD regimen has been tested in a phase 2 single-arm study with encouraging results. Initially, a ponatinib dose of 45 mg daily was used throughout the study. However, due to the increased incidence of severe vascular events, including 2 deaths related to ponatinib, the protocol was amended to reduce the dose of ponatinib to 30 mg daily after achievement of CR, and to 15 mg daily after achievement of CMR, with improved safety [56, 57, 76]. In the most recent update, 86 patients with a median age of 46 years have been treated [57]. The 3-month CMR rate was 74%, and the cumulative CMR rate was 84%. Only 18 patients (21%) underwent HSCT in CR1. With a median follow-up of 44 months, 71% of patients remain alive in remission, and only 3 relapses occurred while on ponatinib. The 5-year event-free survival (EFS) and OS rates were 68% and 74%, respectively. It is worth noting that while none of the TKIs have been compared head-to-head in Ph-positive ALL, one meta-analysis and one propensity-matched score analysis both showed superiority of ponatinib-based regimens over regimens containing earlier generation TKIs [77, 78]. Depth of remission, EFS, and OS rates all favored ponatinib.

In order to decrease treatment-related toxicity, lower intensity regimens have been investigated in Ph-positive ALL, mainly in older patients who are unfit for intensive chemotherapy [11, 58, 60, 64]. Several single-arm trials have evaluated the combination of dasatinib or nilotinib with low-dose chemotherapy in older patients (> 55 years of age). In the EWALL-PH-01 trial, which used dasatinib, the CR rate was 96%, and the major molecular response (MMR) rate was 65% [58]. However, long-term outcomes were not optimal; the 5-year RFS and OS rates were only 28% and 36%, respectively. Additionally, a T315I mutation was present in most relapses (75%). Nilotinib yielded comparable results to dasatinib when combined with similar backbone chemotherapy in the EWAL-PH-02 trial [60]. The CR rate was 94%, and the 4-year RFS and OS were 42% and 47%, respectively.

Lower-intensity regimens are also being evaluated in younger patients, with the goal of reducing reliance on chemotherapy, and thus decreasing treatment-related toxicity. Notably, one randomized trial (GRAAPH-2005) compared the combination of imatinib with either HCVAD or lower-intensity version of the HCVAD (vincristine + prednisone in even cycles, thus, omitting doxorubicin and cyclophosphamide, while keeping methotrexate and cytarabine in odd cycles at standard dosing) in younger patients (median age 47 years). There was no statistically significant difference in 5-year EFS and OS rates between higher-intensity and lower-intensity regimens (42.2% versus 32.1%, P = 0.13, and 48.3%, versus 43.0%, P = 0.37, respectively) [11]. Importantly, this study showed that the combination of lower-intensity chemotherapy plus TKI may lead to similar long-term outcomes, and lower toxicity compared with intensive chemotherapy-based approach. However, there were a few limitations to the trial including the higher-than-expected 60-day mortality with HCVAD regimen (9%) and the intermittent dosing of imatinib (2 weeks on, 2 weeks off), which may not be optimal for continuous suppression of BCR-ABL1 [79]. The combination of dasatinib with prednisone was evaluated in younger patients in the GIMEMA LAL1509 trial (median age: 42 years). Patients who did not achieve CMR by day 85 (82% of the study population) subsequently received subsequent chemotherapy, with or without HSCT, whereas those who achieved CMR continued with dasatinib alone. Using this risk-adapted treatment approach, the 3-year OS rate was 58%. Those who achieved early CMR (18% of the cohort) and thus received no subsequent chemotherapy, had a very promising OS rate of 75% at 30 months. This suggests that early, deep response to lower-intensity therapy may allow for selection of patients who can have excellent outcomes with chemotherapy-free regimens. Similarly, in the phase II CALGB 10701 study, which combined dasatinib with prednisone in induction then added minimal chemotherapy in consolidation, high CR rates were seen (86%), allowing a third of patients to undergo allogeneic HSCT, among whom no relapses occurred at a median follow up of 23 months [80]. An ongoing phase 2 study at MDACC is investigating the combination of mini-HCVD with ponatinib and sequential blinatumomab in the frontline setting.

Several trials also evaluated the frontline combination of TKIs (most at a higher dose) with steroids in elderly frail patients with excellent CR rates and minimal toxicity [59, 62‐64]. However, deep responses were, not unexpectedly, rarely attained, remissions were short, and relapses were common resulting in poor long-term survival. The rates of CMR appear to be higher with successive generations of TKIs (e.g., 46% with ponatinib, 18% with dasatinib, and 4% with imatinib) [59, 62‐64]. Among 42 older patients treated with ponatinib and steroids (median age 68 [range 27-85]), the CMR and 1-year OS rates were 46% and 88%, respectively. Toxicity was high with 45 mg dosing and only 15/42 patients were still receiving this dose at week 24. One death was related to ponatinib [64]. While encouraging for this older population, novel lower-intensity strategies are needed to improve the CMR rate, as this has been shown to translate to superior long-term outcomes [67].

Blinatumomab has shown safety and efficacy in heavily pre-treated R/R Ph-positive ALL in a single-arm multicenter phase 2 trial [14]. Among 45 patients treated (50% with prior exposure to ponatinib, 44% with prior HSCT, and 27% with T315I mutation), the CR/CRi rate was 36%, with 88% of responders achieving MRD negativity. Responses were observed regardless of T315I mutation status. Half of patients were able to undergo HSCT, and the median OS was 7.1 months.

The combination of blinatumomab with TKI (mainly ponatinib) has been shown to be safe and effective in a small case series of 15 patients from MDACC with 50% CR rate and 75% molecular response [81]. The GIMEMA group has recently presented early results from D-ALBA, the first trial investigating the sequential use of TKI/steroid (in induction) and blinatumomab (in consolidation) [65]. Sixty-three patients have been treated thus far with this regimen of prednisone, dasatinib, and blinatumomab. The CR rate was 98%, and the 1-year DFS rate was 88%. Deep molecular response increased throughout therapy (29% after induction, 60% after 2 cycles of blinatumomab, and 80% after 4 cycles). Notably, T315I mutation was noted in 6/15 patients with rising MRD in the induction phase, all of which were cleared after blinatumomab. Several similar trials are evaluating the combination of blinatumomab with dasatinib (NCT02143414, NCT04329325) and ponatinib (NCT03263572) in both frontline and R/R settings.

The combination of InO with bosutinib is being evaluated in a phase 1/2 trial in R/R Ph-positive ALL (NCT02311998). Patients with T315I mutation are excluded. Early results have been presented on 14 patients with CR/CRi and CMR rates of 79% and 55%, respectively [82]. The median EFS and OS were 8.1 and 8.2 months, respectively. Although there is a theoretical concern for overlapping hepatic toxicity with the combination of InO and ponatinib, studies evaluating this combination are warranted given the high efficacy of both of these agents in ALL.

According to the National Institute of Health, the AYA population is defined as patients between 16 and 39 years of age [104]. Several prospective trials that utilized pediatric-inspired intensive regimens in AYA patients have yielded CR rates in 85-90% and long-term EFS and OS in the 60-70% range [105‐112]. Pediatric protocols employ extensive use of asparaginase, which can be associated with significant toxicity in adults (e.g., anaphylaxis, pancreatitis, hepatotoxicity, thrombosis, and coagulopathy), making them more challenging to deliver to older patients. The feasibility and efficacy of a pediatric-inspired regimen dedicated specifically for AYA patients has been recently demonstrated in a prospective multicenter study (CALGB 10403) [113]. The induction mortality was 3% and the CR rate was 89%. The 3-year EFS and OS rates were 59% and 73%, respectively, which are improved compared to historical controls (48% and 55%, respectively). The investigators at MDACC compared a pediatric-inspired regimen (ABFM, which contains daunorubicin, vincristine, asparaginase, steroids, cytarabine, and methotrexate) with the HCVAD regimen in AYA patients in a non-randomized study [114]. The 5-year OS rates were 60% in both groups. As expected, hepatic, pancreatic, and thrombotic toxicities were more common with ABFM, whereas myelosuppression and infectious complications were more common with HCVAD. Induction mortality was low in both groups (1%). These findings appear similar to the CALGB 10,403 results and support HCVAD as an acceptable regimen for AYA patients. In the absence of a randomized study comparing both regimens in the AYA population, it is important that practitioners adopt the protocol that matches their institution’s comfort level, and that they adhere to the protocol in its entirety, as these are key factors in achieving superior outcomes. More recently, the superior survival seen among patients with negative MRD has generated interest in integrating novel therapies early during induction in order to achieve deeper remission and improve cure rates. This is currently being investigated in the Alliance A041501 trial, which is adding InO to the CALGB 10403 backbone in AYA patients with newly diagnosed Ph-negative B cell ALL (NCT03150693).

CD20 is a B cell marker that is expressed in 30-50% of precursor B cell ALL [115]. The addition of an anti-CD20 monoclonal antibody (moAb) to multiagent chemotherapy is a standard of care for younger patients (< 60 years old) with CD20+ B cell ALL (defined as CD20 expression ≥ 20%) [116‐118]. This was first assessed in a prospective trial at MDACC where 12 doses of rituximab added to HCVAD improved outcome of patients who were younger than 60 years in terms of CR duration (67% versus 40%; P < 0.002) and OS rates (3-year OS 75% versus 47%; P = 0.003), compared with historical patients treated with HCVAD alone [118]. No benefit was observed in older patients, which was attributed to the high rate of myelosuppression-related deaths in this group. These results were later confirmed in the GRAALL-2005/R randomized study of adults younger than 60 years, which showed improvement in the 2-year EFS and OS rates from 52 to 65% (P = 0.038), and from 64 to 71% (P = 0.095; with censoring for HSCT, P = 0.018), respectively [117]. Of note, there was no increase in adverse events in patients receiving rituximab. Although there is no definitive evidence for the benefit of rituximab in older adults, it is reasonable to add it to frontline regimens in older adults given its manageable safety profile. In Burkitt leukemia/lymphoma, in which CD20 is universally and strongly expressed, the addition of rituximab to intensive chemotherapy backbone has improved survival and is a standard of care [116, 119, 120].

Ofatumumab is a second-generation anti-CD20 antibody with higher complement-dependent cytotoxicity and slower dissociation rate compared to rituximab [121]. Ofatumumab has been evaluated in a phase 2 study in combination with HCVAD in frontline B cell ALL with any level of CD20 expression (i.e., ≥ 1%) [122]. The clinical benefit was seen across all CD20+ subgroups (< 20% and > 20%). These results appear similar to historical cohorts treated with HCVAD + rituximab with 4-year EFS and OS rates of 59% and 68%, respectively. Therefore, ofatumumab is a reasonable option for CD20+ B cell ALL, especially with low level of CD20 expression—a population where rituximab has not been extensively studied. No clinical trials exist yet on obinutuzumab in ALL.

Despite the relatively low incidence of CNS disease at presentation in ALL (5-10%), CNS relapses are common if no adequate CNS prophylaxis is given (~ 30% of patients in CR, and up to 75% in patients with R/R disease) [123‐126]. Therefore, all current ALL regimens include CNS prophylaxis. The method of prophylaxis has varied according to the regimen being used, including intrathecal (IT) chemotherapy, high dose systemic therapy, radiation, or a combination of them. Efforts have been made to lower the doses or completely omit prophylactic cranial irradiation due to its significant cognitive toxicity, especially for long-term survivors. The combination of effective high-dose systemic therapy with CNS penetration (e.g., methotrexate or cytarabine) with IT chemotherapy has been equally effective, with CNS recurrence incidence of < 6%, similar to what is seen in regimens that used cranial radiation [127, 128]. Furthermore, one meta-analysis showed that cranial radiation in contemporary protocols was beneficial only in patients with overt CNS disease [129]. IT chemotherapy prophylaxis is typically given with alternating doses of methotrexate and cytarabine. The number of IT chemotherapy depends on the predetermined disease risk [128, 130]. For instance, the HCVAD regimen employs 8 IT chemotherapy doses for standard risk B or T cell ALL, 12 for Ph-positive ALL, and 16 for Burkitt leukemia, a risk-adapted approach that has resulted in a CNS recurrence rate < 4% [131].