Novel Therapies in the Treatment of Adult Acute Lymphoblastic Leukemia

Abstract

Purpose of Review

Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy. Advances in multi-agent chemotherapy have resulted in dramatic improvements in the number of pediatric cases that result in a cure; however, until recently, treatment options for older adults or patients with relapsed and refractory disease were extremely limited. This review seeks to describe in greater detail a number of emerging novel treatment modalities recently approved for this cancer.

Recent Findings

In this review we discuss a number of recently approved novel therapies for ALL, including new approaches with targeted tyrosine kinase inhibitors, novel immune based therapies including the bispecific antibody blinatumomab and the antibody-drug conjugate inotuzumab ozogamicin, and the role of cellular therapeutics such as chimeric antigen receptor (CAR) T-cells. We also discuss the impact that advances in diagnostics and disease classification and monitoring have had on treatment.

Summary

A number of advances in ALL have resulted in dramatic changes to the treatment landscape and therapeutic options both at the time of diagnosis and in salvage. These findings are reshaping our treatment paradigms throughout the course of disease.

Introduction

Acute lymphoblastic leukemia (ALL) is a cancer of early lymphoid precursors, most frequently of B-cell or T-cell lineage – or rarely from an NK-cell precursor [1]. The total number of incident ALL cases each year is relatively low in the United States: the projected incident cases of ALL in 2019 is 5930, and roughly 1500 of these estimated to result in death [2]. ALL remains the most common cancer in children, and sustained, coordinated research efforts have led to a remarkable improvement in childhood ALL outcomes over the last 50+ years [3]. Acute lymphoblastic leukemia has a bimodal incidence, with a peak in childhood and another in older adults -approximately 54.2 % of cases afflict those < 20 years of age, whereas 21.7 % occur in those aged 55 or above [2].

Indeed, Pediatric ALL has long been considered as a cancer therapeutic success story with OS reaching approximately 80 %, and select defined subsets approaching > 98 % cure rate [3,4]. These successes have led to new efforts to identify those children most likely to respond, and develop treatments for them with reduced short-term and long-term toxicity. Nonetheless, even though many children respond, disease that relapses or is refractory present a particular challenge, and novel therapies, such as CAR-T therapy, have been pioneered in this setting.

At the same time, survival and outcomes for adults, particularly those over the aged of 55, continues to be poor; population level relative survival in patients aged 15 – 69 diagnosed with ALL in Germany and the US was 43% and 35% respectively in one analysis [5]. Frequently, adults achieve an initial response to induction chemotherapy, but will relapse, with long-term remission rates reaching only 30 – 40% of patients [5–7]. Those aged 55 and above are overly represented in regard to death rates - with the median age of death from ALL being 56, and overall survival at five years is under 25%. This poor survival and toxicities associated with traditional chemotherapy regimens in adults has driven the increasing use of novel therapeutics in their management.

In the last 5 years, a number of novel, highly active therapies have been introduced into the treatment of ALL, including antibody-drug conjugates, cellular therapies including CAR-T cell therapy, and new tyrosine kinase inhibitors (Figure 1) [8]. How these therapies fit in with existing chemotherapy and HSCT is under active investigation, with many trials under way. In this review, we seek to summarize the current landscape of novel therapeutics in ALL, including how new diagnostic testing has advanced treatment paradigms, and then focusing on how new targeted therapies have fared in recent trials and potential directions with these agents moving forward.

Figure 1.

New Therapeutic Targets in Acute Lymphoblastic Leukemia

Classification

The WHO classification of ALL is based first on cell lineage, and recent revisions have emphasized the importance of specific recurrent cytogenetic and molecular features [9,10]. In 2016 updates to the WHO classification included two additional entities in B-cell ALL, B-ALL with translocations involving tyrosine kinases or cytokine receptors (“BCR-ABL1-like” or “Ph-like”) and B-ALL with an intrachromosomal amplification of chromosome 21 (iAMP21) [11]. Both entities have been associated with a worsened prognosis with standard chemotherapy, but may respond to adaptive treatment strategies, such as therapy intensification with iAMP21, or the addition of targeted inhibitors for certain translocations present in BCR-ABL1-like B-ALL. These expand current existing WHO-defined subtypes of ALL, including previously described cytogenetic and molecularly defined entities (Table 1), and are increasingly relevant as they may inform treatment decisions [9,12].

Table 1.

General Prognostic and Treatment Implications based on the revised WHO Classification for Acute Lymphoblastic Leukemia.

WHO Classification of Acute Lymphoblastic Leukemia
B-lymphoblastic leukemia/lymphoma	Prognosis	Targets/Treatment Strategies
B-lymphoblastic leukemia/lymphoma, NOS	No effect in regard to prognosis	Treated as conventional ALL
B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1	Historically unfavorable; may be improved with TKI therapies	TKIs toward Ph Chromosome (imatinib, dasatinib, ponatinib, etc)
B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged	Associated with poor prognosis, common in infants	FLT3, Bcl2-I, HDAC-i trials ongoing to see if benefit
B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1	Most common in childhood, good prognosis	Standard treatment including Asparaginase/MTX
B-lymphoblastic leukemia/lymphoma with hyperdiploidy	Generally a favorable prognostic marker	Lower intensity therapy
B-lymphoblastic leukemia/lymphoma with hypodiploidy	Prognosis in general is poor	Possible targeting of PI3K/mTor pathway/RAS
B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH	Intermediate prognosis	Conventional treatment, no target treatment yet
B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1	No significant effect on prognosis	Standard treatment
Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like	Poor response to chemotherapy	TKI in addition to chemotherapy improves OS
Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21	Adverse	Treatment intensification
TCF3-PBX1+ Rearranged ALL t(1:19)	Favorable outcome	Intensive treatment. TKIs and Ibrutinib improve outcomes
T-lymphoblastic leukemia/lymphoma
TCF3 Provisional entity: Early T-cell precursor lymphoblastic leukemia	Poor outcome	Intensive chemotherapy/HSCT in first CR
Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma	Rare entity, not well defined	Chemotherapy / Unified treatment unknown

Initial diagnostic evaluation

The diagnosis of ALL remains predicated on identifying lymphoblasts with characteristic morphology; in addition to standard assessments, the use of new diagnostic techniques at presentation is increasingly important both for prognostication and treatment selection. Flow cytometry or immunohistochemistry identify the expression of lineage-defining antigens (such as CD3, CD79a, CD19, CD10), and also identify the presence or absence of cell surface targets for therapies directed toward CD19 (e.g. blinatumomab), CD20 (e.g. rituximab), or CD22 (e.g. inotuzumab ozogamicin). Similarly, while cytogenetic analysis helps subclassify disease, such as BCR-ABL positive ALL, other new techniques like gene expression profiling [13] or the use of NGS or FISH, should be considered to identify kinase translocations that characterize Ph-like (or BCR-ABL1-like) B-ALL [14].

New therapies in Acute Lymphoblastic Leukemia

Targeting the Philadelphia Chromosome in ALL

Perhaps no area of ALL treatment has changed more than B-ALL harboring a translocation in BCR-ABL1 -- the Philadelphia Chromosome. The discovery of highly specific and active inhibitors of this novel fusion protein, initially in CML but subsequently also in ALL harboring this translocation, have become critical elements of any treatment plan for this disease subgroup. The BCR-ABL1 fusion - t(9;22) (q34.1;q11.2) – was initially identified as a defining mutation in CML, and is present in a subset of ALL cases, resulting in activation of the ABL kinase and cellular proliferation [15,16]. The BCR-ABL1 gene is typically one of two isoforms depending on the translocation breakpoint, most commonly the p190 isoform in adult ALL, followed by p210 [17,18]. BCR-ABL1 alterations in ALL occur at increasing frequency with advancing age; it is present in few patients with childhood ALL (1–5%), increases in the adolescent and young adult (AYA) population, and may be seen in as many as 50% of adults over age 50 [19].

Historically, the outcomes of patients with ALL with BCR-ABL1 translocation were quite poor, and these patients were categorized as high risk disease. Prior to the availability of directed TKI therapies, median overall survival approximated one year with chemotherapy alone [20,21], and the use of allogeneic hematopoietic cell transplantation, particularly in adults with Ph+ ALL, became a standard approach [22]. Subsequently, a number of specific TKIs with activity against BCR-ABL have been developed: imatinib being the first, followed by dasatinib, nilotinib, ponatinib, and bosutinib. As monotherapy, even early in development, these targeted agents have shown evidence of activity in ALL [23].

Several studies have evaluated the use of BCR-ABL1 directed TKIs combined with steroids – and omitting standard multi-agent cytotoxic chemotherapy – for the treatment of Ph+ ALL in adults. The rate of hematologic response with imatinib and steroids is high and, particularly for older patients who would otherwise be high risk or ineligible for cytotoxic chemotherapy strategies, results in a tolerable treatment strategy with improvement in survival over the dismal historic figures [24]. A challenge with imatinib in both ALL and CML is the expansion or appearance of subclones with mutations that make them resistant to this agent [25]. Some such mutations, for instance Y253H, are specific to imatinib, and potentially overcome by the use of a newer generation TKI. Dasatinib, a second generation TKI more potent toward BCR-ABL1, also has the benefit of penetrating the blood-brain barrier, which can be a sanctuary site in ALL [26]. The use of dasatinib combined with steroids can yield high remission rates, including molecular remissions, with a favorable toxicity profile and few treatment-related deaths [27,28].

As more patients are treated with these regimens, it is apparent that some relapses may occur, often related to the presence of the T315I resistance mutation [27], illustrating the importance of sequential molecular profiling during treatment. More recently, efforts have looked at the use of ponatinib, which is active against Ph+ ALL harboring the T315I mutation, as an option for the initial and salvage treatment [29–31,31]. Early reports suggest encouraging survival with this combination, potentially in part from suppression of T315I clones early in treatment ( NCT01641107, [32]); however, the toxicity profile of ponatinib does require additional monitoring and considerations for dose modifications, particularly around the incidence of vascular events.

Although remission rates are high with TKI and steroids alone, the depth of remission may not achieve molecular clearance, and resistance remains a concern; therefore, combining TKI therapy with multi-agent cytotoxic regimens has also become prevalent, particularly in the treatment of younger patients. TKIs have been combined with various regimens including hyper CVAD [33–35]), AYA regimens [36,37], as well as lower intensive multiagent chemotherapy regimens [38,39]. Early follow-up from these studies suggest encouraging long term responses, favorable compared to those seen with other historical treatments although not prospectively compared to regimens with TKI and steroids alone. Indeed, this encouraging activity of TKI therapy in BCR-ABL1 B-ALL has introduced a new debate regarding the optimal therapy of this subset of patients, including questions as to whether the chemotherapy backbone contributes to responses and long term outcomes, as well as whether transplant is always needed for treatment [40].

Further impacting this treatment decision has been the development of new therapeutics for AML that work through targeting cell surface markers, or cellular therapies. The rationale for these agents is discussed in greater detail in a subsequent section. There are a variety of combinations of interest that seek to use novel agents in combination with TKIs in order to achieve an active regimen with a more favorable toxicity profile than is seen with TKI alone or in combination with traditional cytotoxic agents. A number of trials are currently underway testing TKI in combination with other novel therapies including blinatumomab and inotuzumab ozogamicin for Ph+ B-ALL (NCT02744768, NCT01667133, NCT01914484, NCT00560794, NCT02311998, NCT03263572, among others).

BCR-ABL1-like (Ph-like) ALL

The success of targeted, highly-active therapies in BCR-ABL positive ALL led to further analysis of targetable subsets across ALL patients. Profiling of gene expression in ALL samples identified subgroups of patients who lack the BRC-ABL1 fusion gene, but nonetheless exhibit a similar gene expression pattern as Ph+ ALL positive patients. This subtype of ALL has thus been characterized as “Ph-like ALL,” a group of patients who appear to harbor a particularly poor prognosis akin to Ph+ ALL in the pre-TKI era [41,42]. The prevalence of Ph-like ALL is believed to be approximately 20 % in those aged 21 and above, with particular enrichment in the AYA population, although this varies depending on which subsets of ALL patients are reviewed.

Gene expression profiles that characterize Ph-like B-ALL are often associated with actionable kinase alterations, including CRLF2 rearrangements and JAK2 mutations, as well as fusions involving ABL1/ABL2[13]. It has become increasingly important to identify Ph-like ALL in patients in order to provide critical prognostic information and potentially to target these novel fusion genes. Although the initial studies identifying Ph-like ALL were based on gene expression profiles, this testing is not readily available outside of the research setting. The association between gene expression profiles and specific gene mutations or fusions involving JAK2 or ABL, among others, have prompted the use of FISH or NGS panels to characterize these patients. These panels employ FISH for rearrangements in ABL1, ABL2, CRLF2, and other common genes. Alternatively, some assays use NGS to sequence RNA for novel fusion partners [14]. Regardless of the test chosen, identifying these patients early in diagnosis is becoming increasingly relevant for treatment [43]. For instance, Ph-like ALL may have improved outcomes if using treatment intensification and consideration of allogeneic transplant, particularly for patients who do not achieve MRD negativity [44,45].

Blinatumomab

Therapies targeting B-cell lineage specific antigens show promise across a number of lymphoid malignanices, including B-ALL. In part, this is because patients can survive with even severe B-call depletion – in contrast to therapies that target T-cell or myeloid lineage markers which have more complications related to depletion of each respective compartment. Blinatumomab is a bispecific antibody with the ability to bind CD3 on T-cells and CD19 receptors on B-cells, thus directing a cytotoxic T-cell response toward any leukemic cells expressing this receptor. Blinatumomab was approved for use in the EU in 2014 and in the US in 2015. Bispecific antibodies function by both colocalizing cytotoxic T-cells with the malignant cell of interest – in this case CD19-expressing B-cells – and also by activating the T-cells to result in cell-mediated death [46]. Of note, this method of treatment depends upon an endogenous T-cell response.

Blinatumomab was studied both in patients with morphologic relapse of B-ALL, as well as in the setting of minimal residual disease after treatment. Early studies suggested encouraging activity in R/R CD19+ B-ALL using blinatumomab administered as a 28 day continuous infusion followed by a 2-week treatment-free interval, with a CR/CRh rate of 69% in this small cohort [47]. In general, the safety profile of blinatumomab is favorable, although there are several unique toxicities that can occur and should be monitored, and may necessitate treatment interruption or discontinuation. These include cytokine release syndrome (CRS) and neurotoxicity. Severe CRS may be managed by holding the infusion, administration of corticosteroids, IV fluids, and consideration of other agents such as the IL-6 inhibitor tocilizumab. Severe neurotoxicity is generally managed similarly, with drug discontinuation and corticosteroid administration in addition to other supportive measures [48]. Blinatumomab has a very short half life and as such requires a continuous infusion through the 28 day period; due to the risk of CRS it is started at a lower dose during the first cycle and then escalated on day 7, all in the inpatient setting. Subsequently, patients must exchange cartridges during the infusion period, which requires center expertise and may be prohibitive for some patients. Given these factor, ongoing studies continue to analyze the economic impact of blinatumomab compared to other salvage options [49].

The ALCANTARA trial enrolled patients with relapsed or refractory Ph+ B-ALL; patients must have progressed on prior TKI based therapy. Blinatumomab monotherapy was administered in a 28-day cycle. This reported a CR/CRh rate of 36% among 45 patients treated [50]. Of these responders, 88% of patients achieved negative MRD. Blinatumomab has also been evaluated in Ph-negative disease; one phase 2 trial evaluated 189 patients with R/R Ph-negative ALL and reported CR in 33 % of patients, similar to the Ph+ B-ALL population, with 32 patients able to undergo subsequent HSCT [51]. These studies led to a phase 3 study comparing blinatumomab to standard chemotherapy salvage regimens for relapsed or refractory B-ALL. A total of 405 patients were randomized to receive either blinatumomab or standard-of-care chemotherapy in a 2:1 fashion; patients treated with blinatumomab had an improved remission rate (CR/PR/CRh 44% vs. 25%, P<0.001), as well as a prolonged overall survival (7.7 months vs. 4.0 months, P=0.01) [52], leading to adoption of this agent for the treatment of patients with relapsed and refractory disease.

In addition to the activity seen with frank relapse, blinatumomab may be particularly effective in the setting of measurable residual disease (MRD), and its ability to “convert” to MRD negativity. The BLAST trial assessed the response to blinatumomab in patients with B-ALL with measurable residual disease after prior chemotherapy, found that 78 % of subjects then achieved MRD negativity following 1 cycle of treatment [53]. Encouragingly, many patients in this study had prolonged relapse-free survival intervals, even when censoring at the time of allogeneic hematopoietic cell transplantation. In contrast to patients with frank relapse, the incidence of cytokine release syndrome may be lower when treating patients with MRD alone.

A number of mechanisms have been proposed to explain resistance to or relapse after blinatumomab therapy. These include the presence of extramedullary disease [54], a higher leukemic burden at the time of treatment, PD-L1 expression on tumor cells [55], and loss of or altered CD19 expression on leukemic cells [56].

Based on the activity of blinatumomab in the relapsed/refractory setting, as well as for MRD, current investigations are underway to evaluate blinatumomab as a component of the initial treatment strategy (e.g. NCT03914625). There are similar efforts to look at blinatumomab in other settings; for instance, as post-transplant maintenance to prevent relapse after HSCT (NCT02807883), akin to how post-transplant TKI therapy is employed in Ph+ B-ALL.

Inotuzumab Ozogamicin

Another B-cell target of interest is CD22; this antigen, like CD19, is expressed in the vast majority of B-ALL cases. Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) comprised of a CD22 monoclonal antibody conjugated to calicheamicin[57]. This compound binds to cell surface CD22, where the drug is internalized into leukemic cells and the linked calicheamicin is released, resulting in DNA damage and subsequent cell apoptosis.

Inotuzumab was studied in 90 adult and pediatric patients with relapsed or refractory B-ALL[58,59]. Initially dosed once every 3–4 weeks, subsequent dosing was modified to include fractionated weekly doses based on evidence of improved in vitro efficacy with more frequent dosing. The overall response rate was 58% (CR 19%, CRp 30%, mCR 9%), with a median survival of 6.2 months. A subset of patients experienced veno-occlusive disease after transplant (6 of 36 patients who underwent transplant), which was less common using the fractionated weekly schedule (7% of patients). The concern around VOD is a consideration in patients who otherwise may be considered for transplant after salvage, particularly when alternative therapies may be available at the time of relapse. This risk seems to be mitigated by using fractionated dosing, distancing transplant from the last dose of inotuzumab, and considerations around the conditioning regimen [60].

Inotuzumab was subsequently compared to standard salvage in the INO-VATE ALL trial, a phase 3 study of 326 patients with R/R B-ALL. Of the 218 patients in the intention to treat analysis, the overall response rate was increased in the inotuzumab group (CR 81% vs 29.4%, p<0.001) and was associated with improved overall survival (7.7 months vs 6.7 months, p=0.04). More patients were able to proceed to transplant among those treated with inotuzumab; again, however, there was an increased incidence of all grade VOD in the inotuzumab arm (11%) compared to those receiving standard treatment (1%) [61].

While inotuzumab has encouraging monotherapy response rates, the durability of these responses has also led to evaluation in combination with lower-intensity chemotherapy regimens, particularly in older adults who may not be candidates for allogeneic transplantation. The addition of inotuzumab to “mini-hyper-CVD” has shown high response rates as salvage – with 78% responding and 59% CR, while 82% of responders achieve MRD negativity [62]. Future studies are exploring additional combination partners; including combinations of blinatumomab and inotuzumab as alternating therapies (e.g. NCT03739814).

Chimeric Antigen Receptor T-Cells (CAR-T Therapy)

Cellular therapies have emerged as a highly active option even in patients with multiply relapsed and refractory B-ALL. Adoptive immunotherapy, of which CAR-T therapy is an example of, has been under development for many years [63] (Table 2) and recently approved for the treatment of younger patients up to age 25 with R/R B-ALL. CAR-T cells are engineered T-cells that express a chimeric antigen receptor (CAR) which is modified to recognize a tumor antigen of interest [64]. The CAR construct contains an external antigen binding moiety linked to an intracellular signaling domain – CD3ζ – via a spacer/hinge. 2^nd generation CAR-T cells used in clinical practice also include a second co-stimulatory signal, most commonly 4–1BB or CD28, which amplify T-cell activation and expansion [65]. The choice of a costimulatory domain may have some influence on CAR expansion and persistence; 4–1BB-containing CAR-T products may have longer persistence, while CD28 CARs may favor expansion [66]. Several new strategies include evaluating “universal” T-cell based therapies as a way to bypass the delay currently present with using donor-derived products [67]. Once the CAR-T product is manufactured, it is then infused into the patient, typically following lymphodepleting chemotherapy [68].

Table 2.

CAR-T cell therapy: Select milestones in the treatment of patients with ALL

• 12/1/1989, Eshhar, Gross and Waks generate first chimeric T-cell receptor

• 8/10/2011, Kalos and colleagues administer a CAR-T therapy to 3 patients with multiply refractory CLL

• 2 patients achieved CR

• 2/19/2014, Davile and colleagues treated 16 patients with r/r B-ALL using CD19 directed CAR-T therapy

• CR was seen in 88 % and 7/16 were able to be transitioned to autologous HSCT

• 10/16/2014, Maude and colleagues infused 30 adults & children with CTL019

• 90% CR was observed with 78 % alive at 6 months

• 12/6/2014, Lee et al. report on 20 patients with ALL whom received CTL019.

• CR was achieved in 67%, with 1 year OS of 51.6%

• 5/26/2015, Dai et al., infused 9 patients with r/r B-ALL, 6 of them with extramedullary disease, using anti-CD19 CAR-T cells

• OS of 56% was seen at 18 weeks

• 12/3/2015, Grupp et al. report on the outcomes of 53 children with r/r CD19+ ALL with a CD19 CAR-T cell

• 94% CR was observed within 1 month and OS at 12 months was 78%

• 8/30/2017, Tisagenlecleucel (Kymriah) is FDA approved for treatment of r/r B-ALL in patients up to age 25

• 2/1/2018, Park et al., in a phase 1 trial of 53 patients, report long term outcomes using CD-19 directed CAR T-cells

• CR of 83% was seen and at a median follow up of 29 months, OS was 12.9 months.

• 2/1/2018, Maude et al. report the results of 75 children/adolescents, median age 11, with r/r B-ALL treated with Tisagenlecleucel

• CR was 81% and OS at 12 months 76%.

The initial studies of CAR-T therapy in ALL were predominately in pediatric populations. CAR-T therapies show high rates of initial response, even in highly refractory disease. Initial CAR-T constructs primarily targeted CD19, although other targets have also been developed and are under investigation. Early reports showed that CAR-T cells could be effective in relapsed and refractory B-ALL, with remission rates nearing approximately 90% [69–71]. With the use of CAR-T cells new toxicities have emerged and should be proactively managed during patient treatment. Specifically, CAR-T products, like other immune effector cell (IEC) therapies, can be associated with the development of neurotoxicity (IEC-associated neurotoxicity syndrome or ICANS) and cytokine release syndrome (CRS) [72]. Cytokine release syndrome is characterized by a systemic inflammatory response that may progress to hypotension, vascular leak with respiratory distress, renal failure, and coagulopathy, often between 1–4 days after infusion. CRS is associated with elevated levels of IL-6, and is generally managed with tocilizumab, a humanized monoclonal antibody that targets the IL-6 receptor [73], as well as with the use of corticosteroids. Neurotoxicity (ICANS) may also be seen following CAR-T cell infusion, potentially related to a number of predisposing risks, including a low platelet count, excess inflammation that may disrupt the blood-brain-barrier [74], or even disease-specific factors [75].

Pivotal studies in CAR-T cells have led to the FDA approval of these therapies for relapsed and refractory B-ALL in patients up to age 25; based on the high response rates in this otherwise poor prognosis group and favorable survival outcomes [76,77]. Ongoing considerations include work to identify patients responding to therapy, and how to maintain remission after treatment. Since they are engineered cells, CAR-T populations can be tracked closely over time after infusion. There are varying rates of CAR persistence across study populations and based on different co-stimulatory constructs [78]. Some reports suggest that CAR-T persistence may be associated with sustained remission [69,71] although this likely also varies according to the patient population studied.

Longer follow-up of patients treated with CAR-T cells, predominately in pediatric and AYA populations, has shown encouraging overall survival [76,77], particularly in patients with a lower disease burden at the time of CAR-T therapy. Tisagenlecleucel is a CD-19 directed CAR-T product that was FDA approved for the treatment of relapse or refractory B-ALL in patients up to 25 years of age. This drug was approved largely based on an open-label multicenter trial, ELIANA, which treated 63 patients, age 3–23. The CR/CRi rate in that trial was 83%, and the duration of remission was not reached [76]. The approval was limited to a younger population after other studies in older adults with R/R B-ALL showed excess neurotoxicity, including several deaths. There are likely a number of factors that can lead to severe ICANS, including conditioning regimens [79], and other studies in the older adult B-ALL population are underway.

Measurable Residual Disease Monitoring

While there has been a recent surge in novel therapeutics for B-ALL, these have also been facilitated by significant advances to detect residual disease after treatment. As such, eradication of measurable disease has emerged as a therapeutic endpoint. The ability to detect disease at trace residual levels has been facilitated through advances in flow cytometry and through new molecular diagnostics platforms. These advances mirror the techniques for monitoring BCR-ABL1 transcript levels during TKI therapy for CML and Ph+ B-ALL [80–82]. The translation of these assays to Ph+ B-ALL depends on clearly identifying the transcript of interest, again relevant given the differences between the p190 and p210 gene products for molecular monitoring.

Although BCR-ABL1 provides a highly sensitive assay for disease monitoring, patients with ALL who do not harbor this rearrangement require alternative methods of monitoring. The most frequently employed is the use of flow cytometry to identify and track lymphoblast populations during treatment. This requires a sample with viable cells, and is widely available; however, standardization for flow assessment of MRD may vary significantly across centers [83,84]. Molecular diagnostic assays may be more standardized, since these use common primers, but are not always available at clinical sites, and the sensitivity depends on the assay utilized. These assays may assess for a gene fusion product, such as with BCR-ABL1, or may sequence IGH or TCR gene rearrangements. Increasingly, NGS assays are also used in this setting and may provide the advantage of capturing subclonal dynamics [84]. When employed at specialized centers, molecular assays may achieve greater sensitivity for detecting residual ALL than flow cytometry [85].

The detection of MRD in ALL has implications for consolidation strategies and transplantation. It has long been established that failure to achieve MRD negativity is a poor prognostic factor in ALL, although the exact timing of when to assess MRD, and the cut-off for MRD positivity, varies [83]. The prognosis of different levels of disease detection also vary according to cytogenetic and molecular disease subtypes; patients with higher risk genetic features may not have as favorable prognosis even with deep remissions [45]. In most pediatric studies, MRD detection has guided treatment intensity. Patients with residual detectable disease may benefit from chemotherapy intensification, while those with deep remissions – particularly in combination with otherwise favorable treatment profiles – may be candidates for therapy reduction [86–88]. In adults with ALL, MRD after treatment may be used to guide decisions and timing regarding allogeneic transplantation and use of alternative regimens, such as blinatumomab [89,90].

Novel Therapies under Investigation

Although the therapeutic landscape has dramatically changed for the treatment of ALL, there are significant ongoing efforts to expand treatment availability, address refractory and resistant disease, and treat subgroups of ALL that are not eligible. In particular, novel and effective therapies for T-cell ALL, particularly in the relapsed/refractory setting, represents a great unmet clinical need. While the focus of this review is to discuss recently approved novel therapeutics in ALL, and how these are incorporated into clinical practice, here we also discuss several new treatment paradigms under investigation.

Given the success of CAR-T cells in achieving remission in highly refractory ALL, many efforts are underway to identify new targets or CAR-T constructs that may be effective or lead to improved outcomes. As of April, 2020, there are currently 90 studies on clinicaltrials.gov for CAR-T therapies in ALL that are active or enrolling patients, not only for CD19, but including other targets such as CD22, CD38, among others. Although CAR-T products directed at T-cells may be limited by the toxicities inherent in T-cell depletion, strategies looking at CD7-edited CARs followed by transplant [91], or other such strategies incorporating a “kill-switch” to remove the CAR-T cells after remission, are under evaluation.

T-cell acute lymphoblastic leukemia/lymphoma represents a challenging clinical scenario; there are some existing agents with enhanced activity in this setting, including asparaginase [92], and the nucleoside analog nelarabine [93]. Frequent gain-of-function mutations in NOTCH1 are seen in T-cell ALL, and this remains under investigation as a possible therapeutic target using selective notch inhibitors.

ABL1 fusions with other genes, similar to BCR-ABL1, may have responses to BCR-ABL-directed TKIs, and these are being incorporated into the treatment of this subset of Ph-like ALL, as discussed above. Similar efforts are underway to identify fusions or mutations that may be sensitive to other oral targeted agents. For instance, JAK2 inhibition has been evaluated in Ph-like ALL with CRLF2 rearrangements [94]. Targeting NTRK rearrangements may similarly result in clinical responses [95]. Other targeted inhibitors are being explored in ALL and other hematologic malignancies, illustrating the potential benefit of new molecular testing (RNA fusion assays, NGS panel testing) in identifying treatment options for these patients.

Venetoclax is a BH3-mimetic that functions as a BCL2 inhibitor; preclinical work has shown BCL-2 dependence in ALL cell lines, leading to the investigation of this agent in R/R ALL. Early reports suggest that it may have some encouraging activity in combination with lower intensity regimens such as hyper-CVD [96], although further study is needed. In general, however, targeting the apoptotic machinery in ALL remains of interest, including BCL-2, CDK-9, MCL-1, and others.

Summary

The treatment of ALL has changed dramatically in the last 5 years. A number of new therapies have been approved in the relapsed and refractory setting (Figure 1). Many of these are now being evaluated earlier in disease, often using a risk adapted strategy based on MRD monitoring, in an attempt to extend cure to even more of this patient population. Nonetheless, there remain several areas in great need for new treatments, including T-cell ALL, Ph-like ALL, and better understanding of resistance and relapse after CAR-T or immune directed therapy. These advances are facilitated by dynamic improvements in diagnostic testing that allow for tailored therapy to guide patient care, a paradigm that will continue to guide research and clinical care for ALL.