New approaches to treating challenging subtypes of ALL in AYA patients

Abstract

Purpose of Review:

The treatment of acute lymphoblastic leukemia (ALL) in adolescent and young adult (AYA) patients has markedly improved with the adoption of pediatric-inspired protocols. However, there remain several subtypes of ALL that represent significant therapeutic challenges. Here, we review the current evidence guiding treatment of Philadelphia chromosome positive (Ph+), Philadelphia chromosome-like (Ph-L), and Early T precursor (ETP) ALL in the AYA population.

Recent Findings:

Clinical trials in Ph+ ALL have demonstrated the superior efficacy of second and third generation tyrosine kinase inhibitors (TKIs) to induce and maintain remission. Current efforts now focus on determining the durability of these remissions and which patients will benefit from transplant. For Ph-like and ETP ALL, recent studies are investigating the addition of novel agents to standard treatment.

Summary:

The treatment of Ph+ ALL has significantly improved with the addition of potent TKIs. However, the treatment of Ph-like and ETP ALL remains a challenge. At this time, the judicious use of allogenic transplant is the only current approach to modify this increased risk.

Introduction

It is well known that outcomes for acute lymphoblastic leukemia (ALL) worsen with age. Moreover this worrisome trend has a significant inflection point in adolescence, where risk of relapse significantly increases compared to younger peers [1]. Survival rates in children with ALL are upwards of 80%, while the historical survival rate in adults is almost half of this, at roughly 40%. Over the last decade, dramatic improvements in this survival rate have been made in large part because of a paradigm shift in the treatment of young adults and adolescents (AYA) with ALL, with a new focus on treatment using pediatric-inspired chemotherapy regimens that rely on higher overall doses of steroids, vinka alkaloids, asparaginase, and intensive central nervous system (CNS) prophylaxis. Numerous studies have shown that by administering these regimens to patients up to 40 years of age, survival rates in this population can approach those of the pediatric population. This shift in treatment strategy for the AYA population was highlighted in a 2018 review in JAMA Oncology by Siegel, et al, which revealed that 23 of 25 comparison studies assessing outcomes between pediatric and adult regimens for AYAs with ALL, in addition to one meta-analysis, favor the pediatric regimen [1]. While the majority of studies included in this review are retrospective, more recent prospective trials have further strengthened this approach. In one of these trials Deangelo, et al applied a pediatric-based chemotherapy regimen to 92 patients with ALL aged 18-50 to investigate tolerability of a 30-week asparaginase course previously shown to be associated with favorable outcomes in children. They found that 72% of patients who initiated the asparaginase course were able to tolerate 26 or more doses, which was similar to what the group had reported in pediatric populations. Furthermore, the 67% 4-year overall survival (OS) rate seen in their patient cohort was favorable compared to historical survival rates in adults [2]. A subsequent trial by the NOPHO group applied a common pediatric-inspired treatment protocol to 1500 patients aged 1-45 stratified into risk groups to determine safety and efficacy of their pediatric-inspired chemotherapy regimen. Despite worse outcomes in the adolescent and adult subgroups compared with pediatric patients, their reported 4-year event free survival of 74% +- 4% in patients aged 18-45 still compared favorably to survival rates previously reported in adult patients on traditional adult regimens [3]. Most recently, Stock, et al reported the CALGB 10403 trial that prospectively compared a pediatric regimen used in 295 ALL patients aged 17-39 to historical controls enrolled in prior CALGB adult trials. Median event-free survival in this group was 78.1 months, more than double the historical control of 30 months [4]. Importantly, these dramatic improvements in survival come at a time when the incidence of ALL is growing faster in this age distribution than in the pediatric and adult populations [1].

The improved outcomes using pediatric-inspired chemotherapy regimens do not come without cost. These treatments feature high cumulative doses of steroids, traditional chemotherapy agents, and in particular, asparaginase. Incorporation of asparaginase, an agent that had been used in the treatment of pediatric ALL for decades, into the treatment of adults with ALL has contributed substantially to improved outcomes, but carries with it unique toxicities. It has been found to cause more hepatic dysfunction, pancreatitis, and coagulopathies in AYA patients compared to children. A few patients can also experience serious hypersensitivity reactions [5]. However, the recent large prospective trials discussed above showed significantly favorable benefit to toxicity ratios for the use of their asparaginase-containing regimens. Deangelo, et al demonstrated that a similar percentage of AYA patients were able to tolerate a 30-week asparaginase course compared to children [2]. Although CALGB 10403 did witness higher incidence of hepatic and thrombotic complications during induction therapy compared to younger pediatric patients treated with a similar protocol, toxicities during post remission cycles in its AYA cohort were comparable to those reported in the pediatric population [4]. Fortunately, there are studies that suggest reduced doses of asparaginase may be feasible in attaining therapeutic activity levels while limiting treatment-altering toxicity [6]. Nevertheless, learning how to identify asparaginase toxicity and to manage it is a particular apprehension for oncologists treating ALL in an AYA patient who may not be as familiar with its effects.

One of the reasons posited for the historically lower survival rates in the AYA and adult ALL populations is the increased prevalence of resistant ALL subtypes as patients age. The heterogenous biologic nature of the disease affects outcomes and presents treatment challenges. The two immunophenotypes of the disease, precursor B-cell and precursor T-cell ALL, have different treatment approaches in risk-adapted regimens, with T-cell regimens often employing more intensive CNS prophylaxis. The incidence of T-cell ALL increases with age into adolescence and young adulthood, and although post-induction complete remission rates in AYAs with T-cell ALL approximate those with B-cell ALL, those who relapse with T-ALL tend to have worse outcomes [4]. Moreover, recently identified subsets necessitate further individualization of treatment approach based on their higher rates of treatment resistance. Within T-cell ALL, early T-cell precursor ALL (ETP ALL) is one subset that was initially identified due to its unique immunophenotype and poor outcomes. Additionally, Philadelphia Chromosome-like ALL (Ph-L ALL) has emerged as a relatively common variant of B-cell ALL particularly in the AYA age group and has proven to be more resistant to standard treatment regimens. For example, in the CALGB 10403 trial, 31% of evaluable patients were identified as having Ph-like fusions and these patients’ estimated 3-year event-free survival of 42% compared poorly to the 69% event-free survival (EFS) for patients without the Ph-like signature. Finally, Philadelphia-chromosome positive ALL (Ph+ ALL) accounts for up to 30% of ALL in adults and has historically had a poor prognosis with standard treatment. However, outcomes have been improving with the addition of novel tyrosine kinase inhibitors (TKI) to treatment regimens. These three variants of ALL will be discussed further below, with particular consideration given to their management in AYA patients.

While the majority of ALL patients will reach complete remission (CR) following induction chemotherapy, a significant number relapse, likely due to the presence of leukemic cells below the detection limits of microscopy. Newer methods of analysis (flow cytometry, next generation sequencing) that can identify this level of disease, termed minimal residual disease (MRD), have greatly added to our understanding of treatment response and risk of relapse. Regardless of the genetic makeup of the disease, it has become increasingly apparent that the achievement of undetectable MRD during the course of treatment predicts a better outcome. This was most clearly demonstrated in a 2017 meta-analysis that pooled 39 publications of >13000 adult and pediatric patients with ALL. The study showed an estimated 10-year event-free survival for pediatric patients achieving MRD negativity of 77% compared with 32% for patients who did not achieve MRD negativity. For the adult studies, those who achieved MRD negativity had a 64% EFS at 10 years compared with only 21% in those who were MRD-positive [7]. It should be noted that none of the studies included in the meta-analysis were strictly investigating this effect in the AYA population. However, similar results were seen in the previously mentioned CALGB AYA trial—the 3-year disease-free survival for patients in this trial achieving MRD negativity was 85% versus only 54% for those with detectable MRD. This relationship between MRD status and prognosis is integral to pediatric risk-adjusted regimens, where patients receive escalation of therapy if found to be MRD positive at the end of induction. Additionally, there are ongoing efforts to specifically target MRD to prevent relapse and improve survival. As an example, blinatumomab, a bispecific T cell-engager antibody that directs T cells to CD19+ B cells, has now been approved by the Food and Drug Administration to treat adults with B-cell ALL that are MRD-positive [8].

Lastly, one must appreciate various psychosocial challenges that add additional complexity to the management of ALL in the AYA population. AYA patients must endure a long duration of intense treatment at a time in their lives that, in normal circumstances, would be dedicated to one’s personal and professional development. The rigorous regimens almost always necessitate leaves of absence from school or work which can cause significant financial burdens, delay academic or career achievements, disrupt family life or the ability to find life partners, result in chronic health complications, and leave many survivors with psychologic trauma. Additionally, whereas in the pediatric population patients are often surrounded by family members who can administer medications, provide transportation to appointments, and generally take active roles in the patient’s treatment, AYAs often must navigate their disease with far less support. Some have posited that this independence has contributed negatively to treatment adherence and thus can contribute to the lower survival rates in the AYA population [9]. As a result of these complexities, a multi-disciplinary approach featuring among others psychologists, nutritionists, fertility experts, and social work is crucial to the successful treatment of these patients [10].

Featured here is a review of the current literature surrounding treatment approaches for AYA patients with the following high risk ALL subsets: ETP ALL, Ph+ ALL, and Ph-L ALL.

Early T-Cell Precursor Acute Lymphoblastic Leukemia (ETP ALL):

ETP ALL is a high-risk subset of T-cell ALL that compromises roughly 15% of T-ALL cases and is defined by a specific genetic profile: CD1a⁻, CD8⁻, CD5^weak, & 1 or more myeloid/stem cell marker [11-14]. Early T-cell precursors are early thymic immigrants from bone marrow that retain the ability to differentiate into T-cell and myeloid lineages. Thus, the genetic features of ETP-ALL often straddle that of acute myeloid leukemia (AML) and ALL, and many cases harbor mutations traditionally seen in AML [12, 15, 16]. Individuals with ETP ALL have higher rates FLT3 & DNMT3A mutations, with lower rates of NOTCH mutations (which has been shown to be associated with a good prognosis), compared to non-ETP T-ALL cases [17, 18, 15, 19-21]. These cells have increased genomic instability, and some researchers have hypothesized that their myeloid characteristics result in poor response to traditional T-ALL directed chemotherapy [15, 12, 22].

Data on the outcome of patients with ETP ALL is conflicting, but in many series, these patients have an adverse treatment response and outcome compared to other subsets of T-ALL. Individuals with ETP ALL have decreased response to prednisone, earlier development of drug resistance, and higher rates of failed induction therapy, MRD positivity at the end of induction, and relapse [22, 13, 17, 14]. While initial studies found this disease to confer a poor prognosis, several more recent studies have shown that response-based risk stratification and subsequent therapy intensification can overcome this initially described poor prognosis [23-25]. In the pediatric population, separate studies by Patrick et al. and Sayed et al. found non-inferior outcomes among ETP cases; Patrick et al. showed a 5 year OS of 82.4% vs 90.1%, while Sayed et al. showed 5 year OS of 70.8% vs 76.6% in ETP vs non-ETP cases – neither being statistically significant. Both studies attribute this to the more intensive therapy administered to the ETP groups [25, 24]. In the adult population, Bond et al. found that the use of allogeneic stem cell transplant (SCT) in first complete remission (CR1) could overcome the high-risk features of ETP ALL. While individuals with ETP had higher rates of corticosteroid resistance, early bone marrow chemotherapy resistance, and higher rates of MRD positivity post-induction, there was no statistical difference in EFS or OS when compared to non-ETP cases (5 year OS 59.6% vs 66.5%). This was attributed to the increased frequency of alloSCT in ETP patients (48.9% vs 28.3%) as a result of initial treatment resistance (defined by the study as corticosteroid resistance, early bone marrow chemotherapy resistance, and failure of remission induction), suggesting alloSCT in CR1 based on risk stratification can overcome the effect of early treatment resistance seen in ETP ALL. This study also suggests induction augmentation and therapy intensification alone may be insufficient for successful management of ETP ALL; without transplant, ETP cases had lower OS than non-ETP cases (49.2% vs 67.5%) and there was a trend toward improved OS with alloSCT for ETP ALL patients (hazard ratio 0.36, p=0.07), but not for non-ETP patients (hazard ratio 0.7, p=0.36) [23]. An important caveat of this study is the lack of complete MRD data, thus preventing analysis of whether SCT improved outcomes in ETP patients who achieved complete molecular remission. A multi-center analysis of SCT in T-ALL by Brammer et al. further supports the use of SCT in ETP ALL. Although limited by sample size (16 total ETP patients), these researchers found no statistically significant difference in OS between ETP and non-ETP patients who underwent SCT (47% vs 63%, p=0.5), again highlighting that alloSCT in CR1 may overcome the high-risk features and previously described poor outcomes of ETP ALL (see table 1).

Table 1.

Previous Studies on ETP ALL. EFS = Event Free Survival. OS = Overall Survival. HR = Hazard Ratio. CR = Complete Remission. Cri = Complete Remission with incomplete count recovery. CR1 = First Complete Remission

Study	ALL subtype	Age	Overview	Results (ETP ALL vs other T-ALL)	Takeaways
Coustan-Smith et al.13	T-ALL	0.5-18	Comparison of outcomes between ETP-ALL and T-ALL in pediatric population using standard intensive chemotherapy.	10-year OS 19% vs 85%, 10-year EFS 22% vs 69% (p<0.0001)	Early study demonstrating poor outcomes with standard intensive chemotherapy in pediatric population.
Inukai et al.14	T-ALL	1-18	Comparison of outcomes of ETP-ALL and T-ALL in a pediatric population	4-year EFS 40% vs 70%	Higher rates of relapse in ETP group. Data limited by sample size (N=5 for ETP).
Allen et al.11	T-ALL	1-81 (median 13)	Comparison of outcomes of ETP-ALL and T-ALL	Statistically higher relapse rates in children (HR=11.63, p=0.025), but not for all age groups (HR=4.08, p=0.127)	OS analysis limited by sample size (N=7 for ETP). Higher relapse rates in pediatric population.
Jain et al.17	T-ALL	13-79 (median 30)	Comparison of outcomes between ETP-ALL and other T-ALL. Induction therapy consisted of hyper-CVAD or augmented-BFM. Routine alloSCT in CR1 not done.	CR/CRi rates were 73% vs 91% (p=0.03). Median OS 20 months vs not reached (p=0.008).	Suggests ETP-ALL is a high-risk subset of T-ALL, with worse outcomes when using conventional chemotherapy.
Patrick et al.24	T-ALL	1-24	Comparison of outcomes of ETP-ALL and T-ALL treated with the UKALL 2003 protocol	Non-significantly inferior 5-year EFS and OS (76.7% vs 84.6%, 82.4% vs 90.9%).	High risk features of ETP-ALL may be overcome with risk-stratified treatment intensification
Sayed et al.25	T-ALL	1-18	Comparison of outcomes of subsets of T-ALL treated with different protocols	In the group treated with the Total Therapy Study XIII protocol for high-risk ALL there was a non-significantly inferior outcome for ETP: 70.8% vs 76.6% (p=0.67)	High risk features of ETP-ALL may be overcome with risk-stratified treatment intensification
Bond et al.23	T-ALL	Adults (median age 31.5)	Comparison of outcomes of ETP-ALL vs other T-ALL in adults using early response-based intensification strategies	Non-significantly inferior 5-year EFS and OS (59.6% vs 66.5%). Without transplant ETP cases had inferior 5-year OS (49.2% vs 67.5%, p= 0.02)	AlloSCT in CR1 may overcome the early treatment resistance and high-risk features of ETP-ALL
Brammer et al.31	T-ALL	2-72 (median 31)	Comparison of T-ALL subtypes and MRD on alloSCT outcomes	Non-significantly 3-year OS after SCT in CR1 (47% vs 65%, p=0.5)	AlloSCT in CR1 may overcome the early treatment resistance and high-risk features of ETP-ALL. Study limited by sample size: total of 16 ETP patients, with 10 undergoing alloSCT in CR1.

Currently, the European Society for Blood and Marrow Transplantation recommends SCT in CR1 for adults with ETP, but not for children with ETP [26, 20, 27]. This becomes a grayer area for the AYA population, and the treatment of these patients is variable – some receiving traditional pediatric regimens, others receiving a less intensive version of a pediatric backbone, and others receiving the hyper-CVAD regimen [28, 26, 29, 30]. Our general approach is to pursue SCT in CR1 for AYA patients with ETP if they are good candidates for transplantation and have slower clearance of MRD; however, this may not be appropriate in cases where MRD clears within 12-16 weeks of initiation of treatment of an intensive pediatric regimen. This is based not only on the high-risk features/high relapse rates of ETP-ALL and previous success demonstrated with therapy intensification and SCT, but also the limited options and poor prognosis for relapsed T-ALL cases. Currently nelarabine is the only approved treatment for relapsed T-ALL, and relapsed T-ALL patients fare far worse than relapsed B-ALL individuals [31, 32].

There is promising pre-clinical data for future treatments of ETP ALL. Ruxolitinib has been shown efficacious regardless of JAK mutation status in in-vitro studies – importantly, there is a high rate of JAK/STAT alterations in ETP cases [18, 21]. Currently there is a clinical trial investigating Ruxolitinib in patients with relapsed/refractory ETP-ALL (NCT03613428). As with JAK/STAT alterations, there is a high rate of PIM1 overexpression in ETP cases and pre-clinical research has shown the combination of PIM inhibitors with ponatinib improved survival and decreased tumor burden in ETP mouse models [33]. Other individuals have proposed incorporating traditional AML agents into the treatment of ETP ALL – chemotherapy regimens using high dose cytarabine have been shown effective in certain cases [15, 12]. Additional options include the targeting of apoptotic pathways; a trial investigating venetoclax + navitoclax for the treatment of refractory/relapsed T-ALL is currently underway. Phase I data, while limited by sample size, shows promise – with a response rate of 56% [34].

Philadelphia Chromosome-Positive ALL (Ph+ ALL):

The management and outcomes for Ph+ ALL have dramatically changed with the development of tyrosine kinase inhibitors (TKIs). Prior to their development, the prognosis for Ph+ ALL was dismal, with long term OS <25% in adult populations and <50% in pediatric populations [35, 36]. With the introduction of TKIs, survival rates have greatly improved [26, 37, 38]. Historically, SCT was the only curative approach to treatment of Ph+ ALL cases [39-41]. Now, with the introduction of potent TKIs, the universal need for SCT in AYA patients with Ph+ ALL is less certain. A recent study by Ravandi et al. demonstrated improved relapse-free survival (RFS) and OS in young adults who received dasatinib + chemotherapy with a recommendation to proceed to alloSCT in CR1. In this study, 44 of 94 eligible patients achieved CR and did not undergo HCT. Landmark analysis was performed at 175 days after achieving CR as this was the longest time from achieving CR to undergoing HCT. The 3-year RFS for these patients after this landmark date was 51% and OS was 56%. For the 41 patients who did undergo HCT in CR1, the 3-year RFS was 76%. Importantly, this study included adults up to the age of 60 years (not limited to AYAs) and used a relatively low dose of dasatinib in combination with intensive chemotherapy (70mg daily after a protocol amendment). While the study was not randomized, it demonstrated statistically significant improvement in RFS and OS for those patients who proceeded to alloSCT in CR1 (P=.038 for RFS, P=.037 for OS) [42].

The guidelines for SCT differ between adult and pediatric patients. In the pediatric population, SCT is no longer the standard of care for standard risk cases in CR1 as it has been found that TKI + chemotherapy is non-inferior to SCT [35, 43, 44, 27]. In contrast, SCT is currently recommended in CR1 for adults with Ph+ ALL – provided they can tolerate SCT and have a suitable donor [43, 45, 27]. These conflicting guidelines make it difficult to provide definitive recommendations for the AYA population. Based on past trials demonstrating survival benefit for patients undergoing SCT, many experts in the field recommend SCT in CR1 for AYA patients with Ph+ ALL, especially for young adults with no comorbidities and a suitable donor [41, 29, 43, 37, 38, 45, 46]. If SCT does occur, TKI maintenance post-transplant should occur, provided it can be tolerated by the patient [27, 40].

With the development and continued investigation of newer TKIs, the new targeted antibodies, and sensitive sequential quantitative MRD monitoring, the recommendation for alloSCT in CR1 may evolve. Most of the data supporting SCT in CR1 is based on trials from the pre-TKI era [29, 37]. Depending on the TKI tested, there is conflicting evidence for the use of SCT in CR1. Several studies using imatinib showed a survival benefit for alloSCT in CR1, however, more recent studies using newer generation TKIs suggest alloSCT in CR1 may not be indicated in standard risk patients [38, 45, 47, 29, 37, 48, 36]. One such study by Chang et al. showed comparable results for dasatinib + chemotherapy with or without the SCT [36]. Evolving data suggests newer TKIs are superior to the first generation TKI imatinib [41, 37, 40]. A recent combined study from China and St Jude’s Children Research Hospital Showed superior results when using dasatinib over imatinib [49]. This is the first randomized trial comparing different generation TKIs to each other – an important caveat, however, is this study was performed in a strictly pediatric population (age <18). A MDACC phase II trial on ponatinib + hyper-CVAD demonstrated high rates of long-term survival with the use of this 3^rd generation TKI. Furthermore, no difference in survival was seen when comparing those who underwent SCT to those who did not – 3 year OS 87% in the non-transplant group vs 70% in the alloSCT group [50]. Continued investigation into newer TKIs and their ability avoid SCT is essential moving forward. The morbidity and mortality associated with SCT should not be understated, and the ultimate goal should be to develop regimens that obviate the need for SCT – a large percentage of transplant patients will suffer from chronic graft versus host disease (cGVHD) and SCT-related mortality remains ~20% in AYA patients with ALL [51, 52, 46, 48]. As with the pediatric population, it is possible that SCT in the AYA population will be eventually be reserved for those who fail to achieve CR after 30 days of therapy or who have persistent MRD [26].

Regardless of whether SCT occurs, it is likely that patients should undergo combined chemotherapy + TKI; new studies may also demonstrate feasibility of TKI and targeted antibody treatments with minimal chemotherapy. Traditionally, it was recommended patients receive high intensity chemotherapy, including the hyper-CVAD and BFM-like regimens. Now, however, there are data supporting the use of lower intensity chemotherapy with a second generation TKI as a means of inducing remission in patients who subsequently undergo SCT [53, 48, 37, 46]. With the introduction of the new targeted immune therapies, there are trials currently underway investigating the use of reduced intensity treatments without subsequent transplant. Initial results from an Italian study (NCT02744768) looking into dasatinib + blinatumomab in adults with Ph+ ALL shows promise – with reported 1 year OS of 94.2% (see table 2) [54].

Table 2.

Previous Studies on Ph+ ALL. EFS = Event Free Survival. OS = Overall Survival. HR = Hazard Ratio. CR1 = First Complete Remission. CMR = Complete Molecular Response.

Study	ALL Subtype	Age	Overview	Results	Takeaways
Shen et al.49	Ph+ ALL	0-18	Comparison of dasatinib to imatinib in treatment of Ph+ ALL in pediatric population	Significant improvement in 4-year EFS and OS between dasatinib vs imatinib groups: 71 % vs 48.9% (p=0.005) & 88.4% vs 69.2% (p=0.04)	Newer generation TKIs may prove more effective in treatment of Ph+ ALL when compared to first generation TKIs
Chang et al.36	Ph+ ALL	18-70	Comparison of outcomes for adult Ph+ ALL patients treated with combination chemotherapy + dasatinib vs combination chemotherapy + dasatinib followed by alloSCT	Similar outcomes between the transplant and non-transplant group: 3-year OS 76% vs 71.3% (p=0.56), 3-year RFS 70.5% vs 80.1% (p=0.94)	With newer generation TKIs, routine alloSCT in CR1 may not be indicated
Jabbour et al.50	Ph+ ALL	>18 (median 47)	Phase II trial of ponatinib + hyper-CVAD in treatment of adult Ph+ ALL	Good long-term outcomes: 83% achieved CMR, 3-year OS 76%. No improvement in survival with alloSCT: 3-year OS in transplant group vs non-transplant group was 70% vs 87%.	Ponatinib + combination chemotherapy leads to good long-term outcomes, and may avoid need for routine alloSCT in CR1
Ravandi et al.42	Ph+ ALL	18-60	Outcomes of adult patients with Ph+ ALL treated with dasatinib + combination chemotherapy followed by alloSCT	3-year RFS in patients who did NOT undergo SCT in CR1 (44 pts) was 51%; 3-year RFS for those who did undergo alloSCT in CR1 was 76%; statistically significant improvement in RFS and OS for pts who underwent SCT vs no SCT (NOT randomized however)	Addition of dasatinib to chemo and alloSCT for younger patients with Ph+ ALL is feasible and efficacious. Patients fared better if they received alloSCT, however the study was not randomized and thus warrants further testing.
NCT02744768	Ph+ ALL	≥18	Outcomes of patients treated with dasatinib + blinatumomab	Initial results show a 1-year OS of 94.2%	Addition of blinatumomab to TKI therapy may allow avoidance of intensive chemotherapy

Lastly, MRD monitoring and targeting is an essential component for the management of Ph+ ALL, as MRD is the major driver for relapse risk [55-57]. While SCT can convert MRD positivity, the outcomes for patients who are MRD+ pre-transplant are significantly worse than those who are MRD- at the time of transplant [46]. Growing evidence on the impact of MRD targeting suggests SCT may not be needed in cases with early achievement of MRD negativity [37, 41, 58]. The overall trend for the management of Ph+ ALL seems to be the use of newer generation TKIs with risk modeled SCT via MRD and molecular resistance monitoring.

Philadelphia Chromosome-Like ALL:

Philadelphia Chromosome-like ALL (Ph-L ALL) is a recently described heterogeneous subset of ALL, with a similar gene expression profile to Ph+ ALL, but lacks the characteristic BCR-ABL1 fusion from t[9;22] [59-61]. As with Ph+ ALL, this disease subset is characterized by kinase activations – the majority being JAK/STAT pathway alterations and ABL class fusions – that drive its development [62-66]. Ph-L ALL occurs most frequently in the AYA population, comprising 20-30% of B-cell precursor ALL in this age group and the vast majority of these patients have translocations that result in CRLF2 and/or JAK activation [62, 59, 67, 68]. Patients with Ph-L ALL respond poorly to conventional chemotherapy with elevated rates of induction failure, higher rates of post-induction MRD positivity, and higher relapse rates compared to non-Ph-L cases. Initial studies on this disease subset have shown significantly decreased OS and EFS when compared to other types of B-ALL (excluding Ph+ ALL) [69-71]. Currently, neither a standard diagnostic nor a standard treatment approach exists. However, since many cases contain potentially targetable kinase rearrangements, there is significant research into the efficacy of various TKIs in Ph-L ALL.

At this point in time, the most important step is identifying patients with Ph-L ALL. There are several proposed methods and diagnostic algorithms for doing so, and this topic is largely beyond the scope of this review. At the University of Chicago Medical Center we use a stepwise approach that focuses first on detection CRFL2 overexpression (seen in 50% of Ph-L ALL cases) by flow cytometry, followed by the use of a Ph-L specific Fluorescence In Situ Hybridization (FISH) panel aimed to capture the most commonly seen fusions in Ph-L ALL [70, 65, 59, 72]. Alternatives to this include the use of Ph-L specific low-density arrays (LDA) as an initial screening method, although these LDAs are not currently commercially available [73, 60]. The ultimate hope is that RNA-sequencing will become available and feasible, as this will allow for comprehensive detection of this disease subset [74, 60].

In regards to treatment, pre-clinical data on JAK inhibitors and ABL inhibitors have been promising [75-77, 68]. Whether or not this will translate to clinical results remains to be seen, but there are several case reports demonstrating the success of TKIs in Ph-L ALL and several trials investigating TKI use in Ph-L ALL are currently underway (NCT02883049; NCT03564470; NCT03571321; NCT02420717) [78, 65, 73, 79-83]. Alternative strategies to the use of TKIs, such as inotuzumab or blinatumomab, are also being investigated (NCT03150693; NCT02003222) (see table 3). Given the lack of guidelines in managing Ph-L ALL at this time, we recommend newly diagnosed cases of Ph-L ALL be referred to clinical trials [30].

Table 3.

Current trials on treatment of Ph-L ALL and novel agents for B-ALL. Ph-L ALL = Philadelphia-chromosome like ALL. B-ALL = B-cell precursor ALL. HR = high risk. R/R = relapsed/refractory. TKI= tyrosine kinase inhibitor. HDACi = histone deacetylase inhibitor

Trial	ALL Subtype	Age (years)	Overview
NCT02883049	HR B-ALL and Ph-L ALL	1-30	Phase III randomized trial of combination chemotherapy for newly diagnosed HR B-ALL. Includes a stratum of patients with Ph-L ALL and a predicted TKI-sensitive mutation treated with dasatinib + combination chemotherapy
NCT03564470	Ph-L ALL	14-55	Evaluation of the safety and effect of the HDACi chidamide and dasatinib in Ph-L ALL
NCT03571321	Ph-L ALL	18-39	Phase I trial on ruxolitinib + pediatric-based chemotherapy regimen in AYAs with Ph-L ALL
NCT02420717	R/R Ph-L ALL	10+	Phase II trial comparing ruxolitinib with chemotherapy to dasatinib with chemotherapy in patients with R/R Ph-L ALL
NCT03150693	B-ALL	18-39	Phase III trial assessing efficacy of inotuzumab + frontline therapy in AYAs with newly diagnosed B-ALL
NCT02003222	B-ALL	30-70	Phase III trial comparing combination chemotherapy with blinatumomab to chemotherapy alone in adults with newly diagnosed BCR-ABL negative B-ALL

The role of MRD-based risk stratification and SCT is less clear in Ph-L ALL cases [84, 85]. While some studies have shown that risk-directed therapy based on MRD can overcome the poor prognosis of Ph-L ALL, other studies have shown poor outcomes regardless of MRD status and risk-stratification in this disease subset [86-88, 84]. Specifically, a study at MDACC by Jain et al. found poor outcomes regardless of MRD status, with median OS of 26 months and 23 months in MRD- and MRD+ groups, respectively [71]. Similarly, Heatley et al. found poor outcomes and high relapse rate despite MRD risk-stratification – yet they suggest SCT can salvage some cases [88]. In contrast, Roberts et al. found the poor prognosis of Ph-L ALL can be salvaged with MRD-based risk-directed therapy – with a non-significant 5 year OS of 92.5% vs 95.1% in the Ph-L group vs non-Ph-L group [86]. Our current approach at the University Chicago Medical Center is as follows: we recommend referring Ph-L ALL patients to clinical trial, but if there is any signs of inadequate response – induction failure or persistent MRD positivity – we then use novel the novel agents blinatumomab or inotuzumab with the purpose of achieving MRD negativity and then following this with alloSCT for suitable candidates. We do not take MRD negative patients in CR1 directly to transplant. This approach will evolve with the continued development of target therapies and novel agents.

Local Practice Pattern

At the University of Chicago AYA program, we struggle to implement some of these diverse data points but proceed as follows. Patients that present with ETP ALL are treated per CALGB 10403 through at least consolidation while we search for suitable transplant donors. If a suitable donor is available, we strongly recommend the patient proceed with allogeneic transplant. If a donor is unavailable, we complete treatment per the CALBG 10403 protocol. At this time, we have not incorporated nelarabine into the treatment of these patients. Patients that present with newly diagnosed Ph+ ALL undergo induction with a combination of dasatinib and dexamethasone following the CALGB 10701 protocol. We discuss transplant if a suitable donor is available. If a donor is not available or if the patient is not interested in transplant, we proceed with a methotrexate course for CNS prophylaxis followed by a maintenance course with continued TKI. Lastly, patients with Ph-L ALL are enrolled on the Alliance A041501 trial, which was recently amended to include treatment with blinatumomab for persistent MRD. If the patient fails to achieve CR, fails to clear MRD, or relapses, we treat as relapsed ALL and proceed with allogenic transplant if a donor is available.

Conclusions

The treatment of all subtypes of ALL in the AYA patient population has significantly improved over the last decade. However, the high-risk subtypes of ETP ALL, Ph+ ALL, and Ph-L ALL continue to pose substantial therapeutic challenges in the clinic. While there has been great improvement in Ph+ ALL with the addition of potent TKIs to treatment regimens, studies in the AYA patients remain conflicted about who will benefit from alloSCT. Clinical trials to investigate ETP ALL and Ph-L ALL are ongoing with the hope that either novel immune-based or molecularly targeted therapies will improve upon existing treatment backbones. It is hoped that upon the completion of these trials the field will have tailored regimens for these high-risk subtypes and will determine who will best benefit from alloSCT as a standard component of their treatment plan.