Philadelphia-Positive Acute Lymphoblastic Leukemia in Resource-Constrained Settings

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1		Wellington Fernandes Silva	--	2643	2023-12-13 01:42:33	\|
2	Reference format revised.	Lindsay Dong	+ 4 word(s)	2647	2023-12-18 02:04:14	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers15245783

Remarkable strides have been performed in the treatment of adults diagnosed with Philadelphia-positive lymphoblastic leukemia (Ph+ ALL) through the integration of newer-generation tyrosine-kinase inhibitors and monoclonal antibodies. However, it is crucial to acknowledge that most medical centers worldwide lack access to these therapies. As a result, primary strategies employed for curing this disease continue to rely on a combination of chemotherapy and allogeneic stem-cell transplantation.

acute lymphoblastic leukemia Philadelphia chromosome tyrosine-kinase inhibitor blinatumomab

1. Introduction

The integration of tyrosine-kinase inhibitors (TKI) into frontline treatment was a breakthrough in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) ^[1]. Previously, Ph+ ALL was an almost incurable disease, with few patients able to sustain their response, even with allogeneic stem-cell transplantation (alloSCT) consolidation ^[2]. The combination of TKIs and chemotherapy was able to increase complete molecular remission (CMR) rates and allowed more patients to proceed to alloSCT. Furthermore, long-term remission could be achieved without alloSCT in a smaller subset ^[3]^[4]^[5].

Overall, Ph+ ALL is treated with TKI plus chemotherapy in most countries, followed by standard consolidation with alloSCT ^[1]. Several protocols have been tested over the last decades, with a wide range of intensities of cytotoxic chemotherapy combined with imatinib, dasatinib, nilotinib, and, more recently, ponatinib. Doses of TKIs have also varied across protocols, as well as the monitoring of minimal residual disease (MRD) ^[6]. Traditionally, in Ph+ ALL, the quantification of BCR-ABL1 transcript by real-time polymerase chain reaction (RT-PCR) has been the standard for MRD monitoring, mirroring the follow-up of chronic myeloid leukemia ^[6].

More recently, the medical community has witnessed even greater achievements in Ph+ ALL, with the emergence of newer-generation TKIs, such as ponatinib, and the integration of blinatumomab, a bispecific CD3-CD19 antibody ^[7]. These innovative approaches have achieved unprecedented survival rates, with an estimated 2-year event-free survival (EFS) of 90% for 54 patients with newly diagnosed Ph+ ALL treated with blinatumomab and ponatinib ^[8]^[9].

2. Diagnostic Barriers in Low- to Middle-Income Countries (LMIC)

Patients diagnosed with B-cell phenotype lymphoblastic leukemia should undergo prompt screening for BCR-ABL1 fusions. Ideally, this screening should be conducted using PCR or fluorescence in situ hybridization (FISH) methodologies, as they allow for a timely diagnosis of the fusion. It is essential to seek both BCR-ABL1 transcripts, namely p190 and p210 ^[10]. At the diagnosis, these methodologies have similar sensitivities, being complimentary in a minority of cases where PCR can be negative or with low leukemic burden, where FISH can be suboptimal ^[11]. Summarily, PCR seems to be a more comprehensive method as it is more sensitive, less expensive, and allows the determination of which fusion must be tracked along the treatment ^[11].

Typically, treatment protocols for ALL commence with a week-long pre-phase. This pre-phase usually includes corticosteroids, either with or without cyclophosphamide. The primary goal of this pre-phase is to reduce the disease burden in the peripheral blood, as well as to address any electrolyte and coagulation abnormalities present at the time of leukemia presentation ^[10]^[12]. During this initial period, it is crucial to determine the Philadelphia chromosome status of the patients, which will guide the selection of specific treatment regimens for those who are Philadelphia chromosome-positive. Unfortunately, there are limited data available regarding the turnaround time for BCR-ABL1 testing in LMICs. Performing routine genetic testing for acute leukemia can pose challenges in certain healthcare centers ^[13]^[14]^[15]. A delayed detection of the Philadelphia chromosome can result in patients receiving general induction remission protocols without TKIs, and, regrettably, more intensive treatments than necessary for this patient population. Therefore, it is strongly recommended that all patients receive their Philadelphia chromosome status results within a week to avoid unnecessary, intensive induction treatments (see ‘frontline induction’).

3. Genetic Evaluation of Ph+ ALL

Complimentary genetic evaluation through conventional karyotyping is typically available at most medical centers upon diagnosis of Ph+ ALL and can provide valuable insights. Additional cytogenetic alterations (ACAs) beyond the t(9;22)(q34;q11.2) translocation are detected in 40–60% of Ph+ ALL cases, and their prognostic significance remains a topic of debate ^[16]. The most commonly reported ACAs in Ph+ ALL include the gain of an extra Philadelphia chromosome or the “+der(22)t(9;22),” gain of the X chromosome, trisomy 8 or 21, high hyperdiploidy (greater than 50 chromosomes), monosomy 7, or deletions of chromosomes 7p and 9p, among others ^[17]^[18].

Whereas studies conducted in the pre-TKI era consistently demonstrated poorer survival rates in cases with ACAs, the same cannot be said for patients treated with modern regimens ^[18]. The prognostic impact of ACAs in Ph+ ALL largely depends on the type of alteration and the treatment protocol used. For instance, Aldoss et al. reported that among 78 adult patients with Ph+ ALL who underwent alloSCT and had available cytogenetic data, 53% had any ACA, with monosomy 7 being the most common (29%). In this cohort, primarily treated with imatinib-based regimens, a significant difference in EFS was observed (79.8% versus 39.5%, p = 0.01) ^[19].

Despite being cost-effective and widely accessible, conventional karyotyping is now recognized as suboptimal for examining baseline genomic alterations in Ph+ ALL. Higher-resolution techniques, such as microarray or multiplex ligation-probe analysis (MLPA), have revealed that deletions in the gene encoding Ikaros (IKZF1) on the 7p chromosome are common in Ph+ ALL (70–80%) ^[20]^[21]^[22]. Whereas the isolated impact of IKZF1 deletions on Ph+ ALL remains debatable, the association of this alteration with other copy-number alterations (CNA)—known as the “IKZF1-plus” subgroup—consistently demonstrates poor survival in this disease ^[23]^[24].

The IKZF1-plus subgroup is present in approximately 40% of Ph+ ALL cases and comprises patients with concurrent IKZF1 deletion and CDKN2A/B and/or PAX5 deletions ^[25]^[26]. These genomic alterations are associated with a poor prognosis, independent of the TKI used in therapy (imatinib, dasatinib, or ponatinib), and appear to be resistant to the addition of blinatumomab ^[26]^[27]. Unfortunately, these lesions require screening by multiplex platforms, which are not always available in LMICs.

4. Frontline Induction in Ph+ ALL

Achieving complete remission (CR) is a prerequisite for curing Ph+ ALL. Whereas substantial efforts have been made in the past to increase the rate of MRD negativity after induction, it is now universally accepted that low-intensity induction is both safe and recommended for Ph+ ALL, especially in scenarios where early death is not negligible ^[28]^[29]. Several centers worldwide still offer conventional induction upfront, while BCR-ABL1 testing requires a wait in accordance with their practice.

Chalandon et al. reported a non-inferiority randomized trial comparing reduced-intensity chemotherapy (vincristine, dexamethasone, and imatinib) with a standard arm consisting of Hyper-CVAD plus imatinib. Due to fewer induction-related deaths, the hematologic CR rate was higher in the experimental arm (98.5% vs. 91.0%), with no differences in CMR rates ^[29]. Even though previous experiences with corticosteroids plus TKI have been published, this study validated this approach, even for young patients. In LMICs, this approach holds particular value as there are more reports of induction-related deaths ^[30]^[31].

During this initial phase, once again, early identification of the BCR-ABL1 fusion allows more patients to avoid intensive upfront chemotherapy, reducing early mortality ^[29]^[30]. It is worth noting that the Philadelphia chromosome is more frequent in older patients; therefore, lower-intensity protocols are often more appropriate for most patients ^[32]. These regimens usually combine higher doses of TKI with corticosteroids and/or vincristine. Febrile neutropenia is the most reported event, although peripheral neuropathy and liver toxicity can also occur during this phase. The use of asparaginase alongside TKI is rarely employed in adults, with few reports of increased liver toxicity associated with this combination ^[33].

The induction phase typically lasts for four weeks, and patients are managed through hospitalization. Blood transfusions and antibiotics for febrile neutropenia are routinely required. Anti-infective prophylaxis with trimethoprim-sulfamethoxazole and acyclovir is recommended, and the use of antifungal agents may also be considered ^[10]. It is important to note that azoles can potentially cause liver toxicity, especially when administered alongside TKIs ^[34].

5. Availability of TKIs

In parallel with the chronic myeloid leukemia (CML) scenario, the affordability of TKIs is another obstacle for improving results ^[35]. Although imatinib has lost patent protection for a long time now, making low-cost generic versions of the drug available in most LMICs, the same cannot be said about remaining TKIs. The cost per drug varies greatly among countries worldwide, especially in Latin America. Some countries may deal with higher prices for several medicines compared to those in European countries. This can be the result of ineffective or lack of pricing regulations in some countries, such Chile, Peru, and Mexico ^[36].

When it comes to second- and third-generation TKIs, the situation is more critical in most countries, with a high rate of unaffordability pointed in pharmacoeconomical studies ^[36]. Imatinib generics are routinely available for USD 300–USD 3000/year in several countries, while dasatinib will be available as a generic formulation in the next few years and can be prescribed elsewhere now. The prices of patented TKIs range from USD 150,000 to USD 250,000+/year, being unaffordable even for some developed countries ^[37].

6. Consolidation and Maintenance Therapy

Although CR is achieved in virtually all newly diagnosed Ph+ ALL patients, relapse rates remain high even with continued therapy, resulting in unsatisfactory long-term outcomes ^[6]. Previous studies in elderly populations treated with TKIs plus corticosteroids have shown that, without additional chemotherapy, leukemia progresses rapidly, indicating the need for more intensive post-remission therapy ^[38].

Most treatment protocols have incorporated cytotoxic chemotherapy during this phase, aiming to achieve deeper molecular remission rates and penetrate the blood–brain barrier (BBB) ^[5]. Retrospective data suggest that chemotherapy plays a crucial role in eradicating ABL-mutated clones, which are responsible for driving most relapses in Ph+ ALL ^[39]^[40].

The attainment of CMR is considered essential for curing Ph+ ALL ^[41]. As there have been few randomized trials in this disease, most current recommendations are based on the review of phase II trials and retrospective data. Outcomes obtained after these regimens indicate a complex pattern of MRD response, influenced by both the type of TKI and the associated chemotherapy.

In patients up to 18 years old, a randomized trial comparing dasatinib to imatinib showed that the former outperformed the latter with no additional toxic effects. This trial demonstrated a significant survival benefit with fewer relapses in the dasatinib arm, which can likely be extrapolated to adults ^[42].

Whereas integrating TKIs into chemotherapy backbones is feasible, it may lead to increased toxicity. A study by Ravandi et al. reported that 31 out of 72 patients considered eligible for the Hyper-CVAD plus dasatinib trial received fewer than the intended 8 cycles due to poor tolerance ^[43].

In resource-constrained settings and with the unavailability of newer drugs, adjustments in the consolidation blocks are necessary. Dose reductions, particularly in patients who achieve CMR early, should be considered. Although it is common to interrupt chemotherapy in patients with poor tolerance in clinical practice, clinicians should be aware of the increased risk of relapse in such cases.

7. MRD Monitoring in Ph+ ALL

Extensive literature has provided robust evidence for the use of MRD for prognostication and guiding therapy in ALL ^[44]. However, in the case of Ph+ ALL, the available evidence is more limited and often contentious. In this subgroup, patients are usually monitored by RT-PCR for BCR-ABL1, in bone marrow, in parallel with other conventional methods, such as flow cytometry or the quantitative PCR of rearranged immunoglobulin (IG) genes ^[45]. In LMICs, most MRD studies rely on flow cytometry due to the high costs associated with NGS. The quantification of BCR-ABL1 is variably available in many centers and often requires internal validation for use ^[46].

Overall, it is recommended that Ph+ ALL patients undergo monitoring using both qPCR and flow or IG methods, as they complement each other. The overall concordance between BCR-ABL1 and IG qPCR is 69%, as reported by Cazzaniga et al., who observed significantly higher positivity by BCR-ABL1 in a pediatric cohort ^[47]. This study highlighted an important issue: while BCR-ABL1 is a valuable prognostic and monitoring tool in Ph+ ALL, its prognostic significance in patients with no detectable abnormal B cells is uncertain. In the GRAAPH-2014 trial, 38% of enrolled patients consistently showed discordant results between IG and BCR-ABL1, suggesting the persistence of non-lymphoblastic BCR-ABL1-positive cells.

8. ABL Mutations and Management of TKI

After the establishment of TKI-based therapy in Ph+ ALL, studies on relapsed disease have revealed the frequent occurrence of point mutations in the BCR-ABL1 kinase domain (KD) ^[1]^[48]. Whereas initial evidence suggests that small clones with mutations exist at the time of diagnosis in Ph+ ALL, routine upfront ABL mutation testing is not currently recommended ^[48]^[49]. This is because the presence of these mutations does not always preclude a primary response to TKIs, as chemotherapy and newer agents, such as blinatumomab, play a role in eradicating such small clones ^[1]^[10].

However, the situation is different when it comes to assessing ABL mutations at the time of relapse or treatment failure in Ph+ ALL. In such cases, the incidence of imatinib- or dasatinib-resistant mutations increases, even when less sensitive methods like conventional Sanger sequencing are used ^[28]. Alternative approaches for screening ABL mutations using NGS or digital PCR are not currently recommended outside of research settings, as they do not alter treatment decisions ^[50]. Although there is no formal recommendation, it is widely suggested that Ph+ ALL patients undergo ABL mutation testing only when they experience a loss of molecular response or in the event of relapse. The emergence of the “gatekeeper” T315I mutation confers resistance to imatinib and dasatinib but remains susceptible to ponatinib ^[6].

9. CNS Prophylaxis

Recent protocols have shown that enhancing intrathecal prophylaxis can reduce the occurrence of central nervous system (CNS) relapses ^[51]. In most modern protocols, prophylactic irradiation (RT) is no longer employed. However, CNS-directed therapy can still be considered in cases of CNS-3 disease, particularly if cranial nerve palsy or parenchymal involvement is present ^[52]. In Ph+ ALL, dasatinib has demonstrated efficacy in the CNS and is recommended for patients with CNS disease ^[52]^[53].

10. Allogeneic Stem-Cell Transplantation and Alternative Approaches

Traditionally, alloSCT has been considered the standard consolidation therapy for Ph+ ALL in first CR ^[10]. However, clinical trials focused on deferring this procedure in patients who achieve CMR are lacking. Retrospective reports suggest that there is no survival benefit of alloSCT in patients who attain this level of response ^[29]^[54]^[55].

The decision of whether to proceed with alloSCT after achieving CR in Ph+ ALL should consider several factors: (i) clinical eligibility for the procedure, considering that many patients with this disease may be older or have comorbidities that increase toxicity; (ii) the achievement of CMR; (iii) the presence of higher-risk genetic features, such as IKZF1plus; (iv) the availability of newer-generation TKIs, like ponatinib or monoclonal antibodies (blinatumomab or inotuzumab), in the case of disease progression or loss of CMR; (v) access to the monitoring of the BCR-ABL1 transcript and MRD; And (vi) local toxicity and mortality rates associated with alloSCT, especially in LMICs ^[6]^[56]^[57].

Patients in CMR who are candidates to defer alloSCT should ideally undergo consolidation with intensive chemotherapy while maintaining continuous TKI exposure. These patients should be kept on TKI maintenance indefinitely ^[7]. Initial monitoring by bone marrow aspirate is recommended every 3 months for 1–2 years, followed by BCR-ABL1 monitoring using qPCR in peripheral blood indefinitely ^[10]^[58]. In Figure 1, a suggested management flowchart for Ph+ ALL is provided.

Figure 1. Flowchart of the suggested algorithm for the treatment of Ph+ ALL with chemo plus TKI combinations.

11. Conclusions

In conclusion, effectively managing Ph+ ALL in LMIC presents a multifaceted challenge that demands innovative approaches and collaborative efforts. Whereas the advanced treatments and targeted therapies available in well-resourced settings have significantly improved survival rates for Ph+ ALL patients, the disparities in access to these therapies in resource-limited regions cannot be overlooked. It is crucial for healthcare providers, policymakers, and organizations to work together to develop cost-effective strategies, improve diagnostic capabilities, and expand access to essential treatments. Overall, especially in resource-constrained scenarios, upfront low-intensity regimens are recommended, followed by intensive chemotherapy as for consolidation, always associated with TKI. Imatinib is the most cost-saving TKI, while dasatinib seems to offer deeper responses and arguably increased survival rates in children. In eligible patients, alloSCT should be carefully implemented, considering local mortality and the availability of newer lines of treatment. Optimizing existing resources and fostering international partnerships will be instrumental in bridging the gap and ensuring that Ph+ ALL patients everywhere receive the best possible care, regardless of their geographic location or socioeconomic status.

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Wellington Silva

Eduardo Rego

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Update Date: 18 Dec 2023

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