Current recommendations for therapy-related toxicity management in ALL

Despite the great clinical advances in the field of acute lymphoblastic leukemia (ALL), novel therapies have led to the emergence of unique toxicities that need to be appropriately managed. The latest therapeutic advances and the management of new safety considerations were discussed by Cook and Litzow in a recent publication in Current Hematologic Malignancy Reports.¹ We hereby provide a summary of those considerations and the current supportive care recommendations.

Immune effector cell therapy and toxicity management

The two main immune effector cell therapies that have significantly improved patient outcomes and have evolved the therapeutic field of ALL, are blinatumomab and chimeric antigen receptor T cells (CAR-T).¹

Blinatumomab

This is a bispecific T-cell engager with dual targeting against CD19 expressed on ALL cells, and CD3 on T cells. The approval of blinatumomab for the treatment of relapsed/refractory ALL was sealed in 2017 by the U.S. Food and Drug Administration (FDA) based on the results of the phase III TOWER trial (NCT02013167).² Blinatumomab was compared with standard chemotherapy, and led to significantly longer survival and an almost double complete response rate.² One year later, blinatumomab was also approved for adult and pediatric patients with B-cell precursor ALL who were measurable (minimal) residual disease (MRD)-positive but in remission. This approval was based on the results of the phase II BLAST trial (NCT01207388),³ which reported a 78% complete MRD response rate with blinatumomab.

Chimeric antigen receptor T cells (CAR-T)

CAR-T therapy has revolutionized the field of hematological malignancies, including ALL. Numerous clinical trials have shown that in the relapsed/refractory (R/R) setting CD19-targeted CAR-T therapy leads to high MRD-negative complete response rates ranging from 61–93% across studies.¹ The CD19 CAR-T product tisagenlecleucel was the first CAR-T therapy to be approved by the FDA and it was licensed for the treatment of children and young adults with R/R B-cell ALL.

Toxicity management

Despite the great efficacy of immune effector cell therapies, both blinatumomab and CAR Ts are associated with unique safety concerns that have emerged due to their use. These include the cytokine release syndrome (CRS) and neurotoxicity (NT). Factors that have been associated with the risk of CRS, include high leukemic bone marrow burden, preexisting thrombocytopenia, high CAR-T cell dose, and infusion of CAR Ts with a CD28 costimulatory domain.¹ Although CRS occurs with both therapies, differences exist in their grading assessment and severity. Blinatumomab-induced CRS is graded based on version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE)⁴ and can be suppressed by temporary treatment withdrawal due to the short half-life of blinatumomab. This is not the case with CAR T-induced CRS, as once the infusion is performed, the cells persist and expand, and it is not possible to selectively supress. CAR-T CRS is usually of higher severity than that induced by blinatumomab. The most up-to-date consensus on CRS grading following CAR-T therapy has been provided by the American Society for Transplantation and Cellular Therapies (ASTCT).⁵ The interleukin-6 (IL-6), targeting the monoclonal antibody tocilizumab, has been approved by the FDA for upfront CRS management. Siltuximab (anti-IL-6) and anakinra (anti-IL-1) are currently under investigation for use in CRS treatment and management.¹ In cases of severe CRS, corticosteroids are effectively used together with tocilizumab as management. Table 1 provides a summary of the CTCAE 5.0 and ASTCT CRS grading criteria and current management recommendations.

Table 1. CRS grading and management guidelines for blinatumomab and CAR-T therapy^1,4,5

With regards to NT, the ASTCT has provided a consensus on grading and management. The immune effector cell-associated encephalopathy (ICE) score is used together with neurological evaluations for NT grading. These are shown in Table 2 below. Neurological and critical care management along with dexamethasone, which is able to cross the blood brain barrier (unlike tocilizumab), are the main considerations for NT management. Elevating the head of the bed and using osmotic agents, such as mannitol, should be considered in case of cerebral edema.

Table 2. ASTCT consensus on NT grading¹

Another safety consideration that is commonly associated with immune effector cell therapies is hypogammaglobulinemia. This occurs as a result of ‘on-target, off-tumor’ effect of these therapies on physiological B cells. Thus, it is advised to monitor immunoglobulin levels (mainly IgG) at baseline and monthly for the first year, following CAR T or blinatumomab therapy. For patients with IgG levels < 400 mg/dL or with recurrent infections, intravenous immunoglobulin replacement is advised.¹

Inotuzumab and toxicity management

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated with calicheamicin, an antineoplastic antibody. Inotuzumab was approved in 2017 by the FDA for the treatment of patients with R/R B-cell ALL based on the results of the phase III INO-VATE trial (NCT01564784). The most commonly reported adverse events (AEs) following inotuzumab were hematological and hepatic injury due to the action of calicheamicin. Hepatic damage was observed in the form of transaminitis, hyperbilirubinemia, and sinusoidal obstructive syndrome (SOS). Risk factors for inotuzumab-associated hepatic injury are increased bilirubin prior to treatment, and prior transplantation conditioning therapy with dual alkylators or busulfan.¹

Current prophylactic strategies include the avoidance of dual alkylators or thiotepa-based conditioning regimens if transplantation is considered prior to inotuzumab treatment, and frequent liver function monitoring in the first month after transplantation. Moreover, patients should receive ursodiol prophylaxis and no concomitant hepatotoxic agents. If bilirubin and transaminase levels increase significantly (> 1.5 or > 2.5 times the upper limit of normal, respectively) immediate treatment modification or discontinuation is required. Permanent inotuzumab discontinuation is needed if patients develop SOS.¹ SOS management requires intensive multidisciplinary care with strict fluid management, and in severe cases the potential use of defibrotide.

Tyrosine kinase inhibitor and toxicity management

Patients with Philadelphia chromosome-positive ALL account for approximately 25% of adult ALL and are characterized by tyrosine kinase dysregulation. For such patients, the use of tyrosine kinase inhibitors (TKIs) in combination with chemotherapy has greatly improved outcomes and prognosis.¹ Efficacious first-generation TKIs (such as imatinib) have led the way to more potent second- (nilotinib, dasatinib, bosutinib) and third-generation (ponatinib) TKIs that are currently in use. TKIs are usually well tolerated but do lead to unique AEs, including cardiovascular toxicities. These include QT prolongation, especially following dasatinib, nilotinib, or ponatinib, and repolarization abnormalities leading to sudden death following nilotinib. Moreover, accelerated atherosclerosis and increased incidence of thrombosis have been associated with new generation TKIs, like nilotinib and ponatinib. Ponatinib was in fact suspended temporally in 2013 due to the increased risk of serious thrombotic events reported in the phase II PACE trial (NCT01207440). Nevertheless, due to the lack of better treatment alternatives, its marketing was resumed with a ‘black box’ warning.¹ TKIs are also associated with bleeding complications, especially following dasatinib and ponatinib treatment. Thus, exclusion of patients with bleeding history and maintenance of a higher platelet transfusion threshold are advised for patients on these regimens.¹ Table 3 summarizes the most common AEs reported with TKIs and their current management recommendations.

Table 3. Most common TKI-associated toxicities and management recommendations¹

Asparaginase and toxicity management

Asparaginase has been widely used for the treatment of pediatric patients with ALL but not for adults with ALL as it has not shown efficacy in the latter subset of patients. Due to the lack of asparagine synthetase, tumor cells are unable to survive without circulating asparagine and, thus, rearmament with asparaginase leads to tumor cell death.¹ The initial formulation of asparaginase was derived from Escherichia coli and was linked to hypersensitivity reactions. These are now avoided with the introduction of a new pegylated asparaginase formulation. Interestingly, with advancing age, the incidence of severe AEs increases significantly following asparaginase treatment. The recommended upper age limit for asparaginase treatment has been identified as < 55 years, by the GRAALL-2005 study (NCT00327678).¹ Recent large-scale trials have shown that close monitoring and aggressive management is needed for asparaginase treatment to be feasible in adolescents and young adults between 15–35 years old. Common asparaginase-associated AEs include hepatic injury, pancreatitis, and thrombohemorrhagic complications, like deep vein and central nervous system venous thrombosis. The thrombohemorrhagic risk factors that have been identified in ALL patients are older age, prednisone use, and the presence of a central line.¹ Management of asparaginase treatment aims at careful multimodal monitoring with a low threshold for CNS imaging. It is still unclear whether prophylactic antithrombin III (ATIII) reduces the risk of venous thromboembolism (VTE), but due to the severity of such AEs, the most current consensus recommends the use of ATIII when levels are < 60–70% with a target of 80–120%. VTE prophylaxis and deep vein thrombosis treatment is recommended with low molecular weight heparin (LMWH) administration. In cases of asparaginase-induced bleeding due to hypofibrinogenemia, cryoprecipitate administration in patients with < 50 mg/dL fibrinogen is recommended to normalise its levels.¹ Lastly, the use of fresh frozen plasma is not recommended due to the potential antitumor effect of the contained asparagine.¹ Table 4 summarizes the main toxicity concerns with asparaginase treatment and their management considerations.

Table 4. Most common asparaginase-related toxicities and management recommendations¹

Infection prophylaxis

It is well known that chemotherapeutic induction treatments lead to neutropenia and thus predispose patients to infections. This is further exacerbated in cases where steroids need to be administered. One of the most crucial windows for infection acquisition is during the peri-induction period. Patients with R/R disease or in the posttransplant phase also seem to be at a higher risk for infections. The joint guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Clinical Oncology (ASCO) provide great recommendations for prophylaxis against key bacterial, fungal, and viral infections.⁶

Fluoroquinolones are the recommended antibacterial prophylaxis for neutropenic patients undergoing induction chemotherapy. In cases where these are contraindicated, third- or fourth-generation cephalosporins may be considered.

Due to the risk of invasive fungal infections, mainly by Candida albicans, antifungal prophylaxis is also required for these patients. Lately, there has been an increase in fungal infections that are resistant to the so far standard of care, fluconazole. For this reason, new treatment strategies have been evaluated. In a recent meta-analysis, the use of mold-active prophylaxis was superior to fluconazole in reducing invasive fungal infections. Thus, several working groups recommend the use of mold-active agents, like oral triazoles (posaconazole, voriconazole) for fungal prophylaxis in neutropenic patients. Currently, there is no evidence for the use of amphotericin B as antifungal prophylactic. Prophylaxis against Pneumocystis jirovecii has been traditionally achieved with Bactrim. However, due to its potential for increasing methotrexate levels and delaying its clearance, it is advised to stop Bactrim at least 48 hours prior to methotrexate chemotherapy.¹

Antiviral prophylaxis against herpes simplex virus (HSV) is recommended with the use of Acyclovir in all neutropenic patients. This may be continued even after neutrophil recovery, as secondary prophylaxis against HSV and herpes zoster.¹

In patients receiving CAR-T therapy, there seems to be a higher risk of infection during the first month post infusion. Fluconazole prophylaxis, as well as Bactrim and Acyclovir administration until CD4 > 200 cells/μL are recommended from the start of treatment. Fluoroquinolones are indicated only in very neutropenic patients (< 1000 cells/μL).

Growth factor support

Multiple studies have reported the beneficial role of prophylactic granulocyte colony-stimulating factors (G-CSF) in reducing the incidence and severity of the ALL chemotherapy-induced neutropenia. Although the ASCO 2015 guidelines do not specifically mention the use of G-CSF, the authors recommend its daily administration in patients with ALL who are undergoing induction chemotherapy. In patients receiving CAR-T therapy, administration of growth factors, including G-CSF, is contraindicated due to the likelihood of CRS exacerbation. To date, no clear consensus exists on the administration of growth factors for ALL patients undergoing treatment.

Neuropathy management

Neuropathy is a serious AE that has been associated with multiple therapeutic agents for ALL, including vincristine, nelarabine, cytarabine, and methotrexate. Neurological complications ranging from chemical arachnoiditis to transverse myelopathy, or even irreversible leukoencephalopathy have been observed with such regimens. Currently, there are no known neuroprotective treatments, making neuropathy prophylaxis the main clinical target. For that, cytochrome P3A4 inhibitors should not be used in conjunction with vincristine, and all patients should be assessed for peripheral neuropathy onset. For Grade ≥ 2 neuropathy, treatment discontinuation or dose modification should be considered. For patients specifically on cytarabine and/or methotrexate, regular neurologic, renal, and hepatic assessments are required. Although no neuroprotective agents exist as of yet, promising data have been published regarding the use of duloxetine for the management of chemotherapy-induced neuropathy and regarding hydrocortisone addition to cytarabine/methotrexate for neurological AE mitigation.¹

Conclusion

Along with great therapeutic advances, unique toxicities also emerge; these require careful management and consideration. It is certain that with time, supportive care and prophylactic strategies for ALL will only evolve as we gain further insights into the pathogenesis of these toxicities.