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The dosing of 6-mercaptopurine for patient with a low activity level is incorrect as stated the Preventing Drug-related Problems Section,
paragraph 3, last sentence. The correct dosing is as follows:
If a patient has a low activity level, then 10% of the original 6-mercaptopurine dose should be prescribed; otherwise, standard dosing may be
initiated and adjusted on the basis of tolerability.
INTRODUCTION
Acute lymphoblastic leukemia (ALL), also called acute lymphocytic leukemia, is a heterogeneous hematologic malignancy that develops from the
early version of lymphocytes in the bone marrow.1 Leukemia cells usually invade the blood rather quickly and then spread to other parts of the
body. The term "acute" signifies that the leukemia can progress quickly and, if not treated, is likely fatal within a few months.1
Lymphomas are other types of cancer that begin in the lymphocytes. The main difference between lymphomas and leukemias is that leukemias,
such as ALL, mainly affect the bone marrow or the blood and lymphomas mainly affect the lymph nodes or other organs, though lymphomas may
involve the bone marrow. Sometimes, when cancer is originally diagnosed, there may be cancerous cells in both the bone marrow and the lymph
nodes, making the differential diagnosis between leukemia and lymphoma difficult. If more than 25% of the bone marrow is replaced by
cancerous lymphocytes, the disease is usually considered leukemia.1
It is estimated that there will be 5960 new cases and 1470 deaths due to ALL in the United States (U.S.) in 2018.1 The median age at diagnosis for
ALL is 15 years and 57.2% of patients are diagnosed at the age of 20 years or younger. ALL represents the most common form of childhood
leukemia, yet it is only responsible for 20% of all leukemias in adults.1,2,3
Several risk factors have been associated with the development of ALL. Some of those risk factors include young or advanced age (children < 15
years old or adults > 70 years old), exposure to chemotherapy or radiation therapy, and genetic disorders, particularly Down syndrome.1 Other
genetic conditions that have been associated with increased risks for ALL include neurofibromatosis, Klinefelter syndrome, Fanconi anemia,
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An important diagnostic element for patients with ALL is the detection of the Philadelphia (Ph) chromosome.5 This chromosome is defined as an
abnormality of chromosome 22 in which part of chromosome 9 is transferred to it (t(9;22) BCR-ABL). BCR-ABL is the fusion oncogene that forms
when chromosome 9 attaches to chromosome 22. The altered chromosome 22 is then considered the Ph chromosome.6 Consequently, patients
with ALL are determined to be Ph-positive or Ph-negative and treatment is driven by the presence or absence of this genetic marker.
Various disease-related and patient-specific factors may have prognostic significance for patients with ALL. Factors that can influence the
prognosis for patients include patient age, white blood cell count, immunophenotypic/genotypic subtype, presence of central nervous system
(CNS) disease, and patient response to induction therapy.4
Age is a significant risk factor when considering a patient's prognosis, and it is arguably the biggest determining factor for treating patients with
ALL. Patients are stratified into 3 groups according to age: pediatrics (< 15 years old), adolescents and young adults (AYA; 15-39 years old), and
adults (≥ 40 years old).7 A current trend is to treat AYA patients with pediatric protocols, but researchers have reported disease features in the
AYA group that may explain some of the differences in response between AYA patients and pediatric patients. Treatment for AYA and adult
patients will be discussed in this review.
TREATMENT OVERVIEW
Although the regimens, dose intensities, schedules, and treatment durations may differ between AYA and adult patients with ALL, as well as
among patients with different subtypes of disease, the basic treatment principles are similar and include induction, consolidation, and
maintenance phases of therapy. The most commonly used treatment regimens for ALL include modifications or variations to multi-agent
chemotherapy regimens. For example, the hyper-CVAD regimen is common in adults: it consists of 8 total treatment cycles alternating between
"A" and "B" regimens. The "A" regimen includes cyclophosphamide, vincristine, doxorubicin, and dexamethasone; the "B" regimen includes high-
dose methotrexate and cytarabine.8 In the AYA population, the CALGB 10403 regimen is common: this regimen combines, and alternates
between, cycles of intrathecal cytarabine, intrathecal methotrexate, daunorubicin plus vincristine, a pegylated form of L-asparaginase (PEG-
asparaginase; pegaspargase), vincristine, and cyclophosphamide.9 Regimens for ALL should also include CNS prophylaxis or treatment with
intrathecal chemotherapy (methotrexate, cytarabine, or corticosteroids) or high-dose systemic chemotherapy that penetrates the CNS
(methotrexate). All AYA and adult patients with Ph-positive or Ph-negative ALL should consider participation in a clinical trial, if an appropriate one
is available.
The induction phase of treatment aims to induce remission by decreasing the number of leukemic cells in the bone marrow.1 Induction regimens
typically include a combination of chemotherapeutic agents such as vincristine, anthracyclines, and corticosteroids (with or without L-
asparaginase and cyclophosphamide). There is an ongoing debate regarding which corticosteroid agent is best for the treatment of ALL.10,11
Studies have demonstrated that dexamethasone significantly decreases the risk of isolated CNS relapse and improves event-free survival (EFS)
outcomes compared to prednisone in children aged 1 to 10 years (6-year EFS, 85% vs. 77%).10 Also, in a meta-analysis comparing outcomes of
dexamethasone and prednisone in children, dexamethasone was associated with a significantly reduced event rate (relative risk [RR] 0.80, 95%
CI 0.68-0.94), but no advantages were observed in rates of bone marrow relapse or overall survival (OS). Dexamethasone was associated with a
higher risk of mortality in the induction phase (RR 2.31, 95% CI 1.46-3.66), thus leading to questions if it is truly superior in this phase of
treatment.11
The goal of induction therapy is to achieve remission, while the goal of the consolidation phase is to eliminate any leukemic cells that remain
following induction therapy. This phase may also be referred to as intensification therapy. Combinations of drugs and durations of treatment for
consolidation are widely studied and have large variability due to patient factors and provider preferences. Agents typically used in this phase
include high-dose methotrexate, cytarabine, 6-mercaptopurine, cyclophosphamide, vincristine, corticosteroids, and L-asparaginase.1
The maintenance phase is designed to prevent disease relapse after the induction and consolidation phases.1 Patients with mature B-cell ALL do
not require maintenance therapy. Most maintenance phase regimens consist of daily 6-mercaptopurine and weekly methotrexate for 2 to 3 years
with periodic treatment with vincristine and corticosteroids. However, the variability in the use of oral 6-mercaptopurine is a point of concern
related to the maintenance phase of treatment. The efficacy of maintenance therapy is determined by the metabolism of 6-mercaptopurine to its
chemotherapeutic metabolite 6-thioguanine. Other pathways compete for the metabolism of 6-mercaptopurine and can lead to accumulation of
inactive metabolites.12
An important advancement in the management of ALL includes the emergence of tyrosine kinase inhibitors (TKIs) for the treatment of patients
with Ph-positive disease. These agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients
with relapsed or refractory (R/R) Ph-positive ALL, as well as for first-line treatment for pediatric patients with Ph-positive ALL.13 These agents have
been studied in the adult population as monotherapy in first-line and R/R settings, as well as in combination with chemotherapy during all 3
phases of treatment.
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Historically, Ph-positive ALL has been associated with a poorer prognosis than Ph-negative B-cell ALL. The frequency of Ph-positive ALL among
AYA patients ranges from 5% to 25% and increases with age.14
In a similar study, patients receiving varying chemotherapy regimens plus imatinib were stratified into good-risk (n = 108) or poor-risk (n = 70)
subgroups. There was an overall trend in 4-year DFS for the good-risk patients who received imatinib plus chemotherapy compared to those who
received chemotherapy alone (72.9% vs. 61.7%; p = 0.24).17
Additional studies have shown promising results in the AYA population using other TKIs such as dasatinib 50 mg orally twice daily and ponatinib
45 mg orally daily. Dasatinib was evaluated in combination with hyper-CVAD in patients with previously untreated Ph-positive ALL in a phase II
study of AYA and adult patients (n = 35).The 2-year OS and EFS rates were 64% and 57%, respectively.19 In a separate phase II prospective study
(n = 37), ponatinib was evaluated in combination with hyper-CVAD in AYA and adult patients with Ph-positive ALL.The 2-year OS and EFS rates
were 80% and 81%, respectively.20
Since JM is considered an AYA, her initial options would include a clinical trial, chemotherapy plus TKI, or TKI plus corticosteroids. In addition, all
ALL treatment regimens should include CNS prophylaxis.
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Treatment recommendations for patients with R/R Ph-positive ALL are challenging and these patients have a poor prognosis (i.e., less than 10% of
patients survive 5 years).24 Several different strategies for the treatment of this patient population have been investigated and employed.
TKIs
The emergence of resistance to TKI-containing regimens is a great challenge for patients who experience disease relapse. Point mutations within
the ABL kinase domain and alternative signaling pathways have been noted as mechanisms of resistance; mutations can be identified with
testing to determine the best TKI to use for subsequent therapy. Dasatinib 140 mg orally daily and nilotinib 400 mg orally twice daily are second-
generation TKIs that have demonstrated greater potency in inhibiting BCR-ABL compared to imatinib and may continue to have antileukemic
effects in certain imatinib-resistant cases.25,26 Ponatinib is a third-generation TKI that has been approved for patients in the R/R setting.27This
agent was briefly removed from the market but was reinstated by the FDA following revision to both the prescribing information and risk
mitigation strategies program to address the risk for serious cardiovascular events. Ponatinib 45 mg orally daily has demonstrated evidence of
substantial activity in patients with Ph-positive leukemias resistant to other TKIs.28
Blinatumomab
Blinatumomab is a bi-specific T-cell engager (BiTE) that targets the CD19 antibody on B-cells. It was originally approved by the FDA in 2014 for the
treatment of R/R Ph-negative pre-B-cell ALL.29 In 2017, blinatumomab received full approval for the treatment of all cases of R/R ALL (Ph-positive
and Ph-negative disease). A study evaluated the efficacy and safety of blinatumomab in patients (n = 45) with R/R Ph-positive ALL who
progressed after imatinib and at least 1 second-generation or third-generation TKI. During the first 2 cycles of blinatumomab, 36% of patients
achieved complete remission or complete remission with partial hematologic recovery.30
MOpAD regimen
The MOpAD regimen comprises methotrexate, vincristine, pegaspargase, and dexamethasone. A phase II trial was performed to examine the
safety and efficacy of this regimen in patients (n = 37) with R/R ALL. In this study, the CR and objective response rates were 28% and 39%,
respectively, with a median duration of 4.3 months. Patients with Ph-positive ALL had complete remission and objective response rates of 50%
and 67%, respectively.31
Inotuzumab ozogamicin
Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that targets CD22, a protein on the surface of B-cells. A randomized phase II study
included patients (n = 326) with ALL (Ph-positive and Ph-negative) after first or second relapse. InO was added to standard intensive
chemotherapy (fludarabine and cytarabine plus granulocyte colony-stimulating factor, cytarabine plus mitoxantrone, or high-dose cytarabine for
up to 12 cycles). Compared to standard therapy, InO produced a significantly higher complete remission rate (80.7% vs. 29.4%, respectively; p <
0.001). Data also showed significant benefit in median duration of remission (4.6 vs. 3.1 months; p = 0.03), median PFS (5 vs. 1.8 months; p < 0.001),
and mean OS (13.9 vs. 9.9 months; p = 0.005).32 In 2017, this agent gained full approval from the FDA for the treatment of R/R precursor B-cell
ALL.33A concern with the use of InO is the risk of increased hepatotoxicity and treatment-emergent hepatic veno-occlusive disease.34
JM's options include enrollment in a clinical trial, TKI plus chemotherapy plus HCT, TKI plus corticosteroids plus HCT, or tisagenlecleucel.
AYA patients with Ph-positive ALL be treated in a clinical trial when possible.13 If there is not an appropriate clinical trial available, the
recommended induction therapy would include a multi-agent chemotherapy regimen or corticosteroids combined with a TKI. Maintenance
therapy should consist of a TKI with or without monthly pulses of vincristine/prednisone (for 2-3 years). Weekly methotrexate and daily 6-
mercaptopurine may be added to this regimen, as tolerated.9
For adult patients with Ph-positive ALL, enrollment in a clinical trial when possible is recommended.13 Induction treatment therapy options
includes a combination of vincristine, prednisone, anthracycline, with or without asparaginase and a TKI. All patients should receive adequate
CNS prophylaxis. The recommended maintenance therapy is also the same as for AYA patients.
If TKIs were not used during initial induction therapy, they should be used to treat R/R disease.13 For second-line therapy, patients should be
initiated on one of the following: an alternative TKI alone, a TKI combined with multi-agent chemotherapy, or a TKI combined with corticosteroids.
These options should be combined with allogeneic HCT in eligible patients. Blinatumomab and InO are alternatives for patients resistant to TKIs.
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Tisagenlecleucel is another alternative for patients up to 25 years of age with refractory disease or more than 2 relapses and failures of TKIs.37
Blinatumomab or InO could be considered for JM. Blinatumomab is approved after a patient has failed 2 TKIs. InO is approved if a patient is TKI
intolerant or has refractory disease.
GRAALL regimens
The prospective phase II GRAALL-2003 study (n = 225) evaluated intensified doses of vincristine, prednisone, and asparaginase for AYA and
adult patients with Ph-negative ALL. The induction regimen included the aforementioned agents plus daunorubicin and cyclophosphamide. The
EFS and OS rates at 42 months were 55% and 60%, respectively. The GRAALL-2005 study (n = 209) was similar to the 2003 trial, but
hyperfractionated cyclophosphamide was added during the induction and late intensification phases, and rituximab was added when indicated.
The estimated 2-year EFS in the rituximab group (65%) was higher than that in the control group (52%). These results provide evidence of benefit
with the addition of rituximab to chemotherapy in adults with Ph-negative ALL.40
The addition of rituximab in patients with CD20 expression was assessed in a phase II study that evaluated the addition of rituximab in patients
with previously untreated Ph-negative B-cell lineage ALL (n = 282). The subgroup analysis of patients with CD20-positive ALL treated with hyper-
CVAD plus rituximab had 3-year CRD and OS rates of 67% and 61%, respectively. In addition, younger patients (< 60 years old) with CD20-positive
disease who received this regimen experienced significantly improved CRD (70% vs. 38%; p < 0.001).44
As already presented, multiple initial treatment options for ALL in the AYA population can also be used in adults. For example, the studies that
evaluated hyper-CVAD with or without rituximab regimen, the Linker 4-drug regimen, and the GRAALL-2005 regimenincluded both AYA and adult
patients.40,8,44,45 Typically, the induction regimens for adults with ALL include a backbone of vincristine, corticosteroids, and anthracyclines.1
PB's initial treatment options include enrollment into a clinical trial or a multi-agent chemotherapy regimen. In addition, all ALL treatment regimens
should include CNS prophylaxis.
According to historical data compiled from 1998 to 2002, early relapse (< 18 months after diagnosis) is associated with very poor outcomes,
including a 5-year survival rate of only 21%.48 >The 5-year survival rates vary, depending on if the relapse is classified as an isolated bone marrow
relapse, an isolated CNS relapse, or another type of relapse. In a multivariate regression analysis, early bone marrow and extramedullary relapse
were independent predictors of poorer EFS outcomes.49 Some trials have reported a median OS after relapse of only 4.5 to 6 months and
approximately 20% to 30% of patients experience a second CR with second-line therapies.50,51 Therefore, effective therapeutic strategies are
needed to optimize outcomes in R/R disease.
Nelarabine
Nelarabine is a nucleoside analog that is approved for the treatment of patients with T-cell ALL who have unresponsive or relapsed disease after
at least 2 chemotherapy regimens.52 A phase II trial that evaluated the efficacy of nelarabine as monotherapy in children and adolescents (n =
121) with R/R ALL showed a 55% response rate for first bone marrow relapse and a 27% response rate in the subgroup with a second or greater
bone marrow relapse.The median DFS and OS were both 20 weeks and the 1-year OS was 28%.53
Augmented hyper-CVAD
A phase II study (n = 90) evaluated an augmented version of the hyper-CVAD regimen, which included asparaginase, intensified vincristine, and
intensified dexamethasone for therapy in adults with R/R ALL. Among evaluable patients, the CR rate was 47%; an additional 13% of patients
experienced a pathological CR and 5% experienced a partial remission. The median OS for these patients was 6.3 months.54
Clofarabine
Clofarabine is a nucleoside analog approved for the treatment of pediatric patients (1-21 years old) with R/R ALL who failed at least 2 prior
regimens. Single-agent clofarabine has been associated with severe liver toxicities, but the combination of clofarabine with cyclophosphamide
and etoposide in pediatric patients with R/R ALL has demonstrated response rates of 44% to 52%.56,57 There are currently limited studies for the
use of clofarabine combination regimens for adults with R/R disease. Since the use of clofarabine requires close monitoring and intensive
supportive care measures, patients should only be treated with this agent in centers with expertise in the management of ALL.
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Similar to AYA patients with Ph-positive ALL, AYA patients with Ph-negative ALL should be enrolled in a clinical trial when possible. All treatment
regimens should include CNS prophylaxis. The recommended induction therapy should include multi-agent chemotherapy regimens based on
pediatric-inspired protocols and data from multi-institutional studies. Continuation of the multi-agent chemotherapy for consolidation and
maintenance would be appropriate. 13
For adult patients with Ph-negative ALL, enrollment in a clinical trial when possible is recommended.Induction therapy should include multi-agent
chemotherapy, such as regimens based on the aforementioned protocols. Maintenance therapy with weekly methotrexate, daily 6-
mercaptopurine, and monthly pulses of vincristine/prednisone for 2 to 3 years is recommended.13
In patients with R/R Ph-negative ALL, re-treatment with the same regimen is a reasonable option. Other options for R/R Ph-negative ALL include
blinatumomab or InO.13 Tisagenlecleucel may be appropriate for patients who have experienced more than 2 relapses and are younger than 25
years old.36 Other options include chemotherapy regimens containing clofarabine, nelarabine (in T-cell ALL), VSLI, augmented hyper-CVAD, the
MOpAD regimen, or other cytarabine- or alkylator-containing regimens or chemotherapy with allogeneic HCT if a donor is available.13
Since PB has persistent or late clearance of MRD, treatment options include blinatumomab or allogeneic HCT. Optimal timing of HCT is not clear.
For healthy patients, additional therapy may be considered to eliminate MRD prior to transplant.
CD20-targeting agents have already achieved positive results in the treatment of ALL. Rituximab (a monoclonal anti-CD20 antibody) has been
added to chemotherapy regimens, such as hyper-CVAD, for the treatment of ALL regardless of the presence of the Ph chromosome. Other
CD20-targeting agents include ofatumumab and obinutuzumab. Ofatumumab was studied in combination with chemotherapy regimens and
demonstrated favorable results. The 3-year CRD and OS rates were 78% and 68%, respectively, and ofatumumab was proved safe and effective
in patients with CD20-positive ALL. Obinutuzumab has demonstrated encouraging preclinical results in ALL cell lines but no clinical studies have
been performed yet.58
CD19-targeting agents may also prove to be a viable option in the treatment of ALL, since this protein is present in 90% of pre-B-cell and mature
ALL leukemic cells. Blinatumomab, in particular, has already found its place in the setting of R/R ALL. Other CD19-targeting agents such as
SAR3419 and SGN19a (denintuzumab) may also impact the management of ALL in the future.58
InO is a CD22-targeting agent that has been introduced as a potential option in the setting of R/R ALL. Another agent with similar mechanism is
epratuzumab—a naked, humanized anti-CD22 immunoglobulin G1 that is internalized after binding to CD22. This agent was evaluated as single-
agent therapy followed by standard chemotherapy in patients with relapsed pre-B-cell ALL. This strategy did not achieve improved CR compared
with historical controls, but more patients in the epratuzumab group achieved negative MRD status than in the control group (42% vs. 25%; p =
0.001).58 These results suggest epratuzumab could be tested as a first-line chemotherapy regimen since it may decrease MRD. Since CD22 is
internalized upon binding, favorable outcomes are also expected with other agents in combination with epratuzumab.
Another novel approach to the management of ALL could be the targeting of CD52. This antigen is expressed in 70% of T-cell ALL and pre-B-cell
ALL. Alemtuzumab is a fully humanized monoclonal antibody against CD52. A phase I trial that evaluated the use of alemtuzumab after CR with
induction chemotherapy demonstrated a median OS of 55 months and DFS of 53 months. However, other studies have reported not such
favorable results, as well as significant adverse effects including autoimmune conditions, infusion reactions, and secondary malignancies, with
the use of alemtuzumab. These results may limit further development of alemtuzumab in ALL.58
Several different delivery methods are available for asparaginase in ALL treatment regimens. Pegaspargase is a pegylated form of Escherichia
coli L-asparaginase with a succinimidyl succinate linker. Asparaginase Erwinia chrysanthemi is FDA approved for patients with ALL who have
developed hypersensitivity to E. coli-derived asparaginase. Calaspargase pegol is another asparaginase formulation: this formulation replaces the
succinimidyl succinate linker in pegaspargase with a succinimidyl carbamate linker, which creates a more stable molecule. Calaspargase pegol is
currently in trials and has been shown to achieve a significantly longer period of asparaginase activity compared to pegaspargase.59
PHARMACISTS' ROLES IN IMPROVING OUTCOMES IN AYA AND ADULT PATIENTS WITH ALL
Pharmacists can have a significant impact on patient care in the oncology setting, especially by being a resource for physicians and patients with
ALL. A study performed to analyze the roles of clinical pharmacists in the oncology setting identified several different categories of information
and requests that were submitted to the pharmacists.The most common queries related to the management of adverse reactions secondary to
medications, dosage adjustments of chemotherapy and biologics, supportive care interventions, contraindications, drug-drug interactions,
management of comorbidities, and chemotherapy selection in special populations. The study concluded that pharmacists in the oncology setting
improve patient care and help to update the knowledge of other healthcare professionals.60
As treatment options continue to develop for the management of patients with ALL, pharmacists must be knowledgeable about all aspects of the
therapeutic regimens including dosing, adverse effects, and other drug-related considerations. This information can then be communicated to
both patients and physicians as appropriate. This is a scenario in which the placement of pharmacists on healthcare teams will allow for
increased patient education and reduced physician workload.
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Several drugs, including nonsteroidal anti-inflammatory drugs, penicillin, probenecid, proton pump inhibitors (PPIs), and sulfonamides, are known
to inhibit the elimination of methotrexate. Patients receiving high-dose methotrexate are particularly at risk for this interaction, which results in
increased methotrexate drug levels or toxicity. The competition between methotrexate and PPIs for the transporters is more important at high
concentrations of methotrexate. PPIs should be withheld for several days before and after methotrexate administration to minimize the
magnitude of the interaction. H2-receptor blockers can be used during this period as an alternative to PPIs.61
Due to its metabolism via the TPMT enzyme, 6-mercaptopurine use also requires special consideration, since drugs that interact with that
pathway can impact—and be impacted by—6-mercaptopurine levels.Additionally, co-administration of 6-mercaptopurine with anthracycline-
containing chemotherapy regimens should be avoided due to the increased risk of hepatotoxicity. Pharmacists should analyze patient medication
lists and ensure that no significant drug-drug interactions are evident. In addition, patients should be tested for the TPMT enzyme and
categorized as having low, intermediate, or normal/high activity levels. If a patient has a low activity level, then 90% of the original 6-
mercaptopurine dose should be prescribed; otherwise, standard dosing may be initiated and adjusted on the basis of tolerability.12
Pharmacists also have a role in the management of adverse events due to TKI oral therapy and should provide recommendations for dose
adjustments or switching agents. Specifically, oral TKIs have the potential to cause myelosuppression.When patients present with neutropenia or
thrombocytopenia, therapy might need to be held and dose adjustments should be considered. Adverse effects that can be managed with
adjunct therapy include rash and edema, which can be managed with corticosteroids and diuretics, respectively.62
Some adverse effects can be mitigated simply with proper administration of medication. For example, imatinib and dasatinib should be taken with
food or water to lessen the prevalence of gastrointestinal disturbances. The doses of some TKIs need to be adjusted in patients with renal or
hepatic dysfunction. Therefore, in such patient populations, therapy with dasatinib should be considered, since it does not require dose
adjustments in the settings of renal or hepatic dysfunction.61
Blinatumomab has a unique dosing schedule, as well as the potential for serious complications, and pharmacists can help improve the efficiency
of monitoring therapy with this agent.A typical treatment course consists of up to 2 cycles of blinatumomab for induction followed by 3 cycles for
consolidation and up to 4 additional cycles for continued therapy. This dosing scheme is weight based and resembles a ramp-up dosing
schedule with treatment-free intervals. It is important not to flush the infusion line or intravenous catheter when changing bags of blinatumomab,
since this can lead to excess drug administration and complications.29
Cytokine release syndrome (CRS) is a potentially fatal complication associated with blinatumomab. Because of this risk, pre-medication with
dexamethasone is recommended. Hospitalization is also recommended for the first 9 days of the first cycle and the first 2 days of the second
cycle to monitor for the development of CRS. CRS usually occurs during the first cycle of treatment and can present as seizures or
encephalopathy. Treatment must be closely monitored and this toxicity should be managed by withholding blinatumomab, reducing its dose,
and/or administering tocilizumab. Blinatumomab can also cause infections, neurological toxicities, tumor lysis syndrome, neutropenia, and
elevated liver enzymes.27
As previously mentioned, pegaspargase is a common component of ALL treatment in AYA and adult patients. However, its toxicity profile can
present a significant challenge in clinical management, which is why a pharmacist should be involved in its use. Pre-medications should be used
prior to administration of pegaspargase to decrease the risk of hypersensitivity.63 The reaction can present as rash, flushing, urticaria, and fever
with or without bronchospasm, hypotension, or edema. If a patient experiences a hypersensitivity reaction, additional medications might be
needed, such as hydrocortisone, diphenhydramine, and acetaminophen.
CONCLUSION
Many strides have been made in the management and treatment of ALL. As oncologists and healthcare professionals understand more about the
genetics of leukemia, there will continue to be more advances. With gene expression profiling becoming more prevalent, targeted therapies and
immunotherapies are increasingly relevant and are being heavily studied, which will impact the future of ALL management. Pharmacists have
unique knowledge of drug design, administration, and monitoring and are, therefore, important in every step of the ALL treatment process.
Including pharmacists as part of ALL treatment teams will improve disease management, enhance provider education, increase patient
compliance, and optimize outcomes.
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