Acute Lymphoblastic Leukemia in Adults and Adolescents and Young Adults (AYAs): Pharmacists’ Key Role in Ensuring Best Practices

Acute Lymphoblastic Leukemia in Adolescent/Young Adult and Adult Populations: Pharmacists' Key Roles in Ensuring Best Practices

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, Shwachman-Diamond syndrome, Bloom syndrome, and ataxia telangiectasia.1

DIAGNOSIS AND RISK STRATIFICATION OF ALL

Many of the symptoms of ALL are nonspecific in nature, such as fatigue, weight loss, dyspnea, dizziness, infections, and easy bruising or bleeding. Lymphadenopathy, splenomegaly, and/or hepatomegaly may be observed in approximately 20% of patients.4 A true diagnosis of ALL generally requires demonstration of 25% or greater bone marrow lymphoblasts on hematopathology review of bone marrow aspirate and biopsy materials.

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.

Initial treatment for AYA patients with Ph-positive ALL

JM is a 24-year-old female recently diagnosed with Ph-positive ALL. 

What are her initial therapy options?

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

Hematopoietic cell transplant

In an analysis comparing treatment of Ph-positive ALL in children (n = 38) who only received chemotherapy and those who underwent allogeneic hematopoietic cell transplant (HCT) with chemotherapy, the patients who received the transplant had significantly higher 5-year disease-free survival (DFS) (65% vs. 25%; p < 0.001) and OS (72% vs. 42; p < 0.002).15 It should be noted that these results were not replicated in patients who underwent autologous HCT. Allogeneic HCT has been considered the standard of care for AYA patients with Ph-positive ALL, but the role of HCT has become less clear with the emergence of BCR-ABL-targeted TKIs.

Intensive chemotherapy plus TKIs

In a multicenter study, 92 children and adolescents with high-risk ALL were treated with an intensive chemotherapy regimen (vincristine, asparaginase, corticosteroids, and daunomycin) combined with the TKI imatinib (340 mg/m2/day; given during post-remission induction and maintenance). The results were similar to the results for patients who underwent an allogeneic HCT. The 3-year EFS rate observed with the intensive chemotherapy regimen was 80.5% (95% CI, 64.5%-89.8%).16

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

TKIs plus hyper-CVAD

A phase II study (n = 54) was conducted to evaluate imatinib combined with hyper-CVAD as first-line treatment in AYA and adult patients with ALL; patients received imatinib 600 mg orally daily on days 1 to 14 for 8 cycles followed by 800 mg orally daily during 24 months of maintenance treatment. The 3-year OS rate was 54%.18

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. 

Initial treatment for adult patients with Ph-positive ALL

Before the emergence of TKIs, prognosis and treatment outcomes for ALL were poor. The 3-year OS rates with chemotherapy regimens were less than 20%.21 Incorporation of imatinib into treatment regimens for Ph-positive ALL has led to improvements in outcomes compared to chemotherapy alone. As presented, studies evaluating TKI use with the hyper-CVAD regimen and other multi-agent chemotherapy regimens included AYA and adult patient populations, so these regimens are appropriate options to consider in both of these patient groups.18,19,20 However, older patients may not be able to tolerate aggressive regimens with multi-agent chemotherapy combined with TKIs, so some regimens that are appropriate for younger patients may not be the best choices for adults.

TKIs plus corticosteroids

Studies have evaluated the use of corticosteroids with imatinib as an alternative treatment for adult patients during the consolidation phase. In a small phase II study (n = 29), older patients (> 55 years old) with Ph-positive ALL were treated with chemotherapy induction followed by consolidation therapy with imatinib 600 mg daily and methylprednisolone. The 1-year OS rate was significantly higher than that in a historical control population who received the same induction therapy, but not imatinib, as part of consolidation therapy (66% vs. 43%; p = 0.005). The median OS of the imatinib group was also longer than that of the control group (23 months vs. 11 months; p = 0.004) and the 1-year recurrence-free survival rate was significantly increased with the addition of imatinib (58% vs. 11%; p < 0.001).22 TKIs plus corticosteroids is an acceptable first-line option for induction or consolidation therapy for patients who are aged 55 years or older or for those who have substantial comorbidities.

TKIs in maintenance therapy

Altogether, the addition of TKIs to the treatment of Ph-positive ALL has led to improved outcomes. Specifically, maintenance therapy with TKIs can prevent a relapse after HCT. A prospective study (n = 15) evaluated patients who underwent allogeneic HCT and were given imatinib 400 mg daily for 1 year post-engraftment. Molecular remission was observed in 46% of patients prior to HCT and 80% of patients after HCT.23 This was one of the first studies that showed the feasibility of giving imatinib as maintenance therapy early in the post-HCT period.

Treatment for AYA and adults with R/R Ph-positive ALL

After receiving chemotherapy plus a TKI, JM is determined to have a less than complete response (CR). What are her next treatment options?

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

Chimeric antigen receptor T-cells

Currently, HCT is the only cure for R/R ALL. Unfortunately, many patients are not candidates for transplant. The development of chimeric antigen receptor (CAR) T-cells to treat ALL has been a significant advancement in the field and the use of CAR T-cells is associated with significantly greater OS than current regimens.35 Tisagenlecleucel was fully approved by the FDA in 2017 for the treatment of patients up to the age of 25 years old with R/R precursor B-cell ALL.36

JM's options include enrollment in a clinical trial, TKI plus chemotherapy plus HCT, TKI plus corticosteroids plus HCT, or tisagenlecleucel.

Summary of recommendations for Ph-positive ALL

JM fails 2 different TKIs and she has received an allogeneic HCT. What are her next options?

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. 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.

Initial treatment for AYA patients with Ph-negative ALL

Choosing a treatment for AYA patients with Ph-negative ALL is difficult since they can be treated with either a pediatric (preferred) or an adult protocol. Several multi-agent intensive chemotherapy regimens for pediatric patients with ALL have demonstrated clinical success. These successes have led to the launch of several clinical trials to evaluate pediatric-inspired regimens for the AYA population.

PETHEMA ALL-96 regimen

The PETHEMA ALL-96 regimen is a 5-drug regimen that includes vincristine, daunorubicin, prednisone, L-asparaginase, and cyclophosphamide. A trial evaluating this protocol included adolescent (15-18 years old; n = 35) and young adult (19-30 years old; n = 46) patients. The 6-year EFS and OS rates for the entire patient cohort were 61% and 69%, respectively. No differences were observed in EFS or OS between the adolescent and young adult groups.38

DFCI ALL regimen

The DFCI regimen includes induction with vincristine, doxorubicin, prednisone, L-asparaginase, and high-dose methotrexate. This protocol was developed because of the results of a multicenter phase II trial that evaluated treatment outcomes in patients (n = 75) aged 16 to 50 years with previously untreated ALL (80% of patients were Ph-negative). The estimated 2-year EFS and OS rates were 72.5% and 77%, respectively.39

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

USC ALL regimen

The USC ALL regimen consists of daunorubicin, vincristine, prednisone, and methotrexate with augmented pegaspargase. The protocol was evaluated in patients (n = 51) aged 18 to 57 years with newly diagnosed ALL (58% of patients were Ph-negative). The 7-year OS rate was 51%.41

CALGB 10403 regimen

The CALGB 10403 regimen is based on an ongoing study to evaluate a pediatric-inspired regimen in the treatment of AYA patients (16-39 years old) with newly diagnosed Ph-negative ALL. This protocol includes a 4-drug regimen with intrathecal cytarabine and methotrexate, consolidation, interim maintenance, delayed intensification, and maintenance for 2 to 3 years, plus radiotherapy for certain patients (n = 296). The median EFS for this regimen was 59.4 months and the 2-year EFS rate was 66%.42

COG AALL 0434 regimen

For patients with T-cell ALL, the addition of nelarabine may be a promising approach. Nelarabine is already approved for patients who experience disease relapse after 2 chemotherapy regimens, but it is currently being evaluated for potential addition to first-line regimens for patients with T-cell ALL. During the efficacy phase II study, patients (n = 23) had a median follow-up of 30.4 months and the CR rate was 89%.43

Hyper-CVAD with or without rituximab

In a trial evaluating the efficacy of the hyper-CVAD regimen in AYA and adult patients with previously untreated ALL (n = 288; 83% Ph-negative), the median OS for all patients was 32 months and the 5-year OS rate was 38%. Among patients who experienced CR (92% of patients), the CR duration (CRD) rate was 38%.8

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

Linker 4-drug regimen

A research group evaluated a regimen composed of intensified chemotherapy agents—vincristine, daunorubicin, prednisone, and asparaginase—in AYA and adult patients with ALL (n = 84). The 5-year EFS and OS rates for all patients were 48% and 47%, respectively.45

Initial treatment for adult patients with Ph-negative ALL

PB is a 64-year-old male recently diagnosed with Ph-negative ALL. 

What are his initial therapy options?

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

CALGB 8811 Larson regimen

The CALBG 8811 Larson regimen is based on a trial (n = 197) that evaluated a 5-drug induction regimen of vincristine, daunorubicin, prednisone, L-asparaginase, and cyclophosphamide. Most (71%) of the patients included in this study were Ph-negative. Among this Ph-negative subgroup of patients, the median OS was 39 months and the 3-year OS rate was 62%.46

MRC UKALL XII/ECOG E2993

In a large international trial, previously untreated patients aged 15 to 59 years (n = 1521) were given induction therapy of vincristine, daunorubicin, prednisone, and L-asparaginase for 4 weeks followed by cyclophosphamide, cytarabine, oral 6- mercaptopurine, and intrathecal methotrexate for 4 weeks.Following initial induction, patients who experienced CR received intensification therapy with 3 cycles of high-dose methotrexate and L-asparaginase. From this regimen, patients with Ph-negative disease experienced a 5-year OS rate of 41%.47

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. 

Treatment for AYA and adults with R/R Ph-negative ALL

Several treatment options for R/R Ph-positive ALL can also be applied to patients with R/R Ph-negative disease. Studies that evaluated blinatumomab, the MOpAD regimen, InO, and CAR T-cells included patients with both Ph-positive and Ph-negative disease.29,30,31,32,35 Therefore, these regimens can be used in Ph-negative ALL patients with R/R disease.

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

Vincristine sulfate liposomal injection

Vincristine sulfate liposomal injection (VSLI) is a nanoparticle formulation of vincristine encapsulated in cholesterol liposomes: this formulation prolongs drug exposure to allow for the delivery of increased doses of vincristine without increased toxicities. The use of VSLI was evaluated in a phase II study of adult patients (n = 65) with Ph-negative ALL in second or greater relapse. The CR rate with single-agent VSLI was 20%. The median OS for all patients was 20 weeks and the median OS for patients achieving CR was 7.7 months.55

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.

Summary of recommendations for Ph-negative ALL

After receiving chemotherapy, PB is determined to have late clearance of MRD.  What are his next options?

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.

FUTURE OF ALL MANAGEMENT: NOVEL AND EMERGING THERAPIES

Over the past decade, there has been rapid development in the treatment of ALL. Beyond the expansion in available chemotherapy regimens, immunotherapy is beginning to show promise with unprecedented CR rates.54,58 Specifically, immunotherapy agents targeting CD19, CD20, CD22, and CD52 have produced positive clinical results. Agents of interest include naked monoclonal antibodies, BiTEs, and previously mentioned CAR T-cells.

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.

Improving medication adherence

Pharmacists can significantly impact patient adherence in ALL, especially related to the initiation of oral therapy with TKIs. Pharmacists may facilitate methods such as pillboxes, reminder tools, and individualized patient calendars to ensure adherence for patients taking oral medications at home. Pharmacists should emphasize the benefits of medication adherence, encourage patients to keep appointments, schedule frequent visits to assess for non-compliance, and engage patients regarding understanding of their disease states and medications. Pharmacists can also help minimize the risk of side effects, as well as improve the early management of side effects, by assessing patients' cognitive abilities to follow medication regimens, simplifying regimens as much as possible, and discussing food requirements for the oral agents prescribed.

Preventing drug-related problems

Many different medications are used as part of ALL treatment and each of the medications has special considerations. For example, TKIs are often used for a prolonged period and are often prescribed for patients with comorbidities. Additionally, they are regularly co-administered with treatments that present risks for drug-drug interactions.TKIs are all substrates of the cytochrome P450 3A4 enzyme and are, therefore, affected by co-administration of agents that are either inducers or inhibitors of this enzyme.61

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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