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Philadelphia chromosome-negative acute lymphoblastic leukemia: therapies under development Sameer A Parikh1 & Mark R Litzow*,1
ABSTRACT Although the prognosis of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) has steadily improved over the past decade, less than 50% of patients maintain their remission at 5 years. Several approaches have been explored in the past few years including: monoclonal antibodies – either ‘naked’ (rituximab) or in combination with an immunotoxin (calicheamicin or maytansin), plant toxin (ricin), or bacterial toxin (Pseudomonas or diphtheria), and a novel bispecific T-cell-engaging antibody (blinatumomab); chimeric antigen therapy using autologous T cells that target CD19expressing ALL; and novel agents such as proteasome inhibitors, liposomal vincristine, hypomethylating agents, nelarabine and NOTCH1 inhibitors. This review summarizes treatment approaches currently under investigation for the treatment of adult Philadelphia chromosome-negative ALL.
The treatment of adult patients with acute lymphoblastic leukemia (ALL) has undergone considerable advances in the past decade. The development of combination chemoimmunotherapy [1] , adoption of intensive treatment regimens used in the pediatric setting for young adults with ALL [2] , and use of stem cell transplantation (SCT) [3] have all led to impressive gains in complete remission (CR) rates. Unfortunately, only 25–45% of these patients remain in remission after 5 years, and the overall survival (OS) remains poor at 30–40% [4,5] . Older ALL patients, particularly those >45 years, experience a poor outcome because of a high risk of treatment-related toxicity [6] . Several exciting approaches in the treatment of ALL have been reported in the past few years. These can be broadly categorized into: antibody-based strategies – using monoclonal antibodies directed against surface antigens expressed on ALL blasts such as CD20, CD19, CD22 and CD52; chimeric antigen receptor (CAR) therapy that employs genetically engineered autologous T cells that target ALL; and several other drugs in clinical development such as vincristine sulfate liposomal injection (VSLI), hypomethylating agents, proteasome inhibitors, nelarabine and NOTCH1 inhibitors. This review will summarize the current state of research in Philadelphia chromosome-negative ALL as it pertains to these novel approaches. The management of patients with Philadelphia chromosome-positive ALL is outside the scope of this review.
KEYWORDS
• chimeric antigen receptor therapy • immunotoxin • NOTCH1 inhibitors • novel
monoclonal antibodies • proteasome inhibitors
CD20-positive Philadelphia chromosome-negative B-ALL ●●Monoclonal antibody-based strategies
The premise of monoclonal antibody therapy in ALL is based on the presence of distinct antigens on the surface of the leukemic blast cells. It is widely regarded that for any monoclonal antibody to be clinically effective, at least 20% of the leukemic blasts must express that antigen on Mayo Clinic, Division of Hematology, Department of Medicine, 200 First Street SW, Rochester, MN 55905, USA *Author for correspondence: Tel.: +1 507 284 2511; Fax: +1 507 266 4972; [email protected] 1
10.2217/FON.14.81 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(14), 2201–2212
part of
ISSN 1479-6694
2201
Review Parikh & Litzow their surface [7] . Flow cytometry analysis of 552 patients with ALL revealed the following surface antigens in patients with precursor B-ALL: CD20 (22–30%), CD22 (93–96%), CD19 (100%) and CD33 (17–26%) [8] . Monoclonal antibodies can either be ‘naked’ or linked to chemotherapy and toxin conjugates. Toxinbound monoclonal antibodies are typically internalized by receptor-mediated endocytosis; once internalized, the cytotoxic component is released leading to cell death. Pseudomonas- and diphtheria-based immunotoxins ADP-ribosylate EEF2 and inhibit protein synthesis. By contrast, ricin-based immunotoxins depurinate ribosomal RNA and inhibit protein synthesis (Figure 1) [9] . Table 1 lists the response rates and outcomes of patients with newly diagnosed and relapsed/ refractory B-ALL that have been treated with various monoclonal antibody-based approaches. Anti-CD20 antibody therapy
The addition of rituximab, a naked chimeric antibody against CD20, to standard chemotherapy in a variety of CD20-positive lymphoproliferative neoplasms has led to markedly improved outcomes [17–19] . CD20 expression on ALL blasts varies from 20 to 50% [6] , and glucocorticoid-containing induction chemotherapy has been shown to upregulate this further [20] . In a Phase II study that combined rituximab with hyper-CVAD (fractionated cyclophosphamide, doxorubicin, vincristine and dexamethasone alternating with high-dose cytarabine and methotrexate) in 97 newly diagnosed ALL patients, the CR rate was 95% and the 3-year OS was 45%. When compared with 53 ALL patients historically treated with hyper-CVAD alone, the CR rate was statistically superior; however, no difference in OS was noted. In the subset of patients
Philadelphia chromosome-negative acute lymphoblastic leukemia: therapies under development Sameer A Parikh1 & Mark R Litzow*,1
ABSTRACT Although the prognosis of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) has steadily improved over the past decade, less than 50% of patients maintain their remission at 5 years. Several approaches have been explored in the past few years including: monoclonal antibodies – either ‘naked’ (rituximab) or in combination with an immunotoxin (calicheamicin or maytansin), plant toxin (ricin), or bacterial toxin (Pseudomonas or diphtheria), and a novel bispecific T-cell-engaging antibody (blinatumomab); chimeric antigen therapy using autologous T cells that target CD19expressing ALL; and novel agents such as proteasome inhibitors, liposomal vincristine, hypomethylating agents, nelarabine and NOTCH1 inhibitors. This review summarizes treatment approaches currently under investigation for the treatment of adult Philadelphia chromosome-negative ALL.
The treatment of adult patients with acute lymphoblastic leukemia (ALL) has undergone considerable advances in the past decade. The development of combination chemoimmunotherapy [1] , adoption of intensive treatment regimens used in the pediatric setting for young adults with ALL [2] , and use of stem cell transplantation (SCT) [3] have all led to impressive gains in complete remission (CR) rates. Unfortunately, only 25–45% of these patients remain in remission after 5 years, and the overall survival (OS) remains poor at 30–40% [4,5] . Older ALL patients, particularly those >45 years, experience a poor outcome because of a high risk of treatment-related toxicity [6] . Several exciting approaches in the treatment of ALL have been reported in the past few years. These can be broadly categorized into: antibody-based strategies – using monoclonal antibodies directed against surface antigens expressed on ALL blasts such as CD20, CD19, CD22 and CD52; chimeric antigen receptor (CAR) therapy that employs genetically engineered autologous T cells that target ALL; and several other drugs in clinical development such as vincristine sulfate liposomal injection (VSLI), hypomethylating agents, proteasome inhibitors, nelarabine and NOTCH1 inhibitors. This review will summarize the current state of research in Philadelphia chromosome-negative ALL as it pertains to these novel approaches. The management of patients with Philadelphia chromosome-positive ALL is outside the scope of this review.
KEYWORDS
• chimeric antigen receptor therapy • immunotoxin • NOTCH1 inhibitors • novel
monoclonal antibodies • proteasome inhibitors
CD20-positive Philadelphia chromosome-negative B-ALL ●●Monoclonal antibody-based strategies
The premise of monoclonal antibody therapy in ALL is based on the presence of distinct antigens on the surface of the leukemic blast cells. It is widely regarded that for any monoclonal antibody to be clinically effective, at least 20% of the leukemic blasts must express that antigen on Mayo Clinic, Division of Hematology, Department of Medicine, 200 First Street SW, Rochester, MN 55905, USA *Author for correspondence: Tel.: +1 507 284 2511; Fax: +1 507 266 4972; [email protected] 1
10.2217/FON.14.81 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(14), 2201–2212
part of
ISSN 1479-6694
2201
Review Parikh & Litzow their surface [7] . Flow cytometry analysis of 552 patients with ALL revealed the following surface antigens in patients with precursor B-ALL: CD20 (22–30%), CD22 (93–96%), CD19 (100%) and CD33 (17–26%) [8] . Monoclonal antibodies can either be ‘naked’ or linked to chemotherapy and toxin conjugates. Toxinbound monoclonal antibodies are typically internalized by receptor-mediated endocytosis; once internalized, the cytotoxic component is released leading to cell death. Pseudomonas- and diphtheria-based immunotoxins ADP-ribosylate EEF2 and inhibit protein synthesis. By contrast, ricin-based immunotoxins depurinate ribosomal RNA and inhibit protein synthesis (Figure 1) [9] . Table 1 lists the response rates and outcomes of patients with newly diagnosed and relapsed/ refractory B-ALL that have been treated with various monoclonal antibody-based approaches. Anti-CD20 antibody therapy
The addition of rituximab, a naked chimeric antibody against CD20, to standard chemotherapy in a variety of CD20-positive lymphoproliferative neoplasms has led to markedly improved outcomes [17–19] . CD20 expression on ALL blasts varies from 20 to 50% [6] , and glucocorticoid-containing induction chemotherapy has been shown to upregulate this further [20] . In a Phase II study that combined rituximab with hyper-CVAD (fractionated cyclophosphamide, doxorubicin, vincristine and dexamethasone alternating with high-dose cytarabine and methotrexate) in 97 newly diagnosed ALL patients, the CR rate was 95% and the 3-year OS was 45%. When compared with 53 ALL patients historically treated with hyper-CVAD alone, the CR rate was statistically superior; however, no difference in OS was noted. In the subset of patients
