Curr Hematol Malig Rep (2014) 9:165–173 DOI 10.1007/s11899-014-0202-9
ACUTE LEUKEMIAS (R STONE, SECTION EDITOR)
Novel Antibody Therapy in Acute Lymphoblastic Leukemia Samith T. Kochuparambil & Mark R. Litzow
Published online: 13 March 2014 # Springer Science+Business Media New York 2014
Abstract The treatment of adult acute lymphoblastic leukemia (ALL) poses a tremendous challenge for hematologists. The use of pediatric-based chemotherapy regimens in young adults up to the age of 45 years has resulted in improved outcomes when compared retrospectively with historical controls treated with adult therapy. A better understanding of the molecular landscape of ALL and advances in the field of monoclonal antibody therapy have resulted in the development of several new agents that may provide for a reduction in the toxicity inherent in pediatric-like regimens. The antiCD20 antibody, rituximab, anti CD22 antibody, epratuzumab, anti-CD22 antibody-drug conjugate, Inotuzumab ozogamicin, the bi-specific T-cell engager (BiTE) antibody, Blinatumomab, and chimeric receptor antigen (CAR) therapy are among the emerging agents that have demonstrated the potential to improve response rate and decrease toxicity when used alone or in combination with chemotherapy. Several role-defining phase II and phase III clinical trials with these agents are currently underway in the relapsed/refractory and newly diagnosed ALL settings.
Keywords Acute lymphoblastic leukemia . Chemotherapy . Monoclonal antibodies . CD20 antibody . Rituximab . Anti-CD22 antibody . Epratuzumab . Inotuzumab ozogamicin . Bi-specific T-cell engager (BiTE) antibody . Blinatumomab . Chimeric receptor antigen (CAR) therapy
S. T. Kochuparambil : M. R. Litzow (*) Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected] S. T. Kochuparambil e-mail: [email protected]
Introduction The incidence of acute lymphoblastic leukemia (ALL) in the United States is approximately 1.5/100,000 population, with a bimodal distribution. The peak incidence is between the ages of 2 and 5 years, with a second peak in patients above the age of 50 years [1, 2]. Intensification of chemotherapy and changes in dosage schedules have been associated with improved survival rates in pediatric ALL, with current 5-year event-free survival rates of approximately 85 % [3]. Use of pediatric-based chemotherapy regimens in young adults up to the age of 45 years has resulted in improved outcomes compared with historical controls. A number of factors contribute to the decline in overall survival with increasing age, including increased frequency of adverse genetic features (e.g., Philadelphia chromosome-positive ALL), drug resistance, and poor chemotherapy tolerance resulting in suboptimal dose intensity [4]. Novel, less toxic therapies are needed. Monoclonal antibodies targeting a number of cell surface antigens have shown promise in treatment of adult ALL [5, 6]. Antibodies targeting CD20 (e.g., rituximab) combined with chemotherapy may be of benefit for treatment of adult ALL. Rituximab in combination with chemotherapy is now considered standard of care in Burkitt or Burkitt-like leukemia/ lymphoma and B-cell ALL [6–8]. A number of other monoclonal antibodies are currently being evaluated, with encouraging initial results. These include unconjugated monoclonal antibodies (e.g., ofatumumab, alemtuzumab, and epratuzumab), monoclonal antibodies conjugated to cytotoxins (e.g., inotuzumab ozogamicin ), monoclonal antibodies conjugated to cytotoxic toxins like Pseudomonas or diphtheria toxins (e.g., BL22 and moxetumomab pasudotox) (Fig. 1), and T-cell-engaging bi-specific single-chain (BiTE®) antibodies that engage CD3 on the surface of cytotoxic T-cells and redirect cytotoxic T lymphocytes to lyse CD19-positive target ALL
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Curr Hematol Malig Rep (2014) 9:165–173
Fig. 1 Mechanisms of action of monoclonal antibody (Ab) conjugates. Monoclonal antibodies and their fragments can be conjugated or linked to cytotoxic agents. Chemotherapy and toxin conjugates must be internalized via receptor-mediated endocytosis, whereas internalization is not required for radioisotope conjugates. After internalization, the active cytotoxic component is released and mediates cell death. Ricin-based immunotoxins depurinate ribosomal RNA and inhibit protein synthesis.
Pseudomonas (PE)- and diphtheria (DT)-derived immunotoxins ADP ribosylate elongation factor-2 and inhibit protein synthesis. Antibody drug conjugates mediate cytotoxicity by drug-specific actions (e.g., targeting tubulin by maytansin and auristatin, and induction of DNA breaks by calicheamicin). Copyright 2012. American Society of Clinical Oncology. Reprinted with permission. Abbreviation: dgRTA, deglycosylated ricin A chain
cells ( e.g., blinatumomab) [9, 10]. Chimeric antigen receptor (CAR) cells represent a unique and exciting approach. Recent reports show encouraging results. In this article we will review the therapeutic potential and current status of monoclonal antibody-based therapies and CAR therapy in adults with ALL (Table 1).
Anti-CD20 Antibodies The anti-B cell activity of rituximab was first demonstrated in indolent lymphomas and other low-grade lymphoproliferative disorders. Subsequent studies have shown that adding rituximab to chemotherapy improved survival in aggressive
Curr Hematol Malig Rep (2014) 9:165–173
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Table 1 Trials of monoclonal antibody-based therapies in ALL Antibody
Clinical Trial
Patient Subgroup
Response Rate
Rituximab
MDACC [7] GMALL [8] COG [24] SWOG [26] MDACC [36] GMALL [20] GMALL [21] NCI [40] Pediatric [15]
Newly diagnosed Newly diagnosed REL/REF REL/REF REL/REF REL/REF REL/REF REL/REF REL/REF
OS 77 % (4 years) OS 71 % (5 years) CR 75 % OR 45 % OR 57 % OR 29 % CR/CRi 72 % OR 29 % CR 17 %
Epratuzumab Inotuzumab ozogamicin Blinatumomab Moxetumomab Combotox
Abbreviations: COG, Children’s Oncology Group; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; GMALL, German ALL Study Group; MDACC, MD Anderson Cancer Center; MRD, minimal residual disease; NCI, National Cancer Institute; OR, overall response; OS, overall survival; REL/REF, relapsed/refractory; SWOG, Southwest Oncology Group
lymphomas and CLL [11, 12]. While the prognostic significance of CD20 expression in B cell ALL is uncertain, successful use of rituximab in a variety of B cell lineage malignancies has led to its use in addition to chemotherapy in this context. CD20 expression occurs in blast cells in 40–50 % of patients. Induction chemotherapy, particularly with steroids, increases the frequency of expression of CD20 [13]. Thirty-one patients (29 % ≥60 years) with adult Burkitt lymphoma (BL) and mature B cell acute lymphoblastic leukemia (B-ALL) were treated with hyper-CVAD and rituximab, yielding better clinical outcomes with the addition of the antibody, particularly in the elderly [6]. Although the overall complete remission (CR) rates were similar (86 % vs. 85 %), the estimated 3 year survival, event-free survival (EFS), and disease free survival (DFS) rates for the entire group treated with the rituximab combination were 91 %, 89 %, and 89 %, compared with 66 %, 52 %, and 53 % (P60 years of age [7]. With addition of rituximab, the CR rate was 95 %. At 4 years, the OS for patients who received rituximab was 77 % vs. 50 % for patients who did not. Long-term follow-up is needed. Three out of 37 (8 %) younger patients treated with Rituxan developed secondary blood dyscrasias (acute myelogenous leukemia [AML] at 7 years, myelodysplastic
syndrome at 3.5 years, AML with t (8; 21) at 3 years) without relapse of the high-grade lymphoma. The Cancer and Leukemia Group B (CALGB) 10002 trial in patients with BL and mature B-ALL looked at the addition of 4 doses of rituximab and filgrastim to combination chemotherapy compared with historical controls with chemotherapy alone, in which the cure rate was approximately 50 %. With a median follow-up of 3.2 years, the 2-year EFS and OS were 77 % and 79 %, respectively, (87 % and 87 %, respectively, in patients under age 60). The approximate 2-year survival rates were 90 %, 70 %, and 50 % in the low (n=56), intermediate (n=29), and high-risk groups (n=20) respectively, suggesting that the addition of rituximab was beneficial in BL and B-ALL [8]. In the pre-B-ALL Ph-negative setting, a study by the German multicenter ALL (GMALL) group suggests that the addition of rituximab results in improved outcome. The study included 263 CD20+ ALL patients who were treated with rituximab (8 doses) combined with chemotherapy. Compared to historical controls with chemotherapy alone, the continuous CR rate at 5 years and the 5-year OS were 80 % and 71 %, respectively, compared to 47 % and 57 %, respectively, although there was no evident change in the early death or CR rates. Molecular CR (minimal residual disease [MRD] with a sensitivity of 1/104) rates were 57 % at day 24 and 90 % at week 16 with rituximab, compared with 27 % and 59 %, respectively, in the control group. MD Anderson investigators combined rituximab with hyper-CVAD in 173 pre-BALL patients (97 patients were CD20+) [14]. The control group consisted of 109 patients treated with hyper-CVAD alone (53 patients were CD20+). The overall CR rate was 95 % in the group that received rituximab, and 3-year survival was 50 %. Patients 5 to 70 % blasts in the BM). The remaining patients had MRD, detected by flow cytometry or deep sequencing, at the time of CAR T cell infusion [49•]. Ten of the 12 patients with detectable disease before T cell infusion were able to
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achieve MRD-negative responses. The rapidity of the responses was quite remarkable with MRD-negative results obtained as early as 7 days after T cell infusion [49•]. Six patients developed toxicities including high-grade fever (>40ºC), hypotension, hypoxia, changes in mental status, and seizures. These episodes ran for approximately 1 week before they were ameliorated by treatment with steroids or tocilizumab. The other 7 patients did not experience toxicities [49•]. Chimeric antigen receptor cells targeting CD22 have been developed and tested in vitro and appear promising [50]. Multiple clinical trials using CAR are currently underway and will shed more light on its role in ALL.
Conclusion In B-lineage ALL, monoclonal antibody-based regimens have been associated with impressive responses, especially in the relapsed/refractory setting, and have led to multiple MRDnegative responses. Monoclonal antibody therapies generally have a reasonable toxicity profile. Results of the ongoing phase II and III trials in both relapsed/refractory as well as newly diagnosed settings are keenly anticipated, and will help to clarify the role of monoclonal antibodies in the treatment of adult ALL. Compliance with Ethics Guidelines Conflict of Interest Dr. Samith T. Kochuparambil declares no potential conflict of interest relevant to this article. Dr. Mark R. Litzow is a consultant and has received honoraria from Amgen. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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ACUTE LEUKEMIAS (R STONE, SECTION EDITOR)
Novel Antibody Therapy in Acute Lymphoblastic Leukemia Samith T. Kochuparambil & Mark R. Litzow
Published online: 13 March 2014 # Springer Science+Business Media New York 2014
Abstract The treatment of adult acute lymphoblastic leukemia (ALL) poses a tremendous challenge for hematologists. The use of pediatric-based chemotherapy regimens in young adults up to the age of 45 years has resulted in improved outcomes when compared retrospectively with historical controls treated with adult therapy. A better understanding of the molecular landscape of ALL and advances in the field of monoclonal antibody therapy have resulted in the development of several new agents that may provide for a reduction in the toxicity inherent in pediatric-like regimens. The antiCD20 antibody, rituximab, anti CD22 antibody, epratuzumab, anti-CD22 antibody-drug conjugate, Inotuzumab ozogamicin, the bi-specific T-cell engager (BiTE) antibody, Blinatumomab, and chimeric receptor antigen (CAR) therapy are among the emerging agents that have demonstrated the potential to improve response rate and decrease toxicity when used alone or in combination with chemotherapy. Several role-defining phase II and phase III clinical trials with these agents are currently underway in the relapsed/refractory and newly diagnosed ALL settings.
Keywords Acute lymphoblastic leukemia . Chemotherapy . Monoclonal antibodies . CD20 antibody . Rituximab . Anti-CD22 antibody . Epratuzumab . Inotuzumab ozogamicin . Bi-specific T-cell engager (BiTE) antibody . Blinatumomab . Chimeric receptor antigen (CAR) therapy
S. T. Kochuparambil : M. R. Litzow (*) Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected] S. T. Kochuparambil e-mail: [email protected]
Introduction The incidence of acute lymphoblastic leukemia (ALL) in the United States is approximately 1.5/100,000 population, with a bimodal distribution. The peak incidence is between the ages of 2 and 5 years, with a second peak in patients above the age of 50 years [1, 2]. Intensification of chemotherapy and changes in dosage schedules have been associated with improved survival rates in pediatric ALL, with current 5-year event-free survival rates of approximately 85 % [3]. Use of pediatric-based chemotherapy regimens in young adults up to the age of 45 years has resulted in improved outcomes compared with historical controls. A number of factors contribute to the decline in overall survival with increasing age, including increased frequency of adverse genetic features (e.g., Philadelphia chromosome-positive ALL), drug resistance, and poor chemotherapy tolerance resulting in suboptimal dose intensity [4]. Novel, less toxic therapies are needed. Monoclonal antibodies targeting a number of cell surface antigens have shown promise in treatment of adult ALL [5, 6]. Antibodies targeting CD20 (e.g., rituximab) combined with chemotherapy may be of benefit for treatment of adult ALL. Rituximab in combination with chemotherapy is now considered standard of care in Burkitt or Burkitt-like leukemia/ lymphoma and B-cell ALL [6–8]. A number of other monoclonal antibodies are currently being evaluated, with encouraging initial results. These include unconjugated monoclonal antibodies (e.g., ofatumumab, alemtuzumab, and epratuzumab), monoclonal antibodies conjugated to cytotoxins (e.g., inotuzumab ozogamicin ), monoclonal antibodies conjugated to cytotoxic toxins like Pseudomonas or diphtheria toxins (e.g., BL22 and moxetumomab pasudotox) (Fig. 1), and T-cell-engaging bi-specific single-chain (BiTE®) antibodies that engage CD3 on the surface of cytotoxic T-cells and redirect cytotoxic T lymphocytes to lyse CD19-positive target ALL
166
Curr Hematol Malig Rep (2014) 9:165–173
Fig. 1 Mechanisms of action of monoclonal antibody (Ab) conjugates. Monoclonal antibodies and their fragments can be conjugated or linked to cytotoxic agents. Chemotherapy and toxin conjugates must be internalized via receptor-mediated endocytosis, whereas internalization is not required for radioisotope conjugates. After internalization, the active cytotoxic component is released and mediates cell death. Ricin-based immunotoxins depurinate ribosomal RNA and inhibit protein synthesis.
Pseudomonas (PE)- and diphtheria (DT)-derived immunotoxins ADP ribosylate elongation factor-2 and inhibit protein synthesis. Antibody drug conjugates mediate cytotoxicity by drug-specific actions (e.g., targeting tubulin by maytansin and auristatin, and induction of DNA breaks by calicheamicin). Copyright 2012. American Society of Clinical Oncology. Reprinted with permission. Abbreviation: dgRTA, deglycosylated ricin A chain
cells ( e.g., blinatumomab) [9, 10]. Chimeric antigen receptor (CAR) cells represent a unique and exciting approach. Recent reports show encouraging results. In this article we will review the therapeutic potential and current status of monoclonal antibody-based therapies and CAR therapy in adults with ALL (Table 1).
Anti-CD20 Antibodies The anti-B cell activity of rituximab was first demonstrated in indolent lymphomas and other low-grade lymphoproliferative disorders. Subsequent studies have shown that adding rituximab to chemotherapy improved survival in aggressive
Curr Hematol Malig Rep (2014) 9:165–173
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Table 1 Trials of monoclonal antibody-based therapies in ALL Antibody
Clinical Trial
Patient Subgroup
Response Rate
Rituximab
MDACC [7] GMALL [8] COG [24] SWOG [26] MDACC [36] GMALL [20] GMALL [21] NCI [40] Pediatric [15]
Newly diagnosed Newly diagnosed REL/REF REL/REF REL/REF REL/REF REL/REF REL/REF REL/REF
OS 77 % (4 years) OS 71 % (5 years) CR 75 % OR 45 % OR 57 % OR 29 % CR/CRi 72 % OR 29 % CR 17 %
Epratuzumab Inotuzumab ozogamicin Blinatumomab Moxetumomab Combotox
Abbreviations: COG, Children’s Oncology Group; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; GMALL, German ALL Study Group; MDACC, MD Anderson Cancer Center; MRD, minimal residual disease; NCI, National Cancer Institute; OR, overall response; OS, overall survival; REL/REF, relapsed/refractory; SWOG, Southwest Oncology Group
lymphomas and CLL [11, 12]. While the prognostic significance of CD20 expression in B cell ALL is uncertain, successful use of rituximab in a variety of B cell lineage malignancies has led to its use in addition to chemotherapy in this context. CD20 expression occurs in blast cells in 40–50 % of patients. Induction chemotherapy, particularly with steroids, increases the frequency of expression of CD20 [13]. Thirty-one patients (29 % ≥60 years) with adult Burkitt lymphoma (BL) and mature B cell acute lymphoblastic leukemia (B-ALL) were treated with hyper-CVAD and rituximab, yielding better clinical outcomes with the addition of the antibody, particularly in the elderly [6]. Although the overall complete remission (CR) rates were similar (86 % vs. 85 %), the estimated 3 year survival, event-free survival (EFS), and disease free survival (DFS) rates for the entire group treated with the rituximab combination were 91 %, 89 %, and 89 %, compared with 66 %, 52 %, and 53 % (P60 years of age [7]. With addition of rituximab, the CR rate was 95 %. At 4 years, the OS for patients who received rituximab was 77 % vs. 50 % for patients who did not. Long-term follow-up is needed. Three out of 37 (8 %) younger patients treated with Rituxan developed secondary blood dyscrasias (acute myelogenous leukemia [AML] at 7 years, myelodysplastic
syndrome at 3.5 years, AML with t (8; 21) at 3 years) without relapse of the high-grade lymphoma. The Cancer and Leukemia Group B (CALGB) 10002 trial in patients with BL and mature B-ALL looked at the addition of 4 doses of rituximab and filgrastim to combination chemotherapy compared with historical controls with chemotherapy alone, in which the cure rate was approximately 50 %. With a median follow-up of 3.2 years, the 2-year EFS and OS were 77 % and 79 %, respectively, (87 % and 87 %, respectively, in patients under age 60). The approximate 2-year survival rates were 90 %, 70 %, and 50 % in the low (n=56), intermediate (n=29), and high-risk groups (n=20) respectively, suggesting that the addition of rituximab was beneficial in BL and B-ALL [8]. In the pre-B-ALL Ph-negative setting, a study by the German multicenter ALL (GMALL) group suggests that the addition of rituximab results in improved outcome. The study included 263 CD20+ ALL patients who were treated with rituximab (8 doses) combined with chemotherapy. Compared to historical controls with chemotherapy alone, the continuous CR rate at 5 years and the 5-year OS were 80 % and 71 %, respectively, compared to 47 % and 57 %, respectively, although there was no evident change in the early death or CR rates. Molecular CR (minimal residual disease [MRD] with a sensitivity of 1/104) rates were 57 % at day 24 and 90 % at week 16 with rituximab, compared with 27 % and 59 %, respectively, in the control group. MD Anderson investigators combined rituximab with hyper-CVAD in 173 pre-BALL patients (97 patients were CD20+) [14]. The control group consisted of 109 patients treated with hyper-CVAD alone (53 patients were CD20+). The overall CR rate was 95 % in the group that received rituximab, and 3-year survival was 50 %. Patients 5 to 70 % blasts in the BM). The remaining patients had MRD, detected by flow cytometry or deep sequencing, at the time of CAR T cell infusion [49•]. Ten of the 12 patients with detectable disease before T cell infusion were able to
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achieve MRD-negative responses. The rapidity of the responses was quite remarkable with MRD-negative results obtained as early as 7 days after T cell infusion [49•]. Six patients developed toxicities including high-grade fever (>40ºC), hypotension, hypoxia, changes in mental status, and seizures. These episodes ran for approximately 1 week before they were ameliorated by treatment with steroids or tocilizumab. The other 7 patients did not experience toxicities [49•]. Chimeric antigen receptor cells targeting CD22 have been developed and tested in vitro and appear promising [50]. Multiple clinical trials using CAR are currently underway and will shed more light on its role in ALL.
Conclusion In B-lineage ALL, monoclonal antibody-based regimens have been associated with impressive responses, especially in the relapsed/refractory setting, and have led to multiple MRDnegative responses. Monoclonal antibody therapies generally have a reasonable toxicity profile. Results of the ongoing phase II and III trials in both relapsed/refractory as well as newly diagnosed settings are keenly anticipated, and will help to clarify the role of monoclonal antibodies in the treatment of adult ALL. Compliance with Ethics Guidelines Conflict of Interest Dr. Samith T. Kochuparambil declares no potential conflict of interest relevant to this article. Dr. Mark R. Litzow is a consultant and has received honoraria from Amgen. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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