Acute Leukemias - Persistent unmet needs confer significant commercial opportunity

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Publication Date: 2006-04-06

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While existing treatment strategies for adult acute leukemia may yield satisfactory remission- induction rates, a major clinical concern is the high rate of disease relapse despite attempts to optimize post-remission consolidation therapy. This is acutely problematic among elderly patients who are frequently unable to tolerate the rigors of more intensive treatment approaches.

Scope

Overview of acute leukemias including epidemiology, etiology, disease classification and prognostic variables

Current treatment controversies and novel therapies in the developmental pipeline

Analysis of trial data, marketing factors and commercial potential for key technologies in clinical development

Stakeholder opinions and interview transcripts based on qualitative interviews with key opinion leaders from the US and Europe

Report Highlights
For the innovators of novel and efficacious pharmacotherapy, commercial opportunities within the acute leukemia market are rife. Developers can exploit the high unmet needs that currently prevail in the acute leukemia market by using accelerated approval pathways to expedite market access and drive commercialization.

Future drug development approaches will respond to the increased identification of gene mutations and their ensuing proteonomic manifestations. This approach is more likely to address the heterogeneity of acute leukemia and will contribute to the increasing trend of risk-stratified treatment approaches.

Reflecting a greater understanding of disease biology, the enthusiastic pursuit of Flt-3 inhibition in the development of novel acute myeloid leukemia treatment has resulted in already crowded pipeline, with four products challenging for first-to-market status: Cephalon's CEP-701, Novartis' PKC-412, Millennium's MLN518 and Pfizer's SU11248.

Reasons to Purchase

Identify the areas of unmet need and clinical controversy in acute leukemia treatment

Understand how advancements in acute leukemia prognostication and risk-stratification may shift future treatment paradigms

Assess opportunities and risks for innovative treatments targeting the acute leukemias

CHAPTER 1 EXECUTIVE SUMMARY - page 3
- Datamonitor insight into the acute leukemia market - page 3
  - The acute leukemias comprise a heterogeneous group of diseases - page 3
  - Cytogenetic classification provides the most compelling prognostic information - page 4
  - Current treatment options fail to offer sustained remission - page 4
  - Integration of targeted therapy into treatment protocols provides potential for sustained remission - page 5
  - Pending FDA approval of Gleevec in ALL marks first targeted therapy approval in this indication - page 6
  - Future therapies will fragment the acute leukemia market - page 7
  - Heterogeneity of disease means developers must aim for more homogenous trial groups - page 8
CHAPTER 2 DISEASE OVERVIEW - page 17
- Pathobiology of acute leukemias - page 17
  - Blood cells are formed through a process of hematopoiesis - page 17
  - Hematopoiesis comprises a series of lineage commitment steps - page 18
  - Leukemia is a consequence of imbalances in the maturation and differentiation process - page 19
  - Immunophenotyping may be required to differentiate between lymphoid and myeloid lineages - page 20
- Leukemia subtypes each have their own distinctive epidemiological profile - page 20
  - AML is predominantly a disease of the elderly, while ALL incidence peaks in childhood - page 21
  - Acute myeloid leukemia holds the greatest commercial opportunity in adult acute leukemias - page 26
- Acute myeloid leukemia - page 26
  - Acute myeloid leukemia etiology and risk factors - page 26
  - The clonal origin of AML is suggested by non-random chromosomal abnormalities - page 28
  - Cytogenetics offers valuable prognostic information in AML - page 28
- Staging and classification of AML - page 29
  - New WHO classification system updates the French-American-British classification system - page 31
    - AML with recurrent chromosomal abnormalities - page 33
    - Acute promyelocytic leukemia - page 33
    - Acute myeloid leukemia with multilineage dysplasia - page 34
    - Acute myeloid leukemias and myelodysplastic syndromes, therapy related (t-AML and t-MDS) - page 34
    - Therapy-related AML following treatment with alkylating agents - page 36
    - t-AML/MDS following topoisomerase II inhibitors. - page 37
    - Acute myeloid leukemias, not otherwise categorized - page 37
  - The need for greater molecular monitoring in AML is highlighted by the lack of prognostic indicators for patients with normal karyotype disease - page 38
  - Aberrant signal transduction pathways provide opportunities for the developers of targeted treatments - page 38
- Acute lymphoblastic leukemia - page 39
  - ALL contrasts to AML with fewer definitive risk factors - page 40
  - Morphologic classification of ALL has evolved to incorporate immunogenic and cytogenetic features - page 40
  - Precursor B-cell ALL is associated with the Philadelphia-positive gene - page 42
  - Incidence of mature B-cell ALL increasing concurrent with rise in immunodeficiency - page 43
  - Cytogenetic features help predict ALL prognosis - page 43
    - The presence of the Philadelphia chromosome offers the most compelling prognostic information - page 44
CHAPTER 3 UNMET NEEDS - page 45
CHAPTER 4 CURRENT TREATMENT CONTROVERSIES - page 53
- Overview of AML treatment - page 62
  - Cytarabine-anthracycline combination regimens form the cornerstone of induction therapy for AML - page 62
  - Consolidation therapy is crucial to preventing early relapse - page 62
  - Hematopoeitic stem cell transplantation in first remission is the most aggressive form of consolidation treatment - page 63
  - Despite success of induction and consolidation treatment, high relapse rates prevail among AML patients - page 63
  - Efforts to treat refractory AML rely on experimental strategies - page 64
- Treatment of AML in patients less than 60 years of age - page 65
  - Cytarabine-anthracycline regimens dominate induction therapy in younger AML patients - page 65
  - Agents that prolong remission can expect significant uptake - page 69
    - A process of risk-adjusted consolidation therapy is used for younger AML patients - page 70
    - Consolidation approaches for younger patients with favorable genetics - page 70
    - For younger patients with good cytogenetics autologous transplantation is reserved for first relapse - page 71
    - The benefits of high-dose cytarabine in consolidation are unique to younger patients - page 71
    - Consolidation approaches for younger patients with intermediate and high-risk genetics - page 73
    - Evolution of future treatment approaches for AML in younger patients is likely to shift focus to the incorporation of novel targeted treatments - page 74
- Treatment of AML in patients greater than 60 years of age - page 75
  - Cytarabine-containing regimes remain central to induction therapy in elderly AML - page 76
  - Increasing the intensity of chemotherapy in induction therapy does not increase overall survival - page 76
  - Clinical trial design should encompass cytogenetic stratification for patients with elderly AML - page 79
  - No accepted treatment strategy for elderly-AML in the post remission setting - page 80
  - The benefits of intensive conditioning and autologous HSCT are offset by the higher treatment related mortality in elderly AML - page 81
  - Opinion leaders optimistic about increasing use of the 'mini transplant' in elderly AML - page 82
  - Treatment tree for elderly-AML - page 83
  - Treatment of relapsed AML in elderly patients - page 84
  - Treatment of relapsed AML in elderly patients with Mylotarg - page 85
    - Risk of veno-occlusive disease with Mylotarg - page 86
- Treatment of acute promyelocytic leukemia - page 86
  - The introduction of all-trans-retinoic acid (ATRA) for treatment of APL represents a significant advance - page 87
  - ATRA therapy is associated with retinoic acid syndrome - page 88
  - ATRA combined with an anthracycline firmly grounded in first-line therapy - page 88
  - Consolidation therapy for APL - page 88
  - Trisonex induces remission in refractory APL - page 89
  - Trisenox as first-line consolidation therapy in APL - page 89
  - Hematopoeitic stem cell transplantation is recommended for APL patients in CR2 - page 90
  - Potential role for Mylotarg in relapsed APL - page 90
- High unmet needs prevail in the treatment of adult ALL - page 93
  - Patient-specific factors affecting treatment of elderly ALL - page 93
  - First-line treatment for ALL - page 95
    - Induction therapy - page 96
    - The use of growth factors in ALL is patient-dependent - page 96
  - Consolidation therapy for ALL - page 97
  - Maintenance therapy - page 99
  - Management of Philadelphia-positive ALL - page 100
  - Targeted therapy is already integrated into treatment regimes for ALL - page 100
    - Transplantation is the treatment of choice for Philadelphia-positive patients - page 101
    - Gleevec in combination with chemotherapy for newly diagnosed Philadelphia- positive ALL - page 101
- Philadelphia-positive ALL patients remain a population with significant unmet needs - page 102
- Opinion leaders are disappointed in ALL progress - page 103
CHAPTER 5 DRUGS IN ONGOING CLINICAL DEVELOPMENT - page 104
- Clolar/Evoltra uptake may be restricted by pharamacoeconomic constraints - page 124
  - FDA approval of Clolar in pediatric ALL - page 124
  - Bioenvision receives positive opinion in Europe for pediatric ALL - page 125
  - Clolar demonstrates activity in pediatric AML but not approved by the FDA - page 126
  - First-line-extension expected in 2006 - page 126
  - Two Phase III studies planned in AML following FDA request for additional data - page 127
  - Approval in AML will ensure maximum commercial returns - page 128
  - Increased economic constraints on healthcare systems may restrict uptake - page 128
- PROMISING PHASE II DRUGS - page 129
- Flt-3 inhibition promising for AML - page 131
  - Lestaurtinib (CEP-701), Celphalon, most clinically advanced flt-3 inhibitor - page 131
    - Lestaurtinib has activity in elderly AML - page 133
    - Lestaurtinib may be the first in class to reach the market - page 133
    - Cephalon's recent acquisition of Trisenox will provide invaluable experience of the leukemia market - page 134
  - Targeting multiple pathways, Midostaurin (PKC-412), Novartis - page 134
    - Midostaurin does not induce remission as single agent - page 134
    - Phase 2b trial demonstrates activity in combination with chemotherapy - page 134
  - Next generation Bcr-Abl tyrosine kinase inhibitors eagerly awaited, Nilotinib (AMN107), Novartis - page 136
    - Novartis has the capacity to realize maximum commercial potential of AMN107 - page 137
  - Bristol-Myers Squibb's Dasatinib (BMS-354825) generates excitement in key opinion leaders - page 137
    - Phase I trials suggest 100% hematological response rate in Ph+ve ALL - page 138
    - FDA grants priority review dasatinib - page 138
    - Dasatinib may make it to market before AMN107 - page 138
    - Clinical trial data will discern which agent is more efficacious - page 138
  - Cytotoxics will remain at the cornerstone of acute leukemia treatment - page 140
CHAPTER 6 OPINION LEADER TRANSCRIPTS - page 142
- Contributing experts - page 142
  - US Opinion leader - page 143
  - US Opinion leader - page 154
  - European opinion leader - page 165
  - European opinion leader - page 174
APPENDIX - page 187
- List of tables - page 202
- List of figures - page 205
- About Datamonitor - page 206
  - About Datamonitor Healthcare - page 206
  - Datamonitor Healthcare's research and analysis methodologies - page 207
  - Datamonitor Healthcare's therapy area capabilities - page 207
  - About the Oncology analysis team - page 208
- Disclaimer - page 209

List of Tables
Table 1: Immunophenotyping markers used in AML - page 20
Table 2: Leukemia incidence in the seven major markets, 2006-16 - page 24
Table 3: Frequency of leukemia subtypes in the seven major markets - page 24
Table 4: Crude incidence rates of leukemia (per 100,000) - page 25
Table 5: Leukemia sub-type incidence in the seven major markets 2000-2016 - page 26
Table 6: Prognosis conferred by cytogenetic abnormalities in AML - page 28
Table 7: The French-American-British Classification system of AML - page 30
Table 8: WHO classification of acute myeloid leukemia - page 32
Table 9: Two distinct classes of t-MDS/AML can be related to alkylating agents and topoisomearase II inhibitors - page 36
Table 10: Molecular abnormalities associated with AML and their corresponding prognoses - page 39
Table 11: The French-American-British Classification system of ALL - page 41
Table 12: Morphological, immunogenic and cytogenetic classification of ALL - page 42
Table 13: Three year survival related to cytogenetics in ALL - page 43
Table 14: Recently approved acute leukemia drugs receiving accelerated approval - page 46
Table 15: Elderly AML patients spend significant percentage of life in the hospital - page 52
Table 16: ECOG performance status - page 55
Table 17: Cytogenetic patterns by age in patients with AML - page 57
Table 18: Commonly used agents in AML - page 62
Table 19: Standard induction therapy for AML - page 66
Table 20: High dose cytarabine versus standard cytarabine in AML - page 67
Table 21: High dose cytarabine benefits patients with poor prognosis - page 68
Table 22: Responsiveness to induction therapy declines with age - page 72
Table 23: High dose cytarabine in consolidation therapy only benefits younger patients - page 73
Table 24: Post-induction therapy does not offer improved survival in elderly-AML - page 80
Table 25: Berlin- Frankfurt- Munster and Larson regimes for ALL - page 98
Table 26: Linker regime - page 99
Table 27: Marketed and developmental drugs in acute leukemia - page 104
Table 28: Pivotal Phase II trials for Arranon approval - page 113
Table 29: Cloretazine demonstrates activity in untreated elderly AML - page 123
Table 30: Clolar demonstrates activity in pediatric ALL - page 125
Table 31: Clolar activity in elderly AML - page 127
Table 32: Phase II acute leukemia drugs - page 129
Table 33: Trial results of lestaurtinib in relapsed AML - page 132
Table 34: Midostaurin in combination with chemotherapy in patients with AML - page 135
Table 35: Comparison of AMN107 and dasatinib - page 139

List of Figures
Figure 1: Schematic diagram of hematopoiesis - page 18
Figure 2: Age related incidence of AML and ALL - page 22
Figure 3: Leukemia sub-type incidence in the seven major markets, 2006-16 - page 25
Figure 4: Unmet needs in acute leukemia - page 45
Figure 5: Cytogenetic risk group by age group - page 56
Figure 6: Cytogenetic patterns by age in patients with AML - page 57
Figure 7: Probability of continuous complete remission according to karyotypes - page 59
Figure 8: Overall survival for patients with AML according to karyotype - page 60
Figure 9: Basic principles in the treatment of AML in younger patients (<60 years) - page 75
Figure 10: No overall survival advantage conferred by any one particular anthracycline/anthracenedione in elderly AML - page 77
Figure 11: CR and median survival according to karyotype in elderly-AML - page 79
Figure 12: Treatment tree for elderly AML - page 84
Figure 13: Treatment pathway for patients with APL - page 92
Figure 14: Incidence of Ph+ve cases of ALL increases with age - page 95
Figure 15: SWOG Mylotarg trial in newly diagnosed AML - page 115

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Acute Leukemias - Persistent unmet needs confer significant commercial opportunity

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