Chronic Leukemias - Curative Intent Raises the Bar
Scope
Report Highlights
Reasons to Purchase
Table of Contents
- CHAPTER 1 EXECUTIVE SUMMARY - page 3
- Datamonitor insight into the chronic leukemia market - page 3
- Epidemiology and etiology - page 3
- Classification and prognosis - page 4
- Unmet needs - page 5
- Chronic lymphocytic leukemia - page 5
- Chronic myeloid leukemia - page 7
- Current treatment controversies - page 7
- Chronic lymphocytic leukemia - page 7
- Chronic myeloid leukemia - page 10
- Pipeline products - page 11
- Chronic lymphocytic leukemia - page 11
- Chronic myeloid leukemia - page 13
- Datamonitor insight into the chronic leukemia market - page 3
- CHAPTER 2 INTRODUCTION - page 21
- The chronic leukemias are a significant source of cancer-related morbidity and mortality - page 21
- The advent of immunotherapy is revolutionizing chronic lymphocytic leukeima (CLL) treatment - page 21
- Chronic myeloid leukemia (CML) treatment has been revolutionized by the introduction of Novartis's Gleevec - page 22
- Leukemia subtypes each have their own distinctive epidemiological profile - page 22
- Chronic lymphocytic leukemia has the greatest prevalence rate among all leukemias - page 30
- Two-thirds of newly diagnosed CLL patients are greater than 60 years of age - page 30
- CLL predilication for the male sex - page 30
- US age-adjusted incidence may have decreased secondary to changes in diagnostic criteria - page 31
- Japanese incidence of CLL is significantly lower than that in Western countries - page 31
- CML has contrasting age and sex distribution - page 32
- CML is almost universally associated with a single cytogenetic abnornality - page 32
- Success of Novartis's Gleevec is reflected by increasing pool of CML prevalence - page 33
- Chronic lymphocytic leukemia has the greatest prevalence rate among all leukemias - page 30
- Chronic leukemia etiology and risk factors - page 33
- No clear associations exist for CLL development other than familial history - page 33
- CML contrasts to CLL with definitive associations with environmental exposures - page 34
- Disease staging, patient symptomology and clinical course - page 35
- Choice of CLL staging system a function of geography and historical precident - page 35
- The Rai and Binet systems do not provide adequate information to guide treatment decisions for patients with low- to intermediate-risk CLL - page 37
- Improved risk stratification in CLL will be necessary to mitigate heterogeneity in clinical course - page 38
- CML is a triphasic disease with phase at diagnosis having the greatest prognostic significance. - page 39
- The chronic leukemias are a significant source of cancer-related morbidity and mortality - page 21
- CHAPTER 3 UNMET NEEDS - page 41
- Curative treatment is still elusive in CLL - page 41
- Advances in treatment render NCI response criteria inadequate - page 42
- Eradication of MRD is the key to improved clinical benefit - page 42
- Widespread implementation of effective techniques to detect and quantify MRD will be a prerequisite to improving therapy outcomes - page 43
- Refining treatment outcome predictions in CLL through improved prognostication - page 44
- Molecular genetic characteristics are the focus of ongoing prognostic research - page 44
- Mutational status of IgVH important for predicting PFS and OS - page 45
- Using genomic aberrations to predict response to therapy - page 47
- Quality of treatment responses have already been correlated with specific genomic abberations - page 47
- Developers should harness risk-straftification to improve the efficiency of drug development in CLL - page 48
- Advances in treatment render NCI response criteria inadequate - page 42
- CML unmet needs focus on Gleevec-resistance and primary refractoriness - page 49
- Rates and duration of response to Gleevec dependent on stage of disease - page 49
- Gleevec resistance rates reported at 4% with each year of treatment with no second-line treatment option available - page 50
- Improved MRD eradication offers developmental opportunity - page 51
- Durability of CCR responses to imatinib unknown - page 51
- Curative treatment is still elusive in CLL - page 41
- CHAPTER 4 CURRENT TREATMENT CONTROVERSIES - page 55
- Shifting the CLL treatment paradigm - page 56
- Where appropriate, inidividualized, patient-specific treatment in CLL is moving towards more curative strategies - page 56
- The purine analogues have superceeded alkylator-based approaches in the first-line treatment of younger, healthier patients - page 57
- Fludarabine dominates the purine analogue class in CLL treatment - page 58
- Changes to Medicare prescription coverage should encourage developers to pursue oral formulations - page 59
- The treatment of fludarabine or disease-induced autoimmune hemolytic anemia remains an area of debate - page 60
- Purported clinical benefit offered by combining fludarabine with alkylators is contentious - page 61
- Treatment of fludarabine-refractory disease - page 61
- Chemo-immunotherapy strategies drive the evolution of new CLL treatment paradigms - page 62
- Monoclonal antibodies elicit cytotoxic effects in CLL via multiple mechanisms - page 63
- Single agent rituximab has only modest activity in CLL - page 63
- Combination regimens incorporating fludarabine and rituximab are becoming the new standard of care for first-line CLL treatment - page 66
- Alemtuzumab appears pivotal to approaches for MRD eradication - page 68
- Subcutaneous administration may become the preferred route of administration - page 68
- Residual adenopathy limits alemtuzumab activity - page 70
- Maintenance dosing starts to permeate clinical practice - page 70
- Pharmacoeconomic constraints may be responsible for variance in practice between US and Europe - page 71
- Maintaining dose-intensity not a cause of major concern - page 72
- The evolution of alemtuzumab's place in CLL treatment will rely on optimizing dosing schedules and more clearly definition of target patient populations - page 73
- Alternative immunotherapy approaches show promise - page 73
- Upcoming US Intergroup sudy will help discern between different immunotherapy approaches - page 74
- Bone marrow transplantation (BMT) - page 74
- Likely future role of BMT is in consolidating MRD eradication for high-risk patients - page 74
- Results with autologous transplantation have been generally disappointing - page 75
- Reduced-intesity transplantation offers improved efficacy and broader utility - page 75
- Increasing risk-stratification will fragment the CLL market - page 77
- Heightened pharmacoeconomic vigilance will place novel treatment approaches under increased scrutiny - page 78
- CLL experts believe that targeting alemtuzumab-refractory patients is the most likely source of greater financial rewards - page 78
- Gleevec remains the gold-standard in CML - page 79
- Physicians unwilling to attempt treatment cessation, even in patients who achieve CCR - page 80
- Opportunity exists for novel agent that can improves the rates of molecular remission without the need for chronic administration - page 81
- Molecularly positive disease persists despite significant cytogenetic response rates - page 81
- Suboptimal responders to Gleevec should be targeted by developers evaluating novel pharmacotherapy - page 82
- Dose-escalation of Gleevec to overcome hematologic or cytogenetic resistance - page 82
- Replacing Gleevec as first-line therapy will yield lucrative financial rewards - page 83
- Combinatorial approaches employing Gleevec - page 83
- Definitive role of bone marrow transplantation (BMT) in CML treatment paradigm remains ambiguous - page 84
- Shifting the CLL treatment paradigm - page 56
- CHAPTER 5 PIPELINE DRUGS - page 87
- Immunotherapy approaches to CLL fuelled by success of rituximab and alemtuzumab - page 87
- Passive immunotherapy with single-agent MoAb approaches have demonstrated limited activity - page 88
- Protein Design Laboratories discontinue development of HLA-DR-targeted MoAb, apolizumab - page 88
- Biogen-Idec's lumiliximab (anti-CD23) and Chiron/Xoma's CHIR-12.12 (anti-CD40) in early-stage clinical development - page 89
- Strategies incorporating active immunotherapy are still in their relative infancy, though some early-phase clinical trail results hold promise - page 89
- Vaccine strategies to enhance B-CLL costimulatory molecule expression hold promise - page 89
- Rationaly developed dendritic cell technology nears clinical R&D - page 90
- Xcyte drops CLL indication from developmental program for patented Xcellerate technology - page 90
- KOLs interviewed by Datamonitor express little enthusiasm for novel immunotherapy approaches - page 91
- Ontak (denileukin difitox; Ligand Pharmaceuticals) generates little excitement - page 91
- Despite Phase III study demonstrating statistically significant improvements in ORR, Genasense (oblimersen; Genta) fails to ignite KOLs imagination - page 92
- Fast-track and orphan designation in CLL - page 93
- KOLs skeptical about the Phase III study design - page 93
- Alvocidib (flavopiridol; NCI/Sanofi-Aventis) generates renewed interest - page 94
- Continuous infusion dosing schedules fail to demonstrate clinical activity - page 95
- Promising early data from Phase I study employing modified dosing regimen drives further development - page 96
- Alvocidib's checkered history leaves KOLs cynical about its future clinical potential - page 96
- Early-stage development of histone deacetylases inhibitors means that clinical potential is too early to call - page 97
- Depsipeptide (FK-228; NCI/Gloucester Pharmaceuticals) development in CLL has stalled despite early promise of activity - page 97
- Merck and Co.'s suberanilohydroxamic acid appears a prime candidate for continued investigation - page 98
- Antiangiogenic strategies are also a focus of ongoing developmental efforts - page 99
- Passive immunotherapy with single-agent MoAb approaches have demonstrated limited activity - page 88
- Second-generation tyrosine kinase inhibitors dominate the cml pipeline - page 100
- Two novel Bcr-Abl inhibitors are in clinical trials with promising results; dasatinib and AMN107 - page 101
- Dasatinib's dual inhibition of Src and Bcr-Abl tyrosine kinase potentiates activity - page 101
- Novartis's AMN-107 also demonstrates significant early signs of clinical potential in CML - page 103
- Phase I study shows that AMN-107 confers significant activity and low toxicity in Gleevec-resistant CML - page 103
- Clinical development program moves to Phase II - page 104
- An opportunity for Novartis to consolidate and expand its leading role in the CML therapy market - page 104
- Novartis and BMS sprint to the finish line in the race to commercialize a second-generation TKI - page 104
- Phase IIb study with comparator arm may give dasatinib a head start to approval - page 106
- Multistep inhibition of signal transduction likely to be the focus of future developmental strategies - page 106
- Two novel Bcr-Abl inhibitors are in clinical trials with promising results; dasatinib and AMN107 - page 101
- Immunotherapy approaches to CLL fuelled by success of rituximab and alemtuzumab - page 87
- CHAPTER 6 OPINION LEADER TRANSCRIPTS - page 108
- Contributing experts - page 108
- Opinion leader 1 - page 109
- Opinion leader 2 - page 121
- Opinion leader 3 - page 131
- Opinion leader 4 - page 143
- Opinion leader 5 - page 150
- Contributing experts - page 108
- CHAPTER 7 APPENDIX - page 160
- Bibliography - page 160
- CML response criteria - page 167
- List of tables - page 168
- List of figures - page 170
- About Datamonitor - page 171
- About Datamonitor Healthcare - page 171
- Datamonitor Healthcare's research and analysis methodologies - page 172
- Datamonitor Healthcare's therapy area capabilities - page 172
- About the Oncology analysis team - page 173
- Key therapy team members - page 173
- Nish Saini, Senior Oncology Analyst - page 173
- Disclaimer - page 174
- List of Tables
- Table 1: Leukemia incidence in the seven major markets, 2005-15 - page 24
- Table 2: Leukemia subtype incidence in the seven major markets, 2005-15 - page 24
- Table 3: Crude incidence rates of leukemia (per 100,000) - page 25
- Table 4: Frequency of leukemia subtypes in the seven major markets (%) - page 26
- Table 5: Leukemia subtype incidence in France, 2005-15 - page 26
- Table 6: Leukemia subtype incidence in Germany, 2005-15 - page 27
- Table 7: Leukemia subtype incidence in Italy, 2005-15 - page 27
- Table 8: Leukemia subtype incidence in Spain, 2005-15 - page 28
- Table 9: Leukemia subtype incidence in UK, 2005-15 - page 28
- Table 10: Leukemia subtype incidence in US, 2005-15 - page 29
- Table 11: Leukemia subtype incidence in Japan, 2005-15 - page 29
- Table 12: Binet staging system for CLL - page 36
- Table 13: Relationship between genetic aberrations and disease characteristics in CLL - page 53
- Table 14: Relationship between genetic aberrations and response to treatment - page 54
- Table 15: Current treatment options for CLL - page 55
- Table 16: Current treatment options for CML - page 55
- Table 17: CLL response rates to single-agent rituximab - page 65
- Table 18: CLL response rates to fludarabine-rituximab combinations - page 66
- Table 19: Gleevec combinations under investigation for resistant CML - page 84
- Table 20: CLL developmental pipeline - page 87
- Table 21: CML drugs in ongoing clinical development - page 100
- Table 22: Ongoing clinical trials involving dasatinib - page 102
- Table 23: Comparison of dasatinib and AMN-107 - page 106
- Table 24: CML response criteria - page 167
- List of Figures
- Figure 1: Leukemia subtype incidence in the seven major markets, 2005-15 - page 25
- Figure 2: Relative incidence of CLL in the seven major pharmaceutical markets, 2005 - page 32
- Figure 3: Rai staging system for CLL - page 36
- Figure 4: Rates of response to hematologic and cytogenetic remission in the Phase II and III trials of imatinib - page 50
- Figure 5: The targets in signal transduction - page 107
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