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Stakeholder Opinions: Acute Leukemias

Persistent unmet needs confer significant commercial opportunity

Publication Date   April 2006
Publisher   Datamonitor
Product Type   Report
Pages   205
ISBN Number   not applicable
Product Code   DAT474
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Price £2,170.00

approximately: $3,223 | €2,554

Summary


Introduction

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.

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.

Content


  • Chapter 1 Executive Summary
    • Datamonitor insight into the acute leukemia market
    • The acute luekemias comprise a heterogeneous group of diseases
    • Cytogenetic classification provides the most compelling prognostic information
    • Current treatment options fail to offer sustained remission
    • Integration of targeted therapy into treatment protocols provides potential for sustained remission
    • Pending FDA approval of Gleevec in ALL marks first targeted therapy approval in this indication
    • Future therapies will fragment the acute leukemia market
    • Heterogeneity of disease means developers must aim for more homogenous trial groups
  • Chapter 2 Disease Overview
    • Pathobiology of acute leukemias
    • Blood cells are formed through a process of hematopoiesis
    • Hematopoiesis is comprised of a series of lineage commitment steps
    • Leukemia is a consequence of imbalances in the maturation and differentiation process
    • Immunophenotyping may be required to differentiate between lymphoid and myeloid lineages
    • Leukemia subtypes each have their own distinctive epidemiological profile
    • AML is predominantly a disease of the elderly while ALL incidence peaks in childhood
    • Acute myeloid leukemia holds the greatest commercial opportunity in adult acute leukemias
    • Acute Myeloid Leukemia
    • Acute myeloid leukemia etiology and risk factors
    • The clonal origin of AML is suggested by non-random chromosomal abnormalities
    • Cytogenetics offer valuable prognostic information in AML
    • Staging and classification of AML
    • New WHO classification system updates the French-American-British classification system
    • The need for greater molecular monitoring in AML evidenced by lack of prognostic indicators for patients with normal karyotype disease
    • Aberrant signal transduction pathways provide opportunities for the developers of targeted treatments
    • Acute lymphoblastic leukemia
    • ALL contrasts to AML with fewer definitive risk factors
    • Morphologic classification of ALL has evolved to incorporate immunogenic and cytogenetic features
    • Precursor B-cell ALL is associated with the Philadelphia positive gene
    • Incidence of mature B-cell ALL increasing concurrent with rise in immunodeficiency
    • Cytogenetic features helps predict ALL prognosis
  • Chapter 3 Unmet Needs
    • High rate of accelerated approval for drugs to treat hematological malignancies
    • Drugs targeting acute leukemia are likely to benefit from Fast Track or Orphan drug status
    • An increase in understanding of molecular and biochemical changes in acute leukemias has not yet translated into improved survival
    • The development of agents which address the heterogeneity of acute leukemia are pivotal to improving treatment outcomes
    • Sustained periods of remission remain elusive for patients with acute leukemia
    • Improved second-line treatments needed to overcome multi-drug resistance
    • Less toxic therapy and improved quality of life required for elderly patients with acute leukemia
  • Chapter 4 Current Treatment Controversies
    • Disease specific factors influence prognosis and therapy options
    • Patient specific factors influence prognosis and therapy options
    • The frequency of high-risk karyotypes increases with age
    • Proteonomic conseqeuences of recurring genetic abnormalities provide potential drug targets
    • The presence of high risk karyotypes reduces the probablity of remission and long term survival
    • Developers must be aware of the prognostic significance of cytogenetics when designing clinical trials
    • Despite heterogeneity in disease, developers should aim for homogenous trial group
    • Overview of AML treatment
    • Cytarabine-anthracycline combination regimens form the cornerstone of induction therapy for AML
    • Consolidation therapy is crucial to preventing early relapse
    • Hematopoeitic Stem Cell Transplantation in first remission is the most aggressive form of consolidation treatment
    • Despite success of induction and consolidation treatment, high relapse rates prevail among AML patients
    • Efforts to treat refractory AML rely on experimental strategies
    • Treatment of AML in patients less than 60 years age
    • Cytarabine-anthracycline regimens dominate induction therapy in younger AML patients
    • Agents which prolong remission can expect significant uptake
    • Treatment of AML in patients greater than 60 years age
    • Cytarabine containing regimes remain central to induction therapy in elderly AML
    • Increasing the intensity of chemotherapy in induction therapy does not increase over all survival
    • Clinical trial design should encompass cytogenetic stratification for patients with elderly AML
    • No accepted treatment strategy for elderly-AML in the post remission setting.
    • The benefits of intensive conditioning and autologous HSCT are offset by the higher treatment related mortality in elderly AML
    • Opinion leaders optimistic about increasing use of the 'mini transplant' in elderly AML
    • Treatment tree for elderly-AML
    • Treatment of relapsed AML in elderly patients
    • Treatment of relapsed AML in elderly patients with Mylotarg
    • Treatment of Acute Promyelocytic leukemia (APL)
    • The introduction of all-trans retinoic acid (ATRA) for treatment of APL represents a significant advance
    • ATRA therapy is associated with retinoic acid syndrome
    • ATRA combined with an anthracycline firmly grounded in first-line therapy
    • Consolidation therapy for APL
    • Trisonex induces remission in refractory APL
    • Trisenox as first-line consolidation therapy in APL
    • Hematopoeitic stem cell transplantation is recommended for APL patients in CR2
    • Potential role for Mylotarg in relapsed APL
    • High unmet needs prevail in the treatment of adult ALL
    • Patient-specific factors effecting treatment of elderly ALL
    • First-line treatment for ALL
    • Consolidation therapy for ALL
    • Maintenance therapy
    • Management of Philadelphia-positive ALL
    • Targeted therapy is already integrated into treatment regimes for ALL
    • Philadelphia-positive ALL patients remain a population with significant unmet needs
    • Opinion leaders are disappointed in ALL progress
  • Chapter 5 Drugs In Ongoing Clinical Development
    • Key opinion leaders express optimism over Zarnestra
    • Marqibo, Phase III trials likely to be initiated following partnership with Hana Biosciences.
    • Ceplene, pending EMEA submission for maintenance therapy in AML
    • Arranon (nelarabine; 506U78), GlaxoSmithKline garners FDA approval based in pivotal Phase II trial
    • Mylotarg may have potential to change first-line treatment for AML
    • Key opinion leaders divided on their opinion on Troxatyl
    • Genasense's troubled route to commercialization may obscure key opinion leader opinion
    • Genasense's troubled route to commercialization may hinder Genta's ability to find marketing partner
    • Cloretazine (VNP-40101M), Vion Pharmaceuticals
    • Clolar/Evoltra uptake may be restricted by current pharamacoeconomic constraints
    • Fda Approval Of Clolar In Pediatric All
    • Bioenvision receive positive opinion in Europe for pediatric ALL
    • Clolar demonstrates activity in pediatric AML but not approved by the FDA
    • First-line-extension anticipated 2006
    • Two Phase III studies planned in AML following FDA request for additional data
    • Approval in AML will ensure maximum commercial returns
    • Increase economic constraints on healthcare systems may restrict uptake
    • Promising Phase Ii Drugs
    • Flt-3 inhibition promsing for AML
    • Lestaurtinib (CEP-701), Celphalon, most clinically advanced flt-3 inhibitor
    • Targeting multiple pathways, Midostaurin (PKC-412), Novartis
    • Next generation Bcr-Abl tyrosine kinase inhibitors eagerly awaited, Nilotinib (AMN107), Novartis
    • Bristol-Myers Squibb's Dasatinib (BMS-354825) generates excitement in key opinion leaders
    • Cytotoxics will remain at the cornerstone of acute leukemia treatment
  • Chapter 6 Opinion Leader Transcripts
    • Contributing experts
    • US Opinion leader
    • US Opinion leader
    • European opinion leader
    • European opinion leader
  • List of tables
  • List of figures
    • About Datamonitor
    • About Datamonitor Healthcare
    • Datamonitor Healthcare's research and analysis methodologies
    • Datamonitor Healthcare's therapy area capabilities
    • About the Oncology analysis team
    • Disclaimer
  • List of Tables
    • Table 1: Immunophenotyping markers used in AML
    • Table 2: Leukemia incidence in the seven major markets, 2006-2016
    • Table 3: Frequency of leukemia subtypes in the seven major
    • Table 4: Crude incidence rates of leukemia (per 100,000)
    • Table 5: Leukemia sub-type incidence in the seven major markets 2000-2016
    • Table 3: Prognosis conferred by cytogenetic abnormalities in AML
    • Table 4: The French American British Classification system of AML
    • Table 5: WHO classification of acute myeloid leukemia
    • Table 6: Two distinct classes of t-MDS/AML can be related to alkylating agents and topoisomearase II inhibitors
    • Table 7: Molecular abnormalities associated with AML and their corresponding prognosis
    • Table 8: The French American British Classification system of ALL
    • Table 9: Morphological, immunogenic and cytogenetic classification of ALL
    • Table 10: Three year survival related to cytogenetics in ALL
    • Table 11: Recently approved acute leukemia drugs receiving accelerated approval.
    • Table 12: Elderly AML patients spend significant percentage of life in hospital
    • Table 13: ECOG performance status
    • Table 14: Cytogenetic patterns by age in patients with AML
    • Table 15: Commonly used agents in AML
    • Table 16: Standard induction therapy for AML
    • Table 17: High dose cytarabine versus standard cytarabine in AML
    • Table 18: High dose cytarabine benefits patients with poor prognosis
    • Table 19: Responsiveness to induction therapy declines with age
    • Table 20: High dose cytarabine in consolidation therapy only benefits younger patients
    • Table 21: Post-induction therapy does not offer improved survival in elderly-AML
    • Table 22: Berlin- Frank- Muster regimes and Larson regime for ALL
    • Table 23: Linker regime
    • Table 24: Marketed and developmental drugs in acute leukemia
    • Table 25: Pivotal Phase II trials for Arranon approval
    • Table 26: Cloretazine demonstrates activity in untreated elderly AML
    • Table 27: Clolar demonstrates activity in pediatric ALL
    • Table 28: Clolar activity in elderly ALL
    • Table 29: Phase II acute leukemia drugs
    • Table 30: Trial results of lestaurtinib in relapsed AML
    • Table 31: Midostaurin in combination with chemotherapy in patients with AML
    • Table 32: Comparison of AMN107 and dasatinib
  • List of Figures
    • Figure 1: Schematic diagram of hematopoiesis
    • Figure 2: Age related incidence of AML and ALL
    • Figure 3: Leukemia sub-type incidence in the seven major markets, 2006-16
    • Figure 4: Unmet needs in acute leukemia
    • Figure 5: Cytogenetic risk groups by age group
    • Figure 6: Cytogenetic patterns by age in patients with AML
    • Figure 7: Probability of continuous complete remission according to karyotypes
    • Figure 8: Overall survival for patients with AML according to karyotype
    • Figure 9: Basic principles in the treatment of AML in younger patients (<60 years)
    • Figure 10: No overall survival advantage conferred by any one particular anthracycline/anthracenedione in elderly AML
    • Figure 11: CR and median survival according to karyotype in elderly-AML
    • Figure 12: Treatment pathway for elderly AML
    • Figure 13: Treatment pathway for patients with APL
    • Figure 14: Incidence of Ph+ve cases of ALL increases with age
    • Figure 15: SWOG Mylotarg trial in newly diagnosed AML