Innovative therapeutic modalities in
hematologic Malignancies
Prof. Nossrat Firusian,
Recklinghausen, Germany
Recent Developments in Therapy of hematologic Malignancies
1) Monoclonal Antibodies for targeting B-Cell-surface Antigens
2) Small molecules for targeting Tyrosine-kinase domain of Relevant Receptors (CML)
3) Bortezomib as Inhibitor of Proteasome in Multiple Myeloma
4) Immunmodulation (Thalidomide, Lenalidomide) for Patients with Multiple Myeloma
CMLCLLB-Cell-low Grade LymphomasMultiple Myeloma
CML-Hematocytology
Chromosomal Aberation in CML
FISH in CML
FISH analysis for the bcr-abl hybrid in the left cervical lymph node interphasenuclei. The red signals represent the abl gene and the green signals repre-sent the bcr gene. Arrows show the fusion signal of the bcr-abl fusion gene.
The cell shows 2 bcr-abl fusion signals, 1 isolated abl copy and 1 isolated bcr copy.
Structure of Imatinib
Imatinib:Binding Characteristics
Imatinibo Binds to ABL, precluding adenosine triphosphate (ATP) binding ¹, ²
o Binding to inactive conformation of ABL activation loop critical to the high selectivity ², ³
o Interacts with P loop to prevent normal accommodation of ATP phosphate groups ¹, ²
1. Deininger M et al. Blood. 2005; 105:2640-2653. 2. Schindler T et al. Science. 2000;289:1938-1942. 3. Nagar B et al. Cancer Res. 2002;62:4236-4243.
Grade of Response in Connection with Tyrosin-kinase targeted Therapy in CML
1) Cytogenetic Response: Disaperance of Ph-Chromosom
2)Molecular Response:Decreasing of ABL-BCRFusuion Gene 0,01 % 0,001 %
3)MM Response (MMR):Ph-Chromosom ØABL-BCR 0,001
MMR under targeted Therapy in CML
4 years Follow-up-Result of Dasatinib in Comparison to Results of Imatinib in CML
P. value for MMR: 0,0003
CLL
CLL - Therapy
Wait and Watch Binet A
Chlorambucil with Prednisolone
Elderly and co morbidity
Purinanaloga Fludarabin
DCLLSG
Elderly Patients
Significant better than Chlorambucil Survival?Chlorambucil 64 M.Fludarabin 46 M.
Purinanaloga as single or combined with Cyclophosphamide
Young Patient significant better than Chlorambuciland longer survival
Results of Fludarabin as single orFludarabin + Cyclophosphamide in comparison to
Chlorambucil in younger Patient with CLL
CD 20 – as Target for Therapy of B-Cell Lymphomas
CD 20 = B-Cell differentiation
Antigen present in all differentiation steps of B-Cell Lymphocytes (exception: precurser cells and plasma cells)
95% of all B-Cell Lymphomas
CD 20: non glycosylated Phosphoprotein responsible in Signal Transduction Concerning differentiation and Proliferation of activated B-Cells
RituximabRadioimmunoconjugat
eCD-20 - AB – Y 90
CD-20 - AB – J 131
PFS-Survival comparison between FCR and FC
in Patients with B-CLL
New monoclonal Antibodies for Fludarabin-refractory CLL
1. Alemtuzumab (Compath – 1H) humanised monoclonal IgG1-
k-Antibody of CD 52-Antigen: 17P-Deletion on TP 53-Mutation
Alemtuzumab + Rituximab: Coexpression of CD 20 and CD 52.
Complication: Viral Infection (CMV, HSV) demanding prophylactic Therapy by Co-trimoxazol and
Ganciclovir
2. Ofatumumab (HuMax – CD 20):
CD 20 – monoclonal Antibodies:
In Cases refractory to Fludarabin and Alemtuzumab
Months since beginning of Ofatumumab in Patients refractory to Fludarabine and Alemtuzumab
Months since beginning in Patients refractory to Fludarabine
Survival after Response in Fludarabin and Alemtuzumab refractory Patients with bulky desease
New Therapy of advanced CLL
Agent Target Phase IIILicense3/2014
MonoclonalAB (iv)
ObinatuzumabOfatumumab
CD 20CD 20
B-Cell-LymphomaFoll. Lymphoma
USA: CLLUSA: CLL
Kinase Inhibitors(po)
Ibrutinib
Idelalisib
BTk
PI3k
B-Cell-Lymphoma,MCL, CLL
B-Cell-Lymphoma,CLL
USA: CLL, MCL
License pending
BCL-2 Anagonists(po)
ABT-199 BCL-2 CLL Ø License
Immunmodulations Lenalidomid multipleB-Cell-Lymphoma,
MCL, CLLMultiple Myeloma
Important Agents for time being in Phase III clinical Trails with remarkableCapacity in Lymphoma Therapy
Therapeutic Guidelines for recurrent CLL
1) Purineanaloga in Cases with time interval after firts-line Therapy
2) Bendamustine based Chemotherapy + Rituximab
3) New Antibody modalities with Consideration of Alemtuzumab =Anti CD 52 AntibodyAlemtuzumab is even effective in Patients with high risk molecular Parameters, Deletion of Chromosome 11 or 17 (del 11,9; del 17,8) orP53 mutation. Care CMV reactivation Alemtuzumab + Fludarabin
4) Rituximab
5) Ofatumumab = Anti CD 20
6) Lumiliximab = Anti CD 23
7) Bone marrow Transplantation
Entities of low-grade B-Cell NHL
Marginal Zone B-Cell Lymphoma
(MALT-Type)Immunocytoma
Main Entities of low-grade NHL
B-Cell Small Lymphocytic Lymphoma
Follicle Center Cell-
Lymphoma
Mantle Cell-Lymphoma
Survival of lymphoma categorized as germinal centre derived
Histologic Pattern of Mantle-Cell Lymphoma
and Cyclin D1 staining
Cyclin D1: t (11:14) translocation associated
with overexpression of BCL-1 or
PRAD1 gene with encodes Cyclin D1
Therapy of low-grade NH-Lymphoma(Follicular follicle centre Lymphoma chronology)
Chlorambucil ± Prednisolon
Mitoxantrone, Chlorambucil, Prednisolon
CHOP: Cyclophosphamide, Oncovine, Prednisolone and Adriamycin
Wait and watch?
Recurrent desease
FCM: Fludarabin, Cyclophosphamide, Mitoxantrone (57 – 61% R)
Bendamustin 1963 (70% R)
BOP: Folliculon Lymphoma, Immunocytoma, Mantle-Cell Lymphoma(Total R: 66%, CR: 22%, 5 y. survival: 61%)
Combined Chemotherapy of low-grade NHL
New standarts of Therapy for low-grade B-Cell NHL
Rituximab-Chemotherapy-Combi
Rituximab-CHOP
Rituximab-Benda
Total Response: 92,7 % B R91,3 % CHOP R
CR: 39,6 % B R30,0 % CHOP R
PFS: 54,9 month B R34,8 m.
CHOP R
Rand. StudyRummel et al2009:
Results:
Bendamustin partner of Choise for Rituximab
Progression-free survival under R-Bendamustine and R-CHOP in patients with B-Cell Lymphoma and MCL
Results of Rituximab as maintenance Therapy after induction Therapy of low-
grade NHL
Multiple Myeloma
Mechanism of activation of bortezomib. Proteins are targeted to the 26S proteasome for degradation by a process of polyubiquitination. Bortezomib inhibits the catalytic activity of the proteasome. Ub, ubiquitin.
IMIDS for Therapy of M-Myeloma and otherB-Cell-Lymphomas
Thalidomid
Lenalidomid
New Developments in Multiple Myeloma and Chronology of Treatment
1) Mephalan – Prednisolone (Alexanian)
2) HDCT and autologous Stem Cell Transplantationsince 1985200mg Melphalan /m²± whole Body Radiotherapy
3) Tandem HDTC and autologous Stem Cell Transplantation
within 3 Months survival after 7 years: 42% versus 21%
Multiple Myeloma
Bortezumib / Dexamethason (Veldex) within Patients under
65 y. significant higher RR than VAD
Bortezumib-Cyclophosphamide-Dexa (VCD):Total response 85%, VGPR 36%Patients with 17P-Deletion: Lower RR
Bortezumib-Melphalan-Prednisolone as first line Therapy:Significant higher RR than MP
Lenalidomide-Melphanlan-Prednisolone as first line Therapy:Significant higher RR than MP
Strategies for Patients not compatible for HDCT and (Velcade) Bortezomib based Induction Therapy
Therapeutic procedures in Multiple Myeloma
Pat. age < 65: Induction Therapy followed by CD 34 Allocation
HDCT (Melphalan 200 mg/m²)
Pat. age > 65: Bortezomib (Velcade) d 1, 4, 8, 11
Prednisolon 40 mg/m² x 7
Melphalan 6mg/m² x 7 to be repeated every 3 WeeksMonitoring by analysis of protein Parameters
Multiple Myeloma
Convincing therapeutic effect in majority of patients with Myeloma refractory to MP-combined Therapy even after HDTC + Transplantation.
Thalidomide as partner for combined Therapy:Thalidomide + DexamethasoneThalidomide + VCR, ADM + DexamethasoneResponse: 60 – 71% (16 CR)TAD versus VAD: Response 72% versus 50%
Lenalidomide, Clarithromycin, Dexamethasone as first line Therapy (BIRD Protocol)Total responses: 90% (CR: 38%)
Bortezomib (Velcade)ThalidomideLenalidomide(Revlimid)
New Strategies for Patients not compatible with bone marrow Transplantation
Conclusion
o Small molecule Tyrosin kinase Inhibitors as unique therapeutic Agents for patients with CML and Ph+-ALL
o Monoclonal Antibody therapy has evolved into one of the most successfull and most important therapeutic concepts in B-Cell-Lymphoma
o Proteasom Inhibitors are for time being fundamental Part of Muliple Myeloma treatment
o Combined chemo-Antibody, combined chemo-small molecule or chemo-Bortezomib as standard Therapy of hematologic malignancies