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