慢性淋巴细胞性白血病治疗研究进展.ppt
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慢性淋巴细胞性白血病
治疗研究进展
Diagnosis
? Diagnostic investigations
* Blood count. lymphocytosis of >5 ×109/l.
* Lymphocyte morphology
* Immunophenotyping
? Additional investigations
* bone marrow aspirate and trephine biopsy
* Lymph node biopsy
* Cytogenetic/ FISH analysis.
* Computed tomography scan and/or ultrasound
Scoring system for the diagnosis of CLL
Scores in CLL are usually >3, in other B-cell malignancies the scores are usually <3
Prognostic factors in chronic lymphocytic leukaemiSurvival based on IgV gene
mutation and CD38 expression
Staging systems in chronic lymphocytic leukaemia
Management of CLL
Indications for treatment
? Progressive marrow failure: the development or worsening of anaemia and/or thrombocytopenia
? Massive (>10 cm) or progressive lymphadenopathy
? Massive (>6 cm) or progressive splenomegaly
? Progressive lymphocytosis
* >50% increase over 2 months
* Lymphocyte doubling time <6 months
? Systemic symptoms
* Weight loss >10% in previous 6 months
* Fever >38C for >=2 weeks
* Extreme fatigue
* Night sweats
? Autoimmune cytopenias
Response criteria
Poor prognosis of advanced, relapsed CLL
? First-line Therapy
* Fludarabine ± rituximab
* Chlorambucil (pulse or continuous) ± prednisone
* Cyclophosphamide ± prednisone
* CVP (cyclophosphamide, vincristine, prednisone)
* FC (fludarabine, cyclophosphamide) ± rituximab
? Second-line Therapy
* Alemtuzumab
* PC (pentostatin, cyclophosphamide) ± rituximab
* Chemotherapy (as above) ± rituximab or alemtuzumab
? Radiotherapy
* Splenic irradiation
* Radiotherapy for bulky nodal masses
? Splenectomy
* Symptomatic massive splenomegaly.
* Refractory cytopenias.
* Autoimmune cytopenias
* Hypersplenism
Chemoimmunotherapy
? Alkylating agents.
* Chlorambucil+/-prednisolone/prednisone
* high-dose chlorambucil
* CVP
* CHOP
? Purine analogues
* Fludarabine
* Cladribine
* Pentostatin
? Monoclonal antibodies
* Alemtuzumab
* Rituximab
Fludarabine
CALGB 9011
? Fludarabine 25mg/m2ivD1-5
? Chlorambucil 40 mg/m2 po
? Fludarabine 20mg/m2ivD1-5 plus Chlorambucil 20 mg/m2 po
The treatments were repeated every 28 days for a maximum of 12 cycles
Fludarabine versus chlorambucil in untreated CLL
Fludarabine versus chlorambucil in untreated CLL
Fludarabine versus chlorambucil in untreated CLL
CLL4 protocol of the GCLLSG
for advanced CLL
CLL4 protocol of the GCLLSG
FC versus F in first line therapy: response*
CLL4 protocol: progression-free
and event-free survival
Cladribine versus chlorambucil in CLL
Pentostatin
Monoclonal antibodies
Therapeutic efficacy of alemtuzumab
and rituximab as single agents in CLL
Rituximab monotherapy in relapsed/refractory CLL/SLL
CALGB 9712 protocol
Response to rituximab + fludarabine
Rituximab + fludarabine : progression-free survival
Rituximab + fludarabine : overall survival
Rituximab + fludarabine versus fludarabinein CLL
FCR As Initial Therapy for CLL
? overall response rate of 95%
* CR70%
* PR15%
* NPR 10%
? 4y TTF69%
? Grade 3 to 4 neutropenia52%
FCR for Relapsed and Refractory CLL
? overall response rate 73%
* CR25%
* PR 32 %
* Nodular PR 16 %
? Estimated OS 42m
? Grade 3 to 4 neutropenia62%
CLL7 protocol of the GCLLSG/FCLLSG
Patients at Binet stage A or B without symptoms
Phase II trial of subcutaneous alemtuzumab in untreated CLL (n=41)
? Alemtuzumab 3-10-30 mg thrice weekly to 18 weeks
? Acyclovir, cotrimoxazole, fluconazole
? RR 81%, CR 19%
* 95% CR in PB
* 45% CR in BM (87% RR)
* Node response in 87%
? TTF not reached at 18+ months
? Few first dose reactions
Low-dose subcutaneous alemtuzumab for refractory CLL
? alemtuzumab (10 mg t.i.w. for 18 weeks)
? 50% response rate
? 25% complete response
? favourable toxicity profile
Rituximab and alemtuzumab combination as salvage therapy in CLL
Lumiliximab (IDEC-152)
? PRIMATIZED(r) monoclonal antibody
? Specifically binds to CD23
? Binds Fc?RI and Fc?RII and mediates ADCC
? Binds complement and mediates CDC
Phase I trial of Lumiliximab (IDEC-152)
? Dose escalation: 125, 250, 375, 500mg/m2 weekly; 500 mg/m2 t.i.w. x 1 then weekly x 3; 500mg/m2 t.i.w. x 4
? Patients with progressive CLL; median 3 regimens
? Toxicities - fatigue, nausea, headache, cough
? DLT - neutropenia, headache
? Reduced lymphocytes in 24/25
? Nodes also decreased
Hematopoietic Stem Cell Transplantation
Autotransplantation
Allotransplantation
Non-myeloablative transplantation
慢性淋巴细胞性白血病
治疗研究进展
Diagnosis
? Diagnostic investigations
* Blood count. lymphocytosis of >5 ×109/l.
* Lymphocyte morphology
* Immunophenotyping
? Additional investigations
* bone marrow aspirate and trephine biopsy
* Lymph node biopsy
* Cytogenetic/ FISH analysis.
* Computed tomography scan and/or ultrasound
Scoring system for the diagnosis of CLL
Scores in CLL are usually >3, in other B-cell malignancies the scores are usually <3
Prognostic factors in chronic lymphocytic leukaemiSurvival based on IgV gene
mutation and CD38 expression
Staging systems in chronic lymphocytic leukaemia
Management of CLL
Indications for treatment
? Progressive marrow failure: the development or worsening of anaemia and/or thrombocytopenia
? Massive (>10 cm) or progressive lymphadenopathy
? Massive (>6 cm) or progressive splenomegaly
? Progressive lymphocytosis
* >50% increase over 2 months
* Lymphocyte doubling time <6 months
? Systemic symptoms
* Weight loss >10% in previous 6 months
* Fever >38C for >=2 weeks
* Extreme fatigue
* Night sweats
? Autoimmune cytopenias
Response criteria
Poor prognosis of advanced, relapsed CLL
? First-line Therapy
* Fludarabine ± rituximab
* Chlorambucil (pulse or continuous) ± prednisone
* Cyclophosphamide ± prednisone
* CVP (cyclophosphamide, vincristine, prednisone)
* FC (fludarabine, cyclophosphamide) ± rituximab
? Second-line Therapy
* Alemtuzumab
* PC (pentostatin, cyclophosphamide) ± rituximab
* Chemotherapy (as above) ± rituximab or alemtuzumab
? Radiotherapy
* Splenic irradiation
* Radiotherapy for bulky nodal masses
? Splenectomy
* Symptomatic massive splenomegaly.
* Refractory cytopenias.
* Autoimmune cytopenias
* Hypersplenism
Chemoimmunotherapy
? Alkylating agents.
* Chlorambucil+/-prednisolone/prednisone
* high-dose chlorambucil
* CVP
* CHOP
? Purine analogues
* Fludarabine
* Cladribine
* Pentostatin
? Monoclonal antibodies
* Alemtuzumab
* Rituximab
Fludarabine
CALGB 9011
? Fludarabine 25mg/m2ivD1-5
? Chlorambucil 40 mg/m2 po
? Fludarabine 20mg/m2ivD1-5 plus Chlorambucil 20 mg/m2 po
The treatments were repeated every 28 days for a maximum of 12 cycles
Fludarabine versus chlorambucil in untreated CLL
Fludarabine versus chlorambucil in untreated CLL
Fludarabine versus chlorambucil in untreated CLL
CLL4 protocol of the GCLLSG
for advanced CLL
CLL4 protocol of the GCLLSG
FC versus F in first line therapy: response*
CLL4 protocol: progression-free
and event-free survival
Cladribine versus chlorambucil in CLL
Pentostatin
Monoclonal antibodies
Therapeutic efficacy of alemtuzumab
and rituximab as single agents in CLL
Rituximab monotherapy in relapsed/refractory CLL/SLL
CALGB 9712 protocol
Response to rituximab + fludarabine
Rituximab + fludarabine : progression-free survival
Rituximab + fludarabine : overall survival
Rituximab + fludarabine versus fludarabinein CLL
FCR As Initial Therapy for CLL
? overall response rate of 95%
* CR70%
* PR15%
* NPR 10%
? 4y TTF69%
? Grade 3 to 4 neutropenia52%
FCR for Relapsed and Refractory CLL
? overall response rate 73%
* CR25%
* PR 32 %
* Nodular PR 16 %
? Estimated OS 42m
? Grade 3 to 4 neutropenia62%
CLL7 protocol of the GCLLSG/FCLLSG
Patients at Binet stage A or B without symptoms
Phase II trial of subcutaneous alemtuzumab in untreated CLL (n=41)
? Alemtuzumab 3-10-30 mg thrice weekly to 18 weeks
? Acyclovir, cotrimoxazole, fluconazole
? RR 81%, CR 19%
* 95% CR in PB
* 45% CR in BM (87% RR)
* Node response in 87%
? TTF not reached at 18+ months
? Few first dose reactions
Low-dose subcutaneous alemtuzumab for refractory CLL
? alemtuzumab (10 mg t.i.w. for 18 weeks)
? 50% response rate
? 25% complete response
? favourable toxicity profile
Rituximab and alemtuzumab combination as salvage therapy in CLL
Lumiliximab (IDEC-152)
? PRIMATIZED(r) monoclonal antibody
? Specifically binds to CD23
? Binds Fc?RI and Fc?RII and mediates ADCC
? Binds complement and mediates CDC
Phase I trial of Lumiliximab (IDEC-152)
? Dose escalation: 125, 250, 375, 500mg/m2 weekly; 500 mg/m2 t.i.w. x 1 then weekly x 3; 500mg/m2 t.i.w. x 4
? Patients with progressive CLL; median 3 regimens
? Toxicities - fatigue, nausea, headache, cough
? DLT - neutropenia, headache
? Reduced lymphocytes in 24/25
? Nodes also decreased
Hematopoietic Stem Cell Transplantation
Autotransplantation
Allotransplantation
Non-myeloablative transplantation
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