Ignite Creation Date:
2024-05-05 @ 5:02 PM
Last Modification Date:
2024-10-26 @ 9:27 AM
Study NCT ID:
NCT00373594
Status:
COMPLETED
Last Update Posted:
2010-06-22
First Post:
2006-09-07
Brief Title:
Therapy for Chronic Cold Agglutinin Disease
Sponsor:
University of Bergen
Organization:
University of Bergen
Study Overview
Official Title:
Therapy for Chronic Cold Agglutinin Disease A Prospective Non-randomized International Multicentre Study on the Safety and Efficacy of Rituximab in Combination With Fludarabine
Status:
COMPLETED
Status Verified Date:
2010-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Chronic cold agglutinin disease CAD is a type of autoimmune hemolytic anemia anemia due to destruction of red blood cells by abnormal antibodies Almost all patients also suffer from cold-induced disturbances of blood circulation The purpose of this study is to assess the efficacy and safety of combination therapy with rituximab an antibody against B lymphocytes and fludarabine a cytotoxic drug for CAD Another aim is to try to assess whether these agents in combination are better than single agent therapy with rituximab
Detailed Description:
1 Background
Chronic cold agglutinin disease CAD is mediated by monoclonal cold-reactive autoantibodies that bind to erythrocyte surface antigens causing haemagglutination and complement-mediated haemolysis Anaemia is severe Hb 80 gdL or lower in one-third of patients and complement-induced exacerbation during febrile illness occurs frequently 1-3 Cold-induced circulatory symptoms are present in more than 90 of patients and may be disabling 1 CAD not associated with overt lymphoma or other disease has traditionally been classified as primary or idiopathic However a lymphoproliferative bone marrow disorder can be demonstrated by flow cytometry in 90 and by histology in approximately 75 of these patients characterized by clonal proliferation of CD20κ B-cells 145 The histological features are those of lymphoplasmacytic lymphoma in about 50 of the patients 1
Many standard therapies used in other autoimmune diseases or indolent lymphomas are inefficient eg corticosteroids alkylating agents interferon-α and probably purine analogue single agent therapy 16-8 Treatment with the chimeric monoclonal anti-CD20 antibody rituximab has been shown in prospective studies to induce remission in more than half of patients 910 Almost all responses were partial however and the median response duration was less than one year Further studies are warranted therefore in order to explore the possibilities for increasing the response rate and duration
The purine analogues cladribine and fludarabine are not cyclus dependent and they have yielded partial response rates of 30-75 and complete response rates of 3-10 in lymphoplasmacytic lymphoma 1112 Although probably clinically inefficient as monotherapy in most CAD patients clinical effect of fludarabine has been reported in a single case 13 and cladribine has been shown to induce tumour reduction even in this condition 8 In lymphoplasmacytic lymphoma purine analogue and rituximab combination therapy has resulted in higher response rates and more prolonged remissions as compared to purine analogue single agent therapy 12 The combination has produced favourable results in some patients with the related condition cryoglobulinaemia type I 14 Fludarabine has induced autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia but such events have not been reported in CAD patients 1315 Moreover there are reasons to assume that rituximab therapy will further reduce the risk of this adverse effect of fludarabine 16
2 Clinical study
The clinical study is a prospective non-randomized multicentre study in order to investigate the efficacy and safety of rituximab and fludarabine combination therapy in patients with CAD The protocol has approved by the Regional Medical Research Ethics Committee of Southern Norway Norwegian Medicines Agency EudraCT nr 2004-002936-25 and Norwegian Social Science Data Services Privacy Issue Unit
21 Study objectives
The major study objective is to assess efficacy of rituximab and fludarabine in combination for patients with CAD
The second objective is to assess safety of rituximab and fludarabine in combination for patients with CAD
The third objective is to try to assess whether rituximab and fludarabine in combination are superior to rituximab monotherapy comparing patients who have received both therapies for CAD
22 Study design
A prospective non-randomized international multicentre study
Registration
Treatment
Day 1 Rituximab 375 mgm2 Day 1-5 Fludarabine orally 40 mgm2
Day 28 Rituximab 375 mgm2 Day 28-33 Fludarabine orally 40 mgm2
Day 56 Rituximab 375 mgm2 Day 56-60 Fludarabine orally 40 mgm2
Day 84 Rituximab 375 mgm2 Day 84-88 Fludarabine orally 40 mgm2
Evaluation
23 Dose adjustments
Doses of fludarabine will be adjusted in case of haematological toxicity or renal insufficiency For details see chapter 43
24 Study population
241 Inclusion criteria
1 CAD diagnosis defined by the combination of -
1 Chronic haemolysis
2 Cold agglutinin titre 64
3 Positive direct antiglobulin test when performed with polyspecific antiserum negative or only weakly positive with anti-IgG and strongly positive with anti-C3d
2 The presence of a clonal B-cell lymphoproliferative disorder defined by -
1 Monoclonal IgMκ band by serum electrophoresis and immunofixation and
2 Lymphocyte phenotype with κλ-ratio 35 and CD20κ co-expression using flowcytometric immunophenotyping of bone marrow aspirates
3 Clinical symptoms requiring treatment such as anaemia or Raynaud-like symptoms
4 Informed consent
242 Exclusion criteria
1 An aggressive lymphoma
2 Blood lymphocyte count 50 109L
3 Non-lymphatic malignant disease other than basal cell carcinoma
4 Contra-indications to rituximab or fludarabine therapy
5 Inability to cooperate
25 Response criteria
Responses will be assessed using the following previously published definitions 8917
Complete response CR Absence of anemia no signs of hemolysis no clinical symptoms of CAD undetectable serum monoclonal protein and no signs of clonal lymphoproliferation by bone marrow histology immunohistochemistry and flow cytometry
Partial response PR Stable increase in Hb levels by at least 20 gdL or to the normal range combined with a reduction of serum IgM concentrations by at least 50 or to the normal range improvement of clinical symptoms and transfusion independency
Non-response NR Patients not meeting the criteria for CR or PR
3 Patient examination at inclusion
31 History Clinical and radiological examination
Year of first occurrence of clinical symptoms is registered along with data on haemolytic anaemia circulatory symptoms cold- or fever-induced exacerbation previous therapies lymph node enlargement and spleen size clinical assessment Chest radiograph and abdominal ultrasonography should be done if not performed already during the last four months
32 Blood tests
Haemolysis is detected and quantified based on Hb reticulocyte count x 109L LDH bilirubin and haptoglobin These measurements should be done twice during the last two months before treatment
The following haematological biochemical and immunological assessments should be done once at inclusion
WBC leukocyte differential count platelet count
Iron transferrin or TIBC ferritin cobalamine and folate
CRP
Quantification of IgM IgG and IgA
Serum electrophoreses with immunofixation Immunofixation must be performed even if visual assessment of agarose electrophoreses does not show any monoclonal band
Cold agglutinin titre
Specific direct antiglobulin test DAT direct Coombs test ie using polyspecific antiserum anti-C3d and anti-IgG
Complement assessments C3 C4 and CH50
CMV and VZV antibodies
Freezing of 5 ml serum
Freezing of 5 ml EDTA-blood for possible later DNA-based studies
RemarksSee protocol text
33 Bone marrow examinations
Centres outside Norway should follow the guidelines listed below Norwegian centres should refer to the Norwegian protocol version
I Morphologic assessment of bone marrow aspirate is performed according to the routines of the participating centre
II A bone marrow trephine biopsy should be obtained according to the routines of the department Morphological and immunohistochemical assessments are to be done at a university pathology laboratory by an experienced haematopathologist If possible a fresh biopsy specimen should be preferred
III Flow-cytometric immunophenotyping of bone marrow aspirate should be done at a university hospital laboratory Cells should be washed at 37oC in order to remove cold agglutinins using the previously published procedure 5 Appendix 1 or an equally satisfactory method The antibody panel should comprise CD19 CD20 CD5 kappa lambda and preferably also IgM and IgG The kappalambda ratio should be calculated CD20 expression is registered semi-quantitatively as 0 or
IV If possible 5 ml bone marrow aspirate should be frozen at -70oC for the purpose of later DNA-based examinations
4 Therapy
41 Treatment schedule
Day 1 Rituximab 375 mgm2 Day 1-5 Fludarabine orally 40 mgm2
Day 28 Rituximab 375 mgm2 Day 28-33 Fludarabine orally 40 mgm2
Day 56 Rituximab 375 mgm2 Day 56-60 Fludarabine orally 40 mgm2
Day 84 Rituximab 375 mgm2 Day 84-88 Fludarabine orally 40 mgm2
42 Administration and precautions
Administration and monitoring of rituximab and fludarabine therapy should be in accordance with the manufacturers recommendations the official regulations that apply in the participating country and the routine procedures of the participating unit
43 Dose adjustments
431 Haematological toxicity If ANC10x109L andor platelets75x109L at day 1 of any cycle treatment should be delayed for up to 2 weeks and fludarabine dose should be reduced to 30 mgm2 in the remaining cycles Myelosuppression of the same degree in the subsequent cycles should result in a reduction of the fludarabine dose to 20 mgm2
Adjustments of the rituximab dose should not be done due to myelosuppression
432 Renal insufficiency In patients with a creatinine clearance between 30-60 mlmin the fludarabine dose should be reduced to 20 mgm2 Patients with a creatinine clearance below 30 mlmin are not eligible for the study
5 Evaluation
51 Follow-up during treatment
The parameters listed below must be recorded before each therapy cycle
Clinical condition possible adverse effects need for transfusion Hb reticulocytes count WBC including differential count platelet count CRP LDH ASAT ALAT alkaline phosphatase urea creatinine bilirubin and haptoglobin
Any adverse effects of fludarabine are registered in CRF 2 Appendix 3 Any adverse effects of rituximab are registered in CRF 3 Appendix 4 In case of death or other serious events these should be reported without delay to S Berentsen or G Tjønnfjord as well as the relevant national authorities according to regulations that apply in the participating country
52 Follow-up after treatment first six months
A The following measurements must be done monthly during the first six months after the last cycle of therapy
I All measurements listed in Paragraph 51 II Quantification of immunoglobulin classes In case of reduction of a previously elevated IgM level to the normal range serum electrophoresis with immunofixation should be performed at the next visit
III Number of blood transfusions after the previous registration
B At the first visit after cessation of therapy a new bone marrow biopsy is performed in those patients where histological or immunohistochemical signs of a lymphoproliferative disorder were present at baseline If a lymphoproliferative bone marrow involvement could be detected at baseline by flow cytometry only flow-cytometric immunophenotyping is also repeated at this visit
C Bone marrow examinations should also be repeated four months after the last therapy cycle if the examinations three months before showed signs of lymphoma
53 Long-term follow-up
When more than six months have passed since cessation of treatment patients should be followed every third month for three years or until they need treatment again
Chronic cold agglutinin disease CAD is mediated by monoclonal cold-reactive autoantibodies that bind to erythrocyte surface antigens causing haemagglutination and complement-mediated haemolysis Anaemia is severe Hb 80 gdL or lower in one-third of patients and complement-induced exacerbation during febrile illness occurs frequently 1-3 Cold-induced circulatory symptoms are present in more than 90 of patients and may be disabling 1 CAD not associated with overt lymphoma or other disease has traditionally been classified as primary or idiopathic However a lymphoproliferative bone marrow disorder can be demonstrated by flow cytometry in 90 and by histology in approximately 75 of these patients characterized by clonal proliferation of CD20κ B-cells 145 The histological features are those of lymphoplasmacytic lymphoma in about 50 of the patients 1
Many standard therapies used in other autoimmune diseases or indolent lymphomas are inefficient eg corticosteroids alkylating agents interferon-α and probably purine analogue single agent therapy 16-8 Treatment with the chimeric monoclonal anti-CD20 antibody rituximab has been shown in prospective studies to induce remission in more than half of patients 910 Almost all responses were partial however and the median response duration was less than one year Further studies are warranted therefore in order to explore the possibilities for increasing the response rate and duration
The purine analogues cladribine and fludarabine are not cyclus dependent and they have yielded partial response rates of 30-75 and complete response rates of 3-10 in lymphoplasmacytic lymphoma 1112 Although probably clinically inefficient as monotherapy in most CAD patients clinical effect of fludarabine has been reported in a single case 13 and cladribine has been shown to induce tumour reduction even in this condition 8 In lymphoplasmacytic lymphoma purine analogue and rituximab combination therapy has resulted in higher response rates and more prolonged remissions as compared to purine analogue single agent therapy 12 The combination has produced favourable results in some patients with the related condition cryoglobulinaemia type I 14 Fludarabine has induced autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia but such events have not been reported in CAD patients 1315 Moreover there are reasons to assume that rituximab therapy will further reduce the risk of this adverse effect of fludarabine 16
2 Clinical study
The clinical study is a prospective non-randomized multicentre study in order to investigate the efficacy and safety of rituximab and fludarabine combination therapy in patients with CAD The protocol has approved by the Regional Medical Research Ethics Committee of Southern Norway Norwegian Medicines Agency EudraCT nr 2004-002936-25 and Norwegian Social Science Data Services Privacy Issue Unit
21 Study objectives
The major study objective is to assess efficacy of rituximab and fludarabine in combination for patients with CAD
The second objective is to assess safety of rituximab and fludarabine in combination for patients with CAD
The third objective is to try to assess whether rituximab and fludarabine in combination are superior to rituximab monotherapy comparing patients who have received both therapies for CAD
22 Study design
A prospective non-randomized international multicentre study
Registration
Treatment
Day 1 Rituximab 375 mgm2 Day 1-5 Fludarabine orally 40 mgm2
Day 28 Rituximab 375 mgm2 Day 28-33 Fludarabine orally 40 mgm2
Day 56 Rituximab 375 mgm2 Day 56-60 Fludarabine orally 40 mgm2
Day 84 Rituximab 375 mgm2 Day 84-88 Fludarabine orally 40 mgm2
Evaluation
23 Dose adjustments
Doses of fludarabine will be adjusted in case of haematological toxicity or renal insufficiency For details see chapter 43
24 Study population
241 Inclusion criteria
1 CAD diagnosis defined by the combination of -
1 Chronic haemolysis
2 Cold agglutinin titre 64
3 Positive direct antiglobulin test when performed with polyspecific antiserum negative or only weakly positive with anti-IgG and strongly positive with anti-C3d
2 The presence of a clonal B-cell lymphoproliferative disorder defined by -
1 Monoclonal IgMκ band by serum electrophoresis and immunofixation and
2 Lymphocyte phenotype with κλ-ratio 35 and CD20κ co-expression using flowcytometric immunophenotyping of bone marrow aspirates
3 Clinical symptoms requiring treatment such as anaemia or Raynaud-like symptoms
4 Informed consent
242 Exclusion criteria
1 An aggressive lymphoma
2 Blood lymphocyte count 50 109L
3 Non-lymphatic malignant disease other than basal cell carcinoma
4 Contra-indications to rituximab or fludarabine therapy
5 Inability to cooperate
25 Response criteria
Responses will be assessed using the following previously published definitions 8917
Complete response CR Absence of anemia no signs of hemolysis no clinical symptoms of CAD undetectable serum monoclonal protein and no signs of clonal lymphoproliferation by bone marrow histology immunohistochemistry and flow cytometry
Partial response PR Stable increase in Hb levels by at least 20 gdL or to the normal range combined with a reduction of serum IgM concentrations by at least 50 or to the normal range improvement of clinical symptoms and transfusion independency
Non-response NR Patients not meeting the criteria for CR or PR
3 Patient examination at inclusion
31 History Clinical and radiological examination
Year of first occurrence of clinical symptoms is registered along with data on haemolytic anaemia circulatory symptoms cold- or fever-induced exacerbation previous therapies lymph node enlargement and spleen size clinical assessment Chest radiograph and abdominal ultrasonography should be done if not performed already during the last four months
32 Blood tests
Haemolysis is detected and quantified based on Hb reticulocyte count x 109L LDH bilirubin and haptoglobin These measurements should be done twice during the last two months before treatment
The following haematological biochemical and immunological assessments should be done once at inclusion
WBC leukocyte differential count platelet count
Iron transferrin or TIBC ferritin cobalamine and folate
CRP
Quantification of IgM IgG and IgA
Serum electrophoreses with immunofixation Immunofixation must be performed even if visual assessment of agarose electrophoreses does not show any monoclonal band
Cold agglutinin titre
Specific direct antiglobulin test DAT direct Coombs test ie using polyspecific antiserum anti-C3d and anti-IgG
Complement assessments C3 C4 and CH50
CMV and VZV antibodies
Freezing of 5 ml serum
Freezing of 5 ml EDTA-blood for possible later DNA-based studies
RemarksSee protocol text
33 Bone marrow examinations
Centres outside Norway should follow the guidelines listed below Norwegian centres should refer to the Norwegian protocol version
I Morphologic assessment of bone marrow aspirate is performed according to the routines of the participating centre
II A bone marrow trephine biopsy should be obtained according to the routines of the department Morphological and immunohistochemical assessments are to be done at a university pathology laboratory by an experienced haematopathologist If possible a fresh biopsy specimen should be preferred
III Flow-cytometric immunophenotyping of bone marrow aspirate should be done at a university hospital laboratory Cells should be washed at 37oC in order to remove cold agglutinins using the previously published procedure 5 Appendix 1 or an equally satisfactory method The antibody panel should comprise CD19 CD20 CD5 kappa lambda and preferably also IgM and IgG The kappalambda ratio should be calculated CD20 expression is registered semi-quantitatively as 0 or
IV If possible 5 ml bone marrow aspirate should be frozen at -70oC for the purpose of later DNA-based examinations
4 Therapy
41 Treatment schedule
Day 1 Rituximab 375 mgm2 Day 1-5 Fludarabine orally 40 mgm2
Day 28 Rituximab 375 mgm2 Day 28-33 Fludarabine orally 40 mgm2
Day 56 Rituximab 375 mgm2 Day 56-60 Fludarabine orally 40 mgm2
Day 84 Rituximab 375 mgm2 Day 84-88 Fludarabine orally 40 mgm2
42 Administration and precautions
Administration and monitoring of rituximab and fludarabine therapy should be in accordance with the manufacturers recommendations the official regulations that apply in the participating country and the routine procedures of the participating unit
43 Dose adjustments
431 Haematological toxicity If ANC10x109L andor platelets75x109L at day 1 of any cycle treatment should be delayed for up to 2 weeks and fludarabine dose should be reduced to 30 mgm2 in the remaining cycles Myelosuppression of the same degree in the subsequent cycles should result in a reduction of the fludarabine dose to 20 mgm2
Adjustments of the rituximab dose should not be done due to myelosuppression
432 Renal insufficiency In patients with a creatinine clearance between 30-60 mlmin the fludarabine dose should be reduced to 20 mgm2 Patients with a creatinine clearance below 30 mlmin are not eligible for the study
5 Evaluation
51 Follow-up during treatment
The parameters listed below must be recorded before each therapy cycle
Clinical condition possible adverse effects need for transfusion Hb reticulocytes count WBC including differential count platelet count CRP LDH ASAT ALAT alkaline phosphatase urea creatinine bilirubin and haptoglobin
Any adverse effects of fludarabine are registered in CRF 2 Appendix 3 Any adverse effects of rituximab are registered in CRF 3 Appendix 4 In case of death or other serious events these should be reported without delay to S Berentsen or G Tjønnfjord as well as the relevant national authorities according to regulations that apply in the participating country
52 Follow-up after treatment first six months
A The following measurements must be done monthly during the first six months after the last cycle of therapy
I All measurements listed in Paragraph 51 II Quantification of immunoglobulin classes In case of reduction of a previously elevated IgM level to the normal range serum electrophoresis with immunofixation should be performed at the next visit
III Number of blood transfusions after the previous registration
B At the first visit after cessation of therapy a new bone marrow biopsy is performed in those patients where histological or immunohistochemical signs of a lymphoproliferative disorder were present at baseline If a lymphoproliferative bone marrow involvement could be detected at baseline by flow cytometry only flow-cytometric immunophenotyping is also repeated at this visit
C Bone marrow examinations should also be repeated four months after the last therapy cycle if the examinations three months before showed signs of lymphoma
53 Long-term follow-up
When more than six months have passed since cessation of treatment patients should be followed every third month for three years or until they need treatment again
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None