PREDICTING RELAPSE OF CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED BY ALLOGENEIC STEM CELL TRANSPLANTATION
The invention is directed to a prognostic indicator for CLL patients who have undergone an allogeneic stem cell transplant (SCT). The indicator is based on a method of monitoring levels and changes in levels of correlating clonotypes of the CLLs at successive time points. The prognostic indicator applies to patients who have survived for at least one year from an allogeneic SCT and includes criteria based on the following two measurements: (a) frequency of CLL correlating clonotypes (e.g. in terms of number per 10 6 clonotypes) in an initial clonotype profile (from peripheral blood), and (b) fold change in such CLL correlating clonotype number between such initial measurement and a successively measured clonotype profile.
1 . A method of predicting relapse of a chronic lymphocytic leukemia patient after treatment by allogeneic stein cell transplantation, the method comprising the steps of:
(a) obtaining at least one year after an allogeneic stem cell transplantation successive samples each containing B lymphocytes from the chronic lymphocytic leukemia patient;
(b) generating a clonotype profile from recombined immunoglobulin genes from each sample;
(c) determining numbers of clonotypes correlated with the chronic lymphocytic leukemia in each sample; and
(d) predicting a relapse in the patient whenever in successive clonotype profiles (i) there are at least twenty-five correlating clonotypes per million clonotypes and (ii) there is at least a two-fold increase in the number of correlating clonotypes.
2 . The method of claim 1 wherein said successive samples are separated in time by at least one week.
3 . The method of claim 1 wherein said successive samples are separated in time by at least two weeks.
4 . The method of claim 3 wherein said successive samples are separated in time by less than one year.
5 . The method of claim 4 wherein said successive samples are each taken from blood.
6 . The method of claim 5 wherein said relapse is predicted whenever in said successive clonotype profiles (i) there are at least fifty said correlating clonotypes per million clonotypes and (ii) there is at least a two-fold increase in said number of correlating clonotypes.
7 . The method of claim 1 wherein each of said clonotype profiles contains at least 10 5 clonotypes.
8 . The method of claim 7 wherein each of said clonotype profiles is generated from at least 10 6 sequence reads.
9 . A method of treating a patient suffering from chronic lymphocytic leukemia (CLL) comprising the steps of:
(a) performing an allogeneic stem cell transplantation on the patient;
(b) obtaining at least one year after the allogeneic stem cell transplantation successive samples each containing B lymphocytes from the patient;
(c) generating a clonotype profile from recombined immunoglobulin genes from each sample;
(d) determining numbers of clonotypes correlated with the chronic lymphocytic leukemia in each sample; and
(e) assessing the patient to be free of CLL whenever in successive clonotype profiles (i) there are less than twenty-five correlating clonotypes per million clonotypes and (ii) there is less than a two-fold increase in the number of correlating clonotypes.
10 . The method of claim 9 wherein said successive samples are separated in time by at least one week.
11 . The Method of claim 9 wherein said successive samples are separated in time by at least two weeks.
12 . The method of claim 11 wherein said successive samples are separated in time by less than one year.
13 . The method of claim 12 wherein said successive samples are each taken from blood.
14 . The method of claim 13 wherein said relapse is predicted whenever in said successive clonotype profiles (i) there are less than 10 said correlating clonotypes per million clonotypes and (ii) there is less than a two-fold increase in said number of correlating clonotypes.