Final Report Summary - HAIRY CELL LEUKEMIA (Genetics-driven targeted therapy of Hairy Cell Leukemia)
Hairy Cell Leukemia (HCL) is a rare tumor initially sensitive to chemotherapy, but up to 50% of patients eventually relapses and becomes less responsive to these drugs, which are also quite toxic to the normal bone marrow and to the immune system. Less toxic and more "intelligent" drugs (killing only the leukemic cells and sparing the normal ones) are highly desirable in HCL, but its low incidence has made HCL an orphan in the world of cancer research.
However, a few years ago we identified the genetic cause of HCL in the mutation of one of our genes, called BRAF. We then used the funds awarded by the European Research Council to understand how the mutation of BRAF shapes the particular features of this leukemia (for example the peculiar hairy morphology) and how to harness this understanding to better cure HCL.
We addressed these issues by studying in the laboratory leukemic cells purified from the blood and/or the bone marrow of the HCL patients. By exposing these cells to BRAF inhibitors (i.e. drugs blocking the action of mutated BRAF), we discovered that mutated BRAF is responsible for many characteristics of HCL, in particular for: i) its hairy projections (the leukemic cells become "bald" after blocking mutated BRAF); ii) the expression of molecular markers used in the diagnosis of HCL; and, importantly, iii) the escape from apoptosis (a programmed cell death), which causes the growth of the leukemia in the body of the patients (cell apoptosis is, instead, restored by blocking mutated BRAF).
Such progress obtained in the laboratory translated into a progress also in the HCL patients. Indeed, we used vemurafenib or dabrafenib, two BRAF inhibitors that can be taken simply by mouth, to treat, as outpatients, HCL patients not responding anymore to the conventional chemotherapy, which is usually given intravenously in the hospital. The results on 38 such patients are impressive: all patients except one responded by normalizing the low blood counts (hemoglobin, neutrophils and platelets) produced by the leukemic invasion of the bone marrow; some of these patients (about a third) even got a complete remission, i.e. cleared the disease almost completely from the bone marrow and the spleen (the other main organ affected by HCL). The BRAF inhibitors vemurafenib or dabrafenib caused some side effects in the HCL patients (mostly on the skin and the joints), but these were manageable and, importantly, did not include the dangerous ones of conventional chemotherapy (i.e. suppression of the blood counts and immune-depression). However, patients tended to relapse several months to a few years after the last drug dose (which was given for up to 16 weeks), because not each and every leukemic cell had been killed by vemurafenib or dabrafenib, and these cells represent the reservoir for subsequent leukemia regrowth. Thus, on the one hand we tried to better understand in the laboratory the specific mechanisms underlying resistance to vemurafenib and dabrafenib, and on the other hand, we improved in the clinic the results obtained with BRAF inhibitors by giving them to patients in combination with other "intelligent" drugs, such as rituximab (which boost the immune response against HCL), or an inhibitor of MEK (a gene which is activated by BRAF and thus should be blocked by BRAF inhibitors, but in fact it finds the way to become reactivated in some HCL patients taking vemurafenib or dabrafenib). Indeed, both these two-drug combinations increased to 80-95% the rate of complete remissions in patients previously treated with chemotherapy; in particular, vemurafenib plus rituximab proved to be such a strikingly active treatment that we plan to test it in newly diagnosed patients in a direct comparison to chemotherapy with the aim to define which one of these two treatment strategies is the most effective and the least toxic.
However, a few years ago we identified the genetic cause of HCL in the mutation of one of our genes, called BRAF. We then used the funds awarded by the European Research Council to understand how the mutation of BRAF shapes the particular features of this leukemia (for example the peculiar hairy morphology) and how to harness this understanding to better cure HCL.
We addressed these issues by studying in the laboratory leukemic cells purified from the blood and/or the bone marrow of the HCL patients. By exposing these cells to BRAF inhibitors (i.e. drugs blocking the action of mutated BRAF), we discovered that mutated BRAF is responsible for many characteristics of HCL, in particular for: i) its hairy projections (the leukemic cells become "bald" after blocking mutated BRAF); ii) the expression of molecular markers used in the diagnosis of HCL; and, importantly, iii) the escape from apoptosis (a programmed cell death), which causes the growth of the leukemia in the body of the patients (cell apoptosis is, instead, restored by blocking mutated BRAF).
Such progress obtained in the laboratory translated into a progress also in the HCL patients. Indeed, we used vemurafenib or dabrafenib, two BRAF inhibitors that can be taken simply by mouth, to treat, as outpatients, HCL patients not responding anymore to the conventional chemotherapy, which is usually given intravenously in the hospital. The results on 38 such patients are impressive: all patients except one responded by normalizing the low blood counts (hemoglobin, neutrophils and platelets) produced by the leukemic invasion of the bone marrow; some of these patients (about a third) even got a complete remission, i.e. cleared the disease almost completely from the bone marrow and the spleen (the other main organ affected by HCL). The BRAF inhibitors vemurafenib or dabrafenib caused some side effects in the HCL patients (mostly on the skin and the joints), but these were manageable and, importantly, did not include the dangerous ones of conventional chemotherapy (i.e. suppression of the blood counts and immune-depression). However, patients tended to relapse several months to a few years after the last drug dose (which was given for up to 16 weeks), because not each and every leukemic cell had been killed by vemurafenib or dabrafenib, and these cells represent the reservoir for subsequent leukemia regrowth. Thus, on the one hand we tried to better understand in the laboratory the specific mechanisms underlying resistance to vemurafenib and dabrafenib, and on the other hand, we improved in the clinic the results obtained with BRAF inhibitors by giving them to patients in combination with other "intelligent" drugs, such as rituximab (which boost the immune response against HCL), or an inhibitor of MEK (a gene which is activated by BRAF and thus should be blocked by BRAF inhibitors, but in fact it finds the way to become reactivated in some HCL patients taking vemurafenib or dabrafenib). Indeed, both these two-drug combinations increased to 80-95% the rate of complete remissions in patients previously treated with chemotherapy; in particular, vemurafenib plus rituximab proved to be such a strikingly active treatment that we plan to test it in newly diagnosed patients in a direct comparison to chemotherapy with the aim to define which one of these two treatment strategies is the most effective and the least toxic.