Leukemia: Signal Conduction cut

30. September 2009

Hope for patients with an acute myeloid leukemia: Oncologists in Marburg/Germany were able to show that – with this type of blood cancer – Sorafenib helps, a drug already approved for liver- and kidney cancer.

To fight cancer cells with pinpoint accuracy is a wish nearly all physicians share. They already succeed to do so for several years in patients with myeloid leukemia (CML). With the aid of the specifically effective drug Imatinib, the chances of survival for CML patients improved dramatically. Up to now there was no such treatment opportunity for patients with acute myeloid leukemia (AML). Results of a team of researchers at Marburg University now suggest that also part of the AML patients might be able to profit from a similarly targeted drug.

Like in CML, precursor cells of the granulocytes and monocytes proliferate uncontrolled. If not treated, this disease progresses rapidly and results in death within a few weeks. A little less than half of the AML patients can be healed with chemotherapy or by stem cell transplantation. Particularly those patients with an additional mutation of the FLT-3 gene in the precursor cells commonly relapse. As the group around Andreas Burchert reported in the professional magazine Blood, these patients strongly respond to a monotherapy with the drug Sorafenib. “Within one day, the number of leukemic cells halved and vanished after three to seven days completely from the blood of the patient” says Burchert.

Permanent signal brings uncontrolled multiplication of cells

The oncologist treated a total of six AML patients with a FLT3-gene mutation solely with the active ingredient. All patients had had a relapse before, three after primary chemotherapy, the others after stem cell transplantation. FLT3 carries the construction manual for a protein which is located on the surface of blood stem cells regulating their multiplication. Normally this so-called receptor-tyrosine kinase receives signals from outside and passes them on into the cells which cause them again to proliferate. “If we are looking at the mutated form of the receptor that happens without signals from outside as well”, explains Burchert. “The protein is switched on permanently so to speak and causes the cells to proliferate all the time.”

Sorafenib interrupts the permanent processing of the signal by accumulating on the receptor and thus blocking it. The active agent (brand name: Nexavar) is classified tyrosine kinase inhibitor and is already used for therapy of liver- and kidney cancer. The side effects kept within reasonable limits in patients with AML: The physicians in Marburg observed skin redness, pains in hands and fee as well as diarrhea during treatment.

After the fast disappearance of the leukemic blood cells, the fate of the patients developed very differently. In two patients, despite the treatment with Sorafenib, the cancer cells reappeared, one died 216 days after beginning of the treatment, and the second one was saved by stem cell transplantation. The four remaining patients did not show a resistance against the drug. But two of those patients died after 58 respectively after 221 days from different diseases which most likely had nothing to do with the AML.

Sorafenib shows surprising effect

Particularly impressive – according to the oncologist – is the fact that the two other AML patients, with a relapse after bone marrow transplantation did not show any signs of a return relapse even eight months after beginning the therapy with Sorafenib. This unusual positive course Buchert explains as follows: “Probably the tyrosine kinase inhibitor has a second effect: It might see to it that immune cells of the transplanted bone marrow additionally fight within a so-called ‘donor-against-leukemia’ reaction the still remaining leukemia cells.

Since he now wants to further document this he plans a clinical study with a larger number of patients. Within this placebo-controlled study AML patients with a mutated FLT3 gene will receive Sorafenib prophylactically after bone marrow transplantation in order to avoid relapses from the start. Burchert hopes that the study will begin end of this year.

Other experts like Professor Hubert Serve, director at the Medical Hospital II at Frankfurt University also recommend such a study but are skeptical nonetheless whether AML patients really can be healed by using Sorafenib as a monotherapeutic agent. “Up to now a single substance was never able to prevent a relapse of AML patients in the long run”, says Serve. “Contrary to CML, AML is not a monogenetic disease.” In addition to the FLT3 mutation, a number of additional chromosomal and genetic mutations are known which have to appear in combination in order to actually trigger AML.

Sorafenib extends time slot for bone marrow transplantation

That is why the oncologist in Frankfurt puts his hopes on a combination therapy with Sorafenib plus other therapeutics. Currently Serve heads a phase II study covering entire Germany where 200 newly diagnosed AML patients are treated with Sorafenib in addition to chemotherapy. He expects results mid of next year. Even if Sorafenib by itself might most likely not cause a healing, it still might buy time says Serve. “Looking for a suitable bone marrow donor sometimes takes 2-3 months. Especially for patients with a mutated FLT3 gene, Sorafenib might contribute decisively to keeping the leukemia under control until the transplantation.”

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