Clinical Observation Of Gleevec Combined With Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation For Treatment Of CML

BACKGROND & AIMSChronic myelogenous leukemia (CML) is a malignant colonial disease originated from pluripotential hemapoietic stem cells, which takes up for 20% of all kinds of luekemias. The characteristic cytogenetic abnormality is the formation of Ph chromosome and the BCR/ABL protein. Allogenetic hemapoietic stem cell transplantation is considered to be the curative therapeutic method for CML. However, it is more effective in CP patients than AP or BC ones. Gleevec is honored to be one of the milestones in the progression of treatment of CML and has become the first line treatment for patients of any phase. The major pathology of CML is the activity of tyrosine kinase of P210 protein coded by BCR-ABL fusion gene. And Gleevec can inhibit the activity of tyrosine kinase and therefore block the proliferation of leukemia cells. Many clinical researches showed that Gleevec had higher Hematologic and cytogenetic responses than other medications and it could make the patients of relapse after hematopoietic Stem Cell Transplantation (HSCT) get another remission. However, the efficacy and safety of combination of the above two treatments still require more investigation. This report will evaluate the efficacy and safety of combination of Gleevec and myeloablative allogenetic hemapoieticstem cell transplantation for the treatment of 9 CML patients.METHODSWe collect the information of 9 CML patients, including the phase of disease, dosage, side effects of Gleevec and results of bone marrow morphology, karyotype and BCR/ABL infusion gene examination after administration and on the day +30 and +90 post transplantation. Based on these, we analyze retrospectively the efficacy and safety of the combination of Gleevec and myeloablative HSCT. SPSS 13.0 is used in the statistic analysis.RESULTSIn the 9 cases, 5 were of chronic phase (CP), 2 accelerated phase (AP) and 2 blast crisis (BC). With the treatment of Gleevec(400-600mg/d) for 3 to 6 months, all the complaint such as fever, fatigue, abdominal distention, poor vision and so on disappeared. Only an AP case, except which all the others reached complete hematological response (CHR), still had spleenomegaly. All the 9 cases got to bone marrow remission. The Ph chromosome remains positive in 8 cases and the BCR/ABL gene turned to be negative in 2 cases. All the 4 cases with progressive phase returned to the chronic phase again. After administration of Gleevec, 5 cases suffered from hematological toxicity (4 for grade I; 1 for grade II); 4 cases had gastroenteritis; 2 cases complained of arthralgia and myalgia ; 1 case showed edema. After the treatment of Gleevec for 3-6 months, all the 9 cases received allogeneic HSCT, in which sibling donors for 7 cases and unrelated donors for 2 cases. And the BUCY2 conditioning regimen was given to all of them. The WBC count reached the minimum level (0.1 - 0.2)×10~9/L on the day between +5 to +7d. The median time for neutrophil >0.5×10~9/L was 12 days (8-26 days); that for Platelet > 20×10~9/L was 20 days(8-25 days). No conditioning regimen related toxicities were observed. Grade I acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 3 and 1 case respectively. The spleen was only palpable in the patient with spleenomegaly before transplantation. All patients turned to complete bone marrow remission (BMR) andnormal karyotype. BCR/ABL gene detection showed positive in two cases, weak positive in four and negative in three. DNA short tandem repeat sequences anaglysis (STR) showed complete donor chimerism. Unfortumately, one patient with blast crisis before transplantation relapsed three months after transplantation with myeloblasts high up 18.5% in the bone marrow smear and Ph chromosome and BCR/ABL gene positive again. And he died 28 days later after relapse. All the other cases maintained BMR and normal karyotype without any positive physical manifestation except the relapsed patient in the reassessment on +90d. And BCR/ABL gene detection appeared to be negative in 7 cases and weak positive in 1. The 8 cases were followed up by median time 26 months (11 to 31 months) till now. They maintained the states of complete donor chimerism and BCR/ABL negative. The longest survivor lived for 31 months till now without relapse. The 2-year survival rate was (88.9+10.5)% by Kaplan-meier survival analysis.CONCLUSIONSGleevec can help the patient get into hematological response, even cytogenetic response and make them maintain a better pretransplant state, so that earn time for transplant. Gleevec is safe in the CML patients and don't delay the engraftment or hemapoietic reconstruction. For the CML patients of progressive stage, treatment with Gleevec firstly and then allogenetic HSCT is effective, for which can reach the goal of decreasing the level of Ph positive leukemia cells. The treatment of combination of Gleevec and allogenetic HSCT can be administrated safely in all CML patients and will decrease the rates of relapse and treatment-related complications. However, this observation is of inadequate patients or follow-up, so the efficacy and safety of the combination of Gleevec and allogenetic HSCT need further investigation.