Study Of Clinical Treatment Of Chronic Myeloid Leukemia

Part one Subsequent responses to nilotinib for patients in chronicmyeloid leukemia chronic phase(CML-CP) with dissatisfied efficacy toimatinibObjectiveTo compare the molecular efficacy of nilotinib(N ilot) in patients with diagnosed chronic phase chronic myeloid leukemia(CML-CP) who are dissatisfactory to imatinib(IM) and analyze the prognostic factors.Methods89 CML-CP patients from February, 2004 to July 2014 achieved dissatisfied efficacy during IM therapy and changed to N ilot therap y. 60 were male and 29 were female. Patients in a warning condition were 34 and Patients in a failure condition were 55. The median duration of IM therapy was 19 months. The median duration of N ilot therapy was 12.5 months. The cumulative incidence(CI) of major molecular response(MMR) and CI of molecular response 4.0(MR4.0) were calculated using the Kaplan-Meier method and compared using the log-rank text by SPSS17.0. According to the different molecular response and complete cytogenetic response during therapy, we evaluate the N ilot molecular response.ResultsOf 89 CML-CP patients, the MMR rate is 48.3% and the MR4.0 rate is 27.0%. ①The CI of MMR and MR4.0 at 3 years(3-MMR and 3-MR4.0) was higher in the warning group changing N ilot than the failure gro up. 3-MMR and 3-MR4.0 were higher in patients with CCy R than that with no CC y R(P<0.0001 and P=0.0006). 3-MMR and 3-MR4.0 were 73.9% and 34.8% in patients with BCR-ABL levels ≤10% by 3 months on IM therapy vs 39.4% and 24.2% in patients with BCR-ABL levels >10% by 3 months on IM therapy(P=0.0001 and P=0.1459).3-MMR and 3-MR4.0 of the patients with BCR-ABL levels ≤10% at baseline were higher than that with BCR-ABL levels >10% at baseline(P<0.0001 and P=0.0481).3-MMR and 3-MR4.0 of the patients with BCR-ABL levels ≤10% by 3 months on N ilot therapy were higher than that with BCR-ABL levels >10% by 3 months on N ilot therapy(P<0.0001 and P=0.0008). ②Whether achieved CCy R and BCR-ABL levels ≤10% at baseline on IM therapy are the independent factors of the high c umulative MMR rate. Whether achieved CCy R on IM therapy is the independent factors of the high cumulative MMR rate.ConclusionsNilot is effective to the patients with dissatisfactory to IM. Changing to N ilot in the warming, achieving CC y R on IM or BC R-ABL levels ≤10% at baseline on IM therapy was the favorable objective factors of molecular response. Other therapy should be choosed to the patients who BCR-ABL levels >10% by 3 months on N ilot therapy, for example changing drugs or hematopoietic stem cell transplantation.Part two A clinical and laboratory study of chronic myeloid leukemia withatypical BCR – ABL fusion gene subtypesObjectiveTo explore the clinical and laboratory features of chronic myeloid leukemia(CML) with atypical e14a3、e13a3 and e19a2 BCR- ABL fusion gene subtypes.MethodsWe retrospectively analyzed a cohort of CML patients with Ph chromosome positive confirmed by cytogenetic and FISH but classical e13a3(b2a2)、e14a2(b3a2) and e1a2 fusion transcripts negative confirmed by conventionalrealtime quantification RT-PCR(RQ- PCR). Further RT-PCR was done with the forward primer and reverse primer designed to detect rare atypical BCR- ABL fusion genes including e14a3 and e19a2 transcripts. Direct sequencing analysis was performed on the PCR products and mutations in the BCR-ABL kinase domain were detected. The clinical data of patients were retrospectively analyzed.ResultsNine CML patients were found to have t(9;22) abnormality and BCR- ABL rearrangement confirmed by FISH but classical BCR-ABL fusion genes negative detected by RQ-PCR. Further RT-PCR and sequencing analysis confirmed the fusion of BCR exon14 and ABL exon3 in five CML patients(case1-5), the fusion of BC R exon13 and ABL exon3 in one CML patient(case6) and the fusion of BC R exon19 and ABL exon2 in one CML patient(case7-9). E255 K and I293 T IM-resistant mutation were detected in case 1and 2, respectively. Among five cases with e14a3 transcripts, four were CML-CP, one CML-AP. Four patients were male and one was female. The median age was 48 years old. The patient(case6) with e13a3 transcripts was 40- year-old male with a diagnosis of CML-CP. Among three cases with e19a2 transcripts, one was male and two were female. They were CML-CP and PLT count was more than 1000×109/L. Imatinib(IM) therapy was started in case 1,2,3,4 and hematopoietic stem cell transplantation(HSCT) was undergone in case5 after hydroxyurea(Hu) or interferon failure. Case1 who had E255 K IM resistant mutation, responded poorly to IM and obtained complete cytogenetic remission(CCy R) after converting IM to dasatinib. Case2 and 3 achieved CCy R 6 months later after IM treatment and had been maintained well with IM despite I293 T mutation in case2. Case 4 attained CCy R 3 months later after IM treatment but relapsed and died soon. Case 5 was still in CCy R after HSCT. Case 6 achieved CCy R 3 months later after IM treatment. Case7 with e19a2 transcripts got complete hematologic response after Hu treatment. Thereafter, IM was given and CCy R was achieved soon. The follow-up time of case 8 was 3 months and until now, the BCR-ABL transcript has not been monitored. Case 9 lost follow-up.ConclusionsIncidence of CML with atypical transcripts is extremely low. They could benefit from tyrosine kinase inhibitors or HSC T. Rare and atypical BCR-ABL fusion gene subtypes could be missed by conventional RQ-PCR.