Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia

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1 398 Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia Qifa Uu Zhiping Fan Jing Sun Yu Zhang Xiaoli Uu Dan Xu Bing Xu Ru Feng Fanyi Meng Shuyun Zhou Department of Hematology, Nanfang Hospital, First Military Medical University, Guangzhou , China. Correspondence to: Qifa Liu Tel: This work was supported by the National Scientific Foundation of China (No ); Guangdong Development Foundation (No. 2002C30308). Received May 9, 2004; accepted September 10, OBJECTIVE To evaluate the effects of autologous and allogeneic hematopoi- etic stem cell transplantation (HSCT) for patients with chronic myeloid leukemia(cml). METHODS Fifty-seven patients with CML were treated by HSCT, including 8 cases treated with autologous transplantation purged in vivo and in vitro of minimal residual disease (MRD), 39 cases with related donor allogeneic HSCT (alio-hsct) and 10 cases with unrelated donor alio-hsct. The con- ditioning regimen was a TBI (total-body irradiation) +CY (cyclophos- phamide, CTX) protocol in 32 patients, a modified BuCY (hydroxyurea, busulfan, Ara-C, CTX) protocal in 24 patients, and a MACC ( Melphalan, Ara-C, CTX and chlorethyl cyclohexyl nitrosourea ) protocol in one patient. Cyclosporine (CsA) and methotrexate (MTX) were used in patients with re- lated-donor alio-hsct, and CsA and MTX were added to mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) in unrelated donor alio- HSCT for graft versus host disease (GVHD) prophylaxis. Otherwise, CsA was only used for GVHD prophylaxis in patients with accelerated phase (AP) and blast crisis (BC). The Kaplan-Meier survival analysis model was used to estimate the overall survival (OS) and the disease-free survival (DSF) at 5 years after transplantation. RESULTS Eight patients with autologous transplantation, except for 1 case who died of transplantation-related complications, obtained cytogenetic part or complete remission (CR) within 3 months after transplantation. One patient, who was in BC and obtained CR in hematology before transplantation, had been in molecular CR for 92 months after autologous transplantation. Among the 49 patients treated with alio-hsct, all obtained CR, except for one patient who died of hepatic veno-occlusive disease (VOD) and one who had not obtained CR. The incidence of infection and VOD was 33.3% and 7.0%, respectively, during transplantation. After transplantation the incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) interstitial pneumonia (IP) was 22.8% and 8.8%, respectively. VOD, HC and CMV IP did not occur in patients with autologous transplantation. The incidence of acute GVHD and the frequency of chronic GVHD was 41.0% and 48.6%, respectively, in patients with related and unrelated transplantation. The rate of relapse in patients with autologous and allogeneic transplantation was 57.1% and 12.8%, respectively. The DFS at 5 years after transplantation was 25.0% and 61.7%, respectively, in patients with autologous and related donor transplantation. The DFS at 5 years was 70.7% and 34.1%, respectively, in patients with CP (chronic phase) or AP and BC before transplantation. CONCLUSION Allo-HSCT may have a higher clinical cure rate for CML Chinese Journal of Clinical Oncology cocr@eyou.com Tel(Fax):

2 Stem Cell Transplatation for Chronic Myeloid Leukemia / Qifa Liu et al. 399 patients with CP. The CsA +MTX +MMF +ATG protocol is more effective for acute GVHD prophylaxis and can decrease the incidence and degree of GVHD in patients with unrelated donor transplantation. Autologous transplantation with purged bone marrow can prolong the survival time of CML patients and some may be cured with transplants of this type. KEYWORDS: chronic myeloid leukemia, hematopoielic stem cell transplantation, effect. C hronic myeloid leukemia (CML) is a clonal stem cell myeloproliferative disorder which is caused by the presence of the Philadelphia (Ph) chromosome, a reciprocal chromosomal translocation of the long arms of chromosomes 9 and 22. The disease is characterized by the formation of a BCR-ABL fusion gene and the expression of a P210 fusion protein. The P210 fusion protein has higher tyrosine kinase activity and is the pathologic basis of CML. In recent years, hematopoietic stem cell transplantation (HSCT) is the most effective method for the treatment of CML, and especially allogeneic HSCT (allo-hsct) which has been the only known curative therapy for patients with CML. E~.21 In this article, we retrospectively analyzed the transplant outcome of 57 CML patients who received HSCT in our institution between December 1993 and March PATIENTS AND METHODS Patient characteristics From December 1993 to March 2004, 57 patients with CML were treated with HSCT at our institution. All evaluations were based on data available on May Out of the 57 patients, 32 were men and 15 were women. Median age was 36 years, ranging from 15 to 56. The diagnosis was confirmed by clinical examination and morphologic and cytogenetic analysis of bone marrow before transplantation. Disease status was categorized as 43 patients in chronic phase (CP), 6 in accelerated phase (AP) and 8 in blast crisis (BC) before transplantation. Eight patients were treated with autologous transplantation including 5 patients in CP, 1 in AP and 2 in BC (aquired completed remission, CR). Thirty-nine patients were treated with related donor allo-hsct including 27 patients in CP, 5 in AP and 6 in BC (3 patients CR and 3 no CR pre-transplantation). All of the 10 patients treated with unrelated donor allo-hsct were in CP. Transplantation protocols and conditioning regimens Eight patients were treated with purged bone marrow autologous transplantation (auto-hsct), 39 with related donor allo-hsct and 10 with unrelated donor allo-hsct. Twenty-four patients received bone marrow transplantation (BMT) and 33 peripheral blood stem cell transplantation (PBSCT). The conditioning regimen was a TBI (total-body irradiation) + CY (cyclophosphamide, CTX) protocol in 32 patients, a modified BuCY (hydroxyurea, busulfan, Ara-C, CTX) protocol in 24 patients and a MACe (Melphalan, Ara-C, CTX and chlorethyl cyclohexyl nitrosourea) protocol in 1 patient. E3'4~ HLA matching Of the 39 patients who were treated with a related transplant, 37 patients were HLA serologically matched and 2 cases had a l-locus HLA serological mismatch. Among the 10 patients receiving an unrelated transplant, all the patients were HLA serologically matched, 6 cases were genetically completely matched and 3 cases had 1 genetic locus mismatch and one had a 2-genetic loci mismatch. Additionally, 15 patients were mismatched with ABO-isoantigens. Graft versus host disease( GVHD ) prophylaxis Cyclosporine (CsA) and methotrexate (MTX) were used for GVHD prophylaxis in the patients receiving related transplantation, and CsA and MTX were added to mycophenolate mofetil (MMF) and antithymocytes globulin (ATG) for the patients receiving unrelated transplantation. L4j In addition, CsA was only used for GVHD prophylaxis in the patients with AP and Be. Minimal residual disease (MRD) purged with autologous transplantation in vivo and in vitro Of the 8 patients who were treated with auto-hsct, MRD of 5 patients was purged by interleukin-2

3 400 Chinese Journal of Clinical Oncology 2004/Volume 1/Number 6 activated bone marrow (ABM) combined with bcr/abl antisense oligodeoxynucleotides in vivo and in vitro. I3'51 The other 3 patients' MRD was purged by ABM combined with STI571. The protocol included the following: the patients' bone marrow cells were collected after the patients were treated with STI571 and had obtained cytogenetic complete remission before transplantation, then the MRD was purged with the ABM in vivo and in vitro according to published procedures. E31 Treatment with STI571continued after transplantation and hematopoietic reconstitution. Supportive care Granulocyte colony-stimulating factor (G-CSF) at a dosage of mg/d was given by s.c. injection, starting 3 days after stem cell infusion until the absolute white blood cell count was more than 1.0 x 109/L or the absolute neutrophil count was more than 0.5 x 109/L. Other supportive care included preventing infection, hydration and urinary alkalization and component blood transfusion, etc. Statistical analysis Statistical analyses were performed with statistical software, SPSS Independent-sample t test was used. Kaplan-Meier survival analysis model was used to estimate the overall survival(os) and the disease-free survival (DSF) at 5 years after transplantation. P value <0.05 was considered to be statistically significant. RESULTS Remission after transplantation Auto-H$CT Of all the 8 patients who were treated with auto-hsct, the 3 patients, whose MRD was purged by ABM combined with STI571 and bcr/abl mrna and were negative by PCR assay, were live until the present with survival times of 23, 18, and 16 months, respectively. One patient relapsed in cytogene at 8 months after transplantation, the other 2 patients' bcr/abl mrna continued to be negative. The 5 patients, whose MRD was purged by ABM combined with bcr/abl antisense oligodeoxynucleotides, were all 100% positive for bcr/abl mrna and the Ph + chromosome before transplantation. Of the 5 patients, except for one patient who died of an infection due to a delay ofhematopoietic reconstitution, the percentage ofph cells of the other 4 patients was 15%, 0%, 45% and 19%, respectively, at 3 months after transplantation. One patient, who was in BC and had obtained hematologic CR before transplantation, had obtained molecular CR for 92 months after transplantation until the present. AIIo-HSCT After transplantation 37 patients obtained CR in hematology and 2 patients out of the 39 patients who were treated with related transplantation failed to obtain CR. The 2 patients who did not obtain CR were in BC before transplantation. One of these 2 cases died of hepatic veno-occlusive disease (VOD) and the other had no response to donor lymphocyte infusion (DLI). The percentage ofph cells decreased to 23.0%-0% and the Ph + cells were negative in 33 patients. Assays for bcr/abl mrna were negative in 26 patients when Ph cells and bcr/abl mrna were deteced in 36 patients at 3 months after transplantation. After transplantation all of the 10 patients receiving unrelated transplantation obtained CR in hematology. Ph cells were negative in all the patients and assays for bcr/abl mrna were negative in 8 patients at 3 months after transplantation. GVHD The incidence of acute GVHD was 41.0% and 40.0% in the patients with related and unrelated transplantation, respectively. The incidence of grade III - IV acute GVktD was 12.8% and 20.0% in the patients with related and unrelated transplantation, respectively. One of patients who received related transplantation died of grade IV acute GVHD. The incidence of chronic GVHD was 48.6% and 42.9% in the patients with related and unrelated transplantation, respectively. Other transplant-related complications and death The incidence of infection, VOD and hemorrhagic cystitis (HC) during transplantation was 35.1%, 7.0% and 22.8%, respectively. One patient treated with

4 Stem Cell Transplatation for Chronic Myeloid Leukemia / Qifa Liu et al. 401 auto-hsct died of infection, 1 who received a related transplant died of VOD and 1 treated with an unrelated transplant died of HC. HC occurred in patients who were treated with allo-hsct and the modified BuCY protocol. Five patients suffered from cytomegalovirus (CMV) interstitial pneumonia (IP) after transplantation and 2 of these patients died ofcmv IP. VOD, HC and CMV IP did not occur in the patients with auto-hsct. Two patients who received an unrelated transplant died. of viral encephalitis and lung tuberculosis at 3 and 12 months, respectively, after transplantation.one patient with auto-hsct died of viral myocarditis at 31 months after transplantation. Relapse and disease-free survival(dsf) Out of the 7 patients who underwent auto-hsct, 4 patients relapsed (57.1%) and 3 of them died of relapse, leaving 4 were alive after transplantation. The DSF at 5 years after transplantation was 25%. Out of the 47 patients who received allo-hsct, 6 patients relapsed, the rate was 12.8% after transplantation. The 6 patients who relapsed included 5 patients with a related transplant and 1 with an unrelated transplant. Of these 6 relapsed patients, the 5 patients who had a related transplant were treated with DLI and the 1 with unrelated transplant received recombinant interleukin-2. Except for 1 patient who had no response to DLI, the other 5 patients again obtained CR in cytogene after treatment. Among the 5 patients, 2 of them died of aplastic anemia and GVHD after DLI, respectively. The other 3 patients were live until the present time. The OS and DSF at 5 years was 73.6% and 61.7%, respectively, as shown in Fig The relapse rate was higher in patients who received an auto-hsct compared to allo-hsct and the DSF was lower with auto-hsct treatment compared to allo-hsct. The rates of relapse and DSF were significantly different between autologous and allogeneic transplantation (P<0.01), as shown in Fig ' I allo-transplant auto-transplant Fig.2. The disease-free survival of patients after an autologous and allogeneic transplant. After allo-hsct, the DFS at 5 years in patients with CP or AP and BC before transplantation was 70.7% and 34.1%, respectively (Fig.3). In comparing the 22 patients with related transplantation with the 10 unrelated transplant during the same time, the DSF was significantly different between the 2 groups (P<0.05), as shown in Fig " 1.0" 0.9" " ~ 0.7+ CP E r~ , OS I o ',ti, Fig.1. Overall survival and disease-free survival of patients after an allogeneic transplant , -20 I APorBC Fig.3. The disease-free survival of patients with CP and AP or BC after an allogeneic transplant. I

5 402 Chinese Journal of Clinical Oncology 2004/Volume 1/Number ~'].. ''I' II t i t tel]tea I Fi9.4. The disease-free survival of patients after a related and unrelated transplant. DISCUSSION CML is a malignant clonal myeloproliferative disease. HSCT is the most effective method for the treatment of CML, and especially allo-hsct is the only known curative therapy for patients with CML. Because of fatal complications such as GVHD, IP, etc. and relapse, the DFS at 5 years in CML patients was 50% - 70% after allo-hsct. [1,2,61 Many factors can influence the survival of the patients after allo-hsct, but the most important risk factors are the phase of CML and interval time between diagnosis and transplantation. The longer interval times are between diagnosis and transplant, the worse the outcome is after transplantation. The outcome is better in patients with CP than in patients with AP and BC. tn In our observation of the 57 patients with allo-hsct, the DFS at 5 years after transplantation was significantly lower in patients with AP and BC than in patients with CP. Our results are consistent with other reports. [8,9j In addition, our observations indicated that the incidence of CMV IP was much higher in patients with AP and BC than those with CP. The 5 patients who developed CMV IP all were in AP or BC before transplantation. It suggested that CMV IP may be associated with lung injury caused by repeated chemotherapy before transplantation, but further study is needed. Some studies have shown that the rate of long term survival with related transplantation is higher than that of unrelated transplantation, because the former has a lower incidence of GVHD and a higher incidence of relapse, and the latter has a higher incidence of GVHD and mortality and the lower incidence of relapse into CML. It is critical to decrease the incidence of GVHD and mortality in order to enhance the DFS in CML patients after unrelated transplantation. [10.11] In our study, the protocol of CsA, MTX, MMF and ATG was used for GVHD prophylaxis in 10 patients with unrelated.transplantation. The results showed that there was no difference in the incidence of GVHD between related and unrelated transplantation, but the survival times were shorter in unrelated compared to related transplantation, and infections seemed more frequent in unrelated compared to related transplantation. Two patients who were treated with unrelated transplantation died of infections after transplantation. The results do not exclude the possibility of our small sample size and the short time of observation. More clinical cases need to be accumulated with further study. The value of auto-hsct for CML remains controversial. The majority of studies have indicated that auto-hsct might prolong the duration of survival, but simple auto-hsct can not cure CML. [12-14] In our study, 8 patients were treated by autologous bone marrow transplantation combined with MRD purged by ABM and bcr/abl antisense oligodeoxynucleotides or STI571 in vivo and in vitro. Among the 5 patients treated with auto-hsct purged by ABM combined with antisense oligode0xynucleotides, 1 patient died of transplant-related complications and the other 4 patients obtained partial or complete genetic remission including 1 patient who had obtained complete molecular remission for 92 months. The 3 patients purged by ABM combined with STI571 obtained complete molecular remission for 8 to 23 months after transplantation. The results indicated that autologous transplantation with purged bone marrow can prolong survival time and some patients with CML may be cured with autologous transplantation. In summary our data show that allo-hsct may have a higher clinical cure rate for CML patients in CP. The CsA+MTX+MMF+ATG protocol is more effective for acute GVHD prophylaxis and can decrease the

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