Intensification of pegaspargase in pretransplant chemotherapy regimens reduced relapse of adult Philadelphia chromosome-negative acute lymphoblastic leukemia after transplantation / 中华器官移植杂志

Objective:To explore risk factors for relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adult Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-ALL).Methods:A retrospective analysis was performed for 65 adult Ph-ALL patients undergoing initial allo-HSCT from 2016 to 2018. The effect of baseline level and treatment pre-transplantation for relapse after allo-HSCT was analyzed.Results:There were 37 males and 28 females with a median age of 25(14-58) years during allo-HSCT. And the median follow-up period was 27 months post-HSCT. The 2-year overall survival (OS) was 78.8%(95%CI 67.8%-89.8%) and the 2-year relapse-free survival (RFS) 70.7% (95%CI 58.2%-83.2%). Pre-transplant chemotherapy was offered for 3 to 7 courses and the median dose of polyethylene glycol-conjugated asparaginase (PEG-ASP) was 3 doses (2 000 IU/m 2 per dose). Multiariate analysis revealed that the regimen included more than 4 doses of PEG-ASP pre-HSCT (HR=4.067, P=0.046) was a protective factor for post-transplant relapse (HR=0.193, P=0.009). High-risk chromosome karyotype was a risk factor for relapse (HR=0.193, P=0.009). The 2-year RFS rate was 90.0%(95%CI 79.2%-100.0%) for intensive PEG-ASP group and 56.9%(95%CI 39.1%-74.7%) for control group ( P=0.01). No significant inter-group difference existed in overall survival (OS)( P=0.079). The 2-year OS was 90.6% (95%CI 80.4%-100.0%) in intensive PEG-ASP group and 72.1% (95%CI 56.6%-87.6%) in control group. Conclusions:For adult ph-ALL patients, a higher dose of PEG-ASP in pretransplant chemotherapy regimens may improve post-transplant RFS and achieve a better outcome.

Treatment efficacy of ponatinib as salvage therapy in relapse chronic myeloid leukemia with T315I mutation after allogeneic stem cell transplantation: report of 12 cases / 中华器官移植杂志

Objective To analyze the efficacy of ponatinib as salvage therapy in relapse chronic myeloid leukemia with T315I mutation (CML-T315D after allogeneic stem cell transplantation (allo-HSCT).Methods Twelve patients with CML-T315I (10 cases of T315I mutation before transplantation and 2 cases of T315I mutation at the time of relapse after transplantation) were included in this retrospective analysis.Ponatinib was used as single agent or combined with chemotherapy and/or donor lymphocyte infusion.The samples obtained for RTQ-PCR were also analyzed for the BCR ABL1 mutation by direct sequencing.Scanning of the ABL KD (amino acids 219-506) for the presence of mutations was sequenced by Sanger.Results In 12 patients with relapse after transplantation,2 patients with molecular relapse were treated with only single-agent ponatinib,and among 10 patients with hematologic relapse,1 patient was treated with single-agent ponatinib and 3 patients were given ponatinib combined with donor lymphocyte infusion (DLI),the remaining 6 patients were treated with ponatinib combined with chemotherapy and DLI.After the treatment with ponatinib,11 patients had a good response,10 patients obtained complete hematologic remission (CHR),1 patient obtained partial hematologic remission (PHR) and 1 patient had no response (NR).For cytogenetic response,10 patients obtained complete cytogenetic response (CCyR),1 patient obtained partial cytogenetic response (PCyR) and one patient had no cytogenetic response.For the molecular biological response,9 patients obtained complete molecular response (CMR),1 patient obtained majore molecular response (MMR) and 2 patients had no molecular biological response.The median time to obtain CHR was 36 days (29-96 days),the median time to obtain CCyR was 63 days (32-127 days),and the median time to obtain CMR was 89 days (27-152 days).The median follow-up time after treatment with ponatinib was 598 (range,93-1470) days,9 patients survived and 3 died.Causes of deaths included leukemia relapse (n =2)and ineffective treatment (n =1).The 2-year overall and disease-free survival rate after relapse in 12 patients was 75.0％ ± 12.5％ and 31.7％ ± 14.9％,respectively.Conclusion This small sample data suggested that ponatinib as salvage therapy had a good response to the relapse CML-T315I after allo-HSCT.

Sorafenib combined with chemotherapy and donor lymphocyte infusion as salvage therapy in patients with FLT3-positive acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation / 中华内科杂志

To explore the efficacy of sorafenib combined with chemotherapy and donor lymphocyte infusion (DLI) in patients with FLT3-positive acute myeloid leukemia (AML) relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Of the 14 patients relapsed after allo-HSCT,9 achieved complete remission after salvage therapy of sorafenib combined with chemotherapy and DLI,6 with complete molecular remission,2 with partial remission,and 3 with no response.With a median follow up of 220 (range,30-1 782) days after post-transplantation relapse,7 patients were still alive and 7 died.Salvage therapy of sorafenib combined with chemotherapy and DLI shows a decent therapeutic effect for FLT3-positive AML relapsed after allo-HSCT.

Sorafenib as salvage therapy in refractory relapsed acute myeloid leukemia with positive FLT3 mutation / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the effect of sorafenib as salvage therapy used before and/or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in refractory relapsed FLT3-positive acute myeloid leukemia (AML).</p><p><b>METHODS</b>A total of 16 patients with refractory relapsed FLT3-positive AML, including 10 refractory relapsed pre-transplantation and 6 relapsed after allo-HSCT, were enrolled in this retrospective study. Sorafenib treatment protocols included sorafenib in combination with chemotherapy inducing remission, and sorafenib monotherapy as mauntenance treatment after complete remission (CR).</p><p><b>RESULTS</b>Thirteen of the 16 patients achieved CR after one or two courses of induction therapy, including 7 refractory relapsed pre-transplantation and 6 relapsed after allo-HSCT. With a median follow up of 472 (range, 59-1569) days post-transplantation, 12 patients survived and 4 died. Causes of death included leukemia relapse (n=3) and acute graft-versus-host disease (n=1). The 2-year overall and disease-free survival post-transplantation of the 16 patients were (75.0±10.8) % and (50.5±13.7) % respectively. The main side effect of sorafenib was the skin rash. The incidence of rash was lower in the patients used sorafenib pre-transplantation than those post-transplantation (30.0% vs 75.0%, P=0.043).</p><p><b>CONCLUSION</b>Sorafenib used as salvage therapy befor and/or after transplantation for refractory relapsed FLT3-positive AML could reduce the relapse rate and improve the survival.</p>

Effect of intermediate-dose cytarabine on mobilization of peripheral blood hematopoietic stem cell in acute myeloid leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the impact of courses of intermediate-dose cytarabine (ID-Ara-C) chemotherapy on the efficiency of hematopoietic stem cell mobilization in acute myeloid leukemia (AML) patients with autologous hematopoietic stem cell transplantation (auto-HSCT).</p><p><b>METHODS</b>90 patients with de novo AML undergoing auto-HSCT between August 1999 and November 2012 were enrolled. All patients received the mobilization regimen of cytarabine and etoposide chemotherapy in combination with recombinant human granulocyte-colony stimulating factor (rhG-CSF). Stem cell apheresis was scheduled when blood leukocyte count recovered greater than 4.0 × 10⁹/L or the proportion of CD34⁺ cells greater than 1% in peripheral blood. The impact of ID-Ara-C courses on the mobilization efficiency was analyzed retrospectively.</p><p><b>RESULTS</b>According to the ID-Ara-C courses, patients were divided into group A (<2 courses), B (2 courses), and C (>2 courses). The median doses of CD34⁺ cells (×10⁶/kg) in three groups were 4.7, 2.7, 2.3, respectively (P=0.003). Of the available 87 patients who could be evaluated, 61 (70.1%) cases had CD34⁺ cells greater than 2.0 × 10⁶/kg, and 26 (29.9%) cases less than 2.0 × 10⁶/kg. Of the 26 patients without satisfactory mobilization efficiency, 7 (15.2%) were in group A, 10 (47.6%) in group B, and 9 (45.0%) in group C (χ²=10.05, P=0.007). In addition, patients with satisfactory mobilization efficiency (CD34⁺ cells ≥ 2.0×10⁶/kg) in groups C needed more times of collection, more volume of blood processed, and even high-dose and longer course of rhG-CSF (P<0.05). In univariate analysis. The ID-Ara-C courses and the cumulative dose were significant correlate with mobilization efficiency. In multivariate analysis, the ID-Ara-C courses was an independent correlation factor for mobilization efficiency (odd ratio=0.623, 95% confidence interval=0.418-0.926, P=0.019). The sex, age, cytogenetic risk, the standard chemotherapy courses did not correlate with mobilization efficiency.</p><p><b>CONCLUSION</b>The number of ID-Ara-C courses was independent factor for the mobilization efficiency and should be taken seriously in AML patients with auto-HSCT.</p>

Comparison of clinical efficacy between HLA-mismatched related and HLA-matched unrelated donor hematopoietic stem cell transplantation for hematopoietic malignancies / 中华血液学杂志

<p><b>OBJECTIVE</b>To compare the clinical efficacy of HLA- mismatched related donor (MRD) and HLA-matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies.</p><p><b>METHODS</b>174 patients with hematopoietic malignancies undergoing allogeneic HSCT (allo-HSCT) (82 from MRD and 92 from MUD) between June 2002 and December 2012 were enrolled in this retrospective study. Hematopoietic engraftment, graft versus host disease (GVHD), relapse, overall survival (OS) and disease-free survival (DFS) were compared between MRD and MUD group.</p><p><b>RESULTS</b>There was no significant difference between MRD and MUD group in terms of age, gender, disease type and disease status before transplantation (all P>0.05). The incidence of Ⅰ-IV acute GVHD (aGVHD) was 62.2% and 54.3% in MRD and MUD group (P=0.295); the incidence of III-IV aGVHD between the two groups was 15.9% and 9.8% (P=0.229). The incidence of chronic GVHD (cGVHD) was 28.4% and 45.1% in MRD and MUD group (P=0.036), but there was no significant difference in the incidence of extensive cGVHD between the two groups (9.0% vs 12.2%, P=0.525). The mortality of GVHD was 8.5% and 10.9% in MRD and MUD group (P=0.605). The 10-year OS and DFS were (50.1±6.1)% and (48.8±6.1)% in MRD group, compared with (50.5±6.7)% and (46.3±6.2)% in MUD group (P=0.501, P=0.873, respectively). The 10-year cumulative relapse rate was (21.5±5.7)% and (37.6±7.3)% in MRD and MUD group (P=0.194).</p><p><b>CONCLUSION</b>MRD is equivalent to MUD in efficacy and safety. Without HLA- matched related donors, MRD is superior to MUD because donor source is unlimited and transplantation could be made promptly according to disease status.</p>

A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia / 中华内科杂志

Objective To compare the transplant-related toxicity and the efficacy of busulfan/fludarabine (Bu/Flu) and busulfan/cyclophosphamide (Bu/Cy) as conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia(AML) in the first complete remission (CR1).Methods Totally 32 AML-CR1 patients underwent allo-HSCT were divided into Bu/Cy (Bu 3.2 mg· kg-1 · d-1,7-4 days before transplantation; Cy 60 mg · kg-1 · d-1,3-2 days before transplantation) and Bu/Flu (Bu 3.2 mg · kg-1 · d-1,5-2 days before transplantation; Flu 30 mg · m-2·d-1,6-2 days before transplantation) groups.The regimen-related toxicity (RRT),incidence and severity of graft-versus-host disease (GVHD),3-year cumulative relapse rate,non-relapse mortality (NRM),3-year event-free survival (EFS) rate and overall survival (OS) rate were compared between the two groups.Results The median follow-up duration was 617.5 (6-1261) days.All patients achieved successful engraftment on 30 day after transplantation.There were no significant differences in the median time to neutrophil engraftment (P =0.121) and platelet engraftment (P =0.171) between the two groups.The median duration of neutrophil count under 0.1 × 109/L and platelet count under 20 × 109/L in the Bu/Cy group were significantly longer than those in the Bu/Flu group (P =0.000 and P =0.047).The incidence of grades Ⅱ-Ⅳ RRT were 68.8％ and 25.0％ (P =0.032) in the Bu/Cy and the Bu/Flu groups,respectively.There were no significant differences in the incidence of acute GVHD (P =0.149),chronic GVHD (P =0.149),incidence of NRM (P =0.333),3-year cumulative relapse rates (P =0.834),3-year EFS rate (P =0.362) and OS rate (P =0.111) between the two groups.Conclusion Compared with Bu/Cy,Bu/Flu is a myeloablative condition regimen with milder bone marrow suppression and lower RRT incidence rate in allogeneic HSCT for AML-CR1 patients without compromising the efficacy.

Conditioning regimen with or without total body irradiation for allogeneic hematopoietic stem cell transplantation in acute Ieukemia / 中华器官移植杂志

ObjectiveTo investigate the therapeutic effects of the conditioning regimen with or without total body irradiation on allogeneic hematopoietic stem cell transplantation in acute leukemia.Methods We retrospectively evaluated clinical outcomes in 287 allo-HSCT recipients with acute leukemia (ALL- 105,AML-129,and AUL-53) who received myeloablative conditioning regimen with or without total body irradiation from January 2002 to August 2011.Two hundred and six patients obtained complete remission (CR) and 81 non-remission (NR) before transplantation.One hundred and ninety-nine patients received conditioning with total body irradiation (TBI+ Cy group,9 Gy given over 2 days),and 88 patients received busulfan (BuCy group,3.2 mg·kg-1 ·d-1 ),both followed by cyclophosphamide.ResultsThere were no statistically significant differences in hematopoietic reconstitution,regimen-related toxicity (RRT),graft-versus-host disease (GVHD) and relapse between two groups.For patients with AML and AUL,there was no significant difference in the 5-year survival between the two regimens (P＞ 0.05),while for ALL-CR patients,the TBI + Cy regimen had a higher over survival rate (52.0％ vs.31.3％,LogRank=4.249,P＜0.05) and DFS (50.4％ vs.27.8％,LogRank =4.445,P＜0.05) than BuCy.In TBI + Cy group and BuCy group,the proportion of CD19+ B cells at the first month after HSCT was (4.04 ± 1.86)％ and (1.47 ±0.99) ％ (P＜0.05),that of NK cells at 12th month after HSCT was (23.38 ± 12.19) ％ and (13.11± 7.99) ％ (P＜0.05),and that of CD4+ CD45RO+ cells at 9th month after HSCT was (14.63 ±6.17)％ and (9.07 ± 3.12)％ (P＜0.01),respectively.ConclusionUsing TBI-containing regimen was more effective for treating ALL-CR patients than busulphan-containing regimen,but no difference was found for long-term outcomes in patients with AML and AUL between the two regimens.The 9 Gy TBI-based regimens may not affect recipients' thymic function,T-cells reconstitution and immune tolerance,coming out a non-increase of GVHD.

Mesenchymal stem cells for treatment of steroid-resistant chronic graft-versus-host disease / 中华内科杂志

Objective To assess whether treatment with mesenchymal stem cells (MSCs) is an effective adjunct therapy for refractory extensive chronic graft-versus-host disease (GVHD) resistant to conventional therapy. Methods 12 patients with steroid-resistant extensive chronic GVHD were treated with MSCs. One patient received one dose, 10 received two doses, and the remaining three doses. The MSCs were obtained from HI,A-identical sibling donors (n = 14), haploidentical donors (n = 2), unrelated mismatched donor (n = 1) and third-party HLA-mismatched donors (n = 7). Of the 11 patients treated with multiple infusions, 5 received cells derived from two donors. The median first dose of MSCs was 1.0 (0. 4-2. 1) × 106/kg , the median second dose was 1.2(0. 8-1.9) × 106/kg , and the third dose in one patient was 1.1 × 106/kg. Meanwhile the proportion of CD3+ ,CD4+,CD8+ ,CD19+,CD4+ CD25+ ,FOXP3+,FOXP3+CD4+ and FOXP3+ CD25+ was determined with double fluorescent-labeled antibodies and flow cytometry before and 4 weeks after the MSCs infusion. Results No patients had side-effects during or immediately after the infusions of MSCs. After a treatment course of one to three doses, 3 patients had complete response(CR), 6 showed partial response(PR) and 3 did not respond; the total effective rate was 75% (9/12). Complete resolution was seen in the involvement of skin (3/12), lung (1/3), joints (1/5), liver (3/10), oralcavity (4/12) and eye (2/7). Response rate was not related to donor HLA-match. 3 CR patients discontinued all of the immunosuppressive agents without relapse 100 to 292 days after the MSC infusion and 6 PR patients taped all immunosuppressive agents after 60 to 79 days. Mean follow-up period was 1152(795-1914) days, leukemia free survival rate was 91.7% (11/12) and the overall survival rate was 75% (9/12). The ratio of CD4/CD8 and the proportion of regulatory T cells were significantly higher than that before MSCs treatment. Conclusion Third-party MSCs were as effective as HLA-identical or haploidentical cells. This finding has practical implications and suggests that third-party cells can be prepared and stored frozen to be used for steroid-resistant extensive chronic GVHD therapy. It is concluded that MSCs may prevent the lethal cGVHD after allogeneic hematopoietic stem cell transplantation and raise the survival rate by increasing the ratio of CD4/CD8 and proportion of regulatory T cells in vivo.

A clinical analysis of severe cyclosporine A-related neurotoxicity after allogenic hematopoietic stem cell transplantation / 中华内科杂志

Objective To investigate the morbidity,clinical manifestations,and imageology characteristics,and the influencing factors of severe cyclosporine A(CsA)-related neurotoxicity(SNCT)in the patients after allogenic hematopoietic stem cell transplantation(allo-HSCT).Methods Finding of SNCT was carried out in 164 allo-HSCT recipients from January 2003 to June 2006.Clinical characteristics were analysed,including precursory symptoms and clinical manifestations.Associations between the onset of SNCT with blood CsA levels,age,transplant types,human leucocyte antigen(HIJA)matching,conditioning regimens,antihuman thymocyte globulin(ATG)used in the prevention and treatment for graft-versus-host disease(GVHD)and intravenous corticosteroid used for acute GVHD were analyzed.Statistical analysis was performed with Binary Logistic Regression using SPSS/PC version 11.0.Results Thirteen patients(7.93%)were identified to have SNCT,including seizures(n=8,4.88%),paralysis(n=6,3.66%),coma(n:2,1.22%),cerebllar ataxia(n=3,1.83%)and chondrioid encephalomyopathy (n=1,0.61%).All the patients had precursory symptoms prior SNCT including headache(n=8),agitation(n=4)and hypertension(n=6).Magnetic resonance imaging(MRI)performed in twelve patients after SNCT showed that eleven patients had signal abnormalities in cerebral cortex and cerebral white matter.Six patients examined with computerized tomography(CT)had no abnormal findings.After extenuation or withdrawal of CsA.ten patients had complete recovery.two had partial recovery and one died of SNCT.Simple effect analysis of Binary Logistic Regression showed that the associations between the onset of SNCT with blood CsA levels.transplanta types.HLA matching.ATG used in the prevention and treatment for GVHD and intravenous corticosteroid used for acute GVHD were of statistical significance.The multiple effect analysis of Binary Logistic Regression showed that the associations of the onset of SNCT with blood CsA levels and ATG used had statistical significance and the odds ratio(OR)was 1.007(P=0.006) and 6.727(P=0.030),respectively.Conclusions 91.67%of the allo-HSCT recipients with SNCT have MRI abnormalities.High blood CsA levels and the use of ATG Call elevate the risk of the occurrence of SNCT.

Clinical analysis of recipients of allogeneic hematopoietic stem cell transplantation with a history of pulmonary invasive fungal disease / 中国实用内科杂志

Objective To explore the relapse,therapeutic effect,risk and prognostic factors of the pulmonary invasive fungal disease(IFD)in patients with a history of pulmonary IFD following allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods Fourteen patients with a history of pulmonary IFD received allo-HSCT between March 2005 and October 2006.Before transplantation,10 patients obtained complete remission(CR)and 4 partial remission(PR)after antifungal therapy.Antifungal prophylaxis was initiated on the first day of the conditioning therapy.Logistic regression models were used for multivariable analyses.Results The relapse rate of pulmonary IFD after allo-HSCT was 71.43%(10/14).Of 10 patients in CR,6 relapsed and all four patients in PR relapsed.Seven patients relapsed less than 3 months and 3 relapsed between four and six months after transplantation.Among the 10 patients with a history of IFD who relapsed after transplantation,9 patients received antifungal therapy,4 obtained CR,2 PR again and the other 3 didn't obtain remission.The effective rate of anti-fungal therapy was 66.67% and the pulmonary IFD-related mortality was 35.71%(5/14).There was no significant difference between amphotericin B,itraconazde and voriconazole for antifungal prophylaxis in patients with a history of pulmonary IFD(P=0.122).No risk and prognostic factors of the pulmonary IFD was identified by multivariable analyses.Conclusion Pulmonary was not an absolute contraindication for allo-HSCT,and patients with a history of pulmonary IFD had a higher relapse rate and transplant-related mortality after receiving allo-HSCT.