Efficacy and safety of autologous hematopoietic stem cell transplantation in elderly multiple myeloma patients: a single center retrospective study / 中华血液学杂志

Objective: To evaluate the efficacy and safety of autologous hematopoietic stem cell transplantation (auto-HSCT) in elderly patients (≥65 years old) with multiple myeloma (MM) . Methods: From June 1, 2006 to July 31, 2020, 22 MM patients (≥65 years old) who were diagnosed in the First Affiliated Hospital, Sun Yat-sen University and received novel drug induction followed by auto-HSCT were analyzed retrospectively. These patients were evaluated for important organ functions before transplantation, and the International Myeloma Working Group frail score was used in 2016 to screen out transplant-eligible patients. Results: The median (interquartile range, IQR) age at the time of transplantation of the 22 patients was 66.75 (IQR 4.50) years. A total of 20 patients received stem cell mobilization. The median number of mononuclear cells collected was 4.53×10(8)/kg, that of CD34(+) cells was 3.37×10(6)/kg, and the median number of apheresis procedures performed was 2. After stem cell transfusion, the median time of neutrophil implantation was 11 days, that of platelet implantation was 13 days, and the treatment-related mortality was 0 at 100 days after transplantation. The median follow-up was 48.7 months. The median time to progression time was not reached, and the median overall survival time was 111.8 months. Conclusion: Auto-HSCT is a safe and effective treatment for selected elderly patients of 65 years or older with MM.

High dose melphalan (HDM) is superior to cyclophosphamide plus etoposide and busulfan (CVB) as the conditioning regimen in autologous stem cell transplantation for multiple myeloma / 中华血液学杂志

Objective: To compare the efficacy, response and survival between high-dose melphalan (HDM) and cyclophosphamide+ etoposide+ busulfan (CVB) as the conditioning regimen in autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (NDMM) . Methods: Retrospectively enrolled 123 consecutive NDMM patients who had received PAD induction with subsequent ASCT from Jan 2011 to Aug 2017. The CVB group and HDM group had 82 and 41 patients respectively. Results: ①No differences existed between these 2 groups in non-hematological side effects. ②Patients of CVB group had faster neutrophil and platelet engraftment time, with the median neutrophil engraftment time of 10 (9-35) day vs 11 (9-12) day for patients of HDM group (z=-3.433, P=0.001) , and with median platelet engraftment time of 11 (7-55) day vs 13 (10-35) day for patients of HDM group (z=-3.506, P<0.001) . CVB group entered neutropenia and severe thrombocytopenia more earlier than the HDM group, resulting similar neutropenia duration and severe thrombocytopenia duration between the CVB group and HDM group. However, patients of CVB group had significantly longer fever persistent time and antibiotic administration time. ③The response rate was significantly lower in patients of CVB group vs. patients of HDM group (9/46 vs 14/28, P=0.021) . Further, the minimal residual disease (MRD) negative rate at 3(rd) month post-transplantation seemed to be lower in CVB group than that in HDM group (31.7%vs 48.8%, P=0.065) . ④Both the univariate and multivariate analysis showed that HDM and CVB groups had similar duration to progression (TTP) (P=0.619) and overall survival (OS) (P=0.295) . Conclusion: HDM conditioning regimen is superior to CVB regimen in hematological side effects, tumor burden reduction and administration convenience. However, these two regimen had similar TTP and OS in MM patients receiving ASCT.

Bortezomib-based induction chemotherapy followed by autologous hematopoietic stem cell transplantation and maintenance in 200 patients with multiple myeloma: long-term follow-up results from single center / 中华血液学杂志

Objective: To study the efficacy, safety and long-term outcomes of integrated strategy of bortezomib-based induction regimens followed by autologous hematopoietic stem cell (ASCT) and maintenance therapy in Chinese multiple myeloma (MM) patients. Methods: 200 MM patients receiving integrated strategy of bortezomib--based induction regimens followed by ASCT and maintenance therapy were retrospectively and prospectively analyzed from December 1. 2006 to April 30. 2018. Results: The complete remission rates (CR) and better than very good partial remission rates (VGPR) after induction therapy, transplantation and maintenance therapy were respectively 31% and 75.5%, 51.8% and 87.7%,73.6% and 93.4%. There was no difference between 4 cycles and more than 5 cycles induction chemotherapy. The negative rate of MRD detection by flow cytometry was 17.6% and 38.2% respectively after induction and 3 months after transplantation. The negative rate of MRD gradually increased during the maintenance therapy. The success rate of high dose CTX combined with G-CSF mobilization was 95.5% and transplantation related mortality (TRM) was zero. The median time to progress (TTP) was 75.3 months and the median overall survival (OS) was 99.5 months. TTP of patients obtaining CR and negative MRD after induction were longer that those of no CR and positive MRD. TTP and OS of patients receiving triple-drug induction and ASCT in early stage were longer than those of double-drug induction and ASCT in late stage. LDH≥240 U/L, high risk cytogenetics, ISS II+III stage and HBsAg positive were prognostic factors at diagnosis. However, only MRD and high risk cytogenetics were independent prognostic factors after transplantation and maintenance therapy. The clinical characteristics of patients of TTP ≥6 years were listed below: light-chain type M protein, ISS I stage, normal level of hemoglobin and platelet, normal LDH, HBsAg negative, chromosome 17p-negative, good response and sustained good response. Conclusions: Integrated strategy of bortezomib-based induction regimens followed by ASCT and maintenance therapy can significantly improve the short-term and long-term efficacy. The prognostic factors of TTP in different disease stages were different. Response to treatment, especially MRD, played a more important role in prognostic factors.

Prostaglandin E2 Receptor 4 Agonist Promotes Human CD34Cell Proliferation in vitro by Activating Wnt/β-Catenin Signaling Pathway / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the potential signaling pathway that regulates the proliferation of human CD34cells stimulated by prostaglandin E2 receptor 4 agonist (EP4A) in vitro.</p><p><b>METHODS</b>Twenty samples of peripheral blood containing stem cells were collected from the G-CSF mobilized healthy donors in our department of hematology. Human CD34cells were isolated by magnetic activated cell sorting (MACS) microbeads kit. The Cell Counting Kit-8 (CCK8) assay was used to determine the optimal concentration and time of EP4A to promote human CD34cell proliferation in vitro. Under the optimal condition, quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect mRNA level of β-catenin, and Western blot was used to assay protein expression of β-catenin and P-GSK-3β in human CD34cells treated with EP4A.</p><p><b>RESULTS</b>Culturing with 10 µmol/L EP4A for 72 h, it was found that EP4A promoted human CD34cell proliferation significantly, and the proliferation rate of human CD34cells was 1.36 times higher than that of the control(P=0.002). Under the optimal condition, it was also found that EP4A enhanced the β-catenin expression at both mRNA and protein levels, and up-regulated phosphorylation of GSK-3β in human CD34cells, but these effects could be inhibited by the EP4A antagonist EP4AA.</p><p><b>CONCLUSION</b>EP4A can enhance human CD34cell proliferation in vitro by activating Wnt/β-catenin signaling pathway.</p>

Observation of humoral immunity reconstitution and its relationship with infection after autologous hematopoietic stem cell transplantation for patients with multiple myeloma / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the humoral immunity reconstitution and its relationship with infection in patients with multiple myeloma (MM) after undergoing autologous hematopoietic stem cell transplantation (auto-HSCT).</p><p><b>METHODS</b>Forty-two MM patients undergoing auto-HSCT were included in this study. Peripheral blood were obtained for immunoglobulin detection, including IgG, IgA and IgM before transplantation and 1, 3, 6, 12, 18 and 24 months after transplantation. The time, type, pathogen of infection between 1 and 24 month after transplantation were analyzed.</p><p><b>RESULTS</b>The level of IgA at 6 month [(0.75±0.59) g/L] after auto-HSCT was lower than that of pre-auto-HSCT [(1.04±0.70) g/L], and reached the level of pre-auto-HSCT at 9 months [(0.99±0.52) g/L] after auto-HSCT. The level of IgM reached the level of pre-auto-HSCT [(0.45±0.26) g/L] at 3 months after auto-ASCT [(0.50±0.26) g/L]. The level of IgG reached the level of pre-auto-HSCT [(9.80±2.98) g/L] at 1 month after auto-HSCT [(11.09±2.69) g/L], and higher than that of pre-auto-HSCT at 9 months after auto-HSCT [(12.07±3.57) g/L]. The level of IgG with IgG-type MM was higher than that of patients with light-chain type and IgD-type MM at 6, 9 and 12 months after auto-HSCT. The IgA level of patients who obtained complete remission (CR) is much higher than that of patients who obtained nCR in IgG-type patients. The incidence of infection in 6 month after auto-HSCT was higher than that of (6-12) month and >12 month after auto-HSCT. The incidence of infection was strongly negative correlated with IgA (r =-0.943, P=0.005) and IgG (r=-0.943, P=0.005) level. The frequency of viral infection was also negatively correlated with IgA and IgG.</p><p><b>CONCLUSION</b>The reconstitution time of IgG, IgA and IgM was different in MM patients after auto-HSCT. IgG recovered first, then IgM, and IgM the last. The incidence of infection was negatively correlated with IgA and IgG. With the recovery of IgG and IgA, the incidence of infection was decreased accordingly.</p>

Clinical significance of abnormal protein bands in multiple myeloma treated with bortezomib-based induction regimen and autologous stem cell transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the clinical significance of abnormal protein bands (APB) in multiple myeloma (MM) patients treated with bortezomib-based induction regimen and autologous stem cell transplantation (ASCT).</p><p><b>METHODS</b>Sixty-eight MM patients submitted to bortezomib-based induction therapy and ASCT from January 2007 to July 2012 were retrospectively studied. Monoclonal protein was detected by immunofixation electrophoresis (IFE).</p><p><b>RESULTS</b>Of all 68 patients, 33 (48.5%) patients had APB. At the first emergence of an APB, two patients with light chain type achieved CR and before transplantation, and thirty-one patients were after transplantation with median time of 104 (ranged 33-404) days. The median duration of APB appearance was 105 (ranged 35-801) days. Patients who developed APB compared with those without APB, had a significantly higher CR plus very good partial response (VGPR) rates (100.0% vs 85.7%%, P=0.017) and CR rates (87.9% vs 62.9%) (P=0.03). There were no significant differences in gender, age, HGB, ALB, β2-microglobulin, M protein type, Durie-Salmon and ISS stages, the case number of first line or second line treatment, induction courses of bortezomib-based regimen, and the mode of ASCT. With a median follow-up of 33.4 (ranged 7.0-71.7) months, patients with APB tended to have a longer overall survival (OS) versus non-APB patients, although no significant difference obtained (P＞0.05). Among APB patients, OS was longer in patients whose appearance of APB occurred ＜6 months after transplantation than those ≥ 6 months, but the significant difference was not obtained yet (P＞0.05).</p><p><b>CONCLUSIONS</b>Patients who developed APB had a significantly better response to bortezomib-based induction regimen followed ASCT. APB emergence has a good prognostic significance.</p>

Sequential treatment with bortezomib plus dexamethasone followed by autologous hematopoietic stem cell transplantation in patients with multiple myeloma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Whether the sequential treatment with bortezomib plus dexamethasone (BD) followed by autologous hematopoietic stem cell transplantation (ASCT) could extend the overall survival period in multiple myeloma patients is still not clear. Few large case studies about this therapeutics in multiple myeloma were reported in China. Our purpose was to assess the efficacy and adverse effects of sequential treatment with BD chemotherapy and ASCT in patients with multiple myeloma.</p><p><b>METHODS</b>Fifty-three patients with newly diagnosed or relapsed/refractory multiple myeloma received BD as induction therapy before ASCT. Stem-cell mobilization was undertaken with cyclophosphamide 3 - 5 g/m(2) plus granulocyte colony-stimulating factor 300 µg/d. Target yield was 2.0×10(6) CD34(+) cells/kg. Conditioning for ASCT consisted of melphalan 200 mg/m(2). Thalidomide and/or a-interferon was used as post-transplantation maintenance treatment.</p><p><b>RESULTS</b>The BD chemotherapy before transplantation was effective in 86.7% of the 53 patients, including 22.6% with complete remission (CR), 39.6% with near complete remission (nCR), and 24.5% with partial remission (PR). The best effect was achieved after two treatment courses. Most bortezomib-related adverse effects were classes 1 - 2. All patients were successfully mobilized after BD for autologous peripheral blood stem cell transplantation. The ASCT was effective in 96.3% of patients, including 49.1% with CR, 32.1% with nCR, and 15.1% with PR. The CR rate was significantly increased (49.1% vs. 22.6%, P < 0.05) by sequential ASCT. Within 27 (range, 6 - 53) months of follow-up, the efficacy of ASCT was maintained in 29 patients and further enhanced by post-transplantation maintenance treatment in four patients. Eleven patients died after transplantation. Among the patients undergoing BD/ASCT treatment, overall survival (OS) was significantly better in newly diagnosed patients in comparison to relapsed/refractory patients (P = 0.046).</p><p><b>CONCLUSIONS</b>BD chemotherapy can be used as an induction therapy prior to ASCT in patients with multiple myeloma. Its rate of effectiveness is high and it alleviates symptoms quickly without affecting peripheral blood stem cell collection. The majority of adverse effects are mild (tolerable). Sequential BD with ASCT is the preferred option for transplant patients. First-line ASCT could prolong survival of newly diagnosed patients rather than delayed ASCT.</p>

Significance of sRANKL/OPG ratio in diagnosis of multiple myeloma bone disease / 中国实验血液学杂志

This study was purposed to investigate the relationship between the levels of soluble receptor activator of nuclear factor kappa B ligand (sRANKL) and osteoprotegerin (OPG) in serum of the patients with multiple myeloma (MM) and multiple myeloma bone disease (MBD). The serum levels of sRANKL, OPG, tartrate-resistant acid phosphatase-5b (TRAP-5b) and C-terminal telopeptide of collagen I (CTP-I) which both are indexes for metabolism of osteoclast (OC) in newly diagnosed MM patients (n=42, experimental group) and healthy persons (n=25, control group) were detected by enzyme-linked immunosorbent assay. The roentgenography was used to determine bone damage in MM patients at the same time. According to these results acquired, the correlation of sRANKL/OPG ratio with levels of TRAP-5b/CTP-I, the incidence and degree of bone destruction were analyzed. The results indicated that the level of sRANKL (median value 9.33 microg/L) increased and level of OPG (median value 4.93 microg/L) decreased and the sRANKL/OPG ratio (2.65) increased significantly in experimental group. Compared with control group, the differences in all the corresponding indicators were statistically significant (p<0.05). The sRANKL/OPG ratio was closely related to levels of TRAP-5b (r=0.512, p<0.05) and CTP-I (r=0.481, p<0.05) in MM patients. After all patients in experimental groups were divided into group with bone destruction (n=29) and without bone destruction (n=13), the sRANKL/OPG ratio in the group with bone destruction was 5.13 and much higher than that in group without bone destruction (1.12) (p<0.05). A close correlation between the sRANKL/OPG ratio and degree of bone destruction (r=0.445, p<0.05) was acquired when all MM patients were divided into three groups according to degree of bone destruction, but no difference between the ratio and clinical classification and International Staging System (ISS) in MM patients was found. It is concluded that the sRANKL/OPG ratio in serum of MM patients is significantly elevated, which may be closely related to increase metabolism of OC along with the incidence and degree of bone destruction. In short, the sRANKL/OPG ratio can be used as a reference index for the diagnosis of MBD.

Dynamic observations of beta-catenin in chronic myeloid leukemia and its relationship with cytogenetic response / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the changes in the expression of beta-catenin in patients with chronic myeloid leukemia (CML) in different phases, and explore the relationship between beta-catenin and the cytogenetic response to imatinib mesylate.</p><p><b>METHODS</b>Beta-catenin mRNA and protein expressions were detected by RT-PCR and Western blotting in the bone marrow mononuclear cells (BMMNCs) from 99 CML patients. The expressions of BCR-ABL fusion gene at both the mRNA and protein levels were detected by fluorescence in situ hybridization (FISH) in 94 patients before and during the one-year treatment with imatinib mesylate at the interval of 3 months, and the relationship between beta-catenin and cytogenetic response to imatinib mesylate was analyzed.</p><p><b>RESULTS</b>The expression of beta-catenin increased significantly in patients with blast crisis and accelerated phase (P<0.001), but showed no significant difference between normal subjects and CML patients in the chronic phase (P>0.05). The main cytogenetic remission rate was significantly higher in patients who were consistently negative for beta-catenin than in those consistently positive for beta-catenin or those with a positive transformation (P<0.001).</p><p><b>CONCLUSION</b>Beta-catenin overexpression in the progression of CML, consistent high level of beta-catenin or a positive transformation may indicate a poor response to imatinib, and early measures should be taken to increase the remission rate.</p>

Therapeutic effects of imatinib on chronic myeloid leukemia in different phases and the factors affecting the effects / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the therapeutic effect of imatinib on chronic myeloid leukemia (CML) in different phases and analyze the factors that may affect the effects.</p><p><b>METHODS</b>Eighty-five patients with CML in chronic phase, 24 in accelerated phase and 19 in blastic phase patients were treated with imitinib. The hematologic response, cytogenetic response, molecular response, overall survival (OS), progression-free survival (PFS) and adverse events were analyzed in these groups.</p><p><b>RESULTS</b>The rates of complete hematologic response (CHR), complete cytogenetic response (CCyR) and complete molecular response (CMoR) of the patients in chronic phase were 100%, 82.4% and 21.2%, respectively, and the 5-year OS and PFS of these patients were 92.1% and 84.7%. All these rates were significantly higher than those in patients in accelerated and blastic phases (P<0.0001). The CCyR, CMoR, 5-year OS and PFS in the 42 newly diagnosed patients in chronic phase were 92.9%, 26.3%, 100% and 95.2%, respectively, all significantly higher than those in patients with interferon therapy failure (P<0.001). Severe leukocytopenia and thrombocytopenia occurred at greater frequencey in AP and BP patients than in chronic phase patients (P<0.0001). Non-hematologic toxicity was rarer and milder in patients in chronic phase. Multivariate analysis showed that interferon therapy prior to imitinib treatment and prolonged drug cessation were the independent factors that affected the achievement of cytogenetic response and PFS.</p><p><b>CONCLUSION</b>Early imitinib therapy can be effective and safe, and should be used as the first line drug for CML.</p>

Effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To retrospectively analyze the curative effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia patients (CML).</p><p><b>METHODS</b>Of the 35 CML patients, 26 were males and 9 were females, with a median age of 32 (12 - 50) years. 30 patients were in chronic phase of CML, 5 patients were in accelerated phase. Allo-HSCT from HLA identical siblings was performed for 35 patients, of whom 11 received bone marrow transplantation (BMT) and 24 peripheral blood stem cell transplantation (PBSCT). Conditioning regimens was TBI (total-body irradiation) + CY (CTX) protocol in 8 patients and BU/CY protocol in 27 patients. The average follow-up was 48 months (range 7 - 108 months).</p><p><b>RESULTS</b>34 (97.1%) patients were successfully engrafted. Among them, 21 patients (60.0%) had three years disease-free (DFS) survival. The overall 5-year survival (OS) was 57.1%. Two patients (5.7%) relapsed. Transplant-related mortality occurred in 12 patients. Hemorrhagic cystitis (HC) occurred in 5 patients and HVOD was observed in 1 patient. Acute graft-versus-host disease (aGVHD) occurred in 18 patients (51.4%), among them 7 patients (20.0%) were of grade III-IV. Chronic GVHD was in 17 patients (48.5%). There was no significant difference in 3-years DFS between BMT group and PBSCT group (54.5% vs. 62.5%, P > 0.05). The 3-year disease-free survival (DFS) was 42.9% in TBI/CY group and 55.6% in BU/CY group (P > 0.05). In univariate prognostic analysis model, the DFS at 3 years is 75% and 47.4% for < or =30 years patients and >30 years patients, respectively, P < 0.05. The 3-year DFS of patients with first chronic phase is higher than patients with advanced diseases (61.3% vs. 40%, P < 0. 05). The 3-year DFS in patients of grade I - II GVHD was higher than that in patients of grade III-IV GVHD (81.8% vs. 14.3%, P < 0.05).</p><p><b>CONCLUSION</b>The patients who had transplantation done within 1 year after diagnosis during their first chronic phase of disease and who had low-grade GVHD have better prognosis. Those patients who had III-IV acute GVHD are prone to incorporate severe infection, which was a worse prognostic factor of allo-HSCT for chronic myelogenous leukemia.</p>

Values of soluble thrombomodulin and von Willebrand factor judging reject reaction in liver transplantation / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To find sensitive and specific laboratory examination items for early diagnosing and monitoring liver transplantation reject reaction.</p><p><b>METHODS</b>Randomly investigate 41 liver transplantation patients, among them there were 16 patients with reject reaction (including 12 with acute rejection, 4 with chronic rejection). Plasma soluble thrombomodulin (STM) and von Willebrand factor (vWF) levels were measured before operation and every other day after operation.</p><p><b>RESULTS</b>Plasma STM level increased significantly after operation, two days before rejection and after acute rejection (5.58 ng/ml +/- 0.42 ng/ml, 5.93 ng/ml +/- 0.45 ng/ml, and 7.88 ng/ml +/- 0.29 ng/ml, respectively), so did vWF level (101.2% +/- 4.68%, 104.3% +/- 5.78%, and 127.7% +/- 5.74%, respectively). STM level was much higher in acute rejection than that in chronic rejection (7.88 ng/ml +/- 0.29 ng/ml vs. 6.35 ng/ml +/- 0.54 ng/ml, t = 2.46, P < 0.05), in no reaction group after impacting therapy than in effective group (8.30 ng/ml +/- 0.19 ng/ml vs. 3.82 ng/ml +/- 0.22 ng/ml, t = 12.98, P < 0.01), and in dead group after treatment than in living group (7.98 ng/ml +/- 0.18 ng/ml vs. 6.51 ng/ml +/- 0.41 ng/ml, t = 3.39, P < 0.01).</p><p><b>CONCLUSIONS</b>Plasma STM and vWF can be taken as laboratory items for monitoring liver transplantation rejection. Plasma STM can act as not only an early prognosticating marker, but also suitable to distinguish acute from chronic reject reaction, and as a marker for monitoring impacting therapy effect and judging prognosis.</p>