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BACKGROUND@#Immunotherapies such as adoptive immune cell infusion and immune-modulating agents are widely used for cancer treatment, and the concomitant symptoms, including cytokine release syndrome (CRS) or immune-related adverse events (irAEs), are frequently reported. However, clinical manifestations induced by mismatched donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell (GPBMC) infusion in patients receiving microtransplant (MST) have not yet been well depicted.@*METHODS@#We analyzed 88 cycles of mismatched GPBMC infusion in patients with acute myeloid leukemia receiving MST and 54 cycles of chemotherapy without GPBMC infusion as a comparison. Clinical symptoms and their correlation with clinical features, laboratory findings, and clinical response were explored.@*RESULTS@#Fever (58.0% [51/88]) and chills (43.2% [38/88]) were the significant early-onset symptoms after GPBMC infusion. Patients possessing less human leukocyte antigen-matching loci with the donor or those with unrelated donors experienced more chills (3 [2-5] loci vs. 5 [3-5] loci, P = 0.043 and 66.7% [12/18] vs. 37.1% [26/70], P = 0.024). On the other hand, those with decreased CD4 + /CD8 + T-cell ratio developed more fever (0.8 [0.7-1.2] vs. 1.4 [1.1-2.2], P = 0.007). Multivariable analysis demonstrated that younger patients experienced more fever (odds ratio [OR] = 0.963, 95% confidence interval [CI]: 0.932-0.995, P = 0.022), while patients with younger donors experienced more chills (OR = 0.915, 95% CI: 0.859-0.975, P = 0.006). Elevated ultra-sensitive C-reactive protein levels in the absence of cytokine storm were observed following GPBMC infusion, which indicated mild and transient inflammatory response. Although no predictive value of infusion-related syndrome to leukemia burden change was found, the proportion of host pre-treatment activated T cells was positively correlated with leukemia control.@*CONCLUSIONS@#Mismatched GPBMC infusion in MST induced unique infusion-related symptoms and laboratory changes, which were associated with donor- or recipient-derived risk factors, with less safety and tolerance concerns than reported CRS or irAEs.
Subject(s)
Humans , Leukocytes, Mononuclear , Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Myeloid, Acute/therapy , Unrelated Donors , Granulocyte Colony-Stimulating Factor , Graft vs Host DiseaseABSTRACT
10.3969/j.issn.2095-4344.2013.24.014
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Objective To establish an animal model of severe bone marrow type acute radiation sickness in the BALB/c mice and to provide a good foundation for further investigation of severe bone marrow type acute radiation sickness.Methods BALB/c mice were given 6.0 Gy 60Co γ-rays total body irradiation.The mice were observed twice a day.The changes in body weight,peripheral blood cell counts were recorded once every three days.Histopathological sections of femur were prepared to observe the histomorphological changes.Bone marrow cells were collected to perform colony cultivation on day 1 before irradiation,and 14 d,28 d after irradiation.Results The mice were less active three days after irradiation,but there were no vomiting and loose stools.The white blood cell counts were dropped to the nadirs (3.0 ％) 11 days after irradiation and recovered to 53.7 ％ on day 28 after irradiation.The platelet counts were dropped to the nadirs (8.1％) 14 days after irradiation and recovered to 60.4 ％ on day 28 after irradiation.Histopathological section showed that the bone marrow cavity was almost empty on day 14 after irradiation.Semi-solid bone marrow cell culture results also demonstrated that CFU-GM and CFU-Mix were obviously decreased.They were not yet fully recovered on day 28 after irradiation.All mice were still alive two months after irradiation.Conclusion A murine model of severe bone marrow type acute radiation sickness has been successfully established by exposure to 6.0 Gy 60Co γ-rays.
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Objective To summarize the experimence of nonmyeloablative allogeneic peripheral blood cell transplantation in the treatment of chronic leukemia. Methods Seven patients, including 6 cases of chronic myeloid leukemia (in chronic phase), one of chronic lymphoid leukemia (in third stage), with HLA-identical siblings donor received allogeneic peripheral blood stem cell transplantation after a nonmyeloablative conditioning. Results All of them were engrafted with donor cells (4 with full of donor cells grafted, 3 with mixed chimerism) and recovered hematopoiesis (WBC recovered to more than 0.5 ?10 9/L during postoperative 9 day to 21 day and platelet recovered to more than 30?10 9/L during postoperative 11 day to 28 day). One of them developed a GVHD of degree IV. One of them developed aGVHD of degree I. Conclusion This procedure is much safe, effective and of less complications than the myeloablative condioning regimens and may represent another new approach in the management of patients with chronic leukemia.
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This paper investigate the methods to detect engraftment rate of the four patients with hematological disorders who accepted nonmyeloablative allogeneic peripheral blood stem cell transplantation(NAPBSCT). To find out the best method, their engraftment rates were detected serially at different time after NAPBSCT by means of either FISH, or conventional chromosome analysis combined with R-banding analysis concurrently.The results were carefully compared with one another. All these four sex-mismatched cases were engrafted partially,and two of them changed to full engrafment. The results show no statistically significant difference in 3 groups (conventional method, FISH for hypermetaphase, FISH for interphase nuclei). But the results strongly indicate that FISH is a rapid, precise, objective,and reliable menthod for detection of the engraftment rate,and it is suitable for sex-mismatched NAPBSCT.
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Objective To analyze the related factors of relapse of leukemia after transplantation of nonmyeloablative allogeneic hematopoietic stem cells. Methods Among the twenty-nine patients with acute leukemia who received transplantation of nonmyeloablative allogeneic peripheral blood stem cells, relapse of leukemia occurred in 5 patients. The nonmyeloablative protocol included the pretreatment of CD3 monoclonal antibody, cyclosporine A, cyclophosphamide, cytarabine, and fludarabine was added in 3 patients. Results All the 5 patients went through smoothly the hematopoietic suppression stage, and engraftment of the donor cells was successful. Leukemia relapsed in 4 patients with full donor chimerism (full donor chimerism was converted from the mixed chimerism in 2 patients), and relapse occurred in 1 patient with stable mixed chimerism. Except for 1 patient, all of them did not show acute GVHD or chronic GVHD. Second complete remission after double transplant was achieved in one patient, but leakemia relapsed in two months. In other four patients treatment was given up. Conclusion Transplantation of nonmyeloablative allogeneic peripheral blood stem cells is a safe and effective method for the treatment of acute leukemia.
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To explore the risk factors of graft rejection in non-myeloablative transplantation between HLA-identical siblings and to evaluate methods to increase donor cell engraftment, 8 patients with graft rejection were studied . The results showed that the usage of immunosup-pressive agents, low early engraft rate, and the kind of disease being CML were closely related with graft rejectioa For patients with graft rejection, second non-myeloablative transplantation is a useful way.
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Objective To observe the changes of serum high-sensitivity C-reactive protein (hs-CRP) in 2 patients diagnosed as acute radiation sickness, and to evaluate its clinical significance. Methods Two victims from Shandong province, China were accidentally received a 60 Co irradiation from a dropped 60 Co source in 2004. They were exposed to more than 20Gy (patient A) and 9Gy (patient B) of X-ray irradiation respectively. The patient A was diagnosed as extremely severe bone marrow form of acute radiation sickness (ARS), and patient B was diagnosed as having developed intestinal form of ARS. The two patients successfully got HLA-haploidentical (patient A) and HLA-identical (patient B) peripheral blood stem cell transplantation, and their hematopoiesis recovered, but they cached serious bacterial infection in whole clinical course. Hs-CRP was quantitatively detected by automatically immunoturbidimetric assay. Result The serum level of hs-CRP in the two patients elevated quickly when they suffered from serious bacterial infection, and declined markedly when the infection was controlled effectively. The serum level of hs-CRP also increased slightly when the patients suffered from severe damage on organs or skin function. There existed 3 peak values of hs-CRP level in patient A when kept in the hospital, with a highest value of 188.8mg/L; there existed 4 peak values of hs-CRP level in patient B when kept in the hospital, with the highest value of 377.2mg/L. Conclusion The present results suggested that hs-CRP may be a good indicator to acute radiation sickness complicated with serious bacterial infection, for the hs-CRP levels may fluctuate following the bacterial infection and effectively controlling.
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Objective To report the diagnosis and treatment of an extremely severe bone marrow form of acute radiation sickness complicated with disseminated Trichosporon Asahii in Jining,Shandong province, China.Methods An extremely severe bone marrow form of acute radiation sickness was transfered to our hospital 3 days after the accident on October 24,2004.The patient was performed allogeneic stem cell transplantion from his brother and soon acquired hematogenesis recovery, however, refractory disseminated Trichosporonosis(mainly lung) then occured in the patient.after the hemato-reconstitusion,and gradually aggravate.Result Strong support treatment and high dosage combination of drug therapy were used to combat fungi ,the accumulative dose of Ampghotec (amphotericin B) was 2965mg, the accumulative dose of itraconazole was 4000mg, and the accumulative dose of Caspofungin(concidas) was 3020mg. The refractory disseminated Trichosporon Asahii was once partially controlled, but the radiation injury and infection were still becoming worse even after many kinds of antiinfection drugs, the patient then died of multiple organ failure on d75 after the accident. Conclution The combination of Ampghotec with Caspofungin and Itraconazole in the treatment of disseminated Trichosporon Asahii was effective, no related toxicity occured, which has not been reported before. However, with continuously injury of radiation, we couldn’t cure the Trichosporonosis thoroughly, and the patient finally died of multiple organs failure related with radiation and infection.According to the clinical treatment of the patient, we also acquired the experience that when we resolve the hematogenesis, to promote the immunologic reconstitution and the tissue damage repair, control the whole body radiation damage and infection will be the key point for this kind of patient to survive.
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Objective To investigate the significance of HLA haploidentical peripheral blood stem cell transplantation for the treatment of intestinal form of acute radiation sickness. Methods Patient “A” from Shandong province suffered from a 60 Co radiation accident with a dose of 20-25Gy, and was diagnosed as intestinal form of acute radiation sickness. On the 3rd day after irradiation, total environmental protection (TEP), antibiotics treatment and emergency HLA zygosity with his elder sister were done, and HLA haploidentical peripheral blood stem cell transplantation was performed with a preconditioning regimen of “CTX+ATG+Flu”. The regimen for protecting from GVHD was “CsA/FK506+MMF+CD25+MSC”. Results WBC began to increase on the 17th day after treatment, and WBC recovered to 5.1?109/L on the 19th day, platelet to over 30?109/L, and RCT to normal. Bone marrow image showed hematopoietic recovery of the three cell lineages. Continuously detection of the implantation ratio of donor's cells by STR-PCR, sexual chromosome analysis and HLA zygosity showed stable complete donor-derived chimera. No GVHD was observed. On the 19th days after treatment, chest X-ray films and CT suggested that a mixed bacterial and fungous infection existed in the patient's lungs. The severest skin damage occurred on the 25th day which occupied 14% of whole body surface. The functions of lung, kidney and heart were damaged sequentially. The patient died of multiple organ failure (MOF) 33 days after admission. Conclusion It is the first time to report a successful HLA haploidentical peripheral blood stem cell transplantation for the treatment of intestinal form of acute radiation sickness in China. A successful transplantation might be a key for prolonging the survival period of such a patient.
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This paper investigate the methods to detect engraftment rate of the four patients with hematological disorders who accepted nonmyeloablative allogeneic peripheral blood stem cell transplantation(NAPBSCT). To find out the best method, their engraftment rates were detected serially at different time after NAPBSCT by means of either FISH, or conventional chromosome analysis combined with R banding analysis concurrently.The results were carefully compared with one another. All these four sex mismatched cases were engrafted partially,and two of them changed to full engrafment. The results show no statistically significant difference in 3 groups (conventional method, FISH for hypermetaphase, FISH for interphase nuclei). But the results strongly indicate that FISH is a rapid, precise, objective,and reliable menthod for detection of the engraftment rate,and it is suitable for sex mismatched NAPBSCT.
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Objective To explore the clinical significance of allogeneic peripheral stem cell transplantation in the treatment of acute radiation sickness.Methods Two victims were accidentally irradiated by a 60Co source in a nuclear accident in Jining,Shandong province,China in 2004.They were exposed to more than 20-25 Gy(patient A)and 9-15Gy(patient B)of 60Co-ray,and were diagnosed as having developed intestinal form of acute radiation sickness(ARS)and extremely severe bone marrow form of ARS,respectively.After the treatment with the preparative regimens based on low-doses of fludarabine,antilymphocyte globulin and cyclophosphamide,the two patients successfully received HLA-haploidentical(patient A)and HLA-identical(patient B)peripheral blood stem cell transplantation(PBSCT),respectively,7 days after the exposure.Cyclosporin A combined with mycophenolate mofetil was used for the prevention of graft-versus-host disease(GVHD).In addition,bone marrow mesenchymal stem cells from a donor were administered into patient A by intra-bone marrow injection.Results Both peripheral blood and bone marrow examinations showed the recovery of hemopoiesis after PBSCT,and neither patients displayed obvious clinical signs of GVHD.However,patient A died of septicemia and multi-organ failure on day 33 after the exposure,while patient B died of heart failure dominant multi-organ failure on day 75 after the exposure.Conclusions Allogeneic PBSCT is a feasible and effective treatment for ARS,while infection and multi-organ failure are major causes of death of the patients.
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Objective To report immune-reconstruction in two patients with acute radiation sickness due to 60Co radiation accident after stem cell transplantation.Methods Patient “A” and “B” were diagnosed as intestinal form of acute radiation sickness(ARS)and extremely severe degree bone marrow form of ARS,respectively.Peripheral blood stem cell transplantation was successfully performed in these two patients.During their whole disease course,absolute lymphcyte count,neutrophil leukocyte count,T-lymphocyte subsets,natural killer(NK),and immunoglobulin were sequentially determined.Results Immunoglobulin was decreased after irradiation without any recovery tendency after the transplantation.After irradiation,absolute lymphcyte count decreased rapidly,but recovered partially after the transplantation(maintained at 0.5?109/L).Neutrophilic leukocyte count rose rapidly to normal after the transplantation.NK was lowered obviously after irradiation,and it rapidly recovered to normal level after the transplantation,and maintained at a level higher than normal.After irradiation,the proportion of CD4/CD8 showed a transient rise,followed by an abrupt lowering.After the transplantation,it showed a tendency of elevation,but it did not recover to normal.Conclusions The tendency of lowering of immunoglobulin,lymphocyte count,NK cell count,and CD4/CD8 ratio indicate that there is a rapid deterioration of both cellular and humoral immunity after irradiation.Following the homogeneic peripheral blood transplantation,neutrophil count and NK cell count showed a rapid recovery,lymphocyte count and CD4/CD8 ratio also showed a tendency of slow elevation,but there is no sign of recovery of immunoglobulin.The results indicate that there is a faster recovery of cellular immunity.