bluuebunny/crossref_metadata_2025 huggingface dataset:
Quadruple Therapy with CsA, MTX, MMF and ATG and Triple Therapy with CsA, MTX and ATG for Preventing Graft-Versus-Host Disease in Unrelated Donor Hematopoietic Stem Cell Transplantation.
Authors: Fan Zhiping , Yi Zhengshan , Liu Qifa , Sun Jing , Xu Dan , Zhang Yu , Wei Yongqiang , Ye Changxiong
Published: April 2020

Objective To explore the effective protocol for graft-versus-host disease (GVHD) prophylaxis in unrelated donor hematopoietic stem cell transplantation (URD-HSCT).

Methods 31 patients with leukemia received URD-HSCT, of whom 16 received quadruple therapy (quadruple group) with CsA, MTX, MMF and ATG for GVHD prophylaxis and 15 received triple therapy (triple group) with CsA, MTX and ATG. 22 patients were matched in all HLA genetic loci with donors, seven were mismatched in one HLA genetic locus, 1 in two HLA genetic loci, and 1 in three HLA genetic loci. Total body irradiation (TBI) plus cyclophosphamide (CTX) was adopted in 17 cases and modified BuCY conditioning regimen (hydroxyurea, busulfan, Ara-C, Cyclophosphamide) in the other 14 cases. Immune reconstitution of quadruple group and triple group at 1,3, 6, 9,12 month after transplantation were examined by flow cytometer, and the diference of the two group were estimated with Independent-Samples T test. The incidence of GVHD of the two group was esitimated with Mann-Whitney Test. Kaplan-Meier survival analysis model was used to estimate the overall survival and the disease-free survival (DFS).

Results Immune reconstitution after transplantation of quadruple group and triple group have no significant difference (P>0.05). Acute GVHD (aGVHD) occurred in 9 patients (56.25%) of the quadruple group and in 11 (73.33%) of the triple group, respectively. The incidence of acute GVHD (aGVHD) differed little between the two group (P=0.238). The incidence ofIII~IV°aGVHD in the two group were 6.30% and 26.67%, respectively, and there was no significant difference (P=0.122). 6 patients had chronic GVHD (cGVHD), in the16 cases who could be followed up in quadruple group, 3 of the 11 patients who could be followed up in triple group developed cGVHD postoperatively (P=0.580). Four patients of quadruple group died of hemorrhagic cystitis, mycotic pneumonia, tuberculosis and relapse, respectively. 3 patients of triple group died of GVHD, and the other 3 died of GVHD associated interstitial pneumonia, cytomegalovirus (CMV) pneumonia and pneumocystis carinii infection. The lethality of GVHD of quadruple group and triple group were 0%,26.7%, respectively, and there was significant difference(P=0.027). The one-year disease-free survival rate was 75% and 60% in patients of the quadruple and the triple group, respectively, and significant difference was not noted (P= P=0.188).

Conclusion Compared with triple therapy with CsA, MTX and ATG, CsA+MTX+MMF+ATG procedure dose not worsen the immune reconsititution after transplantation. It can’t decrease the incidence and severity of aGVHD, but can lower the lethality of GVHD in URD-HSCT. The quadruple procedure may lead to higher relapse rate after URD-HSCT.
The Receptor for Hyaluronic Acid Mediated Motility (RHAMM/CD168) Is a Potential Target for Immunotherapy of Patients with B-Cell Chronic Lymphocytic Leukemia.
Authors: Giannopoulos Krzysztof , Hus Iwona , Li Li , Bojarska-Junak Agnieszka , Greiner Jochen , Rolinski Jacek , Dmoszynska Anna , Doehner Hartmut , Schmitt Michael
Published: April 2020

Definition of appropriate target antigens might open new avenues to antigen targeted immunotherapies for patients with B-cell chronic lymphocytic leukemia (B-CLL). We screened the mRNA expression of tumor associated antigens (TAAs), from the literature (fibromodulin, survivin, OFA-iLRP, BAGE, G250, MAGE1, PRAME, proteinase, Syntaxin, hTERT, WT-1), and TAAs defined earlier by serological analysis of cDNA expression libraries from leukemic cells (PINCH, HSJ2, MAZ, MPP11, RHAMM/CD168, NY-Ren60). Peripheral blood mononuclear cells from 43 B-CLL patients and 20 healthy volunteers (HVs) were examined by conventional and quantitative RT-PCR. mRNA of RHAMM/CD168, fibromodulin, syntaxin and NY-Ren60 was expressed in 55–90%, mRNA of HSJ2, MAZ and OFA-iLRP in 90–100% of the patients. No expression of WT-1, h-TERT, BAGE, G250, MAGE1 and survivin was observed. Low (2–20%) expression frequencies of MPP11, PINCH, PRAME and proteinase were detected. RHAMM/CD168, fibromodulin, PRAME and MPP11 showed expression in B-CLL patients, but not in HVs. Because of the exquisite tissue expression of RHAMM/CD168 and its high expression frequency in B-CLL patients even in early stages of disease, mixed lymphocyte peptide culture (MLPC), enzyme-linked immunosorbent spot (ELISPOT) and flow cytometry were performed for antigen specific T cells. In MLPC, RHAMM specific responses by CD8+HLA-A2/R3tetramer+CCR7-CD45RAhigh effector T cells were detected. Moreover, we observed an enhanced RHAMM/CD168 specific CD8+ T cell response after vaccination in one from four HLA-A2 positive B-CLL patients vaccinated with tumor cell lysate pulsed dendritic cells. Therefore, RHAMM/CD168 is an interesting candidate antigen for future immunotherapies in both ZAP-70 (+) and ZAP-70 (−) B-CLL patients.
Long Term Survival of Patients with Chronic Myelocytic Leukemia after Allogeneic Stem Cell Transplant Using a Reduced Intensity Regimen of Melphanlan, Lomustine and Cyclophosphamide.
Authors: Jia Yongqian , Liu Ting , Niu Ting , Xu Caigang , Meng Wentong , Lu Jianchun , Wang Hui
Published: April 2020

Introduction: Non-ablative regimens have been shown to be effective and less toxic than traditional ablative regimens, but they usually need close monitoring and skillful manipulates e.g. donor lymphocyte infusions. In the present study, we used a novel reduced intensity regimen with melphanlan, lomustine and cyclophosphamide to treat patients with chronic myelocytic leukemia and made a long term follow-up.

Methods: 14 patients with median age of 35(23~52) were treated with MCC regimen(Melphanlan 170 mg/m2/d×1, Lomustine 400 mg/m2/d×1, Cyclophosphamide 60 mg/kg/d×2) and the median follow-up time is 6 years; another 16 patients with median age of 33(16~44) were treated with BuCy regimen(Busulfan 4 mg/kg/d×4, Cyclophosphamide 60 mg/kg/d×2) and the median follow-up time is 4 years.

Results: All the patients were engrafted successfully and the platelet recovery to 20×109/L was earlier at median 3 days in patients with MCC regimen. 4 of 10 patients examined in MCC group showed mixed chimerism at day 100 post transplant, whereas only 1 of 12 patients examined in BuCy group showed mixed chimerism. All the patients became complete donor sources later without any DLI. The regimen related toxicity was relatively lower in MCC group, especially the incidence and severity of mucositis and liver dysfunction were decreased significantly. The median duration of hospitalization was 39 days (25~55)for patients with MCC regimen, and 55 days (39~90) for BuCy regimen. The 5 year disease-free survival was 71.4% for MCC group and 62.5% for BuCy group, respectively. The transplant related mortality and relapse rate were 21% and 7% for MCC regimen, whereas 25% and 12% for BuCy regimen.

Conclusions: MCC regimen is an effective and less toxic conditioning regimen and the long term disease-free survival is as the same as that of BuCy regimen. Considering the cost-effect efficacy, MCC regimen may have some prominent advantages over BuCy regimen.

Figure Figure
Target Dose Adjustment of Oral Busulfan Using a Test Dose in Japanese Adults Undergoing Hematopoietic Stem Cell Transplantation.
Authors: Takamatsu Yasushi , Ogata Kentaro , Sasaki Noriaki , Hara Shuuji , Eto Tetsuya , Kato Kouji , Nagafuji Kouji , Abe Yasunobu , Kubota Akira , Choi Ilseung , Imamura Rie , Imamura Yutaka , Taira Naoya , Suzumiya Junji , Tamura Kazuo
Published: April 2020

Oral busulfan (BU) is widely used in patients undergoing hematopoietic stem cell transplantation (HST). Therapeutic effect of BU is related to the area under the plasma concentration-time curve (AUC) or the average plasma concentrations at steady state (Css). It has been shown that BU pharmacokinetics (PK) are highly variable and the dose adjustment according to the BU levels is critical to get the successful results of HST for Caucasians. BU is metabolized mainly in the liver through conjugation with glutathione by glutathione S-transferase (GST). Recent study has shown that the polymorphisms of GST genes are associated with the risk of developing hepatic veno-occlusive disease in patients undergoing HST. Ethnic variation is also demonstrated in relation to a gene deletion polymorphism of GST, suggesting that BU metabolism is influenced by the race. BU PK have been extensively investigated in Caucasians and few studies have focused on Asian people. We therefore underwent a prospective trial of adjusting BU doses depending on the individual BU PK in 36 Japanese patients aged from 16 to 64 years (median; 47 years). All patients received a busulfan-containing conditioning regimen and underwent allogeneic HST. Individual PK were studied following a 0.5 mg/kg test dose of BU administered orally. BU concentrations were measured by a high-performance liquid chromatographic method and individual PK parameters of BU were calculated with a one-compartment model by using Bayesian modeling program. The median clearance (CL/F) was 0.16 L/hr/kg (0.09 to 0.34 L/hr/kg), the median volume of distribution (Vd/F) 0.65 L/kg (range; 0.41 to 0.97 L/kg), the median elimination half-life (t1/2) 2.9 hr (range; 1.9 to 7.0 hr), and the median absorption rate constant (ka) 2.46 /hr (range; 0.53 to 6.03 /hr). BU doses were adjusted to achieve a target BU Css between 800 and 900 ng/mL. Twenty-six (72%) patients were required to reduce BU doses and adjusted BU doses ranged from 0.51 to 1.29 mg/kg/time (median; 0.85 mg/kg/time). After administrating the 6th dose of BU for the conditioning regimen, BU PK were analyzed. Expected Css was significantly correlated with observed Css and predictability of the test dose was 106.4±21.8%. Engraftment was successful in 34 of 36 (94%) patients. Grade 2 to 4 regimen-related toxicity except stomatitis occurred in 4 (11%) patients. These data demonstrate that BU PK vary widely from one patient to another after oral BU in Japanese and individualization of BU doses depending on the BU PK are useful in improving clinical outcome in patients undergoing HST.
Intravenous Busulfan Dosed Once Daily or Four Times Daily as Part of the Standard BuCy Preparative Regimen for Allogeneic Stem Cell Transplantation.
Authors: Shaughnessy Paul J. , Bachier Carlos , Alexander Lorraine , LeMaistre C. F.
Published: April 2020

Intravenous busulfan (IVBu) (Busulfex ESP Pharma) is regularly substituted for oral busulfan as part of the standard busulfan and cyclophosphamide (BuCy) preparative regimen for allogeneic stem cell transplantation (ASCT). Oral busulfan was originally dosed 4 times daily, which led to the current accepted dosing schedule for IVBu. Pharmacokinetics (PK) and busulfan clearance allow for once daily dosing now that IVBu is available. We performed a retrospective review of 36 consecutive patients who received the BuCy preparative regimen with IVBu prior to ASCT. Twenty-one males and 15 females with a median age of 46 years (23–64) were treated for AML (n=15), ALL (n=1), CML (n=8), MDS (n=8), NHL (n=2), and multiple myeloma (n=2). IVBu was dosed 0.8 mg/kg 4 times daily for 16 doses (n=16) or 3.2 mg/kg once daily for 4 doses (n=20) on days -7 to -4, and cyclophosphamide was dosed 60 mg/kg once daily for two doses on days -3 and -2. IVBu was dosed by ideal or adjusted ideal body weight and no PK studies were done. Bone marrow (n=6) or peripheral blood (n=30) stem cells were infused on day 0 from HLA matched siblings (n=26) or unrelated donors (n=9), and one partially matched unrelated donor. Engraftment occurred in 34 patients (pts) (94%). Two pts who failed to engraft had bone marrow grafts with low numbers of total mononuclear cells infused. Regimen related toxicity (RRT) included mild VOD in 2 pts (5%) that self resolved, with one pt receiving IVBu 4 times daily and the other once daily. There was no seizure activity or non-infectious interstitial pneumonitis attributed to RRT in any patient. Other RRT were not significantly different between the patients who received 4 times daily or once daily IVBu. For all patients day 100 mortality was 17%, and at a median follow up of 12 months (1–54) 17 pts (47%) survive. Five of 16 pts (31%) survive who received 4 times daily IVBu, and 12 of 20 pts (60%) survive who received once daily IVBu. Three patients received once daily IVBu as outpatients and no patients received 4 times daily IVBu as outpatients. Financial review between day -7 to day 0, days 1–30, days 61–90, and day-7 to day 90 revealed patient charges were not significantly different at these time points between the once daily and 4 times daily dosing groups. In conclusion, this small retrospective single institution study revealed IVBu dosed once daily by ideal or adjusted ideal body weight appeared to have similar RRT, engraftment, survival and cost compared to 4 times daily IVBu when used as part of the BuCy preparative regimen for ASCT.
Cytokine Gene Expression in Peripheral Blood Mononuclear Cells Points to Interleukin-10 as an Inhibitor of Alloreactivity Following Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning.
Authors: Petersen Soren L. , Madsen Hans O. , Ryder Lars P. , Svejgaard Arne , Dickmeiss Ebbe , Vindelov Lars
Published: April 2020

Cytokines are thought to play an important role in the pathophysiology of Graft-versus-Host disease (GVHD). To study the relationship between cytokines and GVHD, we obtained peripheral blood mononuclear cells (MNC) from 21 patients with hematologic malignancies and their human leukocyte antigen identical sibling donors before and sequentially after hematopoietic cell transplantation (HCT) with nonmyeloablative conditioning. The MNC were cultured for 72 hours either alone or in mixed lymphocyte cultures with irradiated MNC of recipient, donor or HLA-mismatched third-party origin. The gene expression of interleukin (IL)-2, IL-4, IL-10, IL-18, tumor necrosis factor-α and transforming growth factor-β in each culture was then measured by real-time quantitative RT-PCR. The composition of the responder MNC differed between patients and donors and changed following HCT with a possible influence on the results. Early after transplant (day +14) the IL-10 mRNA level in response to recipient or donor antigens was higher in patients who did not develop clinical significant acute GVHD when compared to the level in patients who subsequently developed acute GVHD grades II–IV (p=0.005 and p=0.004, respectively). The IL-10 mRNA level on day +14 was highly correlated to the pre-transplant mRNA level of the recipient MNC but not to the level of the donor MNC, suggesting that the IL-10 mRNA detected on day +14 originated from responder cells of recipient origin. A higher IL-10 mRNA level was found in MNC obtained pre-transplant from recipients who progressed or relapsed after the transplant when compared to the level in patients who did not, p=0.03. In conclusion we find that detection of cytokine gene expression in MNC by real-time quantitative RT-PCR is an interesting tool in the study of the immune responses following HCT. A number of factors are likely to influence the results obtained and in this study we have identified the composition of the MNC as such a factor. Our results suggest a role for IL-10 as an inhibitor of alloreactivity following nonmyeloablative HCT. This inhibition may have dual effects by limiting the degree of acute GVHD and at the same time increase the probability of relapse.
Late Onset Neutropenia and Decreased Immunoglobulin Concentration after Rituximab Combined Autotransplantation for B Cell Lymphoma.
Authors: Hirayama Yasuo , Kohda Kyuhei , Hirata Yasuji , Kuroda Hiroyuki , Matsunaga Takuya , Konuma Yuichi , Yoshida Makoto , Sakai Toshiro , Niitsu Yoshiro
Published: April 2020

Chemotherapy with Rituximab is widely used to treat patients with various B-cell lymphomas and auto-transplantation with Rituximab is promising strategy due to the potential for in vivo purging. However, the possibility of late onset neutropenia and immunoglobulin suppression after auto-transplantation with Rituximab has been indicated. We studied the frequency and degree of these phenomena. We performed a retrospective analysis on 26 consecutive patients at three centers during the period of January 1998 to March 2005.

Thirteen patients (Follicular 8, Marzinal zone B cell lymphoma 2, Diffuse large B 3) received auto-transplantation without Rituximab (R-) compared with 13 patients (Follicular 8, MZBCL 2, DLB 3) received auto-transplantation with Rituximab (R+). In R+ patients pripheral blood stem cells were harvested after High dose AraC followed by three times of Rituximab (375mg/m2 day -2 of AraC, day7, 14). Conditioning regimen consisted of MCEC (MCNU, CBDCA, ETOP, Cy) or TBI+Cy followed by three times of Rituximab (375mg/m2 day 0, 7, 14).

Mean immunoglobulin concentration one month after transplantation was 890 mg/dl for R- vs. 470 mg/dl for R+ (P=0.04). Lowest neutrophil numbers over 4 weeks after transplantation was 1.24X109/L for R- vs. 0.36X109/L for R+ (p=0.02). Late onset neutropenia (<0.5X109/L) were seen in three cases of R+ group, but no case in R- group. Therapy related death was seen one case in R+ group. This case showed low immunoglobulin level after transplantation and died of Pneumocystis Carinii. These data, although preliminary, indicates that the addition of Rituximab to auto-transplantation leads to decrease in immmunoglobulin and neutrophil levels after transplantation.
Assessment of the Aryl Hydrocarbon Receptor Gene as a Therapeutic Target in Childhood T-Lineage Acute Lymphoblastic Leukemia.
Authors: Meier Marrit , den Boer Monique L. , Broekhuis Mathilde J.C. , Stam Ronald W. , van Wering Elisabeth R. , Janka-Schaub Gritta E. , Pieters Rob
Published: April 2020

T-lineage ALL is an unfavorable subtype of childhood ALL and is associated with in-vitro resistance to drugs. Therefore the identification of novel genes that may serve as targets to modulate drug resistance is desirable. We compared the gene expression profile of 28 pediatric T-ALL patients being either sensitive (DNRS) or resistant (DNRR) to daunorubicin. The aryl hydrocarbon receptor (AHR) gene appeared to be highly discriminating between DNRS and DNRR T-ALL patients. AHR is known to mediate signal transduction in response to xenobiotics by activating the transcription of xenobiotic-responsive genes such as CYP1A1 and CYP1A2. Expression analysis by real-time quantitative PCR confirmed that basal AHR mRNA levels in ALL cells derived from patients is correlated with DNR resistance (Rs=0.41, P=0.02). Exposure to DNR of the REH cell line expressing a low AHR level led to a 40-fold induction of AHR mRNA. In two other cell lines (i.e. HL60 and SEMK-2) expressing high levels of AHR the upregulation was only 1.4-fold. In REH, the 40-fold induction of AHR after DNR exposure was inhibited by 40% after pre-exposure to the AHR inhibitors salicylamide (SAL) and geldanamycin (GA). Pre-incubation of leukemic cells of T-ALL patients with SAL or GA prior to DNR exposure had a synergistic effect on DNR sensitivity. In addition, transfection of SEMK-2 cells with AHR-specific siRNA resulted in the reduction of AHR expression by 80% after 24 h and had also a synergistic effect on DNR induced cell kill up to 96 hours after siRNA treatment. We conclude that a high expression of the AHR gene is involved in DNR resistance in childhood T-ALL and that AHR may serve as a very attractive new therapeutic target.
Distribution of CMV Glycoprotein B Genotypes after Allogeneic Hematopoietic Stem Cell Transplantation in China: A Single Center Study.
Authors: Wu Xiaojin , Wu De Pei , Ma Xiao , Sun Aining , Chang Huirong
Published: April 2020

Objective: To study the distribution of CMV glycoprotein B (gB) genotypes in the patients with CMV infection after allo-HSCT

Methods: Seventy-four patients undergoing allo-HSCT were enrolled in this study. After allo-HSCT, all the patients were detected for CMV gB DNA in peripheral blood by haplo-nested PCR methods;The CMV gB DNA positive samples were screened, which were sufficient for enzyme digestion. Glycoprotein B typing was performed through digesting PCR products with RsaIand HinfI;The sequences were mensurated with ABI PRISM 377 XL DNA Sequencer.

Results: The PCR products of thirty-eight patients were digested with enzyme. the distribution of gB genotypes was as follows:I(gB1) 19/38 (50.0%), II(gB2) 3/38 (7.89%),III(gB3) 14/38 (36.84%), and unclassification 2/38 (5.27%).

Conclusion: The distribution of gB genotypes was different in the patients with CMV infection after allo-HSCT; There may be exiting new genotype.
Gene Expression in Leukemic Blasts Persisting at Day 8 of Induction Therapy in Childhood ALL Displays a Common Shift towards Terminally Differentiated B Cells and a Cytoreduction-Associated Impairment of the Translational Machinery.
Authors: Rhein Peter , Scheid Stefanie , Ratei Richard , Hagemeier Christian , Seeger Karl , Kirschner-Schwabe Renate , Schrappe Martin , Spang Rainer , Ludwig Wolf-Dieter , Karawajew Leonid
Published: April 2020

In childhood acute lymphoblastic leukemia (ALL), persistence of leukemic blasts during therapy is of crucial prognostic significance. To approach the mechanisms of therapy resistance, we addressed genome-wide gene expression in blasts persisting after one week of induction therapy (day 8 blasts) and their molecular signatures as compared with blast cells at initial diagnosis (day 0 blasts). In order to approach this issue experimentally, a procedure has been established including flow sorting of leukemic blasts by their leukemia-associated immunophenotype and preparation of cRNA, starting from a small number of cells. Blast cells from 12 patients with precursor B-cell ALL were investigated using Affymetrix HG U133A microarrays, and genes commonly up- or down-regulated in blast cells under therapy were identified in matched pairs of day 8 and day 0 samples. In spite of the heterogeneous clinical features of the patients (mean rate of cytoreduction after 7 days of initial therapy = 82%, range between 33% and 99%), we were able to determine a set of 310 genes whose expression was commonly changed between day 8 and day 0 with an estimated false discovery rate of 0.05. The identified set of genes indicated inhibited cell cycling, reduced metabolism, and expression changes of multiple factors related to B-cell differentiation. These changes collectively suggested that gene expression in day 8 blasts is shifted towards resting mature B cells. To test this hypothesis, we isolated normal B cells from peripheral blood samples of leukemic patients and compared their gene expression to that of leukemic blasts using Principal Component Analysis (PCA). PCA revealed that day 8 samples are positioned between day 0 samples and normal B-cell samples, and statistical significance of this observation could be established using the Jonckheere-Terpstra test. Changes of B-cell differentiation markers on protein level supported this finding. In addition, we analyzed all genes with regard to the correlation of their expression changes with the rates of cytoreduction in peripheral blood. We observed differential impairment of the key components of the translational machinery including ribosome, eukaryotic 43S preinitiation complex and eukaryotic 48S initiation complex. Overall, expression levels of these factors decreased in therapy-sensitive patients but did not change in therapy-resistant patients. Taken together, investigation of leukemia cells persisting during therapy identifies common and individual expression changes which may potentially affect sensitivity towards anti-leukemic agents and offers new insights into the mechanisms of therapy resistance in ALL.
Iron Overload as a Potential Predictor for Short Disease-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation in Acute Leukemia.
Authors: Park Sun Young , Kim Jin Seok , Kim Yuri , Park In Hae , Chun Hyun Ju , Cheong June-Won , Min Yoo-Hong
Published: April 2020

Iron overload is associated with free radical generation and associated with an increase in toxic deaths after hematopoietic stem cell transplantation (HSCT). To evaluate pre-HSCT iron status influencing outcome and incidence of long-term complications, we analyzed 48 adult patients who underwent allogeneic HSCT for acute leukemia in the first complete remission (CR) status. We measured the iron status including serum iron, total iron binding capacity and serum ferritin in patients immediately before allogeneic HSCT. We defined iron overload prior to the HSCT as serum ferritin level ≥ 3000μg/L or transferrin saturation (TS) ≥ 100%. Seven (14.6%) cases were included in the iron overload group; five cases with ferritin level ≥ 3000 μg/L, two cases with TS ≥ 100%. Twenty-nine were the patients with acute myeloid leukemia (AML) and 19 were acute lymphoblastic leukemia (ALL). Thirty-five patients received the myeloablative conditioning regimen and 13 the reduced-intensity transplantation (NST). There were no significant differences in the rate of marrow engraftment and graft failure in relation to iron overload. The incidence of acute graft versus host disease (GVHD) and chronic GVHD in the iron overload group (14.3% and 42.8%, respectively) was not different compared to that in the non-overload group (46.3% and 34.1%, respectively). We analyzed the association between the iron overload and transplantation-related complications. There was no significant difference in the incidence of transplantation-related mortality and venocclusive disease between the two groups. The relapse rate after HSCT was higher in the iron overload group compared to control group (57.1% and 22.0%, respectively), although the statistical difference was not observed. The disease-free survival (DFS) rate at 24 months was significantly lower in the iron overload group (42.9%) compared to the non-overload group (65.6%, log rank test, P = 0.034). In conclusion, iron overload is considered to be one of the poor prognostic variables valid in the allogeneic HSCT settings. Iron chelation therapy before HSCT can be suggested for improving transplantation outcome.
Single Agent Gemtuzumab Ozogamicin (Mylotarg) Can Induce Hematologic Remissions in Patients with Refractory Acute Myelogenous Leukemia (AML) Relapse Following Allogeneic Stem Cell Transplantation but May Precipitate Acute Graft-Versus-Host Disease (GVHD).
Authors: Agha Mounzer E. , Raptis Anastasios , Miller Sarah B. , Taylor Michelle , Mapara Markus Y.
Published: April 2020

Relapse following allogeneic transplantation in the absence of GVHD is usually treated by withdrawing immunosuppressive therapy followed by donor lymphocytes infusions for the induction Graft-versus-Leukemia (GVL) effects. However, if this fails to result in graft-vs-leukemia effects, the prognosis for such patients is usually very poor. Re-induction therapy seldom has an effect on such patients, and the morbidity from full induction is substantial.

Patients: We retrospectively studied five patients with AML, who relapsed following allogeneic stem cell transplantation (SCT). Three patients had their transplant from HLA-identical siblings, and two from matched unrelated donors (URD). Both patients with URD transplant had a one HLA class I antigen mismatch.

Treatment Plan: After withdrawing the immunosuppressive therapy, no signs of GVHD was noted in any of the patients. All patients were then treated with Mylotarg 9 mg/M2 on days 1 and 14. All five patients received both doses. Three patients did not respond and died of progressive leukemia. Two patients achieved complete remission as documented by BM biopsy. One patient who had a one antigen mismatch URD SCT and who had evidence of skin and liver GVHD prior to the relapse, remains in remission without any evidence of GVHD, and off immunosuppressive therapy (day +327 post-BMT). The second patient, who never had GVHD prior to relapse, developed aGVHD of the skin and liver one months after Mylotarg therapy. Despite intensive immunosuppressive therapy, he continued with progressive GVHD of the skin and liver died of GVHD on day +224 post-SCT with no signs of recurrent leukemia.

Conclusions: Gemtuzumab Ozogamicin is effective in inducing hematologic remissions in refractory AML patients who relapse following allogeneic SCT. Mylotarg may precipitate aGVHD and we hypothesize that secondary inflammatory reactions following the cytolytic effects of the immunotoxin may be involved in the induction of GVHD. Caution should be exercised if this treatment is to be combined with donor lymphocyte infusions. Prospective studies are warranted to evaluate the role of Mylotarg in treatment patients in relapse following allo-HSCT and its effect on precipitating GVHD.
Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation in Renal Cell Carcinoma: The EIO Experience.
Authors: Pastano Rocco , Laszlo Daniele , Andreola Giovanna , Gigli Federica , Rabascio Cristina , Raia Valentina , Cazzanti Manuela , Peccatori Fedro , Martinelli Giovanni
Published: April 2020

Background. A less toxic approach than conventional allogeneic stem cell transplantation based on the use of a non-myeloablative and potent immunosuppressive regimen has been previously developed. Aim of such procedure is to establish a mixed chimerism engraftment and to get an immunologic effect against the tumor, eventually potentiated by donor lymphocyte infusion. Such effect is well known to occur in hematological malignancies and is under investigations in solid tumors, mainly renal cell carcinoma (RCC).

Patients and methods. From December 2003 to June 2004 we enrolled 8 pts, median age 57 (34–66), affected by metastatic RCC, in progressive disease (PD) after different lines of therapies. Conditioning regimen was the following: Fludarabine, 30 mg/m2, from day −4 to −2 followed by 2Gy TBI on day 0, when all pts received HLA matched related grafts. Prophylaxis of aGvHD was performed with administration of Cyclosporine (6.25mg/kg) p.o. bid from day −3 to +36 followed by a rapid tapering to +56 and mycophenolate mofetil (15mg/kg) p.o. bid, given from day 0 to +27.

Results. After transplantation five pts achieved a SD (62%), 2 experienced PD and response was not evaluable for one pt who died at +24. Three showed graft rejection at day +56, +90 and +120, respectively. After a median follow-up of 152 days (24–440), 3/8 (37%) patients are still alive: 2 in SD at +386 and +144, despite loss of graft in +90 and in +56, respectively and 1 in PD; 5 (62%) pts have died, 4 because of PD, 1 for aGvHD. Hematological toxicity was mild with no G4 neutropenia or thrombocytopenia; infections occurred in 2/8 (25%) pts, none was fatal. Incidence of aGvHD was 25%(2/8), one of which was G4 fatal aGVHD. No patient suffered from cGvHD.

Conclusions. Our results confirm this regimen is safe and feasible in patients affected by metastatic RCC, but further studies are necessary to clarify the high rate of graft rejections (3/8, 37%) and the low clinical activity of the regimen.
Low Progression-Free Survival for High-Risk Patients Treated with Reduced-Intensity Conditioning Regimen Allogeneic Stem Cell Transplantations with Volunteer Unrelated Donors.
Authors: Tabrizi Reza , Bijou Fontanet , Bouabdallah Krimo , Leguay Thibaut , Marit Gerald , Pigneux Arnaud , Gomez Aurelie , Belloc Francis , Lafarge Xavier , Boiron Jean-Michel
Published: April 2020

Reduced-intensity conditioning regimens (RICR) are increasingly used before allogeneic stem cell transplantation (SCT) for patients not eligible for myeloablative conditioning. The relapse and survival rates after RICR allogeneic SCT were studied in 19 high-risk patients treated between February 2002 and December 2004. Ten males and 9 females with a median age of 47 years (15–55) received PBSC transplantation from a 10/10 (n=15) or 9/10 HLA antigen-matched donor (n=4). Acute leukemia was the main diagnoses (n=12; 6 AML and 6 ALL), the other diagnoses were 3 multiple myeloma, 2 CML, 1 NHL, 1 CLL. All patients had high-risk disease: 12 had second or > 2 complete remission, 5 second partial remission and 2 refractory disease. The preparative regimen consisted of cumulative dose of Busulfan 8mg/kg, Fludarabine 150 mg/m2 and ATG 7.5 mg/kg (Thymoglobulin, Genzyme, Lyon, France). Graft-versus-host disease (GVHD) prophylaxis regimen consisted of cyclosporine A and short-course methotrexate. Median follow-up was 14 months (5–39 months). Engraftment was complete in all but 2 patients with refractory disease and 14 patients achieved 100% donor CD3 (median 56 days, range 18–123). Grade 2 to 3 acute GVHD was seen in 3 (16%) patients, no grade 4 acute GVHD was observed. Grade 1 chronic GVHD was seen in 1 patient. Nine pts relapsed at a median time of 9.5 months, 3 pts had never reached a full CD3 donor chimerism. Twelve pts are alive, seven pts in complete remission, 2 pts with relapsed disease. Three pts relapsed and achieved a subsequent complete remission by chemotherapy, one of them received a second SCT, one a DLI and one other developed hepatic cGVHD and didn’t receive DLI. Five pts died from recurrent disease, One pt died from cerebral toxoplasmosis and one other from cerebral hemorrhage due to a secondary poor graft function. Survival rate was 73% (95% CI 0.52–0.93) at 6 months and 60% (95% CI 0.38–0.83) at 1 year. PFS rate was 73% (95% CI 0.52–0.93) at 6 months and 33% (95% CI 0.09–0.57) at 1 year. In conclusion, in this cohort of pts, the progression-free survival is unsatisfactory. This can be explained by the advanced stage diseases and the low incidence of cGVHD, probably due to high immunosuppressive treatment. A less intensive immunosuppressive protocol can be tested to improve the results in this particular group of patients.

Figure Figure Figure Figure
Clinical Effects of Unrelated-Donor or Related-Donor Hematopoietic Stem Cell Transplantation for Leukemia.
Authors: Liu Qifa , Sun Jing , Xu Dan , Wei Yongqiang , Zhang Yu , Ye Changxiong , Meng Fanyi
Published: April 2020

Patients and Methods: From February 2003 to May 2005, 118 patients with leukemia received URD-HSCT or RD-HSCT at our institution. 43 cases received URD-HSCT and 75 cases received RD-HSCT. The basic conditioning regimens were TBI (total-body irradiation) + CY (CTX) protocol or modified BuCY (hydroxyurea, busulfan, Ara-C and CTX) protocol. Fludarabine, cytosine arabinoside, etoposide and etc. were added to the basic conditioning regimens when treated patients with refractory leukemia or in NR. The 43 patients who were treated with URD-HSCT, included 43 patients matched at 6/6 HLA antigens based on conventional serologic typing methods, 11 at 5/6 HLA antigens, 1 at 4/6 HLA antigens and 1 at 3/6 HLA antigens. Among the 75 patients with RD-HSCT, 69 patients were matched at 6/6 HLA antigens serologically, 6 were matched at 5/6 HLA antigens. The basic protocol GVHD prophylaxis is CsA (cyclosporine) and methotrexate (MTX). Low-dose antithymocytes globulin (ATG) was added to the basic protocol when patients treated with URD-HSCT, and mycophenolate mofetil (MMF) and low-dose ATG added to the basic protocol were used in some patients with URD-HSCT.

Results and Conclusion: The patients treated with URD-HSCT or RD-HSCT have no significant differences in sex, age, disease type and pretransplantation condition. The overall survival was 57.5±0.83% and 58.7±10.5% in patients undergoing URD-HSCT and RD-HSCT, and the 3 year disease-free survival rate was 51.6±8.5% and 49.8±8.3%, respectively. The overall survival and 3 year disease-free survival differed little between unrelated and related transplantation(P>0.05). The relapse rate of leukemia between URD-HSCT and RD-HSCT were 9.3% and 18.8%, respectively, and significant difference was noted (P<0.05). II–IV° acute GVHD (aGVHD) occurred in 58.17% of the patients receiving URD- HSCT and in 33.00% of those with RD-HSCT, especially the incidence of III–IV° severe aGVHD in the two group was 16.0% and 9.0%, respectively, and there were significant differences, too. The mortality caused by GVHD in patients with URD-HSCT was 12.0% and that in RD-HSCT was 9.0%, and it differed little. The incidence of chronic GVHD (cGVHD) in patients who could be followed up after URD-HSCT was 51.15% and that in RD-HSCT was 53.85%, there was no significant difference. The mortality directly caused by infection in the two group was 7% and 4%, respectively, and there was no significant difference. Two patients with URD-HSCT died of venous occlusive disease (VOD), one hemorrhagic cystitis (HC) and one graft rejection, but there was no similar condition in RD-HSCT.
A Early Report of Bone Marrow Transplantation from HLA Mismatched Mother for β-Thalassemia Major.
Authors: Li Chunfu , He Yuelin , Zhang Yuming , Wu Xuedong , Ming Yang , Bai Jin
Published: April 2020

Objective: To study the possibility of Bone Marrow Transplantation for β-thalassemia major using an alternative donor from HLA mismatch mother.

Methods: Three patients withβ-thalassemia major were given a BMT from HLA one-antigen mismatched mothers. The patient-1 was 7 year old, patient-2 was 1.5 and patient-3 was 4, respectively. All of patients were boys The oldest was class III in the Pesano grouping and others were classI-II. Patient-1 and patient-3 were given the conditioning of TBI 300 rad, Bu 14mg/kg, Cy 160mg/kg and ATG-F (patient-1 was 90mg/kg, patient-3 was given 30mg/kg). Patient-2 was given Fudalabine 150mg/kg instead of TBI and ATG-F 30mg/kg. Infused nuclear cells were 5.3x10e8/kg for patient-1, 6x10e8/kg for patient-2 and 19.4x10e8/kg for patient-3, respectively. Donor of patient-3 received G-CSF from day −2 to day 0. The prophylaxis of GVHD included CsA+methylpregnisolone but patient-3 received additionally MMF and anti-CD25 monoclonal antibody (Daclizumab).

Results: Time of follow-up was 4 years for patient-1, 3.2 years for patient-2 and 10 months for patient-3. Patient-1 and patient-3 are EFS and with only mild acute GVHD. Patient-2 was no engraftment.

Conclusions: We conclude that BMT from HLA one-antigen mismatched mother may be used for patients withβ-thalassemia major in some developing countries, such as China, in where the convention treatment of thalassemia was not well performed, whereas there are only three cases in our experiment.
Results of High Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with Chemo-Responsive Multiple Myeloma.
Authors: Ault Kenneth A. , Case Delvyn C. , Boyd Marjorie A. , Thomas Ervin J. , Aronson Frederick R. , Ebrahim Kurt S. , Hedlund Jaquelyn A.
Published: April 2020

29 patients with Stage III multiple myeloma have undergone transplantation at our institution over the past 10 years. Patient selection criteria included age less than 70 years, creatinine less than 2mg/ml, no active infection, cardiac ejection fraction >40%, DLCO > 50% of predicted and no other co-morbid conditions that would jeopardize sur-vival. In addition, there was demonstrated chemo-sensitivity of the disease with at least a 50% decrease in M-component and a decrease in marrow plasmacytosis to less than 10%. After treatment to maximal effect with VAD (3–6 cycles), peripheral blood stem cells were collected. The dose of CD34 positive cells ranged from 1.8 to 17.4 x106/kg. (median 11.4 x 106/kg). 8 patients treated prior to September 2000 received high dose therapy with Melphalan 140mg/m2 and fractionated TBI, 150cGy bid for 5 doses. Patients treated after September 2000 received Melphalan 200mg/m2 without radiation. The median age at transplantation was 52 years (range 29 to 71). There were no treatment related deaths. Days to achieve AGC>500/ul ranged from 5 to 13 (average 6.8). The median length of follow up is 2.7 years. Currently 23 patients are alive, and 18 are free from progression. Overall survival at 5 years is 79%. Progression-free survival at 5 years is 43%.

Figure Figure

Our experience suggests that carefully selected patients with chemo-responsive multiple myeloma have relatively high rates of overall and progression free survival when compared to results reported for a broader population of patients.
Use of Low Dose Oral Vitamin K in the Treatment of Patients with INR Values of More Than 10.0.
Authors: Crowther Mark A. , Garcia David , Ageno Walter , Witt Daniel M. , Schulman Sam , Blostein Mark , Kovacs Michael J. , Kearon Clive , Anderson David , Wells Phil , Ginsberg Jeff S. , Selby Rita , Wang Luqi , Kahn Susan R.
Published: April 2020

The optimal therapy for patients who present with markedly prolonged INR values during warfarin therapy is undefined. Evidence suggests that the risk of bleeding increases directly with the degree of prolongation of the INR. Traditional therapy for patients with excessive warfarin associated anticoagulation has included warfarin withdrawal with or without vitamin K, transfusion therapy and admission to the hospital. As part of an ongoing international study, we prospectively enrolled 32 consecutive warfarin-treated patients presenting with an INR of more than 10.0. Eligible patients had no evidence of active bleeding or need for immediate correction of their INR. All patients received 2.5 mg of oral vitamin K, were not treated with coagulation factor replacement, and were followed over 90 days for clinical events and their INR response. Seventeen of the 32 patients were women, with an average age of 65.8 (range 31 to 89). Treatment of venous thrombosis and atrial fibrillation (12 patients each) were the most common indications for warfarin. Twenty-five patients had a target INR of 2.0 to 3.0; the remainder had a target of 2.5 to 3.5. The mean INR at presentation was 12.9 (range 10.0 to 21.2). Of the 25 patients with a recorded INR value on the day following vitamin K, 19 (76%) had an INR of 6.0 or less (range 1.6 to 17.5, mean 5.0, 2 less than 2.0). On day 7 after study drug, the mean INR was 3.5 (range 1.6 to 17.5). Six (19%) patients reported bleeding over the 90 days after study drug: 1 (3%) bleed was major (retroperitoneal hemorrhage diagnosed the day after study drug) and 3 patients reported epistaxis or bruising within three days of study drug. Two patients reported late bleeding; one had a fall on day 8 at which time the INR was 10.5, and the other had bleeding associated with a surgical procedure 25 days after study drug. No patients had suspected or confirmed thrombosis, and no patients died during follow-up. This the first prospective study of vitamin K monotherapy for patients with INR values above 10, and confirms prior retrospective analyses which suggest that low dose oral vitamin K effectively lowers the INR in such patients. Our preliminary results also suggest that coagulation factor replacement may be unneeded in such patients. The true risk of bleeding, and the impact of degree of prolongation of the INR on the vitamin K response, will require additional patient recruitment.
A Comparison of 3 Staging Systems for the Outcome Following Autologous Stem Cell Transplantation (ASCT) in Patients with Multiple Myeloma (MM).
Authors: Sohn Hee-Jung , Kim Kihyun , Lee Jae-Hoon , Bang Soo-Mee , Kim Dong Hwan , Lee Je-Jung , Suh Cheolwon
Published: April 2020

The Durie-Salmon (DS) stage has been the gold standard for stratification of MM patients. However, the system does not contain beta-2 microglobulin (B2M) widely recognized as the single most powerful prognostic parameter. Recently, The Southwest Oncology Group (SWOG) staging system (Jacobson JL, et al. Br J Haematol122:441–50, 2003) and the International Staging System (ISS) (Greipp PR, et al. J Clin Oncol23:3412–20, 2005) utilizing B2M have been proposed. We aimed to evaluate whether the stage assessed at the time of ASCT by DS, SWOG, or ISS predict outcome following ASCT in patients with MM. Between November 1996 and December 2004, a total of 141 patients with MM who were treated with ASCT at 5 institutions in Korea were available for this analysis. The distribution of patients’ stage at ASCT by 3 staging systems was as Table 1. With a median follow-up of 20 months from ASCT, the median event-free survival (EFS) and overall survival (OS) were 16 months (95% confidence interval [CI], 11–21) and 56 months (95% CI, 38–74), respectively. The median survival of each stage group according to 3 staging systems at ASCT was as Table 2. Differences in EFS among the stage groups were not statistically significant. However, OS after ASCT was dependent on the SWOG stage at the time of ASCT and also significantly longer in patients with ISS stage I than others (NR vs. 39 months, P =.001). In this study, OS following ASCT was influenced by the stage according to SWOG or ISS, but not DS.

The distribution of patients by 3 staging systems Stage I II III IV DS 32 (23%) 23 (16%) 86 (61%) - SWOG 53 (38%) 66 (47%) 16 (11%) 6 (4%) ISS 85 (60%) 34 (24%) 22 (16%) - Median event-free survial and overall survival by 3 staging systems Stage I II III IV P EFS=evnet-free survival, OS=overall survival, NR=not reached, * in months EFS* DS 27 17 13 - .40 SWOG 22 15 24 4 .21 ISS 17 13 10 - .63 OS* DS NR 58 40 - .17 SWOG NR 41 32 17 .045 ISS NR 32 40 - .0042
Treosulfan-Based Tandem High-Dose Chemo-Immuno- Therapy with Autologous Stem Cell Transplantation for Relapsed and Refractory Aggressive B-Cell Lymphomas.
Authors: Reichle Albrecht , Holler Ernst , Berand Anna , Andreesen Reinhard
Published: April 2020

Feasibility and high efficacy of repetitive dose-intensive chemo-immuno-therapy in relapsed and refractory aggressive B-cell lymphoma (adjusted IPI at relapse 2 and 3) was proven by double-induction followed by tandem high-dose chemo-immuno-therapy with stem cell transplantation including a treosulfan-based conditioning regimen. For cytoreduction and stem cell mobilisation, 2 cycles of a cisplatin-based chemotherapy plus rituximab (R), R-VIPE or R-DHAP, were applied followed by two identical cycles of high-dose chemotherapy (HD-CT) consisting of treosulfan 14 g/m2 iv day −4 to day -2, carboplatin 300 mg/m2 iv day −4 to day −2 and etoposide 500 mg/m2 iv day −2 to day −4. Each HD-CT was combined with rituximab 375 mg/m2. Thirty patients (pts), mean age 53 years (range 35–68), stage III: n=9, stage IV: n=21, have been enrolled. 80% of the pts suffered from early relapse within 6 months (n=6) or refractory disease and no available matched related or unrelated donor (n=18), 6 pts had a late relapse (≥ 6 months). All patients received previously CHOP-based CTs. Histology revealed diffuse-large cell lymphoma (n=19), follicular lymphoma Grade 3 (n=6), immunoblastic lymphoma (n=3), and mantle cell lymphoma (n=2). In 7 pts both, low- and high-grade lymphomas were observed. Only one stem cell mobilization was necessary to collect sufficient CD34+ cells for two transplantations. Median hematologic recovery (> 1.0 leukocytes/nl and platelets >20/nl) after 1st and 2nd HD-CT was achieved by day 10 (8–11). No therapy-related death occurred. CTC °III and °IV non-hematologic toxicities were as follows: 11 of 29 pts after 1st HD-CT had °III toxicities (infection, vomiting, enteritis, stomatitis, diarrhea), after 2nd HD-CT 10 of 27 pts, respectively. Complete remission (CR 3 months post transplantation) was achieved in 22 of 30 pts (73%). CR was documented after double-induction (n=2), 1st HD-CT (n=9), and 2nd HD-CT (n=11), PR in 6 pts, and 2 pts had progressive disease during induction CT and HD-CT, respectively. At a median observation time of 19 months (range 3.6 to 4.6 months) 26 pts (87%) are alive. Sequential R-HD-CT results (in poor risk pts) in a median PFS of 14.0 months (CI 8.7 to 19.3 months), median overall survival (OS, intent-to-treat analysis) has not been reached (at 4 years 72%). In conclusion, treosulfan-based tandem R-HD-CT is feasible with a manageable toxicity profile. CR and continuous CR rates argue for a dose-response relationship even in high-risk patients with aggressive B-cell lymphomas. Some poor risk pts seem to be cured with the treosulfan-based HD-chemo-immuno-therapy. In cases of progression rescue therapies may be successfully administered as shown by the favorable OS rate. This study has now been extended as a multicenter trial.