bluuebunny/crossref_metadata_2025 huggingface dataset:
Markers of Iron Overload Are Poor Prognostic Factors in Stem Cell Transplantation.
Authors: Connor Rebecca , Molnar Istvan , Lovato James , Grover Manisha , Hurd David , Pomper Gregory , Torti Suzy V. , Torti Frank M.
Published: April 2020

Transfusional iron overload is common in survivors of acute leukemia and hematopoietic stem cell transplantation and might cause long-term liver dysfunction. Routine evaluation for iron overload in such patients is recommended because excess iron can be readily removed from the body via phlebotomy or chelation. Iron overload might be associated with worse survival after stem cell transplantation in these diseases. We were interested in determining whether levels of the iron binding protein ferritin or the serum transferrin receptor (TfR) were predictive for survival. In a prospective study, we examined the correlation between iron parameters at the time of transplantation and overall survival. Serum ferritin, transferrin saturation, and TfR were measured before preparative regimen on patients who underwent hematopoietic stem cell transplantation between 1999 and 2004 for the diagnosis of aplastic anemia, MDS or acute leukemia (n=79). We used the number of transfusions before transplantation as a measure of iron load. Among these iron markers, serum ferritin correlated the most with the number of transfusions, regardless of remission status. High ferritin (>1,500 ng/ml), low TfR (≤4 μg/ml) and low TfR/log ferritin ratio (≤2) were associated with shorter survival (p=0.005, 0.04, and 0.001 respectively)(Figure 1). Among acute leukemia patients in remission, there was no difference in overall survival between patients with high or low iron markers. Markers of iron excess (serum ferritin >1,500 ng/ml, TfR/log ferritin ratio ≤2) at the time of stem cell transplantation is associated with shorter survival in MDS, aplastic anemia and acute leukemia with active disease. These results demonstrate that knowledge of patient ferritin and TfR levels can aid in risk stratification. The results also suggest that patients with high levels of ferritin may benefit from iron chelation before treatment.

Figure 1: Overall Survival based on iron parameters (A) Serum Ferritin (B) Serum Transferrin Receptor (C) TfR (mcg/ml) divided by log ferritin (ng/ml) Figure 1:. Overall Survival based on iron parameters (A) Serum Ferritin (B) Serum Transferrin Receptor (C) TfR (mcg/ml) divided by log ferritin (ng/ml)
Downregulation of Interleukin-13 by PUVA Treatment in a Human Model of Graft-Versus-Host Disease May Highlight the Importance of This Cytokine in the Mechanism of Extracorporeal Phototherapy Treatment.
Authors: Marshall Scott R. , Wang Xiao N. , McArthy Chris M. , Jackson Graham , Dickinson Anne M.
Published: April 2020

Graft-versus-Host disease (GvHD) remains the most serious complication following haemopoietic stem cell transplantation, with an incidence of 40–60% and can be fatal in up to 50% of cases. Extracorporeal phototherapy (ECP) is a novel treatment of both acute and chronic GvHD involving psoralen and UVA (PUVA) treatment of peripheral blood cells with high reported success even in those resistant to conventional immunosuppressive treatments. ECP appears to induce selective immune suppression without increased rates of infection or disease relapse. It is well tolerated by patients with minimal side effects and therefore is emerging as a highly desirable therapy. However, its mechanism of action remains poorly understood. An in vitro human skin explant model for GvHD has been used to study the role of cytokine changes induced by ECP. The model involves sensitising donor lymphocytes with recipient lymphocytes in vitro in a primary mixed lymphocyte reaction and then evaluating the secondary response on recipient skin biopsies by grading the graft-versus-host reactivity (grades I-IV) histopathologically using the Lerner grading system for GvHD. The assay has been proved to be superior to other assays used to predict clinical GvHD and has been used to investigate the pathophysiology of GvHD. Skin explant supernatants were collected and stored at −80 C and measured in batches using a multiplex Th1/Th2 cytokine assay. In 20 experiments where PUVA treatment of responder cells caused down regulation of GvHR in the skin explant model, statistically significant downregulation of IL-13, IL-5 and IFNgamma (p=<0.05) was demonstrated. No changes of IL-6, IL-1b, IL-10, IL-2, IL-4 or TNFalpha levels were demonstrated. Further evidence for the importance of IL-13 was highlighted in 3 skin explant assays where no downregulation of GvHR was seen with PUVA treatment and IL-13 levels remained high. Jordon et Al (Blood Jan2004) have documented the association between IL-13 production and the incidence of acute GvHD. Our data adds further evidence to challenge the notion that acute GvHD is purely a Th1-type cytokine response and that there may be a significant link between the Th2-type cytokine IL-13 with acute GvHD. Furthermore, downregulation of IL-13 and by PUVA may be important in the control of GvHD. More skin explant assays will be performed to consolidate these provisional findings.
Comparison of Pathology Transform of Liver, Spleen, Intestinal Tract and Skin with Acute Graft-Versus-Host Disease in Mice.
Authors: Wang Chunyan , Tan Huo , Huang Zhenqian , Zhang Huanzhu , Guo Kunyuan
Published: April 2020

Objective: To study the pathology transform of liver, spleen, intestinal tract and skin with acute graft-versus-host disease after myeloablative MHC mismatched BMT in mice.

Methods: The murine model of MHC mismatched BMT was established by using (BALB/c H-2d mouse as the recipient, and C57BL/6H-2b mouse as the donor. 30 recipient mouse were divided into 3 groups (n=10) after irradiation (TBI 60Co 9.0Gy). simple-irradiation group, MHC mismatched GVHD group: the BALB/c H-2d mice were conditioned with 9.0Gy, after a interval of four hours followed by infusion of C57BL/6H-2b mice bone marrow cells (1×107/one) and spleen cells (3×107/one). syngeneic BMT group: C57BL/6H-2b mice were conditioned with 9.0Gy, after a interval of four hours followed by infusion of C57BL/6H-2b mice bone marrow cells (1×107/one). The effect was assessed by hemotopoietic reconstruction, survival time, body weight, histopathology in the recipients.

Rasults:

Life span: survival time was (5.23±0.78) days for the simple-irradiation group, survival time was (14.67±2.34)days for MHC mismatched GVHD group, beyond 30 days for syngeneic BMT group. Pathology results: GVHD pathology manifestation were found in MHC mismatched GVHD group. The severity of GVHD pathology transform in mice were based on the occurrence time of GVHD. The GVHD pathology transform of liver, spleen, intestinal tract and skin in the same mouse were not parallel which GVHD pathology transform of spleen was the severest, the nest were intestinal tract and skin, GVHD pathology transform of liver was the trivial, even more normal. 3 of 10 in GVHD group had skin III-IV GVHD, but normal liver.

Conclusion: The result have shown that the onset time of liver GVHD in four organs was the last in myeloablative MHC mismatched BMT in mice.
Rejection of Primary Lymphoma Cells Derived from c-myc-Transgenic Mice after Haploidentical Transplantation: Treatment of the Tumor May Confer to Resistance Against GvL-Effect.
Authors: Sukumar Madhusudhanan , Wilke Andrea , Mautner Josef , Kolb Hans-Jochem , Bornkamm Georg , Gerbitz Armin
Published: April 2020

The long term prognosis of the High Grade B-cell-lymphoma in adults is still very poor, especially in the case of resistance to chemotherapy. To date allogeneic stem cell transplantation as a last treatment option results in poor outcomes due to high transplant related mortality or disease progression. This dilemma raises the question of whether transplant related mortality could be reduced by earlier transplantation, and whether such tumors can be recognized by an allogeneic graft providing a graft versus lymphoma effect. The immunology behind allogeneic rejection of high grade lymphomas is poorly understood due to a dearth of good animal models. Using a transgenic mouse model in which the human c-myc oncogene is driven by the human immunoglobuline lambda locus mimicking a t(8;22) translocation of Burkitt’s lymphoma, we established primary lymphoma cell lines. C57BL/6c-myc tg mice were crossbred with DBA mice and lymph nodes from tumor bearing F1-mice were explanted and seeded on irradiated human MRC5 fibroblast feeder cells. Approximately 70% of all explanted lymphomas established long term cultures which could be maintained free of feeder cells after 4 to 6 weeks. FACS analysis of lymphoma cells displayed strong CD19 expression, reduced expression of MHC Class I and II and, in several cases, low expression of costimulatory molecules such as CD80, CD86 and CD54. The phenotype was maintained over time with a follow up of up to 4 months. As few as 100 lymphoma cells gave rise to orthotopic tumors or systemic disease within 40 days after s.c. or i.v. injection, respectively. On the contrary, when 50 Mio. F1-lymphoma cells were injected into haploidentical C57BL6 parental animals, no tumor growth could be observed after at least 100 days of follow up. Despite fast growth and low expression of MHC Class I and costimulatory molecules, lymphoma cells were easily rejected in a haploidentical setting. Ex vivo chemotherapy treatment of lymphoma cells resulted in resistance after 2 courses of 100nM Adriamycine. Increased doses up to 500nM Adriamycine further accelerated resistance and growth speed of the cells. Flow cytometric analysis indicated a reduced fraction of apoptotic cells in culture suggesting selection for cells bearing alteration in the apoptotic pathways. In further experiments altered cells will be tested in haploidentical settings to confirm clinical experience in our model.
Effect of Intravenous Busulfan Versus Total Body Irradiation on Donor Chimerism and Acute Graft-Versus-Host Disease (GVHD) after Allogeneic Stem Cell Transplantation (AlloSCT) in Mice.
Authors: Wang Jie , Zhou Xiaotao , Symons Heather , Levy Moshe Y. , Fuchs Ephraim J.
Published: April 2020

The goals of administering transplantation conditioning to leukemia patients undergoing alloSCT are to kill tumor cells, prevent rejection of the donor graft, create “space” for donor hematopoiesis, and provide an overall milieu that favors a donor T cell-mediated “graft-versus-leukemia” effect. However, transplantation conditioning also increases the incidence and severity of acute GVHD by damaging non-hematopoietic tissues and by inducing lymphopenia, which augments the antigen-driven expansion of alloreactive T cells. The purpose of this study was to compare the relative safety and efficacy of transplantation conditioning with intravenous busulfan (Busulfex; ESP Pharma, Edison, NJ) versus total body irradiation (TBI) by administering titrated doses of either agent to mice and comparing their effects on: 1) donor chimerism after syngeneic and semi-allogeneic (parent into F1) SCT; 2) graft rejection after MHC-matched allogeneic SCT; and 3) acute GVHD after semi-allogeneic SCT. Both agents induced titratable donor chimerism after syngeneic BMT, but TBI was more immunosuppressive, since allogeneic marrow engrafted after 700 cGy TBI but not after an equivalently myelotoxic dose of Busulfex (60 mg/kg). When given in equivalently myelotoxic doses, TBI always induced more GVHD than did IV busulfan, as measured by weight loss and the augmentation of donor T cell and myeloid chimerism. As a result, stable mixed hematopoietic chimerism was generated more readily in mice conditioned with nonmyeloablative doses of busulfan than in mice conditioned with equitoxic doses of TBI. These results demonstrate that IV busulfan promotes GVHD to a lesser extent than does an equivalently myelotoxic dose of TBI. IV busulfan may be the preferred agent if stable mixed hematopoietic chimerism is the desired outcome. The relative roles of lymphopenia versus tissue damage in the differential outcomes of TBI versus Busulfex conditioning are being investigated.
Poor Graft Function Following Allogeneic Stem Cell Transplantation: High Rate of Complete Recovery Using Boost CD34+ Selected Peripheral Blood Stem Cells without Further Conditioning.
Authors: Larocca Alessandra , Bruno Barbara , Di Grazia Carmen , Gualandi Francesca , Occhini Domenico , Raiola Anna Maria , Dominietto Alida , Bregante Stefania , Lamparelli Teresa , Van Lint Maria Teresa , Pogliani Enrico Maria , Bacigalupo Andrea
Published: April 2020

Background: we have shown in a previous study that approximately 30% of patients may experience poor graft function (PGF) following an allogeneic hemopoietic stem cell transplant (HSCT); it is uncertain whether a boost of donor stem cells is beneficial in terms of trilineage recovery (TLR) and transplant related mortality (TRM).

Aim of the study: To compare infusion of boost donor stem cells in patients with primary PGF (who failed to achieve sustained graft function) and secondary PGF (patients who developed PGF after complete hematologic recovery).

Methods: we have attempted to rescue PGF using stem cells from the same donor in 54 patients affected by hematologic malignancies: 20 patients received no further infusion (group A), 14 received a boost of unmanipulated marrow or blood cells from the original donor, without further conditioning (group B), and 20 received donor cells after CD34 selection without conditioning (group C).

Results: Respectively 40%, 36% and 75% of patients in groups A, B and C obtained a trilineage recovery (p=0.02). TLR was more frequent in secondary PGF (69%) vs primary PGF (36%) (p=0.09), and more frequent in recipients of PB boost donor cells (p=0.02). There was no effect of donor type on hematologic recovery. TRM was 55%, 64%, 25% respectively in groups A, B and C (p=0.06) and was highly correlated with TLR (p=0.00001). PGF was the primary cause of death in 30%, 21%, 10% in the 3 groups, graft vs host disease in 5%, 36%, 10%.

Conclusion: The study indicates that a boost of CD34 selected PB donor cells is associated with a high chance of trilineage recovery and low risk of acute GvHD. A boost of unmanipulated donor cells does not seem to offer an advantage over no infusion. TRM is lower when using PB CD34 selected cells.

Figure 1: trilineage response in the 3 groups Figure 1:. trilineage response in the 3 groups Figure 2: TRM according to hematologic recovery Figure 2:. TRM according to hematologic recovery
The Different Dynamics of Chimerism Evolution Determines the Success of Myeloablative, Reduced Intensity Conditioning and T-Cell Depleted Allogeneic Stem Cell Transplantation.
Authors: Buño Ismael , Balsalobre Pascual , Simón Ainhoa , Iglesias Gustavo , Manzano Cintia , Carrión Rafael , Serrano David , Gómez-Pineda Alfonso , Díez-Martín José L.
Published: April 2020

Background: The dynamics of chimerism evolution determines the success of allogeneic stem cell transplantation (SCT). Several factors such as the intensity of the conditioning regimen, the T-cell content of the graft or the GVHD prophylaxis, influence the degree of chimerism after SCT. Objective: To evaluate the dynamics of chimerism after different SCT settings (ablative, reduced intensity conditioning -RIC- and T-cell depleted -TCD-) and its influence in the success of the procedure.

Patients and Methods: The study includes 68 SCT: 32 ablative (including 7 from HLA matched unrelated donors -UD-), 19 RIC and 17 TCD (including 8 from haploidentical donors and 2 from UD with 1 HLA disparity). Chimerism analysis was performed by FISH for the sex chromosomes or STR-PCR (sensitivity 1 Samples obtained on days +30, +100, +180, +365 and once a year thereafter, included bone marrow (BM) and peripheral blood (PB). Moreover, chimerism was analyzed in PB and leukocyte lineages (T lymphocytes CD3+, B lymphocytes CD19+ and myeloid cells CD15+ isolated (purity >95%) by immunomagnetic means, AutoMACS, Miltenyi Biotec), every 2 weeks, starting on day +15 (except in ablative), and until complete chimerism (CC) was achieved. Results of chimerism follow-up were censored once the diagnosis of relapse or rejection was established.

Results: The incidence (% patients) of mixed chimerism (MC) on day +30 (ablative: BM 27%, PB 15%; RIC: BM 40%, PB 41%, CD3 40%; TCD: BM 31%, PB 33%, CD3 54%), as well as its dynamics (MC on day +100: ablative BM 8%, PB 4%; RIC BM 8%, PB 15%, CD3 22%; TCD BM 20%, PB 40%, CD3 37%) were different in the three SCT settings. All except 2 CD15 samples analyzed showed CC. Moreover, the percentage of recipient cells (%R) was significantly higher after RIC and TCD than after ablative SCT, as well as in T lymphocytes than in BM or PB (7/8 cases with simultaneous studies showed MC in T lymphocytes and CC in PB). All RIC SCT evolved to CC by day +180 while TCD SCT showed persistent MC (2 patients with stable MC after one year). The incidence of rejection was greater after RIC (2/19) and TCD (4/17) than after ablative SCT (2/32). All these patients showed MC, mainly in T lymphocytes, which allowed early diagnosis and successful treatment with immunosuppression withdrawal and donor leukocyte infusion. Patients with CC in PB/T lymphocytes on day +30 had a higher incidence of GVHD>I than those with MC. In the present series, however, a relationship between chimerism and relapse, disease free survival or overall survival, was not observed.

Conclusions: SCT with greater incidence of MC (RIC and TCD) favor immune tolerance between donor and recipient which reduces the risk/severity of GVHD at the expense of a higher incidence of graft rejection.
BEAC or BEAM Chemotherapy Followed by Autologous Stem Cell Transplantation in Non-Hodgkin’s Lymphoma Patients: Comparative Analysis on Efficacy and Toxicity.
Authors: Koo Ja Eun , Kim Shin , Ko Ock Bae , Lee Danbi , Chong Young Pill , Kang Yoon-Koo , Huh Jooryung , Suh Cheolwon
Published: April 2020

Background: Non-Hodgkin’s lymphoma (NHL) is the major indication of high dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). However, little is known on the comparative efficacy and toxicity of various HDC regimens.

Aims: This study aimed to compare the efficacy and toxicity of BEAC and BEAM regimen.

Methods: Between April 1994 and February 2005, 97 NHL patients were received HDC with BEAC (N=69) or BEAM (N=28) followed by ASCT at Asan Medical Center. We matched one patient received BEAM with two patients received BEAC who has same International Prognostic Index (IPI). Thus total 84 patients (56 in BEAC group and 28 in BEAM group) were analyzed.

Results: Of 84 patients, 55 (65.5%) were male, 29 (34.5%) were female and median age was 40.5 (15–65) years. Baseline characteristics such as age, sex, disease status at ASCT, histology, stage at ASCT, IPI were not different between two groups. Time to neutrophil engraftment (WBC>0.5′109/mm3) was significantly longer in BEAC group (14.5days) than in BEAM group (11.0days, p=0.002). Total amount of RBC transfusion was more in BEAC group than in BEAM group (6.5 units vs. 3.7 units, p=0.037). Time to platelet engraftment (platelet>20′109/mm3) and total amount of platelet transfusion were different between two groups. Patients received BEAM had more frequent WHO grade ≥ 2 diarrhea than those received BEAC (46.4% vs. 19.6%, p=0.010). But, other clinically important toxicity such as mucositis, nausea/vomiting, bleeding were not different between two groups. In addition, neutropenic fever and documented infection were not different between two groups. Two year overall survival (OS) rate was 30% in BEAC group and 66% in BEAM group. Two year event free survival (EFS) rate was 34% in BEAC group and 61% in BEAM group. Both OS and EFS was significantly superior in BEAM group than in BEAC group (p=0.049, p=0.032, respectively).

Summary/Conclusions: BEAM appears to be a superior HDC regimen in the aspect of OS and EFS than BEAC while regimen related toxicity is similar except more frequent diarrhea in BEAM.
Pegfilgastrim after Allogeneic Transplantation - A Alternative to Daily Filgastrim?.
Authors: Wolschke Christine , Zabelina Tatjana , Heinzelmann Marion , Dahlke Joachim , Kroeger Nicolaus M. , Zander Axel R.
Published: April 2020

Long time of aplasie after allogeneic Stem cell- or Bone marrow-transplantation increase the risk of infections complications. Studies showed the positive effect of daily filgastrim to reduce the duration of aplastic time. The use of the Pegfilgastrim promise a simple handle with a single doses after transplantation.

Between December 2004 and July 2005 we observed 19 patients with different diseases after SCT or BMT.

All patients received a single doses subcutaneous injection of 6 mg pegfilgastrim on day 5 after transplantation. The median leucocytes engraftment was on day 16 after transplantation. The incidence of neutropenic infections was 84 percent with fever unknown origin, 21 percent with catheter induced infections and 10 percent with fungal pneumonia. Side effects of the cytokines had not been observed. The median hospitalisation was 33 days. In compared with the daily doses of Filgastrim 5 mg/kg/day was the duration to leucocytes engraftment and the infections profile similar. The use of the single injection doses of 6 mg pegfilgastrim shows a safe and comfortable profile for patients after allogenic transplantation.

Age 17 – 61 years, median 47 years Sex 11 male, 8 female Diseases 8 acute myeloid leukaemia, 1 acute lymphatic leukaemia, 1 chronic myeloid leukaemia, 1 Thalassaemia, 1 non hodgkin lymphoma, 1 osteomyelofibrosis, 5 multiple myeloma, 1 myelodysplastic syndrom Conditioning regime 7 normal conditioning, 12 reduce intensity conditioning Type of transplantation 12 MUD-PBSCT, 5 MMUD-PBSCT, 2 MUD-BMT CD34+ count median 7,9 x 10 6 /kg KG Engraftment of leucocytes median 16 days (10–25 days) Infection disease 16 FUO (84%), 2 fungal-pneumonia (10%), 4 sepsis of catheter (21%) Duration of hospitalisation median 33 days (17 – 47 days)
Treosulfan + Fludarabine +/− Thymoglobulin - An Effective Low Toxicity Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia.
Authors: Holowiecki Jerzy , Giebel Sebastian , Wojnar Jerzy , Krawczyk-Kulis Malgorzata , Wylezol Iwona , Markiewicz Miroslaw , Kruzel Tomasz , Holowiecka-Goral Aleksandra , Kopera Malgorzata
Published: April 2020

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only treatment of proved long-term efficacy in chronic myeloid leukemia (CML). However, high procedure-related toxicity observed after oral busulfan- or TBI-based conditioning limits its applicability and deteriorates outcome. Between 2003–2005 a phase II study was conducted to evaluate the feasibility of a new preparetive regimen consisting of Treosulfan (a soluble alkylyting agent) 14 g/m2/d. on days -6, -5, -4, Fludarabine 30 mg/m2/d on days -5, -4, -3, -2, -1, and, in case of unrelated donor transplants (URD-HSCT), anti-thymocyte globulin (Thymoglobulin) at a total dose of 6 mg/kg. Results were compared to those from the historical control group of CML patients treated with oral Busulfan (16 mg/kg) + Cyclophosphamide (120 mg/kg) (BuCy) in the same institution between 2000–2003. 35 patients (age 35, range 16–52 years) with CML in the 1st chronic phase (n=33) or in 2nd chronic phase (n=2) were included in the study. Median interval from diagnosis to alloHSCT equaled 10 (6–144) months. 22 (63%) patients were given transplant from an unrelated donor, 13 (37%) - from an HLA identical sibling. Bone marrow was used a source of stem cells in 29 patients, peripheral blood - in 6 cases. GVHD prophylaxis consisted of Cyclosporin A and short-course Methotrexate. All patients engrafted after a period of absolute agranulocytosis. Median time to neutrophil recovery >0.5 G/L was 24 (10–42) days, and to PLT >50 G/L - 21 (13–38) days. 1/35 patient experienced grade 3 mucositis; no severe (grade 3–4) neutropenic infection nor VOD was observed. The incidence of grade II acute GVHD was 17%, grade III–IV - 3%. The cumulative incidence of non-relapse mortality (NRM) at 2 years equaled 14% (4/35). Causes of death were: EBV-LPD, late neuroinfection, late fungal infection, acute GVHD.

At 2 years the probability of the overall survival and hematological relapse-free survival equaled 86% (+/−7%) and 83% (+/−7%). Respective rates for the control BuCy group (n=78) were significantly lower: 55% (+/−6%), p=0.02, and 54% (+/−6%), p=0.03. Seven patients in the Treosulfan+Fludarabine group required immunosuppression taper and additional interferone or imatinib treatment because of incomplete donor chimerism or molecular/cytogenetic relapse after initial response.

We conclude that Treosulfan+Fludarabine+/−Thymoglobulin myeloablative conditioning is associated with low organ toxicity, low incidence of acute GVHD and NRM. The regimen is feasible for CML patients and appears superior in comparison with BuCy.
Reduced Intensity Conditioning Unrelated Transplant Plus Cyclosporine and MMF as GVHD Prophylaxis: Results of a Prospective Study.
Authors: Perez-Simon J.A. , Martino R. , de la Camara R. , de Oteiza J. Perez , Moraleda J.M. , Diez-Campelo M. , Sureda A. , Alegre A. , Sierra J. , Miguel J.F. San
Published: April 2020

Some studies have suggested that mycophenolate mofetil (MMF) offers a similar efficacy in terms of GVHD prophylaxis as compared to methotrexate (MTX) but a faster engraftment and a lower incidence of mucositis.

We have analyzed the results of fludarabine (150 mg/m2) and melphalan (140 mg/m2) or busulphan (10 mg/m2) plus Cyclosporine (CsA) and MMF instead of MTX as GVHD prophylaxis in a series of 30 patients undergoing unrelated allogeneic transplantation. Median age was 44 years (18–60). Patients younger than 40 were required to have a previous comorbid condition (8 had a previous autologous transplant; 2 had proven fungal infection; 1 had severe altered lung capacity). Twelve patients were diagnosed with AML, 4 had ALL, 4 MDS, 2 CML, 3 CLL, 3 NHL, 2 MM/WM. Disease status at transplant was 1st or 2nd CR in 12 patients, >2nd CR or PR in 11 patients while the remaining patients had active disease at the time of transplant (relapse, refractory, untreated diasease). Median day to reach > 0,5 x 109 granulocytes / L was +17 and to reach > 20 x 109 platelets / L was +13. At a median follow up of 445 days among patients alive, projected overall survival (OS) and event free survival at 3 years are 47% and 30%, respectively. Overall TRM was 32%. Cumulative incidence of grades 2–4 and 3–4 aGVHD was 67% and 33%, respectively while cumulative incidence of extensive cGVHD was 70%. Gut was the organ most severely involved in aGVHD in 10 out of 16 patients while liver was involved in only 3 cases. Interestingly, among patients who developed aGVHD, incidence of skin (80%) and liver (22%) involvement were similar to that observed in a similar series of patients receiving related donor transplant using the same RIC plus CsA and MTX instead of MMF while the incidence of gut involvement was significantly higher (64% vs 42%).

In conclusion, the RIC used in the current study plus CsA and MMF offers promising results in high risk patients. In terms of GVHD prophylaxis, MMF shows a good efficacy at skin and liver but poor at the gastrointestinal tract.
Prolonged Administration of Aprepitant Does Not Increase Toxicity in Patients Undergoing High Dose Chemotherapy and Autologous Stem Cell Transplant.
Authors: Junagadhwalla Mehnaz , Chilton Joanne , Gentile Teresa
Published: April 2020

Aprepitant is a neurokinin-1 receptor antagonist used for the prevention of chemotherapy induced nausea and vomiting (CINV) with highly emetogenic chemotherapy. The recommended dose for the prevention of CINV is 125 mg orally on day of treatment, followed by 80 mg orally on days 2 and 3. It is known that aprepitant inhibits cytochrome P450 3A4, therefore elevating plasma concentrations of various drugs, including certain chemotherapy drugs such as etoposide. Given the highly emetogenic nature and length of conditioning regimens used in Bone Marrow Transplant (BMT) patients, we elected to treat patients for a longer period of time with aprepitant. Twenty-five patients received aprepitant for an average of 7.6 days, with an initial dose of 125 mg p.o. on day 1 and 80 mg p.o. on subsequent days. Eleven patients were women and the remaining fourteen were men. The youngest transplanted patient was 20 and the oldest was 68 years old. Engraftment was defined as

an absolute neutrophil count (ANC) greater than 1000 x 3 days and number of days until platelet transfusion independence.

The mean day to ANC recovery was 12.3 and the mean day of platelet transfusion independence was 13. This data was based on 24 patients, as one male patient died day +10 secondary to RSV bronchiolitis prior to engraftment. The incidence of mucositis, neutropenic fevers, pulmonary toxicities, and other complications did not differ compared with previously established data. We conclude that aprepitant can be used safely without adding significant toxicity to therapy with high dose chemotherapy in autologous stem cell transplant patients. A randomized prospective trial should be considered to evaluate the efficacy in reducing CINV and to further evaluate toxicity.
Survival Benefit of Asymptomatic Cytomegalovirus Reactivation and Early Lymphocyte Recovery after HLA-Identical Allogeneic Peripheral Blood Stem Cell Transplantation.
Authors: Kim Dong Hwan , Sohn Sang Kyun , Baek Jin Ho , Kim Jong Gwang , Lee Kyu Bo , Park Jae-Hoo
Published: April 2020

Background: Cytomegalovirus (CMV) reactivation (CMV-R) is associated with increased morbidity after allogeneic stem cell transplantation (SCT). However, after the introduction of ganciclovir preemptive therapy, CMV-R can be successfully controlled if the recipient’s immunity recovers. Although many investigations have already focused on CMV-R as a risk factor, data related to the impact of asymptomatic CMV-R on transplant outcomes is scarce. Accordingly, the present study analyzed the differences in the transplant outcomes the immune reconstitution according to the CMV-R after allogeneic PBSCT.

Method: A total of 76 patients undergoing allogeneic peripheral blood stem cell transplantation (PBSCT) were included in the current study. The transplant outcomes and immune reconstitution after 3, 6, and 12 months were analyzed according to the occurrence of CMV-R in 33 patients.

Result: The analysis revealed a favorable prognosis for the group with CMV-R compared to those without CMV-R: p=0.0037 for OS, p=0.0204 for NRM, and p=0.05 for the risk of relapse. CMV-R was also found to correlate to the lymphoid reconstitution (p=0.024). In multivariate analyses, CMV-R was found to be a favorable prognostic factor in terms of OS (p=0.010, hazard ratio [HR] 2.948) and NRM (p=0.05, HR 2.665), along with a higher transplant CD34+ cell dose (p=0.003 for OS, p=0.002 for NRM), standard risk (p=0.023 for OS), and acute GVHD grade 0~2 (p=0.007 for NRM).

Conclusion: In a PBSCT setting, CMV-R did not seem to be a poor prognostic factor in terms of OS and NRM, possibly due to the accelerated lymphoid immune reconstitution associated with CMV-R.

Figure. Survival curve for overall survival (A) and lymphoid immune reconstitution according to CMV reactivation (B) Figure. Survival curve for overall survival (A) and lymphoid immune reconstitution according to CMV reactivation (B)
Heterophilic and Homophilic Interactions of Junctional Adhesion Molecule-C (JAM-C) Mediate Different Intercellular Adhesive Interactions.
Authors: Chavakis Triantafyllos , Orlova Valeria , Song Kaimei , Andrei-Selmer Cornelia L. , Santoso Sentot
Published: April 2020

Junctional adhesion molecules (JAM) are a new subfamily of the Ig superfamily. We recently identified that the third member of this family, JAM-C, expressed on endothelial, epithelial cells and platelets (i) undergoes a heterophilic interaction with leukocyte β2-integrin Mac-1 (CD11b/CD18) (J Exp Med. 2002; 196:679–91) and (ii) that endothelial JAM-C is predominantly localized within tight junctions and mediates neutrophil transendothelial migration in a Mac-1-dependent manner in vitro and in vivo (J Biol Chem. 2004, 279:55602–8). Here, we characterized JAM-C to undergo a homophilic interaction that participates in tumor cell-endothelial cell interactions. As assessed in a purified system, recombinant soluble JAM-C in fluid phase bound to immobilized JAM-C; moreover, JAM-C-transfected CHO cells adhered to immobilized JAM-C. The homophilic interaction of JAM-C was mediated by the isolated amino-terminal Ig-domain (D1) but not the carboxy-terminal Ig-domain (D2) of the molecule. Dimerization of JAM-A is dependent on the sequence RVE in the aminoterminal Ig-domain. This motif is conserved in JAM-C (R64I65E66) and a single amino acid mutation in this motif (E66R) abolished the homophilic interaction of JAM-C. The lung carcinoma cell line NCI-H522 was found to be positive for JAM-C expression. NCI-H522 cells adhered to immobilized JAM-C, as well as to JAM-C-transfected CHO cells, but not to mock-transfected CHO cells or to CHO cells transfected with the JAM-C mutant (E66R). Adhesion of NCI-H522 cells to JAM-C protein or JAM-C-transfected CHO cells was abolished in the presence of soluble JAM-C or the isolated D1. Furthermore, the adhesion of NCI-H522 cells to endothelial cells was significantly blocked by soluble JAM-C or the isolated D1. Thus, JAM-C undergoes a homophilic interaction via the R64I65E66 motif on the membrane-distal Ig-domain of the molecule. The homophilic interaction of JAM-C can mediate tumor cell-endothelial cell interactions and may thereby be involved in the process of tumor cell metastasis. Together, the heterophilic and homophilic interactions of JAM-C mediate distinct adhesive interactions.
Micafungin Is Extremely Effective Against Fungal Infections Complicating Hematological Malignancies: Report of a Multicenter Study by N-FISH (Niigata Fungal Infection Study Group in Hematology).
Authors: Aoki Sadao , Takizawa Jun , Seki Yoshinobu , Takai Kazue , Nikkuni Koji , Maruyama Souichi , Nomoto Nobuhiko , Tsukada Nobuhiro , Aizawa Yoshifusa
Published: April 2020

[Background]Micafungin (MCFG) is a candin antifungal agent, and was marketed in Dec. 2002 in Japan and in Apr. 2005 in the United States. The Niigata Fungal Infection Study Group in Hematology (N-FISH) performed a multicenter prospective study to clarify the therapeutic effects of MCFG on deep fungal infections complicating hematological malignancies.

[Methods]A total of 36 pts. who had been treated in centers belonging to N-FISH between Oct. 2003 and Apr. 2005 were included in this study. They consisted of 14 men and 22 women with a mean age of 53.5 years: 14 pts. with AML, 10 pts. with malignant lymphoma, 6 pts. with ALL, and 6 pts with other diseases. They had a proven fungal infection, or were suspected of having a fungal infection because of fever unresponsive to antimicrobial agents or from laboratory data. Three of them had a proven infection, and 33 were suspected of having a fungal infection. Three of these 33 pts. failed to respond to fluconazole. As a rule, MCFG was administered for more than 14 days until infectious symptoms improved or disappeared. When MCFG was judged ineffective because of the worsening of clinical symptoms despite the administration of MCFG, or when the administration of MCFG was judged difficult because of adverse effects, the drug was discontinued or replaced by other drugs. Two pts. orally received amphotericin B syrup singly.

[Results]The mean dose of MCFG was 2.6 mg/kg (1.5–4.2 mg/kg), and the mean duration of administration was 15.9 days (5–85 days). Complete or partial response was achieved in 31 (86.1%) of the 36 pts., who showed improvements in infectious symptoms. In 4 pts, MCFG was discontinued because of insufficient effects. There were no breakthrough fungal infections within 7 days after the completion of MCFG therapy. Of the 36 pts., 31 (86.1%) and 24 (66.7%) survived 1 and 3 months after MCFG therapy, respectively. The cause of death was exacerbation of the primary disease, and not exacerbation or the onset of a fungal infection. Eight adverse events occurred in 7 pts.: hypoglycemia in 1, liver dysfunction in 3, eosinophilia in 1, kidney dysfunction in 2, and hypokalemia in 1. In 1 of the 3 pts. with liver dysfunction (grade 3), MCFG therapy was discontinued, with rapid improvement of the liver dysfunction. All other adverse events were mild, allowing continued MCFG therapy.

[Conclusion]This multicenter study demonstrated the effectiveness and safety of MCFG therapy for deep fungal infections complicating hematological malignancies. The results suggest that MCFG should be promptly used for fever associated with a fungal infection complicating hematological malignancies.
Hemophagocytic Syndrome (HPS) after Autologous Peripheral Stem Cell Tansplantation (APSCT) for Multiple Myeloma (MM)- Successful Treatment with High Dosages of Intravenous Immunoglobulin (IVIG).
Authors: Ostronoff Mauricio , Domingues Mariana Coutinho , Ostronoff Fabiana , Calixto Rodolfo , Florencio Rodrigo , Souto Ana Patricia , Sucupira Alexandre , Matias Kleber , Tagliari Clemente
Published: April 2020

HPS is characterized by activation of histiocytes with prominent hemophagocytosis in bone marrow and reticulo-endothelial system, resulting in cytopenias. Reactive HPS (R-HPS) is known to be associated with infection, malignancies and autoimmune disorders. We report a case of R-HPS with massive life-threatening gastro-intestinal (GI) tract bleeding after APSCT for MM which responded to high dosages of IVIG. In May 2005, a 54-year old female diagnosed with MM stage III A, achieved CR after 4 cycles of VAD. APSCT conditioning consisted of L-PAM 140mg/m2. 2x106 CD34+ cells/kg were infused. G-CSF 10μg/kg was started on D0. Pt was placed on cefepime and vancomycin (D+4) and amphotericin B (D+7) for FUO and discontinued after neutrophil recovered (D+10). During aplasia, she received 2 packed RBC and 4 PLT transfusions (irradiated and filtrated). On D+12 G-CSF was discontinued. Four days after thrombocytopenia aggravated (PLT 3000/mm3) and she presented with fever (39°C) and disseminated petechiae. Other coagulation tests were normal. A complete search for infection was negative- cultures (urine and blood) and thoracic, abdominal and sinus CT scan. Pt was again placed on cefepime, vancomycin and amphotericin B without defervescence. In the following 3 days, hypovolemic shock due to profuse GI tract bleeding occurred. Upper endoscopy showed diffuse petechiae and bleeding. Bone marrow (BM) aspirate was performed and revealed 3% histiocytes with hemophagocytic activity. R-HPS was diagnosed. Massive RBC and PLT transfusions were started (4x/day) without response. Search for HSV, EBV, HIV, CMV, auto-immune disease and malignancy were negative. She was on prophylactic acyclovir. On D+21 pt received IVIG 1g/kg/day for 2 days and dexamethasone 40mg for 4 days. Hemorrhage resolved and PLT counts improved. However, on D+30 PLT counts dropped again (PLT 24000/mm3) and BM aspirate showed persistent hemophagocytosis with 4% of histiocytes. A new course of IVIG was given and repeated once a week for 2 weeks when it was no longer needed. BM aspirate on D+39 was normal, with no evidence of hemophagocytosis and there was no recurrence of R-HPS. In this case platelet was the more affected cell lineage resulting in severe and life-threatening hemorrhagic syndrome. The immune mechanism of HPS is not clear, but a defect in immune regulation has been hypothesized. R-HPS after auto-BMT is rare event and appears to be associated with hematological and immunological recovery. We believe that IVIG was effective and its known mechanism of action is compatible with current knowledge of HPS pathophysiology. IVIG might be an effective treatment for R-HPS secondary to auto-BMT.
The Role of CD4+CD25+ T Cell and FOXP3 in Allogeneic Hematopoietic Stem Celltransplantation.
Authors: Liu Yuejun , Wu De Pei , Li Caixia
Published: April 2020

Objective To explore the relationship among CD4+CD25+ regulatory T cell, the expression of FOXP3 mRNA levels of donor BM and GVHD in allogeneic hematopoietic stem cell transplantation(allo-HSCT). Methods (1)Thirty patients undergoing allo-HSCT were enrolled in this study. The levels of donor CD4+CD25+ regulatory T cell were compared in the patients with GVHD and those without GVHD by immnofluorescence and flowcytometry. (2)The donor BM expressions of FOXP3 mRNA levels were analyzed by using reverse transcriptase polymerase chain reaction (RT-PCR). Results (1)All patients achieved engraftment. ANC ≥ 0.5′109•L−1and Plt ≥ 20′109•L−1 were at day 14(range, 12~15)and day 18 (range, 15~25) respectively. Acute GVHD occurred in 15 of 30 patients(50.0%) with gradeII°-IV° aGVHD (40.0%). Chronic GVHD developed in 6 (extensive 2, limited 4) out of 30 patients (20.0%). 3 patients relapsed.(2)The levels of CD4+CD25+ regulatory T cell pre-and pro-mobilization were (2.67±0.38) % and (5.01± 1.33)% respectively, no difference were observed(P>0.05).(3)Patients with I°~II° aGVHD demonstrated higher donor-type CD4+CD25+ immune regulatory T cell level than those with III°~IV° aGVHD; Patients with III°~IV° aGVHD showed much lower donor-type CD4+CD25+ immune regulatory T cell level than those without GVHD; no difference were observed between patients withI°~II° aGVHD and those without aGVHD.(4)The transcripts of FOXP3 donor BM were detected in seven donors of thirty recipients who received allo-HSCT. Three relapsed after transplantation;two developedI°aGVHD; and the other two had no GVHD. Donor BM FOXP3 transcripts were never detected in patients with II°~IV° aGVHD. Conclusion(1)Donor-type CD4+CD25+ immune regulatory T cell level was relative to recipient II°~IV° aGVHD. Up-grade donor-type CD4+CD25+ immune regulatory T cell level could reduce the incidence of aGVHD.(2)Donor BM FOXP3 transcripts were detected in patients without serious aGVHD after transplantation.
Basiliximab in the Treatment of Acute Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation.
Authors: Ma Xiao , Wu De Pei , Sun Aining
Published: April 2020

Objective: To explore the efficiency and side-effects of basiliximab in the treatment of steroid-refractory acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT).

Patients and Methods: Basiliximab, a chimeric interleukin-2 receptor antagonist, was evaluated in twenty-eight patients with steroid-refractory acute graft-versus-host disease after Allo-HSCT. Patients were transplanted from a related (n=9) or unrelated (n=6) HLA- identical donor or haplo-identical donor(n=13) because of chronic myelogenous leukemia (chronic phase n=11, accelerate phase n=2), acute myeloid leukemia (n=8), high risk acute lymphocytic leukemia (n=6), high risk non-Hodgkin’s lymphoma (n=1). Basiliximab was given at a dose of 20mg on the day after steroid-refractory acute GVHD had developed, and was repeated on day 4 in all these cases. The efficiency and side-effects of basiliximab were observed at the same time. Basiliximab was repeated again 4 weeks later in some cases of having response.

Result: None had infusion-associated or other side-effects after the treatment with basiliximab. Twenty-two of 28 patients (78.57%) responded to basiliximab, 15/28(53.57%) had a complete response (CR) of acute GVHD and 7/28 (25.00%) had a partial response (PR). Six of 28 patients (21.43%) did not respond. Chronic GVHD developed in 15/24 evaluable patients. Only 9/24 evaluable patients have no chronic GVHD and all had a complete response before.

Conclusion: Basiliximab is safe and effective in the treatment of steroid-refractory acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation(Allo-SCT).
Long Term Effects on GVHD and Survival Following the Use of G-CSF Stimulated Bone Marrow Versus G-CSF Mobilized Peripheral Blood Stem Cells in HLA Matched Sibling Transplant.
Authors: Beaven Anne W. , Shea Thomas C. , Gabriel Don A. , Comeau Terrance , Irons Robert , Moore Dominic T. , Lin Li , Sharf Andrew , Krasnov Carol , Brecher Mark E. , Serody Jonathan
Published: April 2020

Over the past decade, the use of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) during allogenic transplant has become common. Compared to the transplant of unmanipulated bone marrow, PBSCs showed earlier engraftment, but also showed more frequent and extensive chronic graft versus host disease (cGVHD). In an effort to monitor whether G-CSF stimulated bone marrow led to comparable engraftment and overall survival (OS), without increased cGVHD, we followed pts with matched related donors in two nonrandomized, sequential studies. One cohort received G-CSF mobilized PBSCs and the second received G-CSF stimulated bone marrow (GSBM). Eligible pts with ALL (2), AML (9), CML (19), MM (9) or recurrent/refractory NHL/HD (7) were enrolled from February 1994 through December 1998. All pts received busulfan (16mg/kg except MM 14mg/kg) and cyclophosphamide (120 mg/kg) followed by CSA and MTX for GVHD prophylaxis. Details of these studies have been previously published by Serody et al., Biol Blood Marrow Transplant.2000;6:434–40. At the time of the current analysis, the median follow-up for the surviving pts in the group that received PBSCs was 9 years, and 8 years for the group that received GSBM. At last count, 7/20 (35%) of the PBSC pts were still alive and 6 were disease-free. Median OS time and disease-free survival (DFS) time was approximately 3 years. In the GSBM group, 9/26 (35%) were alive and disease-free and one was alive with recurrence. Median OS time was 2 years with a median DFS time of 1.4 yrs. The DFS and OS difference between the PBSC and GSBM cohorts was not statistically significant (p = 0.6 and p = 0.9, respectively). We also divided pts into high risk (HR) (20 patients) and low risk (LR) (26 patients) groups. Analysis of the combined PBSC and GSBM cohorts showed that the LR pts did better than the HR pts. Median survival time for the combined HR pts was about 1 year while the median survival time for LR pts has not been reached (p=0.003). There was no significant difference in outcomes between the HR or LR pts treated with PBSC vs GSBM. At last count, the incidence of cGVHD was 12/20 (60%) in the PBSC cohort, and 11/26 (42%) in the GSBM group (not a statistically significant difference, p=0.37). Earlier, at one year post transplant (Serody et al, 2000), the percentages were 68% versus 37%, respectively, and statistically significant (p=0.049). While the current 18% incidence difference is not statistically significant, this percentage may represent a difference that is clinically relevant and that would be statistically significant with more pts. Unlike the cGVHD results, this latest analysis continued to demonstrate a lack of significant difference in OS and DFS results between the PBSC and GSBM cohorts.