bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Analysis of Clinical Outcomes between Unrelated Donor Peripheral Blood Stem Cell Transplantation and Bone Marrow Transplantation for Leukemia.
Authors: Fan Zhiping , Liu Qifa , Yang Kai , Sun Jing , Xu Dan , Zhang Yu , Wei Yong-qiang , Ye Chang-xiong , Jiang Qianli , Meng Fan-yi
Published: October 2019

Objective To evaluate hematopoietic reconstitution, immune reconstitution, infection, incidence of graft-versus-host disease (GVHD) and other complications between unrelated donor peripheral blood stem cell (PBSC) transplantation and bone marrow (BM) transplantation.

Methods The clinical results in 21 patients receiving a PBSC graft mobilized by granulocyte colony stimulating factor (G-CSF) from unrelated donors were compared to 32 patients receiving unrelated BM transplants.

Results The PBSC graft contained significantly more nucleated cells (P=0.000), and resulted in a significantly shorter time-to-neutrophil (12.43±3.67 versus 16.16±2.99 days) and platelet engraftment (14.67±6.19 versus 21.23±8.25 days), compared to the BM group (P=0.000, 0.003, respectively). T cell reconstitution between the two groups differed little after transplantation. The incidences of early-stage infection were 42.86% and 53.13% (not significant [NS]) in the PBSC and BM groups, respectively. Probabilities of acute graft-versus-host disease (aGVHD) were 61.90% and 71.88% (NS), of grades III to IV aGVHD 23.81% and 15.63% (NS) and of chronic GVHD 47.06% and 43.48% (NS) in the PBSC and BM groups, respectively. The probabilities of relapse were 6.90% and 12.50% (NS) in the PBSC and BM groups, respectively. The 2-year disease free survival (DFS) rates of the two groups were (50.14±12.00) % and (59.81±8.99) %( NS), respectively.

Conclusion G-CSF-mobilized PBSCs engraft rapidly in unrelated donor recipients compared to conventional BM, but T cell reconstitution and the incidence of infection between the two groups differed little. There were no significant differences of the incidence and severity of aGVHD and cGVHD, and 2-year DFS rates between the two groups.
Therapeutic CSF Primed Donor Lymphocyte Infusion Using Cells Reserved at the Time of Transplantation for Patients with Relapsed Hematologic Malignancies after allo-PBSCT.
Authors: Sohn Sang Kyun , Cho YoonYoung , Kim JongGwang , Chae YeeSoo
Published: October 2019

Background

Reharvesting leukocytes from donors for a donor lymphocyte infusion (DLI) is inconvenient and occasionally impossible in case of unrelated donors. The effect of a growth factor-primed DLI is known to be comparable to that of nonprimed DLI for patients with relapsed disease. We reserved some portion of PBSCs harvested at the time of transplantation for the purpose of future DLI for relaping disease.

Method

In total, ninety nine patients (43 high risk, 46 standard disease) with hematologic malignancies who were treated by allo-PBSCT were allocated on an intent-to-treat basis. The dose of CD34+ cells with a range of 2–6*106/kg was transplanted, and additional PBSCs were cryopreserved.

Result

PBSC harvest for transplantation allowed to reserve extra cells in 35 (67.3%) high risk patients and in low risk 25 (55.6%) patients. Among 29 patients (29.9%) who relapsed after allogeneic PBSCT, 19 (65.5%) patients were treated with mainly cytarabine-based chemotherapy followed by cryopreserved PBSC infusion. The median dose of CD3+ and CD34+ cells for the primed DLI was 1.43*108/kg and 4.75*106/kg, respectively. Six (24.9%) out of 19 relapsed patients exhibited a complete response after the primed DLI, and their 1-year survival rate was 36%. The new development or progression of graft-versus-host disease after the primed DLI was observed in 16 (82%) patients. Overall, the survival at 1 year after the primed DLI was 21%.

Conclusion

The induction of a graft-versus-leukemia effect through a primed DLI, using additional PBSCs reserved at the time of transplantation, would appear to be feasible for patients with relapsed hematologic malignancies. Furthermore, this approach seem to be more convenient for donors.
Risk Factors for Predicting CMV Infection in Allogeneic-PBSCT Setting: MNC Dose, Campath Use, and Acute GVHD Grade ≥II.
Authors: Ahn Byung Min , Moon Joon Ho , Cho Yoon Young , Chae Yee Soo , Kim Jong Gwang , Sohn Sang Kyun
Published: October 2019

Risk factors for predicting CMV infection in allogeneic-PBSCT setting: MNC dose, Campath use, and acute GVHD grade ≥II

Background: CMV infection remains an important complication of allogeneic stem cell transplantation (SCT). Campath-1H (anti-CD52) antibodies have been widely used in vivo for T-cell depletion following conventional and reduced intensity conditioning regimens and associated with a significant reduction in GVHD but at the cost of impaired immune reconstitution. We studied the risk factors, for the development of CMV infection after allogeneic SCT, including the use of Campath-1H.

Methods: From Sep. 1998 to May 2006, 122 patients who received allogeneic peripheral blood stem cell transplantation were enrolled. CMV infection was routinely sought by at least weekly screening for CMV related matrix protein pp65 antigenemia after engraftment (WBC>1,500/uL) was achieved. CMV antigenemia was treated with ganciclovir 5mg/kg twice daily i.v. as preemptive therapy for at least 10 days.

Results: The overall incidence of CMV infection was 56/122 (45.9%) cases with a median onset of 44 days post transplants. Risk factors for CMV infection in the multivariate analysis were acute graft-versus-host disease (GVHD) grade II-IV (p=0.015), use of Campath-1H in conditioning therapy (p=0.012), and mononuclear cell (MNC) doses in the transplants (p=0.010). Among conditioning therapies, the use of Campath-1H was associated with increased incidence of CMV infection (75.0%) compared with conventional conditioning therapy (40.9%)(p<0.01) and relatively early occurrence of CMV infection, median 22 days post transplant (p=0.016).

Conclusion:The incidence of CMV infection was strongly associated with acute GVHD, MNC doses, and especially Campath-1H use in an allogeneic PBSCT setting.

Multivariate Analysis for the Incidence of CMV infection RR 95% CI P-value Conditioning: use of Campath-1H 5.112 1.429–18.285 0.012 Acute GVHD, grade II-IV 2.696 1.209–6.010 0.015 Stem cell dose: MNC(×10^8/kg) 1.149 1.034–1.276 0.010 Stem cell dose: MNC ≥10 vs. MNC<10 2.613 1.165–5.859 0.020
Mesenchymal Stem Cells for Treatment of Severe Acute Graft-Versus-Host Disease.
Authors: Le Blanc Katarina , Frassoni Francesco , Ball Lynne , Lanino Edoardo , Sundberg Berit , Lonnies Lena , Roelofs Helene , Dini Giorgio , Bacigalupo Andrea , Locatelli Franco , Fibbe Willem F. , Ringden Olle
Published: October 2019

Mesenchymal stem cells (MSC) from adult bone marrow have the capacity to differentiate into several mesenchymal tissues and inhibit T-cell alloreactivity in vitro. Within the EBMT MSC expansion consortium we have used MSC to treat grades III–IV acute graft-versus-host disease (GvHD) in 40 patients. The MSC dose was median 1.0 (range 0.4–9) 10^6 cells/kg body weight of the recipient. No side-effects were seen after MSC infusions. Nineteen patients received one dose, 19 patients received two doses, two patients received three and five doses respectively. MSC donors were in five cases HLA-identical sibling donors, 19 haploidentical donors and 41 third-party HLA-mismatched donors. Among the 40 patients treated for severe acute GvHD, 19 had complete responses, nine showed improvement, seven patients did not respond, four had stable disease and one patient was not evaluated due to short follow-up. Twenty-one patients are alive between six weeks up to 3.5 years after transplantation. Nine of these patients have extensive chronic GvHD. One patient with ALL has recurrent leukaemia and one patient has denovo AML of recipient origin.

We conclude that MSC have immunomodulatory and tissue repairing effects and should be further explored as treatment of severe acute GvHD in prospective randomized trials.
Double Umbilical Cord Blood Transplant Patients Have a Higher Risk of HHV-6 Infection.
Authors: Chen Sharon F. , DeFor Todd , Thomas Avis J. , Baker K. Scott
Published: October 2019

By age 2 years, 90% of children will have had primary infection with human herpesvirus 6 (HHV-6), which then becomes latent. HHV-6 can subsequently reactivate and cause disease in an immunosuppressed person. To investigate the effect of high-dose acyclovir as a prophylaxis against HHV-6 infection and to investigate the risk factors for having a positive HHV-6 quantitative polymerase chain reaction (PCR) assay, we identified a cohort of hematopoietic cell transplant (HCT) patients who had clinical indications for obtaining a HHV-6 PCR assay from 2003–2005 and evaluated their prospectively collected data. A total of 442 patients, including children and adults, obtained a hematopoietic cell transplantation from 2003–2005. Of this cohort, 137 were tested for HHV-6 with a PCR assay (median age 19 years; range 0.3–68 years). A positive HHV-6 PCR assay was found in 38 of the patients. The cell source included single (n=26) or double umbilical cord blood (UCBT, n=67), bone marrow (BM, n=25) and peripheral blood (PB, n=19). The median age was not significantly different for patients who tested positive compared to those patients who tested negative for HHV-6. About 50% of the patients received high-dose acyclovir. There was no significant difference in the cumulative incidence of a positive HHV-6 PCR assay by post-transplant day 100 in patients who received high-dose acyclovir (1500mg/m2/day) compared to those who did not receive high-dose acyclovir (p=0.8). Double umbilical cord blood transplant patients had 6 times higher risk of a positive HHV-6 PCR assay compared to BM or PB transplant patients, after adjusting for the transplant conditioning regimen (Hazard ratio=6.2, 95%CI 1.79–21.35, p=0.004). Compared to single UCBT patients, double UCBT patients still had 2 times higher risk of a positive HHV-6 PCR assay (95%CI 1.1– 7.4, p=0.03). For double UCBT, a significantly higher rate of positive HHV-6 PCR assay was found for those patients who received a myeloablative conditioning regimen compared to a non-myeloablative regimen (p=0.01). The use of Fludarabine was not significantly different between myeloablative and non-myeloablative conditioning regimens in those patients who received a double UCBT. In summary, we did not find statistical evidence that high-dose acyclovir was an effective prophylaxis against HHV-6 infection, though the analysis may be hampered by low power. We did find that double umbilical cord blood transplant patients are at high risk of having a positive HHV-6 PCR assay compared to BM, PB and single UCBT patients. The underlying reason for this increased risk is unclear and further investigation will be clinically valuable.
Immune Reconstruction Inflammatory Syndrome (IRIS) with Invasive Aspergillosis (IA) in Patients (pts) with Hematological Cancer (Hem-Ca): Clinical and Research Implications.
Authors: Miceli Marisa , Grazziutti Monica , Woods Gail , Krishna Somashekar , Kiwan Elias , Rahman Mazher , Barlogie Bart , Anaissie Elias , Syed Nayyar
Published: October 2019

Background: Assessing IA outcome with conventional criteria is difficult particularly when clinical and radiological worsening coincides with neutrophil recovery. This worsening is assumed to be related to immune reconstitution (IRIS). Because it is not possible to distinguish between pts whose worsening is transient from those who have progressive IA, clinical and radiological deterioration usually prompts invasive diagnostic procedures and therapeutic modifications including investigational agents, surgery, others. Galactomannan (GM) is an Aspergillus-specific polysaccharide released during aspergillosis and detected by the serum GM test. This FDA-approved test is an accepted diagnostic marker for aspergillosis and preliminary data suggest a correlation between GM index (GMI) and outcome.

Purpose: using GMI, to distinguish response from progressive IA among patients with IRIS.

Patients and Methods: patients at risk for IA (11/03–2/06) underwent GMI screening during periods at risk. The clinical and laboratory findings of pts with ≥ 2 (+) GMI (optical density ≥ 0.5) were reviewed.

Results: 30 pts had GMI (+) aspergillosis of the respiratory tract [myeloma 92%; median age: 59 years (27–75); 15 males]. Invasive aspergillosis developed following stem cell transplantation [autologous (11), allogeneic (1)], or conventional chemotherapy (18). 12 of 25 (48%) neutropenic pts (<1000/ml) developed transient clinical and radiological worsening coinciding with neutrophil recovery, suggesting an IRIS. This deterioration coincided with rapidly declining GMI in 7 pts, all of whom survived with complete resolution of IA and without therapeutic modifications while the remaining 5 pts had persistently elevated GMI and rapidly died of IA.

Conclusion: These data establish the presence of IRIS among Hem-Ca pts with IA who suffer clinical and radiologic deterioration coinciding with neutrophil recovery. IRIS is common and occurs among both responders and non-responders. Declining GMI values implies IRIS with response and obviates the need for invasive procedures and / or therapy modification while persistent GMI elevation is indicative of IRIS with progressive infection. Serial GMI testing should be performed to guide management and evaluate pts prior to therapy with investigational antifungal agents.
Erythrocytosis after Allogeneic Bone Marrow Transplantation in the Patients with Severe Aplastic Anemia.
Authors: Park Soo-Jeong , Han Chi-Wha
Published: October 2019

Severe aplastic anemia (sAA) is a bone marrow failure disorder which is mostly a consequence of immunologically mediated stem cell destruction. Stem cell transplantation (SCT) from a histocompatible sibling is a treatment of choice for this disease but major obstacles in success of allogeneic SCT include graft-versus-host disease (GVHD), graft rejection and treatment related toxicities.

We describe two cases of post-transplant erythrocytosis in severe aplastic anemia. About 5 years later, following HLA-matched sibling transplantation, the patients (45-year-old male and 43-year-old male) developed a sustained increase in hemoglobin (>17 g/dL) and hematocrit (> 50%), an increase in the frequency of headache, and new onset of dizziness and malaise. Laboratory findings demonstrated normal ranges of other blood components and serum erythropoietin level, and they did not have smoking or other drugs. Also, they did not have a hepatosplenomegaly or other organ diseases. We initiated a therapeutic phlebotomy program (400 ml q 2–4 weeks and then q 2–3 months for 5 years) in order to lower the hematocrit to available values (Hb < 14.5 g/dL), and to induce iron deficiency (Fig 1). Repeated phlebotomy resulted in a decrease in symptoms and a total volume of blood venesection is about 9,200 – 11,200 ml so far.

Figure 1. Hemoglobin change after bone marrow transplantations. Figure 1. Hemoglobin change after bone marrow transplantations.
Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) for Patients with Refractory or Relapsed Non-Hodgkin’s Lymphoma (NHL).
Authors: de Lavallade Hugues , Bouabdallah Reda , Faucher Catherine , Furst Sabine , El-Cheikh Jean , Vey Norbert , Stoppa Anne-Marie , Sainty Danielle , Arnoulet Christine , Xerri Luc , Cassier Philippe , Gastaut Jean-Albert , Blaise Didier , Mohty Mohamad
Published: October 2019

This study aimed to evaluate the role of RIC allo-SCT for relapsed or refractory non-Hodgkin’s lymphoma (NHL). We report here our experience in 25 consecutive patients transplanted in a single center for high grade (n=17) or follicular NHL (FL; n=8). In the high grade NHL group, median age was 46 (range, 24–63) years, and all 17 patients received 2 or more previous chemotherapy regimens prior to RIC allo-SCT. In addition, 12 patients (71%) had failed autologous SCT and 6 patients (35%) had chemoresistant disease at time of allo-SCT. Among the 8 patients transplanted for a heavily pretreated follicular NHL (FL), median age was 52 (range, 34–59) years and median number of prior lines of therapy was 3 (range, 2–5), with 3 patients (38%) having chemoresistant diseases and 4 patients (50%) relapsing after autologous SCT.

Among the 17 patients with aggressive high grade NHL, we compared the outcome of T-cell and B-cell aggressive NHL. With a median follow-up of 15.4 (range, 3.4-65.2) months, the cumulative incidence of non-relapse mortality was 6%, (95%CI, 0.3%-31%) and the Kaplan-Meier estimate of progression-free survival (PFS) was significantly higher in the T-cell as compared to the B-cell group (P= 0.03; 100% vs. 40% at 3 years).

In the FL group, the cumulative incidence of non-relapse mortality was 25% (95%CI, 3%–65%). Six patients (75%) showed objective disease response with complete remission (CR) occurring concomitantly to graft-versus-host disease, including one CR after donor lymphocytes infusion. With a median follow-up of 19 (range, 7–85) months, 6 patients from the FL group are still alive of whom 5 in CR.

We conclude that a potent graft-vs.-lymphoma (GVL) may be achieved in FL patients, even those with chemoresistant disease or who have relapsed after autologous SCT. In the high grade NHL group, strategies aiming to enhance the GVL effect (Rituximab-based RIC and/or Rituximab maintenance therapy) in the B cell subtype are still needed. However, RIC allo-SCT is a feasible and promising strategy for aggressive NHL, with particularly low toxicity, and T-cell aggressive NHL benefiting most from a potent GVL effect, likely overcoming the poor prognosis usually associated with this phenotype.
Reduced-Intensity Stem Cell Transplantation for Adult T-Cell Leukemia: The Results of a Second Multi-Center Prospective Study and the Impact of Antithymocyte Globulin on Early Relapse.
Authors: Uike Naokuni , Tanosaki Ryuji , Utsunomiya Atae , Choi Ilseung , Masuda Masato , Saburi Yoshio , Tomonaga Masao , Etoh Tetsuya , Hidaka Michihiro , Kannagi Mari , Harada Mine , Okamura Jun
Published: October 2019

As we previously reported(Blood, 2005;NST-1), allogeneic stem-cell transplantation from an HLA identical sibling donor with reduced-intensity conditioning(RIST) consisting of fludarabine(FL), busulfan(BU) and antithymocyte globulin(ATG) for adult T-cell leukemia(ATL) patients(pts) appears to be a feasible treatment modality. Disease relapse, however, was the main cause of treatment failure. We conducted a second phase 1 clinical trial of RIST for ATL pts without ATG(NST-2).

Objectives: We evaluated the safety and feasibility of RIST for ATL using the same conditioning regimen except that we did not use ATG.

Patients and Methods: Between September 2003 and January 2006, 14 pts ranged from 50 and 62 years of age were enrolled. After the conditioning regimen with FL 30 mg/m2/d on days -8 to -3, BU 4 mg/kg/d on days -6 to -5, they received G-CSF-mobilized PB stem cells. The primary end points were either engraftment, as evaluated by the achievement of complete donor chimerism(CC) before d90, or the occurrence of early transplant-related mortality(TRM) before d100.

Results: All 14 pts achieved CC before d90, while two pts died of TRM before d100, thus demonstrating the successful results for the primary end points. The incidence of severe acute GVHD(grade III-IV) was 21%. A disease relapse occurred in 6 pts from d30 to d775, 5 of whom eventually died of ATL. As of July 31, 2006, 6 pts are still alive, while 8 died of either ATL(5 pts) or TRM(3 pts). The event free and overall survivals(EFS, OS) at 2 years were 40% and 43%, respectively. Among the 12 evaluable pts, the HTLV-1 proviral load decreased to an undetectable level after RIST in 9 pts. Therefore, the results of CC before d90(14/14versus[vs]14/15*), TRM before d100(2/14vs2/15*), severe acute GVHD(3/14vs5/15*), disease relapse(6/14vs9/15*), 2 year-EFS (40%vs20%*) or -OS(46%vs33%*) and the anti-HTLV-1 effects(9/12vs8/15*) were closely comparable with those of NST-1*. The incidence of early disease recurrence before d100 tended to be low(21%[3/14]vs44%*[7/16]*), thus resulting in a longer mean survival time(804 days vs 262 days*) after RIST.

Conclusion: Our two studies(NST-1, NST-2) confirmed that, whether ATG was administered or not, RIST is considered to be a feasible treatment modality. Moreover, conditioning without ATG may improve the survival by delaying a disease relapse without increasing the severity of acute GVHD. A third study (phase 2 trial of RIST without ATG) is currently underway.
Fludarabine, Cyclophosphamide and ATG Based, Reduced Intensity Conditioning for HLA-Match Sibling Donor Transplant in Severe Aplasic Anemia (SAA) - Case Report.
Authors: Pawlowska Anna B. , Bolotin Ellen , Falk Peter , Forman Stephen , Rosenthal Joseph
Published: October 2019

Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling is a curative form of therapy for patients with acquired severe aplastic anemia.

Survival has significantly improved over the past 3 decades. The actuarial risk of rejection has been reduced to about 7%. Improved results with survival in excess of 90% have been reported. Current preparative therapies are associated with early and late sequelae such as acute and chronic graft-versus-host disease (aGvHD or chGvHD, respectively) and secondary tumors. Two patients (6 years and 11 years old) with SAA, who had an HLA-identical sibling donor could not proceed with myeloablative therapy at the time of transplant due to delay in results of chromosome stability and fragility in one patient and abnormal pulmonary function in the second. Both received reduced intensity preparative regimen with Fludarabine (30 mg/m2×4 doses) Cyclophosphamide (5 mg/kg×4 doses) and rabbit ATG (1.5 mg/kg×4 doses) followed by an unmanipulated allogeneic BMT from their HLA-identical sibling donors. Graft versus host disease prophylaxis consisted of Cyclosporine from day -1 and Methotrexate 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, +11 after transplant. Myeloid engraftment occurred on day +15 and day +28. The time to a platelet count >20,000 unsupported was +11 days and +29 days. No transplant-related toxicities, including mucositis or alopecia, were recorded. There were no signs for aGvHD or chGvHD. The patients continue with full donor chimerism 27 months and 130 days post transplant, respectively. This data suggests that a non-myeloablative, immunosuppressive regimen is sufficient to provide a stable engraftment in the patients with SAA. This approach may be associated with decreased transplant-related short- and long-term toxicities. A larger study is needed to fully evaluate the outcome and the toxicity associated with this conditioning.
Comparison of Therapeutic Effect between Related Donor and Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) in the Treatment of Leukemia.
Authors: Liu Qifa , Yang Kai , Fan Zhiping , Sun Jing , Xu Dan , Wei Yongqiang , Zhang Yu , Meng Fanyi
Published: October 2019

Objective : To compare the effect for leukemia between related donor hematopoietic stem cell transplantation (RD-HSCT) and unrelated donor hematopoietic stem cell transplantation (URD-HSCT).

Methods: 115 patients received allo-HSCT, of whom 68 received RD-HSCT and 47 received URD-HSCT. All patients are HLA serologically matched. Total body irradiation (TBI) plus cyclophosphamide (CTX) was adopted in 56 cases and modified BuCY conditioning regimen (busulfan, Ara-C, Cyclophosphamide) in 59 cases. T and B cell reconstitution at different time points was assayed by flow cytometer in one year after transplantation. GVHD and nonage infection are observed after transplantation. The diference of haematopoietic and immunological reconstitution between the two groups are estimated with Independent-Samples T test. Kaplan-Meier survival analysis model is used to estimate the overall survival and the disease-free survival (DFS) in two groups.

Results: The time in WBC>1.0×109/L are +13.09±2.39 and +16.28±3.01d(P=0.003), the time in BPC>20×109/L are +14.91±6.62 and +20.21±7.29d(P=0.042), respectively, in related donor bone marrow transplantation (RD-BMT) and unrelated donor bone marrow transplantation (URD-BMT). The time in WBC>1.0×109/L are +12.47±2.96 and +13.13±4.09d(P=0.488), the time in BPC>20×109/L are +12.16±4.24 and +15.67±7.12d(P=0.020), respectively, in related donor peripheral blood stem cell transplantation (RD-PBSCT) and unrelated donor peripheral blood stem cell transplantation (URD-PBSCT). The reconstitution of CD4+CD3+ at 1, 3, 6, 9, 12months and CD45RA+CD4+ at 1 month, and CD8+CD3+ at 3 months were different significantly between RD-HSCT and URD-HSCT(P value was 0.001, 0.017, 0.029, 0.041, 0.015, 0.015, 0.043, respectively). The incidence of II~IV°acute GVHD(aGVHD), chronic GVHD(cGVHD) and the lethality of GVHD are 45.45% and 52.27%(P=0.560), 45.31% and 63.16%(P=0.102), 6.06% and 15.91%(P=0.112), respectively, in RD-HSCT and URD-HSCT groups. The relapse rate are 18.18% and 11.36%(P=0.424), respectively, in RD-HSCT and URD-HSCT groups. The incidence of nonage infection are 42.42% and 47.73% (P=0.696), respectively, in RD-HSCT and URD-HSCT groups.The overall survival and the disease-free survival rate at three-year were 67.80±6.90% and 61.60±7.70%(P=0.133), 62.30±6.90% and 56.80±7.90%(P=0.177), respectively, in RD-HSCT and URD-HSCT groups.

Conclusion The therapeutic effect for leukemia is not different between RD-HSCT and URD-HSCT.
A Novel Plasmodium falciparum Microneme Protein Interacts with Host Band 3 during Red Cell Invasion.
Authors: Li Xuerong , Chen Huiqing , Oh Steven S. , Chishti Athar H.
Published: October 2019

Clinical manifestation of Plasmodium falciparum malaria is directly linked to the blood stage of the parasite life cycle. At the blood stage, circulating merozoites invade red blood cells (RBCs) through multiple receptor-ligand interactions that mediate a complex series of events in a period of approximately one minute. Certain strains of P. falciparum favor an invasion mechanism that depends on sialic acid residues on the host RBC surface, while other strains favor a sialic acid-independent mechanism to invade RBCs. Two putative non-glycosylated extracellular regions of human RBC band 3 termed, 5ABC and 6A, function as an invasion receptor binding the 42 kDa C-terminal processing product of P. falciparum merozoite surface protein-1 (MSP142) and its 19-kDa secondary processing product (MSP119) by a sialic acid-independent mechanism. Earlier, we reported screening of a P. falciparum cDNA library in a yeast two-hybrid system, which led to the identification of P. falciparum merozoite surface protein 9 (MSP9) as another parasite surface protein that interacts with the 5ABC receptor region of band 3. MSP9 formed a co-ligand complex with MSP142 and/or MSP119 in their native forms. Here, we present identification of a novel P. falciparum microneme protein from the previous cDNA library screen. Primary sequence analysis of a positive clone in the library screen revealed a cDNA fragment in the correct open reading frame of a novel P. falciparum gene of 1,221 bps, encoding a hypothetical protein of 406 amino acids. Further sequence analysis predicted it is a membrane protein transversing the lipid bilayer multiple times. Anti-peptide antibody raised against a predicted non-membrane domain recognized a single band at ~49 kDa (calculated mass, 46.9 kDa) from the P. falciparum protein extract by Western blotting. Protein co-localization studies that employed established markers for the merozoite surface, rhoptries, and micronemes by an indirect immunofluorescence assay suggested that the ~49 kDa protein was expressed in micronemes at trophozoite/schizont stages. Immunoelectron microscopy demonstrated that the 49 kDa protein is indeed localized primarily to micronemes in the merozoites. Based on our characterization, we have tentatively named this novel protein as microneme-associated membrane antigen 1 (MAMA1). Functional studies demonstrate that the MAMA1 antibody blocked RBC invasion by P. falciparum (3D7 strain) in vitro, in a concentration-dependent manner. Furthermore, MAMA1 presumably embedded in small vesicles present in the parasite protein extract bound to intact human RBCs, and the MAMA1-RBC binding was neuraminidase and trypsin resistant, but chymotrypsin sensitive. Native MAMA1 bound specifically to the 5ABC peptide of band 3 in our solution binding assay. Together, these results suggest that the novel microneme protein MAMA1 interacts with host band 3 and facilitates merozoite entry during RBC invasion.
Correction of Immunodeficiency Associated with NEMO Mutation by Umbilical Cord Stem Cell Transplantation Using a Reduced-Intensity Conditioning Regimen.
Authors: Tono Chikako , Takahashi Yoshihiro , Terui Kiminori , Sasaki Shinya , Kamio Takuya , Tandai Satoru , Sato Tomohiko , Kudo Ko , Toki Tsutomu , Tachibana Naoki , Yoshioka Takakazu , Nakahata Tatsutoshi , Morio Tomohiro , Nishikomori Ryuta , Ito Etsuro
Published: October 2019

X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is a developmental and immunologic disorder caused by hypomorphic mutations in the nuclear factor-κB essential modulator (NEMO) gene. NEMO is the regulatory subunit of the IκB kinase (IKK) complex, which phosphorylates and degrades NF-κB inhibitor α (IκBα), causing NF-κB activation. Following the identification of amorphic NEMO mutations causing familial incontinentia pigmenti (IP), hypomorphic mutations in NEMO have been identified in XL-EDA-ID patients. Affected boys are susceptible to infections with various microorganisms, mostly pyogenic bacteria and mycobacteria. Stem cell transplantation (SCT) is thought to be the only curative treatment, but successful SCT has not yet been reported. We here report the first successful treatment of the disorder by SCT. The patient was a 3-year-old boy. His mother and maternal grandmother had been diagnosed with IP. He had frequent episodes of enterocolitis, and Enterobacter aerogenes sepsis. Mutation analysis revealed NEMO mutation (1167 insC) in both the patient and his mother. Flow cytometry analysis showed lower NEMO expression in each PBMC lineage, and CD40L induced less up-regulation of CD23, CD54, CD86, and CD95 in the patient’s cells. The patient did not have an HLA-matched related or unrelated bone marrow donor. At 3 years of age, an unrelated UCSCT was performed after written consent was obtained from his parents. Pretransplant conditioning consisted of fludarabin (30 mg/m2/d) from day -7 to day -3, melpharan (70 mg/m2/d) from day -6 to day -5, and rabbit anti-T-lymphocyte globulin (ATG) (2.5 mg/kg/d) from day -5 to day -1. The patient received 4.6 × 107 total nucleated cells/kg from a male donor. The recipient and donor were one antigen mismatched by serology and four loci mismatched by DNA typing. Following uneventful engraftment, NEMO protein expression was normalized and cytokine response was significantly improved. Lineage-specific genetic analysis confirmed full donor chimerism. Six months after UCSCT, the patient is in perfect performance status. This outcome shows that correction of immunodeficiency associated with NEMO mutation is possible by SCT, and UCSCT with a reduced-intensity regimen can be a suitable therapy for affected patients.
Autologous Stem Cell Transplantation (ASCT) for Poor Prognosis Non Hodgkin Lymphomas (NHL).
Authors: Nese Martha C. , Guillermo Cecilia , Isaurralde Hugo , Diaz Lilian , Topolansky Laura , Zunino Juan , Perdomo Susana , Perdomo Ana , Lavagna Graciela , Diaz Andrea , Stevenazzi Mariana , Baubeta Alberto
Published: October 2019

Between 1995 and 2005, we performed 329 hematopoietic stem cell transplantation (HSCT), 286 autoulogous and 43 allogeneic.

Long term results of treatment and outcome of ASCT in 100 Non Hodgkin Lymphoma (NHL) were analyzed. Median age was 47 years (range18 – 64) and the histology was: Follicular Lymphoma 15%, diffuse large B cell lymphoma (DLBCL) 47%, T lymphoma 27% and 11% others. At diagnosis 66% had advanced stage (III/IV), 40% had B symptoms, and 34% had extranodal involvement. Disease status at HSCT was: 5 % primary induction failure, 41% CR1, 20% CR2 +, 7% CRU, 12% relapsed. Number of prior chemotherapy regimens was 47% 2 lines, 20% 3 lines and 3% 4 lines; 27% had received prior induction or consolidation radiotherapy. Condition regimens consisted of BEAC (81%), BEAM (15%), others (4%). Stem cell source: 39% received BM + PBSC and 61% PBSC.

Sixty nine are alive with a median survival of 3448 days (9.5 years). Median overall survival was similar in DLBCL (59%) and peripheral T lymphoma (60%). The best overall survival was observed in CR1 (77%) versus 52% in CR2 and 66% in PR1. Primary cause of death was relapsed or progression (24/31).

We concluded that high dose therapy and autologous HSCT is an effective therapy for patients with poor risk NHL however relapse continues to be the most common cause of treatment failure. Newer strategies such as monoclonal antibody, require further investigation but early reports appear promising in reducing relapses in autologous HSCT.
Maintenance Therapy with Low Dose Thalidomide, Dexamethasone and Clarithromycin (Biaxin) (BLT-D) Following Autologous Transplant (ASCT) for Multiple Myeloma (MM).
Authors: Holmberg Leona A. , Brandvold Aurora , Bensinger William I.
Published: October 2019

Relapse remains a major problem after a standard ASCT for MM. Strategies to prevent relapse have included post transplant maintenance therapy. M Coleman et al (Leukemia and Lymphoma43:1777–1782, 2002) pioneered a regimen of BLT-D to treat in a non-transplant setting MM and reported a high CR/PR response rate (93%). Since the BLT-D regimen showed significant disease response, it seemed reasonable to study this regimen as maintenance therapy after ASCT. Between 7/2003–1/2006, 23 patients (stage II, n=6 and stage III (n=17) were treated. 26% of patients had poor prognostic cytogenetics. 61% had elevated beta 2 microglobulin at initial diagnosis; 30% still had elevated beta 2 microglobulin at time of ASCT. 48% of the patients had received Thalidomide therapy before ASCT. All were conditioned for ASCT with melphalan 200 mg/m2. 30–120 days after recovery from the acute toxicity of ASCT, patients were treated with Biaxin 250 mg po bid, Dexamethasone 20 mg po q week and Thalidomide beginning at 50 mg po daily for 14 days, then increased to 100 mg po daily. After one year of combination therapy, Biaxin and Dexamethasone were stopped and Thalidomide was continued as long as tolerated or until disease progression. The median time to starting therapy was 102 days (range 40–120) post ASCT. Neuropathy was the most common toxicity. Four patients stopped therapy because of significant peripheral neuropathy and four patients required dose reduction of Thalidomide because of neuropathy. Eight patients had reduction in Dexamethasone dosing because of toxicity. One patient stopped Biaxin for rash. Number of infections seen included pneumonia (n=3), viral upper respiratory infection (n=2), sinusitis (n=1) and bronchitis (n=3). One patient withdrew from therapy to undergo elective second ASCT. Three patients have died: infection (n=1), MM progression (n=1) and complications of second ASCT (n=1). In patients who still had detectable MM after ASCT prior to beginning BLT-D therapy, 46% of the evaluable patients to date have been shown to go into complete remission on BLT-D therapy. Three patients have progressed. 18 (78%) out of 23 patients remain alive without disease progression. Median follow-up is 20.5 months (range 6–25). Further follow-up is needed to determine the effect of BLT-D upon relapse and survival of MM ASCT patients.
Serum Ferritin Is an Independent Predictive Marker for Stem Cell Mobilization Efficacy in Patients with Hematologic Malignancy.
Authors: Kim Soo-Jeong , Lee Hye Won , Yoon Sul Hee , Park In-Hae , Kim Yuri , Kim Jin Seok , Cheong June-Won , Min Yoo-Hong
Published: October 2019

Autologous stem cell transplantation has been performed to support high-dose chemotherapy in hematologic malignancy. A good mobilization is mainly achieved with several mobilization chemotherapies followed by granulocyte colony stimulating factor (G-CSF). Although the complex mechanism of mobilization of hematopoietic stem cell (HSC) is not fully understood, it may be the results of interactions between hematopoietic stem cell and microenvironment of bone marrow. So, severe accumulation of iron in bone marrow due to frequent transfusions may have some negative effect on not only HSC engraftment but also HSC mobilization. We evaluated 30 patients, 6 (20%) with multiple myeloma, 16 (53%) with malignant lymphoma and 8 (27%) with acute leukemia in order to assess the impact of serum ferritin and CD34+ HSC mobilization. All patients treated with high dose chemotherapy and G-SCF (5-10ug/kg) before HSC collecting procedure. Serum ferritin, iron, C-reactive protein levels were measured at the first peripheral blood HSC collection. By evaluating the efficacy of CD34+ HSC harvest, 20/30 patients (66%) were considered good mobilizer patients, defined as patients with a CD34+ cells collection of >1*106 CD34+cells/kg/day, and a subset (5/30, 16.7%) as very poor mobilizer (<0.5*106 CD34+cells/kg/day), 5 patients between 0.5 and 1*106 CD34+cells/kg/day as poor mobilizer. There was no significant difference between 3 groups in age, diagnosis, disease status and previous treatment but notable statistical difference was found in serum ferritin level (median 1322 ng/mL in very poor group, 1068 ng/mL in poor group, 625 ng/mL in good group, P=0.027). The number of CD34+ cells/uL in the peripheral blood on the first day of apheresis was a surrogate marker of the efficacy of stem cell harvest (P<0.005) and it showed a strong correlation with serum ferritin (P=0.003). Especially serum ferritin over 1,000 ng/mL was significant correlated with poor mobilization efficacy (P=0.004). Age, diagnosis, disease status and previous chemotherapy had no correlation with mobilization efficacy in our study. In conclusion, severe accumulation of iron, measured by serum ferritin after repeated transfusion was adverse effect on HSC mobilization and serum ferritin might be independent predictive marker for mobilization efficacy.
Targeted Gene Delivery in CD30+ Hodgkin Lymphoma Cells Using Lentiviral Vectors.
Authors: Luong Quang T. , Morizono Kouki , Chen Irvin S.Y. , de Vos Sven
Published: October 2019

Despite the success of combination chemotherapy for the treatment of Hodgkin lymphoma (HL), chemotherapy-resistant disease still remains an unresolved problem with most patients eventually dying due to progression. HL is an ideal disease for targeted therapy. CD30 is a 120-kDa transmembrane glycoprotein belonging to the tumor necrosis factor (TNF)-receptor superfamily and strongly expressed in HL Reed-Sternberg cells. We hypothesize that specific, antibody-mediated, CD30-directed delivery of lentiviral vector constructs, encoding for a lethal cellular toxin, will be an effective anti-lymphoma strategy. However, gene delivery based therapy is limited by the transduction of non-target cells. The technology developed by Morizono et al. [Cell Cycle2005: 4: p854; Nature Medicine2005: 11: p346] demonstrates that lentiviruses can be specifically and effectively directed to target cells by conjugation of an antibody to a modified ZZ SINDBIS viral envelope (m168). In this study, we have used HL cell lines (CD30+: L591, L428, Hs445, RPMI6666) and Burkitt lymphoma (BL) cell lines (CD20+/CD30−: Raji, Ramos). We show that conjugation of an anti-CD30 antibody to m168 (m168anti-CD30), permits specific targeting and transduction of CD30+ Hodgkin lymphoma cells while avoiding CD30− Raji and Ramos cells [range 11–83% for HL cells versus 1–4% for BL cells]. Similarly, targeting of CD20+ cells can be achieved. Several of our HL cell lines (L591, Hs445 and RPMI6666) are CD30+/CD20+ [range 11–25% by flow cytometry] and we show that we can equally transduce these cells with an anti-CD20 antibody conjugated to our lentivirus [range 11–30% for CD20+ HL cells; 3% for L428 cells; 40–47% for BL cells]. In addition, we show in L591 cells, that the re-targeted viruses can transduce a greater percentage of target cells than an unmodified virus [83% for m168anti-CD30 versus 43% for VSVG]. These results demonstrate that the efficacy and specificity of targeted therapy can be greatly enhanced and lay the foundation for the development of more stable anti-CD30 directed lentiviral constructs expressing cellular toxins.
FDG-PET in Peripheral T-Cell Lymphoma.
Authors: Quigley Joanna M. , Bishu Shrinivas , Hankins Jordan H. , Armitage James O.
Published: October 2019

The sensitivity and specificity of fluorine-18 fluoro-deoxy-glucose positron emission tomography (PET) in the evaluation of peripheral T cell lymphomas (PTCL) is not well established. In this abstract, we describe our experience utilizing PET in the diagnostic evaluation of PTCL.

A retrospective review of 2768 PET examinations conducted at our institutionbetween the years 1999–2006 produced twenty-six examinations among twenty-two patients with a biopsy proven diagnosis of PTCL. All patients underwent staging of their disease using both conventional diagnostic methods and PET. Their therapeutic status was also taken into consideration when interpreting PET examinations. PTCL were classified by World Health Organization (WHO) criteria and included: PTCL-unclassified (PTCL-U), anaplastic lymphoma kinase positive (+) and negative (−) anaplastic large cell lymphoma, gioimmunoblastic (AITL n=1), and natural killer T-cell nasal type (NK/T n=1). PET results for each patient were compared against a standard of reference, and the sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PET) of PET were calculated.

PET had an overall sensitivity of 55% and specificity of 100% in PTCL-U. PET had an overall sensitivity of 83% and specificity of 100% in ALCL. PET had an overall sensitivity of 13% and specificity of 0% in cutaneous PTCL. Among patients with non-cutaneous PTCL-U, the sensitivity and specificity were 83% and 100% respectively. Among patients with non-cutaneous ALCL, the sensitivity and specificity were 100% respectively. Excluding those patients with cutaneous PTCL, PET correlated with clinical outcome in 87% of PTCL-U 100% of ALCL patients. The average maximum standard uptake value (g/mL) of abnormal foci demonstrated greater intensity in patients with ALCL (13.1) than those with PTCL-U (8.87) (Figure 1). PET had excellent correlation with CT, physical examination and clinical follow-up at both nodal and extra-nodal sites, but poor correlation at cutaneous sites (Figure 2).

The PPV and NPV of restaging PET in PTCL-U were 75% and 100% respectively. In ALCL, the PPV and NPV of restaging PET were 66% and 100% respectively.

PET is useful for staging and restaging patients with nodal and non-cutaneous extra-nodal involvement in PTCL-U and ALCL. It demonstrates a comparatively low sensitivity in cutaneous PTCL.

Average Maximum SUV (gm/ml) of Abnormal Foci in PTCL-U and ALCL Average Maximum SUV (gm/ml) of Abnormal Foci in PTCL-U and ALCL Positivity (%) of PET vs. Site of Disease by CT, Physical Exam and/or Clinical Follow Up Positivity (%) of PET vs. Site of Disease by CT, Physical Exam and/or Clinical Follow Up
Health-Related Quality of Life of Patients Diagnosed with Indolent Lymphoma.
Authors: Mathias Susan D. , Cimms Tricia A. , Colwell Hilary H. , Reyes Carolina M. , Lubeck Deborah P.
Published: October 2019

Background Numerous treatment options are available for patients with indolent lymphoma (IL), including active treatment and active observation without initiation of therapy, watchful waiting; each is associated with unique, longer term therapeutic and health-related quality of life (HRQL) consequences. We sought to identify key HRQL domains of importance to patients with indolent lymphoma and whether HRQL varies by treatment.

Methods Five focus groups (n=33), supplemented by in-depth one-on-one telephone interviews (n=19) were conducted with IL patients across the US. Patients completed a questionnaire composed of five standard validated instruments related to physical well-being, social/family well-being, emotional well-being, functional well-being (FACT-G), additional concerns (FACT-Lym), physical appearance, psychosocial adaptation to illness (PAIS), and mental health (MHI-5). Questionnaire domains were scored on a 0–100 scale where higher scores indicate better functioning.

Results A total of 52 IL patients (65% female; mean age 53 years) completed the questionnaire. Participants belonged to one of the following treatment categories: Active Treatment (n=18), Previous Treatment (n=25) and Watchful Waiting (n=9). Similarities in FACT scores were found between the Previous Treatment and Watchful Waiting groups. The Watchful Waiting group scored the lowest on both the MHI-5 and the PAIS. Differences were found in Physical Well-Being between the Active Treatment and Previous Treatment groups (67.06 vs. 81.10, respectively, p=0.029). Differences were observed for the PAIS between the Active Treatment and Watchful Waiting groups (83.82 vs. 65.63, respectively, p=0.021) and between the Previous Treatment and Watchful Waiting groups (85.00 vs. 65.63, respectively, p=0.010).

Conclusions Preliminary findings suggest that differences were observed between patients on active treatment, those who have previously been treated and patients who have never been treated, watchful waiting. Further elucidation of these issues is needed to facilitate HRQL evaluation in future studies and more importantly better inform patients and providers of treatment decisions.

Table 1. Mean (Standard Deviation) HRQL Scores of all Patients and by Treatment Categories Domains All Patients (N=52) Active Treatment (N=18) Previous Treatment (N=25) Watchful Waiting (N=9) FACT-G 73.01 (15.56) 67.41 (15.82) 76.21 (14.12) 75.67 (17.30) FACT-Lym 71.35 (15.25) 67.63 (16.09) 73.11 (12.39) 75.02 (18.58) Physical Appearance 76.85 (29.36) 65.00 (31.62) 82.69 (27.74) 87.50 (25.00) PAIS 81.50 (18.77) 83.82 (16.40) 85.00 (18.40) 65.63 (18.60) MHI-5 69.08 (18.00) 69.33 (15.22) 71.36 (18.46) 62.22 (21.92)