bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Correlation of Foxp3 Regulatory Gene Expressions and NK Cells in Early Engraftment after Myeloablative Allogeneic Stem Cell Transplantation.
Authors: Yang Deok-Hwan , Park Chung-Sun , Kim Yeo-Kyeoung , Lee Je-Jung , Kim Hyeoung Joon
Published: October 2019

Regulatory T cells (Tregs) have been established as a key role of self tolerance and preventing proliferation of auto- and alloantigen-reactive T cells. CD4+CD25+ Tregs suppress GVHD in animal models, but in human data on GVHD following stem cell transplantation (SCT) is conflicting. We postulate that CD4+Foxp3+Tregs not only reduce the incidence of acute graft-versus host disease (aGVHD) but inhibit the NK cell functions in patients who received allogeneic SCT. CD4+Foxp3+Tregs also may adversely affect the GVL effect and cause the relapse of disease.

Patients and Methods: 25 patients (AML:13, ALL:9, CML:2, NHL:1) were undergone allogeneic SCT. Nine patients were infused from unrelated donor and five patients were from HLA one-mismatch. Three patients added alemtuzumab to myeloablative conditioning regimen due to HLA mismatch. Peripheral blood mononuclear cell (PBMC) were separated 3 or 4 weeks after SCT when absolute neutrophil count reached above 1000 × 109/L. NK cells were phenotypically analyzed by flow cytometry using directly conjugated antibodies to CD3 and CD56. CD4+ cells were isolated from PBMC using micro-bead (MACS) and the expression levels of Foxp3 mRNA were assessed by quantitative real-time PCR.

Results: 12 patients developed grade 2–4 acute GVHD and 10 patients relapsed. Patients who experienced Gr2-4 aGVHD had significantly lower the relapse rate than those who Gr0-1 aGVHD (P=0.002). Foxp3 gene expressions within CD4+ T cells were significantly lower in Gr2-4 aGVHD patients (median, 4.278 ng/μl) than in Gr0-1 aGVHD patients (median 7.914 ng/μl) except three patients treated with alemtuzumab conditioning (P=0.016). All of three patients used alemtuzumab experienced the relapse and no aGVHD. They also had very lower Foxp3 gene expressions (median, 4.760 ng/μl) than those in Gr0-1 aGVHD patients. Without alemtuzumab used patients, the levels of Foxp3 expression in relapsed patients were significantly higher than those in non-relapsed patients (median, 11.684 ng/μl and 2.031 ng/μl, respectively) (P=0.001). However, we could not find an inverse correlation between NK cell expressions and CD4+Foxp3+Tregs and a positive correlation between infused T cell doses and CD4+Foxp3+Tregs expression.

Conclusion: The levels of CD4+Foxp3+Tregs affect the incidence of aGVHD and predict the risk of the relapse. Alemtuzumab may influence the T cell recovery including regulatory T cells after early post-SCT.
Decreased Serum Levels of Surfactant Protein D (SP-D) Prior Transplant Is Associated with the Development of Bronchiolitis Obliterans (BO) and Idiopathic Pneumonia Syndrome (IPS) Following Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Nakane Takahiko , Nakamae Hirohisa , Kamoi Hiroshi , Koh Hideo , Takeoka Yasunobu , Sakamoto Erina , Kanashima Hiroshi , Ichihara Hiroyoshi , Nakamae Mika , Koh Ki-Ryang , Yamane Takahisa , Hino Masayuki
Published: October 2019

Non-infectious pulmonary complications which occur beyond 3 months of allogeneic hematopoietic stem cell transplantation (allo-HSCT) have become recognized as a critical problem. Above all, bronchiolitis obliterans (BO) and idiopathic pneumonia syndrome (IPS) are difficult to be cured and cause high mortality. Therefore, early identification of patients with higher risk for BO/IPS may lead to improving outcome of allo-HSCT.

Surfactant protein D (SP-D) is one of collectins mainly synthesized by alveolar type II cells. The best known function is to prevent the collapse of alveoli by decreasing surface tension at alveolar air-lipid interface, and SP-D plays an important roles as a mediator in innate immunity in the lung. In clinical practice, high serum SP-D level is used as a marker lung diseases. Recently, low production of SP-D in the alveoli has been considered as an important pathgenesis of adult respiratory distress.

We analyzed serum SP-D levels before allo-HSCT of 42 patients who received allo-HSCT in our institution between November 2001 and February 2006 and survived more than 90 days after transplant. In all patients, 5 patients had BO and 3 had IPS at a median interval of 303 and 117 days of transplantation (range; 100–452 and 95–153 days). As a result of univariate analysis, BO/IPS patients had lower serum SP-D levels prior allo-HSCT and extensive type of cGVHD except lung compared with no BO/IPS patients (p=0.06 and 0.07). KL-6 had also mildly associated with BO/IPS. On the other hand, we couldn’t find the association in sex, age, donor source, conditioning regimen, disease status, aGVHD, and FEV1.0/FVC and SP-A prior HSCT. We could not clarify the precise mechanism of the association between Decreased serum levels of SP-D and the development of BO and IPS following allo-HSCT. However, we speculate that low production of SP-D in the alveoli, which causes innate immune compromise, might contribute to extreme pulmonary alloreaction.
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 Helena , 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, 21 had complete responses, eight showed improvement, eight patients did not respond, two had stable disease and one patient was not evaluated due to short follow-up. Twenty 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.
Mitoxantrone and Melphalan as Conditioning Regimen for Autologous Stem Cell Transplant for Multiple Myeloma.
Authors: Beaven Anne W. , Comeau Terrance , Sharf Andrew , Moore Dominic T. , Serody Jonathan , Shea Thomas C. , Gabriel Don A.
Published: October 2019

High dose Melphalan (Mel) has demonstrated efficacy in the treatment of multiple myeloma (MM). Mitoxantrone (Mit), in combination with vincristine and prednisone, also has demonstrated activity in MM with the benefit of less cardiac toxicity than other standard regimens. In this trial Mel and Mit were combined as a transplant preparative regimen. Mit was given as a prolonged 6 hour infusion on 2 separate days to increase intracellular drug levels and decrease cardiac toxicity (Kaminer et al. Cancer1990; 65, 2619–2623; Koc et al. Hematol Oncol2004;22:43–53).

PATIENTS: 35 patients with a diagnosis of MM were enrolled between 9/98–6/02. Median age was 59 (range, 38–69); 60% had received ≥ 2 previous regimens (range, 1–6). The median time from diagnosis to transplant was 9 months (95% CI, 8–12 months). 57% had stage III disease and 26% stage II at diagnosis; median Beta-2 microglobulin was 3.6 mg/L (available in only 13 patients). All patients completed therapy with Mit 30mg/m2/day infused over 6 hours on days -6 and -5 and Mel 180mg/m2 on day -1.

RESULTS: The median follow-up for survivors was approximately 45 months (range, 3–84 months). The median times to granulocyte and platelet engraftment were 11 days and 14 days respectively. 2 patients failed to engraft; 1 proceeded to allogeneic transplant, the other died on day 28 secondary to sepsis. The 100-day TRM was 2.9%. The median progression free survival (PFS) was 20 months (95% CI, 13–31) (Figure 1) with a median overall survival (OS) of 57 months (Figure 2). 4 patients are alive and progression free more than 48 months out from transplant. 8/35 (23%) of patients achieved a complete response (CR). Of the 8 patients who had a CR, 7 (20% of total patients) are still alive and progression free with a median follow-up of 39 months after transplant (range, 12 to 80 months). The achievement of a CR was significantly associated with longer PFS but not with OS. The mean CD34 count of infused cells was 4.92 ×106/kg and did not appear to be significantly associated with CR rate, OS, or time to engraftment of platelets or granulocytes. Overall, therapy was well tolerated with a median of 8 days (range, 0–15) of any grade of mucositis and a median of 3 days of fever. The mean LVEF on MUGA was 64% pre-transplant and decreased to 58% post-transplant. 1 patient with diabetes and hypertension developed congestive heart failure after discharge from the hospital but with therapy the LVEF returned to normal.

CONCLUSION: The combination of Mel and infusional Mit is an effective regimen with 23% CR rate despite multiple previous therapies. The median OS of 57 months compares well to other transplant trials and patients who achieved a CR demonstrated better long-term PFS.

Figure Figure Figure Figure
Transplantation without Growth Factor. Engraftment Kinetics Following Stem Cell Transplantation for Primary Systemic Amyloidosis.
Authors: Gertz Morie Abraham , Lacy Martha Q. , Dispenzieri Angela , Hayman Suzanne R. , Kumar Shaji K. , Gastineau Dennis A.
Published: October 2019

INTRODUCTION

The use of growth factors filgrastim and sargramostim are associated with often dramatic degrees of fluid retention in patients with amyloidosis who have coexistent cardiac involvement or nephrotic syndrome. Significant degrees of fluid retention can complicate the post transplant management of patients with AL receiving high dose chemotherapy. We report outcomes in a cohort of amyloidosis patients who received no growth factor support post transplant.

PATIENTS AND METHODS

283 consecutive patients seen for stem cell transplant are included in this cohort. In order to be considered evaluable for engraftment the patient must have survived for 30 days or was excluded from analysis. All patients had biopsy verified AL. Patients also had to have visceral organ dysfunction in order to be eligible for stem cell transplant with a minimum of one visceral organ involved.

RESULTS

Among 283 patients transplanted, 244 were evaluable for engraftment. There were 145 men (59%). Renal involvement was present in 163 (67%), cardiac involvement by echocardiography in 47%, hepatic involvement in 16%, and peripheral nerve involvement in 11%. The median age was 56.6 years (range 33–73). The median time from diagnosis of amyloidosis to stem cell transplantation was 4.2 months. A neutrophil count of 500/uL was achieved in 50%, 75%, and 90% of the total group at 14, 16, and 22 days respectively (figure 1). A platelet count of 20,000/uL was achieved in 50%, 75%, and 90% of patients at 14, 19, and 28 days respectively (figure 2). A platelet count of 50,000/uL was achieved in 50%, 75%, and 90% of patients at 18, 28, and 52 days respectively. The median time spent in the hospital for the entire cohort 9 days. 46 of the patients (19%) completed the entire procedure as an outpatient. 75% of patients were discharged within 18 days and 90% were discharged within 32 days. 137 patients were blood culture negative throughout the entire procedure (56%). A blood culture was positive in the remaining 107 patients. 68 of these 107 contained a culture for Staph. coagulase negative. 39 (16%) had bacteremia associated with other organisms.

CONCLUSION

Transplantation of patients with amyloidosis without using growth factor is feasible. The median time to achieve neutrophil and platelet counts of 500 and 20,000/uL respectively is 14 days. It is reasonable to withhold growth factor from AL patients undergoing stem cell transplantation.

Figure Figure Figure Figure
Clonal Evolution in Chronic Lymphocytic Leukemia: Acquisition of High-Risk Genomic Aberrations Associated with Unmutated VH, Resistance to Therapy, and Short Survival.
Authors: Stilgenbauer Stephan , Sander Sandrine , Bullinger Lars , Benner Axel , Leupolt Elke , Winkler Dirk , Kröber Alexander , Kienle Dirk , Lichter Peter , Döhner Hartmut
Published: October 2019

Genomic aberrations were analyzed by fluorescence in situ hybridization (FISH) at various time points during the disease course of 64 patients with chronic lymphocytic leukemia (CLL) from a single institution. After a median time of 42 (23–73) months, 11 of the 64 (17%) patients acquired the following additional aberrations: del(17p13) (n=4), del(6q21) (n=3), del(11q23) (n=2), +(8q24) (n=1), and evolution from monoallelic to biallelic del(13q14) (n=3). The baseline clinical characteristics of the patients with and without clonal evolution were not significantly different. Remarkably, clonal evolution occurred exclusively among cases with unmutated VH status (Figure 1). The group with clonal evolution showed a higher rate of progression in stage (82% vs. 28%), a greater need for treatment (100% vs. 62%), and a higher death rate (67% vs. 28%). The median survival time after the occurrence of clonal evolution was 22 months. Expansion of the clone with del(17p13) was observed in all patients during chemotherapy (chlorambucil n=4, fludarabine n=3, FC n=2, rituximab n=1) indicating in-vivo resistance to treatment (Figure 2). In multivariate analysis, clonal evolution was identified as independent adverse factor with regard to overall survival.

Figure 1 Figure 1. Figure 2 Figure 2.
Outcome of Diffuse Alveolar Hemorrhage in Hematopoietic Stem Cell Transplant Recipients.
Authors: Gupta Sachin , Jain Amit , Gupta Aditya , Warneke Carla L. , Giralt Sergio , Eapen Georgie A.
Published: October 2019

Background: Hematopoietic Stem Cell Transplantation (HSCT) is being widely used as an adjunct to conventional chemoradiotherapy for many hematologic and solid malignancies and some non-malignant hematologic conditions. Diffuse Alveolar Hemorrhage (DAH) is seen in 1 to 19% of HSCT recipients who undergo bronchoscopy. Though, the reported mortality of DAH is 70–100%, the outcomes are changing with advances in preconditioning, stem cell transplantation and intensive care.

Objectives: To study the outcomes of DAH and factors associated with adverse outcomes in HSCT recipients at M.D. Anderson Cancer Center.

Methods: A retrospective review of all adult patients who underwent bronchoscopy after HSCT between January 1, 2002 and December 31, 2004 for a presumptive diagnosis of DAH. Outcome measures were recorded and analyzed over the six months following bronchoscopy. Univariate and multivariate Cox proportional hazards regression models were used to investigate prognostic value of various clinical factors.

Results: Bronchoscopy with BAL was performed in 223 patients for a clinical suspicion of DAH. Blood was seen on bronchoscopy in 87 (39%) patients. All patients received high dose steroids and other supportive care. Fifty-three (61%) met the standard criteria for diagnosis of DAH while 34 had an organism isolated on BAL. Of these 53 patients, 66% were alive at 30 days, and 45% at 6 months. Overall, 42% were alive at the end of follow-up period. Respiratory failure was recorded as the cause of death in 52%. Outcomes were significantly worse in the 34 patients with an organism in BAL. Significant associations existed between poorer overall survival and isolation of an organism in BAL (HR = 1.99, 95% CI: 1.38, 2.87), renal dysfunction (HR = 2.35, 95% CI: 1.60, 3.46), and neutropenia (HR = 2.77, 95% CI: 1.91, 4.01).

Conclusion: The survival of patients with DAH at our center is better then that reported in literature. Isolation of an organism in BAL, renal dysfunction, and neutropenia are associated with increased risk of death among patients undergoing bronchoscopy after HSCT.
Prevention of Oral Mucositis with Palifermin in Patients Treated with High-Dose Chemotherapy and Autologous Stem Cell Transplantation. A Single Center Experience.
Authors: Luthi Francois , Berwert Lorenzo , Frossard Valérie , Marchetti Oscar , Rosselet Anne , Duchosal Michel , Ketterer Nicolas
Published: October 2019

It was demonstrated in a placebo controlled randomized study that Palifemin decrease the severity of oral mucositis in patients (pts) treated with total body irradiation (TBI), high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). The benefit of this treatment in pts who are not receiving TBI-containing conditioning regimen is still unclear. We evaluated prospectively the effect of Palifermin on mucositis prevention in 34 consecutive pts treated with HDCT and ASCT compared to an historical group of pts who did not receive Palifermin.

Between 03/2005 and 05/2006, 34 pts (Group A) treated with Melphalan 200 (n=15) or BEAM (n=19) gave informed consent and received 6 injections of 0.06 mg/kg of Palifermin (3 days (d.) before HDCT and 3 d. following ASCT). Four were excluded from efficacy analysis, 2 of them due to Melphalan dose reduction and 2 due to early discontinuation of Palifermin. They were compared to 77 pts (Group B) treated with Melphalan 200 (n=43) or BEAM (n=34) from 2003 to 2005. WHO grading was used for toxicity assessment.

The median age was 55 years in group A (Range 28–67) and 54 years in group B (Range 19–66). The median count of CD34 cells/kg infused was 4.2 millions (Range 1.96–23.9) in group A and 3.85 millions (Range 1.8–16.2) in group B. The median time for engraftment was the same in both groups and was respectively 11 d. for neutrophils (Range 8–12) and 11 d. for platelets (Range 8–13) in group A, 11 d. for neutrophils (Range 8–13) and 11 d. for platelets (Range 8–18) in group B. Severe oral mucositis (Grade 3 and 4) was lower in group A (17%) than in group B (44%). The incidence of grade 2 or more digestive mucositis was similar in the 2 groups (66% vs.60%) as well as the total opioid use (43% vs 57%). All patients but one in the group B developed fever. Fever of unknown origin were more frequent in group A due to less fever attributed to grade 3 or 4 mucositis.In group A, all but 3 pts developed toxicities. Grade 3 or 4 toxicities consisted in erythematous rash in 15 pts (44%), generalized oedema in 2 and odynophagia in 1. Grade 1 or 2 toxicities were pruritis (24%), rash (32%), localized oedema (26%) and buccal discomfort (41%). 1 pt died at d.12 from an hemophagocytic syndroma and onother at d.90 from a rapidly progressive colorectal cancer.

We conclude that the use of Palifermin reduced the incidence of grade 3 or 4 mucositis in our group of pts treated without TBI, but did not decrease either digestive mucositis or the use of morphinic. The benefit of Palifermin on mucositis prevention has still to be balanced again the risk of discomfort and toxicities of this drug. Large randomized studies are still needed before recommending the systematic administration of Palifermin to pts receiving Melphalan 200 or BEAM as conditioning regimen before ASCT.
No Evidence for Increased Transplant Related Complications in Ph+ Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia with Prior Treatment with Dasatinib.
Authors: Leiba Merav , Shimoni Avichai , Guilhot Francois , Martineau Geraldine , Renaud Marc , Francois Sylvie , Hardan Izhar , Nagler Arnon
Published: October 2019

Stem cell transplantation (SCT) is frequently used as salvage or curative therapy in patients (pts) with advanced chronic myelogenous leukemia (CML) or Ph+ acute lymphoblastic leukemia(ALL) who were previously treated with Imatinib. While one study showed higher incidence of GVHD, VOD and TRM, most studies have demonstrated that Imatinib therapy prior to SCT does not adversely affect transplantation outcome. Dasatinib is a novel dual SRC/ABL kinase inhibitor currently being used in pts with Imatinib-resistant advanced CML or relapsed/efractory Ph+ ALL. Most of these pts will eventually undergo SCT, raising the question of whether Dasatinib therapy may adversely affect transplantation outcome. We report eight pts: CML -6 (CP1-4, low sokal score -3, high sokal score -1, CP2-1, AP-1) and Ph+ ALL -2 who received Dasatinib prior to alloSCT (n=7) or autoSCT (n=1). Donors were matched siblings -4, matched unrelated -2 or mismatch related donor (haploSCT) -1. Five were male and 3 female with a median age of 46.5 (16–56) years. First line therapies included Hydroxyurea or Interferon followed by Imatinib for the CP CML pts and chemotherapy followed by Imatinib for the advanced CML and Ph+ ALL pts. All pts subsequently received Dasatinib 70mg × 2/day due to resistance to Imatinib, resulting in complete hematological response in all, as well as complete (n=5) or partial cytogenetic response (CyR) (n=2) prior to SCT. One pt did not achieve CyR prior to SCT. The pts were conditioned with either a myeloablative protocol (n=5) or a reduced intensity protocol (n=3). GVHD prophylaxis consisted of CSA and MTX (n=6) or complete T-cell depletion (n=1). Pts received a mobilized peripheral blood stem cell graft with 11.4–19.8 × 106 CD34+ cells/kg. The pt who underwent autoSCT was successfully mobilized (2 apheresis cycles yielding 5.7 × 106 CD34+/kg). Dasatinib was stopped 6 days before mobilization. All pts successfully engrafted reaching ANC > 0.5×109/L on day +14 (11–21) and PLT >20×109/L on day +12.5 (11–17). Chimerism was 99.4 – 100%. Transplant related toxicities were minimal. Only one pt developed severe mucositis. No pt developed hyperbilirubinemia or VOD. There was no increased risk of infections. Acute GVHD (Gr II) was observed in only 1 pt, while 2 developed extensive chronic GVHD (1 after stopping immunosuppression). With a median follow-up of 8.5 (2–13) months, six pts are alive, 5 in CR, while 2 died of disease progression. We may conclude that in pts undergoing SCT following Dasatinib there is no evidence that Dasatinib adversely affect post SCT outcome, as no increased transplant related organ toxicities, non-engraftment, GVHD or infections were observed. Larger studies are obviously indicated to confirm our preliminary results.
Baseline Inflammatory Cytokines Predicted Rapid Increase in Symptom Severity to Nadir of Allogeneic BMT.
Authors: Wang Xin Shelley , Williams Loretta , Shi Qiuling , Giralt Sergio A. , Cleeland Charles S.
Published: October 2019

Patients who undergo allogeneic BMT experience a rapid increase in multiple symptoms, including pain, fatigue, poor appetite, drowsiness, dry mouth, and disturbed sleep, from pre-BMT to nadir of white blood cell count. The objective of this study was to prospectively evaluate baseline levels of serum inflammatory cytokines and other factors related to symptom development from pre-BMT to nadir.

Methods: Repeated multiple-symptom assessments with the M. D. Anderson Symptom Inventory (MDASI) were completed for 30 patients with AML/MDS at day of hospital admission (baseline), day of conditioning, day of BMT, day of nadir, and day 11 of BMT. A panel of serum inflammatory cytokines (IL-1ra, IL-6, IL-8, IL-10, IL-12, TNF-a) was assayed at baseline, conditioning, day of BMT, day after BMT, and at nadir.

Results: Patients self reported multiple symptoms that peaked 3 days after nadir. We adjusted for potential confounding factors, including age, sex, race, disease status pre-BMT, infusion dose of CD34+, and conditioning regimen, that could have affected symptom outcomes in the mixed effect models for symptom severity. Race was the only significant factor affecting the severity of the baseline symptom cluster (pain, fatigue, poor appetite, disturbed sleep, drowsiness, and dry mouth) and the change in symptom severity from baseline to peak (P<.0001). We were interested to know if baseline cytokines had any role in symptom development. Of the panel of cytokines tested, IL-6, IL-8, and IL-1b were significant predictors of the severity of symptom cluster from baseline to peak (estimated values from mixed modeling were 1.196, −3.707, and 6.055, all P<.05).

Conclusion: These results provide the first evidence of the role of baseline serum pro-inflammatory cytokines in symptom development from pre-BMT to symptom peak around nadir in patients with AML/MDS who have undergone allogeneic BMT.
A Randomized Trial of Bone Marrow (BM) Versus Peripheral Blood (PB) Allogeneic Hemopoietic Stem Cell Transplants (HSCT) in Patients with Myeloproliferative Disorders.
Authors: Bacigalupo Andrea , van Lint Maria Teresa , Olivieri Attilio , Casini Marco , Angelucci Emanuele , Narni Franco , Selleri Carmine , Di Bartolomeo Paolo , Ciceri Fabio , Fanin Renato
Published: October 2019

Background. Reduced intensity conditioning (RIC) regimens have been widely used over the past years with the aim of reducing transplant related mortality (TRM) of allogeneic hemopoietic stem cells transplants (HSCT). The preferred source is peripheral blood (PB) cells, although this source has not been prospectively compared with bone marrow (BM) iun the setting of RIC transplants.

Aim of the study. To compare BM and PB allogeneic transplants following a RIC regimen in patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML) or idiopathic myelofibrosis (IM).

Methods and patients. This is a prospective multicenter randomized trial: eligible were patients with AML, CML and IM, aged 45–60, with an HLA identical sibling, Conditioning regimen was thiotepa 5 mg/kgx2 and cyclophopshamide 50 mg/kgx2. Graft versus host disease (GvHD) prophylaxis was low dose cyclosporin and low dose methotrexate. Patients were randomized to receive unmanipulated BM (n=36) or unmanipulated PB (n=35), after stratification for disease phase (1st remission, n=47) or advanced disease (n=24). Median age was 51 in both groups and follow up of surviving patients 760 and 756 days respectively.

Results. Engraftment was achieved in all but one patient who has autologous reconstitution. Acute GvHD grade III–IV accurred in 0% vs 12% of BM vs PB patients (p=0.03) and extensive chronic GvHD in 13% vs 37% respectively (p=0.03).

Cumulative incidence (CI) of TRM at 5 years is 6% for BM and 9% for PB (p=0.6). Relapse of the original disease occurred in 61% vs 29% of BM and PB patients (p=0.007) and the CI of relapse related death (RRD) is 39% vs 19% respectively (p=0.07). Actuarial 5 year survival is 47% in BM vs 68% in PB paitents (p=0.3). A COX proportional step down analysis shows chronic GvHD to be a significant favourable factor for RRD and survival. Conclusions. In patients receiving a RIC allogeneic graftTRM is low and comparable in BM and PB transplanst;acute and chronic GvHD is more frequent in PB transplants,relapse is significantly decreased in PB transplants and RRD is also lower,there is a non significant survival advantage for PB patients andthe occurrence of chronic GvHD protects against relapse and favourably influences long term survival.
Phenotypic and Functional Analysis of T-Cells Mobilized in HLA-Matched Sibling Donors Following Treatment with the Chemokine Antagonist AMD3100.
Authors: Rettig Michael , Devine Steven M. , Ritchey Julie , DiPersio John F.
Published: October 2019

We are currently evaluating a novel method for the procurement of peripheral blood stem cells from HLA matched sibling donors using a direct antagonist of the CXCR4/SDF-1 interaction called AMD3100 (A). Donors receive a single subcutaneous injection of A and then undergo a 20 liter leukapheresis (LP) four hours later. The LP product is then cryopreserved and subsequently transplanted following ablative conditioning. To date, we have performed 15 transplants with allografts collected following A alone. In comparison to allografts collected following five days of G-CSF, A mobilized allografts contain approximately 50% less CD34+ cells but 2–3 times more CD3+ cells. Nevertheless, the kinetics of neutrophil and platelet engraftment have been virtually identical to that observed following G-mobilized allografts and grades 2–4 acute GVHD has been observed in only 20% of recipients. We sought to analyze the functional and phenotypic properties of T cells collected following A alone to understand the relatively low rates of acute GVHD despite the transplantation of higher T-cell doses. In 3 donors, extensive T cell phenotyping was performed on donor peripheral blood prior to A, 6 hours following A, and also on the LP product collected after A. Specifically, we were seeking to determine whether any alteration in CD4+ or CD8+ subsets had occurred. We analyzed T-cell subsets using well described markers for central memory, effector memory, naïve, and effector memory RA phenotypes. We also assessed expression of CD62L, CD127, CCR7, and SLAM family members (CD48, CD150, and CD244) on both CD4+ and CD8+ cells. The activation status on CD4 and CD8 cells was assessed using markers for CD25, CD30, and CD69. Finally we assessed for quantitative changes in the mobilization of regulatory T cells by assaying the proportion of CD4+CD25+FoxP3+ cells mobilized following A. In none of these analyses could we detect any significant alteration in the relative ratios of CD4 or CD8 subsets mobilized by A. Finally, the functional capacity of purified CD3+ cells collected following A was assessed using a NOD/SCID xenogeneic GVHD model we have recently developed. In that model, survival of mice transplanted with A mobilized T-cells was similar to that observed with untreated T cells, suggesting that A mobilized T cells retain their GVHD-inducing capacity. In summary, these preliminary data suggest that AMD3100 induces a “pan-mobilization” of T cell subsets without any apparent skewing toward a particular subset. These studies are in contrast to others suggesting subtle phenotypic and functional changes in donor T cells after mobilization with G-CSF. Further studies evaluating A mobilized allografts are ongoing.
Alloreactive Alleles for the IL-10 -1064 Polymorphism in the Donor Associate with Chronic GVHD, in a Chimerism Mediated Fashion, after HLA Identical Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Manzano Cintia , Sanchez-Hernandez Noemi , Barroso Diana , Balsalobre Pascual , Gonzalez-Rivera Milagros , Serrano David , Carrion Rafael , Gomez-Pineda Alfonso , Diez-Martin Jose L. , Buño Ismael
Published: October 2019

Background: Polymorphisms in regulatory sequences of cytokine genes are known to influence their expression and, therefore, the intensity of the immune response. Some of such polymorphisms have been associated with the outcome of allogeneic stem cell transplantation (SCT).

Objective: To evaluate the association between donor (D) and recipient (R) genotype for the IL-10 gene -1082 SNP (single nucleotide polymorphism) and -1064 STR (short tandem repeat) polymorphism with the dynamics of chimerism and the development of complications after SCT.

Patients and methods: 24 HLA-matched conventional SCT. IL-10 genotypes were determined in an -1082 SNP allele-specific PCR (A vs G) including the -1064 STR in the product which is revealed by capillary electrophoresis. Results were analyzed using Fisher’s exact test due to the reduced sample size.

Results: The frequency of alloreactive genotypes (AA or A) for the SNP was 37,5% AA and 79,2% A in the D and 33,3 AA and 95,8% A in the R. No association was observed between the homozygous or heterozygous presence in the D or R of the alloreactive allele for the SNP genotype and the dynamics of chimerism or complications post-SCT. Alleles 4 to 10 for the STR genotype were found in contrast to previous reports (alleles 7–16). The frequency of alloreactive alleles (homozygous, +/+, or heterozygous, +), with greater number of dinucleotide repeats (alleles 8–10 in the present series) for the STR was 8,3% +/+ and 62,5% + in the D and 8,3% +/+ and 50% + in the R. The presence of alloreactive alleles (heterozygous) in the donor was significantly associated with the development of extense chronic GVHD (EcGVHD, Table 1). In patients transplanted from such donors, the incidence of mixed chimerism (MC) in peripheral blood during the first month post-SCT was lower although without statistical significance (Table 1). The higher alloreactivity of these donors favors the establishment of complete chimerism and therefore, increases the incidence of EcGVHD.

Conclusions: The present study shows an association between the presence in the donor of alloreactive alleles for the IL-10 -1064 STR polymorphism and the development of EcGVHD, in a chimerism mediated fashion, after HLA- identical SCT. The analysis of a larger number of patients as well as further cytokines will eventually allow to confirm these observations and to establish this type of studies as a means for an improved management of transplanted patients.

Table 1. Influence of alloreactive alleles (8–10) for the IL-10-1064 STR polymorphism on chimerism and complications post-STC.
Lactate Dehydrogenase (LDH) Level Predicts the Outcome of Patients with Acute Myelogenous Leukemia (AML) Following HLA-Matched Sibling Bone Marrow Transplant (BMT).
Authors: Kalaycio Matt , Rybicki Lisa , Pohlman Brad , Dean Robert , Sweetenham John William , Andresen Steven , Sobecks Ronald , Sekeres Mikkael A. , Advani Anjali , Davis Randall , Brown Stacey , Bolwell Brian
Published: October 2019

Active disease (ActDis), poor-risk cytogenetics, and older age have historically been considered the most important adverse risk factors for survival after BMT for AML. We performed a multivariable analysis of these and other potential risk factors for overall and progression-free survival. From August 1992 to July 2005, we treated 87 patients with AML, who also had informative cytogenetic studies, with high-dose busulfan-containing preparative regimens and an HLA-matched sibling BMT. The median age was 43 years (range 19 to 62). The median LDH level at the time of BMT was 204 U/L (range 93–1555 U/L; normal 100–220 U/L). Forty-one patients were in either first (n= 30) or second complete remission (n=11; CR). 46 patients with ActDis were treated. The 87 patients were then classified according to the SWOG/ECOG (Blood96:4075, 2000), MRC (Blood92:2322, 1998), and CALGB (Blood100:4325, 2002) cytogenetic classification systems. With a median follow-up of 56.0 months (range 4.5–107.8 months), the median relapse-free survival is 13.5 months for patients in CR1 and 4.1 months for patients in CR2. The relapse-free survival of patients with ActDis was 5.5 months. A Cox proportional hazards analysis that included gender, age, LDH, disease status, cytogenetic risk group, preparative regimen, source of stem cells, and CMV status was performed for overall and relapse-free survival. Significant risk factors for shorter survival in univariate analysis included male gender, LDH >330 U/L (but not LDH >220 U/L or per 100 U/L increase), and peripheral stem cells as a source of hematopoietic reconstitution (n = 7). Surprisingly, a male donor to a male recipient was also an adverse risk factor (p<0.001). However, in multivariable analysis, only LDH >330 U/L (p=0.002), source of stem cells (p=0.019), and male donor to male recipient (p<0.001) remained as significant adverse risk factors. In fact, patients with ActDis and an LDH ≤ 330 U/L had similar survival to patients treated in remission, while patients with ActDis and LDH > 330 U/L had significantly worse survival as shown below. We conclude that high LDH (>1.5X upper limit of normal) is a significant adverse risk factor for survival after BMT for AML and predicts outcome better than more traditional risk factors such as age, disease status, and cytogenetic risk profile.

Figure Figure
Polychemotherapy in Combination with Thalidomide Followed by Autologous or Allogeneic Transplantation for Rescue after Autograft or Induction Therapy Failure in Patients with Multiple Myeloma.
Authors: Hegenbart Ute , Schonland Stefan O. , Moehler Thomas , Benner Axel , Gerull Sabine , Goerner Martin , Schaefer Hans-Joerg , Egerer Gerlinde , Dreger Peter , Ho Anthony D. , Goldschmidt Hartmut
Published: October 2019

BACKGROUND: Most patients (pts) undergoing high-dose therapy and autologous transplant for multiple myeloma (MM) develop disease recurrence. The optimal salvage treatment for these patients is not well defined. Autologous (auto-) and allogeneic (allo-) hematopoietic stem cell transplantation (SCT) have been used for salvage therapy.

METHODS: We performed a retrospective analysis of pts with MM (n=118) treated in our institution who had failed after 1st-line therapy or relapsed after auto-SCT. Re-induction was performed with TCED (thalidomide, cyclophosphamide, etoposide and dexamethasone, median number of cycles 3). Seventy-four pts (median age, 59 yrs) received auto-SCT as salvage therapy, whereas 44 pts (median age, 53 yrs, p=0.43) underwent a reduced-intensity allo-SCT (related in 23 pts), using conditioning with 2 Gy total body irradiation and fludarabine in 40 pts or melphalan 140 mg/m2 / fludarabine in 4 pts. The majority of the pts (37 / 44) received allo- SCT a median of 59 (range 33–186) days after auto-SCT. Twenty pts in the auto-group and 9 pts in the allo-group were primary progressive, respectively (p=0.42).

RESULTS: 89 pts (75%) responded to TCED chemotherapy (CR 4 pts, PR 65 pts, MR 22 pts, SD 13 pts). The number of pts progressing after TCED was equal in both groups (p=0.54). Remission status improved in 30 pts after auto-SCT (7 CR) and in 20 pts after allo-SCT (16 CR, p=0.001). After a median follow-up of 24 months for the auto-group and 21 months for the allo-group since the end of TCED therapy, the median event-free survival (EFS, figure 1) and overall survival (OS, figure 2) were 14 months in both groups (p=0.37) and 27 months versus 35 months (p=0.75), respectively. Incidence of chronic GvHD was 82% (62% extensive). TRM was 20% in the allo-group and differed significantly from the auto-group (1%, p=0.007). Three years after end of TCED 12/44 pts are alive (6 pts in CR) in the allo-group compared to 15/74 pts (1 pt in CR) in the auto-group. All but 1 pt with CR > 3 years after allo-SCT have extensive cGvHD.

CONCLUSIONS: Both auto- and allo-SCT are feasible as salvage therapy for MM. Disease recurrence or progression remains the major cause of treatment failure. More CRs and more long term survivors in CR have been observed after allo-SCT confirming the contribution of the GvM-effect. Further concepts are necessary to maintain CR, to prevent relapse or progression and to reduce TRM after allo-SCT.

Figure Figure Figure Figure
Fludarabine-Busulfan Conditioning and In Vivo T-Cell Depletion with Reduced Dose of ATG Followed by Allografting Induces Durable Responses in Patients with Advanced Multiple Myeloma with No Grade III-IV aGvHD.
Authors: Bahlis Nizar J. , Stewart Douglas A. , Savoie Mary Lynn , Brown Christopher , Daly Andrew , Chaudhry Ahsan , Storek Jan , Russell James A.
Published: October 2019

Background: We have investigated a conditioning regimen with Fludarabine and intravenous Busulfan with reduced ATG dose in patients with advanced and poor prognosis myeloma exploring the possibility that a low dose ATG may be sufficient enough to prevent severe GvHD without completely suppressing the graft vs myeloma effect.

Methods: 15 patients received a conditioning regimen consisting of fludarabine 50mg/m2 on days -6 to -2 and IV BU (Busulfex, ESP Pharma) at a “myeloablative” dose of 3.2 mg/kg daily days -5 to -2 inclusive. All pts received Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pre-transplant finishing D0, cyclosporine A and methotrexate with folinic acid.

Results: The median age was 49 years (range 40–61). 14 (93.3%) patients had stage III (DS) disease with a median β2-microglobulin 3.12 mg/dl (1.82–5.75) and 7/11 (63.6%) in whom FISH studies were available had deletion 13, 5/15 (33.3%) patients had relapsed or progressed within 2 years of prior autologous stem cell transplant and 4 (26.6%) had progressed while on thalidomide /Dex salvage treatment. The disease status prior to allogeneic transplant was partial response (PR) in 6/15 (40%) and progressive disease (PD) in 9/15 (60%). 2/15 had plasma cell leukemia. The median number of bone marrow plasma cells prior to allo-transplant was 16% (range 3%-85%). Donors were matched siblings (MRD) for 13 (86.7%) and alternate donors in 2 (13.3%, unrelated with 2 C antigen mismatch). Cell source was blood in 14/15 (93.3%). Acute GVHD grade II-IV occurred in only 1 patient (6.6%) with no grade III-IV acute GVHD. Chronic GVHD occurred in 9/15 (60%). The TRM was 6.6%. Among 14/15 patients evaluable for response, the overall response rate (CR+PR) was 53.3% (2 CR, 6 PR, 1 MR and 5 PD); 37.5% (1CR, 2PR, 1MR and 4PD) for pts with PD at the time of the transplant and 71.4% (4PR, 1MR and 1PD) for pts with del13. After a median follow-up of 40.9 months (range 36–65.2), the estimated OS and PFS at 4 years for all patients is 38.9% (CI 95%: 13.1–64.7%) and 20.0% (CI 95%: 0–40.3%) respectively. For patients with del13 the estimated OS and PFS at 4 years is 38.1% (CI 95%: 0–77.9%) and 0% respectively.

Conclusion: In vivo T-cell depletion with ATG results in a low rate of severe aGvHD with low treatment-related mortality and a substantial number of long-term survivors among patients with advanced multiple myeloma. The detection of deletion 13 by FISH however remains a predictor of short progression free survival.

Figure Figure
Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients - A Single Center Study.
Authors: Stadler Michael , Hertenstein Bernd , Krauter Juergen , Buchholz Stefanie , Dammann Elke , Eder Matthias , Ganser Arnold
Published: October 2019

Allogeneic hematopoietic cell transplantation (alloHSCT) has curative potential in many hematologic malignancies; however, substantial treatment related toxicity has restricted its use to younger patients (mostly under 55 years of age). With the development of conditioning regimens of reduced intensity, alloHSCT is being applied more widely in elderly patients, too. Here we report the results of all consecutive alloHSCT recipients above the age of 55 years transplanted at our institution between October 1996 and April 2006. Among 89 elderly patients transplanted, 50 patients were in the age group over 55 to 60 years, 31 patients in the cohort over 60 to 65 years, and 8 patients were older than 65 years. 36 patients were female and 53 male. Diagnoses included acute lymphoblastic leukemia (ALL, 10 patients), acute myelogenous leukemia (AML, 32), myelodysplastic syndromes (MDS) or secondary AML (30), chronic myelogenous leukemia (CML, 5), agnogenic myeloid metaplasia (AMM, 3), lymphoma (5), and multiple myeloma (4 patients). Advanced disease was present in 63 patients (71%) at the time of transplant. 85 patients (96%) had a WHO performance score of 0 or 1. Conditioning regimen was myeloablative in 20 patients (22%) and of reduced intensity in 69 patients (78%); in 46 patients (52%) irradiation was part of the conditioning regimen. Stem cell source was peripheral blood in 83 patients (93%) and bone marrow in 6 (7%). 32 patients (36%) received a graft from a related donor and 57 (64%) from an unrelated donor. After a median follow-up of 9 months (range: 1 to 104), 24 patients have since relapsed (27%). Treament related mortality was 27% (24 of 89 patients). 34 patients developed acute graft-versus-host disease (GvHD, 38%) and chronic GvHD was diagnosed in 25 of 71 patients at risk (35%). As of August 1st, 2006, 47 of 89 patients were alive and 41 of 89 in complete remission. Probabilities of overall and disease-free survival at three years were 45 and 32%, respectively. Interestingly, overall and disease-free survival were similar among the three age cohorts. In conclusion, according to our experience, alloHSCT is feasible in elderly patients of appropriate performance status, with acceptable relapse rates and toxicity.

Figure Probability of overall survival in elderly patients after alloHSTC Figure Probability of overall survival in elderly patients after alloHSTC
Long-Term Follow-Up of Allogeneic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.
Authors: Kuruvilla John , Bao Qikun , Goldberg Mira , Gupta Vikas , Kiss Thomas L. , Lipton Jeffrey H. , Minden Mark D. , Messner Hans A.
Published: October 2019

Introduction

Allogeneic stem cell transplantation (Allo-SCT) remains an option for patients with chronic lymphocytic lymphoma (CLL). Our program employs a strategy using allo-SCT for patients (pts) with high risk disease based on clinical characteristics and prior therapy. We performed a retrospective analysis to examine long-term disease control and treatment toxicity.

Methods

A total of 52 patients (pts) are included who underwent allo-SCT at our institution between Aug 1989 and Dec 2005. Patients were in a chemosensitive remission at the time of SCT. The conditioning regimen consisted of busulfan (1 mg/kg PO q6h X4 days between 1989–200 and 3.2 mg/kg IV daily X 4days subsequently) and cyclophosphamide 60 mg/kg X 2 days. Cyclophosphamide 60 mg/kg X 2 days and TBI 12 Gy was used for unrelated donor SCT. Reduced intensity conditioning (RIC) SCT were typically performed with Fludarabine 50 mg/m2 for 4 days and 2 Gy TBI. GVHD prophylaxis was with cyclosporine A and methotrexate.

Results

There were 34 males and 18 females. The median age at the time of transplant was 51 years (range 26 to 65). Histologic subtype was: CLL and/or small lymphocytic lymphoma (SLL); 48 and T-prolymphocytic leukemia (PLL): 4. The median number of prior chemotherapy regimens was 3 (range 1 – 10) and was unavailable in 16. Prior chemotherapies included: anthracycline-based: 24, prior purine analog: 32, prior platinum-based: 8, prior auto-SCT: 1, prior rituximab: 5. The median time from diagnosis to allo-SCT was 58 months (range 5 – 260). 10 pts underwent RIC SCT. Graft source was: matched sibling (MSD) bone marrow (BM): 18, MSD peripheral blood stem cells (PBSC): 20, Mismatch related (MMRD) bone marrow (BM): 1, MRD PBSC: 4, matched unrelated donor (MUD) BM: 8, MUD PBSC: 1. At 5 years, the overall survival of the entire cohort is 51% (95% confidence intervals: 34 – 68%) with two long-term survivors of 14 and 17 years. Treatment-related mortality (TRM) was 20 of 52 pts (38%). 4 pts have relapsed ((8% of total cohort) and non-relapse mortality was 1 pt (2%). Overall survival by intensity of SCT conditioning regimen was not significant (p=0.3). TRM was similar in pts who received fully myeloablative SCT (40% vs. 20% in RICSCT group, p=0.29).

Conclusions

Acceptable survival post-SCT is possible using an allo-SCT strategy in CLL. However, TRM remains high in this group of heavily pre-treated patients with a median age of over 50 that predominantly received fully myeloablative allo-SCT. Due to small sample size, the potential benefit of reduced TRM with RICSCT cannot be demonstrated. Ideally, allo-SCT should be considered earlier in the course of the disease based on risk stratification utilizing traditional risk factors and modern prognostic factors such as FISH studies and novel markers.