bluuebunny/crossref_metadata_2025 huggingface dataset:
Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Secondary Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndromes (MDS).
Authors: El-Cheikh Jean , Faucher Catherine , Mohty Mohamad , Stoppa Anne-Marie , Lafage-Pochitaloff Marina , Coso Diane , Moziconacci Marie-Joelle , Bouabdallah Reda , Gastaut Jean-Albert , Blaise Didier , Vey Norbert
Published: April 2020

Secondary AML and high risk MDS represent a poor risk group of myeloid malignancies. We report here the results of a single center retrospective study of allo-SCT in 28 patients (median age, 42 y.) with secondary AML (n=19; 68%) and MDS (n=9; 22%). Eleven patients (39%) had therapy-related AML (t-AML). FAB categories included: AR/ARS: 3, AREB/AREBt: 6, M0: 1, M1–M2: 9, M4–M5: 5, M6: 3, and one patient could not be classified. Cytogenetics features were: poor risk in 20 patients (71%), normal in 5 patients (19%) and not evaluated in 3 (10%). Allo-SCT was performed as first line therapy in 9 patients (32%) of whom 7 MDS and 2 sAML. The remaining 19 patients (68%), were transplanted after initial induction chemotherapy of whom 17 sAML (89%), and 2 MDS (11%). Median interval between diagnosis and allo-SCT was 3.6 months (range, 1–12). 12 patients (43%) were in complete remission at time of allo-SCT, while 9 patients (32%) were refractory or in progression after treatment, and 7 patients (25%) had stable disease. In 25 cases (89%) donor was a HLA identical sibling, and in 3 cases (11%) a matched unrelated donor. The conditioning regimen was fully myeloablative in 19 patients (68%) including Cy-TBI or BU-Mel or a reduced intensity conditioning (RIC) in 9 patients (32%). Nineteen patients (68%) died after transplantation, of whom 12 patients from non relapse causes (GVHD: 5; infections: 6; multi-organ failure: 1). Seven patients (25%) died from relapse or progression of the disease including 5 patients (18%) with AML and 2 patients (7%) with MDS. The one-year cumulative incidence of transplant related mortality (TRM) was 38%, with TRM being significantly lower in the RIC allo-SCT group (13% vs. 43%; P=0.06). With a median follow-up of 30 months, the probability of progression after transplantation at 5 years was 51% (95%CI, 39–73). Five-year overall survival (OS) was 26% (95%CI, 13–48). Most importantly, none of the pre-transplant parameters influenced OS or DFS. In all, these results suggest that standard allo-SCT is associated with a high TRM rate not allowing a breakthrough in the outcome of patients with secondary AML and high-risk MDS. The use of a RIC regimen significantly decreased TRM in this high risk group of patients, likely representing an attractive modality to develop novel strategies and further refine the allogeneic anti-leukemic activity for a better outcome.
Effective Treatment with Imatinib Mesylate and Donor Lymphocyte Infusion Following Relapse after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myeloid Leukemia.
Authors: Li Jianyong , Wu Hanxin , Qian Sixuan , Hong Ming , Xiao Bing , Zhang Run , Ruan Changgeng
Published: April 2020

Imatinib mesylate (STI571) and donor lymphocyte infusion (DLI) were two most effective treatment for chronic myeloid leukemia (CML) relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the combination of STI571 and DLI was rarely reported in the treatment of CML relapse after allo-HSCT. To explore the effect of STI571 with DLI in the treatment of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for CML, two relapsed CML patients after allo-HSCT were treated with short course (<1 month) of STI571 400 mg or 600 mg/d and DLI. Case 1, female, 32 years old (yrs), transformed to acute myeloid leukemia (AML) M2 four months after diagnosis of CML. The patient did not response to STI571 600 mg/d for two months and received HLA haploidentical brother bone marrow transplantation (BMT) without ex-vivo T cell depletion and acquired complete remission (CR). 100 days after transplantation, the patient relapsed in the form of AML-M2. Case 2, female, 54 yrs, five months after diagnosis of CML, she received HLA-identical brother HSCT and acquired CR. Four months after transplantation, karyotyping showed 46, XX, t(9;22)(q34;q11)[7]/46, idem, +mar1, +mar2,+mar3[3], FISH showed 500/1000 donor cells, which suggested disease progression. 31 days (case 1) and 26 days (case 2) respectively after treatment with STI571 and DLI, they acquired CR which was confirmed by morphology, normal karyotype by conventional cytogenetics and X/Y, BCR/ABL FISH, and negative BCR/ABL by FISH and RT-PCR. As of July 2005, the two patients were in continuous complete remission for 25 (case 1) and 24 (case 2) months. We conclude that Imatinib mesylate with DLI is very effective in the treatment CML after relapse following allo-HSCT, and deserve further investigation for its effectiveness and mechanism.
Reduced-Intensity Allogeneic Stem Cell Transplantation for Relapsed/Refractory Hodgkin and Non-Hodgkin Lymphoma.
Authors: Lerner Decio , Azevedo Alexandre M. , Colares Marta , Tavares Rita de Cássia B. , Maradei Simone C. , Lima Joana , Lobo Ana Maria G. , Tabak Daniel G. , Urago Katia , Lima Maria Claudia , Maiolino Angelo , Bouzas Luis Fernando S.
Published: April 2020

There are few treatment options for pts with multiply relapsed or refractory lymphoma. Allogeneic stem cell transplantation has historically been limited in this group by high transplant-related mortality (TRM) rates, and evidence for a clinically relevant graft-versus-lymphoma (GvL) effect has been limited. We evaluated reduced-intensity transplantation (RIT) in these pts with the aim of reducing TRM while exploiting the GvL effect. Between 12/00 and 02/05, 31 pts with an HLA-identical sibling were enrolled, 18 with non-Hodgkin (NHL) and 13 with Hodgkin (HL) lymphoma. Main characteristics were: median age = 33 years (range, 17–60); male gender = 20; histology = diffuse large B cell (9), T-cell anaplastic large cell (2), transformed-large cell (2), mantle cell, lymphoplasmacytic, T-peripheral, diffuse mixed large and small cell (1 each), and Hodgkin lymphoma (13). At study entry, 19 pts (36% NHL, 92% HL) had previously failed autologous transplantation (AT) and even patients who had not received high-dose chemotherapy had failed a median of 4+ lines of therapy. Five patients were in partial remission, 2 in untreated relapse post-AT and 24 had chemorefractory disease. Conditioning consisted of fludarabine (25 mg/m2 x 5 d) and cyclophosphamide (60 mg/kg x 2 d). Twenty nine pts received peripheral blood and 2 received marrow stem cells. GVHD prophylaxis comprised cyclosporin and mini-methotrexate. Early death occurred in 3 pts from aspergillosis, pulmonary fibrosis and cardiac failure. All other patients engrafted, 1 with a progressively autologous pattern of chimerism. The overall incidende of grades II, III and IV acute GVHD was 50%, 10% and 7%, respectively. Chronic extensive GVHD occurred in 7/23 (30%) of evaluable pts. Eight pts (25%) died of progressive disease and 9 (29%) of non-relapse causes at a median of 2.5 (range, 1–12) months. Median overall and disease-free survival for all pts is 15.3 months and 7.9 months, respectively. Differences in overall and disease-free survival were not statistically significant between pts with NHL and HL (15.3 vs 25.2 months, p = 0.7; 5.9 vs 8.1, p = 0.44; respectively). Seven pts remain alive and disease-free (HL = 2/13 [15%]; NHL = 5/18 [27%]; p = 0.66) at median follow-up of 33.7 (range, 13.2 – 54.5) months. Allogeneic RIT is a reasonable therapeutic alternative for pts with relapsed NHL or HL, even those who have relapsed after AT. Mortality rates were acceptable for this heavily pretreated group of patients.
Reduced-Intenisty Unrelated Cord Blood Transplantation for Patients with Advanced Malignant Lymphoma.
Authors: Uchida Naoyuki , Miyakoshi Shigesaburo , Matsumura Tomoko , Yuji Koichiro , Takagi Shinsuke , Kato Daisuke , Kawano Tomomi , Kusumi Eiji , Masuoka Kazuhiro , Wake Atsushi , Taniguchi Shuichi
Published: April 2020

Allogeneic stem cell transplantation has been potentially curative approach for advanced malignant lymphoma. Unrelated umbilical cord blood cell has become a viable source of transplantation for those who lack suitable donors, but the outcome of the transplantation with reduced-intensity conditioning has not been clearly defined yet. We have therefore analysed the outcome of the patients with advanced malignant lymphoma who have undergone reduced-intensity unrelated cord blood transplantation (RI-UCBT). Thirty patients (median age, 47 years; range 27–69 years) underwent RI-UCBT with a preparative regimen consisting mainly of fludarabine 125 mg/m2, melphalan 80 mg/m2, and 4 Gy of total body irradiation since June 2002 to June 2005 with a mean follow-up of 353 days (59–621 days). The types of lymphoma included in this study were DLBCL (11 cases), PTCL (5), Hodgkin disease (5), Follicular lymphoma (5), AITL (2), ALCL (1), and nasal NK/T lymphoma (1). All the patients were heavily treated before proceeding to RI-UCBT, including 9 with prior autologous and 1 allogeneic transplantation. The median infused total cell dose was 2.71 x 107/kg (range, 1.76–4.76 x 107/kg). Graft-versus host disease (GVHD) prophylaxis was composed of cyclosporine or tacrolimus alone. Twenty-four patients (80%) achieved primary neutrophil engraftment at a median of 23 days (12–33 days), and 18 (60%) achieved platelet engraftment at a median of 40 days (26–77 days). Fourteen patients (57.1%) developed grade II to IV acute GVHD at a median of 31 days (15–59 days). Five patients subsequently relapsed and all died within 2 years. Fifteen patients died of non-relapse causes such as infection (8), GVHD (3), IP (2), and others (2). Transplant-related mortality (TRM) within 100 days was 54%. The estimated 1-year probability of overall survival was 24% (95%CI: 1–46%). In subgroup analyses, standard risk patients (CR1, CR2, PR1, n=5) showed 80% while high risk (n=25) showed 13% overall survival at 1 year. These data suggest that RI-UCBT is a feasible option for patients with refractory lymphoma who lack HLA-matched donors. Although the patients in standard risk can expect reasonably good overall survival, the beneficial effect is only limited to small part of the high risk patients. To further improve the outcome, RI-UCBT should be investigated among patients with less advanced diseases in a well-designed clinical trial.

Figure Figure
Reactivation of Cytomegalovirus Following Reduced-Intensity Cord Blood Transplantation for Adult Patients.
Authors: Matsumura Tomoko , Kami Masahiro , Kusumi Eiji , Myojo Tomohiro , Takagi Shinsuke , Kato Daisuke , Yuji Koichiro , Uchida Naoyuki , Masuoka Kazuhiro , Wake Atsushi , Miyakoshi Shigesaburo , Morinaga Shinichi , Kanda Yoshinobu , Taniguchi Shuichi
Published: April 2020

Backgrounds: Cytomegalovirus (CMV) infection is a major complication after allogeneic hematopoietic stem-cell transplantation. We and other groups recently reported the feasibility of cord blood transplantation using reduced-intensity regimens (RI-CBT) for adult patients with advanced hematologic diseases. We have little information on the clinical features of CMV reactivation after RI-CBT.

Patients/methods: We reviewed medical records of 142 patients who received RI-CBT at Toranomon Hospital between January 2002 and March 2005. Median age of the patients was 55 years (range 17–79). Underlying diseases were chemorefractory hematologic diseases (n=136) and severe aplastic anemia (n=6). Conditioning regimens comprised fludarabine 125 mg/m2, melphalan 80 mg/m2 and total body irradiation (TBI) (4–8 Gy). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine (n=86) or tacrolimus (n=56). Median number of total nucleated cells and CD34+ cells was 2.7×106 cells/kg (0.39–4.8), and 0.73×105 cells/kg (0.03–5.7) respectively. HLA disparity was 6/6 (n=3), 5/6 (n=21), 4/6 (n=116), and 3/6 (n=2). All the patients were monitored CMV-antigenemia weekly and received pre-emptive ganciclovir or foscarnet.

Results: CMV antigenemia tested positive in 77 patients on a median of day 36 (range, 4–87) after RI-CBT. Median of maximal CMV antigenemia was 22 per 50,000 leukocytes (range, 1–1806). CMV diseases developed in 18 patients on a median of day 40 (range 15–99); enterocolitis (n=18), and adrenalitis (n=1). CMV-antigenemia remained negative in two patients, when CMV disease was diagnosed. CMV disease was successfully treated using ganciclovir or foscarnet in 17 patients, and the other patient died of septic shock. Multivariate analysis revealed grade II–IV acute GVHD as a risk factor (odds, 95% CI).

Discussion: CMV reactivation and diseases develop early after RI-CBT. Optimal strategy for preventing CMV disease should be established in RICBT.
Very Poor Survival of Patients with AML Who Relapse after Achieving a First Complete Remission: The Eastern Cooperative Oncology Group Experience.
Authors: Rowe Jacob M. , Li Xiaochun , Cassileth Peter A. , Appelbaum Frederick R. , Schiffer Charles A. , Wiernik Peter H. , Litzow Mark R. , Cripe Larry D. , Lazarus Hillard M. , Paietta Elisabeth , Dewald Gordon W. , Weinstein Howard J. , Ogden Angela K. , Woods William G. , Shepherd Lois , Feusner James H. , Bloomfield Clara D. , Tallman Martin S.
Published: April 2020

The optimal post-remission therapy for patients in first complete remission (CR1) continues to be debated. Some centers choose to omit more intensive regimens, such as autologous or allogeneic transplantation, preferring to reserve these for treatment after relapse. Such strategies are mostly based on reports of treatment in second CR, but fail to account for the fact that most relapsed patients do not get into a second CR. The purpose of this retrospective study is to analyze the overall survival (OS) rate of AML patients from the date of first relapse. The data are based on the outcome of 2441 patients entered on 8 consecutive ECOG studies for newly diagnosed AML between 1983 and 1997. The studies included are E3483, PC486, E3993, E4995, E1490, E3997 and the two Intergroup studies E3489 and E2491 (INT0129). The data are arbitrarily divided among patients older or younger than 55 years, as this was the age used in most studies to distinguish between younger and older patients. Of 1699 patients ≤55 years, 1150 (68%) achieved CR1 and 402 (35%) relapsed. The median OS of these patients from first relapse was 6.4 months with a 5-year OS of 11%. If APL patients are excluded and the data are analyzed only by studies for young AML patients (less than age 55 or 60), the median OS from first relapse is 6.2 months with a 5-year OS of only 9%. In the US Intergroup Study (E3489) for patients ≤ 55 years, the median OS from first relapse after an allogeneic transplant, an autologous transplant or consolidation chemotherapy was 6.6, 5.2 and 8 months, respectively with a 5-year OS of 18%, 0% and 0%, respectively. The latter data, however, require cautious interpretation as the numbers in these subgroups are small. These data indicate that patients who relapse after standard initial AML therapy have a dismal OS from the time of relapse. Some die at relapse and only a minority achieve a second CR. Those refractory to reinduction therapy uniformly have a very poor prognosis. These data thus suggest that in planning post-remission therapies approaches most likely to lead to a prolonged leukemia-free survival should be offered rather than reserving such strategies following relapse. Survival from relapse.

Survival from relapse AML (incl APL) n No in CR1 No relapsed (%) Median (months) 2-year survival 5-year survival 55 years ≤ 1699 1150 402 (35%) 6.4 18% 11% >55 years 742 362 237 (65%) 4.7 11% 6%
Non-Myeloablative Hematopoietic Transplant with Sirolimus Immunosuppression: Determinants of Outcome.
Authors: Claxton David F. , Wang Chuancai , Carraher Michelle , Ehmann Christopher , Rybka Witold
Published: April 2020

We added Sirolimus to an established conditioning regimen in an attempt to optimize engraftment and anti-tumor effects while minimizing GVHD. 55 patients patients with advanced hematological malignancies (median age 60) received cyclophosphamide (1gm/m2 days −7 and −6) and fludarabine (25mg/m2 days −7 through −3) prior to peripheral blood cell (51 patients) or marrow (4 patients) transplant. All received sirolimus with tacrolimus, both adjusted to 5–15ng/ml, and methotrexate (5mg/m2 days 1,3, 6) immunoprophyllaxis. Tacrolimus was tapered from days 30–45 in matched siblings (Msib -12 patients) and days 40–100 in (most) alternative donor recipients (AltD- unrelated donor or 5/6 matched related cells - 43 patients) without acute GVHD. Median follow-up is 313 days in AltD patients and 337 days for Msib patients. All Msib cells engrafted, whereas 3/43 AltD recipients showed primary graft failure or secondary graft failure (1/43). Msib recipients engrafted more rapidly than those with AltD transplants (p<0.01). For AltD recipients, the CD34 dose had a positive significant effect on donor engraftment - chimerism (p<0.05 for all points up to D100). Median overall and disease free survival was 287 and 230 days respectively for AltD patients and 303 and 167 days for Msib recipients. Amongst AltD patients, 17/43 survive progression free at D114-1167 (median D416), while in MSib patients only 1/12 survives progression free (p=0.0023 ). Two additional patients are disease free after donor lymphocytes (DLI) or withdrawal of immunosuppression in each group. No patient in the Msib group had transplant related mortality (TRM), but in the AltD group there were nine TRMs, including 7 from GVHD (NS). Multivariate analysis showed CD34 dose and donor types had no significant effect on development of progressive disease (PD). However, in general the odds ratio of any PD decreased exponentially as the level of chimerism increased. For example, at D100 the odds of developing PD decreased by 0.699 times when the level of chimerism increased by 0.1. Multinomial logit analysis showed that compared to GVHD death, the odds ratios for PD death decreased exponentially as the level of chimerism increased. In this series of patients with advanced hematological malignancy, Alternative donor cells provided a higher probability of control of disease, albeit with a trend to higher TRM. Higher CD34 cell doses were associated with improved donor engraftment (chimerism) in AltD recipients. For AltD recipients, risk of PD was reduced by increasing donor chimerism, but increasing chimerism is associated with increased risk of death from GVHD. Efforts to improve control of malignancy via more rapid engraftment of donor cells must be tempered with concern regarding potentially severe GVHD.

Figure Figure
Hematopoietic Stem Cell Transplantation (HSCT) as Curative Therapy for Fanconi Anemia (FA) Patients with Acute Leukemia or Advanced Myelodysplasia (MDS).
Authors: Fraser Christopher J. , Wagner John E. , MacMillan Margaret L.
Published: April 2020

Historically outcomes have been very poor for FA patients with advanced MDS or leukemia. It remains controversial as to whether HSCT is indicated for such patients and there is no consensus as to the optimal conditioning regimen in this setting. Traditionally, conditioning for FA patients has incorporated total body irradiation (TBI). Here, we report results of a pilot study in which we have substituted busulfan for TBI, designed for FA patients with one or more high risk features, identified following analysis of 42 previous consecutive URD FA transplants: advanced MDS or leukemia, age >18 years, or previous proven fungal or gram negative infection. Between 12/02–08/04 6 patients were enrolled, 5 with acute leukemia. Patient and disease characteristics are presented in Table 1. Conditioning consisted of busulfan (total 3.2mg/kg), cyclophosphamide (total 40mg/kg), fludarabine (total 140 mg/m2) and ATG (total dose 75mg/kg); GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. All patients received prophylactic voriconazole for one month prior to transplant. BM was T cell depleted with CD34 selection by Isolex 300i. Five out of six patients achieved neutrophil engraftment. Median time to an ANC>500 was 16 days (range: 11–20 days). One patient developed Grade I acute GVHD; no patient has developed chronic GVHD. The preparative regimen was well tolerated. Toxicities included Grade IV mucositis (n=1), VOD (n=2), hemorrhagic cystitis (n=1) and CMV pneumonia (n=1). Three patients are alive and in remission with a median follow-up of 575 days.

Table 1 Age Diagnosis FANC group Remission status Donor source D+21 chimerism D+60 chimerism Vital status Patient and disease characteristics 5.9 ALL BRCA2 treated; CR 5/6 related BM 100% donor 100% donor alive d+894 21.7 AML A untreated 5/6 URD BM 99.1% donor 100% donor died resp. failure d+99 20.8 SAA A N/A 5/6 URD BM insufficient cells N/A died VOD d+24 6.6 ALL,MDS,Wilm’s BRCA2 ALL treated CR; MDS (7.5% blasts) 6/6 URD UCB 100% donor 100% donor alive d+575 7.1 AML A treated; refractory 4/6 UCB + 5/6 UCB 100% donor #2 54.7% #2; 45.3% recipient died AML relapse d+60 17.3 AML A treated; refractory 5/6 UCB x2 66.7% #1; 31.3% #2; 2% recipient 100% donor #1 alive d+423

These results suggest TBI is not required to achieve durable engraftment and leukemia control, busulfan 3.2 mg/kg is tolerable, and advanced MDS or acute leukemia does not preclude HSCT in FA patients.
High-Dose Melphalan and Autologous Stem Cell Transplantation in Unusual Non-Amyloid Light Chain Deposition Disorders.
Authors: Weichman Karin I. , Seldin David C. , Quillen Karen , Rosenzweig Michael , Dember Laura M. , Skinner Martha , Wright Daniel G. , Sanchorawala Vaishali
Published: April 2020

Light chain deposition disease (LCDD) is caused by a clonal plasma cell disorder in which fragments of monoclonal immunoglobulin light chains, usually with a kappa genotype, are deposited in various tissues in a globular form resulting in organ dysfunction. Crystal-storing histiocytosis (CSH) is another light chain deposition disorder in which monoclonal light chains form intracytoplasmic crystalline deposits. Both LCDD and CSH are uncommon diseases, for which there is limited treatment experience. However, conventional anti-plasma cell chemotherapy with oral melphalan as is used in multiple myeloma has been tried in LCDD with little benefit. Between 1999–2005, five patients with LCDD and one patient with CSH have been treated at Boston University Medical Center with high-dose intravenous melphalan (IVM) followed by autologous peripheral blood stem cell transplantation (SCT). Patients have been treated with either 200mg/m2 of IVM (n=5) or 140 mg/m2 (n=1) depending on age and clinical status and subsequently have been assessed for hematologic responses and for improvements in organ function at 3, 6 and 12 months, and annually thereafter. The median age of patients at the time of treatment has been 45 years (range 34–51). Four patients with LCDD had kappa light chain deposition involving the kidneys and 1 of these patients had extrarenal involvement of the heart on electron microscopy of endomyocardial biopsy as well. One patient with LCDD had lambda deposition involving kidneys only. The patient with CSH had only renal involvement, with kappa light chain plasma cell dyscrasia. All except 1 patient had impaired renal function with creatinine clearance ranging from 21 – 64 ml/min. All treated patients are alive and well at a median follow up of 13.6 months (range 5–24 months). Median survival has not yet been reached. No treatment-related deaths were noted, and treatment-related toxicities were manageable and reversible. All evaluable patients (n=4) have achieved a hematologic complete response of the underlying plasma cell dyscrasia after IVM/SCT. In conclusion, this experience indicates that IVM/SCT is a safe, feasible, and effective modality for the treatment of these unusual light chain deposition disorders.
Intramyocardial Injection of CD133+ Bone Marrow-Derived Stem Cells Improves Cardiac Function Long-Term in the Majority of Selected Patients with End-Stage Ischemic Heart Disease.
Authors: Stockschlaeder Marcus A. , Ghodsizad Ali , Stoldt Volker , Poll Ludger , Scharf Ruediger E. , Gams Emmeran , Klein Michael
Published: April 2020

To improve tissue regeneration of ischemic myocardium, autologous bone marrow-derived stem cells have been injected intramyocardially in 10 patients with end-stage ischemic heart disease. Approx. 60 – 380 ml of bone marrow were harvested from the posterior iliac crest and processed in the operating room under GMP conditions using the automated cell selection device CliniMACS. By using the Duesseldorf protocol, the intraoperative isolation of CD133+-stem cells (1.9−10.0 x 106 cells; purity up to 97%) was achieved in less than 3 hours. Following isolation, autologous CD133+-stem cells were injected in a predefined pattern into the myocardium. Cardiac function was assessed by cardiac MRI and echocardiography three, six, and nine months postoperatively. A significant improvement of cardiac function could be documented in 7 out of 10 patients: ejection fraction (EF) before treatment: 10–22% - after 3 months: 18–30% - after 6 months: 19–30%, after 9 months: 21–31%; left ventricular enddiastolic volume (LVEDV) before treatment: 210 ± 123 ml, after 3 months: 169 ± 80 ml, after 6 months: 162 ± 82 ml, after 9 months: 175 ± 70 ml; left ventricular enddiastolic diameter (LVEDD) before treatment: 79.2 ± 7 mm, after 3 months: 57.4 ± 3 mm, after 6 months: 59.4 ± 4 mm, after 9 months: 56.2 ± 5 mm, respectively. In two patients cardiac function improved only temporarily over the first three months, 1 patient died one month after surgery due to a non-cardiac cause. In conclusion, the sole intramyocardial injection of autologous CD133+-cells proved to be safe and led to a significant gain in heart function in 7 of 10 patients, thereby avoiding or postponing (“bridging”) alternative therapies such as heart transplantaton. The benefial effects of intramyocardially injected bone marrow-derived stem cells might be explained by direcct cellular effects including neovascularization and indirect effects including the formation of growth factors promoting tissue repair.
Outcome of Upfront Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma in African American Versus Non Non-African American Patients.
Authors: Khaled Yasser , Kamboj Ginny , Donthireddy Vijaya , Hnaide Hazem , Oja-Tebbe Nancy , Divine George , Janakiraman Nalini
Published: April 2020

Introduction:

Blacks in the United States are twice as likely to suffer from multiple myeloma as whites. Among African Americans, myeloma is one of the top 10 leading causes of cancer death. Although Multiple Myeloma seems to be more aggressive in African Americans, it is not known if they have worse outcome after autologous peripheral blood stem cell transplantation in comparison to Non African American.

Method:

We performed a retrospective analysis of 86 consecutive patients with Multiple Myeloma who underwent autologous peripheral blood stem cell transplantation between July 1991 and November 2004. Thirty two Patients were African American (37.21%) and fifty four patients were Non-African American (62.79%.). Conditioning regimen was Melphalan-200 in 57 patients and Melphalan140/TBI in 29 patients. No significant statistical differences were observed between African Americans and non African Americans prior to the transplant regarding gender, regimen used, immunoglobulin subtype, cytogenetics, stage, or disease status on univariate analysis.

Results:

There was no significant statistical difference in overall survival or event free survival between African American and non African American. However African American were observed to relapse significantly earlier than non African- American (p=0.0274). Despite the early relapse in African American, survival after relapse was longer for African American compared to non African American (p=0.060), however this result was only marginally significant.

Conclusion:

In this single institution experience, there was no difference in the OS or DFS after upfront autologous peripheral blood stem cell transplantation for Multiple Myeloma in African American and non- African American patients. Although time to progression was significantly shorter in African American versus non African American, surprisingly this was not associated with shorter survival. Despite that these results are limited by the sample size; they are intriguing and need further testing in larger group of patients.
Autologous Peripheral Stem Cell Transplantation(ASCT) for Refractory or Recurrent Hodgkin Lymphoma.
Authors: Koike Mitsuru , Kato Masayuki , Kato Yo , Saito Tasuku , Takimoto Madoka , Irei Michiko , Inoue Yasuyuki , Shibuya Yasushi , Koike Junki , Suzuki Takao , Takahashi Masatomo
Published: April 2020

We performed retrospective analysis of ASCT with high-dose therapy consisting of etoposide and cyclophosphamide with cytosine arabinoside or carboplatinum in 11 pts with primary refractory or recurrent Hodgkin lymphoma.

Pts and method: The patients were treated by ASCT from December 1992 to July 2005 in the hospital. Pts characteristics at initial diagnosis were male 4, female 7, and median age 40 year-old (range 33–40) at initial diagnosis. Histological types were NS: 7, MC: 2 and LP: 2. Clinical stages were 2A:3, 3A: 1, 3B: 3, 4A:2 and 4B: 2. Disease status at ASCT was 1st PR: 8 and 1st recurrence: 2 and 2nd recurrence: 1. Two of 11 pts had a history of prior radiotherapy. Peripheral blood stem cell harvesting was performed followed by late phase of initial chemotherapy or high dose etoposide for salvage therapy with granulocyte stimulating factor. All pts were restaged at 1 month or more after transplantation to evaluate the response to the high dose chemotherapy itself. The response to radiotherapy following ASCT was evaluated 2 months after completion of radiotherapy.

Results: Response to high dose chemotherapy was CR 6 pts and PR 5 pts. Five PR pts were treated with radiation and achieved CR. Cumulative response rate in high-dose chemotherapy with/without radiotherapy was 100%. Median follow-up period was 119 months (range 14–145). No recurrent case was observed. However one of these patients had inexplicable cardiac arrest at 100 months after ASCT. Although the patient survived, it was necessary for her to be in hospital by reason of severe anoxic encephalopathy.

Discussion: ASCT for Hodgkin’s lymphoma seems to be feasible salvage therapy in intractable case. However high-dose chemotherapy alone was poor potential to be cure in our limited experience. If high-dose chemotherapy induces PR, radiotherapy should be scheduled based on careful therapeutic response evaluation of high-dose chemotherapy.
Successful PBSC Mobilization, Collection, Transplantation and Engraftment after Radioimmunotherapy with Yttrium-90 Ibritumomab Tiuxetan for Non-Hodgkin’s Lymphoma (NHL).
Authors: Ely Pamela , Stearns Diane M. , Zaki Bassem I. , Fitzmaurice Thomas F. , Gautier Marc , Lowrey Christopher H. , Bengtson Elizabeth M. , Hill John M. , Schaal Anna D. , Kimtis Elizabeth A. , Root Lynn , Webber Susan , Szczepiorkowski Zbigniew M. , Meehan Kenneth R.
Published: April 2020

Radioimmunotherapy (RIT) is a useful addition to the armamentarium against NHL. Due to concerns about chronic myelosuppression and the possible inability to mobilize stem cells or tolerate further therapy after RIT, this modality has not been commonly utilized in potential transplant candidates. We report the successful mobilization, collection, transplantation and engraftment of 5 patients with NHL following yttrium-90 ibritumomab tiuxetan. Patients had follicular lymphoma, grade I or II (n=3), transformed follicular lymphoma (n=1) or blastic variant mantle cell lymphoma (n=1). Time from RIT to mobilization was 10 months (median; range 7–27 months). The median number of regimens prior to RIT was 2.5 (range 1–4) including prior autologous transplant (n=1). The median number of regimens following RIT and prior to transplant was 1.5 (range 1–2). All patients exhibited chemosensitive disease. Patients were mobilized with R-ICE/G-CSF (n=4) or G-CSF alone (n=1) and required 2.8 leukaphereses (mean; range 2–5). The CD34 yield was 3.8x106 CD34+ cells/kg (median; range 3.4–5.1x106 CD34+ cells/kg). All patients received busulfan, VP-16, ARA-C and cyclophosphamide (BVAC) as the preparatory regimen. One patient received IL-2 from day 0 to day 11. Time to engraftment was 13 days (median; range 9–19 days) for an absolute neutrophil count (ANC) >500 cells/ml and 23 days (median; range 15–44 days) for a platelet count>20x103/ml. The patient on the IL-2 study showed delayed engraftment of both ANC (day 19) and platelets (day 27). The patient with mantle cell lymphoma, who was undergoing his second autologous transplant, exhibited delayed platelet engraftment (day 44). Time to engraftment did not differ significantly for either ANC (p=0.16) or platelets (p=0.10) in 18 RIT-naïve NHL patients receiving BVAC and an autologous peripheral blood stem cell transplant (PBSC) during the same time period. There were no treatment-related deaths. With a median follow up of 12 months, one patient has died of disease recurrence. Two patients remain in complete remission. Two patients are alive with disease (relapse at 12 months and 14 months) and are currently receiving therapy. No patient has demonstrated laboratory or cytogenetic evidence of a myelodysplastic syndrome. In conclusion, heavily pretreated patients who have received radioimmunotherapy with yttrium-90 ibritumomab tiuxetan and subsequently relapse can successfully undergo mobilization, collection, and autologous PBSC transplant. These patients demonstrate full engraftment, durable remissions and tolerate additional therapy should relapse occur following transplant.
Long-Term Renal Outcome of Autologous Stem Cell Transplantation in Light Chain Deposition Disease.
Authors: Lorenz Elizabeth C. , Gertz Morie A. , Fervenza Fernando C. , Leung Nelson
Published: April 2020

Light chain deposition disease (LCDD) is a systemic disorder characterized by deposition of nonamyloid monotypic light chains throughout the body. Renal dysfunction is a ubiquitous manifestation of the disease. Reports suggest that high-dose chemotherapy and autologous stem cell transplantation may be beneficial in the treatment of LCDD. However, the impact of autologous stem cell transplantation on renal function is unclear. This study retrospectively reviewed the effect of autologous stem cell transplantation on renal function in six patients with LCDD. Two patients had concurrent multiple myeloma, and one patient was on hemodialysis prior to transplantation. Patients received chemotherapy with dexamethasone alone or dexamethasone plus thalidomide prior to transplantation. Conditioning was performed with high-dose intravenous melphalan. All patients survived transplantation, but one sustained multi-organ failure shortly afterwards and died. Another patient required temporary hemodialysis following transplantation. All surviving patients achieved a hematologic response, although one ultimately relapsed and required further chemotherapy. Renal parameters also improved. On average, proteinuria levels decreased by 83% in four patients and increased by 1% in one patient. Creatine clearance calculated by the Modification of Diet in Renal Disease (MDRD) Study prediction equation improved by an average of 40%. This review suggests that autologous stem cell transplantation may be an effective therapy for renal dysfunction associated with LCDD.

Clinical Characteristics of LCDD Patients at Presentation Characteristic Number or range Median *Modification of Diet in Renal Disease Study prediction equation Sex 4 male, 2 female Age (years) 35-61 44 Beta-2 microglobulin, μ/ml 3.58-11 4.12 Albumin, g/dl 1.8-4.2 3.85 Creatinine, mg/dl 1.8-5.4 2.45 MDRD*, ml/min 12-50 26.5 Serum M protein, g/dl 0 0 Serum free light chains, mg/dl (n = 5) 2.18-312 19.6 24-hour urine protein, mg 131-10,251 679
AAV8-Factor IX Hepatic Gene Transfer with Transient Immunosuppression Is Safe but Is Abrogated by Low Titers of Neutralizing Antibody in Rhesus Macaques.
Authors: Jiang Haiyan , Patarroyo-White Susannah , Liu Tongyao , Yang Bin , Nagy Dea , He Lin , Scallan Ciaran D. , Sommer Jurg , Zhou Shangzhen , Couto Linda B. , High Katherine A. , Pierce Glenn F.
Published: April 2020

AAV8 vectors have potential in human gene transfer due to improved transduction efficiencies as demonstrated in small animal models, and are also reported to show less cross-reactivity to AAV2 neutralizing antibodies prevalent in humans. To assess this hypothesis, the efficacy and safety of AAV8-human Factor IX (hFIX) was evaluated in rhesus macaques. At doses of 5–20x1012 vg/kg, AAV8-hFIX achieved therapeutic to supraphysiological levels of circulating human FIX via intra-hepatic artery delivery in AAV8-naïve macaques. However, transduction was abrogated in macaques with pre-existing AAV8 neutralizing antibodies at titers as low as 1:5. Intrahepatic delivery of AAV8-hFIX resulted in gene transfer primarily in liver, and was well distributed among individual hepatic lobes. Two macaques that experienced traumatic catheterization developed immediate and delayed (week 4–6) transient transaminitis post surgery. Nevertheless, a significant percentage of AAV8-hFIX transduced hepatocytes persisted despite the liver damage and partial loss of hFIX expression. Transduction was well tolerated in all other macaques. Transient immunosuppression with tacrolimus and mycophenolate mofetil did not impair AAV8-hFIX transduction. The results [1] support AAV8-mediated gene transfer in humans but indicate that both the efficacy achieved and the resistance to pre-existing neutralizing antibodies of AAV8-hFIX are unlikely to be significantly enhanced over AAV2 vector, [2] suggest that a peri-operative insult and likely triggering of innate immunity may result in a later inflammatory response that results in a decrease in transgene protein production, and [3] provide evidence that a short course of immunosuppression does not alter liver transduction by AAV vectors.
Severe Impairment of Dendritic Cell Allostimulatory Activity by Sendai Virus Vectors Is Overcome by Matrix Protein Gene Deletion.
Authors: Armeanu Sorin , Bitzer Michael , Smirnov Irina , Bossow Sascha , Appel Silke , Ungerechts Guy , Bernloehr Christian , Kanz Lothar , Neubert Wolfgang J. , Lauert Ulrich M. , Brossart Peter
Published: April 2020

Delivery of antigens to dendritic cells (DCs) plays a pivotal role in the induction of efficient immune responses ranging from immunity to tolerance. The observation that certain viral pathogens are able to infect DCs has led to a concept where applications of recombinant viruses are employed for antigen delivery with the potential benefit of inducing potent antigen specific T-cell responses directed against multiple epitopes. As a prerequisite for such an application, the infection of DCs by recombinant viruses should not interfere with their stimulatory capacity. In this context we could show, that an emerging neagtive-strand RNA viral vector system based on Sendai virus (SeV) is able to efficiently infect monocyte derived human DCs (moDCs). However, after infection with SeV wildtype the responses of DCs to bacterial lipopolysaccharide (LPS) as a powerful mediator of DC maturation characterized by upregulation of CD83, MHC and costimulatory molecules, enhanced secretion of cytokines and the T cell stimulatory capacity were severly impaired. This was not due to a higher production of IL-10 or inhibition of the nuclear localized expression of Rel-B and c-rel, members of the NF-kB transcription factor family, but was rather the result of an increased apoptosis induction of DC. Interestingly, using various recombinant SeV vectors being devoid of single viral genes we were able to identify the SeV matrix (M) protein as a key component in moDC functional impairment after viral infection. Consequently, usage of M-deficient SeV vectors preserved the allostimulatory activity in infected moDCs despite an efficient expression of all other virally encoded genes, thereby identifying M-deficient vectors as a highly potent tool for the genetic manipulation of DCs.
Stable Gene Transfer and Expression in Human Primary T-Cells by the Sleeping Beauty Transposon System.
Authors: Zhou Xianzheng , Huang Xin , Wilber Andrew C. , Bao Lei , Tuong Dong , Tolar Jakub , Orchard Paul J. , Levine Bruce L. , June Carl H. , McIvor Scott , Blazar Bruce R.
Published: April 2020

The Sleeping Beauty (SB) transposon system is a non-viral DNA delivery system in which a transposase directs integration of an SB transposon into TA-dinucleotide sites in the genome. To determine whether the SB transposon system can mediate integration and long-term transgene expression in human primary T-cells, freshly isolated peripheral blood lymphocytes (PBLs) without prior activation were nucleofected with SB vectors carrying a DsRed reporter gene. Plasmids containing the SB transposase on the same (cis) (n=10) or separate molecule (trans) (n=8) as the SB transposon mediated long-term and stable reporter gene expression in human primary T-cells. We observed that delivery of SB transposase-encoding plasmid in trans effectively mediated stable gene expression in primary T-cells, exhibiting about a 3-fold increase (11% vs. 3% with 10 microgram plasmid on day 21) in potency in comparison with the cis vector (p<0.0001). In addition, a transposase mutant construct was incapable of mediating stable gene expression in human PBLs (n=6, p<0.0001), confirming that catalytic DDE domain is necessary for transposition in human primary T-cells. Immunophenotyping analysis in transposed T-cells showed that both CD4 and CD8 T-cells were transgene positive. SB-mediated high level of transgene expression in human T-cells was maintained in culture for at least 4 months without losing observable expression. Southern hybridization analysis showed a variety of transposon integrants among the 6 DsRed positive T-cell clones and no transposon sequences identifiable in the 2 DsRed negative clones. Sequencing of transposon:chromosome junctions in 5 out of 6 transposed T-cell clones confirmed that stable gene expression was due to SB-mediated transposition. In other studies, PBLs were successfully transfected using the SB transposon system and shown to stably and functionally express a fusion protein consisting of

a surface receptor useful for positive T-cell selection and a “suicide” gene useful for elimination of transfected T-cells after chemotherapy.

This study is the first report demonstrating that the SB transposon system can mediate stable gene transfer in human primary PBLs, which may be more advantageous for T-cell based gene therapies over widely used virus-based or conventional mammalian DNA vectors in terms of simplicity, stability, efficiency and safety.
Clonal Marking of Mouse Hematopoietic Stem and Lymphoid Progenitor Cell Populations.
Authors: Mojica-Henshaw Mariluz P. , Pierce L. Jeanne , Phillips John D. , Planelles Vicente , Spangrude Gerald J.
Published: April 2020

We have developed a method to clonally mark hematopoietic stem and lymphoid progenitor cell populations using a novel sequence tag approach. A library containing an 11-base random sequence tag is cloned into a lentivirus vector, packaged using the VSV-G glycoprotein and HIV-1 capsid, and transduced into freshly isolated mouse hematopoietic stem cell (Thy-1.1lowc-kithigh) or progenitor cell (Thy-1.1negc-kithigh) populations. To minimize artifacts introduced by prolonged culture, we have utilized a 3-hour spinoculation protocol performed in the absence of cytokines. Transduction efficiency was evaluated in vitro by methylcellulose colony assay and liquid cultures, and in vivo by transplanting the transduced cells into lethally irradiated mice. A bicistronic lentivirus vector with a CMV promoter driving expression of a transcript encoding Thy-1.2-IRES-GFP was used to optimize the transduction protocol. Liquid culture assays demonstrated 57% transduction efficiency after 5 days of growth, based on expression of the Thy-1.2 and GFP reporter proteins. Mice transplanted with transduced Thy-1.1negc-kithigh progenitor cells were sacrificed after 16 days, a time at which we have previously observed robust progenitor cell engraftment in the thymus while progeny of Thy-1.1lowc-kithigh HSC have not yet appeared. In 4 of 4 transplanted mice, we observed donor-derived cells in the bone marrow, lymph nodes and thymus. The percentage of total cells expressing the lentivirus-derived transgene ranged from 1.6% of bone marrow cells to 20% of thymocytes. Peripheral blood from mice transplanted with transduced HSC were analyzed and monitored every 4 weeks for transgene expression. We observed that although the Thy-1.2 marker was expressed and maintained up to 14 weeks after HSC transplant, GFP transgene expression was minimal. Based on these preliminary results, we have engineered a new lentivirus vector containing random sequence tags and the Thy-1.2 marker. This strategy provides a simple and efficient way of tracking the progeny of individual cells within a transplanted population, using PCR amplification of the random tags found within mature cell populations derived from the transduced cells. Sequence analysis of individual clones derived from different lineages of cells will enable us to better define the lineage potentials of specific progenitor cell subpopulations.
Provision of Peripheral Blood Stem Cell Service in Developing World: Experience from a Private Medical Center in Malaysia.
Authors: Chin Ng Soo , Teh Alan , Tan K.M.
Published: April 2020

Stem cell transplants (SCT) are potentially life-saving procedures but the availability of such services is limited in the government sector in Malaysia. The cost and logistics of having SCT abroad are daunting. This paper outlined our experience in setting up a SCT unit in a private hospital and reporting on the first hundred cases done over a 4 and a half year period from 1999 to 2004. All cases of SCT were performed with peripheral blood stem cells and in 5 cases (5%) back- up marrow was necessary as <2X10^6 per kg of CD34 positive PBSC was harvested. Autologous SCT was performed on 66 cases for the following indications i.e. Non Hodgkin’s lymphoma (37), Acute myeloid Leukemia (13), multiple myeloma (10) and Hodgkin’s lymphoma (6). Thirty four allogeneic SCT were performed for AML (16), chronic myeloid leukemia (8), acute lymphoblastic leukemia (4), Non Hodgkin’s lymphoma (4), Myelodysplastic syndrome (1) and aplastic anaemia (1). Twenty of the allografts were conventional SCT while 14 had reduced intensity allografts. Transplant related mortality (TRM) was recorded in 4 cases (13.6%) of allogeneic SCT. Three of the deaths were sepsis related. No TRM was seen in autologous SCT. The direct medical cost (included stem cell harvest and the first 3 months post transplant care) of autologous SCT was a mean of US$ 16000 (ranged from US$ 9000 to US$ 20000) while allogeneic SCT cost a mean of US$ 25000 (ranged from US$ 20000 to US$ 60000). Our experiences indicated that SCT is feasible in a private medical center in a developing nation—the SCT results were comparable with established centers but with substantial cost saving as compared with SCT done abroad.