bluuebunny/crossref_metadata_2025 huggingface dataset:
Bortezomib Therapy for Multiple Myeloma in Relapse after Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (RICT).
Authors: Ducastelle Sophie , Revesz Daniela , Troncy Jacques , Mahmoudi Samira , Thomas Xavier , Thiebaut Anne , Nicolini Franck E. , Tavernier Emmanuelle , Le Quoc-Hung , Chelgoum Youssef , Praire Aline , Michallet Mauricette
Published: April 2020

Multiple myeloma (MM) remains incurable and specially of poor prognosis in case of refractory or relapsed disease. However, recent therapeutic advances including the use of new drugs are promising. Although, Bortezomib, new proteasome inhibitor, has proven its efficacy in patients with refractory or relapsed MM, it has not been sufficiently evaluated in the setting of allogeneic hematopoietic stem cell transplantation. Here, we report four cases of MM patients, very heavily pre-treated and all previously transplanted, who received bortezomib associated to dexamethasone for relapse after allogeneic RICT (median time from diagnosis: 68 months, median time from RICT: 41 months). We studied the feasibility, efficacy and safety of bortezomib: two patients achieved a complete remission, one patient a very good partial response, and one had no response. The tolerance was excellent with only one patient who developed a reversible grade 3 hematological toxicity. No GVHD recrudescence was observed. All patients relapsed after completion of bortezomib treatment. This questions about the potential benefit of maintenance therapy with bortezomib. Given the feasibility and the high efficacy of bortezomib combined with dexamethasone in relapsed MM after RICT, our results argue in favour of an immune-modulatory activity of bortezomib. New strategies combining RICT and bortezomib are warranted to increase and maintain an adequate response. Combination RICT and bortezomib regimen are anticipated to further extend survival in relapsed MM.
The Transcription Factors RUNX1/AML1 and RUNX3/AML2 Protect Bcr-Abl-Transformed B-Cells from Imatinib Induced Apoptosis.
Authors: Miething Cornelius , Grundler Rebekka , Mugler Claudia , Pfeifer Heike , Ottmann Oliver , Barwisch Simone , Speicher Michael , Peschel Christian , Duyster Justus
Published: April 2020

The Abl-tyrosine kinase inhibitor Imatinib efficiently targets the Bcr-Abl kinase and produces major cytogenetic responses in most patients with chronic phase CML. In contrast, patients with advanced stage CML or Ph+ ALL frequently become refractory to Imatinib treatment. Resistance arises predominantly from point mutations in the Abl-kinase region, Bcr-Abl amplification or clonal evolution due to secondary genetic aberrations. To screen for genes contributing to clonal evolution, we have employed retroviral insertional mutagenesis in a murine CML/ALL model to identify potential candidate genes leading to Imatinib resistance. We found proviral insertions near the RUNX3/AML2 promoter in Imatinib resistant leukemic clones, leading to upregulation of RUNX3 mRNA expression. To analyze the effects of high RUNX3 levels on Imatinib response, we expressed RUNX3 in a Bcr-Abl-transformed murine pre-B-cell line. Significantly, whereas there was no effect on Imatinib-mediated proliferation inhibition, the cells displayed a marked reduction of apoptosis. A RUNX3R193A mutant carrying a mutation in the DNA-binding domain of RUNX3 did not protect from apoptosis, indicating that transcriptional regulation by RUNX3 was required to induce the anti-apoptotic effects. To allow for a controlled activation of RUNX transcriptional activity and to extend our analysis to other members of the RUNX family of transcription factors, we constructed 4-OH-tamoxifen (TAM) inducible RUNX3/AML2- and RUNX1/AML1-Estrogen receptor (ER) fusion proteins. These fusion proteins readily translocated from the cytoplasm into the nucleus and activated a RUNX-dependent TCRß-luciferase construct upon addition of TAM. Using these constructs, we could demonstrate that activation of RUNX3 as well as RUNX1 protected Bcr-Abl-transformed Ba/F3 cells from Imatinib-induced apoptosis. Furthermore, we found that RUNX1 mRNA levels were significantly upregulated in patients with Ph+ ALL upon resistance development. Taken together, our data indicate that elevated RUNX3 or RUNX1 levels may contribute to Imatinib resistance in Bcr-Abl expressing leukemic cells.
Tumor Control Achieved Despite Loss of Chimaerism in Renal Cell Carcinoma (RCC) Following Non-Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT): A Case Report.
Authors: Andreola Giovanna , Gigli Federica , Rabascio Cristina , Cazzanti Manuela , Peccatori Fedro , Cinieri Saverio , Pastano Rocco , Martinelli Giovanni
Published: April 2020

The achievement of a mixed chimaerism, which eventually converts to full donor chimaerism, after a non-myeloablative allogeneic PBSCT, is thought to be responsible for a graft-versus-tumor effect to occur. Preliminary data from murine models and haematological malignancies suggest that anti-tumor response can be obtained despite loss of donor chimaerism but, to our knowledge, no such data exist on solid tumors.

On February 2004, V.P, affected by metastatic RCC, already pretreated with a-IFN and Vinorelbine, developed progressive disease in the lung and in the retroperitoneum. On July 2004 she was enrolled in a clinical protocol of reduced conditioning allogeneic PBSCT. Conditioning regimen was the following: fludarabine 30 mg/mq from day −4 to −1, and TBI (2 Gy) on day 0, when she also received 8.53x106 CD34+cells/kg from her sister, HLA-full matched, ABO compatible. aGvHD prophylaxis was performed with micophenolate mofetile 15 mg/kg bid, from day 0 to +27 and cyclosporine (Cys) 5 mg/kg bid, from day −2 to +36, followed by a tapering until +56. Chimaerism evaluation, performed on day +28 and +56, showed a full donor engraftment (>90% donor cells) on bone marrow (BM) samples, with 78% of donor CD3+ T cell on peripheral blood (PB). During follow-up, no signs of aGvHD were observed and CMV p65 and PCR remained negative. On day +90, peripheral pancitopenia occurred: WBC-190/mm3, PLT-8000/mm3, Hb-7.5 g/dL, associated with marrow aplasia. Chimaerism evaluation on both BM and PB showed a graft failure, (>95% recipient cells); serological tests were negative (HCV, parvovirusB19, EBV, CMV and adenovirus), no history of drug interaction could be identified. Because of febrile neutropenia she started a large spectrum antibiotic therapy, G-CSF 5 mg/die and an immunosuppressive therapy with metilprednisolone 1mg/kg plus Cys 5 mg/kg, After 5 days she had recovered the WBC while PLT normalization occurred after 45 days. Cys was continued and stopped at day +210. After a follow-up of 386 days from transplantation, she is still in good general condition, off treatment and with stable disease.

On the basis of murine models, the presence of a sustained SD in an otherwise fatal disease, despite loss of graft may suggest the presence of a host-versus-graftimmune response able to promote anti-tumor responses and may promote the development of novel transplant strategies without the risk of GVHD.
Second Neoplasm after Bone Marrow Transplant (BMT).
Authors: Milone Jorge H. , Napal Juan J. , Bordone Javier A. , Prates Virginia , Garcia Cecilia , Morales Victor H. , Etchegoyen Orlando J.
Published: April 2020

Introduction: the second neoplasm, are pathologies described during the post transplant evolution, often associated to immunosuppression. The post transplant lymphoproliferative syndromes, habitually associated to viruses are the most frequent. The BMT is a procedure clearly different from the rest of the transplants, and this difference would also be observed on the incidence and type of tumor in its evolution.

The incidence of second malignancies after BMT is low, and is related to the use of chemotherapy, particulary alkylating. agents radiotheraphy and immunosuppression.

Objective: To analyze the incidence and characteristics of second neoplasm of the patients undergoing BMT in our Institute.

Results: Between 06/93 and 04/05 over a total of 416 transplants, 132 Allogenic and 284 Autologous, 6 cases of second tumor in variable intervals post procedure were stated.

Table 1.

The data reflects an incidence of second neoplasias of 1,4% (6/416). None of then received radiotherapy in conditioning. No lymphoproliferative syndrome was observed; 2 cases of acute leukemias; being the rest solid tumors with expected evolutions for each pathology.

Table 1 Case Disease Conditioning BMT 2nd Tumor Time betwen BMT-Tumor Evolution 1 MM L-PAM AUTO Lung Cancer 120 months Dead 2 CML BuCy ALLO Colon Cancer 72 months Dead 3 MDS BuCy ALLO Merckel cells tumor 60 months Dead 4 NHL CBV AUTO AML 65 months Dead 5 NHL CBV AUTO Bladder Cancer 58 months Alive 26 months 6 NHL CBV AUTO AML 4 months Dead
Fludarabine/Melphalan Conditioning for Allogeneic Stem Cell Transplantation (SCT) in Elderly Patients with AML/MDS.
Authors: Kennedy Glen A. , Butler Jason , Durrant Simon , Hill Geoff R. , Western Robyn , Morton James
Published: April 2020

Aims: To assess the tolerability and efficacy of a reduced-intensity, non-TBI based allogeneic SCT conditioning regimen utilising fludarabine and melphalan (FluMel) in elderly patients with AML /MDS.

Methods: Fludarabine (25mg/m2 D-7 to D-3) and melphalan (120mg/m2 D-2) allogeneic SCT was performed as part of a prospective phase 2 trial to assess the tolerability of the preparative regimen across a range of haematological malignancies. For this analysis, all patients aged >50yrs with AML /MDS who underwent FluMel transplantation were retrospectively reviewed. Standard GVHD prophylaxis was cyclosporine + methotrexate (D1–11). Both HLA-matched siblings and volunteer unrelated donors (VUD) were permitted as stem cell donors. Graft source was G-CSF stimulated PBPC; all grafts were T-cell replete. Survival data was calculated utilising the Kaplan-Meier product-limit method.

Results: In total 20 patients >50yrs (16M and 4F) had received FluMel allogeneic SCT for AML (n=15) or MDS (n=5). Median age at SCT was 60yrs (range 50 to 67yrs). AML transplants were performed in CR1 (n=5), early 1st relapse (n=3), CR2 (n=3), MDS phase post CR1 (n=2), early 3rd relapse (n=1), and primary refractory disease (n=1); 7/15 AML patients had intermediate risk and 7/15 poor risk cytogenetics (1 no data available). All 5 MDS patients were previously untreated; all had INT-1 risk disease on IPSS. Donors were HLA-matched siblings in 14 cases and VUD in 6. A total of 6 patients have died, including 2 prior to engraftment (1 of hepatic failure and 1 from idiopathic pneumonia syndrome) and 4 after day 75 (relapsed AML 2 cases; acute GVHD 1 case; multi-organ failure 1 case). All 18 patients who survived the initial cytopenic period achieved durable engraftment; 10 (50%) subsequently developed acute GVHD, including grades II-IV in 9 cases (45%) and grades III-IV in 3 (15%). Of the 12 patients with follow-up >3mths post-SCT, 9 (75%) developed chronic GVHD, which was extensive-stage in 8 (67%). At a median follow-up of 2.4 yrs (range 0.1–5.2 yrs), overall and event-free survival at 2 years for the whole cohort are both 66%.

Conclusions: Our experience suggests that allogeneic SCT with FluMel conditioning in elderly patients AML /MDS is associated with acceptable treatment-related toxicity and significant long-term survival. Further studies on this transplant approach in older patients are warranted.
Allogeneic Hematopoietic Cell Transplantation (HCT) for Acute Leukemia in First Relapse or Second Remission.
Authors: Lee Je-Hwan , Choi Seong-Jun , Lee Jung-Hee , Lee Young-Shin , Yun SungCheol , Yoon Sung-Soo , Kim Inho , Park Seonyang , Kim Byoung Kook , Jung Chul Won , Kim Kihyun , Ahn Jin Seok , Lee Kyoo-Hyung
Published: April 2020

Allogeneic HCT offers the best chance for long-term survival in patients with acute leukemia after first relapse. A difficult clinical decision for a patient suffering leukemic relapse who has a histocompatible donor is whether to attempt re-induction therapy or proceed directly to HCT. Sixty-five patients with acute leukemia in first relapse or second remission were treated with allogeneic HCT at 3 institutes in Seoul, Korea between Jan 1995 and Sep 2004. We analyzed their post-transplant outcomes and investigated the role of salvage chemotherapy aimed at re-induction of remission before allogeneic HCT. Forty patients received hematopoietic cell graft from a sibling donor, 21 from an unrelated donor, and 2 from a haplo-identical family donor, and 2 received cord blood. Thirteen patients received TBI-based conditioning regimen and 10 received reduced-intensity conditioning regimen. There occurred 34 relapses with 51.3% of 5-y cumulative incidence of relapse (CIR) and there were 22 non-relapse deaths with 34.7% of non-relapse mortality. Probabilities of overall survival and disease-free survival were 20.6% and 14.0% at 5-y, respectively. Multivariate analysis by Gray method for CIR revealed that patients with unfavorable cytogenetics (Philadelphia chromosome-positive or complex karyotype) and those not in remission at the time of HCT had significantly higher CIR (P=0.023 and P=0.031, respectively). Fourteen patients underwent allogeneic HCT after first relapse without salvage chemotherapy aimed at re-induction of remission (“untreated relapse”), 15 patients failed in attempts aimed at re-induction of remission before HCT (“refractory relapse”), and 36 patients attained second remission with salvage chemotherapy before HCT (“second remission”). 5-y CIR for “untreated relapse” (57.1%) was higher than that for “second remission” (42.3%), but lower than that for “refractory relapse” (66.7%). Among patients transplanted in relapse, those with BM blasts ≤ 30% seemed to have lower 5-y CIR than patients in florid relapse (BM blasts > 30%) (57.7% vs. 70.6%). These results do not support the role of salvage chemotherapy aimed at re-induction of remission before allogeneic HCT in patients with acute leukemia after first relapse. At least the patients with early relapse do not appear to receive benefit from salvage chemotherapy before HCT.
Allogeneic Bone Marrow Transplantation in a Child with Hemophilia A and Severe Aplastic Anemia.
Authors: Ostronoff Mauricio , Florencio Rodrigo , Ostronoff Fabiana , Campos Gilma , Arruda Sandra , Vaz Claudia , Souto Ana Patricia , Sucupira Alexandre , Domingues Mariana Coutinho , Calixto Rodolfo , Matias Kleber , Clemente Tagliari
Published: April 2020

Hemophilia A is a blood clotting disorder characterized by a mutation of the factor VIII (FVIII) gene, leading to a deficiency in FVIII. It is the most common type of hemophilia. Inheritance is X-linked; hence males are affected while females are carriers or very rarely display a mild phenotype. 1:10,000 males are affected. We describe a child with a rare association of congenital hemophilia A and acquired severe aplastic anemia (SAA) who was successfully treated with allogeneic bone marrow transplantation (allo-BMT). A 6-year old male, SG, was diagnosed with hemophilia A (FVIII 3%) at 6-month old when he presented with right knee hemarthroses and psoas muscle hematoma. His maternal grandfather was hemophiliac. Since his diagnose, FVIII was infused on average once a month, generally due to hemarthroses and bleeding secondary to trauma. In July 2004, pt presented with progressive pancytopenia. In January 2005 CBC showed: Hb 7g/dl, Ht 22%, WBC 1000/μl (absolute neutrophil count 250/μl) and PLT 23,000/μl. Bone marrow aspirate and biopsy were consistent with SAA. DEB test was negative. Since then he was poly-transfused with PLT and RBC due to increased bleeding tendency, especially hematoma and petechiae. In July 2005 he underwent an allo-BMT from his HLA-identical non-hemophiliac 5-year old brother. For catheter implantation pt received PLT transfusion to achieve a PLT level greater than 50,000/mm3 and 60 units/kg of FVIII to achieve an initial level of 100% followed by 30 units/kg every 12 hours to maintain it continuously at greater than 50% for 3 days. Conditioning consisted of cyclophosphamide 50mg/day from D-5 to D-2 and thymoglobulin 5mg/kg from D-3 to D-1. Cyclosporine and a short course of methotrexate were given for GVHD prophylaxis. 3,5x108 mononuclear cells/kg were infused. Allo-BMT was uneventful. Neutrophil engrafted on D+15 and megakaryocyte (>50,000/mm3) on D+38. During the transplant PLT were kept at greater than 30,000/mm3 with PLT transfusion every 2 days. FVIII was infused when there was more than 2 cm increase in the knee perimeter or any other abnormal bleeding, especially at the catheter implantation site. 6 months after allo-BMT the child is well, with a normal CBC and coagulation tests similar to pre-BMT. Hemophilia and AA association is rare, and to our knowledge, this is the first allo-BMT in a hemophiliac patient to be reported.
Allogeneic Transplant with Standard Conditioning, Reduced Intensity, or Non-Myeloablative Conditioning Regimen for Multiple Myeloma (MM).
Authors: Sahebi Firoozeh , Kogut Neil M. , Spielberger Ricardo , Falk Peter M. , Nademanee Auayporn P. , Popplewell Leslie , Maloney David G. , Rodriguez Roberto , Krishnan Amrita , Nakamura Ryotaro , O’Donnell Margaret R. , Pablo Parker M. , Smith Eileen P. , Stein Anthony S. , Snyder David S. , Zain Jasmine M. , Qian Dajun , Forman Stephen J. , Somlo George
Published: April 2020

We conducted a retrospective analysis of 58 patients who underwent allogeneic stem cell transplantation at our center from 1994 to 2004. Among these 58 patients, 56 received allogeneic transplant from HLA matched sibling and 2 patients received transplant from a matched unrelated donor. Fourteen patients received standard transplant (ST) using different myeloablative chemotherapy regimens with or without fractionated total body irradiation (FTBI, 9 patients). Thirty four patients underwent tandem transplants (autologous transplant followed by non-myeloablative allogeneic transplant; auto-allo group). Conditioning consisted of melphalan (200mg/m2) prior to the autograft, and TBI (200cGy) as part of non-myeloablative allograft. Ten patients received reduced intensity conditioning (RIC) allograft with fludarabine (25 mg/m2 x 5 days) and melphalan (140 mg/m2). The source of stem cells was bone marrow in 14 patients (ST) and peripheral blood in 44 patients. Median age was 44 yrs for ST group (range 25–53), 51 yrs for auto-allo group (range 38–66) and 48 yrs for RIC group (range 43–64). Median follow up was 2.8 yrs for ST group (range 0.2–13.0), 2.8 yrs for auto-allo group (range 0.2–5.0) and 1.1 yrs for RIC group (range 0.2–3.6). There was a statistically significant difference in overall survival (OS) between the different groups with an observed 2 year OS of 50% in the ST group, 76% in the auto-allo group and 42% in RIC group (P=0.04). Disease free survival (DFS) was also statistically different between the different groups at 2 years: 21% in the ST group, 59% in auto-allo group, and 40% in RIC group (p=0.04). The incidence of severe grade III–IV acute graft versus host disease (GVHD) was less in auto-allo group (6% & 6%), as compared to the RIC group (20% & 10%) and ST group (14% & 14%). 2 year non-relapse mortality rates were 43% in ST, 20% in auto-allo group and 29% in the RIC group, and relapse-related mortality rates were 7% in ST group, 4% in auto-allo group and 29% in the RIC group. There was no statistically significant correlation between GVHD and DFS. Our data suggest an improvement in DFS and OS following tandem auto-non-myeloablative allotransplantation or RIC allotransplantation as compared to standard allogeneic transplant. The better outcome following an auto-allograft approach suggests that cytoreduction prior to an allograft may be important for optimal disease control in MM.
Modification or Dose or Treatment Duration Has No Impact on Outcome of AML in Older Patients: Preliminary Results of the UK NCRI AML14 Trial.
Authors: Burnett Alan K. , Milligan Donald W. , Prentice Archie G. , Goldstone Anthony H. , McMullin Mary F. , Hills Robert K. , Wheatley Keith
Published: April 2020

The NCRI AML14 Trial was devised for patients aged over 60 years with de novo or secondary AML or high risk MDS (defined as >10% blasts). There was a non-intensive option which compared Low Dose Ara-C vs Hydroxyurea each with or without All-Trans Retinoic Acid which has been reported previously (Burnett et al Blood2004: 249a), and an intensive approach which we now report. This compared two dose levels of Daunorubicin (50mg/m2 vs 35mg/m2) and Ara-C (200mg/m2 vs 400mg/m2) within a Daunorubicin/Ara-C (3+10) followed by (3+8) schedule. After a 3rd course (MidAC: Mitoxantrone/Ara-C), patients were randomised to receive or not a 4th course (ICE: Idarubicin/Ara-C/Etoposide). In addition some patients (n=200) were randomised to receive PSC-833 in addition to Dauno 35. The results of this randomisation have been reported previously (Burnett et al Blood 2003614a).

A total of 1273 patients entered the trial between December 1998 and closure in May 2005, from 136 centres. Follow-up is complete to 1st April 2005, with median follow-up of 33 months. The median age was 67 (range 44-88). Cytogenetics were known for 67% of patients: of these, 3% had favourable, 74% intermediate and 23% adverse cytogenetics. 72% had de novo AML, 17% had secondary disease and 11% had high risk MDS. The overall CR rate was 62% and the Relapse Risk (RR), Disease Free Survival (DFS), and Overall Survival (OS) were 84%, 13%, and 13% at 5 years. 896 patients were randomised to D50 vs D35. No significant differences were found in CR (63% vs 64% OR 1.04 (95% CI 0.78–1.37)), RR (84% vs 85% OR 0.85 (95%CI 0.65–1.06)), DFS 14% vs 13% OR 0.86 (95% CI 0.70–1.06)), or OS (15% vs 13% OR 0.92, 95% CI (0.72–1.08)). Likewise, there were no significant differences in outcome for the 1264 patients randomised to Ara-C 200 vs 400: CR (62% vs 62% OR 1.00 (95% CI 0.80–1.27)), RR (84% vs 85% OR 1.14 (95% CI 0.95–1.37)), DFS (13% vs13% OR 1.14 (95% CI 0.96–1.14)) or OS (13% vs 12% OR 1.00 (95%CI 0.87–1.14)). In the 255 patients randomised to a total of 4 vs 3 courses the RR (83% vs 76% OR 0.90 95%CI 0.66–1.24), DFS (16% vs 18% OR 0.94 95% CI 0.69–1.28) and OS (23% vs 22% OR 1.05, 95% CI 0.75–1.47) were not significantly different.

From this preliminary analysis we conclude that there is no difference between a reduced dose of Daunorubicin (35mg/m2) compared with standard dose, or between enhanced Ara-C dose (400mg/m2) or standard dose and the confidence intervals are consistent with at most a moderate difference in treatment effect. We found no benefit for giving more than 3 courses of total treatment to patients in this age group, although the confidence intervals here do not rule out moderate, but potentially meaningful differences.
Unrelated Donor Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies.
Authors: Gao Chunji , Da Wanming , Zhang Bolong , Han Xiaoping , Yu Jing , Zhang Yizhuo , Li Honghua , Bo Jian , Zhu Haiyan , Jin Haijie , Wu Xiaoxiong , Wang Quanshun , Li Suxia , Huang Wenrong , Yu Li
Published: April 2020

Objiective To explore feasibility and efficacy of unrelated donor peripheral blood stem cell transplantation (UD-PBSCT) in treatment of hematologic malignancies.

Methods Ten patients with hematologic malignancies undewent high resolution DNA based typing HLA-matched or 1 locus mismatched UD-PBSCT. Busulfan, cyclophosphamide, Ara-C, MeCCNU and antithymocyte globulin (ATG) were used for preparative regimen in all cases. All patients received mycophenolate mofetile, cyclosporin A and short-term methotrexate with CD25 antibody as the graft-versus-host disease (GVHD) prophylaxis.

Results The results showed that rapid engraftment was observed in all cases who presented full donor chimerism at 28 days post transplantation by STR-PCR. The median time of neutrophil recovery >0.5×109/L, platelet recovery >20×109/L was observed at 13, 17.5days respectively post transplantation. The incidence of acute GVHD was 3/10 cases (1case with grade I was recovery by himself, 1case with grade III was cured, 1case with grade VI was died).

Conclusion It is concluded that above-mentioned conditioning and GVHD prophylaxis are effective approaches for unrelated donor peripheral blood stem cell transplantation in treatment of hematopoietic malignancies.
Preliminary Experience with Haploidentical Stem Cell Transplantation for Children with Sickle Cell Disease and Stroke.
Authors: Woodard Joseph , Wang Winfred , Barfield Raymond , Hale Gregory , Horwitz Edwin , Leung Wing , Yusuf Usman , Ware Russell , Handgretinger Rupert , Cunningham John M.
Published: April 2020

Hematopoietic stem cell transplantation has been shown to be curative for approximately 83% of symptomatic children with sickle cell disease who have undergone the procedure. Despite these encouraging results, only 15% of children with symptoms that might merit consideration for transplantation have an available, unaffected HLA-matched sibling donor, severely limiting this therapeutic option. To address this problem, we developed a protocol for children with SCD and stroke using reduced-intensity conditioning and CD34-selected peripheral blood stem cells from haploidentical parental donors. We now report our preliminary experience using this approach in three children with SCD and stroke. After a chemotherapy-only conditioning regimen of fludarabine 150–200 mg/m2, thiotepa 10 mg/kg, i.v. busulfan targeted to a steady state concentration of 900 ng/ml, and OKT3, patients received an average of 27.2 x 106 CD34+cells/kg and 1.1 x 104 CD3+ cells/kg. Two patients required additional immunosuppression with methylprednisolone and OKT3 followed by a CD34 boost after graft rejection. One of these two had durable long-term engraftment, while one had a second rejection. Two of three patients have durable donor engraftment 20 and 24 months after transplantation, respectively. Donor T-cell chimerism evolved from predominantly host-derived to donor-derived over a number of months. One patient developed grade I acute GVHD and none developed chronic GVHD. Two engrafted patients have had no further SCD events. Both have recovery of immune function with normal CD4+ T-cell counts and normal thymic function. This preliminary experience demonstrates the feasibility of using mismatched parental donors for children with sickle cell disease. Future studies will focus on achieving reliable donor engraftment through additional graft manipulation strategies.
Reduced-Intensity Unrelated Cord Blood Transplantation (RICBT) for Myelofibrosis (MF).
Authors: Takagi Shinsuke , Miyakoshi Shigesaburo , Oota Yasunori , Kato Daisuke , Kawano Tomomi , Kusumi Eiji , Matsumura Tomoko , Yuji Koichiro , Uchida Naoyuki , Masuoka Kazuhiro , Wake Atsushi , Yoneyama Akiko , Taniguchi Shuichi
Published: April 2020

Introduction: Although allogeneic hematopoietic stem cell transpslantation is the only curative treatment for patients with MF, the potential role of cord blood transplantation remains still unclear. We report the results of RICBT for hematological diseases with primary and secondary MF.

Patients and Methods: We reviewed medical records of 179 patients with advanced hematological diseases who received RICBT between March 2002 and June 2005 at our institution. Of 179 patients, pre-transplant bone marrow specimens were available for 82 patients. We evaluated bone marrow specimens by aspiration and trephine biopsy. Aspiration may be not enough to evaluate marrow fibrosis, but could reflect fibrotic change in bone marrow (Am J Clin Pathol1971; 56: 25). One patient had primary MF and 47 had secondary. Underlying diseases for secondary MF included AML/MDS (35), ALL (6), CML (1), severe aplastic anemia (2), malignant lymphoma (2), essential thrombocythemia (1). For staging of MF, we used pathological criteria by Michiels (Int J Hematol2000; 76: 133). MF0: no reticulin fibrosis (n=35), MF1: slight reticulin fibrosis (n=38), MF2: marked increase in reticulin and slight to moderate collagen fibrosis (n=8), MF3: advanced collagen fibrosis-osteosclerosis (endophytic bone formation) (n=1). Median age of the patients was 55 years (17–71). Most of the conditioning regimens were fludarabine 125 mg/m2, melphalan 80 mg/m2 and TBI 4 Gy. GVHD prophylaxis was cyclosporine (n=35) or tacrolimus (n=47). The median number of infused nucleated cells: 2.66 x 10e7 cells (1.67_5.24 x 10e7); CD34 positive cells: 0.69 x 10e5 cells (0.11_3.90 x 10e5); HLA disparity: 6/6 (n=4), 5/6 (n=14), 4/6 (n=60), 3/6 (n=4).

Results: Neutrophil engraftment at day 50 was observed in 70.8 % with MF (median 22 days) and 73.7 % without MF (median 22 days). Platelet engraftment at day 100 was observed in 40.0 % with MF (median 42 days) and 60.0 % without MF (median 40 days). There was no statistical significance in neutrophil and platelet engraftment between patients with MF and without MF. Of 48 patients, 6 showed biopsy-proven MF greater than stage 1. Their neutophil and platelet engraftment was observed in 100 % (median 22 days) and 66.7 % (median 48 days), respectively. Cumulative incidence of acute GVHD (II–IV) was 17 % with MF and 28 % without MF. There was no statistical significance. The estimated OS was 25 % with MF and 52 % without MF (p=0.03) (Figure 1). Most cause of death with MF was relapse.

Conclusion: Despite of marrow fibrosis, neutophil and platelet engraftment was not influenced. These results have suggested that RICBT is feasible for MF. However, the existence of MF could be poor prognostic factor of RICBT for hematological diseases due to relapse.

Figure Figure
Single-Institute Analysis of Allogeneic Stem Cell Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.
Authors: Kobayashi Takeshi , Yamashita Takuya , Sakai Miwa , Okuyama Yoshiki , Ohashi Kazuteru , Akiyama Hideki , Hiruma Kiyoshi , Sakamaki Hisashi
Published: April 2020

Purpose

We report the outcomes of allogeneic stem cell transplantation (SCT) for the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in a single center.

Patients and Methods

Between August 1993 and March 2005, 36 patients with Ph+ALL received SCT at Tokyo Metropolitan Komagome Hospital. The median age was 41 years (range; 17 to 60 years). All patients received myeloablative conditioning regimen (cytosine arabinoside, cyclophosphamide and fractionated 12Gy total-body irradiation). Stem cell source of SCT was 14 related donors (bone marrow [n=9] and peripheral blood stem cell [n=5]) and 22 unrelated donors (bone marrow [n=13] and cord blood [n=9]).

Results

Seventeen (47%) of 36 patients are alive at a median of 2.16 years (range; 1.0 to 3.3 years) after transplantation. Three years overall survival (OS) and disease free survival (DFS) for all patients are 42.3% and 35.4%, respectively. Three years OS and DFS are 55.4% and 46.4% for the 24 patients in complete remission (CR) at transplantation, while 36.4% (p<0.001) and 16.7% (p<0.01) for the 12 patients in non-CR, respectively. Stem cell source and patients age do not affect the outcomes. The higher white blood cell counts at diagnosis are associated with poor OS (p=0.003). The median duration from diagnosis to SCT is 7 months (range; 3 to 29 months). Three years OS of the patients who received SCT within 7 months from diagnosis is better than that of the others (59.3% vs. 31.1%, p=0.019).

Conclusion

This analysis suggests that shorter duration between diagnosis and transplantation improve the clinical outcomes of SCT for Ph+ALL, especially performed in CR.
Prognostic Factors for the Engraftment in Cord Blood Transplantation: With Units Shipped from Single Cord Blood Bank, Tokyo Cord Blood Bank.
Authors: Nagamura-Inoue Tokiko , Yan Cui , Satomi Aya , Mugishima Hideo , Asano Shigetaka , Takahashi Tsuneo , Kodo Hideki
Published: April 2020

The better selection of cord blood (CB) unit in recent varied cord blood transplantation (CBT) is crucial for the success of CBT, although it is difficult to compare the units from different cord blood bank (CBB). Here, we analyzed the prognostic factors by age for engrafment in CBT with the units shipped from single CBB, Tokyo Cord blood bank.

Patients and Methods: Units were all processed by HES centrifugation method and cryopreserved with 10% DMSO and Dextran 40 in Tokyo CBB. CD34 was analyzed by gating CD45dim CD34+ with DNA dye or 7-AAD in Trucount beads tube (BD). Patients characteristics are shown in table. Group I included 58u for malignancies and 25 for non-malignancies. Group III included 22 full(Full) vs.22 reduced intensity (RI) conditioniong regimen for malignancies and remaining ones with further reduced intensity regimens. RI regimen consisted maily with reduced dose of TBI (<8Gy) and BU/Melphalan with fludarabin.

Results: Myeloid engraftment in malignancies with Full regimen was seen at 84.3%(median 28days) in Group I, 82.5%(25days) in Group II and 73.0%(30days) in Group III, respectively, whereas with RI regimen in Group III was 67.8%(24days). The patients with non-malignancies in Group I showed 75.0% (26days) of engraftment by Full regimen(n=12) and 100% (24days) by RI regimen(n=8), respectively. HLA disparities had no significant influence on the engraftment in Group I and II. The dose effects of NC and CD34+ cells on the rate and the speed of engraftment were seen in Full regimen in Group I and II for malignancies. Critical dose of CD34+ cells seemed 0.8x105/kg. Even in Group I(children), the patient with CD34+ less than 0.8x105/kg showed 79.6%(43days), whereas those with more than 0.8x105/kg, 85.7%(24days). There was no difference of speed and rate of engraftment between the patients with CD34+ cells 0.8~1.6x105/kg and those with more than 1.6x105/kg. Interestingly, this effect vividly influenced on the engraftment in the patients with RI regimen of Group III. The patients with CD34 + with less than 0.8x105/kg showed only 22.9% of final engraftment, whereas those with over 0.8x105/kg 100% (19 days) in Group III. The dose of CD34+ had some influeced on the survivals, although the main prognostic factors on the long-term survivals was the risk factor of malignancy and age.

Conclusion: CD34+ cell dose should be given high priority for the selection of CB unit, especially in reduced intensity regimen.

Patients Characteristics No. of Patients Group I ( ~ 15 y.o.) n=83 Group II (15 ~ 50 y.o.) n = 76 GroupIII (51 y.o. ~) Age y.o. 5.23±4.81 33.9±10.4 58.3±12.8 BM (kg) 19.7±14.2 52.0±9.1 54.0±13.5 Dose of NC (x10^7/kg) 6.17±3.98 2.63±0.66 2.76±1.10 Dose of CD34 (x10^5/kg) 1.80±1.75 0.81±0.46 0.91±0.95 HLA mismatch 0 18 5 4 (rejection direction) 1 51 33 19 2 14 35 23 3 0 3 0
Immunophenotypical Minimal Residual Disease as a Short Term Endpoint for Monitoring Effects of Targeted Inhibitors in Acute Myeloid Leukemia.
Authors: Hess Corine J. , Feller Nicole , Denkers Fedor , Merle Pauline A. , Ossenkoppele Gert J. , Waisfisz Quinten , Schuurhuis Gerrit Jan
Published: April 2020

At present, a large number of clinical trails make use of inhibitors that target leukemia specific defects, such as BCR-ABL, c-kit mutations or tandem duplications in the FLT3 gene (FLT3-ITD). Irrespective of their target, these studies all share the need for a short term read out parameter. Nowadays remission rate, remission duration and survival are used as a final read out in such studies. Previously we have observed that after different cycles of chemotherapy the frequencies of Minimal Residual Disease (MRD) cells, as determined using aberrant immunophenotypes, is highly correlated with clinical outcome (Feller, Leukemia2004; 18:1380). Based on these observations we have examined whether MRD might function as the desired short term read out. As a proof of principle we have examined this for FLT3-ITD. We determined ITD status in bone marrow (BM) samples of 162 newly diagnosed AML patients by gel electrophoresis and GeneScan analysis. Frequencies of MRD cells were assessed in 316 BM samples of these 162 patients: 146 after 1st, 95 after 2nd and 75 after 3rd cycle of chemotherapy using LAP technology. As also shown by others, FLT3-ITD at diagnosis was predictive for OS (p=0.04, B (exp)=1.80 and RFS (p=0.05, B (exp)=1.91). This study now shows in addition, that in remission patients after 1st cycle (70% of all patients), the presence of an ITD (21% of the cases) at diagnosis is associated with 8.5-fold higher MRD% (median 0.34%, range 0.01-3.3%), compared to wild type FLT3 (median 0.04%, range 0.01–1.27%), p=0.020. Similar to our previous observations, MRD level taken as a continuous variable in the total patient group after 1st cycle was inversely correlated to OS (p=0.041) and RFS (p=0.0001). Using previously described clinically relevant MRD cut-offs, such 8.5-fold differences in frequencies of MRD cells resulted in significant differences in OS and RFS, in the whole range of MRD frequencies (0.01-6.8%). Based on this we conclude that efficacy of FLT3 inhibitors in terms of survival can be predicted with MRD frequency after 1st cycle of therapy that includes the inhibitor. MRD frequency may thus serve as an early read out parameter, for efficacy of targeted therapy in AML.

Figure 1. MRD% in FLT3+ and FLT3− patients who achieved remission Figure 1. MRD% in FLT3+ and FLT3− patients who achieved remission
Cord Blood Transplantation for Adult Acute Lymphoblastic Leukemia.
Authors: Kawano Tomomi , Matsumura Tomoko , Takagi Shinsuke , Kato Daisuke , Yuji Koichiro , Uchida Naoyuki , Masuoka Kazuhiro , Wake Atsushi , Miyakoshi Shigesaburo , Taniguchi Shuichi
Published: April 2020

Backgrounds: Adult acute lymphoblastic leukemia (ALL) has poor prognosis despite intensive chemotherapy. Allogeneic hematopoietic stem cell transplantation is an optimal therapeutic strategy in relapsed ALL patients. HLA-matched unrelated donation is difficult in some cases because of the rapid disease progression. Cord blood transplantation (CBT) excells other measures in its availability, render it particularly effective in urgent situations; however, the outcome of CBT for adult ALL cases has not yet been clarified.

Patients/Methods: We reviewed medical records of 22 adult ALL patients who received CBT at Toranomon Hospital between January 2002 and June 2005. Median age of the patients was 54.5 (range 18–68). Disease status were CR1 (n=4), CR2 (n=3), RL1 (n=8), RL2 (n=1) and primary induction failure (n=6), respectively. 18 patients recieved fludarabine based regimen and the other received CY/TBI myeloablative regimen. Fludarabine based conditioning regimen was consisted of fludarabine (125 mg/m2), melphalan (80–140 mg/m2) and TBI (4–8Gy). GVHD prophylaxis was cyclosporine (n=12) or tacrolimus (n=10). Median total nucleated cell and CD34+ cell counts were 2.6×106 cells/kg (1.6–4.4) and 0.7×105 cells/kg (0.2–3.2), respectively. HLA disparity was 5/6 (n=1), 4/6 (n=20) and 3/6 (n=1).

Results: The probability of disease free survival at 2 years was 59%. Overall survival curves of each conditioning regimen were depicted as below.

Half of the relapsed/refractory ALL patients achieved complete remission and remained disease free after CBT.

Discussion: Adult ALL patients without any suitable donor should be considered as a candidate for CBT.

Figure Figure
Hematopoietic Stem Cell Transplantation (HSCT) for Benign Indications Using Umbilical Cord Blood Units (UCB) That Were Depleted of Plasma, but Not of Red Blood Cells.
Authors: Chow Robert , Jaing Tang-Her , Gjertson David , Rosenthal Joseph , Nademanee Auayporn , Karanes Chatchada , Graham Michael , Tan Patrick , Petz Lawrence D.
Published: April 2020

Background: UCB is an attractive unrelated source for HSCT of benign indications such as hemoglobinapathies, genetic diseases and metabolic disorders, because of less stringent HLA matching requirements, lower incidence and severity of GvHD, and ready availability of a physical inventory; however, unlike BMT or PSCT, cell dosage is a critical factor in success of UCB HSCT. The red cell depletion (RCD) techniques that are widely used by UCB banks incur significant nucleated cell loss after processing. One method of minimizing cell loss during processing is to deplete plasma, but not the red blood cells (PD). A large racially diverse PD UCB inventory of 18,000 units is now available on stem cell registries. We now report our observations of using unrelated PD UCB HSCT for benign indications.

Hypothesis: Usage of unrelated PD UCB for HSCT of benign indications will result in acceptable clinical outcome for myeloid (ANC 500) and platelet engraftment, overall survival (OS), and transplant related mortality (TRM).

Methods: A retrospective analysis was performed on 28 patients with benign disorders who were transplanted with PD UCB in 15 centers and 7 countries, with 13 thalassemias, 5 SAA, 5 WAS, 2 SCID, 1 sickle cell disease, 1 osteopetrosis and 1 metabolic disorder.

Results: The median age of patients was 3.7 years old (range 03–27 years old); median weight 16.0 kg (range 4.5–43 kg); male 57%. Transplant characteristics indicated a median # HLA ABDR matches of 4.0 (5 6/6; 7 5/6; 12 4/6; 3 3/6; 1NA); median pre-freeze TNC dose 7.7 x 107/kg; median post-thaw TNC dose as reported by TC 7.7 x 107/kg; median pre-freeze CD34 dose 3.1 x 105/kg; transplants performed outside of U.S. 68%; double unit transplant 13%; non-myeloablative 6%. The median time to engraftment for ANC 500 (n=21), platelet 20K (n=20), and 50K (n=18) are 14.5 days (range 11–41 days), 47.0 days (range 13–82 days), and 55.0 days (range 21–96 days) respectively. The unadjusted cumulative incidence (C.I.) of ANC500 and platelet 20K and 50K engraftment are 89±7%, 89±7%, and 87±8% respectively. The incidence of reported grade II–IV acute GVHD was 33%, and none had grade III–IV acute GVHD. 50% developed limited chronic GVHD (7/14), and so far only one patient was reported to have extensive chronic GVHD. With a median follow-up of 356 days (range 93–1,100 days), the Kaplan-Meier estimates of 1-year TRM, OS and disease-free survival were 11±6%, 89±6% and 89±6% respectively.

Conclusion: These results demonstrate that HSCT using unrelated PD UCB can be performed safely and effectively in patients with benign disorders. Further study of HSCT using unrelated PD UCB in patients with non-malignant hematological disorders is warranted.
Early Lymphocyte Recovery after Autologous Stem Cell Transplantation Predicts Superior Survival in Mantle Cell Lymphoma.
Authors: Joao Cristina , Porrata Luis F. , Inwards David J. , Ansell Stephen M. , Micallef Ivana N.M. , Johnston Patrick B. , Gastineau Dennis A. , Markovic Svetomir N.
Published: April 2020

Mantle-cell lymphoma (MCL) is characterized by an aggressive clinical course and poor prognosis with a median survival of only 3 to 4 years. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is an effective treatment strategy for MCL demonstrating significantly prolongs progression free survival (PFS) when compared to IFNa maintenance therapy of patients in first remission. We have previously shown that absolute lymphocyte count at day 15 (ALC-15) after ASCT is an independent prognostic factor for survival in hematologic malignancies (non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease, multiple myeloma, primary amyloidosis, acute myelogenous leukemia) and breast cancer. The study of ALC-15 after ASCT as a prognosis factor in NHL included different subtypes of lymphomas. The relationship of ALC-15 after ASCT in patients with MCL has not been specifically addressed. Herein we present data evaluating the impact of early lymphocyte recovery (ALC-15) in patients undergoing ASCT for MCL. We retrospectively reviewed the medical records of 42 consecutive patients (9 females and 33 males) with MCL who underwent ASCT at the Mayo Clinic in Rochester from 1993 to 2005. Based on our previous studies, the ALC-15 threshold was set at 500 cells/μL. The median patient age at transplant was 57 years (range, 37–71) and the median follow-up after ASCT was 25 months (range, 2–106 months). The median overall (OS) and PFS times were significantly better for the 24 patients that achieved an ALC-15 ≥ 500 cells/mL compared with 18 patients with ALC-15 < 500 cells/μL (not reached versus 30 months, P < 0.01 and not reached versus 16 months, P < 0.0006, respectively). Multivariate analysis adjusting for other prognostic factors suggests that ALC-15 is an independent prognostic factor for OS and PFS. ALC-15 ≥ 500 cells/mL is associated with significantly improved clinical outcomes following ASCT in patients with MCL.
Beneficial Prophylactic Antimicrobial Use Against Infectious Complications during Autologous Stem Cell Transplantation: A Result of Randomized Phase II Study in Multiple Myeloma and Non-Hodgkin’s Lymphoma Patients.
Authors: Kim Shin , Cho Yang Hee , Ko Ock Bae , Koo Ja Eun , Lee Danbi , Chong Young Pill , Suh Cheolwon
Published: April 2020

The benefit of using prophylactic antimicrobials in autologous stem cell transplantation (ASCT) is controversial. A prospective randomized phase II comparison study was therefore performed to assess the benefit of prophylactic antimicrobials. Forty consecutive patients with multiple myeloma (MM, 28 patients) or non-Hodgkin’s lymphoma (NHL, 12 patients) were enrolled. After stratification by disease, patients were randomly allocated into control group with no prophylactic antimicrobials (19 patients) or prophylaxis group receiving prophylactic antimicrobials (21 patients) just before the administration of high-dose chemotherapy. Prophylactic antimicrobials comprised domly allocated into apyylactic lacticiprofloxacin 500 mg po bid, fluconazole 100 mg po bid and acyclovir 200 mg po tid; started one day before high-dose chemotherapy initiation and stopped when absolute neutrophil count reached 500/mm3 after nadir or infection occurred. High-dose chemotherapy was high-dose melphalan for MM and BEAM for NHL. Lenograstim 5 μg/kg/day was given from day 1 of ASCT. At least one episode of fever was present in 15/19 (79%) patients in control group much more frequent than 12/21 (57%) patients in prophylaxis group but with no statistically significance (p=0.13) probably due to small sample size of current study. Microbiologically or clinically documented infections occurred in 4 patients (21%) from control group and in no patient from prophylaxis group, with statistically significant difference (p=0.04). Documented infections of patients from control group included 3 staphylococcal bacteremias (1 methycillin-sensitive Staphylococcus aureus, 1 Staphylococcus epidermidis, 1 Methycillin-resistant coagulase-negative staphylococcus) and 1 herpes skin infection. No death, invasive fungal infection, or serious adverse events occurred in either group. The median duration of fever (12 days in control group and16 days in prophylaxis group), therapeutic antimicrobial therapy (9 days in control group and 11 days in prophylaxis group), and hospital stay after ASCT (19 days in both groups) were not different between groups. Median time to neutrophil engraftment was 10 days and median time to platelet engraftment was 11 days in both groups. In conclusion, this small-sized randomized phase II comparison shows that use of prophylactic antimicrobials as current study diminishes microbiologically or clinically documented infection during ASCT significantly.