bluuebunny/crossref_metadata_2025 huggingface dataset:
Allogeneic Stem Cell Transplantation for Relapsed Follicular Non-Hodgkin’s Lymphoma: Single Centre Experience.
Authors: Peyman Amir , Couban Stephen , Thompson Kara , Fernandez Louis , Forrest Donna L. , Nevill Thomas J. , White Darrell J.
Published: October 2019

Between 1993 and 2005, 57 patients with follicular lymphoma underwent high-dose chemo/radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), 49 Allogeneic, (16 Bone Marrow and 33 Peripheral Blood), 6 MIN, 2 MUD. Median age was 47 years. Median days to neutrophil and platelet engraftment after HSCT were 18 and 13 days respectively. Twenty-five patients experienced Acute GVHD and thirty-four had Chronic GVHD (12 mild and 22 extensive). Thirty-three patients were in grade 1, 17 in grade 2, 4 in grade 3 and 3 grade 4. As of their FLIPI score, 4, 14, 21 and 18 patients were calculated to have score of 0, 1, 2 and 3 respectively. Forty-one patients are alive. Two patients have relapsed, one a year and the other two years after HSCT. The 5 year survival was 71.9% (95% CI 57.5–82.2%) and 5 year survival was 67.2% (95% CI 52.3–78.5%). Transplant related mortality rate (TRM) in 5 year was 22.4% (95% CI 63.6–86.8%). No significant differences was found among FLIPI groups 0,1,2 and 3 in terms of overall, relapse-free survival, TRM Allogeneic HSCT for patients with progressive follicular lymphoma is feasible and may result in prolonged disease-free survival.
Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for Treatment of Hematological Malignancies in Children.
Authors: Liu Daihong , Huang Xiao Jun , Liu Kaiyan , Xu Lanping , Chen Huan , Han Wei , Chen Yuhong , Jiang Qian
Published: October 2019

Objective: To evaluate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (HCT) for children with donors from family members.

Patients and methods: Forty-two children under fourteen years old with hematologic malignancies underwent haploidentical HCT. The outcome was analyzed.

Results: Four (9.5%) of the forty-two patients/donor pairs mismatched in one HLA locus, fifteen (35.7%) pairs in two loci and twenty three (54.8%) in three loci. They were followed up for a median of 612 (40–1779) days. All patients achieved stable engraftment. The cumulative incidence of acute graft-versus-host disease (GVHD) grade 2–4 was 57.2%, and that of grade 3–4 was 13.8%. The cumulative incidence of total and extensive chronic GVHD was 56.7% and 29.5%, respectively. The probability of leukemia-free survival was 65.1% in standard-risk group and 49.6% in high-risk group. Fourteen patients died, four from infection, six from relapse of leukemia, two from heart failure, one from severe acute GVHD, and one from lymphoproliferative disorders. The probability of relapse was 13.8% at 1 year and 27.9% at 2 year after transplantation.

Conclusion: The results in this study encourage extending the haploidentical HCT without T-cell depletion to children with an indication for transplantation.
Risk Factor Analysis of Outcomes after Unrelated Cord Blood Transplantation for Children with Hurler’s Syndrome. An Eurocord-Duke University Collaborative Study.
Authors: Boelens Jaap Jan , Rocha Vanderson , Aldenhoven Mieke , Wynn Robert , O’Meara Anne , Cavazzana-Calvo Marina , Ionescu Irina , Parikh Suhag , Prasad Vinod , Escolar Maria , Gluckman Eliane , Kurtzberg Joanne
Published: October 2019

Hurler’s syndrome (HS), the most severe form of mucopolysaccharidosis type-I causes progressive deterioration of the central nervous system and death in childhood. Allogeneic-stem cell transplantation (SCT) before the age of two years halts disease progression and prolongs life. Graft-failure and mixed-chimerism (40–50%) limit the success of SCT for HS. Unrelated-cord blood transplants (UCBT) are suggested to be a good alternative option for bone marrow, however, little is known about risk factors for outcomes after UCBT for this disease. We have analyzed 93 HS children that received an UCBT from 1995 to 2007 and were reported to EUROCORD or transplanted at Duke University. Median age at UCBT was 1, 3 (0, 2–4) yrs, and median follow up was 24 (3–140) mths. The donor was HLA-identical (HLA-A and -B by low resolution and HLA-DRB1 by high-resolution) in 13 cases (16%) and incompatible in 67 cases (84%: most with 1 (54%) and 2(26%) HLA disparities). The median nucleated cell dose/kg and CD34+/kg at infusion were respectively 7.2 (2–22) x 107 and 2, 3 (0, 5–17) x 105. With the exception of 5 patients, all received a Busulfan/Cyclophosphamide (+Fludarabine: 6) regimen. All patients received ATG or Campath (4).

Results: Median days to neutrophil and platelet recovery were 22 (10–46) and 35 (13–82) days, respectively. Mixed-chimerism was found in only 6%. All patients had normal enzyme levels after engraftment. In multivariate analyses for neutrophil recovery, a CD34+-dose of >2.3x105/kg (HR=2.0; p= 0.015) was associated with increased probability of recovery. Acute-GvHD (grade II-IV) was observed in 27%, while chronic-GvHD was seen in 10% at 2 years. Two years overall survival (OS) and disease free survival were 78% and 70%, respectively. For 2 years OS, time from diagnosis to UCBT more than 6 months was associated with increased risk of death (6% for those children transplanted earlier and 30% for those transplanted later: p=0,04). Transplantation improved somatic features of HS. In conclusion, outcomes following UCBT for Hurler’s syndrome are encouraging. UCB appears to be a good alternative allogeneic stem cell source to transplant children with HS. Earlier transplantation and higher cell dose are associated with better outcomes after UCBT for HS patients.
Comparable Outcomes of High-Resolution HLA-Matched Unrelated and HLA-Identical Sibling Donor Stem Cell Transplantation for Childhood Acute Myeloid Leukemia in First Remission.
Authors: Lee Dae-Hyoung , Kwon Young-Joo , Chung Nak-Gyun , Jeong Dae-Chul , Kim Hack-Ki , Cho Bin
Published: October 2019

Purpose: The role of allogeneic stem cell transplantation (SCT) from unrelated donor for childhood acute myeloid leukemia (AML) in first remission remains unclear because of its high transplant-related mortality. In this study, we investigated the role of SCT from high-resolution HLA-matched unrelated donor for childhood acute myeloid leukemia in first remission by comparing the outcomes of SCT from HLA-identical sibling donors and high-resolution HLA-matched unrelated donors. Patients and

Method: Between June 2002 and August 2005, 40 children who have AML in first complete remission received SCT at Saint Mary’s hospital in Korea. In SCT from 17 sibling donors (M-SBMT), low-resolution typing (two-digit level) for HLA-A, -B, -C and -DRB1 was performed and all of donor-recipient pairs were 8/8 matches. Unrelated donors and recipients were typed for HLA-A, -B, and -DRB1 by high-resolution molecular typing (four-digit level). Of the 23 unrelated donor-recipients pairs, 14 were 6/6 matches (M-UBMT) and 9 were 5/6 matches (MM-UBMT). Conditioning regimen consisted of busulfan i.v. and cyclophosphamide. All patients received cyclosporin A and short-course methotrexate for GVHD prophylaxis.

Results: Of the 40 patients, 27 survived event-free with a median follow-up of 38 months (range, 23–57 months). Median times for neutrophil engraftment were 12 days(range, 11–15 days), 11 days(range, 10–16 days) and 12 days(range, 11–15 days) for M-SBMT, M-UBMT and MM-UBMT, respectively. The number of Grade II-IV acute GVHD was 5 (29%), 7 (50%) and 6 (67%) in the M-SBMT, M-UBMT and MM-UBMT, respectively. One patient in MM-UBMT developed grade III acute GVHD. The number of patients who developed chronic GVHD was 2, 6 and 4 in the M-SBMT, M-UBMT and MM-UBMT,respectively. The number of relapsed patients after SCT was 3, 2 and 1 in the M-SBMT, M-UBMT and MM-UBMT and the number of non-relapse death was 2, 2 and 4, respectively. The Kaplan-Meier estimates for event-free survival at 3 years were 70 ± 11%, 71 ± 12% and 44 ± 17% for M-SBMT, M-UBMT and MM-UBMT, respectively without statistical significance (p=0.38). The Kaplan-Meier estimates for overall survival at 3 years were 76 ± 10%, 71 ± 12% and 44 ± 17% for M-SBMT, M-UBMT and MM-UBMT,respectively (p=0.25).

Conclusion: In this study, we showed the outcome of SCT from high-resolpution HLA-matched unrelated donors was comparable with that of SCT from HLA-identical sibling donors in childhood AML in first remission. Therefore, high-resolution HLA-matched unrelated SCT might be recommended in patients without HLA-matched sibling donor in childhood AML in first remission.
Fludarabine, Amsacrine, High-Dose Cytarabine and Total Body Irridation Followed by Allogeneic Stem Cell Transplantation for the Treatment of High Risk or Relapsed Acute Lymphoblastic Leukemia.
Authors: Zohren Fabian , Graef Thorsten , Bruns Ingmar , Czibere Akos , Roland Fenk , Rainer Haas , Guido Kobbe
Published: October 2019

In this prospective study we examined the use of an intensified conditioning regimen followed by allogeneic blood-stem-cell transplantation (BSCT) for the treatment of young adults in physically good condition with relapsed or high risk acute lymphoblastic leukaemia (ALL). Eleven patients with ALL received FLAMSA chemotherapy (fludarabine 30mg/m2 - cytarabine 2000mg/m2 -amsacrine 100 mg/m2 on day −10, − 9, − 8and −7), Anti-Thymocyte-Globulin (ATG 20 mg/kg BW on day −6, −5 and −4) and fractionated TBI (2 x 2 Gy on day −3, − 2 and −1) followed by matched unrelated donor (n=10) or matched sibling donor (n=1) SCT. The principle reasons for high risk stratification were refractory disease during first-line induction therapy (6, 55%), relapse (2, 18%), extramedullary disease manifestation (1, 9%), ALL subtype (6, 55%), unfavorable cytogenetics (5, 45%) and white blood count >30000 μL at time of diagnosis (3, 27%). After a median follow-up time of 604 days (range 202 – 1042 days) 8 patients (73%) are alive and 3 patients (27%) died. The median overall survival was not reached. Two patients died after relapse on days +121 and +449, another patient died from treatment related complications (HUS-TTP) on day +87. One patient relapsed on day +200 and is currently alive, the remaining 7 patients are alive and free of desease. Treatment related toxicities were acceptable. With 6 out of 11 patients developing grade III/IV infections during neutropenia, infectious complications remained of major importance. Other non-haematological side effects seen within this group of patients were less frequent and almost exclusively limited to gastrointestinal toxicities. Five patients (45%) had grade III/IV mucositis and 5 patients (45%) had grade III/IV nausea, while 4 patients (36%) showed grade III/IV diarrhoea. There was no case of acute toxicity related to the cardiavascular or central nervous system. The incidence of acute GvHD (aGvHD) was 36% (n = 4) and limited to grades II-III. Eight patients were evaluable for chronic GvHD (cGvHD). Out of those 4 patients (36%) developed cGvHD (3 limited disease, 1 extensive disease). We conclude that allogeneic transplatation after the FLAMSA-ATG-TBI regimen is feasible and provides effective therapy for this group of high-risk patients.
Initial Cytoreductive Treatment with Thalidomide Plus Bolus Vincristine/Doxorubicin and Reduced Dexamethasone (T-bVAd) Followed by Autologous Stem Cell Transplantation (ASCT) for Multiple Myeloma.
Authors: Jo Jae-Cheol , Kang Byung Wook , Sym Sun Jin , Lee Sung Sook , Jang Geundoo , Lee Dae Ho , Kim Sang-We , Suh Cheolwon
Published: October 2019

High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) after the combined chemotherapy with vincristine, doxorubicin and dexamethasone (VAD) is an effective therapy for newly diagnosed, multiple myeloma. Bolus vincristine/doxorubicin intravenous administration as an outpatient route is convenient and has acceptable efficacy and toxicity. Thalidomide has recently shown significant antimyeloma activity. We studied the efficacy and toxicity of the combination of bolus vincristine/doxorubicin and reduced-dose of dexamethaxone with thalidomide (T-bVAd), administered on an outpatient basis in previously untreated multiple myeloma. From August 2005 to December 2006, 26 patients were enrolled in a prospective study. All patients received T-bVAd, which consisted of vincristine 0.4 mg intravenously i.v., doxorubicin 9 mg/m2 i.v. administered as single bolus dose on days 1 to 4, and dexamethasone 20 mg per os daily for 4 days. Dexamethasone was also given on days 8 to 11, 15 to18 of the each cycle of treatment. The regimen was administered every 4 weeks for four courses. Thalidomide was given daily at a dose of 200 mg at bedtime. Response to treatment was evaluated after each cycle of treatment. After achieving response, the patients were allowed to proceed to high-dose chemotherapy with ASCT. On an intention-to-treat basis, 23 of the 26 patients (88.4%) responded to treatment. Sixteen patients (61.5%) achieved complete and seven (26.9%) partial response. Only three (11.6%) were rated as non-responders. Grade 3 or 4 toxicities consisted of neutropenia (9%), febrile neutropenia (6%), thrombocytopenia (4%) without significant nonhematologic events. Of the 23 patients who showed response, 9 proceeded to single ASCT and 7 tandem ASCT. Median event-free survival and median overall survival were not reached yet. As an induction therapy, T-bVAd administered as an outpatient regimen, seems to be efficient and well tolerated.
Reduced-Intensity Conditioning for Allografting Following Autografting for Myeloma: Lower Relapse Rates Compared with Single or Double Autografting but Similar Overall Survival. The Genoa Experience in 74 Patients.
Authors: Carella A.M. , Catania G. , Biasco S. , Congiu M. , Nati S. , Rossi E. , Vimercati R. , Ciapanna D. , Spriano M.
Published: October 2019

Multiple Myeloma (MM) is the most frequent indication for autolografting and allografting. Autografting (AutoSCT) represents the most effective palliation for these patients. Even the double AutoSCT where there is demonstrated good long-term control in a minority of patients do not appear to result in cure of disease. Myeloablative AlloSCT is penalized by excessive transplant-related mortality (TRM) and toxicity.The introduction of reduced-intensity conditioning for allografting (RICT) has renewed interest in the use of AlloSCT for MM. Recent studies have reported encouraging results with tandem AutoSCT followed shortly thereafter by RICT in MM patients as compared to AutoSCT or myeloablative AlloSCT alone. Here we present the results achieved in our Unit in patients receiving AutoSCT (single or double) compared to patients receiving tandem AutoSCT/RICT. The major results are summarized in the table. In the AutoSCT/RICT group the risk of disease progression was reduced for those patients who achieved full chimerism, acute and/or chronic GVHD. This finding confirms the existence of a graft-versus-myeloma effects. Since the first clinical signs of response of remitters patients were noted between 70 and 120 days and maximum response between 160 and 200 days after RICT (and after DLI in 2 patients) these responses should be considered immunological responses. In conclusion, these data suggest that AutoSCT/RICT significantly reduces the incidence of disease progression but did not impact on overall survival with respect to single or double AutoSCT.

Single Double AutoSCT AutoSCT AutoSCT + RICT (n=15) (n=35) (n=24) Age, median 64 (range 48–73) 62 (range 35–73) 50 (range 34–63) No. prior cycle chemoth., median 5 (range 3–8) 4 (range 3–6) 4 (range 3–6) Conditioning regimen for AutoSCT Melph. 200 mg/m2 Melph. 200 mg/m2 Melph. 200 mg/m2 Conditioning regimen for RICT ==== ==== TBI-Flu (19 pts) Flu-Melph. (5 pts) Days from Dx to AutoSCT, median 210 (range 120–390) 320 (range 120–840) Days from AutoSCT to RICT ==== ==== 80 Overall Survival 73,3% (11/15) 60% (21/35) 66% (16/24) Median Overall Survival 37 (range 10–132) 51 (range 13–147) 28 (range 6–87) Pts alive in CR 1 (6,6%) 4 (26,6%) 10 (41,6%) CR duration, median 20 mo. 56 mo. (range 28–70) 67 mo. (range 8–78) TRM 1 ==== 3
Hematopoietic Cell Transplantation - Comorbidity Index (HCT-CI) as a Surrgoate Marker for Predition of Transplant Outcome for Pateints (pts) with Multiple Myeloma (MM) Undergoing Autologous Stem Cell Transplantation (ASCT): High HCT-CI Score Predicts for Poor Outcome.
Authors: Farhat Mohamed I. , Myint Ronald , Gregory Stephanie A. , Venugopal Parameswaran , Kassar Mohamad , Gimelfarb Alla , Batus Marta , Nangia Julie , Maciejewski John , Law Amanda , Fung Henry C.
Published: October 2019

Background: For all “transplant eligible” pts with MM, established practice guidelines recommend ASCT as part of the front line treatment. However, the definition of “transplant eligible” remains undefined. The HCT-CI is a new tool that encapsulates pre-transplant comorbidities used in predicting transplant outcomes in pts undergoing allogeneic SCT. This scoring system has been shown to be a good predictor for non-relapse mortality (NRM) & survival in pts undergoing alloSCT. In this study, we hypothesize that HCT-CI could predict the transplant outcome on pts with MM undergoing ASCT and could potentially be utilized as a tool for selecting pts with MM for transplant.

Methods: A retrospective analysis of 75 pts with multiple myeloma whom underwent ASCT in our institution between 02/99 and 12/03 with a median follow up of 30 months. Pts were assigned scores based on the HCT-CI. Definitions of comorbidities were as previously reported by Sorror et. al. (Blood2005; 106:2912).

Results: Median age was 56 years (38 – 73); M:F 1:1. 51 pts received a single & 24 had tandem ASCT. The majority of pt. had IgG myeloma (IgG kappa: 45; IgG Lambda 17). Comorbidities (points, number of pts): mild hepatic (1,16), renal (2,6), cardiac (1,8), arrhythmia (1,1), heart valve disease (3,4), cerebrovascular (1,8), DM (1,11), PUD (2,2), inflammatory bowel disease (1,0), Tumor (3,6), pulmonary (2,5), psychiatric (1,8), rheumatologic (2,3), infection (1,6), and obesity (1,10). HCT-CI score of 0 seen in 32%, 1 in 28%, 2–8 in 40% of the pts, with a median score of 1.65. 20 patients died with only one due to NRM. Pts were categorized into 2 groups: low-risk (scores of 0–1) – 46 pts and high-risk (scores 2–8) – 29. Using a cox regression model, the low risk group had a survival advantage (HR = 2.55, P = 0.04). Using Kaplan Meier survival estimate comparing the low risk and high risk group (figure1), the 5 yrs overall survival were 77% & 22% respectively (P = 0.04). While the median survival for the high risk group was 3.52 years, it has not been reached for the low risk group.

Conclusion: Here, we have demonstrated a survival benefit for pts with low (0–1) compared with high (≥ 2) HCT-CI score. In addition, the outcome of pts with high HCT-CI score was also similar to non-transplant pts as published in the literature. This raises the question of “benefit” of ASCT for pts with high HCT-CI score. Thus, HCT-CI may serve as a useful tool to select pts whom would benefit most from ASCT.

Figure 1 Figure 1
Rituximab Improves the Outcome of Upfront Autologous Stem Cell Transplantation in Mantle Cell Lymphoma: A Comparison of Different Strategies.
Authors: Rieger Michael , Witzens-Harig Mathias , Hensel Manfred , Seyfarth Baerbel , Nickelsen Maike , Kneba Michael , Schmitz Norbert , Ho Anthony D. , Dreger Peter
Published: October 2019

Introduction: First-line autologous stem cell transplantation (SCT) is an accepted therapy for mantle cell lymphoma (MCL). We have recently shown that 2 standard doses of rituximab significantly improve the outcome of TBI-based upfront SCT in MCL when administered peritransplant (Haematologica 92:42; 2007). The purpose of the present retrospective analysis was to compare this approach with alternative rituximab-based strategies. Patients and treatment strategies: 34 consecutive patients treated in KI-HH received 3–6 cycles of CHOP prior to stem cell mobilization with Dexa-BEAM (n=20) or DHAP (n=14), followed by TBI-cyclophosphamide-rituximab myeloablation and SCT (CHOP/R-TBI-CY group). Patients treated in HD received 3–8 cycles of R-CHOP for cytoreduction (n=28) and mobilization (n=23; the remaining 5 patients were mobilized with R-DHAP/HAM) followed by BEAM and SCT (R-CHOP/BEAM group). 12 patients of this group received additional rituximab maintenance after SCT.

Results: With a median follow-up of 38 months (9–111), estimated 4-year progression-free survival (PFS) from diagnosis of patients treated with CHOP/R-TBI-CY and R-CHOP/BEAM was 83% and 72% (log rank, p=.38), respectively. Of note, with a median follow-up of 30 months (14–57) there was no relapse in the 12 pts receiving maintenance therapy with rituximab, translating into a significantly better 4-y PFS in patients receiving R-CHOP/BEAM with rituximab maintenance vs those without (100% vs. 56%; p=.021). The PFS difference between the R-CHOP/BEAM group and the CHOP/R-TBI-CY group became borderline significant after omitting the rituximab maintenance patients (p=.055).

Conclusions: In advanced-stage MCL, addition of rituximab improves disease control provided by first-line SCT. Whereas the exact dose and timing of rituximab administration remains to be settled, prospective investigation of post-transplant rituximab maintenance appears to be particularly promising.
Transplantation in the Elderly: The Affect of Age on Clinical Course and Outcomes.
Authors: Canary Marcy , Hill John M. , Meehan Kenneth R.
Published: October 2019

Hematopoietic stem cell transplant (HSCT) is often the treatment of choice for a number of hematologic malignancies at the time of relapse. Historically, older patients have been excluded from receiving HSCT due to concerns about the potential for increased toxicity and treatment related mortality (TRM). We performed a retrospective analysis of patients undergoing autologous HSCT over a six year time period at our institution evaluating age as a prognostic factor. Adult patients (18 years and over) who received a HSCT between the years 2000 and 2006 were evaluated. The patients were divided into two cohorts based on age, the “senior” cohort (≥62 years) and the “younger” cohort (≤61 years). Individual patient chart reviews yielded pertinent information. Of the 181 patients who received a transplant during this time period, 131 patients (median age of 50 years: range 19–61) comprised the “younger” cohort and 50 patients (median age of 66 years: range 62–73) were included within the “senior” cohort. There was no statistical difference between these two groups when the following were evaluated: time to engraftment (p values of 0.13 for neutrophils and 0.2 for platelets), length of hospital stay (p = 0.5), incidence of infection (p = 1), transfer to the ICU (p = 0.08) or TRM (p = 0.3). This analysis is the largest study of its size evaluating outcome of autologous HSCT based on age using current transplant protocols, including primarily peripheral stem cell transplants. It is also the first study to specifically address incidence of infection in older patients, which has been suggested by other studies to increase TRM in elderly patients. Our data indicate that toxicity of autologous HSCT is similar in older patients when compared to younger patients and that this treatment should be offered to elderly patients with hematologic malignancies who may benefit from autologous stem cell transplantation.
Improved Relapse Free Survival Is Predicted by a Negative Pre-Transplant FDG-PET Scan Following Salvage Chemotherapy for Relapsed Diffuse Large B Cell Lymphoma (DLBCL) Treated with Autologous Stem Cell Transplantation.
Authors: Dickinson Michael J. , Hoyt Rosemary , Roberts Andrew , Grigg Andrew , Seymour John Francis , Szer Jeff , Prince H. Miles , Ritchie David
Published: October 2019

Introduction FDG-PET imaging is a powerful predictor of both positive and negative outcome of initial therapy for DLBCL. Existing data on the utility of PET to predict outcome of ASCT have included a range of histological subtypes, limiting its direct applicability to the setting of DLBCL.

Methods Data from 41 consecutive patients who had PET scans immediately prior to undergoing ASCT for treatment of first relapse of de novo DLBCL were analysed. We compared the clinical characteristics, event free survival (EFS) and overall survival (OS) of those with residual FDG avid disease (n=21) against those without FDG avid disease (n=20).

Results The median age was 53(18–71). Patient characteristics are shown in the table. At 3 years, the OS was 67(±8)%, and the EFS was the 62(±8)%. EFS for PET positive patients was 38(±12)% vs 79(±9%) for PET negative patients (p=0.04). OS was 37(±17%) vs 81(±10%) (p=0.08) respectively.

Conclusion Excellent EFS and OS can be anticipated from ASCT when undertaken in those who have achieved a PET negative remission following salvage chemotherapy. Conversely, failure to achieve a PET negative remission after salvage chemotherapy in relapsed DLBCL predicts for a poorer, but not irretrievable outcome after ASCT, suggesting that a proportion of PET positive patients can be successfully salvaged by either ASCT or post-ASCT salvage therapies.

Patient Characteristics PET Positive (n=21) PET negative (n=20) PET negative (n=20) Female 28% 40% Median Age (Range) 53 (28–65) 53(81–71) Salvage Regimen ICE ±R 66% ICE ±R 80% Conditioning Regimen BEAM 47%, SBCNU 23% BuMel 14% other 16% BEAM 25%, SBCNU 25% , BuMel 25% other 25% Rituximab with salvage 71% 95% Rituximab in initial therapy 33% 25% RT with salvage or ASCT 43% 25%
Factors Predicting PBPC Collections in Healthy Adolescents and Children with Solid Tumours.
Authors: Roncon Susana , Barbosa Isabel L. , Lopes Sergio M. , Ferreira Sara , Avila Alcina , Norton Lucilia , Pimentel Pedro , Cravalhais Alzira
Published: October 2019

G-CSF is used for mobilization of hematopoietic cells in healthy adolescent donors and pediatric patients. In both groups it is important to ascertain factors predicting the success of apheresis as well as the number of procedures to achieve the target CD34+ cell number for hematologic recovery. We retrospectively analyzed factors predicting the yield for a target CD34+ cell dose in10 healthy adolescent donors and 43 children with solid tumours who were enrolled in the transplantation program at our center from January 1996 to July 2007. The healthy adolescents (n=10) had a median age of 15 years (range 13–16) and body weight (bw) of 45 kg (range 20–74) and the children with solid tumours (n=42) (Neuroblastoma n=28, Ewing sarcoma n=7 and other solid tumours n=7) had a median age of 4 years (range 1–15) and bw of 17 kg (range 9 – 63). Mobilization regimen consisted of G-CSF in a dosage of 10 μg/kg per day, applied subcutaneously for 5 or 6 days. A pre-collection peripheral blood (PB) CD34+ count was performed in all children, by flow cytometric analysis. Standard volume apheresis was carried out using a Cobe Spectra blood cell separator, through peripheral veins in donors and central lines in patients. We estimated a minimum of 4 x106 and 2x106 CD34+ cells/kg bw receptor for successful engraftment for allogeneic and autologous transplant, respectively. The healthy adolescent donors had high number of PB CD34+ cells (median 62/μl, range 42 – 75) and the majority (7/10) only required a single apheresis to collect sufficient cells for their family related recipients. The neuroblastoma patients with >10/μl PB CD34+ cells collected in one day the target cell dose (median 4.6x106 CD34+ cells/kg, range 2.6 – 27.0). Those with <10/μl PB CD34+ cells underwent 2 apheresis and the majority reached the cell target. The majority of children with Ewing sarcoma and other solid tumours (9/14) also collected >2.0 x106 CD34+ cells/kg in 2 apheresis. In summary all the children with solid tumours received a single course of G-CSF and presented on the 5th day of mobilization a median PB CD34+ cell count of 9/μl (range 1–216). The majority (75%) collected >2.0 x106 CD34+ cells/kg and the remaining (25%) had <10/μl PB CD34+ cells and did not achieve this minimum requirement. We found a correlation between the PB CD34+cell count and the number of apheresis and CD34+ cells yielded both for the adolescent donors and children with solid tumours. Based on these results, a PB CD34+ cell count >10/μl was a good indicator for performing PBPC collections in paediatric patients from our institution.
Early Results of a Clinical Trial Using Targeted Oncolytic Virotherapy in Kaposi Sarcoma Herpes Virus (KSHV) Associated Multicentric Castleman’s Disease (MCD).
Authors: O’Mahony Deirdre , Bernstein Wendy , Wyvill Kathy , Aleman Karen , Whitby Denise , Steinberg Seth , Tosato Giovanna , Pittaluga Stefania , Jaffe Elaine S. , Yarchoan Robert , Little Richard F.
Published: October 2019

Human herpes virus 8, also termed KSHV, is an oncogenic gamma herpesvirus associated with Kaposi’s sarcoma (KS), primary effusion lymphoma and MCD. KSHV-associated MCD (KSHV-MCD), a rare B-cell lymphoproliferative disease almost universally found in association with HIV infection, is characterized by recurrent flares of a systemic syndrome of fatigue, fevers, cytopenias, elevated serum C-reactive protein (CRP), and lytic KSHV replication. Prognosis is poor (median survival 14 months). KSHV open reading frames (ORF) 21 and 36 respectively have the ability to phosphorylate zidovudine and ganciclovir, leading to cell death (Cancer Res2007;67(14):7003–10), and this may be exploitable for oncolytic virotherapy. Ten patients (pts) with symptomatic and biopsy confirmed KSHV-associated MCD have been treated with high dose oral zidovudine (HDAZT) 600mg every 6 hours and valganciclovir (VGCV) 900mg every 12 hours. Treatment length of first cycle is dependent on response, and ranges from 7–21 days. Subsequent cycle length is 21 days with 7 treatment days. Pt characteristics: median age 40 (range 33–56); ECOG PS 2 (1–3); median enrollment CD4 count 189 (range 19–1319 UL); median HIV viral load <50 copies/ml3 plasma (range <50 to 27,500). All pts were on highly active antiretroviral therapy; this was adjusted during time pts were on AZT. 8 pts had a history of KS. Median duration of MCD 3.5 months (range 0.5–45 months); seven pts had received at least one prior therapy for MCD (range 1–6). All had MCD-related constitutional symptoms and CRP above 0.8mg/dl (median 13.1, range 1.06–38.7 mg/dl) at treatment initiation. A total of 83 cycles have been administered to date, with a median of 6 (range 4–23) cycles per pt. 9/10 had documented improvement in constitutional symptoms, C-reactive protein levels or cytopenias. Therapy continues in 5 patients who have had sustained responses (median duration on therapy 7 months, range 3–18). Response was only short-lived in 4 (median duration on therapy 4.5 months, range 3.5–6.5) who then received alternative treatments. Grade (gr) 3 or 4 hematologic toxicity not attributable to disease was seen in only 2 patients. Two infectious events occurred, a staphylococcal skin abscess and streptococcal meningitis. There were no neutropenia associated infections. Treatment toxicity included two patients with fatigue (gr3), 1 with nausea (gr3), 1 with transaminitis (gr3) and one with insomnia (gr3). In summary, this preliminary data suggests that HDAZT and VGCV has activity useful in the management of KSHV-associated MCD. Accrual continues.
Medical Visit Patterns in Cancer Chemotherapy Patients Receiving Erythropoiesis-Stimulating Agents in a Managed Care Setting.
Authors: McKenzie Scott R. , Lefebvre Patrick , Bookhart Brahim K. , Laliberté François , Duh Mei S.
Published: October 2019

Background: Avoiding unnecessary medical visits related to erythropoiesis-stimulating agent (ESA) treatment represents an important consideration for managed-care organizations. Observational data have reported varying visit patterns for cancer chemotherapy patients receiving epoetin alfa (EPO) and darbepoetin alfa (DARB). Few studies have characterized visit patterns in this population during ESA treatment.

Objective and Purpose: The objective of this analysis was to describe visit patterns and identify the proportion of medical visits made exclusively for ESA treatment in cancer chemotherapy patients.

Methods: Analysis of medical claims between 1/2004–12/2005 using the Integrated Health Care Information Systems national database, representing >35 health plans, was conducted. Patients were ≥18 years old, had a cancer diagnosis, received >1 ESA administration, and concurrent chemotherapy (during or within 14 days of ESA initiation). Medical visits during the ESA treatment duration (time from first to last ESA administration) were categorized into mutually exclusive groups based on procedure codes recorded on the visit day: ESA administration, chemotherapy/radiotherapy administration, physician visit, blood count, WBC growth factor administration and other (hydration, antiemetics/antibiotics, etc).

Results: 3,462 EPO and 2,839 DARB patients were identified representing 107,149 unique visits (EPO 62,785, DARB 44,364). Mean ESA treatment duration was similar between groups (Days: EPO 59.3; DARB 57.6, p=0.212). The proportion of visits were categorized into mutually exclusive service groups, presented below.

Conclusion: Cancer chemotherapy patients receiving ESAs incurred visits for many reasons, but primarily for receiving chemotherapy. Less than 5% of all visits were solely related to ESA administration, regardless of ESA received.

Table Service Group EPO DARB Chemotherapy 10.3% 12.2% Chemotherapy + ESA 24.9% 27.3% Physician visit 11.9% 12.5% Physician visit + ESA 13.0% 9.9% Blood count 1.1% 2.1% Blood count + ESA 10.1% 8.4% WBC growth factor 0.3% 0.5% WBC growth factor + ESA 5.9% 6.8% Other 15.9% 14.8% Other and ESA 2.6% 2.6% ESA only 4.1% 2.9% Total 100% 100%
Multimethod Clinical Assessment of Patterns and Prevalence of Nonadherence (NA) to Imatinib Treatment (IMRx) in Patients (Pts) with Chronic Myeloid Leukemia (CML): Results from the ADAGIO Study.
Authors: van Lierde Marie-Anne , Serra Filipo , De Rop Larissa , Strobbe Eric , MacDonald Karen , Vancayzeele Stefaan , De Geest Sabina , Letvak Laurie , Albrecht Tara , Abraham Ivo
Published: October 2019

BACKGROUND. ImRx for CML is a long-term treatment. Patterns and prevalence of NA to ImRx remain largely unknown. Short-term NA trends may be indicative of long-term NA. Methods for clinical NA assessment vary in reliability. A multimethod approach is indicated.

OBJECTIVE. Multimethod estimation of patterns and prevalence of ImRx NA in CML pts at baseline (BL) and follow-up (FU) at 90 days (90d), incl. BL to 90d changes.

DESIGN AND PATIENTS. Data subset from prospective, 90d observational, open-label, multicenter study. 169 evaluable pts on ImRx for minimum 30d at enrollment [1].

METHODS OF NA ASSESSMENT. At BL (NA with prior ImRx) and 90d (NA during study): visual analog scale (VAS) for physicians (phs; mVAS), pts (pVAS), cos (cVAS); Basel Assessment of Adherence Scale for pts (pBAAS; structured interview re NA in past 4 weeks [4wks]); pts reported persistence (pPST); % clinic appointments (%CAPPTS) kept (if any scheduled). At 90d also: % of ImRx taken per pill count (%pts@ImRx).

RESULTS. See Table 1.

CONCLUSIONS. Intuitive adherence ratings (VAS) by phs, pts, and cos are very high and differ from those from structured interview, where about one-third of patients exhibited NA behavior in 4wks prior to BL and FU - despite high persistence. Pill count suggests patterns of under- and overtaking, with only 1 out 7 patients being perfectly adherent. Rate of clinic appointments may be affected by physician scheduling practices and collateral input is a function of availability of collateral person. Consenting to participate in the ADAGIO study did not reduce NA. Though patient self-reports in structured interview (pBAAS) and pill counts have inherent biases, both indices suggest that NA with ImRx may be similar to NA rates in other disease categories. Especially pBAAS and pill count may be useful rapid clinical assessment tools, with pBAAS having the benefit of validated categorical assessment (vs. continuous in other methods). Determinants of NA and the impact of NA on treatment outcomes must be examined.

Table 1 - Multimethod Assessment of Non-Adherence with Imatinib Method BL 90d n M±SD/Min-Max M±SD/Min-Max P mVAS 164 95.0±7.6/60–100 94.9±9.9/0–100 ns pVAS 169 95.3±8.5/25–100 95.7±6.1/75–100 ns cVAS 56 97.1±5.1/80–100 97.4±5.1/75–100 ns %pts@ImRx 162 - 91.0±21.1/29.5–2002.2 71.0% @ < 100% ImRx 14.2% @ 100% ImRx n % NA % NA P pBAAS 163 36.2% 32.5% ns %CAPPTS 51 94.1% 88.2% 0.001 pPST 163 98.8% 100.0% ns
Assesment of the Prevalence and Impact of Anemia on Women Hospitalized for Gynecologic Conditions Associated with Heavy Uterine Bleeding.
Authors: Morrison John , Patel Snehal , Dinh Quinn
Published: October 2019

Objective: Women with heavy uterine bleeding often are untreated or inadequately treated for anemia. This study was conducted to estimate the prevalence and impact of anemia in women hospitalized for gynecologic conditions associated with heavy uterine bleeding.

Study Design: The largest all-payer inpatient care database, the Healthcare Cost and Utilization Project’s 2003 Nationwide Inpatient Sample, was queried using ICD-9-CM codes to identify and group cases with gynecologic diagnoses associated with heavy uterine bleeding into two categories: with or without anemia. Groups were evaluated for demographic characteristics, medical resource utilization, and hospitalization costs using descriptive statistics.

Results: More than 25 percent of the estimated 300,589 women in the study had a diagnosis of anemia. Compared to patients without an anemia diagnosis, those with an anemia diagnosis were more likely to have a blood transfusion (24% versus 0.7%, p<0.0001); an emergency department admission (26.8% versus 3.2%, p<0.0001); and higher hospitalization costs ($5,631 versus $5,101, p<0.0001).

Conclusions: Anemia and blood transfusions are common in women hospitalized for gynecologic conditions associated with heavy uterine bleeding. Greater patient and provider awareness of the prevalence and burden associated with anemia may increase opportunities to reduce blood transfusions and improve general health status and quality of life in this patient population.
Real-Time Quantitative PCR (RQ-PCR) Detection of Minimal Residual Disease (MRD) by Optimized WT1 Assay To Enhance Risk Stratification in Acute Myeloid Leukemia (AML): A European LeukemiaNet Study.
Authors: Cilloni Daniela , Renneville A. , Hermitte F. , Hills R.K. , Daly S. , Jovanovic J. , Gottardi E. , Fava M. , Schnittger S. , Izzo B. , Nomdedeu J. , van der Heijden A. , van der Velden V. , Rohon P. , Ommen H. , Polak J. , Jansen J. , Preudhomme C. , Saglio G. , Grimwade D.
Published: October 2019

Relapse remains the major cause of treatment failure in AML; however, RQ-PCR assays to detect leukemic fusion transcripts have been shown to identify reliably those patients at highest risk of relapse, allowing development of a more individualized treatment approach. In cases lacking a leukemia-specific MRD marker, quantification of genes over-expressed in AML e.g. Wilms’ Tumor gene (WT1) could provide more a precise measurement of disease response and quality of remission, potentially enhancing risk scores such as the one developed by the MRC used to identify those patients most and least likely to benefit from allogeneic transplant in first CR. WT1 is over-expressed in at least 75% of AML cases. Within the European LeukemiaNet we systematically evaluated 9 published and “in house” WT1 assays. Assays were excluded due to demonstrated lack of RNA-specificity or location within the 3′ region of the gene which has been shown to be subject to deletion or mutation in AML. An assay located within the 5′ region associated with superior sensitivity was ultimately selected following parallel testing in 11 labs and evaluated in 238 diagnostic peripheral blood (PB) and 386 bone marrow (BM) samples. WT1 was over-expressed in the majority, with comparable levels in PB and BM (PB - median 4637 WT1 copies/104ABL copies, range 0–1132709; BM - median 7212, 0–750571), as compared to normal BM (median 19.8, 0–213), PB (median 0.01, 0.01–47.6) and PBSCs (median 6.1, 0–39). In cases over-expressing WT1, kinetics of transcript reduction were evaluated following induction. A greater response was associated with a significantly reduced risk of relapse (hazard ratio 0.65 per log reduction (95% CI 0.43–0.96), p=0.03), although this failed to remain significant when adjusted for age, presenting WBC and cytogenetic risk group, which are key variables in the MRC risk index. Indeed, there was a highly significant correlation between larger log reduction in normalized WT1 transcript level and better risk score (p=0.0001). Sequential analysis of PB and BM samples from 15 AML cases with low WT1 expression (<250 copies) showed no significant modulation in transcript level on regeneration after chemotherapy, indicating that in WT1+ AML, transcript levels detected in follow-up samples reliably reflect disease status. This study provides evidence that recognized pre-treatment risk factors for relapse correlate closely with kinetics of response to induction therapy and lend support to the evaluation of early assessment of MRD to develop more robust risk scores, to enhance risk stratification and identify those patients most suited to proceed rapidly to allogeneic transplant.
A Selective and Potent Oral Inhibitor of the JAK2 Tyrosine Kinase Reverses Polycythemia and Leukocytosis Induced by JAK2 V617F in a Mouse Model.
Authors: Zaleskas Virginia M. , Chan Wayne W. , Evangelista Peter , Lazarides Katherine , Chopra Rajesh , Zinda Michael , Huszar Dennis , Van Etten Richard A.
Published: October 2019

A somatic mutation (V617F) in the pseudokinase domain of the non-receptor tyrosine kinase JAK2 is found in virtually all patients with the myeloproliferative disease (MPD) polycythemia vera (PV), and about half of those with essential thrombocythemia and chronic idiopathic myelofibrosis. When expressed in mice by retroviral bone marrow transduction and transplantation, JAK2 V617F but not JAK2 wild-type induces leukocytosis with neutrophilia and recapitulates the entire erythroid phenotype of PV, with polycythemia, reticulocytosis, low plasma Epo, and endogenous erythroid colonies (Zaleskas et al., PLoS ONE2006;1:e18; Wernig et al., Blood2006;107:4274; Lacout et al., Blood2006;108:1652). By analogy to BCR-ABL in chronic myeloid leukemia, JAK2 V617F is therefore a rational target for therapy in PV and other JAK2 V617F+ MPDs. Previous studies with a nonselective and parenteral tyrphostin JAK2 inhibitor suggested that short-term inhibition of JAK2 could decrease reticulocytosis in recipients of JAK2 V617F-transduced marrow (Zaleskas et al., op cit.). Here, we studied one of a novel series of inhibitors of JAK2, AZ-01, which potently inhibited JAK2 kinase activity (IC50 < 1nM) and suppressed proliferation of cell lines carrying the JAK2 V617F mutation. We treated cohorts of Balb/c mice with JAK2 V617F-induced polycythemia and leukocytosis with AZ-01 at 10 mg/kg by oral gavage twice daily, or with vehicle alone. After 28 days of treatment, AZ-01-treated mice had significant reductions in hematocrit, hemoglobin, reticulocytes, and splenomegaly, as well as normalization of peripheral blood leukocyte counts (Figure 1). These results demonstrate that oral administration of a potent and selective JAK2 inhibitor can reverse the hematopoietic abnormalities of JAK2 V617F-induced MPD in mice, and validate JAK2 as a target for therapy of human JAK2 V617F+ MPD.

Figure Figure

An orally available JAK2 inhibitor decreases the leukocyte count, hematocrit, and reticulocyte count in mice with JAK2 V617F-induced MPD. Leukocyte count (left), hematocrit (center) and reticulocyte counts (right) of cohorts of mice with JAK2 V617F-induced MPD treated with vehicle or drug at 10 mg/kg BID. Blood counts were assessed at 15 and 28 days of treatment. Decreases in d28 hematocrit and retic count in the drug-treated cohorts were significant (p=0.008 and p<0.0001, respectively, t-tests).
Distinct Expression Patterns of microRNAs in Activated B Cell (ABC) and Germinal Center B (GC) Subtypes of Diffuse Large B Cell Lymphoma (DLBLC).
Authors: Bastie Jean-Noel , Jais Jean-Philippe , Molina Thierry , Come Emmanuelle , Coiffier Bertrand , Gisselbrecht Christian , Rickman David , de Reynies Aurelien , Briere Josette , Gaulard Philippe , Feugier Pierre , Tilly Herve , Salles Gilles , Haioun Corinne , Leroy Karen
Published: October 2019

The Micro RNAs (miRNAs) are small non-coding, single-stranded RNAs that regulate the expression of genes by hybridizing the mRNA target with complementary sequences that are followed by translational repression, mRNa cleavage or destabilization. There is evidence that miRNA play an important role in carcinogenesis. Aberrant miRNA expression has been found in a variety of human malignancies including B-cell leukemias and lymphomas. The purpose of this study is to determine the miRNA expression patterns in DLBCL and their relationship with clinical characteristics and outcome. We used high throughput quantitative RT-PCR technology (Taqman Low density Arrays) to analyze the expression profile of 365 different mature miRNA in 12 Diffuse Large B-Cell Lymphoma (DLBCL) samples which had been previously characterized at the transcriptional level with Affymetrix HU133A micro-arrays. MiR-155 expression was significantly lower in the 6 samples with a Germinal Center (GC) mRNA profile than in the 6 samples with an Activated B-Cell (ABC) profile. Expression of miR-155 and of different miRNA involved in lymphoid differentiation (miR-181a, miR127) or tumour pathogenesis (cluster miR 17–92) were further evaluated in a series of 64 patients with DLBCL treated with Rituximab associated with chemotherapy (R-CHOP). 28 patients had been enrolled in the LNH98.5 GELA trial between February 1998 and February 2000 and 36 were treated with R-CHOP in GELA centers after the closure of the LNH98-5 trial, between November 2000 and June 2004. The median follow up of these patients is 69 months. Patients median age at diagnosis was 69 years (range 59–82) and 28 patients presented with an International Prognostic Index (IPI) score of more than 3. Mature miRNA expression was determined by quantitative RT-PCR with Applied Biosystems specific miRNA primer and probe sets and normalized to U6 small nuclear RNA expression. MiR-155 expression was significantly higher in patients with a lymphoma of the ABC subtype, defined on the basis of the transcriptional profile (mean delta Ct = − 3.9 in the 41 ABC samples, mean delta Ct = − 1.67 in the 23 GC samples, p<0.00001) and significantly higher in patients with a high (4 or 5) IPI score (p=0.02). A high miR-155 expression was associated with a trend towards a poorer overall survival. The expression of miR-127, miR-181a and the cluster 17–92 were not correlated with clinical outcome. These analyses are currently being extended to a larger series of patients in order to determine whether other miRNA can be used to classify DLBCL samples into ABC and GC subtypes and whether some miRNA have prognostic significance in the era of treatments combining Rituximab and chemotherapy.