bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imatinib 800 mg: Preliminary Results of a Phase II Trial of the GIMEMA CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.
Authors: Rosti Gianantonio , Martinelli Giovanni , Castagnetti Fausto , Testoni Nicoletta , Specchia Giorgina , Bassan Renato , Stagno Fabio , Breccia Massimo , Abruzzese Elisabetta , Saglio Giuseppe , Pane Fabrizio , Simonsson Bengt , Nielsen Johan L. , Hjorth-Hansen Henrik , PorkKa Kimmo , Haznedaroglu Ibrahim , Nagler Arnon , Vignetti Marco , Russo Domenico , Amabile Marilina , Baccarani Michele 
Published: April 2020

Abstract
The conventional treatment of chronic myeloid leukemia (CML) in early chronic phase (ECP) is imatinib 400 mg daily. The estimated rates of major (MCgR) and complete cytogenetic response (CCgR) at 42 months are 91% and 84%, respectively (IRIS Trial - F Guilhot, ASH 2004), with a survival free from accelerated and blastic phase of 84%. The rates of CCgR are significantly different according to Sokal score, being 91%, 84% and 69% for low, intermediate and high risk categories. Phase I and II trials of imatinib have clearly shown a dose-response effect; more importantly, a single center phase II trial of imatinib 800 mg in ECP showed significantly better results vs standard dose, in terms of CCgR (90% vs 74%) and of complete molecular response (28% vs 7% at 18 months) [H. Kantarjian et al, Blood 103 (8), 2004]. The GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) CML WP is conducting a phase II trial of imatinib 800 mg in intermediate Sokal risk in ECP (trial CML/021). Overall, 89 pts (mean age 53 yrs) have been enrolled. Fourty-four patients completed 6 months of treatment: the complete hematological response rate is 100%; the MCgR and CCgR are 90% and 81%, respectively. The 6 months CCgR rate of this trial parallels the IRIS trial one in intermediate risk cases (84%), with a much shorter treatment period. The major molecular response rate at 6 months (RTQ-PCR as ratio BCR-ABL/ABL) is 56% (cut-off ≤ 0.12%) or 41% (cut-off ≤0.05%). The compliance to the treatment improved time by time, being 47% the patients receiving ≥ 80% of the scheduled dose between months 1–3 and 60% between months 4 - 6. A second project, exploring imatinib high dose, is reserved to high risk cases: a multinational working group, within the frame of Leukemianet CML WP, is conducting a phase III randomized trial (1:1) of imatinib 400 mg vs 800 mg in high Sokal risk in ECP. By July 31, 2005, 80 patients have been enrolled: GIMEMA CML WP (44 pts), Nordic Countries - Sweden, Denmark, Norway and Finland (25 pts), Turkey (10 pts) and Israel (1 pt).
Imatinib Mesylate Determines a High Frequency of Major Molecular Responses in Newly Diagnosed Philadelphia Chromosome-Positive Chronic Phase Chronic Myeloid Leukemia (CML) on Behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia (GIMEMA-CML).
Authors: Iacobucci Ilaria , Testoni Nicoletta , Rosti Gianantonio , Amabile Marilina , Poerio Angela , Soverini Simona , Colarossi Sabrina , Gnani Alessandra , Ottaviani Emanuela , Castagnetti Fausto , Terragna Carolina , Renzulli Matteo , Grafone Tiziana , Cilloni Daniela , Pane Fabrizio , Saglio Giuseppe , Baccarani Michele , Martinelli Giovanni 
Published: April 2020

Abstract
Imatinib has became the standard therapy for patients with CML. In order to determine the frequency of molecular response to imatinib and its long-term prognostic implications, we analyzed the results of molecular monitoring in 260 newly diagnosed CML Sokal low-risk patients, enrolled in a prospective clinical trial (protocol CML 023 of the GIMEMA Working Party on CML). Imatinib was given at the dose of 400 mg daily. Bone marrow samples were collected prior to therapy and every 12 months, peripheral blood samples were collected at the same check-points and at 3 months, 6 months and every 6 months thereafter. Relative BCR-ABL expression was measured by real-time quantitative PCR (TaqMan) normalized for ABL and the result was expressed as a ratio of BCR-ABL to ABL multiplied by 100. All experiments were performed in duplicate. The median follow-up time from the time treatment was started is 6 months (range, 1–18).
At the time of writing, are valuable for cytogenetic and molecular analysis at 12 months on imatinb 82 patients. At this time, complete cytogenetic remission (CCgR) was achieved in 90% of patients. Median BCR-ABL/ABL ratio before the start of imatinib was 16.1 (range, 112.6–0.004), it was 0.35 (range, 81.57–0.0006) at 3 months, 0.1 (range, 45.84–0.0002) at 6 months and 0.05 (range, 7.57–0.000001) at 12 months. Considering a major molecular response as reaching an absolute value of BCR-ABL/ABL ratio &lt; 0.05%, we observed how after 12 months of treatment imatinib has determined a major molecular response in 52% of patients. If we were to use an absolute value of BCR-ABL/ABL ratio &lt; 0.12 %, that has been demonstrated to be equivalent at a 3-log reduction (as referred by Hochhaus A), instead of an absolute value of 0.05%, a major molecular response would be achieved in about 70% of early chronic phase patients. BCR-ABL transcripts were undetectable at least one occasion (complete molecular response) in 4% of patient with a CCgR. Only 2 patients (2%) had no response to imatinib, in one of these we found the presence of the point mutation Y253H.
In conclusion, our results demonstrate that imatinib determines a high frequency of complete cytogenetic remission and major molecular remission in newly diagnosed CML patients. Achieving a major molecular response, particularly within the first year of therapy, could be predictive of a durable cytogenetic remission.
Conception and Pregnancy in Patients (pts) with Chronic Myeloid Leukemia (CML) Receiving Therapy with Imatinib Mesylate (IM).
Authors: Ault Pat , Kantarjian Hagop , O’Brien Susan , Koller Charles , Faderl Stefan , Freireich Emil J. , Rios Mary Beth , Cortes Jorge 
Published: April 2020

Abstract
Although pts with CML receiving IM therapy are required to practice contraception while on therapy, there are isolated case reports of conception and pregnancy while on therapy. Here we present our experience with 18 pts who conceived while on IM therapy: 10 females and 8 males. All 10 females received IM for chronic phase (CP) CML. At the time of conception 1 had a complete cytogenetic (CG) response (CG CR), 3 a partial CG response (CG PR), 2 a minor CG response (CG MR), 2 complete hematologic response (CHR), and 2 no response. All pts stopped therapy immediately when pregnancy was recognized. Pts were managed with hydroxyurea (n=3), leukapheresis (n=1), interferon (n=1) or observation. Two pts had a spontaneous and 1 an elective abortion; 7 pregnancies continued uneventfully until delivery (median duration of pregnancy 36 weeks). Eight babies have been born (1 pair of twins): one had hypospadias, 7 were normal. The median age of the children is now 14 months (mo) and all are developing normally. At the time of delivery/abortion, 5 pts were 100% Ph-positive, 3 had still a CG MR and 1 a CG PR [i.e. 5 of 7 evaluable had increased Ph off therapy (1 not tested yet, 2 results pending) (median off therapy 9 months, range 4 to 22 months).] Pts re-started therapy after delivery and again after a median of 18 months after delivery (range 5 to 48 months), 3 have a CG CR, 2 CG PR, 1 CG MR, 2 CHR and 1 unknown. Among 8 males (6 CP, 2 AP) who impregnated their partners while on IM, 9 pregnancies resulted in the birth of 8 healthy babies and 1 spontaneous abortion. One baby had a mild rotation of the small intestine that resolved surgically. There were no complications of the other 7 babies. With a median age of 37 mo (range, 5 to 50), there are no known growth or development problems for any of the babies. This small experience suggests that conception while receiving IM is most frequently associated with a normal pregnancy and healthy babies, provided IM is immediately discontinued. Still, the recommendation to practice effective contraception while on IM should be enforced.
Cardiac and Pulmonary Function Late Effects after Bone Marrow Transplantation in Childhood: Prospective Study on Behalf of EBMT LEWP Group.
Authors: Uderzo Cornelio , Corti Paola , Fedeli Sara , Tana Francesco , Messina Chiara , Pillon Marta , Tridello Gloria , Galambrun Claire , Zintl Felix , Dini Giorgio , Faraci Maura , Fagioli Franca , Nysom Karsten , Verdeguer Amparo , Urban Christian , Tichelli André , Socié Gerard 
Published: April 2020

Abstract
BACKGROUND
Patients (pts) undergoing bone marrow transplantation (BMT) for hematological childhood disorders might present long-term cardiac and pulmonary function (CPF) complications. The current study assessed incidence and risk factors of CPF late sequelae by a multicenter study.
METHODS
From March 1994 to December 1997 we enrolled 220 consecutive children (130 males, median age at BMT 9,5 yrs) who underwent BMT (162 allogeneic and 58 autologous) for malignant (193) and non malignant (27) diseases in 9 EBMT centers. Total body irradiation (TBI) based conditioning regimen was used in 120/220 pts. A total of 165/220 pts were alive at the end of the study with a reliable CPF assessment which consisted of pulmonary function tests (PFTs) and M-Mode echocardiography performed at pre-BMT phase, at 1st year post-BMT and yearly. Statistical analysis to evaluate the difference between pre-BMT and post-BMT CPF was performed by paired t-test, while the assessment of risk factors was based on univariate and multivariate analysis.
RESULTS
Median follow-up of evaluable pts was 5 yrs (range 4–8 yrs). Fifty-five of 220 patients deceased, none for late CPF abnormalities. The 5-year cumulative incidence of lung and cardiac impairment was 35% (hazard rate=0,07) and 23% (hazard rate =0,04) respectively. Patients presenting abnormal PFTs and shortening fraction (SF) at last follow-up were 15% and 12% respectively, even if asymptomatic. Chronic GVHD was a major risk factor in reducing lung function at both univariate (P=0.02) and multivariate analysis (P=0,006). Patients undergoing TBI based conditioning regimen showed a SF impairment at multivariate analysis (P=0,03). Gender, age, diagnosis, pre-BMT anthracyclines, BMT type, non-TBI based conditioning, malignant or non malignant diseases at BMT were not significantly related to pulmonary and cardiac late effects. No difference was ascertained in the cumulative incidence of non relapse mortality in a competing risk setting which suggests that BMT can also be successful for those children who experienced both abnormal PFTs and SF. At the end of the study all surviving pts had a median Lansky index &gt;90.
CONCLUSIONS
Our study focused on low incidence of only asymptomatic CPF late effects in children transplanted for hematological disorders. TBI for cardiac function and C-GVHD for pulmonary function are the most important risk factors. Despite most of the alive pts remains in the normal range both for CPF complications from the beginning of BMT up to 5th year of median follow-up, a continue surveillance at least in adolescent age is recommended.
Prospective Study of Changes in Bone Mineral Density and Turnover in Children after Hematopoietic Cell Transplantation.
Authors: Petryk Anna , Bergemann Tracy L. , Polga Kristen M. , Ulrich Kami J. , Raatz Susan K. , Brown David M. , Robison Leslie L. , Baker Scott K. 
Published: April 2020

Abstract
Osteoporosis is common in adults after hematopoietic cell transplantation (HCT). The data on bone mineral density (BMD) in children after HCT are limited. The goals of this prospective study were to determine the incidence, timing, magnitude and possible predictors of bone loss in children following HCT. The study population included 49 patients (age 5–18 years) who were eligible to receive HCT at the University of Minnesota. The patients were evaluated at baseline, 100 days, 6 months, and 1 year after HCT. Lumbar BMD (BMDL) was assessed by dual-energy x-ray absorptiometry. The number of patients with osteopenia increased from 18% at baseline to 33% one year after HCT, and with osteoporosis from 16% to 19%. Mean areal BMDL z-score decreased from −0.56 to −1.1 by 6 months and at 1 year was −0.94, which was significant compared to standard normal distribution (p=0.004 and p=0.022, respectively). The absolute loss of bone mineral corresponded to 5.3% reduction in areal BMDL and 4.8% reduction in volumetric BMDL. The level of bone-specific alkaline phosphatase decreased by 30% by day 100 (p=0.009), followed by recovery toward baseline by 6 months. The level of osteocalcin &gt;6.5 ng/mL at day 100 predicted recovery from the initial bone loss by 1 year. A reduction in BMDL at 6 months correlated with a cumulative dose of glucocorticoids. In conclusion, this study demonstrates that bone loss is common in children after HCT and is primarily due to suppression of bone formation. Further studies are necessary to validate osteocalcin as a predictive biomarker.
Enhanced Anti-Myeloma Activity by Combination of Receptor Tyrosine Kinase (RTK) Inhibition, Proteasome Inhibition, and Dexamethasone: Therapeutic Implications for t(4;14) and t(14;16) Multiple Myeloma (MM) Subgroups.
Authors: Bisping Guido , Wenning Doris , Kropff Martin H. , Munzert Gerd , Hilberg Frank , Roth Gerald J. , Berdel Wolfgang E. , Kienast Joachim 
Published: April 2020

Abstract
Novel antineoplastic agents have opened perspectives to more selective treatment of multiple myeloma (MM). Targets include FGFR3 or c-maf and VEGFR1 expressed in MM subgroups carrying t(4;14)(p16.4;q32) or t(14;16)(q32;q23), respectively. The t(4;14) MM subgroup, overexpressing FGFR3, has been recently demonstrated to be sensitive to induction of apoptosis by receptor tyrosine kinase (RTK) inhibitors [Bisping, Blood102, 661, 2003; Podar, Blood103, 3474, 2004; Trudel, Blood105, 2941, 2005]. The present study aimed at investigating mechanisms of enhanced anti-myeloma effects of BIBF 1000, a highly selective RTK inhibitor, blocking VEGF and FGF dependent signaling, in combination with the proteasome inhibitor bortezomib and/or dexamethasone in cytogenetically defined MM subgroups. MM cells analyzed included a panel of five t(4;14) and six t(14;16) positive myeloma cell lines as well as fourteen CD138+ sorted primary MM cells with or without t(4;14) (3/11). We found a significant, dose-dependent inhibition of proliferation and induction of apoptosis in t(4;14)+ MM lines (4/5) as well as in primary t(4;14)+ CD138+ sorted marrow derived MM cells (3/3) by incubation with the RTK inhibitor BIBF 1000. Coincubation with the proteasome inhibitor bortezomib, or dexamethasone, or their combination revealed stepwise increased apoptosis in non RAS-mutated t(4;14)+ MM (4/4). Induction of apoptosis by BIBF 1000 in t(4;14)+ cells was associated with inhibition of the phosphorylation of mitogen-activated protein kinase (MAPK p44/42). In contrast, inhibition of MAPK-phosphorylation failed and induction of apoptosis did not appear in n-RAS-mutated t(4;14)+ NCI-H929 cells. In t(14;16)+ MM cells, variable proapoptotic effects of BIBF 1000 (in 5 of 6 lines tested) were significantly enhanced by dexamethasone and/or bortezomib. Interleukin-6 partially antagonized and the pan-caspase inhibitor z-VAD almost completely reverted induced apoptosis upon exposure to these combinations. In t(14;16)+ MM.1S cells, induction of apoptosis by BIBF 1000 was associated with inhibition of the phosphatidyl-inositol-3 kinase/AKT pathway. When combining BIBF 1000, bortezomib, and/or dexamethasone, we found a markedly higher proportion of cleaved caspase-3, caspase-8 and PARP in t(4;14) and t(14;16) MM, while caspase-9 was not activated. The data provide the rationale for clinical evaluation of a combination of this class of targeted tyrosine kinase inhibitors, proteasome inhibitors and dexamethasone in MM with focus on defined cytogenetic subgroups.
Treatment-Related MDS/AML after Autologous Stem Cell Transplantation for Chronic Lymphocytic Leukemia (CLL): An EBMT Survey.
Authors: Dreger Peter , van Biezen Anja , Brukx Kees , Boogaerts Marc , Michallet Mauricette , Milligan Donald , Niederwieser Dietger W. 
Published: April 2020

Abstract
Treatment-related myelodysplastic syndromes and acute myeloblastic leukemia (t-MDS/AML) have emerged as relevant complications of autologous stem cell transplantation (ASCT) for follicular lymphoma. Given the fact that also fludarabine-cyclophosphamide combination chemotherapy, which is increasingly used for primary treatment in CLL, has been implicated in induction of secondary stem cell disorders, t-MDS/AML might be a substantial problem after ASCT for CLL, too. Therefore the purpose of this study was to analyze the incidence and characteristics of t-MDS/AML among those patients who were autografted for CLL and registered in the EBMT database. For each case submitted between 1992 and 2004, centers received a questionaire asking for follow-up information with particular focus on t-MDS/AML.
Results: Of 1139 patients identified from the database, a reply was received for 457. After these 457 autotransplants, 18 cases of t-MDS/AML were observed, giving a crude rate of 3.9%. Median time from ASCT to t-MDS/AML was 28 (10–73) months. Patients with t-MDS/AML had received 2 (1–3) lines of conventional chemotherapy prior to ASCT, containing alkylating agents in 92% and fludarabine in 71% of the patients. Only a single patient had been pretreated with combined fludarabine-cyclophosphamide. High-dose regimens comprised total body irradiation in 71% of the t-MDS/AML cases; and mobilized peripheral blood was used as stem cell source in 92%, containing 2.9 (1.4–7.8) CD34+ cells/kg. Treatment of t-MDS/AML consisted of chemotherapy in 17%, ASCT in 6%, and allo-SCT in 17%, whereas the majority of the patients received supportive care only. Median survival from diagnosis of t-MDS/AML was 8 months with 2 of the 3 allografted patients being alive 10 and 13 months post diagnosis, respectively.
Conclusions: The incidence of t-MDS/AML after ASCT for CLL does not seem to exceed the range reported for follicular lymphoma. t-MDS/AML generally occurs within the first 6 years post transplant and has a very poor prognosis. A particular impact of fludarabine-cyclophosphamide pretreatment could not be detected.
Allogeneic Peripheral Blood Stem Cell Transplants (PBSCT) May Have a Benefit in Acute Lymphoblastic Leukemia (ALL) Outcome.
Authors: Vigorito Afonso C. , Aranha Francisco J.P. , Oliveira Gislaine B. , Eid Kátia A.B. , Statistic Roberto Zulli , Colturato Vergilio , De Souza Mair P. , Lodi Fernanda M. , Bittencourt Henrique , Castro Nelson , Barros José Carlos , Pontes Érica R. , Brandalise Silvia R. , Pereira R. DÁlmeida , Ribeiro A. A. F. , Novis Y. , Hamerschlak Nelson , Ferreira E. , Azevedo Alexandre M. , De Magalhães K. G. , Bouzas Luiz Fernando , Ruiz Milton A. , Maiolino Angelo , Nucci Marcio , Ruiz Jeferson , Pasquini Ricardo , De Souza Cármino A. 
Published: April 2020

Abstract
Hematopoietic stem cell transplantation is a valid alternative as post-remission therapy in ALL. Our aim was analyzed retrospectively the clinical outcomes of 97 ALL patients with HLA identical sibling donors who underwent an allo PBSCT. Median age was 24 ys (2–45), advanced disease was present in 74%, conditioning without irradiation was 56%; GVHD prophylaxis with MTX/CsA was 91%; CD34+ median was 4.6X106/kg (1.2–24); the median follow-up for surviving patients was 22 months (1.6–93). Median day for neutrophils and platelets engraftment was 15 and 13, respectively; no TBI conditioning, no MTX/CsA, were associated significantly with faster neutrophils engraftment; no MTX/CsA with platelets. Cumulative incidence (CI) for ≥ 2 aGVHD was 45%, extensive cGVHD 50%; aGVHD in patients who received TBI conditioning was 34% (P=0.04). The estimates of OS and DFS at 92 months was 21% and 31%, respectively; OS for patients &gt;36ys was 16% (P=0.04), for patients with aGVHD 11% (P=0.03); there was a trend towards better OS and DFS in patients with cGVHD (54%, 63%; P=0.07, P=0.06). CI for relapses was 60%; relapses for cGVHD patients were 36% (P= 0.05), and there was a trend towards higher relapses in advanced disease (66%, P=0.06). TRM was 64%; in those patients with aGVHD, 73% (P=0.008). In multivariate analyses no MTX/CsA was related with the speed of platelets engraftment (P=0.007); TBI conditioning was associated with less aGVHD and TRM (P=0.05, P=0.01); aGVHD had a negative impact on OS with higher TRM (P=0.02, P=0.02). Although not confirmed in the multivariate analyses, fewer relapses, and a trend towards better OS, and DFS were found in patients with extensive cGVHD. However, further follow up will be necessary to confirm these results.
Rituximab Added to an Intensified Salvage Chemotherapy Program Followed by Autologous Stem Cell Transplantation Improve in Relapsed and Refractory Aggressive Non-Hodgkin-Lymphoma.
Authors: Sieniawski Michal , Glossmann Jan-Peter , Reineke Thorsten , Diehl Volker , Engert Andreas , Josting Andreas 
Published: April 2020

Abstract
Background
We investigated the addition of rituximab to an intensified salvage program followed by a myeloablative course with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory aggressive NHL.
Methods
Patients with relapsed or progressive aggressive NHL were treated with two cycles of conventional salvage chemotherapy followed by high-dose sequential chemotherapy and a final myeloablative course with ASCT. Rituximab (375mg/m2) was administered at each treatment cycle. This cohort was compared with a historical control group of patients treated with the same chemotherapy but without rituximab. Patients from both treatment groups were matched according to age, duration of first remission, lactate dehydrogenase (LDH) serum level and B symptoms at relapse/progress.
Results
22 patients were treated with immunochemotherapy and 57 patients with chemotherapy. The overall response rates (ORR) at the final evaluation were 71% (65% CR and 6% PR) for the immunochemotherapy group compared to 65% (59% CR and 6% PR) for the chemotherapy group. In the historical controlled analysis freedom from second failure (FF2F) at two years in the immunochemotherapy group was 64% and overall survival 77%. Within the chemotherapy group FF2F was 25% (p=0,0185) and OS 44% (p=0,0159). In the matched-pair analysis FF2F was 64% in the immunochemotherapy group, compared to 47% in the chemotherapy group (p=0,7274). OS was 82% vs. 70% respectively (p=0,4854). The toxicity was tolerable and comparable in both groups.
Conclusions
The addition of rituximab to an intensified salvage chemotherapy regimen seems to improve the prognosis. However, only prospective randomized trial can offer sufficient data of the value of rituximab in relapsed and refractory aggressive NHL.