bluuebunny/crossref_metadata_2025 huggingface dataset:
Imatinib Is a Substrate for Various Multidrug Resistance Proteins
Authors: Czyzewski Krzysztof , Styczynski Jan
Published: April 2020

An increasing resistance to imatinib is an emerging problem in patients with chronic myeloid leukemia. The aim of the study was assessing possible mechanisms of cellular drug resistance in imatinib-resistant derivates of chronic myeloid leukemia K-562 cell line. A parental K-562 and its imatinib-resistant derivate cell lines were used. Cell lines were tested for cytotoxicity of imatinib, cytarabine, busulfan and etoposide. Multidrug resistance proteins expression, rhodamine retention and daunorubicin accumulation were measured for each cell line. Imatinib was cytotoxic to all tested groups of cells. Exposition of K-562 cell line to low concentrations of imatinib caused an increase of IC50 value of imatinib, while exposition of K-562 cell line to higher concentrations of imatinib decreased IC50 value of imatinib. There was a high correlation between PGP, MRP1 and LRP expression and IC50 for imatinib and etoposide. All tested cell lines were highly resistant to cytarabine. Rhodamine retention alone and in the presence of cyclosporine was the lowest in imatinib-resistant K-562R-0.1 cell line, what suggest high PGP activity in this cell line. Daunorubicin accumulation was the highest in parental K-562 cell line and it decreased in imatinib-resistant cell lines, which were characterized by high PGP, MRP1 and LRP expression. These data suggest that imatinib is a substrate for multidrug resistance proteins, and an increased expression of PGP, MRP1 and LRP play a role in resistance to imatinib in chronic myeloid leukemia.
Effect of Imatinib Mesylate on Platelet Aggregation Abnormalities in BCR-ABL + CML Patients
Authors: Mogalluru Upendra srinivas , Mahapatra Manoranjan , Pati Hara prasad , Saxena Renu
Published: April 2020

Bleeding and thrombotic events complicate the clinical course of chronic myeloproliferative disorders (CMPDs). A spectrum of platelet aggregation abnormalities have been described in CML. Clonal involvement of megakaryocytopoiesis is regarded as the main origin of these abnormalities. Effects of cytoreductive drugs on platelet aggregation abnormalities have been studied which showed no significant corrective effect. Effect of Imatinib mesylate on platelet aggregation abnormalities has not been studied so far. Our study aims at assessing the effect of imatinib mesylate on platelet aggregation abnormalities in BCR-ABL positive CML patients. A total of 50 newly diagnosed BCR-ABL positive CML patients and 30 normal healthy volunteers were enrolled in the study. BCR-ABL by RT-PCR and Platelet aggregation parameters by CHRONOLOG aggregometer using arachidonic acid (AA), collagen, adrenaline (ADR), adenosine diphosphate (ADP) and ristocetin as agonists were measured both at diagnosis and after a minimum of 3 months of imatinib therapy. Platelet aggregation parameters measured for each agonist were Degree of aggregation (DOA) and Rate of Aggregation (ROA). DOA was calculated by increase of transmissions for 1 minute/total maximum transmissions in 2 minutes measurement of platelet aggregation and expressed as percentage. ROA was calculated as the number of 1mm squares under the platelet aggregation curve in 60 seconds. These parameters were calculated for each agonist for all patients and controls and their mean ± 2SD were analyzed. Forty-eight cases were in chronic phase (CP), accelerated (AP) and blast phase (BP) constituted one each. DOA and ROA parameters in 39/48(81%) cases in CP and both AP and BP cases measured with ADP, AA, and ADP as agonists in the pre-imatinib phase showed a statistically significant lower values compared to healthy controls. 3/48 (6%)CP cases showed hyper aggregation with ADR and 6/48(13%) showed normal aggregation parameters. In the post-imatinib phase, aggregation parameters normalized in 32/39 CP cases. AP and BP cases showed persistently lower values. No significant difference is noted in parameters measured using ristocetin and collagen as agonists when compared among pre and post imatinib phases and controls. The normalization of aggregation parameters may be attributed to either partial or complete suppression of clonal abnormal megakaryocytopoiesis and restoration of normal megakaryocytopoiesis by imatinib mesylate therapy in BCR-ABL positive CML.
Dasatinib in the Treatment of CML Patients Aged > 60 Years Resistant/Intolerant to Imatinib
Authors: Latagliata Roberto , Breccia Massimo , Stagno Fabio , De Matteis Silvia , Annunziata Mario , Carmosino Ida , Cannella Laura , Napoleone Laura , Vozella Federico , Sica Simona , Di Raimondo Francesco , Ferrara Felicetto , Alimena Giuliana
Published: April 2020

Dasatinib is a 2nd generation tyrosine-kinase inhibitor active in CML patients resistant or intolerant to Imatinib; at present there is no data on its toxicity and efficacy in elderly patients. To highlight this issue, 37 patients treated with Dasatinib when aged > 60 years were retrospectively evaluated. There were 21 males and 16 females, median age at Dasatinb was 69.3 years (IR 64.9–73.0), Sokal Risk at diagnosis was low in 13 patients, intermediate in 14, high in 5 and not valuable in 5. Twenty-two patients (59.4%) were primary resistant, 4 (10.8%) intolerant and 11 (29.8%) secondary resistant to Imatinib; all but 2 patients were in CP when Dasatinib was started. Median time from diagnosis to Dasatinib treatment was 99.2 months (IR 56.8–124.5); 25/37 patients (67.5%) have been pretreated with IFN ± Ara-C before Imatinib, all patients received Imatinib at standard dose (400 mg/day) followed in 20/37 (54%) by Imatinib at increased dose (600–800 mg/day) with an overall median period of Imatinib treatment of 52.8 months (IR 26.2–60.9). In addition, 7/37 patients (18.9%) received other 2nd line treatment (3 with Nilotinib, 2 with Imatinib + HU and 2 with other drugs) before Dasatinib. Starting dose of Dasatinib was 140 mg/day in 18 patients and 100 mg/day in 19 patients, respectively. After a median period of treatment of 9.4 months (IR 3.0–19.1) all patients were evaluable for toxicity; among 18 patients receiving 140 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 14 (77.7%) and 6 (33.3%) patients, respectively; among 19 patients receiving 100 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 4 (21.0%) and 1 (5.2%) patients, respectively. Pleuro-pericardial effusions occurred in 3 patients, all treated with 140 mg as starting dose. Overall, 3/37 patients (all treated with 140 mg) discontinued permanently Dasatinib due to early toxicity; a dose reduction was needed in 17/37 patients [16/18 (88.8%) treated with 140 mg and 1/19 (5.2%) with 100 mg]. As to response, 28 patients were considered evaluable (≥ 6 months of treatment) and 9 considered as too early; five patients (17.9%) did not have any response (including 3 patients with early Dasatinib discontinuation for toxicity) and 23 (82.1%) achieved Complete Haematological Response (CHR). Furthermore, 11/28 patients (39.2%) achieved a Cytogenetic Response (CyR) (Major CyR in 4 and Complete CyR in 7) and 4/28 patients (14.2%) achieved a molecular response. In conclusion, Dasatinib, when employed at the current recommended starting dose of 100 mg/day; seems effective and very well tolerated also in heavily pretreated elderly subjects; these results are encouraging also for a future use of this drug in early chronic phase elderly patients.
Evidence for Increased Bone Marrow Lymphoplasmocytoid Cells and SDF1 Secretion in imatinib Treated CML. Relationship with Clinical/hemathological Response
Authors: Pierri Ivana , Catellani Silvia , Olcese Francesca , Grasso Raffaella , Colombo Nicoletta , Gobbi Marco , Poggi Alessandro , Zocchi Maria Raffaella
Published: April 2020

Tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec, Novartis, formerly known as STI571) are confirmed to be the first line treatment of Chronic Myelogenous Leukemia (CML) and of a rare form of gastroenteric stromal cancer. It has been reported that in the latter case, the response to the drug in vivo is mainly due to immunocompetent cells, able to produce cytokines with antineoplastic activity. In this study, peripheral blood and bone marrow of 20 CML patients were studied, prior and during treatment with imatinib, to assess morphologic, phenotypic, cytogenetic and biomolecular patterns. Plasma from BM and PB was also tested to evaluate (by ELISPOT and real time polymerase chain reaction) cytokines able to induce B lymphocytes differentiation, and/or proliferation, such as interleukin (IL)-4, IL-6 (ligand for CD126), IL-3, IL-10 or IL-21 together with chemokines MCP-1, SDF-1, IP-10 and IL-8. In 14 out of 20 CML patients a significant increase in the percentage of BM lymphoplasmocytoid cells was observed on imatinib treatment with >10% (range 8–12%) of CD20+CD126+cells. Among this population, two third of cells coexpressed IgM and one third was IgD+, moreover a lower fraction of IgM+CD126+CD20− (3–4%) or IgD+CD126+CD20− (2–3%) cells was found too. In all these patients SDF1 increased in the BM plasma after imatinib (from 10–80pg/ml to 150–450pg/ml) and its receptor CXCR4 was up-regulated on CD20+CD126+cells. In 4 patients the amount of IP-10 in BM plasma and the expression of its receptor CXCR3 were also increased. No significant modification in transcription and secretion of IL-3, IL-4, IL-6, IL-10, IL-21, IL-8 or MCP1 were observed. The lasting 6 patients had<5% of CD20 +CD126+ lymphocytes (range2–4%), 2/3 coexpressing IgM and 1/3 coexpressing IgD. Every patients with increased number of CD126+ B lymphocytes achieved hemathologic remission, 7 of them complete cytogenetic and biomolecular remission. On the other hand, among the patients with low or undetectable CD20+CD126+cells, 2 obtained only hemathological remission. In the 2 relapsed patients, BM CD20+CD126+ lymphocytes decreased from 11% and 8% to 7 and 5%, respectively, with undetectable IgM+ CD126+CD20− or IgD+ CD126+CD20− cells. The increased production of SDF-1, following imatinib administration, might increase BM lymphoplasmocitoid cells, thanks to the double proliferative/chemotactic effect of the cytokine on B cells, with redistribution and in situ differentiation of CD20+ CD126+ lymphocytes. These findings shed some light on the possibility that, even in CML, immunological events may play a role in disease control;moreover they could be useful in monitoring disease outcome.
Late Responders to Imatinib: Is Timing of Achievement of Complete Cytogenetic and Molecular Responses the Same in Previously Treated as Compared to the Newly Diagnosed CML Patients?
Authors: Scholl Vanesa , Bitencourt Roberta , Moellmann Arthur , Hassan Rocio , Rocha Moises , Dobbin Jane , Zalcberg Ilana
Published: April 2020

Appropriate monitoring of the effect of tyrosine kinase (TK) therapy is a relevant issue for CML therapeutic strategy. Although cytogenetics is the gold-standard method for response evaluation, serial quantification of BCR-ABL levels by real time PCR (RQ-PCR) has shown accuracy in predicting therapeutic response. Optimal cytogenetic (CCyR) and molecular (MMR) responses for newly diagnosed chronic phase (CP) CML patients were defined within 12 and 18 months of Imatinib (IM) therapy. However, patients not achieving optimal responses (OpRes) within these times are classified as “late responders”. We evaluated a group of 142 patients (4 year follow up) treated with IM as 2nd line. Patients were classified in 3 groups according to previous treatment: IFN (n=90), SCT (n=11) and HU/IFN ≤3 months (n=41, considered as without treatment). BCR–ABL levels were measured every 3 months, at least 5 times/patient during follow-up. A laboratory-specific conversion factor of 1.33 was generated to convert the BCR-ABL/ABL% values to an International Scale (IS). At the moment, 90 patients are being followed (69 CP, 11 AP). Cytogenetics results were available in 80/90 cases, and 63/80 (79%) (55 CP, 8 AP) achieved CCyR. After 12 months of IM treatment, 30/63 cases (48%) obtained CCyR (early responders), and 33/63 (52%) were late responders. When 18 months were considered as a cut-off time to achieved OpRes, 46 (73%) were considered early and 17 (27%) late responders. Molecular data were available for 74 patients; 45/74 (61%) (40 CP, 5 AP) achieved MMR, and 20 (27%) also showed Complete MR. 10/45 cases (22%) were early responders, and 35/45 (78%) late at 18 months of IM. When evaluating at 24 months, 17 (38%) were early and 28 (62%) were late responders. When only CP patients that achieved CCyR (n=55) and MMR (n=40) were considered, these proportions were maintained. Attainment of CCyR/MMR was similar between patients with and without previous treatment (p=0,26;p=0,09). However, we found a delay in the timing of OpRes achievement in comparison with previous related work analyzing patients in 1st line IM. Thus, to achieve similar frequencies of CCyR/MMR obtained from the use of 1st line IM, previously treated patients needed an extension time of 6 months. Thus we suggest for the patients treated with IM as 2nd line a threshold of 18 months for CCyR and 24 for MMR for the establishment of the OpRes. This swap concept might be important in countries such as Brazil that postponed the introduction of IM as 1st line therapy for CML.
Imatinib Plasma Levels Correlate with Molecular Response in CML Patients
Authors: Rozmanova Sarka , Friedecky David , Polynkova Adriana , Faber Edgar , Rohon Peter , Adam Tomas , Jarosova Marie , Indrak Karel
Published: April 2020

Measurement of imatinib plasma levels is recommended for CML patients on Glivec therapy with suboptimal response or failure. Recently, reports suggesting that imatinib plasma levels correlate both with cytogenetic and molecular response of the patient and may be used for routine management of the treatment were published. We have introduced the examination of imatinib plasma levels into our laboratory follow-up of CML patients in 2007. All patients have signed informed consent before sampling. New capillary electrophoretic method was developed for determination of imatinib plasma levels. Plasma samples were deproteinated by methanol, evaporated, resuspended and directly analyzed. Separation was performed in buffer consisting of 50 mmol/L citrate adjusted with γ-amino-n-butyric acid to pH 4.0. Imatinib was quantified by UV detection in the range 250 – 270 nm (limit of detection is 10 nmol/L). BCR-ABL transcript levels were monitored by TaqMan-based real-time quantitative PCR, the baseline value of BCR-ABL/ABL% was 60%. Here we report comparison of plasma drug levels in CML patients with optimal and suboptimal molecular response. Total 238 samples from 100 CML patients were examined. Patients with major and complete molecular response (n = 68) and patients with suboptimal molecular response (n = 35) were chosen for the final comparison. The actual sample was eligible for analysis providing patient had been treated with standard dose 400 mg daily for at least one year, there was no other evident cause of the suboptimal response (presence of additional cytogenetic abnormalities or BCR/ABL mutation) and the sample was taken 24±6 hours after the ingestion of the drug. Other medication, the actual duration of the therapy (providing it was longer than one year), time interval between the dose and the meal ingestion, weight, body-mass index, body surface area and co-morbidity of patients were not taken into the account. All patients in the suboptimal group have achieved the complete cytogenetic response. Three patients in the suboptimal group have progressed, while there were any such patients in the optimal group. The results showed considerable inter-individual variability between the patients. However, the imatinib plasma levels found in the optimal group significantly higher (median of 2.34 umol/l; range of 0.46 – 6.23) than in the suboptimal group (median of 1.75 umol/l; range of 0.84 – 4.63) p < 0.003. Moreover, patients with negativity in real-time quantitative PCR testing showed a trend for even higher drug plasma levels (median of 3.18 umol/l; range of 0.46 – 6.23, n = 36) p < 0.001. We can conclude that higher imatinib plasma levels are associated with better molecular response to therapy and laboratory measurements may be used for modification of the imatinib dosage.
DC-Based Vaccines Show in-Vitro Activity against Chronic Myeloid Leukemia Cells
Authors: Tan Yuen-Fen , Cheong Soon-Keng , Leong Chooi-Fun , Fadhilah SAW
Published: April 2020

Chronic Myeloid leukemia is a common myeloproliferative disease. Despite recent advances in targeted therapy, only 7–12% of patients achieve molecular remission. Leukemic cells arrange multiple mechanisms to avoid recognition by the immune system. Dendritic cells (DC) are professional antigen presenting cells of the immune system playing a crucial role in the induction of anti-tumor responses. The use of DC is an attractive immunotherapeutic strategy against cancers, especially in minimal residual disease state. In this study, DC vaccine against chronic myeloid leukemia was generated and evaluated in-vitro. Monocytes were isolated and enriched from peripheral blood. These monocytes were subsequently cultured in RPMI medium supplemented with GM-CSF and IL-4 to induce them to become DC. These DC were then co-cultured with tumor lysates obtained from CML cell line in culture medium supplemented with GM-CSF, IL-4 and TNF alpha to become DC-based CML vaccine. The generated DC-based CML vaccines retained their DC morphology, showed strong expression of CD 86 and HLA-DR, and were negative for CD14. Mixed lymphocyte reaction indicated that the generated DC-based CML vaccines were capable of inducing proliferative responses to allogeneic lymphocytes. DC-based CML vaccines were shown to stimulate T cells to express DC-ligands, ie CD28 and CD154, as well as HLA-DR, CD71 and CD 25. In addition, the stimulated T cells were cytotoxic to CML cells used to prepare tumor lysates.
Treatment of Chronic Myelogenous Leukemia in Iran
Authors: Keyhani Manoutchehr , Charoussae Ramezan , Toogheh Gholamreza
Published: April 2020

Treatment of chronic myelogenous leukaemia has been revolutionized during the past ten years all over the world. Even though Iran is oil producing nation. The government contribution to health is a low percentage of general income. According to Iranian law all drugs should be generics if generic is available. For this reason and imatinib production by India the only drug available to Iranian with chronic myelogenous leukaemia through insurance is Indian imatinib. The cost is one tenth of the original Gleevec brand and with general public Insurance all patient could afford the medicine. We have evaluated 3 years response to this generic drugs in Iran. In this cohort study from 1992 –2008 in the Imam Khomeini hospital, Shraiati hospital and Arad hospital the total of 303 patients were studied. 233 patients on imatinib treatment. The median age of Iranian Patient with CML were 40 years and it is 10 years less than other studies.. This disease is more common in the male than female in Iran. The primary response at presentation was 96.2% and 3.8% had no response. Finally the 3 years disease free survival had been 84.2%. In 1st year and 2nd year some patient progressed to blastic and accelerating phase while in the 3rd year very few developed accelerated phase. Kaplan-Meier 1-year disease free survival = 92.3% (SE=1.8) 2-year disease free survival = 88.0% (SE=2.3) 3-year disease free survival = 84.6% (SE=2.6)\

Conclusion: Generic Imatinib is as effective as original and very inexpensive. This kind of medicine should be available to every afflicted patient all over the world.
A Retrospective Study of Introferon-Alpha Treatment on Chinese Patients with Chronic Myeloid Leukemia
Authors: Yan Hua , Shen Zhi-Xiang
Published: April 2020

Introduction: Chronic Myeloid Leukemia (CML) is one of the myeloproliferative malignancies characterized by the reciprocal t(9;22)(q34;q11) chromosome, which causes the generation of Bcr-Abl fusion protein. Interferon-alpha (IFN-alpha) was introduced into clinical application from 1980s’ and showed its treatment benefit mainly in chronic phase CML (CML-CP) patients including achieving hematological remission, prolonging survival. Our retrospective study aimed to evaluate its clinical efficacy as well as toxicities in Chinese CML-CP patients.

Methods: This is a retrospective, multicentric clinical trial. Chinese CML patients in chronic phase received IFN-alpha treatment from 1992 to 2006 were enrolled. Other agents such as hydroxyurea or cytarabine treatment were permitted during treatment excepted for tyrosine protein kinase inhibitors.

Results: 1037 CML-CP patients were into analysis, the median age was 42 yrs (range 9–80) and male: female ratio of 1.6:1. The median time for interferon treatment was 12 months (range from 1 month to 136 months). 86.32% of patients received 300Mu of interferon, three times a week, 10.88% in 300Mu of daily injection, while another 2.8% in 500Mu of interferon treatment, three times a week. Main of additional treatment included hydroxyurea, which was used in 8.9% of patients, and cytarabine treatment in 3.3% of patients. We evaluate the best response reaction during IFN-alpha treatment, 496 out of 1037 patients obtained hematological remission (47.8%). 33 in complete cytogenetic remission (CCR, 3.2%) but unfortunately 60% of them were lost CCR after median of 6–11 months; 89 in partial cytogenetic remission (8.6%); 40 in major cytogenetic remission (3.9%); 301 in minor cytogenetic remission (29%); 78(7.5%) of CML-CP patients worsen into accelerate phase or blast crisis. Non-Hematological toxicities during IFN-alpha treatment mainly included flu-like symptom (24.9%) and fatigue (23.5%) which were transient and most of patients got recovery after second injection whereas 20% of them could not endurable. While hematological toxicities were neutropenia (22.1%, 33% of them were in grade III or IV), and thrombocytopemia (16.9%, 33% of them in grade III or IV).

Conclusion: The IFNalpha is one candidate agent for CML-CP patients in China with moderate toxicities during treatment, but it has little influence on achieving or maintaining complete cytogenetic remission.
Phase II Explorative Study of Intermittent Imatinib (IM) Treatment (INTERIM) in Elderly Patients with Ph+ Chronic Myeloid Leukemia (CML) Who Achieved a Stable Complete Cytogenetic Response (CCgR) with Standard IM Therapy
Authors: Russo Domenico , Malagola Michele , Colombi Chiara , Breccia Massimo , Fogli Miriam , Galieni Piero , Martinelli Giovanni , Mirto Salvatore , Vitolo Umberto , Abruzzese Elisabetta , Alimena Giuliana , Bocchia Monica , Carella Angelo Michele , Pane Fabrizio , Rosti Gianantonio , Saglio Giuseppe , Specchia Giorgina , Baccarani Michele
Published: April 2020

Standard therapy with Imatinib (i.e. daily administration) significantly prolongs the survival of Ph+ CML patients who obtain a complete cytogenetic response (CCgR). Elderly patients (i.e. > 65 yrs) have similar cytogenetic responses and survival, but they usually show a low compliance. This prospective multicenter trial addresses the issue of intermittent administration of Imatinib (INTERIM) in Ph+ CML patients older than 65 years with stable complete cytogenetic response (CCgR) after at least 2 years of standard therapy with IM. Lower doses of IM could be sufficient to maintain the CCgR, to improve the tolerance and to reduce the costs of therapy. For this purpose, IM will be given at the same dose that was given at the time of enrollment by the following intermittent schedule: 1 week on/1 week off for the 1st month (weeks 1–4); 2 weeks on/2 weeks off for the 2nd and 3rd month (weeks 5–12); 1 month on/1 month off from the 4th month thereafter (weeks 13 on). The primary objective of the study is to evaluate the proportion of patients who remain in CCgR with INTERIM. The cytogenetic response (CgR) status will be evaluated at baseline (by conventional cytogenetics on bone marrow and FISH on peripheral-blood) and every 3 months during the study (only by FISH on peripheral-blood). If FISH documents a variation of the baseline value of more than 1% in two consecutive examinations, evaluation of marrow cells metaphases will be performed to confirm the loss of CCgR and to check for additional cytogenetic abnormalities (ACA). In case of loss of CCgR INTERIM will be stopped and standard therapy (daily administration) will be resumed. Quantitative molecular assessment of BCR-ABL transcript by RQ-PCR on peripheral blood is due at baseline and every 3 months during the study and mutational analysis of ABL will be performed in case of loss of CCgR. After 12 months, the patients who are in continuous CCgR are advised to continue the intermittent study schedule and to be followed indefinitely. The study started in May 2008 and, at present, 18 patients have been enrolled. Preliminary data on the first six months will be presented.
Treatment of Chronic Myeloid Leukemia with Imatinib. A Single Centre Experience
Authors: Parente Anna , Sureda Anna , Aventin Anna , Brunet Salut , Martino Rodrigo , Briones Javier , Valcarcel David , Delgado Julio , Nomdedeu Josep , Sierra Jordi
Published: April 2020

With the introduction of imatinib (IM) as first-line therapy for chronic myeloid leukemia (CML) as well as in advanced phases of the disease, the long-term outcome of this hematologic malignancy has dramatically changed.. The aim of this study has been to analyse the experience of our centre with IM therapy in CML patients, focusing on the cytogenetic and molecular responses according to the phase of the disease in which IM was given, as well as the treatment failures and the results of the mutational analysis performed in these situations. Between January 2000 and March 2008, 77 patients with CML [47 men and 30 women, median age 49 years (range, 18–78)] were treated with IM. 33 of them received IM at a dose of 400 mg qd as first-line treatment in de novo chronic-phase (CP), 32 patients received it in late chronic-phase [time from diagnosis to IM, 51 (12–157) months]. Of these 32 patients in late CP, all of them received prior therapy with interferon-alpha, 10 patients received an autologous transplant and 3 of them an allogeneic transplant. Five patients were initially treated with IM 600mg qd because of an accelerate-phase (AP) and the remaining 6 patients were treated with IM 800mg qd because of a blastic-phase (BP).

De novo CP Late CP AP BC CHR(%) 32 (96) 28 (87) 4 (80) 3 (50) Time to CHR in months [median (range)] 1,8 (0,5–6) 1 (3–10) 2 (0,5-4) 3 (1–5) CCR(%) 30 (90) 22 (68) 3 (60) 1 (17) Tims to CCR in months [median (range)] 11 (6–63) 10 (6–36) 12 (7–18) — MMoIR(%) 20 (60) 15 (47) 1 (20) 1 (17) Time to MMoIR in months [median (range)] 18 (6–68) 22 (6–58) — — CMoIR(%) 0 0 0 0 Time to CMoIR in months [median (range)] — — — — Relapses (%) 5 (15) 9 (28) 4 (80) 5 (87) Mutational analysis (n, %) 4 (80) 6 (66) 3 (75) 3 (50)     Positive 2 (50) 2 (33) 1 (33) 0     Negative 2 (50) 4 (67) 2 (67) 3 (100) Second-line treatment     Dasatinib 1 3 0 1     Allo-SCT 1 2 0 1     Others — 3 3 — Follow-up from diagnosis 41 (11–90) 103 (34–215) 107 (37–185) 74 (13–158) Follow-up from beginning of IM 43 (11–97) 52 (6–87) 52 (13–83) 22 (1–88)     Alive 31(94) 22(69) 3(60) 2(33)     Death 2(6) 10(31) 2(40) 4(67)

The results of our centre confirm the ones presented in prospective analysis. There is a small percentage of patients that relapse or progress under IM therapy, and this percentage is significantly higher in patients treated in advanced phases. Mutational analysis is relevant in up 50% of the patients studied, allowing changes in therapy according to the obtained results.
Multivarite Analysis of Risk Factors for Affected Patients Long-Term Persistent Survival after Allogeneic Hematopoietic Cell Transplantation
Authors: Ding Jia-hua , Yu Zhengping , Chen Bao-an , Li Yu-feng , Ding Bang-he , Qian Jun , Cao Xiang-shan
Published: April 2020

Objective To analysis the risk factors for affected patients the long-term persistent survival in 96 patients undergoing Allogeneic Hematopoietic Stem Cell Transplantation, in order to take active prevention and cure measure, and improve trans- plantation curative effect preferably.

Methods We retrospectively analysis 96 cases of patients subject to allo-HSCT. The 11 clinical parameters were selected for univariat -e analysis using a Cox regression:age, sex, morbid state, HLA locus, donor type, donor -recipient blood type, conditioning regimen, aGVHD, HC, VOD, IP. Factors that were significant at the 0.1 level on univariate analysis were evaluated by multivariate an- alysis using a Cox regression. The cumulative incidence of aGVHD and patients survival rate were calculated by the method of Kaplan and Meier.

Results ninty-five patients achieved sustained donor engraftment except one patients not. The median time of leukocyte engraftment was 13 days. The incidence rates of grades I~IV acute GVHD was 43.75%. grades III~‡WaGVHD was 12.50%. Ten patients relapsed and 38 dead, the overall survival at 5 years was 60.42%. The COX method analysis showed that aGVHD and diease states at transplant were significantly risk factors to improved overall survivals(OS), with relative risk [RR] 2.996 and 2.619, respectively.

Conclusion aGVHD and diease states at transplant had significantly improved OS, the key to improvement the outcome 0f allo-HSCT is to reduce the incidence and severity of aGVHD, meanwhile selecting the suitable opportunity for transplantation. We had better do HSCT in CR1to treat that patients with advance refractory and recurrence.
Impact of Chronic Graft Versus Host Disease Over First Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Acute Leukemias and Chronic Myeloid Leukemia
Authors: de Sousa Eulalio Emmerson , Schulz Elizabeth , de Oliveira José Salvador Rodrigues
Published: April 2020

Hematopoietic stem cell transplantation (HSCT) has been a potential curative treatment for hematological malignancies. Graft versus host disease (GVHD) produces the graft versus leukemia (GVL) effect, an immunologic response capable to protect the HSCT recipient against cancer cells. Chronic GVHD (C-GVHD) is one relevant cause of mortality and remains a hazard in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to investigate the influence of the GVL effect associated with the C-GVHD over the disease free survival in patients with acute leukemias (AL) and chronic myeloid leukemia (CML). We studied a retrospective cohort of 192 patients with AL (n=77) and CML (n=115) aged 14–62 years (median 32) who underwent allo-HSCT with identical HLA donors in the Hospitals Sao Paulo and Santa Marcelina, in Sao Paulo, Brazil, from August 1993 to December 2004. We used in our study the criteria of C-GVHD of Seattle cited by Shulman et al (1995) revised by Lee (2003). The C-GVHD incidence was 78.4% (76/97) and 66.7% (36/54) in CML and AL, respectively. First relapse in CML occurred in 14.5% (11/76) of the cases with C-GVHD and in 61.9% (13/21) of the cases without C-GVHD. This fact shows the striking negative correlation and impact between the GVL effect and the incidence of first relapse post allo- HSCT in CML. The clinical severity of C-GVHD influenced significantly and inversely the chance of first relapse, once CML patients with extensive C-GVHD (2/45) had a lower relapse rate than limited disease (9/31) (4.4% versus 29%; p = 0,003). Subdividing CML patients in two groups, early (CML-Chronic Phase, CP) and advanced disease (CML-Accelerated Phase/Blastic Crisis, AP/BC), the first relapse rate was also correlated with the severity of C-GVHD. Relapse rates were 64.3% (9/14), 27.3% (6/22), and 5.6% (2/36) in CML-CP patients with absent, limited, and extensive C-GVHD (p = 0.0001), and 57.1% (4/7), 33.3% (6/9), and 0.0% (0/9) in CML-AP/BC, respectively (p = 0.037). Similarly, AL patients with C-GVHD showed a relapse rate of 27.8% (10/36) compared with 83.3% (15/18) when C-GVHD was absent (P = 0.0001). When we analyzed AL patients by stage of disease at transplantation (early AL patients: in first CR; advanced AL patients: after first relapse or refractory) with and without C-GVHD, patients with early AML (17/29) or early ALL (11/25) had a lower relapse rate than patients with more advanced AL (AML: 23.5% versus 66.7%; p = 0.02; ALL: 18.2% versus 78.6%; p = 0.003). Hence, the presence of C-GVHD in our cohort of AL and CML patients was an important determinant capable of modifying the outcome in these pathologies. The clinical severity of the C-GVHD was the most relevant factor to determine a lower relapse rate in CML patients, despite the stage of disease at time of transplantation.
Pre-Transplant Comorbidity as An Outcome Predictor in Hematopoietic Cell Transplantation for Severe Aplastic Anemia
Authors: Lim Sung-Nam , Lee Je-Hwan , Lee Jung-Hee , Kim Dae-Young , Kim Se-Hyung , Lee Young-Shin , Kang Young-A , Seol Miee , Kang Sol-Ip , Ryu Seong-Gil , Lee Kyoo-Hyung
Published: April 2020

A new hematopoietic cell transplantation specific comorbidity index (HCT-CI), which was modeled to effectively capture comorbidity and predict post-transplant outcomes, has been evaluated in a cohort of patients with a variety of hematologic disorders. In this study, we applied the HCT-CI to 77 patients with severe aplastic anemia who underwent HCT at the Asan Medical Center, Seoul, Korea between February 1995 and September 2007. Pre-transplant HCT-CI score was calculated in each patient using the clinico-pathologic data, which were retrieved from Asan Medical Center Bone Marrow Transplantation Registry Database. HCT-CI score was 0 in 54 patients (70%), 1 in 16 (21%), 2 in four (5%), and 4 in one (1%). The most prevalent comorbidity captured by the HCT-CI was infection (n=11) followed by arrhythmia (n=6). During a median follow-up period of 54.4 months (range, 4.0 to 159.0 months), 19 patients died and 16 experienced primary or secondary graft failure. The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 73.4% and 63.3%, respectively. OS and EFS were significantly different according to HCT-CI score; OS 86.6% and EFS 74.3% in patients with score 0 versus 43.5% and 38.5% in those with score 1 or more (P<0.001 for OS and P=0.001 for EFS). Other significant prognostic factors for OS were age (<30 years vs. ≥30, 90.8% vs. 58.3%, P=.002), pre-transplant transfusion amount (<50 units vs. ≥50, 93.0% vs. 61.0%; P=.005) and time from diagnosis to HCT (<120 days vs. ≥120, 85.2% vs. 61.4%; P=.013), and prognostic factors for EFS were age (<30 years vs. ≥30, 81.0% vs. 48.4%, P=.003) and time from diagnosis to HCT (<120 days vs. ≥120, 77.4% vs. 48.3%; P=.007). Multivariate analysis after adjustment for other variables demonstrated that HCT-CI score (HR 10.022, P<.001 for OS; HR 4.644, P<.001 for EFS), age (HR 8.447, P=.002 for OS; HR 4.060, P=.003 for EFS), time from diagnosis to HCT (HR 5.783, P=.002 for OS; HR 3.956, P=.002 for EFS) were independently significant prognostic factors for both OS and EFS. In conclusion, our data indicate that the presence of pre-transplant comorbidity assessed by HCT-CI may predict worse outcomes after HCT in severe aplastic anemia.
Cystatin C Level as a Marker of Renal Function in Hematopoietic Stem Cell Transplantation
Authors: Muto Hideharu , Ohashi Kazuteru , Ando Minoru , Hanajiri Ryo , Kikuchi Taku , Munakata Wataru , Sakurai Chihiro , Yamamoto Masahide , Kobayashi Takeshi , Yamashita Takuya , Akiyama Hideki , Sakamaki Hisashi
Published: April 2020

Hematopoietic stem cell transplantation (HSCT) recipients have an increased risk of acute kidney injury (AKI) or chronic kidney disease (CKD). However, serum creatinine level may underestimate the prevalence of these renal complications because of decreased lean body mass or concurrent liver disease, which was frequently observed in a HSCT setting. Cystatin C measurement may be more sensitive for detecting impaired kidney function. We retrospectively reviewed the medical records of 70 HSCT (54 allogeneic and 16 autologous) recipients who had at least one chance to monitor serum cystatin C level during last 2 years in our institution, and evaluated cystatin C as a possible new marker which can predict subsequent renal dysfunction. The occurrence of AKI was defined by the RIFLE classification and CKD staging was based on KDOQI criteria. Of 70 transplant recipients, 20 patients developed AKI after median 50.5 days (range 0–283 days) after HSCT, while worsening CKD stage was observed in 21 patients during observational periods. Cystatin C level was not influenced by pretransplant disease status (P=0.153) or autologous transplant (P=0.311), but significantly elevated after allogeneic transplantation (P<0.001). Multivariate analysis disclosed that the use of calcineurin inhibitor was a major cause of cystatin C elevation (Odds ratio 7.00, P=0.045). There was also a strong inverse correlation between cystatin C and estimated GFR (r=−0.684, P<0.001). Proportional hazard modeling analysis revealed that pretransplant cystatin C level (>0.90mg/l) and the episode of AKI after transplantation were a great risk for substantially worsening CKD stage (Hazard ratio 4.21 and 16.0, P=0.042 and P<0.001, respectively). Cystatin C measurement could be a useful clinical tool to identify HSCT recipient at increased risk for CKD.
Identification of Acute Lymphocytic Leukemia Extramedullary Relapse and PTLD after Allo-HSCT by FISH Monitoring Sex Chromosome Chimeric Status
Authors: Du Xuan , Liu Qifa , Zhang Leshi , Song Lanlin , Fan Zhiping , Xu Bing , Sun Jing
Published: April 2020

Objectives : To explore the role of fluorescence in situ hybridization (FISH) monitoring sex chromosome chimeric status in the identification of leukemic extramedullary relapse and post-transplant lymphoproliferative disease (PTLD) in acute lymphocytic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods: Six ALL patients who received sex-mismatched allo-HSCT manifested extravisceral lymphadenectasis or local lump were investigated. The sex chromosome chimeric status in tumor tissues and bone marrow (BM) were monitored by FISH, and EBV-RNA in the tumor tissues were detected by in situ hybridization (ISH).

Results: The sex chromosomes in BM of all 6 patients were 100% donor-derived. Among the sex chromosome chimeric status of tumor tissues, those of three patients were mainly recipient-derived, and the percentage of sex chromosomes derived from recipients were 100%, 100% and 98.0%, respectively, and then they were diagnosed leukemic extramedullary relapse. And those of the other 3 patients were donor-derived, the percentage was 98.5%, 96.0% and 91.5%, respectively, and diagnosed PTLD. EBV-RNA and latent membrane protein (LMP-1) were positive in 2 patients with PTLD and negative in the other 4 patients. One patient with extramedullary relapse obtained partial remission, one with PTLD gained complete remission, and the others died eventually after therapy.

Conclusion: Monitoring the sex chromosome chimeric status by FISH is an effective method to distinguish leukemic extramedullary relapse from PTLD in ALL received sex-mismatched donor HSCT.
Second Allogeneic Stem Cell Transplantation as Treatment for Chronic Myeloid Leukemia Relapse Following a First Reduced Intensity Conditioning Allograft
Authors: Benakli Malek , Hamladji Rose-Marie , Ahmednacer Redhouane , Talbi Amina , Mehdid Farih , Belhadj Rachida , Baazizi Mounira , Rahmoune Nadia , Harieche Farida , Zerhouni Fatiha
Published: April 2020

Background: Relapsed chronic myeloid leukemia (CML) is a possible complication after allogeneic stem cells transplantation (SCT). Treatment options for relapse include chemotherapy, Donor lymphocyte Infusion (DLI) and second SCT. In such treatments, second SCT is the only potentially curative therapy. We report the results of myeloablative transplantation as second SCT in 7 adults patients (pts) with CML relapsed after first reduced intensity conditioning (RIC) allo-SCT.

Patients and methods: Between April 2001 and December 2006, 154 CML pts treated with RIC allo-SCT from an HLA-identical family donor. First RIC-SCT following conditioning using Fludarabine 150 mg/m2 and oral Busulfan 8 mg/m2. GVHD prophylaxis consisted of association Ciclosporine and Mycophenolate (6 pts), one patient received an additional prophylaxis with ATG. Twenty four pts (16%) relapsed, of whom 7 underwent second conventional allograft. The median time between first and second SCT was 11 (range, 3–24) months. As second SCT, the median age was 34 (range, 23–46) years and gender: 3 male, 4 female. Six pts were in second chronic phase and one pt in accelerated phase. In all cases, myeloablative conditioning consisted of Busulfan (8 mg/kg), Etoposide (30 mg/kg) and Cyclophosphamid (120 mg/kg). Second SCT used with another HLA-identical sibling donor in 4 cases. All received G-CSF mobilized peripheral blood stem cells, with median CD34+: 5,85 106/kg (range,3,28–9,34). GVHD prophylaxis was consisted of Ciclosporine-Methotrexate.

Results: All pts had myeloid reconstitution and the median time to achieve 0,5 109/l neutrophils count was 25 (range,15–57) days. One pt needed a boost 40 days after allograft. The median time of aplasia was 20 (range,10–52) days. No acute GVHD noticed. Four pts had chronic GVHD, of whom 3 with extensive form. Although 3 pts died of relapse on 2, 3 and 20 months. Four pts are alive and free of disease on 24, 48, 55 and 55 months respectively after second SCT with complete chimerism of donor origin and negative minimal residual disease, of whom 3 had second allo-SCT with another family donor.

Conclusion: This study suggests that second SCT for CML relapse after RIC-SCT can result in long-term survival for some of pts without lethal treatment related toxicity. Another HLA-identical sibling donor is favourite in this case. Further follow-up and more pts are necessary to validate this series.
Risk Factors Associated with VOD with RIC and MAC Hematopoietic Stem Cell Transplant and the Early Estimation of VOD
Authors: Nagakura Shoichi , Kiyokawa Tetsuyuki , Hidaka Michihiro , Yano Takahiro , Sunami Kazutaka , Okamura Seiichi , Uike Naokuni , Hamaguchi Motohiro , Matsui Takahiro , Horibe Keizo , Sato Kensaku , Kawakita Toshiro , Kawano Fumio
Published: April 2020

BACKGROUND: Despite recent increase of reduced intensity conditioning (RIC) transplantation, mortality rates after RIC and myeloabrative conditioning (MAC) HSCT remain high and hepatic veno-occlusive disease (VOD) cannot accurately predicted.

OBJECTIVE: To determine the value of risk factors associated with the development of VOD after allergenic HSCT with RIC and MAC. Estimating VOD based on clinical factors may further improve results of allogenic HSCT.

PATIENTS AND METHODS: A retrospective review of 415 consecutive allogenic HSCT was performed with attention to VOD, pre-transplant factors and laboratory data in five hematopoietic cell transplantation centers between 2000 and 2005. Patients underwent transplantation with MAC (n=247) or RIC (n=168). Main outcomes and risk factors were analyzed in multivariable analyses (a logistic regression model) with RIC and MAC. Three kind of laboratory data set, pre-transplant (day −10), post-transplant (day 20) and differences from pre-transplant to post-transplantation were analyzed.

RESULTS: VOD occurred in 65 of 415(15.7%) transplant recipients; 40 of 247(16.1%) with MAC and 25 of 168(14.9%) with RIC. Multivariate analyses identified risk factors with the development of VOD with MAC (albumin level, creatinine level) and with RIC (HCT-CI, number of prior chemotherapy regimen, ALT) in pre-transplant laboratory data set. The risk factors of VOD were identified in post-transplant and differences (Table). The Akaike’s information criterion (AIC) of risk factors with differences was better than with the post-transplant.

CONCLUSION: Our results provided risk factors of VOD with MAC and RIC. The estimation of VOD before transplantation may be useful for the selection of conditioning regimens. Differences of laboratory data with the time course of transplant may be useful for the early diagnosis of VOD.

MAC Pre-transpant data Post-transplant data Differences data OR P-Value OR P-Value OR P-Value Age - - 0.945 0.0090 - - Alb 0.290 0.0125 - - - - Cr 10.204 0.0307 1.786 0.0039 1.984 0.0139 TPro - - 0 358 0.0019 - - TBi I - - 1.385 0.0027 1.314 0.0037 Ara-C - - 5.000 0.0139 goodness of fit AIC 106.727 126.499 86.931 RIC Pre-transpant data Post-transplant data Differences data OR P-Value OR P-Value OR P-Value Sex - - 3.401 0.0446 - - HCTCI 3.922 0.0050 2.000 0.0123 - - ImpScore 2.000 0.0314 - - - - TPro - - 0.366 0.0091 - - TBi I - - 1.675 0.0042 2.273 0.0004 ALT 0.969 0.0432 - - - - CY - - - - 5.682 0.0447 goodness of fit AIC 61.552 91.09 52.808
EPOCH-F: A Novel Salvage Regimen for Multiple Myeloma Prior to Reduced-Intensity Allogeneic Stem Cell Transplantation
Authors: Jamshed Saad , Fowler Daniel , Neelapu Sattva , Dean Robert M. , Steinberg Seth M , Odom Jeanne , Snow Kelly , Gress Ronald E , Bishop Michael R
Published: April 2020

Variation in baseline host immune status contributes to inconsistent donor engraftment and may impede maximal graft-versus-myeloma effects after reduced-intensity allogeneic stem cell transplantation (RI-alloSCT) for advanced multiple myeloma. We performed a phase II study to determine the efficacy of a novel salvage regimen, EPOCH-F, which was designed to provide immune depletion and disease control prior to RI-alloSCT, in 22 patients with advanced multiple myeloma. EPOCH is an infusional chemotherapeutic regimen consisting of etoposide, vincristine and adriamycin, with prednisone, cyclophosphamide and fludarabine and given in 21 day cycles prior to RI-alloSCT. Patients received at least 1 and no more than 5 cycles of EPOCH-F gudied by peripheral blood CD4+ T cell count. Pts achieving adequate lymphodepletion proceeded to RI-alloSCT; otherwise patients proceeded to RI-alloSCT after 5 cycles or if there was disease progression during EPOCH-F, regardless of CD4 count. Median age was 53 years (range, 36–65); median time from initial therapy to transplant was 12 months (range, 2–168). Median number of prior therapies was 2 (range, 1–8), while 63% had chemotherapy sensitive disease. 68% of patients had received a novel agent. Patients received a median of 3 cycles (range, 1–5) of EPOCH-F. Therapy was well tolerated with manageable toxicities, mostly hematologic. Neutropenia (grade IV) was the most common toxicity seen in 77% of the administered cycles with only 6 episodes of neutropenic fever. Median lymphocyte count decreased from 1423/μL (range, 335–2788) to 519/μL (range, 102–1420); CD4 count decreased from 320/μL (range, 130–1366) to 115/μL (range, 30–309). In 21 evaluable patients, the overall response rate to EPOCH-F was 22% and 68% had stable disease. 13% of patients achieved CR/nCR. Only 1 patient progressed while on therapy. 20 patients received allograft from HLA matched sibling donors and were evaluable for engraftment. Median Day 100 chimerism was 100% (range 60–100, mean 95). 70% of patients achieved ≥VGPR including CR/nCR, while CR/nCR was seen in 40% of the patients. Median overall survival was 46.1 months. 10 (50%) patients are currently alive. Acute GVHD (grade II–IV) was seen in 47% and chronic GVHD (grade III–IV) was seen in 52% of patients. Treatment-related mortality at 100 days was 5% and 30% at 60 months. EPOCH-F is an active regimen which facilitates consistent and rapid full donor engraftment following RI-alloHSCT from related donors in patients with advanced multiple myeloma.