bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromosomal Abnormalities in Philadelphia Chromosome (Ph)-Negative Metaphases Appearing during Imatinib Mesylate (IM) Therapy in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase.
Authors: Jabbour Elias , Kantarjian Hagop , O’Brien Susan , Verstovsek Srdan , Garcia-Manero Guillermo , Rios Mary Beth , Cortes Jorge 
Published: April 2020

Abstract
The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized mostly in pts who failed prior therapy. Prior exposure to cytarabine has been suggested to be a predisposing factor. This phenomenon has not been yet assessed to date in patients with newly diagnosed CML and treated with IM. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. We assessed the frequency and the significance of this event among 258 newly diagnosed pts with CML receiving IM (800 mg/d n=207, 400 mg/d n=51) as first line of therapy between March 2001 and April 2005. After a median follow-up of 30 months (range, 6–48 months), 19 pts (7%) developed 21 chromosomal abnormalities in Ph-negative metaphases. Thirteen (62%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of IM to appearance of abnormalities was 18 months (range, 3–36 months). The most common cytogenetic abnormalities were: loss of chromosome Y (n=7, 33%), trisomy 8 (n=3, 14%), and deletion of chromosome 7 (n=2, 10%). Excluding loss of chromosome Y abnormalities, the incidence was 5%. All pts achieved a major (Ph &lt; 35%) cytogenetic (CG) response (complete cytogenetic response [CCGR] in 17 [89%] pts). Major molecular response (BCR-ABL/ABL ratio &lt;0.05) was observed in 13 (68%) pts (including 2 with complete molecular response). In all but 4 pts these events have been transient and disappeared after a median of 4 months (range, 3–9 months). In 4 pts (loss of chromosome Y n=3, trisomy 8 n=1), they persisted for a median of 13+ months (range, 6+–24+ months). One pt developed acute myeloid leukemia (associated with -7); none of the other pts has any feature of myelodysplasia. After a median follow-up of 13 months (range, 1–42 months), 17 of the 19 pts are alive. One pt died after allogeneic stem cell transplantation, and one died after 6 months of CCGR from myocardial infarction. One pt lost response to IM. The remaining 16 pts are in major CG response at the last follow-up. We conclude that: 1) cytogenetic abnormalities occur in Ph-negative cells in a small fraction of patients (7%; 5% if loss of Y excluded) in newly diagnosed CML on IM; 2) in the majority of cases, they are transient with no clear clinical consequences; 3) in rare instances (loss of chromosome 7 only in our study) they could reflect the emergence of a new malignant clone necessitating and a close follow-up.
Feasibility of Administering Oblimersen (G3139; Genasense) with Imatinib Mesylate in Patients with Imatinib Resistant Chronic Myeloid Leukemia (CML) - Cancer and Leukemia Group B Study 10107.
Authors: Wetzler Meir , Yu Daohai , Odenike Olatoyosi , Feldman Eric J. , Hurd David D. , Hoke Eva , Hars Vera , Larson Richard A. 
Published: April 2020

Abstract
The CALGB studied the feasibility and effect of oblimersen (G3139; Genasense) with imatinib mesylate in patients with primary imatinib resistant CML. We hypothesized that CML cells that are resistant to imatinib mesylate (i.e., less than a complete hematologic remission after 8 weeks of treatment or less than a major cytogenetic remission after 6 months of treatment) are no longer being driven to proliferate by Bcr/Abl tyrosine kinase activity alone. Instead, the anti-apoptotic protein Bcl-2 would regulate one of the pathways controlling growth and/or viability. Thus, blocking both Bcr/Abl and Bcl-2 simultaneously with imatinib mesylate and G3139, respectively, would result in hematologic and cytogenetic improvement. Preclinical data suggested synergy. G3139 was administered via continuous intravenous infusion with an ambulatory pump over 10 days every 21 days, along with daily oral imatinib. Doses of both drugs were escalated in 3 cohorts; the initial dose of imatinib was 600 mg/day. The median age of the 21 enrolled patients (13 females and 8 males) who received any therapy was 54 years (range, 25–74), with 13 Caucasians and 8 African Americans. Twelve patients had primary imatinib resistance and 8 had secondary imatinib resistance (data are not yet available on 1 patient). Five patients had never achieved complete hematologic remission while only two patients had achieved major cytogenetic remission while on a prior imatinib therapy. Nine patients received 4 mg/kg/day G3139 and 600 mg of imatinib, 7 patients received 7 mg/kg/day G3139 and 600 mg of imatinib, and 5 patients received 7 mg/kg/day G3139 and 800 mg of imatinib. Progressive CML after the first (4 patients), second (1 patient), third (2 patients) or fourth course (1 patient) was noted in 8 patients whose imatinib dose had been reduced from 800 mg to 600 mg/day to comply with study entry requirements. Nine patients completed all 4 planned courses. Grade IV thrombocytopenia and fatigue (both at 7 mg/kg G3139 and 600 mg of imatinib) and deep vein thrombosis (at 7 mg/kg G3139 and 800 mg of imatinib) were noted in one patient each. One patient with primary imatinib resistance achieved complete hematologic remission following 2 courses of therapy at 4 mg/kg G3139 and 600 mg of imatinib. No patients had cytogenetic responses. Although the combination of G3139 and imatinib is safe and feasible, we did not detect clinical benefit in these patients with imatinib-resistant CML using these doses and schedule.
Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukaemia in Complete Molecular Remission for More Than Two Years.
Authors: Rousselot Philippe , Huguet Françoise , Cayuela Jean Michel , Maarek Odile , Marit Gérald , Gluckman Eliane , Reiffers Josy , Mahon François X. 
Published: April 2020

Abstract
Background. Imatinib mesylate (IM, Gleevec®) induces cytogenetic remission (CCR) defined as the disappearance of Philadelphia (Ph) chromosome-positive metaphases in more than 85% of patients with chronic myelogenous leukaemia (CML). However, less than 10% achieve a complete molecular response which may be defined by a minimum residual disease undetectable using polymerase chain reaction (PCR). Virtually all patients in CCR will relapse after IM interruption because of detectable residual disease. In the present study, we have discontinuated IM in patients with undetectable residual disease for more than 2 years.
Patients and method. We prospectively collected the results from 8 CML patients (median age 62 years; 41 years to 82 years) treated with IM (400 mg/day). Residual disease was quantified by RTQ-PCR and expressed as the BCR-ABL/BCR ratio. PCR negativity was controlled independently by two molecular laboratories every 4 months and patients were included in the study if they have been PCR negative during at least 2 years under IM therapy. After IM discontinuation, RTQ-PCR was monitored every month.
Results. According to Sokal’s classification, 4 patients were considered low risk, 3 intermediate risk and one high risk. All patients except one received interferon (treatment duration 3 to 72 months). One of them received an autologous stem cell transplantation for interferon failure. Median duration of IM therapy was 37 months (34 months to 40 months) and median time from CML diagnosis to IM discontinuation was 104 months (43 months to 152 months). RTQ-PCR negativity was observed during 30 months in median (24 months to 46 months) as required for the inclusion in the study. Four patients presented a molecular relapse with a detectable BCR-ABL transcript rising from 0,001% to 0,01% confirmed at least two times after 2 months (2 patients), 3 months and 4 months of IM discontinuation without detectable BCR-ABL kinase domain mutation. IM was then restarted and lead to a novel molecular remission in 2 patients and to a major molecular response in the 2 others. Four other patients are still negative with a follow up of 8, 9, 12 and 13 months after IM discontinuation. Of note, all these patients received interferon before IM therapy and one patient still have detectable serum antinuclear antibodies.
Conclusion. As we have previously reported with interferon, it is possible to stop IM in patients with CML who achieve a molecular remission as we have strictly defined. Early molecular relapses are sensitive to IM re-challenge. Interestingly, we did not observed late relapses at this point. As our patients in persistent molecular remission were previously exposed to interferon, it is possible that IM therapy combined with immune response modifiers could be responsible for a putative cure of the disease.
Phase I Study of Flavopiridol in Combination with Imatinib Mesylate (STI571, Gleevec) in Bcr/Abl+ Hematological Malignancies.
Authors: Grant Steven , Karp Judith E. , Koc Omer N. , Cooper Brenda , Luger Selina , Figg William D. , Egorin Merrill , Druker Brian J. , Jacobberger James W. , Ramakrishnan Viswanathan , Perkins Edward B. , Colevas A. Dimitrios , Roberts John D. 
Published: April 2020

Abstract
Imatinib (Im), a rationally designed inhibitor of the Bcr/Abl kinase as well as other kinases, represents the standard treatment for Bcr/Abl+ malignancies. Im as a single agent, however, is not curative. Flavopiridol (Fl), an investigational cyclin dependent kinase inhibitor, is broadly active in vitro against human leukemia cells (Blood91:2482,1998). Previously we have shown that simultaneous disruption of a survival signaling pathway and a cell cycle regulatory pathway results in a pronounced increase in leukemic cell death (Cancer Res.61:5106,2001) and in more recent preclinical studies demonstrated synergistic interactions between Im and Fl in Bcr/Abl+ leukemia cells, including some that were resistant to Im (Clin Cancer Res8;2976,2002). Based on these considerations, we have initiated a phase I trial to identify appropriate doses of Im+Fl for further investigation. Eligible patients (pts) have CML with a suboptimal response to prior Im, CML in blast crisis, or Bcr/Abl+ acute lymphocytic leukemia (ALL). CML-BC and ALL patients may be Im-naïve. Pts receive Im by continuous daily oral dosing and Fl by 1 hour intravenous infusion weekly x 3 repeated every 4 weeks. Targeted dose levels are (Fl/Im; mg/m2): 30/400, 30/600, 45/600, 60/600, 60/800, 60/1000. Patients are divided into 2 strata based upon blast percentage in peripheral blood or bone marrow: stratum 1, &lt;15%; and stratum 2, ≥15%. For stratum 1 dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelet for &gt; 1 week or grade ≥ 3 non-heme toxicity; for stratum 2, DLT is profound marrow hypoplasia in the absence of persistent leukemia. In stratum 1, 16 pts have been treated at 4 dose levels; in stratum 2, 5 pts in the 1st and 3rd dose level. In stratum 1, 1 DLT has occurred at dose level 4 (cholecystitis requiring cholecystectomy); in stratum 2, 1 DLT has occurred at dose level 3 (sepsis/multi-organ failure which was not clearly related to treatment). The only frequent toxicities have been hematological. 4 pts have experienced objective responses including complete hematological remissions in 2 pts in stratum 1 treated with Im/Fl 30/600 who had been previously treated with Im 800 and complete hematological remissions in 2 pts in stratum 2 (who had not received prior Im). Preliminary studies indicate no Fl impact upon Im pharmacokinetics, and variable post-treatment effects on signaling pathways in CML cells. These findings indicate that a regimen consisting of Fl and Im is tolerable and active in at least some patients with Bcr/Abl+ hematologic malignancies, including some with Im-resistant disease. Pending identification of the MTD and the recommended Phase II dose (RPTD), Phase II trials will be necessary to assess the activity of this strategy more definitively.
Triphasic Exponential Decline of BCR-ABL Transcripts during Imatinib Therapy for Chronic Myelogenous Leukemia.
Authors: Miyamura Koichi , Ohnishi Kazunori , Naoe Tomoki , Takeuchi Hitoshi , Yoshiki Nishimura , Yagasaki Fumiharu , Fujisawa Shin , Kimura Yukihiko , Motoji Toshiko , Imai Kiyotoshi , Yamane Takahisa , Yoshida Shinichiro , Miyawaki Shuichi , Saburi Yoshio , Kitamura Kunio , Ohno Ryuzo 
Published: April 2020

Abstract
In Japan Adult Leukemia Study Group (JALSG) clinical trial, imatinib was used as initial therapy for 171 patients with chronic myelogenous leukemia. We measured levels of BCR-ABL transcripts in the blood of all patients in this trial before and 1, 2, 3, 6 and 12 months after the treatment. Levels of BCR-ABL transcripts were measured by a quantitative real-time polymerase-chain-reaction assay. Results were expressed copy number of BCR-ABL per 1 microgram of RNA. Median number of BCR-ABL transcript was 106,478 at diagnosis and 61328, 24213, 4981, 331 and 98 at 0, 1, 2, 3, 6, 12 months after the treatment, respectively. Three log reductions were obtained 0%, 35.5% and 50.9% of patients at 3, 6 and 12 months of the treatment. Half reduction time between 0 and 1 month (0M–1M) is 1.3 M. In the next month (1M–2M), it is 0.75M and those between 2–3 and 3–4.5 months are 0.44 and 0.51. Thereafter, reduction speed is down because half reduction time is 1.5 between 4.5 and 6 months. After 6 months half time is 4.1months. This reduction curve shows the. Exponential decline value per day are 1.8%, 3.1% and 5.2% during first, second and third month, respectively. Thereafter exponential decline value is decreasing as 4.4% (3M–4.5M), 1.5% (4.5M–6M) and 0.6% (6–12M). In the previous study reported that, successful therapy leads to a biphasic exponential decline of leukemic cells (Nature435:1267–1270, 2005). The first slope is determined by calculating the exponential decline between 0 and 3 months; mean value of 0.05 per day was observed. While the second slope showed 0.008 per day. Our observation suggests that imatinib leads to a triphasic exponential decline of leukemic cells; between 0 and 2 months, much slower declining curve in comparison with between 2–6 months.
Higher Rate of Thrombotic Thrombocytopenic Pupura (TTP) Associated with Graft Versus Host Disease (GVHD) and Unrelated Donor Bone Marrow Transplantation (BMT).
Authors: Oran B. , Aleman A. , Shpall E. J. , Hosing C. , Korbling M. , Anderlini P. , Champlin R. , Donato M. 
Published: April 2020

Abstract
TTP is one of the complications of allogeneic hematopoietic stem cell transplantation (HSCT). In contrast to idiopathic cases, post-transplantation TTP may not be associated with severe von Willebrand factor-cleaving protease deficiency but rather a diffuse endothelial injury. Our aim was to define incidence, risk factors and mortality of TTP following allogeneic HSCT. 1312 patients with lymphoid malignancies (n=605), myeloid malignancies (n=688) or aplastic anemia (AA, n=18) who were treated with ablative preparative regimens (n=614) or reduced intensity regimens (n=697) followed by HSCT from an HLA matched related (MRD, n=694) or unrelated donor (MUD; n=461) and 1–3 antigen mismatched related (MMR, n=99) or unrelated donor (MMUD, n=57) between December 1997 and December 2004 were studied. Patients with prior allogeneic HSCT or graft failure were excluded. GVHD prophylaxis was tacrolimus-based in 1276 (97.3%) and cyclosporine based in 15 (1.1%) patients. Twenty patients did not receive GVHD prophylaxis per protocol. Anti-thymocyte-globulin (ATG) was added in 350 patients. Stem cell sources were bone marrow (n=626), peripheral blood (n=635) or cord blood (n=50).
The following variables were evaluated: age, gender, primary diagnosis, disease status before HSCT, intensity of preparative regimen, stem cell source and acute GVHD(aGVHD) grade ≥2 (time dependent variable).
Of the 1312 patients with a median follow-up from transplantation of 11.4 months (range, 5 days-7.2 years), 77 developed TTP (6%). The actuarial risk of developing TTP was 6.5% at 1 year. The median time of the onset of TTP was 67 days post HSCT (range, 11–1812) with 27 cases (35%) presenting after day 100. Female gender, lymphoid malignancies, unrelated or antigen mismatched related donor and aGVHD grade ≥2 were found to be independent risk factors. (Table1). Among the patients who had aGVHD grade≥2, the median time of interval between the onsets of two events was 25 days (range, 2–335 days). All patients were treated with therapeutic plasma exchange (PE). Of the 77 patients only 1 died of TTP (intracranial hemorrhage). The overall one-year survival after TTP was 29% and the most common cause of death were acute or chronic GVHD (n=35, 55%) and primary disease progression (n=10, 16%).
Stem cell donors other than MRD, lymphoid malignancies and aGVHD≥2 have been established as risk factors associated with development of TTP and therapeutic PE has been shown to decrease TTP related mortality.
Risk factors for TTP after allogeneic HSCT Variables sample size events HR 95% CI p Male 793 33 1.0 Female 518 44 2.2 1.3–3.6 0.002 Myleoid malignancy 688 33 1.0 Lymphoid malignancy 605 42 1.9 1.1–3.3 0.03 AA 18 2 1.3 0.2–8.0 0.75 MRD 694 28 1.0 MUD 461 40 2.9 1.6–5.1 &lt;0.001 MMR 99 7 2.4 0.9–6.0 0.06 MMUD 57 2 1.7 0.4–7.6 0.5 aGVHD ≥2 370 39 3.3 2.0–5.5 &lt;0.001
Frequent Genomic Alterations in Epithelium Measured by Microsatellite Instability Following Allogeneic Hematopoietic Cell Transplantation in Humans.
Authors: Spyridonidis Alexandros , Faber Philipp , Fisch Paul , Waterhouse Miguel , Schmitt-Graeff Annette , Bertz Hartmut , Finke Juergen 
Published: April 2020

Abstract
While typically found in cancers, frameshift mutations in microsatellites have also been detected in chronically inflamed tissues. Allogeneic hematopoietic cell transplantation (HCT) may potentially produce chronic tissue stress through graft-versus-host reactions. Therefore, we examined non-neoplastic epithelial tissues (colon, buccal) obtained 1 to 5061 days after human allogeneic HCT for the presence of genomic alterations at three tetranucleotide (SEE33, THO-1, D14S120) and three mononucleotide (ZP3, BAT26, SRY) microsatellite loci. All except two colon biopsies examined had histological signs of GvHD. No signs of mucositis or oral GvHD were present at the time of buccal sampling. Novel bands indicative of microsatellite instability (MSI) were detected in laser-capture microdissected (LCM) colonic crypts in 12 out of 16 patients (75%) and in buccal smears in 10 out of 24 (42%) allografted patients. In contrast to the allografted patients, no MSI was found in the LCM crypts obtained from 4 patients after intensive chemotherapy or from 7 control subjects with no history of either colon malignancy or chemotherapy, and in the buccal smears obtained from 8 patients after autologous HCT or from 9 healthy controls. MSI was found only at tetranucleotide markers but not at mononucleotides. There was no statistical correlation between the presence of MSI in colon and the underlying disease, the previous history of multiple (&gt;=3) intensive chemotherapies before transplantation, the type of preparative regimen for HCT, the overall GVHD grade any time before sampling or the GvHD stage in colon at sampling. The MSI found in colon, which was often affected by graft-versus-host disease, was not due to loss of expression or nitrosylation of DNA repair proteins (MLH1, MSH2, MSH3, APE-1, XPA). There was no significant association between MSI in the buccal mucosa and patient age, gender, disease, type of conditioning, history of oral GvHD or overall GvHD occured at any point before buccal sampling. Interestingly, we found a significant association between the time of buccal sampling after transplantation and the presence of MSI (p=0.008). MSI was also found in three post-transplant squamous cell cancers examined. The frameshift alterations found in post-transplant tumors often differed from those in the associated non-malignant tissues. Our data show that genomic alterations in epithelium regularly occur after allogeneic HCT. This previously unacknowledged genomic instability after allogeneic HCT may be implicated in the evolution of post-transplant diseases, including secondary cancer.
Autografting Followed Closely by Nonmyeloablative Allografting as Consolidation Immunotherapy Reduces Disease Progression Compared to Tandem Autografting in Multiple Myeloma.
Authors: Carella A.M. , Spriano M. , Corsetti M. T. , Scalzulli P. , Beltrami G. , Lerma E. , Cascavilla N. , Carella M. , Nati S. , Congiu A. , Musto P. 
Published: April 2020

Abstract
Autografting (AutoSCT) has been limited by high-relapse rates and conventional allografting (AlloSCT) by excessive TRM and toxicity in the treatment of Multiple Myeloma (MM). Reduced intensity conditioning for transplant (RICT), a less toxic procedure for AlloSCT that aims to exploit graft versus tumor effect, has been shown to achieve remissions in MM. High-dose therapy/AutoSCT followed shortly thereafter by RICT might improve outcomes in MM as compared to AutoSCT or conventional AlloSCT used alone. We compared two retrospective cohort of patients who underwent either tandem AutoSCT (HDT consisted of Melphalan 200 mg/m2) or AutoSCT followed closely by related RICT (patients with HLA-matched siblings). The two groups were matched for pre-transplant therapy, disease status at transplant, time from diagnosis to transplant. GVHD prophylaxis for RICT patients consisted of CyA/MTX. The major results are summarized in the Table. In the AutoSCT/RICT group the complete remission rate was higher (p=0.004) and the risk of disease progression after transplant was significantly reduced (p=0.005). All patients who reached CR responded after full chimerism and GVHD developed. This finding confirms the existence of a graft-versus-myeloma effect. Since the first clinical signs of response in remitters patients were noted between 70 and 120 days and maximum response between 160 and 200 days after RICT (after DLI in one patient), these responses should be considered immunological responses. These data suggest than an allograft following an AutoSCT significantly reduces the incidence of disease progression.
Tandem ASCT (N=35) ASCT + RICT (n=20) Age, median 56 (range, 38–66) 51 (range, 34–63) Median prior cycles of Chemoth. 4 (range, 3–6) 4 (range, 3–6) Time from Dx to 1st AutoSCT (median mo.) 6 (range, 5–60) 9 (range, 7–42) Conditioning Regimen for AutoSCT Melphalan (200 mg/m2) Melphalan (200 mg/m2) Conditioning Regimen for RICT --- TBI/Fludarabine Complete Remission 14% 50% p=0.004) Disease-Free Survival at 3 yrs 11% 45% (p=0.005) Overall Survival at 3 yrs 66% 70% (p=NS) Median Follow-Up (mo.) 30 (range, 6–104) 38 (range, 5–59) Transplant-Related Mortality 0% 0% Median days from AutoSCT to RICT --- 80