bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of Clinical Response to Dasatinib (BMS-354825) with BCR-ABL Mutation Status in Imatinib- Resistant Patients (pts) with Chronic Myeloid Leukemia (CML) Treated at MD Anderson Cancer Center (MDACC).
Authors: Jabbour Elias , Cortes Jorge , Talpaz Moshe , Jones Dan , O’Brien Susan , Nicaise Claude , Kantarjian Hagop 
Published: April 2020

Abstract
Resistance to imatinib in CML occurs most frequently through mutations of the BCR-ABL kinase domain. Dasatinib is an orally available, dual SRC/ABL kinase inhibitor with 300-fold greater potency than imatinib, and with preclinical activity against all but one (T315I) type imatinib-resistant Bcr-Abl mutants. Dasatinib is currently used to treat pts with CML in chronic phase (CP), accelerated phase (AP), or blast phase (BP) or with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). We analyzed the response to dasatinib among pts with Bcr-Abl kinase mutations. Prior to therapy, peripheral blood samples were analyzed for mutation by DNA sequencing. 26 pts with 13 different imatinib-resistant point mutations in the Bcr-Abl kinase domain were treated (CP n=10, AP n=11, BP n=4, ALL n=1). The most common mutations were G250E/A (n=7, 27%), T315I (n=3, 12%), F317L (n=3, 12%), and E355G/A (n=3, 12%). 20 (77%) pts responded to therapy. Responses were: major molecular remission (MMR) in one pt (4%), complete cytogenetic response (CGCR) in 3 (12%), partial cytogenetic response (CGPR) in 5 (19%), complete hematologic response (CHR) in 6 (23%), partial hematologic response (PHR) in 3 (12%), and return to CP in 2 (8%). 6 pts did not respond: 3 of them were in AP (T315I, L364I, and G250E) and 3 in CP (2 T315I and F317L). Three pts (1 CP [F317L], 2 BP [M351T and E355G]) have lost their response (CGPR, CHR, and PHR) after a median of 3 months (range, 2–4 months) without developing any detectable new mutations. The median duration of response for the other 19 pts was 5+ months (range 1+–14+); 4 pts (1 CP [F486S], 3 AP [E255V and 2 G250E]) have a sustained response (1 MMR, 1 CGCR, and 2 CHR) beyond 6 months. Among 12 pts with P-loop mutations (2 in CP, 8 in AP, 2 in BP) 11 (92%) responded to therapy and their median survival since the start of therapy is 5+ months (range, 1+-11+ months). In 2 pts (CHR) subsequent analysis revealed persistence of mutations (E355G and E255V). In one pt G250E mutation occurred while patient was on treatment, but has remained in CHR. We conclude that clinical activity of dasatinib in imatinib-resistant CML is observed in pts with a wide range of imatinib-resistant Bcr-Abl kinase domain mutations. Pts harboring the T315I mutations are resistant to BMS-354825.
Correlation of Different Responses to Imatinib on Survival of Patients (pts) with Chronic Myelogenous Leukemia (CML) in Accelerated (AP) and Blast Phase (BP).
Authors: Aoki Etsuko , Kantarjian Hagop , O’Brien Susan , Rios Mary Beth , Ravandi Farhad , Verstovsek Srdan , Garcia-Manero Guillermo , Shan Jianqin , Cortes Jorge 
Published: April 2020

Abstract
Imatinib has remarkable activity in CML in all phases, with high rates of hematologic and cytogenetic response. However, in AP and BP responses are frequently less than complete hematologic remission (CHR), including partial hematologic remission (PHR) and return to chronic phase (second CP). The objective of this study was to investigate whether different responses to imatinib conferred a survival advantage in pts with CML in AP and BP. We evaluated 214 pts in AP and 76 pts in BP (11 lymphoid, 63 myeloid, 2 unclassified) treated with imatinib. Median age for AP pts was 49 yrs (range: 22–82 yrs) and for BP, 54 yrs (19–75 yrs). With a median follow-up of 49 months (1.9–67.5 months), 82 (38%) AP and 66 (87%) BP pts have died. A CHR and major cytogenetic (CG) response (MCR) have been achieved in 87% and 53% of AP pts, and 37% and 14% of BP pts, respectively. For AP pts the median overall survival (OS) and progression free survival (PFS) were 65 and 49 months, respectively. In BP pts, median OS and PFS were 7 and 3 months. The OS by best response to imatinib was as follows:
Response No. (%) Median OS (months) p value Median PFS (months) p value CG CR=complete CG response (Ph=0%), CG PR=partial CG response (Ph&lt;35%), CG minor=minor CG response (Ph=35–95%), Marrow CR/PR=marrow complete/partial response Accelerated phase CG CR 96 (45) Not reached &lt;0.0001 Not reached &lt;0.0001 CG PR 13 (6) 43 28 CG minor 13 (6) 48 31 CHR 57 (27) 34 22 PHR 16 (7) 14 6 Resistant 11 (5) 5 3 Blast Phase CG CR 6 (8) Not reached &lt;0.0001 Not reached &lt;0.0001 CG PR + minor 8 (11) 12 5 CHR + PHR 12 (16) 13 11 Second CP 6 (8) 9 4 Marrow CR/PR 9 (12) 5 4 Resistant 25 (33) 4 2
We conclude that although cytogenetic responses confer the most survival advantage in AP and BP after imatinib therapy, hematologic responses are associated with a survival benefit.
Allogeneic Stem Cell Transplantation Using a Reduced Intensity Conditioning (RIC) Regimen Has the Capacity To Produce Durable Remissions and Long Term Disease-Free Survival in Patients with High Risk Acute Myeloid Leukemia (AML).
Authors: Tauro S. , Mackinnon S. , Peggs K. , Begum G. , Mahendra P. , Cook G. , Marsh J. , Milligan D. , Goldstone A. , Hunter A. , Khwaja A. , Chopra R. , Littlewood T. , Peniket A. , Parker A. , Jackson G. , Hale G. , Cook M. , Russell N. , Craddock C. 
Published: April 2020

Abstract
The toxicity of allogeneic stem cell transplantation (SCT) can be substantially reduced by the use of a reduced intensity conditioning (RIC) regimen and this has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with AML and MDS has not yet been defined and consequently their role in the management of these diseases remains conjectural. Seventy-six patients with high risk AML or MDS were allografted using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range 18–71 years). There were 46 males and 30 females; 41 patients received an allograft from an unrelated donor and 35 from a matched sibling donor. The 100 day transplant related mortality was 9% and no patient developed greater than Grade 2 graft-versus-host disease (GVHD). With a median follow-up of 36 months (range 13–70 months) 27 patients were alive and in remission with a 3y actuarial overall survival (OS) and disease-free survival (DFS) rate of 41% and 37% respectively. The 3y OS and DFS of patients with AML in complete remission (CR) at the time of transplantation was 48% and 42% respectively. In a multivariate setting, Cox regression analysis demonstrated prognostic significance of disease stage at the time of transplant with improved DFS in patients with AML in CR at the time of transplantation (HR=2.03, 95% CI=1.02–4.07). Disease relapse was the commonest cause of treatment failure occurring at a median time of 6 months post-transplant. Fourteen out of 27 (52%) patients relapsed within 6 months and 23/27 (85%) within twelve months defining a relatively narrow window for therapeutic intervention to prevent disease recurrence. The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts are capable of producing sustained disease free survival in a significant number of patients with AML who would be ineligible for allogeneic transplantation using a myeloablative conditioning regimen.
Superior 12-yr Survival (66% vs 30%) with 5-yr Continuous (Rc) vs “Discontinuous” Remission (Rd): Results of Total Therapies 1 & 2 (TT1,2) for Multiple Myeloma (MM).
Authors: Barlogie Bart , Rasmussen Erik , Tricot Guido , Milner Teresa , Anaissie Elias , van Rhee Frits , Shaughnessy John , Epstein Joshua , Hollmig Klaus , Zangari Maurizio , Crowley John 
Published: April 2020

Abstract
Background: The extension of overall survival (OS) in MM has been partly linked to increasing CR rates especially with high-dose melphalan. Data bases of TT1 and TT2 were examined to determine whether 5-yr Rc was key to prolonged OS.
Patients and Methods: TT1 enrolled 231 and TT2 668 patients (median follow-up, 4 years). Pre-study characteristics of Rc vs Rd patients surviving &gt;= 5yrs were compared. Furthermore, subsequent OS was examined in the context of pre-treatment variables, TT2 vs TT1 and Rc vs Rd. Only those Rd patients who were event-free (CR or PR) at least 1 year prior to the 5-yr landmark were included in this analysis.
Results: Among 231 TT1 + TT2 patients surviving &gt;= 5yrs, more TT2 patients were Rc compared to Rd (60% vs 19%, p&lt;0.001) and more older patients were Rc (at least 65: 13% vs 3%, p=0.019). Importantly, baseline LDH, B2M, CRP, albumin, presence of cytogenetic abnormalities (CA) and whether thalidomide was part of TT2 were evenly distributed among Rc and Rd groups. Furthermore, the 5-yr risk profile of Rc patients was lower than that of Rd patients: lower bone marrow plasma cell % (at least 33%: 0% vs 14%, p=0.003), higher albumin (less than 3.5g/dL: 7% vs 16%, p=0.047), higher Hb (less than 10g/dL: 4% vs 16%, p=0.023), less frequent CA13 (1% vs 11%, p=0.007). Rc patients had significantly longer subsequent survival than those with Rd (12-year survival from enrollment and 7 yrs post-landmark: 66% vs 30%, p&lt;0.001) (Figure). In addition to Rc, univariately significant factors for post 5-year OS were data at 5 years on CA, albumin, B2M, CRP and creatinine. Rc and no CA at 5yrs were the key factors favoring long subsequent survival; thus, 12-yr OS rates decreased from 57% in the 94 patients with Rc/noCA to 44% in 44 with noRC/noCA; 8 of 9 noRc/CA patients have died by year eight; 1 of the 8 Rc/CA patients has died.
Conclusion: 5-yr Rc appears to be an important prerequisite for prolonged subsequent OS, which could be significantly increased with better therapy (TT2 vs TT1). Post-5-yr favorable survival predictors included several laboratory data at 5yrs, especially absence of CA.
Overall Survival from 5 Years Post Enrollment by Remission Status at 5 Years (Interrupted vs Continuous Remisssion) Overall Survival from 5 Years Post Enrollment by Remission Status at 5 Years (Interrupted vs Continuous Remisssion)
Total Therapy 3 (TT3) Incorporating VelcadeR (V) Intro Upfront Management of Multiple Myeloma (MM): Comparison with TT2 + Thalidomide (T).
Authors: Barlogie Bart , Tricot Guido , Rasmussen Erik , Anaissie Elias , van Rhee Frits , Zangari Maurizio , Hollmig Klaus , Epstein Joshua , Shaughnessy John , Crowley John 
Published: April 2020

Abstract
Background: V effects partial responses in 1/3 of patients with advanced and refractory MM and was more effective when combined with T/dexamethasone (D) in our VTD regimen (Barlogie et al. Blood2004; 103: 20). TT3 was designed to build on the success of TT2 by providing T to all patients and incorporating V in induction, consolidation and maintenance therapies to increase CR to 60% and 2-yr EFS for patients with normal/abnormal metaphase cytogenetics to 95% /75%.
Patients and Methods: TT3 consists of 2 induction cycles with VDT-PACE (PBSC collection after the first cycle), followed by melphalan 200mg/sqm-based tandem transplants with peri-transplant T+D, 2 consolidation cycles with VDT-PACE, 1 year maintenance with VTD and 2 years with T+D. Of the 162 patients enrolled prior to 4/20/2005, 156 completed induction therapy, 147 the first and 113 the second transplant. Response rates, toxicities during induction, and stem cell collection results were compared with 314 TT2+T patients.
Results: First and second transplant on TT3 were completed faster, at medians of 3 and 5 mo, compared to 5 and 10 mo, respectively, on TT2+T (p&lt;0.001/p&lt;0.001); 92%/78% (TT3) vs 89%/68% (TT-2+T) completed first and second transplant, respectively, (p0.24/p=0.028). The probability of achieving near-CR (n-CR: only immunofixation positive) at 12 mo was 81% with TT3 and 64% with TT2+T (p=.001). The median number of CD34/kg (x106) was 27 with TT3 vs 20 with TT2+T (p&lt;.001). Treatment-related mortality (TRM) at 12 mo was 4% with TT3 and 6% TT2+T (p=.3). With a median follow-up of 9 mo, 18 patients have experienced an event and 14 have died (disease-related 7; treatment-related 6, other 1). Compared to event-free TT3 patients, these 18 patients were older (≥ 65 years: 50% vs 27%; p=0.04), more frequently had metaphase abnormalities (50% vs 24%; p=0.02) and had elevated LDH (50% vs 19%; p=0.003). With respect to grade 3–4 toxicities during induction, TT3 patients had fewer thrombo-embolic events, (p&lt;.001), less febrile neutropenia (p=.03), somnolence (p=.007), sensory neuropathy (.005) and dizziness (&lt; .001), but more anorexia (p&lt; .001) and renal insufficiency (p=.004).
Conclusion: TT3 appears to be more effective in inducing ≥ n-CR, compared to TT-2+T, partly due to a higher percentage of patients completing the intended 2 transplants. TRM is not different. It is too early to assess the true CR rate and the 2-y EFS according to cytogenetics.
Early Serum Free Light Chain Responses Following High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis Predict Treatment Outcomes.
Authors: Sanchorawala Vaishali , Wright Daniel G. , Quillen Karen , Fisher Catherine , Skinner Martha , Sedlin David C. 
Published: April 2020

Abstract
AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive deposition of amyloid fibrils derived from monoclonal Ig light chains, leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. Several approaches have been used to define hematologic responses following HDM/SCT and other forms of treatment. The standard definition of a hematologic complete response (CR) that we have used requires that there be no evidence of a persistent monoclonal gammopathy by immunofixation electrophoresis (IFE) of serum and urine proteins, or of a persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic responses according to reductions in free light chain (FLC) measurements. Treatment responses as defined by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a prospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which early FLC responses within weeks of treatment predict hematologic CR, as defined by our standard criteria. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 31 patients with AL amyloidosis, between 2003–2005, 1–3 weeks after treatment with HDM/SCT. Hematologic responses, as defined by standard criteria, as well as FLC responses were subsequently determined at 3, 6 and 12 months. Serum FLC levels or κ/λ FLC ratios were abnormal and informative in 28 patients (90%) prior to HDM/SCT, and these patients were included in subsequent analyses. Twenty patients (71%) achieved normalization of abnormal serum FLC levels or ratios within 1–3 weeks of undergoing HDM/SCT. Of these 20 patients, 13 patients (65%) subsequently achieved a hematologic CR as defined by standard criteria, while 7 (35%) did not, within 3 months following HDM/SCT. In contrast, none of the 8 patients with no demonstrable FLC response within 1–3 weeks of HDM/SCT, were found to have achieved a hematologic CR subsequently. In conclusion, meaningful quantitative FLC responses (or lack of response) can be detected within weeks following HDM/SCT treatment that predict hematologic responses, as defined subsequently by standard criteria based on IFE and marrow studies (p=0.0018 by chi square analysis). Moreover, a lack of an early FLC response predicts for hematologic non-CR. We anticipate that prospective studies of FLC responses in HDM/SCT and other clinical trials for AL amyloidosis will eventually lead to more rapid assessment of treatment responses that will guide therapeutic decisions.
Prognosis in Multiple Myeloma (MM): Characterization of “Losers” (L) in Good Risk and “Winners” (W) in High Risk Disease.
Authors: Anaissie Elias , Rasmussen Erik , Shaughnessy John , Tricot Guido , Barlogie Bart 
Published: April 2020

Abstract
Background: The clinical course of patients with MM is highly variable and, among currently available standard features, the presence of metaphase cytogenetic abnormalities (CA) is the parameter with the single best discriminatory power. The aim of this investigation was to determine, among the 1/3 high-risk patients with CA the W and among the remaining low-risk patients the L.
Patients and Methods: We evaluated the baseline characteristics of &gt; 2500 patients who received at least 1 high-dose melphalan-based autotransplant (AT). Poor risk was defined as pre-AT CA (within 90 days) while good risk was defined as no pre-TX1 CA. Poor outcome was death within 2 years of AT while good outcome was survival for ≥ 5 years. Four groups were identified: 403 patients without CA and &gt;5yr survival (noCA/W), 288 without CA and &lt;2yr survival (noCA/L), 122 with CA surviving &gt;5yr (CA/W) and 350 with CA surviving &lt;2yr (CA/L).
Results: Among both CA and no CA groups, univariately significant pre-AT differentiating features between W vs L were serum albumin &gt; 3mg/dL, b2M&lt;3 mg/dL, CRP&lt;6 mg/dL, hemoglobin &gt; 10 mg/dL and platelet counts &gt; 100/μL, LDH &lt; 190 mg/dL, age &lt; 65, female gender and primary treatment on Total Therapy protocol. By multivariate analysis, independently highly significant pre-AT factors that distinguished the 5 yr survivors from the early death (&lt;2 years) patients included primary treatment on Total Therapy protocol, serum albumin &gt; 3mg/dL, hemoglobin &gt; 10 mg/dL, B2M&lt;3 mg/dL, platelet counts &gt;100/μL and CRP&lt;6 mg/dL. These independent prognostic factors were almost identical for CA and noCA patients except for Hgb which was slightly more important than albumin in the CA population.
Conclusion: Among MM patients receiving AT, treatment on Total Therapy protocol, higher Pre-AT albumin, hemoglobin and platelet count and lower b2M and CRP confer a survival advantage regardless of cytogenetic status (CA or noCA) and distinguish the W among the high-risk disease from the L among the low-risk patients.
Second Autologous Stem Cell Transplant (ASCT) as Salvage Therapy for Relapsed Multiple Myeloma.
Authors: Olin Rebecca L. , Porter David L. , Luger Selina M. , Schuster Stephen J. , Tsai Donald , Nasta Sunita , Perl Alexander , Loren Alison W. , Goldstein Steven , Glatstein Eli , Siegel Donald L. , Vogl Dan T. , Mangan Patricia , Cunningham Kathleen , Stadtmauer Edward A. 
Published: April 2020

Abstract
Introduction: Autologous stem cell transplant (ASCT) as part of initial therapy has been shown to prolong survival of patients with multiple myeloma, with some achieving durable complete remission. However, the majority of patients ultimately relapse after ASCT and require salvage treatment. Options for the treatment of such patients have increased significantly over recent years, including not only novel chemotherapeutic and biological agents but also additional ASCTs. We performed a retrospective analysis of our experience with salvage ASCT for multiple myeloma to determine which clinical variables influence outcome.
Methods: Between October 1992 and February 2005, we performed 342 ASCTs for multiple myeloma. Twenty-six of these were salvage transplants for relapsed disease after prior ASCT, and all were included in the analysis. Patients who received two planned (tandem) ASCTs were not included.
Results: The median age at diagnosis was 47 (range 25–66), and median ISS and DS stages at diagnosis were 1 and 2, respectively. The initial ASCT was melphalan-based in 21/26; six (23%) achieved a complete response (CR) to the initial transplant, and fifteen (58%) achieved a partial response (PR). The median event-free survival (EFS) after the initial transplant was 19.5 months (range 2–60). The median time between initial and salvage ASCT was 2.6 years (range 0.3–7.6). Twenty-two patients (85%) received non-transplant therapy between ASCTs, and the median number of lines of therapy prior to salvage ASCT was 3. At the time of salvage ASCT, the median age was 52.5 (range 28–69). Fourteen patients received melphalan alone, eight received melphalan/TBI, and four received other regimens. Eleven patients (42%) achieved a response to therapy (1 CR, 10 PR). One patient (4%) died of transplant-related toxicity. The median follow-up after salvage ASCT is 12 months (range 0.2–58). Median EFS is 9 months, and median overall survival (OS) is 36 months. The 2-year EFS is 14%, and 2-year OS is 52%. On univariate analysis, both response to and EFS after initial transplant significantly predict improved EFS after salvage transplant (p=0.0008 and p=0.0065 respectively). Both also predict improved OS (p=0.03 and 0.0005 respectively). A greater than 12 month interval between first and second transplant also correlated with OS (p=0.04). There was no significant difference in EFS or OS by preparative regimen. Interestingly, type of response to the salvage transplant (CR/PR or less than PR) did not predict improved EFS or OS.
Conclusion: This study suggests that salvage ASCT after relapse from initial ASCT is a feasible therapy for patients with heavily treated multiple myeloma, particularly those with a prolonged response to the first transplant.
Synergistic Induction of T Cell Acute Lymphoblastic Leukemia by Functionally Distinct Mutations in NOTCH1.
Authors: Chiang Mark Y. , Hong Sai , Shestova Olga , Lee Woojoong , Xu Mina , Pear Warren S. , Aster Jon C. 
Published: April 2020

Abstract
Recent observations that Notch1 mutations are present in more than 50% of human T-ALL patient samples indicate that Notch signals have a central role in the pathogenesis of T-ALL (Weng et al., 2004, Science, 306, 269–271). Notch1 mutations are of two types: i) mis-sense mutations in an extracellular heterodimerization (HD) domain; and ii) frameshift or stop codon mutations that result in deletion of an intracellular PEST destruction box. The likely effect(s) of these mutations is to i) cause heightened proteolytic activation of Notch1, an event that requires the enzyme gamma-secretase; and to ii) increase the duration of Notch1 signaling, respectively. To investigate the contribution of the HD and PEST domain mutations to the pathogenesis of human T-ALL, Notch1 alleles with common HD mutations were introduced retrovirally into hematopoietic progenitor cells, which were then transplanted into lethally irradiated mice. These mice developed transiently circulating abnormal CD4+CD8+ T cells, but failed to develop leukemia after 9 months of monitoring. Similar findings occurred when Notch1 alleles bearing only PEST mutations were introduced into mice, as previously noted by others (Feldman et al., 2000, Blood, 96, 1906–1913). However, when HD mutations were combined with a PEST mutation in cis, the mice developed persistent circulating CD4+CD8+ T cells, leukocytosis, and eventually T-ALL (median time, 18 weeks post-transplantation). These tumors infiltrated lymphoid organs, marrow, and viscera, were monoclonal or oligoclonal, and had intact proviral integrations. Cell lines derived from these tumors are susceptible to gamma-secretase inhibitor-mediated cell death, which indicates a continued reliance on Notch signaling for growth and survival. These results show the utility of the murine BMT assay to score Notch1 mutants found in human T-ALL with respect to leukemogenicity, and suggest that the level of signal that is necessary to induce and sustain Notch1-associated T-ALL is relatively high. It will be of interest to determine if HD domain mutations generally require PEST deletions in cis to induce T-ALL, or if weak and strong mutations of varying leukemogenic potential exist.