bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of HER2 score correction for putative chromosome 17 (Chr-17) aneusomy to increase eligibility for anti-HER2 therapy.
Authors: Minca Eugen C. , Portier Bryce P. , Wang Zhen , Lanigan Christopher , Budd G. Thomas , Tubbs Raymond R.
Published: March 2020

620

Background: HER2 amplification or overexpression status directs therapy choice in breast carcinoma. HER2/Chr-17 ratio is commonly assessed by fluorescence in-situ hybridization (FISH) using a CEP17 centromeric reference probe and ASCO/CAP scoring criteria. However, α-centromeric reference probes may underestimate true HER2 status in cases with para-centromeric amplification. Here we present comprehensive algorithmic testing of an alternative Chr-17 reference locus for resolution of putative CEP17-aneusomic cases in a consecutive series, within a single health system. Methods: 150 of 1256 consecutive breast carcinoma cases accessioned in 2011 within the Cleveland Clinic Health System displayed a mean CEP17 copy number greater than 3.0 by FISH (aneusomy). The patients were reflex-HER2 tested by FISH with a reference probe for the D17S122 locus (17p12) and a corrected HER2/Chr-17 ratio was calculated. Cases with equivocal HER2/D17S122 ratio (1.8-2.2) were further reflex tested for HER2 overexpression by immunohistochemistry (IHC). Results: Of 117 initially non-amplified cases by HER2/CEP17, 20 (17%) were revised to amplified and 18 (15.3%) to equivocal by HER2/D17S122. Of 3 initially equivocal cases, 1 was revised to amplified and 1 remained equivocal. Of the 19 equivocal cases by HER2/D17S122, 3 were revised to positive by IHC. Overall, for CEP17 aneusomic cases tested using this algorithmic approach, 24 of 120 (20%) patients with initial non-amplified or equivocal HER2 status became eligible for anti-HER2-based therapy, which was also considered in 10 equivocal cases with a HER2/D17S122 ratio of 2.0 - 2.2. A significantly lower proportion of initially amplified cases was revised as non-amplified by HER2/D17S122 (1 of 30, 3.3%, p<0.05). Conclusions: Our data, collected within a single health system for a consecutive case series, underscores the clinical limitations of commonly used FISH probes for HER2 testing and demonstrates that algorithmic use of a non-centromeric Chr-17 reference probe alters HER2 status and increases eligibility for anti-HER2 based therapy in a significant proportion of patients.
An assessment of disease features and immune response in breast cancer patients that did not recur after receiving HER2 peptide, AE37 vaccine in a randomized phase II trial.
Authors: Hale Diane F , Perez Sonia A. , Vreeland Timothy J , Trappey Alfred F , Dabney Raetasha Sheavette , Berry John S. , Ardavanis Alexandros , Sears Alan K. , Papamichail Michael , Clifton Guy T. , Pappou Efi , Patil Ritesh , Anastasopoulou Eleftheria , Ponniah Sathibalan , Shumway Nathan M. , Peoples George Earl , Mittendorf Elizabeth Ann
Published: March 2020

625

Background: In a phase I trial of AE37, the Ii-Key hybrid of HER2 derived peptide AE36 (776-790), administered with immunoadjuvant GMCSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T cells with HER2 specific anti-tumor activity. Here we present analysis of immune markers and patient feature that may impact recurrence from an ongoing prospective, randomized, single-blinded Phase IIb trial of AE37+GMCSF v GMCSF alone in adjuvant high risk breast cancer (BC) patients. Methods: After completion of standard therapy; disease-free, node positive or high risk node negative BC patients (pts) were randomized to receive either AE37+GMCSF or GMCSF in 6 monthly intradermal inoculations. Immunologic responses were measured using [3H]-thymidine incorporation assay (in vitro), delayed-type hypersensitivity (DTH) reactions (in vivo) and T regulatory cells (Tregs). Among those vaccinated recurrent pts (VR) are compared to non recurrent (VNR) pts. Results: We have vaccinated 109 pts with 8.3% recurrence rate at 2 year median follow up. VR v VNR were younger (44 v 50 yo p=0.11), had higher grade (67% v 44% p=0.32), more ER/PR- (44% v 38% p=0.75), larger tumors (89% v 50% p=0.06), and node positive (89% v 70% p=0.37). No difference for HER2 status (IHC 3+, 44% v 49% p=0.64). Both VR and VNR responded to vaccine though the mean DTH and proliferative stimulation index was approximately 10% less in VR pts (18 v 20 p=0.73; 1.96 v 2.2 p=0.77 respectively). The most predictive measure was change in Tregs with VR pts less likely to decrease their Tregs levels (50% v 76% p=0.17) after vacination and more likely experience increased Tregs (17% v 8% p=0.48). A decrease in Tregs had an inverse trend towards recurrence (p=0.17). Conclusions: Preliminarily, it appears most pts immunologically respond to vaccine though slightly less for VR in most assays. The changes of Tregs appear to correlate best with disease recurrence. Whether this reflects an association with disease status or a failure of the vaccine is yet to be seen. These levels may become important in predicting risk for clinical recurrence in future vaccine trials.
Functional imaging of HER2-positive metastatic breast cancer using 64Cu DOTA-trastuzumab positron emission tomography (PET).
Authors: Mortimer Joanne E. , Conti Peter , Tong Shan , Reyes Jose , Carroll Mary I. , Poku Kofi , Colcher David , Raubitschek Andrew Antony , Bading James R , Miles Joshua
Published: March 2020

639

Background: We are developing 64Cu-labeled trastuzumab (tras) as a PET imaging agent for women with HER2+ beast cancer. To maximize image quality and minimize HER2 uptake in normal tissues, we pre-administered 2 different doses of cold tras prior to injection of the imaging agent. Methods: Pts with advanced breast cancer were eligible if they had bx confirmed HER2 + disease, had not received anti-HER therapy for 6 mos. and had > 1 non-hepatic site of metastasis > 2 cm outside the biopsy site. All un-derwent staging FDG/PET and bone scan. Prior to injection of 64Cu-tras, pts. received 5 or 50 mg (2 and 4 pts) of cold tras. PET-CT was obtained at 21-25 h and 47-48 h over fields of view chosen in reference to 18F-FDG scans. Uptake in organs and lesions were measured in terms of body wt-normalized SUV. Lesions with intensity > adjacent tissue were considered positive on PET. The number of metastatic sites identified on 64Cu-tras/PET was compared to the number on FDG/PET. Image quality was assessed according to differences between the 2 pretreatment doses. Results: Six pts have been imaged. Tras dose had a marked effect on liver uptake of64Cu [SUV = 23±3 (mean±sd) and 6.3±0.6 for 5 and 50 mg tras, respectively; P < 0.05]. 72 CT+ lesions (32 bone, 28 nodal, 9 liver, 2 breast, 1 lung) were included in D1 and/or D2 scans. Of these, 66 of 72 (92%), 48 of 63 (76%) and 36 of 44 (82%) were detected on FDG, D1 and D2 scans, respectively. Lesion SUVmax was 9±5 (n=37, range 3-23) on D1 and 11±6 (n=27, range 1-29) on Day 2. 64Cu-tras-to-FDG SUVmax ratios were 1.0±0.8 (range 0.2-4.3) and 1.3±1.1 (range 0.2-3.5) for D 1 and 2. Lesion 64Cuuptake trendedliver > bone > nodes. Conclusions: 64Cu-tras/PET visualizes HER2+ lesions in bone, liver and, to a lesser degree, lymph nodes. Pre-administration of cold tras improves the quality of tras/PET, especially of intrahepatic lesions. In the next phase of study we will perform 64Cu-tras/PET in pts with HER2 1+ and 2+ disease.
Outcome of HER2-positive breast cancer patients following metastatic relapse after adjuvant trastuzumab treatment since EMA regulatory approval.
Authors: Spano Jean-Philippe , Vignot Stéphane , Ho Xuan Dung , Zongo Nayi , Magneux Celine , Genestie Catherine , de la Motte Rouge Thibault , Lefranc Jean-Pierre , Khayat David , Gligorov Joseph
Published: March 2020

641

Background: Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2) is approved in France since 2005 for HER2-positive breast cancer patients in the adjuvant setting. Efficacy of this treatment is clearly established but little is known related to patient outcome if they develop metastatic relapse after adjuvant trastuzumab. The aim of this study is to analyse these relapses with a special focus on efficacy of anti-HER2 treatment in this setting. Methods: We analysed 456 patients with HER2-positive early breast cancer treated with trastuzumab containing adjuvant therapy between 2006 and 2011 in two Departments of Medical Oncology from Université Pierre et Marie Curie, Paris, France. Data from patients with metastatic relapse were identified. Disease free survival (DFS) between end of trastuzumab and relapse, quality of response, and time to progression after anti-HER2 new treatment are reported. Results: Relapse rate was 3.3 % after adjuvant trastuzumab (15 pts, median age 53 years, ER+ 40 %). DFS between end of trastuzumab and relapse was 244 days (95% CI: 91 - 397 days). One pt actually had a confirmed HER2-negative metastatic disease. The other 14 pts were treated with anti-HER2 agents at relapse. On 12 evaluable pts, an objective response was observed in 8 pts, stabilisation in 2 pts and progression in 2 pts. Median time to progression after first line metastatic treatment was 222 days (95% CI: 114 - 330 days). Additional data about site of relapse and subsequent therapies are available. Conclusions: Relapse after adjuvant trastuzumab remains a rare event in this real life cohort of breast cancer pts. For these pts, we will present data of the patterns of relapse and response. These data may help us to determine if adjuvant trastuzumab has an impact on outcome of HER2 metastatic disease compared to data in trastuzumab naive metastatic HER2-positive breast cancer pts. We also plan to seek international collaboration to expand our analyses, as well as overall survival.
Switch to nilotinib versus continued imatinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with detectable BCR-ABL after 2 or more years on imatinib: ENESTcmr 12-month (mo) follow-up.
Authors: Lipton Jeffrey Howard , Hughes Timothy P. , Leber Brian , De Souza Carmino , Dorlhiac-Llacer Pedro E , Steegmann Juan Luis , Guerci-Bresler Agnes , Schwarer Anthony P. , Cervantes Francisco , Reynolds John , Collins LaTonya R , Szczudlo Tomasz K. , Spector Nelson
Published: March 2020

6505^

Background: Nilotinib induced significantly faster and deeper molecular responses vs imatinib in the ENESTnd trial. Achieving these deeper molecular responses may increase patient eligibility for future TKI discontinuation studies. Methods: CML-CP pts (N = 207) who achieved a complete cytogenetic response but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib were randomized 1:1 to receive nilotinib 400 mg BID (n = 104) or to continue their imatinib dose (400 or 600 mg QD [n = 103]). The primary endpoint was confirmed CMR (undetectable BCR-ABL by RQ-PCR with a sample sensitivity of ≥ 4.5 logs in 2 consecutive samples). Other endpoints included molecular responses (MMR ≤ 0.1%IS, MR4 ≤ 0.01%IS, and MR4.5 ≤ 0.0032%IS) and BCR-ABL ratio over time. Results: Rate of confirmed CMR was higher in the nilotinib arm vs imatinib by 12 mo (12.5% vs 5.8%) (Table). Rate of CMR (undetectable BCR-ABL in at least 1 sample) by 12 mo was significantly higher on nilotinib vs imatinib (23.1% vs 10.7%; P = .02). Rates of MMR, MR4, MR4.5, and CMR were also superior in pts switched to nilotinib, and these pts had significantly shorter times to achieve these responses. Imatinib-treated pts had minimal evidence of improvement in molecular response vs a median 0.5-log reduction in BCR-ABL by 12 mo for the nilotinib cohort. With 12-mo follow-up, 84% of pts remained on nilotinib and 96% on imatinib. The nilotinib safety profile was consistent with prior studies. Both drugs were well tolerated. Conclusions: Twice as many pts achieved deeper molecular responses after switching to nilotinib vs staying on imatinib. [Table: see text]
The prognostic significance of early molecular and cytogenetic response for long-term progression-free and overall survival in imatinib-treated chronic myeloid leukemia (CML).
Authors: Hehlmann Rudiger , Hanfstein Benjamin , Müller Martin C , Erben Philipp , Lauseker Michael , Fabarius Alice , Schnittger Susanne , Haferlach Claudia , Goehring Gudrun , Krause Stefan W. , Dengler Jolanta , Falge Christiane , Neubauer Andreas , Stegelmann Frank , Pfreundschuh Michael , Spiekermann Karsten , Baerlocher Gabriela M , Hasford Joerg , Saussele Susanne , Hochhaus Andreas ,   for the SAKK and the German CML Study Group
Published: March 2020

6510

Background: In the face of competing first line treatment options for CML early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of an alternative therapy. We sought to evaluate the prognostic impact of early response landmarks. Methods: A total of 1,303 newly diagnosed imatinib-treated patients (pts) from the randomized CML Study IV were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). Median follow-up was 4.7 years (range 0-9). The BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (BCR-ABLIS). The proportion of Philadelphia-chromosome positive metaphases (Ph+) was determined by conventional metaphase analysis. To confirm the prognostic significance of early molecular response, an independent validation sample of 174 pts treated with imatinib within the IRIS trial was analyzed. Results: The persistence of >10% BCR-ABLIS at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with 1-10% BCR-ABLIS (41% of pts; 5-year OS: 94%; p=0.012), and from a group with <1% BCR-ABLIS (31% of pts; 5-year OS: 97%; p=0.004). By cytogenetics high-risk patients could be identified by the persistence of >35% Ph+ (27% of pts; 5-year OS: 87%) as compared to ≤35% Ph+ (73% of pts; 5-year OS: 95%; p=0.036). At 6 months the >1% BCR-ABLIS group (37% of pts; 5-year OS: 89%) showed inferior survival compared to ≤1% (63% of pts; 5-year OS: 97%; p<0.001); survival of the >0% Ph+ group (34% of pts; 5-year OS: 91%) was inferior to 0% Ph+ (66% of pts; 5-year OS: 97%; p=0.015). Regarding the IRIS pts 3 month BCR-ABLIS >10% (25% of pts; 8-year OS: 81%) was associated with inferior survival compared to ≤10% (75% of pts; 8-year OS: 93%; p=0.011). Conclusions: Failure to achieve the response landmarks of 10% BCR-ABLIS or 35% Ph+ at 3 months of imatinib treatment and 1% BCR-ABLIS or 0% Ph+ at 6 months identifies high-risk patients which might benefit from an early change of therapy.
Efficacy and safety of bosutinib (BOS) for Philadelphia chromosome–positive (Ph+) leukemia in older versus younger patients (pts).
Authors: Brummendorf Tim H. , Gambacorti-Passerini Carlo , Schafhausen Philippe , Khoury Hanna Jean , Hochhaus Andreas , Kindler Thomas , Fischer Thomas , Besson Nadine , Leip Eric , Kelly Virginia , Cortes Jorge E.
Published: March 2020

6511

Background: BOS is an oral dual Src/Abl kinase inhibitor with potent activity in Ph+ leukemia. Methods: Efficacy and safety of BOS 500 mg/d was evaluated in older (≥65 y; n = 119) and younger (<65 y; n = 451) pts in 3 cohorts: chronic phase chronic myeloid leukemia (CP CML) after imatinib (IM; CP2L cohort; n = 287); CP CML after IM + dasatinib (DAS) and/or nilotinib (NIL; CP3L cohort; n = 119); and accelerated/blast phase (AP/BP) CML or acute lymphoblastic leukemia after IM ± DAS and/or NIL (ADV cohort; n = 164). Results: Baseline events (≥65 y vs <65 y) included respiratory disorders (35% vs 13%), cardiac disorders (29% vs 9%), and diabetes (4% vs 4%). Median baseline medications were 3 (≥65 y) and 5 (<65 y). Median BOS duration was 11 mo and median follow-up was 31 mo for all pts. 80% of ³65 y and 67% of <65 y pts discontinued BOS, including 32% and 18% due to an adverse event (AE; most commonly thrombocytopenia [6% vs 3%]). Rates of response were similar or lower in older versus younger pts (Table). On-treatment transformation to AP/BP CML was similar between groups. Incidences of nonhematologic treatment-emergent AEs were generally similar between older and younger pts, notably (all grades/grade ≥3 for ≥65 y vs <65 y): diarrhea (85%/9% vs 81%/8%), infection (56%/15% vs 49%/10%), and edema (8%/0% vs 4%/<1%). Common grade ≥3 lab abnormalities (≥65 y vs <65 y) were thrombocytopenia (35% vs 35%), neutropenia (21% vs 25%), and anemia (19% vs 19%). Conclusions: BOS demonstrated similar efficacy and acceptable safety in both older and younger pts across Ph+ leukemia cohorts. [Table: see text]
BCR-ABL kinase domain mutations and resistance in Ph+ acute lymphoblastic leukemia from the imatinib to the second-generation TKI era.
Authors: Soverini Simona , Gnani Alessandra , De Benedittis Caterina , Iacobucci Ilaria , Venturi Claudia , Papayannidis Cristina , Luppi Mario , Merante Serena , Malagola Michele , Russo Domenico , Tiribelli Mario , Salvucci Marzia , Vitale Antonella , Elia Loredana , Vignetti Marco , Foà Robin , Baccarani Michele , Martinelli Giovanni
Published: March 2020

6531

Background: Advent of 2nd-generation TKIs has brought additional treatment options for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients (pts). To analyze the changes they have determined in mutation frequency and type, we have reviewed the database recording the results of BCR-ABL mutation analyses done in our laboratory from 2004 through 2011. Methods: 781 tests on 258 pts were performed by direct sequencing. Results: 143 pts were analyzed because of imatinib resistance; 101 (71%) had one or more mutations (a single mutation in 91 pts; two mutations in 10 pts). Three mutation types were by far the most frequent: T315I (38 pts, 37%), E255K (19 pts, 18%) and Y253H (19 pts, 18%). Of 84 pts who had developed resistance to 2nd- or 3rd-line therapy with dasatinib, nilotinib or bosutinib after imatinib failure, 65 (77%) were positive for Bcr-Abl mutations; 30 (46%) carried multiple mutations (up to four) and in 19 of them (63%) this was consequence of multiple lines of therapy. The most frequent newly acquired mutation in this setting was the T315I, detected in 35/57 (61%) cases acquiring mutations on dasatinib. Mutation analysis was also performed in 15 resistant pts enrolled in a study of dasatinib as 1st-line treatment of Ph+ ALL; 12 pts were positive, 11 of them had a T315I. Taking advantage of a next-generation sequencer (Roche 454), allowing a high sensitive and quantitative mutation scanning of Bcr-Abl, serially collected samples from 24 selected cases who developed mutations and resistance to one or more TKIs were retrospectively analyzed to study the kinetics of expansion of mutant clones. Results will be presented. Conclusions: Although 2nd generation TKIs are more potent and have much fewer insensitive mutations, long-term disease control remains a problem and the T315I becomes an even tougher enemy. The high genetic instability fosters mutational events anytime during TKI treatment and some mutation types (T315I, Y253H) have been observed to emerge and take over very quickly (from <0.01% to 90% in one-two months). Supported by PRIN, AIL, AIRC, Fondazione CARISBO.
Outcomes of patients older than 60 years with acute lymphoblastic leukemia: Survey from the Surveillance, Epidemiology, and End Results (SEER) program.
Authors: Park Jae Hong , Devlin Sean , Tallman Martin S. , Douer Dan
Published: March 2020

6532

Background: The cure rate of pediatric acute lymphoblastic leukemia (ALL) has increased over the last 4 decades to above 80%, compared to a much smaller improvement in adults aged < 60 years. However, outcome information on older ALL patients (age ≥ 60 years) is limited. Only a few clinical trials include the older patients, apply the same regimens developed for adults of all ages, and report a very poor outcome with no improvement over time. We therefore conducted a population-based survey of older ALL patients focusing on early death (ED) rates and changes in outcome over the last 30 years. Methods: Data from 9 population-based cancer registries that participate in the National Cancer Institute’s SEERprogram were used to identify patients aged 60 or older with a diagnosis of ALL. Survival rates at 1, 6, 12 and 24 months were estimated using actuarial methods for 4 calendar periods: 1980-1985, 1986-1992, 1993-1999, and 2000-2006. ED was defined as death occurring within one month of ALL diagnosis. Results: A total of 1066 ALL patients were identified. The ED rate significantly improved over the four study time periods from 20.2% in 1980-1985 to 13.2% in 2000-2006 (p=0.03). The overall survival (OS) at 6 months improved from 32.8% in 1980-1985 to 45.3% in 2000-2006, but at 24 months, only a modest difference in OS was noted across the time period (13.1% in 1980-85 vs. 17.5% in 2000-06). The median survival increased from 3 months to 6 months from the period 1980-1999 to 2000-2006. Conclusions: Although the long-term OS for patients aged 60 and over remains poor, there has been a slight improvement in early mortality and median OS from 1980s to the early 21st century. While the progress in reducing ED and increasing survival at 6 months is encouraging, and may be reflecting better supportive care measures, the limited improvement indicates poor tolerance and lack of efficacy of the toxic, long and complex chemotherapy regimens designed for younger adults. Therefore, future studies should be designed specifically for older ALL patients, focusing on novel, effective, but less toxic therapies, to further improve the short-term OS seen in the past decades and possibly a better overall outcome.
Randomized phase III trial of haploidentical HCT with or without an add back strategy of HSV-TK donor lymphocytes in patients with high-risk acute leukemia.
Authors: Bordignon Claudio , Bonini Chiara , Sarina Barbara , Lambiase Antonio , Ciceri Fabio
Published: March 2020

6541

Background: Suicide gene therapy applied to allogeneic stem cell transplantation has been tested in several trials. When exposed to ganciclovir, donor lymphocytes expressing herpes simplex thymidine kinase suicide gene (TK cells) are selectively eliminated. In a phase I-II trial (Ciceri, Bonini, Lancet Oncology 2009,489-500), TK cells were infused in patients after haploidentical transplantation. Of 50 patients enrolled, 28 received transduced-TK cells and 22 achieved rapid immune reconstitution, with a non-relapse mortality of 14%. GvHD after DLI-TK infusion was reported in 30% of patients and in all cases was fully controlled by ganciclovir treatment. Methods: High risk leukemia patients in first or subsequent complete remission are currently randomized in a 2-arm (3:1 ratio) phase III trial with or without the add-back strategy of HSV-TK donor lymphocytes in patients underwent T-depleted haploidentical stem cell transplant. Primary end point is disease-free survival (DFS), while secondary end points included overall survival, non-relapse mortality, immune reconstitution, acute and chronic GvHD incidence, and relapse incidence. For the primary analysis of DFS 170 patients (127 patients in the experimental group and 43 patients in the control) are required to detect an hazard ratio of 0.55 with at least 80% power for 2-sided 0.05 level test. Patients are eligible for the study if they are older than 18 years-old, absence of timely and suitable HLA matched family or unrelated donor, and have a ECOG performance status < 2. Patients are stratified by state of disease, ECOG PS and country before randomization. Results: Transduced lymphocytes are given to patients between day +21 and day +49 after haploidentical HCT in the absence of spontaneous immune reconstitution and/or development of GvHD. In absence of immune reconstitution and GvHD after the first TK-cells add-back further 3 infusions could be administered 30 days after the last infusion. TK lymphocytes dose is 1 x10^7 CD3/Kg. Conclusions: The study (TK008) is currently open to accrual in EU, US, Israel (clinicaltrials.gov:00914628).
Allogenic stem cell transplant (ASCT) as initial salvage for patients (pts) with acute myeloid leukemia (AML) refractory to high-dose cytarabine-based induction chemotherapy.
Authors: Daver Naval Guastad , De Lima Marcos J.G. , Kantarjian Hagop , Ravandi Farhad , Bilen Mehmet Asim , Pierce Sherry , Khouri Issa F. , Dorkhom Stephan Joseph , Giralt Sergio , Garcia-Manero Guillermo , Nazha Aziz , Mathisen Michael , Pemmaraju Naveen , Cortes Jorge E. , Faderl Stefan , Jabbour Elias
Published: March 2020

6544

Background: Outcomes of pts with AML who are refractory to High-dose Cytarabine (HiDAC) based induction are dismal. ASCT as initial salvage may be effective and potentially superior to repeat induction with combination chemotherapies in such pts. Methods: 1597 AML pts were treated with HiDAC-based induction at MD Anderson Cancer Center between 1995 and 2009. 285 primary refractory pts were identified. 28 (10%) of these underwent ASCT as initial salvage and were reviewed. Results: Median age was 56 years (36 to 77) and 50% were males. Median ECOG PS was 1 (0-2). Antecedent hematological disorders were present in 14 pts (50%). Median white cell count, hemoglobin, platelet count and bone marrow (BM) blast percentage at diagnosis were 3.5 x 109/l (0.6 to 73.6), 7.8 g/l (6.5 to 11.4), 44 x 109/l (9 to 615), and 43% (6-82), respectively. 9 pts (32%) had complex cytogenetics. FLT3 mutations were identified in 2 (15%) of 13 evaluated pts. All pts were refractory to HiDAC-based induction. HiDAC was combined with an anthracycline in 16 pts (57%) and non-anthracycline in 12 pts (43%). Median time from induction to ASCT was 76 days (28 to 184). Median BM blast and peripheral blast at ASCT were 28% (3 to 82) and 4% (0 to 41). 21 pts (75%) had matched related donors (18 sibling and 3 haploidentical) and 7 (25%) had matched unrelated donors. Conditioning regimens were melphalan-based, busulfan-based, fludarabine-based or others in 7 (25%), 10 (36%), 8 (29%) and 3 pts (10%); respectively. Complete remission (CR) was achieved in 23 of 28 pts undergoing ASCT (CR = 82%) with median time to CR of 31 days (26 to 134). 12 pts relapsed with median time to relapse of 5 months (2 to 19). 8 pts remain alive with median follow up of 80 months (28 to 118). Median overall survival (OS) for the entire group is 20 months (5 to 118). In historical series of pts with AML refractory to HiDAC-based induction, salvage chemotherapies induced CR rates of 22% with median OS of 4 months. Conclusions: Initial salvage with allogenic SCT is feasible and yields superior outcomes to salvage chemotherapy in primary HiDAC refractory AML pts. Randomized studies are warranted to further explore this treatment option.
Neurotoxicity after high-dose melphalan.
Authors: Najera Jose Eugenio , Sudhakar Tummala , Bashir Qaiser , Shah Nina , Champlin Richard E. , Qazilbash Muzaffar H. , Giralt Sergio , Hosing Chitra , Popat Uday R. , Ciurea Stefan O.
Published: March 2020

6546

Background: High dose melphalan (HDM) at 200 mg/m2 is the standard preparative regimen for patients with multiple myeloma (MM) and light-chain amyloidosis (AL) undergoing autologous hematopoietic stem cell transplantation (auto-HCT). Neurotoxicity has been seen with HDM. In this report we describe the incidence, clinical manifestations and outcome of HDM- associated neurotoxicity. Methods: We performed a chart review of all patients who received HDM and auto-HCT for MM or AL between January 2007 to December 2009 at the University of Texas MD Anderson Cancer Center (MDACC). HDM- associated encephalopathy was defined as altered mental status, seizure or unexplained loss of consciousness within 30 days of auto-HCT. Patients with documented hemorrhagic or embolic stroke, or metabolic abnormalities were excluded. Results: 451 patients were included. Median age at auto-HCT was 59 years (range: 35-80). Thirty patients (6.6%) had AL and 61 patients (13.5%) had a pre-transplant serum creatinine of > 1.5 mg/dl. Nine patients (2.0%) developed HDM-associated encephalopathy with a median of 13 days (range 4-22) from auto-HCT. Among patients with encephalopathy, 8 (89%) developed changes in mental status ranging from drowsiness and confusion to loss of consciousness, while one patient had tonic-clonic seizures (11%). Of the affected patients there were 6 (66%) females, 8 patients (89%) > 59 years of age and only 2 patients (22%) had a creatinine clearance of < 60 ml/min. One patient was dialysis-dependent. A CT scan or MRI was obtained in all 9 patients. Only one patient had imaging abnormalities reported as posterior reversible encephalopathy syndrome (PRES). Electroencephalogram (EEG) was performed on 6 patients. Epileptiform activity was seen in one patient with clinical seizures. Mild generalized slowing was noted in 2 other patients with mental status changes. Cerebrospinal fluid was obtained in 2 patients and did not show any abnormalities. Complete resolution of neurologic symptoms was seen in all patients prior to hospital discharge, and there were no deaths. Conclusions: HDM-induced encephalopathy was seen in only 2% patients, and it is associated with complete neurologic recovery without any increase in transplant-related mortality.
Dose-intensive cyclophosphamide, etoposide, cisplatin reinduction for relapsed/refractory aggressive non-Hodgkin lymphoma (r/r-aNHL).
Authors: Henning Jan-Willem , Duan Qiuli , Bahlis Nizar J. , Daly Andrew , Duggan Peter , Shafey Mona , Stewart Douglas Allan
Published: March 2020

6548

Background: Approximately 2/3 r/r-aNHL patients (pts) respond to salvage R-ICE or R-DHAP, 1/2 proceed to autologous stem cell transplantation (ASCT), and 1/3 achieve 3 year (yr) progression-free survival (PFS); however, PFS is only 20% if prior Rituximab, time to progression (TTP)<1yr, or age-adjusted International Prognostic Index (aaIPI)=2-3 [JCO 2010;28: 4184-90]. Since 1995, we re-induced poor prognosis r/r-aNHL with dose-intensive Cyclophosphamide 5.25g/m2, Etoposide 1.05g/m2 and Cisplatin 105mg/m2 (DICEP), G-CSF days (d) 14-19, and apheresis d19,20, or 21. Rituximab was added d0,7 after 2006. Methods: We retrospectively analyzed 113 consecutive transplant eligible r/r-aNHL pts [diffuse large B-cell=95, transformed=9, peripheral T-cell=6, other=3] who received one cycle of DICEP (n=93) or R-DICEP (n=20) from 1995-2009. Patient characteristics included: median age=49yr (22-69); primary refractory=68; TTP<1yr=85; elevated LDH=60; ECOG 2-4=42; aaIPI 2-3=59; bulk>10cm=26. Results: Of 113 pts, 77% responded to DICEP and 90% (102) proceeded to ASCT. The median CD34+ cells collected was 19x106/kg (0.3-142). Early treatment-related mortality (TRM) occurred in 3 pts (2.7%), and 4 others developed late second cancers (MDS/AML=2). With 94 months median follow-up (26-194), 5 and 10yr OS rates for all 113pts are 48% and 41%, and PFS rates are 42% and 37%, respectively. 5 year PFS rates for ASCT vs no-ASCT are 46% vs 9%, for relapse aaIPI=0-1 vs aaIPI=2-3 are 53.3% vs 32.1% (p=0.01), and for TTP>1yr vs <1yr are 63.9% vs 35.2% (p=0.009). Other predictors of inferior PFS in univariate analysis were elevated LDH, ECOG 2-4, no response to DICEP; however, PFS for 27 pts who failed prior Rituximab-chemotherapy (56%) was similar to other 86 pts (38%) (logrank p=0.09). Predictors of PFS and OS in multivariate analysis include: TTP<1yr, elevated LDH, bulk, no response to DICEP. Conclusions: (R)DICEP is an effective re-induction regimen for r/r-aNHL, leading to excellent stem cell mobilization and a high chance of proceeding to ASCT. Long-term PFS and OS rates compare favourably to reports of other re-induction regimens, and a prospective multicentre trial is warranted.
The comparison of up-front autologous peripheral stem cell transplantation in first remission and long-lasting intensive chemotherapy protocols in highly aggressive non-Hodgkin’s lymphomas: Results of a retrospective analysis.
Authors: Ozturk Mustafa , Ozaydin Sukru , Oyan Basak , Ozbalak Murat , Arpaci Fikret , Paydas Semra , Ataergin Selmin , Ferhanoglu Burhan , Kocak Necmettin , Gurkan Emel , Ozet Ahmet , Barista Ibrahim
Published: March 2020

6550

Background: Optimal therapy in adult patients with Burkitt’s and lymphoblastic lymphoma are still unknown. Despite long–lasting and intensive chemotherapy protocols, post-transplant relapse is common and the chemotherapy period is time consuming. Methods: In this retrospective study, the results of induction and consolidation chemotherapies followed-by high dose therapy (HDT) and autologous peripheral stem cell transplantation (APSCT) (n=21), which was given in a time period of 3 months were compared to long–lasting and intensive chemotherapy protocols (LICP) (n=39) in patients with Burkitt’s and Lymphoblastic lymphoma, without bone marrow or central nervous system involvement at presentation. Cyclophosphamide, vincristine, prednisolone, doxorubicin (Adriamycin) with or without L–asparaginase were given as induction chemotherapy, followed-by a consolidation chemotherapy with DHAP and up-front HDT. Results: More than 60% of patients in both groups were in the intermediate and high risk group according to International Prognostic Index. There was no significantly difference according to age, gender, bulky disease, stage, Burkitt’s and Lymphoblastic lymphoma ratio in both groups (p>0,05). Median follow up was 32,3 months (min-max: 0-229 months). When HDT and LICP groups were compared: CR achieved in 76,3% and 82,1% of patients (p>0,05); Median PFS was 10,4 months (min-max: 6,1-20,3) and 10,1 months (min-max: 6,3- 69,0) (p>0,05); One year overall survival rate was 64,7% and 74,4% and five year overall survival rate was 50,1% and 56,7% (p>0,05) respectively. Conclusions: The current study suggests that induction and consolidation chemotherapies followed by HDT and APSCT have similar CR, PFS and OS rates when compared to more time consuming LICP therapies. This provides a short period of treatment with a high rate of survival in adult patients with highly aggressive lymphomas in first remission.
Validation of the M. D. Anderson Symptom Inventory multiple myeloma module.
Authors: Shah Nina , Jones Desiree , Mendoza Tito R. , Williams Loretta A. , Wang Xin Shelley , Vichaya Elisabeth G. , Sailors Mary H , Champlin Richard E. , Cleeland Charles S.
Published: March 2020

6551

Background: Validated scales exist for quality of life assessment in patients with multiple myeloma (MM); however, no existing tool comprehensively assesses disease- and treatment-related symptoms in these patients. The aim of this study was to validate a module of the M. D. Anderson Symptom Inventory developed for patients with MM (MDASI-MM). The MDASI-MM includes 13 core symptoms, 6 interference items, and 7 MM-specific items: constipation, muscle weakness, diarrhea, sore mouth/throat, rash, difficulty concentrating, and bone aches. Methods: The MDASI-MM was administered to 2 cohorts of patients with MM. The first cohort (N=86) consisted of cross-sectional symptom data from patients at the beginning of induction chemotherapy or autologous hematopoietic stem cell transplant (HSCT). This cohort was used to demonstrate i) known-group validity, by detecting differences in groups by performance status; ii) concurrent validity, by correlating selected items and subscales from the MDASI-MM with those from the Short Form Health Survey (SF-12) and the EORTC-QLQC30; and iii) reliability, by computing Cronbach alpha values. The second cohort (N=53) consisted of symptom data collected at 2 points: prior to transplant and 7 days post-HSCT. This cohort was used to demonstrate the sensitivity of the MDASI-MM to detect acute worsening of patients’ symptoms post-HSCT. Results: The MDASI-MM detected significant differences in symptoms and interference levels according to patients’ performance status (P < .001). MDASI-MM scores correlated with those from SF-12 subscales for physical, emotional, cognitive, and social functioning (all P <.001) and with comparable items from the EORTC-QLQC30 (such as pain, fatigue, difficulty concentrating, constipation, and diarrhea, all P < .001). Cronbach alphas were 0.85 for symptom severity and 0.87 for interference. The MDASI-MM’s overall mean scores worsened between pre- and post-HSCT (1.32 vs. 2.55 (range = 0-10), P < .001). Conclusions: The MDASI-MM is a valid, reliable, and concise tool that can be used to quantitatively assess symptom severity and interference in clinical trials and care of MM patients.
Maintenance therapy with arsenic after induction in an alternative and long-term case for the prevention of recurrence of acute promyelocytic leukemia during the period between November 2005 and December 2011.
Authors: Aznab Mozaffar , Salimi Ghobad , Navabi Jafar , Jouybari Touraj , Rezaei Mansour , Ataee Mari , Kavianimoghadam Kaveh , Totoonchian Farhoud , Alimoghaddam Kamran
Published: March 2020

6556

Background: Arsenic trioxide has been used in the first line treatment of acute promyelocytic leukemia and also for recurrence after ATRA and chemotherapy. In this study, it we used it in induction of remission and maintenance therapy Methods: Between November 2005 to December 2011, 42 patients admitted in our department with APL diagnosis. There were 27 male and 15 women with a median age of 28 years. Arsenic trioxide started at 0.15 mg/kg intravenous infusion till patient’s bone marrows achieve to complete remission. Then, after 28 days rest, we did consolidation with Arsenic trioxide with the same dosage for 28 more days. We continued treatment with 14 days courses of Arsenic trioxide every 3-4 months for 2 years, as maintenance therapy Results: Four patients died during the first 20 days of treatment. Thirty-eight patients achieved to remission. Two patients refused to continue treatment after achieving to remission and excluded from this study. Thirty-six patients finished whole treatment. After a median follow-up of 54 months, 4 patients died due to disease relapse and one patient relapsed and initiated treatment with Arsenic and ATRA. Five patients faced leukocytosis over 100,000/ml. In these cases we were obligated to discontinue Arsenic for 3-4 days and did chemotherapy by Danourobicin for 2 days. Totally 8 patients died during remission induction and long-term follow up. One year, 3 and 5 years RFS were 97%, 87.1% and 79.4 respectively and we didn’t observe any relapse for patients who remained in remission after 5 years. Finally, 31 patients are alive and free of disease. The overall survival was 79.5% for our cohort. Conclusions: Arsenic trioxide is an effective treatment as the first line therapy for new cases of APL and long term therapy with will reduce the risk of diseases recurrence without any major toxicity in long time.
Bendamustine retreatment of CLL in the outpatient setting.
Authors: Guenther Georg , Wilhelm Stefan , Tessen Hans Werner , Goettel Rainer , Sauer Annette ,   Project Team of Internal Oncology (p.i.o.)
Published: March 2020

6566

Background: Several studies have proven that bendamustine is a highly active drug in the therapy of CLL (Knauf et al. J Clin Oncol. 2009;27:4378-84; Fischer et al. J Clin Oncol. 2011;29:3559-3556). Nevertheless, only few data exist about the real-life use and efficacy of bendamustine-therapies in the non-trial setting. The project group of internal oncology (p.i.o.) therefore implemented a registry for patients in the routine use of bendamustine in the therapy of CLL (Sauer et al. Onkologie 2010;33(suppl 6):12). Since 2008 a total of 616 patients have been registered, out of which 473 have been thoroughly documented. To evaluate whether a retreatment with bendamustine in relapsed CLL is still active and well tolerable we present comparative data on therapies in patients with (group A) or without (group B) bendamustine pretreatment. Methods: 228 documented patients in relapsed situation were retrospectively appointed to one of two groups (see table below). Results: In Group A the ORR was 80 % and the median PFS lasted 15.6 month. In the patients without prior bendamustine treatment the ORR was 84% and the median PFS lasted 21.2 month. In both groups the median OS has not been reached yet. The grade 3/4 toxicities were mostly hematologic and comparable in both groups. Similar grade 3/4 toxicities were observed for neutropenia (about 25% of the patients), thrombocytopenia (16%) and infections (5%). Conclusions: Bendamustine is broadly used in the routine treatment of CLL. Bendamustine-therapies show impressionable high activity and tolerability, even in an advanced-line context with prior exposition to bendamustine. The treatment results are comparable to results of clinical trials and underline the quality and feasibility of bendamustine in the outpatient treatment. Nevertheless, it is to note that this is a registry and that both groups therefore are not composed of randomized patient-populations (cf. ECOG, patients in lines and ratio of rituximab combinations). [Table: see text]
AML patients with IDH1 or IDH2 mutations treated with hypomethylating agents: A case series.
Authors: Benton Christopher Brent , Ravandi Farhad , Andreeff Michael , Kantarjian Hagop , Konopleva Marina
Published: March 2020

6576

Background: Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations play a significant role in acute myeloid leukemia (AML), yet optimal treatment for AML patients with IDH mutations remains unclear. IDH mutations have been associated with a globally hypermethylated genomic state, as the result of increased levels of 2-HG, a regulator of histone methylation. We sought to retrospectively determine responses of patients with IDH-mutated AML to treatment with hypomethylating agents. Methods: We reviewed clinical data for AML patients treated at The University of Texas M. D. Anderson Cancer Center from June 2001 to December 2011 whose stored leukemia samples from bone marrow aspirateshad been tested retrospectively for IDH1 and IDH2 mutations. We searched three databases that contained records for 407 AML patients. We selected patients who had been treated with the hypomethylating agents 5-azacitidine or decitabine, alone or in conjunction with other therapeutics. We retrospectively reviewed the patients’ medical records to obtain demographic, laboratory, treatment, and clinical data. We evaluated response measured by remission status, reduction in bone marrow blasts and peripheral blood blasts, and time to relapse. Results: We identified 104 patients (25.6%) who had either an IDH1 or IDH2 mutation, and of these, 8 patients had also been treated with hypomethylating agents. A ninth AML patient, who is IDH2-mutant, is currently undergoing treatment with decitabine alone. Of these 9 patients, three had a durable complete remission without recovery of blood counts (CRp), three had a partial response (PR), with or without blood count recovery, and three had no response. All 9 patients did have an initial decrease in the percentage of bone marrow blasts, peripheral blood blasts, or both. Conclusions: This series of patients demonstrates the possibility that AML patients with IDH1 or IDH2 mutations benefit from the use of hypomethylating agents, and suggests it is worthwhile to prospectively investigate treatment of patients with IDH-mutated AML using hypomethylating agents.
Real-world response monitoring and tolerability of imatinib-treated chronic myeloid leukemia patients captured in a retrospective research registry.
Authors: Stenehjem David D. , Albright Frederick S. , Guo Min Amy , Chen Lei , Raimundo Karina , Bauer Hillevi , Brixner Diana I.
Published: March 2020

6583

Background: Monitoring tolerability and response to imatinib (IM) is an important aspect of chronic myeloid leukemia (CML) management. The objective of this study is to assess real-world tolerability and response monitoring in IM treated CML patients (pts). Methods: A comprehensive retrospective outcomes research registry of CML pts was created from the University of Utah electronic health record system. Study inclusion was limited to pts diagnosed with CML in chronic phase in 2001 to 2010 and treated with IM as a first-line therapy. Utilization and outcome of cytogenetic and molecular testing within 18 months of IM initiation, rates of adverse drug events (ADEs), and therapy modifications were evaluated by chart review. Results: A total of 92 pts were treated with IM as first-line therapy. Within the first 18 months of treatment, cytogenetic testing was recorded in 45 pts (49%) and of these 33 pts (73%) achieved a complete cytogenetic response (CCyR) in a median of 241 days (range: 110-542); molecular testing was completed in 48 pts (52%) and of these 24 pts (50%) achieved at least a major molecular response (MMR) in a median of 254 days (range: 99-546). Imatinib associated ADEs of any grade (n = 60) occurred in 42 (46%) pts resulting in dose reductions in 15 pts (36%) in a median of 77 days and discontinuation of IM occurred in 9 (21%) pts in a median of 130 days. The IM dose was increased to >400 mg in 21 (23%) pts in a median of 457 days (range: 21-2112). Of pts diagnosed between 2006 to 2010 (n = 34; 37%), 8 (25%) pts transitioned to dasatinib or nilotinib in a median of 397 days (range: 147 to 1057). Reasons for therapy change included physician documented suboptimal response or treatment failure (n = 5) and ADEs to IM (n = 3). Conclusions: Utilization of cytogenetic and molecular testing within 18 months of IM initiation was lower than the National Comprehensive Cancer Network or European LeukemiaNet CML guidelines would suggest. Further research is warranted to understand limited response monitoring and outcomes in non-monitored pts. The ADE rate was similar to clinical trial data. The impact of ADEs on subsequent treatment and outcomes in CML pts deserves further study.
Ofatumumab retreatment and maintenance in patients with fludarabine-refractory CLL.
Authors: Österborg Anders , Dyer Martin J. S. , Mayer Jiri , Hess Georg , Hillmen Peter , Schetelig Johannes , Schuh Anna , Smolej Lukas , Beck Christian , Dreyfus Brigitte , Hellman Andrzej , Kozlowski Piotr , Pfreundschuh Michael , Rizzi Rita , Spacek Martin , Chan Geoffrey , Gupta Ira , Phillips Jennifer , Lisby Steen , Wierda William G.
Published: March 2020

6584

Background: In Study 406, the anti-CD20 monoclonal antibody ofatumumab (ofa), given as monotherapy over 6 months, showed 47% overall response rate (ORR) in patients (pts) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab (FA-ref), or to fludarabine with bulky (>5cm) lymphadenopathy (BF-ref). The effects of ofa retreatment (retx) and maintenance (mt) are unknown. Methods: Pts who responded to ofa and then progressed or had stable disease (SD) in Study 406, were offered retx in Study 416 (NCT00802737; GSK/Genmab) with ofa 1 x 300 mg + 7 x 2000 mg weekly followed by mt with ofa 2000 mg monthly for up to 2 years (if SD or better). Primary endpoint was ORR (1996 NCI-WG). Safety and time to event outcomes were also assessed. Results: Of 29 pts enrolled, 7 had SD and 22 had partial response (PR) and progressed in Study 406. Pts were defined per Study 406: 17 FA-ref, 11 BF-ref, 1 “other”. Pretreatment characteristics were similar between groups. Pts received a median of 12 doses (range 3-32); 86% had 8 doses, 3% received all 32 doses. 72% of pts had infusion-related adverse events (AEs), 41% at 1st infusion, mostly grade 1-2. The most common grade >3 AE occurring up to 60 days after last tx was infection (38%); the most common was pneumonia (17%). 3 pts (10%) had fatal infections, all bronchopneumonia. Clinical efficacy is shown in Table. Comparative analysis to Study 406 is ongoing. Conclusions: The response to ofatumumab (ofa) as induction retreatment and progression-free survival in this limited number of pts was similar to 1st treatment (Study 406). Ofa maintenance had some clinical benefit for pts with advanced CLL. Ofa was well-tolerated with no unexpected toxicities. [Table: see text]