Bachar Samra, Hagop M Kantarjian, Koji Sasaki, Ahmad S Alotaibi, Marina Konopleva, Susan O'Brien, Alessandra Ferrajoli, Rebecca Garris, Cesar A Nunez, Tapan M Kadia, Nicholas J Short, Elias Jabbour
BACKGROUND: The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy has dramatically improved outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). When allogeneic hematopoietic stem cell transplant (HSCT) is performed, maintenance TKI is generally given for a fixed duration. However, the optimal duration of TKI outside of HSCT remains unknown, and the common practice is to continue indefinitely. Here, we report characteristics and outcomes of 9 patients treated with chemotherapy + TKI without HSCT and later discontinued TKI...
November 25, 2020: Acta Haematologica
Wendy Stock, Giovanni Martinelli, Matthias Stelljes, Daniel J DeAngelo, Nicola Gökbuget, Anjali S Advani, Susan O'Brien, Michaela Liedtke, Akil A Merchant, Ryan D Cassaday, Tao Wang, Hui Zhang, Erik Vandendries, Elias Jabbour, David I Marks, Hagop M Kantarjian
BACKGROUND: Patients with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options. METHODS: The efficacy of inotuzumab ozogamicin (InO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open-label, randomized, phase 3 study 1022 (INO-VATE; NCT01564784)...
November 24, 2020: Cancer
Chin Lee Phan, Siew Ngoh Tan, Sen Mui Tan, Sharifah Shahnaz Syed Abd Kadir, Nur Liyana Mohd Ramli, Teck Onn Lim, Ching Ching Ng
Acute lymphoblastic leukemia (ALL) cases with e13a3 fusion transcripts are extremely rare. We report a 24-year-old male with Ph-positive (Ph+) ALL with an aberrant e13a3 fusion transcript treated with CD19-specific chimeric antigen receptor T-cell (CAR-T) therapy. He developed refractory disease post-chemotherapy induction, andreceived allogeneic hematopoietic stem cell transplantation (allo-HSCT) after salvage with imatinib in combination with chemotherapy regimen. Unfortunately, the patient relapsed after +90 days post-transplant...
November 6, 2020: Cancer Genetics
Ting Shi, Huanping Wang, Mixue Xie, Xueying Li, Lixia Zhu, Xiujin Ye
OBJECTIVE: The occurrence of cryptic Philadelphia (Ph) chromosome translocation is rare in BCR-ABL1-positive acute lymphoblastic leukemia (BCR-ABL1+ ALL) and is of unknown significance in the tyrosine kinase inhibitor (TKI) era. METHODS: We retrospectively studied a series of adult patients receiving TKI-based therapy to evaluate the prognostic impact of the normal karyotype (NK) (n=22) in BCR-ABL1+ ALL by comparison with the isolated Ph+ karyotype (n=54). RESULTS: There were no statistically significant differences in clinical characteristics and complete remission rate between the two groups...
2020: Clinics
Hui Liu, Li Xuan, Ren Lin, Lan Deng, Zhiping Fan, Danian Nie, Xudong Li, Xinquan Liang, Dan Xu, Yu Zhang, Na Xu, Jieyu Ye, Hua Jin, Dongjun Lin, Liping Ma, Jing Sun, Fen Huang, Qifa Liu
Relapse is a major cause of treatment failure in Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ALL) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to evaluate the effect of a new pre-emptive tyrosine kinase inhibitors (TKIs) strategy on relapse in Ph+ALL patients with complete remission undergoing allo-HCT. Pre-emptive TKIs initiation was based on BCR/ABL molecular monitoring. TKIs choice was based on BCR/ABL mutations. Donor lymphocyte infusion was recommended in those with poor response to TKIs...
November 17, 2020: Leukemia
Satoshi Nishiwaki, Jeong Hui Kim, Masafumi Ito, Matsuyoshi Maeda, Yusuke Okuno, Daisuke Koyama, Yukiyasu Ozawa, Masaharu Gunji, Masahide Osaki, Kunio Kitamura, Yoko Ushijima, Yuichi Ishikawa, Koichi Miyamura, Isamu Sugiura, Hitoshi Kiyoi
Background: Recently, various blood cell lineages expressing the BCR-ABL fusion gene in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have been reported. However, the biological and clinical significance of these BCR-ABL lineages has not been established; therefore, we aimed to clarify the impacts of these different BCR-ABL -expressing lineages. Patients: Multi-lineage BCR-ABL expression (multi-Ph) was defined as BCR-ABL expression outside of the B-lineage compartment, as determined by fluorescence in situ hybridization (FISH) in peripheral blood neutrophils and bone marrow clots, and flow cytometry-sorted polymerase chain reaction (PCR)...
2020: Frontiers in Oncology
Renato Bassan, Chiara Pavoni, Tamara Intermesoli, Orietta Spinelli, Manuela Tosi, Ernesta Audisio, Filippo Marmont, Chiara Cattaneo, Erika Borlenghi, Sergio Cortelazzo, Irene Cavattoni, Monica Fumagalli, Daniele Mattei, Claudio Romani, Agostino Cortelezzi, Nicola Fracchiolla, Fabio Ciceri, Massimo Bernardi, Anna Maria Scattolin, Lorella Depaoli, Arianna Masciulli, Elena Oldani, Alessandro Rambaldi
An updated strategy combining pediatric-based chemotherapy with risk-oriented allogeneic hematopoietic cell transplantation (HCT) was evaluated in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) and compared with a published control series. Following induction-consolidation chemotherapy, responsive patients were assigned to receive maintenance chemotherapy or undergo early HCT according to the risk stratification criteria and minimal residual disease (MRD) status. Of the 203 study patients (median age 41 years, range 17-67), 140/161 with Ph- ALL achieved complete remission (86...
November 13, 2020: Blood Cancer Journal
Mirko Farina, Simona Bernardi, Lisa Gandolfi, Camilla Zanaglio, Enrico Morello, Alessandro Turra, Tatiana Zollner, Doriana Gramegna, Benedetta Rambaldi, Federica Cattina, Nicola Polverelli, Michele Malagola, Domenico Russo
Background: Myelodysplastic syndromes and acute leukemias after allogeneic stem cell transplantation (allo-SCT) are mainly caused by recurrence of the primitive leukemic clones. More rarely, they originate from donor hematopoietic stem cells, developing the so-called donor cell leukemia (DCL) or myelodysplastic syndromes (DC-MDSs). DCL and DC-MDS can be considered as an in vivo model of leukemogenesis, and even if the pathogenetic mechanisms remain speculative, a genetic predisposition of donor progenitor cells, an altered host microenvironment, and the impairment of immune surveillance are considered the main causes...
2020: Frontiers in Oncology
Shady Adnan-Awad, Daehong Kim, Helena Hohtari, Komal Kumar Javarappa, Tania Brandstoetter, Isabella Mayer, Swapnil Potdar, Caroline A Heckman, Soili Kytölä, Kimmo Porkka, Eszter Doma, Veronika Sexl, Matti Kankainen, Satu Mustjoki
The oncogenic protein Bcr-Abl has two major isoforms, p190Bcr-Abl and p210Bcr-Abl . While p210Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK)...
November 9, 2020: Leukemia
Nobuaki Dobashi
The introduction of imatinib (IM) has led to a paradigm shift in the treatment strategy for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). After introducing IM, second- and third-generation tyrosine kinase inhibitors (TKIs), which have stronger BCR-ABL1 inhibitory activity than IM, have appeared and their therapeutic results are beginning to be reported. However, to date, no comparison study between individual TKI and the current treatment strategy for Ph + ALL has been performed considering either a TKI-based regimen in induction followed by combination chemotherapy with a TKI or allogeneic hematopoietic stem cell transplantation (alloSCT)...
2020: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Marie-Anne Couturier, Xavier Thomas, Emmanuel Raffoux, Françoise Huguet, Céline Berthon, Célestine Simand, Maria-Pilar Gallego-Hernanz, Yosr Hicheri, Mathilde Hunault Berger, Colombe Saillard, Thibaut Leguay, Clémence Loiseau, Marie-Christine Béné, Patrice Chevallier
We retrospectively examined the results of a new chemo-free approach combining blinatumomab with ponatinib (blina/pona) in 26 relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) patients. All but one achieved complete morphologic remission, and 23 achieved a complete molecular response. With a median follow-up of 34.4 months, the median overall (OS) and event-free (EFS) survivals were 20 and 15.3 months, respectively. After blina/pona, 8 patients underwent an allotransplant (allo), while among the 18 non-transplanted cases, 15 received ponatinib in maintenance...
November 6, 2020: Leukemia & Lymphoma
Yasuo Mori, Kensuke Sasaki, Yoshikiyo Ito, Takuro Kuriyama, Toshiyuki Ueno, Masanori Kadowaki, Takatoshi Aoki, Takeshi Sugio, Goichi Yoshimoto, Koji Kato, Takahiro Maeda, Koji Nagafuji, Koichi Akashi, Toshihiro Miyamoto
Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35...
November 5, 2020: Annals of Hematology
Josep-Maria Ribera, Mireia Morgades, Juana Ciudad, Pau Montesinos, Jordi Esteve, Eulalia Genesca, Pere Barba, Jordi Ribera, Irene García Cadenas, Maria Jose Moreno, Daniel Martínez-Carballeira, Anna Torrent, Pilar Martínez-Sánchez, Silvia Monsalvo, Cristina Gil, Mar Tormo, María Tersa Artola, Marta Cervera, José González-Campos, Carlos Rodríguez-Medina, Arancha Bermúdez, Andrés Novo, Beatriz Soria, Rosa Coll, María-Luz Amigo, Aurelio López, Rosa Fernández Martín, Josefina Serrano, Santiago Mercadal, Antònia Cladera, Alberto Daniel Giménez-Conca, M Jesús Peñarrubia, Eugenia Abella, Ferran Vall-Llovera, Jesús M Hernández-Rivas, Antoni Garcia, Juan Miguel Bergua Burgues, Beatriz de Rueda, María-José Sánchez-Sánchez, Alfons Serrano, María Calbacho, Natalia Alonso Vence, Jose-Ángel Méndez-Sánchez, Raimundo García-Boyero, Matxalen Olivares, Susana Barrena, Lurdes Zamora, Isabel Granada, Ludovic Lhermitte, Evarist Feliu, Alberto Orfao
The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-negative (Ph-neg) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph-neg adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15-60 years (y) with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0...
November 4, 2020: Blood
Nazleen Sherali, Tariq Hamadneh, Saba Aftab, Michael Alfonso, Nicholas Tsouklidis
Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype of B cell ALL. It accounts for 20% of all B cell ALL cases and is similar to BCR-ABL1 in gene expression profile but lacks BCR-ABL fusion. It is highly heterogeneous and is characterized by genetic alterations that activate kinase and cytokine receptor signaling. Most of these alterations are amenable to tyrosine kinase inhibitors. Ph-like ALL is prevalent in pediatric and young adults, more common in males, and frequently seen in patients with Hispanic ancestry...
September 28, 2020: Curēus
D N Lin, Q L Li, X J He, H Li, L B Liao, H He, L L Zhou, Z Li, X L Liu, Q F Liu, H S Zhou, R Cao
Objective: To establish a screening system of adult Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) by fluorescence in situ hybridization (FISH) . Method: Based on the genetic characteristics of Ph-like ALL, FISH probes were designed for ABL1, ABL2, JAK2, EPOR, CRLF2, CSF1R, PDGFRB, and P2RY8 gene breakpoints, which were used to screen Ph-like ALL in B-ALL patients without BCR-ABL1, ETV6-RUNX1, MLL, and E2A gene arrangement. Furthermore, it was analyzed in combination with flow immunophenotype, next-generation sequencing for targeted gene mutations, and RNA sequencing (RNA-seq) ...
September 14, 2020: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Robin Foà, Renato Bassan, Antonella Vitale, Loredana Elia, Alfonso Piciocchi, Maria-Cristina Puzzolo, Martina Canichella, Piera Viero, Felicetto Ferrara, Monia Lunghi, Francesco Fabbiano, Massimiliano Bonifacio, Nicola Fracchiolla, Paolo Di Bartolomeo, Alessandra Mancino, Maria-Stefania De Propris, Marco Vignetti, Anna Guarini, Alessandro Rambaldi, Sabina Chiaretti
BACKGROUND: Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment. METHODS: We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment...
October 22, 2020: New England Journal of Medicine
Jonathan A Webster, Leo Luznik, Hua-Ling Tsai, Philip H Imus, Amy E DeZern, Keith W Pratz, Mark J Levis, Ivana Gojo, Margaret M Showel, Gabrielle Prince, Javier Bolaños-Meade, Lukasz P Gondek, Gabriel Ghiaur, W Brian Dalton, Tania Jain, Ephraim J Fuchs, Douglas E Gladstone, Christian B Gocke, Syed Abbas Ali, Carol Ann Huff, Ivan M Borrello, Lode Swinnen, Nina Wagner-Johnston, Richard F Ambinder, Richard J Jones, B Douglas Smith
Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018...
October 27, 2020: Blood Advances
Ching-Hon Pui
The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno-and cellular-therapy approaches together with precise risk stratification. Children with ETV6-RUNX1 or hyperdiploid > 50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment...
October 19, 2020: Frontiers of Medicine
Hiroto Inaba, Charles G Mullighan
The last decade has witnessed great advances in our understanding of the genetic and biological basis of childhood acute lymphoblastic leukemia (ALL), the development of experimental models to probe mechanisms and evaluate new therapies, and the development of more efficacious treatment stratification. Genomic analyses have revolutionized our understanding of the molecular taxonomy of ALL, and these advances have led the push to implement genome and transcriptome characterization in the clinical management of ALL to facilitate more accurate risk-stratification and, in some cases, targeted therapy...
September 10, 2020: Haematologica
Marie Balsat, Victoria Cacheux, Martin Carre, Emmanuelle Tavernier-Tardy, Xavier Thomas
INTRODUCTION: Despite the significant progress that has been made over the last years in the front-line treatment of Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL), relapses are frequent and their treatment remains a challenge, especially among patients with resistant BCR-ABL1 mutations. AREAS COVERED: This manuscript reviews available data for the treatment of adult patients with relapsed/refractory Ph-positive ALL, with a focus on the role of tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and immunotherapy...
October 3, 2020: Expert Review of Anticancer Therapy
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