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Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group
Carroll, Andrew J; Shago, Mary; Mikhail, Fady M; Raimondi, Susana C; Hirsch, Betsy A; Loh, Mignon L; Raetz, Elizabeth A; Borowitz, Michael J; Wood, Brent L; Maloney, Kelly W; Mattano, Leonard A; Larsen, Eric C; Gastier-Foster, Julie; Stonerock, Eileen; Ell, Denise; Kahwash, Samir; Devidas, Meenakshi; Harvey, Richard C; Chen, I-Ming L; Willman, Cheryl L; Hunger, Stephen P; Winick, Naomi J; Carroll, William L; Rao, Kathleen W; Heerema, Nyla A
Hyperdiploidy with greater than 50 chromosomes is usually associated with favorable prognosis in pediatric acute lymphoblastic leukemia (ALL), whereas hypodiploidy with ≤43 chromosomes is associated with extremely poor prognosis. Sometimes, hypodiploidy is "masked" and patients do not have a karyotypically visible clone with ≤43 chromosomes. Instead, their abnormal karyotypes contain 50-78 or more chromosomes from doubling of previously hypodiploid cells. When the hypodiploid and doubled hyperdiploid clones are both present, patients can be identified by traditional test methods [karyotype, DNA Index (DI), fluorescence in situ hybridization (FISH)], but the incidence of masked hypodiploid cases in which only the doubled clone is visible is unknown. We analyzed 7013 patients with B-ALL enrolled in COG AALL03B1 (2003-2011) for whom chromosome studies were available. Of 115 patients with hypodiploidy (25-39 chromosomes), karyotypes of 40 showed only the hypodiploid clone, 47 showed mosaicism with both hypodiploid and hyperdiploid (doubled) karyotypes, and 28 with masked hypodiploidy showed only a hyperdiploid (doubled) clone. Unique karyotypic signatures were identified, and widespread loss of heterozygosity (LOH) was seen in the microsatellite panel for all patients with masked hypodiploidy. An increased awareness of the unusual karyotypic profile associated with a doubled hypodiploid clone and coordinated use of DI, FISH, and LOH studies when indicated can identify patients with masked hypodiploidy and allow appropriate treatment selection.
PMID: 31425927
ISSN: 2210-7762
CID: 4045862
Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group
Horton, Terzah M; Whitlock, James A; Lu, Xiaomin; O'Brien, Maureen M; Borowitz, Michael J; Devidas, Meenakshi; Raetz, Elizabeth A; Brown, Patrick A; Carroll, William L; Hunger, Stephen P
While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18-36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0-3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58-65% vs. MRDpos 10-19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.
PMID: 30957229
ISSN: 1365-2141
CID: 3809042
Replacement of cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide /etoposide during Consolidation/Delayed Intensification does not improve outcome for pediatric B-ALL: a report from the COG
Burke, Michael J; Salzer, Wanda L; Devidas, Meenakshi; Dai, Yunfeng; Gore, Lia; Hilden, Joanne M; Larsen, Eric; Rabin, Karen R; Zweidler-McKay, Patrick A; Borowitz, Michael J; Wood, Brent; Heerema, Nyla A; Carroll, Andrew J; Winick, Naomi; Carroll, William L; Raetz, Elizabeth A; Loh, Mignon L; Hunger, Stephen P
With modern chemotherapy, approximately 90% of patients with pediatric acute lymphoblastic leukemia are now cured. However, subsets of patients can be identified who remain at very high risk of relapse with expected 4-year disease-free survival <80% and are appropriate candidates for intensive therapeutic strategies designed to improve survival. AALL1131 aimed to determine, in a randomized fashion, if the substitution with cyclophosphamide/etoposide (Experimental Arm 1) would improve the 4-year disease-free survival of children, adolescents, and young adults with very high-risk B-cell acute lymphoblastic leukemia compared to a modified Berlin-Frankfurt-Munster regimen (Control Arm). Patients 1-30 years of age with newly diagnosed very high-risk B-cell acute lymphoblastic leukemia were randomized post-Induction in a 1:2 fashion to the Control Arm or cyclophosphamide (440mg/m2 days 1-5)/ etoposide (100mg/m2 days 1-5) (Experimental Arm 1) during Part 2 of Consolidation and Delayed Intensification. Prospective interim monitoring rules for efficacy and futility were included where futility would be determined for a one-sided p-value ≥ 0.7664. The study was stopped for futility as the interim monitoring boundary was crossed [Hazard Ratio 0.606 (95% CI: 0.297 - 1.237)] and the very high-risk arm of AALL1131 was closed February 2017. Using data current as of 12/31/2017, 4-year disease-free survival rates were 85.5 +6.8% (Control Arm) versus 72.3 +6.3% (Experimental Arm 1) (p-value = 0.76). There were no significant differences in Grade 3/4 adverse events between the 2 arms. Substitution of this therapy for very high-risk B-cell acute lymphoblastic leukemia patients on the Children's Oncology Group AALL1131 (NCT02883049) randomized to cyclophosphamide / etoposide during Part 2 of Consolidation and Delayed Intensification did not improve disease-free survival.
PMID: 30545921
ISSN: 1592-8721
CID: 3679252
Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia
Bhojwani, Deepa; Sposto, Richard; Shah, Nirali N; Rodriguez, Vilmarie; Yuan, Constance; Stetler-Stevenson, Maryalice; O'Brien, Maureen M; McNeer, Jennifer L; Raetz, Elizabeth A; Loh, Mignon L; Rheingold, Susan R
Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.
PMID: 30267011
ISSN: 1476-5551
CID: 3314722
Correction: Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia [Correction]
Bhojwani, Deepa; Sposto, Richard; Shah, Nirali N; Rodriguez, Vilmarie; Yuan, Constance; Stetler-Stevenson, Maryalice; O'Brien, Maureen M; McNeer, Jennifer L; Quereshi, Amrana; Cabannes, Aurelie; Schlegel, Paul; Rossig, Claudia; Dalla-Pozza, Luciano; August, Keith; Alexander, Sarah; Bourquin, Jean-Pierre; Zwaan, Michel; Raetz, Elizabeth A; Loh, Mignon L; Rheingold, Susan R
We thank the research coordinators and following physicians at pediatric cancer centers for contributing data to this project: Prashant Hiwarkar and Jayashree Motwani, Birmingham Women's and Children's Hospital, UK; Kelly Malone, Children's Hospital of Colorado, USA; Mylene Bassal, Children's Hospital of Eastern Ontario, Canada; Yoav Messinger and Joanna Perkins, Children's Hospital of Minnesota, USA; Van Huynh, Children's Hospital of Orange County, USA; Richard Ho, Children's Hospital at Vanderbilt, USA; Joanne Chuah and Jessa Morales, Children's Hospital at Westmead, Australia; Donald Wells, Dell Children's Hospital, USA; Nicolas Boissel, Hospital Saint-Louis, France; Tannie Huang, Kaiser Permanente, USA; Stacey Marjerrison, McMaster Children's Hospital, Canada; William Carroll and Joanna Pierro, New York University Langone Medical Center, USA; Ajay Vora, Sheffield Children's Hospital, UK; Donna Lancaster, The Royal Marsden Hospital, UK; Lucie Šrámková, University Hospital Motol, Czech Republic; Chatchawin Assanasen, University of Texas Health Science Center, San Antonio, USA; Rupert Handgretinger, University of Tübingen, Germany.
PMID: 30842605
ISSN: 1476-5551
CID: 3723272
No evidence that G6PD deficiency affects the efficacy or safety of daunorubicin in acute lymphoblastic leukemia induction therapy
Robinson, Katherine M; Yang, Wenjian; Karol, Seth E; Kornegay, Nancy; Jay, Dennis; Cheng, Cheng; Choi, John K; Campana, Dario; Pui, Ching-Hon; Wood, Brent; Borowitz, Michael J; Gastier-Foster, Julie; Larsen, Eric C; Winick, Naomi; Carroll, William L; Loh, Mignon L; Raetz, Elizabeth A; Hunger, Stephen P; Devidas, Meenakshi; Mardis, Elaine R; Fulton, Robert S; Relling, Mary V; Jeha, Sima
BACKGROUND/OBJECTIVES/OBJECTIVE:Anthracyclines are used in induction therapy of pediatric acute lymphoblastic leukemia (ALL) and are known to generate oxidative stress; whether this translates into enhanced antileukemic activity or hemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency is unknown. DESIGN/METHODS/METHODS:Among 726 pediatric patients with newly diagnosed ALL treated at St. Jude Children's Research Hospital, 22 had deficient G6PD activity. We compared the prevalence of positive minimal residual disease (MRD) ≥1% at Day 15/Day 19 of induction or ≥0.01% at Day 42/Day 46 (end of induction) and the number of red blood cell (RBC) transfusions after daunorubicin in induction between patients with or without G6PD deficiency, adjusting for ALL risk group, treatment protocol, age, and gender. RESULTS:There was no difference in Day 15/19 (P = 1) or end of induction MRD (P = 0.76) nor in the number of RBC transfusions (P = 0.73); the lack of association with MRD was confirmed in a dataset of 1192 newly diagnosed male patients enrolled in a Children's Oncology Group trial (P = 0.78). CONCLUSION/CONCLUSIONS:We found no evidence that G6PD deficiency affects daunorubicin activity during induction treatment for ALL.
PMID: 30848065
ISSN: 1545-5017
CID: 3723602
Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics
Qian, Maoxiang; Xu, Heng; Perez-Andreu, Virginia; Roberts, Kathryn G; Zhang, Hui; Yang, Wenjian; Zhang, Shouyue; Zhao, Xujie; Smith, Colton; Devidas, Meenakshi; Gastier-Foster, Julie M; Raetz, Elizabeth; Larsen, Eric; Burchard, Esteban G; Winick, Naomi; Bowman, W Paul; Martin, Paul L; Borowitz, Michael; Wood, Brent; Antillon-Klussmann, Federico; Pui, Ching-Hon; Mullighan, Charles G; Evans, William E; Hunger, Stephen P; Relling, Mary V; Loh, Mignon L; Yang, Jun J
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Characterized by high levels of Native American ancestry, Hispanics are disproportionally affected by this cancer with high incidence and inferior survival, but the genetic basis for this disparity remains poorly understood because of a paucity of genome-wide investigation of ALL in Hispanics. Performing a genome-wide association study in 940 Hispanic children with ALL and 681 ancestry-matched non-ALL controls, we identified a novel susceptibility locus in the ERG gene (rs2836365; P = 3.76 × 10-8, odds ratio [OR] = 1.56), with independent validation (P = 0.01, OR = 1.43). Imputation analyses pointed to a single causal variant driving the association signal at this locus overlapping with putative regulatory DNA elements. The effect size of the ERG risk variant rose sharply with increasing Native American genetic ancestry. The ERG risk genotype was under-represented in ALL with the ETV6-RUNX1 fusion (P < 0.0005) but enriched in the TCF3-PBX1 subtype (P < 0.05). Interestingly, ALL cases with germline ERG risk alleles were significantly less likely to have somatic ERG deletion (P < 0.05). Our results provide novel insights to genetic predisposition to ALL and its contribution to racial disparity in this cancer.
PMID: 30510082
ISSN: 1528-0020
CID: 3520592
Hematopoietic Stem Cell Transplantation Does Not Improve the Poor Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group
McNeer, Jennifer L; Devidas, Meenakshi; Dai, Yunfeng; Carroll, Andrew J; Heerema, Nyla A; Gastier-Foster, Julie M; Kahwash, Samir B; Borowitz, Michael J; Wood, Brent L; Larsen, Eric; Maloney, Kelly W; Mattano, Leonard; Winick, Naomi J; Schultz, Kirk R; Hunger, Stephen P; Carroll, William L; Loh, Mignon L; Raetz, Elizabeth A
PURPOSE/OBJECTIVE:Children and young adults with hypodiploid B-lymphoblastic leukemia (B-ALL) fare poorly and hematopoietic stem cell transplantation (HSCT) is often pursued in first complete remission (CR1). We retrospectively reviewed the outcomes of children and young adults with hypodiploid B-ALL who were enrolled in recent Children's Oncology Group (COG) trials to evaluate the impact of HSCT on outcome. PATIENTS AND METHODS/METHODS:Cytogenetic analyses and DNA index were performed at COG-approved laboratories, and hypodiploidy was defined as modal chromosome number less than 44 and/or DNA index less than 0.81. Minimal residual disease (MRD) was determined centrally using flow cytometry at two reference laboratories. Patients with hypodiploid ALL came off protocol therapy postinduction and we retrospectively collected details on their subsequent therapy and outcomes. Event-free survival (EFS) and overall survival (OS) were estimated for the cohort. RESULTS:Between 2003 and 2011, 8,522 patients with National Cancer Institute standard-risk and high-risk B-ALL were enrolled in COG AALL03B1 ( ClinicalTrials.gov identifier: NCT00482352). Hypodiploidy occurred in 1.5% of patients (n = 131), 98.3% of whom achieved CR after induction therapy. Five-year EFS and OS were 52.2% ± 4.9% and 58.9% ± 4.8%, respectively. Outcomes for patients undergoing CR1 HSCT were not significantly improved: 5-year EFS and OS were 57.4% ± 7.0% and 66.2% ± 6.6% compared with 47.8% ± 7.5% and 53.8% ± 7.6%, respectively ( P = .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% ± 9.3% and 29.3% ± 10.1%, respectively, and HSCT had no significant impact on outcomes. CONCLUSION/CONCLUSIONS:Children and young adults with hypodiploid B-ALL continue to fare poorly and do not seem to benefit from CR1 HSCT. This is especially true for patients with MRD of 0.01% or greater at the end of induction. New treatment strategies are urgently needed for these patients.
PMID: 30742559
ISSN: 1527-7755
CID: 3656062
PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia
Gu, Zhaohui; Churchman, Michelle L; Roberts, Kathryn G; Moore, Ian; Zhou, Xin; Nakitandwe, Joy; Hagiwara, Kohei; Pelletier, Stephane; Gingras, Sebastien; Berns, Hartmut; Payne-Turner, Debbie; Hill, Ashley; Iacobucci, Ilaria; Shi, Lei; Pounds, Stanley; Cheng, Cheng; Pei, Deqing; Qu, Chunxu; Newman, Scott; Devidas, Meenakshi; Dai, Yunfeng; Reshmi, Shalini C; Gastier-Foster, Julie; Raetz, Elizabeth A; Borowitz, Michael J; Wood, Brent L; Carroll, William L; Zweidler-McKay, Patrick A; Rabin, Karen R; Mattano, Leonard A; Maloney, Kelly W; Rambaldi, Alessandro; Spinelli, Orietta; Radich, Jerald P; Minden, Mark D; Rowe, Jacob M; Luger, Selina; Litzow, Mark R; Tallman, Martin S; Racevskis, Janis; Zhang, Yanming; Bhatia, Ravi; Kohlschmidt, Jessica; Mrózek, Krzysztof; Bloomfield, Clara D; Stock, Wendy; Kornblau, Steven; Kantarjian, Hagop M; Konopleva, Marina; Evans, Williams E; Jeha, Sima; Pui, Ching-Hon; Yang, Jun; Paietta, Elisabeth; Downing, James R; Relling, Mary V; Zhang, Jinghui; Loh, Mignon L; Hunger, Stephen P; Mullighan, Charles G
Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.
PMID: 30643249
ISSN: 1546-1718
CID: 3595242
Plasma asparaginase activity and asparagine depletion in acute lymphoblastic leukemia patients treated with pegaspargase on Children's Oncology Group AALL07P4
Schore, Reuven J; Devidas, Meenakshi; Bleyer, Archie; Reaman, Gregory H; Winick, Naomi; Loh, Mignon L; Raetz, Elizabeth A; Carroll, William L; Hunger, Stephen P; Angiolillo, Anne L
The efficacy of asparaginase in acute lymphoblastic leukemia (ALL) is dependent on depletion of asparagine, an essential amino acid for ALL cells. The target level of plasma asparaginase activity to achieve asparagine depletion has been between 0.05 and 0.4 IU/mL. COG AALL07P4 examined the asparaginase activity and plasma and CSF asparagine concentration of pegaspargase when given intravenously in the treatment of NCI high risk ALL. Matched plasma asparaginase/asparagine levels of the clearance of 54 doses of pegaspargase given in induction or consolidation demonstrated that all patients who had a plasma asparaginase level >0.02 IU/mL had undetectable plasma asparagine. No difference was observed in CSF asparagine levels associated with matched plasma asparaginase levels of 0.02-0.049 versus 0.05-0.22 IU/mL (p = .25). Our data suggest that a plasma asparaginase activity level of 0.02 IU/mL can effectively deplete plasma asparagine. The data also indicate that the 95% CI for plasma asparagine depletion after a pegaspargase dose is 22-29 days. Clinical trial registration: clinicaltrials.gov identifier NCT00671034.
PMID: 30626253
ISSN: 1029-2403
CID: 3579922