Publications by authors named "Nyla A Heerema"

186 Publications

Rare t(X;14)(q28;q32) translocation reveals link between MTCP1 and chronic lymphocytic leukemia.

Nat Commun 2021 11 3;12(1):6338. Epub 2021 Nov 3.

Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.

Rare, recurrent balanced translocations occur in a variety of cancers but are often not functionally interrogated. Balanced translocations with the immunoglobulin heavy chain locus (IGH; 14q32) in chronic lymphocytic leukemia (CLL) are infrequent but have led to the discovery of pathogenic genes including CCND1, BCL2, and BCL3. Following identification of a t(X;14)(q28;q32) translocation that placed the mature T cell proliferation 1 gene (MTCP1) adjacent to the immunoglobulin locus in a CLL patient, we hypothesized that this gene may have previously unrecognized importance. Indeed, here we report overexpression of human MTCP1 restricted to the B cell compartment in mice produces a clonal CD5/CD19 leukemia recapitulating the major characteristics of human CLL and demonstrates favorable response to therapeutic intervention with ibrutinib. We reinforce the importance of genetic interrogation of rare, recurrent balanced translocations to identify cancer driving genes via the story of MTCP1 as a contributor to CLL pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-26400-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566464PMC
November 2021

Outcomes in adolescent and young adult patients (16 to 30 years) compared to younger patients treated for high-risk B-lymphoblastic leukemia: report from Children's Oncology Group Study AALL0232.

Leukemia 2021 Nov 1. Epub 2021 Nov 1.

Department of Pediatrics, Maine Children's Cancer Program, Scarborough, ME, USA.

Adolescent and young adult (AYA) patients 16-30 years old with high-risk acute lymphoblastic leukemia (HR-ALL) have inferior outcomes compared to younger HR-ALL patients. AALL0232 was a Phase 3 randomized Children's Oncology Group trial for newly diagnosed HR B-ALL (1-30 years). Between 2004 and 2011, 3154 patients enrolled with 3040 eligible and evaluable for induction. AYA patients comprised 20% of patients (16-21 years, n = 551; 22-30 years, n = 46). 5-year event-free survival and overall survival was 65.4 ± 2.2% and 77.4 ± 2.0% for AYA patients compared to 78.1 ± 0.9% and 87.3 ± 0.7% for younger patients (p < 0.0001). Five-year cumulative incidence of relapse was 18.5 ± 1.7% for AYA patients and 13.5 ± 0.7% for younger patients (p = 0.006), largely due to increased marrow relapses (14.0 ± 1.5% versus 9.1 ± 0.6%; p < 0.0001). Additionally, induction failure rate was higher in AYA (7.2 ± 1.1% versus 3.5 ± 0.4%; p < 0.001) and post-induction remission deaths were significantly higher in AYA (5.7 ± 1.0% versus 2.4 ± 0.3%; p < 0.0001). AALL0232 enrolled the largest number of AYA B-ALL patients to date, demonstrating significantly inferior survival and greater rates of treatment-related toxicities compared to younger patients. Although treatment intensification has improved outcomes in younger patients, they have not been associated with the same degree of improvement for older patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01460-6DOI Listing
November 2021

VpreB Surrogate Light Chain Expression in B-Lineage ALL: A Report from the Children's Oncology Group.

Blood Adv 2021 Oct 18. Epub 2021 Oct 18.

University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States.

Immunotherapies directed against B-cell surface markers have been a common developmental strategy to treat B-cell malignancies. The IgH surrogate light chain (SLC), comprised of the VpreB1 (CD179a) and Lamda5 (CD179b) subunits is expressed on pro- and pre-B cells where it governs preBCR-mediated autonomous survival signaling. We hypothesized that the pre-BCR might merit the development of targeted immunotherapies to decouple "autonomous" signaling in B-lineage acute lymphoblastic leukemia (B-ALL). We used the COG minimal residual disease (MRD) flow panel to assess pre-BCR expression in 36 primary patient samples accrued to COG standard and high-risk B-ALL studies through AALL03B1. We also assessed CD179a expression in 16 cases with Day 29 end-induction samples, pre-selected to have ≥1% MRD. All analyses were performed on a 6-color Becton-Dickinson flow cytometer in a CLIA/CAP-certified laboratory. Among 36 cases tested, thirty-two were at the pre-B and four were at the pro-B stages of developmental arrest. One or both mAbs showed that CD179a was present in ≥20% of the B-lymphoblast population. All cases expressed CD179a in the end-induction B-lymphoblast population. The CD179a component of the SLC is commonly expressed in B-ALL, regardless of genotype, stage of developmental arrest or NCI risk-status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021005245DOI Listing
October 2021

The impact of increasing karyotypic complexity and evolution on survival in CLL patients treated with ibrutinib.

Blood 2021 Jul 27. Epub 2021 Jul 27.

The Ohio State University, Columbus, Ohio, United States.

Complex karyotype defined as ≥3 cytogenetic abnormalities is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (i.e. ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti-CD20 antibody at our institution. We included 456 patients with both treatment-naïve (TN) and RR disease. Median number of prior therapies was 2 (range 0-13), 30% of patients had del(17p), and 75% were IGHV unmutated. 50% had ≥3 cytogenetic abnormalities including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (HR 1.07 (95% CI 1.04-1.10), p<0.0001) and overall survival (HR 1.09 (95% CI 1.05-1.12), p<0.0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (p=0.02). This solidifies karyotypic complexity as an important prognostic factor for CLL patients treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020010536DOI Listing
July 2021

Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq.

Leukemia 2021 May 21. Epub 2021 May 21.

Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Hematopoiesis is hierarchical, and it has been postulated that acute myeloid leukemia (AML) is organized similarly with leukemia stem cells (LSCs) residing at the apex. Limited cells acquired by fluorescence activated cell sorting in tandem with targeted amplicon-based sequencing (LC-FACSeq) enables identification of mutations in small subpopulations of cells, such as LSCs. Leveraging this, we studied clonal compositions of immunophenotypically-defined compartments in AML through genomic and functional analyses at diagnosis, remission and relapse in 88 AML patients. Mutations involving DNA methylation pathways, transcription factors and spliceosomal machinery did not differ across compartments, while signaling pathway mutations were less frequent in putative LSCs. We also provide insights into TP53-mutated AML by demonstrating stepwise acquisition of mutations beginning from the preleukemic hematopoietic stem cell stage. In 10 analyzed cases, acquisition of additional mutations and del(17p) led to genetic and functional heterogeneity within the LSC pool with subclones harboring varying degrees of clonogenic potential. Finally, we use LC-FACSeq to track clonal evolution in serial samples, which can also be a powerful tool to direct targeted therapy against measurable residual disease. Therefore, studying clinically significant small subpopulations of cells can improve our understanding of AML biology and offers advantages over bulk sequencing to monitor the evolution of disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01295-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606012PMC
May 2021

Favorable Trisomies and Predict Cure in Low-Risk B-Cell Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Trial AALL0331.

J Clin Oncol 2021 05 19;39(14):1540-1552. Epub 2021 Mar 19.

Department of Pediatrics, UT Southwestern, Simmons Cancer Center, Dallas, TX.

Purpose: Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL).

Methods: AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics ( fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%.

Results: The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% standard 94.0% ± 0.8%; = .13) with no difference in OS (98.1% ± 0.5% 99.2% ± 0.3%; = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; = .0004; OS hazard ratio 5.42; < .0001).

Conclusion: Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274747PMC
May 2021

FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children's Oncology Group trial AALL0631.

Leukemia 2021 05 23;35(5):1279-1290. Epub 2021 Feb 23.

Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy-induced cytotoxicity in preclinical models. Children's Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post-induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A-r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib (n = 67, 36 ± 6%) vs. chemotherapy only (n = 54, 39 ± 7%, p = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% (p < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 ± 8%. Adding lestaurtinib did not improve EFS overall, but patients achieving potent FLT3 inhibition and those whose leukemia blasts were sensitive FLT3-inhibition ex vivo did benefit from the addition of lestaurtinib. Patient selection and PD-guided dose escalation may enhance the efficacy of FLT3 inhibition for KMT2A-r infant ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01177-6DOI Listing
May 2021

Prognostic impact of minimal residual disease at the end of consolidation in NCI standard-risk B-lymphoblastic leukemia: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2021 04 9;68(4):e28929. Epub 2021 Feb 9.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

The 5-year disease-free survival (DFS) of National Cancer Institute (NCI) high-risk (HR) B-lymphoblastic leukemia (B-ALL) patients with end of induction (EOI) minimal residual disease (MRD) ≥0.1% and end of consolidation (EOC) MRD ≥0.01% is 39 ± 7%, warranting consideration of hematopoietic stem cell transplant (HSCT). However, the impact of EOC MRD in NCI standard-risk (SR) B-ALL patients using COG regimens is unknown. We found that SR patients with MRD ≥0.01% at both EOI and EOC have a 4-year DFS/overall survival (OS) of 72.9 ± 19.0%/91.7 ± 10.8% versus 90.7 ± 2.9%/95.5 ± 2.0% (p = .0019/.25) for those with EOI MRD ≥0.01% and EOC MRD <0.01%. These data suggest that routine use of HSCT may not be warranted in EOC MRD ≥0.01% SR patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28929DOI Listing
April 2021

Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932.

J Clin Oncol 2021 05 7;39(13):1437-1447. Epub 2021 Jan 7.

Department of Pediatrics and the Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Purpose: AALL0932 evaluated two randomized maintenance interventions to optimize disease-free survival (DFS) while reducing the burden of therapy in children with newly diagnosed NCI standard-risk (SR) B-acute lymphoblastic leukemia (B-ALL).

Methods: AALL0932 enrolled 9,229 patients with B-ALL; 2,364 average-risk (AR) patients were randomly assigned (2 × 2 factorial design) at the start of maintenance therapy to vincristine/dexamethasone pulses every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks, and a starting dose of weekly oral methotrexate of 20 mg/m (MTX20) or 40 mg/m (MTX40).

Results: Five-year event-free survival and overall survival (OS) from enrollment (with 95% CIs), for all eligible and evaluable SR B-ALL patients (n = 9,226), were 92.0% (91.1% and 92.8%) and 96.8% (96.2% and 97.3%), respectively. The 5-year DFS and OS from the start of maintenance for randomly assigned AR patients were 94.6% (93.3% and 95.9%) and 98.5% (97.7% and 99.2%), respectively. The 5-year DFS and OS for patients randomly assigned to receive VCR/DEX4 (n = 1,186) versus VCR/DEX12 (n = 1,178) were 94.1% (92.2% and 96.0%) and 98.3% (97.2% and 99.4%) 95.1% (93.3% and 96.9%) and 98.6% (97.7% and 99.6%), respectively ( = .86 and .69). The 5-year DFS and OS for AR patients randomly assigned to receive MTX20 versus MTX40 were 95.1% (93.3% and 96.8%) and 98.8% (97.9% and 99.7%) 94.2% (92.2% and 96.1%) and 98.1% (97.0% and 99.2%), respectively ( = .92 and .89).

Conclusions: The 0NCI-SR AR B-ALL who received VCR/DEX12 had outstanding outcomes despite receiving one third of the vincristine/dexamethasone pulses previously used as standard of care on Children's Oncology Group (COG) trials. The higher starting dose of MTX of 40 mg/m/week did not improve outcomes when compared with 20 mg/m/week. The decreased frequency of vincristine/dexamethasone pulses has been incorporated into frontline COG B-ALL trials to decrease the burden of therapy for patients and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746PMC
May 2021

Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial.

Nat Med 2020 12 26;26(12):1852-1858. Epub 2020 Oct 26.

Foundation Medicine, Cambridge, MA, USA.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-1089-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530434PMC
December 2020

CytoGPS: A large-scale karyotype analysis of CML data.

Cancer Genet 2020 10 2;248-249:34-38. Epub 2020 Oct 2.

Department of Biomedical Informatics, Wexner Medical Center, The Ohio State University, 250 Lincoln Tower, 1800 Cannon Drive, Columbus, OH 43210, USA. Electronic address:

Karyotyping, the practice of visually examining and recording chromosomal abnormalities, is commonly used to diagnose diseases of genetic origin, including cancers. Karyotypes are recorded as text written in the International System for Human Cytogenetic Nomenclature (ISCN). Downstream analysis of karyotypes is conducted manually, due to the visual nature of analysis and the linguistic structure of the ISCN. The ISCN has not been computer-readable and, as such, prevents the full potential of these genomic data from being realized. In response, we developed CytoGPS, a platform to analyze large volumes of cytogenetic data using a Loss-Gain-Fusion model that converts the human-readable ISCN karyotypes into a machine-readable binary format. As proof of principle, we applied CytoGPS to cytogenetic data from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, a National Cancer Institute hosted database of over 69,000 karyotypes of human cancers. Using the Jaccard coefficient to determine similarity between karyotypes structured as binary vectors, we were able to identify novel patterns from 4,968 Mitelman CML karyotypes, such as the co-occurrence of trisomy 19 and 21. The CytoGPS platform unlocks the potential for large-scale, comparative analysis of cytogenetic data. This methodological platform is freely available at CytoGPS.org.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126981PMC
October 2020

Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia.

J Clin Oncol 2020 10 19;38(28):3282-3293. Epub 2020 Aug 19.

Department of Pediatrics and The Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Purpose: Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease.

Patients And Methods: From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation.

Results: The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( = .029). Differences between DFS in a four-arm comparison were significant ( = .01), with no interactions between the MTX and nelarabine randomizations ( = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% 6.9% ± 1.4%, respectively; = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms.

Conclusion: The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526719PMC
October 2020

Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia.

J Clin Oncol 2020 11 14;38(31):3626-3637. Epub 2020 Aug 14.

Division of Hematology, The Ohio State University, Columbus, OH.

Purpose: The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy.

Patients And Methods: This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety.

Results: The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed.

Conclusion: The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605394PMC
November 2020

Impact of Intrathecal Triple Therapy Versus Intrathecal Methotrexate on Disease-Free Survival for High-Risk B-Lymphoblastic Leukemia: Children's Oncology Group Study AALL1131.

J Clin Oncol 2020 08 4;38(23):2628-2638. Epub 2020 Jun 4.

Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: The high-risk stratum of Children's Oncology Group Study AALL1131 was designed to test the hypothesis that postinduction CNS prophylaxis with intrathecal triple therapy (ITT) including methotrexate, hydrocortisone, and cytarabine would improve the postinduction 5-year disease-free survival (DFS) compared with intrathecal methotrexate (IT MTX), when given on a modified augmented Berlin-Frankfurt-Münster backbone.

Patients And Methods: Children with newly diagnosed National Cancer Institute (NCI) high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) or NCI standard-risk B-ALL with defined minimal residual disease thresholds during induction were randomly assigned to receive postinduction IT MTX or ITT. Patients with CNS3-status disease were not eligible. Postinduction IT therapy was given for a total of 21 to 26 doses. Neurocognitive assessments were performed during therapy and during 1 year off therapy.

Results: Random assignment was closed to accrual in March 2018 after a futility boundary had been crossed, concluding that ITT could not be shown to be superior to IT MTX. The 5-year postinduction DFS and overall survival rates (± SE) of children randomly assigned to IT MTX versus ITT were 93.2% ± 2.1% 90.6% ± 2.3% ( = .85), and 96.3% ± 1.5% 96.7% ± 1.4% ( = .77), respectively. There were no differences in the cumulative incidence of isolated bone marrow relapse, isolated CNS relapse, or combined bone marrow and CNS relapse rates, or in toxicities observed for patients receiving IT MTX compared with ITT. There were no significant differences in neurocognitive outcomes for patients receiving IT MTX compared with ITT.

Conclusion: Postinduction CNS prophylaxis with ITT did not improve 5-year DFS for children with HR B-ALL. The standard of care for CNS prophylaxis for children with B-ALL and no overt CNS involvement remains IT MTX.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402996PMC
August 2020

Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia.

Haematologica 2021 06 1;106(6):1608-1615. Epub 2021 Jun 1.

Department of Hematology, The Ohio State University Wexner Medical Center, Columbus, USA.

Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis. Cytogenetic complexity (>3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV. Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation. Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p). In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002). In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (p.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.212571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168513PMC
June 2021

Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study.

Clin Cancer Res 2020 08 24;26(15):3918-3927. Epub 2020 Mar 24.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: The safety and efficacy of ibrutinib, a once-daily Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was demonstrated in this phase Ib/II study. Extended follow-up up to 8 years is described, representing the longest follow-up for single-agent ibrutinib, or any BTK inhibitor, to date.

Patients And Methods: Phase Ib/II PCYC-1102 (NCT01105247) and extension study PCYC-1103 (NCT01109069) included patients receiving single-agent ibrutinib in first-line or relapsed/refractory CLL/SLL.

Results: Overall response rate was 89%, with similar rates in first-line (87%; complete response, 35%) and relapsed/refractory settings (89%; 10%). Estimated 7-year progression-free survival (PFS) rates were 83% in first-line and 34% in relapsed/refractory settings. Forty-one patients had CLL progression ( = 11 with Richter's transformation). Median PFS was not reached with first-line ibrutinib. In relapsed/refractory CLL/SLL, median PFS was 52 months overall, 26 months in patients with chromosome 17p deletion, 51 months with 11q deletion, not reached with trisomy 12 or 13q deletion, and 88 months in patients without these cytogenetic abnormalities. Estimated 7-year overall survival rates were 84% in first-line and 55% in relapsed/refractory settings. Grade ≥3 adverse events (AE) in >15% of patients were hypertension (28%), pneumonia (24%), and neutropenia (18%). These grade ≥3 AEs generally declined over time, except hypertension. AEs leading to discontinuation in ≥2 patients were observed only in the relapsed/refractory setting (sepsis, diarrhea, subdural hematoma, and Richter's transformation).

Conclusions: With up to 8 years of follow-up, sustained responses and long-term tolerability of single-agent ibrutinib were observed with treatment of first-line or relapsed/refractory CLL/SLL, including high-risk CLL/SLL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175012PMC
August 2020

Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331.

J Clin Oncol 2020 02 11;38(6):602-612. Epub 2019 Dec 11.

Department of Pediatrics, University of Texas (UT) Southwestern, Dallas, TX.

Purpose: Children's Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL.

Patients And Methods: AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases.

Results: The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% ( = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% ( = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively.

Conclusion: The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.01086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030893PMC
February 2020

Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force.

Cancer 2020 02 29;126(3):593-601. Epub 2019 Oct 29.

Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University, Atlanta, Georgia.

Background: Optimal chemotherapy for treating mixed-phenotype acute leukemia (MPAL) and the role of hematopoietic stem cell transplantation (HSCT) remain uncertain. Major limitations in interpreting available data are MPAL's rarity and the use of definitions other than the currently widely accepted criteria: the World Health Organization 2016 (WHO2016) classification.

Methods: To assess the relative efficacy of chemotherapy types for treating pediatric MPAL, the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force assembled a retrospective cohort of centrally reviewed WHO2016 MPAL cases selected from banking studies for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Patients were not treated in COG trials; treatment and outcome data were captured separately. The findings were then integrated with the available, mixed literature to develop a prospective trial in pediatric MPAL.

Results: The central review confirmed that 54 of 70 cases fulfilled WHO2016 criteria for MPAL. ALL induction regimens achieved remission in 72% of the cases (28 of 39), whereas AML regimens achieved remission in 69% (9 of 13). The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% ± 8% and 77% ± 7%, respectively. EFS and OS were 75% ± 13% and 84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT (n = 21).

Conclusions: The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy. A prospective trial within the COG is proposed to investigate this approach; AML chemotherapy and/or HSCT will be reserved for those with treatment failure as assessed by minimal residual disease. Embedded biology studies will provide further insight into MPAL genomics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489437PMC
February 2020

Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group.

Cancer Genet 2019 10 30;238:62-68. Epub 2019 Jul 30.

Department of Pathology, The Ohio State University, Columbus, OH, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2019.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768693PMC
October 2019

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

Blood 2019 10;134(15):1227-1237

Department of Paediatric and Adolescent Oncology, University of Manchester, Manchester, United Kingdom.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2018890764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788009PMC
October 2019

CytoGPS: a web-enabled karyotype analysis tool for cytogenetics.

Bioinformatics 2019 12;35(24):5365-5366

Institute for Informatics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.

Summary: Karyotype data are the most common form of genetic data that is regularly used clinically. They are collected as part of the standard of care in many diseases, particularly in pediatric and cancer medicine contexts. Karyotypes are represented in a unique text-based format, with a syntax defined by the International System for human Cytogenetic Nomenclature (ISCN). While human-readable, ISCN is not intrinsically machine-readable. This limitation has prevented the full use of complex karyotype data in discovery science use cases. To enhance the utility and value of karyotype data, we developed a tool named CytoGPS. CytoGPS first parses ISCN karyotypes into a machine-readable format. It then converts the ISCN karyotype into a binary Loss-Gain-Fusion (LGF) model, which represents all cytogenetic abnormalities as combinations of loss, gain, or fusion events, in a format that is analyzable using modern computational methods. Such data is then made available for comprehensive 'downstream' analyses that previously were not feasible.

Availability And Implementation: Freely available at http://cytogps.org.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btz520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954647PMC
December 2019

Excellent long-term survival of children with Down syndrome and standard-risk ALL: a report from the Children's Oncology Group.

Blood Adv 2019 06;3(11):1647-1656

Division of Hematology-Oncology, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA.

The Children's Cancer Group 1991 study was a clinical trial for children with National Cancer Institute standard-risk acute lymphoblastic leukemia (ALL). This trial demonstrated that 5 doses of vincristine and escalating IV methotrexate (MTX) without leucovorin rescue in the interim maintenance (IM) phases resulted in superior event-free survival (EFS) when compared with 2 doses of vincristine, oral (PO) MTX, PO mercaptopurine, and dexamethasone. This report describes a favorable outcome of this regimen in patients with Down syndrome (DS). Forty-four patients with DS were randomized to the arms containing PO MTX during IM, and 31 to those containing IV MTX. Ten-year EFS rates for patients with DS randomized to IV MTX vs PO MTX were 94.4% ± 5.4% vs 81.5% ± 6.6%, respectively. IV methotrexate with strict escalation parameters, as given in this study, was well tolerated, although the mean total tolerated dose received was lower in patients with DS than in those without DS. There was no increase in hepatic toxicity, systemic infections, or treatment-related deaths in patients with DS during IM on either the IV or PO MTX arms, as compared with those without DS. The incidence of mucositis was increased in patients with DS as compared with patients without DS, particularly among patients who received IV MTX. This trial was registered at www.clinicaltrials.gov as #NCT00005945.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019032094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560340PMC
June 2019

Hematopoietic Stem-Cell Transplantation Does Not Improve the Poor Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group.

J Clin Oncol 2019 04 11;37(10):780-789. Epub 2019 Feb 11.

14 New York University Langone Medical Center, New York, NY.

Purpose: 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: 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: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.00884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440386PMC
April 2019

Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG.

Haematologica 2019 05 13;104(5):986-992. Epub 2018 Dec 13.

Department of Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

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 rates <80%; such patients are appropriate candidates for intensive therapeutic strategies designed to improve survival. The AALL1131 trial was designed to determine, in a randomized fashion, whether 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-Münster regimen (control arm). Patients 1-30 years of age with newly diagnosed very high-risk B-cell acute lymphoblastic leukemia were randomized after induction in a 1:2 fashion to the control arm or experimental arm 1 in which they were given cyclophosphamide (440 mg/m days 1-5)/etoposide (100 mg/m days 1-5) 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% confidence interval: 0.297 - 1.237)] and the very high-risk arm of AALL1131 was closed in February 2017. Using data current as of December 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 two arms. Substitution of this therapy for very high-risk B-cell acute lymphoblastic leukemia patients on the Children's Oncology Group AALL1131 trial (NCT02883049) randomized to cyclophosphamide/etoposide during part 2 of consolidation and delayed intensification did not improve disease-free survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.204545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909PMC
May 2019

Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL.

N Engl J Med 2018 12 1;379(26):2517-2528. Epub 2018 Dec 1.

From Ohio State University Comprehensive Cancer Center, Columbus (J.A.W., A.S.R., N.A.H., W.Z., K.A.R., G.L., J.S.B., H.G.O., J.C.B.); the Alliance Statistics and Data Center (A.S.R., A.M.B., B.M.-E., B.F., S.J.M.), Mayo Clinic (W.D., S.A.P., M.L.), Rochester, MN; Washington University School of Medicine, St. Louis (N.L.B.); Duke Cancer Institute, Duke University Medical Center, Durham (D.M.B., H.E.), and First Health of the Carolinas Cancer Center, Pinehurst (C.K.) - both in North Carolina; the University of Rochester Medical Center, Rochester, NY (P.M.B.); Stanford University School of Medicine, Stanford (S.C.), and the City of Hope Comprehensive Cancer Center, Duarte (A.H.) - both in California; Dana-Farber Partners CancerCare (J.R.B., R.M.S.) and the Massachusetts General Hospital Cancer Center (J.S.A.) - both in Boston; Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN (S.N.); University of Chicago Comprehensive Cancer Center (R.A.L.) and Loyola University Chicago (S.E.S.) - both in Chicago; the University of Calgary, Tom Baker Cancer Centre, Calgary, AB, Canada (C.O.); and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (R.F.L.).

Background: Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy.

Methods: Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met.

Results: A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen).

Conclusions: Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1812836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325637PMC
December 2018

Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia.

Oncogene 2019 03 26;38(13):2241-2262. Epub 2018 Nov 26.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-018-0567-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440839PMC
March 2019
-->