TO THE EDITOR:
Allogeneic hematopoietic cell transplantation (HCT) is paramount to the treatment of relapsed refractory hematologic malignancies. In the absence of a matched related or unrelated donor, a mismatched unrelated donor (MMUD) increases the donor options, particularly for patients from ethnic minorities. However, MMUD HCTs have historically conveyed an increased risk of severe (grade 3-4) acute graft-versus-host disease (aGVHD) and treatment-related mortality (TRM).
by
William G Woods;
Anna R.K. Franklin;
Todd A. Alonzo;
Robert B. Gerbing;
Kathleen A. Donohue;
Megan Othus;
John Horan;
Frederick R. Appelbaum;
Elihu H. Estey;
Clara D. Bloomfield;
Richard A. Larson
BACKGROUND A retrospective meta-analysis of adolescents and young adults (AYAs) with acute myeloid leukemia (AML) was performed to determine if differences in outcome exist following treatment on pediatric versus adult oncology treatment regimens.
METHODS Outcomes were compared of 517 AYAs with AML aged 16 to 21 years who were treated on Children's Oncology Group (COG), Cancer and Leukemia Group B (CALGB), and Southwest Oncology Group (SWOG) frontline AML trials from 1986 to 2008.
RESULTS There was a significant age difference between AYA cohorts in the COG, CALGB, and SWOG trials (median, 17.2 versus 20.1 versus 19.8 years, P <.001). The 10-year event-free survival of the COG cohort was superior to the combined adult cohorts (38% ± 6% versus 23% ± 6%, log-rank P =.006) as was overall survival (45% ± 6% versus 34% ± 7%), with a 10-year estimate comparison of P =.026. However, the younger age of the COG cohort is confounding, with all patients aged 16 to 18 years doing better than those aged 19 to 21 years. Although the 10-year relapse rate was lower for the COG patients (29% ± 6% versus 57% ± 8%, Gray's P <.001), this was offset by a higher postremission treatment-related mortality of 26% ± 6% versus 12% ± 6% (Gray's P <.001). Significant improvements in 10-year event-free survival and overall survival were observed for the entire cohort in later studies.
CONCLUSIONS Patients treated on pediatric trials had better outcomes than those treated on adult trials, but age is a major confounding variable, making it difficult to compare outcomes by cooperative group.
by
Thomas B. Alexander;
Zhaohui Gu;
Ilaria Iacobucci;
Kirsten Dickerson;
John K. Choi;
Beisi Xu;
Debbie Payne-Turner;
Hiroki Yoshihara;
Mignon L. Loh;
John T Horan;
Barbara Buldini;
Giuseppe Basso;
Sarah Elitzur;
Valerie de Haas;
C. Michel Zwaan;
Allen Yeoh;
Dirk Reinhardt;
Daisuke Tomizawa;
Nobutaka Kiyokawa;
Tim Lammens
Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.
by
Ann Woolfrey;
Tao Wang;
Stephanie J. Lee;
Michael D. Haagenson;
Ge Chen;
Katharina Fleischhauer;
John Horan;
Katharine Hsu;
Michael Verneris;
Stephen R. Spellman;
Marcelo Fernandez-Vina
The role of pre-existing donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) in hematopoietic cell transplantation (HCT) is the subject of much debate, reflecting the increasing feasibility of successful transplantation across HLA mismatch barriers. In our study of patients transplanted for non-malignant disease (NMD), HLA-mismatching increased the risk of graft failure and was 2 to 3 fold higher for the compared to patients with malignancies.1 After adjustment for other factors, the odds ratio for primary or secondary graft failure for 7/8 and 6/8 matched pairs was 2.81 (1.74–4.54; p<0.0001) and 2.22 (1.26–3.97; p=0.006), respectively.
by
Muna Qayed;
Tao Wang;
Michael T. Hemmer;
Stephen Spellman;
Mukta Arora;
Daniel Couriel;
Amin Alousi;
Joseph Pidala;
Hisham Abdel-Azim;
Mahmoud Aljurf;
Mouhab Ayas;
Menachem Bitan;
Mitchell Cairo;
Sung Won Choi;
Christopher Dandoy;
David Delgado;
Robert Peter Gale;
Gregory Hale;
Haydar Frangoul;
Rammurti T. Kamble;
Mohamed Kharfan-Dabaja;
Leslie Lehman;
John Levine;
Margaret MacMillan;
David I. Marks;
Taiga Nishihori;
Richard F. Olsson;
Peiman Hematti;
Olov Ringden;
Ayman Saad;
Prakash Satwani;
Bipin N. Savani;
Kirk R. Schultz;
Sachiko Seo;
Shalini Shenoy;
Edmund Waller;
Lolie Yu;
Mary M. Horowitz;
John Horan
Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR],.42; 95% confidence interval [CI],.26 to.70; P =.0008), grade II-IV aGVHD (HR,.24; 95% CI,.10 to.56; P =.001), and cGVHD (HR,.32; 95% CI,.19 to.54; P <.001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.36; 95% CI,.20 to.65; P =.0007) and in 2009-2013 (HR,.24; 95% CI..11 to.53; P =.0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.23; 95% CI,.08 to.65; P =.0056) and 2009-2013 (HR,.16; 95% CI,.04 to.67; P =.0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.
Hematopoietic cell transplantation (HCT) is the only readily available cure for many life-threatening pediatric nonmalignant diseases (NMD), but most patients lack a matched related donor and are at higher risk for graft-versus-host disease (GVHD). Use of abatacept (Aba) to target donor T-cell activation has been safe and effective in preventing GVHD after unrelated donor (URD) HCT for malignant diseases (Aba2 trial). Our primary objective was to evaluate the tolerability of Aba added to standard GVHD prophylaxis (cyclosporine and mycophenolate mofetil) in pediatric patients with NMD undergoing URD HCT. In this single-arm, single-center phase 1 trial, 10 patients receiving reduced intensity or nonmyeloablative conditioning underwent URD HCT. Immune reconstitution was assessed longitudinally via flow cytometry and compared to pediatric patients on Aba2. Nine patients successfully engrafted, with 1 primary graft rejection in the setting of inadequate cell dose; secondary graft rejection occurred in 1 patient with concurrent cytomegalovirus viremia. Two deaths occurred, both unrelated to Aba. One patient developed probable posttransplant lymphoproliferative disease, responsive to rituximab and immune suppression withdrawal. No patients developed severe acute or chronic GVHD, and 8 patients were off systemic immunosuppression at 1 year. Immune reconstitution did not appear to be impacted by Aba, and preservation of naïve relative to effector memory CD4+ T cells was seen akin to Aba2. Thus, 4 doses of Aba were deemed tolerable in pediatric patients with NMD following URD HCT, with encouraging preliminary efficacy and supportive immune correlatives in this NMD cohort.
by
Yvonne Suessmuth;
Muna Qayed;
Ben Watkins;
Victor Tkachev;
James Kaminski;
Elizabeth Lake Potter;
Scott N Furlan;
Alison Yu;
Daniel J Hunt;
Connor McGuckin;
Hengqi Zheng;
Lucrezia Colonna;
Ulrike Gerdemann;
Judith Carlson;
Michelle Hoffman;
Joe Olvera;
Chris English;
Audrey Baldessari;
Angela Panoskaltsis-Mortari;
Kayla Betz;
Brandi Bratrude;
Amelia Langston;
John Horan;
Jose Ordovas-Montanes;
Alex K Shalek;
Bruce R Blazar;
Maro Roederer;
Leslie Kean
Organ infiltration by donor T cells is critical to the development of acute graft-versus-host disease (aGVHD) in recipients after allogeneic hematopoietic stem cell transplant (allo-HCT). However, deconvoluting the transcriptional programs of newly recruited donor T cells from those of tissue-resident T cells in aGVHD target organs remains a challenge. Here, we combined the serial intravascular staining technique with single-cell RNA sequencing to dissect the tightly connected processes by which donor T cells initially infiltrate tissues and then establish a pathogenic tissue residency program in a rhesus macaque allo-HCT model that develops aGVHD. Our results enabled creation of a spatiotemporal map of the transcriptional programs controlling donor CD8+ T cell infiltration into the primary aGVHD target organ, the gastrointestinal (GI) tract. We identified the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphodepletion-driven, T cell infiltration. GI-infiltrating donor CD8+ T cells demonstrated a highly activated, cytotoxic phenotype while simultaneously developing a canonical tissue-resident memory T cell (TRM) transcriptional signature driven by interleukin-15 (IL-15)/IL-21 signaling. We found expression of a cluster of genes directly associated with tissue invasiveness, including those encoding adhesion molecules (ITGB2), specific chemokines (CCL3 and CCL4L1) and chemokine receptors (CD74), as well as multiple cytoskeletal proteins. This tissue invasion transcriptional signature was validated by its ability to discriminate the CD8+ T cell transcriptome of patients with GI aGVHD from those of GVHD-free patients. These results provide insights into the mechanisms controlling tissue occupancy of target organs by pathogenic donor CD8+ TRM cells during aGVHD in primate transplant recipients.
We compared outcomes after hematopoietic cell transplantation in patients of African American (n=84) and Caucasian (n=215) descent with severe aplastic anemia. African Americans and Caucasians were matched for age, donor-recipient human leukocyte antigen match, graft type, and transplantation year. The median follow-up of surviving patients was 5 years. In multivariate analysis, overall mortality risks were higher for African Americans compared to Caucasians (relative risk 1.73, P=0.01). The 5-year probabilities of overall survival adjusted for interval from diagnosis to transplantation, and performance score was 58% for African Americans and 73% for Caucasians. The day-100 cumulative incidence of grade III-IV, but not grade II-IV acute graft-versus-host disease (GVHD), was higher in African Americans compared to Caucasians (29% vs. 13%, P=0.006). Although the 5-year cumulative incidence of chronic GVHD was not significantly different between the racial groups, African Americans were more likely to have extensive chronic GVHD compared to Caucasians (72% vs. 49%, P=0.06). Survival differences between Caucasians and African Americans can be attributed to multiple factors. Our data suggest that some of the observed survival differences between Caucasians and African Americans may be explained by higher rates of acute GVHD and severity of chronic GVHD.
Background: We sought to better define the role of hematopoietic cell transplantation (HCT) in first remission (CR1) for high-risk pediatric acute myeloid leukemia (AML).
Procedures: Outcomes were compared among patients aged less than 21 years with cytogenetically defined poor-risk AML treated with chemotherapy, matched related (MRD), or unrelated donor (URD) transplantation in CR1. Poor-risk cytogenetics was defined as monosomy 7/del7q, monosomy 5/del 5q, abnormalities of 3q, t(6;9)(p23;q34), or complex karyotype. Included are patients treated on Children's Oncology Group trials or reported to the Center for International Blood and Marrow Transplant Research from 1989 to 2006.
Results: Of the 233 patients, 123 received chemotherapy, 55 received MRD HCT, and 55 received URD HCT. The 5-year overall survival from the time of consolidation chemotherapy or transplant conditioning was similar: chemotherapy (43%±9%), MRD (46%±14%), or URD (50%±14%), P=0.99. Similarly, multivariate analysis demonstrated no significant differences in survival [(reference group=chemotherapy); MRD HR 1.08, P=0.76; URD HR 1.13, P=0.67] despite lower relapse risk with URD HCT (HR=0.43, P=0.01).
Conclusions: Our findings do not provide support for the preferential use of HCT over chemotherapy alone for children with cytogenetically defined poor-risk AML in CR1.
by
Jason Canner;
Todd A. Alonzo;
Janet Franklin;
David R. Freyer;
Alan Gamis;
Robert B. Gerbing;
Beverly J. Lange;
Soheil Meshinchi;
William G Woods;
John Perentesis;
John Horan
BACKGROUND Studies comparing survival of adolescent and young adult (AYA) patients to that of younger patients with newly diagnosed acute myeloid leukemia (AML) have yielded conflicting results. In order to more accurately characterize relative survival and other outcomes of AYA patients, a cross-study analysis was conducted using data from recent trials conducted by the Children's Cancer Group (CCG) and Children's Oncology Group (COG).
METHODS Data were combined from the CCG-2891, CCG-2941, CCG-2961, and AAML03P1 trials. The data set included 1840 patients, comprising 238 AYA and 1602 younger patients.
RESULTS Overall survival was not significantly different in the 2 groups (AYA, 49% ± 7% versus younger, 54% ± 3% (± 2 standard errors), P =.058). Relapse was lower in AYA patients (30% ± 7% versus 41% ± 3%, P =.002), but treatment-related mortality (TRM) was higher (25% ± 6% versus 12% ± 2%, P <.001). After adjustment for other factors, older age remained strongly associated with TRM (hazard ratio = 2.30, 95% CI = 1.59-3.33, P <.001). Infection accounted for the excess TRM in AYA patients.
CONCLUSIONS Survival in AYA and younger patients with newly diagnosed AML is similar; however, older patients are at higher risk for TRM. More effective strategies for preventing mortality from infection in AYA patients are needed.