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Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study
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Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study Kasiani C Myers*, Elissa Furutani*, Edie Weller, Bradford Siegele, Ashley Galvin, Valerie Arsenault, Blanche P Alter, Farid Boulad, Carlos Bueso-Ramos, Lauri Burroughs, Paul Castillo, James Connelly, Stella M Davies, Courtney D DiNardo, Iftikhar Hanif, Richard H Ho, Nicole Karras, Michelle Manalang, Lisa J McReynolds, Taizo A Nakano, Grzegorz Nalepa, Maxim Norkin, Matthew J Oberley, Etan Orgel, Yves D Pastore, Joseph Rosenthal, Kelly Walkovich, Jordan Larson, Maggie Malsch, M Tarek Elghetany, Mark D Fleming, Akiko Shimamura
Summary
Background Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies.
Lancet Haematol 2019
Methods We did a multicentre, retrospective, cohort study in collaboration with the North American ShwachmanDiamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients.
*Contributed equally
Findings We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9–8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8–not reached) and 0·99 years (95% CI 0·2–2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1–39) for patients with leukaemia and 51% (29–68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia—including the two patients initially diagnosed with myelodysplastic who progressed— two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32–82; n=14) compared with 28% (95% CI 10–50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts. Interpretation Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome.
www.thelancet.com/haematology Published online December 23, 2019 https://doi.org/10.1016/S2352-3026(19)30206-6
Published Online December 23, 2019 https://doi.org/10.1016/ S2352-3026(19)30206-6 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA (K C Myers MD, S M Davies PhD); Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA (K C Myers, S M Davies); Pediatric Hematology– Oncology (E Furutani MD, A Shimamura MD, A Galvin BS, J Larson BS, M Malsch MSN), Division of Hematology and Oncology and Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research (E Weller PhD) and Department of Pathology (B Siegle MD, M D Fleming DPhil), Boston Children’s Hospital, Boston, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA (E Furutani, A Shimamura); Department of Pediatrics, Harvard Medical School, Boston, MA, USA (E Furutani, A Shimamura); Harvard Medical School, Boston, MA, USA; CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada (V Arsenault MD, Y D Pastore MD); Clinical Genetics Branch, National Institutes of Health National Cancer Institute, Rockville, MD, USA (B P Alter MD, L J McReynolds MD); Department of Pediatrics, Bone Marrow Transplantation Service, Memorial Sloan
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Kettering Cancer Center, New York, NY, USA (F Boulad MD); Department of Hematopathology (C Bueso-Ramos MD), and Department of Leukemia (C D DiNardo MD), The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pediatrics, Division of Hematology–Oncology Seattle Children’s and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA (L Burroughs MD); Shands Children’s Hospital, Department of Pediatrics, Division of Pediatric Hematology Oncology (P Castillo MD) and Department of Medicine (M Norkin MD), University of Florida, Gainesville, FL, USA; Department of Pediatrics, Division of Pediatric Hematology Oncology, Vanderbilt University Medical Center, Nashville, TN, USA (J Connelly MD, R H Ho MD); Center for Cancer and Blood Disorders, Joe DiMaggio Children’s Hospital, Hollywood, FL, USA (I Hanif MD); Department of Pediatrics, City of Hope National Medical Center, Duarte, CA, USA (N Karras MD, J Rosenthal MD); Marshfield Clinic Health System, Marshfield, WI, USA (M Manalang MD); Center for Cancer and Blood Disorders, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA (T A Nakano MD); Department of Pediatrics, Division of Pediatric Hematology– Oncology, Indiana University School of Medicine, Indianapolis, IN, USA (G Nalepa MD); Department of Pathology and Laboratory Medicine (M J Oberley MD) and Division of Pediatric Hematology Oncology and Blood and Marrow Transplantation (E Orgel MD), Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Pediatrics, City of Hope National Medical Center, Duarte, CA, USA (J Rosenthal); Division of Pediatric Hematology– Oncology, Department of
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Funding National Institute of Health. Copyright © 2019 Elsevier Ltd. All rights reserved.
Introduction Shwachman-Diamond syndrome is an autosomal recessive disorder characterised by bone marrow failure, exocrine pancreatic dysfunction, additional variable organ system abnormalities, and predisposition to myelodysplasia and acute myeloid leukemia.1 Over 90% of patients with Shwachman-Diamond syndrome carry biallelic mutations in the gene for Shwachman-BodianDiamond syndrome (SBDS; a rare congenital disorder characterised by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, short stature, and variable multi-organ system abnormalties) on chromosome 7q11, encoding a protein involved in ribosomal maturation.2,3 Patients with mutations in SRP54, DNAJC21, and EFL1 can also present with clinical features of Shwachman-Diamond syndrome.4 Myelodysplastic syndrome and acute myeloid leukaemia are major life-threatening complications of ShwachmanDiamond syndrome. Malignant transformation ranges between 5% and 36%, and Shwachman-Diamond syndrome can be unrecognised in young adults with
myeloid malignancies. A Center for International Blood and Marrow Transplant Research (CIBMTR) study found that 4% of young patients undergoing haematopoietic stem cell transplantation (HSCT) for myelodysplastic syndromes had Shwachman-Diamond syndrome.5 Baseline marrow dysmorphologies make the diagnosis of myelodysplastic syndrome and acute myeloid leukaemia challenging in leukaemia predisposition disorders.1,6 Revisions in WHO definitions of myelo dysplastic syndrome and acute myeloid leukaemia warrant reassessment of myelodysplastic syndrome or acute myeloid leukaemia outcomes in ShwachmanDiamond syndrome by means of existing diagnostic criteria. There is no consensus regarding treatment for patients with Shwachman-Diamond syndrome, including the role of pre-HSCT cytoreductive chemotherapy or recommended conditioning regimens before HSCT. Data are sparse, coming from case reports and small case series.7,8 Although myelodysplastic syndrome and acute myeloid leukaemia are now recognised to be
Research in context Evidence before this study We searched Ovid and PubMed on Feb 7, 2019 with the terms “myelodysplastic syndrome”, “acute myeloid leukemia”, “treatment”, “leukemia predisposition”, and “shwachman diamond syndrome”, without restrictions on dates of publication or types of study up to Feb 7, 2019. Reports of malignant transformation in Shwachman-Diamond syndrome—a bone marrow failure, and leukaemia predisposition disorder—vary widely at 5–36%. Moreover, Shwachman–Diamond syndrome is often unrecognised, particularly in adults (eg, typically those aged 20–40 years). A genomic screen of patients with myelodysplastic syndrome in the Center for International Blood and Marrow Transplant Research diagnosed ShwachmanDiamond Syndrome in 4% of young patients aged <40 years (median age 25·1 years [95% CI 18·2–38·2]). Data describing events leading up to malignant transformation in individuals with Shwachman-Diamond syndrome is scarce. Baseline marrow dysmorphologies make the diagnosis of myelodysplastic syndrome challenging, and the significance of cytogenetic clones such as del(20)(q11) or isochromosome (7)(q10) and others in the absence of morphologic myelodysplastic syndrome, increasing blasts, or falling blood counts is unclear. The expert consensus recommendation is to monitor patients for early signs of clonal evolution to facilitate early haemopoietic stem cell transplantation (HSCT) before the onset of acute myeloid leukaemia, but data to inform frequency and method of surveillance strategies are inadequate. There is no consensus regarding treatment for myelodysplastic
syndrome or acute myeloid leukaemia in patients with Shwachman-Diamond syndrome, including the role of pre-HSCT cytoreductive chemotherapy or recommended conditioning regimens for HSCT. Added value of this study This study suggests that poor outcomes of patients with acute myeloid leukaemia or myelodysplastic syndrome and Shwachman-Diamond syndrome results from both high treatment related mortality and high disease resistance. This study also shows the variability and limitations of existing surveillance practices, particularly potential caveats of relying on blood counts alone to detect early clonal disease. It highlights the complexities of pathological diagnosis of malignancy in this cancer predisposition syndrome characterised by dyspoiesis, particularly in identifying patients with advanced myelodysplastic syndrome in urgent need of expeditious transplantation. Implications of all the available evidence The complexities of pathological diagnosis and poor prognosis of patients with acute myeloid leukaemia or myelodysplastic syndrome and Shwachman-Diamond syndrome highlight the need for expert pathological review, and development of novel diagnostic tools for surveillance and use in prospective studies to evaluate the effect of early intervention on overall survival. Novel therapies and HSCT regimens with both decreased toxicity and improved antileukaemic properties are urgently needed to improve the outcomes of these patients.
www.thelancet.com/haematology Published online December 23, 2019 https://doi.org/10.1016/S2352-3026(19)30206-6
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clinically and biologically distinct, previous studies often reported combined outcomes of both diagnoses together.4 We did a multi-institutional, retrospective, cohort study of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia with the aim of describing demographics, disease characteristics, challenges of pathologic diagnosis, surveillance practices, therapy response, and overall survival outcomes. These data form a basis to inform medical management of this leukaemia-predisposition syndrome.
Methods
Study design To identify the patient cohort, we reviewed charts from 17 institutions (appendix p 10) in the USA and Canada in collaboration with the North American ShwachmanDiamond Syndrome Registry. Inclusion criteria consisted of either biallelic mutations in the SBDS gene or a clinical diagnosis of ShwachmanDiamond syndrome as defined by cytopenias and pancreatic dysfunction,9 together with a diagnosis of myelodysplastic syndrome or acute myeloid leukaemia. There were no age restrictions. This study was approved by Cincinnati Children’s Hospital Institutional Review Board (primary Institutional Review Board) and local Institutional Review Boards.
Procedures All histological samples and data extracted from the medical record were de-identified and collected in the Research Electronic Data Capture (REDCap) system.10 We extracted data on genetic and clinical diagnostic and disease features of Shwachman-Diamond syndrome and myleodysplastic syndrome–acute myeloid leukaemia, date of diagnosis, malignancy characteristics, surveillance strategies before diagnosis, treatments received, toxicities, and outcomes. Treatment response criteria were reported as estab lished by local treating physicians. Disease response was assess ed by the local treating physician per their institutional practice or criteria at the time of clinical treatment. Serial bone marrow surveillance was defined as bone marrow examinations done routinely in the absence of symptoms. Masked centralised pathology review following WHO 2016 diagnostic criteria was done by two independent groups of pathologists based at Boston Children’s Hospital, Harvard Medical School (Boston, MA, USA) and Texas Children’s Hospital, Baylor College of Medicine (Houston, TX, USA) with expertise in marrow failure syndromes in the patients with available histological samples.11 If central review indicated a different diagnosis from the local report, patients were reclassified accordingly for further analysis (figure 1).
Statistical analysis Summary statistics are reported for continuous variables (mean [SD] or median [interquartile range]) and binary variables (proportions and exact binomial 95% CIs using Pearson-Klopper method). Fisher’s exact test was used to compare categorical outcomes. Overall survival time was defined as time from initial diagnosis (acute myeloid leukaemia, myelodysplastic syndrome, myelodysplastic syndrome excess blasts 1 or 2) to death from any cause or date of last follow-up. Overall survival was estimated by means of the Kaplan-Meier method and compared with the log-rank test. In the analysis summarising outcomes by central review diagnosis, the local diagnosis is used if histological samples were not available for review. The statistical analysis was performed using the R package.
Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA (K Walkovich MD); and Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA (M T Elghetany MD) Correspondence to: Dr Akiko Shimamura, Boston Children’s Hospital, Boston, MA USA akiko.shimamura@childrens. harvard.edu
See Online for appendix
Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author oversaw the study, and had final responsibility to submit for publication.
Results Patient demographics and disease characteristics are shown in table 1 and appendix (p 5–8). Median year of diagnosis was 2010 (range 2001–17; IQR: 2007–13), and median follow-up was 4·9 years (IQR 3·9–8·4). Data were collected from clinical records dating from March 1, 2001 to Oct 5, 2017. Diagnosis of ShwachmanDiamond syn drome was established by presence of 37 eligible patients identified based on local review 27 myelodysplastic syndrome 10 acute myeloid leukaemia
10 had no samples available for central review 27 had central pathology review 10 confirmed myelodysplastic syndrome 1 confirmed myelodysplastic syndrome-EB1 or 2 4 confirmed acute myeloid leukaemia 1 reclassified from myelodysplastic syndrome to acute myeloid leukaemia 1 reclassified from acute myeloid leukaemia to myelodysplastic syndrome 6 reclassified from myelodysplastic syndrome-EB to myelodysplastic syndrome 3 reclassified from myelodysplastic syndrome to myelodysplastic syndrome-EB1 or 2 1 not myelodysplastic syndrome or acute myeloid leukaemia
1 excluded, not eligible after central review
36 patients included in the analysis (clinical characteristics and overall survival) 26 classified as myelodysplastic syndrome (21 confirmed) 10 classified as acute myeloid leukaemia (5 confirmed)
Figure 1: Study profile EB=excess blasts.
www.thelancet.com/haematology Published online December 23, 2019 https://doi.org/10.1016/S2352-3026(19)30206-6
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Patients (n=36) Age at myelodysplastic syndrome or acute myeloid leukaemia diagnosis <18 years
17 (47%)
≥18 years
19 (53%)
Median (range), years
18 (0·5–47)
Sex Male
16 (44%)
Female
20 (56%)
Bi-allelic SBDS mutations Yes
30 (83%)
NA
6 (17%)
Neutropenia Yes
25 (69%)
No
4 (11%)
NA
7 (19%)
Failure to thrive or pancreatic enzyme use Yes
30 (83%)
No
4 (11%)
NA
2 (6%)
Congenital anomalies and multi-organ involvement* Yes
27 (75%)
No
9 (25%)
Data are n (%). NA=not available. *Denotes presence or absence of congenital anomalies or medical comorbidities outside of the haematopoietic system.
Table 1: Patient characteristics
biallelic SBDS mutations (n=30; appendix pp 3–4) or clinical diagnosis of cytopenias and exocrine pancreatic dysfunction (n=6). Among the 27 patients with histological samples available, central pathology review agreed with local review in 15 (56%) cases; appendix p 9; figure 1). The most common discrepancy was the distinction between low grade myelodysplastic syndrome versus advanced myelodysplastic syndrome with excess blasts. This difference in categorisation highlights the challenges of enumerating blasts in a hypocellular marrow with baseline dys morphologies. One patient with a local diagnosis of myelodysplastic syndrome was excluded from further analyses after determination of marrow morphology within the normative baseline of Shwachman-Diamond syndrome and no cytogenetic abnormalities (appendix p 7). Table 2 shows initial diagnoses and ages at presentation. Nine (35%) of 26 patients with myelodysplastic syndrome and one (10%) of 10 patients with leukaemia were being treated with granulocyte colony-stimulating factor (G-CSF) at time of malignancy diagnosis, which is similar to the North American Shwachman-Diamond syndrome registry of patients with biallelic SBDS mutations, 45 [45%] of 99 patients). Complex karyotypes, defined by three or more numerical or structural chromosomal abnormalities, were seen in eight (36%) of 22 (4 of 26 did not have karyotype data) myelodysplastic syndrome cases and eight (80%) of ten acute myeloid leukaemia cases (p=0·054). 4
Surveillance marrow examinations showed predom inantly hypocellular marrows with frequent mild dyspoiesis of myeloid, erythroid, or megakaryocytic lineages. Baseline morpho logical atypia in surveillance samples was most pronounced in the myeloid lineage, where mature neutrophils often had a combination of incomplete nuclear segmentation and variable hypo granulation (appendix p 1). These features fall within the spectrum of baseline Shwachman-Diamond syndrome marrow morphology. Patients with myelodysplastic syndrome showed subtle but progressively more pronounced lineage dysplasias. Dysmorphic features in the myeloid lineage pre dominated in myelodysplastic syndrome and included prominent nuclear hypolobation (so-called Pelger-Huetlike forms), prominent cytoplasmic hypogranulation, and cases with markedly enlarged myeloid precursors and forms with prominent basophilic cytoplasm. Most cases of myelo dysplastic syndrome also had more significant dyserythropoiesis. 30 (88%) of 36 patients had available data on treatment received. Treatments were heterogeneous (appendix pp 5–8). Ten different initial chemotherapy regimens, including hypomethylating agents (n=2) and cytoreductive chemotherapy (n=8), were delivered. HSCT was initial therapy for 16 patients. 16 different HSCT approaches were reported, including 13 reduced intensity condit ioning and 3 myeloablative conditioning regimens (appendix pp 5–8). Patients with leukaemia had a median time to first treatment of 0·3 months (IQR 2 days–0·9 months) versus 4·7 months (IQR 2·7–6·6) for myelodysplastic syndrome. However, median time to HSCT was similar at 4·6 months (IQR 2·9–5·6) for leukaemia and 4·7 months (3·0–7·3) for myelodysplastic syndrome. 18 (69%) of 26 patients diagnosed with low grade or high-grade myelodysplastic syndrome received therapy for myelodysplastic syndrome consisting of either upfront HSCT (n=14) or upfront chemotherapy (n=4). Of the 14 who received upfront HSCT, ten (71%) achieved a complete response following HSCT of whom seven remain alive with median follow-up of 82 months (IQR 59–94) from diagnosis, two died in remission of treatment-related toxicities (4 months and 6 months post-HSCT), and one died with recurrent disease (9 months post-HSCT). Three patients with myelodysplastic syn drome who underwent upfront HSCT developed graft failure, of whom two died with active disease at 19 and 26 months and one died with unknown disease status at 18 months. One patient is alive 39 months after diagnosis, response to therapy unknown. Only one (25%) of four patients with myelodysplastic syndrome who received upfront chemotherapy achieved a complete response. Of this group, one subsequently underwent HSCT and died at 4 months of multiorgan failure, two died (at 4 months and 7 months) of infection
www.thelancet.com/haematology Published online December 23, 2019 https://doi.org/10.1016/S2352-3026(19)30206-6
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and disease, and one continues on a hypomethylating agent with active disease 56 months after diagnosis. Four patients with myelodysplastic syndrome received no therapy, two died with active disease (at 2 months and 92 months), and two were lost to follow-up with active disease (at 18 months and 121 months). Two patients did not have treatment data available and were lost to followup at 18 and 21 months. Two patients with an initial diagnosis of myelodysplastic syndrome with excess blasts 1 or 2 progressed to leukaemia (at 2·5 months and 3·8 months) before receiving any myelodysplastic syndrome-directed therapy. 12 patients received treatment for acute myeloid leukaemia, including two patients initially diagnosed with myelodysplastic syndrome-with excess blasts 1 or 2 who progressed. Ten (83%) of 12 received pre-HSCT therapy (two with a hypomethylating agent, eight with cytoreductive chemotherapy) with intent to proceed with HSCT; only one patient achieved a complete response. The only patient with normal cytogenetics at initial leukaemia diagnosis was also the only patient who achieved complete response following chemotherapy. This patient remains alive 49 months from diagnosis following a complicated post-HSCT course, including two episodes of graft failure requiring a total of three transplantations. The other nine patients who received upfront pre-HSCT therapy died with median overall survival of 9 months (IQR 4–13). Two patients with leukaemia received HSCT as initial therapy; one achieved a complete response but died of treatment-related complications in remission at 9 months. The other progressed from myelodysplastic syndrome with excess blasts 1 or 2 to leukaemia and underwent HSCT without previous cytoreductive chemotherapy and remains alive without disease at 6 months. At a median follow-up of 4·1 years (IQR 0·3–not estimable), 3-year overall survival from initial leukaemia diagnosis was 11% (95% CI 1–39) and median overall survival was 0·99 years (95% CI 0·2–2·4; figure 2A). At a median follow-up of 5·1 years (IQR 3·3–8·4), 3-year overall survival for myelodysplastic syndrome was 51% (95% CI 29–68), and median overall survival of 7·7 years (95% CI 0·8–not reached; figure 2B). Overall survival analysis separating low-risk and high-risk myelodysplastic syndrome are shown in appendix (p 2). When restricted to patients with central pathology review, 3-year overall survival was 20% (95% CI 1–58) for 5 patients with confirmed acute myeloid leukaemia and 45% (95% CI 22–65%) for 21 patients with confirmed myelodysplastic syndrome. Subgroup analyses showed no effect of age on overall survival by diagnosis with a HR of 1·03 for leukaemia (95% CI 0·98–1·08, p=0·35) and 1·03 for myelodysplastic syndrome (95% CI 0·99–1·08, p=0·11), and no difference in OS was detected by year of diagnosis (HR 1·0, 95% CI 0·9–1·2, p=0·57) or treatment (HR 1·0, 95% CI 0·9–1·1, p=0·83; appendix p 11).
Patients (n=36)
Sex
Female
Median age at myelo dysplastic syndrome or acute myeloid leukaemia diagnosis (range), years Male
Local diagnosis Myelodysplastic syndrome Myelodysplastic syndrome-EB1 or 2 Acute myeloid leukaemia
18 (50%)
10/18 (56%)
8/18 (44%)
14·3 (0·5–45·0)
8 (22%)
4/8 (50%)
4/8 (50%)
16·0 (9·0–30·0)
10 (28%)
6/10 (60%)
4/10 (40%)
33·5 (5·5–47·0)
21 (58%)
10/21 (48%)
11/21 (52%)
16·0 (0·5–45·0)
5 (14%)
3/5 (60%)
2/5 (40%)
13·8 (1·4–20·0)
10 (28%)
7/10 (70%)
3/10 (30%)
31·4 (5·5–47·0) 21·0 (9·0–47·0)
Central diagnosis* Myelodysplastic syndrome Myelodysplastic syndrome-EB1 or 2 Acute myeloid leukaemia Complex karyotype Yes
16 (44%)
9/16 (56%)
7/16 (44%)
No
16 (44%)
8/16 (50%)
8/16 (50%)
12·9 (1·4–45·0)
NA
4 (11%)
3/4 (75%)
1/4 (25%)
15·5 (0·5–20·0)
Bone marrow surveillance Yes
14 (39%)
6/14 (43%)
8/14 (57%)
11·9 (0·5–45·0)
No
19 (53%)
11/19 (58%)
8/19 (42%)
19·0 (1·4–47·0)
NA
3 (8%)
0
18·0 (18·0–37·8)
0
Data are n (%) or n/n (%), unless otherwise stated. EB=excess blasts. NA=not available. *Slides were unavailable for central diagnosis for ten (28%) of 36 patients. For these patients the local diagnosis was used for the central review. These ten patients comprise five with acute myeloid leukaemia, four with myelodysplastic syndrome, and one with myelodysplastic syndrome-EB1 or 2. Among the 16 with complex karyotype, 8 have AML and 8 have MDS and among the 16 without complex karyotype 2 have AML and 14 have MDS.
Table 2: Diagnostic and clinical features
Eight (80%) of ten of those with acute myeloid leukaemia compared with eight (36%) of 22 with myelodysplastic syndrome had complex cytogenetics (p=0·054). Patients with myelodysplastic syndrome with complex karyotype (n=22) had a 3-year overall survival of 15% (95% CI 1–47) compared with 64% (95% CI 34–83) in those without complex karyotype (p=0·15; figure 3A). 33 (92%) of 36 patients (eight of ten with leukaemia, four of five with myelodysplastic syndrome with excess blasts 1 or 2, and 21 of 21 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy. Serial bone marrow surveillance was done for 14 (39%) of 36 patients (nine with myelodysplastic syndrome, two with myelodysplastic syndrome with excess blasts 1 or 2, and three with leukaemia). 19 (53%) did not receive bone marrow surveillance, and three (8%) had unknown surveillance status. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Median follow-up was similar in the no surveillance (4·7 years [IQR 1·5–not estimable; n=19) and surveillance (6·5 years [3·3–not estimable; n=14) cohorts (p=0·79). We observed a median overall survival of 1·1 years (95% CI
www.thelancet.com/haematology Published online December 23, 2019 https://doi.org/10.1016/S2352-3026(19)30206-6
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60 40 20 0
0·5
Acute myeloid 10 (0) 7 (1) leukaemia
1
1·5
2
2·5
3
3·5
4
4 (1)
2 (1)
2 (1)
1 (1)
1 (1)
1 (1)
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B
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8
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7 (2) 2 (1)
6 (3) 1 (1)
4 (5) 0 (2)
2 (6) 0 (2)
1 (7) 0 (2)
B Overall survival (%)
Overall survival (%)
40
With surveillance Without surveillance
100
80 60 40 20 0
2
4
6
8
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Time from diagnosis (years) Myelodysplastic 26 (0) syndrome, myelodysplastic syndrome EB1 or 2
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+
60
Number at risk (number censored) Non-complex karyotype 14 (0) Complex karyotype 8 (0)
100
0
80
0 0
Non complex karyotype Complex karyotype
+
12 (3)
9 (5)
6 (8)
3 (10)
2 (11)
80 60 40 20 0
0
Number at risk (number censored) Without surveillance 19 (0) With surveillance 14 (0)
2
4
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8
10
1 (5) 2 (6)
1 (5) 1 (7)
Time from diagnosis (years) 5 (2) 8 (1)
3 (3) 7 (2)
1 (5) 5 (4)
Figure 2: Overall survival Overall survival (95% CI) for patients with Shwachman-Diamond syndrome and acute myeloid leukaemia (A) or myelodysplastic syndrome (B), according to initial diagnosis. EB1 or 2=with excess blasts 1 or 2.
Figure 3: Overall survival by complex karyotype and bone marrow surveillance status Overall survival (95% CI) by karyotype at initial diagnosis (A). Overall survival (95% CI) by bone marrow surveillance status before diagnosis of myelodysplastic syndrome or acute myeloid leukaemia (B).
0·6–not estimable) versus 7·7 years (0·6–not estimable) and 3-year overall survival estimates of 28% (95% CI 10–50) versus 62% (32–82) for the group without versus with marrow surveillance (p=0·13; figure 3B), suggesting a need for further evaluation. Median age at malignancy diagnosis was 11·9 years (range 0·5–45; IQR 5·6–19·8) for surveillance versus 19·0 years (range 1·4–47; IQR 14·4–31·5) for no-surveillance (p=0·13). There was an absence of uniformity in the specific marrow surveillance tests done, even within patients. No patients had flow cytometry, FISH If not, what does it mean?, or karyotype done on all surveillance marrows. Flow cytometry was done on 49% (n=43), FISH was sent by the treating physician on 72% (n=63), and karyotype was sent by the treating physician on 53% (n=46), of the 87 surveillance marrows. Del20q was present in three cases before diagnosis (one leukaemia, one myelo dysplastic syndrome with excess blasts 1 or 2, and one myelodysplastic syndrome), and iso7q was present in one case of myelodysplastic syndrome with excess blasts 1 or 2 and one case of myelodysplastic syndrome before diagnosis. Monosomy 7 was detected intermittently by FISH at amounts below clinical thresholds for several years before diagnosis in one patient each with leukaemia and myelodysplastic syndrome. One patient with
myelo dysplastic syndrome had del5q present before diagnosis, and another patient with myelodysplastic syndrome had low amounts of del7q and trisomy 8 detected by FISH in several marrows preceding diagnosis. However, karyotypes and FISH were not routinely done on all surveillance marrows. Of the 14 patients with marrow surveillance, there was no clinical concern for myeloid malignancy in four before the diagnostic marrow showing myelodysplastic syndrome (n=3), and myelodysplastic syndrome with excess blasts 1 or 2 (n=1). One patient was noted to have a complete blood count abnormality on the day of surveillance marrow which showed leukaemia. Two patients had no available clinical reports to assess suspicion before marrow examination. Eight of 14 patients who had marrow surveillance had antecedent marrow abnormalities, typically worsening dysplasia before diagnosis of myelodysplastic syndrome (n=5), myelodysplastic syndrome with excess blasts 1 or 2 (n=1), and leukaemia (n=2). One patient had warning signs with increasing dysplasia noted on two separate marrows (at 0·5 years and at 1 year and 6 months) and decreasing absolute neutrophil count on G-CSF before presenting with leukaemia, illustrating the need to proceed rapidly to transplantation. Six patients with
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marrow surveillance had no previous marrow abnormalities leading up to diagnosis of myelodysplastic syndrome (n=3), myelodysplastic syndrome with excess blasts 1 or 2 (n=1), or leukaemia (n=1), but three of these developed peripheral cytopenias leading up to the diagnostic marrow. Six (60%) of 10 patients presenting with leukaemia did not have surveillance and surveillance status was unknown for one. Although surveillance could identify actionable changes before progression to leukaemia, the presentation of one patient with leukaemia without an apparent antecedent dysplastic phase or cytogenetic abnormalities, highlights the limitations of existing surveillance tools and the need for better biomarkers for risk stratification. 15 cases with longitudinal complete blood count data before diagnosis of malignancy were reviewed (four leukaemia, two myelodysplastic syndrome with excess blasts 1 or 2, and nine myelodysplastic syndrome). Six had only mild cytopenias before diagnosis of myelodysplastic syndrome or leukaemia. Two had stable and four had fluctuating blood counts. The absence of progressive changes in blood counts did not preclude marrow disease, suggesting that complete blood count surveillance alone might be less sensitive than combined complete blood count and bone–marrow surveillance. The mean corpuscular volume was stable or decreasing in two of four patients with leukaemia, decreasing in two of two patients with myelodysplastic syndrome with excess blasts 1 or 2, decreasing in three of nine myelodysplastic syndrome patients, and stable in four of nine myelodysplastic syndrome patients.
Discussion This multicentre, retrospective study reports clinical features and outcomes of the largest cohort, to our knowledge, of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. Evolution of diagnostic criteria for myelodysplastic syndrome and leukaemia renders previous studies of Shwachman-Diamond syndrome difficult to extrapolate to existing practice, so central pathology review was done via current standards. Overall survival from myelodysplastic syndrome in our cohort was lower than expected for myelodysplastic syndrome in the absence of Shwachman-Diamond syndrome, and substantially lower in those with leukaemia.12 Treatment failure seemed to be associated with both toxicity of therapy and resistant disease indicating the need for novel approaches. Central pathology review highlighted the complexities in the diagnosis of myelodysplastic syndrome and acute myeloid leukaemia in Shwachman-Diamond syndrome. Myelodysplastic syndrome poses diagnostic challenges even in the non-Shwachman-Diamond syndrome population, with substantial interobserver variability in determination of dysplasia.13–16 Quantitation of blasts in a hypocellular marrow yielded discrepancies between
blast enumeration within the biopsy, versus aspirate or flow cytometry where dilution with blood could be problematic.17–24 Analysis of aberrant antigen expression, which can be seen in myelodysplastic syndrome was not available. Diagnosis after central pathology review differed from local diagnosis in 44% of cases with available slides, perhaps because of morphology challenges and revisions in WHO criteria for myelodysplastic syndrome– leukaemia.11 These data emphasise the value of enlisting the expertise of a haematopathologist experienced with Shwachman-Diamond syndrome. The baseline dysmor phologies noted in all Shwachman-Diamond syndrome marrows pose a major challenge for the morphologic diagnosis of myelodysplastic syndrome. In particular, the late granulocyte precursors and mature granulocytes often have hypo segmented nuclei and can be hypo granular. Dysplasia in the erythroid lineage at baseline in Shwachman-Diamond syndrome is unusual, and, particularly when combined with a progressively increasingly cellular marrow is concerning for myelo dysplastic syndrome, even in the absence of cytogenetic abnormalities. This pattern differs from the prototypical sporadic myelodysplastic syndrome in older adults according to WHO guidelines. However, leukaemia might evolve without apparent antecedent dysplasia or cytogenetic abnormalities. We did not observe a correlation between blast count and severity of dysplasia for myelodysplastic syndrome. Standard chemotherapy approaches for acute myeloid leukaemia led to poor overall survival in our cohort. Many patients were unable to proceed to HSCT owing to disease progression or mortality with chemotherapy. Pre-HSCT cytoreductive chemotherapy in patients with acute myeloid leukaemia and Shwachman-Diamond syndrome did not prevent relapse and carried unacceptably high toxicity (appendix pp 5–7). Further clinical and biological studies are needed to establish whether standard WHO definitions of acute myeloid leukaemia based on percentage of blasts inform the need for future novel cytoreductive therapy for patients with Shwachman-Diamond syndrome. New therapeutic strategies to achieve remission are needed in a bone marrow failure syndrome with poor stem cell reserve and high end-organ toxicities. The role of standard pre-HSCT cytoreductive chemotherapy approaches has also been questioned for Fanconi anaemia, another bone marrow failure and cancer predisposition syndrome, and for patients with either germline or somatic TP53 mutations, who tend to respond poorly to cytotoxic agents but have had some response to hypomethylating agents, especially when combined with venetoclax.25–28 Surveillance and management of patients within clinical practice was highly variable. Only a subset of patients diagnosed with Shwachman-Diamond syndrome were being monitored, and there was marked variability in surveillance testing, even for a given patient over time. The Shwachman-Diamond syndrome draft consensus guidelines recommend marrow surveillance based on
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expert opinion;9 however, published data are sparse regarding the benefit of marrow surveillance on overall survival of patients with leukaemia predisposition. At 3 years, the proportion of patients alive in our study was 28% (95% CI 10–50) for those without marrow surveillance and 62% (32–82) with marrow surveillance. Patients compliant with surveillance might also be more compliant with other aspects of care, contributing to improved outcomes. Comprehensive centralised pro spective collection of data is essential to develop evidencebased surveillance strategies for leukaemia predisposition disorders. Revised International Prognostic Scoring System (IPSS-R) and WHO Classification-Based Prognostic Scoring System (WPSS) have not been validated in patients with myelodysplastic syndrome arising from inherited marrow failure syndromes. Review of complete blood counts before presentation with myelodysplastic syndrome or leukaemia revealed limitations of complete blood counts surveillance alone for early disease detection. Complete blood counts were stable or even normal in some patients with cyto genetic and morphological evolution to myelodysplastic syndrome in bone marrow. Mean corpuscular volume trend was also not a consistent indicator of evolving myeloid malignancy in this cohort, and caution is advised in relying on the mean corpuscular volume for monitoring. This study has several limitations. Its retrospective nature and the absence of complete central pathology review, molecular analysis of clonal evolution, and a comparator group of patients with Shwachman-Diamond syndrome without myelodysplastic syndrome or acute myeloid leukaemia. Additionally, numbers are too small to draw conclusions regarding risks of haematological malignancy on the basis of specific germline SBDS mutations. Similarly, this study was not designed to determine the effect of specific patient characteristics, such as G-CSF treatment before the development of myelodysplastic syndrome or acute myeloid leukaemia. Chronic G-CSF treatment might improve overall survival, thus extending the timeframe within which they are at risk of developing a malignancy, or individuals with severe disease and highest malignancy risk might require higher doses of G-CSF.29 Although we found that surveillance can capture early actionable abnormalities identifying patients at high risk for progression to acute myeloid leukaemia, leukaemia can also develop without any antecedent warning discernible with available surveillance testing. Additional risk stratification strategies are under investigation in a prospective cohort. Somatic clonal abnormalities have been noted at young ages outside the context of myelodysplastic syndrome–leukaemia in patients with a germline genetic predisposition to myeloid malignancies.28 Previous studies have shown that TP53 mutations are common in Shwachman-Diamond syndrome, with or without myelodysplastic syndrome, so it is unclear 8
whether isolated TP53 mutations constitute an actionable finding.5,30 It has been hypothesised that TP53 mutations arise from selective pressures resulting from a failing marrow, and might be initiating events that mediate disease progression to myeloid malignancies. Although somatic mutation analysis (including TP53 analysis) is now available clinically, it is not yet clear how to use this information to inform the treatment plan. Longitudinal studies of clonal evolution with respect to clinical outcomes are needed. A prospective centralised registrybased approach is essential to improve outcomes of patients with rare diseases by identifying patients at risk and systematically collecting clinical data and annotated samples for ongoing biological studies to inform therapeutic decisions. The poor prognosis of patients with Shwachman-Diamond syndrome and acute myeloid leukaemia, and to a lesser extent of those with ShwachmanDiamond syndrome and myelodysplastic syndrome, documented in this study provides a compelling rationale for prospective studies to evaluate the effect of surveillance and early intervention on overall survival. Novel therapeutic options with both decreased toxicity and improved antileukaemic properties are urgently needed for these patients. Additional references are included in the appendix pp 12–16. Contributors All authors participated in study design, data acquisition, analysis, interpretation and revision of the manuscript. KC, EF, and AS additionally drafted the manuscript. All authors have given final approval of the submitted version and agree to be accountable for all aspects of the work related to the accuracy or integrity of the work. Declaration of interests We declare no competing interests. Acknowledgments This work was supported by NIH/NIDDK R24 DK099808 and NCRR/NIH UL1-RR026314-01 (Redcap), NIH T32 HL007574-36 (EF) and in part by the Intramural Research Program of the NIH and the National Cancer Institute (BPA, LJM). One of the patients from Seattle/Fred Hutchinson Cancer Research Center was enrolled in a clinical trial supported in part by the NIH (grant PO1 HL122173). The authors gratefully acknowledge David Steensma for critical review of the manuscript. References 1 Myers KC, Bolyard AA, Otto B, et al. Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr 2014; 164: 866–70. 2 Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet 2003; 33: 97–101. 3 Warren AJ. Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome. Adv Biol Regul 2018; 67: 109–27. 4 Nelson AS, Myers KC. Diagnosis, treatment, and molecular pathology of Shwachman-Diamond syndrome. Hematol Oncol Clin North Am 2018; 32: 687–700. 5 Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med 2017; 376: 536–47. 6 Iwafuchi H. The histopathology of bone marrow failure in children. J Clin Exp Hematop 2018; 58: 68–86. 7 Okcu F, Roberts WM, Chan KW. Bone marrow transplantation in Shwachman-Diamond syndrome: report of two cases and review of the literature. Bone Marrow Transplant 1998; 21: 849–51. 8 Dokal I, Rule S, Chen F, Potter M, Goldman J. Adult onset of acute myeloid leukaemia (M6) in patients with Shwachman-Diamond syndrome. Br J Haematol 1997; 99: 171–73.
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Dror Y, Donadieu J, Koglmeier J, et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci 2011; 1242: 40–55. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42: 377–81. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391–405. Wolfson J, Sun C-L, Wyatt L, Stock W, Bhatia S. Adolescents and young adults with acute lymphoblastic leukemia and acute myeloid leukemia: impact of care at specialized cancer centers on survival outcome. Cancer Epidemiol Biomarkers Prev 2017; 26: 312–20. Steensma DP. How I use molecular genetic tests to evaluate patients who have or may have myelodysplastic syndromes. Blood 2018; 132: 1657–63. Ramos F, Fernández-Ferrero S. Inter-observer agreement in myelodysplastic syndromes. Haematologica 2013; 98: e77. Font P, Loscertales J, Benavente C, et al. Inter-observer variance with the diagnosis of myelodysplastic syndromes (MDS) following the 2008 WHO classification. Ann Hematol 2013; 92: 19–24. Goasguen JE, Bennett JM, Bain BJ, Vallespi T, Brunning R, Mufti GJ. Morphological evaluation of monocytes and their precursors. Haematologica 2009; 94: 994–97. Loken MR, Chu S-C, Fritschle W, Kalnoski M, Wells DA. Normalization of bone marrow aspirates for hemodilution in flow cytometric analyses. Cytometry B Clin Cytom 2009; 76: 27–36. Oliveira AF, Tansini A, Vidal DO, Lopes LF, Metze K, Lorand-Metze I. Characteristics of the phenotypic abnormalities of bone marrow cells in childhood myelodysplastic syndromes and juvenile myelomonocytic leukemia. Pediatr Blood Cancer 2017; 64: e26285. Aalbers AM, van den Heuvel-Eibrink MM, Baumann I, et al. Bone marrow immunophenotyping by flow cytometry in refractory cytopenia of childhood. Haematologica 2015; 100: 315–23. Westers TM, van der Velden VHJ, Alhan C, et al. Implementation of flow cytometry in the diagnostic work-up of myelodysplastic syndromes in a multicenter approach: report from the Dutch Working Party on Flow Cytometry in MDS. Leuk Res 2012; 36: 422–30.
21 Veltroni M, Sainati L, Zecca M, et al. Advanced pediatric myelodysplastic syndromes: can immunophenotypic characterization of blast cells be a diagnostic and prognostic tool? Pediatr Blood Cancer 2009; 52: 357–63. 22 van de Loosdrecht AA, Ireland R, Kern W, et al. Rationale for the clinical application of flow cytometry in patients with myelodysplastic syndromes: position paper of an International Consortium and the European LeukemiaNet Working Group. Leuk Lymphoma 2013; 54: 472–75. 23 Chu S-C, Wang T-F, Li C-C, et al. Flow cytometric scoring system as a diagnostic and prognostic tool in myelodysplastic syndromes. Leuk Res 2011; 35: 868–73. 24 Loken MR, van de Loosdrecht A, Ogata K, Orfao A, Wells DA. Flow cytometry in myelodysplastic syndromes: report from a working conference. Leuk Res 2008; 32: 5–17. 25 Mitchell R, Wagner JE, Hirsch B, DeFor TE, Zierhut H, MacMillan ML. Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia. Br J Haematol 2014; 164: 384–95. 26 Peffault de Latour R, Soulier J. How I treat MDS and AML in Fanconi anemia. Blood 2016; 127: 2971–79. 27 Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med 2016; 375: 2023–36. 28 DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019; 133: 7–17. 29 Donadieu J, Fenneteau O, Beaupain B, et al. Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome. Haematologica 2012; 97: 1312–19. 30 Xia J, Miller CA, Baty J, et al. Somatic mutations and clonal hematopoiesis in congenital neutropenia. Blood 2018; 131: 408–16.
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Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study Kasiani C Myers*, Elissa Furutani*, Edie Weller, Bradford Siegele, Ashley Galvin, Valerie Arsenault, Blanche P Alter, Farid Boulad, Carlos Bueso-Ramos, Lauri Burroughs, Paul Castillo, James Connelly, Stella M Davies, Courtney D DiNardo, Iftikhar Hanif, Richard H Ho, Nicole Karras, Michelle Manalang, Lisa J McReynolds, Taizo A Nakano, Grzegorz Nalepa, Maxim Norkin, Matthew J Oberley, Etan Orgel, Yves D Pastore, Joseph Rosenthal, Kelly Walkovich, Jordan Larson, Maggie Malsch, M Tarek Elghetany, Mark D Fleming, Akiko Shimamura
Summary
Background Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies.
Lancet Haematol 2019
Methods We did a multicentre, retrospective, cohort study in collaboration with the North American ShwachmanDiamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients.
*Contributed equally
Findings We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9–8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8–not reached) and 0·99 years (95% CI 0·2–2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1–39) for patients with leukaemia and 51% (29–68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia—including the two patients initially diagnosed with myelodysplastic who progressed— two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32–82; n=14) compared with 28% (95% CI 10–50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts. Interpretation Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome.
www.thelancet.com/haematology Published online December 23, 2019 https://doi.org/10.1016/S2352-3026(19)30206-6
Published Online December 23, 2019 https://doi.org/10.1016/ S2352-3026(19)30206-6 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA (K C Myers MD, S M Davies PhD); Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA (K C Myers, S M Davies); Pediatric Hematology– Oncology (E Furutani MD, A Shimamura MD, A Galvin BS, J Larson BS, M Malsch MSN), Division of Hematology and Oncology and Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research (E Weller PhD) and Department of Pathology (B Siegle MD, M D Fleming DPhil), Boston Children’s Hospital, Boston, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA (E Furutani, A Shimamura); Department of Pediatrics, Harvard Medical School, Boston, MA, USA (E Furutani, A Shimamura); Harvard Medical School, Boston, MA, USA; CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada (V Arsenault MD, Y D Pastore MD); Clinical Genetics Branch, National Institutes of Health National Cancer Institute, Rockville, MD, USA (B P Alter MD, L J McReynolds MD); Department of Pediatrics, Bone Marrow Transplantation Service, Memorial Sloan
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Kettering Cancer Center, New York, NY, USA (F Boulad MD); Department of Hematopathology (C Bueso-Ramos MD), and Department of Leukemia (C D DiNardo MD), The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pediatrics, Division of Hematology–Oncology Seattle Children’s and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA (L Burroughs MD); Shands Children’s Hospital, Department of Pediatrics, Division of Pediatric Hematology Oncology (P Castillo MD) and Department of Medicine (M Norkin MD), University of Florida, Gainesville, FL, USA; Department of Pediatrics, Division of Pediatric Hematology Oncology, Vanderbilt University Medical Center, Nashville, TN, USA (J Connelly MD, R H Ho MD); Center for Cancer and Blood Disorders, Joe DiMaggio Children’s Hospital, Hollywood, FL, USA (I Hanif MD); Department of Pediatrics, City of Hope National Medical Center, Duarte, CA, USA (N Karras MD, J Rosenthal MD); Marshfield Clinic Health System, Marshfield, WI, USA (M Manalang MD); Center for Cancer and Blood Disorders, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA (T A Nakano MD); Department of Pediatrics, Division of Pediatric Hematology– Oncology, Indiana University School of Medicine, Indianapolis, IN, USA (G Nalepa MD); Department of Pathology and Laboratory Medicine (M J Oberley MD) and Division of Pediatric Hematology Oncology and Blood and Marrow Transplantation (E Orgel MD), Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Pediatrics, City of Hope National Medical Center, Duarte, CA, USA (J Rosenthal); Division of Pediatric Hematology– Oncology, Department of
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Funding National Institute of Health. Copyright © 2019 Elsevier Ltd. All rights reserved.
Introduction Shwachman-Diamond syndrome is an autosomal recessive disorder characterised by bone marrow failure, exocrine pancreatic dysfunction, additional variable organ system abnormalities, and predisposition to myelodysplasia and acute myeloid leukemia.1 Over 90% of patients with Shwachman-Diamond syndrome carry biallelic mutations in the gene for Shwachman-BodianDiamond syndrome (SBDS; a rare congenital disorder characterised by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, short stature, and variable multi-organ system abnormalties) on chromosome 7q11, encoding a protein involved in ribosomal maturation.2,3 Patients with mutations in SRP54, DNAJC21, and EFL1 can also present with clinical features of Shwachman-Diamond syndrome.4 Myelodysplastic syndrome and acute myeloid leukaemia are major life-threatening complications of ShwachmanDiamond syndrome. Malignant transformation ranges between 5% and 36%, and Shwachman-Diamond syndrome can be unrecognised in young adults with
myeloid malignancies. A Center for International Blood and Marrow Transplant Research (CIBMTR) study found that 4% of young patients undergoing haematopoietic stem cell transplantation (HSCT) for myelodysplastic syndromes had Shwachman-Diamond syndrome.5 Baseline marrow dysmorphologies make the diagnosis of myelodysplastic syndrome and acute myeloid leukaemia challenging in leukaemia predisposition disorders.1,6 Revisions in WHO definitions of myelo dysplastic syndrome and acute myeloid leukaemia warrant reassessment of myelodysplastic syndrome or acute myeloid leukaemia outcomes in ShwachmanDiamond syndrome by means of existing diagnostic criteria. There is no consensus regarding treatment for patients with Shwachman-Diamond syndrome, including the role of pre-HSCT cytoreductive chemotherapy or recommended conditioning regimens before HSCT. Data are sparse, coming from case reports and small case series.7,8 Although myelodysplastic syndrome and acute myeloid leukaemia are now recognised to be
Research in context Evidence before this study We searched Ovid and PubMed on Feb 7, 2019 with the terms “myelodysplastic syndrome”, “acute myeloid leukemia”, “treatment”, “leukemia predisposition”, and “shwachman diamond syndrome”, without restrictions on dates of publication or types of study up to Feb 7, 2019. Reports of malignant transformation in Shwachman-Diamond syndrome—a bone marrow failure, and leukaemia predisposition disorder—vary widely at 5–36%. Moreover, Shwachman–Diamond syndrome is often unrecognised, particularly in adults (eg, typically those aged 20–40 years). A genomic screen of patients with myelodysplastic syndrome in the Center for International Blood and Marrow Transplant Research diagnosed ShwachmanDiamond Syndrome in 4% of young patients aged <40 years (median age 25·1 years [95% CI 18·2–38·2]). Data describing events leading up to malignant transformation in individuals with Shwachman-Diamond syndrome is scarce. Baseline marrow dysmorphologies make the diagnosis of myelodysplastic syndrome challenging, and the significance of cytogenetic clones such as del(20)(q11) or isochromosome (7)(q10) and others in the absence of morphologic myelodysplastic syndrome, increasing blasts, or falling blood counts is unclear. The expert consensus recommendation is to monitor patients for early signs of clonal evolution to facilitate early haemopoietic stem cell transplantation (HSCT) before the onset of acute myeloid leukaemia, but data to inform frequency and method of surveillance strategies are inadequate. There is no consensus regarding treatment for myelodysplastic
syndrome or acute myeloid leukaemia in patients with Shwachman-Diamond syndrome, including the role of pre-HSCT cytoreductive chemotherapy or recommended conditioning regimens for HSCT. Added value of this study This study suggests that poor outcomes of patients with acute myeloid leukaemia or myelodysplastic syndrome and Shwachman-Diamond syndrome results from both high treatment related mortality and high disease resistance. This study also shows the variability and limitations of existing surveillance practices, particularly potential caveats of relying on blood counts alone to detect early clonal disease. It highlights the complexities of pathological diagnosis of malignancy in this cancer predisposition syndrome characterised by dyspoiesis, particularly in identifying patients with advanced myelodysplastic syndrome in urgent need of expeditious transplantation. Implications of all the available evidence The complexities of pathological diagnosis and poor prognosis of patients with acute myeloid leukaemia or myelodysplastic syndrome and Shwachman-Diamond syndrome highlight the need for expert pathological review, and development of novel diagnostic tools for surveillance and use in prospective studies to evaluate the effect of early intervention on overall survival. Novel therapies and HSCT regimens with both decreased toxicity and improved antileukaemic properties are urgently needed to improve the outcomes of these patients.
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clinically and biologically distinct, previous studies often reported combined outcomes of both diagnoses together.4 We did a multi-institutional, retrospective, cohort study of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia with the aim of describing demographics, disease characteristics, challenges of pathologic diagnosis, surveillance practices, therapy response, and overall survival outcomes. These data form a basis to inform medical management of this leukaemia-predisposition syndrome.
Methods
Study design To identify the patient cohort, we reviewed charts from 17 institutions (appendix p 10) in the USA and Canada in collaboration with the North American ShwachmanDiamond Syndrome Registry. Inclusion criteria consisted of either biallelic mutations in the SBDS gene or a clinical diagnosis of ShwachmanDiamond syndrome as defined by cytopenias and pancreatic dysfunction,9 together with a diagnosis of myelodysplastic syndrome or acute myeloid leukaemia. There were no age restrictions. This study was approved by Cincinnati Children’s Hospital Institutional Review Board (primary Institutional Review Board) and local Institutional Review Boards.
Procedures All histological samples and data extracted from the medical record were de-identified and collected in the Research Electronic Data Capture (REDCap) system.10 We extracted data on genetic and clinical diagnostic and disease features of Shwachman-Diamond syndrome and myleodysplastic syndrome–acute myeloid leukaemia, date of diagnosis, malignancy characteristics, surveillance strategies before diagnosis, treatments received, toxicities, and outcomes. Treatment response criteria were reported as estab lished by local treating physicians. Disease response was assess ed by the local treating physician per their institutional practice or criteria at the time of clinical treatment. Serial bone marrow surveillance was defined as bone marrow examinations done routinely in the absence of symptoms. Masked centralised pathology review following WHO 2016 diagnostic criteria was done by two independent groups of pathologists based at Boston Children’s Hospital, Harvard Medical School (Boston, MA, USA) and Texas Children’s Hospital, Baylor College of Medicine (Houston, TX, USA) with expertise in marrow failure syndromes in the patients with available histological samples.11 If central review indicated a different diagnosis from the local report, patients were reclassified accordingly for further analysis (figure 1).
Statistical analysis Summary statistics are reported for continuous variables (mean [SD] or median [interquartile range]) and binary variables (proportions and exact binomial 95% CIs using Pearson-Klopper method). Fisher’s exact test was used to compare categorical outcomes. Overall survival time was defined as time from initial diagnosis (acute myeloid leukaemia, myelodysplastic syndrome, myelodysplastic syndrome excess blasts 1 or 2) to death from any cause or date of last follow-up. Overall survival was estimated by means of the Kaplan-Meier method and compared with the log-rank test. In the analysis summarising outcomes by central review diagnosis, the local diagnosis is used if histological samples were not available for review. The statistical analysis was performed using the R package.
Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA (K Walkovich MD); and Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA (M T Elghetany MD) Correspondence to: Dr Akiko Shimamura, Boston Children’s Hospital, Boston, MA USA akiko.shimamura@childrens. harvard.edu
See Online for appendix
Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author oversaw the study, and had final responsibility to submit for publication.
Results Patient demographics and disease characteristics are shown in table 1 and appendix (p 5–8). Median year of diagnosis was 2010 (range 2001–17; IQR: 2007–13), and median follow-up was 4·9 years (IQR 3·9–8·4). Data were collected from clinical records dating from March 1, 2001 to Oct 5, 2017. Diagnosis of ShwachmanDiamond syn drome was established by presence of 37 eligible patients identified based on local review 27 myelodysplastic syndrome 10 acute myeloid leukaemia
10 had no samples available for central review 27 had central pathology review 10 confirmed myelodysplastic syndrome 1 confirmed myelodysplastic syndrome-EB1 or 2 4 confirmed acute myeloid leukaemia 1 reclassified from myelodysplastic syndrome to acute myeloid leukaemia 1 reclassified from acute myeloid leukaemia to myelodysplastic syndrome 6 reclassified from myelodysplastic syndrome-EB to myelodysplastic syndrome 3 reclassified from myelodysplastic syndrome to myelodysplastic syndrome-EB1 or 2 1 not myelodysplastic syndrome or acute myeloid leukaemia
1 excluded, not eligible after central review
36 patients included in the analysis (clinical characteristics and overall survival) 26 classified as myelodysplastic syndrome (21 confirmed) 10 classified as acute myeloid leukaemia (5 confirmed)
Figure 1: Study profile EB=excess blasts.
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Patients (n=36) Age at myelodysplastic syndrome or acute myeloid leukaemia diagnosis <18 years
17 (47%)
≥18 years
19 (53%)
Median (range), years
18 (0·5–47)
Sex Male
16 (44%)
Female
20 (56%)
Bi-allelic SBDS mutations Yes
30 (83%)
NA
6 (17%)
Neutropenia Yes
25 (69%)
No
4 (11%)
NA
7 (19%)
Failure to thrive or pancreatic enzyme use Yes
30 (83%)
No
4 (11%)
NA
2 (6%)
Congenital anomalies and multi-organ involvement* Yes
27 (75%)
No
9 (25%)
Data are n (%). NA=not available. *Denotes presence or absence of congenital anomalies or medical comorbidities outside of the haematopoietic system.
Table 1: Patient characteristics
biallelic SBDS mutations (n=30; appendix pp 3–4) or clinical diagnosis of cytopenias and exocrine pancreatic dysfunction (n=6). Among the 27 patients with histological samples available, central pathology review agreed with local review in 15 (56%) cases; appendix p 9; figure 1). The most common discrepancy was the distinction between low grade myelodysplastic syndrome versus advanced myelodysplastic syndrome with excess blasts. This difference in categorisation highlights the challenges of enumerating blasts in a hypocellular marrow with baseline dys morphologies. One patient with a local diagnosis of myelodysplastic syndrome was excluded from further analyses after determination of marrow morphology within the normative baseline of Shwachman-Diamond syndrome and no cytogenetic abnormalities (appendix p 7). Table 2 shows initial diagnoses and ages at presentation. Nine (35%) of 26 patients with myelodysplastic syndrome and one (10%) of 10 patients with leukaemia were being treated with granulocyte colony-stimulating factor (G-CSF) at time of malignancy diagnosis, which is similar to the North American Shwachman-Diamond syndrome registry of patients with biallelic SBDS mutations, 45 [45%] of 99 patients). Complex karyotypes, defined by three or more numerical or structural chromosomal abnormalities, were seen in eight (36%) of 22 (4 of 26 did not have karyotype data) myelodysplastic syndrome cases and eight (80%) of ten acute myeloid leukaemia cases (p=0·054). 4
Surveillance marrow examinations showed predom inantly hypocellular marrows with frequent mild dyspoiesis of myeloid, erythroid, or megakaryocytic lineages. Baseline morpho logical atypia in surveillance samples was most pronounced in the myeloid lineage, where mature neutrophils often had a combination of incomplete nuclear segmentation and variable hypo granulation (appendix p 1). These features fall within the spectrum of baseline Shwachman-Diamond syndrome marrow morphology. Patients with myelodysplastic syndrome showed subtle but progressively more pronounced lineage dysplasias. Dysmorphic features in the myeloid lineage pre dominated in myelodysplastic syndrome and included prominent nuclear hypolobation (so-called Pelger-Huetlike forms), prominent cytoplasmic hypogranulation, and cases with markedly enlarged myeloid precursors and forms with prominent basophilic cytoplasm. Most cases of myelo dysplastic syndrome also had more significant dyserythropoiesis. 30 (88%) of 36 patients had available data on treatment received. Treatments were heterogeneous (appendix pp 5–8). Ten different initial chemotherapy regimens, including hypomethylating agents (n=2) and cytoreductive chemotherapy (n=8), were delivered. HSCT was initial therapy for 16 patients. 16 different HSCT approaches were reported, including 13 reduced intensity condit ioning and 3 myeloablative conditioning regimens (appendix pp 5–8). Patients with leukaemia had a median time to first treatment of 0·3 months (IQR 2 days–0·9 months) versus 4·7 months (IQR 2·7–6·6) for myelodysplastic syndrome. However, median time to HSCT was similar at 4·6 months (IQR 2·9–5·6) for leukaemia and 4·7 months (3·0–7·3) for myelodysplastic syndrome. 18 (69%) of 26 patients diagnosed with low grade or high-grade myelodysplastic syndrome received therapy for myelodysplastic syndrome consisting of either upfront HSCT (n=14) or upfront chemotherapy (n=4). Of the 14 who received upfront HSCT, ten (71%) achieved a complete response following HSCT of whom seven remain alive with median follow-up of 82 months (IQR 59–94) from diagnosis, two died in remission of treatment-related toxicities (4 months and 6 months post-HSCT), and one died with recurrent disease (9 months post-HSCT). Three patients with myelodysplastic syn drome who underwent upfront HSCT developed graft failure, of whom two died with active disease at 19 and 26 months and one died with unknown disease status at 18 months. One patient is alive 39 months after diagnosis, response to therapy unknown. Only one (25%) of four patients with myelodysplastic syndrome who received upfront chemotherapy achieved a complete response. Of this group, one subsequently underwent HSCT and died at 4 months of multiorgan failure, two died (at 4 months and 7 months) of infection
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and disease, and one continues on a hypomethylating agent with active disease 56 months after diagnosis. Four patients with myelodysplastic syndrome received no therapy, two died with active disease (at 2 months and 92 months), and two were lost to follow-up with active disease (at 18 months and 121 months). Two patients did not have treatment data available and were lost to followup at 18 and 21 months. Two patients with an initial diagnosis of myelodysplastic syndrome with excess blasts 1 or 2 progressed to leukaemia (at 2·5 months and 3·8 months) before receiving any myelodysplastic syndrome-directed therapy. 12 patients received treatment for acute myeloid leukaemia, including two patients initially diagnosed with myelodysplastic syndrome-with excess blasts 1 or 2 who progressed. Ten (83%) of 12 received pre-HSCT therapy (two with a hypomethylating agent, eight with cytoreductive chemotherapy) with intent to proceed with HSCT; only one patient achieved a complete response. The only patient with normal cytogenetics at initial leukaemia diagnosis was also the only patient who achieved complete response following chemotherapy. This patient remains alive 49 months from diagnosis following a complicated post-HSCT course, including two episodes of graft failure requiring a total of three transplantations. The other nine patients who received upfront pre-HSCT therapy died with median overall survival of 9 months (IQR 4–13). Two patients with leukaemia received HSCT as initial therapy; one achieved a complete response but died of treatment-related complications in remission at 9 months. The other progressed from myelodysplastic syndrome with excess blasts 1 or 2 to leukaemia and underwent HSCT without previous cytoreductive chemotherapy and remains alive without disease at 6 months. At a median follow-up of 4·1 years (IQR 0·3–not estimable), 3-year overall survival from initial leukaemia diagnosis was 11% (95% CI 1–39) and median overall survival was 0·99 years (95% CI 0·2–2·4; figure 2A). At a median follow-up of 5·1 years (IQR 3·3–8·4), 3-year overall survival for myelodysplastic syndrome was 51% (95% CI 29–68), and median overall survival of 7·7 years (95% CI 0·8–not reached; figure 2B). Overall survival analysis separating low-risk and high-risk myelodysplastic syndrome are shown in appendix (p 2). When restricted to patients with central pathology review, 3-year overall survival was 20% (95% CI 1–58) for 5 patients with confirmed acute myeloid leukaemia and 45% (95% CI 22–65%) for 21 patients with confirmed myelodysplastic syndrome. Subgroup analyses showed no effect of age on overall survival by diagnosis with a HR of 1·03 for leukaemia (95% CI 0·98–1·08, p=0·35) and 1·03 for myelodysplastic syndrome (95% CI 0·99–1·08, p=0·11), and no difference in OS was detected by year of diagnosis (HR 1·0, 95% CI 0·9–1·2, p=0·57) or treatment (HR 1·0, 95% CI 0·9–1·1, p=0·83; appendix p 11).
Patients (n=36)
Sex
Female
Median age at myelo dysplastic syndrome or acute myeloid leukaemia diagnosis (range), years Male
Local diagnosis Myelodysplastic syndrome Myelodysplastic syndrome-EB1 or 2 Acute myeloid leukaemia
18 (50%)
10/18 (56%)
8/18 (44%)
14·3 (0·5–45·0)
8 (22%)
4/8 (50%)
4/8 (50%)
16·0 (9·0–30·0)
10 (28%)
6/10 (60%)
4/10 (40%)
33·5 (5·5–47·0)
21 (58%)
10/21 (48%)
11/21 (52%)
16·0 (0·5–45·0)
5 (14%)
3/5 (60%)
2/5 (40%)
13·8 (1·4–20·0)
10 (28%)
7/10 (70%)
3/10 (30%)
31·4 (5·5–47·0) 21·0 (9·0–47·0)
Central diagnosis* Myelodysplastic syndrome Myelodysplastic syndrome-EB1 or 2 Acute myeloid leukaemia Complex karyotype Yes
16 (44%)
9/16 (56%)
7/16 (44%)
No
16 (44%)
8/16 (50%)
8/16 (50%)
12·9 (1·4–45·0)
NA
4 (11%)
3/4 (75%)
1/4 (25%)
15·5 (0·5–20·0)
Bone marrow surveillance Yes
14 (39%)
6/14 (43%)
8/14 (57%)
11·9 (0·5–45·0)
No
19 (53%)
11/19 (58%)
8/19 (42%)
19·0 (1·4–47·0)
NA
3 (8%)
0
18·0 (18·0–37·8)
0
Data are n (%) or n/n (%), unless otherwise stated. EB=excess blasts. NA=not available. *Slides were unavailable for central diagnosis for ten (28%) of 36 patients. For these patients the local diagnosis was used for the central review. These ten patients comprise five with acute myeloid leukaemia, four with myelodysplastic syndrome, and one with myelodysplastic syndrome-EB1 or 2. Among the 16 with complex karyotype, 8 have AML and 8 have MDS and among the 16 without complex karyotype 2 have AML and 14 have MDS.
Table 2: Diagnostic and clinical features
Eight (80%) of ten of those with acute myeloid leukaemia compared with eight (36%) of 22 with myelodysplastic syndrome had complex cytogenetics (p=0·054). Patients with myelodysplastic syndrome with complex karyotype (n=22) had a 3-year overall survival of 15% (95% CI 1–47) compared with 64% (95% CI 34–83) in those without complex karyotype (p=0·15; figure 3A). 33 (92%) of 36 patients (eight of ten with leukaemia, four of five with myelodysplastic syndrome with excess blasts 1 or 2, and 21 of 21 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy. Serial bone marrow surveillance was done for 14 (39%) of 36 patients (nine with myelodysplastic syndrome, two with myelodysplastic syndrome with excess blasts 1 or 2, and three with leukaemia). 19 (53%) did not receive bone marrow surveillance, and three (8%) had unknown surveillance status. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Median follow-up was similar in the no surveillance (4·7 years [IQR 1·5–not estimable; n=19) and surveillance (6·5 years [3·3–not estimable; n=14) cohorts (p=0·79). We observed a median overall survival of 1·1 years (95% CI
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A
A
100
100
80
Overall survival (%)
Overall survival (%)
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60 40 20 0
0·5
Acute myeloid 10 (0) 7 (1) leukaemia
1
1·5
2
2·5
3
3·5
4
4 (1)
2 (1)
2 (1)
1 (1)
1 (1)
1 (1)
1 (1)
B
20 0
2
4
6
8
10
7 (2) 2 (1)
6 (3) 1 (1)
4 (5) 0 (2)
2 (6) 0 (2)
1 (7) 0 (2)
B Overall survival (%)
Overall survival (%)
40
With surveillance Without surveillance
100
80 60 40 20 0
2
4
6
8
10
Time from diagnosis (years) Myelodysplastic 26 (0) syndrome, myelodysplastic syndrome EB1 or 2
6
+
60
Number at risk (number censored) Non-complex karyotype 14 (0) Complex karyotype 8 (0)
100
0
80
0 0
Non complex karyotype Complex karyotype
+
12 (3)
9 (5)
6 (8)
3 (10)
2 (11)
80 60 40 20 0
0
Number at risk (number censored) Without surveillance 19 (0) With surveillance 14 (0)
2
4
6
8
10
1 (5) 2 (6)
1 (5) 1 (7)
Time from diagnosis (years) 5 (2) 8 (1)
3 (3) 7 (2)
1 (5) 5 (4)
Figure 2: Overall survival Overall survival (95% CI) for patients with Shwachman-Diamond syndrome and acute myeloid leukaemia (A) or myelodysplastic syndrome (B), according to initial diagnosis. EB1 or 2=with excess blasts 1 or 2.
Figure 3: Overall survival by complex karyotype and bone marrow surveillance status Overall survival (95% CI) by karyotype at initial diagnosis (A). Overall survival (95% CI) by bone marrow surveillance status before diagnosis of myelodysplastic syndrome or acute myeloid leukaemia (B).
0·6–not estimable) versus 7·7 years (0·6–not estimable) and 3-year overall survival estimates of 28% (95% CI 10–50) versus 62% (32–82) for the group without versus with marrow surveillance (p=0·13; figure 3B), suggesting a need for further evaluation. Median age at malignancy diagnosis was 11·9 years (range 0·5–45; IQR 5·6–19·8) for surveillance versus 19·0 years (range 1·4–47; IQR 14·4–31·5) for no-surveillance (p=0·13). There was an absence of uniformity in the specific marrow surveillance tests done, even within patients. No patients had flow cytometry, FISH If not, what does it mean?, or karyotype done on all surveillance marrows. Flow cytometry was done on 49% (n=43), FISH was sent by the treating physician on 72% (n=63), and karyotype was sent by the treating physician on 53% (n=46), of the 87 surveillance marrows. Del20q was present in three cases before diagnosis (one leukaemia, one myelo dysplastic syndrome with excess blasts 1 or 2, and one myelodysplastic syndrome), and iso7q was present in one case of myelodysplastic syndrome with excess blasts 1 or 2 and one case of myelodysplastic syndrome before diagnosis. Monosomy 7 was detected intermittently by FISH at amounts below clinical thresholds for several years before diagnosis in one patient each with leukaemia and myelodysplastic syndrome. One patient with
myelo dysplastic syndrome had del5q present before diagnosis, and another patient with myelodysplastic syndrome had low amounts of del7q and trisomy 8 detected by FISH in several marrows preceding diagnosis. However, karyotypes and FISH were not routinely done on all surveillance marrows. Of the 14 patients with marrow surveillance, there was no clinical concern for myeloid malignancy in four before the diagnostic marrow showing myelodysplastic syndrome (n=3), and myelodysplastic syndrome with excess blasts 1 or 2 (n=1). One patient was noted to have a complete blood count abnormality on the day of surveillance marrow which showed leukaemia. Two patients had no available clinical reports to assess suspicion before marrow examination. Eight of 14 patients who had marrow surveillance had antecedent marrow abnormalities, typically worsening dysplasia before diagnosis of myelodysplastic syndrome (n=5), myelodysplastic syndrome with excess blasts 1 or 2 (n=1), and leukaemia (n=2). One patient had warning signs with increasing dysplasia noted on two separate marrows (at 0·5 years and at 1 year and 6 months) and decreasing absolute neutrophil count on G-CSF before presenting with leukaemia, illustrating the need to proceed rapidly to transplantation. Six patients with
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marrow surveillance had no previous marrow abnormalities leading up to diagnosis of myelodysplastic syndrome (n=3), myelodysplastic syndrome with excess blasts 1 or 2 (n=1), or leukaemia (n=1), but three of these developed peripheral cytopenias leading up to the diagnostic marrow. Six (60%) of 10 patients presenting with leukaemia did not have surveillance and surveillance status was unknown for one. Although surveillance could identify actionable changes before progression to leukaemia, the presentation of one patient with leukaemia without an apparent antecedent dysplastic phase or cytogenetic abnormalities, highlights the limitations of existing surveillance tools and the need for better biomarkers for risk stratification. 15 cases with longitudinal complete blood count data before diagnosis of malignancy were reviewed (four leukaemia, two myelodysplastic syndrome with excess blasts 1 or 2, and nine myelodysplastic syndrome). Six had only mild cytopenias before diagnosis of myelodysplastic syndrome or leukaemia. Two had stable and four had fluctuating blood counts. The absence of progressive changes in blood counts did not preclude marrow disease, suggesting that complete blood count surveillance alone might be less sensitive than combined complete blood count and bone–marrow surveillance. The mean corpuscular volume was stable or decreasing in two of four patients with leukaemia, decreasing in two of two patients with myelodysplastic syndrome with excess blasts 1 or 2, decreasing in three of nine myelodysplastic syndrome patients, and stable in four of nine myelodysplastic syndrome patients.
Discussion This multicentre, retrospective study reports clinical features and outcomes of the largest cohort, to our knowledge, of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. Evolution of diagnostic criteria for myelodysplastic syndrome and leukaemia renders previous studies of Shwachman-Diamond syndrome difficult to extrapolate to existing practice, so central pathology review was done via current standards. Overall survival from myelodysplastic syndrome in our cohort was lower than expected for myelodysplastic syndrome in the absence of Shwachman-Diamond syndrome, and substantially lower in those with leukaemia.12 Treatment failure seemed to be associated with both toxicity of therapy and resistant disease indicating the need for novel approaches. Central pathology review highlighted the complexities in the diagnosis of myelodysplastic syndrome and acute myeloid leukaemia in Shwachman-Diamond syndrome. Myelodysplastic syndrome poses diagnostic challenges even in the non-Shwachman-Diamond syndrome population, with substantial interobserver variability in determination of dysplasia.13–16 Quantitation of blasts in a hypocellular marrow yielded discrepancies between
blast enumeration within the biopsy, versus aspirate or flow cytometry where dilution with blood could be problematic.17–24 Analysis of aberrant antigen expression, which can be seen in myelodysplastic syndrome was not available. Diagnosis after central pathology review differed from local diagnosis in 44% of cases with available slides, perhaps because of morphology challenges and revisions in WHO criteria for myelodysplastic syndrome– leukaemia.11 These data emphasise the value of enlisting the expertise of a haematopathologist experienced with Shwachman-Diamond syndrome. The baseline dysmor phologies noted in all Shwachman-Diamond syndrome marrows pose a major challenge for the morphologic diagnosis of myelodysplastic syndrome. In particular, the late granulocyte precursors and mature granulocytes often have hypo segmented nuclei and can be hypo granular. Dysplasia in the erythroid lineage at baseline in Shwachman-Diamond syndrome is unusual, and, particularly when combined with a progressively increasingly cellular marrow is concerning for myelo dysplastic syndrome, even in the absence of cytogenetic abnormalities. This pattern differs from the prototypical sporadic myelodysplastic syndrome in older adults according to WHO guidelines. However, leukaemia might evolve without apparent antecedent dysplasia or cytogenetic abnormalities. We did not observe a correlation between blast count and severity of dysplasia for myelodysplastic syndrome. Standard chemotherapy approaches for acute myeloid leukaemia led to poor overall survival in our cohort. Many patients were unable to proceed to HSCT owing to disease progression or mortality with chemotherapy. Pre-HSCT cytoreductive chemotherapy in patients with acute myeloid leukaemia and Shwachman-Diamond syndrome did not prevent relapse and carried unacceptably high toxicity (appendix pp 5–7). Further clinical and biological studies are needed to establish whether standard WHO definitions of acute myeloid leukaemia based on percentage of blasts inform the need for future novel cytoreductive therapy for patients with Shwachman-Diamond syndrome. New therapeutic strategies to achieve remission are needed in a bone marrow failure syndrome with poor stem cell reserve and high end-organ toxicities. The role of standard pre-HSCT cytoreductive chemotherapy approaches has also been questioned for Fanconi anaemia, another bone marrow failure and cancer predisposition syndrome, and for patients with either germline or somatic TP53 mutations, who tend to respond poorly to cytotoxic agents but have had some response to hypomethylating agents, especially when combined with venetoclax.25–28 Surveillance and management of patients within clinical practice was highly variable. Only a subset of patients diagnosed with Shwachman-Diamond syndrome were being monitored, and there was marked variability in surveillance testing, even for a given patient over time. The Shwachman-Diamond syndrome draft consensus guidelines recommend marrow surveillance based on
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expert opinion;9 however, published data are sparse regarding the benefit of marrow surveillance on overall survival of patients with leukaemia predisposition. At 3 years, the proportion of patients alive in our study was 28% (95% CI 10–50) for those without marrow surveillance and 62% (32–82) with marrow surveillance. Patients compliant with surveillance might also be more compliant with other aspects of care, contributing to improved outcomes. Comprehensive centralised pro spective collection of data is essential to develop evidencebased surveillance strategies for leukaemia predisposition disorders. Revised International Prognostic Scoring System (IPSS-R) and WHO Classification-Based Prognostic Scoring System (WPSS) have not been validated in patients with myelodysplastic syndrome arising from inherited marrow failure syndromes. Review of complete blood counts before presentation with myelodysplastic syndrome or leukaemia revealed limitations of complete blood counts surveillance alone for early disease detection. Complete blood counts were stable or even normal in some patients with cyto genetic and morphological evolution to myelodysplastic syndrome in bone marrow. Mean corpuscular volume trend was also not a consistent indicator of evolving myeloid malignancy in this cohort, and caution is advised in relying on the mean corpuscular volume for monitoring. This study has several limitations. Its retrospective nature and the absence of complete central pathology review, molecular analysis of clonal evolution, and a comparator group of patients with Shwachman-Diamond syndrome without myelodysplastic syndrome or acute myeloid leukaemia. Additionally, numbers are too small to draw conclusions regarding risks of haematological malignancy on the basis of specific germline SBDS mutations. Similarly, this study was not designed to determine the effect of specific patient characteristics, such as G-CSF treatment before the development of myelodysplastic syndrome or acute myeloid leukaemia. Chronic G-CSF treatment might improve overall survival, thus extending the timeframe within which they are at risk of developing a malignancy, or individuals with severe disease and highest malignancy risk might require higher doses of G-CSF.29 Although we found that surveillance can capture early actionable abnormalities identifying patients at high risk for progression to acute myeloid leukaemia, leukaemia can also develop without any antecedent warning discernible with available surveillance testing. Additional risk stratification strategies are under investigation in a prospective cohort. Somatic clonal abnormalities have been noted at young ages outside the context of myelodysplastic syndrome–leukaemia in patients with a germline genetic predisposition to myeloid malignancies.28 Previous studies have shown that TP53 mutations are common in Shwachman-Diamond syndrome, with or without myelodysplastic syndrome, so it is unclear 8
whether isolated TP53 mutations constitute an actionable finding.5,30 It has been hypothesised that TP53 mutations arise from selective pressures resulting from a failing marrow, and might be initiating events that mediate disease progression to myeloid malignancies. Although somatic mutation analysis (including TP53 analysis) is now available clinically, it is not yet clear how to use this information to inform the treatment plan. Longitudinal studies of clonal evolution with respect to clinical outcomes are needed. A prospective centralised registrybased approach is essential to improve outcomes of patients with rare diseases by identifying patients at risk and systematically collecting clinical data and annotated samples for ongoing biological studies to inform therapeutic decisions. The poor prognosis of patients with Shwachman-Diamond syndrome and acute myeloid leukaemia, and to a lesser extent of those with ShwachmanDiamond syndrome and myelodysplastic syndrome, documented in this study provides a compelling rationale for prospective studies to evaluate the effect of surveillance and early intervention on overall survival. Novel therapeutic options with both decreased toxicity and improved antileukaemic properties are urgently needed for these patients. Additional references are included in the appendix pp 12–16. Contributors All authors participated in study design, data acquisition, analysis, interpretation and revision of the manuscript. KC, EF, and AS additionally drafted the manuscript. All authors have given final approval of the submitted version and agree to be accountable for all aspects of the work related to the accuracy or integrity of the work. Declaration of interests We declare no competing interests. Acknowledgments This work was supported by NIH/NIDDK R24 DK099808 and NCRR/NIH UL1-RR026314-01 (Redcap), NIH T32 HL007574-36 (EF) and in part by the Intramural Research Program of the NIH and the National Cancer Institute (BPA, LJM). One of the patients from Seattle/Fred Hutchinson Cancer Research Center was enrolled in a clinical trial supported in part by the NIH (grant PO1 HL122173). The authors gratefully acknowledge David Steensma for critical review of the manuscript. References 1 Myers KC, Bolyard AA, Otto B, et al. Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr 2014; 164: 866–70. 2 Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet 2003; 33: 97–101. 3 Warren AJ. Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome. Adv Biol Regul 2018; 67: 109–27. 4 Nelson AS, Myers KC. Diagnosis, treatment, and molecular pathology of Shwachman-Diamond syndrome. Hematol Oncol Clin North Am 2018; 32: 687–700. 5 Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med 2017; 376: 536–47. 6 Iwafuchi H. The histopathology of bone marrow failure in children. J Clin Exp Hematop 2018; 58: 68–86. 7 Okcu F, Roberts WM, Chan KW. Bone marrow transplantation in Shwachman-Diamond syndrome: report of two cases and review of the literature. Bone Marrow Transplant 1998; 21: 849–51. 8 Dokal I, Rule S, Chen F, Potter M, Goldman J. Adult onset of acute myeloid leukaemia (M6) in patients with Shwachman-Diamond syndrome. Br J Haematol 1997; 99: 171–73.
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www.thelancet.com/haematology Published online December 23, 2019 https://doi.org/10.1016/S2352-3026(19)30206-6
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