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DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
Maria Armila Ruiz
1
, Binal N. Shah
1
, Guohui Ren
1
, David Shuey
1
,
Richard D. Minshall
2
, Victor R. Gordeuk
1
, Santosh L. Saraf
1
1
Division of Hematology & Oncology, Department of Medicine,
Comprehensive Sickle Cell Center, University of Illinois at Chicago,
Chicago, Illinois, USA
2
Departments of Anesthesiology and Pharmacology, College of Medicine,
University of Illinois at Chicago, Chicago, Illinois, USA
Correspondence
Santosh L. Saraf, Division of Hematology-Oncology, Department of
Internal Medicine, University of Illinois at Chicago, 820 South Wood
Street, Suite 172, Chicago, Illinois, USA.
Email: ssaraf@uic.edu
Funding information
The project described was supported by the National Institutes of
Health through grants R03 HL-146788, and R01 HL-153161 (Santosh
L. Saraf). The content is solely the responsibility of the authors and
does not necessarily represent the official views of the NIH.
ORCID
Maria Armila Ruiz https://orcid.org/0000-0003-1190-4219
Victor R. Gordeuk https://orcid.org/0000-0003-4725-7295
Santosh L. Saraf https://orcid.org/0000-0002-8584-4194
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sickle cell disease: biology, pathophysiology, genetics, translational
medicine, and new research directions. Am J Hematol. 2009;84(9):
618-625.
2. Loghmani H, Conway EM. Exploring traditional and nontraditional roles
for thrombomodulin. Blood. 2018;132(2):148-158.
3. Hirokawa K, Aoki N. Regulatory mechanisms for thrombomodulin
expression in human umbilical vein endothelial cells in vitro. J Cell Phy-
siol. 1991;147(1):157-165.
4. Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a
potentially catastrophic complication of severe sickle cell pain epi-
sodes. Am J Med. 1994;96(2):155-162.
5. Nephrology ISo. KDIGO clinical practice guideline for acute kidney
injury. Kidney Int Suppl. 2012;2(1):1-141.
6. Levey AS, Stevens LA, Schmid CH, et al. A new equation to
estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):
604-612.
7. Srisuwananukorn A, Raslan R, Zhang X, et al. Clinical, laboratory, and
genetic risk factors for thrombosis in sickle cell disease. Blood Adv.
2020;4(9):1978-1986.
SUPPORTING INFORMATION
Additional supporting information may be found in the online version
of the article at the publisher's website.
Received: 1 September 2021 Revised: 14 Decem-
ber 2021
Accepted: 17 Decem-
ber 2021
DOI: 10.1002/ajh.26444
A multicenter, retrospective
study of accelerated
venetoclax ramp-up in
patients with relapsed/
refractory chronic
lymphocytic leukemia
To the Editor:
The efficacy of venetoclax in chronic lymphocytic leukemia (CLL) is
well established.
1–3
Venetoclax is approved with a 5-week dose
ramp-up schedule to mitigate risk of tumor lysis syndrome (TLS);
dosing is increased weekly according to a schedule of 20 mg, 50 mg,
100 mg, 200 mg, reaching a target dose of 400 mg daily in Week 5
per United States prescribing information.
Although this standard 5-week ramp-up is appropriate for most
patients with CLL, rapid disease control is needed for some patients
with very aggressive disease. While many such patients respond to
venetoclax treatment it remains critical, especially for those who pro-
gress on B-cell receptor pathway inhibitor (BCRi) therapies such as
ibrutinib, to rapidly achieve a therapeutically-relevant dose of ven-
etoclax.
4
Thus, certain patients with CLL might benefit from expedited
venetoclax ramp-up, per National Comprehensive Cancer Network
Clinical Practice Guidelines.
Limited data are available on strategies for more rapid escalation
of venetoclax in CLL.
5
We report the first multicenter study to charac-
terize the safety and feasibility of an accelerated venetoclax ramp-up
schedule in patients with rapid progression of relapsed/refractory
(R/R) CLL.
This retrospective chart review was conducted across four large
academic medical centers in the United States from 2019 to 2020.
Patients with R/R CLL who had received prior treatment and had a
documented accelerated venetoclax ramp-up period (<5 weeks) were
retrospectively identified from medical charts. The study period began
1 month before ramp-up initiation and continued until 1 month after
ramp-up completion. The primary endpoint was the proportion of
patients with Grade ≥3 adverse events (AEs) during ramp-up, chosen
to capture a comprehensive safety profile of venetoclax in this setting.
Further details are provided in Appendix S1.
Twenty-eight patients were identified and included in the analysis
(Table S1). Seven patients (25.0%) had an absolute lymphocyte count
(ALC) of ≥100 10
9
cells/L (median 27.5; range 0.03–2160), and 7
patients (25.0%) had lymph node involvement > 5 cm. Median creati-
nine clearance was 84.0 mL/min (range 51.0–136.3).
E105 CORRESPONDENCE
Patients had a median of 3 prior lines of CLL therapy (range 1–7;
Table S1). Last line of therapy was discontinued before venetoclax
ramp-up in 25 patients (89.3%). One patient discontinued last line of
therapy during ramp-up. Two other patients (7.1%) discontinued their
last line of therapy once the stable dose of venetoclax was reached.
Among these three patients who did not discontinue prior therapy
before venetoclax initiation, two patients (7.1%) were receiving
ibrutinib and one patient (3.6%) was receiving idelalisib.
Nine patients (32.1%) experienced Grade ≥3 AEs (primary end-
point; Table S2), including anemia (n=5; 17.9%), neutropenia (n=2;
7.1%), thrombocytopenia (n=1; 3.6%), and febrile neutropenia
(n=1; 3.6%). Additional Grade ≥3 AEs included hyperkalemia (n=2;
7.1%), hypocalcemia (n=2; 7.1%), hypovolemic shock (n=2; 7.1%),
lymphopenia (n=2; 7.1%), cardiovascular insufficiency (n=1; 3.6%),
and hypophosphatemia (n=1; 3.6%). Three patients (10.7%) discon-
tinued venetoclax due to AEs; two did not reach a stable dose and
one patient discontinued after 12 days of ramp-up and a maximum
dose of 200 mg (Table S3).
The venetoclax ramp-up schedules initiated are described in
Table S4. All patients received antihyperuricemic drugs during ramp-
up, and all but one patient (96.4%) received intravenous hydration.
The majority of the patients (n=15, 53.6%) had a ramp-up period of
between 3 and < 5 weeks (Table S5). Twenty-six patients (92.9%)
reached a stable dose of venetoclax; of these, 20 patients (71.4%)
reached the target dose of 400 mg. The median time to reach any sta-
ble dose of venetoclax was 21 days (range 11–25) and was also
21 days (range 18–25) for the 20 patients who reached a stable dose
of 400 mg. All patients underwent accelerated ramp-up as inpatients,
with median hospital stay of 11 days (range 4–28) overall (Table S4).
Timing of hospital admission varied, with 18 patients (64.3%) admitted
1–5 days before ramp-up initiation; 9 (32.1%) admitted on the day of
initiation, and 1 (3.6%) admitted 1 day after initiation.
At least one AE of TLS was experienced by seven patients
(25.0%; Table 1), including five cases of laboratory TLS (17.9%) and
two cases of clinical TLS (7.1%). Two additional patients (7.1%) experi-
enced metabolic abnormalities (hyperuricemia, hypocalcemia, and
acute kidney disease) that did not meet the Howard Criteria for labo-
ratory TLS per investigator assessment. Of the seven patients who
developed TLS (at doses ranging between 20 and 200 mg), six had
event onset within the first week of ramp-up; one had onset in the
second week of ramp-up. Three of five patients (10.7% of all patients)
who experienced a single AE of laboratory TLS did not receive any
interventions because the TLS was self-limited with ongoing hydra-
tion and TLS prophylaxis.
Of the two patients (7.1%; Table 1) who developed clinical TLS,
one was assessed as being at high risk of TLS at baseline, and experi-
enced increased creatinine levels following venetoclax initiation (20 mg
dose); the patient received aggressive hydration and close laboratory
monitoring, with creatinine returning to baseline within 24 h. Ven-
etoclax was escalated to 50 mg, and the patient then experienced grade
4 acute kidney injury, hyperphosphatemia, and hyperkalemia. The other
patient, assessed as being at medium risk of TLS at baseline, experi-
enced hyperphosphatemia, hypocalcemia, and hyperkalemia, 1 day after
initiation of venetoclax monotherapy; hyperuricemia 2 days after initia-
tion; and acute kidney injury 3 days after the single initial dose of
20 mg. Both patients required interventions (Table 1) administered in
an intensive care unit but did not require hemodialysis. All AEs of TLS
(including clinical events) resolved without long-term clinical sequelae.
Between-group comparisons of patients who developed TLS
(n=7, 25.0%) versus patients who did not (n=21, 75.0%) reveal that
none of the baseline patient characteristics analyzed (including ALC
and lymph node size) were significantly associated with subsequent
risk of TLS. None of the genetic features analyzed, number of prior
lines of therapy (≤3 or >3), type of prior line of therapy (BCRis, che-
moimmunotherapy, or other), or timing of discontinuation of prior
therapy (during/after ramp-up or prior to venetoclax initiation) were
found to be associated with the development of TLS.
In this multicenter, retrospective chart review study, 32.1% of
patients with R/R CLL treated with accelerated venetoclax ramp-up
experienced an AE of Grade ≥3 (primary endpoint), and 10.7% of
patients discontinued venetoclax during the treatment period due to
AEs. Rates of discontinuation due to AEs were similar to those
observed in an integrated safety analysis of three phase 1/2 studies of
venetoclax monotherapy (10.0%), although the study period here was
shorter.
6
The median time to reach the approved dose of venetoclax
400 mg was substantially shorter at 21 days than the 35 days per the
standard ramp-up schedule. While TLS was observed in one-quarter of
patients, all TLS events were manageable and recovered without clinical
sequelae. This high rate of observed TLS could be explained in part by
the patient selection, which was enriched for high risk of TLS. These
confirmatory findings will help to inform future changes in dose ramp-
up for patients that require more urgent treatment.
Our data indicate that patients with R/R CLL requiring rapid dis-
ease control could receive a more rapid dose acceleration if they
receive appropriate inpatient monitoring and administration of ade-
quate prophylactic hydration and antihyperuricemics to reduce risk of
TLS. Clinical decision-making should balance the possible increased
risk of TLS with the risk of rapid progression of CLL. The rates of labo-
ratory and clinical TLS noted in our cohort were higher than those
associated with the approved 5-week ramp-up schedule (range 0%–
2.6% laboratory TLS and 0%–0.5% clinical TLS) but lower than rates
reported from other studies of accelerated ramp-up schedules (range
up to 52% laboratory TLS and up to 15% clinical TLS).
1–3,5
Our report describes a select group of patients who were
assessed to be at higher risk of rapid disease progression following
discontinuation of BCRi therapy; therefore, patient selection may
have affected the results. Additional limitations include the heteroge-
neity of the venetoclax ramp-up schedule used in our patients due to
the real-world nature of the study, the challenge of comparing to
other studies that did not use Howard Criteria for TLS, and our rela-
tively small sample size.
Overall, with close inpatient monitoring, accelerated venetoclax
ramp-up was feasible in a population of patients with aggressive R/R
CLL. Although TLS was observed in a higher proportion of patients than
is commonly reported with standard ramp-up, all cases were manageable
and did not result in long-term clinical sequelae. Thus, accelerated
CORRESPONDENCE E106
TABLE 1 Incidence and management of TLS during ramp-up
Patient
identifier AE of TLS
ALC before
venetoclax,
cells 10
9
/L
LN involvement
before
venetoclax
Creatinine
clearance,
mL/min
TLS risk at
venetoclax
initiation
Maximum
venetoclax
dose
reached, mg
Length of
venetoclax
ramp-up, days
Venetoclax
dose at time
of TLS, mg Abnormalities (grade)
b
Intervention
Other AEs reported
with clinical TLS
(grade)
1 Laboratory 139 None 91 Medium 400 22 200 Hyperkalemia (1)
c
[Pre: 4.2; Max: 6.1
d
]
Lasix and IV fluids -
2 Laboratory 296 >5 cm and
≤10 cm
112 High 400 22 100 Hyperkalemia (2)
c,e
[Pre: 5.1; Max: 8.5]
Hypocalcemia (4)
[Pre: 1.07; Max: 1.17]
Calcium gluconate -
3 Laboratory 75 >5 cm and
≤10 cm
>60 High 400 18 20 Hyperphosphatemia (2)
[Pre: 3.8; Max: 5.6]
--
4 Laboratory 173 ≤5 cm >60 Medium 200 12 20 Hyperphosphatemia (1)
[Pre: 4.2; Max:7.2]
Sevelamer -
5 Laboratory 33
a
≤5 cm >60 Medium
a
400 11 20 Hyperphosphatemia (1)
[Pre:3.8; Max:5.3]
Sevelamer -
6 Clinical 1 >10 cm 61 High 50 N/A 20 Acute kidney injury (4)
[Pre: 1.2; Max: 1.57]
Unknown -
50 Hyperphosphatemia (4)
[Pre: 3.3; Max: 6.4]
Sevelamer -
50 Hyperkalemia (4)
[Pre: 3.9; Max: 6.0
c
]
Calcium gluconate
Polyethylene glycol
Hypovolemic shock (4)
7 Clinical 111 <5 cm 51 Medium 20 N/A 20 Hyperphosphatemia (4)
[Pre: 5.7; Max: 11.2]
Hypocalcemia (4)
[Pre: 8.8; Max: 7.3]
Hyperkalemia (4)
[Pre: 4.0; Max: 6.1
c
]
Calcium gluconate
Calcium chloride
Dialysis
Hypovolemic shock (4)
Hyperuricemia (4)
[Pre: 3.9; Max: 5.5]
Allopurinol
Rasburicase
Acute kidney injury (4)
[Pre: 1.3; Max: 1.55]
- Cardiovascular
insufficiency (4)
Abbreviations: AE, adverse event; ALC, absolute lymphocyte count; LN, lymph node; TLS, tumor lysis syndrome.
a
ALC was 33 on the day prior to hydration.
b
Pre- and maximum onset/post-event laboratory values are shown for potassium, phosphate, creatinine, uric acid, and calcium, as appropriate.
c
Whole blood potassium was checked to confirm true hyperkalemia.
d
Sample was hemolyzed.
e
Significant pseudohyperkalemia was observed prior to dosing, and although potassium measurements increased following dosing, pseudohyperkalemia may still have been present.
E107 CORRESPONDENCE
venetoclax ramp-up may benefit patients with aggressive CLL, particu-
larly those progressing on/after BCRi therapy, or patients who would
find a shorter ramp-up schedule performed in the inpatient setting more
convenient than the standard 5-week ramp-up in the outpatient setting.
As all of the patients in our study were treated at experienced academic
centers with close inpatient monitoring, we do not believe that our data
can be extrapolated outside of this setting. A prospective clinical trial of
accelerated venetoclax ramp-up in CLL is now underway
(NCT04843904) to validate the find ings of our retrospective study.
ACKNOWLEDGMENTS
Medical writing support was provided by Hayley Ellis, PhD, of Fis-
hawack Communications Ltd, part of Fishawack Health, and funded
by AbbVie. Matthew S. Davids is a Scholar in Clinical Research from
the Leukemia & Lymphoma Society. Jennifer L. Crombie is supported
by a K12 (K12CA087723). Venetoclax (ABT-199/GDC-0199) is being
developed in collaboration between AbbVie, Inc., and Genentech.
AbbVie, Inc. sponsored the study, contributed to the analysis, and
interpretation of the data, and participated in the writing, review, and
approval of the manuscript. All authors had access to all relevant data.
No honoraria or payments were made for authorship.
CONFLICT OF INTERESTS
Matthew S. Davids: Institutional research grants—Ascentage Pharma,
AstraZeneca,BMS,Genentech,MEIPharma,Novartis,Pharmacyclics,
Surface Oncology, TG Therapeutics, Verastem. Consulting fees—AbbVie,
Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene,
BMS, Celgene, Eli Lilly, Genentech, Janssen, MEI Pharma, Merck, Takeda,
TG Therapeutics, Verastem. Mazyar Shadman: Consulting, advisory
boards, steering committees or data safety monitoring committees—
AbbVie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Ver-
astem, ADC Therapeutics, BeiGene, Cellectar, Bristol-Myers Squibb,
Morphosys, Merck, TG Therapeutics, Innate Pharma, Kite Pharma, Adap-
tive Biotechnologies, Epizyme, and Atara Biotherapeutics. Research
funding—Mustang Bio, Celgene, Bristol-Myers Squibb, Pharmacyclics,
Gilead, Genentech, Abbvie, TG Therapeutics, BeiGene, AstraZeneca,
Sunesis. Sameer A. Parikh: Research funding (provided to institution)
from Pharmacyclics, Janssen, AstraZeneca, TG Therapeutics, Merck,
AbbVie, and Ascentage Pharma for clinical studies in which Sameer
A. Parikh is a principal investigator. Advisory board meetings—
Pharmacyclics, AstraZeneca, Genentech, GlaxoSmithKline, Innate
Pharma, Adaptive Biotechnologies, and AbbVie (he was not personally
compensated for his participation). Chaitra Ujjani: Research—AbbVie,
AstraZeneca,Gilead/Kite,Loxo/EliLilly,PYC.Consulting—AbbVie,
AstraZeneca,Atara,Beigene,Epizyme,Genentech,Gilead/Kite,Incyte,
Jannsen, MorphoSys, PYC, TG Therapeutics, Verastem. Jennifer
Crombie: Research funding (provided to institution)—AbbVie, Bayer,
Merck, Roche. Consulting—Incyte, Karyopharm. Dingfeng Jiang, Cynthia
Llamas, Dai Feng: Employees—AbbVie, may hold stock or options. Nicole
Lamanna: Consulting and advisory boards—AbbVie, AstraZeneca,
BeiGene, Celgene, Genentech, Gilead, Janssen, Pharmacyclics. Research
funding (to institution)—AbbVie, AstraZeneca, BeiGene, Genentech,
Juno, MingSight, Oncternal, TG Therapeutics, Verastem.
AUTHOR CONTRIBUTIONS
All authors had access to relevant data, and participated in the
writing, review, and approval of the manuscript. Matthew S. Davids,
Mazyar Shadman, Sameer A. Parikh, Chaitra Ujjani, Jennifer
L. Crombie, Dingfeng Jiang, Cynthia Llamas, Dai Feng, Nicole
Lamanna—study concept and design; acquisition of data; analysis
and interpretation of data; drafting of the manuscript; critical revi-
sion of the manuscript for important intellectual content; statistical
analysis; obtained funding; administrative, technical, or material sup-
port; study supervision.
DATA AVAILABILITY STATEMENT
AbbVie is committed to responsible data sharing regarding the clinical
trials we sponsor. This includes access to anonymized, individual, and
trial-level data (analysis data sets), as well as other information (eg,
protocols and Clinical Study Reports), as long as the trials are not
part of an ongoing or planned regulatory submission. This includes
requests for clinical trial data for unlicensed products and indications.
This clinical trial data can be requested by any qualified researchers
who engage in rigorous, independent scientific research, and will be
provided following review and approval of a research proposal and
Statistical Analysis Plan (SAP) and execution of a Data Sharing Agree-
ment (DSA). Data requests can be submitted at any time and the data
will be accessible for 12 months, with possible extensions considered.
For more information on the process, or to submit a request, visit the
following link: https://www.abbvie.com/our-science/clinical-trials/
clinical-trials-data-and-information-sharing/data-and-information-
sharing-with-qualified-researchers.html.
Matthew S. Davids
1
, Mazyar Shadman
2,3
, Sameer A. Parikh
4
,
Chaitra Ujjani
3
, Jennifer L. Crombie
1
, Dingfeng Jiang
5
,
Cynthia Llamas
5
, Dai Feng
5
, Nicole Lamanna
6
1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts, USA
2
Division of Medical Oncology, University of Washington, Seattle,
Washington, USA
3
Clinical Research Division, Fred Hutchinson Cancer Research Center,
Seattle, Washington, USA
4
Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
5
AbbVie Inc., North Chicago, Illinois, USA
6
Columbia University Medical Center, New York, New York, USA
Correspondence
Matthew S. Davids, Department of Medical Oncology, Dana-Farber
Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Email: matthew_davids@dfci.harvard.edu
ORCID
Matthew S. Davids https://orcid.org/0000-0003-4529-2003
Mazyar Shadman https://orcid.org/0000-0002-3365-6562
Sameer A. Parikh https://orcid.org/0000-0002-3221-7314
CORRESPONDENCE E108
Chaitra Ujjani https://orcid.org/0000-0003-1977-1510
Jennifer L. Crombie https://orcid.org/0000-0003-3445-5129
REFERENCES
1. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in
patients with CLL and coexisting conditions. N Engl J Med. 2019;
380(23):2225-2236.
2. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with ven-
etoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;
374(4):311-322.
3. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in
relapsed or refractory chronic lymphocytic leukemia. N Engl J Med.
2018;378(12):1107-1120.
4. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lympho-
cytic leukaemia progressing after ibrutinib: an interim analysis of a mul-
ticentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65-75.
5. Koenig KL, Huang Y, Dotson EK, et al. Safety of venetoclax rapid dose
escalation in CLL patients previously treated with B-cell receptor sig-
naling antagonists. Blood Adv. 2020;4(19):4860-4863.
6. Davids MS, Hallek M, Wierda W, et al. Comprehensive safety analysis of
venetoclax monotherapy for patients with relapsed/refractory chronic
lymphocytic leukemia. Clin Cancer Res. 2018;24(18):4371-4379.
SUPPORTING INFORMATION
Additional supporting information may be found in the online version
of the article at the publisher's website.
Received: 23 November 2021 Accepted: 17 December 2021
DOI: 10.1002/ajh.26448
Lymphocytopenia predicts
shortened survival in
myelodysplastic syndrome
with ring sideroblasts
(MDS-RS) but not in
MDS/MPN-RS-T
To the Editor:
More than 10 years ago, we described the association between abso-
lute lymphocyte count (ALC) and survival in myelodysplastic syndromes
(MDS) with
1
or without
2
del(5q); the latter study included 503 patients
with non-del(5q) MDS and reported median survival of 18.5 months for
patients with ALC < 1.2 10
9
/L versus 26.6 months for those with
ALC ≥1.2 10
9
/L (p<.001);
2
the prognostic contribution of ALC in
the study was shown to be independent of the International Prognostic
Scoring System (IPSS).
3
In a subsequent larger study of 889 patients
with primary MDS,
4
we confirmed the prognostic relevance of ALC <
1.2 10
9
/L, in the context of the revised IPSS (IPSS-R),
5
although sig-
nificance was borderline (p=.06).
4
These observations were more
recently confirmed by another retrospective study of 1023 patients
from the Düsseldorf MDS-registry, which included therapy-related and
del(5q) cases;
6
ALC < 1.2 10
9
/L was associated with shorter survival
that was not accounted for by age or cytogenetic risk groups; however,
significance was lost (p=.09) after accounting for bone marrow
(BM) blast percentage and degree of cytopenias. Of note, the
Düsseldorf study
6
included 140 patients with MDS with ring
sideroblasts (MDS-RS), with single lineage (SLD) or multilineage (MLD)
dysplasia, and the prognostic relevance of ALC < 1.2 10
9
/L was most
apparent in MDS-RS-SLD.
6
The objectives for the current study were
to examine the prognostic relevance of lymphocytopenia (ALC < 1.0 or
1.2 10
9
/L; Mayo Clinic reference range 0.95–3.07 10
9
/L) in both
MDS-RS and myelodysplastic/myeloproliferative neoplasm with RS and
thrombocytosis (MDS/MPN-RS-T).
After approval from the institutional review board, we queried
the Mayo Clinic database for myeloid neoplasms to identify
147 patients who met the 2016 World Health Organization (WHO)
diagnostic criteria for either MDS-RS (n=71) or MDS/MPN-RS-T
(n=76).
7
The main diagnostic criterion was the presence of at least
15% BM RS for both MDS-RS and MDS/MPN-RS-T, which in the
case of MDS-RS also included patients with ≥5% BM RS in associa-
tion with SF3B1 mutation. Additional required diagnostic criteria for
both entities included the presence of < 5% BM blasts, < 1% periph-
eral blood (PB) blasts, and, for MDS/MPN-RS-T, presence of platelet
count ≥450 10
9
/L Exclusionary criteria included the presence of
Auer rods, diagnostic criteria for MDS with isolated del(5q), t(3;3)
(q21.3;q26.2), inv (3)(q21.3q26.2), BCR:ABL1, or other rearrangements
of PDGFRA,PDGFRB,FGFR1,PCM1-JAK2.
7
Conventional methods
were used for cytogenetic and next-generation sequencing studies.
Statistical analyses considered parameters at the time of diagnosis
and were performed using JMP Pro 14.0.0 software package, SAS
Institute, Cary, NC.
Table 1 outlines presenting clinical and laboratory features, as well
as postdiagnosis events, in 71 study patients with MDS-RS (median age
73 years, range 41–94; males 63%) and 76 with MDS/MPN-RS-T
(median age 73 years, range 49–93; males 61%). IPSS-R risk distribu-
tions for MDS-RS were 34% very low, 59% low, 4% intermediate, 3%
high, and 0% very high; the corresponding figures for MDS/MPN-RS-T
were 29%, 62%, 3%, 3%, and 2%. SF3B1,JAK2,andASXL1 mutation
frequencies were 100%, 1%, and 11%, respectively, for MDS-RS and
92%, 30%, and 20%, respectively, for MDS/MPN-RS-T. Comparison of
patients with MDS-RS versus MDS/MPN-RS-T revealed the former
with lower absolute neutrophil count (ANC; median 3 vs. 4.6 10
9
/L;
p=.002) and the latter with higher absolute monocyte count (AMC;
median 0.4 vs. 0.5 10
9
/L; p=.05), but otherwise similar ALC (median
1.6 vs. 1.6 10
9
/L; p=.4), degree of anemia (hemoglobin <10 g/dL in
65% vs. 67%; p=.8) and IPSS-R cytogenetic and overall risk distribu-
tion (p=.3 and .8, respectively). Median follow-up for living patients
with MDS-RS was 2.1 years and for those with MDS/MPN-RS-T was
2.8 years. During follow-up, 46 (65%) deaths and 2 (2.8%) leukemic
transformations were documented in MDS-RS and 36 (47%) deaths
and 2 (2.6%) leukemic transformations in MDS/MPN-RS-T. Overall
survival data were similar between MDS-RS (median 5.4 years) and
MDS/MPN-RS-T (median 5.6 years; Figure 1A; p=.98).
E109 CORRESPONDENCE