CLL, CML and MDS: where
do we stand in 2014?
Prithviraj Bose, M.D.
VAHO Spring meeting
April 26th, 2014
What has not changed in CLL
• Indications for treatment

Constitutional symptoms

Progressive marrow failure



Massive or progressive or symptomatic
lymphadenopathy or splenomegaly
LDT < 6 m or > 50% increase in ALC over 2 months
(don’t use LDT alone if initial ALC < 30,000/µl)
AIHA and/or ITP poorly responsive to steroids or
other standard therapy
Hallek M, et al. IWCLL guidelines. Blood 2008; 111(12): 5446-56.
Some definitions revisited
• CLL: ≥ 5000 monoclonal B-cells/µL for ≥ 3 months
• SLL: Lymphadenopathy and/or splenomegaly,
circulating B-cells < 5000/µl
• MBL: < 5000 monoclonal B-cells/µL, no symptoms,
cytopenias, lymphadenopathy or organomegaly;
progresses to CLL @ 1-2% per year
•
CLL/SLL morphology and immunophenotype


Small, mature lymphocytes with a narrow border
of cytoplasm and a dense nucleus with partially
aggregated chromatin without discernible nucleoli
CD5+CD19+CD20+CD23+CD79b+sIg+
Eichhorst B, et al. ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22(suppl 6): vi50-vi54.
Prognostic factors
•
Clinical stage
•
Beta-2-microglobulin
•
Thymidine kinase
•
Soluble CD23
•
CD38 positivity
•
ZAP-70 expression and methylation*
•
IgVH mutational status
•
VH3.21 gene usage
•
Genomic aberrations
Hallek M, et al. Blood 2008; 111(12): 5446-56. *Claus R, et al. J Clin Oncol 2012; 30(20): 2483-91.
Probability of Survival from the Date of Diagnosis among the Patients in the Five Genetic
Categories.
Döhner H et al. N Engl J Med 2000;343:1910-1916.
Associations between Gene Mutations and Clinical Characteristics.
Wang L et al. N Engl J Med 2011;365:2497-2506.
Fludarabine, Cyclophosphamide,
Rituximab (FCR)
•
Standard of care in physically fit patients
•
Improved 3-yr PFS and OS over FC in phase III study*
•
Overcomes the adverse prognostic impact of del11q
•
Rituximab dose is 500 mg/m2 in cycles 2-6
•
Has improved OS over historical controls at MDACC


Frontline: ORR 95%, CRR 72%, 6-yr OS 77%, 6-yr
FFS 51%, median TTP 80 months†
Previously treated: ORR 74%, CRR 30%, median
OS 47 and median PFS 21 months††
*Hallek M, et al. Lancet 2010; 376(9747): 1164-74. †Tam CS, et al. Blood 2008; 112(4): 975-80. ††Badoux XC, et al. Blood 2011; 117(11): 3016-24.
Bendamustine and Rituximab (BR)
• Dose of bendamustine 90 mg/m2 in frontline setting;
70 mg/m2 in R/R setting; 100 mg/m2 when used alone
•
B vs CLB phase III trial in previously untreated Binet
B/C CLL: B significantly improved CR rate, median PFS
and time to next treatment but not OS*
•
Long-term f/u of CALGB 9011 has shown late OS
benefit for fludarabine over chlorambucil
•
BR studied in multiple phase II GCLLSG trials:


†Upfront: ORR 88%, CRR 23%, median EFS 33.9
months and 90.5% alive after 27 months (median)
R/R: ORR 59%, CRR 9%, median EFS 14.7 months
after median f/u of 24 months††
*Knauf WU, et al. Br J Haematol 2012; 159(1): 67-77. †Fischer K, et al. JCO 2012; 30(26): 3209-16. ††Fischer K, et al. JCO 2011; 29(26): 3559-66.
FCR vs BR
•
Frontline phase III trial in 564 physically fit CLL pts
without del17p from 158 sites in 5 countries (CLL10)
•
Median age 62; 22%, 38% and 40% Binet A, B and C
•
At 27.9 months median f/u, ORR identical (97.8%) but
CRR 47.4% with FCR vs 38.1% with BR (p=0.031); rates
of MRD negativity not significantly different
•
2-yr PFS (85% vs 78.2%) and EFS (82.6% vs 75.7%)
significantly favored FCR, but OS no different (94.2%
vs 95.8%); PFS difference disappeared in pts > 65
•
Grade 3-5 toxicity, severe heme toxicity, severe
neutropenia, severe infections all significantly higher
in FCR arm, especially in elderly pts
Eichhorst B, et al. Blood (ASH Annual Meeting Abstracts) November 2013; 122(21): 526.
•
Lenalidomide and Rituximab
An important non-cytotoxic option in salvage setting
•
Tumor flare (enlarged lymph nodes, fever,
lymphocytosis, rash and bone pain) may occur (~15%)
•
ORR 66% in a small (n=59) phase II study at MDACC
•
28-day cycles; R given weekly in cycle 1 and on day 1
in cycles 3-12, LEN started on day 9 of cycle 1 at 10
mg/d and given continuously, indefinitely if of benefit
•
12% CRs; 12% nodular PRs; median TTF 17.4 months
•
Median OS not reached; estimated 3-yr survival 71%
•
Grade 3/4 neutropenia in 73%, grade 3/4 infection or
fever in 24%; 1 grade 3 TLS, 1 VTE
Badoux XC, et al. J Clin Oncol 2013; 31(5):584-91.
Zenz T, et al. Nat Rev Cancer 2010; 10(1):37-50.
Targeting of BCR signaling as a therapeutic strategy in CLL. Red symbols and letters indicate
new therapeutics as discussed in the text.
Hallek M Hematology 2013;2013:138-150
©2013 by American Society of Hematology
Ibrutinib (PCI-32765)
•
An oral, irreversible BTK inhibitor, a critical mediator
of BCR signaling, approved for previously treated CLL
•
Mobilizes CLL cells out of protective stromal niches
into the peripheral blood, where they eventually die
•
Phase Ib/II trial in 85 pts with R/R CLL/SLL: 91% ORR
(including 20% PRs with lymphocytosis) at 420 mg/d;
ORR 71% in phase Ib/II trial in 31 untreated pts ≥ 70*
•
Estimated PFS at 26 months 75%; estimated OS 83%
•
Appears to be effective regardless of risk factors, incl.
del17p, and no. of prior therapies
•
Lymphocytosis noted by day 7, peaked at 4 weeks
(median), followed by gradual decline
Byrd, JC et al. N Engl J Med 2013; 369(1): 32-42. *O’Brien S, et al. Lancet Oncol 2014; 15(1): 48-58
Response to Ibrutinib over Time.
Byrd JC et al. N Engl J Med 2013;369:32-42.
Adverse Events.
Byrd JC et al. N Engl J Med 2013;369:32-42.
Ibrutinib warnings and precautions
•
Grade ≥ 3 bleeding occurred in 5% of MCL and 6% of
CLL pts: caution advised in pts on blood thinners
•
Grade ≥ 3 infections in 25% of MCL & 35% of CLL pts
•
Treatment-emergent cytopenias in 41% of MCL and
35% of CLL pts (neutropenia and thrombocytopenia)
•
Increases in creatinine (maintain adequate hydration)

Upto 1.5 x ULN in 67% of MCL and 23% of CLL pts

1.5 – 3 x ULN in 9% of MCL pts and 4% of CLL pts
o
SPMs occurred in 5% of MCL and 10% of CLL pts
o
Not recommended in pregnancy
IMBRUVICA™ prescribing information. February 2014.
RESONATE trial – ASCO 2014
•
Multi-center, open-label, phase III study in 391 pts
with R/R CLL/SLL
•
Median f/u 9.4 months



o
PFS: 88% at 6 m with ibrutinib vs 8.1 m with
ofatumumab (p<0.001)
OS: At 12 months, median 90% with ibrutinib vs
81% with ofatumumab
ORR: 42.6% with ibrutinib (+ 20% PR with
lymphocytosis) vs 4.1% with ofatumumab
(p<0.001)
No effect of del17p or purine analog resistance
Byrd JC et al. NEJM 2014 May 31. Epub ahead of print.
Progression-free and Overall Survival.
Byrd JC et al. N Engl J Med 2014. DOI:
10.1056/NEJMoa1400376
Ibrutinib resistance
•
Whole-exome sequencing and functional analysis of
identified mutations in patients relapsing on ibrutinib
•
CysSer mutation in BTK at binding site of ibrutinib:
C481S = BTK only reversibly inhibited by ibrutinib
•
R665W and L845F mutations in PLCγ2: gain of
function mutationsautonomous BCR activity
•
PLCγ2 immediately downstream of BTK
•
CARD11 mutations predict for ibrutinib resistance in
DLBCL
•
CARD11 also downstream of BTK
•
Reminiscent of EGFR and KRas in CRC
Woyach JA, et al. N Engl J Med 2014; 370(24): 2286-94.
•
Idelalisib (GS-1101, CAL-101)
A first-in-class PI3Kδ inhibitor
•
Phase III study in 220 previously treated pts with CLL
and decreased renal function, previous therapyinduced myelosuppression, or major comorbidities
•
At 24 weeks, median PFS 93% in idelalisib group vs
46% in placebo group (p < 0.001); 12-month OS 92%
vs 80% favoring idelalisib (p = 0.02)
•
ORR 81% vs 13% favoring idelalisib (p < 0.001); SAEs
40% in idelalisib group vs 35% in placebo group
•
Lymphocytosis peaked at week 2 resolved by week 12
•
Efficacy unaffected by presence or absence of del17p,
p53 mutation or IgVH mutation status
Furman RR, et al. N Engl J Med 2014; 370(11): 997-1007.
Progression-free and Overall Survival.
Furman RR et al. N Engl J Med 2014;370:997-1007.
Changes in Lymph Nodes and Lymphocytes.
Furman RR et al. N Engl J Med 2014;370:997-1007.
Obinutuzumab
•
A humanized, type II glycoengineered anti-CD20 mab
that induces apoptosis more efficiently than
rituximab with greater ADCC and less CDC
•
CLL11 trial: Open-label 3-group trial in previously
untreated CLL pts with comorbidities: 781 pts
randomized 1:2:2 to CLB alone, G-CLB or R-CLB
•
Six 4-wk cycles; G given at 1000 mg IV on d1-2, 8, 15
of cycle 1 and on d1 of cycles 2-6; CLB 0.5 mg/kg PO
on days 1 and 15 of each cycle; standard dosing of R
•
Grade 3/4 infusion reactions in 20% with first dose G
•
Median PFS 26.7 (G) vs 15.2 (R) months; OS similar
•
Benefit for G not seen in del17p pts
Goede V, et al. N Engl J Med 2014; 370(12): 1101-10.
Response Rates and Progression-free Survival with Obinutuzumab–Chlorambucil versus
Rituximab–Chlorambucil.
Goede V et al. N Engl J Med 2014. DOI:
10.1056/NEJMoa1313984
Adverse Events of Grade 3 or Higher, Safety Population.
Goede V et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1313984
•
Obinutuzumab warnings and
precautions
Hep B reactivation
•
PML
•
Infusion reactions (steroid premedication important!)

Similar pattern when combined with B or FC*
o
TLS
o
Infections (contraindicated during active infection)
o
Neutropenia (grade 3/4 in 34% in pivotal trial)
o
Thrombocytopenia (grade 3/4 in 12% in pivotal trial;
acute – within 24 hours - in 5%)
GAZYVA™ prescribing information. November 2013. *Brown JR, et al. Blood Nov 15, 2013; 122(21): 523.
ABT-199 (GDC-0199)
•
A oral, Bcl-2 selective “BH3-mimetic”*
•
CLL is a highly Bcl-2 dependent malignancy†
•
Prelim results from an ongoing phase I trial†† show
an ORR of 84% among 67 pts with R/R CLL or SLL
•
ORR 82% in del17p and 89% in F-refractory disease
•
Most common AEs: diarrhea (43%), neutropenia
(37%), fatigue (33%), URTI (33%), cough (22%)
•
Fatal TLS seen early in trial; avoided with slow dose
escalation
•
Phase II studies ongoing with rituximab and
obinutuzumab
*Souers AJ, et al. Nat Med 2013; 19(2):202-8. †Del Gaizo Moore V, et al. J Clin Invest 2007; 117(1):112-21. ††Cancer Discov 2014; 4(2):OF5.
CAR T-cells
•
Autologous T-cells genetically modified by viral
transduction to express anti-CD19 chimeric antigen
receptor
•
Pts pre-treated with lymphodepleting chemotherapy
•
Initial report described late TLS and MRD-negative CR
sustained for 10 months (no infusional toxicities)*
•
Delayed cytokine release syndrome rapidly reversed
using IL-6 receptor antagonist tocilizumab
•
ORR 40% with durable responses in an ongoing phase
II dose optimization study with short follow-up†
•
As consolidation after PCR, may eradicate marrow
disease better than nodal disease††
Porter DL, et al. *N Engl J Med 2011; 365(8): 725-33 and †Blood Nov 15, 2013; 122(21): 873. ††Park JH, et al. Blood Nov 15, 2013; 122(21): 874.
Treatment algorithm for CLL patients in frontline (A) and second-line (B) indications.
Hallek M Hematology 2013;2013:138-150
©2013 by American Society of Hematology
Management of CLL patients with Richter transformation to diffuse large B-cell lymphoma in
which no clinical trial is available.
Parikh S A et al. Blood 2014;123:1647-1657
©2014 by American Society of Hematology
CML-CP: imatinib still a great drug!
Baccarani M, et al. ELN recommendations. Blood 2013; 122(6): 872-84.
Definitions of response
Oehler VG. Hematology (ASH Education Program Book) 2013; 2013(1):176-83.
CML milestones: ELN guidelines
Baccarani M, et al. ELN recommendations. Blood 2013; 122(6): 872-84.
ELN and NCCN: similarities and
differences
Oehler VG. Hematology (ASH Education Program Book) 2013; 2013(1):176-83.
Recommended testing for disease monitoring adapted from NCCN (2013) and ELN (2009 and
2013).
Oehler V G Hematology 2013;2013:176-183
©2013 by American Society of Hematology
Graphic representation of the estimated outcome with 2 different strategies for frontline CML
therapy.
Cortes J , and Kantarjian H Blood 2012;120:1390-1397
©2012 by American Society of Hematology
Frontline therapy: IM vs 2nd gen TKI
Hughes T, White D. Hematology (ASH Education Program Book) 2013; 2013(1): 168-75.
IM, NIL, DAS: toxicity profiles
Hochhaus A. Hematology (ASH Education Program Book) 2011; 2011(1): 128-35.
Molecular monitoring can detect residual disease during many years of imatinib therapy.
Branford S Hematology 2012;2012:105-110
©2012 by American Society of Hematology
ENESTnd and DASISION: deep
molecular responses
Sweet K, Oehler V. Hematology (ASH Education Program Book) 2013; 2013(1): 184-8.
TKI discontinuation and cure of CML
•
Adverse effects, inconvenience
•
Concept of “operational cure” (late Dr. John Goldman)


Not necessary to eradicate the last Bcr-Abl+ cell
Low level Bcr-Abl transcripts detectable in blood
of healthy individuals (Blood 1995; 86(8): 3118-22 and 1998; 92(9): 3362-7)
o
Unsustainable cost of CML drugs (Blood 2013; 121(22): 4439-42)
o
Survival of CML-CP now similar to general population
o
Trials so far suggest discontinuation safe after > 2 yrs
of CMR; most relapses regained CMR with prompt TKI
reintroduction; but NOT recommended off trial in US
Bose P, Vachhani P. Can We Cure CML without Transplantation? In: Ustun C, Popat UR (Eds). Chronic Myeloid Leukemia: From Daily Management
2nd gen TKI discontinuation trials
•
ENESTgoal (NCT01744665) – open at UVA, soon to
open at Massey (Jaime M. Scott, RN 804-628-1909)
•
Pts with CML-CP on imatinib for ≥1 yr in MMR (≤ 0.1%
on IS) but not yet in MR4.5 (≤ 0.0032% on IS); n = 300



Switch to nilotinib
If MR4.5 achieved, randomized to 1 or 2 yrs of
nilotinib consolidation
If MR4.5 sustained, can discontinue nilotinib
o
DASFREE (NCT01850004): CML-CP on dasatinib for ≥2
yrs and in CMR (≥ MR4.5 or ≤ 0.0032% on IS) for ≥1 yr
o
No sites in eastern US
Bosutinib
•
FDA-approved in 09/12 for CML in all phases with R/I
to prior therapy; NOT for frontline therapy
•
A dual Src/Abl TKI, dose 500 mg once daily with food


Effective after imatinib alone* or after imatinib +
dasatinib/nilotinib†
Does not inhibit the “gatekeeper” T315I mutant
o
Frontline BELA trial failed to meet primary endpoint
of statistically significant improvement in CCyR rate††
o
12 month MMR rate was higher with bosutinib, and
pts reached CCyR and MMR faster††
o
Main toxicities GI and hepatic
*Cortes JE, et al. Blood 2011; 118(17): 4567-76. †Khoury HJ, et al. Blood 2012; 119(15): 3403-12. ††Cortes JE, et al. JCO 2012; 30(28): 3486-92.
Omacetaxine
•
Semi-synthetic derivative of homoharringtonine
•
Approved 10/12 for CP/AP CML R/I to ≥ 2 prior TKIs
•
Not dependent on Bcr-Abl; effective against T315I
•
Protein synthesis inhibitor that down-regulates shortlived anti-apoptotic proteins such as Mcl-1
•
1.25 mg/m2 bid on days 1-14 q28d until HR (max 6
cycles), followed by days 1-7 q28d (maintenance)
•
Major toxicities (grade 3/4) are hematologic
•
Grade 1/2: Diarrhea, nausea, fatigue, headache,
pyrexia, asthenia, infection (MDACC studies)
•
Median PFS 7-8 months in MDACC trials
Cortes J et al. Blood 2012; 120(13): 2573-80 and Am J Hematol 2013; 88(5): 350-4.
Ponatinib
•
3rd gen TKI specifically designed to inhibit Bcr-AblT315I
•
Also inhibits KIT, PDGFR, RET, FGFR, FLT3, VEGFR
•
Initial US approval 12/12, subsequently suspended
•
Currently indicated for CML (any phase) or Ph+ ALL
bearing Bcr-AblT315I or if no other TKI is indicated
•
45 mg qd with or without food; contains lactose
•
Black box warnings for arterial and venous
thrombotic events, heart failure, hepatotoxicity
•
Others: HTN, pancreatitis, neuropathy, hemorrhage,
fluid retention, arrhythmias, myelosuppression,
ocular toxicity
O’Hare T, et al. Cancer Cell 2009; 16(5): 401-12. Cortes JE, et al. N Engl J Med 2013; 369(19): 1783-96. ICLUSIG™ prescribing information. Jan 2014
Proposed treatment monitoring strategy.
Oehler V G Hematology 2013;2013:176-183
©2013 by American Society of Hematology
Classification of Myeloid Neoplasms, According to World Health Organization Criteria.
Tefferi A, Vardiman JW. N Engl J Med 2009;361:1872-1885.
Cytogenetic hallmarks of MDS
Vardiman JW, et al. 2008 revision of WHO classification. Blood 2009; 114(5): 937-51.
Myelodysplastic syndromes: 2014 update on diagnosis, risk‐stratification, and management
American Journal of Hematology
Volume 89, Issue 1, pages 97-108, 24 JAN 2014 DOI: 10.1002/ajh.23642
http://onlinelibrary.wiley.com/doi/10.1002/ajh.23642/full#ajh23642-fig-0001
Hazard Ratios for Death in a Multivariable Model.
Bejar R et al. N Engl J Med 2011;364:2496-2506.
Overall Survival, According to International Prognostic Scoring System (IPSS) Risk Category and
Mutational Status.
Bejar R et al. N Engl J Med 2011;364:2496-2506.
Prognostic scoring systems in MDS
•
IPSS (1997): BM blast %, no. of cytopenias, karyotype
•
IPSS-R (2012): 5 categories; easily age-adjusted,
considers many more chromosomal abnormalities,
recognizes lower blast percentages (>2%) as adverse,
attributes risk to each cytopenia based on severity


Developed in untreated pts, but works in aza/lentreated pts and at times other than at diagnosis
http://www.ipss-r.com, www.mdsfoundation.org/ipss-r/
o
WPSS – WHO subtype, cytogenetics, severe anemia
o
MDACC systems – LR-PSS, MDA-CSS; predictive power
of LR-PSS enhanced by mutation data
Greenberg PL, et al. Blood 1997; 89(6): 2079-88 and 2012; 120(12): 2454-65. Malcovati L, et al. Haematologica 2011; 96(10): 1433-40. GarciaManero G, et al. Leukemia 2008; 22(3): 538-43. Kantarjian H, et al. Cancer 2008; 113(6): 1351-61. Bejar R, et al. J Clin Oncol 2012; 30(27): 3376-82.
Prognostic power of IPSS-R
Greenberg PL, et al. Blood 2012; 120(12): 2454-65.
Hypocellular MDS
•
BM cellularity < 20-30% depending on age
•
New MDACC prognostic model for hypocellular MDS*
•
Treat with immunosuppression (ATG/CsA + steroids)


Predictors of response: younger age, HLA-DR15,
shorter duration of transfusion dependence, low
IPSS score, < 5% BM blasts, presence of PNH+ cells
May not result in survival benefit (Passweg JR, et al. J Clin Oncol
2011; 29(3): 303-9)
o
Alemtuzumab (Sloand EM, et al. J Clin Oncol 2011; 28(35): 5166-73)
o
Eltrombopag (Olnes MJ, et al. N Engl J Med 2012; 367(1): 11-19)
Garcia-Manero G. Am J Hematol 2014; 89(1): 97-108. *Tong WG, et al. Cancer 2012; 118(18): 4462-70. Saunthararajah Y, et al. Blood 2003; 102(8):
Growth factors and iron chelation
•
ESA use with or without G-CSF reasonable in low risk
MDS with significant anemia without other cytopenia;
TPO agonists NOT standard
•
RR 30-60% in meta-analysis (Moyo V et al. Ann Hematol 2008; 87(7): 527-36)
•
Addition of G-CSF increases RR; may improve survival
(Jadersten M, et al. J Clin Oncol 2008; 26(21): 3607-13. Park S, et al. Blood 2008; 111(2): 574-82)

Predictors of response: low blast %, low/int-1
IPSS, low sEpo, RBC TI, short interval between
diagnosis and treatment, unilineage dysplasia
o
Iron overload may independently predict evolution to
AML and reduced survival (Sanz G, et al. Blood 2008; 112: 640).
o
Chelator for ferritin > 2500 ng/mL or > 50-60 PRBC
units (> 1000 or > 20 if SCT planned)
Garcia-Manero G. Am J Hematol 2014; 89(1):97-108. Fenaux P, Ades L. Blood 2013; 121(21):4280-6
Lenalidomide
•
In MDS with del5q31, sustained 67% RBC-TI with
median TTR 4.6 weeks and CyR in 73% (61% CCyR)*
•
Mod-severe drops in ANC (55%) and platelets (44%)*
•
Less RBC-TI in pts with additional cytogenetic
abnormalities and high RBC transfusion needs*
•
FDA-approved at 10 mg/d for transfusion-dependent
anemia due to low or int-1 risk MDS and del5q ±
additional cytogenetic abnormalities
o
RBC-TI rate in non-del5q pts 26% at median 4.8 weeks
o
LEN + EPO promising† : ECOG phase III trial in pts with
low/int-1 risk MDS who have failed ESAs or unlikely to
respond to open at Massey & affiliates
*List A, et al. N Engl J Med 2006; 355(14): 1456-65. Raza A, et al. Blood 2008; 111(1): 86-93. †Komrokji RS, et al. Blood 2012; 120(17): 3419-24.
•
Hypomethylating
agents
5-day azacytidine schedule reasonable for lower risk
pts; keep dose at 75 mg/m2 (Lyons RM, et al. J Clin Oncol 2009; 27(11): 1850-6)
•
Phase III PO aza RCT for lower risk MDS open at VCU

Must have TD anemia and be thrombocytopenic
o
*CALGB 9221: Higher risk MDS/AML, AZA vs BSC:
Significant improvements in RR, median time to AML
transformation/death, QOL
o
†AZA-001: Higher risk MDS/AML, AZA vs SOC: Median
survival 24.5 vs 15 months, significant improvements
in TTP to AML, RBC transfusion requirement, infection
o
††No OS benefit for decitabine
o
Multiple trials evaluating AZA+HDACI
*Silverman LR, et al. J Clin Oncol 2002; 20(10): 2429-40. †Fenaux P, et al. Lancet Oncol 2009; 10(3): 223-32. ††Lubbert M, et al. J Clin Oncol 2011;
Overall survival of patients included in the analysis.
Cutler C S et al. Blood 2004;104:579-585
©2004 by American Society of Hematology
(A) Monte Carlo analysis for low/intermediate-1 International Prognostic Scoring System
(IPSS) myelodysplastic syndromes (MDS).
Koreth J et al. JCO 2013;31:2662-2670
©2013 by American Society of Clinical Oncology
Treatment algorithm for patients with higher-risk MDS.
Sekeres M A , and Cutler C Blood 2014;123:829-836
©2014 by American Society of Hematology