Conditions: Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis, Not Otherwise Specified Myelodysplastic/Myeloproliferative Neoplasm, Not Otherwise Specified
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
This phase II trial studies the effects of luspatercept with or without hydroxyurea in treating patients with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts. Biological therapies, such as luspatercept, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Hydroxyurea may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving luspatercept with or without hydroxyurea may help doctors determine what doses of the combination is safe for patients to take and how the disease responds to the treatment.

Detailed description:
PRIMARY OBJECTIVE:

I. To document the erythroid response rate assessed as per the 2015 International Working Group (IWG) myelodysplastic (MDS)/myeloproliferative neoplasms (MPN) response criteria.

SECONDARY OBJECTIVES:

I. To document response duration, time to acute myeloid leukemia (AML) transformation, AML-free survival (LFS) and overall survival (OS) in patients with MDS/MPN-with ring sideroblasts (RS) and thrombocytosis (T) and MDS/MPN-unclassifiable (U)U with RS.

II. To document safety of luspatercept (luspatercept-aamt) in patients with MDS/MPN-RS-T and MDS/MPN-U with RS.

EXPLORATORY OBJECTIVE:

I. To assess overall health-related quality of life as measured by Hematological Malignancy Specific Patient-Reported Outcome Measure (HM-PRO).

CORRELATIVE RESEARCH OBJECTIVE:

I: To find an effective biomarker of response to luspatercept-aamt.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive luspatercept subcutaneously (SC) on day 1. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study.

COHORT B: Patients receive luspatercept SC on day 1 and hydroxyurea orally (PO) on days 1-21. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study.

After completion of study treatment, patients are followed up every 3 months.

Arms:
arm 1: Patients receive luspatercept SC on day 1. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study. arm 2: Patients receive luspatercept SC on day 1 and hydroxyurea PO on days 1-21. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study.

Interventions: intervention 1: Biospecimen Collection intervention 2: Bone Marrow Aspiration intervention 3: Bone Marrow Biopsy intervention 4: Hydroxyurea intervention 5: Luspatercept intervention 6: Questionnaire Administration
Intervention descriptions: intervention 1: Undergo blood sample collection intervention 2: Undergo bone marrow biopsy and aspirate intervention 3: Undergo bone marrow biopsy and aspirate intervention 4: Given PO intervention 5: Given SC intervention 6: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
 
 
MC200805 
Protocol Version Date: 24Aug2023 
 
 
Mayo Clinic Cancer Center 
 
MC200805, Phase II study to determine the efficacy and safety of luspatercept (ACE-536) in 
patients with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and 
thrombocytosis (MDS/MPN-RS-T) and myelodysplastic/myeloproliferative neoplasms, 
unclassifiable with ring sideroblasts (MDS/MPN-U with RS) 
 
Sponsor/Principal Investigator: 
 
 
 
 
Co-Principal Investigator:      
 
                                                   
               
Co-Investigators: 
 
                                  
 
                                  
     
                                  
 
                                  
 
                                  
 
                                  
 
                                  
 
                                  
 
                                  
                                  
       
                                 
           Statistician: 
 
 
 
                           
√Study contributor(s) not responsible for patient care 
FDA IND #: IND EXEMPT 
Trial Supported by:  
Funding: BMS 
Drug Availability:  
Commercial Agents: Hydroxyurea, aspirin 
Drug Company Supplied: Luspatercept-aamt  
BMS Protocol ID: LU-CL-MDS-PI-14022 
 
Site Investigators & Participating sites: 
 
  
  
  
 
 
  
  
  
 
 


 
 
MC200805 
Protocol Version Date: 24Aug2023 
 
 
Document History 
(Effective Date) 
Activation 
January 17, 2022 
MCCCAmend1 
June 7, 2022 
MCCCAmend2 
MCCCAmend3 
July 13, 2023 
Pending 
 


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Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
  
  
Drug administration, infusion pumps,  
nursing guidelines 
 
 
  
 
Forms completion and submission  
 
 
 
 
Protocol document, consent form, 
regulatory issues 
  
  
 
Non-paraffin biospecimens  
 
 
 
  
 
Serious Adverse Event Reporting 
  
*No waivers of eligibility allowed 
 
 


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Table of Contents 
Protocol Resources ........................................................................................................................................ 3 
Table of Contents .......................................................................................................................................... 4 
Schema .......................................................................................................................................................... 5 
1.0 
Background ................................................................................................................................... 6 
2.0 
Goals ............................................................................................................................................. 8 
3.0 
Registration Patient Eligibility ...................................................................................................... 9 
4.0 
Test Schedule .............................................................................................................................. 12 
5.0 
Grouping Factor: ......................................................................................................................... 15 
6.0 
Registration/Randomization Procedures ..................................................................................... 15 
7.0 
Protocol Treatment ...................................................................................................................... 18 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 20 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 26 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 28 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 39 
12.0 
Descriptive Factors ..................................................................................................................... 40 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 40 
14.0 
Body Fluid Biospecimens ........................................................................................................... 42 
15.0 
Drug Information ........................................................................................................................ 47 
16.0 
Statistical Considerations and Methodology ............................................................................... 52 
17.0  
Pathology Considerations/Tissue Biospecimens......................................................................... 57 
18.0 
Records and Data Collection Procedures . .................................................................................. 57 
19.0  
Budget ......................................................................................................................................... 58 
20.0 
References ................................................................................................................................... 59 
Appendix I 
ECOG Performance Status ............................................................................................... 61 
APPENDIX II: Hydroxyurea and/or aspirin use guidelines. ...................................................................... 62 
APPENDIX III: Disease Progression Criteria ............................................................................................ 63 
 
.


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Schema 
 
 
Registration 
 
 
 
 
Cohort A: Hydroxyurea-
independent  
 
Cohort B: Hydroxyurea-dependent  
 
 
 
 
Events at any time: 
Disease Progression 
Intolerable adverse effects 
Patient refusal 
Lost to follow-up 
Pregnancy 
 
 
↓ 
 
 
Survival Follow-up 
 
Cycle = 21 days 
 
Generic name: Luspatercept-aamt 
Brand name(s): Reblozyl 
Mayo Abbreviation: 
LUSPATERCEPT 
Availability: BMS 
Generic name: Hydroxyurea 
Brand name(s): Hydrea 
Mayo Abbreviation: HYDREA 
Availability: Commercial 


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1.0 
Background  
Myelodysplastic syndrome/myeloproliferative (MDS/MPN) overlap syndromes are classified by 
the World Health Organization (WHO) as a distinct entity under myeloid neoplasms due to their 
unique clinical and biological characteristics. The categories include chronic myelomonocytic 
leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic 
leukemia, MDS/MPN with ring sideroblasts (RS) and thrombocytosis (T) and MDS/MPN, 
unclassifiable (U) (1).  MDS/MPN-RS-T has been defined by the presence of erythroid lineage 
dysplasia with the presence or absence of multi lineage dysplasia and persistent thrombocytosis 
(platelet count > 450 x 109/L), without other disease defining genetic abnormalities.  MDS/MPN-
U is a separate category under MDS/MPN overlap syndrome under which patients meet the 
criteria for MDS/MPN overlap syndrome but do not met criteria for CMML, aCML, JMML, or 
MDS/MPN-RS-T. MDS/MPN-U patients can also have > 15% ring sideroblasts but not classified 
under MDS/MPN-RS-T due to > 1% peripheral blood blasts or > 5% bone marrow blasts (2, 3).  
 
MDS/MPN-RS-T and MDS/MPN-U with RS are characterized by distinct clinical features such 
as anemia, increased risk for thrombosis and differential response rates to conventional agents, 
when compared to similar myeloid neoplasm such as myelodysplastic syndrome with ring 
sideroblasts (MDS-RS). Anemia is a frequent cause of morbidity due to ineffective erythropoiesis 
as a consequence of intracellular iron locking in mitochondria and accelerated erythroid precursor 
apoptosis (4).  Lower hemoglobin level and red blood cell (RBC) transfusion-dependence have 
been associated with adverse cardiovascular outcomes. Erythropoiesis stimulating agents (ESA) 
are often used as first-line agents for the treatment of anemia in myeloid neoplasm with ring 
sideroblasts, including MDS/MPN/RS-T and MDS/MPN-U with RS. However, erythroid 
response rates are seen in approximately 45% patients and often not long-lasting (5). Additional 
therapeutic options such as lenalidomide and hypomethylating agents are effective only in a 
handful of patients with short-lived responses  (2, 5). Therefore, restoration of arrested 
erythropoiesis and reducing morbidity associated with anemia is a significant area of need in 
patients with MDS/MPN overlap syndromes.  
 
Luspatercept-aamt is a first-in-class erythroid maturation agent that specifically binds to 
transforming growth factor-beta superfamily ligands to reduce Smad 2/3 signaling and increase 
late-stage erythropoiesis. The phase 3 MEDALIST trial formally evaluated this drug in lower risk 
MDS-RS and found to achieve a decrease in red blood cell transfusion independence for 8 weeks 
or longer in 38% patients during the first 24 weeks (6). The most frequent adverse events 
included asthenia, fatigue, bone pain, diarrhea, nausea, dizziness and back pain. Based on this 
study, regulatory approval was granted for MDS-RS and MDS/MPN overlap syndrome patients. 
However, the MEDALIST trial did not prospectively test the safety and efficacy of luspatercept-
aamt in a separate large cohort of patients with MDS/MPN overlap syndromes (only a limited 
cohort of 23 MDS/MPN-RS-T patients were included). Further, erythroid responses were 
assessed per the IWG MDS response criteria, whereas contemporary response adjudication in 
MDS/MPN overlap syndromes is done as per the MDS/MPN IWG criteria(7), which is proposed 
in the current trial design.   
 
Due to the unique clinical characteristics among patients with MDS/MPN-RS-T and MDS/MPN-
U with RS such as the presence of thrombocytosis (in the former), increased risk of thrombosis 
(in both) (5), it is important to establish safety of luspatercept-aamt prior to its use in these 
patients.  Our proposed clinical trial is aimed to specifically test the safety and efficacy of 
luspatercept-aamt in  myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and 
thrombocytosis (MDS/MPN-RS-T) and myelodysplastic/myeloproliferative neoplasms, 
unclassifiable with≥15% ring sideroblasts (MDS/MPN-U with RS), both orphan cancers with no 


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effective disease-modifying drugs. Although hypomethylating agents, lenalidomide, and 
erythropoiesis stimulating agents (ESA) are commonly used for these patients, no adequately 
powered clinical trials have confirmed disease biology modification or survival benefit. 
Transfusion-dependent anemia is a frequent clinical manifestation for these patients. In a Mayo 
Clinic study of 40 patients with MDS/MPN-RS-T, erythroid responses to ESA therapy were 
found in 45% patients, and predicted by an EPO level of < 50 IU/L (5). However, a majority of 
patients either lose this response or developed dose-limiting adverse effects such as hypertension, 
thrombocytosis, and venous or arterial thromboembolism. Our group has also shown that patients 
with MDS/MPN-U with RS (>15% RS in diagnostic bone marrow biopsies) have comparable 
clinical features and outcomes to MDS/MPN-RS-T (2).  
 
Due to the clinical equipoise of whether luspatercept-aamt is specifically effective and safe in 
MDS/MPN overlap syndromes, we have designed this phase II clinical study with the aim to 
study the effects of the drug prospectively in a cohort of patients with MDS/MPN-RS-T and 
MDS/MPN-U with RS. As opposed to MDS-RS, hydroxyurea use is an important part of 
treatment strategy in MDS/MPN overlap syndromes, such as MDS/MPN-RS-T due to the 
concomitant thrombocytosis. Therefore, it is also not known whether hydroxyurea can be safely 
combined with luspatercept-aamt and whether it will have impact on erythroid responses (15).   
Concomitant hydroxyurea and aspirin use as per the Essential Thrombocythemia (ET) risk 
stratification system (12) will be assessed along with luspatercept-aamt will also be formally 
assessed, since this a common clinical decision-making process for clinicians caring for patients 
with these disorders.   
1.1 
Treatment 
The disease studied is MDS/MPN-RS-T and MDS/MPN-U with RS, defined as per the 
latest World Health Organization 2016 (WHO) criteria. As iterated above, these diseases 
do not have any effective disease modifying agents.  The aim of this study is to test the 
safety and efficacy of luspatercept-aamt in these patients.  
1.2 
Correlative Research 
The goal of the correlative studies would be to identify a biomarker of response to 
luspatercept-aamt. At enrollment, plasma, DNA, and RNA will be collected and stored 
for patients. We propose measuring the following parameters at enrollment in all patients:  
1.21 
Plasma: Ineffective erythropoiesis due to a perturbed TGF-β superfamily 
signaling and increased Smad-2/3 phosphorylation is a hallmark of myeloid 
neoplasms with RS. The recently discovered hormone, erythroferrone (ERFE) 
has been shown to act as a ligand trap for Smad proteins (8) and implicated in 
iron homeostasis in both Thalassemia Major (9) and Sickle Cell Disease (10). 
Variant ERFE secondary to SF3B1 mutant-induced aberrant splicing has been 
shown to disrupt iron homeostasis in MDS-RS (11).  
Due to the known mechanism of luspatercept-aamt in reducing Smad pathway 
signaling through TGF-β modulation, we propose measuring hepcidin, and its 
known inhibitors related to TGF- β signaling, such as ERFE, growth-differential 
factor-15 (GDF-15) to identify potential biomarkers of erythroid response. Iron 
status will be documented through clinical assays prior to enrollment. In addition, 
we will perform cytokine profiling through a luminex assay. All parameters will 
be measured through ELISA as per previously published methods.  
1.22 
DNA – Stored peripheral blood mononuclear cell (PBMC) DNA at enrollment 
will be used to perform next generation sequencing for myeloid-specific genes (if 


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not done clinically) in order to identify potential genomic biomarkers of response 
in MDS/MPN-RS-T and MDS/MPN-U with RS.   
1.23 
RNA – Bulk RNA-seq will be performed on RNA extracted from PBMCs at 
enrollment and pathway analysis will be carried out to identify predictive 
biomarkers of response. 
All correlative studies will be performed at Mayo Clinic. 
2.0 
Goals  
2.1 
Primary Goal 
To document the erythroid response rate assessed as per the 2015 International Working 
Group (IWG) MDS/MPN response criteria (7) 
2.2 
Secondary Goals 
2.21 
To document response duration, time to acute myeloid leukemia (AML) 
transformation, AML-free survival (LFS) and overall survival (OS) in patients 
with MDS/MPN-RS-T and MDS/MPN-U with RS.  
2.22 
To document safety of luspatercept-aamt in patients with MDS/MPN-RS-T and 
MDS/MPN-U with RS. 
2.3 
Exploratory goals 
2.31 
To assess overall health-related quality of life as measured by Hematological 
Malignancy Specific Patient-Reported Outcome Measure (HM-PRO) 
2.4 
Correlative Research 
The goal of correlative research as enumerated above is to find an effective biomarker of 
response to luspatercept-aamt.  
 


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3.0 
Registration Patient Eligibility 
3.1 
Registration – Inclusion Criteria 
3.11 
Age ≥18 years 
3.12 
Patients with a WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U               
with >15% RS (1). 
3.13 
Prior treatment with lenalidomide, hypomethylating agents, immunosuppressive 
therapy, ESA, or investigational agent is allowed as long as patients have not 
received luspatercept-aamt or sotatercept. If there is prior history of 
investigational agent, there should be an interval equivalent to at least four 
elimination half-lives of the agent prior to enrollment.  
Note: For patients who have received prior lenalidomide, hypomethylating 
agents, or immunosuppressive therapy, there must be ≥6 weeks since the last 
dose before luspatercept-aamt treatment is started.  
3.14 
ECOG Performance Score of 0, 1 or 2. 
3.15 
Requirement of red blood cell transfusions (≥2 units  ≤ 8-weeks prior to 
registration) OR symptomatic anemia with hemoglobin <9.5 g/dL OR hematocrit 
<30% (as long as there is documentation of adequate iron stores (ferritin > 50 
mg/L)  ≤ 5 weeks prior to registration). Symptomatic anemia is defined as fatigue 
with or without exertion, shortness of breath with or without exertion, or decrease 
in exercise tolerance.  
3.16 
The following laboratory values obtained ≤14 days prior to registration:  
• 
Hemoglobin <9.5 g/dL 
• 
Total bilirubin ≤1.5 x ULN 
• 
Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3 x 
ULN (≤5 x ULN for patients with liver involvement) 
• 
Calculated creatinine clearance ≥30 ml/min using the Cockcroft-Gault 
formula below: 
Cockcroft-Gault Equation: 
Creatinine clearance for males =  
(140 - age)(weight in kg) 
 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females =  
(140 - age)(weight in kg)(0.85) 
 
(72)(serum creatinine in mg/dL) 
3.17 
Female of childbearing potential (FCBP) defined as a sexually mature woman 
who:  
1) has achieved menarche at some point,  
2) has not undergone a hysterectomy or bilateral oophorectomy, or  
3) has not been naturally postmenopausal (amenorrhea following cancer therapy 
does not rule out childbearing potential) for at least 24 consecutive months (ie, 
has had menses at any time in the preceding 24 consecutive months) and 
must:  
a.  Must have two negative urine or serum pregnancy tests as verified by the 
investigator prior to starting study therapy. A negative pregnancy test 


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must be done ≤7 days prior to registration. Patient must agree to ongoing 
pregnancy testing during the course of the study, and after end of study 
therapy. This applies even if the subject practices true abstinence* from 
heterosexual contact.  
b.  Either commit to true abstinence*from heterosexual contact (which must 
be reviewed on a monthly basis and source documented) or agree to use, 
and be able to comply with highly effective, contraception without 
interruption during the study therapy (including dose interruptions), and 
for 84 days after discontinuation of study therapy. 
3.18 
Male participants must:  
Practice true abstinence* (which must be reviewed on a monthly basis) or agree 
to use a condom during sexual contact with a pregnant female or a female of 
childbearing potential while participating in the study, during dose interruptions 
and for at least 84 days following investigational product discontinuation even if 
he has undergone a successful vasectomy. * True abstinence is acceptable when 
this is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception). 
3.19a 
Provide written informed consent. 
3.19b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.19c 
Willingness to provide mandatory blood specimens for correlative research 
3.2 
Registration - Exclusion criteria 
3.21 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects: 
• Pregnant persons 
• Nursing persons 
• Persons of childbearing potential who are unwilling to employ highly 
effective contraception 
3.22 
Any of the following prior therapies:  
• 
Surgery ≤3 weeks prior to registration  
• 
Chemotherapy or other agents ≤2 weeks prior to registration.  
3.23 
Uncontrolled intercurrent non-cardiac illness including, but not limited to:  
• 
Ongoing or active infection 
• 
Uncontrolled hypertension (defined as systolic blood pressure ≥140 mmHg 
or diagnostic blood pressure ≥90 mmHg despite use of ≥ 3 anti-hypertensive 
drugs at optimal doses).  
• 
Psychiatric illness/social situations  
• 
Dyspnea at rest due to complications of advanced malignancy or other 
disease that requires continuous oxygen therapy  
• 
Clinically significant (symptomatic) anemia either due to nutritional 
deficiencies or iron, vitamin B12, folate or GI bleeding.  
• 
Any other conditions that would limit compliance with study requirements. 


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3.24 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy.  
NOTE: Patients known to be HIV positive, but without clinical evidence of an 
immunocompromised state (CD4 ≤200 x 106/L), are eligible for this trial. 
3.25 
Receiving any other drug (except hydroxyurea) or investigational agent which 
would be considered as a treatment for the primary disease, that is, MDS/MPN-
RS-T or MDS/MPN-U with RS ≤2 weeks prior to registration.  
3.26 
Other active malignancy ≤3 years prior to registration. Patients on hormonal 
therapy for treated breast or prostate cancer are permitted if they meet other 
eligibility criteria. 
EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.  
NOTE: If there is a history of prior malignancy, they must not be receiving other 
specific treatment (luteinizing hormone-releasing hormone (LHRH) agonists for 
prostate cancer, and treatment with bisphosphonates and receptor activator of 
nuclear factor kappa-B ligand (RANKL) inhibitors) for their cancer.  
 
3.27 
History of myocardial infarction, stroke, embolism, deep vein or arterial 
thrombosis ≤6 months prior to registration, or congestive heart failure requiring 
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.  
 


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4.0 
Test Schedule 
4.1 
Test schedule for MDS/MPN-RS-T and MDS/MPN-U with RS 
 
Tests and procedures 
Active Monitoring Phase 
 
Screening 
(≤30 days 
prior to 
registration 
Every Cycle 
(ie,1,2,3+ 
 up to max 8 
cycles) 
Day 1 
 
Cycle1  
Days 8 and 15 
Week 251 Response 
Assessment Visit/EOT 
24 calendar weeks after first 
dose regardless of dose 
delays. 
Window 
±3 days 
±3 days 
±14 days 
Medical History 
X 
 
 
 
Height 
X 
 
 
 
Physical Examination, 
weight, ECOG PS  
X 
X 
 
X 
Prior and concomitant 
medications/procedures 
X 
Continuous 
 
 
Adverse Event 
Assessment 
X 
X 
X 
X 
Serum or Urine 
Pregnancy Test and 
Counseling2,R 
X 
X 
 
X 
Vital Signs to include BP   
X 
X 
X 
X 
Serum Chemistry3 
X10 
X 
 
X 
Hematology4 
X10 
X 
X 
X 
Von-Willebrand factor (vWF) 
activity 
X 
 
 
 
Serum erythropoietin 
(EPO) 
X 
 
 
 
Serum Ferritin5 
X 
 
 
X 
HIV-1/2 Antigen or 
Antibody screen R,11 
X 
 
 
 
MDS-MPN overlap 
syndrome disease 
Assessment6 
X 
 
 
X 
Bone Marrow Biopsy 
and Aspirate (BMA) and 
Peripheral Blood for 
cytomorphology and 
cytogenetic testing6,7 
X 
 
 
 
Hydroxyurea Medication 
Diary8 (Cohort B only) 
 
X 
X 
 
Optional Hematological 
Malignancy Patient-
Reported Outcome 
Measure (HM-PRO)13 
 
X 
 
X 


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Tests and procedures 
Active Monitoring Phase 
 
Screening 
(≤30 days 
prior to 
registration 
Every Cycle 
(ie,1,2,3+ 
 up to max 8 
cycles) 
Day 1 
 
Cycle1  
Days 8 and 15 
Week 251 Response 
Assessment Visit/EOT 
24 calendar weeks after first 
dose regardless of dose 
delays. 
Mandatory Research 
Blood (plasma, DNA, 
RNA) for Exploratory/ 
Biomarkers (eg, ERFE, 
cytokines, genomic and 
transcriptomic) AssaysR 
(See Section 14.0) 
X12 
 
 
X 
Optional Research Bone 
Marrow Biopsy and 
Aspirate for 
Exploratory/Biomarkers 
(eg, TGF-ß superfamily, 
MDS-associated 
molecular mutations) 
Assays9,R  (See Section 
14.0) 
X12 
 
 
 
Cycle = 21 days 
1 Week 25 Visit and End of Treatment (EOT) Visit may be the same visit. If a subject is discontinued during a regular 
scheduled visit, all EOT procedures should be completed at that visit.  
2 Pregnancy test is required for all female participants of childbearing potential (FCBP) ≤ 7 days prior to registration. Serum 
beta human chorionic gonadotropin (β-hCG) will be performed at screening. A urine (or serum) pregnancy test will be 
repeated prior to the first administration of IP on C1D1, unless the screening pregnancy test was done within 72 hours of 
C1D1. During the Treatment Period, urine or serum pregnancy test is allowed. For males and FCBP, counseling about 
pregnancy precautions and the potential risks of fetal exposure must be conducted prior to each IP administration or on a 
monthly basis (eg, in the event of dose delays).  
3 For serum chemistry, draw a Comprehensive Metabolic Panel (CMP) and uric acid only. CMP includes albumin, total 
bilirubin, total calcium, bicarbonate (CO2), chloride, creatinine, glucose, alk phosphatase, potassium, total protein, sodium, 
AST, ALT, urea nitrogen 
4 Hematology assessment includes a CBC with differential and absolute reticulocyte count  
5 Ferritin samples should be collected within 5 weeks prior to registration.  
6 During the Treatment Period, MDS-MPN overlap syndrome Disease Assessment should be completed by the investigator 
in conjunction with clinical bone marrow collections for cytomorphology and cytogenetics, and/or peripheral blood 
assessment.  
7 During the Screening Period, bone marrow biopsy AND bone marrow aspirate are not required at enrollment, if done 
clinically ≤30 days prior to enrollment. After enrollment in the primary treatment phase, a bone marrow biopsy is collected 
only when adequate aspirate is not attainable. No additional bone marrow biopsies are necessary and will be performed only as 
per clinical indications. Clinical benefit for the drug will be assessed per MDS/MPN response assessment criteria [Section 11, 
(7)].  Marrow response will only be assessed if additional bone marrow biopsy evaluations are available. 
8 Patients will use the pill diary to confirm their daily dose of hydroxyurea, note dose holds, and dose changes. 
9 Remaining BMA, (after quantity sufficient is allocated towards cytomorphology and cytogenetics analysis), will be used for 
exploratory biomarker studies (eg, ERFE, cytokines, genomic and transcriptomic). An additional bone marrow procedure should 
not be performed for these samples. Refer to Section 14.0 for additional information related to biomarker/exploratory samples.  
10 Hemoglobin, total bilirubin, ALT, and AST must be done ≤14 days prior to registration 
11 If HIV positive, a CD4 count must be drawn (this will be research funded) 
12.Research blood and bone marrow samples must be collected after registration, but prior to Cycle 1 Day 1 treatment 
13 HM-PRO will be done every cycle, if patient consents, it does not need to be completed prior to drug infusion. It will be given 
either during in person visits or sent to patient electronically (±7 days of D1 and EOT).  
R Research funded 
 
 


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4.2 
Survival Follow-up  
Window of ±30 days 
 
 
Survival Follow-up1 
Every 3 
months1  
Death 
New Primary 
Survival Follow-up1 
X 
X 
At each occurrence 
 
1 If a patient is still alive 1.5 years after registration, no further follow-up is required. 


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5.0 
Grouping Factor:  
5.1 
Cohort A (hydroxyurea-independent patients) vs. Cohort B (hydroxyurea-dependent 
patients)   
Definition of groups:  
 
Hydroxyurea-independent group: Patients who meet the inclusion criteria and either have 
a platelet count of < 450 x 109/L or they do not meet the criteria for hydroxyurea use per 
ET risk stratification criteria. Patients with prior use of hydroxyurea will be allowed in 
this group as long as use is more than 2 weeks before enrollment (Appendix II).  
 
Hydroxyurea-dependent group: This group includes patients who meet the inclusion 
criteria and have a platelet count > 450 x 109/L AND meet criteria for hydroxyurea use as 
per the ET risk stratification criteria (Appendix II).  
5.2 
There will be no stratification factors.  
6.0 
Registration/Randomization Procedures 
6.1 
Registration: 
6.11 
Registering a patient 
To register a patient, access the Research Registration Application at 
 The Research Registration Application is available 
24 hours a day, 7 days a week. Back up and/or system support contact 
information is available on the website. If unable to access the website, call 
Research Site Management at 
 between the hours of 8 a.m. and 
4:30 p.m. Central Time (Monday through Friday). 
 
Access and training instructions for the Research Registration Application are 
available on the Office of Clinical Trials web page 
  and 
detail the process for completing and confirming patient registration. Prior to 
initiation of protocol treatment, this process must be completed in its entirety and 
a subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent. Patient 
registration via the Research Registration Application can be confirmed in any of 
the following ways: 
 
• 
Contact Research Site Management 
 If the patient was fully 
registered, the Research Site Management staff can access the information 
from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.2 
Verification of materials 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 


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• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
). If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.4 
Correlative Research 
6.41 
Mandatory 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.0, 14.0 and/or 
17.0). 
6.42 
Optional 
An optional correlative research component is part of this study, there will be an 
option to select if the patient is to be registered onto this component (see Section 
14.0). 
Patient has/has not given permission to give his/her bone marrow sample for 
research testing.  
6.5 
Banking 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research of MDS/MPN overlap syndromes at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.6 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic Rochester, Mayo Clinic 
Arizona, or Mayo Clinic Florida under the supervision of a hematologist. 
6.7 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤ 30 days after registration. 
6.8 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 


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6.9a 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
6.9b 
Study drug 
Study drug is available on site.  
6.9c 
Blood draw kits  
For MCF and MCA, blood draw kit is available on site.  MCR will not use kits. 
6.9d 
Patient Questionnaire Booklets, if patient consents 
Patient questionnaire booklets can be found in the Protocol Catalog. They may be printed 
or distributed electronically for each patient. 
6.9e 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 
21 CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure. Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected. Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations.


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7.0 
Protocol Treatment 
7.1 
Treatment Groups 
This parallel cohort phase II protocol will stratify eligible patients based on hydroxyurea 
use at enrollment.  
 
Cohort A (hydroxyurea-independent)  
 
Cohort B (hydroxyurea-dependent)  
 
7.11 
Treatment  
Use actual weight or estimated dry weight if fluid retention. Both Cohorts will 
receive the same schedule of luspatercept-aamt. 
 
Cohort A – Hydroxyurea independent: 
Agent 
Starting Dose 
Level 
Route 
Day 
ReRx 
Luspatercept-aamt1 
1 mg/kg 
Subcutaneous 
1 
Every 21 
Days 
 
Cohort B – Hydroxyurea dependent: 
Agent 
Starting Dose 
Level 
Route 
Day 
ReRx 
Luspatercept-aamt1 
1 mg/kg 
Subcutaneous 
1 
Every 21 
Days 
Hydroxyurea§ 
(optional) 
500 mg (or 
stable dose for 
2 weeks prior 
to enrollment) 
Oral 
Daily* 
Ongoing 
§Hydroxyurea use is optional. The starting dose and ongoing schedule are at the primary 
provider’s discretion based on the recommended Essential Thrombocythemia (ET) risk 
stratification system (12) (See Appendix II).  Patient will be provided a prescription. 
Doses and adjustments will be collected via a patient medication diary  
*Hydroxyurea may be taken before or after luspatercept-aamt injection.  
 
1. Starting as soon as Cycle 3, Day 1 and assessed by the investigator prior to every 
subsequent treatment cycle, participants may have the luspatercept-aamt dose level 
increased in a stepwise manner beyond the starting dose of 1.0 mg/kg to 1.33 mg/kg, 
and up to a maximum of 1.75 mg/kg if all the following criteria are met: 
 
Subject has ≥ 1 RBC transfusion event (for pre-transfusion Hgb of < 9 g/dL) 
during the 2 most recent prior treatment cycles (~6-weeks). 
 
The two most recent prior treatment cycles assessed must be at the same dose 
level. 
 
Subject must not have met protocol dose delay and/or reduction criteria in the 
two most recent treatment cycles (exception of dose delay required due to 
influence of RBC transfusions).  
 
If all criteria above are met, the dose may be increased by 1 dose level. 
 


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The dose level should be titrated individually for each subject and must not exceed 1.75 
mg/kg. Starting dose with dose increases and reductions are presented in Table 8.1. 
7.2 
Self-administration  
Patients may not self-administer luspatercept-aamt. Preparation and administration by a 
healthcare provider is required.  
 
Patient may self-administer hydroxyurea. 
7.3 
Return to consenting institution  
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 21 days during treatment (Active Monitoring Phase). 
7.4 
Treatment by a local medical doctor (LMD) is not allowed. 


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8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
Dose 
Level 
Luspatercept-aamt 
+2 
1.75 mg/kg 
+1 
1.33 mg/kg 
1* 
1 mg/kg 
-1 
0.8 mg/kg 
-2 
0.6 mg/kg 
-3 
Discontinue 
*Dose level 1 refers to the starting dose. Hydroxyurea dose changes will be per 
provider discretion.  
NOTE: If hydroxyurea is discontinued, luspatercept-aamt may be continued. If 
luspatercept-aamt is discontinued, the patient will go to survival follow up (section 4.2.).  
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 5.0* 
unless otherwise specified   
* 
Located at 
 
 
 


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8.2 
Dose Modifications at the start of new cycle of therapy  
A new cycle of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
The ANC is ≥ 500/μL 
• 
The platelet count is > 50 X 109/L.  
• 
Any other non-hematologic treatment –related (possibly, probably, or definitely 
related) adverse event that may have occurred has resolved to baseline severity. 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated 
weekly and a new cycle of therapy will be held until the toxicity has resolved as 
described above.  
If the study drug (luspatercept-aamt) dosing was halted during the previous cycle and was 
restarted with a one-level dose reduction without requiring an interruption for the 
remainder of the cycle, then that reduced dose level will be initiated on Day 1 of the new 
cycle. 
If any drug dosing was omitted for the remainder of the previous cycle or if the new cycle 
is held due to known hematologic toxicity newly encountered on the scheduled Day 1, 
then the new cycle will be started with a one-level dose reduction when toxicity resolves 
to the required level. If a new cycle of therapy cannot be restarted within 4 weeks of the 
scheduled Day 1 due to non-resolution of drug related toxicities, the patient will be 
removed from protocol therapy and will go to survival follow-up. 
 
 


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8.3 
Dose Modifications Based on Interval Adverse Events (occurring within a cycle of 
treatment) 
8.31 
COHORT A: HYDROXYUREA-INDEPENDENT COHORT:  
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Blood and lymphatic 
system disorders 
Any suspected related 
AE > grade 3 
Luspatercept-
aamt 
Dose delay until resolved to < grade 1 or 
baseline, and then reduce dose by one 
level as above.  
Investigations 
>2 dose reductions for 
suspected related AE 
Luspatercept-
aamt 
Discontinue treatment 
 
Hemoglobin increase by 
> 2 g/dL compared to 
pre-dose Hb of previous 
cycle 
Luspatercept-
aamt 
Reduce dose by one level (if change in Hb 
is not influenced by RBC transfusions).  
 
Predose Hb > 11.5 g/dL Luspatercept-
aamt 
Dose delay until Hb is < 11 gm/dL 
 
White blood cell 
increased by >50% 
compared pre-dose 
WBC of previous 
treatment 
Luspatercept-
aamt 
Dose delay; recheck CBC, including 
WBC weekly during dose delay. 
Treatment may be resumed if WBC values 
below upper limit of normal within 2 
weeks. If WBC remains above upper limit 
of normal for >2 consecutive weeks in 
absence of associated condition (such as 
infection or steroid use), continue dose 
delay and collect bone marrow sample to 
assess disease status.  
 
Treatment may be resumed if:  
 
There is absence of disease progression 
per MDS/MPN response criteria 
(Savona M et al. Blood 2015, Appendix 
III) 
 
AND  
 
WBC values return below upper limit of 
normal 
 
Discontinue treatment if there is evidence 
of disease progression or WBC count 
remains above upper limit of normal.  
 
 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
 
Platelet count increase 
by >25% compared to 
pre-dose platelet count 
of previous treatment 
Luspatercept-
aamt 
Reduce luspatercept-aamt dose by 1 dose 
level. Hydroxyurea addition is not 
allowed. If hydroxyurea needs to be 
added, patients will be taken off study. 
Addition of aspirin (along with dosing 
determinations) will be per provider 
discretion  
 
Grade 3 or 4 
hypersensitivity 
reactions 
Luspatercept-
aamt 
Discontinue treatment 
 
Other grade 3 or 4 
adverse reactions 
Luspatercept-
aamt 
• 
Interrupt treatment. 
• 
When the adverse reaction 
resolves to no more than grade 1, 
restart treatment at the next lower 
dose level as mentioned in section 
8.1  
**  Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The 
patient does not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
 
 
 
 


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8.32 
COHORT B: HYDROXYUREA-DEPENDENT COHORT 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Blood and lymphatic 
system disorders 
Any suspected related 
AE > grade 3 
Luspatercept-
aamt 
Dose delay until resolved to < grade 1 or 
baseline, and then reduce dose by one 
level as above.  
Investigations 
>2 dose reductions for 
suspected related AE 
Luspatercept-
aamt 
Discontinue treatment 
 
Hemoglobin increase by 
> 2 g/dL compared to 
pre-dose Hb of previous 
cycle 
Luspatercept-
aamt 
Reduce dose by one level (if change in Hb 
is not influenced by RBC transfusions).  
 
Predose Hb > 11.5 g/dL Luspatercept-
aamt 
Dose delay until Hb is < 11 gm/dL 
 
White blood cell 
increased by >50% 
compared pre-dose 
WBC of previous 
treatment 
Luspatercept-
aamt 
Dose delay; recheck CBC, including 
WBC weekly during dose delay. 
Treatment may be resumed if WBC values 
below upper limit of normal within 2 
weeks. If WBC remains above upper limit 
of normal for >2 consecutive weeks in 
absence of associated condition (such as 
infection or steroid use), continue dose 
delay and collect bone marrow sample to 
assess disease status.  
 
Treatment may be resumed if:  
 
There is absence of disease progression 
per MDS/MPN response criteria (Savona 
M et al. Blood 2015, Appendix III) 
 
AND  
 
WBC values return below upper limit of 
normal 
 
Discontinue treatment if there is evidence 
of disease progression or WBC count 
remains above upper limit of normal.  
 
 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Platelet count increase 
by >25% compared to 
pre-dose platelet count 
of previous treatment 
 
 
 
 
 
 
Luspatercept-
aamt 
Reduce luspatercept-aamt dose by 1 dose 
level. Hydroxyurea dose changes will be 
per provider discretion  
 
Grade 3 or 4 
hypersensitivity 
reactions 
 
 
 
Luspatercept-
aamt 
Discontinue treatment 
 
Other grade 3 or 4 
adverse reactions 
Luspatercept-
aamt 
• 
Interrupt treatment. 
• 
When the adverse reaction 
resolves to no more than grade 1, 
restart treatment at the next lower 
dose level as mentioned in section 
8.1  
• 
Hydroxyurea dose changes will be 
per provider discretion. 
 
 


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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care  
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Blood products 
Concurrent treatment for anemia with blood transfusions is recommended when Hgb is ≤ 
9.0 g/dL or at the discretion of the investigator if Hgb is ≥ 9.0 g/dL and associated with 
symptom(s) of anemia (eg, hemodynamic or pulmonary compromise requiring treatment) 
or comorbidity justifying a threshold ≥ 9.0 g/dL Hgb. Dose adjustment and 
discontinuation of hydroxyurea, per provider discretion, should be considered for Cohort 
B if cytopenias occur. 
 
For any RBC transfusion received during the study, collect hemoglobin value just prior to 
transfusion. 
9.3 
Corticosteroids 
Concurrent corticosteroids used for medical conditions other than MDS/MPN overlap 
disorders is allowed provided subject is on a stable or decreasing dose for ≥ 1 week prior 
to randomization. 
9.4 
Iron Chelation Therapy 
Participants who are using iron-chelating therapies at time of randomization should be on 
a stable dose for at least 8 weeks. 
Concurrent treatment with iron chelation therapies during the Treatment Period is 
allowed at the discretion of the investigator and is recommended to be used per product 
label. 
9.5 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.6 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
9.7 
Prohibited concomitant medications and procedures 
Best supportive care for this study specifically excludes cancer surgery, immunotherapy, 


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biologic therapy, radiotherapy, and systemic chemotherapy where the goal is to eradicate 
or slow the progression of the disease. 
 
The following concomitant medications are specifically excluded during the course of the 
study: 
 
Chemotherapeutic, targeted or investigational agents/therapies 
 
Azacitidine, decitabine or other hypomethylating agents including oral 
hypomethylating agents and combinations 
 
Lenalidomide, thalidomide and other immunomodulating drugs (IMiDs) 
 
Erythropoietin stimulating agents (ESAs) and other RBC hematopoietic growth 
factors (eg, Interleukin-3). 
 
Granulocyte colony stimulating factors (ie, G-CSF, GM-CSF), except in cases of 
neutropenic fever or as clinically indicated per product label.  
 
Androgens, unless to treat hypogonadism 
 
Oral retinoids (topical retinoids are permitted) 
 
Arsenic trioxide 
 
Interferon 
 
 


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10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human participants, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
 
WHO: 
WHAT form: 
WHERE to send1: 
 
All sites 
Pregnancy Reporting 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
Will automatically be sent to 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form:  
  
 
Will automatically be sent to 
 
1.Also send SAE report to CELGENE at 
  
 
 


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Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0 A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site: 
 
a. Identify the grade and severity of the event using the CTCAE version 5.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
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Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) 
on the SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions.  
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report, unless hospitalization is required. Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required. 
• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 


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The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with 
the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition 
requiring the hospitalization has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or 
treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
● Hospitalization for routine maintenance of a device (e.g., battery 
replacement) that was in place before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of 
progression of the cancer. 
 
 


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10.4 
Expedited Reporting Requirements for IND Agents  
10.41 Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND within 30 Days of the 
Last Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour  
3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 
7 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.32 for exceptions to Expedited Reporting 
 
 


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10.42 General reporting instructions 
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form 
 for investigational agents or 
commercial/investigational agents on the same arm.  
Also submit the SAE Report to CELGENE at 
  
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Participants or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Participants or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place participants or others at increased risk of harm, but 
no harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that participants should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 
Clinic Cancer Center Expedited Event Report form 


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The Mayo Clinic Compliance Unit will 
review and process the submission to the Mayo Clinic IRB and work with the 
IND Coordinator for submission to FDA. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND requires expedited reporting within 24-
hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND requires expedited 
reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease that cannot be attributed to a CTCAE 
term associated with Grade 5 should be reported as Grade 5 “Disease 
Progression” under the system organ class (SOC) of General disorders 
and administration site conditions. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 


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10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
For any occurrence of a possible exposure of a pregnant woman to luspatercept-
aamt (this could involve a pregnant patient or female partner of a male subject, or 
a pregnant female who came in contact with the medication while dispensing) or 
exposure (to infant) during lactation. , the subject  should notify the Investigator, 
and the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these participants if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation including all reports of elevated/questionable or indeterminate 
beta human chorionic gonadotropins (b hCGs) or positive urine pregnancy test 
after administration of luspatercept-aamt.  Include this form: 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 


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Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v5.0unless alternate grading is indicated in the table 
below: 
CTCAE  
System/Organ/Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
 
 
 
 
Investigations 
Anemia 
X 
X 
 
White blood cell decreased 
X 
X 
 
Investigations – Other, 
specify: Platelet count 
increased 
X 
X 
 
Platelet count decreased 
X 
X 
 
Neutrophil count decreased 
X 
X 
 
Alanine aminotransferase 
increased 
X 
X 
 
Aspartate aminotransferase 
increased 
X 
X 
 
Blood bilirubin increased 
X 
X 
 
Creatinine increased 
X 
X 
Blood and lymphatic 
system disorder 
Leukocytosis 
X 
X 
Musculoskeletal and 
Connective Tissue 
Disorders 
Bone pain 
X 
X 
 
Arthralgia 
X 
X 
Infections and 
Infestations 
Upper Respiratory Infection 
X 
X 
 
Infections and infestations 
Other, specify: Other 
infections 
X 
X 
Nervous System 
disorders 
Headache 
X 
X 
 
Dizziness 
X 
X 
 
Vertigo 
X 
X 
 
Presyncope 
X 
X 
 
Syncope 
X 
X 


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CTCAE  
System/Organ/Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
General disorders and 
administration site 
conditions 
Fatigue 
X 
X 
 
Flu like symptoms 
X 
X 
Gastrointestinal disorders 
Baseline number of stools 
X 
 
 
Abdominal pain 
X 
X 
 
Diarrhea 
 
X 
 
Nausea 
X 
X 
Vascular disorders 
Hypertension 
X 
X 
Metabolism and 
nutritional disorders 
Hyperuricemia 
X 
X 
Respiratory, thoracic and 
mediastinal disorders 
Cough 
X 
X 
 
Dyspnea 
X 
X 
Immune system disorder 
Allergic reaction 
X 
X 
 
Anaphylaxis 
X 
X 
Cardiac disorders 
Sinus tachycardia 
X 
X 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
BMS Additional Event Reporting Instructions 
10.81 Additional Safety Information:  
All adverse events and Other Reportable Events associated with luspatercept-
aamt  (as defined at 
 in accordance with the 
protocol and applicable law must be reported to CELGENE using the SAE report 


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and timelines as per Sections 10.0 and 10.4. INSTITUTION shall comply with 
CELGENE’s reasonable follow-up requests. 
10.82 
Product Quality Complaints 
All Product Quality Complaints (as defined at 
) 
must be reported promptly to CELGENE at 
, but not to exceed the lessor of one (1) 
business day or three (3) calendar days of becoming aware of the event.  
INSTITUTION shall comply with CELGENE’s reasonable follow-up requests. 
10.83 
Yearly summary safety reports will be submitted for 2 years and will provide 
summaries related to data collected on malignancies including secondary 
primary malignancies. These summary safety data will include incidence of 
secondary hematological malignancies (including de-novo AML and 
transformation to AML), solid tumors, and non-melanoma skin cancer. 
 
 


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11.0 
Treatment Evaluation/Measurement of Effect  
Primary end-point, that is, erythroid response is defined as hemoglobin increase by > 2 g/dL 
from baseline or transfusion independence for > 8 weeks for patients requiring at least 4 
packed red blood cell transfusions in the previous 8 weeks.  
 
Secondary end-point is to assess safety of luspatercept-aamt in patients with MDS/MPN-RS-
T and MDS/MPN-U with RS.  
 
Secondary endpoints such as response will be documented per the standard MDS-MPN 
response criteria per Savona et al. Blood 2015 (5).  
 
Complete remission is defined by presence of all the following improvements.  
a) Bone marrow: < 5% myeloblasts with normal maturation of all cell lines and return to  
normal cellularity (presence of dysplastic changes, which may be interpreted within 
the scope of normal range of dysplastic changes may still exist in the presence of CR 
as allowed in the MDS IWG criteria. Marrow should exhibit age-adjusted 
normocellularity in CR). 
b) Osteomyelofibrosis absent or equal to “mild reticulin fibrosis (<grade 1 fibrosis)  
c) Peripheral blood: 1. WBC < 10 x 109 cells/L, 2. Hgb >11 g/dL, 3. Neutrophils > 1 x 
109/L, 4. No blasts (peripheral blood), 5. Neutrophil precursors reduced to < 2%, 6. 
Monocytes < 1 x 109/L.  
d) Extramedullary disease: Complete resolution of extramedullary disease if present 
before therapy, including palpable hepatosplenomegaly.  
 
Complete cytogenetic remission: Resolution of previously present chromosomal abnormality 
as seen on classic karyotyping with minimal of 20 metaphases or FISH.  
 
Partial remission:  Normalization of peripheral counts and hepatosplenomegaly with bone 
marrow blasts reduced by 50%, but remaining more than 5% cellularity except in cases of 
MDS MPN with < 5% bone marrow blasts at baseline.  
 
Marrow response:  
Optimal marrow response:  Presence of all marrow criteria necessary for CR without 
normalization of peripheral blood in disease is presented above. 
Partial marrow response:  Bone marrow blasts reduced by 50% but remaining more 
than 5% cellularity or reduction and grading of reticulin fibrosis from baseline on at 
least 2 bone marrow evaluations paced at least 2 months apart.  
 
Clinical benefit: 
Requires 1 of the following in the absence of progression or CR/PR: 
Erythroid response: as defined above 
 
Platelet response:  Transfusion independence been previously requiring platelet 
transfusions of at least 4 platelet transfusions the previous 8 weeks.  
 
Neutrophil response 
Pre-treatment < 0.5 x 109/L:  At least 100% increase and an absolute increase > 0.5 x 
109/L 
Pre-treatment > 0.5 x 109/L and < 1 x 109/L:  At least 50% increase and an absolute 
increase of > 0.5 x 109/L.  


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Spleen response: Either a minimum 50% reduction in palpable splenomegaly of a 
spleen that is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm 
at baseline becomes not palpable.  
 
For details, please refer to standard MDS-MPN response criteria per Savona et al. 
Blood 2015 (7). 
 
Stable disease: Failure to achieve at least a partial remission (PR), but no evidence of progression 
for > 8 weeks 
 
Disease Progression criteria as per Appendix III 
12.0 
Descriptive Factors  
12.1 
Prior treatment: 1 vs 2 vs 3+ 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Continuation of treatment 
Patients who achieve a response per criteria mentioned in section 11.0 will continue 
treatment per protocol. 
13.2 
Progressive disease (PD) 
Patients who develop PD (Appendix III) while receiving therapy will go to the survival 
follow-up phase. 
13.3 
Off protocol treatment 
Patients who go off protocol treatment for reasons other than PD (ie. Intolerable adverse 
events, subject refusal/withdrawal of consent, lost to follow-up, pregnancy) will go to the 
Survival Follow up phase per Section 4.0. 
13.4 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. If 
the patient received treatment, the patient may continue treatment at the discretion of the 
physician as long as there are not safety concerns. The patient will remain on treatment, 
patient will be followed , as per section 4.0 of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Patient 
will go off study and no follow up is required.  
13.5 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. If the patient received treatment, the patient may continue treatment at 
the discretion of the physician as long as there are not safety concerns. The patient will 
continue in the Active Monitoring/Treatment phase of the study, as per section 4.0 of the 
protocol. 
13.6 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 


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Notification Form must be submitted. The patient will go off study. No further follow up 
is required.  


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14.0 
Body Fluid Biospecimens 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
Research (Section for 
more information) 
Specimen 
Purpose  
(check all that 
apply) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Baseline1 
Week 
25 
Respon
se 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions 
for Storage 
/Shipping 
DNA/RNA 
Correlative 
Mandatory 
Peripheral 
blood,  
EDTA 
50 ml (five 10 
ml EDTA 
tubes) 
X 
X 
Yes 
(MCR); 
No 
(MCA/
MCF) 
See Section 
14.3 
Exploratory/Biomarkers 
(eg, TGF-ß superfamily, 
MDS-associated 
molecular mutations) 
Assay 
Correlative 
Optional 
Bone 
Marrow 
aspirate 
EDTA 
20 ml (five 
4ml EDTA 
tubes) 
X 
 
Yes 
(MCR); 
No 
(MCA/
MCF) 
See Section 
14.3 
Future Research 
Banking 
Optional 
Bone 
marrow 
biopsy 
Formalin 
Fixed, 
Paraffin 
Embedded 
One block or 
5 slides 5µ 
thickness 
X 
 
Yes 
(MCR); 
No 
(MCA/
MCF) 
See Section 
14.3 
 
1. Baseline research blood and bone marrow samples must be collected after registration but prior to Cycle 1 Day 1 treatment 
 
 


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14.2 
Collection and Processing  
14.21 Research blood collections as per table in Section 14.1 will be done at each 
treating site. All processing will be done at the lead site, Mayo Clinic in 
Rochester, MN.  
14.22 All samples must be collected Monday-Friday ONLY for specimens collected at 
Mayo Clinic Rochester and Monday-Thursday for all other locations.  
14.23 Label specimen tube(s) with MCCC protocol number, MCCC Registration 
number, and time and date of blood drawn. 
14.24 If questions, contact 
at Predolin Foundation Biobank at 
 
14.3 
Shipping and Handling 
14.31 MCA and MCF will use kits for this study. MCR will not use kits for this 
study 
14.311 For MCA, kits will be supplied by the Predolin Foundation 
Biobank on Stabile 6. 
14.311a The kit contains supplies and instructions for collecting 
and shipping specimens. 
14.311b Participating institutions may obtain kits by emailing 
Because we are 
charged for all outgoing kits, a small, but sufficient, 
supply of the specimen collection kits should be ordered 
prior to patient entry.  
14.311c Kits will be sent via Fed Ex Ground at no additional 
cost to the participating institutions. Allow at least two 
weeks to receive the kits. 
14.311d Kits will not be sent via rush delivery service unless the 
participating institution provides their own Fed Ex 
account number or alternate billing number for express 
mail. Cost for rush delivery of kits will not be covered 
by the study. 
14.311e All specimens must be collected and shipped Monday 
– Thursday ONLY. 
14.312 For MCF, kits will be supplied by FL BAP 
14.312a Please contact BAP Lab FL to order kit(s) 
14.312b All specimens must be collected and shipped Monday 
– Thursday ONLY. 
14.32 Shipping Specimens 
For MCA and MCF, baseline blood and bone marrow samples will be shipped 
with a Cool Pak the same day they are collected (Monday-Thursday). Note: 
Week 25 blood samples may be shipped ambient. They should be shipped 
priority overnight. 
If unavoidable, Friday shipping with Saturday delivery can be arranged by 
contacting the laboratory in advance. 


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Please notify Mayo Clinic by email to 
  when specimens 
are being shipped. If questions, please contact 
 
 
 
 
14.33 Handling Specimens 
MNC Collection for Bone marrow or Peripheral blood done at the Predolin 
Foundation Biobank:  
Follow the AML SOPs for processing both the bone marrow (plasma and MNCs) 
and peripheral blood (plasma and MNCs). NOTE: No purity slides. 
Store the bone marrow and peripheral blood plasma in the current AML plasma 
box. 
The bone marrow and peripheral blood MNCs will be divided as follows: 
If less than 5 x 106: 
 Store in RNALater (priority) 
5 x 106 to 10 x 106 recovered: 
 First vial: 5 x 106 stored in RNALater (priority) 
 Second vial: Remaining cells x 106 stored in RNALater 
>10 x 106 to 15 x 106 MNCs recovered divide in 3 ways: 
 First vial: 5 x 106 stored in RNALater (priority) 
 Second vial: 5 x 106 stored in RNALater 
 Third vial: Remaining cells x 106 stored as a pellet 
>15 x 106 to 25 x 106 MNCs recovered divide in 4 ways: 
 First vial: 5 x 106 stored in RNALater (priority) 
 Second vial: 5 x 106 stored in RNALater 
 Third vial: 5 x 106 stored as a pellet 
 Fourth vial: Remaining cells up to 15 x 106 stored as a 2nd pellet 
>25 x 106 to 30 x 106 MNCs recovered divide in 5 ways: 
 First vial: 5 x 106 stored in RNALater (priority) 
 Second vial: 5 x 106 stored in RNALater 
 Third vial: 5 x 106 stored as a pellet 
 Fourth vial: 5 x 106 stored as a 2nd pellet 
 Fifth vial: 5-10 x 106 stored in DMSO and banked 
 
35 x 106 MNCs recovered divide in 6 ways: 
 First vial: 5 x 106 stored in RNALater (priority) 
 Second vial: 5 x 106 stored in RNALater 
 Third vial: 5 x 106 stored as a pellet 
 Fourth vial: 5 x 106 stored as a 2nd pellet 
 Fifth vial: 5-10 x 106 stored in DMSO and banked 
 Remaining bone marrow cells: Cells go to 
laboratory 
 add some S10 and leave at room 
temperature. 


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 Remaining peripheral blood cells: Freeze ten million cells in DMSO 
(place with our aliquots in the CoolCell). The next day transfer the vial to 
the CMD group’s storage box located on our working shelf in the -80 
freezer. Transport to Terra Lasho. 
Greater than 35 x 106 MNCs recovered divide as follows in this order of 
priority: 
 First vial: 5 x 106 stored in RNALater (priority) 
 Second vial: 5 x 106 stored in RNALater 
 Third vial: 5-15 x 106 stored as a pellet 
 Fourth vial: 5-15 x 106 stored as a 2nd pellet 
 Fifth vial: 10-30 x 106 stored in DMSO and banked 
 Peripheral blood cells: Freeze ten million cells in DMSO (place with 
our aliquots in the CoolCell). The next day transfer the vial to the CMD 
group’s storage box located on our working shelf in the -80 freezer. 
Transport to Terra Lasho. 
 Sixth thru Tenth vials: 10.0 x 106 stored in DMSO 
 Remaining bone marrow or peripheral blood cells: Cells go to 
 
laboratory 
 add some S10 and 
leave at room temperature. 
 
Freeze the RNALater and pellet vial at -80o for a minimum of 10 minutes.  
Freeze ALL the DMSO vials per SOP (CoolCell).  
Transport the samples (RNA Later, pellets, DMSO vials 6 thru 10 and any fresh 
cells) in the AML tracking system to 
 using IRB 15-003786. 
Place the processing worksheet on the 7am technologist’s desk. 
The next day the 1st DMSO aliquot is stored in our active AML/CMML/CAR-T 
Liquid Nitrogen box. 
14.4 
Background and Methodology 
14.41 Plasma:  Ineffective erythropoiesis due to a perturbed TGF-β signaling and 
increased Smad-2/3 phosphorylation is a hallmark of myeloid neoplasms with 
RS. The recently discovered hormone, erythroferrone (ERFE) has been shown 
to act as a ligand trap for Smad proteins (Arezes J et al. Blood 2018) and 
implicated in iron homeostasis in both Thalassemia Major (Kautz L et al. Blood 
2015) and Sickle Cell Disease (Mangaonkar A et al. Br J Haematol 2020). 
Variant ERFE secondary to SF3B1 mutant-induced aberrant splicing has been 
shown to disrupt iron homeostasis in MDS-RS (Bondu S et al. Sci Trans Med 
2019).   
14.42 Due to the known mechanism of luspatercept-aamt in reducing Smad pathway 
signaling through TGF-β modulation, we propose measuring hepcidin, and its 
known inhibitors related to TGF- β signaling, namely ERFE, and growth-
differential factor-15 (GDF-15) to identify potential biomarkers of erythroid 
response. Iron status will be documented through clinical assays prior to 
enrollment. All parameters will be measured through ELISA as per previously 
published methods.  
14.43 DNA – Stored peripheral blood mononuclear cell (PBMC) DNA at enrollment 
will be used to perform next generation sequencing for myeloid-specific genes 


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(if not done clinically) in order to identify potential genomic biomarkers of 
response in MDS/MPN-RS-T and MDS/MPN-U with RS.   
14.44 RNA – Bulk RNA-seq will be performed on RNA extracted from PBMCs at 
enrollment and pathway analysis will be carried out to identify predictive 
biomarkers of response. 
 
All correlative studies will be performed at Mayo Clinic (Rochester, MN) 
 


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15.0 
Drug Information 
IND exempt 
• 
Investigator brochure  
BMS contact information:  
 
 
 
15.1 
Luspatercept-aamt (Reblozyl®, ACE-536, BMS-986346) 
15.11 Background: Luspatercept-aamt is a recombinant fusion protein that binds 
several endogenous TGF-β superfamily ligands, thereby diminishing Smad2/3 
signaling. Luspatercept-aamt promoted erythroid maturation through 
differentiation of late-stage erythroid precursors (normoblasts), decreased 
abnormally elevated Smad2/3 signaling and improved hematology parameters 
associated with ineffective erythropoiesis. 
15.12 Formulation: Luspatercept-aamt for injection is a sterile, preservative-free, 
lyophilized cake/powder. Upon reconstitution it consists of 50 mg/mL 
luspatercept-aamt in a 10 mM citrate buffer-based solution (pH 6.5, 9% sucrose, 
0.02% polysorbate 80). The drug product is packaged in a 3-mL glass vial in the 
following strengths: 25 mg/vial and 75 mg/vial.   
15.13 Preparation and storage:  Store luspatercept-aamt vials at 2°C to 8°C. 
Luspatercept-aamt is reconstituted with sterile water for injection (SWFI). 
Luspatercept-aamt should not be reconstituted with bacteriostatic water or any 
other solution.  
A. Reconstitute 25 mg vial with 0.68 mL of SWFI to a final concentration 
of 25 mg/0.5 mL. Reconstitute 75 mg vial with 1.68 mL of SWFI to a 
final concentration of 75 mg/1.5 mL (50 mg/mL). Direct the stream onto 
the lyophilized powder. Let stand for one minute.  
B. Discard the needle and syringe used for reconstitution. The needle and 
syringe used for reconstitution should not be used for subcutaneous 
injections. 
C. Gently swirl the vial in a circular motion for 30 seconds. Stop swirling 
and let the vial sit in an upright position for 30 seconds. 
D. Inspect the vial for undissolved particles in the solution. If undissolved 
powder is observed, repeat Step C until the powder is completely 
dissolved. 
E. Invert the vial and gently swirl in an inverted position for 30 seconds. 
Bring the vial back to the upright position, and let it sit for 30 seconds. 
F. Repeat Step E seven more times to ensure complete reconstitution of 
material on the sides of the vial. 
If the reconstituted solution is not used immediately, store at room temperature at 
20°C to 25°C (68°F to 77°F) in the original vial for up to 8 hours. Discard if not 
used within 8 hours of reconstitution. Alternatively, store refrigerated at 2°C to 
8°C (36°F to 46°F) for up to 24 hours in the original vial. Remove from 
refrigerated condition 15-30 minutes prior to injection to allow solution to reach 
room temperature for a more comfortable injection. Discard if not used within 24 
hours of reconstitution. Do not freeze the reconstituted solution. Discard any 


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unused portion. Do not pool unused portions from the vials. Do not administer 
more than 1 dose from a vial. Do not mix with other medications. 
 
15.14 Administration:  Divide doses requiring larger reconstituted volumes (i.e., 
greater than 1.2 mL) into separate similar volume injections and inject into 
separate sites. If multiple injections are required, use a new syringe and needle 
for each subcutaneous injection. Administer the injection subcutaneously into the 
upper arm, thigh, and/or abdomen. 
 
15.15 Pharmacokinetic information:     
a)  Absorption – Median time to Cmax is 7 days (range, 6-10 days) in beta 
thalassemia or 7 days (range, 5-21 days) in MDS. The absorption of 
luspatercept was not significantly affected by the SC injection sites (upper 
arm, thigh, or abdomen) 
b)  Distribution – The mean volume of distribution of luspatercept-aamt 
was 7 L for patients with beta thalassemia and 9.68L for patients with 
MDS 
c)  Metabolism – Luspatercept-aamt is expected to be catabolized into 
small peptides and amino acids by general protein degradation processes in 
multiple tissues 
d)  Excretion – The mean t½ of luspatercept-aamt was approximately 11 
days in beta thalassemia and 14 days in MDS patients.  Luspatercept is not 
expected to be significantly excreted into urine due to the fact that its large 
molecular mass is above the glomerular filtration size exclusion threshold 
15.16 Potential drug interactions:  No significant drug-drug interactions are known. 
No clinically significant differences in luspatercept-aamt pharmacokinetics were 
noted with concomitant iron-chelation therapy. 
15.17 Known potential adverse events:   
 
Common (> 10%):  
 
Cardiovascular: Hypertension 
 
Gastrointestinal: Abdominal pain, diarrhea, nausea 
Hepatic: Increased serum alanine aminotransferase, increased serum aspartate 
aminotransferase, increased serum bilirubin 
Nervous system: Dizziness, fatigue, headache, vertigo 
Neuromuscular & skeletal: Arthralgia, musculoskeletal pain, ostealgia  
Renal: Decreased creatinine clearance 
Respiratory: Cough, dyspnea 
 
Less Common (1-10%):  
Cardiovascular:  Presyncope, syncope, tachycardia, thromboembolism 
including deep vein thrombosis, ischemic stroke, portal vein thrombosis, 
pulmonary embolism,  
Endocrine & metabolic: Hyperuricemia 
Genitourinary: Urinary tract infection 
Hepatic: Increased direct serum bilirubin, increased serum alkaline phosphatase 
Hypersensitivity: Hypersensitivity reaction 
Immunologic: Antibody development 
Infection: Influenza 
Local: Injection site reaction 


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Nervous system: Cerebrovascular accident, spinal cord compression 
Renal: Renal insufficiency 
Respiratory: Bronchitis, upper respiratory tract infection, viral upper respiratory 
tract infection 
Miscellaneous: Mass 
 
Frequency not defined: Neuromuscular and skeletal: Back pain 
Splenectomized β-thalassemia subjects are at increased risk of developing  
thromboembolic complications. Caution is advised when treating  
splenectomized subjects who had at least 1 other risk factor for developing  
thromboembolic events such as a history of thrombocytosis or 
concomitant use of hormone-replacement therapy. Thromboprophylaxis  
should be considered in subjects with β-thalassemia at higher risk. Patients  
with β-thalassemia are at increased risk of developing extramedullary  
hematopoietic masses; some in the paraspinal region having the potential  
of causing spinal compression. 
15.18 Drug procurement: 
The Mayo Clinic pharmacist will obtain drug from BMS using the drug ordering 
system, IDOS: 
Outdated or remaining drug is to be destroyed on-site per procedures in place at 
each institution. 
15.19 Nursing guidelines 
15.191 GI side effects have been seen. Most commonly abdominal pain, 
diarrhea, and nausea. Manage symptomatically and monitor for 
effectiveness. 
15.192 Monitor LFT’s 
15.193 Patients may experience dizziness and vertigo. Warn patients of this 
possibility and to use caution when standing or doing activities that 
require concentration.  
15.194 Arthralgia and musculoskeletal pain have been seen. Treat 
symptomatically and monitor for effectiveness. 
15.195 Monitor renal function and encourage patients to stay well hydrated. 
15.196 Rarely thrombotic and cardiac events can be seen. Instruct patients to 
report any edema, shortness of breath, chest pain or palpitations to the 
study team immediately or seek out urgent evaluation. Thrombotic 
events are more common in patients with β-thalassemia who have 
undergone splenectomy or those with splenectomy who have at least 1 
other risk factor for developing thromboembolic events.  
15.197 Hypertension is common. Instruct patients on the importance of taking 
any medications for blood pressure as prescribed. Monitor BP and report 
elevated readings to the local investigator. 
 
15.2 
Hydroxyurea for Oral Administration (Hydrea®) 
15.21 Background: Hydroxyurea is an antimetabolite which selectively inhibits 
ribonucleoside diphosphate reductase, preventing the conversion of 


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ribonucleotides to deoxyribonucleotides, halting the cell cycle at the G1/S phase 
and therefore has radiation sensitizing activity by maintaining cells in the G1 
phase and interfering with DNA repair. In sickle cell anemia, Hydroxyurea 
increases red blood cell (RBC) hemoglobin F levels, RBC water content, 
deformability of sickled cells, and alters adhesion of RBCs to endothelium. 
15.22 Formulation: Commercially available for oral administration as:  
 
Capsules: 500 mg  
15.23 Preparation, storage, and stability: Store at room temperature preferably below 
25ºC (77ºF); excursions permitted between 15°C and 30°C (59°F and 86°F). The 
manufacturer does not recommend opening the capsules; observe proper 
handling procedures (eg, wear gloves). 
15.24 Administration:  Refer to the treatment section for specific administration 
instructions. The manufacturer does not recommend opening the capsules. 
15.25 Pharmacokinetic information: 
Distribution: Readily crosses blood-brain barrier; distributes into 
intestine, brain, lung, kidney tissues, effusions and ascites 
Protein binding: 10% to 60% 
Time to peak: 1-4 hours 
Metabolism: 60% via hepatic and GI tract 
Half-life elimination: 3-4 hours 
Excretion: Urine (sickle cell anemia: 40% of administered dose) 
15.26 Potential Drug Interactions: 
Avoid Concomitant Use 
Avoid concomitant use of Hydroxyurea with any of the following: BCG; 
Didanosine; Natalizumab; Pimecrolimus; Stavudine; Tacrolimus 
(Topical); Vaccines (Live)  
Increased Effect/Toxicity: Hydroxyurea may increase the levels/effects 
of: Didanosine; Leflunomide; Natalizumab; Stavudine; Vaccines (Live). 
The levels/effects of Hydroxyurea may be increased by: Denosumab; 
Didanosine; Pimecrolimus; Stavudine; Tacrolimus (Topical); Trastuzumab 
Decreased Effect: Hydroxyurea may decrease the levels/effects of: BCG; 
Sipuleucel-T; Vaccines (Inactivated); Vaccines (Live). The levels/effects 
of Hydroxyurea may be decreased by: Echinacea 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information. U.S. Boxed Warning: Hydroxyurea is 
mutagenic and clastogenic. Treatment of myeloproliferative disorders with long-
term Hydroxyurea is associated with secondary leukemia. 
Known potential toxicities, frequency not defined:   
Cardiovascular: Edema 
Central nervous system: Chills, disorientation, dizziness, drowsiness 
(dose-related), fever, hallucinations, headache, malaise, seizure 
Dermatologic: Alopecia, cutaneous vasculitic toxicities, dermatomyositis-
like skin changes, facial erythema, gangrene, hyperpigmentation, 
maculopapular rash, nail atrophy, nail discoloration, peripheral erythema, 
scaling skin atrophy, skin cancer, skin ulcer, vasculitis ulcerations, violet 
papules 


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Endocrine & metabolic: Hyperuricemia 
Gastrointestinal: Anorexia, constipation, diarrhea, gastrointestinal irritation 
and mucositis, (potentiated with radiation therapy), nausea, pancreatitis, 
stomatitis, vomiting 
Genitourinary: Dysuria 
Hematologic: Myelosuppression (anemia, leukopenia [common; reversal 
of WBC count occurs rapidly], thrombocytopenia); macrocytosis, 
megaloblastic erythropoiesis, secondary leukemias (long-term use) 
Hepatic: Hepatic enzymes increased, hepatotoxicity 
Neuromuscular & skeletal: Peripheral neuropathy, weakness 
Renal: BUN increased, creatinine increased 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Respiratory: Acute diffuse pulmonary infiltrates (rare), dyspnea, 
pulmonary fibrosis (rare) 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
15.29 Nursing Guidelines:  
15.291 Hydroxurea is mutagenic and clastogenic, and therefore has the potential 
to cause chromosomal abnormalities in the pateint that could lead to 
other conditions. Warn patient of this possibility. 
15.292 Myelosuppression is common. Monitor CBC with differential. Instruct 
patient to report any signs or symptoms of infection, or any unusal 
bruising or bleeding to the study team. 
15.293 Patients who are on this agent for long term have an increased risk of 
developing secondary leukemias. Warn patient of this possibility. 
15.294 Nurmerous dermatologic conditions can be seen with hyrdoxurea. Refer 
to section 15.17 for these and instruct patient to report any dermatologic 
signs and symptoms to the study team.  
15.295 Gastrointestinal side effects can be seen (diarrhea, constipation, nausea, 
vomitin, anorexia, etc.). Treat symptomatically and monitor for 
effectiveness. 
15.296 While rare, pulmonary infiltrates, dyspnea and pulmonary fibrosis can 
occur. Instruct patients to report any respiratory symptoms to the study 
team.  
 
 
 


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16.0 
Statistical Considerations and Methodology  
16.1 
Study Design Overview: This is a phase 2 trial with two parallel cohorts with 
independent statistical designs and decision rules. The two cohorts will be based on 
dependence on concurrent hydroxyurea in these patients. The following designs and 
decision criteria will be used for each of the cohorts:  
• 
Hydroxyurea-independent cohort: This phase 2 evaluation within this cohort will 
utilize a Simon minimax two-stage design. Based on published data and our 
experiences with this patient population, we would expect that if this regimen 
was not effective that we would observe at most 10% of patients with an 
erythroid-based response. To be considered promising in these hydroxyurea-
independent patients, we hypothesize a true response rate of at least 40%. 
Constraining Type I error to 0.05 and Type II errors to 0.20 each (i.e. with 80% 
power, α=0.05), this design requires a minimum of 8 patients and a maximum of 
13 patients in this cohort.  
o Decision Rule: Overall, if we observe 4 or more patients with an erythroid 
response in the 13 evaluable patients, we will consider this to be sufficient 
evidence of promising activity in this cohort.  
o Interim analysis: This two-stage design also includes an interim analysis after 
the first 8 evaluable patients have been accrued. If in these 8 patients we see 
at least 2 patients with an erythroid response, we will continue accrual to the 
total of 13 evaluable patients. If at most 1 of these 8 patients have an 
erythroid response, then we will consider this sufficient evidence that this 
agent is not promising in this cohort of HU-independent MDS/MPN-RS-T 
patients. Note that while the first 8 patients are being evaluated for response, 
we will allow accrual to continue given the relatively rare nature of this 
patient population.  
• 
Hydroxyurea-dependent cohort: For this cohort, we will utilize a Simon optimal 
two-stage phase 2 trial design. Given that these patients will be dependent on 
concurrent hydroxyurea, we assume that their likelihood of an erythroid response 
in the absence of other treatment is lower (5%). For this more compromised 
group, we will consider a true response rate of 25% or greater to be promising in 
this cohort of patients. Constraining our Type I to 0.05 and the Type II error rate 
to 0.2 (i.e. with 80% power, α=0.05), this design requires a minimum of 9 
patients and a maximum of 17 patients in this cohort.  
o Decision Rule: Overall, if we observe 3 or more patients with an erythroid 
response in 17 evaluable patients, we will consider this to be sufficient 
evidence of promising activity in this HU-dependent cohort.  
o Interim analysis: This two-stage design also includes an interim analysis after 
the first 9 evaluable patients have been accrued. If in these 9 patients we see 
at least 1 patient with an erythroid response, we will continue accrual to the 
total of 17 evaluable patients. If none of these 9 patients has an erythroid 
response, then we will consider this sufficient evidence that this agent is not 
promising in this cohort of HU-dependent MDS/MPN-RS-T patients. Note 


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that while the first 9 patients are being evaluated for response, we will allow 
accrual to continue given the relatively rare nature of this patient population.  
16.2 
Sample Size 
16.2.1 Sample Size: The maximum sample size required in this study is 30 evaluable 
patients (13 HU-dependent, 17 HU-independent). We will accrue up to an 
additional 10% (3 patients) in order to account for potential ineligible patients or 
patients who withdraw prior to treatment. Thus, the total number of patients 
enrolled is expected to be up to a maximum of 33 patients.  
16.3 
Study Endpoints and Analysis Plans 
Since the two HU dependence-based cohorts will be evaluated in parallel, their endpoints 
will also be evaluated separately. However, for safety endpoints as well as some clinical 
outcomes, we will also evaluate these across all patients while adjusting for HU 
dependence status (i.e. concurrent HU vs. not).  
o Primary Endpoint: erythroid response rate will be defined as the proportion of 
patients who achieve an erythroid response out of the total number of evaluable 
patients (i.e. eligible patients who received at least one dose of treatment on study). 
Assuming that the number of patients who achieve a response is binomially 
distributed, we will calculate the proportion of erythroid responses in each cohort 
along with the corresponding binomial confidence intervals. For evaluation of 
erythroid response across all participants, we will also in an ancillary manner 
evaluate the incidence of erythroid response using a multivariable logistic regression 
model, where we will assess the influence of HU dependence as well as other factors 
of interest.  
o Secondary Endpoints:  
 
Safety and tolerability: The incidence of adverse events (AEs) and the ability 
of patients to stay on treatment will be used to assess safety and tolerability 
of treatment with luspatercept-aamt in each of the cohorts. Incidence of 
severe (grade 3+) AEs as well as toxicities (AEs felt to be at least possibly 
related to study treatment) will be tabulated and evaluated in each cohort 
along with tabulation of specific types of AEs. Time to end of active 
treatment will be evaluated as the time from treatment start date to the time 
patients go off treatment for any reason. This will be summarized within and 
across cohorts using the methods of Kaplan and Meier, and the reasons 
patients discontinue treatment will be summarized.  
 
Time-to-event outcomes: Several time-to-event outcomes will be evaluated 
in the context of this study. These endpoints will be used to help characterize 
the patients within and across cohorts, and factors that affect the distributions 
of these endpoints in these cohorts may be explored. Each of these will be 
evaluated and characterized within each cohort using the methods of Kaplan 
and Meier. Patients who have not had the event of interest by the time of 
their last follow-up for that event will be censored at that time point. Any 
factors influencing these time-to-event outcomes will also be explored using 


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Cox proportional hazards models. The specific time-to-event outcomes to be 
evaluated are as follows:  
o Duration of response: will be defined as the time from first documented 
erythroid response to the time of progression and/or relapse.  
o Time to leukemic transformation: will be defined as the time from study 
entry to the time of transformation to AML.  
o Leukemia-free survival: will be evaluated in all patients who from time 
of treatment to progression to acute myeloid leukemia or death from any 
cause.  
o Overall survival: will be defined as the time from study entry to the time 
of death due to any cause.  
 
Exploratory outcomes: An optional study will assess health-related quality of 
life using the HM-PRO questionnaire. These assessments will be completed 
at the beginning of each cycle of treatment and at end of treatment.  Given 
that this is an optional and exploratory endpoint, change from baseline HM-
PRO scores will be analyzed in a descriptive manner.  
 
Correlative outcomes: Several correlative markers of interest as outlined 
above will be evaluated within and across cohorts. These markers will be 
assessed and summarized alone as well as in relation to erythroid response 
and/or other outcomes of interest. Analyses will also be explored across all 
patients, where cohort (HU dependence) will be adjusted for in the model 
and/or evaluated in the context of effect modification on the outcomes of 
interest and other factors of interest.  
16.4 
Data & Safety Monitoring 
16.41 Safety review 
The principal investigator(s) and the study statistician will review the study 
monthly to identify accrual, adverse event, and any endpoint problems that might 
be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least biannually, based on reports provided by the MCCC Statistical Office. 
16.42 Adverse Event Stopping Rules  
The safety stopping rules to be used in this trial will be across both cohorts using 
a Bayesian toxicity monitoring rule. This rule constrains the maximum 
probability of unacceptable or excessive toxicity at 0.20. For the purposes of 
stopping rules for this patient population, where it is not uncommon for patients 
to experience severe adverse events, we will define excessive or unacceptable 
toxicity as any grade 3 or greater non-hematologic toxicity (an adverse event 
considered to be at least possibly related to study treatment) that is not responsive 
to supportive care. Excluded from this would be grade 3 fatigue as we would not 
consider this treatment-limiting. Assuming a prior distribution of this probability 
of Beta(1,1) and a maximum of N=33 patients, we will utilize these rules starting 
when n=6 patients have been accrued overall and to be evaluated after each 
patient (i.e. cohort size =1) and with a posterior probability >80% (i.e. 
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is >0.20). If the stopping rule thresholds are met, accrual will be temporarily 
suspended for full review by the study team.  
 
Table of rules for toxicity stopping boundaries 
# patients 
# patients with 
unacceptable/excessive toxicity to 
suspend accrual for full review 
6 
2 or more 
7 to 10 
3 or more 
11 to 14 
4 or more 
15 to 19 
5 or more 
20 to 23 
6 or more 
24 to 27 
7 or more 
28 to 31 
8 or more 
32 to 33 
9 or more 
 
16.5 
Subset Analyses for Minorities 
16.51 Study availability 
This study will be available to all eligible patients, regardless of gender, race or 
ethnic origin.  
16.52 Statistical analysis by subset 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analyses will 
look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
16.53 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. With accrual open at all three Mayo Clinic sites, 
we will target improved accrual of minority patient participation. Expected sizes 
of racial by gender subsets are shown in the following table, which also includes 
the planned potential over accrual of 10% for a total of N=33 patients: 


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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
13 
18 
31 
Ethnic Category: Total of all participants 
 
14 
19 
33 
Racial Category 
American Indian or Alaskan Native 
0 
1 
1 
Asian 
0 
0 
0 
Black or African American 
0 
1 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
14 
18 
31 
Racial Category: Total of all participants 
 
14 
19 
33 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


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17.0  
Pathology Considerations/Tissue Biospecimens 
NONE 
18.0 
Records and Data Collection Procedures . 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Survival Follow-up 
See Section 4.  
18.3 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
18.4 
Site responsibilities 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation  
This study requires supporting documentation for diagnosis and progression prior to 
study entry as well as for evidence of response to study therapy and progression after 
study therapy. These documents should be submitted within 14 days of registration (for 
prior to study entry materials) or within 14 days after the visit at which response or 
progression is determined.  
 
ESA therapies ≤ 4 weeks prior to registration and RBC and Platelet transfusions ≤8 
weeks prior to registration will be collected 
18.6 
Labeling of materials 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Overdue lists 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
Cancer Center Systems homepage. 
 
 


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19.0  
Budget 
19.1 
Costs charged to patient: routine clinical care and hydroxyurea 
19.2 
Tests to be research funded: 
HIV screening, CD4, if needed, and pregnancy tests. 
Research blood and bone marrow specimen processing and analyzing  
Luspatercept-aamt SQ injection administration 
19.3 
Other budget concerns: 
BMS will provide Mayo Clinic with funding to support the costs of running this study. 
BMS will provide study drug, luspatercept-aamt, for use in this study 
 
 
 


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20.0 
References 
1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, 
Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification 
of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405. Epub 2016/04/14. 
doi: 10.1182/blood-2016-03-643544. PubMed PMID: 27069254. 
2. Mangaonkar AA, Swoboda DM, Coltro G, Lasho TL, Novotny PJ, Pophali P, Carr RM, 
Binder M, Finke CM, Gangat N, Al-Kali A, Begna KH, Reichard KK, Ketterling RP, Al Ali 
NH, Vafaii P, Zhang L, Padron E, Talati C, Patnaik MM. Clinicopathologic characteristics, 
prognostication and treatment outcomes for myelodysplastic/myeloproliferative neoplasm, 
unclassifiable (MDS/MPN-U): Mayo Clinic-Moffitt Cancer Center study of 135 consecutive 
patients. Leukemia. 2020;34(2):656-61. Epub 2019/09/13. doi: 10.1038/s41375-019-0574-x. 
PubMed PMID: 31511613. 
3. Mangaonkar AA, Patnaik MM. Treatment of Acquired Sideroblastic Anemias. Hematol 
Oncol Clin North Am. 2020;34(2):401-20. Epub 2020/02/25. doi: 10.1016/j.hoc.2019.11.002. 
PubMed PMID: 32089219. 
4. Patnaik MM, Tefferi A. Refractory anemia with ring sideroblasts (RARS) and RARS with 
thrombocytosis: "2019 Update on Diagnosis, Risk-stratification, and Management". 
American journal of hematology. 2019;94(4):475-88. Epub 2019/01/09. doi: 
10.1002/ajh.25397. PubMed PMID: 30618061; PMCID: PMC6408294. 
5. Antelo G, Mangaonkar AA, Coltro G, Buradkar A, Lasho TL, Finke C, Carr R, Binder M, 
Gangat N, Al-Kali A, Elliott MA, King RL, Howard M, Melody ME, Hogan W, Litzow MR, 
Tefferi A, Fernandez-Zapico ME, Komrokji R, Patnaik MM. Response to erythropoiesis-
stimulating agents in patients with WHO-defined myelodysplastic 
syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis 
(MDS/MPN-RS-T). British journal of haematology. 2020;189(3):e104-e8. Epub 2020/03/05. 
doi: 10.1111/bjh.16515. PubMed PMID: 32128785. 
6. Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-
Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi 
F, Giai V, Vyas P, Bowen D, Selleslag D, DeZern AE, Jurcic JG, Germing U, Götze KS, 
Quesnel B, Beyne-Rauzy O, Cluzeau T, Voso MT, Mazure D, Vellenga E, Greenberg PL, 
Hellström-Lindberg E, Zeidan AM, Adès L, Verma A, Savona MR, Laadem A, Benzohra A, 
Zhang J, Rampersad A, Dunshee DR, Linde PG, Sherman ML, Komrokji RS, List AF. 
Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 
2020;382(2):140-51. Epub 2020/01/09. doi: 10.1056/NEJMoa1908892. PubMed PMID: 
31914241. 
7. Savona MR, Malcovati L, Komrokji R, Tiu RV, Mughal TI, Orazi A, Kiladjian JJ, Padron E, 
Solary E, Tibes R, Itzykson R, Cazzola M, Mesa R, Maciejewski J, Fenaux P, Garcia-Manero 
G, Gerds A, Sanz G, Niemeyer CM, Cervantes F, Germing U, Cross NC, List AF. An 
international consortium proposal of uniform response criteria for 
myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 
2015;125(12):1857-65. Epub 2015/01/28. doi: 10.1182/blood-2014-10-607341. PubMed 
PMID: 25624319; PMCID: PMC4915792. 
8. Arezes J, Foy N, McHugh K, Sawant A, Quinkert D, Terraube V, Brinth A, Tam M, LaVallie 
ER, Taylor S, Armitage AE, Pasricha SR, Cunningham O, Lambert M, Draper SJ, Jasuja R, 
Drakesmith H. Erythroferrone inhibits the induction of hepcidin by BMP6. Blood. 
2018;132(14):1473-7. Epub 2018/08/12. doi: 10.1182/blood-2018-06-857995. PubMed 
PMID: 30097509; PMCID: PMC6238155 from Pfizer. N.F., A.S., V.T., A.B., M.T., E.R.L., 
O.C., M.L., and R.J. are Pfizer employees. N.F., O.C., R.J., J.A., K.M., S.J.D., and H.D. are 
named inventors on a patent application currently under evaluation. The remaining authors 
declare no competing financial interests. 


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9. Kautz L, Jung G, Du X, Gabayan V, Chapman J, Nasoff M, Nemeth E, Ganz T. 
Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-
thalassemia. Blood. 2015;126(17):2031-7. Epub 2015/08/16. doi: 10.1182/blood-2015-07-
658419. PubMed PMID: 26276665; PMCID: PMC4616236. 
10. Mangaonkar AA, Thawer F, Son J, Ajebo G, Xu H, Barrett NJ, Wells LG, Bowman L, Clair 
B, Patel N, Bora P, Jung G, Nemeth E, Kutlar A. Regulation of iron homeostasis through the 
erythroferrone-hepcidin axis in sickle cell disease. British journal of haematology. 
2020;189(6):1204-9. Epub 2020/02/08. doi: 10.1111/bjh.16498. PubMed PMID: 32030737. 
11. Bondu S, Alary AS, Lefèvre C, Houy A, Jung G, Lefebvre T, Rombaut D, Boussaid I, Bousta 
A, Guillonneau F, Perrier P, Alsafadi S, Wassef M, Margueron R, Rousseau A, Droin N, 
Cagnard N, Kaltenbach S, Winter S, Kubasch AS, Bouscary D, Santini V, Toma A, Hunault 
M, Stamatoullas A, Gyan E, Cluzeau T, Platzbecker U, Adès L, Puy H, Stern MH, Karim Z, 
Mayeux P, Nemeth E, Park S, Ganz T, Kautz L, Kosmider O, Fontenay M. A variant 
erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome. Sci 
Transl Med. 2019;11(500). Epub 2019/07/12. doi: 10.1126/scitranslmed.aav5467. PubMed 
PMID: 31292266. 
12. Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, 
Randi ML, Bertozzi I, Gisslinger H, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, 
Vannucchi AM, Tefferi A. Development and validation of an International Prognostic Score 
of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). 
Blood. 2012;120(26):5128-33; quiz 252. Epub 2012/10/04. doi: 10.1182/blood-2012-07-
444067. PubMed PMID: 23033268. 
13. Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia treatment algorithm 2018. 
Blood cancer journal. 2018;8(1):2. Epub 2018/01/13. doi: 10.1038/s41408-017-0041-8. 
PubMed PMID: 29321520; PMCID: PMC5802626. 
14. Scherber R, Dueck AC, Johansson P, Barbui T, Barosi G, Vannucchi AM, Passamonti F, 
Andreasson B, Ferarri ML, Rambaldi A, Samuelsson J, Birgegard G, Tefferi A, Harrison CN, 
Radia D, Mesa RA. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-
SAF): international prospective validation and reliability trial in 402 patients. Blood. 
2011;118(2):401-8. Epub 2011/05/04. doi: 10.1182/blood-2011-01-328955. PubMed PMID: 
21536863. 
15. Antelo G, Mangaonkar AA, Coltro G, Lasho T, Finke C, Carr R, Binder M. Response to 
erythropoiesis-stimulating agents in patients in patients with WHO-defined myelodysplastic 
syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis 
(MDS/MPN-RS-T). British Society for Haematology 2020, 189: e64-e118.Epub 2020/03/03. 
doi: 10.1111/bjh.16515 


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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 


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APPENDIX II: Hydroxyurea and/or aspirin use guidelines. 
Since there are no established guidelines to provide cytoreductive and/or anti-platelet therapy to manage 
patients with MDS/MPN overlap syndromes with thrombocytosis (platelet count > 450, 000 X 109/L), we 
recommend the use of risk stratification system of essential thrombocythemia in estimating thrombotic 
risk, also known as IPSET-Thrombosis (12). This risk stratification will only be applied in patients with 
thrombocytosis (platelet count > 450, 000 X 109/L). In this, patients are stratified into low, intermediate 
and high risk, based on the points assigned based on the following variables:  
 
1. Age > 60 years: 1 point 
2. Presence of thrombosis history (arterial or venous): 2 points 
3. Cardiovascular risk factors (i.e hypertension, diabetes mellitus, and active tobacco use): 1 point 
4. Presence of JAK2V617F mutation: 2 points.  
 
Low risk is defined as <2 points; intermediate risk as 2 points, and high risk as > 2 points.       
 
If patient is low risk, then once daily aspirin only is recommended. However, low risk in the presence of 
cardiovascular risk factors, twice-daily aspirin can be considered. 
 
If patient is in the intermediate-risk category, then once-daily aspirin plus hydroxyurea therapy is 
recommended. If no cardiovascular risk factors are present, then twice-daily aspirin only can be 
considered. 
 
In patients in the high-risk category, then hydroxyurea plus twice-daily aspirin should be considered. If 
there is a history of venous thrombosis, then systemic anticoagulation can be substituted in place of twice-
daily aspirin. The treatment algorithm was derived and modified from Tefferi A et al. Blood Cancer J 
2018 (13).   
 
 
 
 
 
 
 
*Avoid aspirin therapy in the presence of extreme thrombocytosis and acquired Von Willebrand 
Syndrome. 
 


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APPENDIX III: Disease Progression Criteria 
 
This appendix contains disease progression criteria derived from Savona MR et al. Blood 2015.  
 
Combination of 2 major criteria, 1 major and 2 minor criteria or 3 minor criteria is defined as disease 
progression.  
 
Major Criteria:  
 
• 
Increase in blast count* 
o <5% blasts: >50% increase and to >5% blasts.  
o 5-10% blasts: >50% increase and to >10% blasts. 
o 10-20% blasts: >50% increase and to >20% blasts. 
 
• 
Evidence of cytogenetic evolution**:  
o Appearance of a previously present or new cytogenetic abnormality in complete 
cytogenetic remission via FISH or classic karyotyping. 
o Increase in cytogenetic burden of disease by >50% in partial cytogenetic remission via 
FISH or classic karyotyping.  
 
• 
New extramedullary disease 
 
• 
Worsening splenomegaly: 
o Progressive splenomegaly that is defined by IWG-MRT: the appearance of a previously 
absent splenomegaly that is palpable at .5 cm below the left costal margin or a minimum 
100% increase in palpable distance for baseline splenomegaly of 5-10 cm or a minimum 
50% increase in palpable distance for baseline splenomegaly of 10 cm 
 
• 
Extramedullary disease outside the spleen: To include new/worsening hepatomegaly, 
granulocytic sarcoma, skin lesions, etc. 
 
Minor criteria: 
o Transfusion dependence*** 
o Significant loss of maximal response or cytopenias >50% decrement from maximum  
remission/response in granulocytes  
o Reduction in Hgb by 1.5g/dL from best response or from baseline as noted on complete blood 
count 
o Increasing symptoms as noted by increase in > 50% as per the Myeloproliferative Neoplasm 
Symptom Assessment Form (MPN-SAF) (14) 
o Evidence of clonal evolution**** 
  
*Blast count measured from bone marrow.  
**Increase in cytogenetic burden of disease by ≥ 50% (via FISH or classic karyotyping). Given variability of fluorescent probes 
used in FISH, cytogenetic normalization via FISH will depend on specific probes used. 
***Transfusion dependency is defined by a history of at least 2 units of red blood cell transfusions in the past month for a 
hemoglobin level, 8.5 g/dL that was not associated with clinically overt bleeding. Cytopenias resulting from therapy should not 
be considered in assessment of progression. 
****The identification of new abnormalities using single nucleotide polymorphism arrays or sequencing or a clearly significant 
increase in mutational burden of a previously detected abnormality. Precise criteria for defining new abnormalities and what 
exactly constitutes a significant increase in mutational burden are open to interpretation; we suggest that this criterion should be 
used conservatively based on current evidence. 

ICF_001.pdf: 
 
 
 
 
 
MC200805 
 
Phase II Study to Determine the Efficacy and Safety of 
Luspatercept (ACE-536) in Patients with 
Myelodysplastic/Myeloproliferative Neoplasms with Ring 
Sideroblasts and Thrombocytosis (MDS/MPN-RS-T) and 
Myelodysplastic/Myeloproliferative Neoplasms, Unclassifiable 
with Ring Sideroblasts (MDS/MPN-U with RS) 
 
NCT05005182 
 
 
Document Date: 06/28/2023 


 
 
Approval Date:  
June 28, 2023 
Not to be used after: June 27, 2024 
 
IRB#: 20-013021 00       E-sign  AS 
Page 1 of 24 
IRB Doc. Ctrl # 10013.34 
 
 
 
 
 
 
 
Name and Clinic Number 
RESEARCH PARTICIPANT CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Study Title: MC200805, Phase II study to determine the efficacy and safety of luspatercept 
(ACE-536) in patients with myelodysplastic/myeloproliferative neoplasms with 
ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) and 
myelodysplastic/myeloproliferative neoplasms, unclassifiable with ring 
sideroblasts (MDS/MPN-U with RS)  
 
IRB#:  
20-013021   
 
Principal Investigator: Dr. Abhishek Mangaonkar and Colleagues 
 
 
 
Key Study Information 
 
 
This section provides a brief summary of the study.  It is important for you to understand why 
the research is being done and what it will involve before you decide.  Please take the time to 
read the entire consent form carefully and talk to a member of the research team before 
making your decision.  You should not sign this form if you have any questions that have not 
been answered. 
It’s Your Choice 
This is a research study.  Being in this research study is your choice; 
you do not have to participate.  If you decide to join, you can still stop 
at any time.  You should only participate if you want to do so. You 
will not lose any services, benefits or rights you would normally have 
if you choose not to take part. 
Research Purpose 
You have been asked to take part in this research because you have a 
diagnosis of myelodysplastic/myeloproliferative neoplasms with ring 
sideroblasts and thrombocytosis (MDS/MPN-RS-T) or 
myelodysplastic/myeloproliferative neoplasms, unclassifiable with 
ring sideroblasts (MDS/MPN-U with RS) with low hemoglobin counts 
(anemia) or requiring RBC blood transfusions. 
 
The purpose of this research is to find out more about the safety of 
luspatercept-aamt either with/without hydroxyurea and what doses of 
this combination are safe for people to take and how the disease 
responds to the treatment in MDS/MPN overlap syndromes. Your 


 
 
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Not to be used after: June 27, 2024 
 
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Name and Clinic Number 
doctor may also have you take aspirin as part of standard clinical care 
in combination with the above medications.  
 
The FDA has approved luspatercept-aamt for patients with anemia 
who require RBC transfusions in some 
myelodysplastic/myeloproliferative neoplasms and myelodysplastic 
syndromes, hydroxyurea for chronic myeloid leukemia treatment, and 
aspirin is recommended as treatment for increased risk of cardiac 
events. However, data specifically in MDS/MPN overlap syndromes is 
not robust. Therefore, this study is being conducted.  
What’s Involved 
To see if you can be in the study, you will need to have some 
screening tests and procedures. If you have already had some of these 
done at a recent doctor’s office visit, then the tests may not need to be 
done again  
 
If you are a person of childbearing potential, a pregnancy test will be 
done before you start treatment.  
 
If you qualify for the study, you will receive luspatercept-aamt every 
21 days as an injection. Hydroxyurea is an oral medication and will be 
taken daily as prescribed by the study doctor in one of the groups.  
 
You will receive treatment for about 6 months. During treatment, you 
will return to Mayo Clinic every 21 days except for Cycle 1, you will 
need to return on Days 8 and 15 for blood work and to have your 
blood pressure monitored.  
 
During these visits, your participation also includes physical exams; 
review of your side effects; routine blood tests; bone marrow aspirate 
and biopsies to follow your disease; mandatory research blood tests, 
optional research bone marrow collections and optional questionnaire 
completion. 
 
Both males and females will need to use a highly effective form of 
birth control during study and for 3 months after the last study dose.  
 
These visits are similar to what you would have even if you aren’t on 
the study.  


 
 
Approval Date:  
June 28, 2023 
Not to be used after: June 27, 2024 
 
IRB#: 20-013021 00       E-sign  AS 
Page 3 of 24 
IRB Doc. Ctrl # 10013.34 
 
 
 
 
 
 
 
Name and Clinic Number 
Key Information 
There are risks to the study drug, luspatercept-aamt, that are described 
later in this document. Some of the very common side effects include 
headaches, bone pain, arthralgia, fatigue, cough, abdominal pain, 
diarrhea and dizziness. 
Many side effects go away shortly after treatment is stopped, but in 
some cases side effects can be serious, long lasting problems, or may 
never go away. There may be side effects that are unknown. It is 
important to review the risk section carefully.  
 
While you are on the study, the costs related to this research such as 
the luspatercept-aamt and the research blood collections will be paid 
for by the research study. However, you or your insurance company 
will need to pay for the tests, procedures, and any other medications 
that are a part of standard of care. If you get injured because of study 
participation, we will help you get treatment; however, the costs for 
this care will be billed to you or your insurance.  
 
We do not know whether luspatercept-aamt with/without hydroxyurea 
will make your cancer better or not. What we learn from this study 
will help doctors know more about this drug combination as a 
treatment for MDS/MPN-RS-T or MDS/MPN-U with RS.  
 
You do not need to be in this study to receive treatment for your 
MDS/MPN-RS-T or MDS/MPN-U with RS. Your doctor will discuss 
what your options are. 
Learn More 
If you are interested in learning more about this study, read the rest of 
this form carefully. The information in this form will help you decide 
if you want to participate in this research or not.  A member of our 
research team will talk with you about taking part in this study before 
you sign this form.  If you have questions at any time, please ask us.    
 
 
 
 
 
 
 
 
 


 
 
Approval Date:  
June 28, 2023 
Not to be used after: June 27, 2024 
 
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IRB Doc. Ctrl # 10013.34 
 
 
 
 
 
 
 
Name and Clinic Number 
 
 
Making Your Decision 
 
 
Taking part in research is your decision.  Take your time to decide.  Feel free to discuss the study 
with your family, friends, and healthcare provider before you make your decision.  Taking part in 
this study is completely voluntary and you do not have to participate. 
 
If you decide to take part in this research study, you will sign this consent form to show that you 
want to take part. We will give you either a printed or electronic copy of this form to keep A 
copy of this form will be put in your medical record. 
 
For purposes of this form, Mayo Clinic refers to Mayo Clinic in Arizona, Florida and Rochester, 
Minnesota; Mayo Clinic Health System; and all owned and affiliated clinics, hospitals, and 
entities. 
 
 


 
 
Approval Date:  
June 28, 2023 
Not to be used after: June 27, 2024 
 
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Name and Clinic Number 
 
Contact Information 
 
 
If you have questions about … 
You can contact … 
 Study tests and procedures 
 Materials you receive 
 Research-related appointments  
 Research-related concern or complaint 
 Research-related injuries or emergencies 
 Withdrawing from the research study 
Principal Investigator:  
Dr. Abhishek Mangaonkar  
Phone: (507) 293-7484 
 
Dr. Mrinal Patnaik 
Phone: (507) 293-7814 
 
Institution Name and Address: 
Mayo Clinic Rochester 
200 First Street 
Rochester, MN 55905 
 
Dr. Cecilia Arana Yi 
Phone: (480) 342-0195 
 
Institution Name and Address: 
Mayo Clinic Hospital  
13400 E. Shea Boulevard  
Phoenix, AZ 85259 
 
Dr. Hemant Murthy 
Phone: (904) 953-2795 
 
Institution Name and Address: 
Mayo Clinic  
4500 San Pablo Road  
Jacksonville, FL 32224 
 Rights of a research participant 
Mayo Clinic Institutional Review Board 
(IRB)  
Phone: (507) 266-4000 
Toll-Free: (866) 273-4681 
 
 


 
 
Approval Date:  
June 28, 2023 
Not to be used after: June 27, 2024 
 
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Name and Clinic Number 
If you have questions about … 
You can contact … 
 Rights of a research participant 
 Any research-related concern or complaint 
 Use of your Protected Health Information 
 Stopping your authorization to use your 
Protected Health Information 
 Withdrawing from the research study 
Research Participant Advocate (RPA) 
(The RPA is independent of the Study 
Team) Phone: (507) 266-9372 
Toll-Free: (866) 273-4681 
 
E-mail:  
researchparticipantadvocate@mayo.edu 
 Billing or insurance related to this research 
study 
Patient Account Services 
Toll-Free: (844) 217-9591  
 
Other Information:  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov and 
https://www.mayo.edu/research/clinical-trials as required by U.S. Law. These Web sites will not 
include information that can identify you. At most, the Web sites will include a summary of the 
results. You can search these Web sites at any time. 
 
A description of this research study will be available on http://www.MayoClinic.org . This 
website will not include information that can identify you. You can search this website at any 
time. 
 
 
Why are you being asked to take part in this research study? 
 
 
You are being asked to take part in this research study because you have a diagnosis of 
myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis 
(MDS/MPN-RS-T) or myelodysplastic/myeloproliferative neoplasms, unclassifiable with ring 
sideroblasts (MDS/MPN-U with RS) with low hemoglobin counts (anemia) or requiring RBC 
blood transfusions.  
 
This study is being conducted at Mayo Clinic only. The plan is to have up to 33 people take part 
in this study at Mayo Clinic. 
 
 
 


 
 
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June 28, 2023 
Not to be used after: June 27, 2024 
 
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Name and Clinic Number 
 
Why is this research study being done? 
 
 
In this study we want to find out more about the side effects of a new drug combination for 
MDS/MPN-RS-T and MDS/MPN-U with RS, luspatercept-aamt with or without hydroxyurea 
and what doses of this combination are safe for people to take and how the disease responds to 
the treatment. There are 2 groups of patients being studied in this trial. One group of patients will 
receive luspatercept-aamt. The other group will receive luspatercept-aamt and hydroxyurea. 
Your study doctor will let you know which group you will be in.  
 
Luspatercept-aamt is approved by the U.S. Food and Drug Administration (FDA) for patients 
with anemia who require RBC blood transfusions with very low- to intermediate-risk MDS-RS 
or with MDS/MPN-RS-T. Hydroxyurea is FDA approved for treatment of resistant chronic 
myeloid leukemia. This drug combination is still experimental and isn’t approved by the U.S. 
Food and Drug Administration (FDA). However, the FDA has allowed the use of this drug 
combination in this research study.  
 
 
Information you should know 
 
 
Who is Funding the Study? 
Bristol Myers Squibb (BMS) is funding the study. They will pay the institution for the research 
costs related to running the study.  
 
Information Regarding Conflict of Interest: 
Your healthcare provider may be referring you to this research study. If your healthcare provider 
is also an investigator on this study, there is the chance that his or her responsibilities for the 
study could influence his or her recommendation for your participation.  If you prefer, your 
healthcare provider will be happy to refer you to another investigator on the research study team 
for you to decide if you want to participate in the study and to see you for the research study 
activities while you are in the study.  
 
 
 


 
 
Approval Date:  
June 28, 2023 
Not to be used after: June 27, 2024 
 
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Name and Clinic Number 
 
How long will you be in this research study? 
 
 
It will take you about 1.5 years to complete this research study, but the investigational agent 
(luspatercept-aamt) will only be given for 24 weeks. During treatment, we will ask you to make 
12 study visits to Mayo Clinic. When you complete your treatment, if your disease gets worse, or 
if you have too many side effects, we will monitor your health by reviewing your medical record, 
contacting you, or contacting your physician every 3 months until 1.5 years from the time you 
enrolled on to the study.  
 
 
What will happen to you while you are in this research study? 
 
 
If you agree to be in this study, you will receive up to 8 cycles of treatment with luspatercept-
aamt, with or without hydroxyurea. Your study doctor will let you know which group you will be 
placed in.  Your doctor may also have you take aspirin as part of standard clinical care in 
combination with the study medications. 
 
During the Screening visit, we will do some tests and procedures to see if you are eligible to take 
part in the research study. Your doctor will review the results of these tests and procedures. If 
you are not eligible, your doctor will tell you why. At this visit, we will:  
• Ask you about your medical history 
• Give you a physical exam, including height, weight, and blood pressure 
• Ask you about your activity level, symptoms, and medications 
• Draw routine blood tests to check your hematology and chemistry blood counts, Von-
Willebrand factor activity to check for risk of bleeding, erythropoietin (EPO) level, 
ferritin to check iron level, and Human Immunodeficiency Virus (HIV) screen  
• Draw a pregnancy test, if you are a person of childbearing potential 
• Bone marrow biopsy and aspirate 
 
If you have already had some of these tests and procedures as part of regular cancer care, it may 
not be necessary for them to be done again. Your doctor will let you know. 
 
If the HIV test result is positive, it is the state law that they be reported to the State Department 
of Health. If your test returns positive, the researcher will tell you how to find medical help and 
counseling, as needed. The test results will also be put in your medical record.  


 
 
Approval Date:  
June 28, 2023 
Not to be used after: June 27, 2024 
 
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Name and Clinic Number 
{{$QNS1Y}} 
{{$QNS1N}}
{{$QNS1IN}} 
{{$QNS1D                                                                                                    }} 
{{$QNS2Y}} 
{{$QNS2N}} 
{{$QNS2IN}} 
{{$QNS2D                                                                                                  }} 
You may need further testing and you may not be able to take part in the study. Your health 
insurer or you will have to pay for the cost of the repeat test, any follow-up medical care, or 
counseling. 
 
If you are eligible for the study, the following will be done for research purposes to help us find a 
blood biomarker that shows response to luspatercept-aamt. 
 
• Mandatory research blood tests (50 mLs (about 3.5 tablespoons)) will be collected. 
• Optional bone marrow aspirate (20 mLs (about 1.5 tablespoons)) will be kept only if 
there is enough left from the clinical aspirate sample. An additional bone marrow 
procedure will not be done.  
 
Tests done only for research purposes are not meant to provide clinical information or help care 
for you. The results are only important for research. Therefore, the results of tests done with your 
information and samples will not be provided to you. In the rare event that a finding might affect 
the health of you or your family, we will contact you and you can choose whether to receive or 
refuse the information. If you decide to follow up and further medical testing or care is needed, 
the costs will be billed to you or your insurance. 
 
Please read the following statement and mark your choice: 
 
If there is enough bone marrow aspirate left from the clinical bone marrow procedure, I 
permit my sample to be used for research for this study:  
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
Questionnaires: 
During this study, we will ask you to fill out a questionnaire about physical, social, and 
emotional health (including treatment side effects or symptoms). The questionnaire will be given 
to you at the study visit for each new cycle of treatment and at Week 25. It can either be 
completed in person or it can be sent electronically to you. This questionnaire is optional, 
meaning you do not need to participate in this to be in the study. If you agree to participate, we 
hope that you will answer all of the questions, but you can skip any questions you don’t want to 
answer. The questionnaires will take about 5-10 minutes to complete. 
 
Please indicate below if you agree to complete questionnaires for this study:  
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
Day 1 of each treatment cycle will be given in the outpatient treatment area. Each cycle is 21 
days. Luspatercept-aamt is given by inserting a needle under your skin, called subcutaneous 


 
 
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injection. Hydroxyurea are taken daily by mouth (oral) while you are on the study. You will be 
given a prescription for hydroxyurea.  
 
During Treatment: 
Prior to Cycles 1-8, Day 1, we will: 
• For Cycle 1, collect a urine or blood pregnancy test, if you are a female of childbearing 
potential and the screening pregnancy test was done more than 72 hours prior to the first 
treatment. For all other cycles, either a urine or blood pregnancy test will be collected. 
• Give you a physical exam, including taking your weight, and blood pressure 
• Ask you about your activity level, symptoms/side effects, and medications 
• Ask you to complete a questionnaire, if you agreed to this 
• Draw routine blood tests to check your hematology and chemistry blood counts,  
• Give you the luspatercept-aamt injection. 
• If you are receiving hydroxyurea, we will give you a medication diary for you to 
complete and return at your next doctor’s visit. A member of the study team will explain 
this to you.  
 
At Cycle 1 Day 8 and 15, we will: 
• Check your blood pressure 
• Draw hematology blood counts 
 
At Week 25 visit, we will:  
• Collect a urine or blood pregnancy test, if you are a female of childbearing potential  
• Give you a physical exam, including taking your weight, and blood pressure 
• Ask you about your activity level, symptoms, and medications 
• Draw routine blood tests to check your hematology and chemistry blood counts, and 
ferritin to check iron level 
• Draw mandatory research blood tests (50 mL (about 3.5 Tablespoons)) 
• Ask you to complete a questionnaire, if you agreed to this 
• Your disease status will be assessed by your study doctor 
• Collect the completed medication diary.  
 
 
What are the possible risks or discomforts from being in this research study? 
 
 
You may have side effects while on study. We do not know all of the side effects caused by 
luspatercept-aamt, or side effects when it is used with hydroxyurea. Side effects may range from 
mild to life- threatening. Many side effects go away shortly after the treatment is stopped, but in 


 
 
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some cases side effects can be serious, long lasting problems, or may never go away. Rarely, side 
effects could cause death. As with any medication, allergic reactions are possible. Other drugs 
may be given to make side effects less serious and less uncomfortable. Talk to the researcher 
and/or your healthcare provider about side effects you are having and ask any other questions.  
 
Risks and side effects of luspatercept-aamt (ACE-536) include:  
Increases in red blood cell count, hemoglobin and hematocrit are expected with treatment of 
luspatercept-aamt. This may result in an increase in your blood pressure. Both your red blood 
cell count and your blood pressure will be monitored by your study doctor during the study.  You 
may have a delay or reduction in study drug dosing to minimize this risk. 
 
Luspatercept-aamt will be given as an injection (shot) under the skin.  As with any drug given 
this way, you may have redness, bruising, or slight swelling at the injection site.  In healthy 
people, bleeding and /or a darker colored skin at the injection site were noticed. You may feel 
some pain when the needle is inserted into the skin or afterwards. Although it does not happen 
often, you could faint or get an infection at the place the needle is inserted. 
 
Adults in ongoing studies noticed the following side effects: 
 
Very common side effects - these happen in at least 1 out of 10 patients:  
• Diarrhea  
• Feeling sick to the stomach (Nausea) 
• Feeling weak and having no energy (Asthenia) 
• Feeling tired (Fatigue) 
• Lung inflammation (Bronchitis) 
• Cold symptoms such as stuffy nose, sneezing, runny nose (rhinitis), sore throat, cough 
(Upper respiratory tract infection) 
• Urinary tract infection 
• Joint pain (Arthralgia) 
• Muscle pain (Myalgia) 
• Pain in bone (Bone pain) 
• Back pain 
• Dizziness  
• Pain in the head (Headache) 
• Shortness of breath (Dyspnea) 
• Fever (Pyrexia) 
• Pain in mouth and throat (Oropharyngeal pain) 
• Nose and throat pain (Nasopharyngitis) 
 


 
 
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Less common side effects - these happen in at least 5 out of 100 people but less than 1 out of 
10 people: 
• Feeling of spinning or whirling (Vertigo, Vertigo Positional) 
• Redness, itching, swelling and/or rash at the injection site (Injection site reactions) 
• Allergic reaction (Hypersensitivity) 
• Flu (Influenza) 
• Fainting (Syncope, Presyncope) 
• High blood pressure (Hypertension) 
• Excess amount of uric acid in the blood (gout) which can cause pain in the joints as well 
as decrease kidney function (Hyperuricaemia) 
• Swelling in legs or arms (Peripheral edema) 
• Unexplained pain 
• Blood clots (Venous or arterial thrombosis/embolism) 
• Cardiovascular events including heart attacks (myocardial infarction) or strokes 
 
Risks and side effects of hydroxyurea include: 
Hydroyxurea will also be used in combination with luspatercept-aamt. Most common adverse 
reactions (>30%) are hematological (blood count abnormalities), gastrointestinal symptoms 
(sores in mouth (stomatitis), nausea, vomiting, diarrhea, constipation), and anorexia (loss of 
appetite). It is possible some of these adverse reactions may be increased in combination with 
luspatercept-aamt. 
 
In the post-marketing phase, following adverse reactions have been reported with hydroxyurea.  
 
• Azoospermia and Oligospermia (sperm count abnormalities) 
• Stomatitis (sores in mouth)  
• Nausea  
• Vomiting  
• Diarrhea 
• Constipation 
• Anorexia (loss of appetite) 
• Skin abnormalities such as maculopapular rash, skin ulceration, cutaneous lupus, 
erythematosus, dermatomyositis-like skin changes, peripheral and facial erythema, 
hyperpigmentation and nail hyperpigmentation (increase skin and nail pigmentation or 
skin discoloration), atrophy of skin and nails (skin and nail tearing and breakdown), 
scaling (dry, flakiness), violet papules (skin changes), alopecia (hair loss) 
• Dysuria (pain with urination),  
• Increase levels of uric acid, urea nitrogen (BUN) and creatine in your blood 
• Headache,  


 
 
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• Dizziness,  
• Drowsiness,  
• Disorientation,  
• Hallucinations, 
• Convulsions 
• Fever 
• Chills  
• Malaise  
• Edema   
• Asthenia (fatigue) 
• Elevation of hepatic enzymes,  
• Cholestasis (blockage of bile ducts) 
• Hepatitis (inflammation of the liver) 
• Lung abnormalities such as diffuse pulmonary infiltrates, dyspnea (shortness of breath), 
pulmonary fibrosis, interstitial lung disease, pneumonitis, alveolitis, allergic alveolitis, 
cough 
• Systemic lupus erythematosus (an autoimmune disorder) 
• Drug-induced fever (pyrexia) (>39°C, >102°F) requiring hospitalization has 
been reported concurrently with gastrointestinal, pulmonary, musculoskeletal, 
hepatobiliary, dermatological or cardiovascular manifestations.  
Onset typically occurred within 6 weeks of initiation and resolved upon discontinuation 
of hydroxyurea. Upon re-administration, fever reoccurred typically within 24 hours. 
 
During this study, you will be closely watched for side effects; also your study doctor will 
perform routine check-ups on you. 
 
In other adult luspatercept-aamt studies treating B-Thal (not treating MDS or MF), blood clots 
occurred in veins or arteries.  Blood clots are common in subjects with B-Thal which means that 
blood clots occur between 1 and 10 of 100 subjects. Examples are blood clots in the limb, 
abdominal veins, the lungs or brain blood vessels. In the B-Thal BELIEVE study, some subjects 
had blood clots. These subjects had two or more risks such as removed spleen, increased number 
of cells that cause clotting (platelets), sex hormone therapy, and smoking. Subjects taking 
luspatercept-aamt (about 3 to 4 out of 100 subjects) had more blood clots than those taking 
placebo (about 1 out of 100 subjects). Please speak with your study doctor and discuss if you are 
at risk of clotting and ways to reduce this risk. 
 
In a luspatercept-aamt study done in very young rats, cancers were found in a few rats given 
higher doses than used in humans. In similar studies done in adult rats and monkeys, no cancers 
caused by luspatercept-aamt were found; however, the importance of this finding to people is not 
yet known. 


 
 
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Risks Associated with Pregnancy  
The risks to an unborn child (fetus) or nursing child from luspatercept-aamt are not known at this 
time. 
 
In animal studies, luspatercept-aamt was harmful to the development of the unborn. So, females 
who can get pregnant must have a negative urine or blood pregnancy test to confirm they are not 
pregnant; this test must be done before and during their involvement in any study with this drug. 
 
If you are a woman:  
If you are pregnant, planning to become pregnant, or you are nursing a baby, you cannot take 
part in this study. If you are able to get pregnant, the study doctor will recommend best choices 
for, as well as the correct use of birth control methods.  This is to make sure there is effective 
prevention of pregnancy while on the study.  Your chosen form of birth control must be the best, 
most highly effective method, by the time you receive your first dose of study drug.  For 
example, birth control pills should be started at least 28 days before your first dose of study drug.  
If you are able to become pregnant, you will have repeat pregnancy tests during the study.  
 
If you have sexual activity that could cause a pregnancy, you must use one of the best birth 
control choices while taking the study drug. This includes at times of dose delays or interruptions 
and for at least 12 weeks after your last dose of study drug. 
 
Approved choices (options) for highly effective birth control are any one of the following: 
• hormonal contraception (for example, birth control pills, injection, implant, 
transdermal patch, vaginal ring);  
• intrauterine device (IUD);  
• tubal ligation (tying your tubes); or 
• a partner with a vasectomy  
 
During the study, you must tell the study doctor and speak with the study doctor or study nurse 
about other birth control choices if:  
• your birth control method changes 
• you experience a problem with your current birth control method, or  
• your ability to become pregnant changes (for example, you have an IUD removed, 
accidently miss taking any of your birth control pills, or stop menstruation/enter 
menopause) 
 
If you think you have become pregnant during the study or within 12 weeks of the last dose of 
study drug, you must tell the study doctor right away. Your study doctor must then require you to 
stop taking the study drug. Also, your study doctor will check on you during the pregnancy and 


 
 
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will ask you questions about the pregnancy.  The study doctor will from time to time check on 
the progress of the pregnancy and final outcome of it. 
 
If you are a man (including those who have had a vasectomy):  
You must use a male latex condom or non-latex condom during sex to stop a pregnancy. 
• at any time while you are taking the study drug,  
• during dose delays or interruptions, or 
• for at least 12 weeks after you take the last dose of study drug.   
Non latex condom must NOT be made out of natural (animal) membrane; it should be made out 
material such as polyurethane. If you have any questions about this information, please ask your 
study doctor.  
 
You should tell the study doctor right away, if you have a female partner who becomes pregnant, 
• at any time while you are taking the study drug OR 
• within 12 weeks after your last dose of study drug 
 
Your study doctor will ask if the results from checkups during and after your partner’s pregnancy 
can be shared with them and the sponsor. This information will help them understand the drug’s 
safety. Your partner does not need to provide details about her pregnancy unless she agrees to do 
so. 
 
Other Research Related Risks:  
 
Genetic Testing 
This study may involve testing your DNA, which is the genetic information you inherited from 
your parents (also known as genetic testing). This testing may include whole exome, RNA or 
targeted sequencing. These tests generate a large amount of information that may provide, now 
or in the future, important insights into your health as well as the health of your biologic family 
members. You will not be notified of the genetic test results and they will not be put into your 
medical record.  
 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes 
it illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. This law generally will protect you in the 
following ways:  
• Health insurance companies and group health plans may not request your genetic 
information that we get from this research.  
• Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums.  


 
 
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• Employers with 15 or more employees may not use your genetic information when 
making a decision to hire, promote, or fire you or when setting the terms of your 
employment 
 
All health insurance companies and group health plans must follow this law.  
 
Be aware that this new Federal law doesn’t protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance. 
 
Blood Draw Risks  
The risks of drawing blood include pain, bruising, lightheadedness, and/or fainting, or rarely, 
infection at the site of the needle stick.  
 
Discomfort with Answering Questionnaires: 
Some questions you will be asked to answer in the study questionnaires may make you feel 
uncomfortable. You may choose not to answer any questions that make you feel uncomfortable. 
 
Standard of Care Risks 
Your doctor will discuss the risks of routine blood tests, bone marrow aspirate and biopsies, side 
effects of hydroxyurea as these tests and procedures are part of your standard clinical care. 
 
Taking Other Medications 
Use of other drugs might result in serious or even life-threatening reactions. Because of this, you 
should tell your study doctor about your use of alcohol or any other drugs (over-the-counter, 
drugs order by your doctor, illegal, herbs, or vitamins) while in this study.   
 
Additional costs  
Taking part in this research study may lead to added costs to you. In some cases, insurance will 
not pay for services ordinarily covered because these services were performed in a research 
study. You should check with your insurance company to see what services will be covered and 
what you will be responsible to pay. 
 
Confidentiality 
As with all research, there is a chance that confidentiality could be compromised; however, we 
take precautions to minimize this risk.  
 
 


 
 
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Are there reasons you might leave this research study early? 
 
 
Taking part in this research study is your decision. You may decide to stop at any time. You 
should tell your doctor if you decide to stop and you will be advised whether any additional tests 
may need to be done for your safety. 
 
In addition, the researchers, the company supplying drug and funding, or Mayo Clinic may stop 
you from taking part in this study at any time:  
• if it is in your best interest,  
• if you do not follow the study rules,  
• if the study is stopped.  
 
If you leave this research study early, or are withdrawn from the study, no more information 
about you will be collected; however, information already collected about you in the study may 
continue to be used. 
 
We will tell you about any new information that may affect your willingness to stay in the 
research study. 
 
 
What if you are injured from your participation in this research study? 
 
 
Where to get help: 
If you think you have suffered a research-related injury, you should promptly notify the Principal 
Investigator listed in the Contact Information at the beginning of this form. Mayo Clinic will 
offer care for research-related injuries, including first aid, emergency treatment and follow-up 
care as needed. 
 
Who will pay for the treatment of research related injuries? 
Care for such research-related injuries will be billed in the ordinary manner, to you or your 
insurance.  You will be responsible for all treatment costs not covered by your insurance, 
including deductibles, co-payments and coinsurance. 
 
 


 
 
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What are the possible benefits from being in this research study? 
 
 
Taking part in this study may not make your MDS/MPN-RS-T or MDS/MPN-U with RS better. 
While doctors hope that the experimental treatment in this study will be more useful against 
MDS/MPN-RS-T or MDS/MPN-U with RS compared to the usual treatment, there is no proof of 
this yet. We do know that the information from this study will help doctors learn more about the 
combination of luspatercept-aamt and hydroxyurea as a treatment for MDS/MPN-RS-T or 
MDS/MPN-U with RS. This information could help future patients. 
 
 
What alternative do you have if you choose not to participate in this  
research study? 
 
 
You don’t have to be in this study to receive treatment for your condition. Your other choices 
may include other investigational therapies, and other treatment options as deemed necessary by 
your clinician such as lenalidomide, hypomethylating agents, immunosuppressive drugs among 
others.  Talk to the Principal Investigator or your doctor if you have any questions about any of 
these treatments or procedures. 
 
 
What tests or procedures will you need to pay for if you take part in this  
research study? 
 
 
You won’t need to pay for tests and procedures which are done just for this research study.  
These tests and procedures are: 
• Collection, processing, and analyzing of research blood tests 
• Analyzing of research bone marrow samples 
• Study drug: Luspatercept-aamt 
• Luspatercept-aamt injection 
• Pregnancy tests, if you are a person of childbearing potential 
• HIV screening test, and a CD4 count, if needed 
 
However, you and/or your insurance will need to pay for all other tests and procedures that you 
would have as part of your clinical care.  You and/or your insurance might also have to pay for 
other drugs or treatments given to help control side effects. These tests and procedures are: 


 
 
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• Physical exams 
• Routine blood tests such as hematology and chemistry tests, Von-Willebrand factor 
activity, EPO and ferritin levels  
• Bone marrow aspirate and biopsy 
• Hydroxyurea medication 
 
You will also be responsible for any co-payments and deductibles.  
 
If you have billing or insurance questions call Patient Account Services at the telephone 
number provided in the Contact Information section of this form. 
 
 
Will you be paid for taking part in this research study? 
 
 
You won’t be paid for taking part in this study. 
 
There is a very small chance that some commercial value may result from the use of your 
sample. This could include new products like a drug or a test to diagnose a disease. If that 
happens, you will not be offered a share in any profits. 
 
 
Will your information or samples be used for future research? 
 
 
Unless you give your permission below, your information or samples collected for this study will 
not be used or shared for future research, even if the identifiable information such as your name, 
Mayo Clinic number or date of birth is removed. 
 
We would like to keep your information and samples for future research. You can still take part 
in this current study even if you don’t want your information or samples used for future research.  
 
Researchers at Mayo Clinic who aren’t involved with this study may ask to use your information 
and/or samples for future research. Researchers at other institutions may also ask for a part of 
your information and/or samples for future studies. Unless you indicate otherwise, the future 
research may be on any topic. No direct benefits to you are expected from the future research. 
Your information and/or samples will only be shared consistent with your consent, and with all 
applicable laws and regulations.   
 


 
 
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{{$QNS3Y}} 
{{$QNS3N}}
{{$QNS3IN}} 
{{$QNS3D                                                                                                     }} 
{{$QNS4Y}} 
{{$QNS4N}}
{{$QNS4IN}} 
{{$QNS4D                                                                                                     }} 
{{$QNS5Y}} 
{{$QNS5N}}
{{$QNS5IN}} 
{{$QNS5D                                                                                                     }} 
If you approve release of your information and/or samples by checking ‘yes’ below, Mayo may 
send the information and/or samples to researchers who request them, but Mayo will not send 
your name, address, phone number, social security number, or any other identifying information 
with the information and/or samples. Your information and/or samples may be sent with a code, 
and only the researchers for this study at Mayo Clinic would be able to link the code to you. 
 
Some future studies may examine your DNA, the genetic information you inherited from your 
parents (genetic testing). If there are findings which may be useful for your health care, the 
researchers may contact Mayo Clinic, so Mayo Clinic can give you the option of learning the 
results. You would be given general information on the potential risks, benefits, and costs of 
choosing to learn about the findings.   
 
To support future research, de-identified genetic information may be placed in databases 
accessible by the internet. Some of the information may be available to anyone using the 
internet, and some will be released only to approved researchers. Combined study information 
(including genomic summary results) may be published, but the information will not identify 
you.  
 
Even though information traditionally used to identify you will not be shared, people may 
develop ways in the future to allow someone to link your genetic information back to you. For 
this reason, confidentiality cannot be guaranteed.  
It is also possible that reidentified information could be used in discriminating ways, and there 
could be additional unknown risks. We will make every effort to protect your confidentiality. 
 
Please read the following statements and mark your choices: 
 
I permit my information and samples to be stored and used in future research of MDS/MPN-
RS-T and MDS/MPN-U with RS at Mayo Clinic: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
I permit my information and samples to be stored and used in future research at Mayo Clinic 
to learn about, prevent, or treat any other health problems: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
I permit Mayo Clinic to give my information and samples to researchers at other institutions: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 


 
 
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You may withdraw your consent for future use of your information and/or samples at any 
time, by writing to the Principal Investigator at the address provided in the “Contact 
Information" section of this consent form. 
 
Your information and/or samples would be removed from any repository where they are stored, 
if possible. Information and/or samples already distributed for research use will not be retrieved.  
 
 
How will your privacy and the confidentiality of your records be protected? 
 
 
Mayo Clinic is committed to protecting the confidentiality of information obtained about you in 
connection with this research study. Information collected during the study will be coded and 
stored in a room with restricted access and/or on a computer that is password protected. If the 
results of the research are made public, information that identifies you will not be used. 
 
During this research, information about your health will be collected.  Under Federal law called 
the Privacy Rule, health information is private.  However, there are exceptions to this rule, and 
you should know who may be able to see, use and share your health information for research and 
why they may need to do so.   
Information about you and your health cannot be used in this research study without your written 
permission.  If you sign this form, it will provide that permission (or “authorization”) to Mayo 
Clinic. 
 
Your health information may be collected from: 
• Past, present and future medical records. 
• Research procedures, including research office visits, tests, interviews and 
questionnaires. 
 
Your health information will be used and/or given to others to: 
• Do the research. 
• Report the results. 
• See if the research was conducted following the approved study plan, and applicable rules 
and regulations. 
 
Your health information may be used and shared with: 
• Mayo Clinic research staff involved in this study.  
• Bristol Myers Squibb/CELGENE, the company providing luspatercept-aamt and funding 
for this study.  
• Public health agencies, if necessary, to complete health reporting requirements 


 
 
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• The Mayo Clinic Institutional Review Board that oversees the research.  
• Federal and State agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health and other United States 
agencies) or government agencies in other countries that oversee or review research. 
• A group that oversees the data (study information) and safety of this research. 
 
How your information may be shared with others: 
While taking part in this study, you will be assigned a code that is unique to you, but does not 
include information that directly identifies you. This code will be used if your study information 
is sent outside of Mayo Clinic. The groups or individuals who receive your coded information 
will use it only for the purposes described in this consent form. 
 
If the results of this study are made public (for example, through scientific meetings, reports or 
media), information that identifies you will not be used. 
 
In addition, individuals involved in study oversight and not employed by Mayo Clinic may be 
allowed to review your health information included in past, present, and future medical and/or 
research records. This review may be done on-site at Mayo Clinic or remotely (from an off-site 
location). These records contain information that directly identifies you.  
However, the individuals will not be allowed to record, print, copy (using paper, digital, 
photographic or other methods), or remove your identifying information from Mayo Clinic. 
 
Is your health information protected after it has been shared with others? 
Mayo Clinic asks anyone who receives your health information from us to protect your privacy; 
however, once your information is shared outside Mayo Clinic, we cannot promise that it will 
remain private and it may no longer be protected by the Privacy Rule. 
 
 
Your Rights and Permissions 
 
 
Participation in this study is completely voluntary. You have the right not to participate at all.  
Even if you decide to be part of the study now, you may change your mind and stop at any time.  
You do not have to sign this form, but if you do not, you cannot take part in this research study. 
 
Deciding not to participate or choosing to leave the study will not result in any penalty.  Saying 
‘no’ will not harm your relationship with your own doctors or with Mayo Clinic. 
 


 
 
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If you cancel your permission for Mayo Clinic to use or share your health information, your 
participation in this study will end and no more information about you will be collected; 
however, information already collected about you in the study may continue to be used. 
 
You can cancel your permission for Mayo Clinic to use or share your health information at any 
time by sending a letter to the address below: 
 
Mayo Clinic 
Office for Human Research Protection 
ATTN:  Notice of Revocation of Authorization 
201 Building 4-60 
200 1st Street SW 
Rochester, MN  55905 
 
Alternatively, you may cancel your permission by emailing the Mayo Clinic Research 
Participant Advocate at: researchparticipantadvocate@mayo.edu 
 
Please be sure to include in your letter or email: 
• The name of the Principal Investigator, 
• The study IRB number and /or study name, and 
• Your contact information. 
 
Your permission for Mayo Clinic to use and share your health information lasts forever, unless 
you cancel it. 
 
There is no expiration or end date related to the Sponsor’s use of your health information 
received from Mayo Clinic as part of this study. 
 
 
 


 
 
Approval Date:  
June 28, 2023 
Not to be used after: June 27, 2024 
 
IRB#: 20-013021 00       E-sign  AS 
Page 24 of 24 
IRB Doc. Ctrl # 10013.34 
 
 
 
 
 
 
 
Name and Clinic Number 
{{$prtPartName                                          }} 
{{$dteParticipantSig                                }} 
{{!$sigWitness}} 
{{$sigParticipant                    }} 
{{$prtPOCName                                       }} 
{{$dtePOCSig                                        }} 
{{$sigPOC                                 }} 
 
Enrollment and Permission Signatures 
 
 
Your signature documents your permission to take part in this research.  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
Printed Name  
 
 
Date (mm/dd/yyyy) 
 
 
Time (hh:mm am/pm)  
 
 
 
 
 
 
 
 
_______________________________ 
Signature 
 
 
 
Person Obtaining Consent  
• I have explained the research study to the participant. 
• I have answered all questions about this research study to the best of my ability. 
 
 
 
Printed Name  
 
 
Date (mm/dd/yyyy) 
 
 
Time (hh:mm am/pm) 
 
 
_______________________________ 
Signature