Imetelstat Sodium in Treating Participants With Primary or Secondary Myelofibrosis

For this pilot study, overall response was defined as achievement of a leukemic response (i.e. a clinically meaningful reduction in Blast cells). This was quantified as \<5% peripheral blood and bone marrow blasts % that lasts for at least two months. Data is reported separately for this arm where response was assessed by this specific criterion.

Time frame: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm D)

Population: All Treated Analysis Set included all participants who received at least one dose of study drug. Data is reported for Arm D: Imetelstat 9.4 mg/kg (Blastic MF/AML) participants whose overall response was assessed by a specific criterion.

OR: HI/PR/CR per IWG. CR: BM:≤5% myeloblasts (all cell lines normal maturation), Peripheral blood:Hgb ≥11g/dL, PLTs ≥100x10\^9/L, Neutrophils ≥1.0x10\^9/L, Blasts 0%. PR: All CR criteria if abnormal before treatment except- BM blasts decreased ≥50% over pretreatment but still \>5%, Cellularity, morphology not relevant. HI responses:1) Erythroid: Hgb increase ≥1.5 g/dL, Relevant reduction of red blood cell(RBC) units transfusions by absolute ≥4 RBC transfusions/8 week (wk) compared with pretreatment transfusion number in previous 8 wk. Only RBC transfusions given for Hgb of ≤9.0 g/dL.2)PLTs:Absolute increase ≥30x10\^9/L starting \>20x10\^9/L PLTs; Increase from \<20x10\^9/L to \>20x10\^9/L and by ≥100%; 3)Neutrophil: ≥100% increase, absolute increase \>0.5x10\^9/L; 4)Progression/relapse after HI:≥1 of following:≥50% decrement from maximum response levels in granulocytes/PLTs, Reduction in Hgb ≥1.5 g/dL,Transfusion dependence. Data is reported separately for arm whose response was assessed per IWG.

Time frame: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm G)

Population: All Treated Analysis Set included all participants who received at least one dose of the study drug. Data is reported for Arm G: Imetelstat 9.4 mg/kg (MDS/MPN or MDS and spliceosome mutations or ring sideroblasts) participants whose overall response was assessed by IWG criteria.

OR:CI/PR/CR per IWG-MRT. CR:Bone marrow (BM):\<5% blasts;≤Grade 1 MF, AND Peripheral blood:Hemoglobin (Hb) ≥100 g/liter (g/L) and \<upper normal limit (UNL);Neutrophil count(NC) ≥1x10\^9/L and \<UNL; Platelet(PLT) count ≥100x10\^9/L and \<UNL;\<2% immature myeloid cells(IMCs), AND Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence of extramedullary hematopoeisis(EMH). PR:All CR criteria plus peripheral blood: Hb≥85 but \<100g/L and \<UNL; NC ≥1x10\^9/L and \<UNL; PLT count ≥50 but \<100x10\^9/L and \<UNL;\<2%IMCs. CI:achievement of anemia (≥20 g/L increase in Hb level), spleen(baseline splenomegaly palpable at 5-10 cm, below left costal margin(LCM), becomes not palpable), symptoms response (50% reduction in total symptom score) without progressive disease (PD) (appearance of new splenomegaly- palpable at least \[≥\]5 cm below LCM)/increase in severity of anemia, thrombocytopenia/neutropenia. Data is reported separately for arms whose response was assessed per IWG-MRT.

Time frame: Up to first 9 cycles of treatment (each cycle was of 21 days for Arms A and B and 28 days for Arms E and F)

Population: Eligible Analysis Set included subset of all participants who received at least one dose of study drug that excludes ineligible participants who did not satisfy each and every eligibility criteria for study entry. Data is reported for arm groups (Arms A, B, E and F) whose overall response was assessed by IWG-MRT criteria.

DOR was measured from the time of initial response until documented disease progression or death whichever occurs first. If no PD/death occurs the DOR is censored at last disease evaluation date for responders. Response is defined as achievement of \<5% peripheral blood and bone marrow blast % that lasts for at least two months. PD is the appearance of new splenomegaly that is palpable at least 5 cm below the LCM. Data is reported separately for arm whose DOR was assessed by a specific criterion. Kaplan-Meier method was used.

Time frame: From time of initial response until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)

Population: All Treated Analysis Set included all participants who received at least one dose of the study drug. Data is reported for Arm D: Imetelstat 9.4 mg/kg (Blastic MF/AML) participants whose DOR was assessed by a specific criterion. Only responders were analyzed for this outcome measure.

Time to response was defined as the duration from study Day 1 to the earliest date that a response is first documented. Response was defined as achievement of a leukemic response (i.e. a clinically meaningful reduction in Blast cells). This was quantified as \<5% peripheral blood and bone marrow blasts % that lasts for at least two months. Data for time to response is reported as per criteria of response assessment.

Time frame: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)

Population: All Treated Analysis Set included all participants who received at least one dose of the study drug. Only responders were analyzed for this outcome measure. Data is reported for Arm D: Imetelstat 9.4 mg/kg (Blastic MF/AML) participants whose overall response was assessed by a specific criterion.

DOR: time of initial response (CR/PR/HI) until documented PD/death whichever occurs first. If no PD/death occurs DOR is censored at last disease evaluation date for responders. Data reported separately for arm assessed per IWG. Kaplan-Meier method was used.

Time frame: From the time of initial response (CR/PR/HI) until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)

Population: All Treated Analysis Set included all participants who received at least one dose of the study drug. Data is reported for Arm G: Imetelstat 9.4 mg/kg (MDS/MPN or MDS and spliceosome mutations or ring sideroblasts) participants whose DOR was assessed by IWG criteria. Only responders were analyzed for this outcome measure.

Transfusion dependency was defined by a history of at least 2 units of red blood cell transfusions in the last month for a hemoglobin level of less than 85 g/L that was not associated with clinically overt bleeding. A participant who was transfusion dependent at baseline was considered transfusion independent if the participant met either of the following conditions: Received no more than 1 unit of red blood cell transfusions in a rolling time interval of 30 days or more, and had a hemoglobin level increase over baseline more than 2 g/dL if participant baseline hemoglobin level was less than 85 g/L and received no transfusion. HI responses included: 1) Erythroid: Hgb increase ≥1.5 g/dL, Relevant reduction of RBC units transfusions by absolute number of \>=4 RBC transfusions/8 week compared with pretreatment transfusion number in previous 8 week. Only RBC transfusions given for Hgb of ≤9.0 g/dL. Data is reported separately for arm assessed as per IWG criteria.

Time frame: Up to approximately 5.7 years

Population: All Treated Analysis Set included all participants who received at least one dose of study drug. Data is reported for Arm G: Imetelstat 9.4 mg/kg (MDS/MPN or MDS and spliceosome mutations or ring sideroblasts) participants whose transfusion independence (HI by erythroid response) was assessed by IWG criteria.

Time to response was defined as the duration from study Day 1 to the earliest date that a response is first documented. Response was defined as HI, PR or CR per IWG criteria. Data for time to response is reported as per criteria of response assessment.

Time frame: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)

Population: All Treated Analysis Set included all participants who received at least one dose of the study drug. Only responders were analyzed for this outcome measure. Data is reported for Arm G: Imetelstat 9.4 mg/kg (MDS/MPN or MDS and spliceosome mutations or ring sideroblasts) participants whose overall response was assessed by IWG criteria.

Transfusion dependency was defined by a history of at least 2 units of red blood cell transfusions in the last month for a hemoglobin level of less than 85 g/L that was not associated with clinically overt bleeding. A participant who was transfusion dependent at baseline was considered transfusion independent if the participant met either of the following conditions: Received no more than 1 unit of red blood cell transfusions in a rolling time interval of 30 days or more, and had a hemoglobin level increase over baseline more than 2 g/dL if participant baseline hemoglobin level was less than 85 g/L and received no transfusion. Anemia response per IWG-MRT Criteria- Transfusion-independent participants: a ≥20 g/L increase in hemoglobin level. Transfusion-dependent participants: becoming transfusion-independent. Data is reported separately for arms assessed as per the IWG-MRT criteria.

Time frame: Up to approximately 5.7 years

Population: Arms A, B, E, F: Eligible Analysis Set included subset of all participants who received at least one dose of study drug that excludes ineligible participants who did not satisfy each and every eligibility criteria for study entry. Arm D: All Treated Analysis Set included all participants who received at least one dose of imetelstat, assessed per IWG-MRT.

DOR measured from time of initial response (CR/PR/CI) until documented PD or death whichever occurs first. If no PD/death occurs DOR is censored at last disease evaluation date for responders. CR:BM: \<5%blasts; ≤Grade 1 MF, AND Peripheral blood:Hb≥100 g/L and \<UNL;Neutrophil count≥1x10\^9/L and \<UNL;PLT count≥100x10\^9/L and \<UNL;\<2% IMCs, AND Clinical:Resolution of disease symptoms;Spleen and liver not palpable;No evidence of EMH.PR:All CR criteria plus peripheral blood:Hb≥85 but \<100g/L and \<UNL;NC≥1x10\^9/L and \<UNL;PLTcount ≥50 but\<100x10\^9/L and\<UNL;\<2%IMCs. CI:achievement of anemia(≥20 g/L increase Hb level),spleen(baseline splenomegaly-palpable at 5-10cm,below LCM,becomes not palpable) or symptoms response(50% reduction in total symptom score) without PD(appearance of new splenomegaly- palpable\[\>= 5 cm below LCM) or increase in severity of anemia, thrombocytopenia or neutropenia. Data is reported separately for arms whose DOR was assessed per IWG-MRT. Kaplan-Meier method was used.

Time frame: From time of initial response until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)

Population: Eligible Analysis Set included subset of all participants who received at least one dose of study drug that excludes ineligible participants who did not satisfy each and every eligibility criteria for study entry. Data is reported for arm groups whose DOR was assessed by IWG-MRT criteria. Only responders were analyzed for this outcome measure.

Time to response was defined as the duration from study Day 1 to the earliest date that a response is first documented. The response CI/CR/PR was assessed by IWG-MRT criteria.

Time frame: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)

Population: Eligible Analysis Set included subset of all participants who received at least one dose of study drug that excludes ineligible participants who did not satisfy each and every eligibility criteria for study entry. Data is reported for arm groups (Arms A, B, E and F) whose overall response was assessed by IWG-MRT criteria. Only responders were analyzed for this outcome measure.

Spleen response per IWG-MRT criteria defined as baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable, OR A baseline splenomegaly that is palpable at \>10 cm, below the LCM, decreases by ≥50%. Baseline splenomegaly that is palpable at \<5 cm, below the LCM, is not eligible for spleen response. Confirmation by Magnetic resonance imaging (MRI) or computerized tomography (CT) showing ≥35% spleen volume reduction is recommended (but not required). Spleen response was assessed only in participants with MF.

Time frame: Up to approximately 5.7 years

Population: Arms A, B, E and F: Eligible Analysis Set included subset of all participants who received at least one dose of study drug that excludes ineligible participants who did not satisfy each and every eligibility criteria for study entry. Arm D: All Treated Analysis Set included all participants who received at least one dose of imetelstat.

OS was defined as the as the interval from Study Day 1 to the date of death from any cause. Survival time of living participants was censored on the last date a participant is known to be alive or lost to follow-up. Overall Survival was estimated by Kaplan-Meier method.

Time frame: From Study Day 1 to the date of death from any cause (Up to approximately 5.7 years)

Population: All Treated Analysis Set included all participants who received at least one dose of imetelstat.

TEAEs defined as those events that 1) occur on or after the first dose of study drug, through the treatment phase, and for 30 days following the last dose of study drug or until subsequent anti-cancer therapy if earlier; 2) any event that is considered study drug-related regardless of the start date of the event; or 3) any event that is present at baseline but worsens in severity or is subsequently considered drug-related by the investigator. Grade \>=3 TEAE defined as events that are severe, life-threatening or disabling, or fatal and considered related to imetelstat as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. An AE was considered related to the study drug if the event was assessed by the investigator as probably or possibly related.

Time frame: From first dose of study drug up to 30 days from the last dose of study drug or until subsequent anti-cancer therapy if earlier (Up to approximately 5.7 years)

Population: All Treated Analysis Set included all participants who received at least one dose of imetelstat.