Anemia-related response end points in myelofibrosis clinical trials: current trends and need for renewed consensus

Figures & data

Table 1. Anemia-related response end points defined by transfusion status or hemoglobin improvement applied across clinical trials of myelofibrosis to date.

Type of anemia assessment	Criteria	Transfusion independent	Transfusion dependent	Transfusion requiring	Examples of clinical trials applying criteria as end points	Ref.
Transfusion status	Gale criteria	No RBC transfusions over any 12-week period, with no hemoglobin requirement	Average of ≥2 RBC units per month over any 12-week period, with no hemoglobin requirement	Not defined	Luspatercept ± ruxolitinib: phase II^† (primary end point [TI] in baseline non-TI patients; assessed through week 24), INDEPENDENCE^† (primary end point [TI]; assessed through week 24) Pacritinib: PERSIST-1, PERSIST-2^† (exploratory end point [TI] in baseline TD patients; assessed through week 24) Pelabresib ± ruxolitinib: MANIFEST (primary end point [TI] in baseline TD patients)	[30,31,34,36–38]
	Rolling 12-week criteria	No RBC transfusions and no hemoglobin levels <8 g/dl over any rolling 12-week period through week 24	Not transfusion independent		Momelotinib: MOMENTUM (exploratory end point [TI]) Pacritinib: PERSIST-2 (retrospective analysis of TI in baseline non-TI patients)	[27,39]
	Terminal 12-week criteria	No RBC transfusions and no hemoglobin levels <8 g/dl in the 12 weeks immediately preceding week 24	≥4 RBC units transfused or a hemoglobin level <8 g/dl in the 8 weeks immediately preceding week 24^‡	Not meeting definitions of transfusion independent or transfusion dependent	Momelotinib: SIMPLIFY-1, SIMPLIFY-2, MOMENTUM (secondary end point [TI])^§	[22–24]
Type of anemia assessment	Criteria	Definition			Examples of clinical trials applying criteria as end points
Hemoglobin improvement	≥1-g/dlincrease	Increase of ≥1 g/dl from baseline, as measured over any rolling 12-week period; may exclude values from a certain period of time following transfusion			Luspatercept ± ruxolitinib: INDEPENDENCE (secondary end point) Momelotinib: MOMENTUM (exploratory end point; assessed though week 24) Pacritinib: PERSIST-2 (retrospective analysis in patients with baseline hemoglobin <10 g/dl; assessed through week 24)	[31,39,40]
	≥1.5-g/dl increase	Increase of ≥1.5 g/dl from baseline, as measured over any rolling 12-week period; may exclude values from a certain period of time following transfusion			Luspatercept ± ruxolitinib: phase II (primary end point in baseline TI patients; assessed through week 24) Pelabresib ± ruxolitinib: MANIFEST (secondary end point in baseline non-TD patients), MANIFEST-2^¶	[29,34,35]
	≥2-g/dl increase	Increase of ≥2 g/dl from baseline, as measured over any rolling 12-week period; may exclude values from a certain period of time following transfusion			Momelotinib: MOMENTUM (exploratory end point; assessed through week 24) Pacritinib: PERSIST-2 (retrospective analysis in patients with baseline hemoglobin <10 g/dl; assessed through week 24)	[39,40]

† Also included assessment of transfusion improvement in baseline non-TI patients, defined as a ≥50% decrease in RBC transfusions over a 3-month period (modified in the luspatercept trials to include a decrease of ≥4 RBC units), as secondary or exploratory end points [30,31,37,38].

‡ In MOMENTUM, TD was defined as ≥4 RBC units transfused, each in response to a hemoglobin assessment ≤9.5 g/dl, in the 8 weeks immediately preceding week 24 [22].

§ Cumulative transfusion burden, time to transfusion and rate of zero transfusions at week 24 were also assessed as secondary or exploratory end points [22–24].

¶ Hemoglobin response defined as a ≥1.5 g/dl mean increase from baseline in the absence of transfusions during the previous 12 weeks.

RBC: Red blood cell; TD: Transfusion dependent; TI: Transfusion independent.

Figure 1. Representative anemia-related data from phase III trials of momelotinib illustrating the impact of baseline transfusion status and anemia-related response definitions on outcomes reported with any potential treatment for anemia in myelofibrosis.

(A) Baseline transfusion status, and (B) week 24 transfusion independence rates per varying definitions, in the SIMPLIFY-1, SIMPLIFY-2 and MOMENTUM trials. In (A), brackets denote the ’non-TI’ patient population (TD + TR).

^aTI defined as no transfusions or hemoglobin levels <8 g/dl in the 12 weeks before randomization.

^bTD defined as ≥4 units transfused or a hemoglobin level <8 g/dl in the 8 weeks before randomization.

^cTD defined as ≥4 units transfused, each associated with a hemoglobin level ≤9.5 g/dl, in the 8 weeks before randomization.

^dRolling 12-week criteria results not previously reported.

^eGale criteria results not previously reported.

BAT: Best available therapy; TD: Transfusion dependent; TI: Transfusion independent; TR: Transfusion requiring.

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