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Tottenham’s Dele Alli, Danny Rose and Eric Dier will miss Thursday’s Europa League last-16 first-leg tie at Borussia Dortmund.
Alli is suspended, fellow midfielder Rose is being rested and left-back Rose felt cramp in his calf in Saturday’s draw with Arsenal.
Jan Vertonghen and Clinton Njie remain sidelined with knee injuries.
“We are in a period that is tough for the players. We need to rotate,” said Spurs boss Mauricio Pochettino.
German side Dortmund, like Spurs, are second in their domestic table.
They are unbeaten in 11 games in all competitions – a run which includes nine wins – and striker Pierre-Emerick Aubameyang has scored 29 goals in 33 games this season.
“I like the way they play but it’s a good challenge for us. We play against one of the best teams in Europe,” said Pochettino.
“The strikers they have – Aubameyang, (Henrikh) Mkhitaryan, (Ilkay) Gundogan in midfield, (Mats) Hummels – they’re internationals and big players.
“They can stay here or go to Real Madrid or Barcelona.”
Dortmund have scored 59 goals in 25 league games this season and have not lost at home.
Asked about Tottenham, Dortmund boss Thomas Tuchel said: “They are a hard-working, highly defensive team who have earned their place for many years as one of the best sides in their league.
“We’ll be tested at the highest level. The tempo in England has gone up again this season. It will be fast; it will be intensive.”