Lawes has picked up a shoulder problem and will miss the final two clashes of the tournament, against France and Ireland.
The Northampton back-five forward missed England’s entire autumn campaign with a head injury, and has also suffered gluteal and calf problems too.
The 34-year-old should have passed 100 England caps in November but has only made one appearance since last summer to remain on 97 appearances.
“We’re waiting for a scan result, but from what we’ve been told he’ll miss the remainder of the tournament,” said assistant coach Kevin Sinfield. “It’s tough for him; we have a wonderful leadership trio with Courtney, Ellis Genge and Owen Farrell.
“His influence in camp has been incredible, we’ll miss him at the weekend and hopefully it’s not too long before he’s back in the fold.”
George Ford has been released from the England camp, leaving Marcus Smith and Farrell as the two fly-halves in the Test ranks.
Smith will therefore face France at Twickenham on Saturday in some capacity, whether off the bench or from the off. The 24-year-old turned in a stellar performance as Harlequins hammered Exeter 40-5 at Twickenham on Saturday, before returning to the England squad on Sunday night.
“I think we were really impressed with how Marcus played last week,” said Sinfield. “All three have been fantastic in camp, George has been wonderful, I loved working with him at Leicester.
“We just felt at this moment in time he should get more minutes at his club, he’s not been long back in the fold. He has been outstanding and we’ve no doubt that if he were to play he would be great for us.
“But the best thing for us at the minute is for him to get more minutes at Sale. I thought Marcus was outstanding for Harlequins, we all did, but he has trained like that for the last six weeks. So we’ve all seen first-hand what he’s capable of, and he’s in the mix this week.”
England have kept Manu Tuilagi in the squad for training, despite the Sale centre being suspended this week. The Samoa-born powerhouse will be available for the trip to Dublin to face Ireland on Saturday, March 18.
England squad vs France confirmed
Forwards: O Chessum, D Cole, B Curry, A Dombrandt, B Earl, E Genge, J George, N Isiekwe, M Itoje, L Ludlam, D Ribbans, K Sinckler, M Vunipola, J Walker, J Willis.
Backs: H Arundell, O Farrell, O Lawrence, M Malins, J Marchant, A Mitchell, H Slade, M Smith, F Steward, M Tuilagi, J Van Poortvliet, A Watson.