Prolymphocytic leukemia (PLL) is a rare variant of CLL. It is a related but distinct B-cell disorder and is one of the B-cell malignancies most often confused with CLL. Most PLL patients are diagnosed initially with PLL; however, some will have initially been diagnosed with CLL, which subsequently transforms and takes on the appearance of PLL.

Unlike CLL, the abnormal lymphocytes seen in PLL are immature cells (prolymphocytes) which are not normally seen in the peripheral blood. The diagnosis is PLL rather than CLL if more than half the leukemic cells are prolymphocytes. If there are prolymphocytes present, but they make up less than half of the abnormal cells, the condition is called mixed CLL/PL. A patient with PLL will typically have a very large spleen and a very high white blood count. Most patients do not have enlarged lymph nodes, but may have non-specific symptoms like tiredness and weight loss. PLL tends to be more aggressive than CLL and is less responsive to therapy.

Approximately 10 percent of patients who have chronic lymphocytic leukemia will have their illness transform and take on the appearance of prolymphocytic leukemia. The condition T-cell PLL has no relationship to CLL or B-PLL.