Key Points• Complex karyotype and fludarabine refractoriness are key risk factors for progression of CLL on venetoclax.• Bruton tyrosine kinase inhibitors are active in patients with CLL after prior therapy with venetoclax.The BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) (P 5 .003). Among patients who received the recommended phase 2 dose of venetoclax or higher ( ‡400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; P 5 .002 and 6.6 [1.5-29.8]; P 5 .005, respectively), whereas del(17p) and/or TP53 mutation were not (P 5 .75). Median postprogression survival was 13 (<1-49.9) months. Bruton tyrosine kinase inhibitors were active in progressive CLL, but outcomes were mixed. Patients with disease that is fludarabine refractory or who have complex cytogenetics should have occult RT excluded before initiating venetoclax therapy. (Blood. 2017;129(25):3362-3370)

Minimal BMI, seen in the majority of patients with DLCL with marrow infiltration, appears not to influence the PFS & OS. However, an increasing degree of marrow involvement is associated with an increasing component of large cells and a poorer prognosis in DLCL patients, independent of other risk factors.

The value of administering sequential courses of chemotherapy containing highdose cytarabine in both induction and consolidation therapy for acute myeloid leukemia (AML) has not been assessed in a prospective randomized trial. Two hundred ninety-two AML patients aged 15 to 60 years were enrolled in the Australasian Leukaemia and Lymphoma Group (ALLG) AML trial number 7 (M7) protocol to evaluate this question. All received induction therapy with the ICE protocol (idarubicin 9 mg/ m 2 ؋ 3; cytarabine 3 g/m 2 twice a day on days 1, 3, 5, 7; etoposide 75 mg/m 2 ؋ 7). Complete remission was achieved in 234 (80%) patients. Two hundred two patients in remission were then randomized to either a further identical cycle of ICE or 2 attenuated courses (cytarabine 100 mg/m 2 daily ؋ 5, idarubicin ؋ 2, etoposide ؋ 5 [IcE]). ICE consolidation therapy was more toxic than IcE, however, the treatment-related death rate was not significantly different. There was no difference between the 2 consolidation arms for relapse-free survival at 3 years (49% for ICE vs 46% for IcE; P ‫؍‬ .66), survival following randomization (61% vs 62%; P ‫؍‬ .91), or the cumulative incidence of relapse (43% vs 51%; P ‫؍‬ .31), and there was no difference within cytogenetic risk groups. Intensive induction chemotherapy incorporating high-dose cytarabine results in high complete remission rates, but further intensive consolidation treatment does not appear to confer additional benefit. (Blood. 2005;105:481-488)

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