Patient Characteristics

Table 1. Table 1. Characteristics of All 80 Patients at Study Entry.

From July 2016 through June 2018, a total of 80 patients (Table 1) initiated study treatment. The median age was 65 years (range, 26 to 83); 30% of the patients were 70 years of age or older. A total of 83% of the patients had unmutated IGHV; 18% had del(17p), 14% had mutated TP53, and 25% had del(11q). Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or del(11q).

Of the 80 patients, 5 withdrew from the study during the ibrutinib-monotherapy phase (reasons for withdrawal are described below) and did not initiate venetoclax. The median follow-up was 14.8 months.

Efficacy

Responses are shown in Figure 1B, and in Table S2 in the Supplementary Appendix. After the initial 3 cycles of ibrutinib monotherapy, most responses were partial. After the addition of venetoclax, the proportions of patients who had complete remission or complete remission with incomplete count recovery and remission with undetectable minimal residual disease in bone marrow increased over time (Figure 1B, and Fig. S1 in the Supplementary Appendix). Of the total 80 patients enrolled, 59 (74%; 95% confidence interval [CI], 63 to 83) had complete remission or complete remission with incomplete count recovery as their best response. After 6 cycles of the combination, 51 of 70 patients (73%; 95% CI, 61 to 83) had complete remission or complete remission with incomplete count recovery, and 28 of 70 patients (40%; 95% CI, 28 to 52) had remission with undetectable minimal residual disease in bone marrow. After 12 cycles of the combination, 29 of 33 patients (88%; 95% CI, 72 to 97) were in complete remission or complete remission with incomplete count recovery, and 20 of 33 patients (61%; 95% CI, 42 to 77) had remission with undetectable minimal residual disease in bone marrow. After 18 cycles of the combination, 25 of 26 patients (96%; 95% CI, 80 to 100) were in complete remission or complete remission with incomplete count recovery, with 18 of 26 (69%; 95% CI, 48 to 86) having remission with undetectable minimal residual disease in bone marrow. Three patients completed 24 cycles of combined therapy; all had complete remission or complete remission with incomplete count recovery, with undetectable minimal residual disease in bone marrow.

Table 2. Table 2. Remission with Undetectable Minimal Residual Disease (MRD) in Bone Marrow, According to Pretreatment Characteristics.

Patients 65 years of age or older had a high rate of response. A total of 74% had complete remission or complete remission with incomplete count recovery, and 44% had undetectable minimal residual disease in bone marrow after 6 cycles of the combination; these rates increased to 94% and 76%, respectively, after 12 cycles of the combination (Table 2). Responses were seen across all high-risk subgroups, independent of IGHV mutation status, FISH category, TP53 mutation, NOTCH1 mutation, and SF3B1 mutation (Table 2).

The estimated 1-year progression-free and overall survival were 98% (95% CI, 94 to 100) and 99% (95% CI, 96 to 100), respectively (Fig. S2A and S2B in the Supplementary Appendix). No patient has had CLL progression. Richter’s transformation developed in one patient; this was a 63-year-old man with CLL with high-risk genomics (unmutated IGHV and NOTCH1 mutation) in whom back pain developed during dose escalation of venetoclax and who was noted to have transformation to diffuse large B-cell lymphoma (DLBCL).

One patient died. This was a 60-year-old man who was having headache and numbness on the right side for 1 week before starting ibrutinib. The patient received 1 day of ibrutinib monotherapy, had progressive neurologic symptoms, and was found to have cryptococcal infection of the central nervous system; ibrutinib treatment was discontinued. The patient died 6 months later from complications of disseminated cryptococcal infection. Given that the patient had symptoms before starting ibrutinib and received only 1 day of ibrutinib, the death was deemed by the treating physician and the first author to be unrelated to ibrutinib.

Stratification According to Risk of Tumor Lysis Syndrome

At the time of ibrutinib initiation, 13% of the patients were at high risk, 72% at medium risk, and 15% at low risk for venetoclax-associated tumor lysis syndrome. At the time of venetoclax initiation, 3% of the patients were at high risk, 43% at medium risk, and 54% at low risk for tumor lysis syndrome. Ibrutinib monotherapy led to downgrading of the risk category in 80% of the high-risk patients and 48% of the medium-risk patients. (For changes in lymph-node tumor burden and absolute lymphocyte count with ibrutinib monotherapy, see Figs. S3 and S4, respectively, in the Supplementary Appendix.) Three patients (two at medium risk and one at low risk for tumor lysis syndrome) had laboratory evidence of tumor lysis syndrome. No patient had clinical evidence of tumor lysis syndrome.

Discontinuation of Study Treatments

A total of 11 patients (14%) discontinued study treatments. Five patients withdrew from the study during ibrutinib monotherapy: 1 each had rash, hypertension, use of prohibited medication, and unrelated infection (cryptococcus), and 1 withdrew consent in order to receive treatment with a local physician. Six patients withdrew from the study during the combination phase: 2 had recurrent neutropenia, and 1 each had DLBCL transformation, fallopian-tube cancer, allogeneic stem-cell transplantation, and hemolytic anemia. The patient with hemolytic anemia later received a diagnosis of myelodysplastic syndrome.

Safety

Table 3. Table 3. Nonhematologic Adverse Events in All 80 Patients.

Toxic effects of grade 3 or higher were noted in 60% of the patients. Nonhematologic adverse events that occurred in at least 5% of the patients are listed in Table 3. Easy bruising, arthralgia, and diarrhea were the most common nonhematologic adverse events. An increase in the aminotransferase level was noted in 5 patients (grade 1 or 2 in 4 patients and grade 3 in 1 patient). Grade 3 or 4 neutropenia occurred in 38 of 80 patients (48%) (grade 3 in 21 patients and grade 4 in 17). The incidence of grade 3 or 4 neutropenia was similar among patients younger than 65 years of age (18 of 37 patients [49%]) and among those 65 years of age or older (20 of 43 patients [47%]). A total of 19 of 80 patients (24%) had grade 3 or 4 neutropenia during ibrutinib monotherapy; 29 of 75 patients (39%) had grade 3 or 4 neutropenia during the combination phase (10 patients had grade 3 or 4 neutropenia during both ibrutinib monotherapy and the combination phase). A total of 19 patients (24%) received granulocyte colony-stimulating factor (G-CSF) support for neutropenia. Grade 3 thrombocytopenia occurred in 2 patients (2%) during the combination phase. No patient had grade 4 thrombocytopenia.

Neutropenic fever occurred in four patients (in one during ibrutinib monotherapy and in three during the combination phase); cultures remained negative in three patients, and one patient had pneumocystis pneumonia. Aspergillus and cryptococcus pneumonia developed in one patient during cycle 1 of ibrutinib monotherapy. Additional infectious complications leading to hospitalization included pneumonia (nonneutropenic, culture negative) in three patients, cellulitis in two patients, and nonneutropenic fever, anaplasmosis infection, septic arthritis, and appendicitis, each in one patient.

The dose of ibrutinib was reduced in 35 of 80 patients (44%). The most common reasons for dose reduction were atrial fibrillation (in 9 patients), neutropenia (in 5), rash (in 5), hypertension (in 3), and myalgia (in 3). The dose of venetoclax was reduced in 18 of 75 patients (24%). The most common reason for dose reduction was neutropenia (in 12 patients). Additional reasons for dose reductions are listed in the Supplementary Appendix.

Atrial fibrillation occurred in 12 patients (15%) (grade 1 or 2 in 4 patients, grade 3 in 7, and grade 4 in 1). Atrial fibrillation developed in 7 patients during ibrutinib monotherapy and in 5 patients during the combination phase (Table S3 in the Supplementary Appendix).