Patient characteristics that predict Richter's transformation in patients with chronic lymphocytic leukemia treated with ibrutinib.

Chronic lymphocytic leukemia (CLL) transformation to aggressive lymphoma, known as Richter's Transformation (RT), has a dismal prognosis. There are limited data evaluating risk of RT in patients treated with ibrutinib. We performed a retrospective analysis to determine prognostic variables associated with development of RT and overall survival (OS) at progression after treatment with ibrutinib. We identified 559 patients with CLL treated with ibrutinib from 2010-2019. After a median follow-up of 44.5 months from ibrutinib start, 179 patients progressed and were included in our analysis. After a median follow-up of 20.8 months from progression, 54 out of 179 patients developed RT. Progression on treatment (hazard ratio [HR] 4.01 [1.60-10.00], p = .003), higher LDH (HR 1.80 for 2-fold increase [1.33-2.43], p = .0001), and lymphadenopathy without lymphocytosis (HR 2.88 [1.15-7.20], p = .02) were independent prognostic variables for the development of RT at progression. Progression with lymphadenopathy without lymphocytosis continued to be an independent prognostic variable of worse OS post-progression. In a subset analysis of 50 patients who obtained a PET-CT at progression, the median SUVmax for patients who would develop RT was 15.2 (n = 30, range: 4.0-46.3) versus those patients who did not develop RT with a SUVmax of 7.7 (n = 20, range: 2.3-27.2) (p = .0030). Median OS from date of RT was 4.0 months, suggesting that prognosis for RT remains poor. A lymph node biopsy to rule out RT should be considered in patients who received ibrutinib who progress on treatment, have an elevated LDH, or progress with lymphadenopathy without lymphocytosis.

Long-term outcomes in patients with relapsed or refractory hairy cell leukemia treated with vemurafenib monotherapy.

Vemurafenib, an oral BRAF inhibitor, has demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL). However, little is known about long-term outcomes and response to retreatment. Herein, we report the results of 36 patients with R/R HCL treated with vemurafenib from the United States arm of the phase 2 clinical trial (NCT01711632). The best overall response rate was 86%, including 33% complete response (CR) and 53% partial response (PR). After a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months). There was no significant difference in the RFS for patients with CR vs PR. Fourteen of 21 (67%) relapsed patients were retreated with vemurafenib, with 86% achieving complete hematologic response. Two patients acquired resistance to vemurafenib with the emergence of new KRAS and CDKN2A mutations, respectively. Six of 12 (50%) responders to vemurafenib retreatment experienced another relapse with a median RFS of 12.7 months. Overall survival (OS) was 82% at 4 years, with a significantly shorter OS in patients who relapsed within 1 year of initial treatment with vemurafenib. Higher cumulative doses or a longer duration of treatment did not lengthen the durability of response. All adverse events in the retreatment cohort were grade 1/2 except for 1 case of a grade 3 rash and 1 grade 3 fever/pneumonia. Our data suggest that vemurafenib retreatment is a safe and effective option for patients with R/R HCL.

The impact of increasing karyotypic complexity and evolution on survival in patients with CLL treated with ibrutinib.

Complex karyotype, defined as ≥3 cytogenetic abnormalities, is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (ie, ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti-CD20 antibody at our institution. We included 456 patients with both treatment-naive and RR disease. Median number of prior therapies was 2 (range, 0-13), 30% of patients had presence of del(17p), and 75% expressed unmutated IGHV. Fifty percent had ≥3 cytogenetic abnormalities, including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .0001) and overall survival (hazard ratio, 1.09; 95% confidence interval, 1.05-1.12; P < .0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (P = .02). This solidifies karyotypic complexity as an important prognostic factor for patients with CLL treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.

Phase 2 study of ibrutinib in classic and variant hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia.

Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis. Cytogenetic complexity (>3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV. Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation. Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p). In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002). In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (p.

A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level -1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m2 cytarabine D5-8, and 8 mg/m2 idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).

Second cancer incidence in CLL patients receiving BTK inhibitors.

Chronic lymphocytic leukemia (CLL) is associated with perturbed immune function and increased risk for second primary malignancies (SPM). Ibrutinib and acalabrutinib (BTKi) are effective therapies for CLL resulting in partial restoration of immune function. The incidence of and risk factors for SPM in CLL patients receiving BTKi are not yet characterized. We retrospectively determined the incidence of SPM in CLL patients treated with ibrutinib or acalabrutinib at our institution between 2009 and 2017, assessed for association between baseline characteristics and SPM incidence, and compared the observed to expected cancer incidence among age, sex, and year matched controls without CLL. After a median of 44 months follow-up, 64/691 patients (9%) were diagnosed with SPM (excluding non-melanoma skin cancer [NMSC]). The 3-year cumulative incidence rate was 16% for NMSC and 7% for other SPM. On multivariable analysis, smoking was associated with increased SPM risk (HR 2.8 [95% CI: 1.6-4.8]) and higher baseline CD8 count was associated with lower SPM risk (HR 0.9 for 2-fold increase [95% CI: 0.8-0.9]). The observed over expected rate of SPM was 2.2 [95% CI: 1.7-2.9]. CLL patients treated with BTKi remain at increased risk for SPM, and secondary cancer detection is an important consideration in this population.

Phase I Study of Veliparib on an Intermittent and Continuous Schedule in Combination with Carboplatin in Metastatic Breast Cancer: A Safety and [18F]-Fluorothymidine Positron Emission Tomography Biomarker Study.

BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Furthermore, the BROCADE studies demonstrated benefit of adding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay. MATERIALS AND METHODS: Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3'-deoxythymidine (18 FLT) positron emission tomography (PET) imaging. RESULTS: Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n = 1), and G3 akathisia (n = 1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUVmax ) of target lesions between baseline and early in cycle 1 based on 18 FLT-PET (day 7-21; ptrend = .006). CONCLUSION: The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18 FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response. IMPLICATIONS FOR PRACTICE: The BROCADE studies suggest that breast cancer patients with BRCA mutation benefit from addition of veliparib to carboplatin plus paclitaxel. This study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, the authors demonstrate that decrease in [18]fluoro-3'-deoxythymidine positron emission tomography (FLT-PET) SUVmax during cycle 1 of therapy is associated with response. Collectively, this study established a safety profile of veliparib and carboplatin in advanced breast cancer while also providing additional data on the potential for FLT-PET imaging modality in monitoring therapy response.

Population pharmacokinetics of lenalidomide in patients with B-cell malignancies.

AIMS: Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose-related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease-related differences in disposition. METHODS: Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5-75 mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates. RESULTS: The data were best fitted by a 1-compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat-free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 L/h (10.8-13.6), 68.8 L (61.8-76.3), and 13.5 h-1 (11.9-36.8) respectively. Patients with impaired renal function (creatinine clearance <30 mL/min) exhibited a 22% reduction in lenalidomide clearance compared to patients with creatinine clearance of 90 mL/min. Cancer type had no discernible effect on lenalidomide disposition. CONCLUSIONS: This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B-cell malignancies. As no differences in pharmacokinetics were found between the observed cancer-types, the unique toxicities observed in CLL may be due to disease-specific pharmacodynamics.