The optimal management approach to advanced or metastatic renal cell cancer of the clear cell type continues to rapidly evolve. Risk stratification of patients into favorable-, intermediate-, and poor-risk categories is now routinely performed. In selected individuals with low-volume indolent disease, active surveillance may be an appropriate option. Cytoreductive nephrectomy and/or surgical metastasectomy may be also be considered for selected patients after evaluation by a multidisciplinary tumor board. Systemic frontline therapy options now include immune checkpoint inhibitor–based combination (IBC) therapies such as pembrolizumab/axitinib, nivolumab/ipilimumab, and avelumab/axitinib. With unusual exceptions, monotherapy with vascular growth factor receptor tyrosine kinase inhibitors or mTOR inhibitors are no longer appropriate options in the frontline setting. Despite the established efficacy of frontline IBC, most patients will ultimately require additional lines of therapy, and oncologists must think carefully when switching to another therapy, particularly in situations of drug intolerance or apparent disease progression. Systemic therapy options after IBC are generally tyrosine kinase inhibitor–based, and ongoing clinical trials will help optimize the treatment algorithm further. Despite many recent drug approvals for renal cell cancer (RCC), there remains a pressing need to identify new therapeutic targets. Finally, other systemic therapy or supportive care approaches must be considered for special patient populations such as those with poor performance status, end-organ dysfunction, brain metastases, or who have undergone metastasectomy.
Relapsed/refractory acute myeloid leukemia (AML) is a devastating disease with a poor prognosis and represents a major unmet medical need. We report on a real-world academic center experience of treating 25 patients with relapsed/refractory AML using venetoclax in combination with decitabine or azacitidine, which is not otherwise widely evaluated in the current literature. Our patients come from a large, socioeconomically and geographically diverse area including the majority of Northern California. Most had ELN Adverse Risk (52%) or Intermediate Risk (44%) AML, and most had an ECOG Performance Status of 1 (64%). Over half (52%) had prior hypomethylating agent exposure, and 40% had Secondary AML. We observed an overall response rate of 52%, with eight patients (32%) achieving composite complete remission. Median overall survival was 5.5 months, and for patients achieving composite complete remission this was 21.6 months. One-year estimated overall survival was 38%. Three patients were able to proceed directly to stem cell transplant for consolidation, and all three were alive at last follow-up, ranging 13.8–24.0 months. We found venetoclax in combination with hypomethylating agents to be well tolerated and potentially efficacious in securing long-term remissions for patients with relapsed/refractory AML.
Elderly and/or unfit patients with acute myeloid leukemia have historically been challenging to manage as they were ineligible for what was considered standard of care treatment with induction chemotherapy. The emergence of venetoclax with hypomethylating agents or low-dose cytarabine has substantially improved outcomes in the frontline setting with manageable toxicity. However, this regimen can be challenging to deliver given its differences from standard intensive chemotherapy. In this review, we summarize the landmark trials that established venetoclax-based combinations as a new standard of care for patients with acute myeloid leukemia not suitable for intense chemotherapy, provide practical clinical pearls for managing patients on these therapies, and offer a brief overview of modifications to these regimens under development to improve their efficacy and/or applicability.
Introduction Venetoclax (VEN) is a potent B-cell lymphoma 2 (BCL-2) inhibitor and demonstrates synergistic anti-AML activity when used in combination with hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC). This regimen has demonstrated high response rates and durable activity in treatment naïve (TN) older patients; however, the efficacy in relapsed and/or refractory (R/R) AML is less well characterized, with one study showing a response rate of 21%. To further characterize VEN plus HMA activity in these populations, we retrospectively reviewed the outcomes of both TN and R/R AML patients treated with VEN plus HMA at the University of California Davis Comprehensive Cancer Center (UCDCCC). Methods Adult patients (≥18 years) with an acute leukemia treated with VEN off protocol between January 1, 2014 through June 22, 2018 were included. Under an IRB-approved protocol, patients were retrospectively reviewed using an electronic medical record generated report. Baseline data included patient demographics, performance status, disease characteristics, prior chemotherapy, bone marrow biopsy studies and labs. Regimen data included other chemotherapy agents received, VEN dose and modifications, antifungal prophylaxis (ppx), and granulocyte colony stimulating factor (GCSF) use. Efficacy outcomes included complete remission (CR), CR with incomplete count recovery (CRi), composite CR (cCR, defined as CR + CRi), morphologic leukemia free state (MLFS), overall leukemia response (OLR, defined as cCR + MLFS), overall survival (OS), and relapse free survival (RFS). Toxicity outcomes were reviewed, including tumor lysis syndrome (TLS), febrile neutropenia (FN), and prolonged pancytopenia. All follow-up clinic visits, hospitalizations and deaths were reviewed. Results Forty-two patients were included (AML, n=41; acute undifferentiated leukemia, n=1). Median age was 67 years [25-88] and 67% were male. Eighteen (43%) had de novo AML, 17 (40%) had preceding myelodysplastic syndrome (MDS), 4 had MDS/myeloproliferative neoplasm (MPN) (10%) and 3 (7%) had primary myelofibrosis. Sixteen were TN (38%), thirteen (31%) had relapsed disease, and 13 (31%) had refractory disease. Median number of prior regimens was 1 [0-6]. Thirty-seven (88%) had an ECOG of 0 to 1 [0-3]. ELN genetic risk classification was intermediate in 19 (45%) and adverse in 22 (52%). VEN was combined with AZA in 12 (29%) and DEC in 30 (71%). Median VEN dose was 400 mg [50-800 mg]. Median follow-up was 17.2 months. For the entire study, the cCR was 43% and the OLR was 57%. See table 1 for cCR and OLR for subgroups including previously untreated, R/R, de novo, secondary AML (sAML), and various molecular and cytogenetic subgroups. Median OS was 6.2 months (Figure 1). For patients with cCR, OLR, and MLFS, median survival was 21.6, 15.1, and 4.9 months respectively (Figure 2). Median OS and median OS in responders for patients with de novo AML, sAML, untreated patients, and R/R patients is shown in Figure 3, Figure 4, and Table 1. Median number of cycles for cCR was 1 [1-6]. Of patients who obtained cCR, 6 (33%) experienced relapse of AML. Median time to relapse was 6.6 [3.4-13.9] months. Eight (19%) patients were bridged to allotransplant. Lab TLS occurred in 1 patient. Seventeen (40%) experienced prolonged pancytopenia. Eighteen (43%) had FN and 4 (22%) received GCSF. Antifungal ppx was used in 41 (98%) patients: micafungin in 17 (40%) and a non-fluconazole azole in 24 (57%). Seven (17%), of which 5 (71%) had R/R AML, were diagnosed with a fungal infection; 5 (71%) were receiving ppx azoles and 2 (29%) micafungin. Three and 6 died within 30 and 60 days of therapy initiation, respectively; all 3 patients who died within 30 days had R/R AML. The most common cause of death was refractory AML at 14 (52%) followed by infection in 9 (33%). Conclusion At UCDCCC, VEN in combination with an HMA is well tolerated and produces high rates of response in adult patients with AML. Response rates for TN AML, sAML and multiple molecular subgroups are consistent with prior reports, while higher than expected response rates and survival were seen in R/R AML. Responses were also seen in post-MDS/MPN and post-MF patients. In extended follow-up, survival has been durable in patients with cCR, but not MLFS. The use of VEN plus HMA combinations in adults with AML represents a viable treatment option for both TN and R/R AML. Disclosures Jonas: AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Genentech/Roche: Research Funding; Glycomimetics: Research Funding; Pharmacyclics: Research Funding; Tolero: Consultancy; Amgen: Consultancy; Forma: Research Funding; Incyte: Research Funding; Esanex: Research Funding; Kalobios: Research Funding; Accelerated Medical Diagnostics: Research Funding; LP Therapeutics: Research Funding.
Background Ponatinib, a third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), + hyper-CVAD showed remarkable activity against Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and may be superior to chemotherapy + earlier generation TKIs in terms of depth of remission, event-free survival (EFS), and overall survival (OS). However, this regimen's efficacy and tolerability have yet to be externally validated. Here, we summarize our real-world experience with ponatinib + hyper-CVAD for untreated Ph+ ALL and other Ph+ acute or blast phase leukemias. Methods We retrospectively analyzed all adults treated at the University of California, Davis (UCD) from March 2012 to May 2021 with ponatinib + hyper-CVAD upfront. The primary endpoints were 3-year OS and EFS. Secondary endpoints were complete molecular response (CMR), measurable residual disease (MRD) negativity by multiparameter flow cytometry (MFC), complete cytogenetic response (CCyR) rates, and adverse events (AEs). Time to event analyses were done via the Kaplan-Meier method. Patients alive were censored at their last follow-up date. Patients undergoing allogeneic hematopoietic cell transplant (HCT) after 6 months of achieving complete remission (CR) were censored at the time of HCT for the landmark analysis. Patients with missing data were excluded from the response analyses. Results We identified 13 Ph+ ALL patients who received ponatinib + hyper-CVAD for initial induction. The baseline characteristics for the Ph+ ALL patients are summarized in Table 1. The median follow-up was 16 months. The median number of hyper-CVAD cycles completed was 8 (range, 1-8) with ponatinib. Two patients proceeded to HCT in CR1, one at 3.5 months after starting induction, and due to difficulty controlling the patient's concurrent multiple myeloma prior to HCT and recovery from anti-neoplastic therapy, the second was delayed to 46 months after starting induction. The 3-year OS and EFS with ponatinib + hyper-CVAD were each 92% (95% confidence interval, 78.9-100) (Figure 1). Landmark analysis completed 6 months following CR showed a 3-year OS of 100% in patients treated with ponatinib + hyper-CVAD without HCT in first CR (CR1). The CMR, CCyR, and MRD-negativity by MFC rates with ponatinib were all 92.3% (12/13). The median time to CMR, CCyR, and MRD-negativity by MFC were 51 days, 22 days, and 53 days, respectively. Notable AEs with ponatinib include neutropenic fever (92%), bacterial infection (69%), transaminitis (38%), venous thromboembolism (31%), invasive fungal infection (15%), hemorrhage (15%), cerebrovascular accident (CVA) (15%), and tumor lysis syndrome (8%). One patient died during induction with ponatinib due to a bacterial infection. Two patients switched to a different TKI due to a CVA after 4 and 24 months. Only 2 patients did not complete 8 cycles of hyper-CVAD, due to death during induction (n=1) and proceeding to HCT after 3 cycles (n=1). As for similar Ph+ leukemias, 3 chronic myeloid leukemia with lymphoid blast crisis (CML-LBC), 1 CML with mixed phenotype blast crisis (CML-MPBC), and 1 with mixed phenotype acute leukemia (MPAL) were treated with ponatinib + hyper-CVAD. The MPAL patient achieved CMR within 55 days, while the CML-MPBC and 2 CML-LBC patients achieved CMR after HCT. The third CML-LBC patient is in CR with ongoing treatment. After median follow-up of 25 months, all 5 were alive, and only the MPAL patient relapsed 28 months after starting treatment and 1 year after HCT. Conclusion To our knowledge, this is the first report externally validating the efficacy and tolerability of ponatinib + hyper-CVAD for Ph+ ALL. We also show the feasibility of using this regimen in patients with Ph+ CML-LBC, CML-MPBC and MPAL. Despite the small sample size and retrospective nature, our study supports existing data demonstrating that this regimen challenges both the designation of Ph+ ALL as a high-risk disease and the trend to transplant in CR1. Our findings support that ponatinib + hyper-CVAD should be considered a standard of care for Ph+ ALL. Figure 1 Figure 1. Disclosures Kaesberg: Incyte: Speakers Bureau. Rosenberg: Takeda, Janssen: Speakers Bureau. Abedi: BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau; Seattle Genetics: Speakers Bureau. Tuscano: Genentech, Pharamcyclics, Abbvie, BMS, Acrotech, Seattle Genetics, Takeda: Research Funding. Jonas: AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement. OffLabel Disclosure: Ponatinib is approved for Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. In this study, we described outcomes with ponatinib in combination with hyperCVAD in the frontline setting, which is off-label.
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