Addition Of Tyrosine Kinase Inhibitors Research Articles

Zanzalintinib (XL092) plus atezolizumab versus regorafenib in previously treated MSS/MSI-low metastatic colorectal cancer (mCRC): The randomized phase 3 STELLAR-303 study.

TPS229 Background: Patients with microsatellite stable/microsatellite instability-low (MSS/MSI-low) mCRC account for ~95% of mCRC cases, and there is a significant unmet need in patients with treatment-refractory MSS/MSI-low mCRC. Although immune checkpoint inhibitors (ICIs) have shown limited activity in this patient population, the addition of tyrosine kinase inhibitors (TKIs) may increase sensitivity to ICIs by promoting an immune-permissive tumor microenvironment. Furthermore, TKI-ICI combinations have demonstrated encouraging clinical activity in patients with mCRC, particularly in subgroups of patients without liver metastases (LM). Most recently, in the phase 3 LEAP-017 study of patients with non–MSI-high/mismatch repair deficient (dMMR) mCRC, although pembrolizumab + lenvatinib did not improve overall survival (OS) vs standard of care, subgroup analysis suggested the potential for clinical benefit in patients without LM (Kawazoe et al, ESMO-WCGI 2023). Zanzalintinib is a novel multi-kinase inhibitor targeting VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER). In a phase 1 study, zanzalintinib alone and in combination with atezolizumab (an anti–PD-L1 ICI) showed preliminary anti-tumor activity and a manageable safety profile across multiple tumor types (Sharma et al, ESMO 2022). Methods: STELLAR-303 (NCT05425940) is a global, randomized, open-label phase 3 study to assess the efficacy and safety of zanzalintinib + atezolizumab versus regorafenib in adult patients with MSS/MSI-low mCRC. Patients must have documented MSI/MMR status (non–MSI-high/dMMR) and RAS status by tissue-based analysis, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and radiographic progression during/after or intolerance to standard of care treatments for mCRC. Prior regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are not allowed. Patients with or without active LM at baseline are eligible; those with definitively treated LM (includes surgical resection, microwave/radiofrequency ablation, or stereotactic body radiation therapy, but not yttrium-90 or chemoembolization alone) are considered to have non-active LM if treated ≥6 months before enrollment with no evidence of radiologic progression on subsequent imaging. Patients are randomized 1:1 to receive zanzalintinib + atezolizumab or regorafenib. Planned enrollment is 874 patients; number of patients with LM will be capped to ensure results of the study are relevant to the real-world mCRC population. Primary endpoint is OS in patients without LM. The key secondary efficacy endpoint is OS in all randomized patients. A hierarchical testing strategy will be employed for primary and key secondary endpoints. Safety will also be assessed. Enrollment is ongoing in the US, Europe, and Asia-Pacific region. Clinical trial information: NCT05425940 .

Good Survival of CAR-T Cell Therapy Bridging to Allo-HSCT for Relapsed/Refractory Ph-Positive B-Cell Acute Lymphoblastic Leukemia

Aims: The addition of tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of Ph-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL). However, there are still a certain proportion of patients resistant to conventional means or relapse after treatment. In current study, the efficacy and safety of CAR-T bridging to allo-HSCT for patients with relapsed/refractory (r/r) Ph+ B-ALL were evaluated. Methods: Between November 2018 and July 2023, 29 consecutive patients with r/r Ph+ B-ALL were included. The median age was 32(2-61) years old, 17 male and 12 female. All patients were not in CR MRD-（complete remission with negative BCR/ABL fusion genes detected by real-time PCR）status, 11 cases in CR MRD+ and 18 cases in NR (not remission). 10 patients had clear extramedullary lesions. 15 patients had mutations in the coding region of the ABL1 gene T315I kinase. 9 patients had a history of allo-HSCT. After CART treatment, the patient sequentially enters the transplant procedure. 5 patients received allo-HSCT from sibling HLA matched donors, 19 patients from haploidentical donors and 5 patients from unrelated donors. Myeloablative conditioning regimens with total body irradiation (fractionated, total 10 Gy) /etoposide (200mg/m 2 x 3) /fludarabine (30mg/m 2 x 5) or cyclophosphamide (1.8g/m 2 x 2) /rabbit anti-T-cell globulin were used. The infusion count of MNC cells was 4.35-15.36×10 8/kg and CD34+ cells was 2.57-8.5×10 6/kg. Cyclosporine, mycophenolate mofetil and short-term methotrexate were employed for graft-versus-host disease (GVHD) prophylaxis. All patients received sensitive TKIs up to 2 years post-transplantation. Results: After CART therapy, 7 of the 11 patients with CR MRD+ status obtained CR MRD-, and 4 still in CR MRD+. 11 of 18 patients with NR status obtained CR MRD-, 6 patients obtained CR MRD+ , and 1 case still in NR. In the allo-HSCT procedure, all patients achieved durable engraftment. 5 patients developed mild aGVHD, 4 patients developed severe aGVHD, 1 patient developed mild cGVHD, and 6 patients developed severe cGVHD. All of them were resolved with immune-suppressants except 1 patient died. CMV reactivation occurred in 14 patients and EBV reactivation in 1 patient. 6 patients developed hemorrhagic cystitis. 14 patients developed definite organ infections, of which 11 were pulmonary infections, the others were intestinal infections, perianal infections, urinary tract infections, and sepsis. 5 patients were infected by the COVID-19 virus during epidemic, and 1 of them progressed to pneumonia. The median follow-up time was 21 (2-46) months, 23 patients are alive to date, of which 22 patients have no leukemia and 1 patient has recurrent molecular MRD and still receiving treatment. The 2 years overall survival (OS) and leukemia-free survival (LFS) both reached 78.6% (95%CI 0.583-0.898). Among the 6 deceased patients, 1 patient with pre-HSCT NR did not achieve remission after transplantation and died of severe aGVHD, 2 patients died of recurrent leukemia after transplantation, and 3 patients died of severe infection. The non-relapse mortality (NRM) was 13.8% (4/29). After treatment, of the 10 patients with extramedullary lesions, 8 (8/10) were living without leukemia. Among the 15 patients with ABL1 gene T315I kinase region mutation, 13 (13/15) were leukemia-free survival. Of the 9 patients with a history of allo-HSCT, 6 (6/9) survived without leukemia. Among the 10 patients with pre-transplantation CR MRD+ status, 8 (8/10) were leukemia-free after transplantation, the 2 years LFS was 80% (95%CI 0.527-0.869). Conclusion: Our results indicate that CAR-T bridging to allo-HSCT is safe and effective for patients with r/r ph+ ALL. The 2 years OS and LFS both reach to 78.6%. The risks associated with treatment are acceptable. Even for patients with extramedullary lesions, patients with mutations in the T315I kinase region of ABL1 gene, and patients with a history of allo-HSCT, good results can be achieved, indicating that CART bridging to allo-HSCT appear to overcome above adverse prognostic factors. Although a proportion of Ph+ALL patients (this proportion seems to be higher than Ph-ALL) still can not achieve CR MRD- after CART treatment, this does not prevent patients from transplantation carrying MRD and achieving good results (2 years LFS is 80%). Therefore, in clinical practice, if it is very difficult for patients to obtain CR MRD-, allo-HSCT is also recommended.

Blinatumomab with Tyrosine Kinase Inhibitor for Ph-Positive B-Acute Lymphoblastic Leukemia (B-ALL): Multicenter Retrospective Review

Background: Ph-positive B-ALL has long been considered an adverse cytogenetic abnormality in ALL, and it is generally recommended to proceed with a stem cell transplant (SCT) in first remission. Historically, the addition of Tyrosine Kinase Inhibitors (TKI) to the stander chemotherapy backbone improved long-term survival, with better results noted in the second-generation than in first-generation TKIs. Recent reports on a non-chemotherapy-based approach with the combination of immunotherapy (Blinatumomab) and TKI showed encouraging results and potentially eliminated the need for consolidative SCT (Foà NEJM 2020, Jabbour Lancet Haematol 2023). In this retrospective analysis, we reviewed all Ph-positive B-ALL treated with blinatumomab and TKI at two major academic centers. Methods: A retrospective review of adolescents and adults (14 years or older) with Ph-positive B-ALL patients who received blinatumomab with TKI at two major institutions (KFSHRC & KFMC) between 7/2018 and 7/2023. Patients who received up to 3 cycles of chemotherapy before being transitioned to therapy with blinatumomab and TKI were considered as frontline if there was no history of relapsed disease. Relapse/refractory patients with Ph-positive B-ALL treated with blinatumomab and TKI were also included in the R/R cohort, excluding patients with prior single-agent exposure to blinatumomab or ponatinib. Patients with a history of CNS disease were included. Chronic myeloid leukemia in a lymphoid blast phase (LBP-CML) treated with blinatumomab and TKI were also included. Patients were assessed for toxicity as well as for efficacy. Results: We identified 17 patients, with a median age of 40 yrs (range, 15-78): 9 pts (53%) were frontline Ph-positive B-ALL, 5 (29%) pts were relapsed/refractory Ph-positive B-ALL, and 3 (18%) were LBP-CML patients. Pt characteristics and outcomes by cohort are outlined in Table. All patients in all the cohorts achieved complete remission and were included in the RFS analysis [ Figure]. Of 7 evaluable pts in the frontline cohort, all patients achieved complete molecular response (CMR) using PCR for BCR::ABL (CMR=100%). No relapse was documented, with a median follow-up of 6.9 months. In the relapse/refractory cohort, all patients achieved complete molecular response (CMR) using PCR for BCR::ABL (CMR=100%). No relapse was documented, with a median follow-up of 6.7 months. In 3 patients with LBP-CML, two patients achieved complete molecular response (CMR) using PCR for BCR::ABL, and one patient achieved MMR (0.036%). No relapse was documented, with a median follow-up of 19.7 months. Only four patients proceeded to SCT, two with LBP-CML and two with newly diagnosed Ph-positive B-ALL. All patients proceeded with SCT in CMR except one with LBP-CML with positive PCR for BCR::ABL at 0.03%, although with undetectable MRD by flow cytometry (<0.01%). Patients were treated with dasatinib (4 patients) and ponatinib (13 patients). The median number of blinatumomab cycles was 4 (1-5). One death occurred at seven months in a patient treated with dasatinib and blinatumomab. The patient presented to the emergency department with pleural effusion and cardiac tamponade and died during her ICU stay with infectious complication. The death is likely contributed to by dasatinib. Conclusion: Although with short follow-up, combining TKI with blinatumomab seems to have a high complete molecular response rate in patients with newly diagnosed and relapsed/refractory Ph-positive B-ALL. Similar to prior reports, patients with newly diagnosed Ph-positive B-ALL perhaps they could be spared the toxicities associated with chemotherapy and the need for allogeneic hematopoietic stem-cell transplantation in the first remission using this approach. Further evaluation of this novel strategy is warranted.

Outcomes of Philadelphia Positive Acute Lymphoblastic Leukemia in Adolescent and Young Adults.

Background Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) accounts for 25% of acute lymphoblastic leukemia cases in the adolescent and young adult (AYA) age subgroup. It is associated with poor outcomes and is considered a standard indication for allogeneic stem cell transplant (Allo-SCT). Improved outcomes have been reported with addition of tyrosine kinase inhibitors (TKIs) to chemotherapy in children and the role of Allo-SCT is now being debated in the first remission. Complete response (CR) at three months is associated with improved survival even without Allo-SCT in first CR. In this study, we have analyzed disease-free survival (DFS), overall survival (OS), and factors affecting survival outcomes of Ph+ALL in the AYA subgroup, in resource-limited settings treated with chemotherapy and TKIs. Materials and methods This is a retrospective, multicenter cohort study of Ph+ ALL AYA patients, aged 18-40 years, and registered between January 2015 and December 2020. Primary objectives are to calculate disease-free survival (DFS) and overall survival (OS). Secondary objectives are to identify prognostic factors affecting response rates and outcomes. List of cases was obtained from hospital information system (HIS) and data were collected from patient case notes and electronic medical records. Data analysis was done utilizing the SPSS statistical program (Armonk, NY: IBM Corp.). Results Forty-nine patients were identified with Ph+ ALL with a median age of 23 years (range: 18-40 years) and a male-to-female ratio of 2.5:1. None of the patients had central nervous system (CNS) disease. White cell count was >30,000 per mm3 in 26% of patients, while 13% had additional cytogenetic abnormalities. Thirty-three percent patients received adult (hyper-cyclophosphamide, vincristine, Adriamycin, and dexamethasone {CVAD}) protocols while 67% received pediatric-inspired (Berlin-Frankfurt-Munster {BFM} 2000 or UK-ALL 2003/2011) protocols. TKI therapy was received by 66% of patients during treatment (early: 37%; late: 29%) and 34% did not receive TKIs due to financial constraints. CR after induction was achieved in 69% cases. Induction mortality was 16%. The median DFS for the entire cohort was 27 months (0.93-53.06) and the median OS was 29 months (8.89-49.10). The median OS in Allo-SCT group was not reached vs 8.0±8.8 months (p=0.05) with chemotherapy only. The OS was significantly better in patients with no additional cytogenetic abnormalities, pediatric-inspired chemotherapy protocols, early use of TKIs in induction phase, Allo-SCT, and post-Allo-SCT use of TKIs. Conclusion Addition of TKIs to pediatric-inspired chemotherapy protocols in Ph+ALL AYA patients and Allo-SCT results in better overall survival. TKI availability remains a significant issue in low-income countries due to significant financial burden on the patients. Allo-SCT continues to be an attractive option, particularly in low-income countries providing an option for cure in Ph+ ALL.

Towards chemotherapy-free treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia

The addition of tyrosine kinase inhibitors (TKIs) to conventional chemotherapy backbones for adults with newly diagnosed Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia has substantially improved treatment outcomes.1,2 However, the long-term outcomes are still unsatisfactory, with treatment-related resistance and toxicity. Over the past 10 years, several clinical trials have incrementally shown improved outcomes and reduced toxicity for these patients. These steps include the upfront use of the third-generation TKI ponatinib, which is active against the gatekeeper mutation, Thr315Ile, in the ABL1 tyrosine kinase domain.

Pediatric Acute Lymphoblastic Leukemia with Pdgfrb Fusions: A Multicenter Retrospective Study

Objective: PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. PDGFRB fusions was mainly observed in B-ALL, but also in T-ALL. Previous studies were mostly limited to anecdotal cases, suggesting that this subtype of ALL had low rate of remission and poor prognosis. The addition of tyrosine kinase inhibitor (TKI) to intensive chemotherapy may improve the outcome, but lack of long-term survival data. Herein, we retrospectively analyzed the clinical characteristics, survival and prognostic factors for 28 pediatric patients with PDGFRB fusions ALL. Methods: This multicenter, retrospective study included pediatric patients with newly diagnosed PDGFRB fusion ALL after treatments according to the CCCG-ALL-2015 and CCCG-ALL-2020 protocols from April 2015 to April 2022 in 10 hospitals in China. All patients completed the followed up. The baseline characteristics and treatment outcomes of these patients, including complete remission, drug resistance, relapse, treatment-related mortality and minimal residual disease (MRD) at end of induction therapy, as well as hematopoietic stem cell transplantation (HSCT) were collected. The outcome was compared between patients treated with and without TKI. Fisher test and nonparametric rank sum test were used for comparative analysis. 4-year event-free survival (EFS) and 4-year overall survival (OS) were estimated by use of Kaplan-Meier methods, and the 4-year cumulative incidence of relapse was calculated by use of a competing risk model gray test. Univariate and multivariate analyses were performed by use of Cox regression. Results: We identified 28 pediatric patients with newly diagnosed PDGFRB fusion ALL, which accounted for approximately 0.5% of childhood ALL. In all 28 patients, 21 (75%) were male and 7 (25%) were female; the median age was 10 (1-16) years old; median white blood cell (WBC) was 29.8 (1.6-627.7) × 10^9/L; 24 (85.7%) were acute B-lymphoblastic leukemia and 4 (14.3%) were acute T-lymphoblastic leukemia; one case (3.5%) was observed accompanied by the CNS involvement at diagnosis. Twenty of the patients received TKI treatment. Only 6 patients underwent hematopoietic stem cell transplantation. For all 28 patients, the median follow-up was 25.5 (3-77) months, the 4-year EFS was 29.2% (95% CI, 13.6-36.4), the 4-year OS was 42.1% (95% CI, 30.6-61.4), and the 4-year cumulative incidence of relapse was 58% (95% CI, 45·6-70·1). Patients in TKI group had a high rate of complete remission after induction therapy compared with those in no-TKI group (90% vs 63.6%). However, no significant differences were observed in the 4-year EFS and 4-year OS between TKI group and no-TKI group (EFS, 21.1% vs 43.8%, P=0.925; OS, 50.1% vs 36.5%, P=0.807). The cumulative incidences of relapse between these two groups also have no remarkable differences (P >0.05). Among the 6 patients who underwent HSCT, 2 patients who achieved CR1 survived and 4 died. Univariate analysis showed that minimal residual disease (MRD) ≥10-4 after induction therapy for D46 and IKZF1 positive had a poor prognosis (all P <0.05). MRD≥10-4 at the end of induction therapy is an independent risk factor for poor prognosis (hazard ratio of event-free, 9.101 [95% CI 2.03-40.86], P =0·004, compared to those with a MRD of <10-4). Conclusion: Pediatric ALL patients with PDGFRB fusions have a poor outcome. This subtype of ALL is associated with high-risk clinical features such as older age, high WBC count at diagnosis, high MRD after induction therapy, and increased risk of leukemia relapse. The addition of TKI to chemotherapy can improve the early remission rate of treatment, but does not improve the long-term survival. Profitably, the TKI treatment can provide an opportunity for subsequent treatment, including HSCT. Additionally, HSCT has indeed potential to reduce the relapse rate for this subtype patients. HSCT is recommended for this subtype patients who achieve CR1. The MRD≥10-4 or more at the end of induction therapy was independently predictive factor for unfavorable outcome and stratified treatment based on MRD may improve survival of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preliminary Results of Phase II Study on Preoperative Intensity-Modulated Radiotherapy with Concurrent Tyrosine Kinase Inhibitor for Patients with Non-Metastatic Extremity and Trunk Soft Tissue Sarcoma

<h3>Purpose/Objective(s)</h3> Preoperative radiotherapy (RT) is one of the recommended treatments for primary extremity and trunk soft tissue sarcoma, however, the pathological remission is relatively low, and survival is not improved. We hypothesized that the addition of tyrosine kinase inhibitor (TKI) will improve the pathological remission rate without significant increase of major wound complications (MWCs). <h3>Materials/Methods</h3> Two phase II study were initiated in our center. Primary or recurrent non-metastatic extremity or trunk soft tissue sarcoma was enrolled. Patients received preoperative intensity-modulated radiotherapy (IMRT) of 50Gy in 25 fractions with concurrent and sequential Anlotinib (12 mg QD for 2 weeks, 3 cycles in total) or Apatinib (500 mg QD, 5 days per week, for 9 weeks in total), followed by wide resection. NCI-CTC 5.0, RECIST 1.1 criteria, and EORTC-STBSG criteria was used to evaluate acute toxicities, clinical response and pathological grading. The primary endpoint was defined as MWCs as per the SR2 criteria within 4 months post-surgery. <h3>Results</h3> From Jul 2020 to Dec 2021, 31 patients were enrolled and completed RT. The median onset age is 55 (22-82) years old. There are 26 and 5 patients with primary untreated and locally relapsed disease, respectively. The median tumor size is 10.5 (3.7-19.5) cm, with 23 patients (74.2%) larger than 8cm. Twenty-seven tumors (87.1%) were evaluated as unresectable or borderline resectable, which was defined as impossible or difficult to conserve limb with non-R2 wide resection. There were 21, 9 and 1 patients having Anlotinib, Apatinib and none, respectively. All except 5 took TKI as per protocol, with 4 patients having dose reduction due to Grade 3 toxicities. The observed ≥Grade 3 toxicities are: hypertension in 4 patients (19.1%) in Anlotinib group and 2 patients (22.2%) in Apatinib group, and one Grade 4 hepatotoxicity in Apatinib group (11.1%). There are 14 (14/30, 46.7%) and 16 patients (16/30, 53.3%) who achieved partial response (PR) and SD as per RECIST 1.1 criteria at 1-month post-radiotherapy, respectively. All the patients who had PR had obvious tumor shrink at the first 1 to 2 weeks during radiotherapy. Six out of 24 patients (25%) who underwent wide resection with at least 6 weeks follow-up had MWCs, with all in lower extremity. There were 4 (4/26, 15.4%), 3 (3/26, 11.5%) and 3 (3/26, 11.5%) patients achieving pathological Grade A, B, and C remission as per EORTC-STBSG criteria, respectively. All the 22 patients with unresectable or borderline resectable tumor had non-R2 limb-conserving wide resection, with 18 R0 and only 4 R1 resection. <h3>Conclusion</h3> For patients with non-metastatic extremity or trunk primary sarcoma, the combination of TKI and pre-operative RT is safe and well-tolerated, and achieve favorable clinical and pathological response. The earlier response with addition of TKI made more patients with unresectable or borderline resectable tumor completely resected by limb-conserving wide resection. NCT05167994, NCT05235100

ALL-004 Philadelphia Chromosome-Positive T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma: A Rare Case Report

T-acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) is a rare and aggressive leukemia. Philadelphia chromosome-positive (Ph+) T-ALL is exceedingly rare and has therapeutic and prognostic significance. The case study herein is a very rare presentation. A case report of a 52-year-old Egyptian female, who presented in 2012 with a 2-month history of fatigue, bone aches, and abnormal vaginal bleeding. Oncology Center Mansoura University. The patient appeared pale with significant splenomegaly. Complete blood count: white blood cell count 6.9 k/µL, microcytic hypochromic anemia with hemoglobin 10.4 g/dL, and platelet count 149 k/µL. A peripheral blood smear showed neutrophil toxic granulation. Bone marrow aspirate (BMA) was infiltrated with 45% blasts, and myeloid and erythroid series were suppressed. No significant dysplasia was noted. Flow cytometry analysis performed on BMA showed an abnormal population of blasts expressing TdT (20%), cytoplasmic CD3 (35%), CD7 (64%), CD2 (62%), CD5 (61%), CD1a (0.38%), CD4 (27%), CD8 (32%), CD10 (3.6%), CD117 (5.4%), CD 34 (2.41%), and CD79a (27%), revealing a case of ALL (T-cell lymphoblastic lymphoma/leukemia). The fluorescence in-situ hybridization (FISH) analysis performed on interphase nuclei obtained from a BMA sample revealed a dual-fusion hybridization signal pattern for BCR and ABL1 probes on chromosomes 9 and 22, indicating t(9:22) in 100%. Cytogenetic analysis revealed an abnormal complex karyotype, 46,XY,t(9;22),(q34;q11.2)[25], in all counted cells. BCR-ABL1 gene rearrangement by quantitative real-time PCR was 100% IS. The patient was diagnosed with a case of T-ALL/LBL with t(9;22);BCR-ABL1 (Ph+). The patient started the MRCUK protocol in combination with imatinib 400 mg/d. She finished maintenance therapy on 10/12/2016. The patient is still on imatinib 400 mg/d. The patient is still in complete remission and in deep molecular response with no detectable minimal residual disease. Ph+ T-ALL is rare. Differentiation between Ph+ T-ALL/LBL and T-LB crisis of chronic myeloid leukemia (CML) was difficult because it is diagnosed with no prior history of CML. The addition of tyrosine kinase inhibitors to intensive chemotherapy has greatly improved the outcomes of Ph+ ALL patients.

Innovative Approaches to the Management of Acute Lymphoblastic Leukemia Across the Age Spectrum.

Adults compose nearly half of all patients diagnosed with acute lymphoblastic leukemia (ALL) and historically have had poor survival compared with pediatric patients. Recently approved therapies, such as monoclonal antibodies, CAR T-cell constructs, and next-generation tyrosine kinase inhibitors, have improved survival in relapsed and refractory ALL, and studies are now examining incorporating these treatments and others into the upfront setting. In adolescent and young adult patients, use of pediatric-based regimens has already improved survival compared with historical controls, and the addition of monoclonal antibodies, such as inotuzumab ozogamicin and blinatumomab, may further enhance this survival benefit. In older adults, approaches have centered on minimizing conventional chemotherapy to decrease toxicity by incorporating monoclonal antibodies and other novel therapies to increase efficacy. With the addition of tyrosine kinase inhibitors to chemotherapy for patients with Philadelphia chromosome-positive ALL, survival of this once poor-prognosis ALL subtype now approaches or exceeds outcomes of other subtypes of adult ALL. Further refinements in the backbone treatment regimen and optimal consolidation approaches will likely improve survival further. Although allogeneic hematopoietic stem cell transplant was previously routinely used as consolidation for adults with ALL, incorporation of measurable residual disease and other risk stratification strategies has enabled better identification of patients who will benefit from allogeneic hematopoietic stem cell transplant. Ongoing clinical trials investigating these approaches will continue the evolution of treatment approaches for adults with ALL, with further improvement in outcomes anticipated.

Addition of tyrosine kinase inhibitors (TKIs) in patients (pts) with unresectable hepatocellular carcinoma (HCC) who progress on first-line immunotherapy (IO).

e16193 Background: Atezolizumab plus bevacizumab is now standard first-line therapy for advanced HCC. Early phase trials in HCC and phase III trials in other solid tumors testing IO and TKI have shown greater antitumor activity with the combination than with either agent alone. Cancer and vascular endothelial cells release VEGF, which not only increases angiogenesis, promoting tumor growth, but also induces an immunosuppressive tumor microenvironment (TME). Preclinical studies suggest that TKIs with anti-VEGF activity have immunomodulatory potential, enabling the infiltration and activation of effector T cells to the TME. Experimental models of HCC with combination of IO plus TKI also reverted immune escape mechanisms mediated by β-catenin, Wnt, and TGFβ activation and by Treg or neutrophil infiltration. At our institution, pts who were treated with IO alone in the front line often had a TKI added on progression of disease (PD). We aimed to evaluate whether the addition of a TKI could rescue IO failure. Methods: We conducted an IRB-approved retrospective chart review of pts with unresectable HCC at Mount Sinai Health System who received IO from 1/2017 to 6/2021 and who subsequently received a TKI on PD. We assessed the objective response rate (ORR), median progression-free survival (mPFS) and overall survival (mOS). Follow-up CT/MRI imaging studies were conducted every 2-3 months after addition of TKI. Results: Of 277 pts who received first-line IO during the study period, 46 evaluable pts subsequently had TKIs added to IO upon PD. Pts were predominantly male (37/46), with median age 63 years, and 38 had cirrhosis. Etiologies of HCC were as follows: 9 HBV, 22 HCV, 15 alcohol-related, 7 NASH-associated. All pts received first-line nivolumab. TKIs added were lenvatinib (44/46) and sorafenib (2). At the start of IO, most pts (31/46) had Child Pugh class A liver disease and performance status ECOG 0 (31/46). TKIs were added upon PD and after a median of 5.8 months (range 2.1-28.1 months) from IO initiation. ORR of IO plus TKI was 15% (7/46; 2 complete responses and 5 partial responses). 16 pts had stable disease, and 13 had PD. Among the 11/46 pts who initially responded to first-line IO, 2 achieved a response with TKI. There were 5 responses among the 35/46 non-responders to first-line IO. TKI-related grade 3-4 adverse events, including liver toxicity, rash, and encephalopathy, led to discontinuation in 7/46 pts. mOS after adding TKI was 9.5 months (95% CI: 6.1-13.7) and mPFS was 5.4 months (95% CI: 3.6-9.7). The mOS and mPFS of adding TKI after PD did not differ between IO initial responders and non-responders. Overall, mOS from IO initiation was 17.6 months (95% CI: 14.5-24.4). Conclusions: Adding a TKI after PD on single agent IO in pts with advanced HCC did not add a signal of clinical benefit compared with reported outcomes from second-line TKIs alone.

What Is the Role of HSCT in Philadelphia-Chromosome-Positive and Philadelphia-Chromosome-Like ALL in the Tyrosine Kinase Inhibitor Era?

Previously, the outcome of paediatric Philadelphia-chromosome–positive (Ph+) ALL treated with conventional chemotherapy alone was poor, necessitating the use of haematopoietic stem cell transplantation (HSCT) for the best outcomes. The recent addition of tyrosine kinase inhibitors (TKIs) alongside the chemotherapy regimens for Ph+ ALL has markedly improved outcomes, replacing the need for HSCT for lower risk patients. An additional poor prognosis group of Philadelphia-chromosome–like (Ph-like) ALL has also been identified. This group also can be targeted by TKIs in combination with chemotherapy, but the role of HSCT in this population is not clear. The impact of novel targeted immunotherapies (chimeric antigen receptor T cells and bispecific or drug-conjugated antibodies) has improved the outcome of patients, in combination with chemotherapy, and made the role of HSCT as the optimal curative therapy for Ph+ ALL and Ph-like ALL less clear. The prognosis of patients with Ph+ ALL and persistent minimal residual disease (MRD) at the end of consolidation despite TKI therapy or with additional genetic risk factors remains inferior when HSCT is not used. For such high-risk patients, HSCT using total-body-irradiation–containing conditioning is currently recommended. This review aims to provide an update on the current and future role of HSCT for Ph+ ALL and addresses key questions related to the management of these patients, including the role of HSCT in first complete remission, MRD evaluation and related actions post HSCT, TKI usage post HSCT, and the putative role of HSCT in Ph-like ALL.

Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Positive Acute Lymphoblastic Leukemia in First Complete Remission: A Systematic Review and Meta-Analysis

IntroductionPhiladelphia positive (Ph+) acute lymphoblastic leukemia (ALL) presents with an aggressive clinical course and carries a high risk for relapse. The addition of tyrosine kinase inhibitors (TKI) has revolutionized the induction and maintenance treatment for this disease and has increased the patients achieving and maintaining complete remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care at this time for patients who achieve first complete remission (CR1); however, its impact on outcomes is debated. This systematic review and meta-analysis aimed to compare the outcomes of TKI maintenance therapy with or without HSCT in Ph+ ALL patients in CR1.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for “ Philadelphia chromosome ”, “hematopoietic stem cell transplantation” and “ protein kinase inhibitors ” from date of inception to May 01, 2021. A total of 1691 records were discovered using database searching. All search results were imported into the Endnote X9.0 reference manager, and duplicates were removed. The primary and secondary screening was performed, and after excluding irrelevant and review articles, a total of 6 (3 retrospectives, 3 phase II randomized controlled trials) original articles were included reporting separate outcomes of TKI maintenance therapy (TKI cohort) and HSCT followed by TKI maintenance therapy (HSCT-TKI cohort) for Ph+ ALL in CR1. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with a 95% Confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the RevMan (version 5.4-1). RESULTSA total of 413 patients from 6 studies were included for this systematic review and meta-analysis. Out of these, 222 (53.8%) had TKI maintenance after consolidation therapy and 191 (46.2%) patients had HSCT followed by TKI maintenance in CR1. The median age of the whole cohort was 49.3 (17-84) years, while the median age for HSCT-TKI patients was 47 (14-84) years. The proportion of males was 26.2% (n=90) in TKI group versus 37.5% (n=137) in the HSCT-TKI group, as reported by 5 studies. The median follow-up was 28 (0.6-149) months. Imatinib mesylate (first-generation TKI) was used in 55.6% (n=125) patients and Dasatinib (second-generation TKI) was given to 44.4% (n=100) patients. (Table 1) Overall survival (OS) was reported from 100% and 93.3% at 1 year to 49% and 33% at 5 years for TKI and HSCT-TKI cohorts, respectively. At median follow-up time of 4 (3-5) years, a trend towards poor OS was seen with TKI group as compared to HSCT-TKI group (OR 0.46, 95% CI 0.17-1.23, I 2=70%); however, the association was not statistically significant. Disease-free survival (DFS) was reported from 49.3% and 71.3% at 4 years to 38.1% and 50.5% at 5 years for TKI and HSCT-TKI cohorts, respectively. At a median follow-up time of 4 (3-5) years, the pooled analysis showed poor DFS for TKI as compared to HSCT-TKI cohort (OR 0.30, 95% CI 0.17-0.53, I 2=0%). Four studies (n=292) reported separate outcomes for relapse, it was 59.1% (87/147) for TKI versus 14.5% (n=21/145) for HSCT-TKI patients, and odds of developing relapse were higher among patients receiving TKI as compared to HSCT-TKI (OR=8.08, 95% CI=3.81-17.14, I 2=0%). ConclusionHematopoietic stem cell transplant in Philadelphia positive acute lymphoblastic leukemia in first complete remission followed by tyrosine kinase inhibitor maintenance therapy confers disease-free and overall survival benefit compared to tyrosine kinase inhibitors maintenance alone. Our findings confirm HSCT as a standard of care in Ph+ ALL in CR1 followed by TKI maintenance and the need for a prospective randomized clinical trial to validate these findings. [Display omitted] DisclosuresLin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding.

Early Maintenance with Tyrosine Kinase Inhibitors Post Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Improves Survival in Ph+ Acute Lymphoblastic Leukemia (ALL) Patients

Introduction: Addition of tyrosine Kinase inhibitors (TKI) to induction chemotherapy in management of Philadelphia chromosome positive (Ph+) ALL has significantly improved remission rates prior to allogeneic HSCT compared to the pre-TKI era. Consolidation with HSCT further prolongs remission and is potentially curative in the majority of patients. However, relapse is the commonest cause of treatment failure post HSCT with the highest incidence occurring within 18 months post-transplant. One possible strategy to minimize the risk of relapse is to commence TKI maintenance early post transplantation; which is increasingly becoming a common practice in many centers. However long term efficacy of this approach has not been established.Methods: A retrospective search for Ph+ ALL patients undergoing allogeneic HSCT from March 2001 to September 2015 (n=150) at our center was performed. From this cohort to determine the impact of prophylaxis we identified a subgroup of patients (n=99) who were in complete molecular response (CMR) before day +90 post HSCT. Subsequently we performed a day +90 landmark analysis to examine the outcome for patients according to whether or not they had commenced TKI maintenance by day +90 in a univariate and multivariate model. TKI maintenance was recommended but the final decision was based on feasibility and patient/physician preference.Results: Of the 99 patients included in the landmark analysis, 58.6% were men and 41.4% were women. Median age of study participants at the time of HSCT was 40 (range 3-64) years with a median follow up duration of 5.2 (range 1.1-15.0 ) years. At time of HSCT, 74.7% patients were in CR1, 16.2% were in CR2, and 9.1% were beyond CR2 or had primary induction failure. The majority of patients (97%) received a myeloablative preparative regimen, including radiation therapy in 31.3%. The median duration of TKI maintenance was 12.1 months (range 1-74 months). Imatinib was the commonest TKI used. Patients who received TKI maintenance (n=38) had superior 10-year probability of PFS and OS compared to patients who did not receive maintenance (n=61) at 68.1% vs 44.8%, p=0.005, and 67.1% vs 47.8%, p=0.004, respectively (Figure 1). TKI maintenance (HR=0.282, CI=0.122-0.654, p=0.001) and disease status pre-HSCT (beyond CR1) (HR=2.909, CI=1.286-6.577, p=0.01) were the two independent predictors for PFS in the multivariate model. Similarly, TKI maintenance (HR=0.244, CI=0.098-0.608, p=0.001) and disease status pre-HSCT (beyond CR1) (HR=3.394, CI=1.449-7.948, p=0.03) were the two independent predictor for OS. Both groups appeared to be well matched for several transplant/disease/treatment related variables.Conclusion: Prophylactic TKI maintenance early post allo-SCT is feasible and is associated with improved PFS and OS. Future prospective studies are needed to define the optimal duration of TKI maintenance to further improve outcomes for this historically adverse group. [Display omitted] DisclosuresOran:Celgene: Research Funding; AROG: Research Funding; Astex: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Kantarjian:Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding.

Discontinuation of Maintenance Tyrosine Kinase Inhibitors in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia outside of Transplant

Background: The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy has dramatically improved outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). When allogeneic hematopoietic stem cell transplant (HSCT) is performed, maintenance TKI is generally given for a fixed duration. However, the optimal duration of TKI outside of HSCT remains unknown, and the common practice is to continue indefinitely. Here, we report characteristics and outcomes of 9 patients treated with chemotherapy + TKI without HSCT and later discontinued TKI. Methods: Among 188 patients with Ph-positive ALL who did not undergo HSCT, 9 of them discontinued maintenance TKI mainly due to side effects. Patients were closely monitored with serial PCR testing for the BCR-ABL1 transcript. Major molecular response (MMR) was defined as BCR-ABL1 transcript ≤0.1% on the international scale for p210 transcripts and a 3-log reduction from baseline for p190 transcripts. Deep molecular remission (DMR) was defined as the absence of quantifiable BCR-ABL1 transcripts with a sensitivity of 0.01%. Molecular relapse was defined as loss of MMR. Treatment-free remission (TFR) was defined from time of TKI discontinuation to molecular relapse, last follow-up, or death from any cause. Results: At the time of TKI discontinuation, transcript level was undetected in 6 patients, <0.01% in 2 patients, and 0.01% in another patient. Prior to discontinuation, the median duration of TKI therapy and of DMR was 70 and 47 months, respectively. No morphological relapse occurred. Three patients (33%) had molecular relapse at a median of 6 months. All 3 resumed TKI therapy, and 2 of them regained DMR after a median of 13 months. After a median follow-up of 49 months, the median TFR was not reached, and the 4-year TFR rate was 65%. The median duration of DMR in patients with and without molecular relapse was 22 and 58 months, respectively (p = 0.096). Conclusion: TKI discontinuation outside of HSCT in Ph-positive ALL in the setting of compelling toxicity may be safe only among a highly selected group of patients with deep and prolonged DMR undergoing close and frequent monitoring. Validation of these findings in prospective clinical trials is highly needed.

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Prognostic Significance of Genetic Alterations in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Hyper-CVAD Plus Dasatinib or Hyper-CVAD Plus Ponatinib

Prognostic Significance of Genetic Alterations in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Hyper-CVAD Plus Dasatinib or Hyper-CVAD Plus Ponatinib

Low Level BCR-ABL1 Gene Fusion Detected By RT-PCR in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia Does Not Predict Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia at Relapse: A 10-Year Single Institution Study

Background The Philadelphia chromosome t(9;22), a reciprocal translocation between chromosomes 9 and 22, results in the gene fusion BCR-ABL1, and occurs in 2-3% of childhood acute lymphoblastic leukemia (ALL). It is detected using cytogenetic and molecular techniques: karyotype, fluorescence in-situ hybridization (FISH) for t(9;22) and reverse transcription polymerase chain reaction (RT-PCR) for BCR-ABL1. Detection has implications for treatment, with the addition of tyrosine kinase inhibitors to chemotherapy regimens improving outcome. Low level BCR-ABL1 transcripts have been reported in blood of healthy individuals. We have observed this finding in bone marrow in newly diagnosed ALL in the absence of the t(9;22) by karyotype or FISH. The significance of low level positivity at diagnosis has not been determined in the setting of childhood Philadelphia chromosome negative (Ph-) ALL. Here we report, for the first time, the molecular evolutionary characteristics of children and adolescents with low level BCR-ABL1 positivity found at diagnosis to relapse. Methods We reviewed 327 patients aged 0-17 years diagnosed with ALL or Acute Leukemia of Ambiguous lineage (ALAL) at The Children's Hospital at Westmead, Sydney, Australia from 1 January 2010 to 30 June 2020. Those positive for the BCR-ABL1 gene fusion by RT-PCR, and negative for t(9;22) by karyotype or FISH were included. Demographics, cytogenetics at diagnosis and relapse, and outcome data were extracted from the medical record. Qualitative BCR-ABL1 analysis was performed using multiplex RT-PCR, followed by nested PCR, on RNA extracted from diagnostic bone marrow (sensitivity 5x10-6). If positive, quantitation was performed using real-time RT-PCR with results expressed as the ratio of BCR-ABL1 over ABL1 (sensitivity 1x10-5). Each PCR included positive and negative controls. Results Of 313 (96%) evaluable patients diagnosed with ALL or ALAL at our institution in the study period, 54 (17%) were positive by RT-PCR for BCR-ABL1 in diagnostic bone marrow. Seven patients were excluded as they had Ph+ ALL-specific treatment after the detection of t(9;22) by karyotype, FISH or other methods. Forty-seven (15%) children with Ph- ALL had low level BCR-ABL1 detected by qualitative PCR. Demographic and cytogenetic characteristics for these patients are summarized in Table 1. All were diagnosed with ALL, the majority (77%) of precursor B-cell lineage including 2 with infant ALL. The e1a2 transcript was identified in 43 (91%) patients, with other transcript types as follows: e4a2 in 1 (2%), e13a2 in 1 (2%), and splicing variants in 2 (4%). BCR-ABL1 quantitation was performed in 43 (91%) and was quantifiable only in 12 (28%) patients, with a median of 0.0008% (range 0.0003 - 0.095%). Forty-five (96%) patients were treated with Berlin-Frankfurt-Munster ALL chemotherapy regimens. The two infant ALL patients were treated on the Interfant06 trial. One received a bone marrow transplant (BMT) in first remission then died after relapse; the other relapsed and died before BMT. Seven (15%) of 47 relapsed, occurring at a median of 21 months (range 2 - 41 months) after diagnosis. Characteristics of these patients are presented in Table 2. Four patients were tested for BCR-ABL1 by RT-PCR in relapse marrow samples; all were negative. No patient with low level BCR-ABL1 positivity at initial diagnosis was diagnosed with Ph+ ALL at relapse. There was no difference in 5-year relapse-free (80% vs 83%, P = .451) or overall survival (86% vs 91%, P = .368) between children with low level BCR-ABL1 positivity (n=47) and those without (n=259). Conclusion BCR-ABL1 low level positivity detected by RT-PCR in the bone marrow of children with newly diagnosed ALL is a relatively common finding, and did not adversely affect outcome for patients treated for Ph- ALL using a contemporary risk-adapted approach. Importantly, this finding did not influence the molecular evolutionary characteristics at the time of relapse in our patient group. Disclosures No relevant conflicts of interest to declare.

Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL.

Children and adults with Philadelphia chromosome-like B cell acute lymphoblastic leukemia (Ph-like B-ALL) experience high relapse rates despite best-available conventional chemotherapy. Ph-like ALL is driven by genetic alterations that activate constitutive cytokine receptor and kinase signaling, and early-phase trials are investigating the potential of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy to improve clinical outcomes. However, preclinical studies have shown that JAK or PI3K pathway inhibition is insufficient to eradicate the most common cytokine receptor-like factor 2-rearranged (CRLF2-rearranged) Ph-like ALL subset. We thus sought to define additional essential signaling pathways required in Ph-like leukemogenesis for improved therapeutic targeting. Herein, we describe an adaptive signaling plasticity of CRLF2-rearranged Ph-like ALL following selective TKI pressure, which occurs in the absence of genetic mutations. Interestingly, we observed that Ph-like ALL cells have activated SRC, ERK, and PI3K signaling consistent with activated B cell receptor (BCR) signaling, although they do not express cell surface μ-heavy chain (μHC). Combinatorial targeting of JAK/STAT, PI3K, and "BCR-like" signaling with multiple TKIs and/or dexamethasone prevented this signaling plasticity and induced complete cell death, demonstrating a more optimal and clinically pragmatic therapeutic strategy for CRLF2-rearranged Ph-like ALL.

Combination therapy with nivolumab and tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma.

e17090 Background: Two immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations are FDA-approved for patients (pts) with metastatic renal cell carcinoma (mRCC). Here we present a multicenter off-protocol experience with IO/TKI combinations after progression on monotherapy. Methods: We performed a retrospective analysis of pts with mRCC who received combination non-FDA approved off-protocol IO/TKI combination therapy from 11/2015 – 1/2019 at MD Anderson Cancer Center and Duke Cancer Institute. Results: 48 pts met criteria for study inclusion. At therapy start: median (med) age 65 years; 75% clear cell histology; 68.8% IMDC intermediate risk (20.8% favorable, 10.4% poor); 81.3% prior nephrectomy; med metastatic sites: 2; med prior systemic treatments: 2; most common metastatic sites: lung (58.3%), lymph node (52.1%), and bone (43.8%). Pts received nivolumab (nivo) in combination with the following: cabozantinib (n = 24, 50%), pazopanib (13, 27.1%), axitinib (6, 12.5%), lenvatinib (2, 4.2%), ipilimumab/cabozantinib (3, 6.3%). Med PFS was 13.7 months and med OS was not reached. The two largest cohorts received nivo + cabozantinib (N+C; med dose 40 mg daily) or nivo + pazopanib (N+P; med dose 400 mg daily). The N+C cohort had higher med metastatic sites (3 vs 2) and was more pretreated with agents unique to their IO/TKI combination (med 2 vs 0). In the N+P group, more pts had started on TKI prior to addition of nivo at progression (69.2% vs 45.8%), and fewer had IO monotherapy with TKI addition (30.8% vs 50%). With a med follow up of 14.0 months after combination start, the N+C cohort had a med PFS of 7.3 months (initiated TKI first: 4.8, IO first: 8.2) and med OS of 18.2 months (TKI first: 11.8, IO first: 24.3). The N+P cohort had med follow up of 20.5 months after combination, med PFS of 21.3 months (TKI first: 16.5, IO first: 21.8), and med OS was not reached. In the N+C group, 87.5% experienced any grade adverse event (AE), most common included fatigue (79.2%), diarrhea (42.7%), nausea (29.2%), hypertension (29.2%), and weight loss (25.0%). In the N+P group, 92.3% experienced any grade AE, including fatigue (76.9%), hypertension (38.5%), diarrhea (30.8%), nausea (30.8%), and weight loss (30.8%). There were no grade ≥3 AEs. Conclusions: Slow disease progression on nivo or TKI may be safely controlled with addition of IO/TKI therapy. Med PFS after addition of nivo to TKI appears similar (N+C) and improved (N+P) compared to nivo monotherapy (Checkmate-025). Med PFS after addition of TKI to IO was also similar (N+C) and improved (N+P) compared to historical controls.

Modulation of oxidative stress/antioxidative defence in human serum treated by four different tyrosine kinase inhibitors.

Recent findings implied the significance of reactive oxygen species (ROS) as a part of tyrosine kinase inhibitors (TKIs) pharmacological activity. Evidences also suggested that toxic effects of TKIs were related to ROS production. The results regarding benefits of vitamin E usage alongside with prescribed TKIs therapy are ambiguous. We aimed to examine oxidative stress and antioxidative defense in human serum treated with four different TKIs and their possible interactions with hydrosoluble vitamin E analog (Trolox). An in-vitro experiment with serum pool as a substitute model was performed. Different parameters of oxidative stress and antioxidative defense were measured in serum pool with and without addition of TKIs (axitinib, crizotinib, nilotinib, and imatinib), before and after addition of Trolox. Z score statistic was used for calculation of Prooxidative and Antioxidative scores. The highest oxidative potential was recorded for samples incubated with imatinib and nilotinib, while the lowest damaging scores were observed for crizotinib and axitinib (nilotinib vs. imatinib, P < 0.05; axitinib vs. imatinib, P < 0.01; crizotinib vs. imatinib, P < 0.001). The best capability for antioxidative protection was seen in samples with nilotinib, then with imatinib, while the lowest level was obtained in samples with crizotinib and axitinib (imatinib and axitinib vs. nilotinib, P < 0.05 for both; crizotinib vs. nilotinib, P < 0.01; axitinib vs. imatinib, P < 0.05, crizotinib vs. imatinib, P < 0.01). Our results demonstrated the opposite effects of Trolox in combination with imatinib and nilotinib. Usage of antioxidant in combination with TKIs should be carefully evaluated in each specific case.