Tyrosine Kinase Inhibitors Exposure Research Articles

Long-term outcomes of chronic myeloid leukemia in children and adolescents - Real world data from a single-institute in Taiwan.

Tyrosine kinase inhibitors (TKIs) have revolutionized chronic myeloid leukemia (CML) treatment, yet long-term pediatric outcomes and growth effects remain limited. This study describes the long-term efficacy and growth impact of TKIs in children and adolescents with CML. We retrospectively reviewed 14 pediatric CML patients treated with TKIs at our institute. The cohort's molecular responses and growth velocities were evaluated over a median follow-up of 15.9 years. MR4.5 was defined as BCR-ABL1/ABL ratio <0.0032%. Cumulative MR4.5 rates, time to response, and growth impacts were described among first- and second-generation TKIs. All patients achieved MR4.5, with second-generation TKIs showing faster responses than imatinib. Growth deceleration was observed in patients initiating TKIs at prepubertal ages, regardless of TKI type. Among four patients who discontinued TKIs, three maintained treatment-free remission (TFR) for a median of 4.0 years. Adverse events from second-generation TKIs led to treatment switches in four among eleven patients (36%). This study shows the sustained efficacy of TKIs in achieving MR4.5 in pediatric CML, with second-generation TKIs providing faster responses. Growth retardation remains a concern for TKI treatment. TKI discontinuation in pediatric CML may be feasible and crucial for shortening TKI exposure and optimizing long-term growth outcomes in prepubertal patients.

Anaplastic Lymphoma Kinase (ALK) Inhibitors Enhance Phagocytosis Induced by CD47 Blockade in Sensitive and Resistant ALK-Driven Malignancies.

Anaplastic lymphoma kinase (ALK) plays a role in the development of lymphoma, lung cancer and neuroblastoma. While tyrosine kinase inhibitors (TKIs) have improved treatment outcomes, relapse remains a challenge due to on-target mutations and off-target resistance mechanisms. ALK-positive (ALK+) tumors can evade the immune system, partly through tumor-associated macrophages (TAMs) that facilitate immune escape. Cancer cells use "don't eat me" signals (DEMs), such as CD47, to resist TAMs-mediated phagocytosis. TKIs may upregulate pro-phagocytic stimuli (i.e., calreticulin, CALR), suggesting a potential therapeutic benefit in combining TKIs with an anti-CD47 monoclonal antibody (mAb). However, the impact of this combination on both TKIs-sensitive and resistant ALK+ tumors requires further investigation. A panel of TKIs-sensitive and resistant ALK+ cancer subtypes was assessed for CALR and CD47 expression over time using flow cytometry. Flow cytometry co-culture and fluorescent microscopy assays were employed to evaluate phagocytosis under various treatment conditions. ALK inhibitors increased CALR expression in both TKIs-sensitive and off-target resistant ALK+ cancer cells. Prolonged TKIs exposure also led to CD47 upregulation. The combination of ALK inhibitors and anti-CD47 mAb significantly enhanced phagocytosis compared to anti-CD47 alone, as confirmed by flow cytometry and fluorescent microscopy. Anti-CD47 mAb can quench DEMs while exposing pro-phagocytic signals, promoting tumor cell phagocytosis. ALK inhibitors induced immunogenic cell damage by upregulating CALR in both sensitive and off-target resistant tumors. Continuous TKIs exposure in off-target resistant settings also resulted in the upregulation of CD47 over time. Combining TKIs with a CD47 blockade may offer therapeutic benefits in ALK+ cancers, especially in overcoming off-target resistance where TKIs alone are less effective.

Abstract A105: Clinical characteristics of Hispanic patients ages 50 and younger with lung adenocarcinoma: A multi-center experience

Abstract Introduction: While uncommon, there has been an increase in non-small cell lung cancer (NSCLC) cases in patients under the age of 50 with little data on young Hispanic patients with NSCLC. This multicenter study describes the clinical characteristics of young Hispanic lung adenocarcinoma patients between two cities with a large Hispanic population. Methods: This retrospective study examined 90 Hispanic patients (18-50 years old) with metastatic lung adenocarcinoma treated at University of Miami (Miami) Sylvester Comprehensive Care Center (n=50), University of Southern California (USC) Norris Comprehensive Care Center/Los Angeles General Medical Center (n=26), and the Memorial Cancer Institute at West (Memorial) (n=14) from 2009-2023. We looked at age at diagnosis, sex, smoking history, stage at diagnosis, brain metastasis at diagnosis, mutations, tyrosine kinase inhibitor (TKI) exposure, and survival status at 24 months, 36 months, and 60 months. Fisher’s exact test was used to compare differences between USC (n=26) in Los Angeles, California, USA and Miami/Memorial (n=64) in Miami, Florida, USA. Results: 63.33% (n=57) of the patients were female. The median age at diagnosis was 41.5 years, including 8.89% (n=8) diagnosed from age 18-30, 33.33% (n=30) diagnosed from age 31-40, and 57.78% (n=52) diagnosed from age 41-50. 63.33% (n=57) identified as never smokers, 30.00% (n=27) identified as former smokers, and 6.67% (n=6) identified as current smokers. 85.56% (n=77) were found to have metastatic disease at diagnosis, including 34.44% (n=31) with brain metastasis at diagnosis. 28.89% (n=26) had an EGFR mutation, 28.89% (n=26) were ALK positive, and 8.89% (n=8) had a KRAS mutation. 55 (61.11%) had been exposed to a TKI. Between treatment sites, there was a greater prevalence of brain metastasis at USC versus Miami/Memorial (15/26, 57.69% vs. 16/64, 25.00%, p&amp;lt;0.01) and a trend towards greater prevalence of EGFR and KRAS mutations (EGFR: 11/26 (42.31%) vs. 15/64 (23.44%), p = 0.12; KRAS: 4/26 (15.38%) vs. 4/64 (6.25%), p = 0.22) and TKI exposure (19/26, 73.08% vs. 36/64, 56.25%, p=0.15) at USC versus Miami/Memorial. Regarding survival for stage IV patients, 37/61 (60.65%) of patients were alive at 24 months, 22/51 (43.1%) at 36 months, and 14/46 (30.4%) at 60 months with a trend towards more USC patients being alive at 36 months (10/18, 55.56% vs. 12/33, 36.36%) and 60 months (6/15, 40% vs. 8/31 25.8%). Conclusion: Young Hispanic lung adenocarcinoma patients are predominantly female, never smokers, diagnosed with metastatic disease, and enriched in EGFR and ALK mutations. There are differences in prevalence of brain metastasis, EGFR and KRAS mutations, TKI exposure, and survival between the USC and Miami/Memorial young lung adenocarcinoma patients. These notable frequencies may be attributed to the different Hispanic subgroups in the west coast versus southeastern USA. This study highlights the need for more attention towards Hispanic ethnicity in the young lung cancer population. Citation Format: Kyle Edwards, Darin Poei, Suset Almuinas de Armas, Coral Olazagasti, Zhonglin Hao, Jorge J. Nieva, Luis E Raez, Gilberto Lopes, Estelamari Rodriguez, Robert Hsu. Clinical characteristics of Hispanic patients ages 50 and younger with lung adenocarcinoma: A multi-center experience [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A105.

Imatinib‑ and ponatinib‑mediated cardiotoxicity in zebrafish embryos and H9c2 cardiomyoblasts.

Tyrosine kinase inhibitors (TKIs) offer targeted therapy for cancers but can cause severe cardiotoxicities. Determining their dose‑dependent impact on cardiac function is required to optimize therapy and minimize adverse effects. The dose‑dependent cardiotoxic effects of two TKIs, imatinib and ponatinib, were assessed in vitro using H9c2 cardiomyoblasts and in vivo using zebrafish embryos. In vitro, H9c2 cardiomyocyte viability, apoptosis, size, and surface area were evaluated to assess the impact on cellular health. In vivo, zebrafish embryos were analyzed for heart rate, blood flow velocity, and morphological malformations to determine functional and structural changes. Additionally, reverse transcription‑quantitative PCR (RT‑qPCR) was employed to measure the gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), established markers of cardiac injury. This comprehensive approach, utilizing both in vitro and in vivo models alongside functional and molecular analyses, provides a robust assessment of the potential cardiotoxic effects. TKI exposure decreased viability and surface area in H9c2 cells in a dose‑dependent manner. Similarly, zebrafish embryos exposed to TKIs exhibited dose‑dependent heart malformation. Both TKIs upregulated ANP and BNP expression, indicating heart injury. The present study demonstrated dose‑dependent cardiotoxic effects of imatinib and ponatinib in H9c2 cells and zebrafish models. These findings emphasize the importance of tailoring TKI dosage to minimize cardiac risks while maintaining therapeutic efficacy. Future research should explore the underlying mechanisms and potential mitigation strategies of TKI‑induced cardiotoxicities.

Abstract 457: Persister cell state-associated lncRNA signatures in non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide, largely due to late-stage diagnosis and a 5-year survival rate of 9%. Targeted therapies for oncogene-dependent tumors like tyrosine kinase inhibitors (TKIs) improve outcomes yet their clinical efficacy is often limited by occult drug-tolerant persister cells (DTPCs), causing recurrence. Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides and typically non-protein coding. They regulate cellular functions by interacting with substrates through their complex secondary structures. Their deregulation is linked to oncogenesis and therapy resistance. While their role in lung cancer has been documented, their involvement in the DTPC state remains unexplored. Our study aims to investigate the role of lncRNAs in mechanisms that drive failure to targeted therapy in NSCLC. We comprehensively analyzed single-cell RNA-seq data from 49 NSCLC biopsies, pre- and during TKI therapy (residual disease, RD). We identified several lncRNAs that were significantly, differentially expressed in RD when compared to treatment naïve (TN) tumors. We orthogonally validated these findings in a minimum of 2 lung cancer cell lines in TN or DTPCs (9-15 days upon TKI exposure in culture) [p&amp;lt;0.05, absolute log2 fold change &amp;gt; 0.3]. We found that MALAT1, HCG11, and EPB41L4A-AS1 (lncRNA-UP signature) displayed significantly increased expression in RD relative to TN tumors and parental cell lines. We also found significant downregulation of LUCAT1 and LINC00152 (lncRNA-DOWN signature) in RD samples. We further performed Kaplan-Meier survival analysis in an independent set of RD samples stratified by differential expression of our lncRNA signatures (n=18/group). The analysis showed improved overall survival in patients whose DTPCs expressed a high level of the lncRNA-UP signature (hazard ratio, HR=0.56; log-rank test p=0.0331). We did not observe significant differences in survival for the lncRNA-DOWN signature. We additionally performed survival analysis using the GEPIA database for lung adenocarcinoma (primarily TN, n= 239/group). Consistently, the analysis showed improved overall survival for high levels of the lncRNA-UP signature (HR=0.71; p=0.029), whereas high levels of the lncRNA-DOWN signature were indicative of inferior outcomes (HR=1.4, p=0.046). We systematically identified DTPC-associated lncRNA signatures from our unique DTPC cohort, indicating that deregulation of lncRNA expression may play a role in acquired drug resistance in lung cancer. DTPC-associated lncRNA expression patterns are linked to differential overall survival, suggesting a possible tumor-suppressive or promoting role and highlighting their potential as predictive biomarkers and therapeutic targets. Further investigation into the functional roles of these lncRNAs and their interplay with coding molecules is warranted. Citation Format: Jovanka Gencel-Augusto, Wei Wu, Trever G. Bivona. Persister cell state-associated lncRNA signatures in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 457.

Molecular Profiling and the Impact of Treatment on Outcomes in Adenoid Cystic Carcinoma Type I and II.

Adenoid cystic carcinoma (ACC) is an uncommon salivary gland cancer with no approved therapies available to treat advanced, incurable disease. Recent molecular profiling efforts have identified two important subtypes: the more aggressive ACC-I is characterized by Notch pathway alterations and MYC amplification whereas ACC-II demonstrates a more indolent phenotype and TP63 overexpression. This retrospective observational cohort study involved de-identified samples from 438 patients with ACC with tumor samples sent for commercially-available molecular profiling (Caris Life Sciences). Next-generation whole-exome and whole-transcriptomic sequencing was performed on primary and metastatic samples. Immunostaining for PD-L1 and RNA deconvolution (quanTIseq) was used to explore the tumor immune microenvironment (TME). Real-world clinical and survival outcome metrics were extracted from insurance claims data. MYC expression was 1.61-fold higher (39.8 vs. 24.7; P < 0.0001) among NOTCH1-mutant ACC-I tumors, whereas MYB/L1 fusion rates were similar among ACC-I/II. The median B-cell fraction in the TME was higher among ACC-II (7.1% vs. 5.8%; P < 0.01), although infiltrating T cells subsets were low among either ACC subgroup (both <1%). When pooling systemic treatment categories, ACC-I patients had worse outcomes with available therapies (HR, 3.06; 95% confidence interval, 1.65-5.68; P < 0.01), with no significant difference in overall survival between ACC-I/II based on chemotherapy or VEGFR tyrosine kinase inhibitor exposure in smaller subsets. We confirmed the previously reported associations with MYC and TP63 in the prognostically relevant subgroups of ACC-I and -II, respectively, and report immunologic differences among these subtypes. Survival outcomes are comparatively worse in ACC-I regardless of treatment type.

Tyrosine kinase inhibitor resistance in de novo BCR::ABL1–positive BCP-ALL beyond kinase domain mutations

AbstractA better understanding of ABL1 kinase domain mutation–independent causes of tyrosine kinase inhibitor (TKI) resistance is needed for BCR::ABL1–positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Although TKIs have dramatically improved outcomes, a subset of patients still experiences relapsed or refractory disease. We aimed to identify potential biomarkers of intrinsic TKI resistance at diagnosis in samples from 32 pediatric and 19 adult patients with BCR::ABL1–positive BCP-ALL. Reduced ex vivo imatinib sensitivity was observed in cells derived from newly diagnosed patients who relapsed after combined TKI and chemotherapy treatment compared with cells derived from patients who remained in continuous complete remission. We observed that ex vivo imatinib resistance was inversely correlated with the amount of (phosphorylated) BCR::ABL1/ABL1 protein present in samples that were taken at diagnosis without prior TKI exposure. This suggests an intrinsic cause of TKI resistance that is independent of functional BCR::ABL1 signaling. Simultaneous deletions of IKZF1 and CDKN2A/B and/or PAX5 (IKZF1plus), as well as deletions of PAX5 alone, were related to ex vivo imatinib resistance. In addition, somatic lesions involving ZEB2, SETD2, SH2B3, and CRLF2 were associated with reduced ex vivo imatinib sensitivity. Our data suggest that the poor prognostic value of IKZF1(plus) deletions is linked to intrinsic mechanisms of TKI resistance other than ABL1 kinase domain mutations in newly diagnosed pediatric and adult BCR::ABL1–positive BCP-ALL.

Patient perspectives on treatment-related toxicities and therapeutic drug monitoring with tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer.

Tyrosine kinase inhibitors (TKIs) have significantly improved treatment-related outcomes of patients with oncogene-driven non-small-cell lung cancer (NSCLC). TKIs are usually well tolerated and used for a prolonged time, although experienced toxicity varies between patients. It is unclear whether patients report all (low grade) toxicities and how these impact their daily lives. The use of therapeutic drug monitoring (TDM) to, for example, manage toxicities is increasingly applied, but there is limited insight into the patient perspective regarding TDM. This qualitative study aims to explore patient perspectives on TKI toxicity and TDM. Five semi-structured focus group interviews were held, each with three to four patients with NSCLC using a TKI and their (care) partners. Two researchers independently performed a directive content analysis. In total, 16 patients and 12 (care) partners participated. Experienced treatment-related toxicities were encountered limitedly and patients felt no boundaries discussing these with their treatment team. However, symptoms were sometimes not reported as they were doubted as treatment related. The concept of TDM-guided dosing to, for example, reduce TKI exposure to account for dosing outside the therapeutic window resulted in feelings of uncertainty regarding treatment efficacy. Patients emphasized the need for thorough research and frequent check-ups to ensure treatment efficacy. Perceived TKI-related toxicities seem limited, although the treatment team should pay attention to symptoms not directly described by patients as treatment related. In general, patients are open to implement TDM-guided dosing, but only if thorough scientific evidence demonstrates retained or enhanced safety and efficacy.

A Comparative Study Evaluating the Quality of Life and Survival Outcomes in Patients Receiving Chemotherapy Versus Oral Tyrosine Kinase Inhibitor in the Third Line and Beyond Setting for Advanced NSCLC

IntroductionThe outcomes in advanced NSCLC have improved owing to the availability of more effective systemic and improved supportive care. This has increased the number of patients who seek treatment in the third line and beyond setting. We conducted this study to compare the quality of life (QoL), toxicity, and outcomes in patients receiving chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) in this setting. MethodsIn this phase 3, randomized, open-label study, patients with stage III or IV NSCLC with disease progression on at least two prior lines of chemotherapy, with a life expectancy of at least 3 months, without prior EGFR TKI exposure, and stable brain metastases (if any) were included. Patients were randomized to receive chemotherapy (gemcitabine or docetaxel or paclitaxel or vinorelbine) or an EGFR TKI (erlotinib or gefitinib). The primary end point was the change in QoL at 8 to 10 weeks; the secondary outcomes were safety and overall survival (OS). Patients underwent clinical evaluation at every visit, and toxicity was assessed as per Common Terminology Criteria for Adverse Events version 4.03. A radiological tumor response assessment was done every 8 to 12 weeks from the start of therapy. The QoL was assessed using the EORTC QLQ C30 and LC13 questionnaires. The change in QoL scores was calculated as the difference between scores at baseline and scores at 8 to 10 weeks (Δ) for each QoL domain. The Mann-Whitney U test was used to compare the mean difference (Δ) for each domain. OS and progression-free survival (PFS) were determined using the Kaplan-Meier method and Cox proportional regression analysis. ResultsA total of 246 patients were enrolled in the study, with 123 in each arm. There was a male predominance with 69.1% male patients in the chemotherapy arm and 70.7% in the EGFR TKI arm. The median age of patients in the chemotherapy arm was 54 years and 55 years in the chemotherapy and EGFR TKI arms, respectively. There was no significant difference in the change in QoL at baseline and the second visit (Δ) in both arms in all domains of EORTC QLQ C30 except cognitive function (p = 0.0045) and LC13 except alopecia (0.01249). The mean Δ Global Health Status was −28 in the chemotherapy arm and −26.8 in the EGFR TKI arm; this was not statistically significant (p = 0.973). The median follow-up was 88.1 months (95% confidence interval [CI]: 39.04–137.15). On the intention-to-treat analysis, the median PFS was 3.13 months (95% CI: 2.15–4.11) in the chemotherapy arm and 2.26 months (95% CI: 2.1–2.43) in the EGFR TKI arm, with hazard ratio at 1.074 (95% CI: 0.83–1.38) (p = 0.58). There were 120 deaths in each arm. The median OS was 7.63 months (95% CI: 5.96–9.30) in the chemotherapy arm and 7.5 months in the EGFR TKI arm (95% CI: 5.85–9.14); hazard ratio at 1.033 (95% CI: 0.80–1.33) (p = 0.805). The toxicity profile was similar in both arms except for a significantly higher incidence of fatigue (p = 0.043), peripheral neuropathy (0.000), alopecia, hypokalemia (0.037), and pedal edema (0.007) in the chemotherapy arm and dry skin (p = 0.000) and skin rash (p = 0.019) in the EGFR TKI arm. ConclusionsThere was no significant difference in most QoL scales (except cognitive function and alopecia), OS, and PFS of patients with advanced NSCLC receiving an EGFR TKI as compared with chemotherapy TKI in the third-line setting. The toxicity profile is consistent with the known toxicities of the agents.

Toxicities Associated with Tyrosine Kinase Inhibitor Maintenance Following Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Use of tyrosine kinase inhibitor (TKI) maintenance following allogeneic hematopoietic cell transplantation (HCT) in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia may help to prevent post HCT relapse but is difficult to administer due to toxicity. However, these toxicities and their impact on maintenance is not fully characterized. Herein, we report our experience at a single, large transplant center to describe toxicities encountered with post HCT TKI maintenance in Ph+ ALL. Methods Ph+ ALL patients (pts) who underwent 1st allogeneic HCT at City of Hope between 2003-2021 and received at least one dose of TKI maintenance were included in this retrospective analysis. Baseline characteristics and toxicities were summarized via descriptive analysis, and groups were compared via Fischer test. Survival analyses were calculated from the time of TKI initiation. Results Baseline characteristics are described in Table 1. Of the 186 pts studied, 50 (26.8%) received imatinib and 136 (73.2%) received a newer generation TKI (NG-TKI: 112 dasatinib, 6 nilotinib, 1 bosutinib, 17 ponatinib) at a median time of 78 days (IQR, 41-134) and 91 days (IQR, 58-129), respectively. A total of 96 patients (51.6%) began TKI maintenance within 90 days of HCT. Post HCT TKI was started prophylactically in 149 patients (80.1%) while 37 patients (19.9%) received TKI preemptively for positive MRD. The MRD status at time of HCT differed between the imatinib group and NG-TKI group. In the imatinib group MRD was negative in 33 of 50 patients (66.0%) compared with 78 of 136 patients (57.4%) in the NG-TKI group (P&amp;lt;0.01). There were 12 (24.0%) vs 18 (13.2%) with an unknown MRD-status at HCT in the imatinib vs NG-TKI groups, respectively ( P&amp;lt;0.01). The median follow-up duration for surviving patients in the entire cohort was 5.5 years (range, 1.0-17.5). The median cumulative TKI exposure was 413.5 days (range, 4-2740). The median cumulative imatinib exposure in patients initially receiving imatinib was 328 days (range, 3-2216), while the median cumulative NG-TKI exposure in patients initially receiving NG-TKI was 268.5 days (range, 3-2740), respectively. The median cumulative exposure of dasatinib, nilotinib, bosutinib and ponatinib were 249 days (range, 3-2740), 222 days (range, 114-839), 371 days, and 576 days (range, 72-921), respectively. Twenty-seven (54.0%) vs 75 (55.2%) patients completed &amp;gt;12 months of initial imatinib and NG-TKI maintenance (P=1.0), respectively. Of the treated patients, 78 pts (41.9%) required at least one dose reduction of their initial TKI due to toxicity; 19 of them (10.2%) required ≥2 dose reductions. When imatinib maintenance was used as the initial TKI, a dose reduction due to toxicity was required in 18 patients (36.0%), of whom 7 patients (14.0%) required ≥2 dose reductions. Initial NG-TKI maintenance required a dose reduction due to toxicity in 60 (44.1%), of whom 12 (8.8%) required ≥2 dose reductions. One hundred and thirty-nine patients (74.7%) had their maintenance TKI therapy interrupted, 122 (65.6%) due to toxicity. Sixty-seven patients (36.0%) did not complete their pre-determined maintenance period owing to toxicity; 70 pts (37.6%) discontinued one TKI, and 11 (5.9%) discontinued two TKIs, due to toxicity. The most common reasons for discontinuing the initial TKI are listed in Table 2, including 45.2% of patients due to toxicity, and 12.9% due to progressive disease. Toxicity-related discontinuations occurred within 6 months on that TKI in 63.0% of patients, and 75.3% within the first 12 months. Five-year overall survival and progression-free survival from the start of TKI were similar between the imatinib and NG-TKI group; 83.1% vs 76.9% (P=0.74) and 72.8% vs 70.5% (P=0.63), respectively (Figure 1). Conclusion Toxicities resulting in dose reductions, interruptions, and discontinuation are common in TKI maintenance post HCT. The toxicity profile (mainly GI and blood count related), frequency, and severity of TKIs in the post HCT setting appears to be different than what has been previously reported in the pre-HCT setting, making it a formidable challenge to meet the recommended cumulative TKI maintenance exposure (2 years) per the NCCN guidelines. While the choice of TKI did not appear to impact on long-term outcomes and relapse rates were not excessive in our analysis, further studies are needed to develop tolerable and personalized TKI maintenance strategies.

Salvage lenvatinib/everolimus combination therapy after immune checkpoint inhibitor and VEGFR tyrosine kinase inhibitor for metastatic renal cell carcinoma.

The optimal treatment for metastatic renal cell carcinoma (mRCC) patients who have progressed after both immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) remains uncertain. Lenvatinib and everolimus (LE) are frequently used in combination as salvage therapy because of their different antitumor mechanisms, but efficacy and toxicity data in this setting are lacking. We retrospectively reviewed charts from two academic centers for 71 adult mRCC patients who received LE after prior ICI and TKI exposure. We evaluated patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details. Outcomes of interest included objective response rate (ORR), time to treatment failure (TTF), overall survival (OS), ≥grade 3 toxicities, and schedule or dosage changes, which were evaluated using descriptive statistics, chi-square test, Cox proportional hazards model, and the Kaplan-Meier method. The median age was 64 (range 31-84). Most patients had clear cell histology (84.5%) and had undergone nephrectomy (80.3%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). The average ORR was 26.8%, while the median TTF was 5.5 months (95% confidence interval [CI], 3.5-7.6) and the median OS was 9 months (95% CI, 7.6-12.9). Intermediate and poor IMDC risks were independently associated with a significantly worse TTF compared to favorable risk (hazard ratio (HR), 3.03, 95% CI, 1.18-7.79), as was ≥4L treatment vs. 2L/3L treatment (HR, 2.02, 95% CI, 1.08-3.8). Of the 71 patients, 57.7% had ≥grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. LE therapy is feasible but has modest efficacies following ICI/TKI treatment. Patients with favorable risk or treated earlier may have a better treatment response. These observations need to be confirmed in prospective studies.

Clonal evolution in tyrosine kinase inhibitor-resistance: lessons from in vitro-models.

Resistance in anti-cancer treatment is a result of clonal evolution and clonal selection. In chronic myeloid leukemia (CML), the hematopoietic neoplasm is predominantly caused by the formation of the BCR::ABL1 kinase. Evidently, treatment with tyrosine kinase inhibitors (TKIs) is tremendously successful. It has become the role model of targeted therapy. However, therapy resistance to TKIs leads to loss of molecular remission in about 25% of CML patients being partially due to BCR::ABL1 kinase mutations, while for the remaining cases, various other mechanisms are discussed. Here, we established an in vitro-TKI resistance model against the TKIs imatinib and nilotinib and performed exome sequencing. In this model, acquired sequence variants in NRAS, KRAS, PTPN11, and PDGFRB were identified in TKI resistance. The well-known pathogenic NRAS p.(Gln61Lys) variant provided a strong benefit for CML cells under TKI exposure visible by increased cell number (6.2-fold, p < 0.001) and decreased apoptosis (-25%, p < 0.001), proving the functionality of our approach. The transfection of PTPN11 p.(Tyr279Cys) led to increased cell number (1.7-fold, p = 0.03) and proliferation (2.0-fold, p < 0.001) under imatinib treatment. Our data demonstrate that our in vitro-model can be used to study the effect of specific variants on TKI resistance and to identify new driver mutations and genes playing a role in TKI resistance. The established pipeline can be used to study candidates acquired in TKI-resistant patients, thereby providing new options for the development of new therapy strategies to overcome resistance.

Salvage lenvatinib/everolimus (LE) combination therapy after immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) for metastatic renal cell carcinoma (mRCC).

e16520 Background: The optimal treatment for mRCC patients (pts) who have progressed after both ICI and TKI remains uncertain. LE is frequently used as a salvage treatment due to different antitumor mechanisms, but efficacy and toxicity data in this setting are limited. Methods: We retrospectively reviewed charts from two academic centers for 71 adult mRCC pts who received LE after prior ICI and TKI exposure. Collected data included patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details using CTCAEv5. Outcomes were objective response rate (ORR) per RECIST 1.1, median time to treatment failure (mTTF), and toxicity. Descriptive statistics, Cox proportional hazards model and Kaplan-Meier method were utilized. Results: The median age was 64 (range: 31–84). Most pts had clear cell histology (84.5%) and had undergone nephrectomy (75%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). Pts received a median of 3 (range 1-10) prior therapy lines (L) and 42 pts had sequential ICI and TKI, while 29 received ICI/TKI combination therapy. Average ORR was 26.8%, but numerically better when given earlier (2L/3L vs. ≥4L: 28.6% vs. 22%). The mTTF was 5.5 months (m) (95% confidence interval [CI], 3.5–7.6 m), which was not significantly changed by sequential or combinational ICI/TKI treatment exposure. In multivariable Cox analyses, int/poor IMDC risk was associated with a significantly worse TTF compared to favorable risk (HR, 2.2, 95% CI, 1.1-4.1; mTTF: 4.5 vs 12.9 m), and so was ≥4L treatment compared to 2L/3L treatment (HR, 3.2, 95% CI, 1.3-7.6; mTTF: 4.5 vs. 6.6 m). In 57 pts with int/poor IMDC risk, ≥4L treatment was associated with a significantly worse TTF (HR, 2.3, 95% CI, 1.2-4.5; mTTF: 3.6 vs. 6.6 m), while prior nephrectomy was associated with a significantly better TTF (HR, 0.46, 95% CI, 0.22-0.97; mTTF: 5.4 vs. 3.1 m) compared to those without nephrectomy. Of the 71 pts, 64% had ≥ grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. Conclusions: LE therapy is feasible but has modest efficacy following ICI/TKI treatment. Pts with favorable risk, prior nephrectomy or early salvage may have a better treatment response. These observations need to be confirmed in prospective studies.

A comparative study evaluating the quality of life in patients receiving chemotherapy versus oral TKI in the third line and beyond setting for advanced non–small-cell lung cancer.

e21195 Background: The outcomes in advanced non-small cell lung cancer (NSCLC) have improved due to the availability of more effective systemic &amp; improved supportive care. This has increased the number of patients who seek treatment in the third line &amp; beyond setting. We conducted this study to compare the quality of life (QoL), toxicity &amp; outcomes in patients receiving chemotherapy &amp; oral tyrosine kinase inhibitors (TKIs) in this setting. Methods: In this phase 3 randomized open-label study patients with stage III/IV NSCLC with disease progression on at least 2 prior lines of chemotherapy, with a life expectancy of at least 3 months, without prior TKI exposure, and stable brain metastases (if any) were included. Patients were randomised to receive chemotherapy(Gemcitabine/docetaxel/paclitaxel/vinorelbine) or TKI (erlotinib or gefitinib). Patients were evaluated at every visit for clinical benefit and toxicity (as per CTCAE v4.3). A radiological tumour response assessment was done every 8-12 weeks from the start of therapy. The QoL was assessed using the EORTC QLQ C-30 &amp; LC-13 questionnaires at baseline and every 8-10 weeks while on treatment. The primary endpoint is the change in QoL scores at 8-10 weeks, the secondary endpoints are safety and overall survival. The change in QoL scores at baseline and scores at 8-10 weeks was determined and the mean difference between the arms was compared using the independent t-test. Overall and progression-free survival was determined using the Kaplan-Meier method and Cox proportional regression analysis. Results 246 patients were enrolled in the study, 123 in each arm. There was a male predominance in both arms. There was no significant difference in the change in the QoL scores from baseline to the subsequent visit (at 8-10 weeks) in both arms in all domains of QLQ C-30 &amp; LC 13 except alopecia. The mean difference in scores for alopecia was 23.73 (+/-52.22) in the chemotherapy arm &amp; -18.35 (+/- 47.32) in the oral TKI arm (p = 0.000). The median follow-up was 88.1 mos (95%CI39.04-137.15). On ITT analysis the median progression-free survival (PFS) was 3.13 mos (95%CI 2.15-4.11) in the chemotherapy arm and 2.26 mos (95%CI 2.1-2.43) in the oral TKI arm, hazard ratio (HR) 1.074 (95% CI 0.833- 1.38), p = 0.6. There were 120 deaths in each arm. The median overall survival (OS) was 7.63 mos (95% CI 5.96-9.30) in the chemotherapy arm and 7.5 mos in the oral TKI arm (95% CI 5.85-9.14); HR 1.024 (95%CI 0.793-1.321),p = 0.9. The toxicity profile was similar in both arms except for CIPN, alopecia, pedal edema which was higher in the chemotherapy arm, &amp; dry skin &amp; skin rash was higher in the oral TKI arm Conclusion In the third line setting there is no significant difference in most QoL domains with similar outcomes( PFS&amp; OS) and toxicity profile is consistent with expected toxicities of the drugs.

Abstract 418: Elacridar potentiates sunitinib efficacy in colorectal cancer models

Abstract For unresectable metastatic colorectal cancer (mCRC), the main treatment strategy is combination chemotherapy, targeted therapy, or immunotherapy. Long-term treatment benefit of these therapies is limited to a small subgroup of patients. To improve treatment outcome, many tyrosine kinase inhibitors (TKIs) have been clinically tested in patients with mCRC. Most failed already in early-phase clinical trials due to intrinsic resistance. ATP Binding Cassette Transporter (ABC)B1- and ABCG2-transporters are known contributors to treatment resistance in mCRC. Therefore, we evaluated whether inhibition of these transporters could potentiate the efficacy of TKIs in colorectal cancer (CRC) models. CRC cell lines, HT29, COLO320 and CACO2 and newly established patient-derived tumor organoids (PDTOs) from mCRC biopsies were first analyzed for the presence of ABCB1 and ABCG2 expression. Models that expressed ABCB1 or ABCG2 were pre-incubated with a non-toxic dose of elacridar, a potent transporter inhibitor, and exposed to a concertation range of three TKIs; sunitinib, cediranib and osimertinib. Next, we measured intracellular drug concentrations using LC/MS-MS one hour after TKI exposure (20 µM) with or without pre-incubation of elacridar. Using the fluorescent properties of sunitinib, we performed live-cell imaging to compare intracellular sunitinib distribution in cells that were or were not pre-incubated with elacridar. ABCB1 and ABCG2 expression was observed in all CRC models except for HT29 cells, which did not express ABCB1. Pre-incubation with elacridar significantly improved sunitinib efficacy in CRC cells. The IC50 decreased from 2.15 µM to 1.17 µM (p = 0.04), from 1.32 µM to 0.44 µM (p = 0.03), and from 4.94 µM to 3.43 µM (p = 0.03) for HT29, COLO320 and CACO2 cells respectively. This effect was not observed for cediranib and osimertinib. Although not significant, for both PDTO models tested, the IC50 for sunitinib decreased from 8.04 µM to 3.29 µM and from 6.93 µM to 4.16 µM. Intracellular sunitinib concentrations in the tested CRC cell models after sunitinib exposure ranged from 2.46 mM to 4.13 mM without elacridar and from 0.38 mM µM to 1.31 mM when pre-incubated with elacridar (p &amp;lt; 0.01). Live-cell imaging of CRC cells revealed a different pattern of intracellular sunitinib accumulation with and without pre-incubation with elacridar. Inhibition of multi-drug resistance proteins ABCB1 and ABCG2 with the clinically tested selective transporter inhibitor elacridar potentiates sunitinib efficacy in CRC models. Interestingly, this was accompanied with reduced intracellular sunitinib accumulation. Further research in mCRC PDTOs is warranted to confirm whether this mechanism is involved in intrinsic TKI resistance and therefore contribute to the early-phase failure of clinical trials testing TKIs for mCRC. Citation Format: Dennis Poel, Kirti K. Iyer, Bob van Gasteren, Beau Dagniaux, Erik van den Hombergh, Nielka P. van Erp, Daniele V. Tauriello, Henk M. Verheul. Elacridar potentiates sunitinib efficacy in colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 418.

Metabolic Adaptation to Tyrosine Kinase Inhibition in Chronic Myelogenous Leukemia Stem Cells

Objectives: BCR-ABL tyrosine kinase inhibitors (TKI) are highly effective in treatment of chronic myelogenous leukemia (CML) but fail to eliminate leukemia stem cells, which persist as a source of disease recurrence. Previous studies have suggested that primitive CML cells rely on upregulated oxidative metabolism for survival. However, there is limited knowledge about the effects of TKI treatment on CML stem cell metabolism and the role of metabolic adaptations in stem cell persistence after TKI treatment. Here we evaluated the metabolic response to TKI treatment in CML stem and progenitor cells using a representative SCL-tTA/BCR-ABL mouse model of CML. Methods: CML mice were treated with the TKI Nilotinib or vehicle for 2 days, to evaluate initial effects of treatment, and for 2 weeks, to evaluate response to continued treatment. Bioenergetics, metabolite profiling, and stable isotope metabolic labeling was performed on BM c-Kit+ progenitor cells obtained from vehicle and TKI treated mice. The effects of TKI treatment on metabolism-related gene expression in CML hematopoietic stem cells (HSC) was studied using single cell RNA-Seq (scRNA) analysis of BM Lin- c-Kit+ Sca-1+ (LSK) cells from CML mice treated with vehicle or TKI for 2 days or 2 weeks. Results: Extracellular flux analysis revealed that TKI treatment initially inhibited oxygen consumption rate (OCR), representing mitochondrial respiration, and extracellular acidification rate (ECAR), representing glycolysis, in CML progenitor cells, but that these were restored with continued TKI treatment. Metabolite profiling using high-resolution mass spectrometry (HRMS) identified significant initial reduction in glycolytic, glutaminolytic and tricarboxylic acid cycle (TCA) intermediates after 2 days of TKI treatment. However, metabolite levels were restored to levels similar to controls with continued TKI treatment. Steady-state metabolic labeling with [U-13C6]-glucose or [U-13C5]-Glutamine showed reduced glycolytic flux, glutaminolysis and TCA intermediates after treatment with TKI for 2 days, but restoration of glycolytic activity and increased glucose-mediated lactate generation, and increased glutaminolytic and TCA cycle activity with continued treatment. The above studies indicate initial inhibition of energy metabolism in CML progenitors with TKI treatment, but metabolic adaptation to continued TKI exposure. scRNA analysis of CML HSC populations showed that TKI exposure led to selective enrichment of primitive HSC subsets characterized by reduced OXPHOS, glycolysis, nucleotide metabolism, and MYC gene signatures. Treatment with TKI for 2 days further reduced metabolic gene signatures, but continued treatment led to restoration of MYC and OXPHOS gene signature expression coupled with enrichment of HSC and quiescence signatures in persistent HSC. TKI-treated stem cells showed increased levels of Hif1a protein and enhanced activity of HIF-1, a key transcriptional regulator of energy metabolism. Treatment of CML mice with a HIF-1 inhibitor, Echinomycin, in combination with TKI treatment, resulted in significant depletion of CML stem cells compared to TKI alone. The combination of HIF-1 inhibitor with TKI treatment also depleted human CML stem cells in xenografted mice. Conclusions: Our results demonstrate metabolic adaptation in CML and progenitor stem cells following TKI treatment, and identify HIF-1 activation as a targetable mechanism to enhance elimination of CML stem cell that persist after TKI treatment.

A Phase II Study of the Combination of Decitabine, Venetoclax and Ponatinib in Patients with Chronic Myeloid Leukemia (CML) in Myeloid Blast Phase (MBP) or Philadelphia-Chromosome Positive (Ph+) Acute Myeloid Leukemia (AML)

Background: Advanced phases of CML and Ph+ AML are therapeutic challenges. Preclinical and early clinical data have shown that combining venetoclax (VEN) with a tyrosine kinase inhibitor (TKI) works synergistically in Ph+ myeloid leukemias (Leonard et. al., Sci Transl Med 2016 and Maiti et. al., Acta Haematologica 2020). We hypothesized that combining a potent TKI (ponatinib) with a hypomethylating agent plus VEN backbone might lead to high rates of response that could facilitate potentially curative allogeneic stem cell transplantation (SCT). Methods: This is a single-arm phase II study (NCT04188405) that enrolled patients (pts) ≥ 18 years (yrs) of age with newly diagnosed or relapsed/refractory advanced phase CML [CML in accelerated phase (CML-AP) or CML-MBP] or Ph+ AML. Pts were required to have an ECOG PS ≤ 3 and adequate liver and renal function. Pts with clinically significant cardiovascular comorbidities, including recent or active myocardial infarction, heart failure, clinically significant arrhythmias, cerebrovascular accident, venous thromboembolism or uncontrolled hypertension were excluded. Pts were treated with a combination of decitabine (DAC) (20 mg/m2/day) x 5 days, VEN (400 mg equivalent dose/day) x 21 days, and ponatinib (45mg/day) x 21 days in cycle 1 and then continuously in cycle 2+ (Fig. 1A). Ponatinib was reduced to 30mg/day for pts in CR/CRi and to 15 mg/day for pts in CMR. For C1 only, pts who had not received ponatinib prior to trial initiation had a lead-in phase of ponatinib monotherapy for 7 days before the initiation of DAC and VEN. Cycles were repeated every 28 days, as permitted by peripheral blood count recovery, and pts could receive a maximum of 24 cycles. Intrathecal prophylaxis with 4 doses of cytarabine was recommended. The primary objective was to determine the overall response rate of the regimen. Results: From July 2020 to May 2022, 12 pts were treated, 1 pt with de novo Ph+ AML and 11 pts with advanced phase CML (2 pts with CML-AP and 9 pts with CML-MBP). The median age of the pts was 45 yrs (range, 28-71 yrs). Three pts (25%) had received no prior therapy (1 each with Ph+ AML, CML-AP and CML-MBP). Nine pts (75%) had prior TKI exposure (including prior ponatinib exposure in 4 pts) and 3 pts (25%) had received prior chemotherapy. Eleven pts (92%) had the p210 transcript of BCR::ABL1. Eight pts (67%) had additional cytogenetic abnormalities, including 5 pts with complex karyotype and 2 pts with a MECOM rearrangement. 4 of 11 tested pts (36%) had an ABL1 kinase domain mutation detected at enrollment (T315I, Q252H, L384M and E255K in 1 pt each). The median number of cycles received was 2 (range, 1-7). Nine pts (75%) responded, including 1 with CR, 3 with CRi and 5 with MLFS as best response. The CR/CRi rate was 33%. Best response was achieved after cycle 1 in 7 of 9 responders. Both pts with CML-AP responded, and 2 of 3 pts without prior TKI exposure responded. One of the responders achieved an MMR. After a median follow-up of 9.1 months, the median overall survival (OS) is 9.5 months, and the estimated 9-month OS is 64%. The median relapse-free survival 5.1 months. Among the 9 responders, 3 pts are in continuous response without SCT, 1 pt proceeded to SCT and is still alive, 3 pts did not undergo SCT and relapsed (2 of whom had a complex karyotype), 1 pt died in MLFS, and 1 pt was lost to follow-up (Fig. 1B). The one pt who proceeded to SCT achieved MLFS as best response pre-SCT and remains in MRD-negative CR 22 months post-SCT. The toxicity profile of the regimen was similar to historical expectations with DAC plus VEN. One pt developed grade 3 mucositis, which was considered related to study therapy. No grade 4-5 related non-hematological adverse events were observed. Related grade 1-2 non-hematological adverse events included rash in 2 pts, and transaminitis, creatinine elevation and mucositis in 1 pt each. Of the 8 pts who received > 1 cycle of study therapy, 4 pts had delay (>1 week) in initiation of a subsequent treatment cycle due to cytopenias; for 2 of these pts the duration of VEN was reduced. The 60-day mortality rate was 0%. Two pts died on the study, one from leukemia and one from infection while in MLFS. Conclusion: The triplet combination of DAC, VEN and ponatinib was well-tolerated in pts with advanced Ph+ myeloid leukemias. In this poor-risk population, a marrow remission rate of 75% was achieved, although durations of remission were modest in the absence of consolidative SCT. This study continues to accrue pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Challenges of Maintenance Tyrosine Kinase Inhibitor Therapy after Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) relapse after allogeneic hematopoietic cell transplantation (HCT) is difficult to manage. One strategy to prevent this is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but the vast majority of data discusses the use of imatinib in this setting, with few reports on newer generation TKIs (NG-TKI). Here, we present our institutional experience with TKI maintenance post-HCT. Methods: Ph+ ALL patients who underwent HCT and received TKI maintenance anytime post-HCT from 2003-2019 were included through retrospective chart review. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), and cumulative incidence of non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and graft-vs-host disease (GVHD). OS and PFS were calculated via the Kaplan Meier method, NRM, CIR, and GVHD were calculated through a competing risk analysis, where CIR was used as a competing risk for NRM and GVHD, and NRM for CIR and GVHD. Results: 110 patients were included, and their baseline characteristics are described in Table 1. 45 (40.9%) patients received imatinib initially, and 65 (59.1%) received NG-TKI initially, of whom, 59 (90.8%) received dasatinib, 4 (6.2%) received nilotinib, and 2 (3.1%) received ponatinib. The median age (range) of the initial imatinib and NG-TKI groups were 42 years (19-64) and 47 (21-73), respectively. 25 (55.6%) vs 43 (66.2%) in the initial imatinib vs NG-TKI groups were >40 years, respectively. 18 (40.0%) vs 39 (60.0%) of the patients receiving initial imatinib vs NG-TKI were female (P=0.052). 20 (44.4%) vs 54 (83.1%) patients in the imatinib vs NG-TKI group underwent HCT ≥2010, respectively (P<0.001). 41 (91.1%) vs 57 (87.7%) in the imatinib vs NG-TKI groups underwent HCT in first complete remission (CR1) (P=0.76), and 21 (46.7%) vs 31 (47.7%) had no measurable residual disease (MRD) detected by PCR at the time of HCT, although 10 (22.2%) vs 10 (15.4%) did not have a PCR report at the time of HCT available (P=0.66). 42 patients (38.2%) required a dose reduction due to toxicity, and 67 patients (60.9%) experienced TKI interruption due to toxicity. Initial imatinib vs NG-TKI maintenance was discontinued in 20 (46.5%) vs 29 (44.6%) due to toxicity, respectively. The median cumulative initial TKI exposure in patients initially receiving imatinib and NG-TKI was 354 days (range, 6-4,473) and 301 days (range, 5-2,740), respectively. Reasons for TKI discontinuation are listed in Table 2. There was no difference in 5-year OS and PFS in patients receiving imatinib vs NG-TKI, 84.1% vs 69.8% (P=0.47) and 75.1% vs 62.5% (P=0.48), respectively. Likewise, 5-year NRM, 5-year relapse, and 4-year GVHD were similar between imatinib vs NG-TKI, 9.0% vs 18.3% (P=0.48), 15.9% vs 19.2% (P=0.92), and 40.7% vs 47.7% (P=0.47), respectively. Univariate analyses showed an improvement in OS and PFS in those who received ≥12 months of TKI maintenance vs those who received <12 months, hazard ratio (HR) 0.26 (95% confidence interval (CI), 0.12-0.55), P<0.001 and HR 0.33 (95% CI, 0.17-0.64), P<0.001. There was no difference in OS and PFS for those who completed ≥12 months of TKI maintenance based on initial TKI of choice, HR 0.85 (95% CI, 0.21-3.51), P=0.8 and HR 0.91 (95% CI, 0.28-2.94), P=0.9. Conclusions: Our findings demonstrate the challenges of delivering post-HCT TKI maintenance. Toxicity leading to TKI interruptions, discontinuation, and dose reduction was common. Post-transplant outcomes were comparable with imatinib and NG-TKI. Therefore, TKI selection for post-HCT maintenance should be based on patient tolerability to maximize TKI maintenance exposure. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy of Ropeginterferon Alpha 2b in Inducing Treatment Free Remission in Chronic Myeloid Leukemia - an International, Randomized Phase III Trial (ENDURE, CML-IX) of the German CML-Study Group

Background: Only a minority of chronic myeloid leukemia (CML) patients can eventually successfully discontinue tyrosine kinase inhibitor (TKI) therapy after achieving a stable deep molecular remission. Mechanisms underlying a durable treatment free remission (TFR) are not well understood but supposedly involve restoration of anti-CML immunity. It was therefore hypothesized that interferon alpha (IFN) - a potent inducer of Th1-immunity and prior standard therapy in CML - might improve the TFR probability. Randomized trials to improve TFR rates in CML are currently lacking. ENDURE, CML-IX (NCT03117816) is a multicenter, international phase III trial evaluating the role of a novel form of pegylated proline interferon-alpha 2b (ropeg-interferon-alpha, ropeg-IFN) in inducing TFR. Patients and Methods: CML patients in stable deep molecular remission (MR4 or better for at least 12 months prior to screening) and with history of at least 3 years of TKI exposure were eligible to participate in this study. Patients in stable molecular remission could also be included if they had failed a former TKI discontinuation attempt (2nd stopper). Patients were randomized 1:1 to receive either ropeg-IFN 100μg s.c. every 2 weeks for 15 months (ropeg-IFN arm) or no further treatment after TKI stop treatment (no treatment arm). The primary efficacy endpoint of the trial was molecular relapse free survival (MRFS) with molecular relapse being defined as loss of major molecular remission (MMR), which is any increase of the BCR::ABL1 transcript level to >0.1% according to the international scale (IS). Time to relapse is defined as the time from randomization to relapse. Secondary endpoints were MRFS at month 6, 12 and 24 after TKI discontinuation. BCR::ABL1 measurable residual disease (MRD) was monitored from peripheral blood and centrally assessed for all centers in Germany and locally at the French centers. There was a post study follow up to collect clinical and molecular data. Results: Between May 2017 and June 2021, 203 evaluable patients (68 female, 135 male) with a median age of 55 years were randomized at 24 centers in Germany and 3 centers in France to receive ropeg-IFN (n=95) or no treatment (n=108) after TKI stop. For 77 patients in the ropeg-IFN arm (81%) and 86 patients in the no treatment arms (80%) it was their first TKI discontinuation attempt. At the time of data cut off in June 2022, the median observation time for all patients was 36 months. The hazard ratio (HR) of molecular relapse for the ropeg-IFN cohort versus the no treatment cohort was 1.03 (95% CI, 0.68 to 0.1.55; log-rank P=0.89). The Kaplan-Meier probabilities of molecular relapse free survival (MRFS) by 6, 12, and 24 months after TKI discontinuation were 73% (95%-CI: 62-81%), 64% (95-CI: 53-73%) and 56% (95%-CI: 45-66%) for the ropeg-IFN versus 67% (95-CI: 57-75%), 60% (95-CI: 50-69%) and 59% (95%-CI: 49-68%) for no treatment (Figure 1). The MRFS at months 6 and 12 after TKI stop (secondary endpoints) were 70% (95%-CI: 60-79%) and 64% (95%-CI: 53-73%) in 91 patients for ropeg-IFN group versus 65% (95-CI: 56-74%) and 59% (95-CI: 49-68%) in 107 and 104 patients for the no treatment group. Of 90 patients who were candidates for restarting TKI due to MMR loss, 82 patients were actually evaluable for TKI restart. Of those, 77 patients re-achieved at least MMR within 12 months (median time to reestablishing MMR was three months). Of the 5 patients who did not regain MMR, one patient withdrew consent and others were treated for only 1, 3, 4, and 11 months after TKI restart. Ropeg-IFN was well tolerated. Hematological and non-hematological WHO grade 3/4 toxicity occurred in 23 patients in the ropeg-IFN (31 adverse events) and in 20 patients in the no treatment arm (26 adverse events). Three deaths were reported on study which were unrelated to CML (cardiac arrest, fall from stairs, unknown). A detailed safety analysis will be presented at the meeting. Conclusion: Ropeg-IFN maintenance after discontinuing TKI-monotherapy does not increase the proportion of patients, who persistently maintain at least an MMR. The German CML-V (TIGER) trial currently explores the impact of IFN maintenance on TFR when patients receive a combination of TKI plus IFN before TKI stop. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CML-415 Treatment Free Remission (TFR) in Chronic Myeloid Leukemia-Chronic Phase (CML-CP), Kuwait Experience

CML is one of the successful stories in oncology. Treatment of CML has evolved and goals of therapy have changed over the years. Treatment free remission (TFR) is becoming an attractive goal in CML patients (pts) especially in younger population. To evaluate the trend of TFR in CML treated pts in Kuwait. Retrospective analysis of CML pts treated in Kuwait Cancer Control Center (KCCC) who had a trial of TFR. Data were collected from the charts and electronic medical records. Pts who stopped tyrosine kinase inhibitor (TKI) due to intolerance or pregnancy were included if they were in deep molecular remission (DMR) (3MR4.0) regardless of the duration of therapy. A total of 42 pts was eligible for TFR. Most of our pts were treated with imatinib (93%). All patients achieved optimal milestones, however pts who stopped treatment in DMR due to intolerance or pregnancy were included. Most of our pts were young with a median age of 38 yrs and had a low risk Sokal/ELTS score. Our cohort of pts had a long duration of TKI exposure (103 mons) and DMR (70 mons). At a median follow up of 50 mons, TFR rate was 74%. As shown in table 2, 10 pts (24%) lost TFR and were able to regain DMR upon re-starting TKI. All of them were treated with imatinib. Successful TFR rates are high among pts treated in Kuwait. This is largely due to a longer duration of therapy and higher percentage of pts with low risk Sokal/ELTS score.