•Dasatinib improved outcomes versus imatinib in Ph+ CML-CP in clinical practice.•Improved outcomes were maintained in patients with intermediate-/high-risk disease.•Improved outcomes were maintained ...across age and BMI subgroups.
Limited data exist comparing dasatinib with imatinib in clinical practice. This study assessed real-world outcomes associated with first-line (1L) dasatinib or imatinib treatment of chronic myeloid leukemia (CML).
This retrospective, observational, United States multisite cohort study analyzed electronic medical record data from adults with Philadelphia chromosome-positive (Ph+) CML in the chronic phase (CML-CP) after 1L dasatinib or imatinib between January 2014 and September 2018. Rates of and times to major molecular response (MMR) and deep molecular response (DMR) were assessed overall and in subgroups (low vs. intermediate/high risk, aged <65 vs. ≥65 years, low/normal vs. high body mass index BMI).
The dasatinib cohort (n = 309) experienced higher rates of MMR (n = 304, 79% vs. 65%, P < .001) and DMR (44% vs. 25%, P < .001) vs. the imatinib cohort with shorter median times to MMR (11.9 vs. 14.7 months, P < .001) and DMR (30.3 vs. 66.1 months, P < .001). Patients with intermediate-/high-risk disease and those aged <65 years had higher MMR and DMR rates and achieved response earlier with dasatinib (P < .01). Patients with low-risk disease treated with dasatinib had higher rates of DMR (60% vs. 32%, P = .01). Across BMI strata, rates of MMR and DMR were higher with dasatinib (P < .05).
Patients with CML-CP treated with 1L dasatinib achieved higher rates of, with shorter times to, MMR and DMR versus 1L imatinib. These clinically meaningful improvements were observed across subgroups.
This retrospective, observational study assessed real-world outcomes with first-line (1L) dasatinib or imatinib treatment of chronic myeloid leukemia in the chronic phase (CML-CP). Patients treated with 1L dasatinib achieved higher rates of, with shorter times to, major molecular response and deep molecular response. Outcomes were maintained across age and BMI subgroups. These findings can help guide treatment selection in CML-CP.
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Patients with relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) have dismal outcomes. Preclinical studies have suggested that T-ALL cells are sensitive to BCL2 ...inhibition. The clinical activity of venetoclax, a selective BCL2 inhibitor, in T-ALL is unknown.
We retrospectively reviewed the efficacy and safety of venetoclax combined with chemotherapy for patients with R/R T-ALL treated at our institution.
Thirteen patients with R/R T-ALL with a median age of 46 years (range, 20-75 years) were treated with venetoclax plus chemotherapy. Five patients (38%) had early T-cell precursor ALL. The patients had received a median of 2 previous lines of therapy (range, 1-11). Venetoclax at a median dose of 200 mg/d for 21 days, generally with a concomitant azole antifungal, was combined with various agents, including hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), asparaginase, nelarabine, decitabine, or other intensive chemotherapy. Of the 10 patients evaluable for bone marrow response, 6 (60%) achieved a remission with bone marrow blasts < 5%, including 3 with complete hematologic recovery. The median overall survival and relapse-free survival were 7.7 and 4.0 months, respectively. No early death or clinically significant tumor lysis syndrome were reported. The median interval to neutrophil recovery and platelet recovery were 15 days and 44 days, respectively, with prolonged cytopenias observed with venetoclax 400 mg/d or when given for > 14 days per cycle.
Combination therapy with venetoclax showed promising clinical efficacy in R/R T-ALL. Further studies are warranted to evaluate the clinical benefit of BCL2 inhibitors in T-ALL.
Combination therapies that included venetoclax were administered to 13 patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma at our institution. Bone marrow responses were achieved in 60% of the evaluable patients, and 2 patients with early T-cell precursor acute lymphoblastic leukemia/lymphoma remained alive in remission. Venetoclax combination therapies are safe, with myelosuppression the main adverse event observed with the addition of venetoclax.
Ponatinib and blinatumomab are effective therapies in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia, and their combination might be a promising treatment ...option. In this study, we aimed to evaluate this chemotherapy-free strategy.
We did a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center, Houston, TX, USA, in patients aged 18 years or older with newly diagnosed or relapsed or refractory Ph-positive acute lymphoblastic leukaemia or chronic myeloid leukaemia in lymphoid blast phase. Patients with an ECOG performance status of 2 or less who had a total bilirubin concentration two-times the upper limit of normal (ULN) or less (≤2·4 mg/dL), alanine aminotransferase and aspartate aminotransferase concentration no more than three-times the ULN, and serum lipase and amylase concentrations no more than three-times the ULN were eligible for inclusion. Ponatinib 30 mg orally and continuous intravenous blinatumomab 28 μg over 24 h (for 28 days each cycle) were given in combination for up to five 42-day cycles, followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as CNS prophylaxis. The primary endpoints were complete molecular response (defined as absence of a detectable BCR-ABL1 transcript by PCR at a sensitivity of 0·01%) in patients with newly diagnosed disease and overall response in patients with relapsed or refractory disease or chronic myeloid leukaemia in lymphoid blast phase. All assessments were done according to the intention-to-treat principle. The trial completed its original target accrual and was amended on March 23, 2022, to enrol an additional 30 patients, thus increasing the sample size to 90 patients. The trial is registered with ClinicalTrials.gov, NCT03263572, and it is ongoing.
Between Feb 6, 2018, to May 6, 2022, 60 (83%) of 72 patients assessed were enrolled and received ponatinib and blinatumomab (40 67% patients had newly diagnosed Ph-positive acute lymphoblastic leukaemia, 14 23% had relapsed or refractory Ph-positive acute lymphoblastic leukaemia, and six 10% had chronic myeloid leukaemia in lymphoid blast phase). 32 (53%) patients were men and 28 (47%) were women; 51 (85%) patients were White or Hispanic; and the median age of participants was 51 years (IQR 36-68). The median duration of follow-up for the entire cohort was 16 months (IQR 11-24). Of patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia, 33 (87%) of 38 evaluable patients had a complete molecular response. 12 (92%) of 13 evaluable patients with relapsed or refractory Ph-positive acute lymphoblastic leukaemia had an overall response. 11 (79%) had a complete molecular response. Five (83%) of six patients with chronic myeloid leukaemia in lymphoid blast phase had an overall response. Two (33%) had a complete molecular response. The most common grade 3-4 adverse events that occurred in more than 5% of patients were infection (22 37% patients), increased amylase or lipase concentration (five 8% patients), increased alanine aminotransferase or aspartate aminotransferase concentration (four 7% patients), pain (four 7% patients), and hypertension (four 7% patients). One (2%) patient discontinued blinatumomab due to tremor. Three (5%) patients discontinued ponatinib secondary to cerebrovascular ischaemia, portal vein thrombosis, and coronary artery stenosis in one patient each. No treatment-related deaths were observed.
The chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response in patients with newly diagnosed and relapsed or refractory Ph-positive acute lymphoblastic leukaemia. Patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia could be spared the toxicities associated with chemotherapy and the need for allogeneic haematopoietic stem-cell transplantation in first response.
Takeda Oncology and Amgen.
High-resolution mass spectra of helium droplets doped with C\(_{60}\) and formic acid (FA) are ionized by electrons. Positive ion mass spectra reveal cluster ions (C\(_{60}\))\(_p\)FA\(_n\)\(^+\) ...together with their hydrogenated and dehydrogenated counterparts. Also observed are ions containing one or more water (W) molecules. The abundance distributions of these ions reveal several interesting features: i) (C\(_{60}\))\(_p\)FA\(_n\)\(^+\) ions are more abundant than hydrogenated (C\(_{60}\))\(_p\)FA\(_n\)H\(^+\) ions even though the opposite is true in the absence of C\(_{60}\) (i.e. if \(p\) = 0); ii) although C\(_{60}\)FA\(^+\) is the most abundant ion containing a single C\(_{60}\), multiple C\(_{60}\) suppress the (C\(_{60}\))\(_p\)FA\(^+\) signal; iii) an enhanced stability of (C\(_{60}\))\(_p\)W\(_1\)FA\(_5\)H\(^+\) and (C\(_{60}\))\(_p\)W\(_2\)FA\(_6\)H\(^+\) mirrors that of W\(_1\)FA\(_5\)H\(^+\) and W\(_2\)FA\(_6\)H\(^+\), respectively. On the other hand, the enhanced stability of C\(_{60}\)FA\(_6\)H\(^+\) finds no parallel in the stability pattern of FA\(_n\)H\(^+\) or FA$_n$$^+\(. Negative ion mass spectra indicate a propensity for non-dissociated (C\)_{60}\()\)_p\(FA\)_n\(\)^-\( anions if \)p \geq 1\( which contrasts with the dominance of dehydrogenated FA\)_n\(-H\)^-$ anions.
Acute myeloid leukemia (AML) patients with any history of cigarette smoking have worse survival outcomes compared to patients that have never smoked. The molecular basis of cigarette smoking or ...cigarette smoke exposure (CSE) impacting AML progression or treatment response is unknown. Altered DNA methylation from smoking persists decades after quitting and has been followed in peripheral blood mononuclear cells (PBMCs) but have not been evaluated in the context of AML. Smoking also causes oxidative stress in PBMCs, but this has yet to be studied in AML patients with a history of smoking.
To model how smoking worsens AML progression, we created a CSE model using a cigarette smoking robot where NOD-SCID mice received 2 hours of CSE 5 days/week or air alone. After 2 weeks of CSE, 100,000 luciferase-tagged, human AML cells were injected via tail-vein and leukemic burden was monitored by bioluminescent imaging. Two cell lines, MOLM13 and MOLM14 carrying the oncogenic fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation, when introduced into CSE mice had enhanced leukemic progression within one week (p-value <0.0001 and <0.001 respectively). MOLM14-bearing mice showed increased leukemic burden 24 days post injection (p-value<0.05). DNA methylation was evaluated by bisulfite sequencing of splenocytes from CSE mice, which was mapped to the human (AML) or mouse (host) genome. Over 200 significant changes in DNA methylation of gene promoters was seen, including hypomethylation of aryl-hydrocarbon receptor repressor (AHRR), an established hallmark of smoking in humans. Indicating that our CSE model recapitulates DNA methylation from smoking in humans. Additionally, GATA-2, a critical protein for hematopoietic differentiation known to be frequently mutated in AML, was also amongst the top hypomethylated genes. We quarried TCGA to understand the implications of altered DNA methylation in AML patients. In AML patients, low GATA-2 methylation showed decreased survival compared to those with high GATA-2 methylation (N=42/group, p-value: 0.000138). The discovery of GATA-2 methylation in smoking models and its attribution as a poor prognostic indicator in AML is novel, which underscores a need to understand the role of GATA-2 methylation in AML.
Reactive oxygen species (ROS) have been implicated in AML progression, drug resistance, and are elevated in otherwise healthy smokers. No significant differences were seen in intracellular ROS in spleen or PBMCs of CSE mice; however, we found more than a two-fold increase of heme oxygenase 1 (HO-1) (p-value:0.0505), a protein involved in antioxidant responses and AML treatment resistance. There was also increased BCL-2 protein expression and a decrease in AHRR expression (p-value: 0.0098) in CSE mouse samples. This suggests that CSE causes oxidative stress and increases pro-leukemic signaling. To address if CSE impacted treatment efficacy, we treated mice with daunorubicin (2 mg/kg, twice weekly via tail-vein) once evidence of engraftment was detected. We found a trend towards increased leukemic burden compared to non-smoking mice which approached statistical significance.
To study the direct impact of CSE on AML, without exposure to the tumor environment, AML cells were treated in vitro with a commercially available cigarette smoke condensate (CSC) that contains the chemicals from cigarette smoke. To mimic the in vivo CSE, MOLM13 cells received two weeks of CSC treatment before being injected into mice. At 3, 10, and 17 days post injection, mice with CSC-treated AML had enhanced leukemic burden (p-value <0.0001, <0.0001, and <0.001). This model revealed that chemicals in cigarette smoke can directly promote AML. On day 14 of CSC treatment, mirroring when the cells were injected into mice, both FLT3-ITD cell lines had increased ROS levels and or glutathione as measured by flow cytometry; this is indicative of CSC-induced oxidative stress.
Cumulatively, these data define novel changes in DNA methylation and redox from smoking or tobacco products with strong potential to drive AML progression and therapy resistance. Future studies will determine if blocking these redox or methylation events can reverse the accelerated AML growth and will aid in the creation of a tailored treatment strategy for AML patients with any history of smoking.
Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; KisoJi: Research Funding; Stemline Therapeutics: Research Funding; Agios: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Cellectis: Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. DiNardo: Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding.
Background: MRD testing in BCP-ALL is critical for appropriate patient management, but little is known regarding sample acquisition and testing heterogeneity across clinical practice settings. These ...factors may impact the quality and reliability of MRD assessment.
Methods: Thirty-minute online surveys were conducted in May 2021 with hematologists/oncologists (HEME/ONCs) in the United States in both academic (acad) and community (comm) settings. Respondents were licensed physicians board certified in oncology and/or hematology who treated ≥2 BCP-ALL patients/year or ≥10 patients in the past 5 years, with over 25% of time spent in the clinical setting; pediatric HEME/ONCs were excluded. Survey enrollment is ongoing, with interim results presented here; a related survey for pathologists (PATHs) is underway.
Results: HEME/ONC respondents (acad n=40, comm n=57, from 29 states) had been practicing as specialists for a median of between 11-15 years (choices were ranges, eg 6-10, 11-15, min-max was 1-34 years), and typically spent over 75% of their time in the clinic; 94% of respondents had ≥5 BCP-ALL patients/year and 92% ordered MRD tests for ≥5 patients/year. Typical timepoints for MRD testing included the end of induction/suspected complete remission, the end of consolidation, and at suspected disease progression; testing after the end of consolidation was infrequent in both groups (Table). Testing for MRD at the end of consolidation was notably more frequent in the academic setting. In both settings, the HEME/ONC ordering the MRD test generally also performed the bone marrow collection procedure (acad: 78%, comm: 56%). Resources consulted on bone marrow collection best practices included UpToDate (21%), ASH and ASCO (13%), NCCN guidelines (13%), and hematology/oncology journals. About half of practices had defined institutional protocols for bone marrow collection (acad: 55%, comm: 47%), nearly all of which were developed internally. The amount of bone marrow sample collected showed high variability, ranging from 1-10 draws (median=3) and 1-30 mL sample per draw (median=5 mL). While 49% of HEME/ONCs performed <5 draws and extracted ≤6 mL per draw, 22% collected 10 mL/draw, and 10% collected 20 mL/draw; the remaining 18% reported >5 draws and/or >6 mL per draw. In both settings, the first pull was identified and labeled in 35% of procedures; in those cases, the first-pull samples were used primarily for MRD testing in 60% of cases as recommended by NCCN guidelines (vs for morphology assessment and cytogenetic studies). HEME/ONCs typically relied on the expertise of pathologists to choose MRD testing methodology.Survey results indicate that external labs (both national clinical reference labs and commercial labs) were most commonly used for MRD assessments (63%); comm HEME/ONCs were more likely to use external reference labs and acad HEME/ONCs were more likely to use in-house labs. When asked to estimate the frequency with which different MRD methods were used, mean responses were 54% flow cytometry and 40% next-generation sequencing. While all HEME/ONCs indicated that MRD results were presented clearly in lab reports, there was a desire to include more guideline information about MRD interpretation and BCP-ALL treatment.
Conclusion: Interim results identified broad heterogeneity in clinical practices affecting sample collection for MRD assessment in Ph- BCP-ALL in the US, indicating several opportunities for harmonization of routine MRD assessment in BCP-ALL. These opportunities include optimization of bone marrow sample collection techniques (volume/draw and identification/use of first pull for MRD), timing/frequency of specimen collection, serial MRD surveillance after consolidation, MRD method chosen, and standardizing reports to include guideline information. There were gaps in awareness of FDA-approved methods of MRD testing for BCP-ALL. Initiatives supporting provider education and harmonization of best practices from professional guideline committees/organizations are needed to optimize outcomes of BCP-ALL patients.
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Hidalgo-Lopez: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Roboz: Janssen: Research Funding; Daiichi Sankyo: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Mesoblast: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Astex: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jasper Therapeutics: Consultancy; Helsinn: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wood: Pfizer, Amgen, Seattle Genetics: Honoraria; Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement. Borowitz: Amgen, Blueprint Medicines: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Velasco: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Elkhouly: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Adedokun: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Zaman: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Iskander: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding.
Introduction
Mixed lineage leukemias (MLL) are an extremely aggressive subset of leukemias that are inherently resistant to several therapies. MLL aberrations (deletion KMT2A and MLL rearrangements) ...are extremely rare in myelodysplastic syndrome (MDS) and little is known regarding their clinical course or outcomes. The aim of the study is to determine the natural course of the disease in our patient population.
Methods
A retrospective cytogenetic database search of patients presenting to a tertiary cancer center from January 2005 to February 2021 with the diagnosis of MDS and CMML with presence of MLL aberrations was conducted. Deletion KMT2A was defined as deletion of 11q23 on cytogenetic studies. Patients who had received prior therapy with hypomethylating agents (HMAs), cytarabine-based regimens, or intensive chemotherapy were excluded. The International Working Group 2006 criteria was used for response assessment. Progression-free survival (PFS) was calculated from date of diagnosis to date of progression from MDS to AML. Overall survival (OS) was determined from the date of diagnosis to the date of death or last follow-up visit.
Results
Between January 2005 to February 2021, 3369 patients (pts) with the diagnosis of MDS (n=2761) and CMML (n=608) were identified. Of these, 30 pts had MLL aberrations with 18 pts with MLL rearrangements (MLL r) and 12 pts with deletion 11q23 (del-KMT2A). Baseline characteristics are present in Table 1.
Among 18 pts with MLL r MDS, 6 pts did not undergo any therapy at our institution. Of the remaining 12, 9 (75%) pts received HMA based therapy, 1 (8%) patient (pt) proceeded to allogeneic stem cell transplant(allo-HSCT) and 2 (17%) pts received intensive chemotherapy (idarubicin, fludarabine and cytarabine). Of the 9 pts who received HMA therapy, 5 (56%) pts had transformation to AML, 2 (22%) pts achieved CR and underwent allo-HSCT, 1 (11%) pt had persistent disease and 1 (11%) developed concurrent metastatic sarcoma and stopped treatment. Out of the 2 (22%) pts who underwent allo-HSCT, 1 pt received maintenance HMA post-transplant but relapsed with transformation to AML after 9 months, and the other was lost to follow up. 1 (11%) pt who had persistent disease received intensive chemotherapy and went into CR and subsequently underwent double umbilical cord transplant and continues to remain in CR. The 2 (17%) pts who received intensive chemotherapy frontline both went into CR, but one developed concurrent malignancy and stopped treatment. The other pt was transitioned to HMA therapy but relapsed with transformation to AML. The 1 patient who received frontline allo-HSCT relapsed with transformation to AML after 5 months. The overall median follow-up duration was 24 months with a median OS of 10 months (Figure 1) and a median PFS of 3.5 months(Figure 2).
12 pts with del-KMT2A were identified, out of which 2 pts did not receive treatment. Of the remaining 10 pts, 8 (80%) received HMA based therapy and 2 (20%) pts received investigational treatments. Of the 8 pts who received HMA therapy, 1 (12.5%) achieved CR and remains in CR, 4 (50%) pts had no response, 2 (25%) had hematological improvement (HI) but one died of other causes and the other elected to stop treatment, 1 (12.5%) pt had transformation to AML. Of the 4 pts with no response, 2 pts elected to stop treatment, with 1 developing concurrent malignancy. Of the remaining 2 pts, 1 pt was placed on an investigational agent and had progression to AML and the other was placed on lenalidomide and then an investigational agent, but ultimately pursued hospice. Of the 2 pts on investigational agents both had persistent disease and one patient died and the other elected to stop treatment due to concurrent illness. The overall median follow-up duration was 154 months with a median OS of 16 months (Figure 1) and median PFS of 8 months (Figure 2). Clinical course is presented in Table 2.
Conclusion
Prognosis of patients with MLL alterations and MDS is very poor. MLL r MDS had worse outcomes with rapid transformation to AML compared to del-KMT2A. New therapies are needed for this group of patients.
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Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Novartis: Honoraria, Research Funding; Immunogen: Research Funding; Aptitude Health: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria.
Background:
Patients with a history of bariatric surgery are often excluded from clinical trials evaluating oral therapies. This is due to concerns that these surgeries alter bioavailability and drug ...metabolism. Oral tyrosine kinase inhibitors (TKIs) are the mainstay treatment for chronic myeloid leukemia (CML). However, the impact of bariatric surgeries on CML treatment outcomes is largely unknown.
Methods:
In a retrospective analysis, we screened patients with CML treated at our institution and identified those who had any type of bariatric surgery including gastric bypass, gastric sleeve surgery or gastric banding. Subsequently, we compared their responses and outcomes to a control cohort of patients without history of bariatric surgery, using propensity score matching for Sokal Risk and body mass index (BMI) at a 2:1 ratio. In addition to cytogenetic and molecular responses, we assessed times to achieving responses and BCR-ABL1 halving times to investigate differences in response dynamics (Branford, Blood 2014). Event-free survival (EFS) was measured from treatment start to loss of response, progression or death, whereas failure-free survival (FFS) additionally accounted for therapy discontinuation for any other reason such as intolerance. Overall survival (OS) was measured from treatment start date to death, or censored at last follow-up. Univariate and multivariate analyses (MVA) were used to assess the association between characteristics and overall survival.
Results:
We identified 28 patients with CML and bariatric surgery, of whom 22 (79%) had their surgery before CML. Their baseline characteristics are summarized below (Figure 1). Despite propensity score matching, patients with bariatric surgery compared to control had a higher BMI at time of CML diagnosis (median: 38 vs 26 Kg/m 2, P<0.0001) and lower Sokal Risk (76% vs 50%, P=0.03). More patients in the bariatric surgery group were treated with imatinib (39% vs 14 %, P=0.02).
Patients with history of bariatric surgery received a higher number of TKIs throughout their CML treatment because of resistance or intolerance compared to control (median of 2, range 1-6 vs median of 1, range 1-3, P<0.0001). They tended to have slower response dynamics evidenced by a lower proportion of patients with BCR-ABL1 <10% at 3 months (71% vs 89%, P=0.09), and a longer halving time (26 vs 19 days, P=0.06). Despite having a similar complete cytogenetic response rate (CCyR) (93% vs 96%, P=0.2), their median time to achieve CCyR was significantly longer (6 months vs 3 months; P<0.0001). In addition, they had longer median time to achieve a major molecular remission (MMR) (12 months vs 6 months, P=0.013) and a lower rate of MR4.5 (61% vs 86%, P=0.02) (Figure 1).
Patients with bariatric surgery and CML had inferior EFS compared to control (5-year EFS rate: 61% vs 87% respectively, P=0.0003) and inferior FFS (5-year FFS rate: 15% vs 77% respectively, P<0.0001). Bariatric surgery was associated with worse OS with a 5-year rate of 81% compared to 95% in the control group (P=0.01) (Figure 1). There was no difference in OS comparing patients who had bariatric surgery and received imatinib as first-line treatment vs those that received other TKIs (P=0.5). To account for the impact of co-variates such as BMI, type of TKI and Sokal Risk on survival, we conducted univariate and multivariate analyses. We found that bariatric surgery was an independent predictor of the risk of death with a hazard ratio (HR) of 13 (95% confidence interval CI, 2.3-71.4, P=0.004). The only other independent predictor of OS in the MVA was age where older patients had an increased risk of death with a HR of 1.1 (95% CI, 1.0-1.2, P<0.0001). However, BMI, Sokal Risk and type of TKI used as frontline therapy were not independent predictors of OS in the MVA.
Conclusion:
Bariatric surgery is associated with slower responses to TKIs in patients with CML, and a lower chance of deep remission. It is also associated with higher rates of treatment failure and worse overall survival. There is an unmet need to design treatment strategies for these patients. Although not readily available in the clinical setting, studies measuring drug level in these patients are needed to assess which TKI has a better bioavailability, which in turn could translate to improved outcomes.
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Kantarjian: Aptitude Health: Honoraria; BMS: Research Funding; Astellas Health: Honoraria; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Immunogen: Research Funding; KAHR Medical Ltd: Honoraria; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; NOVA Research: Honoraria; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Short: Takeda Oncology: Consultancy, Research Funding; NGMBio: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria. Pemmaraju: Roche Diagnostics: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Plexxicon: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Clearview Healthcare Partners: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Incyte: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Affymetrix: Consultancy, Research Funding; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Blueprint Medicines: Consultancy; LFB Biotechnologies: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; DAVA Oncology: Consultancy; MustangBio: Consultancy, Other; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Ravandi: Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Sasaki: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Issa: Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding.
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