Long-term Results of Imatinib Discontinuation in Patients with Chronic-phase Chronic Myeloid Leukemia: A National Multicenter Prospective Study

Objective: The discovery of imatinib was a milestone for chronic myeloid leukemia (CML). As the life expectancy of CML patients has approached that of the general population, research has shifted towards improving quality of life and economic considerations. After 2010, it was shown that some patients could maintain molecular response even after discontinuing imatinib. This national multicenter prospective cohort study aimed to observe the long-term consequences of discontinuing imatinib therapy in adult chronic-phase CML patients. Materials and Methods: We enrolled 41 CML patients from 4 different centers in this non-randomized single-arm trial. Molecular responses of all patients were re-evaluated using real-time polymerase chain reaction at a single center. The median follow-up time after imatinib discontinuation was 48 months (minimum-maximum: 6-81 months). Results: The rate of molecular relapse-free survival at 48 months was 33.2% (confidence interval: 48.2-18.2). Twenty-seven of 41 patients lost their major molecular response, treatment was started again, and deep molecular response was re-achieved with imatinib in all cases. There was no significant relationship between molecular relapse and clinical factors such as duration of treatment or molecular response status. Discontinuing imatinib resulted in savings of approximately 4,392,000 Turkish lira or 245,150 US dollars. Conclusion: Tyrosine kinase inhibitor discontinuation with close molecular monitoring is a safe option and provides important national economic benefits for chronic phase CML patients. This approach should be considered for all eligible patients. This is the first tyrosine kinase inhibitor discontinuation study from Türkiye.

Treatment-free survival after discontinuation of immune checkpoint inhibitors in mNSCLC: a systematic review and meta-analysis.

Background: Recent research has suggested that patients with metastatic non-small cell lung cancer (mNSCLC) can achieve ongoing response after discontinuation of immune checkpoint inhibitor (ICI), but the best time to discontinue and the factors influencing efficacy remain unknown. Method: A systematic search was performed for prospective clinical trials in patients with mNSCLC treated with ICIs published up to July 10, 2022. Eligible studies reported treatment-free survival (TFS) after discontinuation of ICI in partial objective responders. We calculated objective response rate (ORR) and TFS using random-effects models with respective 95% confidence intervals (Cis), and performed subgroup analyses to discuss the specific associations between ORR and TFS and the associated influencing factors. Results: Across the 26 cohorts (3833 patients) included, the weighted mean ORR for all patients was 29.30% (95% CI 24.28% to 34.57%), with ICI plus chemotherapy (48.83%, 95% CI 44.36% to 53.30%) significantly higher than monotherapy (23.40%, 95% CI 18.53% to 28.62%). 395 patients were all patients who were complete or partial responders in the study, 194 discontinued ICI treatment, and nearly 35.5% achieved a durable response. No significant differences in TFS were found between subgroups according to the ICI regimen classification. Four cohorts of patients who completed 35 courses of treatment showed high levels of pooled TFS at 6 (80.18%, 95% CI 53.03% to 97.87%) and 12 months (66.98%, 95% CI 46.90% to 84.47%). Three cohorts of patients discontinued ICI treatment due to treatment-related adverse events (TRAEs) with the TFS rates at 6 (76.98%, 95% CI 65.79% to 86.65%) and 12 months (64.79%, 95% CI 50.20% to 78.19%). Conclusion: Patients with mNSCLC were able to achieve ongoing responses after discontinuation of ICI. In conclusion, the results of this meta-analysis indicate that different treatment regimens, different drugs or different treatment durations may have an impact on TFS.

Who really benefits from intraperitoneal chemotherapy for advanced ovarian cancer? A treatment-free survival analysis of the AICE trial.

OBJECTIVE: To investigate whether peritoneal disease extent can predict the survival benefit of intraperitoneal/intravenous (IP/IV) chemotherapy in ovarian cancer. DESIGN: A treatment-free survival (TFS) analysis. SETTING: Five-centre trial. POPULATION: An extended follow-up of the Additional Intraperitoneal Cisplatin and Etoposide in ovarian cancer (AICE) trial (NCT01669226), with data cut-off on 27 August 2020. Patients were categorised into subgroups with high tumour burden (HTB) and low tumour burden (LTB). METHODS: Overall survival (OS) was divided into time on protocol treatment exposure (T), time free of subsequent treatment or death (TFS) and time after the first subsequent therapy (REL). TFS analyses and quality-adjusted OS were calculated by multiplying the mean time in each health state by its assigned utility: quality-adjusted OS = ut  × T + TFS + urel  × REL. MAIN OUTCOME MEASURES: The area under each Kaplan-Meier curve was estimated using the 96-month restricted mean time, with threshold utility analyses used to illustrate quality-adjusted OS comparisons. RESULTS: In the HTB subgroup, the restricted mean TFS was 33.9 months and 18.7 months in the IP/IV and IV groups, respectively (p = 0.005), with a significant quality-adjusted OS gain (13.2-16.0 months). In the LTB subgroup, IP/IV therapy yielded no survival benefit in either TFS (p = 0.268) or quality-adjusted OS (range: 1.4-6.3 months). CONCLUSIONS: Both TFS and quality-adjusted OS was longer across all utility weight values with IP/IV than with standard IV therapy in the HTB subgroup, whereas patients in the LTB subgroup did not benefit from the therapy. The tumour burden of ovarian cancer should be assessed before deciding on IP/IV versus IV treatment.

Stereotactic radiosurgery for bone metastases in oligometastatic prostate cancer patients: DESTROY-2 clinical trial subanalysis

IntroductionAim of this analysis was to report toxicity and clinical outcomes in oligorecurrent prostate cancer (PCa) patients treated with single fraction stereotactic radiosurgery (SRS) for bone metastases.MethodsWe separately analyzed clinical data of PCa patients with bone oligometastases enrolled in a prospective phase I trial (DESTROY-2). DESTROY-2 was based on SRS delivered using volumetric modulated arc therapy in patients with primary or metastatic tumors in several extra-cranial body sites. Acute and late toxicity, biochemical tumor response, local control (LC), distant metastases-free (DPFS), progression-free (PFS), time to next-line systemic treatment-free (NEST-FS), and overall survival (OS) were calculated.ResultsData on 37 PCa patients, carrying out 50 bone metastases, candidates for curative-intent treatment and treated with SRS at our Institution were collected. SRS dose ranged between 12 and 24 Gy. One grade 1 acute skin toxicity in one patient treated on the hip (24 Gy) and one grade 1 late skin toxicity in a patient with a scapular lesion (24 Gy) were recorded. No cases of bone fracture were registered in the treated population. With a median follow-up of 25 months (range 3–72 months) 2-year actuarial LC, DPFS, PFS, and OS were 96.7%, 58.1%, 58.1%, and 95.8%, respectively. Median and 2-year NEST-FS were 30 months (range 1–69 months) and 51.2%, respectively.ConclusionsData analysis showed few toxicity events, high local control rate and prolonged NEST-FS after linear accelerator-based radiosurgery of bone oligometastases from PCa. The possibility of postponing systemic treatments in patients with oligometastatic PCa by means of SRS should be taken into account. Further prospective studies on larger series are needed to confirm the reported results.

Robot-Assisted Radical Prostatectomy for Potential Cancer Control in Patients with Metastatic Prostate Cancer.

Recently, cytoreductive prostatectomy for metastatic prostate cancer (mPCa) has been associated with improved oncological outcomes. This study was aimed at evaluating whether robot-assisted radical prostatectomy (RARP) as a form of cytoreductive prostatectomy can improve oncological outcomes in patients with mPCa. We conducted a retrospective study of twelve patients with mPCa who had undergone neoadjuvant therapy followed by RARP. The endpoints were biochemical recurrence-free survival, treatment-free survival, and de novo metastasis-free survival. At the end of the follow-up period, none of the enrolled patients had died from PCa. The 1- and 2-year biochemical recurrence-free survival rates were 83.3% and 66.7%, respectively, and treatment-free survival rates were 75.0% and 56.3%, respectively. One patient developed de novo bone metastases 6.4 months postoperatively, and castration-resistant prostate cancer 8.9 months postoperatively. After RARP, the median duration of recovery of urinary continence was 5.2 months. One patient had severe incontinence (>2 pads/day) 24 months postoperatively. RARP may be a treatment option in patients with mPCa who have achieved a serum prostate-specific antigen level < 0.2 ng/mL, and present without new lesions on imaging.

Stereotactic radiosurgery for bone metastases in oligometastatic prostate cancer patients: DESTROY-2 clinical trial subanalysis.

INTRODUCTION: Aim of this analysis was to report toxicity and clinical outcomes in oligorecurrent prostate cancer (PCa) patients treated with single fraction stereotactic radiosurgery (SRS) for bone metastases. METHODS: We separately analyzed clinical data of PCa patients with bone oligometastases enrolled in a prospective phase I trial (DESTROY-2). DESTROY-2 was based on SRS delivered using volumetric modulated arc therapy in patients with primary or metastatic tumors in several extra-cranial body sites. Acute and late toxicity, biochemical tumor response, local control (LC), distant metastases-free (DPFS), progression-free (PFS), time to next-line systemic treatment-free (NEST-FS), and overall survival (OS) were calculated. RESULTS: Data on 37 PCa patients, carrying out 50 bone metastases, candidates for curative-intent treatment and treated with SRS at our Institution were collected. SRS dose ranged between 12 and 24 Gy. One grade 1 acute skin toxicity in one patient treated on the hip (24 Gy) and one grade 1 late skin toxicity in a patient with a scapular lesion (24 Gy) were recorded. No cases of bone fracture were registered in the treated population. With a median follow-up of 25 months (range 3-72 months) 2-year actuarial LC, DPFS, PFS, and OS were 96.7%, 58.1%, 58.1%, and 95.8%, respectively. Median and 2-year NEST-FS were 30 months (range 1-69 months) and 51.2%, respectively. CONCLUSIONS: Data analysis showed few toxicity events, high local control rate and prolonged NEST-FS after linear accelerator-based radiosurgery of bone oligometastases from PCa. The possibility of postponing systemic treatments in patients with oligometastatic PCa by means of SRS should be taken into account. Further prospective studies on larger series are needed to confirm the reported results.

Role of cytogenetic abnormalities detected by fluorescence in situ hybridization as a prognostic marker: Pathogenesis & clinical course in patients with B-chronic lymphocytic leukaemia.

BACKGROUND & OBJECTIVES: B-cell chronic lymphocytic leukaemia (B-CLL) is one of the most common forms of adult leukaemia, with a highly variable clinical course. Specific chromosomal and genetic aberrations are used clinically to predict prognosis, independent from conventional clinical markers. Molecular cytogenetic methods such as fluorescence in situ hybridization (FISH) detect aberrations in up to 80 per cent B-CLL patients. This study was conducted to score the frequencies of recurrent aberrations, i.e., del(13q14), trisomy 12, del(11q22), del(17p13), del(6q21) and IgH (immunoglobulin heavy chain) translocations and to understand their role in prognostication and risk stratification. METHODS: FISH studies were performed on bone marrow aspirate or peripheral blood of 280 patients using commercially available disease-specific probe set. The data were correlated with clinical and haematological parameters such as low haemoglobin, splenomegaly and lymphadenopathy. RESULTS: Chromosomal aberrations were detected in 79 per cent of patients, with del(13q14) (57%) as the most common cytogenetic aberration, followed by trisomy 12 (27%), del(11q22) (22%), t(14q32) (19%), del(17p13) (18%) and del(6q21) (9%). Single or in coexistence with other aberration del(13q14) had a favourable outcome in comparison to del(11q22), t(14q32), del(17p13) and del(6q21) which were associated with advanced stages of the disease. Trisomy 12 had a variable clinical course. INTERPRETATION & CONCLUSIONS: FISH was found to be a sensitive and efficient technique in detecting the prevalence of recurrent cytogenetic abnormalities. Each of these aberrations is an important independent predictor of disease progression and survival which aids in designing risk-adapted treatment strategies for better disease management.

Good treatment-free survival of monoclonal gammopathy of undetermined significance associated pure red cell aplasia after bortezomib plus dexamethasone.

Pure red cell aplasia (PRCA) is a rare syndrome characterized by severe anemia and absence of erythroid precursors. PRCA associated to monoclonal gammopathy of undetermined significance (MGUS) is a scarce condition with less than five cases reported so far. There is no agreement on the treatment of MGUS associated PRCA and treatment- free survival (TFS) is an unmet clinical need. In this report, for the first time, we demonstrated two patients with MGUS associated PRCA obtained rapid remission and maintained TFS after accepting intensive short-term bortezomib plus dexamethasone. The first case was refractory to cyclosporine and prednisone, but achieved complete remission after ten doses of bortezomib. Moreover, he has kept TFS for 12 months. The other case initiated bortezomib plus dexamethasone as soon as making a definite diagnosis. She obtained complete remission after twelve doses of bortezomib and she has maintained a normal level of haemoglobin for 8 months.

Superior Survival in African American Patients Who Underwent Autologous Stem Cell Transplantation for Multiple Myeloma.

INTRODUCTION/BACKGROUND: African American (AA) individuals have a twofold higher incidence of multiple myeloma (MM) compared with other racial groups. Outcomes are affected by factors such as disparate access to care as well as differences in disease biology. PATIENTS AND METHODS: We conducted a single-institution analysis to evaluate the effect of AA race on outcomes of MM patients who underwent autologous stem cell transplantation (ASCT) in the pre-novel and novel agent era. RESULTS: Sixty-one (47%) patients were AA and 69 (53%) were non-AA. Overall, 78 (60%) patients received any novel agent before transplantation and 52 (40%) received only chemotherapy. More non-AA patients received initial induction with a proteasome inhibitor (40 [60%] vs. 17 [28%]; P = .0007), and were treated with post-ASCT maintenance therapy (28 [41%] vs. 14 [23%]; P = .04). Time from diagnosis to ASCT in AA patients was 10 (range, 4-144) versus 8 (range, 3-54) months in non-AA patients (P = .01). Despite this, treatment-free survival (TFS) was equivalent between the 2 groups (x vs. y). Furthermore, AA patients had greater median overall survival (OS) compared with non-AA patients (not reached vs. 108 months; P = .03) and significantly improved OS in multivariable Cox proportional hazards models (adjusted hazard ratio, 0.30; 95% confidence interval, 0.11-0.81; P = .017). Median OS, landmarked at the time of relapse, was improved in AA patients (not reached vs. 68 months for P = .05). CONCLUSION: Our study showed with long follow-up, equivalent TFS after ASCT in AA and non-AA patients yet improved OS. Post relapse survival is improved in AA patients suggesting a better response to salvage therapy.

Sex-dependent association of circulating sex steroids and pituitary hormones with treatment-free survival in chronic lymphocytic leukemia patients.

Chronic lymphocytic leukemia (CLL) is not considered a hormone-regulated cancer although sex is a recognized risk factor with men more frequently diagnosed and developing progressive disease. We hypothesized that variable hormonal exposure may have a sexually dimorphic influence on treatment-free survival (TFS). In 156 CLL cases, we quantitatively profiled 29 circulating steroids (progesterone, adrenal precursors, androgens, estrogens, and catechol estrogens) as well as luteinizing hormone (LH) and follicle-stimulating hormone. Median TFS was shorter for men than that for women (80.7 vs. 135.0 months, P = 0.033). Circulating hormone profiles in CLL patients were significantly different from those of healthy donors. In male CLL cases, higher LH levels were associated with shorter TFS (adjusted hazard ratio (HRadj) 2.11; P = 0.004). In female CLL cases, high levels of the potent androgens testosterone and dihydrotestosterone and the sum of methoxy estrogens were associated with an improved TFS with HRadj values of 0.24 (P = 0.007), 0.54 (P = 0.023), and 0.31 (P = 0.034), respectively. Reduced TFS was observed for women with CLL exhibiting high expression of the steroid-inactivating UGT2B17 enzyme. This study is the first to establish a link between the outcome of CLL patients, sex steroids, and pituitary hormones, revealing a sex-specific hormonal imbalance associated with disease progression.

Active surveillance for localized prostate cancer: update of a prospective single-center cohort.

OBJECTIVE: The purpose of active surveillance (AS) is to reduce overtreatment of men with localized prostate cancer (PCa) without compromising survival. The objective of this study was to update a large Scandinavian single-center AS cohort. Furthermore, the use of curative treatment and subsequent risk of biochemical recurrence were investigated and compared in men with very low-risk, low-risk and intermediate-risk PCa in the cohort. MATERIALS AND METHODS: In total, 451 men were followed on AS and monitored with prostate-specific antigen (PSA) tests, digital rectal examinations and rebiopsies. Recommendation of curative treatment was based on protocolled and predefined risk of progression criteria. Biochemical recurrence was defined as PSA ≥0.2 ng/ml after radical prostatectomy and PSA nadir +2 ng/ml after radiotherapy. RESULTS: Altogether, 34% were defined with very low-risk PCa, 40% with low-risk PCa and 24% with intermediate-risk PCa. The median follow-up was 5.1 years. The estimated 5 year curatively intended treatment-free survival was 60.5% [95% confidence interval (CI) 54.8-66.2%], with no statistically significant difference between men with very low-risk, low-risk or intermediate-risk PCa. The 5 year biochemical recurrence-free survival was 92.3% (95% CI 87.4-97.2), again with no difference between men with very low-risk, low-risk and intermediate-risk PCa. CONCLUSION: AS for very low- to low-risk localized PCa is feasible and safe within the short to intermediate time frame. Men with intermediate-risk PCa had the same risk of undergoing curative treatment as men with low-risk PCa, without compromising biochemical recurrence-free survival.

FcγRIIb expression in early stage chronic lymphocytic leukemia.

In normal B-cells, B-cell antigen receptor (BCR) signaling can be negatively regulated by the low-affinity receptor FcγRIIb (CD32b). To better understand the role of FcγRIIb in chronic lymphocytic leukemia (CLL), we correlated its expression on 155 samples from newly-diagnosed Binet A patients with clinical characteristics and outcome. FcγRIIb expression was similar in normal B-cells and leukemic cells, this being heterogenous among patients and within CLL clones. FcγRIIb expression did not correlate with well known prognostic markers [disease stage, serum beta-2 microglobulin (B2M), IGHV mutational status, expression of ZAP-70 and CD38, and cytogenetics] except for a weak concordance with CD49d. Moreover, patients with low FcγRIIb expression (69/155, 44.5%) required therapy earlier than those with high FcγRIIb expression (86/155, 55.5%) (median 151.4 months vs. not reached; p=.071). These results encourage further investigation on the role of FcγRIIb in CLL biology and prognostic significance in larger series of patients.

Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia is a predictor of early death.

Hypogammaglobulinemia is the most common immune deficiency in chronic lymphocytic leukemia (CLL). However, the prognostic significance in terms of morbidity and mortality remains controversial. We here evaluate the significance of hypogammaglobulinemia in terms of infections, treatment-free survival (TFS), and overall survival (OS). A total of 159 consecutive, newly diagnosed patients were included for analysis. Twenty-five patients (16%) had a moderate or severe infection within one year of diagnosis, but no associations were found between low immunoglobulin (Ig) levels and infections. In multivariate analysis, we found age (>65), high Binet stage, high ß2-microglobulin, and Ig deficiency to be associated with shorter OS. Decreased levels of IgM, deletion of chromosome 17p and unmutated IGHV status had independent negative impact on TFS. Thus, patients with hypogammaglobulinemia did not suffer more from infections early in the disease course, and decreased Ig had independent negative prognostic impact in CLL.

Cervicomedullary tumors in children.

OBJECT: Cervicomedullary tumors (CMTs) represent a heterogeneous group of intrinsic neoplasms that are typically low grade and generally carry a good prognosis. This single-institution study was undertaken to document the outcomes and current treatment philosophy for these challenging neoplasms. METHODS: The charts of all pediatric patients with CMTs who received treatment at St. Jude Children's Research Hospital between January 1988 and May 2013 were retrospectively reviewed. Demographic, surgical, clinical, radiological, pathological, and survival data were collected. Treatment-free survival and overall survival were estimated, and predictors of recurrence were analyzed. RESULTS: Thirty-one children (16 boys, 15 girls) with at least 12 months of follow-up data were identified. The median age at diagnosis was 6 years (range 7 months-17 years) and the median follow-up was 4.3 years. Low-grade tumors (Grade I or II) were present in 26 (84%) patients. Thirty patients underwent either a biopsy alone or resection, with the majority of patients undergoing biopsy only (n = 12, 39%) or subtotal resection (n = 14, 45%). Only 4 patients were treated solely with resection; 21 patients received radiotherapy alone or in combination with other treatments. Recurrent tumor developed in 14 children (45%) and 4 died as a result of their malignancy. A high-grade pathological type was the only independent variable that predicted recurrence. The 5- and 10-year treatment-free survival estimates are 64.7% and 45.3%, respectively. The 5- and 10-year overall survival estimate is 86.7%. CONCLUSIONS: Children with CMTs typically have low-grade neoplasms and consequently long-term survival, but high risk of recurrence. Therapy should be directed at achieving local tumor control while preserving and even restoring neurological function.

Global histone deacetylase enzymatic activity is an independent prognostic marker associated with a shorter overall survival in chronic lymphocytic leukemia patients.

Histone deacetylases (HDAC) play a crucial role in transcriptional regulation and are often deregulated in many cancers. However, global HDAC enzymatic activity has never been investigated in Chronic Lymphocytic Leukemia (CLL). We measured HDAC activity in protein extracts from CD19+ B-cells purified from 114 CLL patients with a median follow-up of 91 months (range: 11-376). HDAC activity was equivalent in CLL and normal B-cells but higher in patients who died during the study than in living patients (152.1 vs. 65.04 pmol; P = 0.0060). Furthermore, HDAC activity correlated with treatment-free survival (TFS; P = 0.0156) and overall survival (OS; P < 0.0001): patients with low HDAC activity (n = 75) had a median TFS and OS of 101 and > 376 months, respectively, whereas patients with high HDAC activity (n = 39) had a median TFS and OS of 47 and 137 months, respectively. Multivariate analyses indicated that HDAC activity is an independent predictor of OS (hazard ratio = 7.68; P = 0.0017). Finally, HDAC activity increased after B-cell receptor stimulation using IgM, suggesting a role for microenvironment stimuli (n = 10; P = 0.0371). In conclusion, high HDAC activity in CLL B-cells is associated with shorter TFS and OS and is an independent marker of OS, refining the use of other prognostic factors. This work provides a biological base for the use of HDAC inhibitors in CLL treatment.

Total expression of HLA-G and TLR-9 in chronic lymphocytic leukemia patients.

Suppressed immune status facilitates immune escape mechanisms that allow chronic lymphocytic leukemia cells to proliferate and expand. The expression of HLA-G could effectively inhibit the immune response. In immune response inhibitory signals follow activation of immune system which might be occur during bacterial or viral infection in CLL patients. In the current study we characterized two components of immune system, inhibitory molecule HLA-G with its receptor - CD85j and Toll-like receptor 9. The material was obtained from 41 CLL patients and 41 HV with similar median age. In CLL patients expression of intracellular and surface HLA-G and soluble HLA-G levels were significantly higher than in HV. We found higher expression of CD85j compared to HV and the positive correlation between expression of HLA-G and CD85j. All the CLL cells expressed TLR-9, and the level of expression positively correlated with expression of HLA-G and CD85j. Patients with higher expression of intracellular expression of TLR-9 have significantly longer treatment-free survival than patients with low expression of TLR-9 (57 months vs. 8 months, respectively). Summarizing in CLL we characterized activatory and inhibitory components of immune system that might be connected functionally. Analysis of TLR-9 expression might have additional prognostic value for CLL patients.