Achievement Of Complete Response Research Articles

Stereotactic radiotherapy for liver oligometastases: a pooled analysis following the estro/eortc consensus recommendations.

A large pooled analysis of liver oligometastases, classified accordingly to the ESTRO/EORTC recommendations, treated by stereotactic radiotherapy (SBRT) and Radiosurgery (SRS) was carried out. The clinical and dosimetric data of patients who underwent SBRT/SRS for liver metastases were analysed in terms of efficacy and toxicity profile. In particular, the Local Control (LC), the Distant Metastases Free Survival (DMFS), the Disease-Free Survival (DFS), the Overall Survival (OS), and the Next Systemic Therapy Free Survival (NEST-FS) rates were analysed. 113 patients (M/F: 49/64), accounting for a total of 150 hepatic lesions (March 2006-February 2023) in two Italian radiotherapy Institutions were evaluated. Median age was 67years old (36-92) and 48 (42.5%) patients had at least one comorbidity. The majority of the lesions were induced (30.7%) or repeated oligoprogressive (12.7%) metastases. 98 lesions were treated with more than one daily fraction (mainly 50Gy in 5 fractions), while 52 were radiosurgery treatments (mainly 32Gy). The treatment response at 3-4months was evaluable in 147 lesions: complete response was 32.0%, partial response 17.0%, and stable disease 32.0%. Actuarial LC, DMFS, DFS, OS, and NEST-FS at 1 year were 75.8%, 37.7%, 34.9%, 78.7%, and 59.4% respectively; while actuarial LC, DMFS, DFS, OS, and NEST-FS at 2 years were 52.1%, 24.9%, 21.9%, 51.3%, and 36.8%, respectively. The achievement of complete response, synchronous oligometastases, and no treatment interruptions correlated with a more favorable outcomes. As per the toxicity profile, we registered only two acute and one late toxicity cases higher than grade 2. Stereotactic treatment for liver metastases seems to be a safe and promising option in terms of local control. The best results in term of outcomes have been obtained in patients with complete response, synchronous oligometastases, favorable histology, and no treatment interruptions.

Machine Learning-Based Prediction of Pathological Responses and Prognosis After Neoadjuvant Chemotherapy for Non–Small-Cell Lung Cancer: A Retrospective Study

BackgroundNeoadjuvant chemotherapy has variable efficacy in patients with non–small-cell lung cancer (NSCLC), yet reliable noninvasive predictive markers are lacking. This study aimed to develop a radiomics model predicting pathological complete response and postneoadjuvant chemotherapy survival in NSCLC. Materials and MethodsRetrospective data collection involved 130 patients with NSCLC who underwent neoadjuvant chemotherapy and surgery. Patients were randomly divided into training and independent testing sets. Nine radiomics features from prechemotherapy computed tomography (CT) images were extracted from intratumoral and peritumoral regions. An auto-encoder model was constructed, and its performance was evaluated. X-tile software classified patients into high and low-risk groups based on their predicted probabilities. survival of patients in different risk groups and the role of postoperative adjuvant chemotherapy were examined. ResultsThe model demonstrated area under the receiver operating characteristic (ROC) curve of 0.874 (training set) and 0.876 (testing set). The larger the area under curve (AUC), the better the model performance. Calibration curve and decision curve analysis indicated excellent model calibration (Hosmer–Lemeshow test, P = .763, the higher the P-value, the better the model fit) and potential clinical applicability. Survival analysis revealed significant differences in overall survival (P = .011) and disease-free survival (P = .017) between different risk groups. Adjuvant chemotherapy significantly improved survival in the low-risk group (P = .041) but not high-risk group (P = 0.56). ConclusionThis study represents the first successful prediction of pathological complete response achievement after neoadjuvant chemotherapy for NSCLC, as well as the patients’ survival, utilizing intratumoral and peritumoral radiomics features.

Prognostic Factors and Treatment Strategy in Patients with Hodgkin Lymphoma and HIV Infection Treated with ABVD and CART: A Retrospective Study from Spanish Group Geltamo

Background Hodgkin lymphoma (HL) is one of the most frequent non-AIDS defining neoplasm in people living with HIV (PLWH). Since the widespread use of combined antiretroviral therapy (cART), the incidence of most types of non-Hodgkin lymphoma affecting PLWH have decreased, but the incidence of HL has increased. The International Prognostic Score (IPS) is the most widely used score for HL. However, its implementation in PLWH is still controversial. Current HL treatment guidelines consider early and advanced stage. In function of the presence of unfavorable risk factors in early stages, an interim PET-CT can be used to guide therapeutic strategy. Unfavorable risk factors have been described by international groups (EORT, GHSG, NCI-C, and NCCN), which are: ≥3-4 involved lymph node areas, elevated RDW, age ≥50 years, ≥1 extranodal involvement and presence of B symptoms. There is a lack of evidence of the impact of this strategy in patients with HIV. Methods Retrospective multicentric study of patients with HIV infection diagnosed with HL in 9 hospitals from the GELTAMO group in Spain, from 1995 to 2022. All patients were treated with ABVD and cART +/- radiotherapy. The main clinical and biological variables were collected. Peripheral absolute neutrophil, lymphocyte and monocyte counts were studied, including L/M ratio and CD4 + lymphocyte count. Moreover, serum lactate dehydrogenase (LDH), albumin and RDW were evaluated. Univariable and multivariable analysis were performed using the binary logistic regression model for complete response (CR) rate and Cox proportional-hazards regression model for overall survival (OS) and progression-free survival (PFS). Survival curves were plotted by the Kaplan-Meier method and compared by the log-rank test. Results Ninety patients were retrospectively analyzed with a median follow up of 5.89 [0,4;24,78] years. The characteristics of the patients are summarized in Table 1. Extranodal involvement, hemoglobin <105 g/L, leucocytosis, high RDW, hypoalbuminemia and high LDH were associated with worse probabilities of complete response (CR) achievement. In the univariate analysis, bone marrow involvement and monocytes count ≥0.6 x10^9/L were associated with shorter overall survival (OS) and progression free survival (PFR) probabilities. A lymphocyte/monocyte (L/M) ratio <1.09 was associated with shorter PFR probabilities. By multivariable analysis, only monocyte count ≥0.6 x10^9/L emerged as an unfavorable prognostic factor for OS and PFS ( Figure 1). Data about treatment strategy and CR achievement is described in Table 1. Most patients (74%) presented advanced stage and the presence of unfavorable prognostic factors (described by international groups) was detected in most of the patients with localized stages ( Table 1). Conclusions High monocyte count is a strong prognostic factor which can be used in PLWH with HL. Most patients with HL and HIV infection present an advanced stage at diagnosis or a localized stage with unfavorable prognosis factors. In patients with localized stage, interim PET-CT guided strategy seems to be feasible.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone (DVRd) and Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (DKRd) As Induction Therapy in Newly Diagnosed Multiple Myeloma

Background: Daratumumab, bortezomib, lenalidomide, dexamethasone (DVRd) and daratumumab, carfilzomib, lenalidomide, dexamethasone (DKRd) are promising induction regimens for newly diagnosed multiple myeloma (NDMM), resulting in deep responses and high minimal residual disease (MRD) negativity rates. Our prior work demonstrated progression-free survival (PFS) benefit in patients with high-risk (HR) NDMM receiving KRd versus VRd. Herein, we examined early outcomes associated with DVRd and DKRd induction in the management of patients with NDMM. Methods: We conducted a chart review study with NDMM patients treated with DVRd (N=107) and compared outcomes with patients treated with DKRd (N=82), of which 68 were on study (NCT03290950) at Memorial Sloan Kettering (MSK) from 10/5/2017 to 5/1/23. Cutoff date for analysis was 7/19/23. Patients who received ≤1 prior cycle of another regimen for MM were included (N=29). Patients who have not completed induction and received <4 cycles of a quadruplet regimen or who received the majority of their quadruplet induction outside of MSK were excluded. Bone marrow biopsies (BMBx) were typically performed for MRD evaluation prior to stem cell collection or at the end of cycle 8. MRD negativity was evaluated by flow cytometry at 10 -5 sensitivity threshold. Discrete patient characteristics were summarized by frequency (percentage) and continuous characteristics were summarized by median (Interquartile Range, IQR). PFS and overall survival (OS) were evaluated by Kaplan-Meier method. Logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Results: Median age was 66 (IQR, 60-70) for DVRd- and 59 (50-65) for DKRd-treated patients (P<0.001). In the DVRd group, 72% were White and 15% Black while the DKRd group had 79% were White and 9% Black. Most of the patients in both groups had RISS Stage 2 disease (DVRd RISS 1/2/3: 33%/61%/7%; DKRd: 35%/60%/5%). With HR cytogenetic abnormality (HRCA) defined as +1q, del(1p), t(4;14), t(14;16), t(14;20), and/or del(17p), 43/100 (43%) in DVRd group and 46/81 (57%) in the DKRd group had cytogenetic abnormalities that met HR criteria (P=0.065). Among the DVRd patients, 57, 28, and 15 had 0, 1, 2+ HRCA, respectively, while in the DKRd group, 35, 30, and 16 had 0, 1, 2+ HRCA, respectively (P=0.2). Median number of cycles was 6 (IQR, 4-6) for DVRd and 8 (IQR, 6-8) for DKRd (P<0.001). At data cutoff, 72 DVRd and 74 DKRd patients completed stem cell collection; among these patients, 41 (57%) DVRd- and 25 (34%) DKRd-treated patients received upfront ASCT. Best overall response rate (ORR) was 98% and 100% for DVRd and DKRd (P=0.5), respectively. Within 8 cycles of therapy, 21 (20%) and 28 (34%) patients achieved a ≥complete response (CR) in the DVRd and DKRd groups, respectively (P=0.024). Additionally, 83 (78%) patients were in ≥VGPR in the DVRd group and 74 (90%) in the DKRd group (P=0.021). There were 2 pts with best response as stable disease in the DVRd group. 86 DVRd pts and 73 DKRd patients had a BMBx within 8 cycles of induction therapy and were evaluable for MRD. Among these patients, 20 (23%) and 38 (52%) achieved MRD negativity for DVRd and DKRd, respectively. Multivariable analysis with clinical variables including type of quadruplet therapy, age, gender, race, R-ISS stage, cytogenetic risk, and number of cycles, demonstrated no significant association with achievement of CR (DKRd [ref] vs DVRd, OR 0.46, 95%CI 0.19-1.04; P=0.064). After a median follow-up of 13 (95%CI, 11-15) months for DVRd and 53 (48-55) months for DKRd, 1-year estimated PFS was 92% (95%CI, 86%-99%) and 94% (89%-99%) for DVRd and DKRd, respectively (P=0.5). Conclusion: In this single-center chart review study, DVRd was compared to DKRd as induction therapy for patients with NDMM. Importantly, DKRd patients were primarily comprised of patients from a clinical trial (NCT03290950), perhaps affecting demographics of the groups (DVRd group had older patients and more Black patients; DKRd group had more cycles of therapy due to trial design). DVRd and DKRd are both associated with high ORR. Although the ≥CR rate was greater with DKRd, on multivariable analysis there was no statistically significant difference between DKRd and DVRd after adjusting for various clinical variables. Data with follow-up outcomes will be presented at the meeting.

Isolated and Dynamic Peripheral Blood Residual Disease Status Characterized By Mass Spectrometry Predicts Outcome in Patients with High Risk Smoldering Multiple Myeloma Treated in the GEM-CESAR Trial

Background: GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the rate of minimal residual disease (MRD) negativity in the bone marrow (BM) assessed by next generation flow (NGF) after autologous stem cell transplantation (ASCT) and sustained 3 and 5 years afterwards. Here, we update the preliminary results presented at ASH2019 about the clinical value of quantitative immunoprecipitation mass spectrometry to assess treatment response in this group of patients. Methods: Pts received induction with six 4-week cycles of KRd (K: 36mg/m 2 twice weekly, R: lenalidomide 25mg po od days 1-21 and d: dexamethasone 40mg po weekly), high-dose melphalan followed by ASCT, consolidation with two further cycles of KRd and up to 2 years of maintenance with Rd (R: 10mg po od, d: 20mg po weekly). Peripheral blood Residual Disease(PRD) was analyzed post-ASCT and at treatment completion (after 2 years of maintenance) using Quantitative Immunoprecipitation Mass Spectrometry with anti IgG/A/M, total k and total l beads using the EXENT ® Solution (The Binding Site, part of Thermo Fisher Scientific). From the 90 pts enrolled in the trial, 61 were analyzed post-ASCT and 35 at the end of treatment. Isotype-matched immunoparesia (IMI) was also evaluated post-ASCT using the heavy/light chain pairs. Kaplan-Meier curves were plotted either from the specific time point investigated or from the last one if dynamics were analyzed. Results: First,PRD was analyzed post-ASCT and at treatment completion and deemed to be positive in 54% (33/61) and 20% (7/35) of patients, respectively. At both time points, PRD assessment discriminated two groups of patients with a very significantly different prognosis: median PFS in PRD+cases post-ASCT was 4.27 years vs not reached in PRD- cases (p=0.0071) (Fig 1A) and after 2 years of maintenance, the median PFS in PRD- cases was not reached vs 1.43 years in PRD+ cases (p=0.0011) (Fig 1B). Importantly, standard response criteria and, more specifically, the achievement of complete response (CR) or better, was not associated with disease outcome. And further, among samples in ³CR, PRD+ was also able to discriminate a group of patients with poorer outcome, with a median PFS of 4.42 years vs not reached in PRD- cases (p=0.0136) Interestingly, when we combined the analysis of the M-protein by mass spectrometry with the identification of severe isotype-matched suppression (uHLC < 50%), PRD+ patients post-ASCT could be further stratified in two subgroups with significantly different median PFS (not reached in those with no severe IMI vs 3.85 years in those with severe IMI, p=0.0384) (Fig 1C). A similar tendency was observed among PRD+cases after 2 years of maintenance (mPFS in those with no severe IMI of 2.5 years vs 9 months in those with severe IMI) although the difference did not reach statistical significance. Then, we analyzed PRD dynamics after ASCT and at the end of treatment. Sustained PRDnegativity during this period was observed in 12 pts (33.3%), and sustained positivity in 6 (16.6%). In 5 pts (13.8%) PRD converted from positive to negative, and in 1 (2.7%) from negative to positive. Whereas sustained PRD+ was associated with a very short median PFS of 1.66 years, patients with sustained PRD- or who converted from PRD+ to PRD- displayed a very favorable outcome with median PFS not reached and significantly different compared to the sustained PRD+ group (p<0,0001) (Fig 1D). Interestingly, the only patient that converted from PRD-to PRD+ had a very poor outcome with a mPFS 3.8 months. By contrast, sustained CR or better according to standard response criteria was not significantly associated with clinical outcome. Conclusion: In this cohort of high-risk smoldering MM patients treated intensively with a curative intention, whereas standard CR or better was not associated with clinical outcome, PRD status defined by mass-spectrometry segregated two groups of patients with different PFS at the 2 time points analyzed. Furthermore, this outcome was better predicted when PRD dynamics were analyzed and/or with the evaluation of severe IMI on PRD+ patients, highlighting once again the relevance of immune recovery as a determinant factor in the evolution of the disease.

Molecular Mechanisms Underlying Response and Resistance to Glofitamab

The prognosis for patients with relapsed or refractory Diffuse Large B-cell Lymphoma (r/rDLBCL) is poor. Glofitamab (a CD20xCD3 T-cell-engaging bispecific antibody) demonstrated high and durable complete response rates and a manageable safety profile in patients with relapsed/refractory (R/R) Large B-cell lymphoma (LBCL). Despite its clinical efficacy and a rapid achievement of complete responses, some patients are refractory to glofitamab treatment, prompting us to investigate the mechanisms underlying response and resistance to glofitamab. To gain insight into these mechanisms, we performed molecular (single cell RNA and TCR sequencing data) and functional (ex-vivo assessment of cytotoxicity, cytokine and cytotoxic granules secretion, activation) characterisation of PBMCs from glofitamab-treated patients who achieved complete response (CR, n=18) or progressed (progressive disease, PD, n=13) by cycle 3, collected in a Phase I/II study (NCT03075696). All patients received glofitamab in a step-up-dose regimen of 2.5/10/30 mg following obinutuzumab pre-treatment (1000 mg) administered 7 days prior to the first glofitamab dose. The PBMC samples were analyzed at baseline (cycle 1 day 1 pre-dose) and on treatment (cycle 2 day 1 pre-dose). The assessment of PBMCs using single cell RNA sequencing did not reveal major differences in abundance of the main immune cell subsets between patients who achieved CR or PD. Paired analysis of on-treatment samples (compared to respective baseline) pointed to a tendency towards decreased frequency of CD8 T cells in patients with CRs and increased frequency of the same in patients with PDs (consisting mainly of an increase of proliferating CD8). Glofitamab treatment further increased the frequency of monocytes and DCs in patients with CRs, and of NKs in both CRs and PDs. Within the DC population, we observed a significant decrease of cDC1 population and increase of the AXL+SIGLEC6+ DC population with high capability of driving T cell activation and proliferation upon treatment in both CR and PD patients. Complementary to changes in cell proportions, we identified gene expression programs associated with response, of which some were shared between two or more cell types while others were cell type-specific. Using established gene expression programs of naiveness, cytotoxicity, and exhaustion, we found that CD8 T cells of CR patients maintain their naive phenotype on treatment, whereas the naiveness of CD8 T cells of PD patients decreases upon treatment. Subsequently, we observed a higher naiveness of CD8 T cells in patients with CRs compared to PDs on treatment. Moreover, CD4 T cells increase their naiveness upon treatment in patients with CRs and decrease in patients with PDs, resulting in higher overall naiveness of CD4 T cells on treatment in CR patients compared to PD patients. In line with the expected mode of action, glofitamab treatment led to an increase of the cytotoxicity and exhaustion scores in CD8 T cells, and of the exhaustion score in CD4 T cells, of both CR and PD patients, reflective of T cell engagement in both patient groups. However, CD8 T cells of PD patients display overall a higher cytotoxicity and exhaustion level compared to CR patients. TCR sequencing data showed a higher clonal diversity in CD4 T cells compared to CD8 T cellsand and enrichment of hyper-expanded clonotypes in the CD8 T cell compared to CD4 T cell compartment . However, we neither detected an increase in the proportion of clonal cells, nor a change in clonal diversity upon treatment, regardless of the patient response group. In addition, we did not find any association between the percent of TCR repertoire occupied by clones of a given size and response or treatment time point. In agreement with the molecular analysis, T cells from CR patients (collected at baseline and on treatment) displayed a tendency towards higher cytotoxicity, cytokine secretion and T cell activation compared to PD patients upon ex vivo re-stimulation with glofitamab, suggestive of a better functional state of T cells from patients with CR compared to PD. Taken together, our work provides a thorough characterization of peripheral blood immune cells from CR and PD patients treated with glofitamab, and provides evidence that T cells from CR patients maintain a fresher/naive and more functional state compared to PD patients, which display T cells in a more advanced differentiation state with lower functionality.

High serum miR-223-3p expression level predicts complete response and prolonged overall survival in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation.

AHSCT is the treatment of choice for newly diagnosed patients with transplant-eligible multiple myeloma (MM). However, considerable variability in response to autologous hematopoietic stem cell transplantation (AHSCT) results in only 50% of patients achieving complete response (CR) after AHSCT, which is directly associated with improved progression-free and overall survival (OS). In this study, we aimed to investigate the potential predictive role of selected serum miRNAs in MM patients who underwent AHSCT. Serum expression level of 6 miRNAs: miR-221-3p, miR-15b-5p, miR-223-3p, miR-320c, miR-361-3p, and miR-150-5p was evaluated in 51 patients who underwent AHSCT. Blood samples were collected at two time points: before conditioning chemotherapy (T1) and fourteen days after transplant (+14) (T2). All selected miRNAs significantly changed their expression level across the procedure- two were up-regulated after AHSCT: hsa-miR-320c (FC 1.42, p<0.0001) and hsa-miR-361-3p (FC 1.35, p=0.0168); four were down-regulated: hsa-miR-15b-5p (FC 0.53, p<0.0001), hsa-miR-221-3p (FC 0.78, p=0.0004), hsa-miR-223-3p (FC 0.74, p=0.0015) and hsa-miR-150-5p (FC 0.75, p=0.0080). Notably, before AHSCT, hsa-miR-223-3p was down-regulated in International Staging System (ISS) III patients (FC=0.76, p=0.0155), and hsa-miR-320c was up-regulated (FC=1.27, p=0.0470). These differences became non-significant after AHSCT. Eight (15.69%) patients achieved CR before AHSCT and 17 patients (33.33%) at +100 days after AHSCT. In multivariate logistic regression analysis, achievement of CR after induction and hsa-miR-223-3p at T1 were independent predictors of CR after AHSCT. In multivariate Cox regression analysis, hsa-miR-223-3p at T1 expression level was associated with prolonged OS (HR 0.06, 95%CI: 0.00 - 0.99, p=0.0488). Serum expression of has-miR-223-3p is a predictor of CR and prolonged OS in MM patients undergoing AHSCT.

Efficacy of Electrochemotherapy in Breast Cancer Patients of Different Receptor Status: The INSPECT Experience.

Electrochemotherapy has been proven to be an efficient treatment for cutaneous metastases of various cancers. Data on breast cancer (BC) patients with cutaneous metastases were retrieved from the INSPECT database. Patients were divided by their receptor status: HER2+, HR+ (ER/PgR+), and TN (triple negative). Groups were similar for histological subtype and location of the nodules. Most patients were previously treated with surgery/systemic therapy/radiotherapy. We found no differences in the three groups in terms of response ratio (OR per patient 86% HER2+, 80% HR+, 76% TN, p = 0.8664). The only factor positively affecting the complete response rate in all groups was small tumor size (<3 cm, p = 0.0105, p = 0.0001, p = 0.0266, respectively). Local progression-free survival was positively impacted by the achievement of complete response in HER2+ (p = 0.0297) and HR+ (p = 0.0094), while overall survival was affected by time to local progression in all groups (p = 0.0065 in HER2+, p < 0.0001 in HR+, p = 0.0363 in TN). ECT treatment is equally effective among groups, despite different receptor status. Response and local tumor control seem to be better in multiple small lesions than in big armor-like lesions, suggesting that treating smaller, even multiple, lesions at the time of occurrence is more effective than treating bigger long-lasting armor-like cutaneous lesions.

Lenalidomide or bortezomib as maintenance treatment remedy the inferior impact of high-risk cytogenetic abnormalities in non-transplant patients with newly diagnosed multiple myeloma: a real-world multi-centered study in China.

Maintenance treatment is a pivotal part in the whole process management of multiple myeloma (MM), which further deepens response and improves survival. However, evidence of maintenance in non-transplant MM patients is inadequate in real-world practice. Here, we retrospectively analyzed the efficacy and survival of 375 non-transplant MM patients from 11 centers between 2010 and 2021 in north China. After a median of seven cycles of front-line regimens, there were 141, 79, and 155 patients receiving lenalidomide maintenance (L-MT), bortezomib maintenance (B-MT), or thalidomide maintenance (T-MT), respectively. Patients on L-MT and B-MT had significantly greater proportions of high-risk cytogenetic abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH), which was defined as 1q21 gain, 17p deletion, adverse immunoglobulin heavy chain (IgH) translocations. Although the progression-free survival (PFS) and overall survival (OS) were comparable among the three groups, L-MT and B-MT remedied the negative impact of HRCAs on survival (PFS of patients with HRCAs vs. patients without HRCAs: L-MT, 26.9 vs. 39.2 months, p=0.19; B-MT, 20.0 vs. 29.7 months, p=0.36; OS not reached in all groups). Patients with HRCAs in the T-MT group presented inferior clinical outcomes compared to standard-risk patients (PFS, 12.1 vs. 22.8 months, p=0.02, HR=1.8, 95% CI 1.0-3.4; OS, 54.9 months vs. NR, p<0.001, HR=3.2, 95% CI 1.5-7.0). Achieving complete response (CR) after induction therapy led to superior PFS compared to other degrees of response, regardless of maintenance medication. Furthermore, maintenance duration over 24 months correlated with favorable survival. Due to the large gap of transplant eligibility in China, optimizing maintenance therapy is important for non-transplant MM patients. In this real-world multi-centered study, our findings suggest that clinicians prefer to prescribe lenalidomide or bortezomib as maintenance therapy in high-risk settings, which are superior to thalidomide in non-transplant MM patients. Achievement of CR and maintenance duration over 2 years are positive factors that influence survival.

Evaluation of Current Antiemetic Therapy Response in Patients Undergoing MEC or HEC Regimens in Portugal.

Chemotherapy-induced nausea and vomiting (CINV) negatively impact cancer patients' quality of life and treatment outcomes. This study evaluated the achievement of complete response to CINV prophylaxis during the first five days after chemotherapy in adult outpatient cancer clinics with solid malignant tumours receiving Moderate or Highly Emetogenic Chemotherapy (MEC or HEC) in Portugal. During the study, patients completed three evaluations, and nausea severity and CINV impact on patients' daily life was assessed. A complete response (no emetic episodes, no use of rescue antiemetic medication, and no more than mild nausea) was observed in 72% of the cycles (N = 161) throughout the five days after chemotherapy. Amongst the patient population, 25% classified their CINV episodes as severe. Though more than half of the patients achieved a complete response, suggesting that a therapeutic effort is being made to minimise this side effect, the overall scenario is barely optimistic. Significantly, new CINV-control measures in MEC/HEC patients should be adopted, specifically avoiding the single use of dexamethasone and 5-HT3 and raising awareness of using NK1-RAs. Thus, it is critical to improve CINV prophylactic treatment and implement practical international antiemetic guidelines in Portuguese clinical practice, envisaging the improvement of supportive care for cancer patients.

SETD2 detection may reveal response to induction therapy and survival profile in acute myeloid leukemia patients

ABSTRACTObjective:SET domain containing protein 2 (SETD2) involves in the progression and development of chemotherapy resistance in acute myeloid leukemia (AML). Hence, this study aimed to investigate the relationship of SETD2 expression with disease risk, features, treatment response, and survival profile in AML.Methods:One-hundred and sixty primary AML patients were retrospectively analyzed. Their bone marrow (BM) samples before and after induction therapy were retrieved for SETD2 detection by RT-qPCR. Moreover, SETD2 expression in BM samples of 20 disease controls (DCs) were also determined.Results:SETD2 expression was downregulated in AML patients compared to DCs (P < 0.001). Higher SETD2 expression related to white blood cells ≤10 × 109/L despite not reaching statistical significance (P = 0.062). One-hundred and nineteen (74.4%) AML patients achieved complete response (CR), while the remaining 41 (25.6%) did not achieve that. Furthermore, increased SETD2 expression was associated with CR achievement (P = 0.015). Survival analyses displayed that SETD2 high (vs. low) was related to prolonged event-free survival (EFS) (P = 0.001) and overall survival (OS) (P = 0.021). Moreover, increased SETD2 quartile was correlated with favorable EFS (P = 0.004) and OS (P = 0.042). After adjustment using multivariate Cox’s regression analysis, higher SETD2 quartile was independently related to prolonged EFS [hazard ratio (HR): 0.766, P = 0.013] and OS (HR: 0.669, P = 0.013). It was also noticed that SETD2 expression was elevated during the induction therapy (P < 0.001).Conclusion:Detection of SETD2 may assist in estimating treatment response and survival profile in AML patients.

Achievement of Complete Response and Drug-Free Status by Atezolizumab plus Bevacizumab Combined with or without Curative Conversion in Patients with Transarterial Chemoembolization-Unsuitable, Intermediate-Stage Hepatocellular Carcinoma: A Multicenter Proof-Of-Concept Study

Introduction: Atezolizumab plus bevacizumab therapy is extremely effective in the treatment of intermediate-stage hepatocellular carcinoma (HCC), with a response rate of 44%, as reported in the IMbrave150 trial. When tumor shrinkage is obtained, achieving complete response (CR) is possible in many cases using curative conversion with resection, ablation, or superselective transarterial chemoembolization (TACE) with curative intent. This concept, i.e., curative conversion by combining systemic therapy and locoregional therapy, has not been reported before. This multicenter proof-of-concept study was conducted to show the value of curative conversion in immunotherapy-treated intermediate-stage HCC meeting TACE-unsuitable criteria. Methods: This study included 110 consecutive Child-Pugh A patients who received atezolizumab plus bevacizumab as first-line treatment for unresectable and TACE-unsuitable intermediate-stage HCC at seven centers in Japan. CR rate, drug-free rate, time to CR, change in liver function, efficacy in positron emission tomography (PET)-positive HCC, progression-free survival (PFS), and overall survival (OS) were assessed in patients who achieved CR using resection, ablation, superselective TACE with curative intent following atezolizumab plus bevacizumab or atezolizumab plus bevacizumab alone. Results: Clinical or pathological CR was achieved in 38 patients (35%) (median observation period: 21.2 months). The modalities of curative conversion in 35 patients were as follows: resection, 7; ablation, 13; and superselective TACE, 15. Three patients achieved clinical CR with atezolizumab plus bevacizumab therapy alone. Among the 38 CR patients, 25 achieved drug-free status. PFS was not reached, and 3 patients experienced recurrence after reaching CR. Regarding OS, there were no deaths in any of the CR patients. The albumin-bilirubin score did not deteriorate after locoregional therapy or resection. Of seven PET-positive patients who achieved CR with atezolizumab plus bevacizumab followed by curative conversion, five achieved drug-free status. Conclusion: The achievement of CR rate by curative conversion in patients treated with atezolizumab plus bevacizumab as the preceding therapy for unresectable and TACE-unsuitable intermediate-stage HCC was 35%. Overall, 23% of patients achieved drug-free status and no recurrence was observed from this patient subgroup with CR and drug-free status. Thus, achieving CR and/or drug-free status should be a therapeutic goal for patients with intermediate-stage HCC without vascular invasion or extrahepatic spread.

Treatment outcome of patients newly diagnosed with multiple myeloma at the National Center of Hematology in Iraq

Background: Multiple myeloma (MM) is a clonal proliferation of malignant plasma cells that results in the production of a monoclonal paraprotein with a light or heavy chain that is seen in the urine and/or serum. The ultimate goal of the MM therapy is the achievement of complete response (CR). The aim of this study is to evaluate the efficacy of the commonly used therapeutic protocols of MM utilized at the National Center of Hematology in Baghdad, Iraq. Materials and Methods: Fifty-two patients with MM were enrolled consecutively for a cross-sectional study between July 2015 and May 2022 at one of Iraq’s major hematology institutions, the National Center of Hematology, Mustansiriyah University. The enrolled patients were evaluated for the overall response rate (ORR), which constitutes CR, very good partial response, and partial response, in comparison to non-response (NR), which constitutes stable disease and progressive disease. Responses to the main MM triple therapeutic regimens used in Iraq, VCD, VRD, and VTD, were evaluated. These regimens are composed of cyclophosphamide (C), bortezomib (V), thalidomide (T), lenalidomide (R), and dexamethasone (D). According to its availability, subsequent autologous stem cell transplantation (ASCT) was performed for some patients. Results: Of the 52 enrolled patients, 50 (96.2%) were assessed at a median follow-up time of 60.5 months. The mean ± SD age of the enrolled patients was 61.5 ± 11.0 years, and the male-to-female ratio was 3:2. However, two patients (3.8%) died before the end of the follow-up. The most common features the patients presented with were bone pain and/or backache in 67.3% of the patients, followed by lower limb weakness and mass (1.9% each). The radiological changes include osteolytic lesions in 34.6% and vertebral wedging in 15.4% of the patients. The most frequent laboratory findings were anemia (69.2%), with hemoglobin levels of 10.0 ± 1.5g/dL, detection of IgG-kappa paraprotein (51.9 %), and high levels of serum calcium in 23.1% (11.7 ± 1.1mg/dL) and serum creatinine in 21.2% (3.3 ± 1.5mg/dL) of the patients. ORR was 88.5%, while NR was reported in 11.5% of the patients. The outcomes were stratified according to the treatment used. It was found that ORR showed statistically significant differences and the VRD group demonstrated the best (P &lt; 000.1). Twenty-one (40.4%) patients underwent subsequent ASCT, and the ORR showed non-significant differences compared to that when patients did not undergo transplantation (P &gt; 0.05). Conclusions: In this study, VRD was the most effective protocol with a better ORR. In addition, the age of the patients presenting with MM in Iraq was less than in western countries. Also, most of the patients were presented with bone lesions, and IgG was the predominant type of myeloma paraproteins.

Rituximab, Cyclophosphamide, Etoposide and Prednisone for the Treatment of Post-Transplantation Lymphoproliferative Disorder

Introduction: Post-transplantation lymphoproliferative disorder (PTLD) is a rare disorder with few established therapies. Solid organ transplant (SOT) patients who develop PTLD are often frail. While some patients respond to reduction of immunosuppression (RI) or rituximab monotherapy, aggressive or relapsed disease frequently requires chemoimmunotherapy. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is a standard of care first-line chemoimmunotherapy for large B-cell lymphomas, but this regimen is often poorly tolerated by frail SOT patients with significant mortality, early discontinuation of therapy, neuropathy and cardiac toxicity. We report our institutional experience with rituximab, cyclophosphamide, etoposide, prednisone (R-CEP), as an alternative, anthracycline-sparing regimen for patients with PTLD. Methods: We retrospectively reviewed records within the Lymphoma Program of the University of Pennsylvania to identify patients who received R-CEP for PTLD. R-CEP was administered on day 1 of each cycle, every 3 weeks for six total cycles in outpatient clinic: rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, and etoposide 100 mg/m2 IV. Three patients received alternative etoposide dosing administered as 50mg/m2 IV on days 1-3. Prednisone was optional and administered at physician discretion; doses ranged from continuous SOT immunosuppression dose to 100 mg daily on days 1 to 5 of each cycle. Overall response rates (ORR), progression free survival (PFS), response duration (RD), and overall survival (OS) were assessed. Adverse effects were described by CTCAE v5. Results: Thirty-four patients were identified (see Table 1 for Patient Characteristics). Eleven patients (32%) initially were managed with RI alone; 2 of 11 (18%) responded for ≥ 6 months before progressive disease (PD). Twenty-four patients (71%) received rituximab monotherapy (either initially or for PD after RI) with 14 of 24 (58%) responding for ≥ 6 months before PD. All who received RI and/or rituximab monotherapy had PD before starting R-CEP. Seven patients (21%) were first treated with R-CEP due to aggressive initial presentation of PTLD. ORR at six months after completion of R-CEP was 47% with 15 complete responses (CR) and 1 partial response (PR). Median follow-up was 9.8 years (range 0.25-12 years). 46% and 41% of patients remained progression-free at 24 and 60 months, respectively (Figure 1). Median response duration (RD) was 47 months (95%CI: 5-NE). Of those who achieved CR at 6 months, median RD was not reached; 93% and 83% of patients in CR maintained responses at 24 and 60 months, respectively. Median OS was 45 months (95%CI: 13-NE), with 58% and 47% of patients alive at 24 and 60 months, respectively. Of the 21 patients who died, 12 (57%) died from PD, 2 (9%) from infections after receiving further salvage therapy, and the remainder from causes unrelated to PTLD. Fifty percent of patients received their first cycle while hospitalized. Seventy-four percent of patients had neutropenia (41% grade 3-4 neutropenia) and 23% had febrile neutropenia. Eight patients had grade 3-4 anemia and 6 developed grade 3-4 thrombocytopenia. Ten patients (29%) required hospitalization during treatment, most commonly for febrile neutropenia, anemia, or dehydration. There were no instances of neuropathy, cardiac toxicity, or treatment-related mortality. Of the 18 patients who did not complete all 6 cycles of chemoimmunotherapy, 11 (61%) stopped due to PD, 4 (22%) due to toxicity (most commonly cytopenias), 2 (11%) elected early stop after achievement of CR, and 1 (6%) due to a need for treatment of a secondary primary malignancy. Patients with PD commonly received R-CHOP for systemic progression (including heart transplant recipients) or radiation therapy for localized disease. Conclusions: R-CEP is a promising alternative to R-CHOP for frail PTLD patients based on our observed efficacy and toxicity and warrants further investigation. Cytopenias were less common than historically reported for PTLD patients treated with R-CHOP (Trappe et al 2012). There was no treatment-related mortality, whereas reported treatment-related mortality with R-CHOP for PTLD is 11% (Trappe et al 2012). Study limitations include its retrospective nature, small sample size, and heterogeneous PTLD population with respect to SOT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Decisional Role of Interim PET in Relapsed/Refractory Classical Hodgkin Lymphoma Treated with Begev Chemotherapy As First Salvage

Achievement of complete response (CR) before autologous stem cell transplantation (ASCT) is one of the main predictive factors of outcome in patients (pts) affected by relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) eligible to high-dose chemotherapy. The predictive role of interim PET during salvage treatment is well established in pts treated with IGEV or ICE but has not been investigated in pts receiving BEGEV (Bendamustine, Gemcitabine and Vinorelbine) as first salvage treatment. With the aim to investigate the predictive value of PET after 2 cycles of BEGEV (PET2) in terms of CR rate and survival, we retrospectively collected data of consecutive R/R cHL pts eligible to ASCT treated from 2011 to 2021 in 3 Italian centres. PET scans were locally evaluated using Deauville Score (DS), considering a score 1-3 negative and consistent with CR. Early relapse was defined as a relapse occurring ≤12 months from the end of first-line therapy. Survival functions were calculated from the date of initiation of BEGEV chemotherapy. Ninety-four cHL R/R pts receiving BEGEV as first salvage therapy were included. Fifty-one (54.3%) pts were male. First-line therapy consisted in 2 to 6 ABVD chemotherapy cycles accordingly to clinical stage followed by consolidation radiotherapy (RT) in 24 (25.5%) pts. At relapse, median age was 37 years (range: 18-71 years), 51 (54.3%) pts were in stage III-IV, 16 (17%) pts had B symptoms and 34 (36.2%) pts had extranodal involvement (EI). Fifty-one (54.3%) pts were primary refractory, 23 (24.5%) pts had an early and 20 pts (21.3%) a late relapse. PET2 was performed in 86 (91.5%) pts, and resulted negative in 61 (70.9%) and positive in 25 (29.1%) pts (DS 4 in 17 and DS 5 in 8 pts). PET after 4 BEGEV cycles (PET4) was performed in 82 (87.2%) pts and resulted negative in 63 (67%) and positive in 19 (20.2%) pts (DS 4 in 10 and DS 5 in 9 pts). Complete response after 4 BEGEV was achieved in 55/61 (90.2%) PET2 negative pts and 7/25 (28%) PET2 positive pts. Considering pts evaluable for both PET2 and PET4, PET2 positive pts had a statistically lower probability to achieve CR at PET4 when compared to PET2 negative pts (Odds ratio: 0.07, CI 95%: 0.02-0.29; p<0.00001). Autologous SCT was performed in 81 (86.2%) pts, following BEGEV in 56 pts (69.1%) and after further salvage treatments in 25 (30.9%). A post-ASCT consolidation strategy was performed in 24 (29.6%) pts, and consisted in RT in 18 pts and brentuximab-vedotin in 6 pts. Ten pts received an allotransplant: in 3 cases allotransplant was planned in a tandem modality, while in 7 cases was performed after further salvage treatments for post-ASCT relapse or progression. With a median follow-up of 36.4 months (interquartile range: 20.1-50.0), 3-years overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) for the whole study population were 91.7%, 61.6% and 53.9%, respectively. No significant differences in OS were detected according to PET2 result. Conversely, both 3-years PFS and EFS were significantly superior in PET2 negative vs PET2 positive pts: 3-years PFS was 61.6% (CI 95%: 52.1-72.9) in PET2 negative and 43.6% (CI 95%: 27.9-68.4) in PET2 positive pts (p=0.0004) (Figure 1), while 3-years EFS was 71% (CI 95%: 59.8-84.3) and 23.3% (CI 95%: 11.3-48.1), (p<0.001). Univariable analysis of PFS was performed using Cox regression model and evaluating adverse risk factors at relapse (primary refractory and early relapse vs late relapse, presence of EN involvement and B-symptoms) and demonstrated a significantly inferior PFS for pts with EI (HR 1.94, CI 95% 1.01-3.74, p=0.47) and primary refractory disease or early relapse (HR 2.02, CI 95%: 1.01-4.04, p=0.047), but not for pts with B symptoms (HR 1.05, CI 95%: 0.43-2.51, p=0.9). Multivariate Cox regression model of PFS evaluating presence of EI at relapse (HR 1.55 , CI 95%: 0.74-3.25, p=0.240), time to relapse (primary refractory and early relapse vs late relapse, HR 0.84 (CI 95%: 0.36-1.96, 0.683) and PET2 result, identified PET2 positivity as the only predictive factor for PFS (HR 3.24, CI 95%: 1.55-6.77, p=0.002). In conclusion, R/R cHL pts with PET2 positive during BEGEV salvage treatment had a lower probability to achieve CR after 2 additional BEGEV cycles and a significantly inferior PFS, and could benefit from early exposure to new therapeutic strategies before ASCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ibrutinib and Ixazomib in Relapsed/Refractory Mantle Cell Lymphoma: Precog 0404

Background: Bruton's tyrosine kinase inhibitors (BTKi) are highly effective in relapsed/refractory (r/r) mantle cell lymphoma (MCL) but have a progression-free survival (PFS) of roughly 2 years. Proteasome inhibitors are active in r/r MCL, although the single-agent activity of bortezomib is modest (ORR 33%), and administration is limited by peripheral neuropathy. Ixazomib (Ixa) is an oral proteasome inhibitor with a lower incidence of peripheral neuropathy. We evaluated the safety and efficacy of ixa and ibrutinib (ibr) in r/r MCL. Methods: Patients (pts) with r/r MCL ≥18 years old were eligible. Both ibr-naïve and ibr-pretreated pts were eligible for phase 1. Pts were divided into two cohorts (ibr-naïve and ibr-pretreated) for the phase 2 portion. The ibr-pretreated cohort was closed early due to slow enrollment. We evaluated 2 dose levels (DLs) of ixa (3mg and 4mg, days 1, 8, and 15 of a 28 day cycle) in the phase 1 study, and all pts received ibr 560mg daily. Treatment continued until disease progression or unacceptable toxicity. Pts were enrolled in a 3+3 manner, and the 4mg dose level was expanded to 6 pts evaluable for dose limiting toxicity (DLT). Pts were monitored for DLT during cycle 1, defined as grade 3 thrombocytopenia with significant bleeding, select grade 3 non-hematologic toxicities, grade 4 thrombocytopenia, grade 4 febrile neutropenia, grade 4 non-hematologic toxicity, or any grade 5 toxicity. In addition, any toxicity-related dose delay > 7 days of ibr or ixa or an inability to receive all 3 doses of ixa during cycle 1 were considered DLT's. The primary endpoint for the phase 2 study was complete response (CR) within the first 12 months of study treatment. We targeted a CR rate of 40% (based on a historical CR rate of 21% with ibr monotherapy) for the ibr-naïve cohort. We planned for a sample size of 31 pts per cohort, and ibr-naïve pts treated at the RP2D in the phase 1 study were counted for the phase 2 primary endpoint. Results: 43 pts were enrolled to the study overall, with a median age of 70 (range 52-84) and 74% were male. Twelve pts were treated in the phase 1 study (including 3 pts treated at DL1 and 9 at DL2). Eleven pts enrolled to the phase 1 study were ibr-naïve and 1 was ibr-pretreated. Three pts enrolled at DL2 were replaced during the phase 1 study due to growth factor administration (n=1) and difficulty adhering to the therapy administration schedule (n=2) and were not evaluable for DLT. One pt treated at DL2 experienced a grade 3 lung infection that was classified as a DLT, while the other 5 evaluable pts did not experience a DLT. As a result, DL2 was the RP2D. Thirty-five ibr-naïve pts were treated at the RP2D. Prior lines of therapy were 1 (n=25), 2 (n=6), and 3 (n=4). Remaining baseline characteristics are summarized in the Table. The combination was active with a CR rate (95% CI) of 42.9% (26.3, 60.6), and ORR of 77.1% (59.9, 89.6). The median duration of treatment is 8 cycles (range: 1-23), with 8 of 35 (23%) pts remaining on treatment after a median of 12 cycles (range: 6-19). Reasons for treatment discontinuation for the remaining 27 pts were AE (n=13), progression (n=9), death due to AE, MD discretion, and treatment delay > 21 days (n=1 each). Pts who discontinued therapy due to AE's received 1-2 cycles (n=4), 3-6 cycles (n=4), or 7+ cycles (n=5). With a median follow-up of 16.8 months; the 2-year PFS was 44%, and the 2-year OS was 91% (See Figure). Median duration of response was 16.7 months. Grade3+ AE's occurring in > 1 patient included: hypertension, lymphopenia, neutropenia, thrombocytopenia, rash, syncope, and atrial fibrillation. One pt with known cardiovascular comorbidities experienced a grade 5 aortic injury that was deemed possibly related to ibrutinib. AE's leading to treatment discontinuation included: rash (n=2), atrial fibrillation (n=2), hepatic failure, sepsis, fatigue/anorexia, peripheral neuropathy, muscle spasms, arthralgia, thrombocytopenia, diarrhea, heart failure (n=1 each). Conclusion: The combination of ibr and ixa resulted in a substantial improvement of CR rate beyond ibr monotherapy for ibr-naïve pts. However, with sustained treatment > 1/3 of pts required treatment discontinuation due to AE, some of which were likely related to ibr. PFS approximates that seen with ibr monotherapy. Further exploration of this combination may identify scenarios in which a fixed duration of treatment maximizes achievement of CR, which is important as a potential bridge to an alternative therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictors of Hematologic Complete Response Achievement and Maintenance in Patients with AL Amyloidosis Treated with Non-Transplant Chemotherapy

Predictors of Hematologic Complete Response Achievement and Maintenance in Patients with AL Amyloidosis Treated with Non-Transplant Chemotherapy

P030: Baseline IgM amount can identify patients with adverse outcome despite a PET-2 adapted treatment in classical Hodgkin Lymphoma: results from a real-life single-center study i

Background: Hodgkin Lymphoma is characterized by an inflammatory background in which the reactive myeloid cells may exert an immune suppressive effect that advances progression of disease. Immunoglobulin M is first antibody isotype to be produced during an immune response, but it plays also an immunoregulatory role, therefore we investigated if it could have any clinical impact on prognosis. Experimental design: In this retrospective, observational, single – center study, we evaluated 212 newly diagnosed Hodgkin Lymphoma (HL) patients, including 132 advanced stage cases, with a median follow up of 60.3 months (range 60–204); 109 (51%) were men, with a median age of 31 years (range 15–77), 64 patients showed bulky disease, while 119 suffered from B symptoms at the onset. The median baseline values for IgM, IgA and IgG were, respectively: 86.0 (range 5.0–336.0 mg/dL), 197.5 (range 5.0–336.0 mg/dL) and 1110.00 (range 157.0–2763.0 mg/dL). 49/212 (23%) patients had a baseline IgM value lower than 50mg/dL. White blood cell count and type were determined by electrical impedance method. Nephelometry was used for immunoglobulins quantification. Results: PFS at 60 months was 54.1% versus 81.1 % respectively in patients with IgM ≤50 mg/dL or IgM>50 mg/dL (p<0.001). A level of 50 mg/dl of IgM at baseline resulted in 84.1% sensitivity and 45.5% specificity in predicting achievement of complete response in the whole cohort (area under curve - AUC - 0.62, p=0.013). In multivariate analysis, only baseline IgM ≤50 mg/dl and presence of large nodal mass (< 7 cm) were independent baseline variables able to predict clinical outcome while after two cycles of treatment only IgM ≤50 mg/dl at baseline and PET-2 status were independent predictors of PFS. Thus, we stratified the advanced stage patients in three groups based on clinical variables available at diagnosis: low risk group was defined as absence of LNM and baseline IgM >50; standard-risk was defined by either presence of LNM or baseline IgM ≤50 mg/dL; high risk group was defined by both presence of LNM and IgM ≤50 mg/dL at baseline. The 60-months PFS estimates were significantly different among the three groups, respectively 83.5, 59.5 and 40.0%, p=<0.0001. Conclusion: IgM amount at diagnosis is a valuable prognostic factor much earlier than PET-2 and it can also provide information in PET-2 negative patients. This can help identify at baseline different HL classes at risk of treatment failure.

AML-396 Venetoclax-Containing Regimens Improve Outcomes of Intensive Treatment and Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Extramedullary Acute Myeloid Leukemia

The optimal treatment strategy for patients with extramedullary acute myeloid leukemia (eAML) is questionable, especially as applied to extramedullary tumor persistence while bone marrow response is achieved. To determine whether venetoclax-containing regimens, intensive treatment, and allogeneic hematopoietic stem cell transplantation (alloHSCT) can improve outcomes in patients with eAML. Overall, 27 patients with verified eAML were included: 14 were male and 13 were female with a median age of 40 years (13-84). Standard ("7+3"), high-intensity ("HiDAC", "FLAG±Ida"), and low-intensity chemotherapy regimens were administered to all patients. Ten patients (37%) received venetoclax with 5-azacytidine (VEN-AZA) because of comorbidities or refractory disease. AlloHSCT was performed in 17 patients (63%). According to the 2017 ELN risk stratification system, 18.5% (5/27) were favorable risk, 25.9% (7/27) were intermediate risk, and 55.6% (15/27) were adverse risk. Patients with favorable genetic alterations achieved bone marrow remission more frequently (100% vs. 44%, P=0.044) but did not have advantages in the rate of complete extramedullary response (75% vs. 68%, P>0.05). Using HiDAC enabled eradication of extramedullary lesions in case of failure of standard and low-intensity regimens (85% vs. 0%, P=0.044) and decreased the rate of early (during the first 12 months) relapse (38% vs. 100%, P=0.019). The overall response rate to VEN-AZA was 70% (7/10). Five patients (50%) achieved complete eradication of extramedullary tumor after venetoclax; among them, 3 still had persistent extramedullary disease after HiDAC. Performing alloHSCT in first complete remission decreased the risk of early relapse (12% vs. 80%, P=0.015) and demonstrated better median overall survival (38.85 vs. 7.57 months, P=0.013) and relapse-free survival (38.85 vs. 3.78 months, P=0.0021) compared to alloHSCT performed in second and subsequent complete remissions. Favorable genetic aberrations do not increase the frequency of extramedullary response. Intensive treatment helps to achieve complete eradication of extramedullary tumor and reduces early relapse rate. Using VEN-AZA is effective among patients with eAML, including patients who were refractory to intensive treatment, and allows complete response achievement before alloHSCT. The best time to perform the alloHSCT among patients with eAML is the first complete remission.

Deepening Responses after Upfront Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction Therapy

High-dose melphalan followed by autologous stem cell transplantation (ASCT) remains the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Achievement of complete response (CR) and minimal residual disease (MRD) negativity are associated with improved progression-free survival (PFS) and overall survival (OS). With superior triplet- and quadruplet-based induction regimens, a higher proportion of patients are achieving deep responses of at least a very good partial response (VGPR) or better. The probability of achieving different levels of deeper hematologic responses post-ASCT based on the pre-ASCT depth of response is less clear in the existing literature but would be of value to patients and providers in discussing the added benefit of ASCT. We assessed the rate of deepening the hematologic response with upfront ASCT in patients with NDMM, mainly to MRD-negative CR, based on the response achieved after induction therapy. We retrospectively reviewed 210 patients with NDMM who underwent upfront ASCT at Mayo Clinic Rochester between May 1, 2018, and July 31, 2019. In addition to the availability of next-generation flow cytometry (NGF) testing for MRD status, which yielded a sensitivity of 10-5, the more sensitive mass spectrometry-based assessment of peripheral blood (ie, MASS-FIX) for monoclonal proteins was used rather than conventional immunofixation. Pre-ASCT, 23 patients (11%) achieved MRD-negative CR, which increased to 66 patients (31%) post-ASCT. Of 187 patients not in MRD-negative CR pre-ASCT, 45 (24%) converted to MRD-negative CR. Patients with MRD-positive CR before ASCT had the highest rates of conversion to MRD-negative CR. HR cytogenetics did not impact rates of MRD-negative CR achievement post-ASCT irrespective of pre-ASCT IMWG response (P=1.0). Overall, irrespective of IMWG response, 43 patients (20%) were MRD-negative pre-ASCT (19 in VGPR, 24 in CR or sCR), and 102 patients (49%) were MRD-negative post-ASCT (36 in VGPR, 66 in CR or sCR). Among 85 patients with VGPR post-ASCT, 36 achieved MRD negativity, of whom 8 (22%) progressed, whereas 49 had MRD-positive disease, of whom 24 (49%) progressed (P=.014). Upfront ASCT in patients with NDMM led to deeper responses, with 24% converting to MRD negative CR and more than doubling of the total rate of MRD negativity irrespective of IMWG response depth.