Case Report: CAR-T cells and subsequent maintenance with ponatinib in an adult Philadelphia acute lymphoblastic leukemia patient with hematological and extramedullary relapse after allogeneic stem cell transplantation.

Relapsed or refractory (r/r) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) still represent an unmet clinical need despite the new immune therapies available for these patients. We report the case of a Ph + ALL relapsed one year after allogeneic stem cell transplant. After one DLI was started CAR-T program with brexucabtageneautoleucel, using as bridging treatment ponatinib, vincristine and prednisone. Brexu-cel infusion was performed in 2023, without CRS or ICANS onset. One month after Brexu-cel infusion BM aspirate and CT-PET showed recovery of full donor chimerism, MRD negativity and complete metabolic remission. Subsequently was started maintenance with ponatinib: at last follow-up, the patient persisted in leukemia-free status. CAR-T cells represent the most powerful treatment for r/r Ph + ALL but there is no consensus about the optimal bridging strategy and also regarding the management algorithm during "post CAR-T phase". Here, we report the efficacy of ponatinib as a bridge to anti-CD19 CAR-T cell therapy and as post CAR-T maintenance. Our experience suggests that a preserving approach with TKI associated to low-dose chemotherapy can be the optimal bridging therapy prior to CAR-T and that an "MRD-guided" and "TKI-based" maintenance strategy can represent the best choice for Ph + ALL which satisfactorily responds to CAR-T.

Effectiveness of biosimilar pegfilgrastim in patients with multiple myeloma after high-dose melphalan and autologous stem cell transplantation.

Multiple myeloma (MM) is the main indication for autologous stem cell transplantation (ASCT). Novel supportive therapies (e.g., granulocyte colony-stimulating factor) have significantly improved post-ASCT-related mortality; however, data on biosimilar pegfilgrastim-bmez (BIO/PEG) in this setting is lacking. This prospective cohort study compared Italian patients with MM who received BIO/PEG post-ASCT with data collected retrospectively from historical control groups from the same center who received either filgrastim-sndz (BIO/G-CSF) or pegfilgrastim (PEG; originator). The primary endpoint was time to neutrophil engraftment (three consecutive days with an absolute neutrophil count ≥ 0.5 × 109/L). Secondary endpoints included incidence and duration of febrile neutropenia (FN). Of the 231 patients included, 73 were treated with PEG, 102 with BIO/G-CSF, and 56 with BIO/PEG. Median age was 60 years and 57.1% were male. Neutrophil engraftment was reached after a median of 10 days in the BIO/PEG and PEG groups and 11 days in the BIO/G-CSF group. Among patients who achieved neutrophil engraftment earlier than this (i.e., day 9), 58% (29/50) were on PEG; of those who achieved it later (i.e., day 11), 80.8% (59/73) were on BIO/G-CSF. FN incidence was higher with BIO/G-CSF (61.4%) versus PEG (52.1%) or BIO/PEG (37.5%) (p = 0.02 among groups). Patients on BIO/PEG had less frequent grade 2-3 diarrhea (5.5%) compared with BIO/G-CSF (22.5%) or PEG (21.9%); grade 2-3 mucositis was most frequent in the BIO/G-CSF group. In conclusion, pegfilgrastim and its biosimilar displayed an advantageous efficacy and safety profile compared with biosimilar filgrastim in patients with MM post-ASCT.

The power of telemedicine to improve CAR-T cell therapy programs: lessons learned from COVID-19 pandemic.

PURPOSE: CAR-T programs will burden increasingly on healthcare systems, since the implementation of these therapies involves: multidisciplinary team collaboration, post-infusion hospitalization with risk of life-threatening toxicities, frequent in hospital visits and prolonged follow-up which heavily influence patients' quality of life. In this review we propose an innovative, telehealth-based, model for monitoring CAR-T patients: this method was used for managing a case of COVID-19 infection occurred two weeks after CAR-T cell infusion. METHODS: Several benefits for management of all these aspects of CAR-T programs could be made using telemedicine: for example, telemedicine real-time clinical monitoring could reduce the COVID-19 contagion risks for CAR-T patients. RESULTS: Our experience confirmed feasibility and utility of this approach in a real-life case. We believe that use of telemedicine for CAR-T patients could improve: the logistics of toxicity monitoring (frequent vital sign checks and neurologic assessments), the multidisciplinary team communication (patient selection, specialists consulting, coordination with pharmacists, etc.), the decrease in hospitalization time and the reduction of ambulatory visits. CONCLUSIONS: This approach will be fundamental for future CAR-T cell program development, enhancing patients' quality of life and cost-effectiveness for healthcare systems.

Netupitant/palonosetron without dexamethasone for preventing nausea and vomiting in patients with multiple myeloma receiving high-dose melphalan for autologous stem cell transplantation: a single-center experience.

Chemotherapy-induced nausea and vomiting (CINV) is one of the most frequent adverse events compromising quality of life (QoL) in patients undergoing autologous stem cell transplantation (ASCT). However, CINV prophylaxis is still lacking uniformity for high-dose melphalan (HDM), which is used to condition patients with multiple myeloma (MM). Netupitant/palonosetron (NEPA) is administered with dexamethasone (DEXA) for CINV prevention in several chemotherapy regimens. Our study aims to assess the efficacy of NEPA, without DEXA, in preventing CINV in 106 adult patients with MM receiving HDM and ASCT. All patients had antiemetic prophylaxis with multiple doses of NEPA 1 h before the start of conditioning and after 72 h and 120 h. A complete response (CR) was observed in 99 (93%) patients at 120 h (overall phase). The percentage of patients with complete control was 93%. The CR rate during the acute phase was 94% (n = 100). During the delayed phase, the CR rate was 95% (n = 101). Grade 1 nausea and vomiting were experienced by 82% and 12% of the patients, respectively. Grade 2 nausea was reported in 18% and vomiting in 10% of patients. Our results showed, for the first time, that NEPA, without DEXA, was a well-tolerated and effective antiemetic option for MM patients receiving HDM followed by ASCT.

A comparative effectiveness study of lipegfilgrastim in multiple myeloma patients after high dose melphalan and autologous stem cell transplant.

G-CSF administration after high-dose chemotherapy and autologous stem cell transplantation (ASCT) has been shown to expedite neutrophil recovery. Several studies comparing filgrastim and pegfilgrastim in the post-ASCT setting concluded that the two are at least equally effective. Lipegfilgrastim (LIP) is a new long-acting, once-per-cycle G-CSF. This multicentric, prospective study aimed to describe the use of LIP in multiple myeloma patients receiving high-dose melphalan and autologous stem cell transplantation (ASCT) and compare LIP with historic controls of patients who received short-acting agent (filgrastim [FIL]). Overall, 125 patients with a median age of 60 years received G-CSF after ASCT (80 patients LIP on day 1 post-ASCT and 45 patients FIL on day 5 post-ASCT). The median duration of grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 10 [9]/L) was 5 days in both LIP and FIL groups, whereas the median number of days to reach ANC ≥ 0.5 × 10 [9]/L was 10% lower in the LIP than in the FIL group (10 vs 11 days), respectively. Male sex was significantly associated with a faster ANC ≥ 0.5 × 10 [9] L response (p = 0.015). The incidence of FN was significantly lower in the LIP than in the FIL group (29% vs 49%, respectively, p = 0.024). The days to discharge after ASCT infusion were greater in patients with FN (p < 0.001). The study indicates that LIP had a shorter time to ANC recovery and is more effective than FIL for the prevention of FN in the ASCT setting.

Granisetron transdermal system and dexamethasone for the prevention of nausea and vomiting in multiple myeloma patients receiving chemo-mobilization: An observational real-world study of effectiveness and safety.

PURPOSE: Cyclophosphamide (CY) in a dose of 2-4 g/m2 is widely used for hemopoietic progenitor stem cells mobilization. CY administration is associated with several adverse effects, including chemotherapy-induced nausea and vomiting (CINV). This study aimed to evaluate the efficacy and tolerability of granisetron transdermal system (GTDS) plus dexamethasone in the management of CINV in MM patients undergoing chemo-mobilization with CY. METHODS: In this single-center, prospective, observational, real world study, GTDS plus dexamethasone was administered to MM patients receiving chemo-mobilization based on CY 2 g/m2 plus G-CSF in an outpatient setting. The rate of complete response was evaluated as the main outcome. Other outcomes were rate of complete control of CINV, incidence of nausea/vomiting of any grade and safety. RESULTS: A total of 88 patients were enrolled. A complete response was achieved in 45.5 % of patients; among them, 39.77 % attained complete control of CINV. Nausea and vomiting never occurred in 34.1 % and 45.5 % of patients, respectively. No episodes of grade 3-4 nausea and/or vomiting were documented. GTDS was safe and well tolerated. CONCLUSION: In real world, GTDS provided an innovative, effective, and well-tolerated control of CINV in MM patients after chemo-mobilization with CY. The study found out effectiveness of a non-invasive delivery system of antiemetic.

Challenge to Predict Mobilized Peripheral Blood Stem Cells on the Fourth Day of Granulocyte Colony-Stimulating Factor Treatment in Healthy Donors: Predictive Value of Basal CD34+ Cell and Platelet Counts.

A longitudinal, prospective, observational, single-center cohort study on healthy donors was designed to identify predictors of CD34+ cell mobilization on day 4 after granulocyte colony-stimulating factor (G-CSF) administration. As potential predictors of mobilization, age, sex, body weight, height, blood volume, WBC count, peripheral blood (PB) mononuclear cell count, platelet (Plt) count, and hematocrit and hemoglobin levels were considered. Two different evaluations of CD34+ cell counts were determined for each donor: baseline (before G-CSF administration) and in PB on day 4 after G-CSF administration. One hundred twenty-two consecutive healthy donors with a median age of 47.5 years were enrolled. The median value of CD34+ on day 4 was 43 cells/µL (interquartile range, 23 to 68), and 81.1% of donors had ≥20 cells/µL. Basal WBC count, Plt count, and CD34+ were significantly higher for the subjects with CD34+ levels over median values on day 4. A multivariate quartile regression analysis, adjusted by sex, age, basal CD34+, and basal Plt count, showed a progressively stronger relationship between baseline CD34+ and Plt levels and the CD34+ levels on day 4. The basal CD34+ cut-off level to predict the levels of CD34+ on day 4 was either ≤2 cells/µL or ≥3 cells/µL and that of basal Plt count was ≤229 × 109/L or ≥230 × 109/L, respectively, to determine whether mobilization therapy should or should not be attempted. PB stem cell mobilization with G-CSF was highly effective on day 4, and herein we describe a model for predicting the probability of performing PB stem cell collection after a short course of G-CSF.

A Comparative Assessment of Quality of Life in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation Through an Outpatient and Inpatient Model.

Outpatient autologous stem cell transplantation (ASCT) has proven to be feasible in terms of physical morbidity and mortality outcomes, but little data exist on the impact of this procedure on quality of life (QoL). The purpose of this prospective, observational, longitudinal cohort study was to compare the effects of inpatient (n = 76) and outpatient (n = 64) modes of care on QoL in patients with multiple myeloma who underwent ASCT. Patients were treated according to their preference for the inpatient or outpatient model. QoL was assessed using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) at baseline (7 days before ASCT; T1) and at days +7 (T2) and +30 (T3) after ASCT. Overall, inpatients achieved higher mean values at each time point (86.05 ± 15.54 at T1, 89.23 ± 19.19 at T2, and 87.96 ± 13.6 at T3) compared with outpatients (85.62 ± 14.51 at T1, 87.42 ± 23.41 at T2, and 83.98 ± 20.2 at T3), although the differences did not reach statistical significance. Inpatients showed higher mean scores than outpatients in physical well-being (7.67 ± 5.7, 15.44 ± 6.34, and 12.96 ± 6.03, respectively, versus 5.89 ± 4.33, 13.92 ± 7.05, and 8.84 ± 6.33, respectively; P < .05). Mean scores on social/family well-being were significantly higher in the outpatient group compared with the inpatient group (22.93 ± 13.29, 21.14 ± 5.31, and 21.64 ± 4.58, respectively, versus 20.59 ± 3.79, 19.52 ± 5.12, and 20.01 ± 3.97, respectively; P = .003). There were no significant between-group differences with respect to functional well-being and emotional status. Among adults at a single institution undergoing ASCT for MM, the use of outpatient care compared with standard transplantation care did not result in improved QoL during transplantation. Further research is needed for replication and to assess longer-term outcomes and implications.

Identifying and managing CAR T-cell-mediated toxicities: on behalf of an Italian CAR-T multidisciplinary team.

INTRODUCTION: Chimeric antigen receptor (CAR)-T-cell therapy is a new treatment for patients with hematologic malignancies in which other therapies have failed. AREAS COVERED: The review provides an overview for recognizing and managing the most acute toxicities related to CAR-T cells. EXPERT OPINION: The development of immune-mediated toxicities is a common challenge of CAR-T therapy. The mechanism that determines this toxicity is still unclear, although an unfavorable tumor microenvironment and a pro-inflammatory state put patients at risk. The monitoring, diagnosis, and treatment of post-CAR-T toxicities must be determined and based on international guidelines and internal clinical practice. It is urgent to identify biomarkers that can identify patients at greater risk of developing complications. The adoption of consistent grading criteria is necessary to improve toxicity management strategies continually. The first-line therapy consists of supportive care and treatment with tocilizumab or corticosteroids. An early start of cytokine blockade therapies could mitigate toxicity. The plan will include cytokine release prophylaxis, a risk-adapted treatment, prevention of on-target/off-tumor effect, and a switch on/off CAR-T approach.

Letermovir Prophylaxis for Cytomegalovirus Infection in Allogeneic Stem Cell Transplantation: A Real-World Experience.

Despite effective treatments, cytomegalovirus (CMV) continues to have a significant impact on morbidity and mortality in allogeneic stem cell transplant (allo-SCT) recipients. This multicenter, retrospective, cohort study aimed to evaluate the reproducibility of the safety and efficacy of commercially available letermovir for CMV prophylaxis in a real-world setting. Endpoints were rates of clinically significant CMV infection (CSCI), defined as CMV disease or CMV viremia reactivation within day +100-+168. 204 adult CMV-seropositive allo-SCT recipients from 17 Italian centres (median age 52 years) were treated with LET 240 mg/day between day 0 and day +28. Overall, 28.9% of patients underwent a haploidentical, 32.4% a matched related, and 27.5% a matched unrelated donor (MUD) transplant. 65.7% were considered at high risk of CSCI and 65.2% had a CMV seropositive donor. Low to mild severe adverse events were observed in 40.7% of patients during treatment [gastrointestinal toxicity (36.3%) and skin rash (10.3%)]. Cumulative incidence of CSCI at day +100 and day +168 was 5.4% and 18.1%, respectively, whereas the Kaplan-Meier event rate was 5.8% (95% CI: 2.4-9.1) and 23.3% (95% CI: 16.3-29.7), respectively. Overall mortality was 6.4% at day +100 and 7.3% at day +168. This real-world experience confirms the efficacy and safety of CMV.

Quality of life outcomes in multiple myeloma patients: a summary of recent clinical trials.

Introduction: Management of multiple myeloma (MM) has improved over recent years. Health-related quality of life (HRQoL) data is becoming increasingly important, owing to improved survival outcomes. Areas covered: The authors performed an expert review of the literature to identify evidence-based data available on HRQoL in frontline and relapsed/refractory MM (RRMM) patients. Expert opinion: De-novo patients should be informed that the HRQoL is expected to improve during first-line treatment with different degrees of possible deterioration during the first cycles. Achievement of a maximal response should be strongly considered, particularly in the frontline setting, but must also be balanced with tolerability, HRQoL, and patient preferences. The same degree of improvement in HRQoL cannot be expected during conventional relapse treatments, where patients should be prepared only for stabilization of HRQoL. However, focusing attention only on measures such as toxicity may provide just a partial view of overall treatment effectiveness. Nonetheless, the authors believe the added value of taking into consideration the patient's perspectives and the importance of patient-reported outcomes in the evaluation of treatment effects should be considered mandatory. The incorporation of quality of life assessment into clinical and research practice has the potential of improving treatment outcomes.

p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells.

Histone acetyltransferase and histone deacetylase (HDAC) determine the acetylation status of histones, and thereby control the regulation of gene expression. HDAC inhibitors have been found to inhibit the growth of a variety of tumor cells in vitro and in vivo. We demonstrated previously that the short-chain fatty acid compound butyrate and its derivative tributyrin (both HDAC inhibitors) arrest cell growth and induce differentiation in human neuroblastoma (NB) cells. In the current study we investigated the effect of the HDAC inhibitor valproic acid (VPA) on proliferation and differentiation in human NB cells (SJ-N-KP, AF8). Treatment with VPA resulted in a strong inhibition of cell proliferation and induction of cell differentiation, as revealed by neurite outgrowth and increase of acetylcholinesterase specific activity. Moreover, we addressed the question of whether the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1) are involved in the mechanism of action of members of the short-chain fatty acids class (VPA, sodium butyrate and tributyrin) of HDAC inhibitors, in human NB cells. We demonstrated that p21(Cip1) is a common target of induction of transcription and protein expression for all the three compounds, while only VPA induced a concomitant increase of p27(Kip1) gene expression. These results suggest that p21(Cip1) could be involved in the inhibition of proliferation and induction of differentiation in human NB cells induced by treatment with VPA or tributyrin or sodium butyrate. Moreover, p21(Cip1) could be applied in the molecular monitoring of drug action in the possible therapeutic application of these short-chain fatty acid members of HDAC inhibitors for human NB treatment.

RXRgamma and PPARgamma ligands in combination to inhibit proliferation and invasiveness in colon cancer cells.

Nuclear retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs are potential candidates as drug target for cancer prevention and treatment. We investigated if the rexinoid 6-OH-11-O-hydroxyphenantrene (IIF) potentiates the antitumoral properties of PPARgamma ligands as ciglitazone and pioglitazone, on two colon cancer cell lines: HCA-7 and HCT-116. Drugs inhibited cell growth and induced apoptosis synergistically. The combination resulted in a decrease of cyclooxigenase-2, metalloproteinases-2 and -9 expression level and activity while PPARgamma, RXRgamma and tissue inhibitors of metalloproteinase-1 and -2 expression were increased. Finally, IIF potentiated PPAR transcriptional activity by enhancement of peroxisome proliferator response elements transactivation.

Epigenetic modifiers as anticancer drugs: effectiveness of valproic acid in neural crest-derived tumor cells.

Valproic acid (VPA) is an established drug in the long-term therapy of epilepsy. Recently, VPA has demonstrated antitumor activity as a histone deacetylase (HDAC) inhibitor. In this study, the anticancer properties of VPA on neural crest-derived human tumor cell lines G361 melanoma, U87MG glioblastoma and SKNMC Askin tumor cells were investigated. The effect of VPA on cell growth, apoptotic activity and invasive ability were evaluated. Firstly, VPA induced cell growth inhibition and apoptotic activity, as demonstrated by sulforhodamine B protein assay, annexin V assay and by Western blot analysis for Bcl2 and Bax expression levels, in all three cell lines. In addition, VPA led to a decrease of HDAC-1 protein level, as assessed by Western blot analysis. Treatment with VPA caused a decrease in the invasive ability of all three cell lines. Since the invasion process involves a complex system of tightly regulated proteases, matrix metalloproteinases (MMPs) and their tissue-specific inhibitors (TIMPs), the effect of VPA on MMP and TIMP expressions was analysed. Exposure to VPA resulted in a decrease of MMP2 and MMP9 activity and expression level, as assesssed by gelatin zymography and Western blot analysis. In addition, exposure to VPA led to enhanced expression of TIMP1, as assessed by Western blot. Taken together, our results, besides providing further evidence that VPA may represent a promising therapeutic strategy in cancer treatment, may help in the design of new protocols geared at the treatment of neural crest-derived tumors.