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.

Venetoclax durable response in adult relapsed/refractory Philadelphia-negative acute lymphoblastic leukemia with JAK/STAT pathway alterations.

High-risk relapsed/refractory adult Philadelphia-negative (Ph-) B-cell acute lymphoblastic leukemia (B-ALL) is a great challenge due to limited possibilities to achieve and maintain a complete response. This also applies to cases with extramedullary (EM) involvement that have poor outcomes and no accepted standard therapeutic approaches. The incidence of EM localization in relapsed/refractory B-ALL is poorly investigated: data on patients treated with blinatumomab reported a 40% rate. Some responses were reported in EM patients with relapsed/refractory B-ALL treated with inotuzumab ozogamicin or CAR-T. However, molecular mechanisms of response or refractoriness are usually investigated neither at the medullary nor at EM sites. In the complex scenario of pluri-relapsed/refractory B-ALL patients, new target therapies are needed. Our analysis started with the case of an adult pluri-relapsed Ph- B-ALL patient, poorly sensitive to inotuzumab ozogamicin, donor lymphocyte infusions, and blinatumomab in EM disease, who achieved a durable/complete response after treatment with the BCL2-inhibitor venetoclax. The molecular characterization of medullary and EM samples revealed a tyrosine kinase domain JAK1 mutation in the bone marrow and EM samples at relapse. By comparing the expression level of BCL2- and JAK/STAT pathway-related genes between the patient samples, 136 adult JAK1 wt B-ALL, and 15 healthy controls, we identified differentially expressed genes, including LIFR, MTOR, SOCS1/2, and BCL2/BCL2L1, that are variably modulated at diverse time points and might explain the prolonged response to venetoclax (particularly in the EM site, which was only partially affected by previous therapies). Our results suggest that the deep molecular characterization of both medullary and EM samples is fundamental to identifying effective and personalized targeted therapies.

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.

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.

Chimeric Antigen Receptor T-Cell Therapy: What We Expect Soon.

The treatment landscape for hematologic malignancies has changed since the recent approval of highly effective chimeric antigen receptor T-cell therapies (CAR-T). Moreover, more than 600 active trials are currently ongoing. However, early enthusiasm should be tempered since several issues are still unsolved and represent the challenges for the coming years. The lack of initial responses and early relapse are some hurdles to be tackled. Moreover, new strategies are needed to increase the safety profile or shorten the manufacturing process during CAR-T cells therapy production. Nowadays, most clinically evaluated CAR-T cells products are derived from autologous immune cells. The use of allogeneic CAR-T cells products generated using cells from healthy donors has the potential to change the scenario and overcome many of these limitations. In addition, CAR-T cells carry a high price tag, and there is an urgent need to understand how to pay for these therapies as many of today's current payment systems do not feature the functionality to address the reimbursement gap. Finally, the clinical experience with CAR-T cells for solid tumors has been less encouraging, and development in this setting is desirable.

Initial Surgical Strategy for the Treatment of Type A Acute Aortic Dissection: Does Proximal or Distal Extension of the Aortic Resection Influence the Outcomes?

(1) Background: We sought to analyze and compare the outcomes in terms of early and late mortality and freedom from a redo operation in patients undergoing surgical treatment for a type A acute aortic dissection in relation to the initial surgical treatment strategy, i.e., proximal or distal extension of the aortic segment resection, compared with isolated resection of the supracoronary ascending aorta. (2) Methods: This is a retrospective study in which we included 269 patients who underwent operations for a type A acute aortic dissection in the Department of Cardiac Surgery of Tor Vergata University from May 2006 to May 2016. The patients were grouped according to the extent of the performed surgical treatment: isolated replacement of the supracoronary ascending aorta (NE, no extension), replacement of the aortic root (PE, proximal extension), replacement of the aortic arch (DE, distal extension), and both (BE, bilateral extension). The analyzed variables were in-hospital mortality, postoperative complications (incidence of neurological damage, renal failure and need for prolonged intubation), late mortality and need for a redo operation. (3) Results: Unilateral cerebral perfusion was performed in 49.3% of the patients, and bilateral perfusion-in 50.6%. The overall in-hospital mortality was 31.97%. In the multivariate analysis, advanced age, cardiopulmonary bypass time and preoperative orotracheal intubation were independent predictors of in-hospital mortality. In the population of patients who survived the surgery, the probability of survival at 92 months was 70 ± 5%, the probability of freedom from a redo operation was 71.5 ± 5%, the probability of freedom from the combined end-point death and a redo operation was 50 ± 5%. The re-intervention rate in the general population was 16.9%. The overall probability of freedom from re-intervention was higher in patients undergoing aortic root replacement, although not reaching a level of statistical significance. Patients who underwent aortic arch treatment showed reduced survival. (4) Conclusions: In the treatment of type A acute aortic dissection, all the surgical strategies adopted were associated with satisfactory long-term survival. In the group of patients in which the aortic root had not been replaced, we observed reduced event-free survival.

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.

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.

Post-chemotherapy cognitive impairment in hematological patients: current understanding of chemobrain in hematology.

Introduction: Cognitive impairment caused by chemotherapies, a condition known as chemobrain, is a possible side effect that affects alertness, learning, memory, and concentration.Areas covered: Chemobrain has been principally investigated as a possible side-effect among cancer patients. However, numerous drugs used to treat hematological malignancies can determine the appearance of chemobrain. In this review, we have examined some commonly used drugs for the treatment of hematological malignancies which are known to have a deleterious action on cognitive functions.Numerous mechanisms have been suggested, comprising the direct neurotoxicity of chemotherapeutic drugs, oxidative stress, genetic predisposition, cytokine-provoked damage, histone modifications, immune alteration, and the action of chemotherapeutic on trophic factors and structural proteins of brain cells.Expert commentary: Cognitive dysfunction provoked by the treatment of hematological diseases is an actual challenge in clinical practice. Actually, there are no totally efficient and innocuous treatments for this syndrome. It is important that further investigations specify the existence of predictors and gravity factors to pre- and post-therapy cognitive change and identify the influence of tumor treatments on the cognitive alterations in long-term, cancer survivors. Moreover, future studies are needed to analyze the interactions between genetic risk, amyloid accumulation, intrinsic brain networks, and chemotherapy.

Mechanical Heart Valve Replacement in a Low-Middle Income Region in the Modern Era: Midterm Results from a Sub-Saharan Center.

BACKGROUND: The management of patients with mechanical heart valves remains a major concern in populations with limited resources and medical facilities. This study reports the clinical outcomes of patients who underwent mechanical valve implantation in a sub-Saharan center over an 8-year period. METHODS: A total of 291 mechanical valves were implanted in 233 patients in our institution between February 2008 and June 2016. A total of 117 patients underwent mitral valve replacement (MVR, 50.2%), 57 had aortic valve replacement (AVR, 24.4%), and 59 underwent both AVR and MVR (double valve replacement [DVR], 25.7%). The mean age at surgery was 27.6 ± 13.4 years (range, 7-62 years). Rheumatic etiology was found in 80.6% of the patients. Hospital mortality, late deaths, and valve-related events were reviewed at follow-up (839 patient-years, range: 1-9.4 years, complete in 93%). RESULTS: The 30-day mortality was 4.7% (11/233). The overall survival at 1 and 6 years for the whole cohort was 88.8 ± 2.1% and 78.7 ± 3.3%, respectively. The 6-year survival for AVR, MVR, and DVR was 89.3 ± 4.8%, 73.2 ± 5.4%, and 79.3 ± 5.8%, respectively (p = 0.15). The freedom from neurologic events and anticoagulation-related bleeding at 6 years was 93.1 ± 2.1% and 78.9 ± 3.7%, respectively. No patient had reoperation at follow-up. No case of prosthetic valve thrombosis was identified. Eight full-term pregnancies were reported. CONCLUSION: This preliminary experience reports acceptable midterm results after mechanical heart valve implantation in our region. Both accurate surgical evaluation and strategies, either financial or social, facilitating patient's education and medical assistance are crucial to ensure good results. Long-term follow-up and further studies comparing current nonthrombogenic options are warranted to draw reliable conclusions.

Infectious Aortic Root Pseudoaneurysm after Bentall Procedure: To Treat or Not to Treat by Redo Operation?

We present a case of a 75-year-old man who developed an early aortic bioprosthesis endocarditis due to Klebsiella pneumoniae complicated by aortic root pseudoaneurysm after Bentall procedure. A prompt surgical option was hypothesized, but we decided to wait and keep on clinical observation and antibiotic therapy. One year after discharge, we observed stable clinical conditions and echocardiographic findings. A question: to treat or not to treat by redo operation an infectious aortic root pseudoaneurysm?

Surgical Repair of a Giant Aorto-Left Ventricular Fistula.

Aortoventricular fistula, a rare congenital or acquired defect of the aortic wall, is characterized by an abnormal connection between the aorta and one of the ventricles. Symptom severity correlates with the diameter of the fistula and with the acute or chronic timing of presentation. The diagnosis is usually made by using echocardiography, and surgical treatment is necessary to avoid progression to heart failure. We describe the case of a 27-year-old woman who underwent successful surgical repair of an aortoventricular fistula that originated from the right coronary sinus and extended into the left ventricle through the interventricular septum. In addition to the patient's case, we briefly discuss this unusual condition.

Lymphocyte Subsets and Inflammatory Cytokines of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma.

Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to a malignant situation. Regarding malignancy, the role of lymphocyte subsets and cytokines at the beginning of neoplastic diseases is now incontestable. In this review, we have concentrated our attention on the equilibrium between the diverse lymphocyte subsets and the cytokine system and summarized the current state of knowledge, providing an overview of the condition of the entire system in MGUS and MM. In an age where the therapy of neoplastic monoclonal gammopathies largely relies on drugs capable of acting on the immune system (immunomodulants, immunological checkpoint inhibitors, CAR-T), detailed knowledge of the the differences existing in benign and neoplastic forms of gammopathy is the main foundation for the adequate and optimal use of new drugs.

An Unexpected Risk Factor for Early Structural Deterioration of Biological Aortic Valve Prostheses.

BACKGROUND: An alarming rate of early failure has been recently reported for the LivaNova (previously Sorin) Mitroflow (LivaNova, London, UK) bioprosthesis. Here, we aimed at verifying if this possible underperformance is confirmed in a large, single-center experience and identifying the risk factors associated with early deterioration. METHODS: In all, 459 Mitroflow valves have been implanted from July 2009 to December 2013 (patients' mean age 73 years; 204 women). Surviving patients have undergone yearly clinic and echocardiographic follow-up. Dysfunction was defined as moderate if the mean gradient was more than 30 mm Hg or severe if it exceeded 40 mm Hg. The population was divided on the basis of a dimensional mismatch, the model of the prosthesis (LX or DL: follow-up to 4 years), and patient's age at the time of implantation. RESULTS: Cumulative freedom from moderate valve dysfunction was 81% ± 3% at 60 months. It was lower with patient-prosthesis mismatch (71% ± 5% versus 92% ± 3%; p = 0.0065) and with the more recent DL model (at 42 months: 78% ± 6% versus 96% ± 2%; p < 0.0001). Cumulative freedom from severe dysfunction was 93% ± 2% at 5 years. Again, it was inferior among patients with a mismatch (86% ± 4% versus 100%; p = 0.0013) and for the DL model (42 months: 92.5% ± 3% versus 98.5% ± 1%; p = 0.0309). Smaller prostheses showed higher rates of early degeneration. CONCLUSIONS: The LivaNova Mitroflow valve appears to be prone to early deterioration. Smaller size prostheses should be used cautiously and avoided with patient-prosthesis mismatch. The DL model anticalcification treatment seems unable to prevent early degeneration, and possibly contributes to even earlier failure.

Cardiac surgery with extracorporeal circulation and concomitant malignancy: early and long-term results.

AIMS: We retrospectively evaluated early and long-term results of cardiac surgery using extracorporeal circulation (ECC) in patients affected by malignancies and the potential influence of ECC on malignancy progression during follow-up. METHODS: Out of 7078 patients referred for cardiac surgery from January 2001 to December 2012, 241 consecutive patients (3.4%) (mean age 72 ±â€Š8 years; men 170) had malignancy either known before or detected during hospital stay. Organ malignancies were present in 201 patients (83%) and hematological malignancies in 40 (17%). Early stages of cancer (I-II, in remission) were present in 180 (75%) patients, and advanced stages (III-IV for organ malignancies , multiple organ involvement for hematological malignancies) in 61 (25%). EuroSCORE I and II were 8.6 ±â€Š5.4 and 3.8 ±â€Š2.1%, respectively. Cardiac surgery with ECC consisted in isolated (n = 176) or multiple procedures (n = 65). Follow-up (mean 57 ±â€Š40 months) was 99% complete. RESULTS: In-hospital mortality was 5.8% (n = 14); 1.67% (n = 4) died from cancer-related causes. Ten-year survival was 65 ±â€Š5%, and freedom from cardiac death was 92 ±â€Š3.5%. Freedom from cancer-related death was 90 ±â€Š3% for patients operated on in early stages of cancer compared with 60 ±â€Š8.4% for those who operated on in advanced stages (P < 0.0001), and 89 ±â€Š2.6% for organ malignancies compared with 48 ±â€Š13% for hematological malignancies (P = 0.0002); hematological malignancies different from Hodgkin/non-Hodgkin lymphoma affected long-term survival (P < 0.05). Progression of malignancy was observed in 29 patients (12.8%) at 18 ±â€Š10 months. CONCLUSION: Cardiac surgery in cancer patients is not associated with increased in-hospital mortality and provides satisfactory freedom from cardiac death. Long-term survival in early stages of cancer appears satisfactory. Time interval between ECC and progression of malignancy during follow-up should apparently exclude a close relationship of ECC on cancer progression. Hematological malignancies seem to have a negative impact on the overall outcome.

Surgery for rheumatic mitral valve disease in sub-saharan African countries: why valve repair is still the best surgical option.

Rheumatic valve disease, a consequence of acute rheumatic fever, remains endemic in developing countries in the sub-Saharan region where it is the leading cause of heart failure and cardiovascular death, involving predominantly a young population. The involvement of the mitral valve is pathognomonic and mitral surgery has become the lone therapeutic option for the majority of these patients. However, controversies exist on the choice between valve repair or prosthetic valve replacement. Although the advantages of mitral valve repair over prosthetic valve replacement in degenerative mitral disease are well established, this has not been the case for rheumatic lesions, where the use of prosthetic valves, specifically mechanical devices, even in poorly compliant populations remains very common. These patients deserve more accurate evaluation in the choice of the surgical strategy which strongly impacts the post-operative outcomes. This report discusses the factors supporting mitral repair surgery in rheumatic disease, according to the patients' characteristics and the effectiveness of the current repair techniques compared to prosthetic valve replacement in developing countries.

Surgical approach to aortic valve replacement after previous bilateral internal thoracic artery grafting.

The authors present a manubrium-sparing sternotomy technique for aortic valve replacement in patients who have undergone previous myocardial revascularization with both internal thoracic arteries. They have found that preoperative 64-multislice computed tomographic imaging facilitates surgical planning by delineating the course of patent grafts and, in particular, the relationship between the sternum and the right internal thoracic artery graft. A manubrium-sparing sternotomy can in such instances avoid injury to the right internal thoracic artery graft during both resternotomy and adhesion dissection, thus reducing surgical risk and operative time.