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.

Do CAR-T and Allogeneic Stem Cell Transplant Both Have a Place in Lymphoid Neoplasms?

Allogeneic stem cell transplantation (allo-SCT) represented the first immunotherapy to treat hematologic malignancies: it has been considered as a cure for the disease and never as an approach to extend the life of patients. The success of allo-SCT derives both from the ability to treat patients with intensive chemoradiotherapy and from the potent graft-versus-leukemia effects mediated by donor immunity. Although considerable progress has been made in the last years, significant barriers still remain in the form of disease relapse, graft-versus-host disease, infectious complications, and regimen-related toxicities. Moreover, the treatment of hematologic malignancies, particularly acute lymphoblastic leukemia and certain forms of lymphomas, has been revolutionized by the commercial introduction of genetically modified autologous T-lymphocyte therapy (CAR-T). Our review discusses current standards and the shifting paradigms in the indications for allo-SCT and the role of CAR-T cell therapy for lymphoid neoplasms.

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.

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.

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.

CART-Cell Therapy: Recent Advances and New Evidence in Multiple Myeloma.

Despite the improvement in survival outcomes, multiple myeloma (MM) remains an incurable disease. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) represents a new strategy for the treatment of relapsed/refractory MM (R/R). In this paper, we describe several recent advances in the field of anti-BCMA CAR T-cell therapy and MM. Currently, available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CART therapy is safety. Cytokine release syndrome (CRS) andneurologic toxicity are well-described adverse effects. In the MM trials, most CRS events tended to be grade 1 or 2, with fewer patients experiencing grade 3 or higher. Another critical point is the extended timeline of the manufacturing process. Allo-CARs offers the potential for scalable manufacturing for on-demand treatment with shorter waiting days. Another issue is undoubtedly going to be access to this therapy. Currently, only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise.

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.

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.

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.

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.

Italian real-life experience with brentuximab vedotin: results of a large observational study of 40 cases of relapsed/refractory systemic anaplastic large cell lymphoma.

Between November 2012 and July 2014, in accordance with national law 648/96, brentuximab vedotin was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma outside a clinical trial context. A large Italian observational retrospective study was conducted on the use of brentuximab vedotin in everyday clinical practice to check whether clinical trial results are confirmed in a real-life context. The primary endpoint of this study was best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and safety profile. A total of 40 heavily pretreated patients were enrolled. Best response was observed after a median of four cycles in 77.5%: globally, 47.5% patients obtained a complete response, 64.2% in the elderly subset. The overall response rate was 62.5%. At the latest follow up, 15/18 patients are still in complete remission (3 with consolidation). The progression-free survival rate at 24 months was 39.1% and the disease-free survival rate at the same time was 54% (median not reached). All the long-term responders were aged <30 years at first infusion. The treatment was well tolerated even in this real-life context and no deaths were linked to drug toxicity. Brentuximab vedotin induces clinical responses quite rapidly, i.e. within the first four cycles of treatment in most responders, thus enabling timely use of transplantation. For patients ineligible for transplant or for those in whom a transplant procedure failed, brentuximab vedotin may represent a feasible effective therapeutic option in everyday clinical practice.

Recombinant human erythropoietin in very elderly patients with myelodysplastic syndromes: results from a retrospective study.

Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80-99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6-10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) patients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p = 0.004), ferritin <200 ng/ml (p = 0.017), Hb >8 g/dl (p = 0.034), and a high-dose rHuEPO treatment (p = 0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5-68.4) in responders versus 30.6 months (95 % CI 7.3-53.8) in resistant patients (p = 0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.

Revised International Prognostic Scoring System (IPSS) predicts survival and leukemic evolution of myelodysplastic syndromes significantly better than IPSS and WHO Prognostic Scoring System: validation by the Gruppo Romano Mielodisplasie Italian Regional Database.

PURPOSE: The definition of disease-specific prognostic scores plays a fundamental role in the treatment decision-making process in myelodysplastic syndrome (MDS), a group of myeloid disorders characterized by a heterogeneous clinical behavior. PATIENTS AND METHODS: We applied the recently published Revised International Prognostic Scoring System (IPSS-R) to 380 patients with MDS, registered in an Italian regional database, recruiting patients from the city of Rome (Gruppo Romano Mielodisplasie). Patients were selected based on the availability of IPSS-R prognostic factors, including complete peripheral-blood and bone marrow counts, informative cytogenetics, and follow-up data. RESULTS: We validated the IPSS-R score as a significant predictor of overall survival (OS) and leukemia-free survival (LFS) in MDS (P < .001 for both). When comparing the prognostic value of the International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), and IPSS-R, using the Cox regression model and the likelihood ratio test, a significantly higher predictive power for LFS and OS became evident for the IPSS-R, compared with the IPSS and WPSS (P < .001 for both). The multivariate analysis, including IPSS, WPSS, age, lactate dehydrogenase, ferritin concentration, Eastern Cooperative Oncology Group performance status, transfusion dependency, and type of therapy, confirmed the significant prognostic value of IPSS-R subgroups for LFS and OS. Treatment with lenalidomide and erythropoiesis-stimulating agents was shown to be an independent predictor of survival in the multivariate analysis. CONCLUSION: Our data confirm that the IPSS-R is an excellent prognostic tool in MDS in the era of disease-modifying treatments. The early recognition of patients at high risk of progression to aggressive disease may optimize treatment timing in MDS.

Very long-lasting remission of refractory T-large granular lymphocytes leukemia and myeloma by lenalidomide treatment.

BACKGROUND: Large granular lymphocyte leukemias (LGLLs) represent a spectrum of biologically distinct lymphoproliferative diseases originating from either mature T cells (CD3+) or natural killer (NK) cells (CD3-). Both T-cell and NK-cell LGL leukemia can manifest as indolent or aggressive neoplasia. These rare lymphoproliferative disorders are often associated with autoimmune diseases and impaired hematopoiesis. Symptomatic patients are treated with immunosuppressive drugs. The co-association of T-LGLL with clonal B-cell disorders is reported in more than 10% of patients. CASE PRESENTATION: We describe the case of a 57-yr-old white male patient with no history of autoimmune disorders, with refractory T-LGLL and myeloma who was treated with bortezomib and subsequently with lenalidomide. After 30 months of on-going lenalidomide therapy, the patient is in partial remission from myeloma and in continuous complete hematological remission from T-LGLL. CONCLUSIONS: As far as we know, this is the first report of a patient with refractory T-LGLL treated with bortezomib and lenalidomide. As refractory T-LGLL is a challenging condition, we think that lenalidomide and bortezomib deserve further investigation.