Stem Cells Collection and Mobilization in Adult Autologous/Allogeneic Transplantation: Critical Points and Future Challenges.

Achieving successful hematopoietic stem cell transplantation (HSCT) relies on two fundamental pillars: effective mobilization and efficient collection through apheresis to attain the optimal graft dose. These cornerstones pave the way for enhanced patient outcomes. The primary challenges encountered by the clinical unit and collection facility within a transplant program encompass augmenting mobilization efficiency to optimize the harvest of target cell populations, implementing robust monitoring and predictive strategies for mobilization, streamlining the apheresis procedure to minimize collection duration while ensuring adequate yield, prioritizing patient comfort by reducing the overall collection time, guaranteeing the quality and purity of stem cell products to optimize graft function and transplant success, and facilitating seamless coordination between diverse entities involved in the HSCT process. In this review, we aim to address key questions and provide insights into the critical aspects of mobilizing and collecting hematopoietic stem cells for transplantation purposes.

Sarcopenia does not impact the outcome of patients with Multiple Mieloma consolidated with autologous Hematopoietic Stem Cell Transplantation.

Sarcopenia has been associated with chronic diseases and cancer. Aim of this study was to evaluate sarcopenia in Multiple Myeloma patients undergoing autologous stem cell trans-plantation. In 68 eligible patients' measurement of skeletal muscle area (cm2) on computed tomography scans at the level of the L3 vertebra (L3-SMI) was performed. 37(54%) patients were categorized as sarcopenic: 26 males with L3-SMI values < 52.4 cm2/m2, and 11 women with L3-SMI values < 38.9 cm2/m2. The majority of sarcopenic patients included were older than 60 years (69%, p=0.0005), and with BMI <25 (75%; p=0.0000). A significant association was found between sarcopenia and Sorror score value > 1 (p=0.02). The Kaplan Meyer curve showed a median OS of 73.5 months for non-sarcopenic patients vs. 86.5 months for sarcopenic patients, suggesting that sarcopenia is not an independent prognostic factor in this cohort of patients.

Fluorodeoxyglucose-Positron Emission Tomography in Relapsed/Refractory Hodgkin Lymphoma: A Practical Approach.

BACKGROUND: Positron emission tomography (PET) with the use of 18F-fluorodeoxyglucose (FDG), implemented with low-dosage computer tomography, is to be considered as the most important evolution of imaging in the management and assessment of classical Hodgkin lymphoma patients. SUMMARY: According to Lugano response criteria, FDG-PET is mandatory to define metabolic response to frontline therapy and moreover it is important in the definition of nonresponders or refractory disease patients. Refractory disease is reported in about 15% of patients, with some variations based on the choice of first-line chemotherapy, and particularly in advanced stages, up to 40% eventually relapse within 3 years. KEY MESSAGES: The aim of this review was to highlight a practical way to use FDG-PET in the subset of HL, with some notes of its use in first-line patients, and particularly centered on relapsed or refractory setting with a final focus of the evaluation of response by FDG-PET in the new treatment era of immunocheckpoint inhibitors.

Role of CD68 in the tumor immune microenvironment in Hodgkin's lymphoma.

INTRODUCTION: Despite the high rate of cure in classical Hodgkin Lymphoma (cHL), some patients experienced a refractory disease, sometimes, hardly curable. In the pathogenesis of cHL, Reed Sternberg Cells (HRSC), which represent only less than 1% of tumor cells, are not the only protagonist; in fact, the role of tumor microenvironment is essential in survival, tumor growth, and progression of the disease due to the interaction between immune cells, chemokines, and cytokines. AREAS COVERED: In this review, the current significant literature was discussed. Many studies demonstrated the role of macrophages CD68+ as 'protumor', especially in supporting HRSC survival through cell-to-cell and paracrine interactions. Increased infiltration of CD68 macrophages correlate with a poor prognosis. This review examines the interaction between CD68 macrophages, HRSC and cHL milieu, and the consequent clinical impact, providing an up-do-date portrait of these immune cells with possible translational and therapeutic applications. EXPERT OPINION: We can suggest that a high baseline CD68 macrophages in cHL patients could contribute to the identification of high-risk patients and help clinicians to choose the best treatment, in the context of refractory disease. A macrophage target strategy in association with chemotherapy or biological therapy could represent a promising approach for future studies and investigations.

Neuroradiology of acute pathologies in adults with hematologic malignancies: a pictorial review.

Hematopoietic and lymphoid tumors are a heterogeneous group of diseases including lymphomas, multiple myeloma (MM), and leukemias. These diseases are associated with systemic involvement and various clinical presentations including acute neurological deficits. Adult patients with hematologic malignancies (HM) are at risk for developing a wide array of acute conditions involving the nervous system. HM in adults may present as tumoral masses responsible for mass effect, possibly resulting in acute neurological signs and symptoms caused by tumor growth with compression of central nervous system (CNS) structures. Moreover, as result of the hematologic disease itself or due to systemic treatments, hematologic patients are at risk for vascular pathologies, such as ischemic, thrombotic, and hemorrhagic disorders due to the abnormal coagulation status. The onset of these disorders is often with acute neurologic signs or symptoms. Lastly, it is well known that patients with HM can have impaired function of the immune system. Thus, CNS involvement due to immune-related diseases such as mycotic, parasitic, bacterial, and viral infections linked to immunodeficiency, together with immune reconstitution inflammatory syndrome, are frequently seen in hematologic patients. Knowledge of the etiology and expected CNS imaging findings in patients with HM is of great importance to reach a fast and correct diagnosis and guide treatment choices. In this manuscript, we review the computed tomography (CT) and magnetic resonance findings of these conditions which can be related to the disease itself and/or to their treatments.

Circulating Endothelial Cell Kinetic in Patients with Multiple Myeloma Who Receive Autologous Hematopoietic Stem Cell Transplantation.

INTRODUCTION: Neoangiogenesis has a crucial role in multiple myeloma (MM), and circulating endothelial cells (CECs) contribute to neovascularization by inducing tumor progression and metastasis and by repairing damage to bone marrow vasculature after stem cell transplantation (HSC). We recently proved in a national multicenter study the possibility to reach a high-level standardization in CEC count and analysis based on a polychromatic flow cytometry Lyotube (BD). Our study aimed at assessing the kinetics of CECs in patients with MM undergoing autologous hematopoietic stem cell transplantation (Au-HSCT). METHODS: Blood samples for analysis were collected at different time points before (T0, T1) and after (T2, T3, T4) Au-HSCT. For each sample, 20 × 106 leukocytes were processed as already described (Lanuti 2016 e 2018) through a multistep procedure. CECs were eventually identified as 7-ADDneg/Syto16pos/CD45neg/CD34pos/CD146pos. RESULTS: Twenty-six MM patients were enrolled in the study. Overall, we observed a constant increase of CECs values from T0 to T3 (day of neutrophil engraftment) followed by decrease at T4 (100 days after transplantation). Using the median value of CECs at T3, we could define a cut-off concentration of 618/mL, with patients with more infective complications having CECs above that value (9/13 vs. 2/13; p = 0.005). CONCLUSION: CECs value may be a function of endothelial damage caused by conditioning regimen, as suggested by the increase of their level during the engraftment period. A more severe endothelial damage is reflected by the increase of infective complications in patients with higher CECs value at T3.

Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group.

The multiple myeloma (MM) treatment has changed over the last years due to the introduction of novel drugs. Despite improvements in the MM outcome, MM remains an incurable disease. Daratumumab is a human IgGK monoclonal antibody targeting CD38 with tumor activity associated with immunomodulatory mechanism. In combination with standard of care regimens, including bortezomib (Vd) or lenalidomide (Rd), daratumumab prolonged progression-free survival (PFS) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) and in new diagnosis MM. We report the data of the MM GIMEMA Lazio group in 171 heavily treated pts who received daratumumab, lenalidomide and dexamethasone (DRd) or daratumumab, velcade and dexamethasone (DVd). The overall response rate was 80%, and the overall survival (OS) and PFS were 84% and 77%, respectively. In addition, pts treated with DRd showed a better median PFS compared to pts treated with DVd, at 12 and 24 months, respectively. The most common hematologic treatment-emergent adverse events (TAEs) were neutropenia, thrombocytopenia, and anemia. The most common nonhematologic TAEs were peripheral sensory neuropathy and infections. Our data confirmed that DRd or DVd therapy is effective and safe in RRMM pts, and our real-life analysis could support the physicians regarding the choice of optimal therapy in this setting of pts.

Autologous stem cell transplantation in multiple myeloma patients over 70 years: A GIMEMA Lazio Working Group experience in a retrospective case-control study.

High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is the standard treatment for young patient ≤65 years with multiple myeloma (MM). The role of auto-SCT in elderly patients older than 70 years remains controversial in the era of novel agents and especially since the recent introduction of monoclonal antibodies (AbMo). In this study, we evaluated 12 patients with MM over 70 years old undergoing auto-SCT (elderly graft cohort) in seven centers of GIMEMA Working Group Lazio. We compared the baseline characteristics, treatment and outcome with 97 MM elderly patients who did not receive auto-SCT (nontransplant patients) from the same registry who were ≥ 70 years old, but did not undergo auto-SCT. The median progression free survival (PFS) for graft versus no-graft cohort was 56.4 versus 26.1 months, respectively. There was a trend for better PFS among graft compared to nontransplant patient (p = .1). On the other hand, the median overall survival for transplant versus nontransplant cohort was 107.6 versus 49.5 months (p = .02). Despite the small number of patients aged ≥70 years and ≤74 years, it seems that auto-SCT is well tolerated, safe and effective. Therefore, we propose that it should be considered an important treatment option in the era of new drugs in elderly fit patients with MM.

MiR-22, a serum predictor of poor outcome and therapy response in diffuse large B-cell lymphoma patients.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive, heterogeneous neoplasm where prognostication and therapeutic decision are challenging. The available prognostic tools are not able to identify all patients refractory to treatment. MicroRNAs, small RNAs frequently deregulated in cancer, stably circulate in biofluids, representing interesting candidates for non-invasive biomarkers. Here we validated serum miR-22, an evolutionarily conserved microRNA, as a prognostic/predictive biomarker in DLBCL. Moreover, we found that its expression and release from DLBCL cells are related to therapy response and adversely affect cell proliferation. These results suggest that miR-22 is a promising complementary or even independent non-invasive biomarker for DLBCL management.

A novel scoring system for TIGIT expression in classic Hodgkin lymphoma.

Clinical use of immune-checkpoints inhibitors (anti PD-1/PD-L1) resulted very effective for the treatment of relapsed/refractory classic Hodgkin Lymphoma (CHL). Recently, T cell Ig and ITIM domains (TIGIT) has been recognized as an immune checkpoint receptor able to negatively regulate T cell functions. Herein, we investigated the expression of TIGIT in CHL microenvironment in order to find a potential new target for inhibitor therapy. TIGIT, PD-1 and PD-L1 expression was evaluated in 34 consecutive patients with CHL. TIGIT expression in T lymphocytes surrounding Hodgkin Reed-Sternberg (HRS) cells was observed in 19/34 patients (56%), of which 11 (58%) had advanced stages. In 16/19 (84%) cases, TIGIT+ peritumoral T lymphocytes showed also PD-1 expression. All 15 TIGIT- patients had PD-L1 expression in HRS cells (100%) while among 19 TIGIT+ patients, 11 (58%) were PD-L1+ and 8 (42%) were PD-L1-. Using a new scoring system for TIGIT immunoreactivity, all TIGIT+ cases with higher score (4/19) were PD-L1-. Our results confirm co-expression of TIGIT and PD-1 in peritumoral T lymphocytes. Of relevance, we demonstrated a mutually exclusive expression of TIGIT and PD-L1 using new TIGIT scoring system able to identify this immunocheckpoints' modulation. These results pave the way to new therapeutic strategies for relapsed/refractory CHL.

The neutrophil/lymphocyte ratio ≥3.5 is a prognostic marker in diffuse large B-cell lymphoma: a retrospective analysis from the database of the Italian regional network 'Rete Ematologica del Lazio per i Linfomi' (RELLI).

In solid tumors and lymphomas, the neutrophil/lymphocyte (N/L) ratio at diagnosis has been shown to be a prognostic factor. The aim of our study was to validate the originally reported N/L ratio cut-point of 3.5 in patients with diffuse large B-cell lymphoma (DLBCL) registered in an Italian real-life database. The prognostic role of the N/L ratio at diagnosis on event-free survival (EFS) and overall survival (OS) was assessed in 505 patients with DLBCL. Patients with an N/L ratio <3.5 (n = 249) had a 4-year EFS probability of 76% and OS probability of 86%, significantly higher than the 4 year EFS rate of 48% and OS rate of 64% in patients with N/L ratio ≥3.5 (n = 256, both p<.0001). The N/L ratio was an independent prognostic factor in the multivariate analysis including the IPI score, and could separate patients with a low/intermediate risk IPI (IPI <3).

Gonadal Function Recovery and Fertility in Women Treated with Chemo- and/or Radiotherapy for Hodgkin's and Non-Hodgkin Lymphoma.

BACKGROUND: Fertility and gonadal function represent one of the most important aspects for long-term lymphoma survivors. AIMS: The aim of our study was to determine possible risk factors, such as age at treatment, chemotherapeutic regimen, protection with oral contraceptives (OCs), and gonadotropin-releasing hormone (GnRH) analogues in female patients treated for Hodgkin's lymphoma (HL) or non-Hodgkin lymphoma (NHL) at a reproductive age. METHODS: Patients between the age of 16 and 50 years at the time of HL or NHL diagnosis were selected. Eligible patients were requested to respond to a questionnaire by phone interview about fertility, menstrual status, sexual aspects, and treatment with OCs or GnRH analogues during chemotherapy. RESULTS: The resumption of menstrual activity was associated with the use of the OCs and GnRH analogues during chemotherapy (p = 0.008 and 0.034, respectively). At univariate analysis, the use of OCs during chemotherapy was associated with a lower risk of amenorrhea (prevalence ratio [PR] = 0.37; 95% CI 0.17-0.82). A higher age at the time of treatment correlated positively with therapy-induced amenorrhea, with a difference of 12.8 years between the mean age at diagnosis of the women with therapy-induced amenorrhea and those who resumed their menses. Amenorrhea was significantly higher in women receiving R-CHOP than in women treated with ABVD (PR = 6.00; 95% CI 2.32-15.54). Moreover, NHL had an infertility PR of 1.51 (95% CI 0.86-2.45) at multivariate analysis compared to HL. CONCLUSIONS: This study suggests a possible role of pharmacological prophylaxis with OCs and GnRH analogues.

Prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan and stem cell transplantation: review of the evidence and suggestions.

INTRODUCTION: High-dose melphalan (HDMel) is the most common conditioning chemotherapy regimen for autologous stem cell transplantation (SCT) in patients affected by multiple myeloma (MM). No consensus exists for the emetogenicity or prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in this regimen. METHODS: Data on the incidence and efficacy/safety of CINV prophylaxis among patients affected by MM undergoing autologous SCT with the HDMel regimen was extracted from electronic databases and analyzed. RESULTS: Eleven studies involving multiple CINV prophylaxis regimens were identified and included. No consensus on HDMel emetogenicity was reached, but most studies summarized the emetogenicity as moderate-high risk. An aprepitant-based three-drug regimen (aprepitant + serotonin receptor antagonist (5HT3RA) + dexamethasone) showed better efficacy than a two-drug regimen (5HT3RA + dexamethasone) for CINV prevention without increasing the frequency in adverse events. CONCLUSIONS: The aprepitant-based three-drug regimen should be the regimen of choice for CINV prophylaxis for MM patients undergoing autologous SCT with HDMel conditioning.

Impact of IFN lambda 3/4 single nucleotide polymorphisms on the cytomegalovirus reactivation in autologous stem cell transplant patients.

Cytomegalovirus (CMV) infection represents one of the main cause mortality after Stem Cell Transplantation. Recently, a protective effect of the T allele of rs12979860 IL28B Single Nucleotide Polymorphisms (SNPs) against CMV infection in the allogenic stem cell transplantation was suggested. We investigate whether the rs12979860 IL28B SNP and the relative rs368234815 (IFNλ4) genotype may affect the incidence of active CMV infection in Autologous stem cell transplantation (Auto-SCT) setting. The study included 99 patients who underwent to Auto-SCT. IL28 and IFNΔ4 SNPs were correlated with CMV reactivation along with other clinical and treatment parameters. CMV reactivation by CMV DNAemia was evaluated once a week until day 100 from Auto-SCT. CMV reactivation was documented in 50% (TT-ΔG/ΔG), 35% (CC-TT/TT) and 29.2% (CT-TT/ΔG) of the patients respectively. No differences in CMV copies number were recorded at reactivation between different IL28/IFNλ4 genotypes. The analysis of patients older than 60 years showed a significantly higher incidence of active CMV infection in the TT-ΔG/ΔG (83%) population with respect to CC-TT/TT (21%) and CT-TT/ΔG (40%) patients. Our data suggest a negative role of TT-ΔG/ΔG genotype in the CMV reactivation in Auto-SCT. The exposure to rituximab and the pre-infusion presence of anti CMV IgG also significantly influenced CMV reactivation.

An integrated system for the monitoring of therapy and drug's side effects in Lymphoproliferative disorders.

The wide diffusion of telecommunication systems and the availability of cheap computational devices, such as smart wearable, PDA and smartphones, is multiplying the number of collaborative and remote-monitored applications accessible to a large mass of people. In particular, this scenario makes it possible the implementation of specific systems that improve the control of patients with minimal impact on the quality of their lives. This paper moves in this context and presents a general system for the continuous monitoring at home of therapy and disease symptoms. Indeed, starting from a specific application aiming at monitoring patients with Lymphoproliferative disorders and the side effects related to specific drugs used in treatment of these diseases, in this paper we present a more general framework easy customizable to the requirements of different applications. In particular, the proposed system has been designed to be easily tuned to a larger class of disorders and, in our opinion, it can be applied in almost all the scenarios where patients require a strict monitoring of their conditions in their home environment. The paper presents the model, the architecture and the implementation of the system.

Primary bone lymphoma of the talus: a challenging diagnosis.

PURPOSE: Diagnostic challenges are common in clinical practice and diagnostic or classification criteria for musculoskeletal conditions cannot overshadow clinical skills. METHODS: We present the case of a young man who complained of prolonged articular pain and mild swelling of the right ankle in the absence of other remarkable data. Apparently fulfilling the Budapest diagnostic criteria for complex regional pain syndrome, the patient was treated accordingly, but the pain increased over time. Then the patient underwent an additional diagnostic workup including synovial and bone biopsies in 2 separate occasions with the second one demonstrating diffuse lymphoid infiltrate compatible with lymphoma. RESULTS: The conclusive diagnosis of primary diffuse large B-cell lymphoma of the talus was made and adequate treatment initiated. CONCLUSIONS: The diagnostic difficulties as well as the importance of a multidisciplinary approach for complex cases are highlighted in this report.

A case of transplantation-associated thrombotic microangiopathy with cardiac involvement successfully treated with plasma exchange.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is occasionally described as a serious complication after allogeneic and, more rarely, autologous stem cell transplantation (SCT). It is characterized by poor outcome with high mortality rate. Plasma exchange (PE) has been reported as successful first-line therapy in other thrombotic microangiopathies. However, unlike to idiopathic forms, response to PE are usually suboptimal in TA-TMA and the use of PE remains controversial, because the exact mechanism of injury is not yet understood. The kidney is the most commonly affected organ and injury has rarely been reported elsewhere in the body, such as in lungs and gastrointestinal tract. Although several case reports have documented myocardial infarctions in patients presenting classic thrombotic thrombocytopenic purpura (TTP), there are no reports documenting cardiac involvement in TA-TMA. We describe a case of a 66-year-old man who experienced TA-TMA accompanied by cardiac ischemia after autologous SCT for multiple myeloma, successfully treated with PE. The immediate start of PE induced a complete remission of TA-TMA and disappearance of cardiac ischemic signs and symptoms except of a residual chronic renal failure.

A retrospective study on 73 elderly patients (≥75years) with aggressive B-cell non Hodgkin lymphoma: clinical significance of treatment intensity and comprehensive geriatric assessment.

OBJECTIVE: The clinical outcome of elderly (≥75years) patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL) is not firmly established because few studies have specifically addressed this issue. In addition, the usefulness of a comprehensive geriatric assessment (CGA) in B-NHL still needs to be deeply explored. MATERIALS AND METHODS: We evaluated the prognostic factors of 73 patients aged ≥75years (median age: 78) with B-NHL treated by clinical judgment with curative anthracycline-based approaches (n=36) or with conservative treatments without anthracyclines (n=37). Analysis of clinical outcomes also included baseline CGA stratification. RESULTS: The curative approaches resulted in a better clinical outcome than conservative approaches [overall response rate: 91.2% vs. 69.7%, P=0.003; 2-year progression-free survival: 47.2% vs. 21.6%, P=0.006; and 2-year overall survival (OS): 58.3% vs 24.3%, P=0.003] with similar safety profiles. Independent of treatment type, patients classified as "fit" and "intermediate" by CGA presented with better OS compared to patients classified as "frail" (P<0.001). Patients classified as "fit" and "intermediate" who were receiving curative treatments presented with a significantly better OS when compared with those treated conservatively on the basis of clinical judgment. A curative anthracycline-based therapy (P=0.048), the response to treatment (P=0.017) and a "frail" condition (P=0.031) were the only factors affecting OS in multivariate analysis. CONCLUSIONS: Present data indicates that even in elderly patients with B-NHL curative anthracycline-based therapies are more effective than conservative approaches. However, choice of treatment should rely more on objective than on subjective parameters. Therefore, further prospective trials are warranted to better define the CGA role in hematopoietic malignancies.