Acute GVHD classification based on the dynamics of GVHD skin involvement from its appearance to the start of systemic treatment.

We conducted a prospective study aimed at investigating the prognostic value of the dynamic of a-GVHD progression from cutaneous to visceral involvement. In 108 consecutive patients who underwent allogeneic HSCT, we classified a-GVHD according to a "GHVD skin dynamic": 18/82 patients started Corticosteroid (CS) within 48 h (Group 1); 13/82 started CS within days 3-7 (Group 2); Group 3A (n 31) was defined when Skin GVHD Overall Grade 1, left untreated for 1 week, showed an increase in involved body surface area <5 %; Group 3B (n 20), was defined when Skin GVHD Overall Grade 1, left untreated at 1 week, had an increase in involved body surface area >5%. These four groups had distinctive 2-y OS. Patients could be then grouped into "poor risk" (Group 1 and Group 3B) and "good risk" (Group 2 and Group 3A). "Poor risk" had inferior OS in univariate and multivariate analysis, (HR 2.222; 95% CL: 1.017-4.855; p 0.04). Among the patients with skin-only Grade 1 GVHD, subgroup 3A had an OS of 75.1% versus 39.8% found in subgroup 3B (p = 0.03). The dynamic of skin GVHD may be used to classify a-GVHD and guide treatment in Overall Grade 1 skin-only GVHD.

Transient Leukemoid Reaction from T-Cell Large Granular Lymphocytes Post Autologous Stem Cell Transplant in a Patient Affected by Hodgkin Lymphoma.

Monoclonal T-cell lymphocytosis has been reported in patients with concomitant autoimmune diseases, viral infections, or immunodeficiencies. Referred to as T-cell large granular lymphocytic leukemia (T-LGLL), most cases cannot identify the triggering cause. Only small case series have been reported in the literature, and no treatment consensus exists. T-cell lymphocytosis may also appear after the transplant of hematopoietic stem cells or solid organs. Rare cases have been reported in patients undergoing autologous stem cell transplant (ASCT) for hematological diseases (including multiple myeloma or non-Hodgkin's lymphoma). Here, we describe the singular case of a patient who underwent ASCT for Hodgkin's lymphoma and displayed the onset of T-LGLL with an uncommonly high number of lymphocytes in peripheral blood and their subsequent spontaneous remission.

Handheld Ultrasound or Conventional Ultrasound Devices in Patients Undergoing HCT: A Validation Study.

Abdominal ultrasound exams play a major role in the diagnosis of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD). The development of portable hand-held ultrasound devices (HHUS) has been shown to facilitate the diagnosis of many diseases, but little data on the value of HHUS in the diagnosis of SOS/VOD are available. We performed a study aimed at validating portable ultrasound (US) devices in the setting of hematopoietic stem cell transplant (HCT). Sixteen evaluable patients undergoing allogeneic HCT were studied using conventional US and HHUS during the first 3 weeks after transplant. The results obtained demonstrate that there is a close correlation between conventional and handheld ultrasound examination in the measurement of the right hepatic lobe (r = 0.912, p < 0.0001), the left hepatic lobe (r = 0.843, p < 0.0001), the portal vein (PV) (r = 0.724, p < 0.0001), and the spleen (r = 0.983, p < 0.0001) based on Pearson's correlation. The same data, analyzed through Lin's concordance correlation coefficient, evidenced a substantial level of agreement in the comparison of the spleen and right hepatic lobe, while a lower grade of agreement in the measurement of the portal vein and left hepatic lobe. Moreover, there was good agreement between results obtained by the two types of ultrasound devices in assessing ascites (p < 0.0001), gallbladder thickening (p < 0.0001), and the direction of PV flow (p < 0.0001). HHUS device allows the study of HokUs-10 parameters with an excellent agreement with conventional US, and may contribute to SOS/VOD diagnosis.

Leishmania Infection during Ruxolitinib Treatment: The Cytokines-Based Immune Response in the Setting of Immunocompromised Patients.

Ruxolitinib is a JAK1/2 inhibitor that has revolutionized the approach to myelofibrosis. On the one side, this drug can rapidly improve the symptoms related to the hematological disease; on the other side, the inhibition of JAK1/2 can lead to immunosuppression which may increase the risk of infections, due to a change in the cytokine balance in favor of anti-inflammatory cytokines, to direct inhibition of immune cells, and to the suppression in the production of specific antibodies. In this patient setting, much is known about possible viral and bacterial infections, while little is reported in the literature concerning parasitic infections, specifically leishmaniasis. Leishmania is a parasitic infection that can cause serious problems in immunosuppressed patients. The parasite can invade the bloodstream and cause a wide range of symptoms, including fever, weight loss, and anemia. In severe cases, it can lead to multi-organ failure and, rapidly, death. Early diagnosis and prompt treatment are essential especially for these patients, unable to respond adequately. In this case and the following review of the existing literature, the cytokine kinetics and the production of specific anti-Leishmania antibodies represent characteristic aspects capable of providing a more in-depth understanding of the mechanisms underlying these complex clinical cases in an immunocompromised patient.

Combination of Interleukin-6, C-Reactive Protein and Procalcitonin Values as Predictive Index of Sepsis in Course of Fever Episode in Adult Haematological Patients: Observational and Statistical Study.

Haematological patients represent a vulnerable population to opportunistic infections, mainly due to the disease itself and chemotherapy-induced neutropenia. The level of immune suppression strongly increases the importance of timely antibiotic treatment in order to prevent sepsis-related mortality. During the initial fever episode, serum biomarkers are usually used to estimate the probability of blood stream infection prior to the results of microbial diagnosis. A new serum biomarker combination study on a febrile haematological population, including C-reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT), is proposed in order to improve their predictive accuracy. In our prospective study, CRP, IL-6 and PCT were evaluated in 34 immunosuppressed haematological patients immediately after the onset of 51 fever episodes, either during the course of standard chemotherapy or high-dose chemotherapy and autologous stem cell transplant. The fever episodes were divided into documented infections and fever alone. Receiver operating characteristic analysis (ROC) was performed for each biomarker and a combination of all three biomarkers (multiROC) to define a new predictive index. Significant differences were evidenced between the two groups (documented infection and no infection) for both PCT and IL-6 (p = 0.03 and p = 0.035, respectively), but none for CRP (p = 0.1). The composite parameter is more reliable than any single biomarker alone, with an area under the curve (AUC) of 79% and with high sensitivity and specificity. IL-6 gave the closest response compared to the composite index. Composite parameters of serum biomarkers could be used for an early diagnosis of infection at fever onset in haematological patients.

Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology.

Endothelial dysfunction (ED) is frequently encountered in transplant medicine. ED is an argument of high complexity, and its understanding requires a wide spectrum of knowledge based on many fields of basic sciences such as molecular biology, immunology, and pathology. After hematopoietic stem cell transplantation (HSCT), ED participates in the pathogenesis of various complications such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy (TA-TMA), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), and engraftment syndrome (ES). In the first part of the present manuscript, we briefly review some biological aspects of factors involved in ED: adhesion molecules, cytokines, Toll-like receptors, complement, angiopoietin-1, angiopoietin-2, thrombomodulin, high-mobility group B-1 protein, nitric oxide, glycocalyx, coagulation cascade. In the second part, we review the abnormalities of these factors found in the ED complications associated with HSCT. In the third part, a review of agents used in the treatment of ED after HSCT is presented.

Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives.

Allogeneic hematopoietic stem cell transplantation (HSCT) for high-risk acute myeloid leukemia (AML) represents the only curative option. Progress has been made in the last two decades in the pre-transplant induction therapies, supportive care, selection of donors and conditioning regimens that allowed to extend the HSCT to a larger number of patients, including those aged over 65 years and/or lacking an HLA-identical donor. Furthermore, improvements in the prophylaxis of the graft-versus-host disease and of infection have dramatically reduced transplant-related mortality. The relapse of AML remains the major reason for transplant failure affecting almost 40-50% of the patients. From 10 to 15 years ago to date, treatment options for AML relapsing after HSCT were limited to conventional cytotoxic chemotherapy and donor leukocyte infusions (DLI). Nowadays, novel agents and targeted therapies have enriched the therapeutic landscape. Moreover, very recently, the therapeutic landscape has been enriched by manipulated cellular products (CAR-T, CAR-CIK, CAR-NK). In light of these new perspectives, careful monitoring of minimal-residual disease (MRD) and prompt application of pre-emptive strategies in the post-transplant setting have become imperative. Herein, we review the current state of the art on monitoring, prevention and treatment of relapse of AML after HSCT with particular attention on novel agents and future directions.

The Impact of Graft CD3 Cell/Regulatory T Cell Ratio on Acute Graft-versus-Host Disease and Post-Transplantation Outcome: A Prospective Multicenter Study of Patients with Acute Leukemia Undergoing Allogeneic Peripheral Blood Stem Cell Transplantation.

Although it is well known that tumor site- or bone marrow-infiltrating regulatory T cells (Tregs) might be correlated with worse outcomes in solid tumors and acute leukemias by promoting immune surveillance escape, their contribution to the immediate post-allogeneic transplantation phase by peripheral blood (PB) allografts remains unclear. Moreover, the Treg content in stem cells harvested from PB has been suggested to be correlated with acute graft versus-host-disease (aGVHD) and immunologic recovery after allogeneic PB stem cell transplantation (allo-PBSCT). This study aimed to investigate the impact of the graft content of Tregs, as graft CD3+/Tregs ratio (gCD3/TregsR), on acute GVHD and post-allo-PBSCT outcomes. We prospectively enrolled 94 consecutive patients at 9 Italian centers of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) with acute myelogenous (n = 71; 75%) or lymphoblastic (n = 23; 25%) leukemia in complete remission who underwent matched related donor (n = 35; 37%) or unrelated donor (n = 59; 63%) allo-PBSCT. The median graft CD3+ cell, Treg, and gCD3/TregsR values were 196 × 106/kg body weight (range, 17 to 666 × 106/kg), 3 × 106/kg (range, 0.1 to 35 × 106/kg), and 71 (range, 1 to 1883), respectively. The discriminatory power of the gCD3/TregsR value to predict grade ≥II aGVHD was assessed by estimating the area under the receiver operating characteristic (ROC) curve (AUC). Any grade and grade ≥II aGVHD occurred in 24 (26%) and 17 (18%) allo-PBSCT recipients, respectively. By ROC analysis, AUC (0.74; 95% confidence interval [CI], 0.608 to 0.866; P = .002) identified 70 as the optimal gCD3/TregsR cutoff value predicting the appearance of grade ≥II aGVHD with 76% sensitivity and 71% specificity. Patients were subdivided into a high (ROC curve value ≥70) gCD3/TregsR group (HR; n = 48) and a low (ROC curve value <70) gCD3/TregsR group (LR; n = 46). The incidence of grade II-IV aGVHD was lower in the LR group compared with the HR group (9% [4 of 46] versus 27% [13 of 48]) in both univariate analysis (odds ratio [OR], 4.8; 95% CI, 1.44 to 16.17; P = .015) and multivariate analysis (OR, 5.0; 95% CI, 1.34 to 18.93; P = .017), whereas no differences were documented taking into account aGVHD of any grade. The overall survival, disease-free survival, nonrelapse mortality, and relapse rates at 2 and 3 years were 61% and 54%, 62% and 55%, 15% and 23%, and 27% and 30%, respectively. Of note, gCD3/TregsR did not significantly correlate with relapse (P = .135). Taken together, our data from this prospective multicenter study confirm the value of Tregs in preventing aGVHD while maintaining the graft-versus-leukemia effect. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

The role of ponatinib in adult BCR-ABL1 positive acute lymphoblastic leukemia after allogeneic transplantation: a real-life retrospective multicenter study.

The experience of third-generation tyrosine kinase inhibitor ponatinib treatment in Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph'+ ALL) patients post-allogeneic transplantation is limited. We retrospectively collected data on 25 Ph'+ ALL patients who were started on ponatinib after allogeneic transplantation between July 2015 and July 2019 from nine transplantation centers in Italy. Ponatinib was given in prophylaxis in five (20%), as pre-emptive treatment in seven (28%), and as salvage therapy in thirteen (52%) patients. It was combined with donor leukocyte infusions in ten patients. Half of the patients (12/25) harbored T315I mutation of BCR/ABL1, while in the remaining mutational analysis was negative or not performed. Among the 20 patients who received ponatinib as pre-emptive/salvage treatment, complete molecular response was achieved in 15 (75%) patients. Estimated overall survival at 2-year post-initiation of treatment in the whole cohort was 65% (respectively 60%, 60%, and 78% for the prophylaxis, pre-emptive, and salvage therapy groups). In patients with T315I-positive mutational status, the estimated 2-year survival was 40%. Fourteen patients (56%) experienced toxicity, requiring temporary or definitive suspension of treatment. In conclusion, treatment of Ph'+ ALL patients with ponatinib after transplantation is effective, although the question of adequate drug dose and treatment duration remains unanswered.

Low content of clonogenic progenitors on day+18 is associated with acute graft-versus-host disease and predicts transplant-related mortality.

A marrow reaction associated with acute-graft-versus-host disease (a-GVHD) has been demonstrated in experimental models; its existence in human transplantation is controversial. The aim of the present study was to investigate whether clonogenic marrow precursors are an early marker for a-GVHD and transplant-related mortality (TRM). We prospectively studied 133 patients for colony-forming units-granulocyte-monocyte (CFU-GM) at day +18/+19 posttransplantation. CFU-GM frequency below the 25th percentile was predictive of an acute GVHD score I°-IV° when evaluated in multivariate logistic regression analysis (odds ratio = 13.551, 95% confidence interval [CI]: 1.583-116.031, p = 0.01). In the group with a clonogenic frequency below the 25th percentile, the cumulative incidence of GVHD grades II-IV was significantly more frequent with respect to the group with a frequency greater than the 25th percentile, 86% versus 54% (Gray test: p = 0.02). In multivariate Cox proportional analysis, a CFU-GM frequency below the 25th percentile at day +18 was associated with reduced overall survival (OS) (hazard ratio = 1.778, 95% CI: 1.022-3.093, p = 0.04). Patients with a frequency of CFU-GM greater than the 25th percentile had increased TRM with respect to patients with a clonogenic cell frequency greater than the 25th percentile (33.5% vs. 13.0%, p = 0.01). Patients were divided based on median content of viable CD34+ cells, and measurement of viable CD34+ cells was predictive for OS (p = 0.005) and TRM (p = 0.003). A weak correlation was observed between CFU-GM frequency in marrow at day +18 and levels of IL-2 receptor (IL-2R) in plasma (r = -0.226, p = 0.03). We conclude that marrow progenitor cell counts, on day +18 may be a useful marker for identifying patients at risk for severe a-GVHD, TRM, and inferior survival.

Plerixafor on-demand in association with low-dose cyclophosphamide and G-CSF in the mobilization of patients with multiple myeloma: High effectiveness, low toxicity, and affordable cost.

In CD34+ cells mobilization of patients with multiple myeloma (MM), the use of Cyclophosphamide (CTX) at a dose of 2 g/m2 has low efficacy although also lower toxicity. The suboptimal mobilizing effect of low-dose CTX, however, may be overcome by plerixafor (PLX) on demand. We conducted a prospective multicenter study in 138 patients with MM to evaluate CTX 2 g/m2 in association with granulocyte-colony stimulating factor (G-CSF) and on-demand PLX. We compared results with a historical group of MM patients (n = 138) mobilized using CTX at a dose of 4 g/m2. CD34+ cells greater than 2 × 106/kg in max three aphereses were harvested in 98.6% of patients in the on-demand PLX study group while in 84.0% in the historical group, (p = 0.0001). In the on-demand-PLX study group, a successful harvest greater than 5 × 106/kg in max three aphereses was observed in 85.5% of patients versus 62.3% of patients in the historical control group, (p=0.0001). In the on-demand-PLX study group, 4.3% (6/138) of patients had febrile complications. Salvage mobilization in the on-demand PLX study group was 1.4%. In conclusions, on-demand PLX + CTX 2 g/m2 + G-CSF 10 µg/kg has higher efficacy and lower toxicity compared with CTX 4 g/m2 + G-CSF. An analysis of costs is presented.

Preliminary Results of a Combined Score Based on sIL2-Rα and TIM-3 Levels Assayed Early After Hematopoietic Transplantation.

Assays of cytokines in the plasma at the onset of graft-vs. -host disease (GVHD) can predict disease severity and treatment-related mortality (TRM); however, the optimal time during which cytokines should be tested and the specific panel of cytokines with the highest predictive ability remain unknown. We chose a predefined time point, 18 days after hematopoietic stem cell transplantation (HSCT), to measure the levels of six cytokines in the plasma: soluble interleukin-2 receptor alpha (sIL2-Rα), T-cell immunoglobulin domain and mucin domain-3 (TIM-3), suppression of tumorigenicity-2 (ST-2), intercellular adhesion molecule (ICAM-1), interferon-gamma (IFN-γ), and interleukin-6 (IL-6). The study included 95 patients, who underwent allogeneic hematopoietic transplantation at our institution. Plasma levels of sIL2-Rα and TIM-3, measured as continuous data, had predictive value for overall survival (sIL2-Rα, p = 0.002; TIM-3, p = 0.0007), while TRM could be predicted by sIL2-Rα (p = 0.0005), IFN-gamma (p = 0.01), and IL-6 (p = 0.0001). No cytokine was associated with the risk of relapse. Patients were categorized into groups, according to cytokine thresholds determined by receiver operating characteristic curve analysis (sIL2-Rα ≤ or > 8,100 pg/ml; TIM-3 ≤ or > 950 pg/ml) and multivariate analysis was conducted. High levels of both TIM-3 and sIL2-Rα were significant predictors of poor survival [TIM-3 > 950 pg/ml: hazard ratio (HR) = 6.214 (95% CI 1.939-19.910), p = 0.002 and sIL2-Rα > 8.100 pg/ml: HR = 2.644 (95% CI 1.308-5.347), p = 0.006]. Using these cutoff thresholds, we constructed a composite scoring system that could distinguish three different groups of patients with varying rates of TRM: high risk, 41.7%; intermediate risk, 10.8%; and low risk, 7.1% (Gray's test: p = 0.001). If confirmed in a validation cohort, this composite scoring system could be used to guide the modulation of post-transplant immune suppressive therapy.