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Hemorrhagic cystitis (HC) is a highly impacting complication in allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 12%–37% of patients. The impact of transplant- and patient-specific variables has been described, with a possible role for JCV and BKV, which may be cooperating with cytomegalovirus (CMV). Here, we analyze 134 letermovir-exposed, CMV-free patients, treated with the same cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, describing risk factors for HC. The overall incidence of HC was 23%. Patients with HLA mismatched transplant, higher comorbidity score, and receiving three alkylating agents with TBF (thiotepa, busulfan, and fludarabine) conditioning regimen had a higher risk of HC in multivariate analysis (OR: 4.48, 6.32, and 1.32, respectively). A HC-score including male gender, TBF conditioning, and HLA-mismatch stratifies the risk of HC in the first 100 days after HSCT. The role of BKV and JCV was not highly impacting in those patients, suggesting a possible synergistic effect between CMV and JCV in causing HC. HC can be interpreted as the combination of patient-related factors, chemotherapy-related toxicities—especially due to alkylating agents—and immunological elements.

Flow cytometry (FCM) and quantitative PCR (qPCR) are conventional methods for assessing CAR-T expansion, while digital droplet PCR (ddPCR) is emerging as a promising alternative. We monitored CAR-T transcript expansion in 40 B-NHL patients post-infusion of CAR-T products (axi-cel; tisa-cel; and brexu-cel) with both His-Tag FCM and ddPCR techniques. Sensitivity and predictive capacity for efficacy and safety outcomes of ddPCR were analyzed and compared with FCM. A significant correlation between CAR-T counts determined by FCM and CAR transcripts assessed by ddPCR (p < 0.001) was observed. FCM revealed median CD3+CAR+ cell counts at 7, 14, and 30 days post-infusion with no significant differences. In contrast, ddPCR-measured median copies of CAR-T transcripts demonstrated significant lower copy numbers in tisa-cel recipients compared to the other products at day 7 and day 14. Patients with a peak of CAR transcripts at day 7 exceeding 5000 copies/microg gDNA, termed “good CAR-T expanders”, were more likely to achieve a favorable response at 3 months (HR 10.79, 95% CI 1.16–100.42, p = 0.036). Good CAR-T expanders showed superior progression-free survival at 3, 6, and 12 months compared to poor CAR-T expanders (p = 0.088). Those reaching a peak higher than 5000 copies/microg gDNA were more likely to experience severe CRS and ICANS. DdPCR proves to be a practical method for monitoring CAR-T expansion, providing quantitative information that better predicts both treatment outcomes and toxicity.

The various aspects of an advanced placement seminar in the history of Europe are presented. Descriptions of the high school that offers the seminar, their admissions policy, and seminar coordination are included. Thirty-six unit topics, organized in the form of a calendar of lessons and assignments also are listed, as are a number of sample essay questions that have appeared on previous advanced placement European history examinations. (DB)

Patients with acute promyelocytic leukemia (APL) often show some clinical and/or laboratory features of coagulopathy. However, the evidence of alterations in blood clotting tests seems not to correspond to clinically significant thrombotic or hemorrhagic complications in low and intermediate risk APL patients. Presentation of patients with APL is often characterized by coagulopathy.1 At diagnosis, a percentage close to 76% of APL patients have some clinical and/or laboratory features of coagulopathy, from skin or soft tissue bleedings to intracranial hemorrhage.2–3 While physicians pay attention to bleeding-related complications in APL, it is also important to note that it is not uncommon to develop thrombotic events, particularly in patients on treatment.4 Lately, the introduction of new drugs such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) allowed for reducing complications: bleeding events were predominant rather than severe thrombotic events (29% vs. 12%).5

Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by clonal proliferation of mature myeloid lineages derived from stem cells (erythrocytes, leukocytes and magakaryocytes) with variable megakaryocyte atypia associated with reticulin and / or collagen bone marrow (BM) fibrosis, osteosclerosis, ineffective erythropoiesis, angiogenesis, extramedullary hematopoiesis and abnormal expression of cytokines. Allogeneic hemopoietic stem cell transplantation (alloHSCT) is currently the only curative approach for patients with myelofibrosis, and for this reason the number of allografts for these indications have been growing over the past years. Unfortunately relapse of myelofibrosis (MF) after an alloHSCT occurs in 10-40% of cases: patients usually present with a declining donor chimerism, and a reappearance of driver mutations if present; BM biopsy is usually consistent with typical megakaryocyte abnormalities and stromal fibrosis. Ultimately BM cells exhibit progressive loss of donor chimerism, and the relapse is therefore of recipient origin. Here we report two allografted MF patients who relapsed in donor cells.

Background: Imatinib, dasatinib, and nilotinib are tyrosine kinase inhibitors (TKIs) approved in Italy for frontline treatment of chronic-phase chronic myeloid leukemia (CP-CML). The choice of TKI is based on a combined evaluation of the patient’s and the disease characteristics. The aim of this study was to analyze the use of frontline TKI therapy in an unselected cohort of Italian patients with CP-CML to correlate the choice with the patient’s features. Methods: A total of 1967 patients with CP-CML diagnosed between 2012 and 2019 at 36 centers throughout Italy were retrospectively evaluated; 1089 patients (55.4%) received imatinib and 878 patients (44.6%) received a second-generation (2G) TKI. Results: Second-generation TKIs were chosen for most patients aged <45 years (69.2%), whereas imatinib was used in 76.7% of patients aged >65 years (p <.001). There was a predominant use of imatinib in intermediate/high European long–term survival risk patients (60.0%/66.0% vs. 49.7% in low-risk patients) and a limited use of 2G-TKIs in patients with comorbidities such as hypertension, diabetes, chronic obstructive pulmonary disease, previous neoplasms, ischemic heart disease, or stroke and in those with >3 concomitant drugs. We observed a greater use of imatinib (61.1%) in patients diagnosed in 2018–2019 compared to 2012–2017 (53.2%; p =.002). In multivariable analysis, factors correlated with imatinib use were age > 65 years, spleen size, the presence of comorbidities, and ≥3 concomitant medications. Conclusions: This observational study of almost 2000 cases of CML shows that imatinib is the frontline drug of choice in 55% of Italian patients with CP-CML, with 2G-TKIs prevalently used in younger patients and in those with no concomitant clinical conditions. Introduction of the generic formulation in 2018 seems to have fostered imatinib use.

We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m2 and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II-IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; P = 0.08), while incidence of grade III-IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo (P = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; P = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% (P = 0.6), 73% versus 76% (P = 0.5), and 54% versus 53% (P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.

The current COVID-19 pandemic has placed unprecedented stress on the healthcare system, including HSCT. Several international organizations have created guidelines for managing different aspects of HSCT in the context of the pandemic. Comparing 2019 and 2020, our transplant center performed the same number of transplants. In both periods, transplants were mainly for patients with acute leukemia; thus, the urgency criteria was respected in light of pandemic restraints. Transplants by sibling donors and cord blood units remained the same, while transplants by unrelated donors were increased, in particular from European registries, and transplants by haploidentical donors were decreased. This change was made in light of the necessity of cryopreserving all apheresis products. We decided against cryopreserving bone marrow products due to the greater risk of drastic reduction in CD34 + cell count during the process. For urgent cases with only a haploidentical donor available, we opted for the use of PBSC following stimulation with G-CSF. GvHD prophylaxis was performed with PTCY on days + 3 + 5, cyclosporine with tapering from day + 100, and mycophenolic acid until day + 90 post-HSCT. Post-transplant outcomes such as graft failure, sepsis, and GVHD were not affected by the changes implemented. As a result of logistic difficulties, we halted our Car-T program from the start of the lockdown in March 2020 until September 2020. In accord with international guidelines, we were able to continue our HSCT program in the order to ensure a lifesaving treatment for patients with hematologic diseases for whom this procedure cannot be postponed.

Here, we report real-world evidence on the safety and efficacy of nilotinib as a first-line treatment in elderly patients with chronic phase CML, treated in 18 Italian centers. Sixty patients aged > 65 years (median age 72 years (65–84)) were reported: 13 patients were older than 75 years. Comorbidities were recorded at baseline in 56/60 patients. At 3 months of treatment, all patients obtained complete hematological response (CHR), 43 (71.6%) an early molecular response (EMR), while 47 (78%) reached a complete cytogenetic response (CCyR). At last follow-up, 63.4% of patients still had a deep molecular response (MR4 or better), 21.6% reached MR3 as best response and 11.6% persisted without MR. Most patients (85%) started the treatment at the standard dose (300 mg BID), maintained at 3 months in 80% of patients and at 6 months in 89% of them. At the last median follow-up of 46.3 months, 15 patients discontinued definitively the treatment (8 due to side effects, 4 died for unrelated CML causes, 1 for failure, 2 were lost to follow-up). One patient entered in treatment-free remission. As to safety, 6 patients (10%) experienced cardiovascular events after a median time of 20.9 months from the start. Our data showed that nilotinib could be, as first-line treatment, effective and relatively safe even in elderly CML patients. In this setting, more data in the long term are needed about possible dose reduction to improve the tolerability, while maintaining the optimal molecular response.

Microbiota changes during allogeneic hematopoietic stem cell transplantation has several known causes: conditioning chemotherapy and radiation, broad-spectrum antibiotic administration, modification in nutrition status and diet, and graft-versus-host disease. This article aims to review the current knowledge about the close link between microbiota and allogeneic stem cell transplantation setting. The PubMed search engine was used to perform this review. We analyzed data on microbiota dysbiosis related to the above-mentioned affecting factors. We also looked at treatments aimed at modifying gut dysbiosis and applications of fecal microbiota transplantation in the allogeneic stem cell transplant field, with particular interest in fecal microbiota transplantation for graft-versus-host disease (GvHD), multidrug-resistant and clostridium difficile infections, and microbiota restoration after chemotherapy and antibiotic therapy.

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Introduction: In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR. Methods: CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation. Results: After a median observation time of 33 months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4 months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found (p = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib (p = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss. Discussion: Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during

CD4+ and CD8+ chimeric antigen receptor T cells (CAR-T) play different roles in the in vivo anti-tumour response, but the role of the CD4+/CD8+ ratio among infused CAR-T has not been clearly defined yet. We analysed leftovers from infused anti-CD19 CAR-T bags of 31 patients with aggressive B-cell lymphomas. The median ratio was 1.44, lower for brexu-cel compared to tisa-cel and axi-cel. The CAR+CD4+/CD8+ ratio was influenced by lactate dehydrogenase levels at apheresis, not by age, previous treatments or the CD4+/CD8+ ratio in peripheral blood. Patients with a response at 3 months after CAR-T (M3) had a lower CAR+CD4+/CD8+ ratio in the infused products compared to non-responders (ratio 0.74 vs. 2.47, p = 0.011). A CAR+CD4+/CD8+ ratio higher than the cut point of 1.12 was associated with an increased risk of treatment failure at M3 (OR 23.3, p = 0.012) and M6 (OR 10, p = 0.028). The median 6-month PFS was 76% for patients with a ratio lower than 1.12% vs. 31% for the others. The prognostic role of the CAR+CD4+/CD8+ ratio was independent of the costimulatory domain (CD28 vs. 4-1BB) of the product (OR 16.41, p = 0.041). Our data indicate a crucial role for CD8+ CAR-T and the CAR+CD4+/CD8+ ratio in predicting CAR-T efficacy.

Chronic lymphocytic leukemia (CLL) patients have a greater predisposition to develop autoimmune complications. The most common of them is autoimmune hemolytic anemia (AIHA) with a frequency of 7–10% of cases. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity. CLL B-cells have damaged apoptosis, produce less immunoglobulins, and could be responsible for antigen presentation and releasing inflammatory cytokines. CLL B-cells can act similar to antigen-presenting cells activating self-reactive T helper cells and may induce T-cell subsets imbalance, favoring autoreactive B-cells which produce anti-red blood cells autoantibodies. Treatment is individualized and it depends on the presence and severity of clinical symptoms, disease status, and comorbidities. Corticosteroids are the standardized first-line treatment; second-line treatment comprises rituximab. Patients not responding to corticosteroids and rituximab should be treated with CLL-specific drugs as per current guidelines according to age and comorbidities. New targeted drugs (BTK inhibitors and anti BCL2) are recently used after or together with steroids to manage AIHA. In the case of cold agglutinin disease, rituximab is preferred, because steroids are ineffective. Management must combine supportive therapies, including vitamins; antibiotics and heparin prophylaxis are indicated in order to minimize infectious and thrombotic risk.

Infusion-related reactions are among the worst complications of obinutuzumab (G) administration and occur predominantly during the first infusion. We reported another adverse event related to the first G infusion, a subclinical coagulopathy. We retrospectively analyzed a cohort of 13 pts with chronic lymphocytic leukemia treated with a frontline G-chlorambucil regimen. Six pts developed non-overt disseminated intravascular coagulopathy (DIC) (46%) after the first administration of G. The coagulopathy was subclinical and self-limited in all pts, not requiring any intervention apart from the suspension of anticoagulant therapy in one pt. We observed a drop in the platelet count, an elevation of D-dimer levels, and an elongation of activated partial thromboplastin time. We found a significant difference in the platelet count between the pts with DIC and those withouts; in fact, all the six pts with non-overt DIC had a platelet count greater than 100 × 109/L, while in the other group only one (p = 0.019). A trend towards a lower lymphocyte count and a higher CD20 expression was found in the pts with DIC. No other correlation between the DIC complication and the clinical or laboratory characteristics of the patients was found. The pathogenesis of the G-related non-overt DIC could be related to the consumption of the platelets after the lysis of lymphocytes, probably triggered by the damage associated molecular patterns. Despite its limitations, this study describes a new adverse event and identifies a specific subgroup of patients whose clinical management at the time of the infusion of G may need to be refined.

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

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Secondary antibody deficiency (SAD) is a frequent manifestation of chronic lymphocytic leukemia (CLL) that increases the risk of infections. However, no formal guideline are available regarding the eligibility for prophylaxis or the delivery method, dosage, frequency of administration and duration of immunoglobulin replacement therapy (IgRT). The aim of this study was to assess the efficacy and safety of subcutaneous IgRT (SCIg) and its impact on quality of life (QoL) of CLL pts in the Covid-19 era. Ten CLL pts with SAD were treated with subcutaneous IgRT (SCIg) at our institution between October 2019 and December 2020. Median age was 66 years and five patients had comorbidities. Seven patients were receiving therapy for CLL when treatment with SCIg was initiated. All pts received 10 g total dose hyaluronidase-free SCIg independently from body weight. The IgG level and CD4/CD8, CD19 and CD16/56 lymphocytes subset were recorded at baseline and every 3 months. No patient experienced infectious events nor Covid-19 mediated interstitial pneumonia while on SCIg therapy. All patients tolerated well the therapy and experienced an increase of IgG levels, which was then stable in time. We conclude that SCIg administration in CLL pts with SAD is efficacious and safe as infectious prophylaxis. This route of administration appears particularly advantageous in the Covid-19 era, because of the self-administration at home which results in improvement in the QoL and reduced treatment expenditures.

The aim of this review is to update the current status of allogeneic hemopoietic stem cell transplants (HSCT) for patients with myelofibrosis (MF). We have first summarized the issue of an indication for allogeneic HSCT, discussing several prognostic scoring systems, developed to predict the outcome of MF, and therefore to identify patients who will benefit of an allogeneic HSCT. Patients with low risk MF are usually not selected for a transplant, whereas patients with intermediate or high risk MF are eligible. A separate issue, is how to predict the outcome of HSCT: we will outline a clinical molecular myelofibrosis transplant scoring system (MTSS), which predicts overall survival, ranging from 90% for low risk patients, to 20% for very high risk patients. We will also discuss transfusion burden and spleen size, as predictors of transplant outcome. The choice of a transplant platform including the conditioning regimen, the stem cell source and GvHD prophylaxis, are crucial for a successful program in MF, and will be outlined. Complications such as poor graft function, graft failure, GvHD and relapse of the disease, will also be reviewed. Finally we discuss monitoring the disease after HSCT with donor chimerism, driver mutations and hematologic data. We have made an effort to make this review as comprehensive and up to date as possible, and we hope it will provide some useful data for the clinicians.

Background and Objectives: While tyrosine kinase inhibitors (TKIs) have transformed CP-CML management, limited data exist on their use in clinical practice. Methods: SIMPLICITY (NCT01244750) is an observational study in CP-CML patients, exploring first-line (1L) TKI use and management patterns in the US and Europe. Over half of the patients recruited in Europe are from Italy (n=266). This is an analysis of the Italian cohort and a comparison with the rest of the European SIMPLICITY population. Baseline demographic, factors influencing the choice of first-line TKI, response monitoring patterns and predictors of monitoring, and treatment interruptions, discontinuations and switching by index TKIs are presented for the Italian cohort in the first year of treatment and compared with that for the overall European SIMPLICITY cohort. Results: Italian patients received 1L imatinib (IM; retrospective [(n=31]; prospective [n=106]), dasatinib (DAS; n=56) or nilotinib (NIL; n=73). Documented cytogenetic response monitoring by 12 months was lower than expected, but almost all patients had documented molecular response monitoring. Fewer patients discontinued first-line TKI by 12 months in Italy compared with the rest of the European SIMPLICITY population (p=0.003). Of those with ≥12 months follow-up since the start of 1L TKI, only 7.1% (n=19) of Italian patients switched to a second-line TKI, a third less than in the rest of the European SIMPLICITY population. Of interest, intolerance as opposed to resistance, was the main reason for switching. Conclusions: This analysis provides valuable insights into management and treatment patterns in Italian patients with CML within routine clinical practice.

It is judged safe to discontinue treatment with tyrosine kinase inhibitors (TKI) for chronic myeloid leukemia (CML) in experimental trials on treatment-free remission (TFR). We collected a total of 293 Italian patients with chronic phase CML who discontinued TKI in deep molecular response. Seventy-two percent of patients were on treatment with imatinib, and 28% with second generation TKI at the time of discontinuation. Median duration of treatment with the last TKI was 77 months [Interquartile Range (IQR) 54;111], median duration of deep molecular response was 46 months (IQR 31;74). Duration of treatment with TKI and duration of deep molecular response were shorter with second generation TKI than with imatinib (P<0.001). Eighty-eight percent of patients discontinued as per clinical practice, and reasons for stopping treatment were: toxicity (20%), pregnancy (6%), and shared decision between treating physician and patient (62%). After a median follow up of 34 months (range, 12-161) overall estimated TFR was 62% (95%CI: 56;68). At 12 months, TFR was 68% (95%CI: 62;74) for imatinib, 73% (95%CI: 64;83) for second generation TKI. Overall median time to restart treatment was six months (IQR 4;11). No progressions occurred. Although our study has the limitation of a retrospective study, our experience within the Italian population confirms that discontinuation of imatinib and second generation TKI is feasible and safe in clinical practice

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Acute promyelocytic leukemia is a variant of acute myeloid leukemia characterized by t(15;17) and PML/RAR alfa fusion gene. The discovery of the molecular pathogenesis has led to entitle all-trans retinoic acid (ATRA) as the first targeted therapy for acute leukemia. It is usually associated to anthracycline-based chemotherapy with high response rates, but potential long-term sequelae including therapy-related malignancies have been observed. Arsenic trioxide (ATO) was added to obviate these complications and investigational trials aimed to a new strategy with the incorporation of arsenic trioxide (ATO) into initial therapy instead of chemotherapy in selected patients. ATRA plus ATO without chemotherapy was the first attempt to treat low and intermediate-risk patients with APL. Our study aims to describe a monocentric cohort of patients with newly diagnosed APL effectively treated with ATO plus ATRA underlying its efficacy together with the high grade of tolerability of this association. From January 2009 to December 2019 23 APL patients were diagnosed and treated with ATO plus ATRA regimen: 14 males and 9 females patients with a median age of 45 years (range 18-72), for the majority intermediate risk (15 patients, 65%). The treatment was well tolerated and all patients achieved molecular remission after a median time of 3 months (range 1-6 months). All patients proceeded to consolidation phase as outpatients, they maintained complete molecular response at a median time of 44 months (range 15-127) except for 1 patient. All but one patient are alive and in response at a median follow-up of 48 months (range 9-141) without late effects. ATO plus ATRA regimen shows advantages in comparison to chemotherapy; in fact it allowed to treat patients in which chemotherapy could even not be applicable and it did not show secondary hematological diseases. The association of ATO to ATRA as chemo-free regimen enabled to treat APL even without chemotherapy.

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This retrospective study assessed the effectiveness of eltrombopag (EPAG), a thrombopoietin receptor agonist, in the treatment of poor graft function (PGF) following an allogeneic haemopoietic stem cell transplantation (HSCT). Complete response was defined as normalization of blood counts, whereas partial response was defined as transfusion independence. A total of 48 patients with full donor chimerism after HSCT, received EPAG for a median of 120 days (range 10–591). Patients with uni- bi- or tri-lineage cytopenia started treatment at a median of 95 days (range 17–877) after HSCT. The overall response rate was 75%: 24 patients had a complete response and 12 had a partial response. Positive predictors of response were an HLA-matched donor, a CD34+ dose at transplant > 4 × 106/kg, and starting EPAG treatment at least 90 days after HSCT. Patients with more than one positive predictor had a response rate of 92% for the overall patient cohort and 94% for patients with tri-lineage cytopenia. One-year survival was 89% for complete responders, 60% for partial responders and 20% for non-responders (p = 0.0004). EPAG improves peripheral blood counts in patients with poor graft function following HSCT. Response to EPAG can be predicted and has a significant impact on survival.

We report the outcome of 19 patients who experienced primary graft failure (PrGF) after a haploidentical (HAPLO), unmanipulated bone marrow transplant. The median age of patients was 52 years; the conditioning regimen of the first HAPLO transplant was either full dose total body irradiation (TBI) or fludarabine, busulfan, and thiotepa (TBF); PTCY was given to all patients together with cyclosporine and mycophenolate. All 19 patients with PrGF received a second HAPLO graft, at a median interval of 42 days (34–82) after HSCT, using the Baltimore protocol and G-CSF mobilized PB from the same (n = 13) or another HAPLO family donor (n = 6). GvHD prophylaxis was again PTCY-based; 14/19 patients had trilineage recovery (74%) and 1-year survival was 66%. Engraftment at second HAPLO was seen in 7/8 patient with, and in 5/7 patients without donor-specific antibodies (DSA). In a multivariate logistic regression analysis on the original group of 503 patients, there was a trend for a reduced dose of busulfan, to increase the risk of PrGF (p = 0.1). In conclusion, patients with PrGF following a HAPLO transplant, can be rescued with a second early HAPLO transplant, using the same or a different donor.

The aim of this retrospective study was to assess the rate of full donor chimerism (F-DC) in patients with myelofibrosis, prepared for an allogeneic stem cell transplant, with one or two alkylating agents. We analyzed 120 patients with myelofibrosis, for whom chimerism data were available on day +30. There were two groups: 42 patients were conditioned with one alkylating agent (ONE-ALK), either thiotepa or busulfan or melphalan, in combination with fludarabine, whereas 78 patients were prepared with two alkylating agents, thiotepa busulfan and fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years), were less frequently splenectomized pre-HSCT (31% vs 59%), had more frequently intermediate-2/high DIPSS scores (90% vs 74%), were grafted more frequently from alternative donors (83% vs 33%) and received more frequently ruxolitinib pre-HSCT (26% vs 7%). The proportion of patients with F-DC on day +30, in the TBF vs the ONE-ALK group, was respectively 87% vs 45% (P <.001). The 5-year cumulative incidence of relapse was 9% in the TBF group, vs 43% for the ONE-ALK group (P <.001). The 5-year actuarial disease-free survival was 63% for TBF and 38% for the ONE-ALK group (P =.004). In conclusion, early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis, undergoing an allogeneic HSCT. The combination of two alkylating agents in the conditioning regimen, provides a higher chance of achieving full donor chimerism on day+30, and thus a higher chance of long term disease free survival.

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We have studied the number of days alive outside the Hospital (DAOH) and the number of readmissions within the first 100 days after transplant in 185 patients who received an allogeneic hemopoietic stem cell transplant (HSCT). The donors were matched siblings (SIB; n=61), or alternative donors (ALT; n=124). The median number of DAOH for SIB transplants (78 days, range 21-84) was significantly greater than DAOH for ALT donor grafts (73 days, range 2-87) (p=0.0003). Other positive predictors of DAOH were the use of reduced-intensity regimens (p=0.01), grade 0-I acute graft versus host disease (GvHD) (p=0.0006), and a comorbidity index equal or less than two (p=0.04). Fifty-one patients required readmission (22%), which was predicted by grade II-IV acute GvHD (p=0.009), higher comorbidity index (p=0.06), and ALT donors as compared to SIBS (p=0.08). The CI of readmission was 18% (95%CI 10-31) for SIB and 30% (95%CI 23-39) for ALT donor grafts. The non relapse mortality (NRM) for patients readmitted was 25% (95%CI 15-43%), compared to 5% (95%CI 2-12%) for patients not readmitted (p=0.0001). In a multivariate analysis, readmission was the strongest predictor of non-relapse mortality (NRM) (HR 2.0) (p=0.0006) and survival (HR 3.4) (p<0.0001). In conclusion: ALT donor transplants have lower numbers of DAOH, as compared to SIB grafts, which implies longer stay in hospital and higher costs. Readmission to hospital within 100 days, is predicted by acute GvHD, comorbidity index, donor type, and has a significant strong impact on non-relapse mortality and survival.

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his is a multicenter retrospective comparison of 2 myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days) and fludarabine (BUFLU) versus thiotepa, busulfan, and fludarabine (TBF). Eligible for this study were patients allografted between January 2008 and December 2018 in 10 transplant centers, with AML in first or second remission: 201 patients received BUFLU, whereas 253 received TBF. The 2 groups (BUFLU and TBF) were comparable for age (P = .13) and adverse AML risk factors (P = .3). The TBF group had more second remissions and more haploidentical grafts. The donor type included HLA-identical siblings, unrelated donors, and family haploidentical donors. The 5-year cumulative incidence of nonrelapse mortality (NRM) was 19% for BUFLU and 22% for TBF (P = .8), and the 5-year cumulative incidence of relapse was 30% and 15%, respectively (P = .0004). The 5-year actuarial survival was 51% for BUFLU and 68% for TBF (P = .002). In a multivariate Cox analysis, after correcting for confounding factors, the use of TBF reduced the risk of relapse compared with BUFLU (P = .03) and the risk of death (P = .03). In a matched pair analysis of 108 BUFLU patients matched with 108 TBF patients, with the exclusion of haploidentical grafts, TBF reduced the risk of relapse (P = .006) and there was a trend for improved survival (P = .07). Superior survival of patients receiving TBF as compared with BUFLU is due to a reduced risk of relapse, with comparable NRM. The survival advantage is independent of donor type and AML risk factors.

The occurrence of both lymphoproliferative disorder and breast cancer is a rare event. While the condition of coexistence of lymphoma and breast carcinoma has been described in the lymph nodes [1] and in the spleen [2], no reports have been published concerning the same association in the bone. When there is a clinical suspicion that there may be a concurrence of diseases, radiological exams are carried out but the diagnosis requires histological confirmation with either biopsy or aspiration [3].