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The occurrence of acute myeloid leukemia (AML) within six months from a diagnosis of breast cancer (BC) is rarely reported in the literature, and it is associated with a poor prognosis. We report herein the case of a 40-year-old woman referred to our centre affected by BC and simultaneous AML. The patient proved refractory to first line therapy and achieved complete remission (CR) with a clofarabine-based regimen followed by allogeneic stem cell transplantation (ASCT). Both during salvage chemotherapy and after ASCT, the patient presented severe infectious complications ( acute cholecistytis and Nocardia pneumonia, respectively) treated with surgery, and currently she is alive in CR for both diseases after 29 months of follow-up. The case highlights the importance of a diagnostic assessment of any unexplained cytopenia in association with solid neoplasia under treatment, underlining the feasibility and priority of a timely treatment of the haematological neoplasm in order to achieve long-term survival.

A comprehensive analysis of 220 patients diagnosed with APL between 1993 and 2022 is here reported. Overall, 214 patients (97.2%) received induction therapy. Complete response (CR) was achieved in 97.4%, 100%, 100%, and 27% of patients treated with AIDA protocol, AIDA + Ara-C, ATRA + ATO, and ATRA monotherapy, respectively. Molecular complete response (CR MRD -) was achieved in 96.8% cases, and 142 patients proceeded to maintenance therapy. Overall, the 3-year and 5-year overall survival (OS) rates were 80.8% (95% CI, 78.1-83.5) and 79.1% (95% CI, 76.4-81.8), respectively. Considering only patients who completed induction and maintenance therapy, the 5-year OS rates were 82.1% (95% CI, 77.5-86.7) for the AIDA0493 cohort, 87.5% (95% CI, 84.4-91.1) for the AIDA2000 cohort, and 100% for the APL0406 cohort (p = 0.044). Additionally, the disease-free survival (DFS) rates were 65.7% (95% CI, 60.4-70.9), 70% (95% CI, 65.8-75.2), and 95.1% (95% CI, 91.7-98.5) (p = 0.016), respectively. Among low and intermediate-risk patients, age > 70 years (p = 0.027) and relapse (p < 0.001) were significantly associated with reduced outcomes. This study contributes to the advancement of our understanding of APL treatment, underscoring the ongoing need for research to enhance outcomes and explore new therapeutic approaches and prognostic factors., Competing Interests: Declarations. Informed consent: obtained. Clinical trial registration: Not applicable. Competing interests: Massimo Breccia (corresponding author) is an Editor of the journal Annals of Hematology., (© 2024. The Author(s).)

Background: The introduction of all- trans retinoic acid (ATRA) and arsenic trioxide (ATO) has radically improved the prognosis of acute promyelocytic leukemia (APL), with cure rates above 80%. While relapse occurs in less than 20% of cases, addressing this issue remains challenging. Identifying effective salvage therapies for relapsed APL is crucial to improve patient outcomes., Methods: A retrospective analysis was performed on a multicentric cohort of 67 APL patients in first relapse, treated in three Italian hematology centers from June 1981 to November 2021. The overall survival (OS) and cumulative incidence of relapse (CIR) were calculated, and predictive factors were assessed using Cox regression models., Results: Overall, 61 patients (91%) received ATO ± ATRA (40.3%), chemo-based regimens (40.3%), or ATRA ± Gemtuzumab ozogamicin (GO) (10.4%). Complete remission (CR) was achieved in 98.2% of patients (molecular CR, n = 71.4%). With a median follow-up time of 54.5 months, the 5-year OS was 73% in the ATO ± ATRA group, 44% in the chemo-based group, and 29% in the ATRA ± GO group ( p = 0.035). The 5-year OS rate was also higher for transplant recipients vs. non-recipients within the chemo-based cohort (50% vs. 33%, p = 0.017), but not in the ATO-based cohort ( p = 0.12). ATO-based salvage therapy resulted in better OS in both univariate ( p = 0.025) and multivariate analyses ( p = 0.026). The 2-year CIR was higher in patients without molecular CR vs. patients in molecular CR (66% vs. 24%, p = 0.034). Molecular CR was a significant predictor of second relapse in both univariate ( p = 0.035) and multivariate analyses ( p = 0.036)., Conclusions: Our findings support the efficacy of ATO-based therapies in first relapse of APL and confirm the achievement of molecular remission as an independent outcome predictor in both first and second APL relapse.

We analyzed 140 patients with a median age of 51 years; 21% had WBC ≥ 100 × 10 9 /L, and 52% had an NPM1 co-mutation. Until 2018, 101 patients received chemotherapy; thereafter, 39 received 3+7+midostaurin. The overall CR rate was 64%, higher in NPM1 mutant patients (73%). Univariate analysis showed that NPM1 mutation ( p = 0.032) and WBC < 100 × 10 9 /L ( p = 0.013) positively influenced the response, with a trend for FLT3i administration ( p = 0.052). Multivariate analysis confirmed WBC count as an independent prognostic factor ( p = 0.017). In CR1, 41/90 patients underwent allogeneic and 18 autologous transplantation. The median EFS was 1.1 vs. 1.6 years in autografted and allografted patients, respectively ( p = 0.9). The one-year non-relapse mortality was 0.00% for autologous and 28% for allogeneic transplants ( p = 0.007); CIR at 1 and 3 years was higher in autologous transplants (39% vs. 15% and 57% vs. 21%, p = 0.004). The median survival was not reached in the FLT3i group. Overall, 69 patients received stem cell transplantation (18 autologous, 51 allogeneic). Post-transplant FLT3i was resumed in eight patients, all alive after a median of 65 months. Allogeneic transplantation is crucial in FLT3-mutated AML, but the next challenge will be to identify which patients can benefit from transplants in CR1 and in which to intensify post-transplant therapy.

Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990-1994) to 58 years (2015-2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990-1994) to 54 (2015-2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015-2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990-1994) to 70% (2015-2021), p < 0.001, with a decrease in relapse incidence (RI) from 49% to 38%, while non-relapse mortality (NRM) remained unchanged (4%). After allo-HSCT, 3-year-OS increased from 33% (1990-1999) to 46% (2015-2021) (p < 0.001); 3-year RI remained at 39% and 1-year-NRM decreased to 19% (p < 0.001). Our data reflect advancements over 32 years and >40,000 transplants, providing insights for evaluating emerging DLBCL therapies., (© 2024. The Author(s).)

Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury due to microvascular platelet-rich thrombi. iTTP pathophysiology is based on a severe ADAMTS13 deficiency, the specific von Willebrand factor (vWF)-cleaving protease, due to anti-ADAMTS13 autoantibodies. Early diagnosis and treatment reduce the mortality. Frontline therapy includes daily plasma exchange (PEX) with fresh frozen plasma replacement and immunosuppression with corticosteroids. Caplacizumab has recently been added to frontline therapy. Caplacizumab is a nanobody that binds to the A1 domain of vWF, blocking the interaction of ultra-large vWF multimers with the platelet and thereby preventing the formation of platelet-rich thrombi. Caplacizumab reduces mortality due to ischemic events, refractoriness, and exacerbations after PEX discontinuation. Until now, the criteria for response to treatment mainly took into account the normalization of platelet count and discontinuation of PEX; with the use of caplacizumab leading to rapid normalization of platelet count, it has been necessary to redefine the response criteria, taking into account also the underlying autoimmune disease. Monitoring of ADAMTS13 activity is important to identify cases with a low value of activity (<10IU/L), requiring the optimization of immunosuppressive therapy with the addition of Rituximab. Rituximab is effective in patients with refractory disease or relapsing disease. Currently, the use of Rituximab has expanded, both in frontline treatment and during follow-up, as a pre-emptive approach. Some patients do not achieve ADAMTS13 remission following the acute phase despite steroids and rituximab treatment, requiring an individualized immunosuppressive approach to prevent clinical relapse. In iTTP, there is an increased risk of venous thrombotic events (VTEs) as well as arterial thrombotic events, and most occur after platelet normalization. Until now, there has been no consensus on the use of pharmacological thromboprophylaxis in patients on caplacizumab because the drug is known to increase bleeding risk., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Autologous stem cell transplantation (auto-HSCT) is a part of the therapeutic strategy for various oncohematological diseases. The auto-HSCT procedure enables hematological recovery after high-dose chemotherapy, otherwise not tolerable, by the infusion of autologous hematopoietic stem cells. Unlike allogeneic transplant (allo-HSCT), auto-HSCT has the advantage of lacking acute-graft-versus-host disease (GVHD) and prolonged immunosuppression, however, these advantages are counterbalanced by the absence of graft-versus-leukemia. Moreover, in hematological malignancies, the autologous hematopoietic stem cell source may be contaminated by neoplastic cells, leading to disease reappearance. In recent years, allogeneic transplant-related mortality (TRM) has progressively decreased, almost approaching auto-TRM, and many alternative donor sources are available for the majority of patients eligible for transplant procedures. In adults, the role of auto-HSCT compared to conventional chemotherapy (CT) in hematological malignancies has been well defined in many extended randomized trials; however, such trials are lacking in pediatric cohorts. Therefore, the role of auto-HSCT in pediatric oncohematology is limited, in both first- and second-line therapies and still remains to be defined. Nowadays, the accurate stratification in risk groups, according to the biological characteristics of the tumors and therapy response, and the introduction of new biological therapies, have to be taken into account in order to assign auto-HSCT a precise role in the therapeutic strategies, also considering that in the developmental age, auto-HSCT has a clear advantage over allo-HSCT, in terms of late sequelae, such as organ damage and second neoplasms. The purpose of this review is to report the results obtained with auto-HSCT in the different pediatric oncohematological diseases, focusing on the most significant literature data in the context of the various diseases and discussing this data in the light of the current therapeutic landscape., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Testi et al.)

Gemtuzumab ozogamicin (GO), is an anti-CD33 monoclonal antibody, approved for AML CD33 + , those patients with low and intermediate-risk who obtain a complete response may also be candidated for consolidation with autologous stem cell transplantation (ASCT). However, there are scant data on the mobilization of hemopoietic stem cells (HSC) after fractionated GO. We retrospectively studied data from five Italian centers and identified 20 patients (median age 54 years, range 29-69, 15 female, 15 NPM1 mutated ) that attempted HSC mobilization after fractionated doses of GO + "7 + 3" regimen and 1-2 cycles of consolidation (GO + HDAC + daunorubicin). After chemotherapy and standard G-CSF, 11/20 patients (55%) reached the threshold of 20 CD34 + /µL, and HSC were successfully harvested, while 9 patients (45%) failed. The median day of apheresis was Day + 26 from the start of chemotherapy (range 22-39 days). In good mobilizer patients, the median circulating CD34 + cells were 35.9 cells/µL and the median CD34 + harvested were 4.65 × 10 6 /kg of patients' body weight. With a median follow-up of 12.7 months, at 24 months from the first diagnosis, 93.3% of all 20 patients were alive and the median overall survival was 25 months. The 2-year RFS rate from the timepoint of the first CR was 72.6%, while the median RFS was not reached. However, only five patients underwent ASCT and achieved full engraftment.In conclusion, in our cohort of patients, the addition of GO reduced HSC mobilization and harvesting, which was reached in about 55% of patients. Nevertheless, further studies are warranted to evaluate the effects of fractionated doses of GO on HSC mobilization and ASCT outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To evaluate the benefits and safety of the empiric antibiotic treatment (EAT) active against KPC- K. pneumoniae in febrile neutropenic patients with acute leukaemia (AL) who are colonised by KPC- K. pneumoniae., Patients and Methods: A 7-year (2013-2019) retrospective observational cohort study was conducted at the Haematology, Sapienza Rome University (Italy) on 94 febrile neutropenia episodes (FNE) in AL patients KPC- K. pneumoniae carriers treated with active EAT., Results: Eighty-two (87%) FNE were empirically treated with antibiotic combinations [38 colistin-based and 44 ceftazidime-avibactam (CAZAVI)-based], 12 with CAZAVI monotherapy. Successful outcomes were observed in 88/94 (94%) FNE, 46/49 (94%) microbiologically documented infections, and 24/27 (89%) gram-negative bloodstream infections (GNB-BSI). Mortality due to infective causes was 4.2% (2.1% within 1 week). KPC -K. pneumoniae infections caused 28/94 FNE (30%) and KPC -K. pneumoniae- BSI was documented in 22 FNE (23.4%) (85% of GNB-BSI), in all cases patients received active EAT, and 21 survived. KPC -K.pneumoniae- BSI mortality rate was 4.5%. CAZAVI-based EAT showed better results than colistin-based EAT (55/56 vs 33/38, p = 0.037), overall and without EAT modification (41/56 vs 20/38, p = 0.02). Empirical combinations including CAZAVI were successful in 98% of cases (43/44 vs 33/38 for colistin-based EAT, p = 0.01), without modifications in 82% (36/44 vs 20/28, p = 0.02). All deaths occurred in patients treated with colistin-based EAT (4/38 vs 0/56, p = 0.02). CAZAVI-containing EAT was the only independent factor for an overall successful response (HR 0.058, CI 0.013-1.072, p = 0.058). Nephrotoxicity occurred in 3(8%) patients undergoing colistin-based EAT (none in those undergoing CAZAVI-based EAT, p = 0.02)., Conclusion: KPC- K. pneumoniae infections are frequent in colonised AL patients with FNE. EAT with active antibiotics, mainly CAZAVI-based combinations, was effective, safe, and associated with low overall and KPC -K. pneumoniae- BSI-related mortality., Competing Interests: Dr. A. Micozzi and Dr. G. Gentile report support for attending meetings and travelling from Pfizer and Gilead. The other authors report no conflicts of interest in this work., (© 2023 Micozzi et al.)

COVID-19 disease has a strong impact on hematological patients; those receiving autologous hematopoietic stem cell transplantation (aHSCT) represent a particularly vulnerable group, in which the effectiveness of vaccination is very variable. Chiarucci et al. showed that patients affected by non-Hodgkin lymphoma (NHL) and treated with rituximab experienced a lower rate of immunization against SARS-CoV-2 (54%), as well as significantly lower IgG antibody titers. In our multicenter retrospective observational study, we included 82 patients who underwent aHSCT, divided into two groups: 58 patients vaccinated after aHSCT (group A) and 24 vaccinated before getting transplantation (group B). In group A, 39 (67%) patients had positive serology, and the rate of positivity increased with time after aHSCT. In the subgroup of patients with NHL, the administration of rituximab predicted negative serology, particularly when administered in the 6 months before vaccination (13% response rate). Patients affected by plasma cells had a higher rate of positivity (83% overall), independently of the time to aHSCT. In group B, no patient who initially showed positive serology became negative after transplantation, so the aHSCT did not affect the response to the vaccination. Our study confirmed the role of rituximab as a negative predictor of response to SARS-CoV-2 vaccination, whereas the conditioning and transplantation procedure itself seemed to be less important., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Autore, Stirparo, Innocenti, Papa, Marchesi, Togni, Mariani, Torrieri, Salvatori, Fazio, Metafuni, Giammarco, Sora, Falcucci, Ferrari, Trisolini, Capria, Tafuri, Chiusolo, Sica and Laurenti.)

Background: Chronic kidney disease is a major public health issue, with about 13% of the general adult population and 30% of the elderly affected. Patients in the last stage of this disease have an almost uniquely high risk of death and cardiovascular events, with reduced adherence to therapy representing an additional risk factor for cardiovascular morbidity and mortality. Considering the increased penetration of mobile phones, a mobile app could educate patients to autonomously monitor cardiorenal risk factors., Objective: With this background in mind, we developed an integrated system of a server and app with the aim of improving self-monitoring of cardiovascular and renal risk factors and adherence to therapy., Methods: The software infrastructure for both the Smit-CKD server and Smit-CKD app was developed using standard web-oriented development methodologies preferring open source tools when available. To make the Smit-CKD app suitable for Android and iOS, platforms that allow the development of a multiplatform app starting from a single source code were used. The integrated system was field tested with the help of 22 participants. User satisfaction and adherence to therapy were measured by questionnaires specifically designed for this study; regular use of the app was measured using the daily reports available on the platform., Results: The Smit-CKD app allows the monitoring of cardiorenal risk factors, such as blood pressure, weight, and blood glucose. Collected data are transmitted in real time to the referring general practitioner. In addition, special reminders improve adherence to the medication regimen. Via the Smit-CKD server, general practitioners can monitor the clinical status of their patients and their adherence to therapy. During the test phase, 73% (16/22) of subjects entered all the required data regularly and sent feedback on drug intake. After 6 months of use, the percentage of regular intake of medications rose from 64% (14/22) to 82% (18/22). Analysis of the evaluation questionnaires showed that both the app and server components were well accepted by the users., Conclusions: Our study demonstrated that a simple mobile app, created to self-monitor modifiable cardiorenal risk factors and adherence to therapy, is well tolerated by patients affected by chronic kidney disease. Further studies are required to clarify if the use of this integrated system will have long-term effects on therapy adherence and if self-monitoring of risk factors will improve clinical outcomes in this population., (©Antonio Vilasi, Vincenzo Antonio Panuccio, Salvatore Morante, Antonino Villa, Maria Carmela Versace, Sabrina Mezzatesta, Sergio Mercuri, Rosalinda Inguanta, Giuseppe Aiello, Demetrio Cutrupi, Rossella Puglisi, Salvatore Capria, Maurizio Li Vigni, Giovanni Tripepi, Claudia Torino. Originally published in JMIR Bioinformatics and Biotechnology (https://bioinform.jmir.org), 15.11.2022.)

The past three decades have brought major therapeutic advances in treating acute promyelocytic leukemia (APL) both in adults and children. The current state-of-the-art treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in combination or not with chemotherapy results in long-lasting remission and cure in more than 90% of newly diagnosed patients. These treatments have made relapse a rare event. The detection of PML-RARA transcript by polymerase chain reaction (PCR) during treatment and follow-up can predict a hematological relapse. All studies have suggested a survival benefit in patients with molecular relapse given pre-emptive therapy compared with those treated at the time of overt hematological relapse. ATO-based regimens seem to be effective for achieving a second molecular complete remission (CR). Patients in second molecular CR are generally considered candidates for autologous hematopoietic stem cell transplant (HSCT), while for those with a persistent molecular disease, allogeneic HSCT should be offered if a suitable donor is identified. Except for sporadic pediatric reports, most of the evidence for using HSCT to treat relapsed/refractory APL comes from adult literature. Therefore, we now provide a review of published pediatric data that evaluated the role of HSCT in children with refractory/recurrent APL disease., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Management of patients with concomitant acute lymphoblastic leukemia (ALL) and COVID-19 infection is challenging. We describe the clinical history of a 40-year-old male with relapsed B-common ALL who developed Sars-CoV2 prior to treatment initiation with inotuzumab. Since the patient was asymptomatic for COVID-19, the first dose of inotuzumab was administered, followed by remdesivir as prophylaxis. However, a worsening in respiratory findings led to a delay in administering the following doses of inotuzumab. Interestingly, even if the patient did not receive the full inotuzumab cycle, he achieved a complete hematologic remission: furthermore, he spontaneously developed anti-sars-COV2 antibodies. COVID-19 treatment also included convalescent plasma, leading to negativization of the viral load. The patient, after COVID-19 recovery, received a second full cycle of inotuzumab, underwent allogeneic transplantation, and is currently in complete hematologic and molecular remission, in good clinical conditions, five months from allograft., Competing Interests: Competing interests: The authors declare no conflict of Interest.

The 2017 version of the European LeukemiaNet (ELN) recommendations, by integrating cytogenetics and mutational status of specific genes, divides patients with acute myeloid leukemia into 3 prognostically distinct risk categories: favorable (ELN2017-FR), intermediate (ELN2017-IR), and adverse (ELN2017-AR). We performed a post hoc analysis of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) AML1310 trial to investigate the applicability of the ELN2017 risk stratification to our study population. In this trial, after induction and consolidation, patients in complete remission were to receive an autologous stem cell transplant (auto-SCT) if categorized as favorable risk or an allogeneic stem cell transplant (allo-SCT) if adverse risk. Intermediate-risk patients were to receive auto-SCT or allo-SCT based on the postconsolidation levels of measurable residual disease as measured by using flow cytometry. Risk categorization was originally conducted according to the 2009 National Comprehensive Cancer Network recommendations. Among 500 patients, 445 (89%) were reclassified according to the ELN2017 criteria: ELN2017-FR, 186 (41.8%) of 455; ELN2017-IR, 179 (40.2%) of 445; and ELN2017-AR, 80 (18%) of 455. In 55 patients (11%), ELN2017 was not applicable. Two-year overall survival (OS) was 68.8%, 51.3%, 45.8%, and 42.8% for the ELN2017-FR, ELN2017-IR, ELN2017-not classifiable, and ELN2017-AR groups, respectively (P < .001). When comparing the 2 different transplant strategies in each ELN2017 risk category, a significant benefit of auto-SCT over allo-SCT was observed among ELN2017-FR patients (2-year OS of 83.3% vs 66.7%; P = .0421). The 2 transplant procedures performed almost equally in the ELN2017-IR group (2-year OS of 73.9% vs 70.8%; P = .5552). This post hoc analysis of the GIMEMA AML1310 trial confirms that the ELN2017 classification is able to accurately discriminate patients with different outcomes and who may benefit from different transplant strategies. This trial was registered as EudraCT number 2010-023809-36 and at www.clinicaltrials.gov as #NCT01452646., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: During the lockdown that started in Italy on 10 March 2020 to address the COVID-19 pandemic, aggressive procedures were implemented to prevent SARS-CoV-2 transmission in SARS-CoV-2-negative patients with haematological malignancies. These efforts progressively reduced Klebsiella pneumonia carbapenemase-producing K. pneumoniae (KPC-KP) spread among these patients. Here we evaluated the potential effects of measures against COVID-19 that reduced KPC-KP transmission., Patients and Methods: We analysed KPC-KP spread among 123 patients with haematological malignancies, hospitalized between March and August 2020, who were managed using measures against COVID-19. Their outcomes were compared with those of 80 patients hospitalized during the preceding 4 months (November 2019-February 2020)., Results: During March-August 2020, 15.5% of hospitalized patients were KPC-KP positive, compared with 52.5% in November 2019-February 2020 ( P  <   0.0001); 8% and 27.5% of patients in these two groups were newly KPC-KP positive, respectively ( P  =   0.0003). There were eight new KPC-KP-positive patients during January 2020 and none during June 2020. The weekly rate of hospitalized KPC-KP-positive patients decreased from 50% during March 2020 to 17% during August 2020. Four KPC-KP bloodstream infections (BSIs) were experienced by 123 patients (3%) in March-August 2020, and seven BSIs (one fatal) by 80 patients (8%) in November 2019-February 2020 ( P  =   0.02). Consumption and expense of ceftazidime/avibactam administered to KPC-KP-positive patients significantly decreased in March-August 2020., Conclusions: Aggressive strategies to prevent SARS-CoV-2 transmission were applied to all hospitalized patients, characterized by high levels of KPC-KP endemicity and nosocomial transmission. Such measures prevented SARS-CoV-2 infection acquisition and KPC-KP horizontal transmission. Reduced KPC-KP spread, fewer associated clinical complications and decreased ceftazidime/avibactam consumption represented unexpected 'collateral benefits' of strategies to prevent COVID-19., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Background: KPC-K.pneumoniae bloodstream infection (KPC-KpBSI) mortality rate in patients with hematological malignancies is reported about 60%. The initial treatment active against KPC-K.pneumoniae is crucial for survival and KPC-K.pneumoniae rectal colonization usually precedes KPC-KpBSI. We evaluated the impact on KPC-KpBSI mortality of the preemptive use of antibiotics active against KPC-K.pneumoniae, as opposed to inactive or standard empiric antibiotics, for the empiric treatment of febrile neutropenia episodes in patients with hematological malignancy identified as KPC-K.pneumoniae intestinal carriers., Methods: We compared the outcomes of KPC-KpBSIs occurring in high-risk hematological patients known to be colonized with KPC-K.pneumoniae, during two time periods: March2012-December2013 (Period 1, initial approach to KPC-K.pneumoniae spread) and January2017-October2018 (Period 2, full application of the preemptive strategy). The relative importance of the various prognostic factors that could influence death rates were assessed by forward stepwise logistic regression models., Results: KPC-KpBSI-related mortality in hematological patients identified as KPC-K.pneumoniae carriers dropped from 50% in Period 1 to 6% in Period 2 (p < 0.01), from 58 to 9% in acute myeloid leukemia carriers(p < 0.01). KPC-KpBSIs developed in patients identified as KPC-K.pneumoniae carriers were initially treated with active therapy in 56% and 100% of cases in Period 1 and Period 2, respectively (p < 0.01), in particular with an active antibiotic combination in 39 and 94% of cases, respectively(p < 0.01). The 61% of KPC-KpBSI observed in Period 1 developed during inactive systemic antibiotic treatment (none in Period 2, p < 0.01), fatal in the 73% of cases. Overall, KPC-KpBSI-related mortality was 88% with no initial active treatment, 11.5% with at least one initial active antibiotic (p < 0.01), 9% with initial active combination. Only the initial active treatment resulted independently associated with survival., Conclusions: In high-risk hematological patients colonized by KPC-K.pneumoniae, the empiric treatment of febrile neutropenia active against KPC-K.pneumoniae reduced KPC-KpBSI-related mortality to 6% and prevented fatal KPC-KpBSI occurrence during inactive systemic antibiotic treatment., (© 2021. The Author(s).)

Early recognition of Ph-like acute lymphoblastic leukemia cases could impact on the management and outcome of this subset of B-lineage ALL. To assess the prognostic value of the Ph-like status in a pediatric-inspired, minimal residual disease (MRD)-driven trial, we screened 88 B-lineage ALL cases negative for the major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2Ar) enrolled in the GIMEMA LAL1913 front-line protocol for adult BCR/ABL1-negative ALL. The screening - performed using the BCR/ABL1-like predictor - identified 28 Ph-like cases (31.8%), characterized by CRLF2 overexpression (35.7%), JAK/STAT pathway mutations (33.3%), IKZF1 (63.6%), BTG1 (50%) and EBF1 (27.3%) deletions, and rearrangements targeting tyrosine kinases or CRLF2 (40%). The correlation with outcome highlighted that: i) the complete remission (CR) rate was significantly lower in Ph-like compared to non-Ph-like cases (74.1% vs 91.5%, p=0.044); ii) at time point 2 (TP2), decisional for transplant allocation, 52.9% of Ph-like cases vs 20% of non-Ph-like were MRD-positive (p=0.025); iii) the Ph-like profile was the only parameter associated with a higher risk of being MRD-positive at TP2 (p=0.014); iv) at 24 months, Ph-like patients had a significantly inferior event-free and disease-free survival compared to non-Ph-like patients (33.5% vs 66.2%, p=0.005 and 45.5% vs 72.3%, p=0.062, respectively). This study documents that Ph-like patients have a lower CR rate, EFS and DFS, as well as a greater MRD persistence also in a pediatric-oriented and MRD-driven adult ALL protocol, thus reinforcing that the early recognition of Ph-like ALL patients at diagnosis is crucial to refine risk-stratification and to optimize therapeutic strategies.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (β -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

Whilst autologous stem cell transplantation (auto-SCT) is considered standard of care for relapsed/refractory classical Hodgkin lymphoma, the role of auto-SCT in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined due to limited data. We report the first study on auto-SCT for NLPHL with a larger cohort. Eligible for this retrospective registry study were patients reported to the EBMT between 2003 and 2013, aged 18 or older with relapsed/refractory NLPHL who underwent first auto-SCT with disease chemosensitive to salvage therapy. NLPHL transformed to diffuse large B cell lymphoma were excluded. Sixty patients (83% male; median age 40 years) met the eligibility criteria. The median time between diagnosis and transplant was 21 months (IQR 13-58), and the median number of prior treatment lines was 2 (range 1-5), including rituximab in 63% of the patients. At auto-SCT, 62% of the patients were in complete remission (CR) and 38% in partial remission. Seventy-two percent of the patients received BEAM as high-dose therapy. With a median follow-up of 56 months (range 3-105), 5-year progression-free and overall survival (OS) were 66% and 87%, respectively. Univariate comparisons considering age, time from diagnosis to transplant, prior chemotherapy lines, and prior rituximab use failed to identify significant predictors for any survival endpoint except for being in CR at the time of auto-SCT (vs PR, P = .049) for OS. Auto-SCT in patients with relapsed/refractory NLPHL who are sensitive to salvage therapy gives excellent disease control and long-term survival independent of the time interval between diagnosis and transplant., (© 2017 Wiley Periodicals, Inc.)

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) spread and infections in patients with haematological malignancies are a serious concern especially in endemic areas. Treatment failures and delay in appropriate therapy for CRKP infections are frequent and the mortality rate associated with CRKP bacteremia in neutropenic haematological patients is reported about 60%., Methods: Haematological patients harboring CRKP hospitalized between February 2012 and May 2013 in an Italian Teaching hospital were examined. Conditions favouring CRKP spread in a haematological unit, risk factors for bacteremia in CRKP-carriers and for CRKP bacteremia-related death were evaluated in this observational retrospective study., Results: CRKP was isolated in 22 patients, 14 (64%) had bacteremia. Control measures implementation, particularly the weekly rectal screening for CRKP performed in all hospitalized patients and contact precautions for CRKP-carriers and newly admitted patients until proved CRKP-negative, reduced significantly the CRKP spread (14 new carriers identified of 131 screened patients vs 5 of 242 after the intervention, p = 0.001). Fifty-eight percent of carriers developed CRKP bacteremia, and acute myeloid leukemia (AML) resulted independently associated with the bacteremia occurrence (p = 0.02). CRKP bacteremias developed mainly during neutropenia (86%) and in CRKP-carriers (79%). CRKP bacteremias were breakthrough in 10 cases (71%). Ten of 14 patient with CRKP bacteremias died (71%) and all had AML. The 70% of fatal bacteremias occurred in patients not yet recognized as CRKP-carriers and 80% were breakthrough. Initial adequate antibiotic therapy resulted the only independent factor able to protect against death (p = 0.02)., Conclusions: The identification of CRKP-carriers is confirmed critical to prevent CRKP spread. AML patients colonized by CRKP resulted at high risk of CRKP-bacteremia and poor outcome and the adequacy of the initial antibiotic therapy may be effective to improve survival. To limit the increase of resistance, the extensive use of antibiotics active against CRKP should be avoided, but in the setting of high CRKP pressure and high-risk CRKP-colonized haematological patients, timely empiric antibiotic combinations active against CRKP could be suggested as treatment of febrile neutropenia.

Selective splenic artery embolization (SSAE) is a nonsurgical intervention characterized by the transcatheter occlusion of the splenic artery and/or its branch vessels using metallic coils or other embolic devices. It has been applied for the management of splenic trauma, hypersplenism with portal hypertension, hereditary spherocytosis, thalassemia and splenic hemangioma. We hereby describe a case of a patient affected by idiopathic thrombocytopenic purpura (ITP) and warm auto-immune hemolytic anemia (AIHA) both resistant to immunosuppressive and biological therapies, not eligible for a surgical intervention because of her critical conditions. She underwent SSAE and achieved a hematologic complete response within a few days without complications. SSAE is a minimally invasive procedure to date not considered a standard option in the management of AIHA and ITP. However, following the progressive improvement of the techniques, its indications have been extended, with a reduction in morbidity and mortality compared to splenectomy in patients with critical clinical conditions. SSAE was a lifesaving therapeutic approach for our patient and it may represent a real alternative for the treatment of resistant AIHA and ITP patients not eligible for splenectomy.

Mucormycosis is the third cause of invasive mycosis after candidiasis and aspergillosis in AML patients, representing a poor prognostic factor associated with a high rate of fatal outcome. We report a case of a patient with AML and a concomitant pulmonary mucormycosis at diagnosis, who obtained a complete remission both of her AML and of the fungal infection. The incidence of the infection at the onset of leukemia is extremely unusual, and, to our knowledge, the sporadic cases reported in the literature are included in heterogeneous series retrospectively examined. In our case, Liposomal Amphotericin B as single agent appeared incapable of controlling the infection, so anti-infective therapy was intensified with posaconazole and simultaneously antileukemic treatment with 5-azacitidine was started, with the understanding that the only antifungal treatment would not have been able to keep the infection under control for a long time if not associated with a reversal of neutropenia related to the disease. We observed a progressive improvement of the general conditions, a healing of pneumonia and a complete remission of the leukemic disease, suggesting that a careful utilization of the new compounds available today, in terms of both antifungal and antileukemic treatment, may offer a curative chance a patient who would have otherwise been considered unfit for a potentially curative therapeutic strategy.

Background: Posaconazole is effective as primary antifungal prophylaxis of invasive fungal diseases in patients with acute myeloid leukemia., Design and Methods: The impact of primary antifungal prophylaxis administered during front-line chemotherapy for acute myeloid leukemia was evaluated by comparing 58 patients who received oral amphotericin B (control group) to 99 patients who received oral posaconazole (posaconazole group). The primary endpoint was the incidence of proven/probable invasive fungal diseases. Secondary endpoints included incidence of invasive aspergillosis, survival at 4 and 12 months after the diagnosis of acute myeloid leukemia and costs., Results: Proven/probable invasive fungal diseases were documented in 51.7% of patients in the control group and in 23.2% in the posaconazole group (P=0.0002). Invasive aspergillosis was documented in 43% of patients in the control group and in 15% in the posaconazole group (P=0.002). No survival difference was observed in patients aged over 60 years. In patients aged 60 years or less, a statistically significant survival advantage was observed at 4 months, but no longer at 12 months, in the posaconazole group (P=0.03). It was calculated that in the posaconazole group there was a mean 50% cost reduction for the antifungal drugs., Conclusions: Primary antifungal prophylaxis with posaconazole during front-line chemotherapy was effective in preventing invasive fungal diseases in a "real-life" scenario of patients with acute myeloid leukemia, resulted in an early but transitory survival advantage in younger patients and was economically advantageous.

Long-term survival of relapsed/refractory acute myeloid leukemia (AML) remains a major problem, particularly in patients not eligible for transplantation.We hereby evaluated the feasibility and efficacy of adding Gemtuzumab Ozogamicin to salvage chemotherapy (Ara-C, Idarubicine, Peg-Filgrastim) in relapsed/refractory AML. The main endpoints were: the rate of complete remissions (CR) and the proportion of patients capable of undergoing a stem cell transplant.Fourty-two patients were enrolled. The overall CR rate was 76% and no induction deaths were reported. In 56% of patients, a transplant procedure could be performed. The treatment schedule proved feasible and well tolerated, providing a high CR rate and a useful bridge to transplant.

We designed a phase 1-2 study to evaluate the safety and the efficacy of increasing doses of bendamustine (160 mg/m², 180 mg/m², and 200 mg/m² given on days -7 and -6) coupled with fixed doses of etoposide, cytarabine, and melphalan (BeEAM regimen) as the conditioning regimen to autologous stem cell transplantation for resistant/relapsed lymphoma patients. Forty-three patients (median age, 47 years) with non-Hodgkin (n = 28) or Hodgkin (n = 15) lymphoma were consecutively treated. Nine patients entered the phase 1 study; no patients experienced a dose-limiting toxicity. Thirty-four additional patients were then treated in the phase 2. A median number of 6 × 10⁶ CD34(+) cells/kg (range, 2.4-15.5) were reinfused. All patients engrafted, with a median time to absolute neutrophil count > 0.5 × 10⁹/L of 10 days. The 100-day transplantation-related mortality was 0%. After a median follow-up of 18 months, 35 of 43 patients (81%) are in complete remission, whereas 6 of 43 relapsed and 2 of 43 did not respond. Disease type (non-Hodgkin lymphomas vs Hodgkin disease) and disease status at transplantation (chemosensitive vs chemoresistant) significantly influenced DFS (P = .01; P = .007). Remarkably, 4 of 43 (9%) patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell transplantation. In conclusion, the new BeEAM regimen is safe and effective for heavily pretreated lymphoma patients. The study was registered at European Medicines Agency (EudraCT number 2008-002736-15).

Introduction: Systemic Epstein-Barr-virus-positive T cell lymphoproliferative disease of childhood is an extremely rare disorder, characterized by clonal proliferation of Epstein-Barr-virus-infected T cells with an activated cytotoxic phenotype. The disease is more frequent in Asia and South America, with only few cases reported in Western countries. A prompt diagnosis, though often difficult, is a necessity due to the very aggressive clinical course of the disease., Case Presentation: We report the clinicopathological features of fulminant T cell lymphoproliferative disease that arose in the setting of acute primary Epstein-Barr virus infection. Our patient, a 23-year-old man, presented to our facility with persisting fever, hepatosplenomegaly and severe pancytopenia. On bone marrow biopsy, an abundant lymphoid infiltrate was observed. Immunophenotypic and molecular studies revealed that the atypical lymphoid cells displayed a CD8+, Epstein-Barr-encoded-RNA-positive T cell phenotype with clonal rearrangement of the T cell receptor genes, the final diagnosis being systemic Epstein-Barr-virus-positive T cell lymphoproliferative disease. On reviewing the literature we found only 14 similar cases, all presenting with very aggressive clinical courses and requiring extensive phenotyping and molecular techniques for final diagnosis., Conclusion: Though extremely rare, this disease can occur in Europe, and a comprehensive diagnostic approach is thus recommended in all case of Epstein-Barr-virus-positive lymphoproliferative disorders. Unfortunately, at present no specific treatment is available; however, prompt administration of anti- Epstein-Barr virus treatment and rapid attempts to control the hemophagocytic syndrome are indicated.

Laboratory diagnosis of hantavirus cardiopulmonary syndrome (HCPS) in Brazil has been performed mostly by detection of IgM antibodies to recombinant antigen purified from Sin Nombre virus and Andes virus (ANDV). Recently, a recombinant nucleocapsid (rN) protein of Araraquara virus (ARAV), a Brazilian hantavirus, was obtained in Escherichia coli. To evaluate ARAV rN as antigen for antibody detection, serum samples from 30 patients from Argentina seropositive for hantavirus were tested. All samples were positive for IgG and IgM by enzyme-linked immunosorbent assay (ELISA) using either ARAV rN or ANDV rN antigens. In Brazil, six of 60 serum samples from patients with suspected HCPS (10%) were positive for IgM by ELISA using ARAV rN antigen and 7 were positive using ANDV rN antigen. For results obtained with 90 serum samples analyzed by IgM ELISA with ANDV rN antigen, the sensitivity of the IgM ELISA using ARAV rN antigen was 97.2%, the specificity was 100%, the positive predictive value was 100%, and the negative predictive value was 98.1%. The results show that ARAV rN is a suitable antigen for diagnosis of hantavirus infection in Brazil and Argentina.

The main purpose of this report is to focus on the importance of an accurate etiologic diagnosis of gastrointestinal complications during chemotherapy for acute myeloid leukemia, taking into account that a syndrome characterized by bowel wall thickening associated with diarrhea and abdominal pain may have etiologies different from neutropenic enterocolitis (NE) and in such a case necessitate a different treatment approach. We describe a case of a 46-year-old woman affected by acute myeloid leukemia presenting the onset of a syndrome with clinical features of NE. Supportive therapy for NE was instituted, but during treatment the patient presented a life-threatening gastrointestinal bleeding and was submitted in emergency to hemicolectomy. Following surgery, the patient recovered completely and she is currently alive in complete remission after receiving allogeneic bone marrow transplantation. Histological examination of the surgical specimens showed that the acute abdominal syndrome was related to massive infiltration of the bowel by leukemia cells. A correct baseline evaluation and a prompt diagnosis of the complication may help in making the therapeutic decision, which in our case led necessarily to a surgical procedure, because the bleeding was due to post-chemotherapy necrosis of the leukemic infiltrating tissue. A close collaboration between the hematologist and the surgeon may provide guidelines for behavior in such cases, giving these patients the possibility of survival and the opportunity to carry on the treatment planned for the primary disease.

Mantle cell lymphoma (MCL) is rarely cured with standard-dose chemotherapy. From January 1997 to February 2000, 28 previously untreated advanced-stage MCL patients younger than 61 years of age were treated at 9 Italian hematologic departments with 3 cycles of standard-dose debulking chemotherapy followed by a high-dose rituximab-supplemented sequence (R-HDS) including intravenous administration of high-dose cyclophosphamide, high-dose cytarabine, high-dose melphalan, and high-dose mitoxantrone plus melphalan. Study end points included toxicity, clinical and molecular response rates, long-term event-free survival (EFS), and overall survival (OS) rates, as well as the ability to harvest tumor-free peripheral blood stem cells. Optimal amounts of polymerase chain reaction-negative (PCR-negative) CD34+ cells were collected from all 20 informative patients. One patient died of toxicity. All 27 patients assessable for response achieved a complete response (CR), of which 24 remain in continuous complete remission (CCR) after a median follow-up of 35 months. Three patients had transient evidence of PCR-detectable disease in the bone marrow. The OS and EFS rates at 54 months were 89% and 79%, respectively. These results compare with the 42% OS rate and the 18% EFS rate observed in 35 age-matched historic controls treated with standard-dose chemotherapy at the participating centers. The use of rituximab in combination with high-dose chemotherapy represents a very effective in vivo purging method. The R-HDS regimen can be safely applied in a multicenter hematology setting and leads to long-term EFS and OS in the majority of patients with an otherwise incurable disease.

We have treated 20 patients, affected by acute myelogenous leukemia in advanced phase of the disease, with intravenous high-dose recombinant interleukin-2 (IL2) as induction treatment, achieving a complete remission (CR) in 11/20 of patients (55%). All CR patients were planned to receive a maintenance program with lower subcutaneous doses of IL2 until relapse. Currently, 5/11 patients are alive in continuous complete remission with a minimum follow-up of 9 years from IL2 induction. In the aim to investigate the treatment's side-effects during or after prolonged IL2 therapy, we decided to submit these patients to a clinical and immunological evaluation. Four patients have been evaluated as one, who independently stopped IL2 after 6 years, refused the check-up. No organ-specific treatment sequelae that may decrease the quality of life or may be life-threatening were found, concerning renal, liver and cardiovascular function. Endocrine abnormalities were detected in three patients, the most serious being a severe hypothyroidism, which prompted cessation of IL2 maintenance after 6 years and required thyroid supplementation treatment. Immunological studies were carried out prior to the last IL2 cycle and showed high levels of CD3-positive T cells expressing the IL2 receptor alpha chain (CD25), both in the peripheral blood and in the bone marrow. Our study shows that low-dose IL2 can be given for a prolonged period of time without serious organ-specific late sequelae and with a good quality of life.

Thrombotic thrombocytopenic purpura (TTP) is a severe disorder affecting the microcirculation of multiple organ systems. Plasma therapy has significantly reduced the mortality rate. Infections, pregnancy, cancers, drugs, and surgery were frequently associated with the initial episodes and relapses. Women who are either pregnant or in the postpartum period make up 10-25% of TTP patients, suggesting the interrelationship between TTP and pregnancy. The introduction of aggressive treatment with plasma transfusion or plasmapheresis improved maternal and fetal survival rates. We describe a case of a first successful pregnancy concomitant to a late relapse of TTP, in which the identification of important risk factors for both TTP and pregnancy allowed us easier hematological and obstetrical management. Proposed guidelines for pregnancy-related TTP management and a brief review of current treatment options for this rare condition are also included.

Bone marrow transplantation (BMT) is a sophisticated procedure consisting of the administration of high-dose chemoradiotherapy followed by intravenous infusion of hemopoietic stem cells to reestablish marrow function when bone marrow is damaged or defective. BMT is used in the treatment of solid tumors, hematologic diseases, and autoimmune disorders. Artificial nutrition, total parenteral nutrition in particular, is provided to patients undergoing BMT to minimize the nutritional consequences of both the conditioning regimens (eg, mucositis of the gastrointestinal tract) and complications resulting from the procedure (eg, graft versus host disease and venoocclusive disease of the liver). Although artificial nutrition is now recognized as the standard of care for BMT patients, defined guidelines for the use of artificial nutrition in this clinical setting are lacking. During the past 2 decades, artificial nutrition in BMT patients has moved from simple supportive care to adjunctive therapy because of the possible benefits, not strictly nutritional, of specialized nutritional intervention. Although data exist documenting the beneficial role of special nutrients, such as lipids and glutamine, in the management of BMT recipients, the results obtained to date are controversial. The reasons for this controversy may reside in the heterogeneity of the patients studied and of the study designs. This review focuses on the need to correctly identify the different patterns of BMT to achieve reproducible and reliable data, which may in turn be used to devise precise guidelines for the use of specialized artificial nutrition in BMT patients.

Background and Objectives: Neurologic symptoms are present in 60% of patients with thrombotic thrombocytopenic purpura (TTP) on initial examination and ultimately develop in about 90% of cases during the course of the disease. Despite central nervous system involvement being frequent, abnormalities in the brain of patients with TTP are infrequent on neuroimaging (CT/MRI) and neurophysiologic (EEG) evaluation, often reversible and mainly limited to symptomatic stages of the disease. The aim of our study was to establish the value of a complete neurologic screening as part of the work up of TTP., Design and Methods: We prospectively evaluated 16 TTP patients, performing serial neurologic, neuroimaging and EEG examinations, independently of the presence of an objective central nervous system involvement., Results: Our study shows that a complete neurologic evaluation is of modest help in improving the diagnosis of TTP, but may be useful for the neurologic management., Interpretation and Conclusions: Accurate neuroimaging and, especially, EEG evaluation and monitoring allowed us to identify patients who could benefit from anticonvulsive therapy, avoiding the unnecessary administration of the latter. The prognostic utility of complete neurologic screening in TTP remains to be conclusively demonstrated in larger prospective neurologic studies.

Background and Objectives: The potential role of autologous stem cell transplantation (ASCT) as an alternative therapeutic strategy in chronic myelogenous leukemia (CML) has been widely explored in pilot studies, but the clinical results in terms of survival have so far been evaluated only retrospectively and in heterogeneous groups of patients. The goal of our prospective study was to evaluate the feasibility and long-term efficacy of unmanipulated ASCT followed by low-dose interferon-alpha in a homogeneous group of patients affected by CML in a very early phase of disease., Design and Methods: Twenty-six unselected consecutive patients with CML in chronic phase underwent stem cell collection at diagnosis, then received cytoreductive treatment with hydroxyurea and, subsequently, a busulphan-melphalan myeloablative regimen followed by unmanipulated stem cell graft within one year of diagnosis. Interferon was given a median of 6.5 months after transplant at escalating doses, starting from 0.5 x 10(6) IU 3 times/week, on the basis of the clinical and hematologic tolerance., Results: Median chronic phase duration from diagnosis is 9 years. The ten-year projected probability of overall survival from diagnosis is 55% with a median follow-up of surviving patients of 9.5 years (8-10.5); median survival has not been reached after ten years., Interpretation and Conclusions: Our experience suggests that high-dose therapy followed by unmanipulated peripheral blood stem cell transplantation and low-dose interferon-alpha is a feasible approach, which results in long-term survival in newly diagnosed CML patients. These data need to be confirmed in controlled trials comparing ASCT with other therapeutic approaches, such as the use of interferon-alpha alone or in combination with other agents.

Background and Objectives: To investigate the feasibility of peripheral blood stem cell (PBSC) transplantion in patients with high-risk chronic lymphocytic leukemia (CLL) in remission after fludarabine therapy, the clinical impact of minimal residual disease (MRD) monitoring and the immunologic reconstitution after transplantation., Design and Methods: Twenty CLL patients, in clinical complete remission (CR) after fludarabine, were offered an unmanipulated PBSC transplant and were longitudinally monitored for MRD and immunologic reconstitution., Results: Due to unsatisfactory PBSC collection, 4 patients received bone marrow cells. All patients engrafted. Two patients died, one due to infection and one because of another neoplasia. Thirteen patients are at present in clinical CR after a median follow-up of 17 months and 18 patients are alive with a survival probability of 0.87 (+/-0.04) at 52 months after transplant. Fifteen patients had a molecular remission. Three of them showed a molecular relapse 16-28 months after autograft, followed by a clinical relapse 10-16 months later. Three of the four patients who remained persistently rearranged could be revaluated over time and showed an immunologic relapse 11-26 months after transplant; two of these had a clinical relapse 12 and 7 months later. A marked and persistent impairment of both the B- and T-immunologic compartments was recorded in the horizontal follow-up., Interpretation and Conclusions: Unmanipulated PBSC autograft is a feasible procedure that produces prolonged molecular remissions in high-risk CLL patients. Persistence or reappearance of a molecular signal after engraftment is predictive of subsequent immunologic and clinical CLL recurrence. The long -lasting impairment of the host immune repertoire after fludarabine followed by autograft has to be taken into account in the patients' management.

Reverse-transcription polymerase chain reaction (RT-PCR) of the PML/RAR alpha fusion gene may predict relapse in acute promyelocytic leukemia (APL) patients in hematologic complete remission (CR). We have prospectively studied by RT-PCR 15 PML/RAR alpha+ APL patients undergoing autologous bone marrow transplantation (ABMT) in second CR. The median time of first CR duration was 12 months (range, 6 to 40). All patients were reinduced with all-trans retinoic acid (ATRA), followed in 12 of 15 cases by mitoxantrone and Ara-C as consolidation. Fourteen patients received the BAVC (BCNU, Ara-C, m-AMSA, and VP-16) schedule as conditioning regimen. Unpurged marrows were collected immediately before conditioning treatment, analyzed by RT-PCR, and reinfused at median of 2 months (range, 2 to 7) from the achievement of second CR. Seven patients were PCR+ and eight PCR for PML/RAR alpha in their pretransplant marrows. All seven patients of the former group remained PCR+ during the follow-up and relapsed at a median time of 5 months (range, 2 to 9) from ABMT and 9 months (range, 4 to 14) from second CR. Of the eight PCR- patients, all remained PCR- during the follow-up controls. One patient relapsed at 10 months from ABMT, one died of a secondary (PML/RAR alpha-) leukemia, and six are in hematologic and molecular remission at a median time of 28 months (range, 15 to 60) after ABMT and 32 months (range, 17 to 62) from second CR. Our results indicate that, in APL patients in second CR, ABMT with PML/RAR alpha- marrow cells is likely to result in prolonged clinical and molecular remissions. Conversely, patients who test PCR+ after reinduction necessitate the use of alternative aggressive approaches, including unrelated allogeneic transplant.