Treatment in patients with acute myeloid leukemia/high-risk myelodysplastic syndrome with hypomethylating agents: Day-hospital management compared to home care setting.

OBJECTIVES: Aim of the study was to evaluate the role of a Domiciliary Hematologic Care Unit (DHCU) compared to standard DH setting in the active frontline treatment with hypomethylating agents (HMAs) +/- venetoclax of frail patients with acute myelogenous leukemia/high-risk myelodysplastic syndromes (AML/HR-MDS). METHODS: All patients with newly diagnosed AML/HR-MDS unfit for intensive care and treated frontline with HMAs from January 2010 to April 2021 were retrospectively included. RESULTS: Among 112 patients (62 AML/50 HR-MDS), 69 (61.6%) were treated in a standard DH setting and 43 (38.4%) were followed by DHCU, allocated to DH or DHCU by responsible physician. Overall response rate was 29/69 (42.0%) in DH versus 19/43 (44.1%) in DHCU (p = .797). Median response duration was 8.7 months (95%CI 7.0-10.3) in DH versus 13.0 months (95%CI 8.3-17.6) in DHCU (p = .460). Infections were also equally reported. Median overall survival of patients treated in DH was 13.7 months (95%CI 9.9-17.4) compared to 13.0 months (95%CI 6.7-19.3) of patients managed by DHCU (p = .753). CONCLUSIONS: Home care management of HMA is feasible and effective, with results similar to standard DH setting: this approach is thus adequate to offer active therapies in frail patients with AML/HR-MDS considered up to now ineligible.

Pulmonary infections in patients with acute myeloid leukemia receiving frontline treatment with hypomethylating agents.

Pulmonary infections (PIs) are a major complication of Acute Myeloid Leukemia (AML) treated with hypomethylating agents (HMA). We retrospectively evaluated 147 AML patients treated frontline with HMA in 2 Centers. Total number of HMA cycles was 1397. There were 88 episodes of PI in 64 patients (43.5%). Thirty-five/147 patients at risk (23.8%) developed at least 1 episode of early PI (during cycles 1-2). Median OS in patients who developed early PI was 3.3 months (95% CI 0.8 - 5.8) versus 10.5 months (95% CI 8.4 - 12.7) in patients without PI or with PI beyond the 2nd cycle (p < .001). Early PIs were an independent factor predicting lower survival (OR 1.94, 95% CI 1.28 - 2.93; p = .002). In conclusion, early PIs are common in AML patients receiving HMA and are associated with an unfavorable outcome. The results of our study raise the issue of a tailored infection prevention strategy.

Treatment Sequencing and Outcome of Chronic Lymphocytic Leukemia Patients Treated at Fondazione Policlinico Universitario Agostino Gemelli IRCCS: A Thirty-Year Single-Center Experience.

BACKGROUND: This monocentric retrospective study describes the treatment patterns and outcomes of chronic lymphocytic leukemia (CLL) patients. METHODS: Adult CLL patients treated between 1992 and 2022 were included. The time to next treatment (TTNT) was defined as the time from the treatment's start to the start of a subsequent therapy or death. The time to next treatment failure or death (TTNTF) was defined as the time from treatment discontinuation to the discontinuation of a subsequent therapy or death. RESULTS: Of 637 registered patients, 318 (49.9%) received treatment. We evaluated 157 cBTKi-exposed, 34 BCL2i-exposed cBTKi-naïve, and 26 double-exposed patients. The five-year TTNT values in the cBTKi-exposed patients were 80% (median NR), 40% (median 40 months), and 21% (median 24 months) months in the first line (1L), second line (2L), and beyond the second line (>2L), respectively (p < 0.0001). The five-year TTNT values in the BCL2i-exposed patients were 83% (median NR), 72% (median NR), 12% (median 28 months) in the 1L, 2L, and >2L, respectively (p = 0.185). The median TTNTF was 9 months (range 1-87) after cBTKi and 17 months (range 8-49) after both a cBTKi and BCL2i. CONCLUSIONS: This study suggests that, in CLL patients, the earlier we used targeted therapies, the better was the outcome obtained. Nonetheless, the poor outcomes in the advanced lines of therapy highlight the need for more effective treatments.

Multicentre validation of a prognostic index for overall survival in chronic lymphocytic leukaemia.

We wish to validate in a multicentric CLL population a nomogram and a risk score recently developed to predict overall survival (OS). Complete records from 1037 CLL patients were retrospectively collected to estimate OS and time to treatment (TTT). Cox models were used to test the independence of age, ß-2-microglobulin, absolute lymphocyte count (ALC), sex, Rai stage and number of involved lymph node regions (LNR). Accuracy of prognostic models was tested with the concordance index (c-index). Median follow-up was 5.5 years, with 151 deaths and 475 treated patients. Median OS was not reached (65% survival rate at 13.9 years), median TTT was 6 years. We confirmed the ability of the prognostic score to predict OS and TTT in three risk groups, with results comparable with those reported in the original report. However, ALC and Rai stage were not independent predictors, whereas the Binet staging system, which incorporates LNR variable, showed independent predictive power; furthermore, both 5- and 10-year OS estimates from nomogram were lower compared to real data. When separately analysed, the impact of therapy on OS was not selected as independent predictor of OS in our series. According to these results, we proposed a simpler four-variable model (age, sex, Binet staging, ß-2-microglobulin) and a new nomogram. This model had a c-index of 0.78 versus 0.76 of the six-variable model (p = 0.043), showing better predictive accuracy. External validation and refinement are needed on independent data sets, possibly from cancer registry patients' series.

Comparison between oral and intravenous fludarabine plus cyclophosphamide regime as front-line therapy in patients affected by chronic lymphocytic leukaemia: influence of biological parameters on the clinical outcome.

The fludarabine plus cyclophosphamide (FC) regimen was reported to be superior to chlorambucil or fludarabine alone in terms of complete response (CR), overall response (OR) and progression-free survival (PFS) in previously untreated patients with chronic lymphocytic leukaemia (CLL). In the present study, we compared the efficacy and toxicity of FC administered through oral and intravenous route in 65 untreated patients affected by advanced CLL. No statistical differences were noticed between the two routes of administration in terms of OR, PFS, time to re-treatment (TTR) and overall survival (OS) of analysed patients. We also assessed the influence on the clinical outcome of the mutation status of the immunoglobulin variable region heavy chain (IgVH) gene, of the cytogenetic abnormalities and of the expression of ZAP70 and CD38 in patients' primary samples. Among the 58 evaluable patients, 31 (53%) achieved a CR and 18 (31%) a partial response. The median PFS was 35 months, median TTR was 42 months and median OS was not reached after 45 months (range, 1-161). A significantly lower OR rate was noticed in patients with high-risk cytogenetic abnormalities (del 17p, del 11q). In this study, high-risk cytogenetic abnormalities and unmutated IgVH genes were independent predictors of TTR. These results underline the importance of biological stratifications in front-line treatment of CLL patients. We confirm that FC is an effective regimen with mild toxicities; it could be recommended for patients with low-risk biological parameters who represent, in our experience, about 30% of the total.

The coexistence of chronic lymphocytic leukemia and myeloproliperative neoplasms: a retrospective multicentric GIMEMA experience.

Although the coexistence of chronic lymphocytic leukemia (CLL) and myeloproliferative neoplasms (MPN) has been sporadically reported in the literature, no systematic studies on this disease association are available. We retrospectively analyzed 46 patients affected by CLL/MPN referred by 15 Italian GIMEMA centers. The aim of this retrospective multicenter study was to define the following: clinico-biological characteristics, possible familiarity, clinical course of both diseases, and influence of MPN chemotherapy on the course of CLL. Among 46 patients, 30 patients were males, 16 patients were females; median age was 71 years. Only one case had familiar CLL. Myeloproliferative disorders consisted of essential thrombocytemia in 18 cases, polycythemia vera in 10 cases, chronic myeloid leukemia in 9 cases, primary myelofibrosis in 6 cases, and MPN/myelodysplastic syndrome in 3 cases. The lymphoproliferative disorder was diagnosed as monoclonal B-cell lymphocytosis in 8 patients and as Binet Stage A CLL in 38 patients. After a median follow-up of 49 months, 9 patients experienced progressive CLL and only 6 patients required treatment after a median of 57.5 months. The biological profile confirmed a subset of low-risk CLL. Twenty patients received chemotherapy for MPN without influence on the course of CLL: lymphocyte counts remained unchanged after 3, 6, and 12 months of treatment. This series is the largest so far reported in literature. The diagnosis of concomitant CLL/MPN is a rare event and lymphoproliferative disorders present a clinical indolent course with a low-risk biological profile. MPN therapy does not interfere with the prognosis of patients with CLL.

Chronic lymphocytic leukemia-associated immune thrombocytopenia treated with rituximab: a retrospective study of 21 patients.

INTRODUCTION: There are no standard therapies for chronic lymphocytic leukemia (CLL)-associated immune thrombocytopenia (IT) so far. PATIENTS AND METHODS: We report the results of therapy with single agent rituximab in 21 patients with CLL-associated IT. The mean age at CLL and IT diagnosis was 64 and 68 yr, respectively. IT developed at a mean time of 44 months from the diagnosis of CLL. In four cases, IT was diagnosed at the same time as CLL. For three patients, IT was considered fludarabine-related and two patients showed autoimmune hemolysis also. All patients but one received steroids as first-line treatment for IT. Some patients received intravenous high-dose Ig, vincristine, and Cytoxan also, without beneficial effect. After a mean time of 43 d from the diagnosis of IT, all patients were scheduled to receive rituximab at a dosage of 375 mg/mq/weekly. RESULTS: Eighteen (86%) patients completed the scheduled four cycles of rituximab. Irrelevant first infusion side effects were seen only in one patient. Twelve (57%) patients showed a complete response (CR), six (29%) patients a partial response (PR), and three (14%) patients did not respond. In responding patients, the mean duration of response was 21 months (4-49 months). At a mean follow-up of 28 months, 14 (66%) patients were still alive, 10 (48%) of them in CR and three (14%) in PR. CONCLUSIONS: This retrospective analysis prove that rituximab is an effective and well-tolerated alternative treatment for CLL-associated IT.

Low-dose valganciclovir as preemptive therapy for cytomegalovirus infection occurring in allogeneic stem cell transplant recipients.

Few data are available to date on the dose of oral valganciclovir as cytomegalovirus (CMV) preemptive therapy in stem cell transplantation patients. This study aimed to evaluate the efficacy and safety of low-dose valganciclovir (900 mg/day) as preemptive treatment in allotransplanted recipients. Valganciclovir was used in 34 patients who underwent allogeneic stem cell transplantation for hematological malignancies at the dose of 900 mg oral administration/day (12 patients, group 1) or 1,800 mg oral administration/day (22 patients, group 2). Thirty-two out of 34 patients (94%) obtained negativization of polymerase chain reaction for CMV at a median of 12.5 days from the beginning of valganciclovir administration (10/12 patients of group 1, 22/22 patients of group 2). We conclude that oral administration of valganciclovir can induce clearance of CMV viral load in about 2 weeks; moreover, lower-dose oral valganciclovir (900 mg/day) has a comparable efficacy to the proposed standard dose (1,800 mg/day).

Early diagnosis followed by front-line autologous peripheral blood stem cell transplantation for patients affected by POEMS syndrome.

The acronym POEMS refers to polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes. This disease is progressive and weakening for patients and lead to death generally for neurological problem without therapy. We treated four patients affected by POEMS syndrome with front-line chemotherapy and autologous peripheral blood stem cell transplantation (aPBSCT). After a median follow-up of 40.5 months (range 12-52), all patients are alive with slow but progressive improvement in neurological disease, skin changes, performance status and without evidence of clonal plasmacytosis and organomegaly. In conclusion early diagnosis is crucial to obtain best response and improve clinical outcome.

Oral fludarabine and cyclophosphamide as front-line chemotherapy in patients with chronic lymphocytic leukemia. The impact of biological parameters in the response duration.

We tested the efficacy and safety of oral fludarabine and cyclophosphamide as front-line therapy in chronic lymphocytic leukemia (CLL) and assessed the influence of immunoglobulin variable region heavy chain (IgVH) gene mutation status, interphase cytogenetic abnormalities, and expression of ZAP-70 and CD38 on clinical outcome. Thirty-seven patients with previously untreated CLL received oral fludarabine (30 mg m(2)) and oral cyclophosphamide (250 mg m(2)) for three consecutive days every 4 weeks for six cycles. Eighteen patients had unmutated and 15 had mutated IgVH genes. Nine patients had the 'high risk' cytogenetic abnormality del(11q22.3) or del(17p13.1). Fifteen patients were ZAP-70-positive and eight patients were CD38-positive. Among the 35 valuable patients, 14 patients (40%) obtained a complete response and 13 (37%) a partial response. The median progression-free survival (PFS) was 23 months and median time to re-treatment (TTR) was 38 months. A significantly lower overall response rate (43% vs. 85%, p = 0.011), a shorter PFS (22 vs. 27 months, p = 0.015), and a shorter TTR (22 vs. 40 months, p = 0.031) were noticed in the 'high risk' cytogenetic abnormalities group; TTR was also shorter in IgVH-unmutated than in IgVH-mutated patients (26 vs. 41 months, p = 0.035). Hematologic toxicity included grade IV neutropenia (ten patients) and grade III/IV anemia (three patients). Gastrointestinal toxicity was mild and no patient required hospitalization. The oral combination of fludarabine and cyclophosphamide is an effective, safe, and well-tolerated regimen that, if confirmed with larger series, will be appropriate especially in patients with low risk biological parameters.

Low incidence of secondary neoplasia after autotransplantation for lymphoproliferative disease: the role of pre-transplant therapy.

To asses the real contribution of pre-transplantation treatment in the incidence of secondary neoplasia after autologous transplant for lymphoproliferative disorders, we used stringent inclusion/exclusion criteria. One hundred and forty-two patients out of 323 that underwent autologous transplantation for lymphoproliferative disorders were studied. The risk factors that were evaluated with univariate and multivariate analysis included: gender, sex, age, diagnosis, radiotherapy, and chemotherapy prior to conditioning regimen, disease status at peripheral blood stem-cell transplantation (PBSCT) and type of harvest. Three patients developed secondary myelodysplastic syndrome/acute myeloid leukemia (sMDS/AML) and three patients developed solid neoplasia. By univariate analysis diagnosis chronic lymphocytic leukemia and use of fludarabine and monoclonal antibodies were the only variables significantly associated with the development of sMDS/AML. By multivariate analysis, the variables associated with sMDS/AML were the use of fludarabine and disease status at PBSCT. By univariate analysis, we found that radiotherapy and the use of monoclonal antibodies were significantly associated with the development of secondary solid neoplasia. Multivariate analysis confirmed that the only two variables significantly associated with new cancers were radiotherapy and prior treatment with monoclonal antibodies. We report the lowest incidence of sMDS/AML after autologous stem-cell transplantation for lymphoproliferative malignancies. Major reasons could be ascribed to the stringent inclusion/exclusion criteria used to establish the real incidence of sMDS/AML because of chemo-radiotherapy used before transplant procedure. The low incidence of secondary solid tumors could be caused by the absence of total body irradiation as part of the conditioning regimen or the short follow-up.

Low-dose thalidomide in combination with oral fludarabine and cyclophosphamide is ineffective in heavily pre-treated patients with chronic lymphocytic leukemia.

Elevated levels of TNF-alpha have been associated with progressive disease in patients with chronic lymphocytic leukemia (CLL). Thalidomide has been shown to inhibit production of TNF-alpha. We investigated the effects of thalidomide on clinical outcome and TNF-alpha serum levels in five pre-treated CLL patients. The schedule consisted on daily thalidomide (Thal), oral fludarabine (Flu) and oral cyclophosphamide (CTX). Median duration of treatment was 60 days; four patients stopped treatment for disease progression and one patient for neurological toxicity. Serum TNF-alpha levels did not show any decrease during treatment. Low-dose thalidomide is not effective in CLL patients with refractory disease.

Low-dose intravenous alemtuzumab therapy in pretreated patients affected by chronic lymphocytic leukemia. A single center experience.

We report the efficacy and safety of intravenous low-dose alemtuzumab (10 mg three times weekly for 10 weeks) in 12 patients with relapsed or refractory chronic lymphocytic leukemia. Low-dose alemtuzumab induced significant responses in these patients (16% complete remission, 25% partial remission), with mild hematologic and extrahematologic side effects and a low rate of infections, even in the presence of long-lasting severe immunosuppression.

Comparison of ZAP-70/Syk mRNA levels with immunoglobulin heavy-chain gene mutation status and disease progression in chronic lymphocytic leukemia.

BACKGROUND AND OBJECTIVES: The protein tyrosine kinase ZAP-70 has recently emerged as a major prognostic indicator in chronic lymphocytic leukemia (CLL). ZAP-70 is structurally and functionally homologous to Syk, a key mediator of B-cell receptor signaling. We therefore evaluated ZAP-70 expression in CLL B cells using Syk as an intracellular standard. DESIGN AND METHODS: The relative amounts of ZAP-70 and Syk were determined in purified B cells from 92 CLL patients using a novel reverse transcriptase/polymerase chain reaction (RT-PCR) procedure that co-amplifies both transcripts with equal efficiency. The ZAP-70/Syk mRNA ratio was correlated with VH gene mutation status, median treatment-free survival and FACS analysis of ZAP-70 expression. RESULTS: ZAP-70 was expressed in the majority of cases with unmutated VH genes (88%), but also at lower levels in a substantial fraction of cases with mutated VH genes (44%). High levels of ZAP-70, defined as ZAP-70/Syk mRNA ratios above 0.25, were observed mainly in cases with unmutated VH genes and correlated with short treatment-free survival. In contrast, no difference was observed in the median treatment-free survival between patients with low ZAP-70/Syk ratios (0.05-0.25) and patients with no or negligible ZAP-70 expression (ZAP-70/Syk<0.05). In 73 cases ZAP-70 expression was investigated by RT/PCR and FACS analysis; concordance with VH gene mutation status was 86% and 71%, respectively. INTERPRETATION AND CONCLUSIONS: ZAP-70 is frequently expressed in CLL B cells, but only high levels correlate with unmutated VH gene status and progressive disease. Expression of ZAP-70 can be accurately assessed by analysis of the ZAP-70/Syk mRNA ratio, thus providing an alternative to FACS analysis.

Cytomegalovirus reactivation during alemtuzumab therapy for chronic lymphocytic leukemia: incidence and treatment with oral ganciclovir.

BACKGROUND AND OBJECTIVES: Although alemtuzumab (campath-1H) has been successfully used in patients with untreated or previously treated chronic lymphocytic leukemia (CLL), a variable incidence of cytomegalovirus (CMV) reactivation has been described. No prospective reports currently provide results of the use of oral ganciclovir as pre-emptive therapy in patients with CMV reactivation during alemtuzumab treatment. DESIGN AND METHODS: We designed a prospective study in 12 patients with pretreated CLL with the aim of evaluating the incidence of CMV reactivation during alemtuzumab treatment and the role of oral ganciclovir as pre-emptive therapy and in preventing CMV organ disease. RESULTS: In the 12 CLL patients being treated with alemtuzumab, 8 patients (66%) had CMV reactivation, as detected by antigenemia and/or CMV DNA. No patient showed clinical evidence of CMV disease. The alemtuzumab was discontinued and the patients were immediately treated with oral ganciclovir 1000 mg tid. After a median of 14 days of antiviral therapy all patients achieved negative CMV polymerase chain reaction (PCR) assays and/or antigenemia. No patients showed further CMV reactivation up to the end of the study. INTERPRETATION AND CONCLUSIONS: CMV reactivaction, studied with periodic analysis of antigenemia and PCR, is frequent in previously treated CLL patients receiving alemtuzumab therapy although only sporadic cases of CMV disease have been reported. Using oral ganciclovir, the response to therapy was prompt, there was no progression to CMV disease, and no relevant clinical toxicity, thus sparing unnecessary hospitalization. Oral ganciclovir may be used as pre-emptive therapy in all patients who develop CMV reactivation during alemtuzumab treatment.

Immune recovery of lymphocyte subsets 6 years after autologous peripheral blood stem cell transplantation (PBSCT) for lymphoproliferative diseases. A comparison between NHL, HD and MM in group of 149 patients.

To evaluate the normalization of lymphocyte subsets several years after autologous peripheral blood stem cell transplantation (aPBSCT) and to detect any differences based on the underlying lymphoproliferative diseases, we analyzed the immunological recovery of 149 patients with Non Hodgkin's Lymphoma (NHL), Hodgkin's Disease (HD), Multiple Myeloma (MM). Lymphocyte recovery was assessed before the transplant, on days 15, 30, 60, 90, 120 and on years 1, 2, 4, 6. Analysis of a total of 709 lymphocytes, including total lymphocyte count, CD3 +, CD4 +, CD8 +, CD4 +/CD8 + ratio, CD19 +, CD3 + HLA-DR +, CD16 + 56 +, was performed. The normalization of total lymphocyte counts was achieved between days 14 to 22 following PBSCT. CD3 + cells count showed a normalization after 2 years in the HD and NHL groups and after 4 years in MM group. CD4 + subset achieved normalization during the sixth year in the 3 groups. The CD8 + and CD19 + lymphocytes subsets achieved normal values in the 3 groups at day 60 and at day 120 respectively. CD16 + 56 + and CD3 +/HLA-DR + lymphocytes showed median values above the normal range starting from day 30. Immunological recovery was similar in all 3 groups. Moreover, the recovery of all subsets evaluated was similarly demonstrated within 6 years after aPBSCT.

Intralesional administration of rituximab for treatment of CD20 positive orbital lymphoma: safety and efficacy evaluation.

B-cell lymphomas constitute the most frequent malignant neoplasm of the ocular adnexal, often presenting with localized disease. Five patients with primary localized CD20 positive B cell non Hodgkin ocular adnexal lymphomas received intralesional rituximab at the dose of 5mg once a week for one month, followed by 10mg weekly in case of incomplete response. Four of five patients obtained regression of symptoms and 2 of them showed complete response. No patients experienced side effects besides pain on the site of the injection. Local treatment with Rituximab for OAL is a safe and useful first-line therapeutic option.

Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease.

Regulatory T-cells (Treg) actively maintain immunological self-tolerance and play a significant role in the progression of cancer. Treg cell numbers have been evaluated in 80 patients with previously untreated chronic lymphocytic leukemia (CLL) and in 40 normal healthy volunteers. Treg cells are higher in CLL patients than in controls and correlate with disease status (more advanced clinical stage, peripheral blood B-cell lymphocytosis, absolute CD38+ B-cell number, and more elevated LDH levels). No correlation was found with ZAP-70 expression, IgVH mutational status and cytogenetic abnormalities. This data shows that Treg cell number is abnormal in CLL patients.

Allogeneic transplantation for chronic lymphocytic leukemia.

Even if Chronic lymphocytic leukemia (CLL) often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT) CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment.Allogeneic transplant has potential curative role in CLL, however burden with very high transplant related mortality (TRM) rates of 38-50%. A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT) has been the introduction of non-myeloablative or reduced intensity conditioning (RIC) regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL) activity.THE MAJOR COMPLICATIONS OF ALLOGENEIC SCT IN CLL ARE: chronic graft-versus-host-disease (GVHD) affecting quality of life, high graft rejection and infection rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients.Sensitive minimal residual disease (MRD) quantification has strong prognostic impact after transplant.