Timing of BNT162b2 vaccine prior to COVID-19 infection, influence disease severity in patients with hematologic malignancies: Results from a cohort study.

The COVID-19 pandemic continues to pose challenges to the treatment of hemato-oncology patients. Emergence of COVID-19 variants, availability of vaccine boosters and antiviral treatments could impact their outcome. We retrospectively studied patients with hematologic malignancies and confirmed COVID-19 during the Omicron outbreak. Of 116 evaluated patients, 16% developed severe or critical COVID-19. Diagnosis of chronic lymphocytic leukemia (CLL) was significantly associated with severe COVID-19 (p = 0.01). The vaccine effectiveness was related to the timing of the vaccine, with patients who received a mRNA vaccine within 7-90 days prior to COVID-19 being less likely to develop severe disease compared to all other patients (p = 0.019). There was no correlation between disease severity and antiviral therapies. Importantly, 45% of patients undergoing active hematological treatment had to interrupt their treatment due to COVID-19. In conclusion, patients with hematologic malignancies are at a considerable risk for severe COVID-19 during the Omicron outbreak, with patients with CLL being the most vulnerable. mRNA vaccines have the potential to protect hematological patients from severe COVID-19 if administered within the previous 3 months. Hematological treatment interruption is a frequent adverse outcome of COVID-19 infection.

Haematological patients' perception of home transfusions: Effect of the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic has led to a growing interest in hospital-at-home programmes, including home transfusion services. We studied whether the pandemic had influenced patients' perception of home transfusions. MATERIALS AND METHODS: We conducted a survey among haematology patients who receive transfusions in the hospital day care facility. Patients were asked about the burden of day care transfusions and whether they would prefer receiving home transfusions. The survey was conducted during the COVID-19 pandemic, and the results were compared with a survey performed before the pandemic (baseline). RESULTS: Sixty patients were included in the COVID-19 cohort and 31 patients in the baseline cohort. There was a non-significant decrease in the proportion of patients willing to receive home transfusions during the pandemic compared with baseline (35% vs. 47%, respectively, p = 0.28). More patients in the COVID-19 cohort were afraid to receive home transfusions (60% compared with 48% at baseline, p = 0.29), and fewer patients believed that hospital transfusion impaired their quality of life (19% compared with 36% at baseline, p = 0.09). These unexpected results may be partly attributed to the shorter time needed to arrive at the hospital during the pandemic and a greater fear of having transfusion-related adverse effects at home. CONCLUSIONS: Our results show that the pandemic did not increase the willingness of patients to receive home transfusions, with a non-significant drift towards refusal of home transfusions. Patients' opinions should be taken into consideration when planning for future home transfusion services, by creating a comprehensive approach to patients' needs.

Ruxolitinib for Refractory Macrophage Activation Syndrome Complicating Adult-Onset Still's Disease.

Macrophage activation syndrome is the most frequent life-threatening complication of adult-onset Still's disease. This is a nearly fatal case of a young patient, which has been refractory to corticoste- roids, anakinra, tocilizumab, cyclosporine A, and etoposide, but eventually responded miraculously to salvage therapy with ruxolitinib. We review recent pertinent data related to the therapeutic value of ruxolitinib for macrophage activation syndrome triggered by adult-onset Still's disease.

Venetoclax in combination with FLAG-IDA-based protocol for patients with acute myeloid leukemia: a real-world analysis.

Venetoclax in combination with intensive therapies is explored in both the upfront and relapse/refractory (R/R) setting, and available data suggest that such regimens are effective albeit with added hematological and infectious toxicity. We conducted a multicenter retrospective cohort study of patients with acute myeloid leukemia (AML) treated with venetoclax in combination with FLAG-IDA protocol. Twenty-five patients were included in this analysis (median age 53.4 years). Most patients were treated for R/R AML (n = 24, 96%) with a median of one (range 0-3) previous lines of therapy and 44% of patients (n = 11) having prior allogeneic hematopoietic cell transplantation (HCT). Median follow-up was 10 (range, 4-26) months. Platelet and neutrophil recovery were observed at a median of 31 (95% CI 17.6-38.3) and 23 (95% CI 20-28) days, respectively. The most common adverse events were infectious (blood stream infections, 48% and invasive fungal infections, 32%). Thirty-day mortality was 12%. Composite complete remission (CRc) was 72% for the entire cohort and 91% in patients treated for post-HCT relapse. Incidences of relapse-free and overall survival at 12 months were 67% (95% CI 58-76%) and 50% (95% CI 31-69%), respectively. Real-world data show that the addition of venetoclax to FLAG-IDA protocol is effective in patients with high-risk AML, most notably in the post-HCT relapse setting. Prophylaxis and surveillance for infections are crucial.

Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients after Allogeneic HCT or CD19-based CART therapy-A Single-Center Prospective Cohort Study.

Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.

BNT162b2 COVID-19 vaccine is significantly less effective in patients with hematologic malignancies.

Patients with hematologic malignancies have an increased risk of severe COVID-19 infection. Vaccination against COVID-19 is especially important in these patients, but whether they develop an immune response following vaccination is unknown. We studied serologic responses to the BNT162b2 vaccine in this population. A lower proportion of patients were seropositive following vaccination (75%) than in a comparison group (99%; p < 0.001), and median (interquartile range [IQR]) antibody titers in patients were lower (90 [12.4-185.5] and 173 [133-232] AU/ml, respectively; p < 0.001). Older age, higher lactate dehydrogenase, and number of treatment lines correlated with lower seropositivity likelihood and antibody titers, while absolute lymphocyte count, globulin level, and time from last treatment to vaccination correlated with higher seropositivity likelihood and antibody titers. Chronic lymphocytic leukemia patients had the lowest seropositivity rate followed by indolent lymphoma. Patients recently treated with chemo-immunotherapy, anti-CD20 antibodies, BCL2, BTK or JAK2 inhibitors had significantly less seropositive responses and lower median (IQR) antibody titers (29%, 1.9 [1.9-12] AU/ml; 0%, 1.9 [1.9-1.9] AU/ml; 25%, 1.9 [1.9-25] AU/ml; 40%, 1.9 [1.9-92.8] AU/ml; and 42%, 10.9 [5.7-66.4] AU/ml, respectively; p < 0.001). Serological response to BNT162b2 vaccine in patients with hematologic malignancies is considerably impaired, and they could remain at risk for severe COVID-19 infection and death.

Venetoclax combinations induce high response rates in newly diagnosed acute myeloid leukemia patients ineligible for intensive chemotherapy in routine practice.

Combinations of the BCL-2 inhibitor, venetoclax, with either hypomethylating agents (HMA) or low dose cytarabine (LDAC), have shown promising results in clinical trials of AML patients unfit for intensive therapy. We report on the efficacy and safety of venetoclax combinations in AML patients treated outside of clinical trials. Complete remission (CR) + CR with incomplete count recovery (CRi) were achieved in 61% of patients, with similar CR+CRi rates in with secondary AML, and in patients who were previously treated with HMA (61% and 43%, respectively). Relapse occurred in 25% of patients, with a median event-free survival (EFS) of 11.7 months (95% CI, 10.09-13.35) in responding patients. At a median follow up of 8.7 months, the median overall survival (OS) was 9.8 months (95% CI 6.42-13.3) in the entire cohort. In multivariate analysis adverse karyotype was the only negative predictor of CR/CRi (p = .03), while both ECOG performance status (PS) and adverse karyotype were significantly associated with shorter OS (p = .023 and .038, respectively). Median OS was higher in patients achieving CR/CRi and in patients proceeding to allogeneic stem cell transplantation (allo-SCT). Treatment was well tolerated, with side effects similar to those described in the randomized clinical trials. Tumor lysis syndrome (TLS) occurred in 12% of patients. Our data support the efficacy and safety of venetoclax combinations in newly diagnosed AML patients not eligible for intensive therapy. According to our data, secondary AML patients could benefit from venetoclax combinations similarly to de-novo AML patients, and allo-SCT could be offered to selected patients achieving CR/CRi.

Venetoclax is safe and efficacious in relapsed/refractory AML.

Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% (n = 17) recovered also their platelet count. In 15 (52% of those who survived > 2 months), CR/CRi was confirmed by bone marrow examination. The median OS from venetoclax initiation of all the patients and of those who survived more than 2 months was 5.5 and 6.5 months, respectively. In conclusion, this study demonstrates that venetoclax is safe and active also in AML patients with advanced disease.

Safety and efficacy of blinatumomab: a real world data.

Despite improvement in survival of newly diagnosed adult precursor B-acute lymphoblastic leukemia/lymphoma (B-ALL), the results of relapsed/refractory disease are poor. Blinatumomab, a bispecific monoclonal antibody directed against CD19/CD3 show clinical activity against relapsed/refractory B-ALL and in minimal residual disease (MRD)-positive patients.We report our "real-world" experience with blinatumomab in patients with relapsed/refractory B-ALL.Twenty-one patients, at a median age 52 years with median disease duration of 10 months, were included. Indications for treatment were hematological relapse (n = 17), MRD positivity (n = 2), inability to continue intensive chemotherapy (n = 1), and bridging to a second alloSCT (n = 1). Blinatumomab was given as first salvage in 11 patients and after at least one prior salvage treatment in eight.Complete response (CR) was newly achieved in 47% and was maintained in 75% of patients with baseline CR. At a median follow-up of 12.4 months, 13 patients were alive, and 11 in CR. Median leukemia-free survival was 8.7 months, and median overall survival was 15.2 months. Median leukemia-free survival and overall survival were not reached in patients proceeding to alloSCT compared to 5.1 and 15.2 months, respectively, for patients who did not receive stem cell transplantation.Treatment was well tolerated with neurological events reported in two patients (10%) and GI events in three patients (14%). Cytokine storm was reported in four patients (19%).In conclusion, treatment with blinatumomab is effective and tolerable in adult patients with relapsed/refractory B-ALL outside of a clinical trial stetting.

[CURRENT CRITERIA FOR THE DIAGNOSIS OF MYELOPROLIFERATIVE NEOPLASMS - WHAT IS IMPORTANT TO KNOW?]

INTRODUCTION: The understanding of the basic molecular mechanisms of myeloproliferative neoplasms in the last few years led to updating of their diagnostic criteria in the recent classification of myeloid and lymphoid neoplasms by the WHO, which was published in 2017. The major changes relating to the diagnosis of myeloproliferative neoplasms include lowering of the hemoglobin threshold and mandatory bone marrow biopsy as major criteria for the diagnosis of polycythemia vera, as well as adding acquired mutation in either CALR or MPL in addition to the common JAK2V617F mutation as a major criterion for diagnosing essential thrombocythemia or myelofibrosis. We review the newest discoveries on the pathogenesis of myeloproliferative neoplasms, highlighting the relevant new additions to their diagnostic criteria, and relevant therapeutic considerations.

Prevalence of Paroxysmal Nocturnal Hemoglobinuria Clones in Myeloproliferative Neoplasm Patients: A Cross-Sectional Study.

INTRODUCTION: The myeloproliferative neoplasms (MPN) are clonal diseases that confer an increased risk of thrombohemorrhagic complications. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease associated with an increased thrombotic risk. Small PNH clones are prevalent in aplastic anemia and myelodysplastic syndrome patients, but their prevalence in MPN patients is unknown. PATIENTS AND METHODS: Consecutive patients with MPN followed up at a single center were recruited. PNH clones were analyzed in erythrocytes and white blood cells by flow cytometry. RESULTS: PNH clones were detected in 2% of patients and were more common in JAK2 V617F positive patients. We could not detect any differences in clinical manifestations or complications in patients either with or without PNH clones because of the small patient numbers. CONCLUSION: The prevalence of PNH clones in MPN is similar to that described in myelodysplastic syndromes. Whether PNH clones influence MPN phenotype and complications should be studied prospectively in larger patient cohorts and over long-term follow-up.

Midostaurin in combination with intensive chemotherapy is safe and associated with improved remission rates and higher transplantation rates in first remission-a multi-center historical control study.

The addition of midostaurin, a FLT3-inhibitor, to intensive chemotherapy (IC) was previously shown to improve outcome of younger patients with FLT3-mutated AML. The toxicity and efficacy of adding midostaurin to IC in patients not originally included in the RATIFY study or with intensified daunorubicin dosing are unknown. We conducted a retrospective, multi-center, historical-control study to characterize the safety and efficacy of adding midostaurin to IC in a "real-world" setting. Sixty-nine adult patients were included in the analysis (midostaurin n = 34, historical controls n = 35) with a mean follow-up of 18.4 (± 15) months. Median age of patients was 60 (range 26-82) years; 32% and 20% of patients were > 65 and 70 years, respectively. No differences in baseline characteristics were noted between the groups. Midostaurin was administered with 90 mg/m2 daunorubicin in 29% of patients; One-third of patients experienced dose reductions/interruptions during midostaurin therapy. Overall toxicity was comparable between the midostaurin and control groups.CR/CRi rates were higher in patients treated with midostaurin compared with controls (80% vs. 57%, p = 0.047) and significantly more patients in the midostaurin group were transplanted in first remission (95% vs. 68%, p = 0.04).Median OS and DFS were higher in the midostaurin vs. control group (not reached vs. 11 months (p = 0.085) and 13 vs. 6 months (p = 0.09), respectively). In our analysis, midostaurin was not associated with increased toxicity including in older patients, in those with secondary AML or when administered with intensified daunorubicin dosage. Higher remission rates in the midostaurin group and increased transplantation rates in first CR were associated with a trend towards better outcomes.

Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the Mucin 1 C-terminal subunit (MUC1-C) plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples, and xenograft models of CTCL were used to assess synergy of GO-203 with decitabine, a hypomethylating agent. Present studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) levels and decreased levels of scavenger molecules, NADP, NADPH, glutathione, and TIGAR, critical to intracellular redox homeostasis. Dual exposure to GO-203 and decitabine resulted in marked downregulation of DNA methyl transferases demonstrating significant synergy of these agents in inducing global and gene specific hypomethylation. Accordingly, treatment with decitabine and GO-203 upregulated the ROS generating enzymes, NADPH oxidase 4 and dual oxidase 2 potentially due to their effect on epigenomic regulation of these proteins. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death in CTCL cell lines, patient-derived primary samples and in a murine xenograft model. These findings indicate that decitabine intensifies MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for patients with CTCL. Mol Cancer Ther; 16(10); 2304-14. ©2017 AACR.

Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning.

Reduced-toxicity conditioning with fludarabine and treosulfan is a dose-intensive regimen with enhanced anti-leukemia effect and acceptable toxicity in AML/MDS. HLA-C regulates natural-killer (NK) cell function by inhibiting Killer immunoglobulin-like receptors (KIR) and is divided into C1 and C2 epitopes. The missing-ligand theory suggests that missing recipient KIR ligands drives NK-alloreactivity after SCT, in the absence of HLA-mismatch by activating unlicensed donor NK cells. We analyzed SCT outcomes in 203 patients with AML/MDS, median age 58 years, given SCT from matched-siblings (n = 97) or matched-unrelated donors (n = 106), using two treosulfan doses (total 36 or 42 g/m2 ). 34% expressed one HLA-C group 1 allele (C1C1), 19% one HLA-C group 2 allele (C2C2), and 48% both KIR ligands (C1C2). Median follow-up was 48 months. 5-year relapse, nonrelapse mortality (NRM) and leukemia-free survival (LFS) rates were 38%, 27%, and 36%, respectively. Relapse rates were 43%, 45%, and 26% in patients expressing C1C1, C1C2, and C2C2 ligands, respectively (P = .03). Multivariate-analysis identified chemo-refractory disease (HR 3.1, P = .003), poor cytogenetics (HR 1.7, P = .08), female donor to male recipient (HR 0.4, P = .01) and C2C2 ligands (HR 0.4, P = .04) as independent factors predicting relapse. HLA-C ligands were not associated with GVHD or NRM. LFS was 33%, 30%, and 46%, respectively (P = .07). Chemorefractory disease (HR 3.1, P = .0004) and C2C2 group ligand (HR 0.6, P = .06) independently predicted LFS. Treosulfan dose did not predict any SCT outcome. In conclusion, missing HLA-C group 1 ligand is associated with reduced relapse risk, similar NRM and improved LFS, after HLA-matched SCT with treosulfan conditioning in AML/MDS.

Bone marrow stroma protects myeloma cells from cytotoxic damage via induction of the oncoprotein MUC1.

Multiple myeloma (MM) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co-culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co-culture of MM cells with stroma cells, on expression of the MUC1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis. Co-culture of stroma with MM cells resulted in increased MUC1 expression by tumour cells. The effect of stromal cell co-culture on MUC1 expression was not dependent on cell contact and was therefore thought to be due to soluble factors secreted by the stromal cells into the microenvironment. We demonstrated that MUC1 expression was mediated by interleukin-6 and subsequent up-regulation of the JAK-STAT pathway. Interestingly, the effect of stromal cell co-culture on tumour resistance was partially reversed by silencing of MUC1 in MM cells, consistent with the potential role of MUC1 in mediating resistance to cytotoxic-based therapies.

MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia.

Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in acute myeloid leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, in comparison with normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b+ Gr1+ MDSCs in bone marrow and spleen. Coculture of the AML cell lines MOLM-4, THP-1 or primary AML cells with donor peripheral blood mononuclear cells elicited a cell contact-dependent expansion of MDSCs. MDSCs were suppressive of autologous T-cell responses as evidenced by reduced T-cell proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that the expansion of MDSCs in AML is accomplished by tumor-derived extracellular vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken-up myeloid progenitor cells, resulting in the selective proliferation of MDSCs in comparison with functionally competent antigen-presenting cells. The MUC1 oncoprotein was subsequently identified as the critical driver of EV-mediated MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins. Moreover, we demonstrate that the microRNA miR34a acts as the regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs.

High-Risk, Advanced-Stage Hodgkin Lymphoma: The Impact of Combined Escalated BEACOPP and ABVD Treatment in Patients Who Rapidly Achieve Metabolic Complete Remission on Interim FDG-PET/CT Scan.

The escalated BEACOPP (escBEACOPP) regimen improves the outcome of patients with advanced-stage Hodgkin lymphoma (HL) but is associated with cumbersome toxicity. We analyzed the survival outcome of high-risk, advanced-stage HL patients treated with response-adapted therapy. escBEACOPP was administered for 2 cycles, and after complete remission (CR) or partial remission (PR) was observed on FDG-PET/CT, treatment was de-escalated to 4 cycles of ABVD. Sixty-nine patients were evaluated, of them 45 participated in the multicenter, phase II prospective study between 2001 and 2007. Sixty patients had an international prognostic score ≥3. At a median follow-up of 5.6 years, 4 patients had died, 2 of them due to advanced HL. After the initial 2 cycles of escBEACOPP, 52 (75%) patients were in CR and 17 (25%) had a PR. Progression-free survival and overall survival (OS) were 79 and 93%, respectively. OS was predicted from the results of early-interim FDG-PET/CT: 98% of the patients in CR and 79% of those with a PR (p = 0.015). Hematological toxicity was more frequent during the first 2 cycles of escBEACOPP than in the ABVD phase. In conclusion, this retrospective analysis indicates that combined escBEACOPP-ABVD therapy is well tolerated and efficacious in HL patients who achieve negative early-interim PET results, while a positive PET result partially identified those with a worse prognosis.

Salvage therapy with ARA-C and gemtuzumab ozogamicin in AML patients relapsing after stem cell transplantation.

Acute myeloid leukemia (AML) relapse is often associated with a poor outcome, especially after allogeneic stem cell transplantation (Allo-SCT). In patients relapsing early after SCT treatment, options are further limited by the fear for increased toxicity. We report our experience with ARA-C and gemtuzumab ozogamicin (GO) combination in relapsed post-SCT AML patients. Therapy consisted of ARA-C (1 gr/m(2)) for 4 days followed by one dose of GO 9 mg/m(2) on day 5 and was supported by donor stem cells when possible. Responding patients not developing graft versus host disease (GVHD) were eligible for immunotherapy with donor lymphocyte infusion (DLI) or a second Allo-SCT. Sixteen patients, median age 53 years (range 31-63), are included in this analysis. Patients underwent SCT for high-risk AML (n = 11) or AML relapse (n = 5), and 81 % had an early post-SCT relapse. Responses were achieved in 60 % of evaluable patients (CR-5 CRp-4). Median probabilities of survival (OS) and event-free survival (EFS) in the entire cohort, responding and non-responding patients were 103 and 76 days, 183 and 97 days, and 79 and 16 days, respectively. At 1-year follow-up, 25 % of patients were alive; however, all had relapse. Treatment resulted in grade 3-4 neutropenia and thrombocytopenia in all patients, and 27 % each had grade 3-4 hyperbilirubinemia or elevation of liver enzymes. One patient died during treatment due to intracranial hemorrhage. Of the six patients proceeding to second SCT or receiving DLI, three patients developed mild veno-occlusive disease (VOD). Combination therapy with ARA-C and GO after SCT results in short-term disease control and limited toxicity and could be considered for patients who are candidates for further immunotherapy.

Outcome differences in patients with precursor B cell acute lymphocytic leukemia over time: a retrospective analysis.

BACKGROUND: Acute lymphocytic leukemia (ALL) is a rare disease with a poor outcome in adults. Over the years different protocols have been developed with the aim of improving the outcome. The German study group protocols (GMALL), which are the most frequently used in our institutions, changed significantly between the periods 1989-93 and 1999-2003. OBJECTIVES: To investigate whether the change in protocols over the years resulted in an outcome difference at two hospitals in Israel. METHODS: We thoroughly reviewed the records of 153 patients from Sheba Medical Center and Soroka Medical Center, of whom 106 comprised the study group. The patients were divided into two groups according to the treatment protocol used: 40 patients with the 1989/93 protocol and 66 with the 1999/2003 protocol. Outcome was analyzed for the two groups. RESULTS: We found a significant difference in disease-free survival (DFS) between the two groups for B cell-ALL (B-ALL) patients who achieved complete remission after induction. There was no difference in overall survival. We did not find any difference in outcome for T cell-ALL patients or for CD20-positive patients. CONCLUSIONS: In our retrospective analysis, GMALL 99/2003 led to a better DFS for B-ALL patients who were in complete remission after induction. This is possibly related to the differences in medications between the protocols but may also be due to better supportive care. Despite the proven advantage of the newer protocols regarding overall survival, in our experience there was no other significant difference between the two regimens.

Digoxin-associated decrease in parathyroid hormone (PTH) concentrations in patients with atrial fibrillation.

BACKGROUND: Parathyroid hormone (PTH) secretion is regulated mainly by the calcium sensor receptor. Recently, other components of calcium homoeostasis have been revealed, namely the effect of Klotho on stimulation of PTH secretion by the recruitment of Na-K-ATPase and by its being a cofactor in the inhibitory effect of FGF 23 on PTH secretion. It seems that ouabain, a Na-K-ATPase inhibitor, prevents the increase in PTH secretion in a hypocalcemic environment, as observed in mouse and bovine tissues. We hypothesized that digoxin, which is similar to ouabain in its effect on the sodium pump, might decrease PTH levels in humans. METHODS: Twenty patients with atrial fibrillation were studied. Ten patients were treated with digoxin and the other ten patients with verapamil. Baseline chemistry parameters were determined and 0·25 mg digoxin injected. Plasma PTH concentrations, ionized calcium concentrations and digoxin levels were recorded at 30 min, 1 h, 2 h and 4 h postinjection. RESULTS: Baseline blood parameters were similar in both groups. In the control group plasma PTH concentrations increased, whereas in the digoxin group, they decreased. Ionized calcium concentrations did not change over time in either groups. There seemed to be blunting of the circadian rhythm of PTH levels in the morning hours. CONCLUSIONS: Although the patients were normocalcemic, plasma PTH concentrations decreased with digoxin treatment. The effect of the sodium pump on PTH secretion might be important in human PTH homoeostasis and might be a potential target for the treatment of disturbances in calcium homoeostasis.