Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

Background: This two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells. Patients and methods: Patients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab-containing regimen were enrolled into subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL and mantle cell lymphoma (MCL). Treatment was MOR208, 12 mg/kg intravenously, weekly, for 8 weeks. Patients with at least stable disease could continue treatment for an additional 4 weeks. Those with a partial or complete response after 12 weeks could receive extended MOR208 treatment (12 mg/kg, either monthly or every second week) until progression. The primary end point was overall response rate. Results: Ninety-two patients were enrolled: DLBCL (n = 35), FL (n = 34), other iNHL (n = 11) and MCL (n = 12). Responses were observed in DLBCL, FL and other iNHL cohorts (26%, 29% and 27%, respectively). They lasted ≥12 months in 5/9 responding patients with DLBCL, 4/9 with FL and 2/3 with other iNHL. Responses in nine patients are ongoing (>26 months in five instances). Patients with rituximab refractory disease showed a similar response rate and progression-free survival time to patients with non-refractory disease. The most common adverse events (any grade) were infusion-related reactions (12%) and neutropenia (12%). One patient experienced a grade 4 infusion-related reaction and eight patients (9%) experienced grade 3/4 neutropenia. No treatment-related deaths were reported. Conclusions: MOR208 monotherapy demonstrated promising clinical activity in patients with R-R DLBCL and R-R FL, including in patients with rituximab refractory tumors. These efficacy data and the favorable safety profile support further investigation of MOR208 in phase II/III combination therapy trials in R-R DLBCL. ClinicalTrials.gov number: NCT01685008.

Managing hematological cancer patients during the COVID-19 pandemic: an ESMO-EHA Interdisciplinary Expert Consensus.

BACKGROUND: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. METHODS: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. RESULTS AND CONCLUSION: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic.

Efficacy and safety of a nanofiltered liquid intravenous immunoglobulin product in patients with primary immunodeficiency and idiopathic thrombocytopenic purpura.

BACKGROUND AND OBJECTIVES: In the production process of a new 5% liquid intravenous immunoglobulin (IVIG-L) product (Nanogam(®) ), a combined pepsin/pH 4·4 treatment/15-nm filtration (pH 4·4/15NF) step and a solvent-detergent (SD) treatment step were incorporated to improve the virus inactivating/reducing capacity of the manufacturing process. Two prospective uncontrolled multicentre studies were performed to evaluate the safety and efficacy of this product. MATERIALS AND METHODS: Efficacy, including pharmacokinetics, of IVIG-L was studied for 6 months in 18 primary immunodeficiency (PID) patients, succeeded by a long-term follow-up study (mean 2·2 years, n=17). Second, in 24 patients with idiopathic thrombocytopenic purpura (ITP), IVIG-L was studied for efficacy for 14 days. In both studies, adverse events and vital signs were recorded to study safety. RESULTS: In PID patients treated with IVIG-L, 0·60 and 0·38 severe infections per patient per year were reported during, respectively, the short-term and long-term follow-up. Pharmacokinetic studies resulted in an IgG half-life of 30·9 ± 11·3 days and a mean IgG trough level of 6·8 ± 1·2 g/l. In the ITP study, all patients showed an increase in platelet counts after infusion with IVIG-L, and 20/24 patients responded with a platelet count >50 × 10(9) /l (83·3%) within 1 week. IVIG-L infusions did not cause clinical relevant changes in laboratory parameters or vital signs. CONCLUSIONS: In clinical studies, IVIG-L (Nanogam®) demonstrated to be efficacious, well tolerated and safe.

Correlation of Smac/DIABLO protein expression with the clinico-pathological features of breast cancer patients.

Smac/DIABLO protein promotes caspase-dependent apoptosis by inhibition of inhibitor of apoptosis protein (IAP) family members. The role of Smac/DIABLO in breast cancer has not been yet established. Therefore, the aim of the study was to assess the expression of this protein in tumor cells from breast cancer patients. The expression of Smac/DIABLO was analyzed in 62 breast cancer patients by flow cytometry. The obtained results were compared with expression of this protein in benign breast tumor tissue, which served as the control (11 patients with fibroadenoma). Expression of caspase-3 proteins in breast cancer was also evaluated. Smac/DIABLO expression in breast cancer was correlated with clinical and pathological data. Although the expression of Smac/DIABLO protein was found in all examined samples of both the breast cancer and fibroadenoma patients, the median expression of Smac/Diablo in breast cancer was significantly lower than in the control (39.1% vs. 48.1%; p=0.0047). Smac/DIABLO expression correlated with expression of caspase-3 (p=0.000008). In pT1 breast cancer patients, expression of Smac/DIABLO protein was higher than in those with pT2-3 (p=0.02). Diffuse cancer infiltration significantly correlated with lower expression of Smac/DIABLO protein (p=0.02). Moreover, there was a loose correlation between low expression of Smac/DIABLO protein and cancer embolus in minor blood and lymphatic vessels (p=0.08). Our results indicate that expression of Smac/DIABLO inversely correlates with the tumor stage, which may suggest that this protein may play an important role in the breast cancer development.

Distribution and clinical significance of blood dendritic cells in children with juvenile idiopathic arthritis.

BACKGROUND: A role for dendritic cells (DC) in the development of adult rheumatoid arthritis has been suggested. To date, this problem has been poorly explored in juvenile idiopathic arthritis (JIA). OBJECTIVE: To analyse distribution and maturation status of blood DC (BDC) in JIA. METHODS: Absolute BDC counts were assessed by the "single platform" method in peripheral blood (PB) of 47 untreated children with JIA and 32 healthy controls. Moreover, BDC were investigated in JIA synovial fluid (SF). When the panel of monoclonal antibodies against BDC antigens (BDCA) was used, three BDC subpopulations were determined: myeloid type 1 (mDC1; BDCA-1+/HLA-DR+/CD19-), myeloid type 2 (mDC2; BDCA-3+/HLA-DR+/CD14-) and plasmacytoid (pDC; BDCA-2+/HLA-DR+/CD123+). RESULTS: A considerable deficiency of all subtypes of BDC was found in the PB of children with JIA. BDC counts in JIA SF were significantly higher than in PB both from children with JIA (p<0.001) and healthy children (p<0.001). SF BDC, especially mDC1 and mDC2 subtypes, had significantly higher expression of maturation markers (CD40, CD80, CD86 or CD83 antigens) than those from PB. A smaller number of PB BDC at diagnosis correlated significantly with poor response to treatment. CONCLUSIONS: A deficiency of BDC in PB is accompanied by enrichment of SF with those cells. Probably, circulating BDC migrate to joints where they undergo maturation and help to mediate and maintain the local immune response. Interestingly, the level of PD BDC deficiency seems to influence the outcome in children with JIA.

The influence of palifermin (Kepivance) on oral mucositis and acute graft versus host disease in patients with hematological diseases undergoing hematopoietic stem cell transplant.

In this multicenter study, we assessed the use of palifermin (recombinant human-keratinocyte growth factor 1) in the prevention of oral mucositis (OM) and acute GvHD (aGvHD) induced by a hematopoietic stem cell transplant (HSCT). Fifty-three patients with hematological diseases received three doses of palifermin (60 mug/kg once daily i.v.) pre- and post-conditioning regimens (total six doses). A retrospective control group of 53 transplant patients received no palifermin. There was a significant reduction in the incidence of OM of WHO (World Health Organization) grades 1-4 (58 vs 94%, P<0.001), 3-4 (13 vs 43%, P<0.001) and the median duration of OM (4 vs 9 days, P<0.001) in the palifermin group compared to the control group. The incidence of analgesics (32 vs 75.5%, P<0.001), opioid analgesics (24 vs 64%, P<0.001) and total parenteral nutrition (11 vs 45%, P<0.001) was also significantly reduced. The analysis of distribution of affected organs revealed that aGvHD was less prevalent in the palifermin group (P=0.036). There was no significant difference in the onset of any OM after HSCT, time to engraftment and length of hospitalization between groups. The drug was generally well tolerated and safe. Our results suggest that the use of palifermin reduces OM and probably aGvHD after HSCT, but a randomized trial is needed.

The role of p73 in hematological malignancies.

The P73 gene is a homologue of the P53 tumor suppressor. Owing to its structural similarity with p53, p73 was originally considered to have tumor suppressor function. However, the discovery of N-terminal truncated isoforms with oncogenic properties showed a 'two in one' structure of its product, p73 protein. The full-length variants are strong inducers of apoptosis, whereas the truncated isoforms inhibit proapoptotic activity of p53 and the full-length p73. Thus, p73 is involved in the regulation of cell cycle, cell death and development. Moreover, it plays a role in carcinogenesis and controls tumor sensitivity to treatment. p73 is commonly expressed in tumor cells in hematological malignancies. Overexpression of p73 protein and aberrant expression of its particular isoforms, with very low frequency of P73 hypermethylation or mutations, were found in malignant myeloproliferations, including acute myeloblastic leukemia. In contrast, hypermethylation and subsequent inactivation of the P73 gene are the most common findings in malignant lymphoproliferative disorders, especially acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphomas. Assessment of P73 methylation may provide important prognostic information, as was confirmed in patients with ALL. This review summarizes some aspects of p73 biology with particular reference to its possible pathogenetic role and prognostic significance in hematological malignancies.

Pharmacological and clinical studies on purine nucleoside analogs--new anticancer agents.

More recently, three novel purine nucleoside analogs, including clofarabine, nelarabine and immucillin H, have been introduced into clinical trials. These agents have different metabolic properties, novel mechanism of action, and are undergoing phase I-II clinical studies for the treatment of hematopoietic malignancies. Pharmacology and anticancer activity of PNA are the subjects of this review.

Purine nucleoside analogues for the treatment of hematological malignancies: pharmacology and clinical applications.

The purine nucleoside analogues (PNAs), fludarabine (FA), 2-CdA (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2'-deoxycoformycin, DCF) represent a group of cytotoxic agents with high activity in lymphoid and myeloid malignancies. PNAs share similar chemical structure and mechanism of action. Several mechanisms could be responsible for their cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. Induction of apoptosis through the mitochondrial pathway, direct binding to apoptosome or modulation of p53 expression all lead to apoptosis, which is the main end-point of PNA action. However, individual PNAs exhibit significant differences, especially in their interaction with enzymes involved in adenosine and deoxyadenosine metabolism. Synergistic interactions between PNAs and other cytotoxic agents (alkylating agents, anthracycline antitumor antibiotics, cytarabine, monoclonal antibodies) have been demonstrated in both preclinical and clinical studies. PNAs are highly effective in chronic lymphoid leukemias and low grade B- and T-cell non-Hodgkin's lymphomas, including Waldenström's macroglobulinemia. DCF and 2-CdA are currently the drugs of choice in hairy cell leukemia. Moreover, clinical studies have confirmed the efficacy of PNAs alone or in combination protocols in the treatment of acute myeloid leukemia and myelodysplastic syndromes. Finally, PNAs, especially FA, play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients. The toxicity profiles of PNAs are similar for all agents and consist mainly of dose-limiting myelotoxicity and prolonged immunosuppression. Three other compounds: clofarabine, nelarabine and immucillin-H are currently being evaluated clinically.

Alkylating agents and nucleoside analogues in the treatment of B cell chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. The natural clinical course is highly variable and chemotherapy is usually not indicated in early and stable disease. Treatment is needed in the progressive form of this leukemia. Chlorambucil, with or without steroids, has been for many years the drug of choice in the treatment of CLL. More recently, treatment approaches have included nucleoside analogues, (NA) fludarabine (FAMP) and cladribine (2-CdA, 2-chlorodeoxyadenosine), which seem to be the treatment of choice for patients failing standard therapies. Their role as first line therapy is being investigated in randomized trials and the results have recently been published. These studies have shown a higher overall response and complete remission (CR) rate and longer response duration in patients treated initially with NA than with chlorambucil or cyclophosphamide-based combination regimens. In contrast, overall survival is similar in patients treated with NA and alkylating agents. However, the randomized trials were designed as crossover studies which may influence survival. Combined use of NA with other cytotoxic drugs, cytokines, monoclonal antibodies and other agents may increase the CR and prolong survival time. However, the results of randomized trials comparing combination treatment with NA alone are not yet available. In conclusion, alkylating agents still have an important place in the routine management of the majority of CLL patients. NA should be routinely used as second line treatment and possibly as first line therapy in younger patients, who are candidates for potentially curative treatment such as stem cell transplantation and/or monoclonal antibodies.

2-Chlorodeoxyadenosine (Cladribine) in the treatment of patients with chronic lymphocytic leukemia 55 years old and younger.

The aim of the study was to determine the effectiveness of 2-chlorodeoxyadenosine (2-CdA) administered in 2-h i.v. infusions in the treatment of B cell chronic lymphocytic leukemia (B-CLL) in patients 55 years old and younger. One hundred and thirteen patients received three to 10 courses of 2-CdA administered at a dose of 0.12 mg/kg daily for 5 consecutive days. Sixty-seven patients were previously treated with chlorambucil and prednisone, COP and some of them also with CHOP, and 46 were untreated. Complete remission (CR) was achieved in 21 (18.6%) (19 in untreated and two in previously treated) patients and partial response (PR) in 38 (33.6%) (23 and 15, respectively) giving an overall response rate in 52.2%. The differences in CR and overall response rate between previously treated and untreated patients were statistically significant (P = 0.001). Surface immunophenotyping by flow cytometry using dual-color staining on the peripheral blood and/or bone marrow was performed in 38 patients who responded to 2-CdA therapy. Residual disease had been demonstrated in five out of 17 (29.4%) patients who were in CR and in all 21 investigated PR patients. 2-CdA-induced thrombocytopenia occurred in 24 (35.8%) of previously treated and in 13 (28.3%) previously untreated patients (P = NS). Neutropenia was observed in eight (11.9%) and in five (10.9%) patients, respectively (P = NS). Severe infections, including pneumonia and sepsis, occurred more often in previously treated (44.8%) than untreated patients (26.1%) (P < 0.05). Twenty-seven (23.9%) patients died, 11 because of infections, five because of drug-related thrombocytopenia and hemorrhage, one because of second malignancy and eight because of disease progression. In conclusion, our results indicate that 2-CdA is an effective agent in younger patients with B-CLL, especially used as a first line therapy.

Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia.

The objective of the study was to determine the effectiveness and the toxicity of a combined chemotherapy consisting of cladribine (2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in the treatment of previously untreated B cell chronic lymphocytic leukemia (B-CLL). From August 1998 to December 2000 2-CdA was administered at a dosage of 0.12 mg/kg for 3 (CMC3) or 5 (CMC5) consecutive days, mitoxantrone at 10 mg/m2 on day 1 and cyclophosphamide at 650 mg/m2 on day 1 to 62 patients with advanced or progressive B-CLL. The cycles were repeated at 4 week intervals or longer if severe myelosuppression occurred. Twenty patients received CMC5 and 42 patients CMC3. Within the analyzed group an overall response (OR) rate (CR+PR) of 64.5% (95% CI: 52.7-76.3%) was reported, including 29.0% CR. There was no difference in the CR rate between the patients treated with CMC5 (30%) and CMC3 (28.6%) (P = 0.9), nor in the OR rate (55.0% and 69.0%, respectively, P = 0.3). Residual disease was identified in seven out of 18 (38.9%) patients who were in CR, including two treated with CMC5 and five treated with CMC3 protocols. CMC-induced grade III or IV thrombocytopenia occurred in 12 (19.4%) of patients, including four (20%) CMC5-treated and eight (19%) CMC3-treated patients (P= 0.8). Neutropenia grade III or IV was observed in seven (35%) and 11 (26.2%) patients, respectively (P = 0.8). Severe infections, including pneumonia and sepsis, occurred more frequently after CMC5 (11 patients, 55.0%) than CMC3 (10 patients, 28.6%) (P = 0.03) Fourteen patients died, including six treated with CMC5 and eight treated with CMC3 (30% and 19%, respectively). Infections were the cause of death in nine patients, including four in the CMC5 group and five in the CMC3 group. In conclusion, our results indicate that the CMC programme is an active combined regimen in previously untreated B-CLL patients; its efficiency seems to be similar to that observed earlier in B-CLL patients treated with 2-CdA as a single agent. However, toxicity, especially after CMC5 administration, is significant. Therefore, we recommend the CMC3 but not the CMC5 programme for further evaluation.

Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study.

To assess the efficacy of an original DAC-7 regimen: daunorubicine (DNR) 60 mg/m2/day, days 1-3; cytarabine (AraC) 200 mg/m2/day, days 1-7; cladribine (2-CdA) 5 mg/m2/day, days 1-5, 400 untreated adult acute myeloid leukemia patients (including 63 with preceding myelodysplastic syndrome), aged 45 (16-60) years were randomized to either DAC-7 (n=200) or DA-7 (without 2-CdA, n=200). The overall CR rate equaled 72% for DAC-7 and 69% for DA-7 arm (P=NS). After a single course of DAC-7 induction, the CR rate equaled 64% and was significantly higher compared to 47% in the DA-7 arm (P=0.0009). Median hospitalization time during the induction was 7 days shorter for DAC-7 compared to the DA-7 group (33 vs 40 days, P=0.002). Toxicity was comparable in both groups. The probability of 3-year leukemia-free survival (LFS) for DAC-7 and DA-7 group equaled 43 and 34%, respectively (P=NS). There was a trend toward higher LFS rate for patients aged >40 years receiving DAC-7 compared with DA-7 regimen (44 vs 28%, P=0.05). This study proves that addition of 2-CdA increases antileukemic potency of DNR+AraC regimen, thus resulting in a higher CR rate after one induction cycle when compared to DA-7, without additional toxicity. It shortens hospitalization time and may improve long-term survival in patients aged >40 years.

Prognostic factors in Hodgkin's disease: multivariate analysis of 327 patients from a single institution.

On the basis of a retrospective study of 327 patients with Hodgkin's disease (HD), the prognostic significance of several factors, accepted previously and recently proposed, has been analyzed with regard to response to treatment and the survival time. Multivariate regression analysis strongly decreased the number of potentially prognostic parameters. The only independent, pretreatment factors negatively influenced by either time of survival or response to treatment were the following: age at diagnosis of more than 45 years, advanced (IIIB/IV) clinical stage, poor clinical status according to Karnofsky's scale (score less than 70), presence of systemic symptoms, mixed cellularity/lymphocyte depletion histological type, multisite peripheral nodal localization of the disease, abdominal lymphadenopathy, and large primary tumor mass (bulky disease). Short time to achieve complete remission (during the first four courses of chemotherapy) has proven to be significantly positive predictive factor. Cumulative dose of cytostatics lower than programmed was a significantly negative prognostic factor that correlated with a shorter time of survival. Lack of or a too-low dose of radiotherapy had the same predictive value. High activity of serum lactate dehydrogenase correlated moderately with poor response to the first-line treatment but did not influence the survival time. Other clinical, morphological, and biochemical parameters influenced neither the prognosis nor the response to treatment. Additionally, immunohistochemical examinations for proliferating cell nuclear antigen and the protein products of the p53 and bcl-2 genes were performed on the lymph nodes obtained from the patients with HD. High expression of proliferating cell nuclear antigen, p53, and BCL-2 correlated with poor response to the treatment and/or short time of survival. Statistical analysis has led us to the conclusion that the pretreatment expression of these oncoproteins can be taken into consideration as a new prognostic factor in HD.

Abnormalities of the P53, MDM2, BCL2 and BAX genes in acute leukemias.

Abnormalities of the P53 network have been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). The purpose of this study was to define P53 gene mutations, to detect MDM2 gene amplification and to estimate mRNA expression of P53, MDM2, BCL2 and BAX genes in patients with ALL and AML. Twenty-five patients with ALL and 65 patients with AML, both recently diagnosed, were included into this study. Exons 5-8 of the P53 gene with flanking intronic sequence were amplified by the polymerase chain reaction (PCR) method and subjected to mutation screening by single-strand conformation polymorphism analysis (SSCP). Mutation of the P53 gene was found in one patient of the 25 with ALL and in five patients of the 65 with AML. Sequence analysis was subsequently performed. One mutation in intronic sequence in ALL and four missense mutations and one silent nucleotide substitution in AML were identified. Amplification of MDM2 gene was detected by multiplex-PCR analysis in only one sample from patient with ALL, but was not observed in any case of AML. To gain further insight into the role of P53 network in the evolution of acute leukemias, the P53, MDM2, BCL2 and BAX mRNAexpressions in portion samples from patients with ALL and AML were analyzed using multiplex RT-PCR. Although a low frequency of molecular disturbances of the P53 and the MDM2 genes was detected in this study, there was a high percentage of cases with increased mRNA level of P53 and MDM2. A high frequency of BCL2 mRNA overexpression and a relatively low frequency of BAX mRNA overexpression detected in both analyzed leukemias in this study, indicate that altered transcription of these genes may be involved in leukemogenesis.