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Background The aim of this study was to evaluate patient preference and satisfaction for the subcutaneous (s.c.) versus intravenous (i.v.) formulation of rituximab given with chemotherapy in previously untreated patients with CD20+ diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients and methods Patients received eight cycles of rituximab according to 2 schedules: Arm A received 1 cycle rituximab i.v. (375 mg/m2) and 3 cycles rituximab s.c. (1400 mg) then 4 cycles rituximab i.v.; Arm B received 4 cycles rituximab i.v. (375 mg/m2) then 4 cycles rituximab s.c. (1400 mg). Alongside rituximab, both arms received 6–8 cycles of chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), cyclophosphamide, vincristine, prednisone (CVP), or bendamustine as per standard local practice). Preference for s.c. or i.v. administration was evaluated using the Patient Preference Questionnaire (PPQ) at cycles 6 and 8. Patient satisfaction and convenience were assessed using the Cancer Therapy Satisfaction Questionnaire (CTSQ), and Rituximab Administration Satisfaction Questionnaire (RASQ) at cycles 4 and 8. Results At the primary data cut-off (19 January 2015), the intent-to-treat population comprised 743 patients. The majority had DLBCL (63%) and baseline characteristics were balanced between arms. At cycle 8, 81% of patients completing the PPQ preferred rituximab s.c. Preference was not impacted by treatment sequence or disease type. Patient satisfaction as measured by RASQ was higher for s.c. versus i.v. CTSQ scores were similar between arms. Adverse events were generally balanced between administration routes and no new safety signals were detected. Conclusion Most previously untreated patients with CD20+ DLBCL or FL preferred s.c. to i.v. rituximab administration. Patient satisfaction with rituximab treatment was generally greater with s.c. administration. Registered clinical trial number NCT01724021 (ClinicalTrials.gov).

In patients with hematological malignancies at high risk for relapse, a mismatched hematopoietic stem cells transplants can be offered with no undue delay between decision-making and transplantation as virtually all patients have a full-haplotype mismatched member who could serve immediately as a donor. Using a T-cell depletion approach, these patients can benefit from a graft-vs-leukemia effect in the absence of both acute and chronic graft-vs-host disease. Over the past decade, efforts have concentrated on developing new conditioning regimens, optimizing the graft processing and improving the posttransplant immunological recovery. The innovative strategy based on the selective depletion of alpha/beta-positive T lymphocytes from G-CSF-mobilized peripheral blood precursor cells has shown very promising results in the setting of the pediatric transplantation. This paper reports the outcome in adult patients with hematological malignancies.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disorder characterized by intravascular hemolysis, thrombosis and bone marrow failure. Acute kidney injury, including acute renal failure, have been reported in patients with PNH. We report the case of a 36-year-old male patient with PNH who developed acute kidney injury following an infection of undetermined diagnosis. Although hemolysis was initially controlled and renal function stabilized following packed red blood cell transfusion and empirical levofloxacin and prednisone, he later experienced recurrent episodes of hemolysis and hematuria requiring monthly red blood cell support. Given the high risk of thromboembolic events, treatment with standard-dose eculizumab was started. The patient’s hematologic values improved, renal function was maintained, and no thromboembolic events occurred.

Background Rituximab in combination with chemotherapy is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). To improve patient convenience and to reduce healthcare resource burden, a subcutaneous (SC) formulation of rituximab has been developed and has been shown to be clinically comparable to intravenous (IV) rituximab. The aim of this study was to evaluate patient preference for rituximab IV or SC administration. Methods Prefmab (NCT01724021) is a randomized, open-label, crossover phase IIIb study. Eligible patients were aged ≥18 to ≤80 years with previously untreated CD20+ DLBCL (IPI 1-4 or 0 with bulky disease) or FL (FLIPI grade 1-3a), at least 1 bidimensionally measureable lesion ≥1.5cm at its largest dimension by computed tomography, and an ECOG performance status ≤3; all provided written informed consent. Patients received 8 cycles of rituximab according to 2 schedules: Arm A received 1 cycle of rituximab IV (375mg/m2) and 3 cycles of rituximab SC (1400mg) then 4 cycles of rituximab IV; Arm B received 4 cycles of rituximab IV (375mg/m2) then 4 cycles of rituximab SC (1400mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (CHOP [cyclophosphamide, doxorubicin, oncovin, prednisone], CVP [cyclophosphamide, vincristine, prednisone], or bendamustine as per standard local practice). A Patient Preference Questionnaire (PPQ) was conducted post-rituximab therapy at cycles 6 and 8. The primary endpoint was overall preference for rituximab IV or SC. The strength of patient preference was also assessed (very strong, fairly strong, or not very strong). Adverse events (AEs), including administration-related reactions, were evaluated according to NCI-CTCAE version 4.0. Results At the primary data cut-off (January 19, 2015), the intent-to-treat population comprised 743 patients (Arm A: n=372; Arm B: n=371). The majority of patients had DLBCL (63%). The median age was 60 years (range 18-80) and baseline characteristics were balanced between arms. One hundred and twenty patients discontinued immunochemotherapy treatment prematurely, primarily due to AEs (n=52), but entered follow-up. A further 108 patients (Arm A: n=48; Arm B: n=60) discontinued the study and did not complete follow-up, primarily due to death (53 patients [DLBCL: n=48; FL: n=5], 19 of whom died due to progressive disease [DLBCL: n=16; FL: n=3]), patient request/withdrawal of consent (n=23), or AEs (n=9). Rates of study discontinuation and treatment discontinuation were balanced between arms. The PPQ was completed by 620 patients at cycle 6 and 591 at cycle 8. At cycle 6, rituximab SC was preferred by 80% (n=495) of patients (Arm A: 79%; Arm B: 81%) and rituximab IV by 10% (n=62; Arm A: 11%; Arm B: 9%), while 10% (n=63) had no preference (Arm A: 10%; Arm B: 10%). At cycle 8, the respective values were 81% (n=477; Arm A: 77%; Arm B: 84%), 11% (n=66; Arm A: 13%; Arm B: 10%), and 8% (n=48; Arm A: 10%; Arm B: 6%). The strength of patient preference for rituximab SC or IV is shown in Figure 1. Of patients who preferred rituximab SC, the main reasons were 'less time in the clinic' (cycle 6: 68%; cycle 8: 69%) and 'feels more comfortable during administration' (cycle 6: 37%; cycle 8: 37%). The mean cumulative rituximab administration time (mean ± standard deviation) was 865 ± 401 min for rituximab IV compared with 37 ± 100 min for rituximab SC. AEs were generally balanced between rituximab IV and SC administration, with the exception of gastrointestinal disorders (IV: 55%; SC: 31%) in patients with FL, notably nausea (IV: 28%; SC: 11%), constipation (IV: 14%; SC: 6%), and vomiting (IV 12%; SC 2%). No new safety signals were detected. Conclusions Most previously untreated patients with CD20+ DLBCL or FL preferred SC compared with IV administration of rituximab, mainly due to reduction in the duration and discomfort of administration. Figure 1. Figure 1. Disclosures Rummel: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plenteda:Roche: Other: Sub-investigator. Mendoza:Roche: Employment. Smith:Roche: Employment. Osborne:Roche: Employment. Grigg:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Among the three classic Philadelphia-negative myeloproliferative neoplasms (Phneg MPN), myelofibrosis (MF) is the most severe in terms of survival and quality of life, with very limited therapeutic options. Although the pathogenesis of Phneg MPN remains still poorly understood, aberrant megakaryocytopoiesis is a common, distinctive feature. Specifically, in MF, bone marrow megakaryocytes (MKs) are hyperplastic and show typical morphological abnormalities such as hypolobated nuclei, tendency to form tight clusters and impaired capacity to generate pro-platelets (pro-PLTs) in-vitro. Recent data proved that MF-MK hyperplasia is a consequence of both increased proliferation and reduced apoptosis of MK progenitors, likely correlated to the over-expression of the anti-apoptotic gene Bcl-xL (Ciurea et al. Blood 2007). Protein Kinase Cε (PKCε) is a novel, calcium-independent PKC isoform, capable to modulate cell proliferation, differentiation and survival. Our group showed that PKCε plays a crucial role in normal and malignant hematopoiesis (Mirandola et al. Blood 2006; Gobbi et al. Stem Cells 2007; Gobbi et al. Blood 2009). During in-vitro erythroid and megakaryocytic differentiation of normal CD34+ progenitors, PKCε levels are finely tuned with a virtually opposite kinetic: progressively increasing during erythroid maturation while peaking early and then decreasing during MK maturation. Forced expression of PKCε in the later phases of megakaryocytopoiesis delays MK differentiation, proving that PKCε silencing is required for MK full differentiation. Here we investigated the expression of PKCε in primary myelofibrosis (PMF)-MK progenitors and we tested whether PKCε modulation may affect megakaryocytic differentiation of PMF-CD34+ cells. CD34+ cells were immunomagnetically isolated from 5 PMF patients and 2 G-CSF mobilized donors (controls, C) and then cultured up to 14 days in serum-free medium supplemented with 200 ng/mL thrombopoietin, 50 ng/mL Stem Cell Factor and 3 ng/mL Interleukin-3. MK differentiation was assessed by morphological analysis and in-vitro pro-PLT generation. Consistently with current literature, also in our serum-free based culture, PMF-MKs showed impaired differentiation associated with abnormal morphology (smaller size, round and hypolobated nuclei) and reduced pro-PLT generation when compared to C (Fig. 1 panel A). First, we demonstrated by Western Blot analysis (WB), that PMF-CD34+ displayed higher levels of PCKε, phosphorylated PKCε (pPKCε), Bcl-xL and Bcl-2 (Fig. 1, panel B ). Figure 1. Figure 1. This is consistent with their augmented proliferative capacity in MK-differentiating medium [median fold increase of PMF cultures was significantly higher than C (12.91 vs 1.09, respectively, p Additionally, during in-vitro MK differentiation, PKCε levels of PMF-MKs were significantly higher than C-MKs at any time point of the culture analyzed by WB (a representative picture is shown in Fig. 1, panel C). Consequently, we sought to determine whether PKCε inhibition was able to restore a normal in-vitro MK maturation assessed by: i) MK morphology ii) pro-PLT formation, iii) number of PLTs released in the culture medium (evaluated as number of CD41+/calcein AM+ cells, as described in Gobbi et al. Blood 2013). PKCε activity was pharmacologically modulated in two different experiments by the εV1-2 (CEAVSLKPT) peptide conjugated to TAT47-57 (CYGRKKRRQRRR) by a cysteine disulfide bound (Brandman J. Biol. Chem. 2007). As shown in Fig. 2, treatment with εV1-2 was capable to restore a normal MK morphology (panel A) and adequate pro-PLT formation (panel B). Addition of the sole vehicle (TAT47-57) in the culture medium did not provide any improvement on cell maturation, proving that the effects we observed were entirely attributable to PKCε-inhibition by εV1-2. Figure 2. Figure 2. Additionally, a clear trend in terms of increase of the number of PLTs released in the media of PMF cultures treated with εV1-2 was shown (Fig. 2, panel C). Our data demonstrate for the first time a potential involvement of PKCε in the pathogenesis of MF and that PKCε inhibition may revert, in-vitro, the abnormal megakaryocytopoiesis that typifies this neoplasm. Since PKC and PKCε are currently under investigational use in a number of diseases, PKCε inhibition may configure as a new potential therapeutic strategy for MF patients. Disclosures: No relevant conflicts of interest to declare.