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The phase III GALLIUM trial assessed the safety and efficacy of obinutuzumab-based versus rituximab-based immunochemotherapy in patients with previously untreated follicular lymphoma (FL) or marginal zone lymphoma (MZL). At the primary analysis, the trial met its primary end point, demonstrating improvement in investigator-assessed progression-free survival (PFS) with obinutuzumab-based versus rituximab-based immunochemotherapy in patients with FL. We report the results of the final analysis in the FL population, with an additional exploratory analysis in the MZL subgroup. Overall, 1202 patients with FL were randomized 1:1 to obinutuzumab- or rituximab-based immunochemotherapy followed by maintenance with the same antibody for up to 2 years. After a median 7.9 (range, 0.0–9.8) years of follow-up, PFS remained improved with obinutuzumab- versus rituximab-based immunochemotherapy, with 7-year PFS rates of 63.4% versus 55.7% (P = 0.006). Time-to-next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR (P < 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported. These data demonstrate the long-term benefit of obinutuzumab-based immunochemotherapy and confirm its role as a standard-of-care for the first-line treatment of advanced-stage FL, taking into account patient characteristics and safety considerations.

Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50–70 days post-auHSCT, followed by the second dose at 1–2 months (M) later. In cohorts of 114–1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing ≥2 of four assessed activation markers) were similar between 18–49 and ≥50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response.

Effective and tolerable treatments are needed for older patients with classical Hodgkin lymphoma. We report results for older patients with classical Hodgkin lymphoma treated in the large phase III ECHELON-1 study of frontline brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Modified progression-free survival per independent review facility for older versus younger patients (aged ≥60 vs.

Abstract Objectives A congenital loss of cytotoxic lymphocyte activity leads to a potentially fatal immune dysregulation, familial haemophagocytic lymphohistiocytosis. Until recently, this disease was uniformly associated with infants or very young children, but it appears now that the onset may be delayed for decades. As a result, some adults are being mis‐ or under‐diagnosed because of their ‘atypical’ symptoms that are not recognised as immunodeficiency. The clinical picture and histopathology can overlap with those of haematologic malignancy, further complicating the diagnostic thought process. The spectrum of atypical symptoms is poorly defined, and therefore, it is important to describe these cases and the attendant immunological and cellular changes associated with familial haemophagocytic lymphohistiocytosis, in order to improve diagnosis and prevent unintended consequences of symptomatic therapies. Methods A 45‐year‐old patient presented with suspected T‐cell lymphoma and was treated with combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone) supplemented with granulocyte‐colony stimulating factor (G‐CSF). To mobilise stem cells for autologous transplantation, the patient was then treated with high‐dose G‐CSF and rapidly developed haemophagocytic lymphohistiocytosis. Symptoms resolved temporarily with intensive immunosuppression with alemtuzumab and durably with a subsequent allograft. Results The patient was found to be a carrier of bi‐allelic mutations in the STXBP2 protein that is essential for cytotoxic lymphocyte function, and the initial diagnosis has been revised as familial haemophagocytic lymphohistiocytosis. Conclusion This case highlights the difficulty in distinguishing atypical/late‐onset familial haemophagocytic lymphohistiocytosis from a malignant process as well as a possible exacerbation of the disease with G‐CSF therapy.

Abstract: Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation. Age and dose were risk factors for pleural effusion (P < .01 and .047, respectively). Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced (P = .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions (P = .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.

We evaluated early disease progression and its impact on overall survival (OS) in previously untreated follicular lymphoma patients in GALLIUM (clinicaltrials.gov identifier: 01332968), and investigated the effect on early disease progression of the two randomization arms: obinutuzumab-based versus rituximab-based immunochemotherapy. Cause-specific Cox regression was used to estimate the effect of treatment on the risk of disease progression or death due to disease progression within 24 months of randomization and to analyze OS in patients with or without disease progression after 24 months. Mortality in both groups was analyzed 6, 12, and 18 months post randomization (median follow up, 41 months). Fewer early disease progression events occurred in obinutuzumab (57 out of 601) versus rituximab (98 out of 601) immunochemotherapy patients, with an average risk reduction of 46.0% (95%CI: 25.0-61.1%; cumulative incidence rate 10.1% vs. 17.4%). At a median post-progression follow up of 22.6 months, risk of mortality increased markedly following a progression event [HR of time-varying progression status, 25.5 (95%CI: 16.2-40.3)]. Mortality risk was higher the earlier patients progressed within the first 24 months. Age-adjusted HR for OS after 24 months in surviving patients with disease progression versus those without was 12.2 (95%CI: 5.6-26.5). Post-progression survival was similar by treatment arm. In conclusion, obinutuzumab plus chemotherapy was associated with a marked reduction in the rate of early disease progression events relative to rituximab plus chemotherapy. Early disease progression in patients with follicular lymphoma was associated with poor prognosis, with mortality risk higher after earlier progression. Survival post progression did not seem to be influenced by treatment arm.

Patients with X-linked agammaglobulinemia (XLA) have failure of B-cell development with lack of immunoglobulin (Ig) production. While immunoglobulin replacement therapy (IgRT) is beneficial, XLA patients remain at risk for infections, structural lung damage, and rarely, neoplasia. Allogeneic stem cell transplantation (alloSCT) may offer a potential cure, but is associated with significant life-threatening complications. Here, we present a 25-year old XLA patient who developed pre-B acute lymphocytic leukemia (ALL) with somatic TP53 mutation, and treatment for this high-risk malignancy involved full myeloablative conditioning and a HLA-matched sibling alloSCT. Full donor chimerism was achieved for CD3+ and CD3- cell fractions. The patient remains in morphological and flow cytometric remission 14 months post-transplant, with late-onset oral GvHD requiring low dose prednisolone and cyclosporin. Following IgRT discontinuation at 4 months post-transplantation, humoral immunity was established within 14 months as reflected by normal numbers of total B cells, memory B cells, serum IgG, IgM, and IgA, and production of specific IgG responses to Prevenar-13 vaccination. This is only the second reported case of an XLA patient with pre-B-ALL, and the most detailed report of engraftment following alloSCT in XLA. Together with the two previous XLA cases treated with alloSCT, our report provides evidence for the potential for successful humoral reconstitution with alloSCT in patients with B-cell intrinsic antibody deficiency. These observations may be relevant given IgRT, while beneficial, remains an imperfect solution to long-term infectious complications.

Abstract. The proportion of patients with acute myeloid leukemia (AML) cured is increased by administering high-dose cytarabine (HiDAC). It remains uncertain whether to administer HiDAC as induction or consolidation, and whether ≥1 cycle of HiDAC is required. Our retrospective study of 416 adult AML patients, excluding good risk cytogenetics, compared a single cycle of HiDAC-based therapy followed by 2 cycles of standard-dose cytarabine (SDAC) (HiDAC induction cohort) with SDAC-based chemotherapy followed by 2 cycles of HiDAC-based chemotherapy (HiDAC consolidation cohort). Complete remission (CR) rate was greater in the HiDAC induction cohort (90% vs 78%, P

While eradication from haul roads was achieved, more work is required to eradicate P. cinnamomi from stockpiles and bunds. We can now implement different management strategies to the construction of bunds and stockpiles to facilitate eradication. Infestation by Phytophthora cinnamomi results in large financial and management constraints to environmental managers. This pathogen was considered impossible to eradicate until recent success with treatments including host removal, herbicide and fungicide application, soil fumigation and physical root barriers. We investigated the most benign of these treatments; keeping the area devoid of living host material. In a Western Australian mine site within a Mediterranean climate, haul roads, stockpiles and roadside bunds had P. cinnamomi colonised Pinus stem plugs buried at multiple depths. Over time, we examined the effects of soil moisture and temperature in different soil conditions and types to compare the recovery of the pathogen. Results: Within 12 months, the pathogen could not be recovered from the haul roads. In the stockpiles, depth produced significantly different results. In 3 of the 4 sites, the pathogen was not recovered at 10 cm after 20 months. By 12 months, at 50 cm, there was an 80% reduction in recovery, but only one stockpile had no recovery from 50 cm, which occurred by 36 months. Bunds were up to 1.75 m high and had variable results for plugs buried at 30 cm, influenced by height, the types of soils and shading. One of the smallest bunds was the only bund where the pathogen was not recoverable (by 22 months). This study provides strong support for using a fallow period to reduce or eliminate P. cinnamomi inoculum.

The ability of cytotoxic lymphocytes (CL) to eliminate virus-infected or cancerous target cells through the granule exocytosis death pathway is critical to immune homeostasis. Congenital loss of CL function due to bi-allelic mutations in PRF1, UNC13D, STX11, or STXBP2 leads to a potentially fatal immune dysregulation, familial haemophagocytic lymphohistiocytosis (FHL). This occurs due to the failure of CLs to release functional pore-forming protein perforin and, therefore, inability to kill the target cell. Bi-allelic mutations in partner proteins STXBP2 or STX11 impair CL cytotoxicity due to failed docking/fusion of cytotoxic secretory granules with the plasma membrane. One unique feature of STXBP2- and STX11-deficient patient CLs is that their short-term in vitro treatment with a low concentration of IL-2 partially or completely restores natural killer (NK) cell degranulation and cytotoxicity, suggesting the existence of a secondary, yet unknown, pathway for secretory granule exocytosis. In the current report, we studied NK and T-cell function in an individual with late presentation of FHL due to hypomorphic bi-allelic mutations in STXBP2. Intriguingly, in addition to the expected alterations in the STXBP2 and STX11 proteins, we also observed a concomitant significant reduction in the expression of homologous STXBP1 protein and its partner STX1, which had never been implicated in CL function. Further analysis of human NK and T cells demonstrated a functional role for the STXBP1/STX1 axis in NK and CD8+ T-cell cytotoxicity, where it appears to be responsible for as much as 50% of their cytotoxic activity. This discovery suggests a unique and previously unappreciated interplay between STXBP/Munc proteins regulating the same essential granule exocytosis pathway.

The GAUDI study assessed safety and preliminary efficacy of induction therapy with obinutuzumab plus chemotherapy, followed by maintenance therapy with obinutuzumab alone, in previously untreated patients with follicular lymphoma. Assignment to chemotherapy was decided on a per-center basis before the patients’ enrollment. Patients (n=81) received four to six cycles of obinutuzumab plus bendamustine every 4 weeks or six to eight cycles of obinutuzumab plus CHOP every 3 weeks. Patients with an end-of-treatment response were eligible for obinutuzumab maintenance therapy every 3 months for 2 years or until disease progression. Induction treatment was completed by 90% of patients in the obinutuzumab plus bendamustine group and 95% in the obinutuzumab plus CHOP group, while maintenance was completed by 81% and 72% of patients, respectively. All patients experienced at least one adverse event during induction, most commonly infusion-related reactions (58%), the majority of which were grade 1/2. The most common hematologic adverse event was grade 3/4 neutropenia (36% during induction and 7% during maintenance). One treatment-related death occurred during the maintenance phase. At the end of induction, 94% of patients had achieved an overall response, with complete response based on computed tomography in 36%. The progression-free survival rate at 36 months was 90% in the obinutuzumab plus bendamustine group and 84% in the obinutuzumab plus CHOP group. These results demonstrate that induction therapy with obinutuzumab plus bendamustine or obinutuzumab plus CHOP, followed by obinutuzumab maintenance, is associated with tolerable safety and promising efficacy. This study is registered at ClinicalTrials.gov as NCT00825149.

In the treatment of diffuse large B-cell lymphoma, a persistently positive [18F]fluorodeoxyglucose positron emission tomography (PET) scan typically carries a poor prognosis. In this prospective multi-center phase II study, we sought to establish whether treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90Y-ibritumomab tiuxetan–BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk diffuse large B-cell lymphoma patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year progression-free survival from a historically unfavorable rate of 40% to a rate of 65%. Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17–20 of cycle 4 and assessed according to International Harmonisation Project criteria. Median age of the 151 evaluable patients was 57 years, with 79% stages 3–4, 54% bulk, and 54% International Prognostic Index 3–5. Among the 143 patients undergoing interim PET, 101 (71%) were PET-negative (96 of whom completed R-CHOP), 42 (29%) were PET-positive (32 of whom completed R-ICE and 90Y-ibritumomab tiuxetan-BEAM). At a median follow up of 35 months, the 2-year progression-free survival for PET-positive patients was 67%, a rate similar to that for PET-negative patients treated with R-CHOP-14 (74%, P=0.11); overall survival was 78% and 88% (P=0.11), respectively. In an exploratory analysis, progression-free and overall survival were markedly superior for PET-positive Deauville score 4 versus score 5 (P=0.0002 and P=0.001, respectively). Therefore, diffuse large B-cell lymphoma patients who are PET-positive after 4 cycles of R-CHOP-14 and who switched to R-ICE and 90Y-ibritumomab tiuxetan-BEAM achieved favorable survival outcomes similar to those for PET-negative R-CHOP-14-treated patients. Further studies are warranted to confirm these promising results. (Registered at: ACTRN12609001077257).

Post-induction aplasia for acute myeloid leukemia/myelodysplastic syndrome is a high-risk period for invasive fungal diseases. The effectiveness of fluconazole, itraconazole solution, voriconazole and posaconazole prophylaxis used consecutively from December 1998 to January 2010 in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing remission-induction chemotherapy was retrospectively evaluated. A total of 216 consecutive patients received 573 prophylaxis courses. Breakthrough-invasive fungal disease incidence in fluconazole, itraconazole, voriconazole, posaconazole recipients was 25%, 16%, 14% and 3%, respectively. Voriconazole/posconazole versus fluconazole/itraconazole combined was associated with significant reductions in breakthrough-invasive fungal disease incidence (20% vs. 8%, P=0.011), premature discontinuations (46% vs. 22% P

Background Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols.Design and Methods In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine.Results Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P