Infection risk and antimicrobial prophylaxis in bendamustine-treated patients with indolent non-Hodgkin lymphoma: An Australasian Lymphoma Alliance study.

Infection and lymphopenia are established bendamustine-related complications. The relationship between lymphopenia severity and infection risk, and the role of antimicrobial prophylaxis, is not well described. This multicentre retrospective study analysed infection characteristics and antimicrobial prophylaxis in 302 bendamustine-treated indolent non-Hodgkin lymphoma patients. Lymphopenia (<1 × 109 /L) was near universal and time to lymphocyte recovery correlated with cumulative bendamustine dose. No association between lymphopenia severity and duration with infection was observed. Infections occurred in 44% of patients (50% bacterial) with 27% hospitalised; 32% of infections occurred ≥3 months post bendamustine completion. Infection was associated with obinutuzumab and/or maintenance anti-CD20 therapy, prior therapy and advanced stage. Twenty-four opportunistic infections occurred in 21 patients: ten varicella zoster virus (VZV), seven herpes simplex virus (HSV), one cytomegalovirus, one progressive multifocal leucoencephalopathy, one nocardiosis, one Pneumocystis jiroveci pneumonia (PJP) and three other fungal infections. VZV/HSV and PJP prophylaxis were prescribed to 42% and 54% respectively. Fewer VZV/HSV infections occurred in patients receiving prophylaxis (HR 0.14, p = 0.061) while PJP prophylaxis was associated with reduced risk of bacterial infection (HR 0.48, p = 0.004). Our study demonstrates a significant infection risk regardless of lymphopenia severity and supports prophylaxis to mitigate the risk of early and delayed infections.

Chronic lymphocytic leukaemia Australasian consensus practice statement.

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in Australia and New Zealand (ANZ). Considerable changes to diagnostic and management algorithms have occurred within the last decade. The availability of next-generation sequencing and measurable residual disease assessment by flow cytometry allow for advanced prognostication and response assessments. Novel therapies, including inhibitors of Bruton's tyrosine kinase (BTKi) and B-cell lymphoma 2 (BCL2) inhibitors, have transformed the treatment landscape for both treatment-naïve and relapsed/refractory disease, particularly for patients with high-risk genetic aberrations. Recommendations regarding appropriate supportive management continue to evolve, and special considerations are required for patients with CLL with respect to the global SARS-CoV-2 pandemic. The unique funding and treatment environments in Australasia highlight the need for specific local guidance with respect to the investigation and management of CLL. This consensus practice statement was developed by a broadly representative group of ANZ experts in CLL with endorsement by peak haematology bodies, with a view to providing this standardised guidance.

Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial.

PURPOSE: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). PATIENTS AND METHODS: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. RESULTS: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2-8) cycles. CONCLUSIONS: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.

Robust SARS-CoV-2 T cell responses with common TCRαß motifs toward COVID-19 vaccines in patients with hematological malignancy impacting B cells.

Immunocompromised hematology patients are vulnerable to severe COVID-19 and respond poorly to vaccination. Relative deficits in immunity are, however, unclear, especially after 3 vaccine doses. We evaluated immune responses in hematology patients across three COVID-19 vaccination doses. Seropositivity was low after a first dose of BNT162b2 and ChAdOx1 (∼26%), increased to 59%-75% after a second dose, and increased to 85% after a third dose. While prototypical antibody-secreting cells (ASCs) and T follicular helper (Tfh) cell responses were elicited in healthy participants, hematology patients showed prolonged ASCs and skewed Tfh2/17 responses. Importantly, vaccine-induced expansions of spike-specific and peptide-HLA tetramer-specific CD4+/CD8+ T cells, together with their T cell receptor (TCR) repertoires, were robust in hematology patients, irrespective of B cell numbers, and comparable to healthy participants. Vaccinated patients with breakthrough infections developed higher antibody responses, while T cell responses were comparable to healthy groups. COVID-19 vaccination induces robust T cell immunity in hematology patients of varying diseases and treatments irrespective of B cell numbers and antibody response.

Prospective comprehensive profiling of immune responses to COVID-19 vaccination in patients on zanubrutinib therapy.

Zanubrutinib-treated and treatment-naïve patients with chronic lymphocytic leukaemia (CLL) or Waldenstrom's macroglobulinaemia were recruited in this prospective study to comprehensively profile humoral and cellular immune responses to COVID-19 vaccination. Overall, 45 patients (median 72 years old) were recruited; the majority were male (71%), had CLL (76%) and were on zanubrutinib (78%). Seroconversion rates were 65% and 77% following two and three doses, respectively. CD4+ and CD8+ T-cell response rates increased with third dose. In zanubrutinib-treated patients, 86% developed either a humoral or cellular response. Patients on zanubrutinib developed substantial immune responses following two COVID-19 vaccine doses, which further improved following a third dose.

Toxicity associated with high-dose intravenous methotrexate for hematological malignancies.

Intravenous high-dose methotrexate (HD-MTX) is a critical chemotherapeutic agent in hematological malignancies, however, data are lacking on how to predict and prevent toxicities such as kidney injury. We retrospectively analyzed 539 episodes of HD-MTX (≥1 g/m2) delivered to 144 patients for treatment of prophylaxis of CNS hematological malignancy across three Australian institutions and correlated risk factors with toxicity. Clinically relevant (CTCAE v4.03 grade 2-4) nephrotoxicity occurred on 36 (7%) occasions and was mostly grade 2. Multivariate analysis revealed that doses ≥6 g/m2 (HR 5.02, 95%CI 1.46-17.2, p = 0.01) and interacting/nephrotoxic drugs (HR: 7.15, 91%CI: 2.18-23.512, p = 0.001) were the only factors associated with nephrotoxicity. 48-hour methotrexate level, hypoalbuminemia and increasing age were associated with prolonged clearance but not nephrotoxicity. Mucositis, liver dysfunction and cytopenias were transient and mild in most cases. We have demonstrated that the most common risk factors for nephrotoxicity are modifiable which may assist clinical decision-making when administering this important drug.

Review of Venetoclax in CLL, AML and Multiple Myeloma.

Venetoclax is a highly selective and effective B-cell lymphoma-2 (BCL-2) inhibitor, which is able to reinstate the apoptotic potential of cancer cells. With its full repertoire yet to be explored, it has changed the therapeutic landscape in haematological malignancies, and most particularly chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML) and multiple myeloma (MM). In CLL, it has shown remarkable efficacy both as monotherapy and in combination therapy. Based on data from MURANO and CLL14 studies, fixed-duration combination therapy of venetoclax with anti-CD20 antibody is now the standard of care in numerous countries. In AML, although of limited efficacy as a single agent, venetoclax combination therapy has demonstrated encouraging outcomes including rapid, durable responses and acceptable toxicity, particularly in the older, unfit patient population. Multiple myeloma with translocation (t)(11;14) harbours high BCL-2/ myeloid cell leukaemia sequence-1 (MCL-1) and BCL-2/BCL-XL ratio and is, therefore, particularly suited for venetoclax-based therapy. Despite a wide ranging and evolving clinical role in these diseases, venetoclax treatment is not curative and, over time, clonal evolution and disease relapse appear to be the norm. While a variety of distinct resistance mechanisms have been identified, frequently emerging in a sub-clonal pattern, the full picture is yet to be characterised. Further illumination of the complex interplay of various factors is needed to pave the way for rational combination therapies aimed at circumventing resistance and improving durability of disease control. Serial molecular studies can aid in identification of new prognostically significant and/or targetable mutations.

Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: Beyond Ibrutinib.

Bruton tyrosine kinase inhibitors have indisputably transformed the treatment landscape of chronic lymphocytic leukemia, but require continuous therapy to maintain response. This places emphasis on their unique toxicity profile and potential loss of efficacy owing to resistance. Data from single-arm clinical studies are suggestive of comparable efficacy and favorable toxicity profiles of next-generation Bruton tyrosine kinase inhibitors. This is supported by the ASPEN study in Waldenstrom's macroglobulinemia, which convincingly demonstrated that zanubrutinib has a better toxicity profile than ibrutinib. Novel, reversible Bruton tyrosine kinase inhibitors are showing the potential to improve long-term efficacy by overcoming common mechanisms of resistance.

Management of Ibrutinib Toxicities: a Practical Guide.

PURPOSE OF REVIEW: Ibrutinib is a first-in-class, highly potent Bruton tyrosine kinase inhibitor which has become standard of care for patients with chronic lymphocytic leukaemia and other lymphoproliferative disorders. It requires indefinite administration which places emphasis on toxicity and long-term tolerance. RECENT FINDINGS: Extensive use of ibrutinib in studies and clinical practice has better defined its full toxicity profile which has made its use more challenging than initially foreseen. In particular, dysrhythmias, bleeding, infections and constitutional symptoms have been reported and can result in dose reduction or discontinuation of ibrutinib. Herein, we review the common as well as rare but important toxicities and discuss approach and management on a practical level. We also highlight that patients should be regularly monitored for adverse events and proactively treated to minimise side effects and avoid disruption.

Haematological features, transfusion management and outcomes of massive obstetric haemorrhage: findings from the Australian and New Zealand Massive Transfusion Registry.

Massive obstetric haemorrhage (MOH) is a leading cause of maternal morbidity and mortality world-wide. Using the Australian and New Zealand Massive Transfusion Registry, we performed a bi-national cohort study of MOH defined as bleeding at ≥20 weeks' gestation or postpartum requiring ≥5 red blood cells (RBC) units within 4 h. Between 2008 and 2015, we identified 249 cases of MOH cases from 19 sites. Predominant causes of MOH were uterine atony (22%), placenta praevia (20%) and obstetric trauma (19%). Intensive care unit admission and/or hysterectomy occurred in 44% and 29% of cases, respectively. There were three deaths. Hypofibrinogenaemia (<2 g/l) occurred in 52% of cases in the first 24 h after massive transfusion commenced; of these cases, 74% received cryoprecipitate. Median values of other haemostatic tests were within accepted limits. Plasma, platelets or cryoprecipitate were transfused in 88%, 66% and 57% of cases, respectively. By multivariate regression, transfusion of ≥6 RBC units before the first cryoprecipitate (odds ratio [OR] 3·5, 95% CI: 1·7-7·2), placenta praevia (OR 7·2, 95% CI: 2·0-26·4) and emergency caesarean section (OR 4·9, 95% CI: 2·0-11·7) were independently associated with increased risk of hysterectomy. These findings confirm MOH as a major cause of maternal morbidity and mortality and indicate areas for practice improvement.

The effect of tyrosine kinase inhibitor interruption and interferon use on pregnancy outcomes and long-term disease control in chronic myeloid leukemia.

The management of CML in pregnancy is challenging with the need to balance disease control against potential teratogenic effects of TKI therapy. In this multi-center case-cohort study of 16 women in chronic phase, CML ceased TKI treatment pre- or post-conception during their first pregnancy. Thirteen patients were on imatinib; 9 ceased their TKI prior to conception and 7 ceased at pregnancy confirmation. Twelve patients had achieved either MMR or better at time of TKI cessation. Eleven women lost MMR during pregnancy and two patients lost CHR. Fourteen women reestablished MMR on TKI recommenced. The depth molecular response prior to conception appeared to correlate well with restoration of disease control on TKI recommencement though duration of MMR did not appear to be as important. While interruption of TKI treatment for pregnancy usually leads to loss of molecular response, loss of hematological response is uncommon and disease control is reestablished with resumption of therapy in the majority of women.

Fertility in premenopausal women post autologous stem cell transplant with BEAM conditioning.

There is currently minimal data on fertility outcomes in premenopausal women undergoing autologous stem cell transplant (ASCT) with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. A retrospective analysis of fertility outcomes in premenopausal females aged between 18 and 40 yr who underwent BEAM/ASCT for lymphoma between 1995 and 2011 was performed at four transplant centres. Of 41 premenopausal women who underwent BEAM conditioning, 25 met the inclusion criteria with the main exclusion criterion being inadequate documentation. Eighteen had Hodgkin lymphoma, and seven had non-Hodgkin lymphoma. Median number of chemotherapy regimens pretransplant was 2 (1-3). Seventeen women (68%) with a median age at transplant of 25 yr (range 17-33) recovered their menses. The comparative group without recovery was older with a median age of 34 yr (range 20-40) (P = 0.007). Ten patients, with a median age at transplant of 22 yr (range 17-30), had 15 naturally conceived pregnancies. Chemotherapy regimens and lymphoma type did not obviously influence the incidence of menses recovery or conception. The incidence of recovery of menses and fertility in premenopausal women undergoing BEAM/ASCT for lymphoma is substantial. Younger age at transplant correlates with superior fertility outcomes.

Severe intravenous immunoglobulin-induced hemolysis with pigment nephropathy managed with red cell exchange.

We report on the use of red cell exchange in a case of severe intravenous immune globulin induced hemolysis and pigment nephropathy. Renal impairment and hemoglobinuria were not ameliorated by supportive measures including hydration. Partial red cell exchange with group O blood reduced hemoglobinuria and appeared to stabilize renal function. This is the first report on the use of red cell exchange in this clinical setting. J. Clin. Apheresis 31:464-466, 2016. © 2015 Wiley Periodicals, Inc.