Acalabrutinib and high-frequency low-dose subcutaneous rituximab for initial therapy of chronic lymphocytic leukemia.

Bruton tyrosine kinase inhibitors are an effective therapeutic agent for previously untreated patients with chronic lymphocytic leukemia but require indefinite treatment that can result in cumulative toxicities. Novel combinations of agents that provide deep remissions could allow for fixed duration therapy. Acalabrutinib, unlike ibrutinib, does not inhibit anti-CD20 monoclonal antibody-dependent cellular phagocytosis, making it a suitable partner drug to rituximab. Using standard dosing (375 mg/m2) of rituximab causes loss of target membrane CD20 cells and exhaustion of the finite cytotoxic capacity of the innate immune system. Alternatively, using high-frequency, low-dose (HFLD), subcutaneous rituximab limits loss of CD20 and allows for self-administration at home. The combination of HFLD rituximab 50 mg administered twice a week for 6 cycles of 28 days with the addition of acalabrutinib starting in week 2 was evaluated in a phase II study of 38 patients with treatment naive chronic lymphocytic leukemia. Patients achieving a complete response with undetectable minimal residual disease after 12 or 24 cycles of acalabrutinib could stop therapy. All patient responded, including one with a complete response with undetectable minimal residual disease in the peripheral blood and bone marrow at 12 months who stopped therapy. At a median follow-up of 2.3 years 2 patients with high-risk features have progressed while on acalabrutinib monotherapy. We conclude that HFLD rituximab in combination with acalabrutinib is an effective and tolerable self-administered home combination that provides a platform to build upon regimens that may more reliably allow for fixed-duration therapy. This trial was registered at www.clinicaltrials.gov #NCT03788291.

Influenza in New Zealand Before 1918: A Preliminary Report.

In the present article, I aimed to test the hypothesis that possible fatal immunological reactions to the A/H1N1 virus of the 1918 "Spanish" influenza pandemic were the result of previous exposure to the A/H3N8 virus of the 1890-1892 "Russian" influenza pandemic. Using newspapers and official death records to reconstruct mortality peaks from influenza and excess pneumonia deaths in New Zealand before 1918 enabled comparisons with peaks of influenza mortality by age in 1918 from individual death records. For males, mortality peaks in the 1885, 1890-1892, 1894, and 1898 influenza outbreaks appeared to match those from the 1918 pandemic. For females, peaks of deaths in 1918 corresponded to those from the influenza outbreaks of 1887 and 1890-1892. The highest mortality rates for both sexes were among those 28-32 years of age. Although they lend strong support to the hypothesis of fatal immunological reactions derived from early exposure to a different influenza virus, the results from this study also raise more questions: Given that the A/H1N1 virus of 1918 was exceptionally virulent, why did so few children 5-15 years of age die from it? Influenza normally kills only the very young and the very old. In addition, why did twice as many European males as females die in the young-adult age groups, whereas Maori males and females died at almost identical rates?

Remembering the 1918 influenza pandemic: national survey of memorials and scope for enhancing educational value around pandemic preparedness.

AIM: To systematically identify physical memorials to the 1918 influenza pandemic in an entire country. METHODS: Internet searches, contact with local historians and field expeditions were conducted. RESULTS: Despite the high impact of the 1918 influenza pandemic in New Zealand (~8,600 deaths), only seven publicly accessible local memorials which referred this pandemic were identified. Another 11 memorials were identified, but these were in private settings or did not refer to the pandemic. There is no national memorial and a marked contrast exists with the number of war memorials (260 times more per 1,000 deaths for one war), and for 20 smaller mass fatality events (one of which has eight memorials alone). The current educational value of these pandemic memorials is likely to be minimal since only three are in cities, there is a lack of supporting signage and there are no links to online resources. CONCLUSIONS: Despite the major impact of the 1918 influenza pandemic in New Zealand, publicly accessible memorials were found to be rare. This was in marked contrast to other disaster-related memorials and particularly to war memorials. There appears to be major scope for enhancing public education around the persisting threat of future pandemics via improved use of physical memorials and linkages to online resources.

Was rurality protective in the 1918 influenza pandemic in New Zealand?

AIMS: This study aimed to examine the impact of rurality on mortality rates from pandemic influenza in New Zealand in 1918. METHODS: Mortality data was obtained from death certificates (in a published source) and denominator population data from the 1916 census (for the European population only). Analyses were conducted on cities (n = 4), towns (n = 111), counties (n = 97). RESULTS: The influenza mortality rate for the towns and cities was more than twice that of the counties that represented rural settings (rate ratio (RR) = 2.13, 95% CI = 2.00-2.27). However, larger towns (population >2000 people) had a significantly lower mortality rate than smaller towns (RR = 0.81, 95%CI = 0.74-0.88). Similarly, cities had a lower mortality rate than larger towns (RR = 0.89, 95%CI = 0.83-0.95). CONCLUSIONS: These results are suggestive that rurality may have provided some protection from mortality during this influenza pandemic. This may have been due to a mix of remoteness and greater social distancing among rural residents. However, the differences in mortality rates between towns and cities may have reflected other factors such as the more organised provision of community care in the larger towns and cities, when compared to smaller towns.