Pentostatin (2′-deoxycoformycin; dCF) and cladribine (2-chlorodeoxyadenosine; CdA) are highly effective agents for the treatment of hairy cell leukemia. Although their precise mechanisms of action in this disease are still unknown, a number of mechanisms have been postulated. dCF is a potent inhibitor of adenosine deaminase (ADA), and treatment results in the accumulation of deoxyadenosine (dAdo) and adenosine (Ado) in the plasma. dAdo is phosphorylated by deoxycytidine kinase in lymphocytes to deoxyadenosine monophosphate (dAMP), which is subsequently converted to deoxyadenosine triphosphate (dATP). CdA is the chlorinated derivative of deoxyadenosine, is resistant to degradation by ADA, and accumulates in lymphocytes as CdATP. Both dATP and CdATP cause an initial accumulation of DNA strand breaks in lymphocytes and this results in the activation of p53, the release of cytochrome c from mitochondria, and apoptosis. CdA has several unique mechanisms of action over dAdo and these include the incorportation of CdATP into DNA, the inhibition of DNA polymerase β, and the phosphorylation of CdA to CdATP by deoxyguanosine kinase in mitochondria. These additional modes of action produce further DNA breaks in CdA-treated cells and explain the more potent activity of CdA compared to dCF and the greater myelosuppression with this agent. The cells die by apoptosis, but the DNA strand breaks also cause the activation of poly(ADP-ribose) polymerase (PARP), with resultant cellular depletion of nicotinamide adenine dinucleotide (NAD) and ATP. The induction of necrosis by PARP activation may explain the activity of these analogs in some patients with p53 mutations.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

In population studies, the relative survival in chronic lymphocytic leukemia (CLL) decreases with age. In this study, we demonstrated in a cohort of 189 patients from a CLL clinic that overall survival was lower in the sub-cohort of patients aged ≥ 70 years, but causes of death were similar for all age groups, being progressive CLL, secondary malignancies and infections. As normal individuals age, the plasma levels of inflammatory cytokines, such as interleukin-6 (IL-6) and IL-8, can increase. In our patients with CLL, IL-6, IL-8 and tumor necrosis factor-α (TNF-α) levels increased with age to a greater degree than in normal individuals, and the levels correlated closely with plasma β₂-microglobulin and with one another. In addition, in patients ≥ 70 years, IL-6 was found to be a better prognostic marker than immunoglobulin variable heavy chain gene (IgV_H) status. In vitro studies demonstrated that IL-6 and IL-8 could enhance the binding of CLL cells to stromal cells, suggesting that their clinical activity may be mediated through their effects on the microenvironment. Thus, plasma IL-6 is an important prognostic marker for the elderly with CLL, and this study highlights that the utility of prognostic markers may depend on patient age.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

A retrospective analysis on 587 patients with chronic lymphocytic leukemia (CLL) assessed risk factors for skin cancer and the influence of skin cancers on survival and incidence of solid tumors (STs). Patients underwent skin surveillance and were followed for a median of 6.65 years. The relative risk for skin cancer increased prior to CLL diagnosis rising 4-fold one-year post-diagnosis. Independent predictors for skin cancer were male gender (p = .0001), age ≥70 years (p = .0036) and prior chemotherapy (p = .0116). There was no increase in mortality from skin cancer and neither skin cancer nor chemotherapy increased the risk for a ST. The development of a ST was an independent predictor of survival (p < .0001) and 43% of deaths were related to STs. Thus, regular skin surveillance can prevent increased mortality from skin cancer, but not STs, in CLL. Close skin monitoring is required for elderly males who received chemotherapy.

To better understand the relationship between baseline immunoglobulin measurements and subsequent clinical outcomes in chronic lymphocytic leukemia (CLL), we performed a retrospective analysis on 660 patients with CLL (72%), monoclonal B-cell lymphocytosis (MBL) (13%), and small lymphocytic lymphoma (SLL) (14%), diagnosed between 2005 and 2014 at CancerCare Manitoba. Of 511 patients who had their first immunoglobulin level determined within 3 months of diagnosis, abnormal (either increased or decreased) immunoglobulin M (IgM), IgG, and IgA values were observed in 58% of patients with CLL, 27% of patients with MBL, and 20% of patients with SLL. Immunoglobulin deviances were similar for MBL and CLL Rai stage 0 and for SLL and Rai stages I and II; for CLL, IgG and IgA abnormalities occurred with increasing frequency with advancing Rai stage. In contrast, the frequency of IgM abnormalities was similar in all patient groups. IgA abnormalities significantly correlated with high β2-microglobulin (B2M) expression, whereas abnormal IgG and IgA levels were associated with the use of IGHV1-69, 3-21, and 3-49 subtypes. Increases in IgG or IgM were commonly associated with the presence of a CLL-type M-band, whereas oligoclonal bands were frequently observed with increased IgA levels. Although abnormal levels of IgG and IgA at diagnosis were independent predictors for future immunoglobulin replacement, only abnormal IgA levels were associated with shorter time to first treatment and overall survival. These findings indicate that both reduced and elevated levels of IgG and IgA at diagnosis are important and independent prognostic markers for infection in CLL, with IgA being more relevant as a marker of disease progression and survival.