RE-MIND: Comparing Tafasitamab + Lenalidomide (L-MIND) with a real-world lenalidomide monotherapy cohort in relapsed or refractory diffuse large B-cell lymphoma

Purpose: Tafasitamab, an Fc-modified, humanized, anti-CD19 monoclonal antibody, in combination with lenalidomide, demonstrated efficacy in transplant-ineligible patients with relapsed/refractory (R/R) diffuse largeB-cell lymphoma (DLBCL), in the single-arm, phase II L-MIND study (NCT02399085). RE-MIND, a retrospective observational study, generated a historic control for L-MINDto delineate the contribution of tafasitamab to the efficacy of the combination. Patients and Methods: Data were retrospectively collected from patients with R/R DLBCL treated with lenalidomide monotherapy for comparison with tafasitamab + lenalidomide-treated patients (L-MIND). Key eligibility criteria were aligned with L-MIND. Estimated propensity score-based Nearest Neighbor 1:1 Matching methodology balanced the cohorts for nine prespecified prognostic baseline covariates.The primary endpointwas investigator-assessed best overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). Results: Data from 490 patients going through lenalidomide monotherapy were collected; 140 qualified for matching with the L-MIND cohort. The primary analysis included 76 patients from each cohort who received a lenalidomide starting dose of 25 mg/day. Cohort baseline covariates were comparable. A significantly better ORR of 67.1% (95% confidence interval, 55.4-77.5) was observed for the combination therapy versus 34.2% (23.7-46.0) for lenalidomide monotherapy [odds ratio, 3.89 (1.90-8.14); P < 0.0001]. HigherCR rates were achieved with combination therapy compared with lenalidomide monotherapy [39.5% (28.4-51.4) vs. 13.2% (6.5-22.9)]. Survival endpoints favored combination therapy. Lenalidomide monotherapy outcomes were similar to previously published data. Conclusions: RE-MIND enabled the estimation of the additional treatment effect achieved by combining tafasitamab with lenalidomide in patients with R/R DLBCL

Wnt5a induces ROR1 to complex with HS1 to enhance migration of chronic lymphocytic leukemia cells.

ROR1 (receptor tyrosine kinase-like orphan receptor 1) is a conserved, oncoembryonic surface antigen expressed in chronic lymphocytic leukemia (CLL). We found that ROR1 associates with hematopoietic-lineage-cell-specific protein 1 (HS1) in freshly isolated CLL cells or in CLL cells cultured with exogenous Wnt5a. Wnt5a also induced HS1 tyrosine phosphorylation, recruitment of ARHGEF1, activation of RhoA and enhanced chemokine-directed migration; such effects could be inhibited by cirmtuzumab, a humanized anti-ROR1 mAb. We generated truncated forms of ROR1 and found its extracellular cysteine-rich domain or kringle domain was necessary for Wnt5a-induced HS1 phosphorylation. Moreover, the cytoplamic, and more specifically the proline-rich domain (PRD), of ROR1 was required for it to associate with HS1 and allow for F-actin polymerization in response to Wnt5a. Accordingly, we introduced single amino acid substitutions of proline (P) to alanine (A) in the ROR1 PRD at positions 784, 808, 826, 841 or 850 in potential SH3-binding motifs. In contrast to wild-type ROR1, or other ROR1P→︀A mutants, ROR1P(841)A had impaired capacity to recruit HS1 and ARHGEF1 to ROR1 in response to Wnt5a. Moreover, Wnt5a could not induce cells expressing ROR1P(841)A to phosphorylate HS1 or activate ARHGEF1, and was unable to enhance CLL-cell motility. Collectively, these studies indicate HS1 plays an important role in ROR1-dependent Wnt5a-enhanced chemokine-directed leukemia-cell migration

Splenic marginal zone lymphoma: a prognostic model for clinical use.

The Integruppo Italiano Linfomi (IIL) carried out a study to assess the outcomes of splenic marginal zone lymphoma and to identify prognostic factors in 309 patients. The 5-year cause-specific survival (CSS) rate was 76%. In univariate analysis, the parameters predictive of shorter CSS were hemoglobin levels below 12 g/dL (P < .001), albumin levels below 3.5 g/dL (P = .001), International Prognostic Index (IPI) scores of 2 to 3 (P < .001), lactate dehydrogenase (LDH) levels above normal (P < .001), age older than 60 years (P = .01), platelet counts below 100 000/μL (P = .04), HbsAg-positivity (P = .01), and no splenectomy at diagnosis (P = .006). Values that maintained a negative influence on CSS in multivariate analysis were hemoglobin level less than 12 g/dL, LDH level greater than normal, and albumin level less than 3.5 g/dL. Using these 3 variables, we grouped patients into 3 prognostic categories: low-risk group (41%) with no adverse factors, intermediate-risk group (34%) with one adverse factor, and high-risk group (25%) with 2 or 3 adverse factors. The 5-year CSS rate was 88% for the low-risk group, 73% for the intermediate-risk group, and 50% for the high-risk group. The cause-specific mortality rate (x 1000 person-years) was 20 for the low-risk group, 47 for the intermediate-risk group, and 174 for the high-risk group. This latter group accounted for 54% of all lymphoma-related deaths. In conclusion, with the use of readily available factors, this prognostic index may be an effective tool for evaluating the need for treatment and the intensity of therapy in an individual patient. © 2006 by The American Society of Hematology

HS1, a Lyn Kinase Substrate, Is Abnormally Expressed in B-Chronic Lymphocytic Leukemia and Correlates with Response to Fludarabine-Based Regimen

In B-Chronic Lymphocytic Leukemia (B-CLL) kinase Lyn is overexpressed, active, abnormally distributed, and part of a cytosolic complex involving hematopoietic lineage cell-specific protein 1 (HS1). These aberrant properties of Lyn could partially explain leukemic cells’ defective apoptosis, directly or through its substrates, for example, HS1 that has been associated to apoptosis in different cell types. To verify the hypothesis of HS1 involvement in Lyn-mediated leukemic cell survival, we investigated HS1 protein in 71 untreated B-CLL patients and 26 healthy controls. We found HS1 overexpressed in leukemic as compared to normal B lymphocytes (1.38±0.54 vs 0.86±0.29, p<0.01), and when HS1 levels were correlated to clinical parameters we found a higher expression of HS1 in poor-prognosis patients. Moreover, HS1 levels significantly decreased in ex vivo leukemic cells of patients responding to a fludarabine-containing regimen. We also observed that HS1 is partially localized in the nucleus of neoplastic B cells. All these data add new information on HS1 study, hypothesizing a pivotal role of HS1 in Lyn-mediated modulation of leukemic cells’ survival and focusing, one more time, the attention on the BCR-Lyn axis as a putative target for new therapeutic strategies in this disorder

Fluctuating systems driven between nonequilibrium states: Extractability of work and constraints on the final distribution

This work deals with fluctuating systems taken out-of-equilibrium by some \u201cactivating event\u201d, and then driven by acting upon selected parameters. First we establish general conditions under which an average amount of work can be extracted during the driven transformation; this is what we term extractability of work. Second, from the premise that work is extracted on average, we derive a mutual bound between a measure of the final system\u2019s disequilibrium, the free energy variation, and the average amount of energy involved in the activation phase. As a special case, we consider the situation in which the disequilibrium is quantified by the polarization over an a priori unbiased periodic degree of freedom

Intrinsic timing in classical master equation dynamics from an extended quadratic format of the evolution law

The paradigm of Markov jump process is widely employed in disparate contexts, like for instance in ecology, epidemiology and chemistry, any time the state-space is discrete and a tracked entity (the system) stochastically jumps from site to site. The classical master equation describes the system's evolution in terms of site occupation probabilities starting from a given initial condition associated with the initial knowledge about the system. For the master equation of Markov processes admitting stationary occupation probabilities, it is here derived an equivalent quadratic format in an extended space of mutually interrelated variables having physical dimension of inverse of time. The evolution in the probability space is thus mirrored by the evolution in the extended space. This universal format potentially allows one to unveil general traits underlying the master equation dynamics. Here we specifically consider the emergence of an intrinsic rate which, behaving as a state function in the probability space, introduces a timing during the relaxation process. This specific feature has to be taken an empirical discovery which derives from the analysis of numerical calculations; a possible direction towards a formal proof is however proposed. The conjecture made here is that such intrinsic timing is a typical trait (i.e., normally present) of the Markov jump processes

Dissipation-recurrence inequalities at the steady state

For Markov jump processes in out-of-equilibrium steady state, we present inequalities which link the average rate of entropy production with the timing of the site-to-site recurrences. Such inequalities are upper bounds on the average rate of entropy production. The combination with the finite-time thermodynamic uncertainty relation (a lower bound) yields inequalities of the pure kinetic kind for the relative precision of a dynamical output. After having derived the main relations for the discrete case, we sketch the possible extension to overdamped Markov dynamics on continuous degrees of freedom, treating explicitly the case of one-dimensional diffusion in tilted periodic potentials; an upper bound on the average velocity is derived, in terms of the average rate of entropy production and the microscopic diffusion coefficient, which corresponds to the finite-time thermodynamic uncertainty relation in the limit of vanishingly small observation time

Inequalities for overdamped fluctuating systems

In many ambits of the chemical sciences it happens to deal with complex systems udergoing thermal fluctuations in the overdamped regime of the motion (i.e., multidimensional diffusive processes). Although such stochastic dynamics are well specified in terms of the Fokker\u2013Planck\u2013Smoluchowski equation for the time-dependent probability density, the solution becomes rapidly unfeasible as the number of degrees of freedom increases beyond a few units. Here we present a strategy, based on inequalities for \u201ccompletely monotone decreasing\u201d functions viewed as convex functions of time, to by-pass such a difficulty and aimed to achieve only bounds (but with low computational effort) on some quantities that pertain the system\u2019s dynamics. Namely, we derive (i) a lower bound for the maximum value of the probability density that develops from a given initial condition, and (ii) a lower bound on the correlation time for a generic self-correlation function. The former bound is quantified by means of simple operations on the initial condition, while the latter is gained by the knowledge of an initial \u201cpiece\u201d of correlation function to be supplied, for instance, by molecular or Brownian dynamics simulations. Some practical applications are discussed

Tagged-moiety viewpoint of chemical reaction networks

In this work we consider mass action chemical reaction networks, either closed or open, and focus on the hopping path that a tagged moiety makes from molecule to molecule because of the occurrence of the reactions. We develop the tool for simulating the stochastic paths by means of a Gillespie-like algorithm and provide examples of the master equation counterpart for simple archetype problems of general interest. Both stationary and transient conditions are taken into account. An explanatory case is adopted to illustrate the approach

Diffusive model to assess the release of chemicals from a material under intermittent release conditions

We consider the archetype situation of a chemical species that diffuses in a material and irreversibly escapes through the interface. In our setup, the interface switches between two states corresponding to ‘release phase’ (absorbing boundary) during which the species is released to the exterior, and ‘pause phase’ (reflecting boundary) during which the species is not released and its concentration profile inside the material partially relaxes back to uniformity. By combining numerical solution of the diffusion equation and statistical analysis of the outcomes, we derive upper and lower bounds and an empirical approximation for the amount of species released up to a certain time, in which the only information about the release-pause alternation schedule is the number of release phases and the average duration of a release phase. The methodology is developed thinking especially to dermal exposure assessment in the case of a slab-like homogeneous material irreversibly releasing chemicals during a number of contacts. However, upon proper extensions, this approach might be useful for inspecting other situations that are encountered, for instance, when dealing with leakage of chemicals in environmental contexts and regulatory toxicology