How many cells with CLL-like phenotype (that is essentially CD19+ CD5+) are there in normal peripheral blood? Quite important question for understanding the cellular origin and for proper estimation of MRD in CLL. Lets not further deepen into human B-cell biology, consider PB CD5+ B-cells "circulating marginal zone B-lymphocytes" and try to make multiple independent estimations. See joint GEIL-GOELAMS trial by Durrieu et al. in Cytometry Part B: Clinical Cytometry early view for details.

Two antibody panels were tested in 49 apparently healthy volunteers.

1. CD19+/CD5+/CD43int/CD79blo showed 1.17 × 10−4 (95% CI: 0.63–2.03 × 10−4) of WBC

2. CD19+/CD5+/CD81lo/CD22lo showed 0.76 × 10−4 (95% CI: 0.41–1.48 × 10−4) of WBC

Notably these 2 panels are used in the gating strategy for MRD evaluation as per 2007 standardized approach. However 2 other panels in Rawstron recommendations (those with CD38/CD20 and CD45/CD14/CD19/CD3) were not included. Light chain specific Abs were also not used because of presumably polyclonal nature of studed cells.

In partial dilution experiments both 4-colored combinations were able to discriminate CLL cells from normal cells in dilutions up to 10-4. Using ROC curves authors also showed sensitivity of 87.5% and a specificity of 91% for the threshold of 4x10-4 for discrimination between normal CD19+CD5+ cells and CLL cells. In clinical experiments there were 9,8% of pts with CLL-like cells in the gray zone between 1x10-4 and 4x10-4 - those cases where clinical correlation and repeated testing (or perhaps following the 2007 recommendations) might help in elucidating MRD status.

However all of this might become uninteresting with the advent of ROR1-specific Abs.

Survival of 1325 pts with CLL over 40 years in Israel

A big epidemiological review from Israeli nation-wide Clalit medical conglomeration was recently pre-published in Am J of Hematology on behalf of Israeli CLL Study Group partially funded by M.Keating's CLL global research foundation. This article has Prof. Aaron Polliack in co-authors.

As stated on CLL global site, Israeli populations maintain close communities, thus preserving their ancestry and gene pools which is ideal for studying the effect of ancestry on the clinical, biological and genetic characteristics of CLL.

The database of ICLLSG currently includes information on 1325 patients, 764 males and 561 females diagnosed in the period between January 1968 and December 2010. Askenazi Jews form stable majority of 68,6%.

- The median patient age at diagnosis in the database was 69 years: older in 2000-2010 than in 1990-1999 and 1968-1989 (71 vs 68 vs 66 years; p=0.0001).

- The proportion of patients free of CLL-related symptoms at diagnosis was highest in the most recent cohort (84.0% vs 78.3 % in the 1990s or 71.7% prior; p=0.0001).

- FCR in 1st line was given only to 28 pts with CR in 9 (32.1%) and PR in 17 (60.7%) - still superior results compared to older regimens

- Only 8 pts went through allogeneic SCT

- Among 685 deaths 322 were attributed to CLL progression and Richter transformation (48). The second largest cause were cardiovascular and metabolic (?) events with 243 deaths. Infections accounted for 46 deaths and other malignancies for 50.

- The median survival for the entire cohort was 10.9 years (95% CI, 10.1-11.6) with 11.9 years (95% CI, 10.8-15.0) for women and 10.1 (95% CI ,9.0-11.2) years for men. The estimated survival at 5 and 10 years from diagnosis was 78.0% and 53.0%. The estimated survival was 12.2 years (95% CI, 11.5-13.4 years) for Binet stage A; 8.5 years (95% CI, 7.3-10.1 years) for stage B and 6.4 years (95% CI, 4.4-7.8 years) for stage C.

- 65.6% of pts at Binet A stage had stable disease for a median time of 70 months of follow-up.

- Younger CLL patients had significantly lower survival expectancy than the general population. However this was not true for pts older than 70. Patients with CLL at the age of 50 had a 1.8-fold higher risk to die from CLL compared to those aged 70.

- Atypical morphology of CLL cells (p<0.0001), paraproteinemia (p=0.0417), positive DAT (p<0.0001) were significant factors for shorter survival.

- Ethnic origin had no influence on survival (p=0.704)

- Over the time median age of CLL pts in Israel increased (currently 21% are older than 80) due to increasing overall life expectancy.

Finally authors conclude that "After 40 years of wondering and searching for the optimal treatment in CLL, we have not still reached the Promised Land".