The CLL12 trial protocol: a placebo-controlled double-blind Phase III study of ibrutinib in the treatment of early-stage chronic lymphocytic leukemia patients with risk of early disease progression

Abstract Prognosis of B-cell chronic lymphocytic leukemia (CLL) is based on clinical staging whose limitation is the failure to assess whether the disease will progress or remain stable in early stage (Binet A, or Rai 0, I, II) patients. We previously reported that soluble CD23 (sCD23), a protein derived from the B-cell membrane CD23 Ag, is selectively elevated in the serum of CLL patients. This prospective study assessed the predictive value of serum sCD23 level measured at study entry on the overall survival of all CLL patients and on disease progression of stage Binet A patients. Prognostic value of repeated measurements of sCD23 over time in stage A patients was also analyzed. One hundred fifty-three CLL patients were prospectively followed with a median follow-up of 78 months. Eight clinical or biological parameters were collected from the date of the first sCD23 measurement. At study entry, by Cox model, Binet staging (P = .0001) and serum sCD23 level (P = .03) appeared as prognostic factors for survival. Patients with sCD23 level above median value (> 574 U/mL) had a significantly worse prognosis than those with lower values (median survival of 53 v 100+ months, P = .0001). During follow-up, sCD23 doubling time increased by 3.2 the risk of death (P = .001). Among stage A patients (n = 100), sCD23 determination at study entry was the sole variable predictive of disease progression, patients with sCD23 level above 574 U/mL had a median time progression of 42 months versus 88 months for those with lower levels (P = .0001). Stage A patients who doubled their sCD23 level exhibited a 15-fold increased risk of progression (P = .0001) and, in addition, the sCD23 increase preceded by 48 months disease progression. We conclude that in CLL patients, serum sCD23 level provides significant additional prognostic information in terms of overall survival. Most interestingly, among early stage patients, sCD23 determination at diagnosis and during the course of the disease may help to the early identification of patients who will rapidly progress to upper stages.

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Serum Levels of Soluble CD23, but not Soluble CD25, Predict Disease Progression in Early Stage B-Cell Chronic Lymphocytic Leukemia

Leukemia & Lymphoma ◽

10.3109/10428199709058320 ◽

1997 ◽

Vol 27 (5-6) ◽

pp. 523-532 ◽

Cited By ~ 30

Author(s):

W. U. Knauf ◽

I. Langenmayer ◽

B. Ehlers ◽

B. Mohr ◽

D. Adorf ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Disease Progression ◽

Early Stage ◽

Serum Levels ◽

Lymphocytic Leukemia ◽

Soluble Cd25 ◽

Soluble Cd23 ◽

Cell Chronic Lymphocytic Leukemia ◽

Predict Disease Progression

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Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group (GCLLSG)

Haematologica ◽

10.3324/haematol.2019.231027 ◽

2019 ◽

Vol 105 (11) ◽

pp. 2598-2607 ◽

Cited By ~ 8

Author(s):

Sonia Jaramillo ◽

Andreas Agathangelidis ◽

Christof Schneider ◽

Jasmin Bahlo ◽

Sandra Robrecht ◽

...

Keyword(s):

Clinical Trials ◽

Chronic Lymphocytic Leukemia ◽

Early Stage ◽

International Prognostic Index ◽

Prognostic Index ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Prognostic Impact ◽

Advanced Stage ◽

Multicenter Clinical Trials

Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinicobiological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: i) early-stage patients (watch-and-wait arm of the CLL1 trial) (n=592); ii) patients in need of treatment, enrolled in 3 phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1861). Subset #1 was associated with del(11q), higher CLL international prognostic index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (HR: 4.2, CI: 2-8.6, p<0.001), and shorter time-to-next-treatment (TTNT) in the advanced-stage cohort (HR: 2, CI: 1.2-3.3, p=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M-CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset # 2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients.

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Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2018-09-873695 ◽

2019 ◽

Vol 133 (25) ◽

pp. 2651-2663 ◽

Cited By ~ 1

Author(s):

Emanuela M. Ghia ◽

Laura Z. Rassenti ◽

Donna S. Neuberg ◽

Alejandro Blanco ◽

Fouad Yousif ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Disease Progression ◽

Hedgehog Signaling ◽

Lymphocytic Leukemia ◽

Early Disease ◽

Mutation Status ◽

Enhanced Sensitivity ◽

Genes Encoding ◽

Treatment Naïve ◽

Hh Signaling

Abstract Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+. Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.

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