The prognostic value of smudge cells (Gumprecht shadows) in chronic lymphocytic leukaemia

Introduction: Smudge cells (Gumprecht shadows) are chronic lymphocytic leukaemic cells ruptured during peripherial blood smear preparation. It has been demonstrated to be linked to reduced expression of the cytoskeletal protein vimentin and its inverse correlation with the clinical outcome of the disease. Aims: Investigation of the percentage of smudge cells, CD38-, ZAP-70-positive cells and the time to treatment in patients with chronic lymphocytic leukaemia. Methods: Authors investigated the percentage of smudge cells, CD38- and ZAP-70-positive cells in the peripheral blood of 50 patients with chronic lymphocytic leukaemia and their correlation with the time to treatment. Results: 21 patients required treatment in the follow-up period. Their median smudge cell percentage was 9.9%, while it was 26.8% in the non-treated group. The cut-off value of smudge cell positivity was set to 20%. 59.3% of the patients with less than cut-off had to be treated in the follow-up time compared to 21.7% of patients with more smudge cells. These findings were similar to the prognostic value of CD38 and ZAP-70. The necessity of treatment increased to 75–77.8% with the combination of investigated markers. The time to treatment was 19 months when smudge cells were less than 20%, but above 20% it was 36.15 months. In case of low smudge cell percentage and CD38 positivity the time to treatment was 14.14 months and in case of high smudge cell percentage and CD38 negativity it was 32.92 months. In discordant cases the time to treatment was 18.43 months. The authors also present a case report that demonstrates the relationship between the percentage of smudge cells and apoptotic cells with annexin V and 7-AAD staining. Conclusions: Estimation of smudge cells on a blood smear could be a simple and cheap prognostic test in chronic lymphocytic leukaemia with sensitivity similar to CD38 and ZAP-70 estimation. Combination of these tests raised the sensitivity of their prognostic value. Orv. Hetil., 2012, 153, 1732–1737.

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Prognostic value of absolute monocyte count in chronic lymphocytic leukaemia

Orvosi Hetilap ◽

10.1556/oh.2015.30126 ◽

2015 ◽

Vol 156 (15) ◽

pp. 592-597

Author(s):

László Szerafin ◽

János Jakó ◽

Ferenc Riskó

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

Prognostic Value ◽

Lymphocytic Leukaemia ◽

Treatment Time ◽

Monocyte Count ◽

Time To Treatment ◽

Causes Of Mortality ◽

The Absolute ◽

The Impact ◽

Overal Survival

Introduction: The low peripheral absolute lymphocyte and high monocyte count have been reported to correlate with poor clinical outcome in various lymphomas and other cancers. However, a few data known about the prognostic value of absolute monocyte count in chronic lymphocytic leukaemia. Aim: The aim of the authors was to investigate the impact of absolute monocyte count measured at the time of diagnosis in patients with chronic lymphocytic leukaemia on the time to treatment and overal survival. Method: Between January 1, 2005 and December 31, 2012, 223 patients with newly-diagnosed chronic lymphocytic leukaemia were included. The rate of patients needing treatment, time to treatment, overal survival and causes of mortality based on Rai stages, CD38, ZAP-70 positivity and absolute monocyte count were analyzed. Results: Therapy was necessary in 21.1%, 57.4%, 88.9%, 88.9% and 100% of patients in Rai stage 0, I, II, III an IV, respectively; in 61.9% and 60.8% of patients exhibiting CD38 and ZAP-70 positivity, respectively; and in 76.9%, 21.2% and 66.2% of patients if the absolute monocyte count was <0.25 G/l, between 0.25–0.75 G/l and >0.75 G/l, respectively. The median time to treatment and the median overal survival were 19.5, 65, and 35.5 months; and 41.5, 65, and 49.5 months according to the three groups of monocyte counts. The relative risk of beginning the therapy was 1.62 (p<0.01) in patients with absolute monocyte count <0.25 G/l or >0.75 G/l, as compared to those with 0.25–0.75 G/l, and the risk of overal survival was 2.41 (p<0.01) in patients with absolute monocyte count lower than 0.25 G/l as compared to those with higher than 0.25 G/l. The relative risks remained significant in Rai 0 patients, too. The leading causes of mortality were infections (41.7%) and the chronic lymphocytic leukaemia (58.3%) in patients with low monocyte count, while tumours (25.9–35.3%) and other events (48.1 and11.8%) occurred in patients with medium or high monocyte counts. Conclusions: Patients with low and high monocyte counts had a shorter time to treatment compared to patients who belonged to the intermediate monocyte count group. The low absolute monocyte count was associated with increased mortality caused by infectious complications and chronic lymphocytic leukaemia. The absolute monocyte count may give additional prognostic information in Rai stage 0, too. Orv. Hetil., 2015, 156(15), 592–597.

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Consolidation with Alemtuzumab in First Remission Induces Pronounced MRD Reduction and Clinical Remissions - Update on a Randomized Phase III Trial of the German CLL Study Group (GCLLSG).

Blood ◽

10.1182/blood.v104.11.2506.2506 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2506-2506 ◽

Cited By ~ 2

Author(s):

Matthias Ritgen ◽

C. Schweighofer ◽

Günther Fingerle-Rowson ◽

Barbara Eichhorst ◽

Raimunde Busch ◽

...

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

Late Stage ◽

Clinical Remission ◽

Lymphocytic Leukaemia ◽

Phase Iii ◽

Remission Induction ◽

Control Group ◽

Consolidation Therapy ◽

Phase Iii Trial

Abstract The monoclonal antibody alemtuzumab is known to be effective in combination or alone in patients with late stage chronic lymphocytic leukaemia. Flow cytometric studies on minimal residual disease (MRD) showed the high potency beyond clinical response criteria even in late stage chronic lymphocytic leukaemia (CLL). The aim of the phase III trial of the GCLLSG was to investigate the role of alemtuzumab as consolidation therapy in CLL patients in first clinical remission after fludarabin (F) or F plus cyclophosphamide (FC). Patients in partial or complete clinical remission were randomized to either arm A (alemtuzumab 3 x 30 mg i.v. for up to 12 wks) or no further treatment (arm B). From 21 eligible patients 11 (1CR, 1 nPR, 9PR) were randomized to arm A. All patients received standard infection prophylaxis with famciclovir and trimethoprim/sulfamethoxazole. Before, at 6 and 12 weeks after start of consolidation therapy and regulary during follow up blood and bone marrow samples were send for molecular MRD assessment by allele specific real time PCR. The PCR allowed MRD assessment with a sensitivity of at least 10E-4 in 11 eligible cases. Results: MRD analysis showed clear reduction of CLL content by first line treatment to a median MRD level of 2.2E-3. Short after alemtuzumab treatment all treated patients showed pronounced MRD reduction to a median MRD level of 5.0E-5. During molecular follow-up median MRD level remained below 1E-4 for one year with a tendency to increase afterwards. After a median follow-up of 31.3 months from start of initial treatment occurred one relapse in the treatment arm compared to 7 of 10 in arm B. The median progression free survival (PFS) calculated from start of consolidation therapy was significantly shorter in the control group versus the treatment group (pfs 25.2; p= 0.04). Nevertheless due to severe acute infections (CTC III and IV) this study had to be stopped prematurely. Conlusion: The addition of alemtuzumab as a consolidation regimen after remission induction by F or FC is highly effective and leads to sustained MRD reduction below 10E-4. This translates into significant improved clinical outcome even in this small patient cohort compared to the control group. Encouraged by the molecular responses the GCLLSG initiated a new phase I/II trial as a dose finding study in CLL patients after F based induction of clinical remission.

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Percentage of Smudge Cells on Blood Smear Predicts Prognosis in Chronic Lymphocytic Leukemia: A Multicenter Study.

Blood ◽

10.1182/blood.v110.11.745.745 ◽

2007 ◽

Vol 110 (11) ◽

pp. 745-745

Author(s):

Grzegorz S. Nowakowski ◽

James D. Hoyer ◽

Tait D. Shanafelt ◽

Diane F. Jelinek ◽

Laura Z. Rassenti ◽

...

Keyword(s):

Multicenter Study ◽

Blood Smear ◽

Independent Predictor ◽

Continuous Variable ◽

Lymphocytic Leukemia ◽

Initial Finding ◽

Time To Treatment ◽

Cell Percentage ◽

Blood Smears ◽

The Impact

Abstract Background: Smudge cells are ruptured CLL cells seen on blood smears of CLL patients. For over a century, smudge cells were thought to represent an artifact of slide preparation. We recently showed that smudge cell formation was inversely proportional to leukemic B cell vimentin content. Vimentin is a cytoskeletal protein critical for lymphocyte rigidity and migration; high vimentin content is related to poor prognosis in CLL. Concordantly, in an initial small cohort of patients from a single institution, we found that patients with a low (<30%) percentage of smudge cells on a blood smear have a shorter time to treatment (Mayo Clin Proc.2007;82:449–53). In the current study, we evaluated the impact of smudge cell percentage on prognosis of patients with CLL seen at member institutions of the CLL Research Consortium (CRC). Methods: Archived blood smears from untreated patients with CLL were evaluated for smudge levels. All blood smears were prepared manually in a standard fashion from blood obtained by CRC Tissue Core and stained with WrightGiemsa stain. Smudge cells were defined as broken cells with no intact cytoplasm and a disrupted nuclear membrane. A total of 200 lymphocytes and smudge cells were counted on each slide and the results were expressed as the percent smudge cells. The association between the percentage of smudge cells, prognostic factors (IgVH status, CD38, ZAP-70 and FISH) and time to initial therapy (TTT) was examined. Results: We calculated smudge cell percentage on blood smears obtained prior to treatment for 337 CLL patients. The median smudge cell percentage was 32 (range 2–95%). The percentage of smudge cells was lower in CD38 positive patients (mean 33% vs. 38% in CD38 negative patients, p=0.04). No difference in smudge cell percentage was observed based on IgVH gene mutation status or Zap70 expression. Smudge cell percentage as a continuous variable was associated with prolonged TTT, exponential coefficient 0.98, p=0.04. Using our previously published cutoff of 30% to stratify patients in low and high risk categories, the estimated median time to first therapy of patients with smudge cell percentage ≤30% (n=178) was 7.8 years versus not reached in patients in patients with > 30% (n=159) of smudge cells, p=0.0036, (Figure 1). Ten years from diagnosis, 62% of patients with ≤30% of smudge cells versus 39% of patients with >30% of smudge cells required therapy. In multivariate analysis, the low percentage of smudge cells (≤30%) was an independent predictor of the shortened time to treatment (HR 1.86, 95%CI 1.09–3.16, p=0.02). Conclusion: This multicenter study confirms our initial finding that the percentage of smudge cells on a blood smear is an independent predictor of clinical outcome in patients with CLL. The estimation of smudge cell percentage on routine blood smear provides a simple and inexpensive prognostic test available to nearly all patients with a diagnosis of CLL worldwide. It also allows reanalysis and risk stratification of previously completed trials provided that blood smears have been archived. Further studies of the role of the cytoskeleton in CLL biology are warranted and ongoing in our laboratory. Figure Figure

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