Abstract
BACKGROUND: THAL has been used as immunomodulatory therapy alone (Tefferi et. al. Blood 200;96:4007), or with steroids (
Methods: We analyzed a cohort of PMF patients who had received THAL therapy (alone or in combination with corticosteroids) from our institution and analyzed their clinical course and response to THAL therapy. Marrow trephines were evaluated in a systematic fashion (CYL in a blinded fashion to clinical course) for cellularity and degree of reticulin fibrosis (0–4+). Subsequently, megakaryocytes were assessed for quantitative (increased, decreased, or normal) and qualitative (size (large or small) and presence or absence of morphologic dysplasia). T cells were assessed by immunohistochemical staining for CD8 with an emphasis on number of T cell clusters per trephine, and the pattern of those clusters (large vs. small). Finally, an estimation of numbers of T cells per high power histology field was conducted in 3 distinct areas, and an average per marrow trephine obtained. All histologic features were then compared with PMF prognostic scores, and labs at presentation. Amongst those who received THAL, baseline histology was compared to response and in those patients with serial marrows longitudinal changes were assessed.
Results: A cohort of 140 patients with PMF was analyzed, 65 having received THAL along the course of their illness (53 (82%) along with prednisone) and 75 from a comparison group who never received THAL. Patients from both groups had similar PMF prognostic scores and presentations. Comparison of baseline histologic features demonstrated that individuals with a baseline increases in T cell numbers (>100 per high power field) were significantly more likely to subsequently respond to THAL therapy (p<0.01). Additionally, analysis of megakaryocyte morphology demonstrated that those patients in which megakaryocytes were atypical for PMF (i.e. small) were significantly more likely to have thrombocytopenia and were less likely to respond to THAL (p=0.05). Independent assessment of the prognostic value of these individual histologic features upon survival failed to reveal any direct impact upon survival by Kaplan-Meier Analysis.
Table 1. Comparison of Histologic Features in 140 patients with Myelofibrosis
| Group . | Cell . | Fibrosis ≥3 . | Meg Numbers . | Meg Size . | T Cell clusters . | T-Cells (per HPF) . | >100 Tcells (per HPF) . |
|---|---|---|---|---|---|---|---|
| Control (N=75) | 72% (10–100) | 33% | 91% Increased | 21% Small | 4 (0–16) | median 80 (13–258) | 37% |
| THAL ALL (N=65) | 60% (5–95) | 62% | 79% Increased | 38% Small | 3 (0–14) | median 93 (20–500) | 43% |
| -THAL Responders (N=28) | 60% (5–95) | 56% | 82% Increased | 22% Small (p=0.05) | 5 (0–10) | median 113 (45–198) | 61% (p<0.01) |
| -THAL Non Responders (N=37) | 60 (5–95) | 67% | 76% Increased | 48% Small | 3 (0–14) | median 70 (20–500) | 26% |
| Group . | Cell . | Fibrosis ≥3 . | Meg Numbers . | Meg Size . | T Cell clusters . | T-Cells (per HPF) . | >100 Tcells (per HPF) . |
|---|---|---|---|---|---|---|---|
| Control (N=75) | 72% (10–100) | 33% | 91% Increased | 21% Small | 4 (0–16) | median 80 (13–258) | 37% |
| THAL ALL (N=65) | 60% (5–95) | 62% | 79% Increased | 38% Small | 3 (0–14) | median 93 (20–500) | 43% |
| -THAL Responders (N=28) | 60% (5–95) | 56% | 82% Increased | 22% Small (p=0.05) | 5 (0–10) | median 113 (45–198) | 61% (p<0.01) |
| -THAL Non Responders (N=37) | 60 (5–95) | 67% | 76% Increased | 48% Small | 3 (0–14) | median 70 (20–500) | 26% |
A subgroup of patients who received THAL (N=12) had a second post therapy marrow available for analysis for comparison of THAL effects upon the marrow, although the numbers were small, there was no statistically significant differences upon histologic parameters analyzed including cellularity, degree of fibrosis, megakaryocyte morphology, or T cell clustering or numbers. Inclusion of prednisone in the regimen had no impact on histologic prognostic observations.
Conclusions: THAL therapy for MF patients can be associated with significant clinical benefit for cytopenias and splenomegaly, and interestingly patients with increased marrow T-cell populations at baseline have a clear increased likelihood of response. Although this analysis is unable to gauge mechanism, it would suggests a greater potential for immunomodulation in patients with a robust T-cell population. Additionally, analysis of megakaryocytes suggests the presence of small megakaryocytes may in contrast represent a more resistant phenotype of disease with more thrombocytopenia and THAL resistance.
Disclosures: No relevant conflicts of interest to declare.
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