Prognostic significance of delayed thrombocytopenia after allogeneic stem cell transplant
Authors: Francesco Zaja, Antonella Geromin, Francesca Patriarca, Simona Puglisi, Michela Cerno, Alessandra Sperotto, Marta Lisa Battista, Miriam Isola, Renato Fanin
Journal: American Journal of Hematology (2011)

Previous studies showed that late-onset thrombocytopenia is a strong negative prognostic indicator of survival in allogeneic hematopoietic stem cell transplant (SCT) recipients and, in particular, in those cases where thrombocytopenia is related to chronic graft versus host disease (cGVHD) [1-12]. To investigate this issue, 71 adult patients who survived for ≥3 months with median follow-up time of 21 months (range, 3–44 months) after SCT were evaluated. Twenty-seven patients (38%) developed thrombocytopenia with a median platelet count of 29 × 109/L. Patients with and without thrombocytopenia had similar baseline clinical characteristics, transplant type, and status at transplant. The incidence of mortality was significantly higher in patients with post-SCT thrombocytopenia (70% vs. 14%; P < 0.0001). The principal causes of mortality in this group were primary disease (58%), cGVHD (16%) and infections (10.5%). In multivariate analysis only thrombocytopenia was significantly associated with overall survival (HR 9.77; 95% CI, 3.63–26.33; P < 0.0001). Thirty-two patients developed cGVHD and 13 had concomitant thrombocytopenia. The incidence of mortality was significantly higher in patients with post SCT thrombocytopenia compared with patients without thrombocytopenia (61.5% vs. 10.5%; P = 0.005). The occurrence of post-SCT thrombocytopenia appears to be a strong negative predictor of survival. Late-onset thrombocytopenia is observed in around 20–40% of patients undergoing allogeneic hematopoietic stem cell transplant (SCT) [1, 2]. With the exception of cases in which thrombocytopenia reflects a recurrence of the underlying malignancy, several other factors may cause this complication including graft loss, infectious conditions (particularly cytomegalovirus [CMV] or other herpes virus-related infection or reactivation), secondary microangiopathy observed following utilization of calcineurin inhibitors and, in particular, the onset of chronic graft-versus-host disease (cGVHD). Previous studies show that late-onset thrombocytopenia is a strong negative prognostic indicator of survival in transplant recipients and in particular in those cases where thrombocytopenia is related to GVHD. Furthermore, post SCT thrombocytopenia and GVHD appear to be strongly related since thrombocytopenia is correlated with a higher incidence of advanced acute and cGVHD, and represents one of the major prognostic factors influencing post-transplant mortality [1, 2, 12]. We retrospectively evaluated the incidence and prognostic significance of post-SCT thrombocytopenia in a single center transplant population. In total, 71 adult patients were selected for analysis; baseline characteristics are summarized in Table I. Briefly, median age was 52 years, 62% of patients received reduced intensity conditioning (RIC), stem cells were sourced from a matched unrelated donor for 65% of patients, 80% of cases used stem cells from peripheral blood, and the median number of CD34-positive reinfused stem cells was 5.6 × 106/kg. Forty-two percent of patients had acute leukemia, 35% had lymphoma or chronic lymphocytic leukemia (CLL), and 48% and 20% of patients, respectively, were in complete or partial remission at transplant. The median follow-up after SCT was 21 months (range, 3–44 months). Twenty-seven of 71 patients (38%) developed post-SCT thrombocytopenia after a median time of three months from transplant (range, 1–13 months), with a median number of platelets of 29 × 109/L (range, 7–86 × 109/L). Platelet count was >50 < 100 × 109/L in eight patients and ≤50 × 109/L in 19 among whom 9 had ≤20 × 109/L. Thrombocytopenia was transient in 5 and persistent in 22 patients; in this last group the median duration of thrombocytopenia was three months. Patients with and without thrombocytopenia were similar in baseline clinical characteristics, type of transplant, and status at transplant (Table II). Thrombocytopenia was associated with cGVHD in 10 out of 24 patients (42%) (three patients with thrombocytopenia were not evaluable for cGVHD), disease relapse in seven patients (26%; five acute leukemia and two lymphomas), CMV infection in four patients (15%), graft failure in two patients, and microangiopathy in one patient; three patients had idiopathic thrombocytopenia. Thrombocytopenia was complicated with major intestinal bleeding and cerebral bleeding in four and two patients, respectively. The incidence of mortality was significantly higher in patients with post-SCT thrombocytopenia compared with patients without thrombocytopenia (19 out of 27 [70%] vs. 6 out of 44 [14%] patients; P < 0.0001)2 (Fig. 1). The cause of mortality in patients with thrombocytopenia included: primary disease in 11 patients (58%; acute leukemia in five patients, lymphoma in three patients, one patient each myelodysplasia, chronic myeloid leukemia, and multiple myeloma), cGVHD in three patients (16%), infections in two patients (10.5%), one patient each with cerebral bleeding, cardiac stroke and multiorgan failure. Patient survival after 12, 24, and 33 months was 93%, 87%, and 87% in patients without thrombocytopenia vs. 41%, 41%, and 7% in patients with thrombocytopenia, respectively (P < 0.0001)2 (Fig. 1). In univariate analysis using Cox proportional hazard model, overall survival (OS) showed a significant association with status at transplant (no response/progression vs. complete remission Hazard Ratio [HR] 2.74; 95% confidence interval [CI], 1.11–6.79; P = 0.03) and thrombocytopenia (HR 9.77; 95% CI, 3.63–26.33; P < 0.0001). In multivariate analysis only thrombocytopenia was significantly associated with OS (HR 9.77; 95% CI, 3.63–26.33; P < 0.0001). In order to eliminate possible bias related to disease-related mortality we repeated the analysis excluding 15 patients who died because of primary diseases and not for SCT related mortality. Fifteen out of the remaining 56 patients developed post SCT thrombocytopenia and again, the incidence of mortality was significantly higher in patients with thrombocytopenia, i.e. 8 out of 15 (53%) vs. 4 out of 41 (10%) (P = 0.001). In univariate analysis using Cox proportional hazard model, thrombocytopenia resulted the only variable significantly associated with OS (HR 7.83; 95% CI, 2.34–26.00; P = 0.001). Of the 68 patients for whom cGVHD was evaluable, 32 (47%) developed cGVHD, and 13 had concomitant thrombocytopenia (Table II). The incidence of mortality in this group was significantly higher in patients with post-SCT thrombocytopenia compared with patients without thrombocytopenia (8 out of 13 [61.5%] vs. 2 out of 19 [10.5%] patients; P = 0.005). This retrospective analysis confirms the incidence and prognostic significance of post-SCT thrombocytopenia. In our survey 38% of patients developed thrombocytopenia, which was related with a higher risk of mortality. cGVHD was the most frequent condition associated with thrombocytopenia and the mortality rate in patients with cGVHD and thrombocytopenia reached 61.5%. Thrombocytopenia itself, regardless of the cause, and the combination of cGVHD and thrombocytopenia appears to be strong negative prognostic factors for survival in patients undergoing allogeneic SCT. It is notable that thrombocytopenia was secondary to recurrence of acute leukemia in only 5 of 27 patients (18.5%); therefore, in the majority of patients the poor prognostic significance of thrombocytopenia seems not to be strictly related to or a consequence of the activity of the primary disease but, appears to be epiphenomenon of a proinflammatory or proimmunologic detrimental condition. This status may in part help understand the frequent occurrence of severe infectious complications which (rather then bleeding) likely represent the main cause of mortality in patients with post SCT persistent thrombocytopenia [1, 3]. The pathogenic process of cGVHD-related thrombocytopenia is complex and only partially understood. Biological and clinical evidence support an autoimmune-like thrombocytopenia with increased platelet destruction; [4] this is also supported by the response to some therapeutic strategies used to treat classical immune thrombocytopenia including steroids, high dose intravenous immunoglobulin, splenectomy, and rituximab [13-17]. However, a mechanism consistent with impaired platelet production has also been suggested. Glycocalicin index, plasma thrombopoietin (TPO), and circulating B cells producing anti-GPIIb-IIIa antibodies were measured and compared in 23 SCT recipients who had prolonged and isolated thrombocytopenia with no apparent cause, SCT recipients without thrombocytopenia, and in patients with idiopathic thrombocytopenic purpura or aplastic anemia [18]. Despite the frequent occurrence of an antiplatelet antibody response, patients with post-SCT thrombocytopenia showed a glycocalicin index and TPO status similar to that seen in patients with aplastic anemia; TPO levels were normal in approximately 30% of patients [18]. Recently, Bao et al. showed an improved regulatory T-cell (T-regs) activity in patients with chronic primary immune thrombocytopenia (ITP) treated with thrombolytic agents, suggesting a possible role of platelet count in improving T-reg function and restoring immune tolerance [19]. On the basis of this and on the similarity to ITP, the stimulation of thrombopoiesis with the thrombolytic agents could be beneficial in some patients with persistent post-SCT thrombocytopenia, both on platelet count and on cGVHD manifestations. In conclusion, post-SCT thrombocytopenia appears to be a strong negative predictor of survival. cGVHD seems to be the most frequent pathologic condition associated with thrombocytopenia. The management of post-SCT thrombocytopenia may influence patient outcome. This retrospective analysis that evaluated the incidence of late-onset thrombocytopenia post SCT as well as its clinical and prognostic relevance. The primary endpoint of this study was to evaluate the impact of thrombocytopenia (from any cause) on survival. Secondary endpoints were to look for potential relationships between thrombocytopenia, cGVHD development, and other clinical and transplant conditions. For this analysis we evaluated consecutive patients who underwent SCT from January 2007 to December 2008 at the Department of Hematology and SCT of the Udine University Hospital, Italy. Patients (aged ≥18 years) who had undergone SCT using a related or unrelated matched donor and who had survived for ≥3 months after SCT were included in the analysis. Patients were analyzed for the development of late-onset thrombocytopenia, defined as a platelet count of ≤100 × 109/L ≥3 months following SCT. Evaluation of blood cell count was performed at least once per month. Patients were stratified according to the type of transplant (related vs. unrelated), stem cell source (peripheral blood vs. bone marrow), conditioning regimen (conventional [CON] vs. reduced intensity [RIC]), primary disease, and status at transplant. Thrombocytopenia was distinguished as persistent or transient in the presence of a ≥ or <30 day duration of platelet count reduction, respectively. Clinical conditions related or associated with the development of thrombocytopenia (i.e. cGVHD, infectious complications, relapse, microangiopathy, or other) were evaluated. Quantitative variables were tested for normal distribution using the Shapiro-Wilk test. Comparisons between groups were performed with t test or U-Mann Whitney test, depending on Shapiro-Wilk test results. χ2 tests were used to analyze categorical values; when assumptions for χ2 test were not verified, Fisher's exact test was used. Survival curves were estimated using the Kaplan-Meier method. Overall survival (OS) was analyzed using log-rank tests and Cox proportional hazard models, after the proportional hazards assumption had been verified. Kaplan-Meier overall survival curves in patients with and without post-SCT thrombocytopenia. Zaja Francesco*, Geromin Antonella*, Patriarca Francesca*, Puglisi Simona*, Cerno Michela*, Sperotto Alessandra*, Battista Marta*, Isola Miriam , Fanin Renato*, * Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi", DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, 33100 Udine, Italy, Cattedra di Statistica, Università degli Studi, 33100 Udine, Italy.