European LeukemiaNet-defined primary refractory acute myeloid leukemia: the value of allogeneic hematopoietic stem cell transplant and overall response.

We sought to appraise the value of overall response and salvage chemotherapy, inclusive of allogeneic hematopoietic stem cell transplant (AHSCT), in primary refractory acute myeloid leukemia (prAML). For establishing consistency in clinical practice, the 2017 European LeukemiaNet (ELN) defines prAML as failure to attain CR after at least 2 courses of intensive induction chemotherapy. Among 60 consecutive patients (median age 63 years) correspondent with ELN-criteria for prAML, salvage was documented in 48 cases, 30/48 (63%) being administered intensive chemotherapy regimens and 2/48 consolidated with AHSCT as first line salvage. 13/48 (27%) attained response: CR, 7/13 (54%), CRi, 2/13 (15%), MLFS, 4/13 (31%). The CR/CRi rate was 9/48 (19%), with CR rate of 7/48 (15%). On univariate analysis, intermediate-risk karyotype was the only predictor of response (44% vs 17% in unfavorable karyotype; P = 0.04). Administration of any higher-dose (>1 g/m2) cytarabine intensive induction (P = 0.50), intensive salvage chemotherapy (P = 0.72), targeted salvage (FLT3 or IDH inhibitors) (P = 0.42), greater than 1 salvage regimen (P = 0.89), age < 60 years (P = 0.30), and de novo AML (P = 0.10) did not enhance response achievement, nor a survival advantage. AHSCT was performed in 12 patients with (n = 8) or without (n = 4) CR/CRi/MLFS. 1/2/5-year overall survival (OS) rates were 63%/38%/33% in patients who received AHSCT (n = 12) vs 27%/0%/0% in those who achieved CR/CRi/MLFS but were not transplanted (n = 5), vs 14%/0%/0% who were neither transplanted nor achieved CR/CRi/MLFS (n = 43; P < 0.001); the median OS was 18.6, 12.6 and 5.6 months, respectively. Although CR/CRi/MLFS bridged to AHSCT (n = 8), appeared to manifest a longer median OS (20 months), vs (13.4 months) for those with no response consolidated with AHSCT (n = 4), the difference was not significant P = 0.47. We conclude AHSCT as indispensable for securing long-term survival in prAML (p = 0.03 on multivariate analysis), irrespective of response achievement.

Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients.

In a recent International Working Group on Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) study, prior arterial events and hypertension were predictors of subsequent arterial thrombosis whereas prior venous events and age ≥65 years predicted venous thrombosis in polycythemia vera (PV). In the current study, we sought to validate the above findings and identify additional predictors of arterial versus venous thrombosis. At a median follow up of 109 months, thrombosis after diagnosis occurred in 128 (22%) patients; 82 (14%) arterial and 57 (10%) venous events. On multivariate analysis, prior arterial events (<0.0001), hyperlipidemia (p = 0.03), and hypertension (p = 0.02) predicted subsequent arterial events. In comparison, prior venous events (p = 0.05), leukocytosis ≥11 × 109/L (p = 0.002), and major hemorrhage (p = 0.02) were predictors of subsequent venous events. Salient associations with arterial thrombosis included age ≥ 60 years, hypertension, diabetes, hyperlipidemia and normal karyotype whereas age ≤ 60 years, females, palpable splenomegaly and history of major hemorrhage were associated with venous thrombosis. TET2 or ASXL1 mutations did not impact arterial nor venous thrombosis. In conclusion, we identify distinct associations for arterial versus venous thrombosis in PV and confirm that a prior arterial or venous thrombotic event is the most reliable predictor of subsequent events.

Prognostic relevance of lymphocytopenia, monocytopenia and lymphocyte-to-monocyte ratio in primary myelodysplastic syndromes: a single center experience in 889 patients.

Current prognostic models for myelodysplastic syndromes (MDS), including the Revised International Prognostic Scoring System (IPSS-R), do not account for host immunity. We retrospectively examined the prognostic relevance of monocytopenia, lymphocytopenia and lymphocyte-to-monocyte ratio (LMR) in a cohort of 889 patients with primary MDS. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformation were documented. In univariate analysis, subnormal absolute lymphocyte count (ALC) <0.9 × 109/l; P=0.001), ALC<1.2 × 109/l (P=0.0002), subnormal absolute monocyte count (AMC) <0.3 × 109/l (P=0.0003), LMR (P⩽0.0001) and LMR⩾5 (P=0.03) were all associated with inferior overall survival. In multivariable analysis that included other risk factors, significance was retained for LMR (P=0.02) and became borderline for ALC <1.2 × 109/l (P=0.06). Analysis in the context of IPSS-R resulted in P-values of 0.06 for ALC<1.2 × 109/l, 0.7 for monocytopenia and 0.2 for LMR. Leukemia-free survival was not affected by ALC, AMC or LMR. The observations from the current study suggest a possible detrimental role for altered host immunity in primary MDS, which might partly explain the therapeutic benefit of immune-directed therapy, including the use of immune modulators; however, IPSS-R-independent prognostic value for either ALC or AMC was limited.

Prognostic impact of bone marrow fibrosis in polycythemia vera: validation of the IWG-MRT study and additional observations.

In 2012, the International Working Group for Myeloproliferative Neoplasms (MPN) Research and Treatment (IWG-MRT) reported an associations between mild bone marrow (BM) fibrosis (⩾grade 1) in polycythemia vera (PV) and a lower incidence of thrombosis during the clinical course and a higher risk of fibrotic progression. The objective in the current study of 262 patients with PV was to validate these observations and also identify other risk factors for myelofibrosis-free survival (MFFS). About 127 (48%) patients displayed ⩾grade 1 reticulin fibrosis at the time of diagnosis; presenting clinical and laboratory features were not significantly different between patients with or without BM fibrosis. In univariate analysis, BM fibrosis had no significant impact on overall, leukemia-free or thrombosis-free survival, whereas a significant association was noted for MFFS (P=0.009, hazard ratio 2.9; 95% confidence interval 1.32-6.78); other risk factors for MFFS included leukocytosis ⩾15 × 109/l, presence of palpable splenomegaly and abnormal karyotype. During multivariable analysis, leukocytosis ⩾15 × 109/l, palpable splenomegaly and ⩾grade 1 BM reticulin fibrosis remained significant. The current study validates the previously observed association between ⩾grade 1 BM reticulin fibrosis in PV and subsequent fibrotic progression, and identifies leukocytosis and palpable splenomegaly as additional risk factors for fibrotic progression; additional studies are required to clarify the impact of BM fibrosis on thrombosis and that of abnormal karyotype on MFFS.

Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia.

Mutations involving epigenetic regulators (TET2~60% and ASXL1~40%) and splicing components (SRSF2~50%) are frequent in chronic myelomonocytic leukemia (CMML). On a 27-gene targeted capture panel performed on 175 CMML patients (66% males, median age 70 years), common mutations included: TET2 46%, ASXL1 47%, SRSF2 45% and SETBP1 19%. A total of 172 (98%) patients had at least one mutation, 21 (12%) had 2, 24 (14%) had 3 and 30 (17%) had >3 mutations. In a univariate analysis, the presence of ASXL1 mutations (P=0.02) and the absence of TET2 mutations (P=0.03), adversely impacted survival; while the number of concurrent mutations had no impact (P=0.3). In a multivariable analysis that included hemoglobin, platelet count, absolute monocyte count and circulating immature myeloid cells (Mayo model), the presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (P=0.003) retained prognostic significance. Patients were stratified into four categories: ASXL1wt/TET2wt (n=56), ASXL1mut/TET2wt (n=31), ASXL1mut/TET2mut (n=50) and ASXL1wt/TET2mut (n=38). Survival data demonstrated a significant difference in favor of ASXL1wt/TET2mut (38 months; P=0.016), compared with those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (21 months) and ASXL1mut/TET2mut (16 months) (P=0.3). We confirm the negative prognostic impact imparted by ASXL1 mutations and suggest a favorable impact from TET2 mutations in the absence of ASXL1 mutations.

Calreticulin mutations and long-term survival in essential thrombocythemia.

The impact of calreticulin (CALR) mutations on long-term survival in essential thrombocythemia (ET) was examined in 299 patients whose diagnosis predated 2006. Mutational frequencies were 53% for Janus kinase 2 (JAK2), 32% for CALR and 3% for MPL; the remaining 12% were 'triple-negative'. We confirmed the association of mutant CALR (vs JAK2V617F) with younger age (P=0.002), male sex (P=0.01), higher platelet count (0.0004), lower hemoglobin (P<0.0001), lower leukocyte count (0.02) and lower incidence of recurrent thrombosis (0.04). Triple-negative patients were also younger than their JAK2-mutated counterparts (P=0.003) and displayed lower hemoglobin (P=0.003), lower leukocyte count (<0.0001) and lower thrombotic events (P=0.02). Median follow-up time was 12.7 years and 47% of the patients were followed until death. Survival was the longest for triple-negative and shortest for MPL-mutated patients. Median survival was 19 years for JAK2 and 20 years for CALR-mutated cases (P=0.32); the corresponding figures for patients of age ⩽65 years were 26 and 32 years (P=0.56). The two mutational categories were also similar for leukemic (P=0.28) and fibrotic (P=0.28) progression rates. The current study is uniquely characterized by its very long follow-up period and provides accurate estimates of long-term survival in ET and complements current information on mutation-specific phenotype and prognosis.