Therapy related‐chronic myelomonocytic leukemia (CMML): Molecular,cytogenetic, and clinical distinctions from de novo CMML

Therapy related myeloid neoplasms (t‐MN) including therapy related myelodysplastic syndromes (t‐MDS) and acute myeloid leukemia (t‐AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t‐CMML. T‐CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t‐CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t‐MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t‐CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t‐CMML in comparison to d‐CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t‐CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4‐3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5‐3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5‐3.7). In summary, we highlight the unique genetics and independent prognostic impact of t‐CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t‐MN.     

Allogeneic stem cell transplantation as initial salvage for patients with acute myeloid leukemia refractory to high‐dose cytarabine‐based induction chemotherapy

Outcomes of patients with acute myeloid leukemia (AML) who are refractory to high‐dose Cytarabine (HiDAC)‐based induction are dismal. Allogeneic hematopoietic stem cell transplantation (AHSCT) as initial salvage may be effective and potentially superior to conventional salvage chemotherapy. Eighteen percent (285 of 1597) of AML patients were primary refractory to HiDAC‐based regimens at the MD Anderson Cancer Center between 1995 and 2009. AHSCT was the initial salvage in 28 cases. These patients were compared against 149 patients who received salvage chemotherapy, but never received AHSCT. Patients receiving salvage chemotherapy were older, had higher bone marrow blasts percentage, and higher incidence of unfavorable cytogenetics (P < 0.001). Median time from induction to AHSCT was 76 days. Objective response was achieved in 23 of 28 patients (82%) undergoing AHSCT. The incidence of grade III/IV acute and chronic graft versus‐host‐disease was 11% and 29%, respectively. Median follow up for living patients is 80 months. Median overall survival (OS) was 15.7 months and 2.9 months for AHSCT and chemotherapy, respectively (P < 0.001); the 3‐year OS rates were 39% and 2%, respectively. ASHCT as initial salvage therapy was identified as an independent prognostic factor for survival in multivariate analysis (HR = 3.03; P < 0.001). Initial salvage therapy with AHSCT in patients with primary HiDAC refractory AML is feasible and may yield superior outcomes to salvage chemotherapy. Am. J. Hematol. 89:395–398, 2014. © 2013 Wiley Periodicals, Inc.     

Long-term survival after induction therapy with idarubicin and cytosine arabinoside for de novo acute myeloid leukemia

 We treated 153 patients with de novo acute myeloid leukemia (AML) with two induction courses of conventional-dose cytosine arabinoside (ara-C) and idarubicin (AIDA) followed by either a third course of AIDA, high-dose ara-C or bone-marrow transplantation. The complete remission (CR) rate for all patients was 63.4%, with a higher CR rate for patients with a normal (versus unfavorable) karyotype (73.2% vs 52.5%;P=0.038). The probability of overall survival (OS) was 30.7% after 5 years (26.3% after 7 years). Improved OS at 5 years could be observed for patients up to 50 years old versus patients older than 50 years of age (37.6% vs 19.9%;P=0.001) and patients with a normal (versus unfavorable) karyotype (42.9% vs 14.1%;P=0.0016). Disease-free survival (DFS) after 5 years was 33.2% for all 97 CR patients and was significantly better for patients with a normal (versus unfavorable) karyotype (44.3% vs 12.3%;P=0.003). Multivariate analysis revealed that the age for OS (P<0.02) and the karyotype for both OS (P<0.03) and DFS (P<0.05) were independent prognostic factors. In conclusion, AIDA is an effective and well-tolerated induction regimen (even in elderly patients) with a 5-year survival of more than 30% when combined with ara-C-containing postremission therapy. The karyotype is the most powerful prognostic factor for predicting the outcome of patients treated with this protocol. Received: 10 December 1999 / Accepted: 25 February 2000     

BAALC overexpression retains its negative prognostic role across all cytogenetic risk groups in acute myeloid leukemia patients

Overexpression of brain and acute leukemia cytoplasmic (BAALC) gene confers poor prognosis in cytogenetically normal acute myeloid leukemia (AML) patients, while less defined is its role in AML with abnormal karyotype. We evaluated the effect of BAALC overexpression on outcome of 175 adult AML patients with different cytogenetic risks. Karyotype was favorable in 13, intermediate in 117 and unfavorable in 45 patients, respectively. Quantitative BAALC expression was determined by real‐time PCR, with cut off value set at 50th percentile. BAALC was overexpressed in 87/175 (50%) patients, without association with cytogenetic status. High BAALC was associated with unmutated NPM (P = 0.006) and CD34 positivity (P < 0.0001). Complete remission (CR) was attained in 111 patients (63%), and was maintained at 5 years in 52 ± 7%. BAALC overexpression had a negative impact on CR achievement (P = 0.04), while did not influence relapse probability. Median survival was 22 months with a 5‐years overall survival (OS) of 35%. Factors with a negative impact on OS were older age (P = 0.0001), unfavorable cytogenetic (P = 0.005), ABCG2 overexpression (P = 0.03) and high BAALC levels (P = 0.01). We observed a worse outcome in patients with high BAALC expression through all cytogenetic risk categories: 5‐years OS was 100% vs. 71% in patients with favorable cytogenetics (P = 0.05), 55% vs. 40% in cases with intermediate karyotype (P = 0.04) and 34% vs. 23% in unfavorable cytogenetic subgroup (P = 0.02). BAALC overexpression identified AML patients with poor prognosis in all cytogenetic groups. Though relatively rare, BAALC positivity in patients with favorable or unfavorable karyotype significantly worsened survival. Am. J. Hematol. 88:848–852, 2013. © 2013 Wiley Periodicals, Inc.     

De novo acute myeloid leukemia with 20–29% blasts is less aggressive than acute myeloid leukemia with ≥30% blasts in older adults: a Bone Marrow Pathology Group study

It is controversial whether acute myeloid leukemia (AML) patients with 20–29% bone marrow (BM) blasts, formerly referred to as refractory anemia with excess blasts in transformation (RAEBT), should be considered AML or myelodysplastic syndrome (MDS) for the purposes of treatment and prognostication. We retrospectively studied 571 de novo AML in patients aged > 50 years, including 142 RAEBT and 429 with ≥30% blasts (AML30), as well as 151 patients with 10–19% BM blasts (RAEB2). RAEBT patients were older and had lower white blood count, but higher hemoglobin, platelet count, and karyotype risk scores compared to AML30, while these features were similar to RAEB2. FLT3 and NPM1 mutations and monocytic morphology occurred more commonly in AML30 than in RAEBT. RAEBT patients were treated less often with induction therapy than AML30, whereas allogeneic stem cell transplant frequency was similar. The median and 4‐year OS of RAEBT patients were longer than those of AML30 patients (20.5 vs 12.0 months and 28.6% vs 20.4%, respectively, P = 0.003); this difference in OS was manifested in patients in the intermediate UKMRC karyotype risk group, whereas OS of RAEBT patients and AML30 patients in the adverse karyotype risk group were not significantly different. Multivariable analysis showed that RAEBT (P < 0.0001), hemoglobin (P = 0.005), UKMRC karyotype risk group (P = 0.002), normal BM karyotype (P = 0.004), treatment with induction therapy (P < 0.0001), and stem cell transplant (P < 0.0001) were associated with longer OS. Our findings favor considering de novo RAEBT as a favorable prognostic subgroup of AML. Am. J. Hematol. 89:E193–E199, 2014. © 2014 Wiley Periodicals, Inc.     

Preoperative level of serum amyloid A is superior to C‐reactive protein in the prognosis of esophageal squamous cell carcinoma

Preoperative elevations in the levels of serum amyloid A (SAA) or C‐reactive protein (CRP) have been reported to be prognostic indicators in several malignancies. The aim of this study is to evaluate the serum levels of SAA and CRP in the prognosis of esophageal squamous cell carcinoma (ESCC). In total, 252 patients with ESCC who had undergone surgery with curative‐intent were retrospectively recruited. The specificity, sensitivity, and prognostic value of SAA or CRP levels were measured as the area under the receiver operating characteristic (ROC) curve (AUC). The clinical value of SAA and CRP levels as prognostic indicators was evaluated using Cox's proportional hazards model. The 1‐, 3‐, and 5‐year overall survival (OS) rates for the entire cohort of patients with ESCC were 71.0%, 61.0%, and 43.0%, respectively. The correlation between the levels of SAA and CRP was significant (r² = 0. 685, P < 0.001). The ROC analysis showed that the levels of CRP were associated with a significantly lower overall accuracy than were the SAA levels (AUC, 0.615 vs. 0.880; P < 0.001). For the complete cohort, the median OS was 52.0 months longer in patients with low preoperative serum levels of SAA (72.0 months) compared with patients who had high SAA levels (20.0 months, P < 0.001). The median OS among patients with low CRP levels was also longer compared with the patients who had high CRP levels (72.0 vs. 51.0 months, respectively; P < 0.001). Subgroup analyses showed that the preoperative elevated levels of SAA could find significant differences in OS for stage I, stage II, and stage III (P < 0.001, P = 0.001, and P < 0.001, respectively), whereas the increased levels of CRP could only find a difference in OS for stage II cancers. After a multivariate analysis, preoperative elevated level of SAA was found to be an independently and significant prognostic factor (P < 0.001). Our study indicates that the preoperative levels of SAA and CRP can act as prognostic factors, and that elevated levels of these proteins are associated with negative effects on the survival of patients with ESCC. SAA showed a higher prognostic value than CRP in both cohort and subgroup analysis.     

Peripheral blood blast clearance is an independent prognostic factor for survival and response to acute myeloid leukemia induction chemotherapy

In patients with acute myeloid leukemia (AML), rapid reduction of circulating blasts with induction chemotherapy may serve as an in vivo marker of chemosensitivity. We performed a retrospective analysis of 363 patients with untreated AML who received induction chemotherapy in order to determine the relationship between day of blast disappearance (DOBD) and complete remission (CR) rates, event‐free survival (EFS), and overall survival (OS). DOBD ≤ 5 vs. >5 was identified as the most discriminating cutoff for OS. DOBD > 5 was observed in 35 patients (9.6%). The CR rate for patients with DOBD ≤ 5 vs. >5 was 74.0 and 28.6%, median EFS was 9.4 and 1.8 months, and median OS was 17.1 and 5.8 months, respectively (P < 0.001 for all). DOBD > 5 was independently associated with a lower CR rate and shorter EFS and OS (P < 0.001 for all). DOBD > 5 retained prognostic significance for EFS and OS when patients were stratified by cytogenetic risk group, de novo vs. secondary or therapy‐related AML, European LeukemiaNet‐based risk groups, and whether CR was achieved. We propose DOBD > 5 as a simple and early marker of disease resistance that identifies patients with poor prognosis who otherwise may not be identified with existing risk stratification systems. Am. J. Hematol. 91:1221–1226, 2016. © 2016 Wiley Periodicals, Inc.     

Allogeneic hematopoietic stem cell transplantation could improve survival of cytogenetically normal adult acute myeloid leukemia patients with DNMT3A mutations

DNMT3A mutations are frequent in cytogenetically normal acute myeloid leukemia (cn‐AML) patients and associated with poor survival. The role of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in DNMT3A^mut cn‐AML patients remains unclear. In this study, we retrospectively analyzed the prognostic impact of DNMT3A mutations and explored the role of allo‐HSCT in 308 cn‐AML patients who received consolidation of intensive chemotherapy or allo‐HSCT in our center from March 2005 to May 2014. In the whole cohort, 63 patients (20.5%) were identified with DNMT3A exon 23 mutations and R882H was the most frequent variant. DNMT3A^mut patients had shorter overall survival (3‐year OS: 31.9% vs. 52.0%, P = 0.009) and disease‐free survival (3‐year DFS: 21.8% vs. 40.1%, P = 0.004) compared with DNMT3A^wt patients. Based on FLT3/NPM1/CEBPA mutations, 308 cn‐AML patients were divided into favorable/intermediate group (n = 262) and unfavorable group (n = 46). There were no significant differences in 3‐year OS and 3‐year DFS between DNMT3A^mut and DNMT3A^wt patients in both favorable/intermediate and unfavorable groups. Additionally, in multivariate analysis, DNMT3A mutation remained an independent adverse prognostic factor for the survival. In the DNMT3A^mut cohort, 23 complete remission (CR) patients received allo‐HSCT consolidation and 32 CR patients received chemotherapy consolidation, dramatic differences were observed in 3‐year OS (51.7% vs. 28.9%, P = 0.048) and 3‐year DFS (41.6% vs. 14.9%, P = 0.024) between allo‐HSCT group and chemotherapy group. Collectively, DNMT3A mutation is a poor prognostic factor for cn‐AML patients and allo‐HSCT could improve survival of cn‐AML patients with DNMT3A mutations. Am. J. Hematol. 90:992–997, 2015. © 2015 Wiley Periodicals, Inc.     

Characteristics of acute myeloid leukemia with myelodysplasia‐related changes: A retrospective analysis in a cohort of Chinese patients

We retrospectively analyzed 449 patients with AML under the WHO classification of AML 2008 and probed implications of this classification in diagnosis and treatment of acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) among them. The clinical presentations, biological features, treatments, and prognosis of patients diagnosed with AML‐MRC were analyzed and compared with those of AML not otherwise specified (AML‐NOS). In all patients, 115 (25.6%) were diagnosed as AML‐MRC including 64 males and 51 females with median onset age of 48 years (range from 17 to 78). Their complete remission (CR) rate was 60.9% and relapse rate was 57.1%. The observed median overall survival (OS) and disease‐free survival (DFS) were 10 and 5 months, respectively, which was significantly shorter than those of AML‐NOS patients (P < 0.05). The prognosis of AML‐MRC patients with myelodysplastic syndrome (MDS)‐related cytogenetics sole was similar to those with history of MDS or myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Patients with MDS‐related cytogenetic abnormalities and/or history of MDS or MDS/MPN predisposed significantly shortened CR, OS, and DFS than AML‐MRC patients with only multilineage dysplasia (MLD) and AML‐NOS patients (P < 0.05). Multivariate analysis showed that age, cytogenetics, and history of MDS or MDS/MPN were independent prognostic factors. Patient diagnosed as AML‐MRC presented distinctive clinical and biological features. Presence of MLD does not change the prognosis. Am. J. Hematol. 89:874–881, 2014. © 2014 Wiley Periodicals, Inc.     

Absolute lymphocyte count at the time of first relapse predicts survival in patients with diffuse large B‐cell lymphoma

Peripheral blood absolute lymphocyte count (ALC) is a survival prognostic factor in hematological malignancies. No reports have addressed whether ALC at the time of first relapse (ALC‐R) predicts survival. Thus, we assessed the prognostic significance of ALC‐R in diffuse large B‐cell lymphoma (DLBCL). Patients were required to have been diagnosed with first relapsed DLBCL, have ALC‐R values, and to be followed at Mayo Clinic, Rochester. From Feb 1987 until March 2006, 97 first relapsed DLBCL patients qualified for the study. The overall survival (OS) and progression‐free survival (PFS) were measured from the time of first relapse. The value of ALC‐R ≥ 1.0 × 10⁹/L was used for the analysis. Both groups (ALC‐R ≥ 1 or < 1 × 10⁹/L) were balanced for the international prognostic index at relapse (IPI‐R) (P = 0.3), and for autologous stem cell transplantation (P = 0.4). Superior OS and PFS were observed with an ALC‐R ≥ 1.0 × 10⁹/L (N = 60) versus ALC‐R < 1.0 × 10⁹/L (N = 37) [median OS: 28.7 months, 5 years OS rates of 39% versus median OS: 10.2 months, 5 years OS rates of 14%, P < 0.002; and median PFS: 14.8 months, 5 years PFS rates of 21% versus median PFS: 6.5 months, 5 years PFS rates of 8%, P < 0.004, respectively]. ALC‐R was an independent prognostic factor for OS [RR = 0.4, P < 0.01] and PFS [RR = 0.5, P < 0.005]. ALC‐R predicts survival suggesting that host immunity is an important variable predicting survival in first relapsed DLBCL. Am. J. Hematol. 2009. © 2008 Wiley‐Liss, Inc.     

Thrombosis and survival in essential thrombocythemia: A regional study of 1,144 patients

To identify prognostic factors affecting thrombosis‐free survival (TFS) and overall survival (OS), we report the experience of a Regional cooperative group in a real‐life cohort of 1,144 patients with essential thrombocythemia (ET) diagnosed from January 1979 to December 2010. There were 107 thrombotic events (9.4%) during follow‐up [60 (5.3%) arterial and 47 (4.1%) venous thromboses]. At univariate analysis, risk factors for a shorter TFS were: age >60 years (P < 0.0054, 95% CI 1.18–2.6), previous thrombosis (P < 0.0001, 95% CI 1.58–4.52) and the presence of at least one cardiovascular risk factor (P = 0.036, 95% CI 1.15–3.13). Patients with a previous thrombosis occurred ≥24 months before ET diagnosis had a shorter TFS compared to patients with a previous thrombosis occurred <24 months (P = 0.0029, 95% CI 1.5–6.1); furthermore, patients with previous thrombosis occurred <24 months did not show a shorter TFS compared with patients without previous thrombosis (P = 0.303, 95% CI 0.64–3.21). At multivariate analysis for TFS, only the occurrence of a previous thrombosis maintained its prognostic impact (P = 0.0004, 95% CI 1.48–3.79, RR 2.36). The 10‐year OS was 89.9% (95% CI 87.3–92.5): at multivariate analysis for OS, age >60 years (P < 0.0001), anemia (P < 0.0001), male gender (P = 0.0019), previous thromboses (P = 0.0344), and white blood cell >15 × 10⁹/l (P = 0.0370) were independent risk factors. Previous thrombotic events in ET patients are crucial for TFS but their importance seems related not to the occurrence per se but mainly to the interval between the event and the diagnosis. Am. J. Hematol. 89:542–546, 2014. © 2014 Wiley Periodicals, Inc.     

Fludarabine and cytarabine versus high‐dose cytarabine in consolidation treatment of t(8; 21) acute myeloid leukemia: A prospective,randomized study

Acute myeloid leukemia (AML) patients with t(8;21) aberration often have favorable outcomes, however, relapse still occurs in 30–40% patients, with only 50–60% of patients with t(8;21) AML cured with regimens containing high‐dose cytarabine (HD‐Ara‐C). To evaluate the effects of fludarabine and cytarabine (FA) consolidation therapy for t(8;21) AML patients, a prospective randomized study was performed. A total of 45 patients with t(8;21) AML after achieving complete remission (CR) were randomly assigned to receive four course consolidation with FA (n = 23) or HD‐Ara‐C (n = 22). Our study showed that at 36‐months, relapse‐free survival (RFS) was 81.73% in the FA arm and 50.73% in the HD‐Ara‐C arm (P = 0.04), overall survival (OS) was 91.1% and 48.4% (P = 0.01) in the FA arm and in the HD‐Ara‐C arm respectively; whereas cumulative incidence of relapse (CIR) was 18.27% and 47.39%, in the FA arm and in the HD‐Ara‐C arm respectively (P = 0.05). In our study, treatment with FA, MRD2 status (reduction ≥ 3‐log) and absence of c‐kit mutations were identified as independent prognostic factors for lower risk of relapse, improved RFS and OS. We also found RFS for patients without c‐kit mutations was 100% in FA arm, and 57.8% in HD‐Ara‐C arm at 36 months (P = 0.005); OS of both groups at 36 months was 100% and 51.4%, respectively (P = 0.004), suggesting a benefit of consolidation therapy with FA for t(8;21) AML patients, especially, those without c‐kit mutations (Clinicaltrials.org ID NCT# 02024308). Am. J. Hematol. 92:12–17, 2017. © 2016 Wiley Periodicals, Inc.     

The prognostic value of monosomal karyotype (MK) in higher‐risk patients with myelodysplastic syndromes treated with 5‐Azacitidine: A retrospective analysis of the Hellenic (Greek) Myelodysplastic syndromes Study Group

In this study, we investigated the incidence and prognostic impact of monosomal karyotype (MK) in 405 higher‐risk Myelodysplastic Syndromes (MDS) patients treated with 5‐AZA. The MK was present in 66 out of 405 (16.3%) patients, most of whom had complex karyotype (CK). MK was strongly associated with CK and the cytogenetic risk defined according to IPSS‐R, as well as with high‐risk disease, according to IPSS (P = .029), IPSS‐R (P < .001), and WPSS (P < .001) classification systems. The overall response rate (ORR) was not different between MK+ and MK– patients (46.6% vs. 46.2%). At 28 months median follow‐up, the median duration of response was 11 months in the entire cohort, 9.5 months in MK+ patients and 11 months in MK‐patients (P = .024). The estimated median time to transformation to acute myeloid leukemia for MK+ patients was 17 months vs. 23 months for MK– patients (P = .025). The estimated median OS for MK+ patients was 12 months vs. 18 months for MK– patients (P < .001). Multivariate Cox regression analysis revealed that performance status (P < .001), IPSS‐R (P < .001), and MK (P = .002) were independently associated with overall survival (OS). In a subgroup consisting of high and very‐high risk patients according to IPSS‐R, MK– patients showed better OS rates compared to MK+ patients (estimated median OS: 17 months vs. 12 months, P = .002). In conclusion, we found that MK is associated with reduced OS in patients with higher‐risk MDS treated with 5‐AZA. Furthermore, we showed that in MDS with high or very‐high IPSS‐R risk score, MK can further distinguish patients with worse outcome.     

Dynamic assessment of RBC‐transfusion dependency improves the prognostic value of the revised‐IPSS in MDS patients

RBC‐transfusion dependency (RBC‐TD) is an independent prognostic factor for poor overall survival (OS) in the WHO classification‐based prognostic scoring system (WPSS) for MDS patients. However, WPSS did not include cytopenia, whereas revised International Prognostic Scoring System (IPSS‐R) did not include RBC‐TD. Thus, neither of these prognostic scoring systems incorporates both cytopenia and RBC‐TD. We aimed to test whether RBC‐TD adds prognostic value to the IPSS‐R. We analyzed MDS patients not treated with disease‐modifying therapy, and enrolled in SA‐MDS Registry (derivation cohort; n = 295) and Dusseldorf registry (Germany; validation cohort; n = 113) using time‐dependent Cox proportional regression and serial landmark analyses. In the derivation cohort, RBC‐TD patients had inferior OS compared to RBC transfusion‐independent (RBC‐TI) patients (P < 0.0001) at 6‐ (18 vs. 64 months), 12‐ (24 vs. 71 months), and 24‐months (40 vs. 87 months). In a Cox proportional regression analysis, RBC‐TD was an independent adverse prognostic marker in addition to age, sex, and IPSS‐R variables (P < 0.0001). A prognostic index (PI) was derived using these Cox‐proportional regression model variables. In the validation cohort, this PI classified patients into four prognostic groups with significantly different OS (P < 0.001) as in the derivation cohort. In conclusion, multivariate analysis by Cox proportional hazards regression and serial landmark analyses clearly demonstrates that development of RBC‐TD at any time during the course of MDS is associated with poor OS, independent of IPSS‐R. This study demonstrates that dynamic assessment of RBC‐TD provides additional prognostic value to IPSS‐R and should be included in treatment decision algorithms for MDS patients.     

Clinical and pathological characteristics of peripheral T‐cell lymphomas in a Spanish population: a retrospective study

We investigated the clinicopathological features and prognostic factors of patients with peripheral T‐cell lymphoma (PTCL) in 13 sites across Spain. Relevant clinical antecedents, CD30 expression and staining pattern, prognostic indices using the International Prognostic Index and the Intergruppo Italiano Linfomi system, treatments, and clinical outcomes were examined. A sizeable proportion of 175 patients had a history of immune‐related disorders (autoimmune 16%, viral infections 17%, chemo/radiotherapy‐treated carcinomas 19%). The median progression‐free survival (PFS) and overall survival (OS) were 7·9 and 15·8 months, respectively. Prognostic indices influenced PFS and OS, with a higher number of adverse factors resulting in shorter survival (P < 0·001). Complete response (CR) to treatment was associated with better PFS (62·6 vs. 4 months; P < 0·001) and longer OS (67·0 vs. 7·3 months; P < 0·001) compared to no CR. CD30 was expressed across all subtypes; >15% of cells were positive in anaplastic lymphoma kinase‐positive and ‐negative anaplastic large‐cell lymphoma and extranodal natural killer PTCL groups. We observed PTCL distribution across subtypes based on haematopathological re‐evaluation. Poor prognosis, effect of specific prognostic indices, relevance of histopathological sub‐classification, and response level to first‐line treatment on outcomes were confirmed. Immune disorders amongst patients require further examination involving genetic studies and identification of associated immunosuppressive factors.     

Bone marrow cellularity at day 14 is the most important predictive factor for response in patients with AML who require double‐induction chemotherapy: Analysis from a large,single institution experience

In patients with acute myeloid leukemia (AML), the presence of residual disease at day 14 after primary induction therapy warrants consideration of a second induction cycle. However, data to guide retreatment decisions in such patients are presently limited. Here, we retrospectively reviewed data from 176 patients with AML treated at our institution with a second induction chemotherapy regimen because of day 14 residual disease. Clinical variables and nadir bone marrow features were assessed for correlations with complete remission (CR) and overall survival (OS). In our patient group, 59% achieved CR after a second induction course. Median OS for the entire group was 12.40 months (95% CI, 9.90‐14.90) but 19.07 months (95% CI, 13.13‐25.01) for those who attained a CR. Nadir marrow hypocellularity (P < 0.001) at day 14, absolute blast reduction of >50% (P = 0.030), and de novo disease status (P = 0.018) were significantly correlated with CR achievement after re‐induction. Marrow hypocellularity at day 14 was the most significant predictor of CR on multivariate analysis (P < 0.001). Nadir marrow features did not independently correlate with OS when accounting for CR status. Re‐induction was successful in achieving CR in most patients. Study patients who did not achieve CR were more likely to have nonhypocellular marrows.     

Monosomal karyotype improves IPSS‐R stratification in MDS and AML patients treated with Azacitidine

IPSS‐R classifies cytogenetic abnormalities into five prognostic groups for survival. Monosomal karyotype (MK) is not a subgroup of IPSS‐R. Additional prognostic information from MK in poor and very poor karyotype has been recently shown. The aim of our study was to determine the prognostic value of IPSS‐R and MK for response and survival in AZA‐treated high‐risk MDS and AML with 20–30% of blasts patients. The study population included 154 patients who were classified according to IPSS‐R. IPSS‐R was not predictive of response (intermediate, 64%; poor, 44%; very poor, 56%; P = 0.28) or survival (intermediate, 25 months; poor, 12 months; very poor, 11 months; P = 0.14). Twenty‐one patients (15%) presented with MK and had a median OS of 9 months. Patients with a very high IPSS‐R score without MK had a median OS of 15 months, while patients with a high IPSS‐R score without MK had a median OS of 13 months (P = 0.18). We reclassified patients into the following three groups to include MK status: very high (MK only; OS median: 9 months), high (very high IPSS‐R without MK and high IPSS‐R without MK; OS median: 14 months) and intermediate (OS median: 25 months). As in recent publication including MK prognostic, we confirmed that this classification was predictive for survival in AZA treated patients (P = 0.008). IPSS‐R failed to discriminate between the prognostic subgroups. Stratification with MK has value in the prognosis of our cohort of AZA‐treated patients. Am. J. Hematol. 88:780–783, 2013. © 2013 Wiley Periodicals, Inc.     

Early mortality and overall survival of acute myeloid leukemia based on facility type

Cancer health disparities may exist based on the facility type. We aimed to determine the association between the academic status of centers and outcomes of patients with acute myeloid leukemia (AML). Using the National Cancer Data Base, we compared 1‐month mortality and long‐term overall survival (OS) of 60 738 patients with AML, who received first course treatment between 2003 and 2011 at academic or nonacademic centers (community cancer program, comprehensive community cancer program, and others). Multivariate analysis was done using logistic regression for one‐month mortality and Cox regression with backward elimination approach for OS. Patients treated at academic centers differed from those at nonacademic centers in that they were younger with a median age of 62 versus 70 years (P < .0001), more often an ethnic minority (P < .0001), had lower education level (P = .005), lower co‐morbidity score (P < .0001), a different income (P < .0001), and insurance profile (P < .0001), and more often received chemotherapy (P < .0001) and transplant (P < .0001). Receipt of care at nonacademic centers was associated with worse 1‐month mortality (29% vs. 16%, P < .0001) and 5‐year OS (15% vs. 25%; P < .0001). After adjusting for prognostic covariates, the 1‐month mortality (odds ratio, 1.52; 95% confidence interval, CI 1.46‐1.59; P < .0001) and OS were significantly worse in nonacademic centers, compared to academic centers. Our large database study suggests that the receipt of initial therapy at academic centers is associated with lower 1‐month mortality and higher long‐term OS. Investigation of the underlying reasons may allow reducing this disparity.     

A genome‐wide single‐nucleotide polymorphism‐array can improve the prognostic stratification of the core binding factor acute myeloid leukemia

Core binding factor (CBF) AML with the D816 C‐KIT gene mutation demonstrate inferior treatment outcomes. However, the remaining cases without the D816 C‐KIT mutation imply a requirement of more sophisticated dissection of the patients according to their prognosis. In this study, we analyzed the prognostic value of a single nucleotide polymorphism array (SNP‐A) based karyotyping combined with metaphase cytogenetics (MC) to facilitate further stratification of CBF AML patients. A total of 98 CBF AML patients were included and genome‐wide Human SNP 6.0 Arrays (Affymetrix) were performed using marrow samples taken at diagnosis. Overall, 40 abnormal lesions were identified in 25 patients (26%). Survival of the patients with the abnormal lesion(s) detected by SNP‐A and/or MC was worse than those without lesions in terms of the 2‐year overall survival (OS; 57.5% vs. 76.4%, P = 0.028), event‐free (EFS; 45.7% vs. 66.2%, P = 0.072), and leukemia‐free survival (LFS; 49.0% vs. 77.4%, P = 0.015), specially in the subgroup with inv(16)/t(16;16) (40.9% vs. 80.2% OS, P = 0.040) and in the subgroup without the D816 C‐KIT mutation (61.6% vs. 82.7% OS, P = 0.038). Multivariate analysis confirmed the prognostic impact of the abnormal SNP‐A and/or MC lesion on EFS (HR 2.011, P = 0.047), and LFS (HR 3.231, P = 0.005) in the overall CBF AML. This study suggests that the combined use of SNP‐A with MC in the CBF AML can provide important prognostic value, especially in the inv(16)/t(16;16) subgroup or in the patients without the D816 C‐KIT mutation. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.     

The prognostic significance of polyclonal bone marrow plasma cells in patients with relapsing multiple myeloma

Prior studies have revealed that the presence of increasing number of polyclonal plasma cells (pPCs) in the bone marrow (BM) are associated with better outcomes in newly diagnosed multiple myeloma (MM) patients. This effect has not been studied in patients with MM at the time of disease relapse. We determined the prognostic value of depletion of pPCs in the BM by 7‐color multiparameter flow cytometry in a series of 174 relapsing MM patients. The time to next therapy (TTNT) in those with <5% pPCs was 9.4 months versus 13.9 months in those with ≥5% pPCs (P = .0091). The median overall survival (OS) in those with <5% pPCs was 21.4 months, while the median OS was not reached in those patients with ≥5% pPCs (P = .019). Of the 109 patients with standard risk cytogenetics, the median OS of those with <5% pPCs was 28.4 months, while the median OS was not reached in those with ≥5% pPCs (P = .033). As such, <5% pPCs in the BM appears to have prognostic utility in identifying a subset of relapsing MM patients, even with standard‐risk cytogenetics, who have a particularly adverse outcome.