Hong-Xia Shi

Superior Graft-versus-Leukemia Effect Associated with Transplantation of Haploidentical Compared with HLA-Identical Sibling Donor Grafts for High-Risk Acute Leukemia: An Historic Comparison

The outcomes of an historic comparison of 117 consecutive, high-risk, acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) from HLA-mismatched/haploidentical donors (HID, n = 81) or HLA-identical sibling donors (ISD, n = 36) without the use of in vitro T cell depletion (TCD), between the period of January 2005 and April 2009 were compared. Full engraftment was achieved in 98% of patients in the HID group and 97% in the ISD group. The cumulative incidences of grades II-IV acute graft-versus-host disease (aGVHD) in the HID and ISD cohorts were 49% and 24%, respectively (P = .014) with a relative risk (RR) of 2.99 (1.25-7.21) (P = .014). The incidence of chronic GVHD (cGVHD) did not differ significantly between the 2 cohorts. The 2-year cumulative incidence of relapse was significantly lower in HID (26%) than in ISD patients (49%) (P = .008). The 2-year cumulative incidence of nonrelapse mortality (NRM) was comparable in recipients of HID (34%) and ISD grafts (38%) (P = .85). The 3-year probability of overall survival (OS) was higher in HID patients (42%) than in ISD (20%) (P = .048) patients. Our comparisons suggest that HID transplants can achieve a stronger graft-versus-leukemia (GVL) effect than ISD for high-risk acute leukemia patients.

Prevalence and prognostic significance of c-KIT mutations in core binding factor acute myeloid leukemia: A comprehensive large-scale study from a single Chinese center

To clarify the prevalence and prognostic significance of c-KIT mutations in patients with core binding factor acute myeloid leukemia (CBF-AML), a total of 351 patients who were categorized as pediatric t(8;21), adult t(8;21), pediatric inv(16), or adult inv(16) were screened at diagnosis for c-KIT mutations in exons 17 and 8 using direct sequencing. A total of 250 patients underwent follow-up. Overall, 36.5% of the patients had a c-KIT mutation. Adult t(8;21) and inv(16) patients had mutations predominantly in exons 17 and 8, respectively. Higher White blood cell (WBC) count, WBC index, and AML1-ETO transcript levels in adult t(8;21) patients were significantly associated with c-KIT mutations and mutations in exon 17 (P≤0.030). c-KIT mutations in adult t(8;21) patients were significantly correlated with a high cumulative incidence of relapse (CIR, P=0.0070) at 2 years and a low 2-year disease-free survival (DFS, P=0.013) and overall survival (OS, P=0.0055). However, no significant difference was revealed in the effect of c-KIT mutations on outcome of adult inv(16) and pediatric t(8;21) patients (all P>0.05). Multivariate analysis revealed that c-KIT mutation is an independent prognostic factor for relapse, DFS, and OS (P≤0.016) in adult t(8;21) AML patients. Therefore, with regard to c-KIT mutation, CBF-AML is a heterogeneous disease. c-KIT mutations have a strong adverse effect on the relapse and survival of adult t(8;21) AML patients.

NPM1-mutated acute myeloid leukemia of monocytic or myeloid origin exhibit distinct immunophenotypes.

Acute myeloid leukemia with mutated nucleophosmin (NPM1m+AML) is a heterogeneous entity. We investigated whether NPM1m+AML with monocytic or myeloid differentiation have distinct immunophenotype. The study included 160 NPM1m+AMLpatients and 178 AML patients without NPM1 mutation and recurrent cytogenetic abnormality (NPM1wt-AML). We analyzed the immunophenotype by flow cytometry. NPM1 mutation was detected by PCR. Compared with NPM1wt-AML patients, NPM1m+AML patients showed higher positive rates of CD33 and CD9 and lower positive rates of CD34, HLA-DR, CD7, CD15 and CD117 (all P<0.05). HLA-DR, CD64, CD14, CD11b, CD15, CD4, CD9 and CD10 were higher (P<0.001) and CD117 was lower (P<0.01) in monocytic NPM1m+AML compared with myeloid NPM1m+AML. Similar rates of lymphoid antigen (CD19, CD2, and CD7) and myeloid antigen (CD13, CD33) positivity were detected in monocytic and myeloid NPM1m+AML. Compared with NPM1wt-AML, CD34 expression was lower both in myeloid and monocytic NPM1m+AML subgroups, although HLA-DR was lower in NPM1m+AML compared with NPM1wt-AML only in myeloid subgroup. Comparisons of NPM1m+AML and NPM1wt-AML showed no differences in monocyte-associated markers such as CD14 and CD11b in myeloid and monocytic subgroup. Myeloid NPM1m+AML correlated with the female gender (P=0.001), lower WBC counts (P=0.04) and higher WT1 transcripts (P=0.006) compared with monocytic NPM1m+AML.These results suggested monocytic and myeloid-derived NPM1m+AML exhibit distinct immunophenotypes.

Frequency and allele burden of CALR mutations in Chinese with essential thrombocythemia and primary myelofibrosis without JAK2V617F or MPL mutations

CALR mutations are detected in about 50% of persons of predominately European descent with essential thrombocythemia (ET) or primary myelofibrosis (PMF) with wild-type alleles of JAK2 and MPL. We studied 1088 Chinese with diverse myeloproliferative neoplasms including ET (N=234) and PMF (N=50) without JAK2(V617F) or MPL exon 10 mutations. CALR mutation was detected in 53% (95% CI, 46-60%) of subjects with ET and 56% (95% CI, 41-70%) of subjects with PMF. 152 CALR mutations were identified clustering into 15 types including deletions (N=8), insertions (N=3) and complex indels (N=4). We also identified 9 new mutations. Mean (±SD) mutant allele burden was 31±12% (range, 0.5-69%). Persons with PMF had higher CALR mutant allele burdens than those with ET (38±8% vs. 29±12%; P<0.001). Amongst persons with CALR mutations, those with PMF had different clinical features from those with ET. These data may be useful for diagnosing ET and PMF in Chinese who are about 40% of all persons with ET and PMF and for monitoring therapy-response. They also highlight similarities and differences in CALR mutations between Chinese and persons of predominately European descent with these diseases.

PRAME and WT1 transcripts constitute a good molecular marker combination for monitoring minimal residual disease in myelodysplastic syndromes

Abstract PRAME and WT1 transcript levels were simultaneously measured in 312 bone marrow samples collected from patients with newly diagnosed myelodysplastic syndromes (MDS) and 111 samples collected during the treatment of 17 patients. Both the positive rate and the > 1-log increase expression frequency of PRAME were similar to those of WT1 (74.4 % vs. 77.6%; 51.6% vs. 49.0%), and 88.1% of patients overexpressed at least one marker. Moreover, the frequencies of PRAME expression with higher degrees of increase were significantly higher compared with those of WT1 expression (> 2-log increase: 30.8% vs. 3.8%; > 3-log increase: 9.0% vs. 0%; all p < 0.001). PRAME had a higher log increase than WT1 in 53.3% of the patients with overexpressed WT1. Both PRAME and WT1 transcript levels generally fluctuated within the normal range after hematopoietic stem cell transplant in all 10 patients in continuous complete remission. Six out of seven patients were predicted relapse by the combined detection: sustained positivity, or significant increase to be positive for both WT1 and PRAME in three patients, earlier by PRAME than WT1 or by PRAME alone in three patients. Thus, PRAME and WT1 transcripts constitute a good molecular marker combination for monitoring minimal residual disease in MDS.

The clinical value of the quantitative detection of four cancer-testis antigen genes in multiple myeloma

BackgroundCancer-testis (CT) antigen genes might promote the progression of multiple myeloma (MM). CT antigens may act as diagnostic and prognostic markers in MM, but their expression levels and clinical implications in this disease are not fully understood. This study measured the expression levels of four CT antigen genes in Chinese patients with MM and explored their clinical implications.MethodsReal-time quantitative polymerase chain reaction (qPCR) was used to quantify the expression of MAGE-C1/CT7, MAGE-A3, MAGE-C2/CT10 and SSX-2 mRNA in 256 bone marrow samples from 144 MM patients.ResultsIn the newly diagnosed patients, the positive expression rates were 88.5% for MAGE-C1/CT7, 82.1% for MAGE-C2/CT10, 76.9% for MAGE-A3 and 25.6% for SSX-2. The expression levels and the number of co-expressed CT antigens correlated significantly with several clinical indicators, including the percentage of plasma cells infiltrating the bone marrow, abnormal chromosome karyotypes and the clinical course.ConclusionMAGE-C1/CT7, MAGE-A3, MAGE-C2/CT10 and SSX-2 expression levels provide potentially effective clinical indicators for the auxiliary diagnosis and monitoring of treatment efficacy in MM.

Concordant optimal molecular and cytogenetic responses at both 3 and 6 months predict a higher probability of MR4.5 achievement in patients with chronic myeloid leukemia treated with imatinib

Abstract To investigate the impact of the combination of early molecular and cytogenetic responses on the achievement of MR4.5, 228 newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib were categorized into 3-month and 6-month concordant optimal, discordant, concordant warning, and failure groups. Among them, 85.3% at 3 months and 78.1% at 6 months had concordant molecularly and cytogenetically defined responses. At both 3 and 6 months, patients with discordant, concordant warning and failure responses had similar 3-year MR4.5 rates, and all were significantly lower than the rate in patients with concordant optimal responses. Patients with concurrent 3-month and 6-month concordant optimal responses had a significantly higher 3-year MR4.5 rate than those with other responses, and 3-month and 6-month concurrent molecular optimal, but not cytogenetic optimal responses. Therefore, achieving concordant optimal molecular and cytogenetic responses at both 3 and 6 months with imatinib treatment are associated with MR4.5 achievement.

Is there an epidemic of chronic lymphocytic leukaemia (CLL) in China

BACKGROUND Chronic lymphocytic leukaemia (CLL) is 10- to 20-fold less common in Asians (including Han Chinese) compared with persons of predominately European descent. Why is unknown but seems predominately genetic. We observed an increasing frequency of new cases of CLL at our Haematology Centre beginning 2011 and wondered why. OBJECTIVE Determine the cause(s) for this increased frequency. METHOD We interrogated the context of CLL diagnosis in 483 consecutive subjects seen at the Institute of Haematology of a large referral hospital in Beijing. 3 cohorts were considered based on why a CBC was done to establish the CLL diagnosis: (1) a CBC-testing situation unrelated to a health condition such as a routine annual health exam or application for employment or medical insurance (termed routine CBC); (2) an unrelated medical condition such as a cold, influenza, heart disease etc. (termed CBC for other disorders); and (3) signs and/or symptoms consistent with CLL such as lymph-adenopathy, hepato- or splenomegaly, fatigue, B-symptoms etc. (termed CBC for possible CLL). RESULTS Data regarding context of CLL diagnosis were available for 389 subjects (81%). Proportions of subjects in the 3 cohorts were 44% (95% confidence interval [CI]; 39, 49%), 24% (20, 28%) and 32% (28, 37%). The proportion of subjects whose evaluation of CLL was prompted by an abnormal CBC not for possible CLL (cohorts 1 and 2) increased over the surveillance interval (r = 0.164; P = 0.001) as did median age at diagnosis (r = 0.207; P < 0.001). Age at diagnosis was correlated with probability of CLL being suspected because of an abnormal routine CBC (r = 0.249; P < 0.001); 42% (32, 53%) amongst subjects ≤50 years versus 86% (75, 92%; P < 0.001) among those >70 years. Consistent with this, older subjects were diagnosed at Rai stage-0 with asymptomatic disease compared with younger subjects (P < 0.001). CONCLUSION Our data suggest much of the increased frequency of CLL at our centre and likely elsewhere in China predominately reflects ascertainment bias. Other variables may also operate.

Prevalence and outcomes of uncommon BCR-ABL1 fusion transcripts in patients with chronic myeloid leukaemia: data from a single centre

To explore the type, prevalence and outcomes in chronic myeloid leukaemia (CML) patients with uncommon BCR‐ABL1 transcripts in the era of tyrosine kinase inhibitors (TKIs), uncommon BCR‐ABL1 transcripts were screened in 4750 patients by multiplex polymerase chain reaction (PCR), and type‐specific real‐time quantitative PCR was regularly performed for molecular monitoring. A total of 19 uncommon transcripts, including e1a2, e1a3, e6a2, e8a2, e12a2, unusual e13a2, e13a3, unusual e14a2, e14a3 and e19a2 were identified in 83 (1·7%) patients. The three most frequent types were e19a2, e13a3/e14a3 and e1a2. Compared with the 571 newly diagnosed CML patients in chronic phase with common e13a2/e14a2 transcripts receiving frontline imatinib therapy, patients with the e19a2 (n = 16) and e1a2 (n = 11) transcripts had significantly reduced probabilities of 1‐year complete cytogenetic response (CCyR, P = 0·0004 and 0·016) and major molecular response (MMR, P = 0·0018 and 0·0035), and patients with the e13a3/e14a3 transcript (n = 10) had significantly increased probabilities of 1‐year CCyR (P = 0·0072) and MMR (P = 0·0073). Patients with the e19a2 transcript had low probabilities of 2‐year event‐free survival (EFS, P = 0·0004) and progression‐free survival (P = 0·0067), and patients with the e1a2 transcript had low probability of 2‐year EFS (P < 0·0001). Therefore, uncommon BCR‐ABL1 fusion transcripts are rare and diverse in patients with CML and may be relevant for TKI therapy outcomes.

CD20 expression sub-stratifies standard-risk patients with B cell precursor acute lymphoblastic leukemia

Patients with standard-risk adult acute lymphoblastic leukemia (ALL) treated with chemotherapy do not have satisfactory outcomes. To more precisely classify ALL patients and optimize treatment, we re-evaluated the risk stratification system by examining CD20 expression and other classic risk factors at diagnosis. We retrospectively analyzed response to induction chemotherapy of 217 consecutive patients with newly diagnosed Philadelphia-negative B cell precursor-ALL. Survival analyses were conducted for the 136 patients who were intended to be treated with chemotherapy alone. Among the 217 patients, 69 (31.8%) were considered standard risk based on age <35 years, white blood cell count <30 × 109/L, absence of central nervous system involvement, and high-risk cytogenetic abnormalities. Seventy-four patients (34.1%) expressed CD20 on ≥20% of leukemia blasts and were considered CD20 positive. We found that fewer CD20-positive than CD20-negative patients achieved durable first complete responses (CR1 ≥3 months) (81.1% vs. 94.9%, P=0.002). Within the standard-risk group, more CD20-negative than CD20-positive patients achieved CR (100% vs. 83.3%, P=0.003) and durable CR1 (100% vs. 82.4%, P=0.014). For patients in the CD20-negative standard-risk, CD20-positive standard-risk, CD20-negative high-risk, and CD20-positive high-risk groups, the 3-year cumulative incidence of relapse was 42.6%, 70.0%, 59.3%, and 69.5%, respectively (P=0.118); the 3-year disease-free survival rates were 52.1%, 0%, 20.7%, and 13.7%, respectively (P=0.006); and the 3-year overall survival rates were 55.8%, 13.8%, 23.6%, and 16.9%, respectively (P=0.006). Our results suggest that patients with CD20-negative standard-risk B cell precursor-ALL have favorable prognosis compared with CD20-positive standard-risk or CD20-negative or -positive high-risk patients. CD20-positive standard-risk ALL patients may need other therapeutic modalities bridging to allogeneic hematopoietic stem cell transplantation.