Truncated CSF3 receptors induce pro-inflammatory responses in severe congenital neutropenia

Severe congenital neutropenia (SCN) patients are prone to develop myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML). Leukaemic progression of SCN is associated with the early acquisition of CSF3R mutations in haematopoietic progenitor cells (HPCs), which truncate the colony-stimulating factor 3 receptor (CSF3R). These mutant clones may arise years before MDS/AML becomes overt. Introduction and activation of CSF3R truncation mutants in normal HPCs causes a clonally dominant myeloproliferative state in mice treated with CSF3. Paradoxically, in SCN patients receiving CSF3 therapy, clonal dominance of CSF3R mutant clones usually occurs only after the acquisition of additional mutations shortly before frank MDS or AML is diagnosed. To seek an explanation for this discrepancy, we introduced a patient-derived CSF3R-truncating mutation in ELANE-SCN and HAX1-SCN derived and control induced pluripotent stem cells and compared the CSF3 responses of HPCs generated from these lines. In contrast to CSF3R-mutant control HPCs, CSF3R-mutant HPCs from SCN patients do not show increased proliferation but display elevated levels of inflammatory signalling. Thus, activation of the truncated CSF3R in SCN-HPCs does not evoke clonal outgrowth but causes a sustained pro-inflammatory state, which has ramifications for how these CSF3R mutants contribute to the leukaemic transformation of SCN.     

Absence of mutations in the granulocyte colony-stimulating factor (G-CSF) receptor gene in patients with myelodysplastic syndrome/acute myeloblastic leukaemia occurring after treatment of aplastic anaemia with G-CSF

The development of myelodysplastic syndrome/acute myeloblastic leukaemia (MDS/AML) has been reported in patients with aplastic anaemia (AA) after administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF). Similarly, patients with severe congenital neutropenia (SCN) have an increased risk of developing MDS/AML after treatment with rhG-CSF. Point mutations in the G-CSF receptor gene are found in about 20% of SCN patients who are predisposed to MDS/AML. We investigated the occurrence of mutations in the G-CSF receptor in eight patients with AA who developed MDS/AML. No mutations were detected around the cytoplasmic domain of the gene in our patients, indicating that the mechanisms of clonal evolution to MDS/AML in patients with AA might be different from those with SCN.     

A Phase II intra‐patient dose‐escalation trial of weight‐based darbepoetin alfa with or without granulocyte‐colony stimulating factor in myelodysplastic syndromes

This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate‐1 risk myelodysplastic syndrome (MDS). Intra‐patient dose escalation of DA was undertaken in three 6‐week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte‐colony stimulating factor (G‐CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight‐based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G‐CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low‐level non‐neutralizing anti‐DA antibodies. Our data indicate that weekly weight‐based dosing of DA, with the addition of G‐CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower‐risk MDS patients. Am. J. Hematol, 2009. © 2008 Wiley‐Liss, Inc.     

Rituximab plus hyper‐CVAD alternating with MTX/Ara‐C in patients with newly diagnosed mantle cell lymphoma: 15‐year follow‐up of a phase II study from the MD Anderson Cancer Center

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long‐term follow‐up results for patients treated with these regimens. We present long‐term survival outcomes from a pivotal phase II trial of rituximab, hyper‐fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R‐HCVAD/MA) . At 15 years of follow‐up (median: 13·4 years), the median failure‐free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15‐year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10‐year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5–12·2%). In patients with newly diagnosed MCL, R‐HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one‐third of the younger patients (≤65 years).     

Stem cell transplantation in patients with severe congenital neutropenia with evidence of leukemic transformation

Severe congenital neutropenia (SCN) is a hematologic condition characterized by arrested maturation of myelopoiesis at the promyelocyte stage of development. With appropriate treatment using recombinant human granulocyte-colony-stimulating factor (r-HuG-CSF), SCN patients are now surviving longer, but are at increased risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but transplantation outcomes after malignant transformation are not well established. We report results for six patients with SCN who underwent HSCT for MDS or AML between 1997 and 2001 at two transplant centers. Two patients transplanted for MDS survived. Both of these patients were transplanted without being given induction chemotherapy. Four patients, who all received induction chemotherapy for AML prior to HSCT, died. Administering induction chemotherapy prior to HSCT resulted in significant morbidity. Rapid transplantation should be the goal for the SCN patient once the diagnosis of MDS/AML is established. SCN patients should be monitored carefully for progression to MDS in order to be treated with HSCT as soon as they have progressed and before developing AML. For SCN patients who progress to AML, HSCT should still be considered, even though the risks appear to be greater.     

Abrupt evolution of Philadelphia chromosome‐positive acute myeloid leukemia in myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a clonal disorder arising from an alteration in multipotent stem cells, which lose the ability of normal proliferation and differentiation. Disease progression occurs in approximately 30% MDS cases. Specific chromosomal alterations seem responsible for each step in the evolution of acute myeloid leukemia (AML). Multiple genetic aberrations occur during the clonal evolution of MDS; however, few studies report the presence of the Philadelphia (Ph) chromosome. We report a rare case of Ph‐positive AML, which evolved during the course of low‐risk MDS. The patient, a 76‐year‐old man with mild leukocytopenia, was diagnosed with MDS, refractory neutropenia (RN). After 1.5 yr, his peripheral blood and bone marrow were suddenly occupied by immature basophils and myeloblasts, indicating the onset of AML. A bone marrow smear showed multilineage dysplasia, consistent with MDS evolution. Chromosomal analysis showed an additional t(9;22)(q34;q11) translocation. Because progression occurred concurrently with emergence of the Ph chromosome, we diagnosed this case as Ph‐positive AML with basophilia arising from the clonal evolution of MDS. The patient was initially treated with nilotinib. A hematological response was soon achieved with disappearance of the Ph chromosome in the bone marrow. Emergence of Ph‐positive AML in the course of low‐risk MDS has rarely been reported. We report this case as a rare clinical course of MDS.     

Safety and efficacy of healthy volunteer stem cell mobilization with filgrastim G‐CSF and mobilized stem cell apheresis: results of a prospective longitudinal 5‐year follow‐up study

Background and Objectives G‐CSF‐mobilized peripheral blood stem cells have long replaced marrow as the major source for allogeneic transplants. Conclusive evidence questioning the long‐term safety of G‐CSF for donors has not been provided, but the cumulative number of followed donors remains insufficient to rule out rare adverse events. A long‐term active follow‐up study of G‐CSF‐mobilized healthy volunteer donors was therefore performed. Patients and Methods Two hundred and three successive donors were evaluated pre‐apheresis, subjected to G‐CSF‐mobilization/apheresis, and actively followed for 5 years by the same physicians and laboratories. Follow‐up laboratory work included standard biochemical/haematological tests and T‐cell phenotyping. Results Donor epidemiology was typical for reported stem cell donor cohorts. Acute adverse effects of G‐CSF and apheresis were mild and transient, consistent with the previous reports. Mean circulating CD34⁺ cells after nine doses of G‐CSF were 124 per μl. Other biochemical/haematological parameters were also altered, consistent with G‐CSF treatment. Spleen enlargement was modest. At first follow‐up, all clinical and laboratory parameters had normalized. Leucocyte/lymphocyte counts and CD4/CD8 ratios were the same as during premobilization work‐up and remained unchanged throughout. A single severe but likely unrelated adverse event, a case of papillary thyroid carcinoma, was reported. Conclusion The studies add an observation time of almost 500 donor years to the growing body of evidence of the long‐term safety of G‐CSF for allogeneic donor stem cell mobilization.     

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.     

Enumerating bone marrow blasts from nonerythroid cellularity improves outcome prediction in myelodysplastic syndromes and permits a better definition of the intermediate risk category of the Revised International Prognostic Scoring System (IPSS‐R)

The Revised International Prognostic Scoring System (IPSS‐R) has been recognized as the score with the best outcome prediction capability in MDS, but this brought new concerns about the accurate prognostication of patients classified into the intermediate risk category. The correct enumeration of blasts is essential in prognostication of MDS. Recent data evidenced that considering blasts from nonerythroid cellularity (NECs) improves outcome prediction in the context of IPSS and WHO classification. We assessed the percentage of blasts from total nucleated cells (TNCs) and NECs in 3924 MDS patients from the GESMD, 498 of whom were MDS with erythroid predominance (MDS‐E). We assessed if calculating IPSS‐R by enumerating blasts from NECs improves prognostication of MDS. Twenty‐four percent of patients classified into the intermediate category were reclassified into higher‐risk categories and showed shorter overall survival (OS) and time to AML evolution than those who remained into the intermediate one. Likewise, a better distribution of patients was observed, since lower‐risk patients showed longer survivals than previously whereas higher‐risk ones maintained the outcome expected in this poor prognostic group (median OS < 20 months). Furthermore, our approach was particularly useful for detecting patients at risk of dying with AML. Regarding MDS‐E, 51% patients classified into the intermediate category were reclassified into higher‐risk ones and showed shorter OS and time to AML. In this subgroup of MDS, IPSS‐R was capable of splitting our series in five groups with significant differences in OS only when blasts were assessed from NECs. In conclusion, our easy‐applicable approach improves prognostic assessment of MDS patients.     

Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis.     

Azacitidine in the ‘real‐world’: an evaluation of 1101 higher‐risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario,Canada

The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher‐risk disease treated with azacitidine (AZA) in the ‘real‐world’ remains largely unknown. We evaluated 1101 consecutive higher‐risk MDS patients (International Prognostic Scoring System intermediate‐2/high) and low‐blast count acute myeloid leukaemia (AML; 21–30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5‐2‐2. Overall, median number of cycles was 6 (range 1–67) and 8 (range 6–14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7–12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6–19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML.     

Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia

Severe congenital neutropenia (SCN) is a BM failure syndrome with a high risk of progression to acute myeloid leukemia (AML). The underlying genetic changes involved in SCN evolution to AML are largely unknown. We obtained serial hematopoietic samples from an SCN patient who developed AML 17 years after the initiation of G-CSF treatment. Next- generation sequencing was performed to identify mutations during disease progression. In the AML phase, we found 12 acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, co-occurred in a subpopulation of progenitor cells already in the early SCN phase. This population expanded over time, whereas clones harboring only CSF3R mutations disappeared from the BM. The other 9 mutations were only apparent in the AML cells and affected known AML-associated genes (RUNX1 and ASXL1) and chromatin remodelers (SUZ12 and EP300). In addition, a novel CSF3R mutation that conferred autonomous proliferation to myeloid progenitors was found. We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development. The sequential gain of 2 CSF3R mutations implicates abnormal G-CSF signaling as a driver of leukemic transformation in this case of SCN.     

The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy

In patients with severe congenital neutropenia (SCN), sepsis mortality is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported. We studied 374 patients with SCN and 29 patients with Shwachman-Diamond syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. In SCN, sepsis mortality was stable at 0.9% per year. The hazard of MDS/AML increased significantly over time, from 2.9% per year after 6 years to 8.0% per year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for sepsis mortality and 21% for MDS/AML. A subgroup of SCN patients (29%) received more than the median dose of G-CSF (> or = 8 microg/kg/d), but achieved less than the median absolute neutrophil count (ANC) response (ANC < 2.188 x 10(9)/L [2188/microL] at 6-18 months). In these less-responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared with 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. Risk of MDS/AML may be similar in SDS and SCN. In less-responsive SCN patients, early hematopoietic stem cell transplantation may be a rational option.     

G‐CSF Priming,clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia,advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm

Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony‐stimulating factor (G‐CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G‐CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse‐free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg m^?2 day^?1 × 5 and cytarabine at 2 g m^?2 day^?1 × 5 after G‐CSF priming in 50 newly‐diagnosed patients ages 18–64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64–88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71–93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well‐tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders. Am. J. Hematol. 90:295–300, 2015. © 2014 Wiley Periodicals, Inc.     

Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia

Severe congenital neutropenia (SCN) is a heterogeneous bone marrow failure syndrome predisposing to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We studied 82 North American and Australian SCN patients enrolled in the Severe Chronic Neutropenia International Registry who were on long-term treatment with granulocyte colony-stimulating factor and for whom the neutrophil elastase ( ELA2 ) gene was sequenced. There was no significant difference in the risk of MDS/AML in patients with mutant versus wild-type ELA2 : the respective cumulative incidences at 15 years were 36% and 25% ( P  =   0·96). Patients with either mutant or wild-type ELA2 should be followed closely for leukaemic transformation.     

Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5‐aza‐2′‐deoxycytidine (Decitabine)

Although azanucleoside DNA‐hypomethylating agents (HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), very few outcome predictors have been established. Expression of the β‐like globin gene locus is tightly regulated by DNA methylation, is HMA‐sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine (DAC). Pre‐treatment HbF was already elevated (>1·0% of total haemoglobin) in 7/16 and 12/36 patients, and HbF was induced by DAC in 81%/54% of MDS/AML patients, respectively. Elevated pre‐treatment HbF was associated with longer median overall survival (OS): 26·6 vs. 8·6 months for MDS (hazard ratio [HR] 8·56, 95% confidence interval [CI] 1·74–42·49, P = 0·008, with similarly longer progression‐free and AML‐free survival), and 10·0 vs. 2·9 months OS for AML (HR 3·01, 95% CI 1·26–7·22, P = 0·014). In a multivariate analysis, the prognostic value of HbF was retained. Time‐dependent Cox models revealed that the prognostic value of treatment‐induced HbF induction was inferior to that of pre‐treatment HbF. In conclusion, we provide first evidence for in vivo HbF induction by DAC in MDS/AML, and demonstrate prognostic value of elevated pre‐treatment HbF, warranting prospective, randomized studies.     

Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long‐term safety and efficacy

Romiplostim can improve platelet counts in about 50% of patients with low‐ or intermediate 1‐risk (lower risk) myelodysplastic syndromes (MDS) and thrombocytopenia, but its long‐term toxicity and efficacy are not known. This open‐label extension study evaluated the long‐term safety and efficacy of romiplostim in 60 patients with lower risk MDS and platelet counts ≤50 × 10⁹/l. The primary endpoint was adverse event (AE) incidence. Secondary endpoints were efficacy parameters, including bleeding events and platelet response. Median (range) treatment time in the extension study and the median observation times thereafter were 25 (2–181) and 57 (11–209) weeks, respectively. Treatment‐related AEs and serious AEs were reported in 14/60 (23%) and 4/60 (7%) patients, respectively. Progression to acute myeloid leukaemia (AML) occurred in two patients after 44 and 46 weeks. Patients (n = 34, 57%) with a platelet response were further evaluated for length of response. Median (range) response duration was 33 (7–174) weeks; 28/34 (82%) patients had a continuous response. Five of 34 patients (15%) had grade ≥3 bleeding events; three when the platelet count was >50 × 10⁹/l. There were no new safety concerns and the rate of progression to AML was low; response to romiplostim was maintained for most patients.     

Positive impact of chronic graft‐versus‐host disease on the outcome of patients with de novo myelodysplastic syndrome after allogeneic hematopoietic cell transplantation: a single‐center analysis of 115 patients

To evaluate the impact of graft‐versus‐host disease (GVHD) and prognostic factors for patients with myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (allo‐HCT), we retrospectively reviewed 115 patients with MDS or acute myeloid leukemia with multilineage dysplasia (AML‐MLD) after allo‐HCT at our center. Eighty one patients received reduced‐intensity conditioning (RIC) regimens, whereas 34 received myeloablative conditioning regimens. Although the RIC group was significantly older and included more patients with poor cytogenetic risk, no difference in 4‐yr overall survival (OS) was seen between the two groups. In a multivariate analysis, covariates associated with a worse OS were the French‐American‐British stage of refractory anemia excess blasts in transformation/AML‐MLD at peak, poor cytogenetic risk, bone marrow blasts of 20% or higher at HCT and the absence of chronic GVHD (cGVHD). By using semi‐landmark analyses, we found that the presence of cGVHD significantly improved OS in high‐risk patients or the RIC group. However, there was no difference in OS between those with and without cGVHD among low‐risk MDS patients. These findings suggest that the graft‐versus‐leukemia effect may be more beneficial in high‐risk patients who do not receive intensive preparative regimens.     

Long term follow‐up of allogeneic stem cell transplantation in patients with myelodysplastic syndromes using busulfan,cytosine arabinoside,and cyclophosphamide

We report here the 10‐year follow‐up of 86 patients who underwent allogeneic stem cell transplantation (ASCT) for myelodysplastic syndrome (MDS). All patients received the busulfan, cytosine arabinoside, and cyclophosphamide (BAC) preparative regimen which consisted of busulfan 16 mg/kg, cytosine arabinoside 8 g/m² IV, and cyclophosphamide 120 mg/kg IV. Fifty‐nine patients (69%) had de novo MDS; 26 (30%) had secondary MDS (treatment related), and one had a preceding aplastic anemia which progressed to MDS before transplant. Cytogenetics (80 patients) was classified as good (34%), intermediate (17%), or poor (42%). With a median follow‐up for survivors of 124 months, the 10‐year Kaplan‐Meier estimates for overall survival (OS) was 43% (95% confidence interval [CI]: 31–53%). Cumulative nonrelapse mortality (NRM) and relapse was 43% (95% CI: 32–54%) and 19% (95% CI: 11–27%), respectively. No patient relapsed after 2 years. In patients with RAEB‐T/AML, 10‐year relapse‐free survival (RFS), relapse, and NRM was 36%, 36%, and 27%, respectively. Younger age (P = 0.05), human leukocyte antigen (HLA) match (P = 0.002), good risk cytogenetics (P = 0.008), and having a related donor (P = 0.03) significantly improved overall and RFS in the multivariable analysis. The long‐term follow‐up of patients receiving the BAC regimen with ASCT in this study indicated durable relapse‐free and OS with acceptable toxicity in this group of patients with high‐risk features. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Successful salvage of RAEB/AML relapsing early post allograft with FLAG‐Ida conditioned mini‐allograft: a report of two cases

Management options are often limited for patients with AML or high grade myelodysplasia (MDS) relapsing within a year of allogeneic transplantation. We report, in two such patients, the use of re‐induction with FLAG‐Ida chemotherapy, followed by the infusion of GCSF‐mobilized blood stem cells from the same HLA‐matched donor. Both patients achieved durable complete remissions with good quality of life and longer disease‐free survival than after the first myeloablative allografts. This mini‐allograft approach offers a practical, well‐tolerated salvage and a potentially curative treatment for relapsed AML/high grade MDS patients failing a first conventional myeloablative allogeneic transplants.