Vicky Sandhu

Relation of Clinical Response and Minimal Residual Disease and Their Prognostic Impact on Outcome in Acute Myeloid Leukemia

PURPOSE Both presence of minimal residual disease (MRD) and achievement of complete remission (CR) with incomplete platelet recovery (CRp) rather than CR after induction therapy predict relapse in acute myeloid leukemia (AML). These results suggest a correlation between response (peripheral count recovery) and MRD at the time of morphologic remission. Here we examine this hypothesis and whether MRD and response provide independent prognostic information after accounting for other relevant covariates. PATIENTS AND METHODS We retrospectively analyzed data from 245 adults with AML who achieved CR, CRp, or CR with incomplete blood count recovery (CRi) after induction therapy. Bone marrow samples were collected on or closest to the first date of blood count recovery, and MRD was determined by 10-color multiparameter flow cytometry. RESULTS The 71.0% of patients who achieved CR had MRD less frequently and had lower levels of MRD than the 19.6% of patients achieving CRp and 9.4% achieving CRi. Although pretreatment covariates such as cytogenetics, monosomal karyotype, relapsed or refractory rather than newly diagnosed AML, and FLT3 internal tandem duplication were associated with relapse, their prognostic effect was much lower once MRD and response were taken into account, the univariable statistical effect of which was not materially affected by inclusion of pretreatment covariates. CONCLUSION Our data indicate that post-therapy parameters including MRD status and response are important independent prognostic factors for outcome in patients with AML achieving remission. MRD status and type of response (CR v CRp or CRi) should play important, and perhaps dominant, roles in planning postinduction therapy.

Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission.

PURPOSE To determine the frequency of allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). PATIENTS AND METHODS Between January 1, 2008, and March 1, 2011, 212 newly diagnosed patients with AML received treatment at our center. Ninety-five patients age less than 75 years with intermediate- or high-risk AML achieved a complete remission, and 21 patients achieved a morphologic remission with incomplete blood count recovery. RESULTS Seventy-eight (67%; 95% CI, 58% to 76%) of 116 patients received HCT at a median of 2.8 months (range, 0.5 to 19 months) from their CR1 date. The median age was 57 years in both the HCT patient group (range, 18 to 75 years) and the non-HCT patient group (range, 24 to 70 years; P = .514). Between the HCT patients and the non-HCT patients, the mean Eastern Cooperative Oncology Group performance status was 1.1 compared with 1.5, respectively (P = .005), and the average HCT comorbidity score within 60 days of CR1 was 1.7 and 2.1, respectively (P = .68). Twenty-nine (76%) of 38 non-HCT patients were HLA typed, and matched donors were found for 13 of these 29 patients (34% of all non-HCT patients). The most common causes for patients not receiving transplantation in CR1 were early relapse (within 6 months) in 12 patients (32%), poor performance status in eight patients (21%), and physician decision in five patients (13%). CONCLUSION HCT can be performed in CR1 in the majority of patients with AML for whom it is currently recommended. The main barriers to HCT were early relapse and poor performance status, highlighting the need for improved therapies for patients with AML of all ages.

Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS

Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high‐risk myelodysplastic syndrome (MDS). Thirty‐four patients ≥60 years old (median age 70 years; range, 60–83) were randomized to receive tosedostat (120 mg on days 1–21 or 180 mg continuously) with 5 d of either cytarabine (1 g/m2/d) or decitabine (20 mg/m2/d) every 35 d. Twenty‐nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS‐refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3‐internal tandem duplication mutations. Median follow‐up was 11·2 months (range, 0·5–22·3), and median survival was 11·5 months (95% confidence interval, 5·2–16·7). Twenty‐three patients (67·6%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3–4 non‐haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials.

Value of routine ‘day 14’ marrow exam in newly diagnosed AML

2013). 8 Vainstein V, Buckley SA, Shukron O, Estey EH, Abkowitz JL, Wood BL et al. Rapid rate of peripheral blood blast clearance accurately predicts complete remission in acute myeloid leukemia. Leukemia 2014; 28: 713–716. Differential association of calreticulin type 1 and type 2 mutations with myelofibrosis and essential thrombocytemia: relevance for disease evolution Leukemia (2015) 29, 249–252; doi:10.1038/leu.2014.270 Recent advances in myeloproliferative neoplasms (MPNs) have highlighted the prevalence of mutations in the calreticulin gene (CALR), bringing a major new actor in these disorders. Numerous studies have highly contributed to understanding of the role of JAK2 and MPL in the pathogenesis of MPN development and progression. In contrast to JAK2 mutations that are associated in a causative manner with polycythemia vera, myelofibrosis (MF) or essential thrombocytemia (ET), CALR mutations are only associated with ET and MF. Indeed, CALR mutations were reported in 25% of ET and in 35% of MF patients who were non-mutated for JAK2 and MPL. All recurrent CALR mutations that have been observed lead to a frame-shift generating a common 36 amino-acid C-terminal end and loss of the KDEL motif. Among these mutations, two variants are largely predominant: type 1, a 52-bp deletion (p.L367fs*46) and type 2, a 5-bp insertion (p.K385fs*47). They account for 85% of the CALR mutations in ET and primary myelofibrosis (PMF). There is strong evidence that the clinical features of CALR and JAK2-mutated ET and PMF are different and represent two facets of these disorders, although they both activate the JAK/STAT signaling pathway. It remains possible that the different CALR mutants exert different signaling activities. Thus, it would be important to characterize the potential differences between the different CALR mutations and also the phenotype of MPN devoid of JAK2, MPL and CALR mutations, now called triple-negative MPNs to understand whether they represent a homogeneous population. A total of 572 MPN patients negative for JAK2 and MPL mutations were collected according to sex, age at diagnosis and main clinical characteristics from several French and Belgian hospitals under the auspices of French Intergroup of Myeloproliferative disorders. The mutational status of CALR was determined using previously described high-resolution sizing of fluorescent dye-labeled PCR amplification of exon 9, with Sanger sequencing controls. Beyond its contribution to mutant detection, highresolution sizing also allows to estimate the allelic burden. Laboratory data and clinical parameters were obtained at diagnosis. The GraphPad Prism statistical package (GraphPad Software, Inc., La Jolla, CA, USA) was used to perform statistical analysis on these data, as described in Supplementary Information. The median age at diagnosis of the entire patient series was 59 years (range, 7–92); 241 were males (43.1%). In our series, 396 patients were diagnosed as ET (including potential unidentified prefibrotic stage of myelofibrosis), 108 as MF (including PMF and post-ET MF) and 68 as mixed myelodysplastic syndrome (MDS)/ MPN. We identified mutations localized in exon 9 of CALR in 368 patients (63.3%). The remaining 204 patients were designated as triple negative. The global distribution of CALR mutations in our series was similar to previous studies with 206 type 1 mutations (56%), 119 type 2 mutations (32%) and 43 other mutations (12%) representing 17 different CALR variants (Figure 1a). Importantly, nine were previously described but eight represented new variants (Figure 1b). Notably one of them, p.Glu378Cysfs*36, shortened the consensus C-terminal end to 33 amino acids only. In contrast to the rather low numbers of JAK2 and MPL mutation variants, the growing number of CALR genomic variants identified implies that these mutants might not be completely biologically equivalent, despite the common loss of the KDEL motif and the acquisition of a new functional domain. Differences in the sequence of the C-terminal domain could indeed reach up to 25 amino acids, which is predicted to change the properties of the protein. Our striking result is the distribution of CALR mutation type according to the MPN type. In MF there is an overrepresentation of type 1 CALR mutation (70%) and an underrepresentation of type 2 CALR mutation (13%) as compared with patients with ET that have a distribution of CALR mutations comparable to the global series of patients (Figure 1a; P= 0.0002). In MPNs, it has been highlighted that different allelic burdens of JAK2V617F and MPLW515K/L are associated with different phenotypes. In our series, a higher allelic burden of CALR mutation was found in MF (Po0.0001; Table 1). Even if it affects a small number of patients, it is to be noted that a high allelic burden (over 60%) was more frequent in MF (5/35 = 14.3%) than in ET (6/158 = 3.8%; P= 0.0256). This highly suggests the presence of rare homozygous mutations as described by Klampfl. However, and contrary to that study, we observed a high allelic burden mainly Accepted article preview online 12 September 2014; advance online publication, 14 October 2014 Letters to the Editor

Prognostic significance of acquired copy-neutral loss of heterozygosity in acute myeloid leukemia.

Chromosomal abnormalities are important in the diagnosis and prognosis of patients with acute myeloid leukemia (AML). Genomic microarray techniques detect recurrent copy‐neutral loss of heterozygosity (cnLOH) in addition to copy number aberrations. However, the clinical utility has not been fully established. Therefore, in the current study, the authors examined the prognostic impact of acquired cnLOH in patients with AML, including complete remission (CR) rate, duration of CR, and overall survival (OS).

A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age.

Outcomes for older adults with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are generally poor, and new effective therapies are needed. We investigated oral clofarabine combined with low‐dose cytarabine (LDAC) in patients aged 60 years and above with relapsed or refractory AML or high‐risk MDS in a phase I/II trial. A 3 + 3 dose escalation of oral clofarabine was followed by a phase II expansion with the aim of obtaining a complete response (CR) rate ≥30%. We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. A total of 35 patients, with a median age of 72 years, were treated. Of 26 patients enrolled at the MTD, 4 had treatment‐related grade 3–4 non‐haematological toxicities, but none died within 28 d. The observed CR rate and median survival were 34% [95% confidence interval (CI), 18–50%] and 6·8 months overall and 38% [95% CI, 19–57%] and 7·2 months at the MTD. The median disease‐free survival was 7·4 months. Fifty‐two percent (23/44) of cycles administered at the MTD were done without hospital admission. This combination of oral clofarabine and LDAC demonstrated efficacy with a CR rate of >30% and acceptable toxicity in older patients.

Infusion of a non-HLA-matched ex-vivo expanded cord blood progenitor cell product after intensive acute myeloid leukaemia chemotherapy: a phase 1 trial

BACKGROUND The intensive chemotherapy regimens used to treat acute myeloid leukaemia routinely result in serious infections, largely due to prolonged neutropenia. We investigated the use of non-HLA-matched ex-vivo expanded cord blood progenitor cells to accelerate haemopoietic recovery and reduce infections after chemotherapy. METHODS We enrolled patients with a diagnosis of acute myeloid leukaemia by WHO criteria and aged 18-70 years inclusive at our institution (Fred Hutchinson Cancer Research Center) into this phase 1 trial. The primary endpoint of the study was safety of infusion of non-HLA-matched expanded cord blood progenitor cells after administration of clofarabine, cytarabine, and granulocyte-colony stimulating factor priming. The protocol is closed to accrual and analysis was performed per protocol. The trial is registered with ClinicalTrials.gov, NCT01031368. FINDINGS Between June 29, 2010, and June 26, 2012, 29 patients with acute myeloid leukaemia (19 newly diagnosed, ten relapsed or refractory) were enrolled. The most common adverse events were fever (27 [93%] of 29 patients) and infections (25 [86%] of 29 patients). We observed one case of acute infusional toxicity (attributed to an allergic reaction to dimethyl sulfoxide) in the 29 patients enrolled, who received 42 infusions of expanded progenitor cells. The following additional serious but expected adverse events were observed (each in one patient): grade 4 atrial fibrillation, grade 4 febrile neutropenia, lung infection with grade 4 absolute neutrophil count, colon infection with grade 4 absolute neutrophil count, grade 4 changed mental status, and one death from liver failure. No unexpected toxicity or graft-versus-host disease was observed. There was no evidence of in-vivo persistence of the expanded progenitor cell product in any patient beyond 14 days or induced alloimmunisation. INTERPRETATION Infusion of the expanded progenitor cell product seemed safe and might provide a promising treatment method for patients with acute myeloid leukaemia. FUNDING Biomedical Advanced Research and Development Authority in the US Department of Health and Human Services and Genzyme (Sanofi).

Correlation between peripheral blood and bone marrow regarding FLT3-ITD and NPM1 mutational status in patients with acute myeloid leukemia.

It is more convenient to use peripheral blood (PB) than bone marrow (BM) for various laboratory studies if the former can serve as well as the latter. In patients with newly diagnosed acute myeloid leukemia (AML) and more than 30% blasts in PB there is considerable concordance between PB and BM in

Idarubicin, cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high‐risk myelodysplastic syndrome

Previous studies suggest that idarubicin/cytarabine(ara‐C)/pravastatin (IAP) is an active salvage regimen for patients with AML. We therefore investigated this regimen in patients with newly‐diagnosed AML or MDS (≥10% blasts). Patients were eligible if the anticipated treatment‐related mortality (TRM) was <10%. Patients received pravastatin (1,280 mg/day po; days 1–8), cytarabine (1.5 g/m2/day; days 4–7), and idarubicin (12 mg/m2/day, days 4–6). Up to 3 cycles of consolidation with a shortened course was permitted. The primary endpoints were “good CR” rate (CR on day 35 without minimal residual disease) and TRM in the first 28 days. The study was to stop if after each cohort of 5 patients (a) the Bayesian posterior probability was < 5% that the true “good CR rate” was ≥ 70% or (b) the posterior probability was >25% that the TRM rate was ≥5%. Twenty‐four patients were included. Conventional CR was achieved in 15 (63%) patients but only 12 (50%) achieved “good CR”. 4 of 12 (33%) patients with “good CR” relapsed at median of 16 weeks (10.5–19). Five (21%) patients had refractory disease. Survival probability at 1 year was 72% (48.7–64). Two (8.3%) patients died within 28 days from multiorgan failure. The most common grade 3–4 adverse effects were febrile neutropenia (75%) and diarrhea (25%). Based on the stopping rules accrual ceased after entry of these 24 patients. IAP did not meet the predefined efficacy criteria for success. Therefore, we would not recommend this regimen for phase three testing in this patient subset. Am. J. Hematol. 90:483–486, 2015.

Low platelet count reduces subsequent complete remission rate despite marrow with <5% blasts after AML induction therapy.

Low platelet count reduces subsequent complete remission rate despite marrow with <5% blasts after AML induction therapy