Effect of Dose Ratio on Mitoxantrone and Daunorubicin in Acute Myeloid Leukemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

PurposeTo investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS), disease-free survival (DFS), and relapse in patients of all ages with acute myeloid leukemia (AML).MethodsWe searched published reports at the Medline, Embase, and Cochrane Databases as well as other databases from inception through July 2019. There was no restriction on date of publication or language (PROSPERO registration CRD42018095843).ResultsWe enrolled 12 randomized controlled trials that included data of 4583 AML patients whose disease was untreated or relapsed/refractory, and compared the CR, death during induction therapy, DFS, and OS between mitoxantrone and daunorubicin. Mitoxantrone significantly increased the CR rate (relative risk = 1.07; 95% confidence interval [CI], 1.01, 1.14; P = .03) and DFS (hazard ratio = 0.87; 95% CI, 0.79, 0.96; P = .005) compared to daunorubicin. However, there was no significant difference in death during induction therapy (relative risk = 1.00; 95% CI, 0.81, 1.24; P = .99) and OS (hazard ratio = 0.94; 95% CI, 0.87, 1.01; P = .077) between the two drugs.ConclusionAlthough more studies are needed to compare mitoxantrone with higher-dose daunorubicin, the results showed that compared to daunorubicin, mitoxantrone can significantly improve CR and DFS in patients of all ages. These findings suggest that mitoxantrone may be a better choice than daunorubicin as an induction chemotherapy agent for AML patients, especially in developing countries.     

Impact of Blood Count Recovery-based Complete Remission Before Allogeneic Hematopoietic Stem Cell Transplantation on Survival in Patients With Acute Myeloid Leukemia

BackgroundPatients who achieve complete remission (CR) with incomplete blood count recovery (CRi) in acute myeloid leukemia (AML) have inferior overall survival and lower progression-free survival. The aim of this study was to define whether blood count recovery-based CR before allogeneic hematopoietic stem cell transplantation (alloHSCT) had an impact on survival in patients with AML.Materials and MethodsThis study has been performed in a retrospective manner. One hundred one patients with AML who received an alloHSCT in our transplant center at Hacettepe University Hospital between the years 2001 and 2018 were evaluated. CRi were defined as bone marrow CR with absolute neutrophil count < 1000/mm³ and/or platelet count < 100.000/mm³. CR and CRi were confirmed just before alloHSCT in bone marrow and peripheral blood, respectively.ResultsA total of 101 patients were entered into the study between 2001 and 2018. Median follow-up for all survivors was 38 months (range, 6-220 months). The 5-year overall survival for patients who were in CRi and patients who were in CR before transplantation were 58% and 67%, respectively (P = .68). The 5-year progression-free survival for patients who were in CRi and patients who were in CR before transplantation were 68% and 64%, respectively (P = .99).ConclusionIn conclusion, we observed equivalent posttransplant outcomes between patients who were in CR and patients who were in CRi before alloHSCT. We assume that alloHSCT eliminated the negative effect of pre-transplant blood count levels.     

Allogeneic Stem Cell Transplantation in Patients With FLT3-ITD Mutated AML: Transplantation in CR1 Is the Decisive Factor for Good Outcome

BackgroundPatients with internal tandem duplication in fms-related tyrosine kinase receptor gene 3 (FLT3-ITD)-mutated acute myeloid leukemia (AML) have a dismal prognosis and the only curative option seems to be allogeneic stem cell transplantation (alloSCT). However, its timing is still matter of debate.Patients and MethodsWe retrospectively analyzed 73 consecutive AML patients with FLT3-ITD (median age 53, range 20-68 years) allografted with consistent policy to try to refer them all for upfront alloSCT in first complete remission (CR1).ResultsWith a median follow-up of 44 (range, 5-135) months the 5-year overall survival (OS)/disease-free survival (DFS) probabilities were 49%/47%. The cumulative incidence of relapse and nonrelapse mortality (NRM) were 37% and 14%, respectively. The estimated 5-year OS for patients who received transplantation in CR1 was 62% versus 0% for patients who received transplantation beyond CR1. Multivariable analysis identified stem cell transplantation beyond CR1 as the key factor for poor OS (hazard ratio [HR], 5.41; P < .0001), DFS (HR, 4.41; P = .0002), and high relapse incidence (HR, 8.08; P < .0001). Acute graft versus host disease Grade ≥3 predicted higher NRM (HR, 3.80; P = .059) as well as inferior OS (HR, 2.04; P = .0079). No association of patient age, nucleophosmin status, donor type, conditioning, and other variables on the survival was detected.ConclusionAlloSCT should be regarded with urgency as soon as CR1 is achieved in this subset of AML patients.     

Allogeneic hematopoietic cell transplantation in intermediate risk acute myeloid leukemia negative forFLT3-ITD,NPM1- or biallelicCEBPA mutations

BackgroundThe value of allogeneic hematopoietic cell transplantation (alloHCT) as postremission treatment is not well defined for patients with intermediate-risk acute myeloid leukemia (AML) withoutFLT3-ITD, biallelicCEBPA-, orNPM1 mutations (here referred to asNPM1^mut-neg/CEBPA^dm-neg/FLT3-ITD^neg AML) in first complete remission (CR1).Patients and methodsWe addressed this question using data from two prospective randomized controlled trials on intensive induction- and risk-stratified postremission therapy. TheNPM1^mut-neg/CEBPA^dm-neg/FLT3-ITD^neg AML subgroup comprised 497 patients, aged 18–60 years.ResultsIn donor versus no-donor analyses, patients with a matched related donor had a longer relapse-free survival (HR 0.5; 95% CI 0.3–0.9,P =0.02) and a trend toward better overall survival (HR 0.6, 95% CI 0.3–1.1,P =0.08) compared with patients who received postremission chemotherapy. Notably, only 58% of patients in the donor group were transplanted in CR1. We therefore complemented the donor versus no-donor analysis with multivariable Cox regression analyses, where alloHCT was tested as a time-dependent covariate: overall survival (HR 0.58, 95% CI 0.37–0.9,P =0.02) and relapse-free survival (HR 0.51, 95% CI 0.34–0.76;P =0.001) for patients who received alloHCT compared with chemotherapy in CR1 were significantly longer.ConclusionOutside clinical trials, alloHCT should be the preferred postremission treatment of patients with intermediate riskNPM1^mut-neg/CEBPA^dm-neg/FLT3-ITD^neg AML in CR1.Cinicaltrials.gov identifierNCT00180115, NCT00180102     

Invasive fungal diseases during first induction chemotherapy affect complete remission achievement and long-term survival of patients with acute myeloid leukemia

We retrospectively evaluated, in a logistic-regression-model, the role of proven/probable invasive fungal diseases (PP-IFD), occurring during first induction chemotherapy, on the achievement of complete remission (CR) and overall survival (OS) in 198 acute myeloid leukemia (AML) patients. A PP-IFD was documented in 34 (17.2%) patients. Younger age, good performance status at AML diagnosis and no development of a PP-IFD (OR 4.09, 95% CI 1.71–9.81, p < 0.0001) were independent factors associated to CR achievement. Younger age, good performance status, favorable genetic risk and no development of PP-IFD (HR 1.86, 95% CI 1.20–2.88, p = 0.005) were independent factors associated to OS at 3 years.     

Effect of adding gemtuzumab ozogamicin to induction chemotherapy for newly diagnosed acute myeloid leukemia: a meta-analysis of prospective randomized phase III trials

BackgroundGemtuzumab ozogamicin (GO) is a targeted antineoplastic agent comprised of a recombinant anti-CD33 humanized antibody linked to calicheamicin. Previous trials have showed conflicting results concerning the efficacy and toxicity of adding GO to induction chemotherapy for newly diagnosed acute myeloid leukemia (AML). A systematic review and meta-analysis was conducted to resolve this controversial issue.Patients and methodsSummary data from five randomized phase III trials compared adding GO to induction chemotherapy with induction chemotherapy alone for newly diagnosed AML were meta-analyzed. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and relapse-free survival (RFS), and pooled odds ratios (ORs) and 95% CIs for complete remission (CR) rate, incidences of resistance disease, relapse and toxicity were calculated.ResultsData of 3596 patients (1798 GO and 1798 controls) from five randomized phase III trials were analyzed. Compared with induction chemotherapy alone, adding GO significantly prolonged OS (HR 0.93, 95% CI 0.86–1.00, P = 0.05) and RFS (HR 0.87, 95% CI 0.79–0.95, P = 0.003), decreased the incidences of resistant disease (OR 0.71, 95% CI 0.55–0.93, P = 0.01) and relapse (OR 0.75, 95% CI 0.63–0.90, P = 0.002), but had no effect on CR rate (OR 1.15, 95% CI 0.91–1.46, P = 0.24). Sensitivity analysis yielded similar results. Subgroup analysis identified that cytogenetics might be an influencing factor for the effect of adding GO. In addition, the risks of grade 3–4 nausea/vomiting, diarrhea and liver aspartate transaminase (AST) elevation were increased in GO arm.ConclusionsAdding GO to induction chemotherapy for newly diagnosed AML can significantly prolong OS and RFS, decrease incidences of resistant disease and relapse, but may increase risks of grade 3–4 nausea/vomiting, diarrhea and liver AST elevation.     

Role of Allogeneic HCT as Postremission Therapy for Transplant-Eligible Adult Lymphoblastic Leukemia/Lymphoma After Frontline Hyper-CVAD

BackgroundHyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with cytarabine and methotrexate (hyper-CVAD) is a commonly used regimen in adults with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). Adult patients fit for pediatric-inspired protocols have an excellent outcome with chemotherapy alone. However, it is unclear whether patients receiving hyper-CVAD should undergo allogeneic hematopoietic cell transplantation (HCT) as postremission therapy. Our aim was to examine the role of HCT at first complete remission (CR1) in adult ALL/LBL after hyper-CVAD.Patients and MethodsAdult patients with newly diagnosed ALL/LBL receiving frontline hyper-CVAD from 2008 to 2018 were identified and records retrospectively extracted.ResultsA total of 85 patients were identified and included for further analysis. The median (range) age was 23 (14-68) years, and 56 (66%) were male. A total of 24 (28%) had adverse cytogenetics, and 48 (56%) had at least one risk factor. All patients received hyper-CVAD as induction; induction failure was seen in 10 (12%). A total of 38 patients continued the hyper-CVAD course, while the remaining 47 received HCT in CR1. Three-year event-free survival (EFS) and overall survival for the entire cohort were 51.4% and 61.6%, respectively. Median follow-up of alive patients was 39.9 (3.8-123.8) months. At multivariable analysis for EFS, induction failure was associated with worse outcome (hazard ratio [HR], 4.8; 95% confidence interval [CI] 1.7-13.7; P = .003), whereas HCT in CR1 improved outcome (HR, 0.42; 95% CI 0.18-0.97; P = .044). Furthermore, HCT in CR1 was the only prognostic factor for overall survival (HR, 0.3; 95% CI 0.11-0.85; P = .023).ConclusionHCT at CR1 resulted in a favorable EFS and overall survival in ALL/LBL patients after hyper-CVAD frontline therapy. Given that hyper-CVAD is a widely used protocol for adult patients, further examination of this observation is warranted.     

Prognostic relevance of achieving cytogenetic remission in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome following induction chemotherapy

Cytogenetic findings at diagnosis have influence on prognosis in patients with acute myelogenous leukaemia (AML) or MDS who undergo induction chemotherapy. Assessment of remission and treatment decisions are based on cytological findings. We analyzed the prognostic impact of cytogenetic remission status in 118 patients with abnormal karyotype who received induction chemotherapy. Initial cytogenetics were: 28 good-risk (14× t(15;17), 9× t(8;21), 5× inv(16)), 44 intermediate-risk, and 46 high-risk karyotypes. Eighty-three patients achieved complete remission (CR) and 20 achieved partial remission. Twenty-six of the patients who reached cytological CR retained an abnormal karyotype after induction, 13 of whom had been classified as standard-risk and therefore did not receive intensified consolidation. Sixty-one patients achieved cytogenetic CR (CCR), including 24 out of 28 (86%) patients with low-risk cytogenetics. The CCR rate was lower in patients with intermediate-risk (48%) or poor-risk cytogenetics (28%). Median survival (excluding patients with AML M3) of the CCR group was 37 months, as compared to 11 months in patients with persistence of abnormal karyotype (p < 0.0001). This difference remained statistically significant when calculated only for patients with intermediate-risk karyotypes (p = 0.03).Cytogenetic analysis after induction chemotherapy provides meaningful information especially in patients with intermediate-risk karyotypes. Patients with a persisting abnormal karyotype must be regarded as high-risk patients who should receive intensified treatment.     

Propensity-score Matched Comparison of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia

BackgroundRelapsed/refractory acute myeloid leukemia (AML) confers a poor prognosis, and there is no single standard of care first-line salvage regimen. FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) is a common salvage regimen with a favorable toxicity and efficacy profile in poor-risk AML.Materials and MethodsWe conducted a single-center, retrospective analysis of first relapse/primary refractory patients with AML that received salvage chemotherapy from January 2009 to July 2019. We propensity-score matched patients 1:1 (based on age at diagnosis, cytogenetic risk group, Charlson comorbidity index, de novo vs. secondary AML, and whether or not they received an allogeneic stem cell transplant in first complete remission) into 2 groups, FLAG (Group 1) or non-FLAG (Group 2) as first-line salvage regimen, with 66 patients in each group. The primary endpoint was overall response rate (complete response and complete response with incomplete hematologic recovery).ResultsThe median patient age was 59 years (range, 19-80 years). Patients treated with FLAG had a higher overall response rate (complete response/complete response with incomplete hematologic recovery) (71.2% vs. 50.0%; odds ratio, 2.47; 95% confidence interval [CI], 1.21-5.08; P = .013), longer event-free survival (8.9 vs. 2.1 months; hazard ratio [HR], 0.58; 95% CI, 0.39-0.86; P = .005), and longer overall survival (14.2 vs. 5.9 months; HR, 0.62; 95% CI, 0.41-0.93; P = .019). Patients who received FLAG had a shorter median duration of neutropenia (22 vs. 34 days; HR, 0.43; 95% CI, 0.29-0.64; P < .001).ConclusionThis analysis supports the FLAG regimen as an effective and well-tolerated salvage therapy for patients with relapsed/refractory AML.     

Acute Myeloid Leukemia Patients Requiring Two Cycles of Intensive Induction for Attainment of Remission Experience Inferior Survival Compared with Patients Requiring a Single Course of Induction Chemotherapy

BackgroundAchievement of initial remission remains the most important clinical factor predicting long term survival in acute myeloid leukemia (AML) patients treated with intensive chemotherapy. Yet, whether the patient subset in need of a second cycle of intensive induction chemotherapy to reach remission experiences inferior outcomes compared to patients reaching remission after a single cycle of therapy, remains uncertain.Patients and MethodsRetrospective analysis of 302 consecutive AML patients treated with intensive induction chemotherapy in our institution in 2007-2020.ResultsMedian patient age was 55 years with a median follow-up duration of 23 months. In terms of European LeukemiaNet (ELN) 2017 classification, 122 patients (40%) were designated as favorable risk disease, 108 patients (36%) were intermediate risk, and 71 patients (24%) were adverse risk. A hundred and seventy-seven patients (60%) attained remission following initial chemotherapy while 58 patients (20%) required an additional cycle of intensive chemotherapy for remission. Patients requiring 2 cycles to reach remission were less likely to be NPM1 mutated (33% versus 51%; P=.025) or be in the ELN 2017 favorable risk category (25% versus 57%; P<.001). In multivariate analysis achievement of remission following 2 cycles of intensive compared with a single cycle resulted in significantly inferior survival [hazard ratio (HR)=1.67, 95% CI, 1.07-2.59; P=.025] whereas leukemia-free survival was not significantly impacted (HR=1.26, 95% CI, 0.85-1.85) (P=.23). Relapse rates also did not differ to a significant degree between groups (45% versus 47%, P=.8).ConclusionAttainment of an early remission significantly impacts long term survival in AML patients.     

Prognostic and Therapeutic Value of Day 14 Bone Marrow Aspiration in Adult Acute Myeloid Leukemia Patients

BackgroundEarly blast clearance to induction chemotherapy in acute myeloid leukemia (AML) is an important prognostic indicator of treatment outcome in addition to genetics and molecular genetics. We evaluated the prognostic value of bone marrow aspiration (BMA) at day 14 (D14) and impact on outcome to asses the timing of a second induction.Patients and MethodsThis retrospective study included 303 adult AML patients managed at the National Cancer Institute, Cairo University, from the beginning of 2010 to the end of 2014.ResultsMedian age was 34 years (range, 18-67 years). Sixty-six percent had early blast clearance with < 5% blasts and 34% had ≥ 5% blasts at BMA D14; 38 patients died early during or shortly after induction. Initial blast load (bone marrow and peripheral blood) and initial platelet count were significantly higher in those with disease that did not respond to therapy compared to those whose disease did respond to therapy at D14 (P < .001, .035, and .006, respectively). The median disease-free survival for early blast clearance at D14 was 18.5 months, versus 18.7 months for those with late response to therapy (day 28), and was only 1.3 months for patients who received immediate second-line therapy on the basis of BMA D14 (P < .001). The median overall survival for early blast clearance was 13.6 months, versus 7.2 months for those with late response to therapy, and only 1.3 months for patients who received immediate second-line therapy on the basis of BMA D14 (P < .001).ConclusionBMA D14 has a significant prognostic impact on the therapeutic outcome of AML patients (complete remission, disease-free survival, and overall survival); however, a second induction in patients with BMA D14 blasts > 5% should be delayed until neutrophil recovery to minimize death in aplasia.     

Fludarabine and cytarabine in patients with acute myeloid leukemia refractory to two different courses of front-line chemotherapy

The most effective regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after two different courses of front-line chemotherapy has not been established. We therefore evaluated the efficacy, toxicity, and prognostic factors for achieving CR following treatment with fludarabine and cytarabine in 25 newly diagnosed AML patients who did not respond to initial therapy with idarubicin and cytarabine followed by mitoxantrone and etoposide. CR was achieved in 32% of patients; in 55% of patients with intermediate-risk karyotype and in 14% with unfavorable-risk. Eight percent died of infectious complications. Median duration of overall survival was 6.6 months (95% CI 3.4 months to ∞); 3.4 months (95% CI 0.8-8.6 months) for patients with an unfavorable-risk karyotype and 18.1 months (95% CI 5.0 months to ∞) with an intermediate-risk karyotype (p = 0.02). Our data suggest that poor-risk karyotype patients are unlikely to benefit from third course treatment with fludarabine-cytarabine, and that this regimen merits further investigation in AML patients with good or intermediate-risk karyotype that have persistent leukemia after two courses of front-line chemotherapy.     

Effect of the Thiotepa Dose in the TBF Conditioning Regimen in Patients Undergoing Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Complete Remission: A Report From the EBMT Acute Leukemia Working Party

BackgroundAllogeneic stem cell transplantation is a potentially curative therapy for patients with acute myeloid leukemia (AML) after achieving complete remission (CR). The aim of this study is to evaluate the optimal dose of thiotepa, administered as part of the thiotepa-busulfan-fludarabine (TBF) conditioning regimen for allogeneic stem cell transplantation in adults with AML in CR.Patients and MethodsIn a retrospective multicenter analysis, we identified 240 patients allotransplanted from matched related or unrelated donors or T replete haplo-identical donors. We compared the transplantation outcomes of patients who received 5 mg/kg thiotepa and 2 days of intravenous busulfan at 6.4 mg/kg (T1B2F) versus those who received 10 mg/kg thiotepa with 2 days of intravenous busulfan at 6.4 mg/kg (T2B2F). The median follow-up was 20 months.ResultsOn univariate analysis, the incidence of acute graft versus host disease (GVHD) grade II to IV was significantly lower in the T1B2F group (19%) versus 32% in the T2B2F group (P = .029). This result was confirmed on multivariate analysis; acute GVHD was higher for patients receiving T2B2F (hazard ratio, 2.22; P = .024). No significant change in non-relapse mortality, progression-free survival, or overall survival was observed between the 2 groups.ConclusionT2B2F is associated with a higher incidence of acute GVHD compared with T1B2F. These results suggest that a lower dose-intensity of thiotepa and busulfan in the TBF regimen may yield better results in patients with AML in CR.     

Interest of cytogenetic and FISH evaluation for prognosis evaluation in 198 patients with acute myeloid leukemia in first complete remission in a single institution

The prognostic interest of cytogenetic remission and fluorescent in situ hybridization (FISH) evaluation in patients with abnormal karyotype acute myeloid leukemia (AML) has been poorly studied. Among 198 patients that reached complete remission (CR), 24 did not reach cytogenetic remission (CyCR). CyCR had no prognosis impact, especially in patients with intermediate or unfavorable cytogenetic. Twenty of 52 evaluated patients in CyCR did not reach FISH CR. FISH CR was associated with better OS (p = 0.004) and tended to be associated with better disease-free survival (DFS) (p = 0.08). FISH evaluation may be a useful tool for prognosis evaluation and minimal residual disease (MRD) assessment in patients with abnormal cytogenetic AML.     

Lenalidomide Plus Hypomethylating Agent as a Treatment Option in Acute Myeloid Leukemia With Recurrent Genetic Abnormalities—AML With inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

IntroductionAcute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic neoplasm. The cytogenetic changes associated with AML affect the response rate and survival and are one of the most important independent prognostic factors. AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM accounts for 1% to 2% of all forms of AML and has been associated with a younger age at diagnosis, a poor response to standard induction chemotherapy, and very poor long-term prognosis.Patients and MethodsWe performed a single-center, retrospective cohort study comparing the outcomes with hypomethylating agent (HMA) plus lenalidomide to those with standard intensive induction therapies for newly diagnosed and relapsed/refractory AML with inv(3).ResultsOf the 15 patients, 4 (26.7%) had received lenalidomide and HMA as primary therapy. The overall response rate (ORR) was 100% for the 4 patients who had received lenalidomide with HMA as first-line induction therapy. The ORR was 27.3% (3 of 11) for the patients who had received other induction regimens (P = .0256). The duration of response for first induction therapy was an average of 7.4 months after lenalidomide plus an HMA and a mean of 1.5 months after induction with other chemotherapy regimen (P = .057). The ORR for induction and reinduction therapy was also assessed, with an ORR of 21.4% (6 of 28) for alternative chemotherapy regimens and an ORR of 75% (6 of 8) for induction and reinduction with lenalidomide plus HMA (P = .0046).ConclusionsThe high ORR and reasonable duration of response could allow for potentially curative allogeneic hematopoietic cell transplantation for these patients with high-risk AML. Our initial data suggest that lenalidomide plus HMA is a promising approach for patients with AML with inv(3).     

Outcome of Childhood Acute Myeloid Leukemia With FLT3-ITD Mutation: The Experience of Children’s Cancer Hospital Egypt, 2007-17

IntroductionThe presence of FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutation in pediatric acute myeloid leukemia (AML) is associated with high rates of induction failure and worse survival. Its presence places the patient into a high-risk group. We aimed to describe the outcome of pediatric AML with FLT3-ITD mutation.Patients and MethodsWe performed a retrospective analysis of cases of AML from July 2007 till July 2017 at Children’s Cancer Hospital Egypt.ResultsSeventy-one patients had FLT3 gene mutation out of 687 patients with AML. Sixty-five patients had FLT3 gene mutation with allelic ratio > 0.4; 43 (66.1%) of 65 patients experienced complete remission (CR). Of the 43 patients, 16 patients maintained CR, 18 patients relapsed after first CR, 8 patients died, and 1 patient was lost to follow-up. Patients with relapsing disease died after salvage chemotherapy, except for one patient, who was alive after second CR. Allogeneic bone marrow transplantation (allo-BMT) was performed for 9 (13.8%) of 65 patients in first CR, of whom 8 were alive and in CR, and 1 patient experienced disease relapse and died. Seven patients (10.7%) were alive without allo-BMT. Three years’ overall and event-free survival for patients with FLT3-ITD mutation with high allelic ratio was 26.9% and 22.8%, respectively. Three years’ overall and event-free survival for patients treated with allo-BMT was 77.8% and 78.8%, respectively, versus patients treated without allo-BMT, 16.3% and 12.8%, respectively.ConclusionFLT3-ITD mutation in pediatric AML was associated with poor treatment outcomes, and the survival of relapsing patients was extremely poor. Allo-BMT in first remission was the best treatment option. Alternative donor transplants and FLT3 inhibitors are needed to improve outcome in developing countries.     

Allogeneic Hematopoietic Stem-Cell Transplantation Improves Disease-Free Survival Compared to Pediatric-Inspired Berlin-Frankfurt-Münster Chemotherapy in Adult Acute Lymphoblastic Leukemia

IntroductionAcute lymphoblastic leukemia (ALL) is a malign disease with poor prognosis in adults. After remission is achieved by induction therapy, administration of allogeneic hematopoietic stem-cell transplantation (AHSCT) is one of the standard treatment in adult ALL patients. Pediatric-inspired chemotherapy has been demonstrated to improve outcomes of adult ALL. The aim of this study was to compare the Berlin-Frankfurt-Münster-95 chemotherapy (BFM-95) regimen and AHSCT results in ALL patients with first complete remission.Patients and MethodsForty-seven patients who received the BFM-95 regimen and 83 patients who underwent AHSCT were compared. Primary endpoints were comparison of overall survival (OS) and disease-free survival (DFS) between groups.ResultsThere was no significant difference between the groups in terms of age, gender, or performance status. In BFM-95 and AHSCT, relapsed disease occurred in 11 (23.4%) and 24 (28.9%), respectively; the respective values for treatment-related mortality were 6 (12.7%) and 10 (12%) (P = .32 and .91). Five-year DFS was 38% with BFM-95 and 57% with AHSCT (P = .014). There was no 5-year OS difference in both groups (64% vs 60%, P = .13). While leukocyte count < 30 × 10⁹/L at the time of diagnosis (hazard ratio, 2.7; P = .021) and prophylaxis of central nervous system (hazard ratio, 2; P = .036) were prognostic for OS, the only factor that had a prognostic effect on DFS was AHSCT (hazard ratio, 1.6; P = .041).ConclusionAHSCT currently offers no special OS advantage but increases DFS compared to the BFM-95 regimen. AHSCT may be considered at first complete remission in patients at low risk of transplant-related mortality.     

Extraskeletal osteosarcoma: A European Musculoskeletal Oncology Society study on 266 patients

PurposePrognosis of extraskeletal osteosarcoma (ESOS) is reported to be poorer than that of skeletal osteosarcoma. This multicenter retrospective study aimed to evaluate factors influencing ESOS prognosis.Patients and methodsMembers of the European Musculoskeletal Oncology Society (EMSOS) submitted institutional data on patients with ESOS.ResultsData from 274 patients treated from 1981 to 2014 were collected from 16 EMSOS centres; 266 patients were eligible. Fifty (18.7%) had metastases at diagnosis. Of 216 patients with localised disease, 211 (98%) underwent surgery (R0 = 70.6%, R1 = 27%). Five-year overall survival (OS) for all 266 patients was 47% (95% CI 40–54%). Five-year OS for metastatic patients was 27% (95% CI 13–41%). In the analysis restricted to the 211 localised patients who achieved complete remission after surgery 5-year OS was 51.4% (95% CI 44–59%) and 5-year disease-free survival (DFS) was 43% (95% CI 35–51%). One hundred twenty-one patients (57.3%) received adjuvant or neoadjuvant chemotherapy and 80 patients (37.9%) received radiotherapy. A favourable trend was seen for osteosarcoma-type chemotherapy versus soft tissue sarcoma-type (doxorubicin ± ifosfamide) regimens. For the 211 patients in complete remission after surgery, patient age, tumour size, margins and chemotherapy were positive prognostic factors for DFS and OS by univariate analysis.At multivariate analysis, patient age (≤40 years versus >40 years) (P = 0.05), tumour size (P = 0.0001) and receipt of chemotherapy (P = 0.006) were statistically significant prognostic factors for survival.ConclusionPatient age and tumour size are factors influencing ESOS prognosis. Higher survival was observed in patients who received perioperative chemotherapy with a trend in favour of multiagent osteosarcoma-type regimen which included doxorubicin, ifosfamide and cisplatin.     

Decitabine Compared With Conventional Regimens in Older Patients With Acute Myeloid Leukemia: A Meta-Analysis

BackgroundThe incidence of acute myeloid leukemia (AML) increases with age. The overall prognosis remains poor for older patients. Studies on the efficacy of decitabine, an epigenetic agent, in older patients with AML have reported conflicting results.Materials and MethodsFor this meta-analysis, we performed a literature search and collected 38 studies (including 3298 patients with AML) to evaluate the role of decitabine in elderly patients with AML. We used complete response (CR) or overall response (OR) rate as indicators of effectiveness.ResultsPatients treated with decitabine have a higher CR/OR rate than those treated with low-dose cytarabine (CR, 2.60; 95% confidence interval [CI], 1.64-4.14; OR, 4.88; 95% CI, 1.98-12.04) or CAG/HAG (low-dose epirubicin and cytarabine with granulocyte stimulating factor/low-dose homoharringtonine and cytarabine with granulocyte stimulating factor) regimens (CR, 2.53; 95% CI, 1.98-3.23; OR, 2.89; 95% CI, 2.24-3.73). However, patients treated with decitabine had a CR rate equivalent to those treated with intensive chemotherapy (CR, 0.58; 95% CI, 0.28-1.22; P = .15). Use of decitabine in combination with other regimens resulted in a higher CR/OR rate than did use of decitabine alone (P < .001); there was no significant difference in infection rates and early death rates (P > .05).ConclusionThe findings presented in this article show that decitabine is effective and safe for the treatment of older patients with AML.     

Outcomes of Autologous Hematopoietic Cell Transplantation Compared With Chemotherapy Consolidation Alone for Non–High-Risk Acute Myeloid Leukemia in First Complete Remission in a Minority-Rich Inner-City Cohort With Limited Access to Allografts

IntroductionIn the United States, autologous hematopoietic cell transplantation (autoHCT) has fallen out of favor over chemotherapy consolidation for non–high-risk acute myeloid leukemia (AML) when allogeneic hematopoietic cell transplantation (alloHCT) is unfeasible, which is common in racial minorities because of donor registry under-representation and socioeconomic challenges. We compared autoHCT consolidation outcomes with chemotherapy alone in a minority-rich cohort in the Bronx.Patients and MethodsWe identified adults with favorable or intermediate cytogenetic risk AML in first complete remission after induction at Montefiore Medical Center from 1999 to 2015, and analyzed 81 patients who received consolidation with ≥2 cycles of chemotherapy, of whom 28 received autoHCT.ResultsThe cohort predominantly consisted of ethnic/racial minorities (69%). Age, sex, race, presenting white cell count, and cytogenetic risk were similar between groups. The autoHCT group had longer relapse-free (RFS; 43 vs. 11 months; P = .003) and overall (OS) survival (not reached vs. 36 months; P = .043). Adjusted multivariable analysis showed significant benefit of autoHCT over chemotherapy alone for RFS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.37-0.75; P < .001) and OS (HR, 0.61; 95% CI, 0.40-0.95; P = .027).ConclusionIn this inner-city non–high-risk AML cohort, autoHCT provided OS and RFS benefit compared with chemotherapy alone. AutoHCT might constitute a valuable option for ethnic/racial minorities affected by significant barriers to alloHCT, whereas integration of measurable residual disease can help select patients more likely to benefit.