Surgery in rare bleeding disorders: the prospective MARACHI study.

Background: Despite the wide use of bleeding scores and the reliability of clotting factor level measurement, bleeding risk stratification before surgery remains challenging in patients with rare inherited bleeding disorders. Objectives: This multicenter observational prospective study assessed in patients with rare coagulation factor deficiency, the perioperative hemostatic management choices by hemostasis experts and the bleeding outcomes after surgery. Methods: One hundred seventy-eight patients with low coagulation activity level (factor [F] II, FV, combined FV-FVIII, FVII, FX, or FXI <50%) underwent 207 surgical procedures. The bleeding outcome, Tosetto's bleeding score, and perioperative hemostatic protocols were collected. Results: Among the 81 procedures performed in patients with severe factor deficiency (level ≤10%), 27 were done without factor replacement (including 6 in patients at high bleeding risk), without any bleeding event. Factor replacement therapy was used mainly for orthopedic procedures. In patients with mild deficiency, 100/126 surgical procedures were carried out without perioperative hemostatic treatment. In patients with FVII or FXI deficiency, factor replacement therapy was in function of the procedure, bleeding risk, and to a lesser extent previous bleeding history. Tranexamic acid was used in almost half of the procedures, particularly in case of surgery in tissues with high fibrinolytic activity (76.8%). Conclusions: The current perioperative hemostatic management of patients with rare bleeding disorders appears to be adapted. Among the 207 procedures, only 6 were associated with excessive bleeding. Our findings suggest that rather than the bleeding score, factor level and surgery type are the most relevant criteria for perioperative factor replacement therapy.

Hereditary predisposition to malignant myeloid hemopathies: Caution in use of saliva and guideline based on our experience.

Background: Predisposition to myeloid malignancies is a field at the border of hematology and genetics. Knowledge in this domain has so rapidly increased that WHO defined in 2016 the new "Myeloid Neoplasms with Germline Predisposition" category of tumors. High throughput sequencing is frequently performed in tumors either for diagnosis or prognosis, but this approach may identify potential germline variants that have to be confirmed on non-infiltrated tissues. Method: In this study, we systematically compared NGS data from genetic analysis performed on all sample types (bone marrow, blood, saliva, skin fibroblasts and hair follicles) in 29 patients, and 44 of their relatives (blood and saliva). Results: We showed that saliva was usable for relatives, but only for 24% (7/29) of our patients. Most of patients' saliva were either "non-contributive" (14/29 i.e., 48% because clearly or probably infiltrated) or "inconclusive" (8/29 corresponding to 28%). Conclusion: The recommendations for the use of saliva we present here focus on the importance of collecting saliva during remission when possible. Moreover, we propose hair follicles as an alternative to skin biopsy, that remains the gold standard especially in case of allogenic hematopoietic stem cells transplantation. Technological progresses have revolutionized the diagnosis of predisposition to solid or hematological malignancies, and it is very likely that new techniques will help to manage the familial predisposition in the future.

Antifungal Prophylaxis in AML Patients Receiving Intensive Induction Chemotherapy: A Prospective Observational Study From the Acute Leukaemia French Association (ALFA) Group.

BACKGROUND: Although recommended in patients with acute myeloblastic leukaemia (AML) after induction chemotherapy, real-life use of antifungal prophylaxis (AFP) is different among centres. MATERIALS AND METHODS: This is an ancillary study to a randomized trial on intensive induction chemotherapy in AML patients (ALFA-0702/NCT00932412), where AFP with posaconazole was recommended. IFIs were graded by investigators and by central reviewers according to the revised EORTC definitions. Experts conclusions were compared to the investigators' ones. RESULTS: A total of 677 patients were included. Four AFP strategies were reported: Group-1: no AFP (n = 203, 30%), Group-2: posaconazole (n = 241, 36%), Group-3: posaconazole with other AFP (n = 142, 21%), Group-4: other AFP (n = 91, 13%). Experts graded more IFI than investigators: proven/probable IFI, 9.0% (n = 61) versus 6.2% (n = 42). The cumulative incidence at day60 of probable/proven IFI was 13.9% (Group-1); 7.9% (Group-2); 5.6% (Group-3); and 6.6% (Group-4). IFI onset was 26 (19-31) days after induction in Groups 2-3, versus 16 (9-25) days in Group 1 and 20 (12-24) days in Group 4 (P< .001). After a median follow-up of 27.5 months (0.4-73.4), the mortality rate was 38.3%, with 5.4% attributed to IFI. In multivariate analysis, IFI occurrence was an independent risk of death (HR5.63, 95%-CI 2.62-12.08, P< .001). EORTC recommendations were applied in only 57% of patients. In patients without IFI, the rate of AML complete remission was higher. CONCLUSIONS: In AML patients, AFP delayed the onset of IFI in addition of decreasing their rate. The frequent misidentification of IFI impacts their appropriate management according to recommendations. hematological remission was more frequent in patients without IFI.

Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study.

We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.

Population pharmacokinetics and Bayesian estimators for intravenous mycophenolate mofetil in haematopoietic stem cell transplant patients.

AIMS: Intravenous mycophenolate mofetil (IV MMF), a prodrug of mycophenolic acid (MPA), is used during nonmyeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease. The aims of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies to allow for individual dose adjustment of intravenous mycophenolate mofetil administered by infusion in haematopoietic stem cell transplant patients. METHODS: Sixty-three MPA concentration-time profiles (median [min-max] = 6 [4-7] samples) were collected from 34 HCT recipients transplanted for 14 (1-45) days and administered IV MMF every 8 hours, concomitantly with cyclosporine. The database was split into development (75%) and validation (25%) datasets. Pharmacokinetic models characterized by a single compartment with first-order elimination, combined with two gamma distributions to describe the transformation of MMF into mycophenolic acid, were developed using in parallel nonparametric (Pmetrics) and parametric (ITSIM) approaches. The performances of the models and the derived Bayesian estimators were evaluated in the validation set. RESULTS: The best limited sampling strategy led to a bias (min, max), root mean square error between observed and modeled interdose areas under the curve in the validation dataset of -11.72% (-31.08%, 5.00%), 14.9% for ITSIM and -2.21% (-23.40%, 30.01%), 12.4% for Pmetrics with three samples collected at 0.33, 2 and 3 hours post dosing. CONCLUSION: Population pharmacokinetic models and Bayesian estimators for IV MMF in HCT have been developed and are now available online (https://pharmaco.chu-limoges.fr) for individual dose adjustment based on the interdose area under the curve.

[Second allogeneic hematopoietic stem cell transplant: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Seconde allogreffe : recommandations de la Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Disease recurrence and graft dysfunction after allogeneic hematopoietic stem cell transplantation (allo-HSCT) currently remain among the major causes of treatment failure in malignant and non-malignant hematological diseases. A second allo-HSCT is a valuable therapeutic option to salvage those situations. During the 8th annual harmonization workshops of the french Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines on feasibility, indications, donor choice and conditioning in the case of a second allo-HSCT. In case of relapse, a second allo-HSCT with reduced intensity or non-myeloablative conditioning is a reasonable option, particularly in patients with a good performance status (Karnofsky/Lansky>80%), low co-morbidity score (EBMT score≤3), a longer remission duration after the first allo-HSCT (>6 months), and who present low disease burden at the time of second allo-HSCT. Matched related donors tend to be associated with better outcomes. In the presence of graft dysfunction (primary and secondary graft rejection), an immunoablative conditioning regimen is recommended. A donor change remains a valid option, especially in the absence of graft-versus-host disease after the first allo-HSCT.

A mutation of the human EPHB2 gene leads to a major platelet functional defect.

The ephrin transmembrane receptor family of tyrosine kinases is involved in platelet function. We report the first EPHB2 variant affecting platelets in 2 siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts. Whole-exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2 gene. P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous. The p.R745C variant within the tyrosine kinase domain was associated with defects in platelet aggregation, αIIbß3 activation, and granule secretion induced by G-protein-coupled receptor (GPCR) agonists and convulxin, as well as in thrombus formation on collagen under flow. In contrast, clot retraction, flow-dependent platelet adhesion, and spreading on fibrinogen were only mildly affected, indicating limited effects on αIIbß3 outside-in signaling. Most importantly, Lyn, Syk, and FcRγ phosphorylation, the initial steps in glycoprotein VI (GPVI) platelet signaling were drastically impaired in the absence of platelet-platelet contact, indicating a positive role for EPHB2 in GPVI activation. Likewise platelet activation by PAR4-AP showed defective Src activation, as opposed to normal protein kinase C activity and Ca2+ mobilization. Overexpression of wild-type and R745C EPHB2 variant in RBL-2H3 (rat basophilic leukemia) cells stably expressing human GPVI confirmed that EPHB2 R745C mutation impaired EPHB2 autophosphorylation but had no effect on ephrin ligand-induced EPHB2 clustering, suggesting it did not interfere with EPHB2-ephrin-mediated cell-to-cell contact. In conclusion, this novel inherited platelet disorder affecting EPHB2 demonstrates this tyrosine kinase receptor plays an important role in platelet function through crosstalk with GPVI and GPCR signaling.

Arsenic trioxide is required in the treatment of newly diagnosed acute promyelocytic leukemia. Analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group.

In standard-risk acute promyelocytic leukemia, recent results have shown that all-trans retinoic acid plus arsenic trioxide combinations are at least as effective as classical all-trans retinoic acid plus anthracycline-based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher-risk acute promyelocytic leukemia, and access to arsenic remains limited for front-line treatment of standard-risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared arsenic, all-trans retinoic acid and the "classical" cytarabine for consolidation treatment (after all-trans retinoic acid and chemotherapy induction treatment) in standard-risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher-risk disease. Patients with newly diagnosed acute promyelocytic leukemia with a white blood cell count <10x109/L, after an induction treatment consisting of all-trans retinoic acid plus idarubicin and cytarabine, received consolidation chemotherapy with idarubicin and cytarabine, arsenic or all-trans retinoic acid. Patients with a white blood cell count >10x109/L received consolidation chemotherapy with or without arsenic. Overall, 795 patients with acute promyelocytic leukemia were enrolled in this trial. Among those with standard-risk acute promyelocytic leukemia (n=581), the 5-year event-free survival rates from randomization were 88.7%, 95.7% and 85.4% in the cytarabine, arsenic and all-trans retinoic acid consolidation groups, respectively (P=0.0067), and the 5-year cumulative incidences of relapse were was 5.5%, 0% and 8.2%. (P=0.001). Among those with higher-risk acute promyelocytic leukemia (n=214), the 5-year event-free survival rates were 85.5% and 92.1% (P=0.38) in the chemotherapy and chemotherapy plus arsenic groups, respectively, and the corresponding 5-year cumulative incidences of relapse were 4.6% and 3.5% (P=0.99). Given the prolonged myelosuppression that occurred in the chemotherapy plus arsenic arm, a protocol amendment excluded cytarabine during consolidation cycles in the chemotherapy plus arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first-line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation in which we found myelosuppression to be significant. (ClinicalTrials.gov Identifier: NCT00378365).

Assessment of the nutritional status of adult patients with acute myeloid leukemia during induction chemotherapy.

OBJECTIVE: To the best of our knowledge, few studies have evaluated the nutritional status in patients with acute myeloid leukemia (AML) during induction treatment. The aim of this retrospective study was to describe nutritional status of newly diagnosed adult patients with AML at admission and during induction chemotherapy. METHODS: We included consecutive newly diagnosed adult patients with AML who were admitted to the Department of Hematology (Limoges University Hospital) from April 2010 to January 2014. Nutritional assessment included body mass index (BMI) and weight loss to diagnose undernutrition. Weekly laboratory tests were collected and total energy expenditure was calculated to adapt food intake. RESULTS: Of 95 patients, 14 (15%) presented with undernutrition at admission: low BMI values (P < 0.001) and weight loss >5% for 9.5% patients. After chemotherapy induction, 17 patients (18%) were undernutrition (P = 0.05). Patients without undernutrition had a significantly lower median weight, BMI, and serum albumin level at discharge compared with their admission values (P < 0.05); whereas their serum transthyretin levels were higher (P = 0.03). They also had shorter hospital stays than patients with undernutrition (31 versus 39 d; P = 0.03) and longer survival at 12 mo (89.9 versus 58.3%; P = 0.002). CONCLUSIONS: Patients with AML with good nutritional status undergoing induction chemotherapy have shorter hospital stays and longer survival.

Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Short intensive chemotherapy is the standard of care for adult patients with Burkitt's leukaemia or lymphoma. Findings from single-arm studies suggest that addition of rituximab to these regimens could improve patient outcomes. Our objective was to test this possibility in a randomised trial. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients older than 18 years with untreated HIV-negative Burkitt's lymphoma (including Burkitt's leukaemia) from 45 haematological centres in France. Exclusion criteria were contraindications to any drug included in the chemotherapy regimens, any serious comorbidity, poor renal (creatinine concentration >150 µmol/L) or hepatic (cirrhosis or previous hepatitis B or C) function, pregnancy, and any history of cancer except for non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma. Patients were stratified into two groups based on disease extension (absence [group B] or presence [group C] of bone marrow or central nervous system involvement). Patients were further stratified in group C according to age (<40 years, 40-60 years, and >60 years) and central nervous system involvement. Participants were randomly assigned in each group to either intravenous rituximab injections and chemotherapy (lymphome malin B [LMB]) or chemotherapy alone by the Groupe d'Etude des Lymphomes de l'Adulte datacentre. Randomisation was stratified by treatment group and centre using computer-assisted permuted-block randomisation (block size of four; allocation ratio 1:1). We gave rituximab (375 mg/m(2)) on day 1 and day 6 during the first two courses of chemotherapy (total of four infusions). The primary endpoint is 3 year event-free survival (EFS). We analysed all patients who had data available according to their originally assigned group. This trial is registered with ClinicalTrials.gov, number NCT00180882. RESULTS: Between Oct 14, 2004, and Sept 7, 2010, we randomly allocated 260 patients to rituximab or no rituximab (group B 124 patients [64 no rituximab; 60 rituximab]; group C 136 patients [66 no rituximab; 70 rituximab]). With a median follow-up of 38 months (IQR 24-59), patients in the rituximab group achieved better 3 year EFS (75% [95% CI 66-82]) than did those in the no rituximab group (62% [53-70]; log-rank p stratified by treatment group=0·024). The hazard ratio estimated with a Cox model stratified by treatment group, assuming proportionality, was 0·59 for EFS (95% CI 0·38-0·94; p=0·025). Adverse events did not differ between the two treatment groups. The most common adverse events were infectious (grade 3-4 in 137 [17%] treatment cycles in the rituximab group vs 115 [15%] in the no rituximab group) and haematological (mean duration of grade 4 neutropenia of 3·31 days per cycle [95% CI 3·01-3·61] vs 3·38 days per cycle [3·05-3·70]) events. INTERPRETATION: Addition of rituximab to a short intensive chemotherapy programme improves EFS in adults with Burkitt's leukaemia or lymphoma. FUNDING: Gustave Roussy Cancer Campus, Roche, Chugai, Sanofi.

Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: a French Acute Myeloid Leukemia Intergroup trial.

Core-binding factor acute myeloid leukemia is a favorable acute myeloid leukemia subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, disrupting RUNX1 (previously CBFA/AML1) or CBFB transcription factor functions. The receptor tyrosine kinase KIT is expressed in the vast majority of these acute myeloid leukemias and frequent activating KIT gene mutations have been associated with a higher risk of relapse. This phase II study aimed to evaluate dasatinib as maintenance therapy in patients with core-binding factor acute myeloid leukemia in first hematologic complete remission, but at higher risk of relapse due to molecular disease persistence or recurrence. A total of 26 patients aged 18-60 years old previously included in the CBF-2006 trial were eligible to receive dasatinib 140 mg daily if they had a poor initial molecular response (n=18) or a molecular recurrence (n=8). The tolerance of dasatinib as maintenance therapy was satisfactory. The 2-year disease-free survival in this high-risk population of patients was 25.7%. All but one patient with molecular recurrence presented subsequent hematologic relapse. Patients with slow initial molecular response had a similar disease-free survival when treated with dasatinib (40.2% at 2 years) or without any maintenance (50.0% at 2 years). The disappearance of KIT gene mutations at relapse suggests that clonal devolution may in part explain the absence of efficacy observed with single-agent dasatinib in these patients (n. EudraCT: 2006-006555-12).

CD68-positive tumor-associated macrophages predict unfavorable treatment outcomes in classical Hodgkin lymphoma in correlation with interim fluorodeoxyglucose-positron emission tomography assessment.

Finding new prognostic factors to identify patients with Hodgkin lymphoma (HL) at risk of treatment resistance or relapse remains challenging in daily practice. We evaluated the relationship between CD68 expression, interim positron emission tomography (iPET) results and outcome in 158 patients with HL diagnosed from February 1995 to July 2011. Immunohistochemistry (anti-CD68) gave two groups: low with ≤25% positive cells (121 patients) and high with >25% (37 patients). Five-year overall survival was higher in the low group (88.4% vs. 63.2%, p=0.0151), as was progression-free survival (74.5% vs. 40.7%, p=0.0003). In 68 patients evaluable, iPET correlated with CD68: 13/52 patients (25%) in the low group had positive iPET as compared to 11/16 patients (68%) in the high group (p=0.0016). This study confirms the prognostic value of CD68 in HL. We found a correlation between CD68 and iPET suggesting potential for a better stratification.

Pharmacokinetic tools for the dose adjustment of ciclosporin in haematopoietic stem cell transplant patients.

AIMS: Ciclosporin A (CsA) is used in the prophylaxis and treatment of acute and chronic graft vs. host disease after haematopoietic stem cell (HSCT) transplantation. Our objective was to build and compare three independent Bayesian estimators of CsA area under the curve (AUC) using a limited sampling strategy (LSS), to assist in dose adjustment. METHODS: The Bayesian estimators were developed using in parallel: two independent parametric modelling approaches (nonmem® and iterative two stage (ITS) Bayesian modelling) and the non-parametric adaptive grid method (Pmetrics®). Seventy-two full pharmacokinetic profiles (at pre-dose and 0.33, 0.66, 1, 2, 3, 4, 6, 8 and 12h after dosing) collected from 40 HSCT patients given CsA were used to build the pharmacokinetic models, while 15 other profiles (n = 7) were kept for validation. For each Bayesian estimator, AUCs estimated using the full profiles were compared with AUCs estimated using three samples. RESULTS: The pharmacokinetic profiles were well fitted using a two compartment model with first order elimination, combined with a gamma function for the absorption phase with ITS and Pmetrics or an Erlang distribution with nonmem. The derived Bayesian estimators based on a C0-C1 h-C4 h sampling schedule (best LSS) accurately estimated CsA AUC(0,12 h) in the validation group (n = 15; nonmem: bias (mean ± SD)/RMSE 2.05% ± 13.31%/13.02%; ITS: 4.61% ± 10.56%/11.20%; Pmetrics: 0.30% ± 10.12%/10.47%). The dose chosen confronting the three results led to a pertinent dose proposal. CONCLUSIONS: The developed Bayesian estimators were all able to predict ciclosporin AUC(0,12 h) in HSCT patients using only three blood with minimal bias and may be combined to increase the reliability of CsA dose adjustment in routine.

Tumour lysis syndrome and acute kidney injury in high-risk haematology patients in the rasburicase era. A prospective multicentre study from the Groupe de Recherche en Réanimation Respiratoire et Onco-Hématologique.

In tumour lysis syndrome (TLS), metabolic alterations caused by the destruction of malignant cells manifest as laboratory abnormalities with (clinical TLS) or without (laboratory TLS) organ dysfunction. This prospective multicentre cohort study included 153 consecutive patients with malignancies at high risk for TLS (median age 54 years (interquartile range, 38-66). Underlying malignancies were acute leukaemia (58%), aggressive non-Hodgkin lymphoma (29.5%), and Burkitt leukaemia/lymphoma (12.5%). Laboratory TLS developed in 17 (11.1%) patients and clinical TLS with acute kidney injury (AKI) in 30 (19.6%) patients. After adjustment for confounders, admission phosphates level (odds ratio [OR] per mmol/l, 5.3; 95% confidence interval [95% CI], 1.5-18.3), lactic dehydrogenase (OR per x normal, 1.1; 95%CI, 1.005-1.25), and disseminated intravascular coagulation (OR, 4.1; 95%CI, 1.4-12.3) were associated with clinical TLS; and TLS was associated with day-90 mortality (OR, 2.45; 95%CI, 1.09-5.50; P = 0.03). In this study, TLS occurred in 30.7% of high-risk patients. One third of all patients experienced AKI, for which TLS was an independent risk factor. TLS was associated with increased mortality, indicating a need for interventional studies aimed at decreasing early TLS-related deaths in this setting.

Loss of the Y chromosome in Philadelphia-positive cells predicts a poor response of chronic myeloid leukemia patients to imatinib mesylate therapy.

In chronic myeloid leukemia (CML), cytogenetic abnormalities found in addition to the t(9;22) translocation may impact the response to therapy. Loss of the Y chromosome is generally overlooked in this context, owing to its relatively frequent occurrence in healthy elderly patients. In this multicenter retrospective study, the outcome after imatinib treatment of 30 CML patients with karyotype showing Y chromosome loss (Y-) was compared to 30 Y+ control males diagnosed and treated at the same time in the same institutions. Y- patients had significantly delayed cytogenetic and molecular responses, lower event-free survival and shorter overall survival than Y+ patients. The negative impact of this abnormality was particularly marked when it occurred in a sub-clone (clonal evolution) rather than in all mitoses. These data indicate that loss of the Y chromosome should be taken into account in the prognostic evaluation of chronic myelogenous leukemia patients.

Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia.

PURPOSE: To determine the antitumor activity and safety of a combination of gemtuzumab ozogamicin (GO), intermediate-dose cytarabine, and mitoxantrone (MIDAM) in patients with refractory or relapsed CD33(+) acute myeloid leukemia (AML). PATIENTS AND METHODS: We treated 62 patients with refractory (n = 18) or relapsed (n = 44) CD33(+) AML. Median age was 55.5 years. Salvage regimen consisted of GO 9 mg/m(2) on day 4, cytarabine 1 g/m(2) every 12 hours on days 1 through 5, and mitoxantrone 12 mg/m(2)/d on days 1 through 3. Median follow-up time was 26.5 months. RESULTS: Thirty-one patients (50%) achieved complete remission (CR), and eight patients (13%) had CR with delayed platelet recovery (CRp); the overall response (OR; CR + CRp) rate was 63%. A significantly higher OR rate was achieved in patients who had relapsed versus refractory AML (73% v 39%, respectively; P = .007) and patients with CD33 expression more than 98% of the blast population versus less than 98% (79% v 52.3%, respectively; P = .03). The overall, event-free, and disease-free survival rates were 41%, 33%, and 53% at 2 years, respectively. Leukocytosis more than 20,000/microL at MIDAM therapy, high-risk cytogenetics, and absence of postremission therapy were adverse prognostic factors. Age, disease status, and/or CD33 expression did not influence survival parameters. Four early toxic deaths occurred; a grade 3 to 4 hyperbilirubinemia rate of 16% was observed, and two patients had veno-occlusive disease (3%). CONCLUSION: The MIDAM regimen seems to be an effective salvage regimen for refractory/relapsed CD33(+) AML patients. These encouraging results support the need for a randomized phase III trial before considering this combination of GO and chemotherapy as superior or the standard of care treatment for refractory/relapsed CD33(+) AML patients.