Luca Maurillo

Toward Optimization of Postremission Therapy for Residual Disease–Positive Patients With Acute Myeloid Leukemia

PURPOSE Despite the identification of several baseline prognostic indicators, the outcome of patients with acute myeloid leukemia (AML) is generally heterogeneous. The effects of autologous (AuSCT) or allogeneic stem-cell transplantation (SCT) are still under evaluation. Minimal residual disease (MRD) states may be essential for assigning patients to therapy-dependent risk categories. PATIENTS AND METHODS By multiparametric flow cytometry, we assessed the levels of MRD in 142 patients with AML who achieved complete remission after intensive chemotherapy. RESULTS A level of 3.5 x 10(-4) residual leukemia cells (RLCs) after consolidation therapy was established to identify MRD-negative and MRD-positive cases, with 5-year relapse-free survival (RFS) rates of 60% and 16%, respectively (P < .0001) and overall survival (OS) rates of 62% and 23%, respectively (P = .0001). Of patients (n = 77) who underwent a transplantation procedure (56 AuSCT and 21 SCT procedures); 42 patients (55%) were MRD positive (28 patients who underwent AuSCT and 14 patients who underwent SCT) and 35 patients (45%) were MRD negative (28 patients who underwent AuSCT and seven who underwent SCT). MRD-negative patients had a favorable prognosis, with only eight (22%) of 35 patients experiencing relapse, whereas 29 (69%) of 42 MRD-positive patients experienced relapse (P < .0001). In this high-risk group of 42 patients, we observed that 23 (82%) of 28 of those who underwent AuSCT experienced relapse, whereas six (43%) of 14 who underwent SCT experienced relapse (P = .014). Patients who underwent SCT also had a higher likelihood of RFS (47% v 14%). CONCLUSION A threshold of 3.5 x 10(-4) RLCs postconsolidation is critical for predicting disease outcome. MRD-negative patients have a good outcome regardless of the type of transplant they receive. In the MRD-positive group, AuSCT does not improve prognosis and SCT represents the primary option.

Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program.

The efficacy of azacitidine for the treatment of high‐risk myelodysplastic syndromes has prompted the issue of its potential role even in the treatment of acute myeloid leukemia (AML).

Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia†

Rituximab in sequential combination with fludarabine (Flu) allowed patients with B‐cell chronic lymphocytic leukemia (B‐CLL) to achieve higher remission rates and longer response duration. Based on their recent experience in indolent non‐Hodgkin lymphomas, in this study, the authors attempted to demonstrate whether consolidation/maintenance therapy with rituximab could prolong the response duration in this patient population.

Valproic Acid at Therapeutic Plasma Levels May Increase 5-Azacytidine Efficacy in Higher Risk Myelodysplastic Syndromes

Purpose: Epigenetic changes play a role and cooperate with genetic alterations in the pathogenesis of myelodysplastic syndromes (MDS). We conducted a phase II multicenter study on the combination of the DNA-methyltransferase inhibitor 5-azacytidine (5-AZA) and the histone deacetylase inhibitor valproic acid (VPA) in patients with higher risk MDS. Experimental Design: We enrolled 62 patients with MDS (refractory anemia with excess blasts, 39 patients; refractory anemia with excess blasts in transformation, 19 patients; and chronic myelomanocytic leukemia (CMML), 4 patients) and an International Prognostic Scoring System (IPSS) rating of Intermediate-2 (42 patients) or high (20 patients). VPA was given to reach a plasma concentration of >50 μg/mL, then 5-AZA was added s.c. at 75 mg/m2 for 7 days in eight monthly cycles. Results: The median overall survival was 14.4 months. At a median follow-up of 12 months (range, 0.7-21.0), the disease progressed in 20 patients, with 21% cumulative incidence of progression. Of 26 patients who completed eight cycles, 30.7% obtained complete or partial remission, 15.4% had a major hematologic improvement, whereas 38.5% showed stable disease. Drug-related toxicity was mild. Favorable prognostic factors for survival were IPSS Intermediate-2 and plasma VPA of ≥50 μg/mL (log rank = 0.013 and 0.007, respectively). Analysis of polymorphisms important for the metabolism of the drugs used in the trial showed that carriers of the CYP2C19*2 variant of cytochrome P450 required higher VPA doses to achieve the target VPA plasma concentration of 50 μg/mL on day 1 of 5-AZA treatment (P = 0.0021). Conclusion: Our data show that the 5-AZA/VPA combination is active and safe in patients with MDS with a poor prognosis. Achievement of VPA therapeutic levels may indeed increase 5-AZA efficacy.

Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult acute myeloid leukemia

A total of 143 adult acute myeloid leukemia (AML) patients with available karyotype (K) and FLT3 gene mutational status were assessed for minimal residual disease (MRD) by flow cytometry. Twenty-two (16%) patients had favorable, 115 (80%) intermediate, and 6 (4%) poor risk K; 19 of 129 (15%) carried FLT3-ITD mutation. Considering postconsolidation MRD status, patients with good/intermediate-risk K who were MRD(-) had 4-year relapse-free survival (RFS) of 70% and 63%, and overall survival (OS) of 84% and 67%, respectively. Patients with good- and intermediate-risk K who were MRD(+) had 4-year RFS of 15% and 17%, and OS of 38% and 23%, respectively (P < .001 for all comparisons). FLT3 wild-type patients achieving an MRD(-) status, had a better outcome than those who remained MRD(+) (4-year RFS, 54% vs 17% P < .001; OS, 60% vs 23%, P = .002). Such an approach redefined cytogenetic/genetic categories in 2 groups: (1) low-risk, including good/intermediate K-MRD(-) with 4-year RFS and OS of 58% and 73%, respectively; and (2) high risk, including poor-risk K, FLT3-ITD mutated cases, good/intermediate K-MRD(+) categories, with RFS and OS of 22% and 17%, respectively (P < .001 for all comparisons). In AML, the integrated evaluation of baseline prognosticators and MRD improves risk-assessment and optimizes postremission therapy.

Azacitidine for the treatment of lower risk myelodysplastic syndromes : a retrospective study of 74 patients enrolled in an Italian named patient program.

Azacitidine induces responses and prolongs overall survival compared with conventional care regimens in patients who have high‐risk myelodysplastic syndromes (MDS). However, limited data are available concerning the efficacy and safety of azacitidine in patients who have lower risk MDS.

Pretransplant minimal residual disease level predicts clinical outcome in patients with acute myeloid leukemia receiving high-dose chemotherapy and autologous stem cell transplantation

A total of 31 adult patients with AML entered in the EORTC/GIMEMA AML-10 trial, who received autologous stem cell transplantation (ASCT) after induction and consolidation chemotherapy, were prospectively evaluated for minimal residual disease (MRD) by multidimensional flow cytometry (MFC). Using a cutoff level of 3.5 × 10−4 leukemic cells pre-ASCT, 12 patients (39%) were stratified to MRD high-risk group and 19 (61%) into MRD low-risk group. During follow-up, all patients who were in the high-risk group relapsed at a median time of 7 months; in the low-risk group, five patients relapsed at a median time of 11 months and 14 remained in remission for 56 (range 7–80) months (P=0.00004). Longitudinal MFC determinations post-ASCT showed increased MRD levels in three of the five patients who underwent subsequent relapse, while disease recurrence was unpredicted in the remaining two cases. The pre-ASCT MRD status was the factor most strongly associated with relapse risk in the multivariate analysis (P=0.0014). We conclude that: (1) pre-ASCT MRD status predicts successful outcome in patients receiving ASCT; (2) high-dose chemotherapy conditioning regimen followed by ASCT has no impact on the unfavorable prognostic value of high pre-ASCT MRD level; and (3) sequential MRD monitoring post-ASCT may allow the prediction of impending relapse.

Fulminant B hepatitis in a surface antigen-negative patient with B-cell chronic lymphocytic leukaemia after rituximab therapy.

Fulminant B hepatitis in a surface antigen-negative patient with B-cell chronic lymphocytic leukaemia after rituximab therapy

High rate of remissions in chronic myelomonocytic leukemia treated with 5-azacytidine: results of an Italian retrospective study

1 Istituto di Ematologia, Universit à Cattolica del Sacro Cuore, Roma, Italy, 2 Dipartimento di Biotecnologie Cellulari ed Ematologia, Universit à La Sapienza, Roma, Italy, 3 Istituto di Ematologia, Fondazione Policlinico Tor Vergata, Roma, Italy, 4 Ematologia, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy, 5 Dipartimento di Onco-Hematology, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy, 6 Divisione di Ematologia, Dipartimento di Medicina Traslazionale, Universit à del Piemonte Orientale Amedeo Avogadro, Novara, Italy, 7 S.Orsola-Malpighi University Hospital, Department of Hematology and Oncological Sciences “Ser à gnoli”, Bologna, Italy, 8 Dipartimento di Ematologia, Ospedale Sant ’ Andrea, Universit à La Sapienza, Roma, Italy and 9 Ematologia, AOU Careggi, Universit à di Firenze, Firenze, Italy

Chromosomal Aberration of the 11q23 Locus in Acute Leukemia and Frequency of MLL Gene Translocation Results in 378 Adult Patients

Structural abnormality of the 11q23 band (11q23+) bearing the MLL gene translocation (MLL+) is a recurrent chromosome change observed in 3% to 7% of acute lymphoblastic leukemias and in 3% to 4% of acute myeloblastic leukemias. The resolution of conventional cytogenetics (CC) in detecting 11q23 rearrangement is limited when the translocative partner has a telomeric location; furthermore, CC can barely discriminate between true 11q23+/MLL+ and rearrangements clustering within the 11q22~25 region without MLL involvement (MLL–). We characterized a series of 378 consecutive patients with adult acute leukemia by using CC, fluorescence in situ hybridization (FISH), and multiplex karyotyping (MFISH) analysis. Our aim was to define the frequency of cryptic MLL+ cases and the frequency of MLL+ within 11q22~25+ cases. As expected, FISH was more sensitive than CC in detecting MLL+ cases, but rather unexpectedly, 9 (45%) of 20 patients with 11q22~25+ were MLL–. A better characterization of 11q22~25+/MLL– leukemias is relevant for the identification of new, recurrent translocations. Moreover, these cases should be readily distinguishable from 11q23+/MLL+ cases. We recommend that karyotypic analysis always be complemented by molecular or FISH methods to unravel MLL rearrangements.