Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA) pathway are events linked to the pathogenesis ...of acute myeloid leukemia (AML) that can be targeted by specific treatments. A pilot study was carried out in eight refractory or high-risk AML patients not eligible for intensive therapy to assess the biological and therapeutic activities of the HDAC inhibitor valproic acid (VPA) used to remodel chromatin, followed by the addition of ATRA, to activate gene transcription and differentiation in leukemic cells. Hyperacetylation of histones H3 and H4 was detectable at therapeutic VPA serum levels (>or=50 microg/mL) in blood mononuclear cells from seven of eight patients. This correlated with myelomonocytic differentiation of leukemic cells as revealed by morphologic, cytochemical, immunophenotypic, and gene expression analyses. Differentiation of the leukemic clone was proven by fluorescence in situ hybridization analysis showing the cytogenetic lesion +8 or 7q- in differentiating cells. Hematologic improvement, according to established criteria for myelodysplastic syndromes, was observed in two cases. Stable disease and disease progression were observed in five and one cases, respectively. In conclusion, VPA-ATRA treatment is well tolerated and induces phenotypic changes of AML blasts through chromatin remodeling. Further studies are needed to evaluate whether VPA-ATRA treatment by reprogramming differentiation of the leukemic clone might improve the response to chemotherapy in leukemia patients.
To report the clinical findings and long-term results of front-line, third-generation MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) chemotherapy and ...mediastinal involved-field radiotherapy (IFRT) in 85 consecutive, previously untreated patients with primary mediastinal large B cell lymphoma (PMLBCL) diagnosed and managed at a single institution.
Between 1991 and April 2004, 92 consecutive, untreated patients with PMLBCL were treated at our institution. The median age was 33 years (range, 15-61 years), 46 patients (50%) showed a mediastinal syndrome at onset; 52 patients (57%) showed a low/low-intermediate (0 to 1) and 40 patients (43%) an intermediate-high/high (2 to 3) International Prognostic Index (IPI) score. Eighty-five patients were treated with standard chemotherapy (MACOP-B), and 80 underwent mediastinal IFRT at a dose of 30-36 Gy.
After a MACOP-B regimen, the overall response rate was 87% and the partial response rate 9%. After chemotherapy, (67)Ga scintigraphy/positron emission tomography results were positive in 43 of 52 patients (83%), whereas after IFRT 11 of 52 patients (21%) remained positive (p < 0.0001). After a median follow-up of 81 months (range, 2-196 months), progression or relapse was observed in 15 of 84 patients (18%). The projected 5-year overall survival and progression-free survival rates were 87% and 81%, respectively. The 5-year overall survival and progression-free survival rates were better for patients with an IPI of 0 to 1 than for those with an IPI of 2 to 3 (96% vs. 73% p = 0.002 and 90% vs. 67% p = 0.007, respectively).
Combined-modality treatment with intensive chemotherapy plus mediastinal IFRT induces high response and lymphoma-free survival rates. Involved-field RT plays an important role in inducing negative results on (67)Ga scintigraphy/positron emission tomography in patients responsive to chemotherapy.
In the last decades, the global epidemiological impact of invasive candidiasis (IC) in patients with hematologic malignancies (HM) and in hematopoietic stem cell transplant (HSCT) recipients has ...decreased and the incidence of invasive aspergillosis exceeded that of Candida infections. The use of prevention strategies, first of all antifungal prophylaxis with triazoles, contributed to the reduction of IC in these populations as demonstrated by several epidemiological studies. However, relatively little is known about the current epidemiological patterns of IC in HM and HSCT populations, because recent epidemiological data almost exclusively derive from retrospective experiences and few prospective data are available. Several prospective, controlled studies in the prophylaxis of invasive fungal diseases have been conducted in both the HM and HSCT setting. On the contrary, most of the prospective controlled trials that demonstrated the efficacy of the antifungal drugs echinocandins and voriconazole in the treatment of candidemia and invasive candidiasis mainly involved patients with underlying conditions other than HM or HSCT. For these reasons, international guidelines provided specific indications for the prophylaxis strategies in HM and HSCT patients, whereas the recommendations on therapy of documented Candida infections are based on the results observed in the general population and should be considered with caution.
To assess the role of 18Ffluorodeoxyglucose (18FFDG) positron emission tomography/computed tomography (PET/CT) after rituximab and anthracycline-containing chemoimmunotherapy in patients with primary ...mediastinal large B-cell lymphoma (PMLBCL).
Among 125 patients prospectively enrolled, 115 were eligible for central review of PET/CT scans at the completion of standard chemoimmunotherapy, by using a five-point scale. Consolidation radiotherapy (RT) was permitted and given to 102 patients.
Fifty-four patients (47%) achieved a complete metabolic response (CMR), defined as a completely negative scan or with residual 18FFDG activity below the mediastinal blood pool (MBP) uptake. In the remaining 61 patients (53%), the residual uptake was higher than MBP uptake but below the liver uptake in 27 (23%), slightly higher than the liver uptake in 24 (21%), and markedly higher in 10 (9%). CMR after chemoimmunotherapy predicted higher 5-year progression-free survival (PFS; 98% v 82%; P=.0044) and overall survival (OS; 100% v 91%; P=.0298). Patients with residual uptake higher than MBP uptake but below liver uptake had equally good outcomes without any recurrence. Using the liver uptake as cutoff for PET positivity (boundary of score, 3 to 4) discriminated most effectively between high or low risk of failure, with 5-year PFS of 99% versus 68% (P<.001) and 5-year OS of 100% versus 83% (P<.001).
More than 90% of patients are projected to be alive and progression-free at 5 years, despite a low CMR rate (47%) after chemoimmunotherapy. This study provides a basis for using PET/CT to define the role of RT in PMLBCL.
The anti-CD33 antibody calicheamicinconjugate gemtuzumab ozogamicin (GO) was used to treat 16 patients with acute promyelocytic leukemia (APL) who had relapsed at the molecular level. Of these ...patients, 8 were experiencing a first, 5 a second, 2 a third, and 1 a fourth relapse. GO was administered at 6 mg/m2 for 2 doses, and patients achieving a new molecular remission (MR) (ie, negativity of the reverse transcriptase–polymerase chain reaction RT-PCR test for PML/RARα) received a third dose. MR was obtained in 9 (91%) of 11 patients tested after 2 doses and in 13 (100%) of 13 patients tested after the third dose. Of the 3 remaining patients, 1 achieved MR after one GO administration and received no further therapy owing to hepatic toxicity, and 2 showed disease progression during treatment. Quantitative RT-PCR studies showed that responding patients experienced a dramatic decline (at least 2 logs) of the PML/RARα transcript after the first GO dose. Of 14 responders, 7 remained in sustained MR for a median of 15 months (range, 7-31 months) while 7 experienced relapse at 3 to 15 months. GO was administered again in 2 patients with relapse, and both obtained a new MR. These data indicate that GO is highly effective as a single treatment for patients with molecularly relapsed APL including those with very advanced disease.
The incidence of non‐Hodgkin lymphoma in patients 80 years of age or older is 50 times higher than in 20‐ to 24‐year‐olds. Very elderly patients are often not treated with standard immunochemotherapy ...because of poor performance status, comorbidities, and toxicity concerns. We retrospectively analyzed data for 29 patients diagnosed with diffuse large B‐cell lymphoma or grade 3B follicular lymphoma and treated with rituximab in combination with nonpegylated liposomal doxorubicin between January 2010 and August 2015. The median age was 84 years. The overall 3‐year survival, cause‐specific survival, and progression‐free survival rates were 46%, 55%, and 44%, respectively. Among prognostic factors, only the achievement of complete remission strongly correlated with overall survival, cause‐specific survival, and progression‐free survival rates. Treatment caused very mild toxicity, without treatment‐related hospitalization or toxic deaths.
Introduction:
The initial approach to elderly patients with Diffuse Large B-cell lymphoma (DLBCL) is usually based on the subjective judgment of the physician on the individual patient's ability to ...tolerate treatment with curative intent. "Comprehensive Geriatric Assessment" (CGA) is based on the use of the ADL (Activity of Daily Living), IADL (Instrumental ADL) and CIRS-G (Comorbidity Index Rating Scale for Geriatrics) scales and represents a tool to standardize initial patients fitness assessment and for planning systemic therapy. So far CGA has been rarely used in prospective studies and lacks a formal validation in patients with lymphoma.
Objectives:
FIL is conducting a prospective study with the aim of validating the use of CGA on a large series of elderly patients with DLBCL and to test a CGA based approach to the patient. CGA results will be used to define treatment goals that are the cure for the FIT subjects, and palliation for the FRAILs. Treatment goal for the UNFIT is cure with less toxic regimens.
Methods:
This study is conducted using a web based platform, accessible from the reserved area of the FIL website, to perform a quick and objective CGA evaluation of consecutive patients ≥ 65 years with untreated DLBCL. Patients younger than 80 years, without impairment of ADL and IADL and without severe comorbidities were considered FIT; those with intermediate fragility or those older than 80 years with FIT profile were classified as UNFIT (UN); those with severe impairment of ADL, IADL and CIRS and those older than 80 years with an UN profile were classified as FRAIL (FR). Informed consent was required to enrol patients in this study; the planned sample size was 1000 patients.
Results:
The study started in December 2013. At time of current analysis 792 patients have been registered by 45 centres: 328 (41%), 207 (26%), and 257 (33%) were classified as FIT, UN and FR, respectively.
Median age was 77 years (yrs) (65-95); 73 (65-79), 80 (65-95) and 81 (65-95) yrs for FIT, UN and FR patients respectively; overall 65% were in stage III-IV. By univariate analysis, the three categories differed in terms of median age (p<0.001), B-symptoms (p=0.035), ECOG PS>1 (p<0.001), elevated LDH (p=0.035) and IPI score (p=0.004).
Fourty-nine percent of cases were defined as UN only because of age (≥80 yrs); other reasons for UN were impairment of IADL, ADL in 30% and 18%, respectively. Only 3% of cases were UN due to CIRS (5-8 comorbidities of grade 2). Regarding FRAIL patients 27% of patients were classified in this group due to CIRS impairment, 24% and 18% due to IADL and ADL impairment, respectively. In remaining 31%, patients were FRAIL due to age ≥80 yrs (Figure 1). The most frequent altered ADL items among UN and FR patients were continence (15%) and bathing (30%), respectively; regarding IADL the most frequent altered items were buying and food preparation for either UN (19% and 12%) and FR (53% and 41%). Most frequent grade 3 comorbidities among the 257 FR patients were those referred to heart (16%), vascular system (9%), muscoloskelatal (7%), and genitourinary (5%).
Data on planned treatment were available in 643 patients. Rituximab was used in all but 6 (2%), 18 (12%), and 35 (17%) FIT, UN, and FR cases.
Treatment with curative intent (full doses R-CHOP-like regimens) was used in 94% and 65% of FIT and UNFIT cases; surprisingly curative intent was declared also in 38% of FRAIL cases. Six percent, 25% and 26% of FIT, UN and FR patients were treated with an attenuated R-CHOP-like immuno-chemotherapy regimens.
Palliative regimens were used in 36% and 10% of FR and UN patients respectively.
Conclusion:
The preliminary data of Elderly Project showed that, with the CGA criteria as adopted in this study, the 59% of elderly patients with DLBCL at diagnosis were not FIT.
Rituximab and doxorubicin containing regimen seems to be the reference treatment for FIT, UN and also for a significant proportion of FR patients but the actual value of using this approach for non-FIT patients is not clear and will be assessed with this project.
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Abstract
About 60% of patients with diffuse large B-cell lymphoma (DLBCL) may be cured by primary chemotherapy with an R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) ...regimen. Most of the rest will die of the disease, mainly due to the occurrence of tumor drug resistance. Many efforts have been made to explain the molecular mechanisms of drug resistance in patients with cancer, including those with DLBCL. This exploratory study was designed to correlate the mRNA expression levels of candidate genes mainly involved in the doxorubicin pathway (ABCB1, GSTP1, TOPO2α, BCL2, PKCβII) with the outcome of 54 patients with DLBCL undergoing a dose-dense R-CHOP regimen. After multivariate analysis, high GSTP1 (p = 0.003) and TOPO2α (p = 0.02) gene expressions were associated with shorter overall survival and progression-free survival, respectively, suggesting that these genes may represent an unfavorable prognostic factor in the case of R-CHOP treatment. These biomarkers may be useful for selecting patients eligible for personalized chemotherapy after validation in an independent set.
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