International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017).

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

FLORENCE: a randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk.

BACKGROUND: Serum uric acid (sUA) control is of key relevance in tumor lysis syndrome (TLS) prevention as it correlates with both TLS and renal event risk. We sought to determine whether febuxostat fixed dose achieves a better sUA control than allopurinol while preserving renal function in TLS prevention. PATIENTS AND METHODS: Patients with hematologic malignancies at intermediate to high TLS risk grade were randomized to receive febuxostat or allopurinol, starting 2 days before induction chemotherapy, for 7-9 days. Study treatment was blinded, whereas daily dose (low/standard/high containing allopurinol 200/300/600 mg, respectively, or fixed febuxostat 120 mg) depended on the investigator's choice. The co-primary end points, sUA area under curve (AUC sUA1-8) and serum creatinine change, were assessed from baseline to day 8 and analyzed through analysis of covariance with two-sided overall significance level of 5%. Secondary end points included treatment responder rate, laboratory and clinical TLS incidence and safety. RESULTS: A total of 346 patients (82.1% intermediate TLS risk; 82.7% assigned to standard dose) were randomized. Mean AUC sUA1-8 was 514.0 ± 225.71 versus 708.0 ± 234.42 mgxh/dl (P < 0.0001) in favor of febuxostat. Mean serum creatinine change was -0.83 ± 26.98% and -4.92 ± 16.70% for febuxostat and allopurinol, respectively (P = 0.0903). No differences among secondary efficacy end points were detected. Drug-related adverse events occurred in 6.4% of patients in both arms. CONCLUSION: In the largest adult trial carried out in TLS prevention, febuxostat achieved a significant superior sUA control with one fixed dose in comparison to allopurinol with comparable renal function preservation and safety profile. CLINICAL TRIAL REGISTRATION: NCT01724528.

Treatment of relapsed or refractory aggressive non-hodgkin lymphoma with two ifosfamide-based regimens, IMVP and ICE.

We report the outcomes of 45 patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) treated with a combination of ifosfamide, carboplatinum and etoposide (ICE) and 28 patients treated with a combination of ifosfamide, methotrexate and etoposide (IMVP) during two 5-year periods. The response rate (RR) to ICE was 47%, 2-year overall survival (OS) 31% and 2-year event-free survival (EFS) 22%. These results were similar to those obtained with IMVP (RR 39%, 2-year OS 23%, 2-year EFS 13%; p=0.355 for RR, 0.275 for OS, 0.668 for EFS). Higher IPI scores and refractoriness to treatment were negative prognostic factors, immunophenotype (B vs. T) had no influence on prognosis. Changing from IMVP to ICE does not substantially improve the outcome of patients with relapsed or refractory aggressive NHL. Patients with relapsed/refractory aggressive B-NHL do not have a superior outcome in comparison to those with T-NHL if treated with chemotherapy alone.

Long-term results of conventional-dose salvage chemotherapy in patients with refractory and relapsed Hodgkin's disease (Croatian experience).

BACKGROUND: The aim of this study was to analyze outcome of patients with Hodgkin's disease (HD) in whom first-line chemotherapy with mustine/vincristine/procarbazine/prednisone (MOPP) had failed. PATIENTS AND METHODS: From January 1982 to December 1989 among 210 patients treated with MOPP and radiotherapy to initial bulky sites, 65 patients were primary refractory to or relapsed after initial treatment. RESULTS: Twenty-nine of 65 patients (44%) were primary refractory to initial chemotherapy, 20 relapsed within 12 months after complete remission (CR) and 16 relapsed after CR that lasted more than 12 months. Patients with primary refractory HD and early relapse (<12 months after CR) were treated with doxorubicin/bleomycin/vinblastine/darcarbazine. In patients with late relapse (>12 months after CR) MOPP was repeated. The median follow-up for all patients was 115 months. The overall response rate was 63%. Thirty-three patients (51%) achieved a second CR and eight patients (12%) partial response. Remission rate was greatest in patients with late relapse (CR >12 months) (75 versus 55% for early relapse versus 35% for primary refractory HD) (P <0.01). At 10 years, overall and failure-free survival rates were 21 and 16%, respectively. Patients who were in first remission longer than 12 months had a superior overall survival (37 versus 18% for early relapse) and failure-free survival (24 versus 10% for early relapse). No patient with primary refractory HD was alive beyond 52 months after initial treatment failure (P <0.01). Main prognostic factors were duration of the first remission and tumor bulk at relapse. CONCLUSIONS: Our results confirm previous observations that a significant proportion of patients with HD who experience induction treatment failure cannot be cured with conventional treatment and probably need more aggressive therapy.

Bone marrow immunoscintigraphy in haematological patients with pancytopenia: preliminary results.

The aim of this study was to assess the clinical value of bone marrow immunoscintigraphy using the (99m)Tc labelled anti-NCA-95 antigranulocyte antibodies (AGAb) and of AGAb bone marrow uptake ratio (UR) in the initial diagnostic work-up of diseases with depression of the bone marrow. Twenty-four whole-body bone marrow scans were performed in 23 patients (11 women, 12 men; median age 46 years, range 17-74 years) 5 h after i.v. injection of 370 MBq of AGAb. The UR was calculated from the posterior view drawing an irregular region of interest around the sacroiliac and a background areas. The mean UR in pancytopenic patients was 2.3+/-1.5 (range 0.3-5.8), thus being significantly lower (P=0.45 x 10(-6)) than the mean UR in a control group of 50 patients (mean UR 7.3+/-2.3; range 4.4-12.6) obtained previously. Considering patient age, there was no overlap between UR of pancytopenic patients and the respective normal ranges. The bone marrow appearance on scans seemed to be characteristic for the different haematological diseases investigated. In six patients with myelofibrosis, bone marrow scans demonstrated diffusely decreased bone marrow activity and prominent splenic uptake, possibly related to extramedullary haematopoiesis. In aplastic anaemia, highly reduced and patchy marrow uptake was observed in four patients (five scans), in one of them persisting even after blood cell counts had recovered to the near-normal range. In another two patients with aplastic anaemia, diffusely decreased bone marrow uptake was obtained. In patients with myeloid leukaemia, bone marrow patterns were almost normal probably because the target antigen is often expressed on neoplastic myeloid cells, too. Bone marrow extension was a common finding in these patients. There is an obvious differentiation between haematological patients with pancytopenia and normal subjects by means of AGAb bone marrow uptake ratio. The distinct patterns of AGAb distribution may be indicative for particular haematological diseases.

Effects of a membrane-metallopeptidase blocking agent thiorphan in long-term cultures of human bone marrow.

Thiorphan [(DL-3-mercapto-2-benzylpropanoyl)-glycine], a drug blocking the activity of membrane metalloendopeptidase EC 3.4.24.11 (CD10, CALLA), was added to long-term cultures of human bone marrow. Progression of the cultures was assessed by cell counts, cytology and clonogenic (GM-CFU) ability of the non-adherent cells in the supernatant and by morphology of the adherent stromal layer. A stimulatory effect on hematopoiesis was noted.

Analysis of clonality in T-lymphoproliferative diseases by multiplex PCR.

Distinction between benign and malignant T-cell lymphoproliferative diseases can be difficult using morphological criteria. Using multiplex polymerase chain reaction system we have tested a series of patients with various lymphoproliferative disorders to detect clonal T-lymphocyte populations. Results show that clonal amplification products were obtained from all 10 patients with T-cell lymphoproliferative disorders while the amplification of DNA samples from B-cell neoplasms and normal individuals revealed polyclonal amplification products. By splitting the multiplex primer mix, the patient specific T-cell receptor gamma rearrangement was determined: five out of ten patients showed the exclusive presence of a single T-cell receptor gamma gene rearrangement. Three patients exhibited two rearranged T-cell receptor gamma genes, while in two patients positive reactions were obtained with three pairs of primers for variable and joining segments. Molecular analysis of rearranged T-cell receptor genes by multiplex polymerase chain reaction represents a useful and rapid tool for confirming diagnosis, to determine the extent of disease and to monitor the response to therapy.

Treatment of chronic myeloid leukemia in relapse after umbilical cord blood transplantation.

Umbilical cord blood (UCB) is increasingly used as a source of hematopoietic progenitor cells for allotransplantation. Donor-derived buffy coat cells are considered optimal treatment for leukemia relapses after transplantation of allogeneic bone marrow. Experience with relapses after UCB transplants are sparse. Here we report a girl who received an UCB transplant for chronic myeloid leukemia, relapsed after three years, failed to respond to donor buffy coat cells, but achieved a complete hematologic, cytogenetic, and molecular remission on interferon-alpha.

Donor buffy-coat infusion and chemotherapy for leukemia in relapse after marrow transplantation.

A patient relapsing with blastic lymphoid transformation of chronic myeloid leukemia after bone marrow transplantation received donor buffy-coat infusion. Low-dose chemotherapy was added because of a rapid WBC increase. Complete hematologic and cytogenetic remission was obtained. The patient remained in complete hematologic and cytogenetic remission for four months until he died in an accident. Two patients with acute leukemia failed to respond to a similar treatment.

Molecular monitoring of minimal residual disease in acute promyelocytic leukemia by the polymerase chain reaction assay for the PML/RAR alpha (retinoic acid receptor-alpha) fusion transcript in patients treated with all-trans retinoic acid followed by chemotherapy.

Five acute promyelocytic leukemia (APL) patients who achieved a complete remission (CR) with all-trans retinoic acid (ATRA) underwent residual disease monitoring through reverse transcription polymerase chain reaction (PCR) for PML/retinoic acid receptor-alpha (PML/RAR alpha) fusion transcript. All received consolidation chemotherapy in CR, one in the form of autologous bone marrow transplantation (ABMT). In four of the patients PCR was positive for the PML/RAR alpha transcript immediately after ATRA treatment and/or after the first consolidation chemotherapy course. In the patient treated with ABMT, positivity was still detected six months after ABMT. One patient given five repeated courses of chemotherapy was PCR negative for PML/RAR alpha after 14 months in CR. Our pilot study confirmed that ATRA is a highly efficient induction therapy for APL in various stages of the disease, but ATRA alone cannot cure the disease. PCR should be considered a fundamental assay for assessing minimal residual disease in CR that will influence further treatment strategies and permit evaluation of treatment results.

High incidence of conservative RAS mutations in acute myeloid leukemia.

RAS mutations are found in about 25% of acute myeloid leukemia (AML) cases. The importance of these changes is unknown. If RAS mutations confer growth advantage to leukemia subclones in which they emerge, substantially more nonconservative than conservative mutations should be found. The incidence of conservative mutations was not reported previously. We sequenced N-RAS and K-RAS codons 12 and 13 and N-RAS codon 61 in 20 subjects with newly diagnosed AML. Four nonconservative N-RAS mutations and 4 conservative K-RAS mutations were found. There were no differences between subjects with AML and nonconservative RAS mutations and those with conservative or without RAS mutations. Additional studies are needed to examine the incidence of conservative RAS mutations in subjects with AML.

Prostaglandin E2 for prophylaxis of oral mucositis following BMT.

Between October 1988 and December 1990, 60 patients with leukaemia (25 with AML, 19 ALL and 16 CML) undergoing BMT were randomised in a double-blind clinical trial to receive prostaglandin E2 (PGE) (Prostin E2, 0.5 mg per tablet) or placebo for prophylaxis of oral mucositis. Patients had to dissolve tablets in the mouth three times daily starting 7 days before BMT and continuing until 21 days after BMT. The incidence of severe oral mucositis was similar for both groups, 55% in patients receiving PGE and 52% in patients receiving placebo. The duration of severe mucositis did not differ between PGE and placebo groups (chi-square 0.95, p = NS). The incidence of HSV infection was significantly higher in patients receiving PGE. Patients with HSV infection receiving PGE also had a higher incidence of severe oral mucositis. The results presented indicate that PGE is not effective for prophylaxis of oral mucositis in BMT recipients.

Ph1-chromosome positive acute lymphoblastic leukemia: is t(9;22) the initial abnormality?

We report a case of pre-B-cell acute lymphoblastic leukemia (ALL) with the Ph1-chromosome, t(9;22) translocation and P190 associated BCR/ABL rearrangement. One cell with the Ph1-chromosome and t(9;22) also had del(5q). Interestingly, another diploid cell with iso(17q) lacked the Ph1-chromosome and t(9;22). This finding, similar to one reported in chronic myelogenous leukemia, is consistent with the possibility that abnormality manifest as chromosome instability antedates the Ph1-chromosome and t(9;22) in some cases of Ph1-chromosome positive acute leukemia.

Analysis of BCR/ABL abnormalities in mRNA from 20-year-old paraffin-embedded tissue for BCR/ABL rearrangement by polymerase chain reaction.

We studied whether it is possible to obtain sufficient mRNA from old paraffin-embedded samples of spleen and bone marrow for reverse transcription and polymerase chain reaction analysis. Spleen tissue from 6 subjects with chronic myelogenous leukemia was studied for rearrangement of BCR and ABL genes. Analysis was successful in 4 cases. These data indicate the feasibility of retrospective analysis of tissue samples of special interest by molecular techniques.