Characteristics, outcomes, prognostic factors and treatment of patients with T-cell prolymphocytic leukemia (T-PLL).

BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive disease. In this study, we report our experience from 119 patients with T-PLL. PATIENTS AND METHODS: We reviewed the clinico-pathologic records of 119 consecutive patients with T-PLL, who presented to our institution between 1990 and 2016. RESULTS: One hundred and nineteen patients with T-PLL were analysed. Complex karyotype and aberrations in chromosome 14 were seen in 65% and 52% patients, respectively. Seventy-five patients (63%) were previously untreated and 43 (37%) were initially treated outside our institution. Sixty-three previously untreated patients (84%) received frontline therapies. Overall, 95 patients (80%) have died. Median overall survival (OS) from diagnosis was 19 months [95% confidence interval (CI) 16-26 months]. Using recursive partitioning (RP), we found that patients with hemoglobin < 9.3 g/dl, lactate dehydrogenase (LDH) ≥ 1668 IU/l, white blood cell ≥ 208 K/l and ß2M ≥ 8 mg/l had significantly inferior OS and patients with hemoglobin < 9.3 g/dl had inferior progression-free survival (PFS). In multivariate analysis, we identified that presence of pleural effusion [hazard ratio (HR) 2.08 (95% CI 1.11-3.9); P = 0.02], high LDH (≥ 1668 IU/l) [HR 2.5 (95% CI 1.20-4.24); P < 0.001)], and low hemoglobin (< 9.3 g/dl) [HR 0.33 (95% CI 0.14-0.75); P = 0.008] were associated with shorter OS. Fifty-five previously untreated patients received treatment with an alemtuzumab-based regimen (42 monotherapy and 13 combination with pentostatin). Overall response rate, complete remission rate (CR) for single-agent alemtuzumab and alemtuzumab combined with pentostatin were 83%, 66% and 82%, 73% respectively. In patients who achieved initial CR, stem cell transplantation was not associated with longer PFS and OS. CONCLUSION: Outcomes in T-PLL remain poor. Multicenter collaborative effort is required to conduct prospective studies.

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia.

BACKGROUND: Acute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia. RESULTS: Histone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior. CONCLUSION: This study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups.

High prevalence of HBV genotype D in Syria and the clinical characteristics of hepatitis B e antigen-negative chronic hepatitis B.

Hepatitis B virus (HBV) genotype D and hepatitis B e antigen (HBeAg) negative chronic hepatitis are the most prevalent in Mediterranean countries. No data have ever been published on their prevalence in Syria, a country of intermediate endemicity for HBV. The aims of the current study were to determine the HBV genotype distribution in Syria, the prevalence of HBeAg-positive and HBeAg-negative chronic hepatitis and to analyse the clinical characteristics of each group. A total of 220 patients were included. Ninety-seven percent of the patients were of genotype D, and 72% were HBeAg negative. The HBeAg-negative patients were older, had a lower viral load, had more cirrhosis and the mode of contamination was known less than for HBeAg-positive patients. These findings have major implications in understanding the natural history of the infection and are of great relevance in the choice of therapy.

Treatment of donor graft failure with nonmyeloablative conditioning of fludarabine, antithymocyte globulin and a second allogeneic hematopoietic transplantation.

Graft failure is a life-threatening complication of allogeneic stem cell transplantation (SCT). We assessed the feasibility of performing a second SCT after such failure when fludarabine and antithymocyte globulin (ATG) are used for non-myeloablative conditioning and tacrolimus for graft-versus-host disease (GVHD) prophylaxis. Nine patients with SCTs for various hematologic malignancies were enrolled, eight with primary and one with secondary graft failure. The median time between the first and second SCT was 53 days. Eight patients had the same donor for their second SCT, and one had a cord blood transplant. Three patients were not evaluable because of early death; the other six had evidence of donor cell engraftment. Six of the nine patients developed acute grade II-IV GVHD, the main cause of death. Overall, we found that fludarabine and ATG conditioning before a second SCT allows engraftment of donor hematopoiesis. Future studies should include more intense GVHD prophylaxis.

High survival rate with the LMT-89 regimen in lymphoblastic lymphoma (LL), but not in T-cell acute lymphoblastic leukemia (T-ALL).

The most appropriate treatment for lymphoblastic lymphomas (LL) remains uncertain. We treated 27 patients with newly diagnosed LL according to an LMT-89 protocol, which is a modified version of the LMT-81 protocol previously reported in pediatric patients. The median age was 31 years. Mediastinal enlargement was present in 25/27 patients, with pleural effusion in 12. Four patients had central nervous system involvement and 12 had bone marrow involvement and 24/27 (89%) had advanced Ann Arbor stage III-IV disease. Complete remission (CR) was achieved in 20/27 patients, unconfirmed complete remission in three patients (residual mediastinal lesion on computed tomography scan) and four failed induction therapy (ORR: 85%). Twelve patients (44%) remained in continuous CR with a median follow-up of 95 months. Survival at 3 years (when all the events occurred in our series) was 63%. Bone marrow involvement was associated with a poor outcome. Overall survival was 85+/-20% in patients without bone marrow involvement compared to 37+/-30% in patients with bone marrow involvement. The Ann Arbor stage, age and serum lactate dehydrogenase level did not influence outcomes. This LMT-89 protocol is a safe regimen and is highly effective in advanced LL without bone marrow involvement.

Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate.

Mutations of the BCR-ABL kinase domain are a common mechanism of resistance to imatinib in chronic myeloid leukemia. We screened for mutations 171 patients failing imatinib therapy. Sixty-six mutations in 23 amino acids were identified in 62 (36%) patients not responding to imatinib. Phosphate-binding loop (P-loop) mutations were the most frequent (n=24; 36%). By multivariate analysis, factors associated with development of mutations were older age (P=0.026) prior interferon therapy (P=0.026), and accelerated phase or blast phase at time of imatinib failure (P=0.001). After a median follow-up of 38 months (range, 4-68 months) from the start of imatinib therapy, seven patients with non-P-loop and two with P-loop mutation died. By multivariate analysis, development of clonal evolution and higher percentage of peripheral blood basophils were associated with worse survival from the time of imatinib failure. Mutation status had no impact on survival. When survival was measured from the time therapy started, non-P-loop mutations together with duration of response and transformation at the time of failure to imatinib were associated with shorter survival. In conclusion, P-loop mutations were not associated with poor outcome, suggesting that the prognosis of patients who fail imatinib is multifactorial.

Comparison of clinical outcomes and prognostic utility of risk stratification tools in patients with therapy-related vs de novo myelodysplastic syndromes: a report on behalf of the MDS Clinical Research Consortium.

While therapy-related (t)-myelodysplastic syndromes (MDS) have worse outcomes than de novo MDS (d-MDS), some t-MDS patients have an indolent course. Most MDS prognostic models excluded t-MDS patients during development. The performances of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Global Prognostic System (MPSS), WHO Prognostic Scoring System (WPSS) and t-MDS Prognostic System (TPSS) were compared among patients with t-MDS. Akaike information criteria (AIC) assessed the relative goodness of fit of the models. We identified 370 t-MDS patients (19%) among 1950 MDS patients. Prior therapy included chemotherapy alone (48%), chemoradiation (31%), and radiation alone in 21%. Median survival for t-MDS patients was significantly shorter than for d-MDS (19 vs 46 months, P<0.005). All models discriminated survival in t-MDS (P<0.005 for each model). Patients with t-MDS had a significantly higher hazard of death relative to d-MDS in every risk model, and had inferior survival compared to patients with d-MDS within all risk group categories. AIC Scores (lower is better) were 2316 (MPSS), 2343 (TPSS), 2343 (IPSS-R), 2361 (WPSS) and 2364 (IPSS). In conclusion, subsets of t-MDS patients with varying clinical outcomes can be identified using conventional risk stratification models. The MPSS, TPSS and IPSS-R provide the best predictive power.

A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials.

Most clinical trials exclude patients with poor performance or comorbidities. To study whether patients with these characteristics can be treated within a clinical trial, we conducted a study for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with poor performance, organ dysfunction or comorbidities. Primary endpoint was 60-day survival. Study included stopping rules for survival and response. Treatment consisted on a combination of azacitidine and vorinostat. Thirty patients (16 with MDS, 14 with AML) were enrolled. Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. No stopping rules were met. Main adverse events (AEs) were grades 1 and 2 gastrointestinal toxicities. In view of these results, we expanded the study and treated 79 additional patients: 27 with azacitidine (AZA) and 52 with azacitidine and vorinostat (AZA+V). Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rate was 79% (AZA=67%, AZA+V=85%, P=0.07). Median overall survival was 7.6 months (4.5-10.7). Median event-free survival was 4.5 months (3.5-5.6). Main AEs included grades 1 and 2 gastrointestinal toxicities. Our results suggest this subset of patients can be safely treated within clinical trials and derive clinical benefit. Relaxation of standard exclusion criteria may increase the pool of patients likely to benefit from therapy.

Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL.

Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=<0.001). The 3-year overall survival estimates for the BFR and FCR groups were 82 and 51% (P=0.03), and the 3-year PFS estimates were 63% and 27% (P=0.001), respectively. The 2-year treatment-related mortality was 8 and 23% and the incidence of grade 3 or 4 GvHD was 4% and 10%, respectively. This study is the first to report that addition of bendamustine to alloSCT conditioning for CLL patients is associated with improved survival and lower mortality, myelosuppression, and GvHD.

A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials.

This corrects the article DOI: 10.1038/leu.2016.303.

A phase II study of decitabine and gemtuzumab ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome.

Decitabine may open the chromatin structure of leukemia cells making them accessible to the calicheamicin epitope of gemtuzumab ozogamicin (GO). A total of 110 patients (median age 70 years; range 27-89 years) were treated with decitabine and GO in a trial designed on model-based futility to accommodate subject heterogeneity: group 1: relapsed/refractory acute myeloid leukemia (AML) with complete remission duration (CRD) <1 year (N=28, 25%); group 2: relapsed/refractory AML with CRD ⩾1 year (N=5, 5%); group 3: untreated AML unfit for intensive chemotherapy or untreated myelodysplastic syndrome (MDS) or untreated myelofibrosis (MF; N=57, 52%); and group 4: AML evolving from MDS or relapsed/refractory MDS or MF (N=20, 18%). Treatment consisted of decitabine 20 mg/m(2) daily for 5 days and GO 3 mg/m(2) on day 5. Post-induction therapy included five cycles of decitabine+GO followed by decitabine alone. Complete remission (CR)/CR with incomplete count recovery was achieved in 39 (35%) patients; group 1= 5/28 (17%), group 2=3/5 (60%), group 3=24/57 (42%) and group 4=7/20 (35%). The 8-week mortality in groups 3 and 4 was 16% and 10%, respectively. Common drug-related adverse events included nausea, mucositis and hemorrhage. Decitabine and GO improved the response rate but not overall survival compared with historical outcomes in untreated AML ⩾60 years.

Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides.

Established prognostic tools in patients with myelodysplastic syndromes (MDS) were largely derived from untreated patient cohorts. Although azanucleosides are standard therapies for higher-risk (HR)-MDS, the relative prognostic performance of existing prognostic tools among patients with HR-MDS receiving azanucleoside therapy is unknown. In the MDS Clinical Research Consortium database, we compared the prognostic utility of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Prognostic Scoring System (MDAPSS), World Health Organization-based Prognostic Scoring System (WPSS) and the French Prognostic Scoring System (FPSS) among 632 patients who presented with HR-MDS and were treated with azanucleosides as the first-line therapy. Median follow-up from diagnosis was 15.7 months. No prognostic tool predicted the probability of achieving an objective response. Nonetheless, all five tools were associated with overall survival (OS, P=0.025 for the IPSS, P=0.011 for WPSS and P<0.001 for the other three tools). The corrected Akaike Information Criteria, which were used to compare OS with the different prognostic scoring systems as covariates (lower is better) were 4138 (MDAPSS), 4156 (FPSS), 4196 (IPSS-R), 4186 (WPSS) and 4196 (IPSS). Patients in the highest-risk groups of the prognostic tools had a median OS from diagnosis of 11-16 months and should be considered for up-front transplantation or experimental approaches.

[Acute tumor lysis syndrome: update on therapy]. / Traitement actuel du syndrome de lyse tumorale.

PURPOSE: The tumor lysis syndrome (TLS) is a set of complications that can arise from treatment of high burden, drug sensitive and rapidly proliferating neoplasm particularly of hematological origin. This syndrome can be observed before any treatment because of spontaneous tumoral cellular death, and is generally worsened when chemotherapy is initiated. CURRENT KNOWLEDGE AND KEY POINTS: Although TLS is primarily observed during therapy of acute leukemia, Burkitt's lymphomas and lymphoblastic lymphomas, it can also be observed in other hematological malignancies and during the treatment of rare solid tumors. Important progress has recently been made in the management of TLS. The use of urate oxydase can rapidly control TLS induced hyperuricemia, which help to prevent the risk of calcium phosphate crystal precipitation. FUTURE PROSPECTS AND PROJECTS: A global strategy for the management of SLT, combining adapted hydration, urate oxydase, and a close cooperation between intensive care units and hematology units can control this complication in most of the patients. The early management of TLS can, indeed, have an impact on the global therapy of these patients who need to be treated with high-dose anti-cancer agents with renal elimination.

Blinatumomab for the treatment of adult acute lymphoblastic leukemia.

The marker CD19 is frequently expressed on the surface of malignant B cells including non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL), which makes it an attractive target for antineoplastic therapy (1). T cells are part of the immune surveillance system for malignant cells (2). Blinatumomab is a bispecific T cell engager (BiTE(®)) antibody that binds both CD3-positive T cells and CD19-positive B cells via its two variable antigen-binding domains. Once bound to both the T and B cell, blinatumomab induces T-cell activation and subsequently perforin-mediated malignant B-cell death. It has shown efficacy in ALL with minimal residual disease, relapsed/refractory ALL, and NHL in phase I and II clinical trials. With a favorable safely profile and promising results, blinatumomab was granted accelerated FDA approval to treat B-cell ALL in December 2014. Herein, we will review the most relevant data related to blinatumomab in ALL.

An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies.

Since its reclassification as a distinct disease entity, clinical research efforts have attempted to establish baseline characteristics and prognostic scoring systems for chronic myelomonocytic leukemia (CMML). Although existing data for baseline characteristics and CMML prognostication have been robustly developed and externally validated, these results have been limited by the small size of single-institution cohorts. We developed an international CMML data set that included 1832 cases across eight centers to establish the frequency of key clinical characteristics. Of note, we found that the majority of CMML patients were classified as World Health Organization CMML-1 and that a 7.5% bone marrow blast cut-point may discriminate prognosis with higher resolution in comparison with the existing 10%. We additionally interrogated existing CMML prognostic models and found that they are all valid and have comparable performance but are vulnerable to upstaging. Using random forest survival analysis for variable discovery, we demonstrated that the prognostic power of clinical variables alone is limited. Last, we confirmed the independent prognostic relevance of ASXL1 gene mutations and identified the novel adverse prognostic impact imparted by CBL mutations. Our data suggest that combinations of clinical and molecular information may be required to improve the accuracy of current CMML prognostication.

Stem cell transplantation for chronic lymphocytic leukemia: should not more patients get a transplant?

Novel therapeutic approaches with conventional chemotherapy and monoclonal antibody combinations have improved the complete remission rates in chronic lymphocytic leukemia. However, cure remains elusive, particularly in fludarabine-refractory patients, whose prognosis remains poor. Autologous stem cell transplantation (SCT) has been explored for such patients, lengthening the time to treatment failure in selected patients, but there is little hope that it will improve the cure rate. The strategy is particularly ineffective in patients with poor biological prognostic factors, such as abnormal cytogenetics and unmutated immunoglobulin heavy-chain variable region. Allogeneic SCT remains the only curative approach, producing an extended disease-free survival in 25-60%, mainly via the graft-versus-leukemia effect. The treatment-related mortality with such an approach has been significant, however, with a 30-40% risk of death within 100 days of the transplant. Nonmyeloablative (NMA) conditioning regimens may produce high response rates and lower morbidity, especially for patients with chemosensitive disease. Randomized trials designed according to the new biologic prognostic parameters described in chronic lymphocytic leukemia are required to better define the role of NMA SCT in the near future.

Outcome of elderly patients with aggressive Non-Hodgkin's lymphoma refractory to or relapsing after first-line CHOP or CHOP-like chemotherapy: a low probability of cure.

We retrospectively evaluated the outcome of 94 consecutive elderly patients treated at our center for an aggressive lymphoma without a low-grade component. Median survival was 26 months and 5-year overall survival was 39% (27-50%). We then evaluated the outcome of patients refractory to or relapsing after CHOP or CHOP-like chemotherapy. Twenty patients were refractory to first-line therapy and only 1/20 is alive with active lymphoma. Eight patients achieved a partial response and only 3 maintained the partial response while the other 5 patients died. Only 2 of the 27 patients who relapsed after a first complete remission achieved a second sustained complete remission. This study suggests that conventional-dose second-line chemotherapy yields disappointing results in elderly patients with aggressive lymphomas.

[Castelman's disease. Report of two cases with review of the literature]. / Maladie de Castelman. Apropos de deux cas et revue de la littérature.

Castelman's disease, an unusual condition of unknown cause, consisting of a massive proliferation of lymphoid tissue. Three histologic variants (hyaline vascular, plasma-cell, and mixed) and two clinical types (localized and multicentric) of Castelman's disease have been described. Localized disease can be cured with surgery or radiotherapy, but complete remission in patients with multicentric disease have been achieved only with prednisone or chemotherapy given at the time of diagnosis. The aim of this study is to report two cases of retroperitoneal Castelman's disease with review of the literature. The first patient, of 36 years old, presented for abdominal pain with anorexia and weight loss. The abdomino-pelvic CT scan showed a 6 cm retroperitoneal mass. The biopsy of this lesion suspected a lymphoproliferative disease. At laparotomy total excision of mass was made and the final histology revealed a hyalino-vascular type of Castelman's disease. The second patient, of 26 years old, presented for left lombar pain with weight loss. The abdominopelvic CT Scan showed a 6.5 cm retroperitoneal mass. The biopsy of this lesion showed a Castelman's disease. At laparotomy total excision of mass was made and the final histology confirmed a hyalino-vascular type of Castelman's disease.

[Otosclerosis: experience at the Hotel-Dieu in France. 71 surgical cases]. / Otospongiose: expérience de l'Hôtel-Dieu de France. A propos de 71 cas opérées.

Otosclerosis is one of the common causes of hearing loss. The incidence varies between 0.1% and 2%. In Lebanon otosclerosis is a common entity that has not been well evaluated. To the best of our knowledge there is no epidemiologic analysis of the incidence or outcomes of otosclerosis in Lebanon. We collected the number of stapedectomies performed for otosclerosis in different hospitals between Jan. 1994 and Dec. 1995. We also retrospectively reviewed the charts of 71 cases who underwent stapedectomy at Hôtel-Dieu de France-St Joseph University Hospital Medical Center, Beirut, Lebanon. Between 1992 and 1996 the incidence of otosclerosis in Lebanon as revealed through stapedectomy is 5/100,000. We report also on the pathology, technique, complications and outcomes of stapedectomy surgery for otosclerosis in Hôtel-Dieu Hospital. Further epidemiologic studies and screening is required to reveal the exact incidence of this common entity that could be underdiagnosed or untreated in our country.