Management of ibrutinib treatment in patients with B-cell malignancies: clinical practice in Portugal and multidisciplinary recommendations.

OBJECTIVES: Ibrutinib, a potent inhibitor of the Bruton tyrosine kinase, has revolutionized the treatment of many B-cell malignancies. Ibrutinib has an established favorable toxicity profile with up to 8 years of experience in clinical trials; however, despite ibrutinib's favorable toxicity profile, dose reductions and treatment discontinuations are becoming more evident in clinical practice, particularly in the setting of specific clinical contexts and patient characteristics. This manuscript is set to provide practical recommendations on the management of patients treated with this agent in daily practice. METHODS: A group of multidisciplinary experts from Portugal met to discuss and highlight practical recommendations, supported on both literature and clinical insights, for the management of the treatment with ibrutinib. RESULTS/DISCUSSION: Handling of both toxicities and drug-drug interactions during ibrutinib treatment poses several challenges to healthcare providers and can benefit from a multidisciplinary approach. The involvement of specialties, such as cardiology, infectiology and pharmacology, can bring an added value to patient care, not only in anticipating/managing safety issues and dose adjustments but also in enhancing adherence to treatment, ultimately improving the risk/benefit balance. CONCLUSION: By involving a multidisciplinary group of experts, this work provides a set of key recommendations to optimize care and outcomes for ibrutinib-treated patients. Despite not being a fully comprehensive review on the topic, it is intended as a framework to hematologists and other healthcare professionals who manage these patients in their daily clinical practice.

Association of TLX1 gene polymorphisms with the risk of acute lymphoblastic leukemia and B lineage acute lymphoblastic leukemia in Han Chinese children.

BACKGROUND: Studies on gene polymorphism association are centered on childhood acute lymphoblastic leukemia (ALL), a common hematological malignancy in children younger than 16 years. Single-nucleotide polymorphisms (SNPs) in some genes, such as ARID5B and CDKN2B, are associated with the risk of childhood ALL. T-cell leukemia homeobox 1 (TLX1), a member of the HOX gene family, was identified based on its abnormal expression in T-lineage leukemia. This study aimed to determine whether TLX1 is associated with B-ALL and which SNP plays a significant role in ALL. METHODS: A total of 217 cases of ALL and 241 controls were included in this study. Six tag SNPs (rs75329544, rs946328, rs12415670, rs2075879, rs17113735, and rs1051723) were selected, and genotyping was carried out on Sequenom MassARRAY platform. RESULTS: Rs17113735 was possibly the risk locus associated with increased risk for ALL, whereas rs946328 was possibly associated with decreased risk for ALL. Moreover, rs17113735 was likely to be the risk locus for B-cell ALL (B-ALL), and rs2075879 was associated with decreased risk for B-ALL (P < .05). All SNPs in the two sample types (ALL and B-ALL samples) demonstrated linkage disequilibrium except between rs75329544 and rs2075879. Haplotype analysis showed no significant difference between the cases and controls in the two sample types. CONCLUSION: TLX1 gene polymorphisms are associated with ALL (rs17113735 and rs946328) and possibly play a significant role in B-ALL (rs17113735 and rs2075879). This work provides a reference for the diagnosis and therapy of this disease.

Circulating microfilariae in haematological malignancies: do they have a role in pathogenesis?

Filariasis is very common in tropical countries. It is endemic in the coastal areas of India. We report four cases of haematological malignancy where peripheral blood and bone marrow smears did not show any microfilariae but conventional cytogenetic preparations from all the four cases showed the presence of parasites. Their morphology confirmed the diagnosis of all cases as bancroftian filariasis. Therefore all types of cytogenetic preparations should be screened carefully in the endemic areas along the coastal zones of India for the presence of this parasite.

Immunophenotypic subtyping of leukemic cells from Iranian patients with acute lymphoblastic leukaemia: association to disease outcome.

BACKGROUND: Immunophenotypic characterization of the leukemic cells has been widely used as a tool for diagnosis, classification, stratification and prognosis of leukaemia. OBJECTIVE: To investigate the immunophenotypic subtype profiles of Iranian patients with acute lymphoblastic leukemia (ALL) and its association to disease outcome. METHODS: In this study, a total of 60 Iranian patients with ALL were immunophenotyped by flow cytometry using a panel of monoclonal antibodies specific for CD2, CD3, CD5, CD10, CD13, CD14, CD19, CD20, CD33, CD34, CD45, HLA-DR and TdT molecules. RESULTS: The samples were initially categorized into T-ALL (n=9), B-ALL (n=50) and mixed lineage (n=1) based on the expression patterns of CD3 and CD19 molecules. B-ALL patients could further be classified into four subtypes, including Pro-B (n=7, 11.7%), Pre-B I (n=28, 46.7%), Pre-B II (n=13, 21.7%) and immature/mature B cells (n=2, 3.3%) on the basis of expression of CD10, CD19, CD20, HLA-DR and TdT. Clinical manifestations and laboratory findings of the patients did not reveal association with immunophenotypic subtypes of ALL, with the exception of mediastinal mass and WBC count at the time of diagnosis which were found to be significantly higher in patients with T-ALL compared with B-ALL (p=0.001 and 0.014), respectively. CONCLUSION: Our results indicate that overall the immunophenotypic profile of Iranian ALL patients is similar to previous reports and it might be used for monitoring of minimal residual disease and prognosis.

Prevalence and natural history of monoclonal and polyclonal B-cell lymphocytosis in a residential adult population.

BACKGROUND: Monoclonal B-cells can be detected in the peripheral blood of some adults without B-cell malignancies, a condition recently termed monoclonal B-cell lymphocytosis (MBL). The risk of individuals with MBL progressing to a B-cell malignancy is unknown. Polyclonal B-cell lymphocytosis (PCBL) has not been systematically studied in the general population. METHODS: We obtained lymphocyte subset counts on 1,926 residential adults aged 40-76 years in a series of environmental health studies between 1991 and 1994. We then conducted two follow-ups in 1997 and 2003 on consenting participants with B-cell lymphocytosis, which included nine participants with MBL. To ascertain the clinical implications of MBL, we reviewed medical records and death certificates. RESULTS: The overall prevalence of MBL was 0.57% (11/1,926): nine cases at baseline and two additional cases identified at follow-up. Two (19%) MBL cases subsequently developed a B-cell malignancy; MBL persisted in the remaining nine cases (81%). All PCBL cases where no clone emerged regressed to normal B-cell counts over the follow-up period. MBL was significantly more frequent in residents near a hazardous waste site than in the control populations (age-adjusted OR 6.2; 95%CI 1.1-36.2). CONCLUSION: MBL confers an elevated risk for developing a B-cell malignancy, although it occurs only in a minority of cases. PCBL is most often a transient state, but a monoclonal population can emerge and persist. Prospective studies are needed to distinguish stable from progressive forms of B-cell lymphocytosis and to clarify the etiologic role of environmental exposures.

Lymphoid neoplasms in Bulgaria according to the WHO classification (2001). The experience of the National Center of Haematology.

The aim of the present study was to assess the incidence of lymphoma subtypes in the largest cohort of patients in Bulgaria, referred to the National Center of Haematology and Transfusiology between 01.01.2003 and 31.12.2004, applying the WHO classification criteria, including precursor and mature cell neoplasias, plasmacytoma and Hodgkin lymphomas. A total of 790 cases were newly diagnosed. Hodgkin lymphomas comprised 24.6% of the cases, B-cell neoplasias - 66.5% whereas T/NK-cell neoplasias - 6.9% of the total. Specimens were inadequate for subclassification in 2.2% of the cases. Detailed data on the subtypes are presented and compared to reported data from other geographic locations.

Incidence and clinicobiologic characteristics of leukemic B-cell chronic lymphoproliferative disorders with more than one B-cell clone.

Leukemic B-chronic lymphoproliferative disorders (B-CLPDs) are generally believed to derive from a monoclonal B cell; biclonality has only occasionally been reported. In this study, we have explored the incidence of B-CLPD cases with 2 or more B-cell clones and established both the phenotypic differences between the coexisting clones and the clinicobiologic features of these patients. In total, 53 B-CLPD cases with 2 or more B-cell clones were studied. Presence of 2 or more B-cell clones was suspected by immunophenotype and confirmed by molecular/genetic techniques in leukemic samples (n = 42) and purified B-cell subpopulations (n = 10). Overall, 4.8% of 477 consecutive B-CLPDs had 2 or more B-cell clones, their incidence being especially higher among hairy cell leukemia (3 of 13), large cell lymphoma (2 of 10), and atypical chronic lymphocytic leukemia (CLL) (4 of 29). In most cases the 2 B-cell subsets displayed either different surface immunoglobulin (sIg) light chain (n = 37 of 53) or different levels of the same sIg (n = 9 of 53), usually associated with other phenotypic differences. Compared with monoclonal cases, B-CLL patients with 2 or more clones had lower white blood cell (WBC) and lymphocyte counts, more frequently displayed splenomegaly, and required early treatment. Among these, the cases in which a CLL clone coexisted with a non-CLL clone were older and more often displayed B symptoms, a monoclonal component, and diffuse infiltration of bone marrow and required early treatment more frequently than cases with monoclonal CLL or 2 CLL clones.

Rheumatoid arthritis and B-cell chronic lymphocytic leukemia.

The association between lymphoproliferate malignancies, especially lymphoma, and rheumatoid arthritis (RA) has been confirmed by several studies. However; there are few reports of RA patients who developed B-cell chronic lymphocytic leukemia (B-CLL) and vice versa. We report a patient with B-CLL who developed RA and another with RA who presented with B-CLL during follow-up. We discuss the incidence of B-CLL among the RA population and the possible interaction of the pathogenetic mechanisms of these two entities.

Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia.

To investigate if decreased exposure to common childhood infections is associated with risk of childhood acute lymphoblastic leukaemia (ALL) we conducted a case-control study of 1842 newly diagnosed and immunophenotypically defined cases of ALL under age 15, and 1986 matched controls in the US. Data regarding day care, sibship size and common childhood infections were obtained through parental interviews. Data were analysed stratified by leukaemia lineage and separately for 'common' childhood ALL (age 2-5 years, CD19, CD10-positive). Neither attendance at day care nor time at day care was associated with risk of ALL overall or 'common' ALL. Ear infections during infancy were less common among cases, with odds ratios of 0.86, 0.83, 0.71 and 0.69 for 1, 2-4, 5+ episodes, and continuous infections respectively (trend P = 0.026). No effect of sibship size or birth interval was seen. With one exception (ear infections), these data do not support the hypothesis that a decrease in the occurrence of common childhood infection increases risk of ALL.

CD5-expressing B-cell lymphomas/leukemias: relatively high frequency of CD5+ B-cell lymphomas with an overall poor prognosis in Nagasaki Japan.

To characterize CD5+ B-cell neoplasms in Japan, where chronic lymphocytic leukemia (CLL) is rare and of different subtypes in comparison with Western countries, we collected 58 cases of CD5+ B-cell lymphomas/leukemias and analyzed their clinicopathologic features. According to the French-American-British (FAB) and standard histologic classification, the cases corresponded to small lymphocytic lymphoma (SLL, group I; n = 22, consisting of CLL, n = 10, CLL/PL, n = 3, and CLLmixed, n = 7); intermediate differentiated lymphoma/mantle cell lymphoma (IDL/MCL, group II, n = 18); and others with CD5-positive lymphomas (group III, n = 18). The CD5+ B-cell lymphomas showed morphologic and prognostic variability among the three groups. The clinical and immunophenotypic features were remarkably consistent in leukemic disease being seen in 73% of all cases, splenomegaly in 63%, and intense CD19, CD20, surface membrane immunogobulin M (SmIgM) or SmIgM and SmIgD, light-chain expression, and no CD10 expression. The median survival time of groups I, II, and III was 7.8, 3.3, and 0.8 years, respectively. These findings suggest that CD5 antigens may serve as valid markers for the prognosis and clinical features of B-cell lymphomas and that CD5+ B-cell lymphomas with an overall poor prognosis occurs at a relatively high frequency in Japan. This also suggests that a combination of immunophenotypic and morphologic features is of value for characterizing CD5+ B-cell neoplasms.

Morphological and immunophenotypical characterization of Japanese B-cell lymphocytic leukemia.

We have analyzed the clinical and laboratory features of 42 patients with B-cell leukemia. Based on the FAB criteria, the cases were classified in 3 groups: I) typical CLL 15, II) atypical CLL 9 which included 6 cases with large cells, and III) B-cell lymphoma in leukemic phase 18. Cases diagnosed as typical CLL (group I) had similar features to those seen in CLL patients from Western countries. The morphology and markers in cases from group III corresponded to B-cell lymphoma in leukemic phase. On the other hand, group II included 3 cases classified as atypical CLL according to FAB criteria. 1 CLL/PL and 2 mixed CLL and 6 cases with rather distinct features, namely: 1) lymphocytosis (42 +/- 41 x 10(9)/l in average) with large mature-looking lymphocytes with abundant cytoplasm: 2) an immunological profile consistent with CLL but, in addition with the consistent expression of CD38; 3) absence of a monoclonal band in the serum and 4) a clinical course and prognosis similar to CLL. Our findings suggest the existence of a B-cell disorder in Japan very close to CLL but distinct from typical and atypical CLL as seen in Western countries. Further studies would clarify whether such an entity is exclusively confined to Japan having a distinct natural history.

Extrahepatic primary malignant neoplasms associated with hepatocellular carcinoma: high occurrence of B cell tumors.

In a consecutive series of 317 patients with hepatocellular carcinoma (HCC), 32 (10.1%) had 35 extrahepatic primary malignant neoplasms (PMNs) (3 patients had triple cancers). Twenty-five PMNs occurred before the diagnosis of HCC, 7 were synchronous and 3 metachronous. These 35 PMNs were: 6 cancers of the colon, 3 of the stomach, 1 of the rectum, 4 of the breast, 2 of the lung, 1 of the larynx, 3 of the prostate, 1 of the penis, 1 of the urinary bladder, 1 of the uterus, 2 of the skin, and the remaining 10 were immunoproliferative cancers, all of B cell origin (7 non-Hodgkin's lymphoma, 2 multiple myeloma, and 1 chronic lymphocytic leukemia). Thus, in this series, B-lymphocyte-derived neoplasms were the most frequent PMNs associated with HCC. These 10 patients showed no difference for age, male:female ratio, HCC cytotype, presence of cirrhosis, alcohol abuse, markers related to hepatitis B and C virus, and serum level of alpha-fetoprotein when compared with the 22 patients with HCC and other PMNs and the 285 with HCC alone. B cell neoplasms constitute half of the synchronous or metachronous cancers, and must, therefore, be kept in mind in the management of HCC patients.

ProMACE day 1/MOPP day 8 chemotherapy for prolymphocytic leukemia: a case report of prolonged survival.

The treatment result of a case of de novo B-cell prolymphocytic leukemia (B-PLL) is described. The diagnosis was established with histologic, ultrastructural and immunologic studies. The patient was treated with chemotherapy using a total of seven cycles of ProMACE Day 1/MOPP Day 8 lymphoma regimen. Complete remission was achieved after 5 cycles of chemotherapy. The patient remains disease free after a 7-year follow up. This is the first case of PLL being treated with such a regimen and the only case reported achieved such prolonged survival. Results of other treatment modalities are reviewed.