Ana Planinc-Peraica

Treatment of chronic lymphocytic leukemia in early and stable phase of the disease : long-term results of a randomized trial

Abstract: In 1982 the IGCI CLL cooperative group decided to investigate the usefulness of treating, at diagnosis B‐cell chronic lymphocytic leukemia (CLL) in early and stable phase of the disease. From January 1982 to December 1986, 148 patients were randomized either to receive immediate treatment with chlorambucil (CLB) or to defer therapy to the time of progression. The early and stable phase of the disease was defined by a total tumor mass (TTM) score < 9, the absence of anemia or thrombocytopenia and a doubling time > 12 months. The main end‐point of the study was survival. At the last evaluation in April 1993, after a median follow‐up of 75 months, no significant difference was found in overall survival between early vs. deferred treatment patients from every cause of death as well as from death due to CLL‐related causes only. The same results were obtained when the patients in more favorable stages, such as Binet stage A and TTM < 4.5, were considered. Interestingly, the incidence of epithelial cancer was similar in the two groups. Early treatment was associated with a significantly better response and a lower progression rate. From this long‐term experience, it can be concluded that immediate chemotherapy with CLB is not beneficial for CLL patients in early and stable phase of the disease in terms of survival.

2-Chlorodeoxyadenosine treatment in non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia resistant to conventional chemotherapy: Results of a multicentric experience

Abstract Among the purine analogs, 2-chlorodeoxyadenosine (2-CDA) is particularly effective for the treatment of hairy cell leukemia and Waldemstroms macroglobulinemia. Both efficacy and toxicity of 2-CDA were evaluated in previously treated patients affected with chronic lymphoproliferative disorders such as low-grade non-Hodgkins lymphoma (NHL) and B-cell chronic lymphocytic leukemia (CLL). Thirty cases, mainly refractory, 16 affected with CLL, were included from six centers of the International Society for Chemo-Immunotherapy (IGCI). 2-CDA was administered in a 2 h i.v. infusion for 5–7 days at the standard dose of 0.1 mg/kg/day every 4 weeks. The median number of cycles was 3. Of 30 cases, eight (26.7%) achieved a complete remission (CR), nine (30%) a partial remission (PR), and two (6.7%) a minor response, while five cases (16.6%) did not respond, and six (20%) were considered early deaths. The overall response rate (CR+PR) was 56.7%, with a median response duration of 12 months (range 3–28+) and a better response in CLL patients. Considering that the majority of patients were heavily pretreated, toxicity was acceptable, with 40% of cases not presenting any toxic effect. The main toxicity consisted in infectious complications. Based on the results of the present study, we confirm that 2-CDA is an effective drug in these lymphoproliferative disorders, suggesting its possible use either alone or in combination, also as first-line therapy.

The differential diagnostic capacity of serum amyloid a protein between infectious and non-infectious febrile episodes of neutropenic patients with acute leukemia

We studied the behavior of four major acute phase proteins (SAA, CRP, ACT and AGP) in pyrexial occurrences of 16 neutropenic patients with acute leukemia. Altogether 37 febrile episodes were recorded; 27 were infectious in origin (microbiologically documented infection and clinically documented infection, MDI/CDI group) and 10 were pyrexias of unknown origin (PUO group). In the MDI/CDI group the mean value for the highest individual SAA concentration was 282 +/- 161 mg/l and in the PUO group 95 +/- 79 mg/l. The corresponding mean values were 4.0 mg/l (range 0.2-5.5 mg/l) in 10 control patients with 1 year remission and 0.8 mg/l (range < 0.1-1.2 mg/l) in 30 healthy adults. The peak value of SAA rose above 100 mg/l in 85% of our MDI/CDI pyrexias and in 40% of PUO. More reliable results were obtained when the difference between the value on the day when pyrexia occurred and the previous day was calculated. In that case, the difference was above 75 mg/l in 23 of 27 (85%) MDI/CDI pyrexias and in none of 10 (0%) PUO. In the MDI/CDI group the mean difference was 204 +/- 137 mg/l while it was only 26 +/- 19 mg/l in the PUO group. The statistical significance was very high (p < 0.0001). The CRP monitoring was very inferior to SAA while ACT and AGP monitorings were unsatisfactory.

Exacerbation of Psoriasis after Treatment with Alpha-Interferon

Rajko Kušec, MD, Slobodanka Ostojić, MD, Ana Planinc-Peraica, MD, Hrvoje Minigo, MD Branimir Jakšić, MD, PhD, Department of Hematology, Clinical Hospital ‘O Novosel’ Zajčeva 19, 41000 Zagreb (Yugoslavia) Dear Sir, At the International Symposium on Interferons and Related Lym-phokines held in Berlin 1989, Harrison [1] described the exacerbation of psoriasis after treatment with α-interferon. As we have observed a similar behaviour of the psoriatic process under treatment with α-interferon we would like to briefly present our experience with a comment on the possible explanation for this phenomenon. We have treated a 54-year-old male patient with hairy cell leukaemia and psoriasis with recombinant α2b-interferon. Therapy with α-interferon (Intron A; Schering) in doses of 3 MU s.c. thrice weekly was started because of the activation of malignant disease. The condition had been stable previously for 9 years not requiring specific or supportive therapy (splenec-tomy was performed early at the time of diagnosis). A psoriasis with skin and joint involvement was established 3 years from the diagnosis of hairy cell leukaemia. The disease was stationary with usual topical therapy and occasionally nonsteroid analgesics. A month after starting α-interferon treatment, which was already showing haematological improvement, the exacerbation of psoriatic skin manifestations occurred with arthralghias, limitations of movement in affected joints and swelling of small finger joints. This condition did not conform with a pattern of typical interferon-related side-effects. Interferon treatment was discontinued for a month with a substantial improvement of psoriasis entering again a stationary phase. After this period α-interferon was restarted, and again exacerbation of psoriasis was noted. This resulted in the definite exclusion of the patient from αinterferon treatment for hairy cell leukaemia. The cause for this finding is not clear. At the same symposium a study detecting various interferons in psoriatic skin was presented providing data on the presence of α-interferon in the active disease, while it was absent in the stable phase or normal skin [2]. Searching for other mechanisms that could mediate/regulate a psoriatic process, an increased adrenal activity during interferon therapy should be considered [3], which, we believe, deserves further clarification. References Harrison P: Exacerbation of psoriasis with alpha interferon (abstract). J Invest Dermatol 1989;93:555.

Primary mediastinal large B-cell lymphoma: a single-center study of clinicopathologic characteristics.

Primary mediastinal large B-cell lymphoma (PMLBCL) is a subset of LBCL with unique clinicopathologic features. Some studies have raised the question of differences in biological features and clinical course among patients from different parts of the world. We conducted a retrospective clinicopathologic analysis of 24 patients with PMLBCL from a single center in Croatia. We also conducted the first investigation of the frequency of lymphotropic viruses human herpesvirus 6 (HHV-6) and HHV-8 in lymphoid lesions of this disease.The clinical characteristics of the patients were as expected, with high International Prognostic Index scores, elevated serum lactate dehydrogenase (LDH) levels, and bulky disease being adverse prognostic factors. Only 6 patients (25%) showed CD30 expression, and Bcl-6 protein expression was, in our series, prognostically favorable (P = .0401). One patient’s tumor had detectable HHV-6 genome sequence, but no HHV-8 sequences were detected in any tumors. Two thirds of the patients received CHOP chemotherapy (cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone) with a relatively low complete remission rate (43.8%; median follow-up, 33.8 months). This study confirmed the moderate preponderance among PMLBCL patients of young females with B symptoms and elevated LDH levels.The CHOP regimen proved effective as first-line therapy only in patients with limited disease. Therefore, other third-generation chemotherapy protocols may be considered for treatment, especially in patients with bulky and advanced disease.

The role of microRNA in myelodysplastic syndromes: beyond DNA methylation and histone modification

Myelodysplastic syndromes (MDS) are heterogeneous group of hematologic disorders of mostly elderly and based on distinct clinical phenotypes. Current paradigm of their pathogenesis relies on somatic gene mutations combined with the predisposing defective osteohematopoietic niche, but due to the breakout in epigenetic research scientific focus has steered toward two most common epigenetic modifications: methylation mechanisms and histone modification. At the same time, relatively few studies have been undertaken regarding the third epigenetic pathway – microRNAs – in MDS. The main aim of this review is to provide the basics of microRNA biology and function in oncogenesis, showing the complexity of mechanisms behind this single‐stranded 22 nucleotides long RNA molecule, with further focus on its implication in MDS pathology and clinical context. By extensive literature search, we have shown enough evidence for their deregulation in MDS. However, few studies have addressed the issue on pathogenic events in MDS and its association with specific microRNAs. Preliminary research in clinical setting has shown the possible utility of microRNAs in terms of prognosis and therapy, although we are only beginning to understand various implications of microRNAs in MDS and further extensive research is warranted to answer multiple questions arising from interconnection of this epigenetic mechanism in MDS.

Meningeal Infiltration of Chronic Myelomonocytic Leukemia

Chronic Myelomonocytic Leukemia (CMML) is a hematologic malignancy considered a subtype of Myelodysplastic Syndrome (MDS)/Myeloproliferative Disease (MPD). According the World Health Organization (WHO) two subtypes of CMML, CMML-1 and CMML-2 are defined depending on the percentage of blasts in Bone Marrow (BM) and Peripheral Blood (PB). The clinical presentation is variable, but the majority of patients present with fatigue, weight loss, fever, night sweats and splenomegaly, less often skin infiltration or serous effusions. Meningeal leukemic involvement is rarely a presenting feature of CMML. We are reporting a case of 67-year old male with central nervous system involvement of CMML.

Rituximab Maintenance Strategy in Advanced Follicular Lymphoma: Facts and Controversies

Rituximab is a chimeric monoclonal CD20 antibody used in the treatment of CD20 positive non-Hodgkin lymphomas and has revolutionized treatment approach to these hematologic malignancies in the last decade. The main aim of this review is to present data on the use of rituximab in the treatment of follicular lymphoma (FL). We will focus on rituximab maintenance strategies in the first and second line treatment. This approach has improved the outcome in FL patients with better progression-free survival in all patients and better overall survival in relapsed setting. Regardless of good results, this strategy has generated controversies in medical community in the range from the lack of overall survival benefit in first line setting, adverse effects of possible overtreatment and toxicities to its unknown role in the era of novel agents. The existing data suggest that rituximab maintenance should be a rational therapeutic option for all patients with FL responding to fi rst line therapy and transplant-ineligible patients responding to reinduction.