Risk for second malignancies in non-Hodgkin's lymphoma survivors: a meta-analysis.

BACKGROUND: Late side-effects are becoming an important issue in non-Hodgkin's lymphoma (NHL) survivors. We intended to estimate pooled relative risk (RR) of secondary malignant neoplasms (SMNs), to evaluate site-associated RR and the impact of different treatments. DESIGN: We carried out an electronic search of Medline and EMBASE seeking articles investigating the risk of SMNs and reporting RR measures. The studies were evaluated for heterogeneity before meta-analysis and for publication bias. Pooled RRs were estimated using fixed- and random-effects models. RESULTS: A total of 23 studies met the inclusion criteria. Pooled RRs of SMNs overall and for solid tumors were 1.88 and 1.32, respectively. We found an excess of risk for several specific cancer sites. Radiotherapy alone did not increase the risk for SMNs, while chemotherapy and combined treatments augmented the RR. Regression analyses revealed a positive significant association for all SMNs with total body irradiation, and for solid SMNs with younger age. No publication bias was observed. CONCLUSIONS: Our results indicate that NHL patients experience a higher risk for SMNs than the general population and that various treatments have different impact on RR. More information will be necessary to evaluate possible interactions with genetic susceptibility and environmental exposure.

Prognostic models for diffuse large B-cell lymphoma in the rituximab era: a never-ending story.

BACKGROUND: Improved treatment have modified survival outcome in patients with diffuse large B-cell lymphoma (DLBCL) and altered the importance of previously recognized prognostic markers. DESIGN AND METHODS: To evaluate International Prognostic Index (IPI) score before and after rituximab introduction and to validate the absolute lymphocyte count (ALC)/revised International Prognostic Index (R-IPI) model, we carried out a retrospective analysis on a total of 831 patients with DLBCL. RESULTS: Our results show that IPI lost its discriminating power with the introduction of rituximab. The analysis of our second set allowed us to validate the ALC/R-IPI model. The R-IPI and ALC/R-IPI could still be used for designing clinical trials, but both have difficulty recognizing a high percentage of poor prognosis patients, though it remains an important goal of a good prognostic model considering the modest impact of salvage treatments on survival. CONCLUSIONS: A new model on the basis of significant variables in the rituximab era and built on a large database of patients treated with rituximab is urgently needed. As prognostic models are changing with the efficacy and mechanisms of action of treatment utilized, looking for a new prognostic score is a never-ending story in which researchers are trying to hit a continuously moving target.

Positive self-perception and corticospinal excitability: Recalling positive behavior expands peripersonal space boundaries.

Converging evidence suggests that peripersonal space has dynamic properties, that can be influenced by motor and cognitive factors. Here, we investigated whether changes in self-perception may impact upon peripersonal representation. Specifically, employing non-invasive brain stimulation, we tested whether corticospinal excitability elicited by objects placed in the vertical peripersonal vs extrapersonal space can be influenced by changes in self-perception after recalling a personal experience inducing the feeling of high power (vs. positivity vs. low power). In a preliminary study (Study 1, N = 39) participants were presented with an object, whose position was manipulated in the horizontal vs vertical space. We assessed corticospinal excitability by measuring Motor Evoked Potentials (MEPs) using Transcranial Magnetic Stimulation with Electromyography co-registration (TMS-EMG). In the horizontal condition, we replicated the well-known motor facilitation induced by objects falling in the peri vs extrapersonal space, while in the vertical dimension MEPs were higher in the extrapersonal space. In the main experiment (Study 2), participants (N = 55) were randomly assigned to feel high power, low power, or a general positive emotion and were asked to observe the same object positioned either in the peripersonal or in the extrapersonal vertical space. Results showed that in the low power condition MEPs were higher in the extrapersonal vs peripersonal, as in Study 1, while in high power and positive conditions MEPs were not influenced by distance. Taken together, our findings suggest a dissociable pattern of motor facilitation underlying vertical vs horizontal space perception and, crucially, that changes in self-perception can influence such a representation.

A putative helical cytokine functioning in innate immune signalling in Drosophila melanogaster.

In invertebrates and vertebrates, innate immunity is considered the first line of defense mechanism against non-self material. In vertebrates, cytokines play a critical role in innate immune signalling. To date, however, the existence of genes encoding for invertebrate helical cytokines has been anticipated, but never demonstrated. Here, we report the first structural and functional evidence of a gene encoding for a putative helical cytokine in Drosophila melanogaster. Functional experiments demonstrate that its expression, as well as that of the antimicrobial factors defensin and cecropin A1, is significantly increased after immune stimulation. These observations suggest the involvement of helical cytokines in the innate immune response of invertebrates.

Ratios between the abundance of messenger RNA and the corresponding protein of two growth-related genes, c-myc and vimentin, in leukemia blast cells.

The abundance of the mRNAs of two growth-related genes, vimentin and c-myc, and that of the corresponding proteins have been studied in unstimulated and phytohemagglutinin-stimulated lymphocytes as well as in 18 populations of leukemic blast cells. The quantitative assay was carried out by densitometric scanning of Northern and Western blots. In normal lymphocytes the mRNA and the protein of both genes were almost undetectable. The phytohemagglutinin stimulation led to a sharp increase of the mRNA and the proteins of vimentin and c-myc. The increase was followed by a progressive fall of the gene products. The rate of decrease of the two mRNAs was similar to that of the corresponding proteins. In some leukemic populations very similar amounts of the vimentin protein were accompanied by amounts of the mRNA differing at least 25 times. Not unlikely, very similar amounts of p62c-myc corresponded to mRNA abundances differing at least 16 times. The coordinated biogenesis of both messenger RNAs and proteins, which occurs in mitogen-stimulated lymphocytes, is substituted, in approximately 30% of the leukemic blast cell populations, by molecular events leading to the accumulation of an excess of mRNA.

Immune-mediated and unusual complications during interferon alfa therapy in chronic myelogenous leukemia.

PURPOSE: Long-term treatment with interferon alfa (IFN alpha) can produce or exacerbate immune-mediated complications (IMC). The purpose of this study was to analyze the experience with IMC and unusual complications in patients with chronic myelogenous leukemia (CML) undergoing IFN alpha treatment. PATIENTS AND METHODS: The occurrence of IMC and unusual complications was evaluated in patients with Philadelphia chromosome (Ph)-positive CML. RESULTS: Well-documented and clinically evident complications developed in 35 patients after a median of 14 months of IFN alpha treatment. These included 28 (5%) of 581 patients with Ph-positive CML treated with IFN alpha-containing regimens at M.D. Anderson Cancer Center (MDACC) and seven patients referred for opinion or problems who were on other studies. Hypothyroidism occurred in 11 patients (2%), immune-mediated hemolysis in seven (1%), and connective tissue diseases in 11 (2%). Other unusual occurrences included congestive heart failure (CHF; n = 4), porphyria cutanea tarda (PCT; n = 3), membranous glomerulonephritis (MGN; n = 1), and vitiligo (n = 1). IFN treatment was discontinued in 19 patients and the dose was reduced in five. Ten of 11 patients (91%) with immune-mediated hypothyroidism and eight of 11 (73%) with connective tissue diseases had some degree of cytogenetic response at the time of the event. CONCLUSION: Although the frequency of IMC is low, patients treated with IFN alpha should be monitored for signs and symptoms of autoimmunity.

Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia.

PURPOSE: To determine, in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) on interferon alfa (IFNalpha), whether combining pretreatment characteristics and early response profiles would distinguish patients with differential benefits that would allow better decisions on subsequent therapy. PATIENTS AND METHODS: A total of 274 patients treated from 1982 through 1990 with IFNalpha regimens were analyzed. A second group of 137 patients treated with IFNalpha and low-dose cytarabine (ara-C) between 1990 and 1994 was later used to confirm the guidelines derived from the original study group analysis. Patients' pretreatment factors and response to IFNalpha therapy at 3, 6, and 12 months were analyzed in relation to subsequent achievement of major cytogenetic response. After univariate analysis of prognostic factors, a multivariate analysis selected, at 6 months, independent pretreatment factors that added to the response status in predicting subsequent outcome. The results were then applied at the 3- and 12-month periods and confirmed in the subsequent population. RESULTS: Response to IFNalpha therapy at 3, 6, and 12 months was a significant predictor of later major cytogenetic response. The presence of splenomegaly > or = 5 cm below the costal margin (BCM) or thrombocytosis > or = 700 x 10(9)/L pretreatment added significant independent prediction to response. At 6 months, patients with a partial hematologic response (PHR) or resistant disease had a less than 10% chance of achieving a later major cytogenetic response, as were those in complete hematologic response (CHR) and who had pretreatment splenomegaly and thrombocytosis. Applying the model at 3 months showed that only patients with < or = PHR and pretreatment splenomegaly or thrombocytosis at 3 months had such a low major cytogenetic response rate. Finally, at 12 months, patients with CHR still had a 15% to 25% chance of having a major cytogenetic response later if they did not have pretreatment splenomegaly and thrombocytosis. CONCLUSION: This analysis allows better selection of patients with Ph-positive CML on IFNalpha therapy for continuation of IFNalpha versus changing therapy early in the course of CML. For treatment programs that choose to change patients to other investigational therapies (eg, intensive chemotherapy and/or autologous stem-cell transplantation [SCT]), baseline outcome expectations are provided for patients continued on IFNalpha therapy, against which the results of new approaches can be compared.

Expression of the myeloperoxidase gene in acute and chronic myeloid leukemias: relationship to the expression of cell cycle-related genes.

The expression of the myeloperoxidase (MPO) gene was studied, by means of Northern blot analysis in 14 cases of acute myeloid leukemia (AML), 11 cases of chronic myeloid leukemia (CML), and 6 cases of CML blast crisis, and in HL60 cells before and after induction of terminal differentiation with retinoic acid (RA), phorbol esters (TPA), or vitamin D. The expression of a panel of cell cycle-related genes, namely C-MYC, histone H3, ornithine decarboxylase, P53, vimentin, and calcyclin, was also studied in the same cell populations. Our results indicate that: (a) MPO gene expression (steady state mRNA levels) is strictly confined to the first stages of myeloid differentiation, reaching its peak at the promyelocyte stage and becoming undetectable in mature granulocytes and monocytes; (b) cells devoid of any detectable MPO enzymatic activity such as leukemic basophils have a high content of MPO mRNA; and (c) MPO gene expression is not related to the growth activity of the cell population. Finally, our results show that the pattern of expression of growth-regulated genes in the neoplastic myeloid disorders AML, CML, and CML blast crisis is remarkably different.

Long-term follow-up results of alpha-interferon-based regimens in patients with late chronic phase chronic myelogenous leukemia.

The aim of this analysis was to evaluate the efficacy of alpha-interferon (alpha-IFN) regimens in late chronic phase (diagnosis >12 months) chronic myelogenous leukemia (CP-CML). Long-term follow-up results were evaluated in 137 patients with Philadelphia chromosome (Ph)-positive late CP-CML. The alpha-IFN programs were sequential studies with human leukocyte alpha-IFN (seven patients), recombinant alpha-IFN alone (15 patients) or with IFN-gamma (29 patients), hydroxyurea (HU) (19 patients), or low-dose cytarabine (Ara-C) (67 patients). Overall, 57% of the patients achieved complete hematological response (CHR), and 7% obtained partial hematological response. Nineteen patients (15% of the 123 evaluable patients) had a cytogenetic response which was major (Ph-positive <35%) in 10 patients (8%). A trend for better responses was observed with shorter disease duration. The median overall survival from start of therapy was 49 months, with an estimated 5-year survival rate of 41%. Some common pretreatment prognostic factors associated with response did not show statistical associations when applied in late CP-CML; however, characteristics such as smaller spleen size, and lower percentages of peripheral blood and marrow blasts and basophils were associated with better survival experience. When patients were subgrouped according to risk, no significant differences in the incidence of cytogenetic response and in survival outcomes were observed among various risk groups. This study confirms that alpha-IFN-based regimens have a modest activity in late CP-CML, and supports the need to develop investigational strategies aimed at improving patient prognosis in this phase.

Alfa-interferon in the treatment of essential thrombocythemia: clinical results and evaluation of its biological effects on the hematopoietic neoplastic clone. Italian Cooperative Group on ET.

The efficacy of alfa-interferon (alfa-IFN) in essential thrombocythemia (ET) patients has been reported by several authors. The aim of this study is to assess the magnitude of the effect of alfa-IFN on the neoplastic clone. As of December 1993, 11 ET patients received alfa-IFN at a dose of 3-6 MU/s.c./day for 6 months. Ten of 11 obtained complete hematological remission (CHR) and one achieved partial hematological remission. Megakaryocyte concentration was reduced in six cases. The spleen,which was enlarged in four patients, decreased in size in two patients. Seven of eight patients who were symptomatic at diagnosis obtained resolution of symptoms. In order to obtain indications about the structural modifications induced by alfa-IFN in ET megakaryocytes (Mks), Fourier-transform infra-red microspectroscopy analysis performed on 10 single Mks of each patient, was done in seven of 11 patients; the analysis showed a reduction of A1/A2 ratios (A1 integrated area of the band at 1080 cm(-1) due to the nucleic acids absorption; A2 integrated area of the band at 1540 cm(-1) due to proteic components absorption) in five cases, and in three of these five patients A1/A2 ratios achieved normal values. After alfa-IFN treatment we did not observe any change in the methylation pattern of DNA from the granulocyte fraction. Our results confirm the efficacy of alfa-IFN in ET patients, and the decrease of A1/A2 ratios in several patients is a demonstration of the depth of the effect of alfa-IFN on the neoplastic clone. The results of clonality studies showed the persistence of clonal hematopoiesis. Whether higher alfa-IFN dose and/or more prolonged alfa-IFN therapy may allow a restoration of polyclonal hematopoiesis remains to be determined and should be explored in future clinical trials.

All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in the chronic phase.

Since in vitro observations indicated that all-trans retinoic acid (ATRA), especially in combination with IFNalpha, can exert significant suppressive effects on Ph+ cells, we investigated the effects and the pharmacokinetic profile of ATRA in a selected cohort of patients with Ph+ chronic myeloid leukemia (CML) in chronic phase. Eighteen patients were treated with ATRA at a dose of 80 mg/m2/day (p.o.), divided into two equal doses after meals, for 7 consecutive days every other week for a maximum of 12 courses (1 course = 1 week on and 1 week off). Pharmacokinetic profiles of ATRA were evaluated during intermittent therapy on days 1 and 7 of course 1; on day 1 of course 2; on day 1 of course 6. Out of the 18 patients treated with ATRA, 11 (61%) went off study before the sixth course of treatment because of progressive hyperleukocytosis (seven cases), or thrombocytosis (one case), or refusal (three cases). Seven (39%) patients completed the first six courses (12 weeks) of treatment with ATRA and two of them (11%) maintained a white blood cell (WBC) <10 x 10[9]/l which was induced by the pretreatment with hydroxyurea. One patient completed the 12th course of ATRA maintaining WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpable. The treatment with ATRA was well tolerated and only one patient discontinued the therapy because of non-hematological side-effects. The area under the concentration-time curve (AUC) decreased significantly (P< 0.001) during the first week of therapy. By adopting an intermittent dosing regimen, 1 week on/ 1 week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs equivalent to the ones achieved on day 1 of course 1. In conclusion, our results showed that ATRA alone appeared to be unable to control the WBC expansion in the CML patients in chronic phase. Moreover, it did not induce any remarkable cytoreductive effects on the platelet count and on the hemoglobin level. The major interest of ATRA would be in combination with other therapies. If ATRA was given in combination with IFNalpha or other agents, dose reduction of these would not be planned. On the basis of the pharmacokinetic profile, ATRA should be administered intermittently rather than continuously.

Human vascular renin-angiotensin system and its functional changes in relation to different sodium intakes.

A growing body of evidence supports the existence of a tissue-based renin-angiotensin system (RAS) in the vasculature, but the functional capacity of vascular RAS was not investigated in humans. In 28 normotensive healthy control subjects, the metabolism of angiotensins through vascular tissue was investigated in normal, low, and high sodium diets by the measurement of arterial-venous gradient of endogenous angiotensin (Ang) I and Ang II in two different vascular beds (forearm and leg), combined with the study of 125I-Ang I and 125I-Ang II kinetics. In normal sodium diet subjects, forearm vascular tissue extracted 36+/-6% of 125I-Ang I and 30+/-5% of 125I-Ang II and added 14.9+/-5.1 fmol x 100 mL(-1) x min(-1) of de novo formed Ang I and 6.2+/-2.8 fmol x 100 mL(-1) x min(-1) of Ang II to antecubital venous blood. Fractional conversion of 125I-Ang I through forearm vascular tissue was about 12%. Low sodium diet increased (P<.01) plasma renin activity, whereas de novo Ang I and Ang II formation by forearm vascular tissue became undetectable. Angiotensin degradation (33+/-7% for Ang I and 30+/-7% for Ang II) was unchanged, and vascular fractional conversion of 125I-Ang I decreased from 12% to 6% (P<.01). In high sodium diet subjects, plasma renin activity decreased, and de novo Ang I and Ang II formation by forearm vascular tissue increased to 22 and 14 fmol x 100 mL(-1) x min(-1), respectively (P<.01). Angiotensin degradation did not significantly change, whereas fractional conversion of 125I-Ang I increased from 12% to 20% (P<.01). Leg vascular tissue functional activities of RAS paralleled those of forearm vascular tissue both at baseline and during different sodium intake. These results provide consistent evidence for the existence of a functional tissue-based RAS in vascular tissue of humans. The opposite changes of plasma renin activity and vascular angiotensin formation indicate that vascular RAS is independent from but related to circulating RAS.

Treatment of B-cell non-Hodgkin's lymphoma with anti CD 20 monoclonal antibody Rituximab.

Rituximab is a chimeric anti CD-20 monoclonal antibody containing human IgG1 kappa constant regions, with murine variable regions. The anti-lymphoma effects of Rituximab are probably due to complement and antibody-dependent cell-mediated cytotoxicity, and induction of apoptosis. Phase II trials have demonstrated a strong activity of rituximab alone in indolent B non-Hodgkin lymphoma, especially in patients with follicular lymphoma. The most utilized dose-schedule is 375 mg/m(2) weekly x 4. The association with chemotherapy or with interferon-alpha increases Rituximab efficacy. More recently, Rituximab have showed activity also in diffuse large cell lymphoma, mantle cell lymphoma and in other B-malignancies. Good results have also been obtained utilizing Rituximab for in vivo purging. However, we are still far from having found a definite position for Rituximab in the treatment of lymphoproliferative disorders. The aim of future studies should be to develop new strategies that will hopefully produce the most effective Rituximab-based regimens in order to find the Rituximab key position in the treatment of B-malignancies

Studies on a new series of THA analogues: effects of the aromatic residues that line the gorge of AChE.

A series of N-monoalkylsubstituted 1,2,3,4-tetrahydro-9-aminoacridines have been prepared after modelling simulation of the AChE-inhibitor complex. Molecular modelling has predicted a number of hydrophobic residues to be involved in the catalytic mechanism of this interaction between the binding sites of AChE and this series of aminoacridines. In these compounds the acridine moiety becomes sandwiched between the rings of PHE330 and TRP84. In particular, the alkyl chain shows the important role of aromatic groups as binding sites. Their in vitro inhibitory properties (enzyme from Electrophorus electricus) confirm the aromatic groups as a general and significant characteristic of the mechanism of AChE inhibition.

The role of interferon-alpha in the treatment of myeloproliferative disorders.

The interferons are cytokines with a wide array of biological properties. In hematological malignancies the most used IFN class is -alpha; it has been used for thirty years but the mode of action is still not absolutely clear. Nevertheless, the benefits of IFN-alpha for the treatment of CMD have been described in particular for CML and less for PV, ET and MMM. IFN-alpha is presently considered the golden standard of therapy for CML patients not eligible for SCT; the antileukemic effect has been well documented by hematological and cytogenetic response. The survival advantage for IFN treated patients is remarkable in comparison with patients treated with conventional chemotherapy. Recently, the combination IFN-alpha plus Ara-C has demonstrated to increase the rate of major cytogenetic response and to prolong survival. To date, there is not a generally accepted treatment for ET, PV and MMM, which can reduce the risk of thromboembolism and/or hemorragic events. In several subsets of ET and PV patients, IFN-alpha can be considered as first line therapy. IFN-alpha is usually associated with the development of early and later side effects, that reduce the enthusiasm for its use. In the future PEG-IFN-alpha would improve the quality of life of IFN-treated CMD patients.

Persistent polyclonal B lymphocytosis: morphological, immunological, cytogenetic and molecular analysis of an Italian case.

We describe a case of persistent polyclonal B-cell lymphocytosis (PPBL) studied by morphological, immunological, cytogenetic and molecular analysis. PPBL is a rare lymphoproliferative disorder with an unclear natural history. Although a few cases of malignancies are observed during PPBL, this disorder is usually considered to be an indolent syndrome. A longer follow-up in a larger number of patients is needed in order to clarify the natural history of PPBL and its potential to transform into a malignancy. As PPBL is a rare disease, establishing an international PPBL registry could be the most effective way to understand the natural history of this disease and to discover its etiologic factors.

Age-related and vasomotor stimuli-induced changes in renal vascular resistance detected by Doppler ultrasound.

Indirect measurement of renal vascular resistance by duplex Doppler waveform analysis was evaluated in relation to aging and some pathophysiological conditions. Baseline renal resistive index (RRI) (peak systolic frequency shift - lowest diastolic frequency shift/peak systolic frequency shift) was measured in healthy controls aged 20 to 85 years by analyzing the blood flow velocity waveform of interlobar arteries. RRI changes induced by sympathetic activation (cold pressor test and handgrip test) or by fluid load were evaluated. Both repeatability and reproducibility were very good, as the intra and interoperator variations were all less than their reproducibility coefficients. RRI showed a significant increase with aging (ANOVA P < .001), particularly evident in subjects older than 50 years. Both the cold pressor test and handgrip test induced in all the subjects (n = 16) a significant increase in RRI (P < .001), from 0.59 +/- 0.04 to 0.69 +/- 0.04 (12 +/- 6%) for the cold pressor test and from 0.57 +/- 0.03 to 0.66 +/- 0.03 (15 +/- 2%) for the handgrip test. In eight subjects intravenous fluid load (0.25 mL/kg/min of 0.9% NaCl for 120 min) caused a significant decrease in RRI (P < .001), from 0.62 +/- 0.02 to 0.53 +/- 0.01 (17 +/- 2%), which was inversely related to mean blood pressure rise (r = 0.71, P < .001). These data show that pulsed wave Doppler analysis is an accurate method for an indirect evaluation of changes in renal vascular resistance induced by common vasomotor stimuli.

Primary systemic anaplastic large-cell lymphoma (CD30+): advances in biology and current therapeutic approaches.

In 1985, Stein et al demonstrated the expression of the lymphoid activation antigen CD30/Ki by neoplastic cells. Fifteen years after the first description, anaplastic large-cell lymphomas (ALCL) are now thought to be a heterogeneous group in terms of their clinical, morphologic, phenotypic, cytogenetic, and molecular biology features. However, on the basis of a specific genetic anomaly and expression of a chimeric nucleophosmin anaplastic lymphoma kinase (NPM-ALK) protein and its variants, a distinct clinicopathologic entity defined as "ALK-positive lymphoma" or "ALKoma" can be recognized. Based on molecular and clinical criteria, 3 entities of primary ALCL can be identified: primary systemic ALK positive, primary systemic ALK negative, and primary cutaneous ALCL. This review focuses on advances in the knowledge of primary systemic ALCL biology and discusses therapeutic approaches based on ALK expression. The presence of this protein appears to be an important prognostic factor and, combined with an age-adjusted International Prognostic Index, could allow researchers to design more specific clinical trials aimed at finding new, more efficacious and less toxic treatments.

Detection of PML-RAR alpha fusion transcript in Ph positive leukemia with acute promyelocytic phenotype lacking the t(15;17) cytogenetic abnormality.

A 39-year-old woman was diagnosed with acute promyelocytic leukemia (APL) with disseminated intravascular coagulation syndrome. The hematologic examination showed a morphologic, cytochemical, and immunophenotypic picture typical of an APL, with a marked leukocytosis and a mixed population of hypergranular and microgranular promyelocytes. The cytogenetic analysis showed a 46,XX,t(9;22) karyotype, without any alterations of chromosomes 15 and 17. The t(15;17) translocation was not evident in FISH experiments, while a molecular analysis revealed the presence of a PML-RAR alpha chimera.

The role of alpha-interferon in essential thrombocythaemia, polycythaemia vera and myelofibrosis with myeloid metaplasia (MMM): a concise update.

Treatment of essential thrombocythaemia (ET), polycythaemia vera (PV), and myelofibrosis with myeloid metaplasia (MMM) patients is frequently a difficult issue. To date, there is no generally accepted treatment for these diseases which can reduce the risk of thromboembolism and/or haemorrhagic events, avoid any increase in the frequency of secondary myelofibrosis and terminal blast transformation and decrease the reticulin content in the bone marrow of MMM patients. The most frequently used myelosuppressive agent is hydroxyurea (HU), but widespread application has failed to demonstrate that is not leukaemogenic. In patients with MMM, conflicting results have been obtained following alpha-IFN treatment. Haematological responses have been seen in 50% of the patients. Usually the patients showing good responses had a hyperproliferative type of disease. In only one case was a reduction of reticulin content of the bone marrow observed. Thus, these findings do not indicate alpha-IFN as a first-line therapy. On the other hand, the results of several reports in ET and PV patients have shown a reduction in the abnormal proliferation of megakaryocytes and erythroid elements, following alpha-IFN treatment. A reduction in spleen size has also frequently been seen. Together with the improvement of haematological parameters, clinical symptoms have also responded positively. Long term control of these diseases can be obtained with a well-tolerated low dose of alpha-IFN. However, PV and ET are not usually characterized by cytogenetic abnormalities, making it very difficult to demonstrate the disappearance of clonal haemopoiesis following alpha-IFN therapy, even if this does occasionally occur, as evident from the two cytogenetic convertions described in the literature. As compared to myelosuppressive drugs or phlebotomy, alpha-IFN thus represents an attractive new treatment, able to exert a fundamental influence on these diseases, presumably without any untoward leukaemogenic or gonadotoxic activity.