Indolent systemic mastocytosis treated with narrow-band UVB phototherapy: study of five cases.

BACKGROUND: Mastocytoses represent a heterogeneous group of stem cell disorders marked by an abnormal hyperplasia and accumulation of mast cells in one or more tissues, including bone marrow, gastrointestinal tract, liver, spleen, lymph nodes and skin. Indolent systemic mastocytosis (ISM) is characterized by red-brownish and pruriginous maculopapular lesions, a bone marrow infiltration without functional impairment and an indolent clinical course with a good prognosis. In particular, the most common cutaneous symptoms are urticarial rash and mild-to-high pruritus. OBJECTIVES: This study analyses the clinical outcome of patients affected by ISM with prevalent pruriginous cutaneous symptoms and a scarce response to anti-histamines treated using narrowband ultraviolet B (NB-UVB) phototherapy. METHODS: Narrowband ultraviolet B phototherapy was administered in a UV-irradiation cabin equipped with fluorescent UVB lamps with a peak emission at 311-313 nm. The perception of pruritus severity was assessed using the Visual Analogue Scale (VAS) before starting the treatment and at each control. RESULTS: A complete remission of the cutaneous lesions and pruritus was documented in all patients after a median of 40.3 UV treatments and a median cumulative dose of 51.4 J/cm(2), with a lasting remission over a 6-month follow-up. The median VAS score at the beginning of the treatment was 86.6 (SD=6.64), whereas it decreased to 6.66 (SD=3.75) after 3 months of therapy. CONCLUSIONS: Our work provides evidence that NB-UVB phototherapy is useful for the treatment of the cutaneous symptoms and pruritus in ISM.

WT1 transcript amount discriminates secondary or reactive eosinophilia from idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia.

Idiopathic hypereosinophilic syndromes (HES) comprise a spectrum of indolent to aggressive diseases characterized by persistent hypereosinophilia. Hypereosinophilia can result from the presence of a defect in the hematopoietic stem cell giving rise to eosinophilia, it can be present in many myeloproliferative disorders or alternatively it may be a reactive form, secondary to many clinical conditions. The hybrid gene FIP1L1-PDGRFalpha was identified in a subset of patients presenting with HES or chronic eosinophilic leukemia (CEL). In spite of this, the majority of HES patients do not present detectable molecular lesions and for many of them the diagnosis is based on exclusion criteria and sometimes it remains doubt. In this study we explored the possibility to distinguish between HES/CEL and reactive hypereosinophilia based on WT1 transcript amount. For this purpose, 312 patients with hypereosinophilia were characterized at the molecular and cytogenetic level and analyzed for WT1 expression at diagnosis and during follow-up. This study clearly demonstrates that WT1 quantitative assessment allows to discriminate between HES/CEL and reactive eosinophilia and represents a useful tool for disease monitoring especially in the patients lacking a marker of clonality.

SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis.

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

Clinical and cytologic characteristics of blastic phase in Ph-positive chronic myeloid leukemia treated with alpha-interferon.

We report 72 blastic crises (BC), occurring in 238 Ph+ chronic myeloid leukemia (CML) patients treated in chronic phase (CP) with alpha-interferon (IFN) for a median time of 51 months (range 7-96). The 238 patients were grouped by Sokal's risk at diagnosis in low- (LR), intermediate- (IR) and high-risk (HR), and by CP treatment. Group 1: 160 patients (57% LR, 31% IR, 12% HR) given IFN alone in early CP. Group 2: 31 patients (65% LR, 32% IR, 3% HR) given IFN alone in late CP. Group 3: 23 patients (78% LR, 22% IR) given IFN before and after autologous stem cell transplantation (ASCT). Group 4: 24 patients (83% LR, 17% IR) given IFN after ASCT. Of the 72 BC, 52 (72%) were myeloid (My), and 20 (28%) lymphoid (Ly). Overall BC incidence was similar in all CP treatment groups, although with a prevalence of Ly BC in groups 3 + 4 vs groups 1 + 2, (p = NS); the incidence of BC was higher in HR patients (P = NS), but on the whole it was lower than expected on the basis of historical controls. Lymphoid BC was more frequent in LR than in IR + HR patients (P < 0.05), and was more frequent in responders to IFN, than in non-responders (P < 0.05). In conclusion, a subset of patients with low risk at diagnosis, better response to IFN and proneness to evolve into Ly BC can be identified. The role played by IFN in this context remains to be defined.

Evolving modalities of treatment with interferon alfa-2b for Ph1-positive chronic myelogenous leukaemia.

We have administered interferon alfa-2b, alone or in combination with chemotherapy, to 126 Ph1-positive chronic myelogenous leukaemia patients. Of 71 early chronic phase (CP) patients (less than 12 months from diagnosis), 41 (58%) obtained a complete haematological response (CHR). Daily interferon was more effective than intermittent administration. In previously untreated patients, the response was significantly influenced by risk status at diagnosis. Thirty-four out of 71 (48%) patients improved cytogenetically, the median of Ph1+ mitoses declining from 100% to 66% with complete Ph1-suppression in one case. Of 46 late CP patients (greater than 12 months from diagnosis), 32 (70%) achieved CHR with interferon alone or combined with chemotherapy. All 10 patients with disease well controlled by chemotherapy obtained stable CHR with interferon alone. Of 36 partial responders to conventional chemotherapy, 22 (61%) obtained CHR on interferon plus low-dose hydroxyurea. Ph1 mosaicism was reached by 16 (35%) late CP patients (median Ph1+ cells 75%). Of nine accelerated phase patients on interferon plus chemotherapy, one attained CHR, and two responded partially. At a median follow up of 36 months, of 41 CHR patients in early CP, 15 are controlled on interferon, 12 have had autologous bone marrow transplantation (BMT), and two allogeneic BMT. Blastic transformation (BT) has occurred in eight of 41 CHR patients (19%) versus 17 of 30 (57%) non-responders and partial responders to interferon. At a median follow up of 22 months, of 32 late CP patients obtaining CHR, 26 remain on interferon, one had allogeneic BMT, one had autologous BMT, and one developed BT (versus five out of 14 with less than CHR). These studies confirm the haematological and cytogenetic efficacy of interferon in CML and indicate that the disease status at the start of treatment is critical in determining the success of therapy.

Hydroxyurea and 6-mercaptopurine in the treatment of chronic granulocytic leukemia.

From 1975 to 1981, 92 patients with newly diagnosed Ph'-positive chronic granulocytic leukemia entered two consecutive studies. The initial trial (Study I, 1975-1978) tested the efficacy of hydroxyurea (HU) as single agent in 45 consecutive patients. In an effort to improve results obtained with HU alone, from 1978 to 1981, 47 new patients entered a second trial (Study II), which consisted of a continuous treatment with a combination of HU and 6-mercaptopurine (6-MP), at doses adjusted so as to maintain the leukocyte counts between 4 and 12 X 10(9)/L. The aim of this second study was to prolong the duration of chronic phase (CP) by the addition of 6-MP to HU and by a stricter continuous control of the size of the total granulocytic mass (TGM). Both regimens were well tolerated. Median duration of CP was 43 months in Study I and 41 months in Study II. Median survival was 51.5 months and 45 months respectively. These data indicate that neither the addition of 6-MP to HU alone, nor the effort to keep a smaller TGM, play a substantial role in postponement of blastic transformation in CGL.

Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients.

Imatinib mesylate (STI571), a specific Bcr-Abl inhibitor, has shown a potent antileukemic activity in clinical studies of chronic myeloid leukemia (CML) patients. Early prediction of response to imatinib cannot be anticipated. We used a standardized quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR) for BCR-ABL transcripts on 191 out of 200 late-chronic phase CML patients enrolled in a phase II clinical trial with imatinib 400 mg/day. Bone marrow samples were collected before treatment, after 12, 20 and at the end of study treatment (52 weeks) while peripheral blood samples were obtained after 2, 3, 6, 10, 14, 20 and 52 weeks of therapy. The amount of BCR-ABL transcript was expressed as the ratio of BCR-ABL to beta2-microglobulin (beta2M). We show that, following initiation of imatinib, the early BCR-ABL level trends in both bone marrow and peripheral blood samples made it possible to predict the subsequent cytogenetic outcome and response. We propose this method as the method of choice for monitoring patients on imatinib therapy. QRT-PCR studies may be able to identify degrees of molecular response that predict both complete cytogenetic response and long term stability, as well as patterns of response that provide an early indication of relapse and imatinib resistance.

Efficacy trial of pipobroman in essential thrombocythemia: a study of 24 patients.

Pipobroman (PB) was tested in a prospective efficacy trial in 24 previously untreated patients with essential thrombocythemia and followed up for a median of 47 months (range, 12-120). Plateletpheresis was not done. Hematologic complete response (platelet count less than 450 X 10(9)/L for 3 consecutive months) was achieved in 92% of the cases, in a median time of 12 weeks (range, 2-22). However, continuous low-dose maintenance therapy with PB was necessary to avoid recurrences of the disease. Major thrombocythemia-related complications were observed in 20% of the cases; the 5-year overall and complication-free survival rates were 92% and 75%, respectively. No acute or chronic toxicity was observed; no drug-induced amenorrhea and subsequent acute leukemia occurred. PB does appear to be efficacious in essential thrombocythemia; however, the evaluation of its leukemogenic risk will await further experience.

Muco-cutaneous changes during long-term therapy with hydroxyurea in chronic myeloid leukaemia.

Hydroxyurea is an antimetabolite agent used in the treatment of myeloproliferative disorders and sickle cell anaemia. Although hydroxyurea is relatively well tolerated, adverse effects often involve skin and mucous membrane during long-term therapy. A group of 510 patients affected by chronic myeloid leukaemia from 1977 to 1998 has been considered. Only 158 patients were treated with hydroxyurea and fulfilled inclusion/exclusion criteria of this study. A spectrum of severe cutaneous and mucosal changes (inflammatory and neoplastic) was seen in about 13% of patients (21 patients out of 158) and was studied in detail. Cutaneous and mucosal atrophy were observed in all 21 patients. Skin atrophy was often characterized by numerous telangiectases, especially on legs and on sun-exposed sites (16/21). Cutaneous, mucosal and nail hyperpigmentation was evident, albeit with variable extent, in 10 of the 21 patients. Severe stomatitis and glossitis with flattening of papillae were another common finding. Five patients, who received a particularly long treatment with hydroxyurea, developed squamous-cell neoplasms on sun-exposed sites (both squamous-cell carcinomas and keratoacanthomas). Acral changes were characteristic and constant, including acral erythema (21/21), dermatomyositis-like changes on the dorsa of hands (7/21), ulcers localized on acral areas of legs, on genitalia and oral mucosae (20/21). The frequency and the variety of these muco-cutaneous changes are reported and the mechanisms by which hydroxyurea may induce this muco-cutaneous syndrome-like group of changes, are proposed.

Chronic myelogenous leukemia and exposure to ionizing radiation--a retrospective study of 443 patients.

Exposure to ionizing radiations (Rx) has been implicated as a causative factor of chronic myelogenous leukemia (CML). We performed a retrospective study of 443 consecutive CML patients, looking for a history of significant exposure to Rx, and evaluated the clinical and hematological characteristics in order to find any difference between radiation-related CML patients and those with de novo CML. We identified 406 patients without known exposure to mutagens (group I) and 37 patients with prior significant exposure to Rx (group II). In comparison to patients of group I, those of group II showed particular clinical and hematological features: significantly lower incidence of bulky splenomegaly (p < 0.05) and hyperleukocytosis (WBC > 100 x 10(9)/l; p < 0.05); significantly higher incidence of anemia (Hb < 10 g/dl; p < 0.01). Patients with radiation-related CML had a significantly better survival than those with de novo CML (median survival 61 months vs 42 months; p < 0.05). In conclusion, this study of a large cohort of CML patients indicates that the subgroup of patients with a history of significant exposure to ionizing radiation has particular clinical and hematological features at onset (lower tumor burden, higher frequency of anemia) and a better survival.

Combination chemotherapy with alternating MOPP-ABVD in advanced Hodgkin's disease.

Fifty untreated adult patients with advanced Hodgkin's disease (HD) were given alternating MOPP-ABVD chemotherapy in a prospective eight-cycle program. This series included 33 patients with stage II-III disease and bulky lymphoma and/or B symptoms, and 17 patients with stage IV disease. Nodular sclerosis amounted to 52%, and systemic symptoms were present in 70% of patients. The median follow-up was 50 months from the initiation of therapy (range: 36-78 months). The complete remission rate was 80%, with no differences according to the main patient characteristics before therapy, except for bulky (65%) versus non bulky (88%) disease (p = 0.05). The actuarial 4-year overall (OS) and relapse-free survival were 78% and 71%, respectively. No clear-cut pretreatment characteristics showed an influence on survival, although there was a trend favoring non bulky versus bulky disease (p = 0.08). The actuarial 4-year OS of complete responders was 92%; all 13 patients who died had evidence of HD; the cause of death was disease progression and organ failure in 11 cases, acute myelomonocytic and opportunistic infections with AIDS in the other two cases, respectively. No severe pancytopenia episodes or life-threatening complications occurred during therapy; gastrointestinal and neurological toxicity were mild and no patient refused to complete the treatment. Menstruating women were given estrogen-progesterone combinations, and all continued to have regular menses throughout chemotherapy and afterwards; a young woman had a normal pregnancy resulting in a normal live birth. Only one case of stable amenorrhea was observed. Oligospermia after chemotherapy was seen in seven of 10 tested males, and azoospermia in one case.(ABSTRACT TRUNCATED AT 250 WORDS)

Extramedullary disease in Ph'-positive chronic myelogenous leukemia: frequency, clinical features and prognostic significance.

Of 349 consecutive patients with Philadelphia-positive chronic myelogenous leukemia (Ph' + CML), 14 (4%) developed extramedullary disease (EMD) during their illness. The sites of EMD were: bone (57%), lymph nodes (29%), skin and soft tissues (21%), central nervous system (14%). The median time from diagnosis of CML to the occurrence of EMD was 48 months. At the time of diagnosis of EMD, 7 patients were hematologically in chronic phase, while 7 showed features of accelerated or blastic CML. For patients lacking medullary blastic transformation criteria, the median time from diagnosis of EMD to blast crisis was 4 months. The overall median survival from development of EMD was 5 months. In conclusion, EMD may occur during the course of CML either in the context of a frank blastic transformation, or as an isolated tumoral infiltrate which heralds an impending blast crisis. Its recognition requires a prompt change to acute-phase chemotherapy.

Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients.

BACKGROUND AND OBJECTIVES: Polycythemia vera (PV) is a myeloproliferative disorder, characterized by the expansion of the red cell mass. Our purpose was to evaluate the efficacy of pipobroman (PB) in the long-term control of PV and to assess early and late events. DESIGN AND METHODS: From June 1975 to December 1997, 163 untreated patients with PV (median age 57 years, range 30-82) were treated with PB in a single Institute for a median follow-up of 120 months. The diagnosis was made according to the Polycythemia Vera Study Group criteria. PB was given at the dose of 1 mg/kg/day until hematologic response (hematocrit < 45% and platelets < 400x109/L) and of 0.3-0.6 mg/kg/day as maintenance therapy. RESULTS: Hematologic remission was achieved in 94% of patients in a median time of 13 weeks (range 6-48). Median overall survival was 215 months, with a standardized mortality ratio of 1.7. The cumulative risk of death was 11%, 22%, and 26% at 7, 10, and 12 years, respectively. The incidence of thrombotic events was 18.4x105 person-year and the cumulative risk was 6%, 11%, 16%, and 20% at 3, 7, 10, and 12 years respectively. Acute leukemia occurred in 11 patients, myelofibrosis in 7, and solid tumors in 11. The 10-year cumulative risk of leukemia, myelofibrosis, and solid tumors was 5%, 4%, and 8%, respectively. In the logistic analysis age over 65 (p = 0.0001) and thrombotic events at diagnosis (p = 0.001) were significantly correlated with a higher risk of death. Female gender (p = 0.02) and age over 65 (p = 0.01) significantly influenced the occurrence of thrombotic complications. Age was the only significant risk factor for leukemia (p = 0.04) and for solid tumors (p = 0.03), while the duration of PB treatment did not influence these risks. No significant risk factor was demonstrated for myelofibrosis. INTERPRETATION AND CONCLUSIONS: This study demonstrates in a large series of patients, observed for a long period, that pipobroman is effective in the long-term control of PV. The risk of early thrombotic complications at 3 years is 6% and the 10-year risk of acute leukemia, late myelofibrosis, and solid tumors is 5%, 4%, and 8%, respectively. The duration of pipobroman treatment did not correlate with these events.

Bone marrow and blood involvement by non-Hodgkin's lymphoma: a study of clinicopathologic correlations and prognostic significance in relationship to the Working Formulation.

In a series of 172 patients with non-Hodgkin's lymphoma (NHL) classified according to the Working Formulation (WF) the overall incidence of bone marrow infiltration (BM+) at diagnosis was 39%: 59% for low-grade (LGML), 30% for intermediate-grade (IGML), and 25% for high-grade malignant lymphomas (HGML). The features most significantly correlated with the presence of BM+ were a low grade of histological malignancy, the degree of splenomegaly and high values of LDH, while those correlated with the extent of BM+ were a non-focal pattern of BM disease, the presence of blood involvement at diagnosis, and the degree of BM fibrosis. Blood involvement was detected at diagnosis in 13% of patients, and a further 16% developed a leukemic phase during the course of the disease. Blood involvement correlated significantly with splenomegaly, bulky disease, advanced clinical stage, and extent of BM+. The presence of BM infiltration 'per se' at diagnosis did not significantly affect prognosis. However, the extent of BM disease was correlated with a poorer outcome in IGML and HGML patients. Regarding peripheral blood involvement, in LGML patients only late leukemic conversions were significantly associated with a worse prognosis. In patients with IGML and HGML, either initial or subsequent blood involvement was correlated with significantly poorer outcome.

Treatment of terminal-phase chronic myelogenous leukemia with intermediate-dose cytarabine and hydroxyurea.

We used intermediate doses of Ara-C (IDAra-C) in the treatment of 15 patients with chronic myelogenous leukemia (CML) in blast crisis and, combined with hydroxyurea, in 20 CML patients in accelerated phase. Patients with blastic CML received intensive 5-day courses of IDAra-C 600 mg/m2 every 12 h as a 2-h infusion. Of 15 patients, three achieved complete response (CR) and three partial response (PR), for an overall response rate of 40 per cent. All patients developed severe leukopenia and thrombocytopenia, and two died in hypoplasia. Except nausea and vomiting requiring medication, other nonhematologic toxicities were uncommon. Median response duration was 4 months (range 1 to 7 months). Survival was 5 months for responders and 1.5 months for nonresponders. Patients with CML in accelerated phase were treated with two-day courses of IDAra-C 600 mg/m2 every 12 h by 2-h infusion, every two-three weeks. Daily hydroxyurea 1-1.5 g/day was administered between courses. Of 20 patients, 15 (75 per cent) achieved a good PR with rapid improvement of the symptoms of disease acceleration. The median duration of response was 11 months (range 3 to 38 months); duration was over 24 months in five patients. The median survival from the start of IDAra-C was 13 months for responders and 3.5 months for nonresponders. We conclude that IDAra-C is an effective approach for CML in terminal phase. Its use in 5-day induction courses for blast crisis CML has a response rate comparable to that achieved with high-dose Ara-C. In patients in accelerated phase, the combination of short courses of IDAra-C with hydroxyurea is a well-tolerated treatment able to improve substantially the clinical and hematologic symptoms of disease progression.

Mitoxantrone and etoposide: an effective regimen for refractory or relapsed acute myelogenous leukemia.

23 adult patients with refractory or relapsed acute myelogenous leukemia (AML) received salvage chemotherapy with mitoxantrone and etoposide. The regimen consisted of mitoxantrone, 10 mg/m2/d by 30-min infusion, and etoposide 100 mg/m2/d by 30-min infusion, given 12 h apart for 5 consecutive d. Of 23 patients treated, 13 met the criteria for highly refractory disease (6 primary resistant; 4 with early relapse during maintenance; 3 relapsed and refractory to reinduction). 10 patients had relapsed off-therapy more than 6 months after achieving first CR. Overall, 14 patients (61%) achieved a complete remission (CR): 6/13 (46%) with refractory AML, and 8/10 (80%) with relapsed AML. 2 patients had a partial remission, 2 died in aplasia, and 5 were nonresponders. In responding patients, the median time for recovery of granulocyte count was 27 d. The most important nonhematologic side effect was oral mucositis, which was severe in 35% of cases. No signs of cardiac toxicity were observed. The median CR duration was 5 months (range, 2 to 12+ months). The combination of mitoxantrone and etoposide appears a highly effective and relatively well tolerated salvage regimen for refractory and relapsed AML. Its incorporation into first-line induction and consolidation programs for newly diagnosed AML patients should be considered.