Successful mobilization of Ph-negative blood stem cells with intensive chemotherapy + G-CSF in patients with chronic myelogenous leukemia in first chronic phase.

The aim of the study was to investigate the feasibility of mobilizing Philadelphia chromosome negative (Ph-) blood stem cells (BSC) with intensive chemotherapy and lenograstim (G-CSF) in patients with CML in first chronic phase (CP1). During 1994-1999 12 centers included 37 patients <56 years. All patients received 6 months' IFN, stopping at median 36 (1-290) days prior to the mobilization chemotherapy. All received one cycle of daunorubicin 50 mg/m2 and 1 hour infusion on days 1-3, and cytarabine (ara-C) 200 mg/m2 24 hours' i.v. infusion on days 1-7 (DA) followed by G-CSF 526 microg s.c. once daily from day 8 after the start of chemotherapy. Leukaphereses were initiated when the number of CD 34+ cells was >5/microl blood. Patients mobilizing poorly could receive a 4-day cycle of chemotherapy with mitoxantrone 12 mg/m2/day and 1 hour i.v infusion, etoposide 100 mg/m2/day and 1 hour i.v. infusion and ara-C 1 g/m2/twice a day with 2 hours' i.v infusion (MEA) or a second DA, followed by G-CSF 526 microg s.c once daily from day 8 after the start of chemotherapy. Twenty-seven patients received one cycle of chemotherapy and G-CSF, whereas 10 were mobilized twice. Twenty-three patients (62%) were successfully (MNC >3.5 x 10(8)/kg, CFU-GM >1.0 x 10(4)/kg, CD34+ cells >2.0 x 10(6)/kg and no Ph+ cells in the apheresis product) [n = 16] or partially successfully (as defined above but 1-34% Ph+ cells in the apheresis product) [n = 7] mobilized. There was no mortality during the mobilization procedure. Twenty-one/23 patients subsequently underwent auto-SCT. The time with PMN <0.5 x 10(9)/l was 10 (range 7-49) and with platelets <20 x 10(9)/l was also 10 (2-173) days. There was no transplant related mortality. The estimated 5-year overall survival after auto-SCT was 68% (95% CI 47 - 90%), with a median follow-up time of 5.2 years.We conclude that in a significant proportion of patients with CML in CP 1, intensive chemotherapy combined with G-CSF mobilizes Ph- BSC sufficient for use in auto-SCT.

T-cell-rich B-cell lymphoma - diagnostic and therapeutic aspects.

BACKGROUND: Morphologically, T-cell-rich B-cell lymphoma (TCRB-NHL) may be indistinguishable from Hodgkin's disease (HD). Immunophenotyping may be helpful in the separation of these entities. TCRB-NHL is occasionally misdiagnosed and treated as HD. However, information is limited regarding clinical characteristics and outcome of this patient population. Furthermore, knowledge concerning any association with Epstein-Barr virus (EBV) in TCRB-NHL, as well as the immunophenotype of reactive T-cells and the expression of T-cell intracellular antigen-1 (TIA-1), granzyme B (GrB) and the CD3-zeta-chain is limited. PATIENTS AND METHODS: We have re-evaluated 251 tumour biopsies from patients aged > or =15 years with HD diagnosed 1985-1994. Reclassification from HD to TCRB-NHL was done in 12 cases (5%). Six TCRB-NHL patients initially diagnosed and treated as B-NHL were also included. All TCRB-NHL biopsies were analysed for latent membrane protein 1 (LMP-1), CD4, CD8, CD56, CD57, TIA-1, GrB and CD3-zeta-chain. RESULTS: Twelve cases of TCRB-NHL were initially subclassified as HD (lymphocyte predominance 5, nodular sclerosis 3, and mixed cellularity 4). Of these 12 TCRB-NHL patients, 6 were given radiotherapy alone, 5 MOPP/ABVD or similar combination chemotherapy, and one patient combined modality treatment. Male sex (p<0.05) and inguinal involvement (p<0.001) were significantly more frequent when TCRB-NHL patients receiving HD treatment (n=12) were compared with the remaining patients with confirmed (conf) HD, while no significant differences were seen with regard to stage, bone marrow infiltration, splenomegaly or cause-specific survival. Similar results were achieved when all TCRB-NHL patients (n=18) were compared to conf HD patients. Lymphoma cells in three samples stained positively for LMP-1. A decreased expression of CD3-zeta-chain was seen in 9/14 tumour biopsies. CONCLUSION: Immunohistochemistry makes it possible to identify cases of TCRB-NHL that are morphologically difficult to distinguish from HD. The outcome of TCRB-NHL patients treated as having HD was comparable with that of the remaining HD population.

A prospective comparison of fine-needle aspiration cytology and histopathology in the diagnosis and classification of lymphomas.

INTRODUCTION: Surgical biopsy examination is the gold standard for lymphoma diagnostics. However, fine-needle aspiration cytology (FNAC) offers several advantages in that it is quick, inexpensive, and the aspiration procedure has very few complications. This prospective study compares the diagnostic outcome between FNAC and surgical biopsy. MATERIALS AND METHODS: A total of 103 patients (>15 years) with lymphadenopathy and accessible lymph nodes underwent both diagnostic procedures. Immunophenotyping was performed on both FNAC and histopathological specimens. The updated KIEL classification was used for primary diagnosis and the WHO classification for reclassification. RESULTS: FNAC- and histopathology-based diagnoses were concordant in 76 patients. In 10 patients, there was a major diagnostic discordance: four differed with regard to degree of malignancy (low- versus high-grade NHL), three lymphoma versus reactive changes, and three regarding Hodgkin's lymphoma versus anaplastic large cell lymphoma. In 10 patients there was some (minor) discordance regarding subclassification: in eight patients the results of immunophenotyping differed, in two cases there were discrepancies in the cell type classification. In the remaining seven cases, there were diagnostic difficulties due to an insufficient sample. two serious adverse events occurred following surgical biopsy. CONCLUSIONS: FNAC is an accurate method in the diagnosis of lymphomas when the cytologic diagnosis is corroborated by immunophenotyping. However, an increasing use of FNAC for primary diagnosis and classification of lymphomas may result in a loss of archival tissue for complementary analyses, reclassification, and research purposes. In addition, some of the lymphoma entities are impossible to diagnose with use of the FNAC technique.

Response to splenectomy is durable after a certain point in time in adult patients with chronic immune thrombocytopenic purpura.

Splenectomy may lead to a good response in 60-80% of adult patients with corticosteroid refractory idiopathic thrombocytopenic purpura (ITP) but, the long-term response to splenectomy still remains less well defined. We assessed the long-term efficacy and safety of splenectomy in adult patients with chronic ITP. A cohort of 59 splenectomised ITP patients (M/F = 25/34; median age 39 yr; range 14-75) were followed up for a median of 18 yr (range 2-32). No life-threatening surgical complications were observed. The overall response rate was 78% with 59% complete remission (CR) and 19% partial remission (PR). CR and PR patients were younger than non-responding patients at time of diagnosis (median age: 36 yr vs 48 yr, P = 0.03) and at splenectomy (median age: 38 yr vs 51 yr, P = 0.02). Among the 46 responding patients, eventually 17 had relapse. No disease progression occurred after 12.1 and 7.3 yr for patients in CR or PR, respectively. One case of fatal septicaemia was recorded. We conclude that splenectomy is an effective and safe treatment in adult patients with chronic ITP failing to respond to corticosteroid treatment and importantly, our findings support the view that response to splenectomy is durable after a certain point in time.

Intensive treatment and stem cell transplantation in chronic myelogenous leukemia: long-term follow-up.

In the present study we combined interferon (IFN) and hydroxyurea (HU) treatment, intensive chemotherapy and autologous stem cell transplantation (SCT) in newly diagnosed chronic myelogenous leukemia patients aged below 56 years, not eligible for allogeneic SCT. Patients who had an HLA-identical sibling donor and no contraindication went for an allogeneic SCT (related donor, RD). After diagnosis, patients not allotransplanted received HU and IFN to keep WBC and platelet counts low. After 6 months patients with Ph-positive cells still present in the bone marrow received 1-3 courses of intensive chemotherapy. Those who became Ph-negative after IFN + HU or after 1-3 chemotherapy courses underwent autologous SCT. Some patients with poor cytogenetic response were allotransplanted with an unrelated donor (URD). IFN + HU reduced the percentage of Ph-positive metaphases in 56% of patients, and 1 patient became Ph-negative. After one or two intensive cytotherapies 86 and 88% had a Ph reduction, and 34 and 40% became Ph-negative, respectively. In patients receiving a third intensive chemotherapy 92% achieved a Ph reduction and 8% became Ph-negative. The median survival after auto-SCT (n = 46) was 7.5 years. The chance of remaining Ph-negative for up to 10 years after autologous SCT was around 20%. The overall survival for allo-SCT RD (n = 91) and URD (n = 28) was almost the same, i.e. approximately 60% at 10 years. The median survival for all 251 patients registered was 8 years (historical controls 3.5 years). The role of the treatment schedule presented in the imatinib era is discussed.

Hodgkin's lymphoma in the elderly with special reference to type and intensity of chemotherapy in relation to prognosis.

BACKGROUND AND OBJECTIVES: In general, elderly patients with Hodgkin's lymphoma (HL) have a less favorable prognosis than do younger ones. Inadequate therapy, often due to decreased tolerance to treatment, contributes to the poor outcome. This study was undertaken to evaluate potential clinical factors of importance for prognosis with special reference to relative dose intensity (RDI) of chemotherapy (CT). DESIGN AND METHODS: Eighty-eight consecutive elderly (>60 years) HL patients diagnosed between 1973-1994 who received up-front CT+/-radiotherapy (RT) were included (median age 72 years, range 60-92; median follow-up time 78 months, range 49-206). The calculations of RDI of CT were based on Hryniuk's model. RESULTS: The 5-year overall (OS) and cause-specific (CSS) survival was 39% and 51%, respectively, in patients who received CT+/-RT. Nine of the 14 patients who only received 1 cycle of CT died within 6 months from diagnosis without achieving complete remission (CR). However, the remaining 5 patients in this group survived 14-97+ months. Patients with a RDI >65% had a significantly better OS (p=0.029) and CSS (p=0.024) than those with a RDI 65%. Patients who received ABVD-based CT with a RDI >65% had a significantly better OS (p=0.0011) than those who were treated with ABVD-based CT with a RDI 65%, or MOPP-like therapy, irrespective of received RDI. INTERPRETATION AND CONCLUSIONS: Prognosis remains heterogeneous and the significance of established prognostic factors is limited in elderly HL patients. Patients who received a low RDI of CT and those receiving non-ABVD-based treatment fared worse. However, also elderly patients can enjoy long-standing complete remission following minimal treatment.

Intensive chemotherapy in patients with chronic myelogenous leukaemia (CML) in accelerated or blastic phase--a report from the Swedish CML Group.

In attempting to restore the chronic phase (CP) of chronic myelogenous leukaemia (CML), the Swedish CML group utilized an intensive chemotherapy protocol for 83 patients (aged 16-79 years) in accelerated (AP, n = 22) or blastic phase (BC, n = 61). Most patients received a combination of mitoxantrone (12 mg/m2/d) and etoposide (100 mg/m2/d) together with cytosine arabinoside (1 g/m2 b.i.d) for 4 d. Overall, 39 patients (47%) achieved a second CP (CP2)/partial remission (PR). Responding patients < 65 years were eligible for ablative chemotherapy followed by an allogeneic (SCT) or a double autologous stem cell transplant (ASCT). Seventeen of 34 responders < 65 years failed to proceed to transplantation as a result of early disease progression (n = 15) or disease-related complications (n = 2). The remaining 17 patients underwent SCT (n = 9; including four unrelated donor SCT) or ASCT (n = 8). Only one of the eight ASCT patients had a second ASCT; the remaining seven failed because of progression (n = 5) or hypoplasia (n = 2). The median duration of CP2/PR was 6 months (range 1-72 months). Five patients achieved a longer CP2/PR than CP1. The 1 year survival was 70% for SCT/ASCT patients (median survival 21 months), 50% for responding patients overall, but only 7% for non-responders (P < 0.001). Three SCT/ASCT patients are long-term survivors (65+, 66+ and 73+ months). In conclusion, approximately half of the patients achieved a CP2/PR after intensive chemotherapy, with a clear survival advantage for responders vs non-responders. Subsequent SCT/ASCT was feasible for half of the responders (< 65 years), and one individual underwent double ASCT. Novel therapeutic options for CML patients in AP/BP are needed.

A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life.

We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo 500 U/l and >/= 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.

High-dose cytarabine in upfront therapy for adult patients with acute lymphoblastic leukaemia.

In this national study, we have evaluated a new intensive chemotherapy protocol for adult patients with untreated acute lymphoblastic leukaemia (ALL). One hundred and fifty-three patients with median age 42 years received induction therapy with high-dose cytarabine (Ara-C), cyclophosphamide, daunorubicin, vincristine and betamethasone. A high complete remission (CR) rate (90%) was achieved in patients < 60 years compared with 70% in patients > 60 years (P = 0.004). The estimated 3 year overall survival for all patients was 29% (CI 21-36%) and the estimated continuous complete remission (CCR) at 3 years for the patients achieving CR according to the protocol was 36% (CI 27-45%). A favourable pretreatment characteristic was pre-B phenotype, especially for patients < 40 years without any high-risk factor, with an estimated CCR at 3 years of 62% (CI 41-82%). Stem cell transplantation (SCT) as post-remission therapy, mainly for high-risk patients, gave an estimated 3 year disease free survival (DFS) after SCT of 39% (CI 24-54%). No significant differences in DFS could be found between autologous, related or unrelated donor transplantation. We conclude that this intensive protocol resulted in a high CR rate combined with acceptable side-effects and a favourable CCR for patients with pre-B ALL.