Limited role for surveillance PET-CT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy.

BACKGROUND: The usefulness of positron emission tomography with computed tomography (PET-CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied. METHODS: We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET-CT after achieving complete metabolic response (CMR) following primary therapy. RESULTS: Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8-133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI ≥3. Including indeterminate scans, PET-CT retained high sensitivity 95% and specificity 97% for relapse. CONCLUSION: Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI ≥3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial.

The frequency, manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy.

BACKGROUND: Fludarabine-based chemoimmunotherapy has well-recognised efficacy and short-term toxicity in the treatment of lymphoid malignancies. However, the presence and significance of prolonged cytopenias after completion of treatment have not been thoroughly quantified. METHODS: Sixty-one patients receiving initial therapy with fludarabine-based regimens were categorised according to the presence of post-treatment cytopenias (haemoglobin <110-130 g/l depending on sex and age, neutrophils <2.0 x 10(9)/l, or platelets <140 x 10(9)/l) lasting >3 months. RESULTS: Persistent cytopenias unrelated to persistent disease were found in 43% of patients. Cytopenias were associated with clinically important rates of infection and transfusion requirement (P = 0.03) and predicted for worse overall survival (61% versus 96% at 60 months, P = 0.05). Increasing age predicted for persistent cytopenias (P = 0.02), but the presence of pretreatment cytopenias and delivered dose intensity were not predictive. The median times to resolution of anaemia, neutropenia, and thrombocytopenia were 7, 9, and 10 months, respectively. CONCLUSIONS: Cytopenias often persist >3 months after first-line fludarabine combination therapy and can lead to important clinical sequelae. Although cytopenias generally resolve over time, treating physicians should be aware of these factors when considering fludarabine combination chemotherapy and when documenting treatment response status in chronic lymphocytic leukaemia.

A phase II study of dexamethasone, ifosfamide, cisplatin and etoposide (DICE) as salvage chemotherapy for patients with relapsed and refractory lymphoma.

The 4-day combination of dexamethasone, ifosfamide, cisplatin, and etoposide (DICE) is a salvage regimen for lymphoma. We report a prospective phase II multi-center trial of a modified DICE regimen in relapsed or refractory Hodgkin (HL) or non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), constituting a single day of intravenous administration followed by 3 days of oral administration, aimed at reducing inpatient days without losing efficacy. Forty patients (median age 56, range 25 - 79) were included: 28 (70%) NHL, 9 (23%) HL and 3 (8%) CLL. Fifty-three per cent had received 2 prior treatment regimens. International Prognostic Index (IPI) was 2 in 75% of NHL patients. Patients aged 55 and those with previous autologous stem cell transplantation (ASCT) started on a lower-dose regimen, with dose escalation possible in 2 patients. Overall response rate was 41%. Thirty-eight per cent of patients had stable disease. With a median of 3.1 years of follow-up, estimated progression-free survival (PFS) and overall survival (OS) rates at 3 years were 15% and 43% respectively. OS was longer in the < 55 compared to the 55 age cohort (P = 0.0091), longer for HL than NHL (P = 0.59 and 0.039 respectively) and longer for Low/Low-Int IPI than High/High-Int IPI (P = 0.0074 and 0.0009 respectively). Median duration of inpatient stay was 3 days. There were no treatment-related deaths. In conclusion, this modification of DICE is an effective and well tolerated salvage regimen, even in this poor prognosis group of patients. Further clinical studies of DICE in first relapse and in older patients, possibly with the addition of rituximab, are warranted.

Interferon-alpha-2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia.

BACKGROUND: Treatment with interferon and subcutaneous cytarabine produces superior cytogenetic responses in chronic myeloid leukaemia (CML) than treatment with interferon alone, but at the expense of greater toxicity. Cytarabine ocfosfate (YNK01) is an oral precursor of cytarabine that may overcome some of the inconvenience and toxicities associated with subcutaneous cytarabine administration. PATIENTS AND METHODS: We studied the efficacy and tolerability of combination therapy with interferon-alpha-2b and YNK01 in patients with newly diagnosed, untreated CML. Forty patients were treated with interferon-alpha-2b (5 MU/m2/day) plus monthly courses of YNK01 (600 mg/day for 10 days) for 1 year. RESULTS: The 6-month complete haematological response rate was 63% and the 1-year major cytogenetic response rate was 30%, with 10% of cytogenetic responses being complete. With a median follow-up of 57 months, the estimated 5-year overall survival was 86% (95% confidence interval 70% to 94%). Treatment tolerability was poor, with toxicity leading to discontinuation of one or both drugs in 60% of cases. The median daily dose of interferon alpha-2b was 7.75 MU and the median dose of YNK01 was 600 mg/day for each 10-day treatment cycle. CONCLUSIONS: Interferon-alpha-2b and YNK01 produce cytogenetic responses comparable to those achieved with interferon-alpha-2b and parenteral cytarabine, although toxicity was excessive. Alternate dosing strategies may enhance the tolerability of YNK01.

Treatment of patients with advanced mycosis fungoides and Sézary syndrome with alemtuzumab.

OBJECTIVES: Alemtuzumab (anti-CD52, Campath-1H) has recently been shown to be effective in the treatment of a range of hematological malignancies, including B-cell chronic lymphocytic leukemia and T-cell prolymphocytic leukemia. We undertook a phase II study to evaluate the safety, tolerability and efficacy of alemtuzumab in patients with relapsed or refractory advanced stage cutaneous T-cell lymphoma. PATIENTS AND METHODS: A total of eight patients were enrolled, seven with mycosis fungoides/Sézary syndrome (MF/SS) and one with large-cell transformation of MF. Seven patients had disease refractory to multiple previous therapies. Alemzumab (30 mg) was administered intravenously three times per week for 12 wk or until maximum response. RESULTS: The overall response rate was 38%, with three patients achieving partial remission, two patients with stable disease and three patients with progressive disease (PD) during treatment. The time to progression was short, with all patients developing PD within 4 months of starting alemtuzumab. Response duration in the three PR patients was also brief, with responses lasting less than 3 months in all three cases. Significant hematological and immunosuppressive toxicity was observed, with both grade 3-4 cytopenias and significant infectious complications occurring in a majority of cases. CONCLUSIONS: Our findings suggest that in heavily pretreated, refractory, advanced stage MF/SS, although alemtuzumab has biological activity, it is associated with significant toxicity and only modest clinical utility. As such, combination regimens incorporating alemtuzumab merit further investigation in this difficult to treat patient group.

Effects of glycosylated recombinant human granulocyte colony-stimulating factor after high-dose cytarabine-based induction chemotherapy for adult acute myeloid leukaemia.

The Australian Leukaemia Study Group (ALSG) investigated whether G-CSF would accelerate haemopoietic recovery after induction treatment for acute myeloid leukaemia (AML) intensified with high-dose cytarabine, and therefore improve response rates and survival. Patients were randomised to receive lenograstim (glycosylated recombinant human G-CSF) 5 microg per kg body weight subcutaneously daily from day 8 after starting chemotherapy, or no cytokine, following chemotherapy with cytarabine 3 g/m2 every 12 h on days 1, 3, 5, and 7, together with idarubicin 9 or 12 mg/m2 on days 1, 2, and 3, plus etoposide 75 mg/m2 on days 1 to 7 inclusive. Patients had untreated AML, and were aged 16 to 60 years. Overall, 54 evaluable patients were randomised to receive lenograstim and 58 to no cytokine. Patients in the lenograstim arm had a significantly shorter duration of neutropenia <0.5 x 10(9)/l compared to patients in the no cytokine arm (median 18 vs 22 days; P = 0.0005), and also shorter duration of total leucopenia <1.0 x 10(9)/l (17 vs 19 days; P = 0.0002), as well as a reduction in duration of treatment with therapeutic intravenous antibiotics (20 vs 24 days; P= 0.015) and a trend to reduced number of days with fever >38.0 degrees C (9 vs 12 days; P = 0.18). There were no differences between the two groups in platelet recovery, red cell or platelet transfusions, or non-haematological toxicities. For patients achieving CR after their first induction course, a reduction in the time to the start of the next course of therapy was observed in the lenograstim arm, from a median of 40.5 days to a median of 36 days (P = 0.082). The overall complete response rates to chemotherapy were similar, 81% in the lenograstim arm vs 75% for the no cytokine arm (P = 0.5), and there was no significant difference in the survival durations. We conclude that the granulopoietic stimulating effect of G-CSF is observed after induction therapy for AML intensified by high-dose cytarabine, resulting in an improvement in a number of clinically important parameters with no major adverse effects.

Cure of pulmonary Rhizomucor pusillus infection in a patient with hairy-cell leukemia: role of liposomal amphotericin B and GM-CSF.

We describe a case of successfully treated multifocal pulmonary Rhizomucor pusillus, a condition which has previously been universally fatal. A 77 year-old man had a background of chronic neutropenia due to hairy-cell leukemia, splenectomy, corticosteroid therapy and an obstructing left ureteric transitional-cell carcinoma. He was successfully treated with 3 months of high-dose liposomal amphotericin B and 7 months of granulocyte-macrophage colony-stimulating factor. Treatment was complicated by mild reversible deterioration of renal function. There was a near complete radiological response to the therapy at 6 months and the patient remains well 20 months following diagnosis of R. pusillus and 13 months following cessation of treatment.

Safe mobilization of normal progenitors in advanced chronic myeloid leukemia with intensive chemotherapy and granulocyte-colony stimulating factor.

Twenty-one patients with advanced chronic myeloid leukemia (late chronic phase (n = 8), accelerated phase (n = 11) and blast crisis (n = 2)) were treated with idarubicin, cytarabine, and etoposide followed by G-CSF and subsequent collection of peripheral blood progenitor cells in the early recovery phase. Treatment was reasonably well tolerated with no deaths or intensive care admissions. Despite the advanced phase of disease and heavy pretreatment with cytotoxics and interferon-alfa, 11 of 21 patients (52%) achieved a cytogenetic response. Of the nine major cytogenetic responses (complete (n = 3) and partial (n = 6)), seven achieved adequate progenitor collections for consideration for autologous transplantation. The only predictor of response was disease duration (P = 0.02). With a median follow-up of 1171 days from treatment it appears unlikely that G-CSF contributed to disease progression. Survival post-IcE was predicted by disease stage (P = 0.0001). Intensive chemotherapy followed by G-CSF allowed adequate yields of predominantly Philadelphia chromosome negative progenitor cells to be obtained from one-third of patients with advanced CML.

Low-dose versus standard-dose lenograstim prophylaxis after chemotherapy: a randomized, crossover comparison.

PURPOSE: Granulocyte colony-stimulating factor (G-CSF) administered prophylactically after chemotherapy reduces the duration and severity of neutropenia. This randomized crossover study was designed to assess whether a lower dose of G-CSF is as effective as a standard dose of 5 microg/kg daily. PATIENTS AND METHODS: Patients who received standard-dose chemotherapy regimens expected to cause neutropenia received G-CSF (lenograstim) that started the day after chemotherapy for 14 days or until the absolute neutrophil count (ANC) recovered to greater than 10 x 10(9)/L. The lenograstim dose was randomly allocated to be 2 or 5 microg/kg daily in the first cycle of chemotherapy and crossed over to the alternate dose for the second cycle. The study was designed to accrue 40 assessable patients to provide a power of 80% to detect a difference in duration of neutropenia of 1 day. Fifty-two patients were randomized to treatment and 43 patients completed two cycles of identical chemotherapy. RESULTS: There was little neutropenia irrespective of the dose used. Twenty-three patients (53%) had no grade III or IV neutropenia and 30 patients (70%) had no grade IV neutropenia. Crossover trial methodology was used to assess the difference in outcome caused by the lower dose compared with the standard dose (estimated treatment effect). There was no significant difference in the measures of neutropenia, hospitalization, or other clinical outcomes. The 95% confidence interval (one-sided) for the additional duration of neutropenia caused by the lower dose of lenograstim was 0.43 days or less for grade III or IV neutropenia and 0.34 days or less for grade IV neutropenia. CONCLUSION: Lenograstim 2 microg/kg provides similar protection to 5 microg/kg against neutropenia that complicates standard-dose chemotherapy. The use of a lower dose has important implications for the cost-effectiveness of prophylactic G-CSF therapy.

Peripheral blood CD34+ cell count reliably predicts autograft yield.

A reliable measure to predict peripheral blood progenitor cell (PBPC) autograft CD34+ cell content is required to optimize the timing of PBPC collection. We prospectively examined the peripheral blood (PB) CD34+ cell count in 59 consecutive patients with various malignancies and analyzed the correlation between the PB CD34+ cell count and various parameters in the PBPC autograft. Two hundred and thirty-five collections were performed with a median of 4.0 collections per patient (range, 2-10). The median PB CD34+ cell count at the time of collection was 39 x 10(6)/1 (range, 0.0-285.6). The PBPC autograft parameters measured were the CD34+ cell, colony-forming unit granulocyte-macrophage (CFU-GM) and mononuclear cell (MNC) content. There was a strong linear correlation between PB CD34+ cells/l and autograft CD34+ cells/kg (r = 0.8477). The correlation with CFU-GM/kg (r = 0.5512) was weaker. There was no correlation between autograft CD34+ cells/kg and PB WBC (r= 0.0684), PB MNC (r = 0.1518) or PB platelet count (r = 0.2010). At our institution we aim to obtain a minimum of 0.5 x 10(6) CD34+ cells/kg with each day of collection. We demonstrate that such a collection can be reliably obtained if the PB CD34+ cell count exceeds 5.0 x 10(6)/l.

Prognostic markers of disease activity in Hodgkin's disease.

The erythrocyte sedimentation rate (ESR), liver alkaline phosphatase (ALP), serum copper (Cu) and urinary nucleoside excretion (UNs) have been proposed as independent prognostic markers in Hodgkin's Disease (HD). However, their prognostic value has not satisfactorily been directly compared to recognised clinical prognostic factors. One hundred and sixty-eight patients with HD had the above markers performed prior to initial treatment. At a median follow-up of 10.9 yrs, the predicted 10 year relapse free survival (RFS) and overall survival (OS) for the entire cohort is 64% and 66%, respectively. In general, patients with elevated markers were significantly less likely to achieve CR, remain in CR and survive. However, multivariate analysis revealed this was due to the association of elevated markers with stage and constitutional symptoms. Following therapy, elevated markers were also correlated with evidence of clinically detectable disease. We conclude that although UNs, Cu, ALP and ESR reflect disease activity, they do not provide independent information beyond that of clinical assessment.

Hypereosinophilic syndrome or chronic eosinophilic leukemia: report of a case with a lytic bone lesion.

Some cases of hypereosinophilic syndrome and myeloproliferative disorders exhibit common features and thus pose diagnostic and therapeutic problems. We describe a 68-year-old patient who presented with such features and developed lytic lesion in the tibia. Based on our case and a review of literature we suggest that cases like ours should be classified and treated as chronic eosinophilic leukemia (a myeloproliferative disorder) rather than as a hypereosinophilic syndrome or as an atypical chronic myeloid leukemia.

High dose chemotherapy and autologous bone marrow transplantation in advanced Hodgkin's disease.

OBJECTIVE: To present the use of high dose chemotherapy with autologous bone marrow transplantation as salvage therapy for advanced Hodgkin's disease in Australia. DESIGN: A prospective open study for patients whose disease was resistant to conventional treatment. SETTING: The bone marrow transplantation units of four Australian tertiary hospitals. PATIENTS: Seventeen patients (median age 30 years) entered and completed the study. The stage of the disease at initial diagnosis was I or II (seven patients), III (seven patients) and IV (three patients). Histological types were lymphocyte predominant (one), nodular sclerosis (12), mixed cellularity (three) and unknown (one). Therapy before consideration for transplantation included radiotherapy (13), mustine, vincristine, procarbazine and prednisone (MOPP--17 patients) or doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD--13 patients) and other chemotherapy regimens (five). The median interval from diagnosis to transplantation was 29 months (range, 9-178 months). The patient's disease was classified as sensitive (nine) or resistant (eight) to treatment, depending on the response to the most recent course of chemotherapy. INTERVENTIONS: Morphologically normal autologous bone marrow was harvested and cryopreserved. The conditioning regimen given was cyclophosphamide, carmustine and etoposide (14) or busulphan and cyclophosphamide (three). The marrow was then infused. MAIN OUTCOME MEASURES: Remission (complete or partial), disease-free survival and overall survival. RESULTS: Over all, 10 of 17 patients (59%) entered or remained in complete remission and four of 17 (24%) achieved partial remission. The overall actuarial survival at 30 months was 70%. Eight of the nine patients with treatment-sensitive disease (89%) remain disease-free at a median of 22 months (range, 18-29 months) after transplantation. Two of the eight patients with resistant disease (25%) are disease-free at 20 and 28 months. There was one procedure-related death from haemorrhage and four disease-related deaths at six, seven, eight and 13 months after transplantation. CONCLUSION: Autologous bone marrow transplantation may provide an effective salvage therapy in advanced Hodgkin's disease, particularly for patients with treatment-sensitive disease and a low tumour burden.