Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma.

PURPOSE: Bisphosphonates have been found to reduce the incidence of skeletal-related events (SREs) in patients with multiple myeloma. This is the first double-blind, randomized, placebo-controlled study to assess the efficacy of ibandronate, a third-generation amino-bisphosphonate, in preventing SREs in advanced-stage multiple myeloma patients. PATIENTS AND METHODS: Patients with multiple myeloma stage II or III were randomly assigned to receive either ibandronate 2 mg or placebo as a monthly intravenous (IV) bolus injection for 12 to 24 months in addition to conventional chemotherapy. SREs such as peripheral pathologic or vertebral fractures, hypercalcemia, severe bone pain, and bone radiotherapy or surgery were analyzed. Bone-turnover markers were also studied. Finally, post hoc analyses of bone morbidity and survival were performed. RESULTS: Ninety-nine patients per treatment group were assessable for efficacy analysis. The occurrence of SRE per patient year and the time to first SRE were not significantly different between the two treatment groups. In overall evaluation, no differences were found between the treatment groups regarding bone pain, analgesic drug use, quality of life, and median survival (33.1 v 28.2 months, respectively). Explorative post hoc analyses revealed that ibandronate patients with strongly suppressed bone-turnover markers (> or = 30% and > or = 50% mean reduction of serum osteocalcin and urinary C-terminal telopeptides) developed significantly less bone morbidity. Ibandronate was tolerated well during as many as 25 therapy cycles. CONCLUSION: Monthly injections of ibandronate 2 mg IV neither reduced bone morbidity nor prolonged survival in the overall population of stage II/III multiple myeloma patients.

Monocyte dysfunction in patients with multiple myeloma and lymphoplasmacytic disorders is related to serum paraprotein levels.

We have investigated monocyte function in 30 patients with lymphoplasmacytic disorders and in 21 age and sex matched normal controls. Marked abnormalities of all facets of monocyte function were demonstrated in six patients with multiple myeloma (MM) and a single patient with Waldenström's macroglobulinaemia (WM) plus significant paraproteinaemia. Serious infection occurred in three of these patients. An inverse relationship between the level of the serum paraprotein and impairment of monocyte phagocytosis plus killing of Candida albicans was observed. Crossover studies suggested that these abnormal findings were constitutive and not reversed by removal of the serum paraprotein. The data suggest that monocyte function is constitutively abnormal in patients with MM and can be further, but reversibly, inhibited by high paraprotein levels. Further research is required to confirm these findings, ascertain whether monocyte function can be normalized using chemotherapy or growth factors, and if so, whether their tumouricidal functions could be harnessed in the treatment of this currently incurable condition.

Kinetic characteristics of de novo and secondary AML cells influence their response to haemopoietic growth factor (HGF) priming and correlate with clinical outcome.

This study has assessed the effect of in vitro haemopoietic growth factor (HGF) priming on the S phase activity of cells from patients with de novo AML and AML secondary to MDS. The occurrence of receptors for G-CSF, GM-CSF, IL-3 and SCF on marrow cells was assessed using immunofluorescent ligand binding assays. Additionally, patients responses to first phase induction chemotherapy was recorded to examine whether in vitro kinetic data might correlate with clinical outcome. All kinetic and receptor assays were performed in normal marrow cells to ascertain their response to priming. Incubation of AML cells in serum free medium (SFM) +/- G + GM-CSF, IL-3, SCF, G + GM-CSF + SCF or IL-3 + SCF prior to S phase assessment revealed that priming permutations inclusive of SCF were most effective but also that the baseline level of S phase activity with SFM alone influenced the subsequent response to priming. Regardless of AML group, samples with low baseline S phase activity (< 10%) were significantly more responsive than those with high (> 10%) SFM S phase levels. However there was no corresponding difference in the percentages of cells bearing receptors. In both AML groups, low baseline S phase activity was observed more frequently in samples from patients who achieved CR. Normal samples possessed receptors for all HGFs and were responsive to all priming permutations except SCF alone. This study raises four points: (a) it may be prudent to reserve the use of priming HGFs for those patients with low baseline S phase activity whose cells respond in vitro and to use SCF in these priming cocktails; (b) the presence of receptors capable of ligand binding in AML samples did not guarantee kinetic response; (c) normal progenitors were responsive to priming which may have implications for haemopoietic reconstitution post therapy; and (d) the kinetic characteristics of AML progenitors may influence clinical outcome regardless of whether treatment includes HGFs.

G CSF: A First Line Therapy for Autoimmune Neutropenia?

This paper studies the use of recombinant human Granulocyte Colony Stimulating Factor (rh G CSF) as a single treatment modality in serologically proven autoimmune neutropenia. We present six cases, all of whom had severe neutropenia resulting in recurrent infections and oral ulceration. A response, characterised by an increase in mean neutrophil count and a reduction in infective episodes, was demonstrated in all cases.

The role of midazolam-induced sedation in bone marrow aspiration/trephine biopsies.

This study was undertaken in 102 adult patients to evaluate the safety and efficacy of intravenous (i.v.) midazolam in the setting of bone marrow aspiration and trephine biopsy (BMAT). Combined local anaesthetic (LA) and sedation was used in 87% of patients and 13% received LA alone. Amnesia occurred in all sedated patients with only 9% experiencing a mild degree of post-procedure pain. This contrasted sharply with the non-sedated group, in whom 85% had intense pain during the biopsy followed by protracted local discomfort in approximately 54%. Drowsiness and some psychomotor impairment were the only notable sedation-related side-effects in approximately 20%. None required assisted ventilation. There was a resounding patient preference for BMAT with sedation. Considering the ease of use, safety and efficacy of i.v. midazolam, the availability of flumazenil as a reversal agent and the undoubted positive effects on quality of life, we would advocate using it in BMAT provided that there were no contraindications.

Haemopoietic growth factors, the cell cycle of acute myeloblastic leukaemia progenitors and sensitivity to cytosine arabinoside.

We describe an 'in vitro' model which permits assessment of acute myeloblastic leukaemia (AML) progenitor cells' response to Ara-C alone and in conjunction with recombinant human (rh) cytokines by evaluating cell cycle characteristics of purified AML blast progenitors and their chemosensitivity in clonogenic culture before and after cytokine priming. Parallel investigation of Ara-C/cytokine treatment on normal CFU-GM progenitors was included as these cells are important for post-therapeutic reconstitution of haemopoiesis. Kinetic and clonogenic findings for AML marrows were extremely variable with G+GM-CSF or IL-3 priming. However, inclusion of rhSCF and resultant synergism with the other cytokines, introduced a pronounced element of consistency in AML results. Normal CFU-GM responded to rhG+GM-CSF or IL-3 with increased kinetic activity and sensitivity to Ara-C. rhSCF synergised strongly with the other factors, causing increased cell cycling and attainment of maximal chemosensitivity 'in vitro'. No correlation was evident between 'in vitro' findings for AML samples, patient FAB types or clinical outcome. This study highlights the fact that both normal and AML cells can be targeted by rh cytokines, particularly when rhSCF is included in priming cocktails.

Fatal autoimmune pancytopenia following bone marrow transplantation for aplastic anaemia.

We report a case of autoimmune pancytopenia 10 months after allogeneic bone marrow transplantation (BMT) for severe aplastic anaemia (SAA). The autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenic purpura (ITP) were refractory to conventional immunosuppressive therapy which included steroids, azathioprine, vincristine and intravenous immunoglobulin. Splenectomy led to a recovery of the thrombocytopenia but the haemolysis continued despite further immunosuppressive therapy. Four months after the onset of haemolysis granulocyte-specific antibodies were detected. The patient subsequently received total lymph node irradiation (TLI) with a peripheral blood stem cell transplant (PBSCT) from his original donor, but died 9 days later from cerebral aspergillosis. The severe nature of autoimmune cytopenias and their lack of response to conventional treatment following allogeneic BMT is discussed further.

The effect of haemopoietic growth factors on the cell cycle of AML progenitors and their sensitivity to cytosine arabinoside in vitro.

This study examines the effect of pretreatment in liquid culture of acute myeloid leukaemic (AML) progenitors with recombinant human IL-3 or G and GM-CSF. Prior to and following cytokine priming, the sensitivity of cells to cytosine arabinoside (Ara-C) at concentrations ranging from 10(-12) to 10(-4) M was assessed in clonogenic culture. In addition, the initial percentage of AML cells in S phase was assessed and their subsequent kinetic response to cytokine treatment evaluated by FACScan analysis. Light-density marrow cells (LDMCs) from 19 AML patients were initially T-cell and monocyte depleted in order to remove potential sources of endogenous cytokine production prior to in vitro investigation. LDMCs were incubated in liquid phase for 7 d in a chemically defined complete medium with or without cytokines. Clonogenic data from fresh AML LDMCs not pretreated with growth factors demonstrated a heterogenous response to Ara-C. In only 4/15 marrows tested clonogenically was there any improvement in sensitivity to Ara-C following cytokine priming. S-phase data on all 19 marrows were similarly variable either before or after cytokine preincubation. There was no discernible correlation between clonogenic and kinetic data, nor could any relationship be established between in vitro findings and the FAB subtypes of patients or clinical outcomes. In summary, it would appear that the cell-cycle status of AML cells is likely to be only one of many contributory factors governing the sensitivity of AML progenitors to Ara-C. The clinical response of AML patients to cytokine therapy in association with cell-cycle-specific cytotoxic agents may therefore be variable and unpredictable.

The effect of rh-cytokines on the sensitivity of normal human CFU-GM progenitors to Ara-C and on the S-phase activity of light density human bone marrow cells.

This study examines the effect of pre-incubation in liquid phase of normal human CFU-GM progenitors with recombinant human (rh) cytokines prior to exposure to cytosine arabinoside (Ara-C) in clonogenic culture. Light density marrow cells (LMDCs) were preincubated in Biorich (chemically defined serum-free complete medium) with G + GM-CSF or IL-3 prior to semi-solid culture with Ara-C (10(-4) M-10(-12) M). Cell cycle analysis was performed by flow cytometry pre- and post-rh-cytokine treatment. Data from 26 normal marrows studied clonogenically, demonstrated a 60% reduction in CFU-GM with 10(-4) M Ara-C. Preincubation in Biorich medium with the addition of G + GM-CSF or IL-3 caused a significant enhancement of sensitivity to Ara-C across the dose curve. Biorich medium alone had an apparent protective effect resulting in amelioration of the cytotoxic effect of Ara-C. Cell cycle analysis of eight subjects showed significant recruitment into S-phase following pre-treatment with cytokines. A reduction in S-phase activity was noted in cells pre-incubated in Biorich alone. In summary, it would appear that cytokines can enhance the sensitivity of normal CFU-GM to Ara-C in vitro possibly due to an increase in S-phase activity. Pre-incubation in nutrient medium without cytokines resulted in cell quiescence.

Can platelet volume predict progressive hypertensive disease in pregnancy?

Increase in platelet size has been found in conditions with increased platelet destruction and use. This increase in platelet size can be found in patients with moderate or severe hypertension in pregnancy, even in the presence of a normal platelet count. The goal of this study was to investigate whether an increase in platelet size was present before the manifestation of the disease and therefore could be used to predict the progression of the disease before it is clinically apparent. Three hundred normal primigravid pregnancies were studied between 28 and 30 weeks' gestation, and blood was taken to assess platelet count and mean platelet volume. Two hundred sixteen patients had no hypertensive problems during their pregnancy, 84 developed hypertension, 62 had mild hypertension only with diastolic blood pressures between 90 and 99 mm Hg, 13 had moderate hypertension with diastolic blood pressures between 100 and 109, and nine had severe hypertension with diastolic blood pressure above 110. No difference was found between these groups in the parameters measured. Therefore it was felt that platelet volume may not be a useful screening test in a low-risk population. A second study was carried out to investigate the serial changes in these parameters in patients at risk of progressive disease. Thirty-four patients with essential hypertension were followed from 24 weeks with serial blood sampling to study changes in platelet size. An additional 40 patients with mild pregnancy-induced hypertension were also studied. From these patient groups, 20 patients developed severe hypertension. The mean platelet volume increased significantly at least 1 week before the hypertension became clinically apparent. There was no change in platelet count at this time. It is concluded that increasing platelet size can predict which patients are likely to progress to severe disease before it becomes clinically obvious.

Hemibody irradiation. An effective second-line therapy in drug-resistance multiple myeloma.

The authors report the results of treatment of 41 patients with melphalan-resistant multiple myeloma using single half-body irradiation (HBI) or double half-body irradiation (DHBI). Patients were grouped using prognostic classification reported by the Medical Research Council. Patients in group I and II showed the best response to therapy with reduction in serum of urinary paraprotein and improvement in symptoms, most notably a marked reduction in bone pain. In these groups five patients have survived over 2 years after therapy. The therapeutic response appeared better in those patients who received DHBI as opposed to those whom treated with single HBI. Patients in group III did not achieve prolonged survival but effective relief of bone pain was a consistent finding in these patients also. Thus HBI represents an alternative to combination chemotherapy as second-line treatment of patients with melphalan-resistant multiple myeloma. A comparative study of HBI versus combination chemotherapy is now indicated to establish which therapeutic approach is most effective.

Successful treatment of refractory Hodgkin's disease by high-dose combination chemotherapy and autologous bone marrow transplantation.

Forty-four patients with refractory Hodgkin's disease were treated with high-dose combination chemotherapy followed by autologous bone marrow rescue. Twenty-two patients (50%) entered complete remission within 6 months of the procedure and four other patients are free of disease progression. Only two patients have subsequently relapsed from complete remission (CR). Bone marrow suppression was the predictable major toxicity of this procedure, and two patients (4.5%) died of sepsis during the aplastic phase. High-dose therapy with autologous bone marrow transplantation (ABMT) appears to be an effective salvage regimen for patients with refractory Hodgkin's disease.

Management of non-Hodgkin lymphoma in adults in Scandinavia, United Kingdom, and The Netherlands. Report from the European School of Oncology intercity meeting at Huddinge Hospital, 3rd June, 1988.

Current treatment strategies in northern Europe of non-Hodgkin lymphoma are presented. High-grade malignant lymphomas have been treated with doxorubicin-containing polychemotherapy in various modes. The advantage of six-drug regimens over CHOP-like therapy is as yet not proven. Patients with the ability to tolerate the calculated dose have good prognosis. High-dose therapy and bone marrow transplantation should be considered in poor-risk patients with lymphoblastic lymphomas in first remission, patients with all high-grade histologies in partial remission after first-line therapy and patients with relapse that are still responsive to therapy. Preliminary results from autologous bone marrow transplantation in follicular lymphoma are also encouraging. Chlorambucil induces multiple remissions in follicular lymphoma, with a median duration of the 1st, 2nd and 3rd remission being the same. The watch and wait strategy seems justified initially in most asymptomatic generalized low-grade malignant lymphomas. Systemic therapy is required in aggressive stage II-IV lymphomas. A meticulous investigation is needed for stage I patients before giving local treatment only. Immune phenotyping is of great value for diagnosis and staging. Liver, but not bone marrow involvement seems to be an adverse prognostic factor. Follicular lymphoma is an example of a dynamic tumour with gradual cellular changes associated with new and more malignant clinical signs.

Alpha-interferon therapy for essential thrombocythaemia.

18 patients with symptomatic essential thrombocythaemia were treated with recombinant alpha interferon (2a or 2b). Subcutaneous dosage regimens, which were well-tolerated, selectively lowered the platelet count and relieved symptoms in all patients, whether previously treated or untreated. Recombinant alpha-interferon may offer a non-leukaemogenic alternative therapy for these patients.

Differential phthalocyanine photosensitization of acute myeloblastic leukaemia progenitor cells: a potential purging technique for autologous bone marrow transplantation.

The potential value of sulphonated aluminium phthalocyanine (AISPc) as a purging agent for bone marrow autografts in acute myeloblastic leukaemia (AML) has been studied using in vitro clonogenic assays for normal (GM-CFC) and leukaemic (AML-CFC) progenitor cells. In nine out of 13 cases, the leukaemic blasts were found to be highly sensitive to AISPc. In six of the sensitive cases clonogenic assays revealed that only 2 +/- 1% of AML progenitor cells survived AISPc treatment under conditions which permitted a GM-CFC recovery of 60 +/- 11%. AISPc photosensitization was also shown to selectively eliminate the leukaemic cell line K562 from an in vitro model of minimal residual disease. Thus photosensitization using AISPc may be an effective method of purging marrow autografts in some cases of AML. Evaluation of the sensitivity of AML clonogenic cells at diagnosis may identify those patients in whom AISPc photo-purging may be of benefit at the time of an autologous bone marrow transplant.

Management of multiple myeloma.

This article reviews the diagnostic approach to a patient with suspected multiple myeloma. Studies of chemotherapeutic regimens are reviewed and the alternative therapeutic options available at different stages of disease progression are discussed. These include newer modalities of treatment such as hemi-body irradiation as second-line therapy, bone marrow transplantation in plateau-phase and the role of alpha interferon.

Comparison of the sensitivity of normal and leukaemic myeloid progenitors to in-vitro incubation with cytotoxic drugs: a study of pharmacological purging.

The sensitivity of myeloid leukaemic colony forming cells (AML-CFC), to five cytotoxic drugs has been compared in two culture systems with the sensitivity of normal myeloid progenitor cells (GM-CFC). No increased sensitivity was found for AML-CFC to any of the chemotherapeutic agents studied. AML-CFC were significantly less sensitive than normal GM-CFC to mafosfamide at the doses commonly used to purge bone marrow autografts. It is suggested that AML cells probably display similar sensitivity to cytotoxic agents as normal myelopoietic cells at a similar stage of differentiation. Hence complete elimination of the leukemic clone by pharmacological purging may be incompatible with bone marrow re-engraftment. We conclude that purging AML autografts with any of the agents examined has little scientific basis.