Treatment sequences and drug costs from diagnosis to death in multiple myeloma.

Novel therapies for multiple myeloma (MM) have improved patient survival, but their high costs strain healthcare budgets. End-of-life phases of treatment are generally the most expensive, however, these high costs may be less justifiable in the context of a less pronounced clinical benefit. To manage drug expenses effectively, detailed information on end-of-life drug administration and costs are crucial. In this retrospective study, we analysed treatment sequences and drug costs from 96 MM patients in the Netherlands who died between January 2017 and July 2019. Patients received up to 16 lines of therapy (median overall survival: 56.5 months), with average lifetime costs of €209 871 (€3111/month; range: €3942-€776 185) for anti-MM drugs. About 85% of patients received anti-MM treatment in the last 3 months before death, incurring costs of €20 761 (range: €70-€50 122; 10% of total). Half of the patients received anti-MM treatment in the last 14 days, mainly fully oral regimens (66%). End-of-life treatment costs are substantial despite limited survival benefits. The use of expensive treatment options is expected to increase costs further. These data serve as a reference point for future cost studies, and further research is needed to identify factors predicting the efficacy and clinical benefit of continuing end-of-life therapy.

Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study.

PURPOSE: To describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients. METHODS: HRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment ("watch and wait"), chlorambucil treatment only, and patients with other treatment(s). RESULTS: HRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy. CONCLUSIONS: CLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment.

Real-world costs of chronic lymphocytic leukaemia in the Netherlands.

We performed a comprehensive cost calculation identifying the main cost drivers of treatment of chronic lymphocytic leukaemia in daily practice. In our observational study 160 patient charts were reviewed repeatedly to assess the treatment strategies from diagnosis till the study end. Ninety-seven patients (61%) received ≥1 treatment lines during an average follow-up time of 6.4 years. The average total costs per patient were €41,417 (€539 per month). The costs varied considerably between treatment groups and between treatment lines. Although patients were treated with expensive chemo(immuno-)therapy, the main cost driver was inpatient days for other reasons than administration of chemo(immuno-)therapy.

Late-onset cardiotoxicity of chemotherapy and radiotherapy.

An increasing number of patients with malignant lymphoma are becoming long-term survivors following treatment with chemotherapy (CT) and/or radiotherapy (RT). Therefore, late therapy-related complications are becoming increasingly clear. We present three young patients to illustrate the dire consequences of late-onset cardiotoxicity as sequel to potentially curative treatment. We advise yearly life-long follow-up of CT/RT patients treated with curative intent. Echocardiography should be performed when cardiac murmurs arise. Prevention of further cardiac damage by reducing other cardiac risk factors as well as endocarditis prophylaxis when indicated is recommended.

CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma.

PURPOSE: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. RESULTS: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P =.01) and doxorubicin (median, 95.4% v 93.3%; P =.04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. CONCLUSION: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.

Effects of bryostatin-1 on chronic myeloid leukaemia-derived haematopoietic progenitors.

Bryostatin-1 belongs to the family of macrocyclic lactones isolated from the marine bryozoan Bugula neritina and is a potent activator of protein kinase C (PKC). Bryostatin has been demonstrated to possess both in vivo and in vitro anti-leukaemic potential. In samples derived from chronic myeloid leukaemia (CML) patients, it has been demonstrated that bryostatin-1 induces a macrophage differentiation, suppresses colony growth in vitro and promotes cytokine secretion from accessory cells. We investigated the effect of bryostatin-1 treatment on colony-forming unit-granulocyte macrophage (CFU-GM) capacity in the presence of accessory cells, using mononuclear cells, as well as in the absence of accessory cells using purified CD34-positive cells. Cells were obtained from 14 CML patients as well as from nine controls. Moreover, CD34-positive cells derived from CML samples and controls were analysed for stem cell frequency and ability using the long-term culture initiating cell (LTCIC) assay at limiting dilution. Individual colonies derived from both the CFU-GM and LTCIC assays were analysed for the presence of the bcr-abl gene with fluorescence in situ hybridization (FISH) to evaluate inhibition of malignant colony growth. The results show that at the CFU-GM level bryostatin-1 treatment resulted in only a 1.4-fold higher reduction of CML colony growth as compared to the control samples, both in the presence and in the absence of accessory cells. However, at the LTCIC level a sixfold higher reduction of CML growth was observed as compared to the control samples. Analysis of the LTCICs at limiting dilution indicates that this purging effect is caused by a decrease in output per malignant LTCIC combined with an increase in the normal stem cell frequency. It is concluded that bryostatin-1 selectively inhibits CML growth at the LTCIC level and should be explored as a purging modality in CML.

Role of TNF alpha in bryostatin-induced inhibition of human hematopoiesis.

In previous studies bryostatin has been shown to cause dose-dependent stimulatory or inhibitory effects on colony formation in acute myeloid leukemias. In this study we investigated the inhibitory effect of high dose bryostatin-1 (bryo-1) on normal human bone marrow mononuclear cells (BMNC) colony-forming capacity. Preculturing BMNC for 24 h with 250 nM bryo-1 reduced colony formation by 66 +/- 11% whereas this treatment did not reduce clonogenic capacity of highly purified CD34+ BMNC. When precultures with bryo-1 were performed in the presence of several cytokine neutralizing antibodies abrogation of the inhibitory effect could only be demonstrated by anti-TNF alpha. However, preculturing of BMNC or CD34+ cells with a wide range of TNF alpha concentrations as well as TNF alpha neutralization in supernatant of bryo-1-stimulated BMNC failed to affect the inhibitory effect on CD34+ cells. Both indicate that TNF alpha was not the only factor responsible for the inhibitory effect. Depletion of CD14+ cells from BMNC cultures showed that upon bryo-1 exposure the monocytes served as the main source of TNF alpha but not as a source of the inhibitory cytokine(s): in CD14+-depleted cultures the combination of exogenous added TNF alpha and bryo-1 resulted in an inhibition of colony formation comparable to that found in crude BMNC. In contrast, purified CD34+ cultures were not directly affected by bryo-1 and TNF alpha. However, clonogenic growth of purified CD34+ cells was inhibited if mononuclear cells were preincubated with TNF alpha alone for 24 h, and the supernatant of these cultures was used together with bryo-1. These results show that bryo-1-induced inhibition of clonogenic cell growth is not mediated by a direct effect of bryo-1 on CD34 cells but is a result of a process involving production of TNF alpha by CD14+ cells upon bryo-1 stimulation together with the induction of (a) secondary factor(s) by TNF alpha, which together with bryo-1 itself is inhibitory towards clonogenic cell growth.

High-dose melphalan with re-infusion of unprocessed, G-CSF-primed whole blood is effective and non-toxic therapy in multiple myeloma.

In order to shorten the pancytopenic period following high-dose melphalan 140 mg/m2 (HDM) treatment of multiple myeloma patients, we studied the effects of re-infusing granulocyte colony stimulating factor (G-CSF) [Filgrastim, Neupogen]-primed unprocessed whole blood. 30 patients with multiple myeloma were treated with HDM. One litre of blood after 5 or 6 days stimulation with G-CSF (10 micrograms/kg) was drawn, kept unprocessed for 1 day and re-infused 24 h after chemotherapy. Time to granulocyte recovery (> 0.5 x 10(9)/1) and platelet recovery (> 20 x 10(9)/1) were assessed as well as length of hospital stay, number of transfusions and antibiotic use. These 30 patients were compared with 20 historical control patients who were similarly treated but without stem cell support. The response rate was 75% (21/28) including a complete remission (CR) rate of 29% (8/28). Two early deaths due to Aspergillus pneumonia were observed. The median overall survival after HDM has not been reached after a median follow-up of 14 months. 10 patients showed progression at a median of 7 months. Currently, 23 patients are alive with a median follow-up time of 14 months. Haematological recovery was significantly faster in the study group as compared to the historical control group. The neutrophil count reached 0.5 x 10(9)/1 at a median of 14 days after infusion of 1 litre of unprocessed whole blood compared with 38 days in the historical control group. A platelet count of 20 x 10(9)/1 was reached at a median of 26 days compared with 36 days in the historical control group. Length of hospital stay decreased from a median of 43 to 18.5 days. The number of days with antibiotics was reduced from a median of 21 to 6 days. HDM is effective therapy for multiple myeloma. Toxicity of the regimen is considerably reduced by the use of G-CSF-stimulated unprocessed whole blood, an easy to perform and cheap technique to mobilise and collect stem cells.

Heterogenous effects of bryostatin on human myeloid leukemia clonogenicity: dose and time scheduling dependency.

The potent anti-neoplastic actions displayed in vitro by bryostatins have led to the introduction of short-term bryostatin-1 infusions in phase I clinical trials. Because bryostatin (bryo) undergoes a rapid clearance in vivo, we were interested in its scheduling effects on acute myeloid leukemia (AML) clonogenicity. Therefore, we assessed the primary plating efficiency (PE1) of AML samples in response to several bryo concentrations after various preincubation periods in a semi-solid colony forming assay. Whereas continuous exposure to 10 nM bryo during the assay period reduced the PE1 in nearly all samples tested, preincubation of eight AML patients' specimens for 1, 2, 3 or 4 days with bryo in a dose range of 0.1-10 nM showed a heterogenous PE1 response. Stimulatory as well as inhibitory effects on leukemic clonogenic growth were seen within individual specimens depending on dose and preincubation time with no single incubation time or concentration that caused unequivocal common overall inhibition of clonogenic growth in most or all of the samples. Higher doses of bryo also failed to result in specific inhibition of leukemic cells: 4/8 samples showed an increased clonogenic response to 250 nM bryo whereas normal bone marrow progenitor cells were consistently inhibited in their clonogenicity at this dose. A marked similarity, i.e. undulatory effects with increasing bryo concentrations, was found for HL60 leukemic cells. In conclusion, the effects of bryo on clonogenic leukemia cell growth are strongly dependent on scheduling and dose varying between and within individual AML samples. These results caution against in vivo bryo pulse therapy, as currently applied, for treatment of AML.

Effects of bryostatin-5 and hematopoietic growth factors on acute myeloid leukemia cell differentiation, proliferation, and primary plating efficiency.

We examined the effect of bryostatin-5 (bryo-5) with and without a combination of myeloid growth promoting factors on human acute myeloid leukemia (AML) cell growth, maturation, and primary plating efficiency. In vitro treatment of AML samples with bryo-5 induced a macrophage-like cell differentiation as evidenced by morphological changes, esterase staining, and cell surface expression of CD11a and CD18. AML cells exposed to growth factors doubled their cell numbers following culture, this increase being abrogated by co-exposure to bryo-5. An antiproliferative effect, as well as the antagonistic interaction of bryo-5 with growth factors, was confirmed in methylcellulose clonogenic assays. Together, these findings indicate that the compound bryo-5 exerts an anti-proliferative effect on AML cells and counteracts growth factor induced leukemic proliferation.

Bryostatin-5 stimulates normal human hematopoiesis and inhibits proliferation of HL60 leukemic cells.

In this study we explored the effects of bryostatin-5 on the clonogenic response of normal bone marrow mononuclear (BM) cells and HL60 myeloid leukemia cells. Leukemic HL60 colony formation was strongly inhibited by bryostatin-5 depending on dose and schedule. An inhibitory effect on HL60 colony formation was readily demonstrated after 1 h of exposure, reaching a maximal inhibitory effect at 96 h. Normal BM cells differed in their clonogenic response: short-term exposure to bryostatin-5 resulted in increased clonogenicity while longstanding exposure to bryostatin-5 permitted the survival of a substantial fraction of committed progenitors. This differential modulation of normal and leukemic myeloid clonogenicity by bryostatin-5 suggests a possible role for bryostatin-5 in the treatment of acute myeloid leukemia.

The differentiation inducing effect of bryostatin 5 on human myeloid blast cells is potentiated by vitamin D3.

Bryostatin 5 is a macrocyclic lactone which activates protein kinase C (PKC). PKC activation has been implicated in leukemic cell differentiation. We have examined the effect of PKC activation by bryostatin 5 on human acute myeloid cell differentiation in the presence and absence of vitamin D3. In vitro treatment of 20 patient samples of acute myeloid leukemias in a 4 days culture system with 10 nM bryostatin 5 induced strongly adherent macrophage-like cells in all cases. Bryostatin 5 induced a significant (p = 0.00006) increment in esterase activity in a majority of the samples, which was further enhanced by vitamin D3. CD14 expression was significantly (p = 0.035) enhanced with the combination of bryostatin 5 and vitamin D3. Nitroblue tetrazolium (NBT) reducing ability was, however, nearly abolished (p = 0.0007). A loss of CD34 expression occurred during cell culture; this loss was enhanced by vitamin D3, but prevented partly by bryostatin 5. Together these findings indicate that exposure to bryostatin 5 leads to a strong macrophage-like cell differentiation in human myeloid leukemia and that VD3 has an additional effect. These findings strengthen the potential role of bryostatins as possible antileukemic agents.

Peripheral blood progenitors mobilised by G-CSF (filgrastim) and reinfused as unprocessed autologous whole blood shorten the pancytopenic period following high-dose melphalan in multiple myeloma.

Growth factor granulocyte colony-stimulating factor (G-CSF; filgrastim) is effective at progenitor release into the peripheral blood. After high-dose chemotherapy haematopoietic reconstitution occurs after reinfusion of these peripheral blood progenitor cells (PBPC). However, the collection by leukapheresis and further processing of PBPC are very time consuming and expensive. We have studied the transplantation potential of a small volume of unprocessed autologous whole blood after G-CSF mobilisation. Six patients with plasma cell disorders received G-CSF 10 micrograms/kg sc during 6 days. Subsequently 11 of whole blood was collected by phlebotomy, kept unprocessed at room temperature and reinfused 24 h after high-dose melphalan 140 mg/m2. CFU-GM content was 845 per ml blood (median, range 320-3472) and CD34+ cells rose to a median percentage of 0.9 (range 0.4-2.0). Haematological recovery was significantly faster in the study group compared with the control group of 20 patients who received the same dose of melphalan without reinfusion of PBPC. The neutrophil count reached 0.5 x 10(9)/l at a median of 12.5 days after infusion of PBPC vs 38 days in the control group (p = 0.0003). The platelet count reached 20 x 10(9)/l after a median of 23.5 days vs 38 days (p = 0.0218). The shortened recovery was reflected by less transfusions, less antibiotic use and shortening of hospital stay (19 days vs 43 days, p = 0.0003). We conclude that this easy technique of mobilisation and collection of PBPC is very effective for hastening haematologic recovery after high-dose chemotherapy.

Malignant Leydig cell tumor of the testis in complete remission on o,p'-dichlorodiphenyl-dichloroethane.

A 56-year-old patient is described who presented with retroperitoneal lymph node metastases 2 years after resection of a Leydig cell tumor of the left testis. The patient did not suffer from endocrinological imbalance. Surgical removal of the metastases alleviated abdominal symptoms for 1 year. o,p'-Dichlorodiphenyl-dichloroethane (o,p'-DDD) treatment was started at the time of recurrence of the retroperitoneal mass and the appearance of a hepatic metastasis. Tumors were remarkably responsive to o,p'-DDD, since 2 complete remissions could be obtained for extended periods. The o,p'-DDD was tolerated reasonably well and serum levels of 15 to 20 mg./l. were sustained for many months. Unfortunately, the patient could not be cured with this effective treatment.

Late relapse of testicular cancer. A case report and a review of the literature.

A case of disseminated testicular cancer relapsing after 6 and 8 yr is reported, and the literature on late relapses is reviewed. About 4% of potentially cured testicular cancer patients do relapse after two or more years. Early detection is important and we recommend an indefinite follow-up, because salvage therapy can be effective when the extent of disease is limited.

Bilateral excision of perinephric fat and fascia (Gerota's fasciectomy) in the treatment of intractable chyluria.

A case is described of a 59-year-old black man with massive chyluria, probably due to previous infection with Wuchereria bancrofti. Notably, no edema was present despite a urinary protein loss of 40 gm. per day resulting in a serum albumin level of 13 gm./l. Conservative treatment after lymphography, including prolonged bedrest and a medium chain triglyceride diet, was unsuccessful. Bilateral excision of the perinephric fascia and fat (Gerota's fasciectomy) in 2 separate operative sessions finally resulted in complete resolution of the chyluria.

"Spontaneous" catheter fracture and embolization of a totally implanted venous access port.

A case of "spontaneous" fracture of the catheter of a totally implanted venous access device is reported. The distal part of the catheter migrated into a pulmonary artery branch and could not be retrieved. The cause and consequences of this rare complication are discussed. It is emphasized that the integrity of a totally implanted venous access device should be ascertained before cytostatic agents are administered.