Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for transplant-ineligible myeloma: AMaRC 03-16.

ABSTRACT: In newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumab-containing arm showed a significant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% (P = .0002); 24 months, 36% vs 52% (P = .0001); and 30 months, 27% vs 41% (P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were significantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369).

Immunoglobulin replacement vs prophylactic antibiotics for hypogammaglobulinemia secondary to hematological malignancy.

ABSTRACT: Immunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological malignancies but have never been directly compared. In this randomized controlled feasibility trial conducted in 7 hospitals in Australia and New Zealand, we enrolled patients with secondary hypogammaglobulinemia with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Participants were randomized in a 1:2 ratio to immunoglobulin (0.4 g/kg per 4 weeks IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. Participants allocated to antibiotics were allowed to crossover after grade ≥3 infections. The primary outcome was proportion of patients alive on the assigned treatment 12 months after randomization. Between August 2017 and April 2019, 63 patients were randomized: 42 to antibiotics and 21 to immunoglobulin. Proportion of participants alive on allocated treatment at 12 months was 76% in the immunoglobulin and 71% in the antibiotic arm (Fisher exact test P=.77; odds ratio, 0.78; 95% CI, 0.22-2.52). The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm (log-rank test, P=.65). Three participants in the immunoglobulin and 2 in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on immunoglobulin, with similar rates of major infections. Our findings support the feasibility of progressing to a phase 3 trial. Trial registration #ACTRN12616001723471.

Economic evaluation: immunoglobulin vs prophylactic antibiotics in hypogammaglobulinemia and hematological malignancies.

ABSTRACT: Patients with hematological malignancies are at high risk of developing hypogammaglobulinemia (HGG) and infections. Immunoglobulin (Ig) is one recommended option to prevent these infections, but it is expensive, and its cost-effectiveness compared with other prevention strategies remains unknown. We conducted a trial-based economic evaluation from the Australian health care system perspective to estimate the 12-month cost-effectiveness of prophylactic Ig vs prophylactic antibiotics in 63 adults with HGG and hematological malignancies participating in the RATIONAL feasibility trial. Two analyses were conducted: (1) cost-utility analysis to assess the incremental cost per quality-adjusted life year (QALY) gained; and (2) cost-effectiveness analysis to assess the incremental cost per serious infection prevented (grade ≥3) and per any infection (any grade) prevented. Over 12 months, the total cost per patient was significantly higher in the Ig group than in the antibiotic group (mean difference, AU$29 140; P < .001). Most patients received IVIg, which was the main cost driver; only 2 patients in the intervention arm received subcutaneous Ig. There were nonsignificant differences in health outcomes. Results showed Ig was more costly than antibiotics and associated with fewer QALYs. The incremental cost-effectiveness ratio of Ig vs antibiotics was AU$111 262 per serious infection prevented, but Ig was more costly and associated with more infections when all infections were included. On average and for this patient population, Ig prophylaxis may not be cost-effective compared with prophylactic antibiotics. Further research is needed to confirm these findings in a larger population and considering longer-term outcomes. The trial was registered at the Australian and New Zealand Clinical Trials Registry as #ACTRN12616001723471.

Hypereosinophilic syndrome with cutaneous manifestations successfully treated with Dupilumab as a sole agent: A case report.

Hypereosinophilic syndrome describes a process in which eosinophils in the peripheral blood are persistently increased, with variable clinical manifestations. Finding efficacious treatments for this disease can be challenging. This case describes a 72-year-old man with idiopathic hypereosinophilic syndrome with cutaneous manifestations who was successfully treated with dupilumab as a single agent therapy. There was complete clinical and biochemical resolution of disease (eosinophils levels decreased from 4.13 to 0.92) without complications.

Longitudinal study of intravenous versus subcutaneous immunoglobulin replacement therapy in hematological malignancy.

AIM: To present findings from a longitudinal study on infection risk, mortality, and patient perspective of intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) treatment for patients with hypogammaglobulinemia secondary to hematological malignancy or its treatment (abbreviated as SID). METHODS: Observational study period included final year of IVIg (13 patients) and of the first 3 years of SCIg (17 patients) with SID. Data were collected on clinical outcomes from medical records and patient perception via study specific questionnaire. RESULTS: The median age was 63 years (53-76 years), and for 82.4% of patients their hematological malignancy was in complete remission. The annual mean serum IgG trough levels remained stable over the 4 years and were 7.0 g/L (±2.77 g/L) with IVIg, and 8.0 g/L (±1.75 g/L), 8.7 g/L (±2.75 g/L), and 7.6 g/L (±2.89 g/L) (year 1, 2, and 3, respectively) with SCIg. While the annual infection rate was similar, the rate of hospitalization due to infection fluctuated, with 37%, 9%, 15%, and 32% in year 1, 2, 3, and 4 respectively. There were no systemic adverse events with IVIg or SCIg. Patients reported a strong preference for SCIg. One patient died due to progression of underlying disease and infection within the study period. CONCLUSION: SCIg was the preferred treatment mode over IVIg in our cohort, but both were well tolerated without any systemic adverse events in 4-year follow up. The dosage and serum IgG levels were stable throughout. However, the number of infections requiring hospitalization fluctuated. It is anticipated that these findings encourage more hospitals to offer SCIg for SID patients.

Bortezomib use and outcomes for the treatment of multiple myeloma.

BACKGROUND: The public subsidy in Australia of bortezomib (Velcade) for untreated non-transplant multiple myeloma patients was based on the VISTA trial. AIMS: To ascertain the health outcomes of bortezomib in 'real world' transplant-ineligible elderly patients, compared to trial data. METHODS: Patient and treatment data were extracted from an oncology information system, laboratory information system and medical chart audits for three Queensland public hospitals. RESULTS: We identified 74 patients; the median age was 75 years. Our cohort comprised 47% patients who were International Staging System stage III, 45% at stage II and 8% at stage I. Patients who had comorbidities, such as cardiac disease (41%), pulmonary disease (14%), diabetes (22%), peripheral neuropathy (14%) and other comorbidities (41%) at baseline were included. The common regimens prescribed were VMP, CVD and VD, and most patients (n = 73) received bortezomib on a once-weekly or twice-a-week basis. The overall response rate was 81%. Half (53%) of the patients did not complete their planned therapy due to toxicity (30%), suboptimal response or disease progression (15%), or death on treatment (8%). Overall survival was 40.7 months and progression free survival was 17.7 months. CONCLUSIONS: Our patients were older, had worse disease characteristics and more comorbidities than patients in the VISTA trial. While response rates were similar, survival outcomes appeared worse. Bortezomib-based treatment in the real world setting still carries a high risk of toxicity in the elderly population.

Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy.

Immunoglobulin replacement therapy (IRT) has an important role in minimizing infections and improving the health-related quality of life (HRQoL) in patients with immunodeficiency, who would otherwise experience recurrent infections. These plasma-derived products are available as intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin (SCIg). The global demand for these products is growing rapidly and has placed pressure on supply. Some malignancies and their treatment (as well as other medical therapies) can lead to secondary hypogammaglobulinemia or secondary immunodeficiency (SID) requiring IRT. Although IVIg use in this cohort has well-established therapeutic benefits, little is known about SCIg use. A literature search in July 2015 found only 7 published articles on SCIg use. These articles found that both IRT modes had equivalent efficacy in regard to reduction of bacterial infections. In addition, SCIg was reported to produce higher serum IgG trough levels compared with IVIg on equivalent dosage with the added benefit of fewer adverse effects. Patient HRQoL reports demonstrate preference for SCIg because of reduced adverse effects and hospital visits. There are no health economic models published on SCIg use in SID, but models on primary immunodeficiency disease and IRT conclude that SCIg provided greater economic benefits than IVIg. The findings of this small number of reports suggest that SCIg therapy for patients with SID is likely to be beneficial for both the patient and health care providers. To substantiate wider use of SCIg in SID, larger and more detailed studies are needed to accurately quantify the effectiveness of SCIg.

Outcome of treatment of adult acute lymphoblastic leukemia with hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone/methotrexate, cytarabine: results from an Australian population.

The optimal initial therapy for treatment of adult acute lymphoblastic leukemia is yet to be defined. Hyper-CVAD has become a widely used treatment for adult acute lymphoblastic leukemia, although publication of outcomes is largely limited to single-center experience. We performed a retrospective analysis of 63 patients treated with Hyper-CVAD at two Australian institutions between 1995 and 2007. Complete remission was obtained in 86% of patients, with an induction mortality of 8%. Treatment-related toxicity was high, resulting in premature cessation of planned treatment in 29% of patients achieving CR. Survival estimates were comparable to previously published experience, with estimated 5-year overall and progression-free survival of 48% and 42%, respectively. Allogeneic stem cell transplant was performed in 22% of patients in first complete remission, with encouraging survival outcomes (estimated 5-year overall survival 75%, progression free survival 82%). Hyper-CVAD is an effective and tolerable induction strategy for adult ALL, and is suitable for use prior to allogeneic stem cell transplant in first complete remission.

Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.

Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.

Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.

Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.

Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.

Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors.

A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.