Paul Cannell

Dasatinib therapy for systemic mastocytosis: four cases.

To the Editor: Systemic mastocytosis (SM) is an uncommon disorder characterised by clonal proliferation and tissue infiltration by mast cells. Effective treatment options for patients with this disease are currently limited. Malignant mast cells are derived from stem cells with activating mutations of the KIT receptor tyrosine kinase (1, 2). The KIT mutation has been implicated in a significant proportion of SM cases (3). Dasatinib (BMS-354825; Bristol-Myers Squibb, New York, NY, USA) is a novel tyrosine kinase inhibitor which has been proven effective in inhibiting D816V positive mast cells in vitro (4, 5). There are currently no published clinical studies evaluating dasatinib in patients with SM. We report four cases of SM treated with dasatinib. The clinical, histological and genetic features of each case are summarised in Table 1. D816V mutation was detected in unfractionated bone marrow cells using a PCR assay (6), while fluorescence in situ hybridisation (FISH) studies were performed for FIP1L1-PDGFRa (7). Mast cell tryptase was measured using the UniCAP 100 (Pharmacia & Upjohn Diagnostics, Uppsala, Sweden) immunoabsorbant assay. Bone marrow trephine biopsies were examined and graded for the extent of involvement by mast cells as outlined in Table 1. Dasatinib was obtained from Bristol-Myers Squibb on compassionate grounds. Case 1 is a 20-year-old female who presented with pruritic skin rash, anorexia, diarrhoea and weight loss of 15 kg (18% of total body weight). Treatment with dasatinib 50 mg daily commenced with concomitant hydrocortisone (100 mg intravenously) and anti-histamine for the first three doses. A moderate exacerbation of skin rash, pruritus and nausea occurred 1 h after the first dose and resolved at 4 d. Dasatinib dose was increased to 50 mg twice daily at 1 month. A moderate reduction in pruritus, improved appetite and weight gain of 10 kg occurred after 6 months, though there was not significant change on repeat bone marrow biopsy. Case 2 is a 52-year-old male who presented with symptomatic pericardial effusion, hepatomegaly and splenomegaly (6 cm). Bone marrow biopsy showed myelodysplasia and diffuse infiltrates of mast cells. Initial treatment with imatinib was not effective and the patient developed moderate diarrhoea and generalised pruritic skin rash. Treatment with dasatinib commenced at 70 mg twice daily with concomitant antihistamines. The patient suffered significantly worse diarrhoea, pruritus and headaches from day 2 to day 5. Complete remission of diarrhoea and skin rash occurred after day 5. Bone marrow examination at 7 months revealed histological response (see Table 1). After 11 months, the patient developed acute myeloid leukaemia and dasatinib therapy ceased. Case 3 is a 60-year-old female who presented with an 18-month history of pruritic skin rash, headaches and lethargy. Early treatment including prednisolone, cladribine, nilotinib, interferon-alpha and splenic radiotherapy was ineffective and the patient developed grade 4 pancytopenia. Dasatinib therapy commenced 5 yr after initial diagnosis. Dose was escalated from 20 mg twice daily to 70 mg twice daily over 3 d, with administration of corticosteroid (hydrocortisone 100 mg intravenously, one dose only) and anti-histamines prior to each dose. Prednisolone 37.5 mg daily was weaned over the following 6 wk. No adverse effects occurred during early treatment. There was no evidence of significant clinical or histological response despite dose increase to 90 mg twice daily and then 110 mg twice daily. Dasatinib therapy ceased after 2 months. Two months later the patient died of complications related to sepsis. Case 4 is a 49-year-old man who was diagnosed with indolent systemic mastocytosis with prominent mast cell degranulation symptoms (ISMSY) after presenting with anaphylactic shock on a background of four previous episodes of anaphylaxis. Interferon-alpha, cladribine, prednisolone and intravenous human immunoglobulin were ineffective and episodes of anaphylaxis occurred with increasing frequency. Dasatinib commenced at 4 yr after diagnosis. Concomitant therapy included ranitidine (ceased with first dasatinib dose), dexchlorpheniramine, sodium cromoglycate, ketolifen and montelukast. No adverse effects were observed. Episodes of anaphylaxis occurred with the same frequency. Dasatinib therapy ceased after 6 months. Dasatinib was generally well tolerated. Cases 1 and 2 suffered early adverse effects that are likely to have been mediated by mast cell mediator release. A similar phenomenon is observed with other cytoreductive agents in SM (8). Cases 3 and 4 showed no response to dasatinib therapy. Both had been heavily pretreated prior to commencing treatment. This small series suggests that dasatinib has some in vivo activity in SM, treating symptoms and reversing disease progression in some patients. The doi:10.1111/j.1600-0609.2008.01048.x European Journal of Haematology ISSN 0902-4441

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 μg 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 × 109/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 × 109/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°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.

Results of the APML3 trial incorporating all-trans-retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia

Background Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. Design and Methods In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine. Results Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001). Conclusions The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459)

Infections in patients managed at home during autologous stem cell transplantation for lymphoma and multiple myeloma.

A group of 51 patients with multiple myeloma, non-Hodgkin’s lymphoma or Hodgkin’s disease receiving high-dose chemotherapy and autologous peripheral blood stem cell rescue received chemotherapy and clinical care in the peritransplant period at home. This group was compared with 88 cases with the same diagnoses, receiving the peripheral stem cell transplant over the same time period as an inpatient in a high efficiency particulate air filtered bone marrow transplant unit. Patients were treated at home based on choice, geographic accessibility, availability of an educated care giver and a clean home environment, and comprehension of the concepts of infection and aseptic techniques. Febrile neutropenia and sepsis were not increased in the home group and no episodes of septic shock were seen in this group. Patients at home received prophylactic oral ciprofloxacin and roxithromycin during the phase when the absolute neutrophil count was <1 × 109/l. Fewer gram-negative infections, but no diminution in gram-positive infections or in the rate of fever were seen in patients at home. Empiric therapy with a third generation cephalosporin, teicoplanin and tobramycin was instituted in 31 patients who developed a fever greater than 38.5°C. Of this group of 31, 18 required admission to hospital, 12 because of febrile neutropenia which persisted or was considered unsuitable for management at home due to sepsis. The remaining 13 with febrile neutropenia remained at home throughout, as did the 20 cases not developing neutropenic fever. This study demonstrates the feasibility of managing carefully selected patients in their home environment when at risk from febrile neutropenia or other septic complications following autologous peripheral stem cell support.

A phase II study of Rituximab in rheumatoid arthritis patients with recurrent disease following haematopoietic stem cell transplantation.

Summary:Haematopoietic stem cell transplantation (HSCT) has been used recently as an effective therapy in patients with resistant rheumatoid arthritis (RA). Although disease control occurs in the majority of cases, recurrence is common, often coinciding with B-cell reconstitution. We hypothesized that Rituximab, a monoclonal anti-CD20 antibody, would have activity in this group of patients. We treated 10 RA patients (8F:2M, median age 46.5 years), who had recurrent disease post HSCT. All patients received two doses of Rituximab 1 g, 2 weeks apart with no major adverse sequelae and were followed for 12 months. A total of eight out of 10 patients experienced major clinical responses as measured by the American College of Rheumatology (ACR) criteria, with 50–70% improvement in disease parameters. Responses were equivalent to previous responses attained with HSCT. Disease responses were maximal at 4–8 months post Rituximab and correlated with B-cell lymphopenia and a reduction of rheumatoid factor titre. Disease recurrence occurred in 6/9 responders within 12 months and four patients were subsequently retreated, with major responses again attained. This study provides further evidence that B-cell depletion leads to a significant improvement in disease activity in patients with severe RA and provides data for future trials of HSCT and Rituximab therapy.

Unrelated cord blood transplantation for patients with primary or secondary myelofibrosis.

To determine whether umbilical cord blood transplantation (UCBT) is an alternative cure for myelofibrosis (MF), we evaluated 35 UCBTs reported to Eurocord. Seven patients had secondary acute myeloid leukemia (AML) at UCBT, and median age at UCBT was 54 years. Twenty-four patients received a reduced-intensity conditioning (RIC) regimen, and 17 of 35 patients received total body irradiation (2 to 12 Gy)-fludarabine-cyclophosphamide (TCF) conditioning. The median follow-up was 24 months. The cumulative incidence of neutrophil recovery at 60 days was 80%. Fifteen patients relapsed after UCBT. The 2-year overall survival and event-free-survival (EFS) rates were 44% and 30%, respectively. All patients given TCF achieved neutrophil and platelet recovery, and the use of TCF was associated with superior EFS in the RIC population (44% versus 0%, P = .001). Patients with transformation to AML had similar outcomes to patients with less advanced stages. In conclusion, despite graft failure remaining a major concern, the role of UCBT in the management of MF, especially using RIC TCF-based regimens, deserves further investigation to improve results.

Acute graft-versus-host disease after liver transplant: Novel use of etanercept and the role of tumor necrosis factor α inhibitors

Acute graft‐versus‐host disease following orthotopic liver transplantation is a rare but feared complication arising in 1% to 2% of cases with a dismal prognosis. It most often presents as fever, rash, and diarrhea with or without pancytopenia. Patients die from complications of marrow failure such as sepsis or bleeding. Because of its low incidence, there is no clear treatment protocol for this complication. Both increasing and withdrawing immunosuppression have been attempted with variable success. Although anti–tumor necrosis factor α therapy has been widely used for the treatment of steroid‐resistant acute graft‐versus‐host disease in the hematopoietic stem cell transplant setting, there previously have been no reported cases of its use in liver transplantation. The aim of this report is to review a case of acute graft‐versus‐host disease and the use of etanercept to manage this complication. Etanercept has never previously been used in liver transplantation complicated by acute graft‐versus‐host disease. In the hematology literature, the success of its use is offset by significant rates of serious infectious (especially fungal) complications. However, preliminary results are encouraging and offer insight into its use as a potentially viable therapeutic option. We report the first successful use of etanercept in liver transplantation–associated graft‐versus‐host disease, albeit complicated by invasive aspergillosis, and recommend concurrent antifungal prophylaxis when the drug is used in this setting. Liver Transpl 15:421–426, 2009.

Unrelated Donors Selected Prospectively by Block-matching Have Superior Bone Marrow Transplant Outcome

Previous retrospective studies have demonstrated improved outcome in patients whose donors were matched for non-HLA markers in the MHC as well as for HLA genes. Forty patients receiving transplants from unrelated donors were typed prospectively for HLA and non-HLA markers. Non-HLA markers near HLA-B (beta-block markers) and in the DRB1 introns (delta-block markers) were used to assess MHC match between donors and recipient. Patients whose donors were matched at the beta- and delta-blocks had improved event free survival (63%) compared to patients whose donors were mismatched at one or both blocks (25%) (p < 0.05). Patients whose donors were matched at the beta-block had significantly less severe acute graft versus host disease (p < 0.05). In order to investigate the basis for improved outcome block matching was correlated with HLA matching as determined by DNA sequencing. Beta-block matching was highly correlated with matching for exons 2 and 3 of HLA-B but less so for HLA-C. Delta-block matching was highly correlated with matching for exon 2 of HLA DRB1. It is concluded that matching for non-HLA markers in the MHC improves matching for HLA genes. Further studies are required to determine whether matching for non-HLA markers improves outcome to a greater extent than matching for the HLA genes alone.

Second cancer risk in adults receiving autologous haematopoietic SCT for cancer: a population-based cohort study

Population-based evidence on second cancer risk following autologous haematopoietic SCT (HCT) is lacking. We quantified second cancer risk for a national, population-based cohort of adult Australians receiving autologous HCT for cancer and notified to the Australasian Bone Marrow Transplant Recipient Registry 1992–2007 (n=7765). Cancer diagnoses and deaths were ascertained by linkage with the Australian Cancer Database and National Death Index. Standardized incidence ratios (SIRs) were calculated and Cox regression models were used to estimate within-cohort risk factors treating death as a competing risk. During a median 2.5 years follow-up, second cancer risk was modestly increased compared with the general population (SIR 1.4, 95% confidence interval 1.2–1.6); significantly elevated risk was also observed for AML/myelodysplastic syndrome (SIR=20.6), melanoma (SIR=2.6) and non-Hodgkin lymphoma (SIR=3.3). Recipients at elevated risk of any second cancer included males, and those transplanted at a younger age, in an earlier HCT era, or for lymphoma or testicular cancer. Male sex, older age (>45 years) and history of relapse after HCT predicted melanoma risk. Transplantation for Hodgkin lymphoma and older age were associated with lung cancer risk. Second malignancies are an important late effect and these results inform and emphasize the need for cancer surveillance in autologous HCT survivors.

Phase i clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: Study NPI-0052-102 final results

Purpose: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors. Experimental Design: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. Results: Forty-two patients with advanced malignancies received Schedule A (0.1–0.9 mg/m2 over 1–10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075–0.6 mg/m2 over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m2 over 10 minutes; Schedule B was 0.5 mg/m2 over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (∼15–416 L) and clearance (∼0.9–22 L/minutes). Conclusions: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559–66. ©2016 AACR.