Matthew Greenwood

Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy

PURPOSE Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee. RESULTS Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). CONCLUSION Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.

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.

Tolerability to romidepsin in patients with relapsed/refractory T-cell lymphoma

BackgroundHistone deacetylase inhibitor romidepsin has demonstrated durable clinical responses and tolerability in patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma (PTCL, CTCL). Selection of novel drug therapies for patients with relapsed/refractory aggressive lymphoma requires not only considerations regarding efficacy but also careful evaluation of toxicities as well as overall clinical benefit. The purpose of this analysis was to examine common adverse events (AEs) reported in pivotal trials of romidepsin in relapsed/refractory PTCL or CTCL and to more clearly define the overall AE profile in these populations.MethodsPatients with relapsed/refractory PTCL or CTCL were treated with romidepsin at 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 of 28-day cycles for up to 6 cycles; patients with at least stable disease could extend therapy until progressive disease or another withdrawal criterion was met. All enrolled patients who received ≥ 1 dose of romidepsin were included in the AE analyses.ResultsOverall, safety profiles of common AEs were similar, although patients with relapsed/refractory PTCL had more frequent hematologic toxicities and grade ≥ 3 infections. In both patient populations, the greatest incidence of grade ≥ 3 AEs and the majority of discontinuations due to AEs occurred during cycles 1–2. Early discontinuations were primarily related to infection, thrombocytopenia, or electrocardiogram abnormalities, confirming the need to closely monitor patients with poor bone marrow reserve or other comorbidities. Despite this, 28% of patients with relapsed/refractory PTCL and 36% of patients with relapsed/refractory CTCL continued on romidepsin treatment for ≥ 6 cycles.ConclusionsThis study demonstrates that patients with relapsed/refractory PTCL or CTCL have similar AE profiles with romidepsin treatment, although patients with PTCL experienced more frequent and more severe hematologic toxicities and more frequent grade ≥ 3 infections. The greatest incidence of grade ≥ 3 AEs and the majority of discontinuations due to AEs occurred during treatment cycles 1–2. Extended dosing of romidepsin can be tolerated in responding patients.Trial registrationNCT00426764NCT00106431

Invasive pneumococcal disease following adult allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients are at high risk of invasive pneumococcal disease (IPD). We investigated the incidence and risk factors of IPD in alloHSCT recipients from 4 regional transplant centers over an 11‐year period. This study aimed to inform future improvements in post‐transplant care.

Romidepsin induces durable responses in patients with relapsed or refractory angioimmunoblastic T-cell lymphoma.

Peripheral T‐cell lymphoma (PTCL) is a heterogeneous group of mature, post‐thymic, T‐ and natural killer‐cell non‐Hodgkin lymphomas (NHL)— nearly all subtypes are associated with a poor prognosis. Regardless of subtype, patients with PTCL typically receive induction chemotherapy (commonly CHOP[cyclophosphamide+doxorubicin+vincristine+prednisone]) as first‐line treatment. Except for anaplastic lymphoma kinase– positive anaplastic large cell lymphoma, outcomes are generally poor and many responding patients rapidly relapse. Achievement of durable responses in patientswith relapsed/refractory PTCL is difficult, and there arefewtreatmentoptions. Angioimmunoblastic T‐cell lymphoma (AITL) is a common subtype of PTCL (16% of diagnoses in the USA, 18% in Asia and 29% in Europe). The 5‐year overall survival (OS) in patients with AITL is reported to be just 32%, and AITL is characterised by generalised lymphadenopathy, extranodal involvement, hypergammaglobulinemia, and advanced stage at presentation. Immune dysregulation commonly results in infections, which are a frequent cause of death in patients with AITL. Romidepsin is a structurally unique, potent, bicyclic class I selective histone deacetylase inhibitor approved for the treatment of all subtypes of relapsed/refractory PTCL. In the pivotal phase 2 trial conducted in patients with relapsed/refractory PTCL, romidepsin treatment resulted in durable responses with manageable toxicity. The objective response rate (ORR) was 25% (33/130), including 15% confirmed/unconfirmed complete responses (CR/CRu), and the median duration of response (DOR) was 28 months. Patient baseline characteristics (including PTCL subtype) or prior treatments did not significantly affect response rates. The most frequent romidepsin‐related adverse events (AEs) were gastrointestinal and asthenic conditions, which were primarily grade 1/2 and rarely resulted in drug discontinuation. Here, we report updated data from the pivotal phase 2 study focused on patients with AITL. In the overall study, eligible patients had PTCL (measurable disease by International Working Group [IWG] criteria 14 and/or measurable cutaneous disease) relapsed/refractory to ≥1 therapy, Eastern Cooperative Oncology Group performance status of zero to two and adequate bone marrow and organ function at enrollment. Patients with significant cardiac abnormalities were

Utility of 18fluoro-deoxyglucose positron emission tomography for prognosis and response assessments in a phase 2 study of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma

This study examined the utility of PET scans for assessing prognosis and response to treatment in patients with relapsed/refractory PTCL receiving romidepsin. For patients with stable disease or partial response by conventional criteria, PET status better differentiated durability of response than conventional response category. Routine PET use may aid in treatment planning in patients with PTCL.

Factors determining pbsc mobilization efficiency and nonmobilization following ICE with or without rituximab (R-ICE) salvage therapy for refractory or relapsed lymphoma prior to autologous transplantation

ICE/R‐ICE (ifosfamide, carboplatin, and etoposide without or with rituximab) chemotherapy followed by autologous stem cell transplantation is an established regimen in refractory/relapsed lymphoma. Few studies have addressed which factors are important in determining peripheral blood stem cell (PBSC) mobilization efficiency or nonmobilization following ICE/R‐ICE. Between 2004 and 2013, 88 patients with refractory/relapsed lymphoma who received ICE/R‐ICE salvage‐chemotherapy prior to granulocyte colony stimulating factor (G‐CSF) stimulated PBSC mobilization at a single center were identified. Mobilization efficiency was assessed by time from ICE/R‐ICE to day of harvest, duration of G‐CSF use, days to peripheral blood (PB) CD34+ ≥15/µL, PB CD34+ number on harvest day, CD34+ yield and nonmobilization rate. Median PB CD34+ at harvest were 54/μL (7–524); median days to first apheresis was 15 (11–30); median harvested total CD34+ were 5.46 × 106/kg (0.96–44.36); 71 patients (80.7%) successfully mobilized; 20 (22.7%) patients were poor mobilizers; 14 (15.9%) patients were considered nonmobilizers with maximal PB CD34+ <7/µL and did not proceed to apheresis. Six of 20 poor mobilizers were apheresed with PB CD34+ 7–12/µL, 50% were successfully harvested. No differences were found between ICE and R‐ICE regimens. Impaired mobilization efficiency was associated with age, remission status, >1 line of induction chemotherapy, four cycles ICE/R‐ICE and grade 4 neutropenia. Prior bone marrow (BM) involvement was associated with nonmobilization. The majority of patients can be successfully mobilized with ICE/R‐ICE. Prior BM involvement is associated with high rates of nonmobilization following ICE/R‐ICE. Such patients may benefit from novel mobilization agents and/or alternative salvage regimens to ICE/R‐ICE. J. Clin. Apheresis 29:322–330 2014.

Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse

We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft‐versus‐host disease (GVHD) on OSR.

Assessing pilot vial material as a surrogate for functional and phenotypic stem cell markers in cryopreserved haematopoietic stem cell product

Assessing pilot vial material as a surrogate for functional and phenotypic stem cell markers in cryopreserved haematopoietic stem cell product

Addition of low dose total body irradiation to fludarabine melphalan reduced intensity conditioning is feasible, tolerable, and may improve outcomes in patients with high-risk acute myeloid leukaemia and other high risk myeloid malignancies.

To the Editor: Allogeneic haemopoietic stem cell transplantation (allo-HSCT) following induction and consolidation chemotherapy reduces relapse for all AML risk groups. Age over 60 years is an independent poor prognosticator on multivariate analyses. Reduced intensity conditioning (RIC) has permitted older and poorer performance status patients to receive allo-HSCT as a potentially curative treatment. RIC for AML in CR1 reduces treatment related mortality (TRM) by almost half compared to myeloablative conditioning. Furthermore, RIC results in similar disease free survival (DFS) and overall survival (OS) and significantly reduces nonrelapse mortality (NRM) for patients over the age of 40 years [1]. While RIC produces durable engraftment and demonstrable graft versus malignancy effect [2], less intense regimens carry an increased risk of graft failure, and relapse [3]. These data suggest further development of RIC conditioning protocols should focus on reduction of disease relapse without increasing TRM. In Australia, the most commonly used RIC regimen is fludarabine-melphalan (FluMel) [4,5]. This is usually administered intravenously over 6 days: fludarabine 25 mg/m D-7 to D-3 and melphalan 140 mg/m D-2 [6]. This regimen has acceptable treatment related toxicities and yields stable engraftment [7]. When oral fludarabine is used, it results in similar donor engraftment and chimerism to intravenous formulations [8,9]. Oral fludarabine has been used for over 10 years in our centre with the benefits of reduced hospitalization. As high-risk AML and myeloid malignancies have an increased risk of relapse, intensification of conditioning may offer a survival advantage [10]. Our aim was to intensify conditioning to improve clinical outcomes in high-risk disease without additional toxicities or NRM. We considered addition of low dose total body irradiation (TBI) to be a feasible manipulation of Flu-Mel conditioning. First, engraftment is possible with low doses of TBI at 2 or 4 Gy with minimal toxicities [11–13]. Second, low dose TBI is safe, tolerable, easy to administer, low in cost, and does not lengthen hospitalization. From January 2010 until time of writing, our institution adopted a risk-adapted approach that conditioned all MAC ineligible patients with high-risk AML or other myeloid malignancies with Flu-Mel-TBI. This consisted of oral fludarabine (40 mg/m) days 6 to -2 inclusively, intravenous melphalan (140 mg/m) day -2, and low dose TBI (200cGy day -1, or 400cGY fractionated on days -1 and 0). TBI dose was determined by physician preference. Patients self-administered oral fludarabine at home, and were admitted from D-2 for intravenous melphalan until discharge following engraftment and stabilization of medical issues. Supportive care was uniform for all patients. This included barrier nursing in single rooms with high efficiency particular air filters and protective isolation in a purpose-built ward. All patients received a low bacterial load diet. Antimicrobial prophylaxis included azole fungal prophylaxis, valaciclovir for herpes virus prophylaxis, and a pre-emptive approach to cytomegalovirus. Total parenteral nutrition (TPN) and conversion to intravenous medications was used for patients intolerant of oral intake. Graft versus host disease (GVHD) prophylaxis was uniform for all patients, consisting of cyclosporine (3 mg/kg intravenously daily, targeted to 100–200 mg/L with therapeutic drug monitoring), methotrexate (15 mg/m intravenously days 11, 3, 6, 11), and prednisolone, dosed as per Ruutu et al. [14]. Twenty-four patients with AML or high-risk myeloid malignancies were referred for allo-HSCT in this period. Fourteen consecutive patients with high-risk disease ineligible for conventional-intensity allo-HSCT but suitable for RIC were conditioned with FluMel-TBI; 13 had AML and 1 had myelofibrosis. All patients received 400cGy TBI apart from 1 patient transplanted for myelofibrosis who received 200cGy. Patients were judged to have high-risk AML if they had primary induction failure, unfavorable cytogenetics or molecular features, secondary AML, and relapsed disease. Of 13 AML patients, 7 patients had 1, and 6 patients had 2 risk factors. The patient with myelofibrosis had an IPSS (international prognostic scoring system) of 4. Median age was 60.5 years (range 27–69). If age> 60 was included as an independent risk factor, then 3 patients had 1, 8 patients had 2, and 3 patients had 3 risk factors. Patients and transplant characteristics are summarized in Table I. Median follow-up was 12.7 months (range 0.8–106.2 months). PBSC graft contained a median of 5 (range 3.38–8.42) 3 10 CD341 cells per kg. Median duration of hospitalization was 23.5 days (range 17–32 days), similar to AML patients conditioned with FluMel during the same period in our institution (23.5 days, range 15–72). Median time to neutrophil and platelet engraftment for the remaining patients was 17 and 20 days, respectively. Mucositis grade II–IV occurred in 3 (21%), 2 (14%), and 2 (14%) patients, respectively. Severe sepsis requiring admission to the intensive care unit occurred in 3/14 (21%) patients; of these, 2/3 requiredaggressive fluid management and 1/3 required inotropic support. One patient died of Pseudomonas aeruginosa infection, while 1 with Staphylococcus haemolyticus and and 1 with Escheria coli infection were both successfully treated. Hepatic sinusoidal obstructive syndrome occurred in 2/14 (14%) patients and both recovered following treatment with defibrotide (10 mg/kg twice daily for 14 days or until resolution). Posterior reversible encephalopathy syndrome occurred in 1/14 (7%) patients secondary to cyclosporine. Acute kidney injury requiring short-term dialysis occurred in 1/14 (7%) patients. Graft failure occurred in 1(7%) patients who died of sepsis in aplasia. Three (21%) patients received TPN following admission to the intensive care unit for severe sepsis. Donor chimerism was 100% for all patients who had chimerism studies performed (n5 12). Cytogenetic or molecular remission was achieved in all but one patient who died in aplasia. aGVHD occurred in 6 patients (43%), severity Glucksberg Stages I–IV in 2 (14%), 1 (7%), 1 (7%) and 2 (14%) patients, respectively. Chronic GVHD occurred in 6 patients (43%), 4 (29%) had mild and limited, 1 (7%) had moderate and limited, and 1 (7%) had severe and extensive disease. Engraftment, nonhaematopoietic toxicities, GVHD, and clinical outcomes are summarized in Table 4. NRM at D100 was 7%. One patient died at D25 due to infection prior to engraftment. One year NRM was 28%; two patients died of infection (D25, D244) and two died of acute GVHD (D111 and D178). Relapse occurred in 14% (2/14) at a median of 4.5 months (range 3 to 6 months) from allo-HSCT, both died of relapsed disease. Estimated 1 year DFS and OS was 57, and 50% at 3 years. In this series of older, high-risk patients with uniformly poor prognosis myeloid malignancies, the combination of Flu-Mel and low dose TBI appears to be tolerable with an acceptably low early relapse rate. Our results compare favourably with similar intensified RIC regimens including FLAMSA-RIC [15] and TBI added to Flu-ivBu-ATG. The FLAMSA-RIC protocol described by Schmid et al. used fludarabine-Ara-C-amsacrin followed by 400cGy TBI-cyclophosphamide-antithymocyte globulin (ATG) RIC and prophylactic donor lymphocyte infusions. For a group of high-risk AML patients (n5 75, median age 52 years), OS and DFS was 42% and 40% at 2 years, 23% died of refractory or relapsed leukaemia, and NRM was 20% at D100 and 33% at 1 year. Reported toxicities in this study included 28% grade I/II mucositis, and 26 episodes grade III/IV regimen related toxicity including 5 deaths in aplasia. 37/75 patients experienced a septic episode which included 31 patients with radiologically documented pneumonia. . Russell et al reported that the addition of 400cGy TBI to Fludarabine and IV Busulfan (n5 22), together with ATG reduced relapse rates from 79% to 33% when compared to Flu-ivBU alone (n5 34) in a retrospective analysis. In that study, the exact DFS, OS and NRM cannot be determined due to inclusion of low-risk patients in survival analyses. However, the authors reported no difference in NRM across risk groups when TBI was included in the conditioning. In comparison to the two studies summarized above, our combination of low dose TBI with oral Fludarabine and IV Melphalan resulted in a low early relapse rate, enables reliable engraftment, and was straightforward to administer. Despite small numbers and short median follow-up, Flu-Mel-TBI appears to be a tolerable RIC regimen with intensive antileukemia effect and acceptable NRM in MAC ineligible patients with high risk AML/myeloid neoplasms. Further prospective studies are warranted.