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Keywords:

  • Hodgkin lymphoma;
  • HDAC inhibitor;
  • LBH589;
  • panobinostat

Summary

  1. Top of page
  2. Summary
  3. Design and methods
  4. Results and discussion
  5. Discussion
  6. Conflict of interest disclosure
  7. References

There are few treatment options for patients with Hodgkin Lymphoma (HL) who relapse after conventional therapies. Panobinostat is an orally available pan deacetylase inhibitor with evidence of activity in myeloid malignancies and cutaneous T cell lymphoma. Thirteen HL patients were treated with escalating doses of this novel agent in a phase IA/II multicentre study. A computed tomography partial response was achieved in 5/13(38%), and a metabolic response by 18F-fluoro-2-deoxy-d- glucose positron emission tomography scanning in 7/12 (58%) evaluable patients. This report describes the preliminary evidence of anti-tumour activity seen in the early phase of this study, which recently closed to accrual.

Histone deacetylases (HDACs) remove acetyl groups from lysine moieties within histones resulting in condensed chromatin conformation and repression of gene transcription in normal cells. Increased HDAC activity is associated with the survival of malignant cells in vitro, partly through the relatively reduced expression of pro-apoptotic genes and up-regulated transcription of anti-apoptotic genes (Bolden et al, 2006). This and similar observations have led to the development of HDAC inhibitors (HDACi) as anti-cancer agents. Indeed, as these drugs also inhibit deacetylase function on multiple non-histone proteins, they are more correctly termed deacetylase inhibitors (DACi). DACi are broadly divided into Class I-DAC and pan-DAC inhibitors.

Panobinostat (LBH589) is a novel orally bioavailable hydroxamic acid-derived pan DACi. In vitro studies demonstrate that target pathways include those of transforming growth factor-β, heat shock protein 90, (Bhalla et al, 2007; Zhou et al, 2008) nuclear factor κB(Maiso et al, 2006; Nishioka et al, 2008). Moreover, in patients with cutaneous T cell lymphoma (CTCL), we have demonstrated that panobinostat has rapid and sustained effects in vivo on target genes involved in cell cycle regulation, gene transcription factors, angiogenesis and immune regulation (Ellis et al, 2008).

Early phase studies of DACi show that in addition to activity against CTCL, DACi also have efficacy in myeloid malignancies (Spencer et al, 2007; Ellis et al, 2008). More recently, there have been early reports of activity in Hodgkin Lymphoma (HL); a phase I study of vorinostat demonstrated disease stabilization in four of 12 patients with HL (O’Connor et al, 2006). Others have reported activity in HL with the class-1 DACi, MCGD0103(Younes et al, 2007).

Here we report that, in a preliminary assessment of a phase IA/II trial of panobinostat in patients with advanced haematological malignancies (Spencer et al, 2007), there was evidence of clinical response in heavily pre-treated patients with HL.

Design and methods

  1. Top of page
  2. Summary
  3. Design and methods
  4. Results and discussion
  5. Discussion
  6. Conflict of interest disclosure
  7. References

Trial design, patient selection and treatment

Patients with advanced haematological malignancies including lymphoma and myeloma, refractory to, or who were not otherwise candidates for standard therapy, were entered into this two-arm, phase IA/II dose-escalation study of panobinostat.

Patients received panobinostat either Monday/Wednesday/Friday (MWF) every week (Arm 1) or MWF every other week (Arm 2). A cycle of therapy was defined as 28 days of treatment. The starting dose levels in Arm 1 and Arm 2 were 20 and 30 mg, respectively; however, no patients with HL were included in these cohorts. The first dose levels evaluated for HL in Arm 1 and Arm 2 were 30 and 45 mg, respectively.

The trial closed to accrual in March 2009. Patients with HL are described in this report based on a database cut-off of May 2008. The trial was approved by the institutional ethics committees and is in accordance with the Helsinki Declaration (5th revision, 2000).

A 3-parameter Bayesian logistic regression model with overdose-control was used to guide dose escalation. Maximum tolerated dose (MTD) was estimated as the dose level with the highest posterior probability of dose limiting toxicity (DLT) in the target range [20%, 35%], provided that there was less than 25% chance that the posterior probability of DLT exceeded 35%. A minimum of six evaluable patients at each dose level was required prior to dose escalation, and a minimum of 12 evaluable patients were required at the MTD level.

Response assessment

Disease response was assessed with an 18F-fluoro-2-deoxy-d- glucose positron emission tomography (18FDG-PET) scan after the first month of treatment, and with PET and computed tomography (CT) scans after the second month. Subsequent assessments have been with second-monthly CT and optional monthly 18FDG-PET scans. Results of PET scans were interpreted locally on the basis of a radiologist’s visual assessment of FDG response. In the absence of established formal criteria for partial responses by PET and for the purposes of this report, a metabolic partial response (PR) was defined by the local radiologist’s impression of substantial but incomplete resolution of FDG avidity, the lack of any new lesions, or increased physical size of target lesions. Where maximum standardized uptake value (SUVmax) was evaluable, patients were considered to have achieved a metabolic remission on the basis of visual assessment and least a 25% reduction in SUVmax of marker lesions from baseline values. CT responses were assessed by the investigator according to standard guidelines (Cheson et al, 1999).

Results and discussion

  1. Top of page
  2. Summary
  3. Design and methods
  4. Results and discussion
  5. Discussion
  6. Conflict of interest disclosure
  7. References

Patient characteristics

Data from 13 patients with classical HL were evaluable (Table I). Infection with human immunodeficiency virus was an exclusion criteria. Time from initial diagnosis to trial entry ranged from 2 to 11 years, a median of 5 (3–16) lines of chemotherapy had been delivered, and time from last therapy ranged from 2 to 53 months (median 6 months). All had received radiation therapy and autologous transplantation and in addition, seven had undergone allogeneic stem-cell transplantation. Median time from last stem cell transplant was 40 months. Nine patients had lymphoma-related constitutional symptoms at the time of study enrolment, and four had asymptomatic disease progression detected by PET and CT scanning.

Table I.   Anti-tumour activity of panobinostat.
Dose level (mg)Age (years)/ genderWHO PS at trial entryDisease-related symptoms at trial entry*Best response by PET (cycle end)Best response by CT (cycle end)Best response of symptomsCycles started (reason for discontinuation)
  1. *Disease-related symptoms include B symptoms as well as other cancer-related symptoms: mass effects, pain, nausea, pruritis and fatigue. WHO PS World Health Organization performance status; PET, 18F-fluoro-2-deoxy-d- glucose positron emission tomography; CT, computed tomography; MWF, treatment administered on Monday, Wednesday and Friday; SD, stable disease; PR, partial response; CR, complete response; PD, progressive disease.

  2. †ongoing.

Arm 1 – MWF every week, = 9
3022/F0AbsentPR (2)PR (4)No baseline symptoms16†
16/F2PresentPR (1)SD (+15%) Unchanged3 (PD/death)
4024/F1AbsentSDSD (–32%) No baseline symptoms4 (PD)
31/M1PresentPR (1)PR (2)Improved5 (PD)
30/M1PresentPR (1)PR (2)Improved3†
6027/M2PresentSDPR (3)Improved4†
49/F1AbsentSDSD (−38%)No baseline symptoms4†
23/M2PresentSDSD (+8%)Unchanged2 (PD)
22/M0AbsentPR (2)SD (−36%)No baseline symptoms4†
Arm 2 – MWF every other week, = 4
4529/M0PresentPR (4)SD (−29%)Complete disappearance13†
30/M0PresentSDSD (−46%)Complete disappearance9 (PD)
41/M0Presentnot donePR (2)Improved10†
6019/M1PresentPR (1)SD (−32%)Improved5 (PD)

Responses

Reduction in metabolic activity was observed in seven of 12 patients evaluable for PET response (58%) (Table I). This comprised one patient who was assessed by visual response alone and five patients where response was assessed by a measured reduction in SUVmax as described. Representative images from two patients are shown in Figure 1. As assessed by CT scanning, five patients (38%) achieved formal CT partial responses (>50% reduction of sum of product diameter; SPD). A further three patients had a substantial (29–46%) reduction in SPD. Seven of nine patients (78%) with lymphoma-related constitutional symptoms at baseline have experienced substantial symptomatic improvement, allowing three to continue work during therapy, including one previously requiring hospitalization with disease-related symptoms, and another who had been unable to work for more than 3 years due to ongoing therapies. We observed that symptomatic improvement occurred early in the course of therapy (Table I), and appears to correspond temporally to a metabolic response on the PET scan. Of the seven patients receiving ongoing therapy at the time of this assessment (July 2008) two patients have experienced disease control for more than 13 months.

image

Figure 1.  Radiological responses. (A) Case 1, 22-year-old female, initially diagnosed June 2004. Prior therapy included chemotherapy (four regimens), mantle radiotherapy and autologous stem cell transplant. Enrolled in February 2007, ongoing treatment in Cycle 16. PET at 2 months showed marked reduction in FDG activity of the bulky mediastinal mass. CTs at baseline (left) and after six cycles of therapy (right) show a partial response. Case 2, (B) 29-year-old male, initially diagnosed June 1996. Prior therapy included chemotherapy (four regimens), immunotherapy, radiotherapy, autologous and subsequent allogeneic stem cell transplants. Widespread extra nodal disease including spleen, vertebrae, pelvic bones and marrow. Enrolled in April 2007, ongoing treatment at Cycle 13. PET imaging after 2 months of treatment (left) and 4 months of treatment (right) with reduced FDG-avidity in all bone sites and in the spleen.

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Panobinostat appears to be well tolerated. Toxicity data was available for a total of 128 patients with various malignancies treated on the study (Ottmann et al, 2008). The most common grade 3/4 toxicities overall have been thrombocytopenia (43%), neutropenia (22%), febrile neutropenia (20%), fatigue (20%), and anaemia (11%). Thrombocytopenia was the most common grade 3/4 toxicity in the group of HL patients referred to in this report (10 patients), and was a dose-limiting toxicity in 4. Grade 3/4 neutropenia (one patient), sepsis (one patient), fatigue (one patient) and hyperbilirubinaemia (one patient) were observed, but did not result in a dose reduction. During dose escalation (which included non-HL patients) in Arm 1, grade 4 thrombocytopenia was observed in four of 14 evaluable patients at the 40 mg dose level; while at the next level, 60 mg, grade 4 thrombocytopenia was observed in each of the four patients enrolled. Based on these observations and the MTD estimated by the logistic regression model, the 40 mg dose level administered MWF every week, was selected for future studies.

Discussion

  1. Top of page
  2. Summary
  3. Design and methods
  4. Results and discussion
  5. Discussion
  6. Conflict of interest disclosure
  7. References

Although follow up of this cohort is short, with a median of 4 months, the early reduction of FDG-avidity in seven of 12 patients, a CT-defined partial response in five patients, and a sustained response beyond 10 months for three patients, suggests a substantial anti-tumour effect of single agent panobinostat in HL. This is supported by improvements in constitutional symptoms and performance status.

The mechanism of DACi activity in HL is largely unknown. The resistance of Reed-Sternberg (RS) cells to apoptosis is due in part to the development of autonomously acting or deranged extra- and intra-cellular growth signalling pathways (Skinnider, 2002). One such derangement is the constitutive activation of the interleukin 13 receptor on the RS cell, post-receptor activation of Janus kinase (JAK)1 and JAK3 and subsequently activation of signal transducer and activator of transcription (STAT)3 and STAT6. STAT3 activation promotes RS cell survival in cell line studies; (Baus & Pfitzner, 2006) meanwhile STAT6 up-regulation leads to increased expression of the anti-apoptotic protein BCL-xL and the CCR4 ligands TARC (thymus and activation-regulated chemokine/CCL17) and MDC (macrophage-derived chemokine/CCL22) (Skinnider, 2002; Buglio et al, 2008). TARC and MDC are elevated in HL, (Skinnider, 2002; Niens et al, 2008) decrease in response to anti-HL therapy (Younes et al, 2007; Buglio et al, 2008) and function as chemo-attractants for CD4+ Th2 lymphocytes, which are characteristic of the non-malignant infiltrate surrounding RS cells (Skinnider, 2002). While the PET findings may be due to a direct tumoricidal effect of panobinostat on malignant RS cells, the reduced FDG activity seen in patients who have responded to panobinostat may also reflect changes in the activity of the reactive non-malignant cellular background, reflecting a shift in the reactive cellular infiltrate away from the exaggerated T-helper cell type 2 response. Further exploratory studies are warranted.

A Phase II international multi-centre trial of single-agent panobinostat for HL patients with relapsed disease is underway.

Conflict of interest disclosure

  1. Top of page
  2. Summary
  3. Design and methods
  4. Results and discussion
  5. Discussion
  6. Conflict of interest disclosure
  7. References

Prince:Novartis: Membership on advisory committees, Speakers Bureau. Ritchie:Novartis: Membership on advisory committees. Ottmann:Novartis: Honoraria, Membership on advisory committees, Speakers Bureau. Spencer:Novartis: Membership on advisory committees, Speakers Bureau Liu:Novartis Oncology: Employment. Parker:Novartis Oncology: Employment. Scott:Novartis Oncology: Employment. DeAngelo:Novartis: Speakers Bureau, Membership on advisory committees.

References

  1. Top of page
  2. Summary
  3. Design and methods
  4. Results and discussion
  5. Discussion
  6. Conflict of interest disclosure
  7. References
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