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Homoharringtonine in Combination with Imatinib for Patients with CML Who have Achieved Partial or Complete Cytogenetic Responses.
  Rifca Le Dieu, Marco Bua, Catharina Andreasson, Eduardo Olavarria, John M. Goldman, Jane F. Apperley, David Marin.
  Haematology, Imperial College London, London, United Kingdom
 
Introduction
 

Homoharringtonine (HHT) is a plant alkaloid that binds to ribosomal peptidyl transferase thus blocking the translation phase of protein synthesis and resulting in apoptosis

HHT has been shown to be active in patients in all phases of CML

In vitro studies using CML cell lines have shown HHT to have synergistic or additive effects when combined with imatinib

For this study, an hemi-synthetic formulation of HHT (sHHT) was used with the subcutaneous route of administration




  
  Objective  
  To explore this synergism in vivo we looked at patients with chronic phase CML who had achieved at least a minor cytogenetic response on imatinib but now had an apparent plateau of BCR-ABL transcript numbers at suboptimal levels to see if that molecular response could be improved by the addition of sHHT  
 
  Patient population  
  BCR-ABL kinase mutation screening

• Patients were screened for BCR-ABL kinase domain mutations at the time enrolment in the trial
• We carried out a hemi-nested RT-PCR to amplify the BCR- ABL in the first step and the ABL kinase domain in the second
• The PCR product was subjected to direct sequencing

Patient Characteristics

  
 
  Methods  
 

Inclusion Criteria

Patients had to meet all the following criteria:
• Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia in chronic phase
• Treatment with imatinib at a minimum dose of 400mg/d for at least 2 years
• Achievement of at least a minor cytogenetic response (defined as at least 35% of Ph-negative marrow metaphases)
• A plateau in BCR-ABL transcripts (measured on at least 4 occasions over a minimum period of 1 year with the latest value not lower than the previous minimum value)

Exclusion Criteria

Patients were excluded if:
• Their imatinib dose had been modified over the preceding 12 months
• They had other significant concomitant disease

Protocol

• Imatinib was continued at the previous dosage
• sHHT was supplied by the manufacturer as a lyophilised powder containing 5 mg of drug (Myelostat®, Stragen- Switzerland). It was reconstituted in normal saline to a final concentration of 2 mg/ml and administered subcutaneously
• Patients were taught to self-administer the drug
• For the first 3 patients the initial dose of sHHT was 1.25 mg/m_ twice daily (BID) for 3 consecutive days. This led to prolonged aplasia. These patients were not included in the evaluation
• Subsequently, sHHT was given at a dose of 1.25 mg/m_ BID for 1 day (dose level 1a)
• The dose of sHHT was escalated every 2 courses as guided by the absolute neutrophil count (ANC) and platelet count on day +28 of the preceding course:



• Dose levels of sHHT:
Dose level 1a: 1.25mg/m2 BID for 1 day (2 doses)
Dose level 1b: 1.25mg/m2 BID for 1 _ days (3 doses)
Dose level 2a: 1.25mg/m2 BID for 2 consecutive days (4 doses)
Dose level 2b: 1.25mg/m2 BID for 2 _ consecutive days (5 doses)
Dose level 3: 1.25mg/m2 BID for 3 consecutive days (6 doses)
• Treatment with sHHT was discontinued if a patient:
- achieved a complete molecular response
- did not achieve a reduction in the transcript level of at least
0.5 log after 6 courses
• Response was assessed by serial monitoring of peripheral blood levels of BCR-ABL transcripts assayed by quantitative real-time reverse transcriptase PCR

  
 
  Efficacity Results  
  Results

• After addition of sHHT, transcript levels declined by > 0.5 log in 7 cases and > 1 log in 5 cases
• 2 patients achieved complete molecular responses
• The 2 patients not in complete cytogenetic response at enrolment achieved this (patient nos. 1 and 8)
• There was no clear relationship between dose level and response

  
 
Evolution of the BCR-ABL transcript level in patient #6 and #8

  
 
BCR-ABL kinase domain mutations

• Mutations were found in 2 patients - nos. 7 and 8
• In both cases, the mutation was a M244V substitution in the ATP phosphate-binding loop (P-loop) which has been associated previously with resistance to imatinib
• Both patients responded to the addition of sHHT		  
 
  Toxicity  
  Myelosuppression in first 3 patients

• The first 3 patients were treated with 1.25mg/m_ BID for 3 days:
- all had neutropenia (grade III in 2, grade IV in 1) – all responded rapidly to G-CSF
- all had thrombocytopenia (1 grade III lasting 7d, 2 grade IV that took 14d and 42d to revert to grade II) – those with grade IV required platelet support
• As a result, the protocol was amended as described

Myelosuppression in subsequent patients

• Dose related effect
• Grade III neutropenia observed on 3 occasions
• Grade III thrombocytopenia observed on 2 occasions
• No grade IV haematological toxicity observed

Asthenia

• Asthenia was observed in all patients
• 2 patients withdrew consent due to grade II asthenia
• Typically lasted for the duration of the injections then a further 2-3 days
• No relationship between the severity of asthenia and sHHT dosage


Other toxicity

• All patients had reactions at the site of injection (grade I) which took 3-7 days to resolve
• Nausea (grade I) was observed in 3 patients despite use of antiemetics
• The following occurred on one occasion in different patients: transient fever, conjunctivitis, diarrhea, muscle pain.		  
 
  Conclusion  
  We have shown that the addition of sHHT to imatinib therapy in chronic phase CML can improve the molecular response and is well tolerated

In particular, patients who acquire mutations associated with imatinib resistance can respond to the addition of sHHT

We believe these preliminary clinical observations justify further study of the use of sHHT in patients on imatinib who fail to obtain low levels of minimal residual disease

For future studies, we would recommend starting at a dose of 1.25mg/m_ twice daily for one and a half days (3 doses) and escalating the dose thereafter according to tolerance		  
 
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