A Pilot Study Investigating the Safety and Efficacy of Injectable Hemin (Panhematin®) in Patients with Low to Intermediate-1 Risk Myelodysplastic Syndrome.

J. M. Shammo¹, K. Shell¹, D. Rhoades¹, A. Rizman¹, K. E. Anderson², M. Holmay³, I. Miller¹, S. Gregory¹

¹Rush University Medical Center, Chicago, IL, ²University of Texas Medical Branch, Galveston, TX, ³Director CNS Medical Liaisons, Lundbeck, Inc.

Injectable hemin (Panhematin) is an iron-containing metalloporphyrin that is approved for the treatment of acute intermittent porphyria. Preclinical data indicate that hemin administration has the potential to stimulate progenitor cell growth and gamma globin chain synthesis. Clinical trial data from Europe on the use of hemin in myelodysplastic syndrome (MDS) suggest it can result in hematologic improvements in a subset of patients (Volin 1988, Timonen 1992).

This was an investigator initiated study aimed at evaluating the safety and efficacy of Panhematin in patients with low or intermediate-1 risk MDS. Response assessments were done at week 8, as defined by the International Working Group. Secondary endpoints included the alterations of ferritin, porphyrin, and hemoglobin F levels from baseline with treatment

Between 6/2007 and 10/2008, 6 patients (median age 73.5, range 64-80, men = 5, women = 1) were treated. All patients had a diagnosis of low or intermediate-1 risk MDS (International Prognostic Scoring (IPSS) score of 0-1), were transfusion-dependent or had hemoglobin values of ' 10 g/dL, had ' 10% blasts in bone marrow and peripheral blood, had platelet counts > 50,000/ microL and absolute neutrophil counts (ANC) > 500/microL. Patients received daily doses of Panhematin® at 3 mg/kg IV on days 1 through 4 of week 1, and weekly on day 1 of weeks 2 through 8. Efficacy and safety assessments, including bone marrow biopsies, were performed on Week 8. Partial and complete responders in any of the three cell lines were allowed to continue treatment for as long as they benefit. Patients who did not demonstrate a response or those whose disease had progressed at Week 8 were withdrawn from the study.

Five of 6 patients completed 8 weeks of treatment and were evaluable for response assessment. One patient withdrew his consent. One patient received an additional 4 weekly doses after achieving an erythroid response and was later retreated for an additional 16 weeks. All other patients had stable disease and four of them remained transfusion dependent. Only 1 (with RARS) out of 5 evaluable patients met criteria for hematologic response. His baseline hemoglobin (Hb) of 7.3g/dL increased to 8.5g/dL at week 8, and peaked at 8.7g/dL at week 9. His bone marrow biopsy at week 8 revealed a decrease in ringed sideroblasts from 73% to 51%. Once off treatment, this patient's Hb dropped back to a near baseline level of 7.0g/dL. Approximately a year later (after protocol amendment allowed for re-treatment), he was retreated and his Hb again increased to 8.2 g/dL at week 8, peaking at 8.8 g/dL. In two patients with RARS (the responder and another patient), it was noted that the erythrocyte protoporphyrin level was initially elevated and rose even higher at week 8. Similarly, erythrocyte porphobilinogen deaminase (PBGD) and uroporphyrinogen decarboxylase (UROD) activities increased with treatment, especially in the one patient who responded. In that patient, these activities decreased again after treatment ended. The reticulocyte count increased from 0.0294 to 0.0411 × 10 6/mcL only in this patient. There was no correlation observed between response to panhematin and HbF levels. Treatment was well tolerated in all patients and no major toxicities were observed.

In this small study of hemin treatment of patients with low to Int-1 risk MDS, one patient responded with increases in hemoglobin and in reticulocytes. The increases in reticulocytes and in erythrocyte PBGD and UROD in the responder may indicate an increase in erythropoeisis resulting in a larger proportion of young erythrocytes in peripheral circulation after treatment. Clearly, such observations need validation in larger studies, which may result in better understanding of MDS disease biology.

Shammo:ovation pharmaceutical: Research Funding. Off Label Use: the use of Panhematin in MDS.