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Is polycythemia vera curable with recombinant interferon alfa (rIFNα)?
The Future – Abstracts of the 8th International Hematology Expert Meeting / Leukemia Research 44 S1 (2016) S1–S12
Tolerance was good. In PVN-1, 8% of patients dropped out due to toxicity in the first year, compared with 10% in the American study. However, these figures were not so low in the long term, being 35% and 22% respectively. Although these results are promising, there are still open questions regarding the long-term safety and efficacy of the treatment. The primary endpoint in the PVN-1 study is the response rate. The secondary endpoints are tolerance and evolution of % JAK2 V617F. 40 patients were enrolled, and we present the analyses after a median follow-up of 75 months. The total haematological response rate was 89% and no vascular event has yet been reported. 70% of patients stopped the drug after a median time of 42 months: 38% due to complete haematological response, 27% due to toxicity (mostly during the first 2 years) and 5% for other reasons. The IFN doses were gradually decreased when there was a complete haematological response and then stopped completely. Toxicity was seen in a variety of forms, including fatigue and auto-antibodies. Auto-immune phenomena were probably the main cause of discontinuation in the long-term. The relapse-free survival was 94% at 5 years and 81% at 3 years in the patients who stopped taking IFN. Of the 14 patients who stopped IFN, 4 had haematological relapses, but 10 remained in complete haematological response off therapy. The molecular response was also impressive; the median JAK2 mutant burden decreased from 45% before IFN therapy to 5% at 72 months. 8 patients even achieved complete molecular response. There was no predictive factor for complete molecular response. It can be shown in vitro that AOP2014 (monoPEG IFN) has a specific antiproliferative effect on JAK2-mutated cell lines as well as on primary cells derived from PV patients. IFN- also targets calreticulin-mutated cells, as a significant decrease in the mutant allele burden has been shown in a series of CALR-mutated ET patients treated with IFN-. Under IFN treatment, several reports showed that bone marrow histology can reverse to normal in selected PV patients, and that even low grade fibrosis can disappear in patients with early stages of myelofibrosis. In conclusion, clinical experience for more than 30 years and more recent clinical and biological data obtained with pegylated forms suggest that IFN- is probably the best first-line therapy in PV, and that it can also be useful in ET and perhaps in some patients with myelofibrosis. Is polycythemia vera curable with recombinant interferon alfa (rIFNα)? R.T. Silver Weill Cornel Medical College, New York, USA The proposed 2015 WHO major criteria for the diagnosis of polycythemia vera (PV) replace the incorrect 2008 criteria which are inadequate: 1. Presence of JAK2 mutation(s) 2. Hemoglobin (Hb) >16.5 g/dl (men) and >16 g/dl (women) Or hematocrit (Hct) >49% (men) and >48% (women) Or increased blood volume >125% estimated red cell mass as determined by Cr51 studies 3. Bone marrow biopsy showing hypercellularity, with trilineage growth and megakaryotypic atypia The minor criterion is: 1. Subnormal serum erythropoietin (EPO) level These have not been tested prospectively as yet. Serum levels are normal in 20% of cases. Iron deficiency in aspirates is also of diagnostic value. What was the role of phlebotomy before interferon? Patients require 1–25 phlebotomies per year, most often about 8 per year. The phlebotomy rate should be used as a criterion for patients to measure activity of disease. The role of phlebotomy is to counteract the rise in blood viscosity. A haematocrit of 45% is regarded as target in men and 42% in women. The problem of phlebotomy only as a treatment of choice is that the patient may suffer from asthenia and iron deficiency. There is also probably an association with myelofibrosis, since the marrow abnormality is not being treated or suppressed. The most frequent cytoreductive treatment is still hydroxyurea. However, there are problems with toxicity and lack of efficacy with this drug.
Recombinant interferon alfa was first given to 55 PV patients and all developed a clinical complete or partial response; there were no bleeding or thrombotic episodes (Figure 1). There was a major reduction in spleen size. Progression free survival was excellent. Interferon also reverses fibrosis over 3–4 years. Lower doses of interferon tend to give an incomplete molecular response, but is coupled with less frequent toxicity. It is probably better to go for the clinical response. Other clonal changes have been found with interferon such as TET2 may persist despite eradication of JAK2. More mutations were seen in poor responders to interferon alfa thus rIFN will not presently cure PV. 100
80
P ercen t (% )
S10
60
40
20
0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 252 264 276 288 300 312 324 336 348 360
Months Figure 1. Thrombohemorrhagic events: remarkable thrombosis-free survival in 55 patients who had clinical CR or PR. From Silver, RT. Cancer 107:451-58, 2006 [1].
Possible models to cure PV would be killing stem cells, exhausting stem cells or immunological control. If the tumour burden is low, activation of the cell cycle in the bone marrow could preferentially deplete the abnormal haematopoietic stem cells and perhaps lead to a cure. A combination of interferon and JAK2 inhibitors would be a possible future approach. Interferon is currently the best treatment for the proliferative aspects of PV. References: [1] Silver, RT: Long-term effects of the treatment of polycythemia vera (PV) with recombinant interferon-alpha (rIFN). Cancer 2006 Aug 1; 107(3): 451-8. [2] Silver RT, Hasselbalch HC. Optimal therapy for polycythemia vera and essential thrombocythemia: Preferred use of interferon therapy based on phase 2 trials. Hematology 2016 Feb 22. [Epub ahead of print] MPN and transplantation J. Clausen First Department of Internal Medicine, Elisabethinen Hospital, Linz, Austria A brief overview is presented on the use of busulfan-fludarabine based conditioning regimens in allogeneic haematopoietic stem cell transplantation (HSCT). Busulfan (Bu) plus fludarabine (Flu) is a well-established drug combination for HSCT conditioning. Various busulfan doses have been combined with fludarabine, resulting in regimens that may be designated as FB1 to FB4, corresponding to 1 to 4 days of iv Bu, each 3.2 mg/kg (or 125–130 mg/m2). The FB1 regimen is considered non-myeloablative (NMA, as for example 2 Gy of total body irradiation with fludarabine). FB2 is a commonly used reduced intensity conditioning (RIC) regimen. FB3 and FB4 are myeloablative but reduced toxicity conditioning (RTC) regimens, compared to the classic busulfan/cyclophosphamide (BuCy). To assess whether increased Bu doses were associated with better disease control, four recent studies were reviewed (Mohty et al., Cancer 2015;121(4): 562–9; Kröger et al., Bone Marrow Transplantation 2015;50(Suppl 1):S5–5, Meeting Abstract: O006; Rambaldi et al. Lancet Oncol 2015;16(15):1525–36; Bredeson et al., Biol Blood Marrow Transplant 2008;14:993–1003). The first three were prospective studies;
Tolerance was good. In PVN-1, 8% of patients dropped out due to toxicity in the first year, compared with 10% in the American study. However, these figures were not so low in the long term, being 35% and 22% respectively. Although these results are promising, there are still open questions regarding the long-term safety and efficacy of the treatment. The primary endpoint in the PVN-1 study is the response rate. The secondary endpoints are tolerance and evolution of % JAK2 V617F. 40 patients were enrolled, and we present the analyses after a median follow-up of 75 months. The total haematological response rate was 89% and no vascular event has yet been reported. 70% of patients stopped the drug after a median time of 42 months: 38% due to complete haematological response, 27% due to toxicity (mostly during the first 2 years) and 5% for other reasons. The IFN doses were gradually decreased when there was a complete haematological response and then stopped completely. Toxicity was seen in a variety of forms, including fatigue and auto-antibodies. Auto-immune phenomena were probably the main cause of discontinuation in the long-term. The relapse-free survival was 94% at 5 years and 81% at 3 years in the patients who stopped taking IFN. Of the 14 patients who stopped IFN, 4 had haematological relapses, but 10 remained in complete haematological response off therapy. The molecular response was also impressive; the median JAK2 mutant burden decreased from 45% before IFN therapy to 5% at 72 months. 8 patients even achieved complete molecular response. There was no predictive factor for complete molecular response. It can be shown in vitro that AOP2014 (monoPEG IFN) has a specific antiproliferative effect on JAK2-mutated cell lines as well as on primary cells derived from PV patients. IFN- also targets calreticulin-mutated cells, as a significant decrease in the mutant allele burden has been shown in a series of CALR-mutated ET patients treated with IFN-. Under IFN treatment, several reports showed that bone marrow histology can reverse to normal in selected PV patients, and that even low grade fibrosis can disappear in patients with early stages of myelofibrosis. In conclusion, clinical experience for more than 30 years and more recent clinical and biological data obtained with pegylated forms suggest that IFN- is probably the best first-line therapy in PV, and that it can also be useful in ET and perhaps in some patients with myelofibrosis. Is polycythemia vera curable with recombinant interferon alfa (rIFNα)? R.T. Silver Weill Cornel Medical College, New York, USA The proposed 2015 WHO major criteria for the diagnosis of polycythemia vera (PV) replace the incorrect 2008 criteria which are inadequate: 1. Presence of JAK2 mutation(s) 2. Hemoglobin (Hb) >16.5 g/dl (men) and >16 g/dl (women) Or hematocrit (Hct) >49% (men) and >48% (women) Or increased blood volume >125% estimated red cell mass as determined by Cr51 studies 3. Bone marrow biopsy showing hypercellularity, with trilineage growth and megakaryotypic atypia The minor criterion is: 1. Subnormal serum erythropoietin (EPO) level These have not been tested prospectively as yet. Serum levels are normal in 20% of cases. Iron deficiency in aspirates is also of diagnostic value. What was the role of phlebotomy before interferon? Patients require 1–25 phlebotomies per year, most often about 8 per year. The phlebotomy rate should be used as a criterion for patients to measure activity of disease. The role of phlebotomy is to counteract the rise in blood viscosity. A haematocrit of 45% is regarded as target in men and 42% in women. The problem of phlebotomy only as a treatment of choice is that the patient may suffer from asthenia and iron deficiency. There is also probably an association with myelofibrosis, since the marrow abnormality is not being treated or suppressed. The most frequent cytoreductive treatment is still hydroxyurea. However, there are problems with toxicity and lack of efficacy with this drug.
Recombinant interferon alfa was first given to 55 PV patients and all developed a clinical complete or partial response; there were no bleeding or thrombotic episodes (Figure 1). There was a major reduction in spleen size. Progression free survival was excellent. Interferon also reverses fibrosis over 3–4 years. Lower doses of interferon tend to give an incomplete molecular response, but is coupled with less frequent toxicity. It is probably better to go for the clinical response. Other clonal changes have been found with interferon such as TET2 may persist despite eradication of JAK2. More mutations were seen in poor responders to interferon alfa thus rIFN will not presently cure PV. 100
80
P ercen t (% )
S10
60
40
20
0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 252 264 276 288 300 312 324 336 348 360
Months Figure 1. Thrombohemorrhagic events: remarkable thrombosis-free survival in 55 patients who had clinical CR or PR. From Silver, RT. Cancer 107:451-58, 2006 [1].
Possible models to cure PV would be killing stem cells, exhausting stem cells or immunological control. If the tumour burden is low, activation of the cell cycle in the bone marrow could preferentially deplete the abnormal haematopoietic stem cells and perhaps lead to a cure. A combination of interferon and JAK2 inhibitors would be a possible future approach. Interferon is currently the best treatment for the proliferative aspects of PV. References: [1] Silver, RT: Long-term effects of the treatment of polycythemia vera (PV) with recombinant interferon-alpha (rIFN). Cancer 2006 Aug 1; 107(3): 451-8. [2] Silver RT, Hasselbalch HC. Optimal therapy for polycythemia vera and essential thrombocythemia: Preferred use of interferon therapy based on phase 2 trials. Hematology 2016 Feb 22. [Epub ahead of print] MPN and transplantation J. Clausen First Department of Internal Medicine, Elisabethinen Hospital, Linz, Austria A brief overview is presented on the use of busulfan-fludarabine based conditioning regimens in allogeneic haematopoietic stem cell transplantation (HSCT). Busulfan (Bu) plus fludarabine (Flu) is a well-established drug combination for HSCT conditioning. Various busulfan doses have been combined with fludarabine, resulting in regimens that may be designated as FB1 to FB4, corresponding to 1 to 4 days of iv Bu, each 3.2 mg/kg (or 125–130 mg/m2). The FB1 regimen is considered non-myeloablative (NMA, as for example 2 Gy of total body irradiation with fludarabine). FB2 is a commonly used reduced intensity conditioning (RIC) regimen. FB3 and FB4 are myeloablative but reduced toxicity conditioning (RTC) regimens, compared to the classic busulfan/cyclophosphamide (BuCy). To assess whether increased Bu doses were associated with better disease control, four recent studies were reviewed (Mohty et al., Cancer 2015;121(4): 562–9; Kröger et al., Bone Marrow Transplantation 2015;50(Suppl 1):S5–5, Meeting Abstract: O006; Rambaldi et al. Lancet Oncol 2015;16(15):1525–36; Bredeson et al., Biol Blood Marrow Transplant 2008;14:993–1003). The first three were prospective studies;