© 1991 S. Karg er A G . Basel 0001 -5792/91 /0851-0016 S 2.75/0
Acta Haematol 1991;85:16-19
Comparison of Low-Dose versus Standard-Dose Alpha-Interferon Regimen in the Hairy Cell Leukemia Treatment1 Pier Luigi Zinzani, Francesco Lauria, Donatella Raspadori, Marina Buzzi, Donatella Benfenati, Monica Bocchia, Damiano Rondelli, Sante Tura Institute of Hematology ‘L. e A. Seragnoli’, Bologna University, Bologna, Italy
Key Words. Hairy cell leukemia • a-Interferon • Low-dose a-interferon • Standard-dose a-interferon Abstract. In a randomized clinical trial, the effects of standard doses of alpha-interferon (a-IFN) compared with the effects of half of these doses were evaluated in patients with hairy cell leukemia. There were 14 patients treated with standard-dose (3 MU/day i.m. for 6 months, then 3 MU three times/week for a further 6 months) and 10 patients with low-dose a-IFN (1.5 MU/day with the same schedule and forthe same period). The over all response rate, the quality, and the duration of response were rather similar in both groups. The rapidity of response in normalizing the peripheral blood counts was similar, even increased in low-dose-treated patients, consisting mainly in clearing the number of circulating hairy cells (p 12 g/dl, platelets > 100x 10Vl, and absolute neu trophil count > 1.5 x 10Vl; (2) a partial response (PR) required a 50% reduction in the marrow HC infiltrate and in the degree of splenomegaly with normalization of the peripheral blood counts: (3) a minor response (MR) was the restoration of at least 1 of previ ously abnormal hematological values. The Wilcoxon test was used for statistical analysis.
Table 1. Clinical characteristics and results following a-IFN treatment in 24 HCL patients subdivided according to the a-IFN dose
Age, years, median Range Sex, M/F Previous splenectomy Splenomegaly No splenomegaly Hb (mean, g/dl) Neutrophils (mean, x 10Vl) Platelets (mean, x 109/1) Hairy cells (mean, x lOVl) Response Complete response Partial response Minor response Survival, months, median Range Current status Alive and well Alive, progressed Dead
Standard dose n = 14
Low dose n= 10
56 36-76 13/1 3 9 2 10.1 0.55 89 1.65
61 51-64 9/1 1 5 4 10.7 0.57 90 1.70
2 8 4 34 21-54
1 8 1 32 20-53
12 3 2
10 0 0
Table 2. Mean hematological values (± SD) registered in standard (S)- and low (L)-dose-treated patients at diagnosis and after 1,2, 3, 6 and 12 months of therapy
At diagnosis
1
2
3
6
12
Hemoglobin, g/dl S-dose L-dose
10.1 ±2.0 10.7 ±2.4
10.7 ± 1.5 11.1 ± 1.5
11.5 ± 1.4 12.5 ± 1.3
12.0 ± 1.6 13.2 ± 1.3
12.8 ± 1.7 14.0 ± 1.2
14.1 ± 1.4 14.6 ± 1.7
Neutrophils, x 10Vl S-dose L-dose
0.55 ±0.70 0.57 ± 0.70
1.06 ±0.70 0.81 ±0.68
1.34 ± 0.87 1.40 ±0.60
1.71 ±0.95 1.60 ±0.59
2.36 ± 1.09 1.82 ±0.69
2.17 ± 1.33 2.18 ±0.81
Platelets, x I09 S-dose L-dose
89.7 ± 67.5 90.1 ±61.5
100.7 ±33.1 130.7 ±58.5
145.5 ±85.0 144.5 ±80.0
149.5 ±83.8 130.7 ±47.4
146.9 ±57.2 134.3 ±34.1
151.2 ± 70.5 159.5 ±59.5
Hairy cells, x I09 S-dose L-dose
1.96 ±2.5 1.70 ±2.5
0.91 ± 1.4 0.35 ±0.6
0.82 ± 1.9 0.15 ±0.2
0.33 ±0.05 0.06 ± 0.03
0.18 ±0.03 0.03 ±0.01
0.07 ± 0.02 0.00
Downloaded by: Vanderbilt University Library 129.59.95.115 - 1/13/2019 11:46:13 PM
Months of therapy
Zinzani/Lauria/Raspadori/Buzzi/Benfenati/Bocchia/Rondelli/Tura
Results
sion of the disease. All patients are alive with a me dian follow-up of 32 months (range: 20-53) from the onset of a-IFN.
Of the 14 HCL patients treated with standard-dose a-IFN, 2 achieved a CR, 8 a PR (overall good re sponse 71%) and the remaining 4 obtained only an Discussion MR. Two of the minor responders showed a further progression of the disease and were subsequently This study demonstrates, in a small group of HCL treated with 2-deoxycoformycin. Despite an evident and rapid clinical and hematological response, both patients, that the standard treatment of 3 MU/day of patients died after the second administration because a-IFN is not superior to the treatment with 1.5 MU/ of cerebral hemorrhage and because of an apparently day, neither in the remission rate, nor in the rapidity unrelated cardiac failure, after 8 and 9 months from and duration of response. It is well known that in recent years, the outlook the onset of the a-IFN treatment, respectively. Concerning the hematologic changes, as reported for the HCL patients has significantly improved since in table 2, there was a progressive improvement of pe the introduction of the a-IFN therapy by Quesada et ripheral blood counts in these patients, evident from al. [4] in 1984. Several subsequent larger studies have the third month of therapy but complete only after 12 confirmed the results of this initial report and docu months. Almost all patients complained about grade mented a response rate of 80-90% [5-9]. Because a 1-2 ‘flu-like’ symptoms for the first 2-3 weeks, whilst clear dose-response relationship had not been demon grade 2 fatigue with myalgia was reported in 10 of 14 strated and the well-documented toxic effects of inter patients and occurred after 1-4 months of treatment. feron therapy significantly affected many patients’ Severe asthenia occurred in 4 patients, and an altera quality of life, some studies have been conducted in tion of the liver function tests was observed in 1. This order to assess the adequate dose [10-13]. A prelimi latter and another patient required a dose reduction nary randomized study was reported in 1986 in which a lymphoblastoid interferon was used [10], The results and a discontinuation of the a-IFN. One of the complete responder patients and 2 of of this study suggested that a low dose of a-IFN (i.e. the partial responders showed a progression of the 0.2 M U/m2 given daily) was as effective as the stan disease, 4, 12, and 20 months respectively, after com dard dose of interferon in inducing a hematologic re pletion of the a-IFN therapy. All 3 were retreated mission, although the median time to recovery of nor with a-IFN and reachieved an adequate response. mal peripheral blood cell counts appeared to be The median follow-up of living patients, from the on somewhat longer with the lower than with the higher set of the a-IFN therapy, was 34 months (range: dose. The toxic effects of this real low-dose regimen were minimal. Conversely, other investigators [11, 21-54). Among the 10 HCL patients treated with low-dose 12], using the same schedule, were unable to confirm a-IFN, 1 achieved a CR, 8 a PR (overall good re the same results and found that the very low-dose sponse 90%) and 1 a MR. No significant difference in a-IFN regimen was significantly less effective than the response rate was observed in the other group of the standard dose in inducing a response and in nor patients. Furthermore, a good progressive improve malizing the peripheral blood cell counts in HCL pa ment of the hematological values was registered in the tients. On the basis of these inconsistent reports [11, low-dose-treated patients (table 2) apparently supe 12], we established a simple randomized study com rior (but statistically not significant) to that observed paring two different dose regimens: standard dose in the standard-dose-treated patients. Interestingly, (3 MU/day) and low dose (1.5 MU/day). The overall the decrease in the HC count during the first 3 months response rate was quite similar in both groups. The was more evident in these patients, and after the first quality of the response to low-dose a-IFN was equal month the improvement was even statistically signifi to that observed in the standard-dose-treated patients and consisted mainly in clearing the number of circu cant (p
Acta Haematol 1991;85:16-19
Comparison of Low-Dose versus Standard-Dose Alpha-Interferon Regimen in the Hairy Cell Leukemia Treatment1 Pier Luigi Zinzani, Francesco Lauria, Donatella Raspadori, Marina Buzzi, Donatella Benfenati, Monica Bocchia, Damiano Rondelli, Sante Tura Institute of Hematology ‘L. e A. Seragnoli’, Bologna University, Bologna, Italy
Key Words. Hairy cell leukemia • a-Interferon • Low-dose a-interferon • Standard-dose a-interferon Abstract. In a randomized clinical trial, the effects of standard doses of alpha-interferon (a-IFN) compared with the effects of half of these doses were evaluated in patients with hairy cell leukemia. There were 14 patients treated with standard-dose (3 MU/day i.m. for 6 months, then 3 MU three times/week for a further 6 months) and 10 patients with low-dose a-IFN (1.5 MU/day with the same schedule and forthe same period). The over all response rate, the quality, and the duration of response were rather similar in both groups. The rapidity of response in normalizing the peripheral blood counts was similar, even increased in low-dose-treated patients, consisting mainly in clearing the number of circulating hairy cells (p 12 g/dl, platelets > 100x 10Vl, and absolute neu trophil count > 1.5 x 10Vl; (2) a partial response (PR) required a 50% reduction in the marrow HC infiltrate and in the degree of splenomegaly with normalization of the peripheral blood counts: (3) a minor response (MR) was the restoration of at least 1 of previ ously abnormal hematological values. The Wilcoxon test was used for statistical analysis.
Table 1. Clinical characteristics and results following a-IFN treatment in 24 HCL patients subdivided according to the a-IFN dose
Age, years, median Range Sex, M/F Previous splenectomy Splenomegaly No splenomegaly Hb (mean, g/dl) Neutrophils (mean, x 10Vl) Platelets (mean, x 109/1) Hairy cells (mean, x lOVl) Response Complete response Partial response Minor response Survival, months, median Range Current status Alive and well Alive, progressed Dead
Standard dose n = 14
Low dose n= 10
56 36-76 13/1 3 9 2 10.1 0.55 89 1.65
61 51-64 9/1 1 5 4 10.7 0.57 90 1.70
2 8 4 34 21-54
1 8 1 32 20-53
12 3 2
10 0 0
Table 2. Mean hematological values (± SD) registered in standard (S)- and low (L)-dose-treated patients at diagnosis and after 1,2, 3, 6 and 12 months of therapy
At diagnosis
1
2
3
6
12
Hemoglobin, g/dl S-dose L-dose
10.1 ±2.0 10.7 ±2.4
10.7 ± 1.5 11.1 ± 1.5
11.5 ± 1.4 12.5 ± 1.3
12.0 ± 1.6 13.2 ± 1.3
12.8 ± 1.7 14.0 ± 1.2
14.1 ± 1.4 14.6 ± 1.7
Neutrophils, x 10Vl S-dose L-dose
0.55 ±0.70 0.57 ± 0.70
1.06 ±0.70 0.81 ±0.68
1.34 ± 0.87 1.40 ±0.60
1.71 ±0.95 1.60 ±0.59
2.36 ± 1.09 1.82 ±0.69
2.17 ± 1.33 2.18 ±0.81
Platelets, x I09 S-dose L-dose
89.7 ± 67.5 90.1 ±61.5
100.7 ±33.1 130.7 ±58.5
145.5 ±85.0 144.5 ±80.0
149.5 ±83.8 130.7 ±47.4
146.9 ±57.2 134.3 ±34.1
151.2 ± 70.5 159.5 ±59.5
Hairy cells, x I09 S-dose L-dose
1.96 ±2.5 1.70 ±2.5
0.91 ± 1.4 0.35 ±0.6
0.82 ± 1.9 0.15 ±0.2
0.33 ±0.05 0.06 ± 0.03
0.18 ±0.03 0.03 ±0.01
0.07 ± 0.02 0.00
Downloaded by: Vanderbilt University Library 129.59.95.115 - 1/13/2019 11:46:13 PM
Months of therapy
Zinzani/Lauria/Raspadori/Buzzi/Benfenati/Bocchia/Rondelli/Tura
Results
sion of the disease. All patients are alive with a me dian follow-up of 32 months (range: 20-53) from the onset of a-IFN.
Of the 14 HCL patients treated with standard-dose a-IFN, 2 achieved a CR, 8 a PR (overall good re sponse 71%) and the remaining 4 obtained only an Discussion MR. Two of the minor responders showed a further progression of the disease and were subsequently This study demonstrates, in a small group of HCL treated with 2-deoxycoformycin. Despite an evident and rapid clinical and hematological response, both patients, that the standard treatment of 3 MU/day of patients died after the second administration because a-IFN is not superior to the treatment with 1.5 MU/ of cerebral hemorrhage and because of an apparently day, neither in the remission rate, nor in the rapidity unrelated cardiac failure, after 8 and 9 months from and duration of response. It is well known that in recent years, the outlook the onset of the a-IFN treatment, respectively. Concerning the hematologic changes, as reported for the HCL patients has significantly improved since in table 2, there was a progressive improvement of pe the introduction of the a-IFN therapy by Quesada et ripheral blood counts in these patients, evident from al. [4] in 1984. Several subsequent larger studies have the third month of therapy but complete only after 12 confirmed the results of this initial report and docu months. Almost all patients complained about grade mented a response rate of 80-90% [5-9]. Because a 1-2 ‘flu-like’ symptoms for the first 2-3 weeks, whilst clear dose-response relationship had not been demon grade 2 fatigue with myalgia was reported in 10 of 14 strated and the well-documented toxic effects of inter patients and occurred after 1-4 months of treatment. feron therapy significantly affected many patients’ Severe asthenia occurred in 4 patients, and an altera quality of life, some studies have been conducted in tion of the liver function tests was observed in 1. This order to assess the adequate dose [10-13]. A prelimi latter and another patient required a dose reduction nary randomized study was reported in 1986 in which a lymphoblastoid interferon was used [10], The results and a discontinuation of the a-IFN. One of the complete responder patients and 2 of of this study suggested that a low dose of a-IFN (i.e. the partial responders showed a progression of the 0.2 M U/m2 given daily) was as effective as the stan disease, 4, 12, and 20 months respectively, after com dard dose of interferon in inducing a hematologic re pletion of the a-IFN therapy. All 3 were retreated mission, although the median time to recovery of nor with a-IFN and reachieved an adequate response. mal peripheral blood cell counts appeared to be The median follow-up of living patients, from the on somewhat longer with the lower than with the higher set of the a-IFN therapy, was 34 months (range: dose. The toxic effects of this real low-dose regimen were minimal. Conversely, other investigators [11, 21-54). Among the 10 HCL patients treated with low-dose 12], using the same schedule, were unable to confirm a-IFN, 1 achieved a CR, 8 a PR (overall good re the same results and found that the very low-dose sponse 90%) and 1 a MR. No significant difference in a-IFN regimen was significantly less effective than the response rate was observed in the other group of the standard dose in inducing a response and in nor patients. Furthermore, a good progressive improve malizing the peripheral blood cell counts in HCL pa ment of the hematological values was registered in the tients. On the basis of these inconsistent reports [11, low-dose-treated patients (table 2) apparently supe 12], we established a simple randomized study com rior (but statistically not significant) to that observed paring two different dose regimens: standard dose in the standard-dose-treated patients. Interestingly, (3 MU/day) and low dose (1.5 MU/day). The overall the decrease in the HC count during the first 3 months response rate was quite similar in both groups. The was more evident in these patients, and after the first quality of the response to low-dose a-IFN was equal month the improvement was even statistically signifi to that observed in the standard-dose-treated patients and consisted mainly in clearing the number of circu cant (p
