Effect of Recombinant Interferon Alpha-2 on the Growth of Hematopoetic Progenitor Cells in Chronic Myelogenous Leukemia and Its Relationship to the Clinical Efficacy

1988 ◽  
pp. 34-41 ◽  
Author(s):  
D. Geissler ◽  
W. Aulitzky ◽  
H. Tilg ◽  
I. Von Lüttichau ◽  
G. Konwalinka ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Interferon Alpha ◽  
Clinical Efficacy ◽  
Myelogenous Leukemia ◽  
Recombinant Interferon ◽  
Recombinant Interferon Alpha

scholarly journals Interferon alpha-2b as therapy for Ph'-positive chronic myelogenous leukemia: a study of 82 patients treated with intermittent or daily administration

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 642-647 ◽  
Author(s):  
G Alimena ◽  
E Morra ◽  
M Lazzarino ◽  
AM Liberati ◽  
E Montefusco ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Interferon Alpha ◽  
Response Rate ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Complete Suppression ◽  
Recombinant Interferon ◽  
Hematologic Response ◽  
Interferon Alpha 2B ◽  
Ifn Alpha

The authors treated a total of 82 patients with Ph′-positive chronic myelogenous leukemia (CML) with recombinant interferon alpha-2b (IFN alpha-2b). Sixty-five patients in chronic phase (CP), 28 of whom were untreated and 37 pretreated, and nine patients in accelerated phase (AP), were started on IFN three times a week. Patients in CP were randomized to receive 2 or 5 X 10(6) IU/m2, while patients in AP were all given the dose of 5 X 10(6) IU/m2, in addition to concomitant chemotherapy. Patients in CP who were unresponsive to the lower dose were crossed to the higher dose. Of 63 evaluable patients in CP, 43 (68%) responded, 29 (46%) achieved complete hematologic response (CHR), and 14 (22%) achieved partial hematologic response (PHR). The response rate appeared to be significantly influenced by the IFN dose in pretreated patients. Of the nine patients in AP, two attained PHR and one CHR. More recently, eight previously untreated CP cases were submitted to daily IFN administration at doses from 2 to 5 X 10(6) IU/m2. This daily schedule was also applied to patients who had obtained, with the intermittent treatment, a PHR persisting unmodified for six months (nine patients) or an unstable CHR (five patients). Seven of the eight previously untreated patients, and five of the nine PHR patients crossed to daily IFN reached CHR. In the total series of previously untreated patients, the response rate proved to be significantly influenced by the initial risk status. Cytogenetic improvement was seen in 37 of 53 responders (70%) treated for more than 3 months, the median of Ph′-positive cells declining from 100% to 65% (range 0% to 95%). Complete suppression of Ph′ chromosome was observed in one case. The cytogenetic response was persistent for over 6 months in 21 patients, but the lowest value of Ph′ positivity was usually unstable. At a median follow-up of 56 weeks, 23 of 36 (64%) CHR patients remain in continued disease control with IFN. A blastic transformation (BT) occurred in seven of 21 unresponsive patients and in one of the 36 CHR patients. The authors' data confirm that IFN alpha- 2b, especially at daily doses, is effective in inducing clinical and cytogenetic response in a good proportion of patients with CML in the benign phase. Longer follow-ups will define the exact influence of this agent on the natural course of the disease.

scholarly journals Synergistic antiproliferative effect of recombinant interferon-gamma with recombinant interferon-alpha on chronic myelogenous leukemia hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM)

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1293-1299 ◽  
Author(s):  
C Carlo-Stella ◽  
M Cazzola ◽  
A Ganser ◽  
G Bergamaschi ◽  
P Pedrazzoli ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Bone Marrow Cells ◽  
Myelogenous Leukemia ◽  
Target Cells ◽  
Suppressive Activity ◽  
Recombinant Interferon ◽  
Accessory Cells

Abstract Recombinant interferons, alpha (rIFN-alpha) and gamma (rIFN-gamma), have been demonstrated to have significant antitumor activity as single agents in the treatment of chronic myelogenous leukemia (CML). Due to their possible synergistic efficacy, a combination rIFN therapy in CML has been proposed. To establish a biologic basis for this, we have studied the suppressive effects of rIFN-alpha and rIFN-gamma on the in vitro growth of CML-derived progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, CFU-GM), the optimal conditions for rIFN synergism, and the possible role of hematopoietic accessory cells (T-lymphocytes and monocytes- macrophages) in mediating rIFN-induced growth inhibition. When added to unseparated bone marrow cells, rIFN-alpha and rIFN-gamma significantly reduced colony formation, with 50% inhibition occurring at 71 and 186 U/mL for CFU-GEMM, 40 and 152 U/mL for CFU-Mk, 222 and 1,458 U/mL for BFU-E, and 119 and 442 U/mL for CFU-GM, respectively. A small amount of rIFN-gamma (5 U/mL) acted synergistically with increasing doses of rIFN- alpha, and the values of 50% inhibitory concentrations fell outside the lower limit (10 U/mL) used in our experiments. This synergy was evident even when rIFN-gamma was added 72 hours after the initiation of cultures; however, it was completely lost when the target cells were depleted of accessory cells. When a low dose of rIFN-alpha (5 U/mL) was added to rIFN-gamma, the 50% inhibitory concentration values were decreased up to tenfold. These studies (1) confirm that CML-derived hematopoietic progenitors are responsive to the suppressive activity of both rIFN-alpha and rIFN-gamma in vitro, (2) demonstrate that different mechanisms are responsible for the suppressive activity of the two rIFNs, and (3) characterize their synergistic interaction, providing a basis for future clinical trials aimed at investigating combination rIFN therapy in CML.

scholarly journals Synergistic antiproliferative effect of recombinant interferon-gamma with recombinant interferon-alpha on chronic myelogenous leukemia hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM)

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1293-1299
Author(s):  
C Carlo-Stella ◽  
M Cazzola ◽  
A Ganser ◽  
G Bergamaschi ◽  
P Pedrazzoli ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Bone Marrow Cells ◽  
Myelogenous Leukemia ◽  
Target Cells ◽  
Suppressive Activity ◽  
Recombinant Interferon ◽  
Accessory Cells

Recombinant interferons, alpha (rIFN-alpha) and gamma (rIFN-gamma), have been demonstrated to have significant antitumor activity as single agents in the treatment of chronic myelogenous leukemia (CML). Due to their possible synergistic efficacy, a combination rIFN therapy in CML has been proposed. To establish a biologic basis for this, we have studied the suppressive effects of rIFN-alpha and rIFN-gamma on the in vitro growth of CML-derived progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, CFU-GM), the optimal conditions for rIFN synergism, and the possible role of hematopoietic accessory cells (T-lymphocytes and monocytes- macrophages) in mediating rIFN-induced growth inhibition. When added to unseparated bone marrow cells, rIFN-alpha and rIFN-gamma significantly reduced colony formation, with 50% inhibition occurring at 71 and 186 U/mL for CFU-GEMM, 40 and 152 U/mL for CFU-Mk, 222 and 1,458 U/mL for BFU-E, and 119 and 442 U/mL for CFU-GM, respectively. A small amount of rIFN-gamma (5 U/mL) acted synergistically with increasing doses of rIFN- alpha, and the values of 50% inhibitory concentrations fell outside the lower limit (10 U/mL) used in our experiments. This synergy was evident even when rIFN-gamma was added 72 hours after the initiation of cultures; however, it was completely lost when the target cells were depleted of accessory cells. When a low dose of rIFN-alpha (5 U/mL) was added to rIFN-gamma, the 50% inhibitory concentration values were decreased up to tenfold. These studies (1) confirm that CML-derived hematopoietic progenitors are responsive to the suppressive activity of both rIFN-alpha and rIFN-gamma in vitro, (2) demonstrate that different mechanisms are responsible for the suppressive activity of the two rIFNs, and (3) characterize their synergistic interaction, providing a basis for future clinical trials aimed at investigating combination rIFN therapy in CML.

scholarly journals Interferon alpha-2b as therapy for Ph'-positive chronic myelogenous leukemia: a study of 82 patients treated with intermittent or daily administration

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 642-647 ◽  
Author(s):  
G Alimena ◽  
E Morra ◽  
M Lazzarino ◽  
AM Liberati ◽  
E Montefusco ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Interferon Alpha ◽  
Response Rate ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Complete Suppression ◽  
Recombinant Interferon ◽  
Hematologic Response ◽  
Interferon Alpha 2B ◽  
Ifn Alpha

Abstract The authors treated a total of 82 patients with Ph′-positive chronic myelogenous leukemia (CML) with recombinant interferon alpha-2b (IFN alpha-2b). Sixty-five patients in chronic phase (CP), 28 of whom were untreated and 37 pretreated, and nine patients in accelerated phase (AP), were started on IFN three times a week. Patients in CP were randomized to receive 2 or 5 X 10(6) IU/m2, while patients in AP were all given the dose of 5 X 10(6) IU/m2, in addition to concomitant chemotherapy. Patients in CP who were unresponsive to the lower dose were crossed to the higher dose. Of 63 evaluable patients in CP, 43 (68%) responded, 29 (46%) achieved complete hematologic response (CHR), and 14 (22%) achieved partial hematologic response (PHR). The response rate appeared to be significantly influenced by the IFN dose in pretreated patients. Of the nine patients in AP, two attained PHR and one CHR. More recently, eight previously untreated CP cases were submitted to daily IFN administration at doses from 2 to 5 X 10(6) IU/m2. This daily schedule was also applied to patients who had obtained, with the intermittent treatment, a PHR persisting unmodified for six months (nine patients) or an unstable CHR (five patients). Seven of the eight previously untreated patients, and five of the nine PHR patients crossed to daily IFN reached CHR. In the total series of previously untreated patients, the response rate proved to be significantly influenced by the initial risk status. Cytogenetic improvement was seen in 37 of 53 responders (70%) treated for more than 3 months, the median of Ph′-positive cells declining from 100% to 65% (range 0% to 95%). Complete suppression of Ph′ chromosome was observed in one case. The cytogenetic response was persistent for over 6 months in 21 patients, but the lowest value of Ph′ positivity was usually unstable. At a median follow-up of 56 weeks, 23 of 36 (64%) CHR patients remain in continued disease control with IFN. A blastic transformation (BT) occurred in seven of 21 unresponsive patients and in one of the 36 CHR patients. The authors' data confirm that IFN alpha- 2b, especially at daily doses, is effective in inducing clinical and cytogenetic response in a good proportion of patients with CML in the benign phase. Longer follow-ups will define the exact influence of this agent on the natural course of the disease.

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