- Email: [email protected]
Acute myelogenous leukemia: Morphologic classification and response to therapy
Leukemia Research,Vol. 3, No. 3, lap. 171-173. ~) Pergamon Press, Ltd. 1979. Printed in Great Britain.
0145-2126/790601-0171 $02.00:0
BRIEF COMMUNICATION
ACUTE MYELOGENOUS LEUKEMIA: MORPHOLOGIC CLASSIFICATION AND RESPONSE TO THERAPY* KENNETH A. FOON, FARAMAREZ NAIEM, CORALEE YALE and ROBERT PETER GALE~Departments of Medicine (Hematology-Oncology), Pathology, Biomathematics, and the UCLA Bone Marrow Transplant Team, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90024, U.S.A.
(Received I January 1979. Accepted 26 January 1979)
INTRODUCTION A VAR1ET¥of clinical and laboratory parameters have been reported to be useful in predicting response to therapy in patients with acute myelogenous leukemia (AML) including age, performance status, blast or platelet count, splenomegaly, the presence of bleeding or infection, a history of preleukemia, smoldering leukemia or refractory anemia [4, 6, 9], and the level of serum lysozyme [2]. Recently, cytokinetic parameters, such as labeling index, growth fraction [8, 12] and marrow growth patterns have likewise been reported to predict therapeutic response [I 1, 15]. All of these data are controversial and there does not appear to be consistent criteria for predicting response to therapy. Several studies have correlated morphologic classification with disease outcome but these data are controversial [4, 9, 10, 16]. This may relate to the lack of a reproducible classification schema for AML. Recently, a French-American-British (FAB) group proposed a classification system based on morphologic and eytoehemical criteria [1, 7] that is widely accepted. In the present study, we investigated the usefulness of the FAB classification in predicting response to therapy in 56 patients with AML. PATIENTS AND METHODS Sixty-eight patients with AML entered the study between 1 January 1975 and 1 March 1978. Details of this study have been previously reported [5]. Briefly, patients received induction chemotherapy with 1-3 cycles of TAD, an intensive 7-day course of ara-C, thioguanine and daunorubicin. Those achieving a complete remission received consolidation therapy with two additional 5-day cycles of TAD. Maintenance therapy consisted of monthly cycles of these drugs with or without immunotherapy. Patients who relapsed were treated v,-ith cis-platinum [cis-diaminine-diehloroplatinum 0I)] and 5-azacytidine. Pretreatment blood and bone marrow specimens with complete cytochemical studies were available in 56 patients. Slides were prepared for light microscopy using standard techniques [13]. Stains used for morphologic and cytochemical studies included Wrights, Giemsa, myeloperoxidase, chloroacetate esterase, ~-napthyl ASD esterase and periodic acid Schiff (PAS) [17, 18]. Slides were classified by criteria suggested in the FAB classification. A separate category (M-7) was used for eases that did not conform to the FAB classification. Remissions were defined by standard criteria [3].
RESULTS Data on 56 patients are indicated in Table 1. Most patients had either undifferentiated AML (M-l; 27~o), differentiated AML (M-2; 28~) or myelomonocytic leukemia (M-4; 25 ~). Two patients had progranulocytic leukemia (M-3) and five had acute monocytic * Supported by Grants CA-15688, CA-23175, CA-12800 from the National Cancer Institute. t Robert Peter Gale is a Scholar of the Leukemia Society of America. To whom reprint requests should be sent. 171
172
KENNETHA. FOONet al.
leukemia (M-5). There were no cases of erythroleukemia (M-6). In/'our patients we were unable to classify the leukemia by the suggested criteria. Patients with myelomonocytic leukemia tended to be older, while those with differentiated A M L and progranulocytic leukemia tended to be younger. These differences were not significant. Nor were there significant differences between any of the groups with regard to sex, pretreatment hematologic parameters, organomegaly, bleeding, infection, performance status or other factors thought to be o f prognostic value. TABLE 1. CLASSIFICATION OF PATIENTS WITH
AML AND RESPONSE TO THERAPY
Classification
Description
Number of cases (~)
M-1 M-2 M-3 M-4 M-5 M-6 "M-7. . . .
Undifferentiated Myelogenous Progranulocytic Myelomonocytic Monoeytic Erythroleukemic Unclassified"
15 (27) 16 (28) 2 (4) 14 (25) 5 (9) 0 4 (7)
55 (21-80) 32 (7-67) 34 (33, 34) 55 (45-82) 43 (21--63) . . 51 (25-60)
56
50
Total
Age (range)
Complete remissions (~) 87 88 I00 93 60 . 75 86
Duration (days)
Survival (days)
327 358 1004+ 260 449
398 417+ 1039+ 362+ 597 +
304+
338+
358
626
.
Response to chemotherapy is indicated in Table 1. The complete remission rate was 86 9/0. There was no significant difference in response rate for any of the groups. Median remission duration was 358 days. While patients with progranulocytic leukemia (M-3) and monocytic leukemia (M-5) had the longest duration of remission, there were too few cases for critical analysis. The three largest groups, undifferentiated A M L (M-l), more differentiated A M L (M-2), and myelomonocytic leukemia (M-4) had comparable durations of remission and survival. DISCUSSION Our data indicate that morphologic classification using the FAB system in patients with A M L is not useful in predicting the response to induction chemotherapy, remission duration or survival. This data is similar to that reported by others using different methods of classification [4, 7, 9, 10, 14]. Conflicting data has also been reported. For example, Wiernik and coworkers [16] and Currie [2] using morphologie criteria and lysozyme levels to classify their patients, reported higher remission rates and longer remission durations in patients with monocytic leukemia compared to those with myelocytic leukemia. This trend was not confirmed in the present study. Our failure to detect a relationship between morphologic classification and therapeutic response may relate to the effectiveness of the TAD regimen. Hopefully, more sophisticated hematologic and immunologic techniques may permit the identification of patients most likely to benefit from therapy. REFERENCES 1. BENNETTJ. M., CATOVSKYD., DANIELM., FLANDRING., GALTOND. A. G., GRALNICKH. R. & SULTANC. (1976) Proposals for the classification of the acute leukemias. Br. J. Haemat. 33, 451. 2. CLrRmEG. (1976) Prognostic significance of serum lysozyme in adult acute myelogenous leukemia, Lancet i, 835.
Acute myelogenous leukemia
173
3. ELLISON R. R., HOLLAND, J. R., WEIL M., JACQUILLATC., BOIRON M., BERNARD J., SAWITSKYA., ROSNER F., GUSSOFFB., SILVERR. T., KARANASA., CLrrrNER, J., SPURR C. L., HAYESD. M., BLOMJ., LEONE L. A., HAURANIF., KYLE R., HUTCHISONJ. L., FORCIERR. J. & MOON J. H. 0968) Arabinosyl cytosine : a useful agent in the treatment of acute leukemia in adults. Blood 32, 507. 4. ELLISON R. R., WALLACE J. H., HOAGLAND H. C., WOOLFORD D. C. & GLIDEWELL O. J. (1975) Prognostic parameters in acute myelocytic luckemia as seen in the acute leukemia group B. In Advances in the Bio-Sciences 14; Workshop on Prognostic Factors in Human Acute Leukemia. Reisensburg, Germany, 1-3 October 1973, p. 51. Pergamon Press, New York. 5. GALER. P. & CUNE M. J. (1977) High remission-induction rate in acute myeloid leukemia. Lancet i, 497. 6. GEHANE. A., SMrrH T. L., FREIREICHE. J., BODEY G., RODRIOOEZV., SPEERJ. & McCREOIE K. (1976) Prognostic factor in acute leukemia. Seminars in Oncology 3, 271. 7. GRALNICKH. R., GALTOND. A. G., CATOVSKYD., SULTANC. & BENNETTJ. M. (1977) Classification of acute leukemia. Ann. intern. Med. 87, 740. 8. HART S. H., GEORGES. L., FREI E., BODY G. P., NICKEgSONR. C. & FRE.mEICHE. J. (1977) Prognostic significance of pretreatment proliferation activity in adult acute leukemia. Cancer 39, 1603. 9. HENDERSONE. S., WALLACEJ. Y., SCHARLAWC., RAKOWSKI1., ELLISONR. R. & HOLLANDJ. F. (1975) Factors influencing prognosis in adult acute myelocytic leukemia. In Advances in the Biosciences 14; Workshop on Prognostic Factors in Human Acute Leukemia. Reisensburg, Germany, 1-3 October 1973, p. 51. Pergamon Press, New York. ] 0. MEDICALRESEARCHCOUNCIL'SWORKING PARTYON LEUKAEMIAIN ADULTS(I 975) The relation between morphology and other features of acute myeloid leukemia and their prognostic significance. Br. J. Haemat. 31 (Suppl.), 165. 11. MOOREM. A. S., SPITZER G., WILUAMSN., METCALFD. & BUCKLEYJ. (1977) Agar studies in 127 cases of acute leukemia: the prognostic value of reclassification of leukemia according to in vitro growth characteristics. Blood 44, 1. 12. MURPHY S. B., AUR R. J. A., StMONEJ. V., GEORGES. & MAUERA. M. (1977) Pretreatment cytokinetic studies in 94 children with acute leukemia. Relationship to other variables at diagnosis and to outcome of standard treatment. Blood 49, 683. 13. NAEIM F., GALE R. P. & SMITH G. S. (1978) Morphologic aspects of bone marrow transplantation in patients with aplastic anemia. Human Path. 9, 295. 14. SHAW M. T. (1976) The cytochemistry of acute leukemia: a diagnostic and prognostic evaluation. Seminars in Oncology 3, 219. 15. SPITZER G., DICKE K. A., GEHAN E. A., SMITH T., McCREDIE K. B., BARLOGIEB. & FREIRECH E. J. (1976) A simplified in vitro classification for prognosis in adult acute leukemia: the application of in vitro results in remission-predictive models. Blood 48, 795. 16. WrERNIK P., SCrnM'PFFS., SCmFFER C., LICHTENEELDJ., AIS~r~RJ., O'CONNELL J. & FOPd,mR C. (1976) Randomized clinical comparison of daunorubicin alone with a comparison of daunorubicin, cytosine arabinoside, 6-thiognanine and pyrimethimine for the treatment of acute non-lymphocytic leukemia. Cancer Treatment Rep. 60, 41. 17. WILCOX R. B., GOLDE D. W. & CraNE M. J. (1976) Cytochemical reactions of human hematopoietic cells in liquid culture. J. Histochem. Cytochem. 24, 979. 18. YAM U T., L~ C. Y. & CROSSe W. H. (1971) Cytochemical identification of monocytes and granulocytes. Am. J. Path. 55, 283.
0145-2126/790601-0171 $02.00:0
BRIEF COMMUNICATION
ACUTE MYELOGENOUS LEUKEMIA: MORPHOLOGIC CLASSIFICATION AND RESPONSE TO THERAPY* KENNETH A. FOON, FARAMAREZ NAIEM, CORALEE YALE and ROBERT PETER GALE~Departments of Medicine (Hematology-Oncology), Pathology, Biomathematics, and the UCLA Bone Marrow Transplant Team, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90024, U.S.A.
(Received I January 1979. Accepted 26 January 1979)
INTRODUCTION A VAR1ET¥of clinical and laboratory parameters have been reported to be useful in predicting response to therapy in patients with acute myelogenous leukemia (AML) including age, performance status, blast or platelet count, splenomegaly, the presence of bleeding or infection, a history of preleukemia, smoldering leukemia or refractory anemia [4, 6, 9], and the level of serum lysozyme [2]. Recently, cytokinetic parameters, such as labeling index, growth fraction [8, 12] and marrow growth patterns have likewise been reported to predict therapeutic response [I 1, 15]. All of these data are controversial and there does not appear to be consistent criteria for predicting response to therapy. Several studies have correlated morphologic classification with disease outcome but these data are controversial [4, 9, 10, 16]. This may relate to the lack of a reproducible classification schema for AML. Recently, a French-American-British (FAB) group proposed a classification system based on morphologic and eytoehemical criteria [1, 7] that is widely accepted. In the present study, we investigated the usefulness of the FAB classification in predicting response to therapy in 56 patients with AML. PATIENTS AND METHODS Sixty-eight patients with AML entered the study between 1 January 1975 and 1 March 1978. Details of this study have been previously reported [5]. Briefly, patients received induction chemotherapy with 1-3 cycles of TAD, an intensive 7-day course of ara-C, thioguanine and daunorubicin. Those achieving a complete remission received consolidation therapy with two additional 5-day cycles of TAD. Maintenance therapy consisted of monthly cycles of these drugs with or without immunotherapy. Patients who relapsed were treated v,-ith cis-platinum [cis-diaminine-diehloroplatinum 0I)] and 5-azacytidine. Pretreatment blood and bone marrow specimens with complete cytochemical studies were available in 56 patients. Slides were prepared for light microscopy using standard techniques [13]. Stains used for morphologic and cytochemical studies included Wrights, Giemsa, myeloperoxidase, chloroacetate esterase, ~-napthyl ASD esterase and periodic acid Schiff (PAS) [17, 18]. Slides were classified by criteria suggested in the FAB classification. A separate category (M-7) was used for eases that did not conform to the FAB classification. Remissions were defined by standard criteria [3].
RESULTS Data on 56 patients are indicated in Table 1. Most patients had either undifferentiated AML (M-l; 27~o), differentiated AML (M-2; 28~) or myelomonocytic leukemia (M-4; 25 ~). Two patients had progranulocytic leukemia (M-3) and five had acute monocytic * Supported by Grants CA-15688, CA-23175, CA-12800 from the National Cancer Institute. t Robert Peter Gale is a Scholar of the Leukemia Society of America. To whom reprint requests should be sent. 171
172
KENNETHA. FOONet al.
leukemia (M-5). There were no cases of erythroleukemia (M-6). In/'our patients we were unable to classify the leukemia by the suggested criteria. Patients with myelomonocytic leukemia tended to be older, while those with differentiated A M L and progranulocytic leukemia tended to be younger. These differences were not significant. Nor were there significant differences between any of the groups with regard to sex, pretreatment hematologic parameters, organomegaly, bleeding, infection, performance status or other factors thought to be o f prognostic value. TABLE 1. CLASSIFICATION OF PATIENTS WITH
AML AND RESPONSE TO THERAPY
Classification
Description
Number of cases (~)
M-1 M-2 M-3 M-4 M-5 M-6 "M-7. . . .
Undifferentiated Myelogenous Progranulocytic Myelomonocytic Monoeytic Erythroleukemic Unclassified"
15 (27) 16 (28) 2 (4) 14 (25) 5 (9) 0 4 (7)
55 (21-80) 32 (7-67) 34 (33, 34) 55 (45-82) 43 (21--63) . . 51 (25-60)
56
50
Total
Age (range)
Complete remissions (~) 87 88 I00 93 60 . 75 86
Duration (days)
Survival (days)
327 358 1004+ 260 449
398 417+ 1039+ 362+ 597 +
304+
338+
358
626
.
Response to chemotherapy is indicated in Table 1. The complete remission rate was 86 9/0. There was no significant difference in response rate for any of the groups. Median remission duration was 358 days. While patients with progranulocytic leukemia (M-3) and monocytic leukemia (M-5) had the longest duration of remission, there were too few cases for critical analysis. The three largest groups, undifferentiated A M L (M-l), more differentiated A M L (M-2), and myelomonocytic leukemia (M-4) had comparable durations of remission and survival. DISCUSSION Our data indicate that morphologic classification using the FAB system in patients with A M L is not useful in predicting the response to induction chemotherapy, remission duration or survival. This data is similar to that reported by others using different methods of classification [4, 7, 9, 10, 14]. Conflicting data has also been reported. For example, Wiernik and coworkers [16] and Currie [2] using morphologie criteria and lysozyme levels to classify their patients, reported higher remission rates and longer remission durations in patients with monocytic leukemia compared to those with myelocytic leukemia. This trend was not confirmed in the present study. Our failure to detect a relationship between morphologic classification and therapeutic response may relate to the effectiveness of the TAD regimen. Hopefully, more sophisticated hematologic and immunologic techniques may permit the identification of patients most likely to benefit from therapy. REFERENCES 1. BENNETTJ. M., CATOVSKYD., DANIELM., FLANDRING., GALTOND. A. G., GRALNICKH. R. & SULTANC. (1976) Proposals for the classification of the acute leukemias. Br. J. Haemat. 33, 451. 2. CLrRmEG. (1976) Prognostic significance of serum lysozyme in adult acute myelogenous leukemia, Lancet i, 835.
Acute myelogenous leukemia
173
3. ELLISON R. R., HOLLAND, J. R., WEIL M., JACQUILLATC., BOIRON M., BERNARD J., SAWITSKYA., ROSNER F., GUSSOFFB., SILVERR. T., KARANASA., CLrrrNER, J., SPURR C. L., HAYESD. M., BLOMJ., LEONE L. A., HAURANIF., KYLE R., HUTCHISONJ. L., FORCIERR. J. & MOON J. H. 0968) Arabinosyl cytosine : a useful agent in the treatment of acute leukemia in adults. Blood 32, 507. 4. ELLISON R. R., WALLACE J. H., HOAGLAND H. C., WOOLFORD D. C. & GLIDEWELL O. J. (1975) Prognostic parameters in acute myelocytic luckemia as seen in the acute leukemia group B. In Advances in the Bio-Sciences 14; Workshop on Prognostic Factors in Human Acute Leukemia. Reisensburg, Germany, 1-3 October 1973, p. 51. Pergamon Press, New York. 5. GALER. P. & CUNE M. J. (1977) High remission-induction rate in acute myeloid leukemia. Lancet i, 497. 6. GEHANE. A., SMrrH T. L., FREIREICHE. J., BODEY G., RODRIOOEZV., SPEERJ. & McCREOIE K. (1976) Prognostic factor in acute leukemia. Seminars in Oncology 3, 271. 7. GRALNICKH. R., GALTOND. A. G., CATOVSKYD., SULTANC. & BENNETTJ. M. (1977) Classification of acute leukemia. Ann. intern. Med. 87, 740. 8. HART S. H., GEORGES. L., FREI E., BODY G. P., NICKEgSONR. C. & FRE.mEICHE. J. (1977) Prognostic significance of pretreatment proliferation activity in adult acute leukemia. Cancer 39, 1603. 9. HENDERSONE. S., WALLACEJ. Y., SCHARLAWC., RAKOWSKI1., ELLISONR. R. & HOLLANDJ. F. (1975) Factors influencing prognosis in adult acute myelocytic leukemia. In Advances in the Biosciences 14; Workshop on Prognostic Factors in Human Acute Leukemia. Reisensburg, Germany, 1-3 October 1973, p. 51. Pergamon Press, New York. ] 0. MEDICALRESEARCHCOUNCIL'SWORKING PARTYON LEUKAEMIAIN ADULTS(I 975) The relation between morphology and other features of acute myeloid leukemia and their prognostic significance. Br. J. Haemat. 31 (Suppl.), 165. 11. MOOREM. A. S., SPITZER G., WILUAMSN., METCALFD. & BUCKLEYJ. (1977) Agar studies in 127 cases of acute leukemia: the prognostic value of reclassification of leukemia according to in vitro growth characteristics. Blood 44, 1. 12. MURPHY S. B., AUR R. J. A., StMONEJ. V., GEORGES. & MAUERA. M. (1977) Pretreatment cytokinetic studies in 94 children with acute leukemia. Relationship to other variables at diagnosis and to outcome of standard treatment. Blood 49, 683. 13. NAEIM F., GALE R. P. & SMITH G. S. (1978) Morphologic aspects of bone marrow transplantation in patients with aplastic anemia. Human Path. 9, 295. 14. SHAW M. T. (1976) The cytochemistry of acute leukemia: a diagnostic and prognostic evaluation. Seminars in Oncology 3, 219. 15. SPITZER G., DICKE K. A., GEHAN E. A., SMITH T., McCREDIE K. B., BARLOGIEB. & FREIRECH E. J. (1976) A simplified in vitro classification for prognosis in adult acute leukemia: the application of in vitro results in remission-predictive models. Blood 48, 795. 16. WrERNIK P., SCrnM'PFFS., SCmFFER C., LICHTENEELDJ., AIS~r~RJ., O'CONNELL J. & FOPd,mR C. (1976) Randomized clinical comparison of daunorubicin alone with a comparison of daunorubicin, cytosine arabinoside, 6-thiognanine and pyrimethimine for the treatment of acute non-lymphocytic leukemia. Cancer Treatment Rep. 60, 41. 17. WILCOX R. B., GOLDE D. W. & CraNE M. J. (1976) Cytochemical reactions of human hematopoietic cells in liquid culture. J. Histochem. Cytochem. 24, 979. 18. YAM U T., L~ C. Y. & CROSSe W. H. (1971) Cytochemical identification of monocytes and granulocytes. Am. J. Path. 55, 283.