- Email: [email protected]
Hypocellular acute leukemia
Hypocellular Acute Leukemia
ROBERT CLARA ROBERT
B. HOWE,
M.D.
D. BLOOMFIELD, W.
McKENNA,
M.D. M.D.
Minneapolis, Minnesota
From the Sections of Hematology and Medical Oncology, Department of Medicine and the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota. This work was supported in part by the Ernest Johnson Memorial Leukemia Research Fund, NHLB Training Grant #5T32 HL07062, the Masonic Hospital Foundation and the Minnesota Medical Foundation. Reprint requests should be addressed to Dr. Robert Howe, University of Minnesota Hospitals, Box 480 Mayo Memo&l Building, Minneapolis, Minnesota 55455. Manuscript accepted October 6, 196 1.
We examined the clinical features and therapeutic response of a group of patients with acute leukemia and hypoceiiuiar bone marrow. Therapists have generally avoided, delayed or modified therapy because of hypoceituiarity. We demonstrated not only that aggressive therapy is possible, but also that the remission rate is high (complete remission = 73 percent) and survival prolonged (Z > 40 months). Advances in the management of acute leukemia during the past decade have made the achievement of complete remission almost routine [l-3]. The increasing incidence of long-term remissions has, in fact, raised the hope of cure for many of these patients [4]. However, there remain subsets of patients with acute leukemia in whom the disease proves refractory to therapy or for whom therapy is not generally recommended [5-71. One such group consists of patients who clearly have bone marrow failure and increased numbers of blast forms in the bone marrow but whose bone marrow biopsy specimens are hypocellular. They are sometimes considered to have “smoldering” acute leukemia [5], a myelodysplastic syndrome or preleukemia [6]. However, the term hypoplastic or hypocellular acute leukemia most accurately reflects this condition, which behaves clinically like more typically hypercellular acute leukemia. We describe a group of 29 patients who presented with bone marrow failure involving all cell lines, most dramatically involving the granulocyte series, and who had morphologic findings diagnostic of acute leukemia even though the bone marrow biopsy specimens were hypocelluiar. They are generally over the age of 50, are predominantly male and have nonspecific symptoms and a paucity of physical findings. It has generally been recommended that chemotherapy be withheld from such patients because of a poor response [5-81. However, the patients in the present series who were not treated had a poor prognosis: nearly all have benefited from aggressive chemotherapy in terms of improved bone marrow function and survival. PATIENTS AND METHODS The records of all patients presenting to the University of Minnesota Hospitals in whom the diagnosis of acute leukemia was made between June 1967 and February 1980 were reviewed. We identified 270 patients in whom the diagnosis of acute leukemia could clearly be made. All bone marrow biopsy specimens classified as normocellular or hypocellular were reviewed. No patient with treatment-related leukemia [S] was included. Twenty-nine patients qualified as having hypocellular bone marrow based on criteria to be discussed.
March 1982
The American Journal of Medicine
Volume 72
391
HYPOCELLULAR
ACUTE
LEUKEMIA-HOWE
ET AL.
Figure 1. Representative trephine biopsy specimens of (let?) slightly, (middle) moderately, and (right) markedly hypocellular bone marrow specimens from patients with acute leukemia (original magnification X 100, reduced by 30 percent).
alone; or aggressive therapy, treatment
Bone marrow specimens were obtained and processed as previously described [lo]. In addition to routine stains, bone marrow smears from all patients were studied for myeloperoxidase activity by Kaplow’s method [ 1l] and with the periodic acid-Schiff reaction. Bone marrow cellularity was evaluated in bone marrow sections in all patients; 25 patients had one or more posterior iliac crest trephine biopsy speci-
regimens always including an anthracycline drug and cytosine arabinoside [l-3]. Since this was a retrospective study, there was no randomization of patients to treatment groups. It has been our policy to provide aggressive management of bleeding and febrile complications to all patients. Decisions to attempt remission-induction chemotherapy were made by the patient and family after discussion of risks and benefits with the attending physician. Complete remission criteria were those of Cancer and Leukemia Group B [ 151.
mens of at least 2 cm length and aspirated bone marrow particle sections available for examination: four patients had only bone marrow particle sections. In addition, cellularity was evaluated in direct bone marrow smears and marrow particle smears and quantitative data were obtained from centrifuged marrow aspirates as previously described [lo]. The bone marrow was considered hypocellular only when information derived from all these types of specimens indicated hypocellularity [ 121. Although the possibility of sampling error exists, the reliability of these estimations has been established by others [ 13,141. Specimens were considered markedly hypocellular when the marrow space was predominantly occupied by adipose tissue and less than 15 percent of the marrow consisted of hematopoietic elements; moderately hypocellular when 15 to 30 percent of the marrow space consisted of hematopoietic cells; and slightly hypocellular when 30 to 40 percent of the marrow was occupied by hematopoietic tissue (Figure 1). Charts of all patients were reviewed for duration and type of symptoms prior to diagnosis, physical findings at the time of diagnosis, laboratory findings, treatment and survival from time of diagnosis. Treatment was classified as supportive only, that is, blood transfusions and antibiotics as required; moderately aggressive therapy, treatment consisting of drugs such as prednisone, hydroxyurea, vincristine, and 6-mercaptopurine, daunorubicin alone or cytosine arabinoside
392
March 1992
RESULTS Twenty-nine patients were identified in whom the diagnosis of acute leukemia could be made and who had bone marrow biopsy specimens with less than normal cellularity for the patient’s age. Twenty of the 29 patients had markedly [5] or moderately [ 151 hypocellular bone marrow; nine patients had slightly’ hypocellular bone marrow. The myeloblast percentage ranged from 5 to 70 percent with a median of 28 percent when first examined. The highest pretreatment blast percentage ranged from 14 to 70. In addition to the elevated blast counts, morphologic abnormalities in the maturing hematopoietic cell lines could be identified in 20 patients. There was definite evidence of involvement of more than one cell line in the leukemic process in 14 patients, and seven showed evidence of panmyelosis. There was variability in the predominant abnormal cell line from patient to patient. In 24 patients, the granu-
The American Journal of Medicine Volume 72
HYPOCELLULAR
locyte series was predominantly involved; in three, the erythroid line; in two, the monocytic. In eight of the patients, the initial bone marrow blast percentage was less than 20 percent at diagnosis. Three of these patients had myeloblasts with Auer rods. In six of the eight, follow-up bone marrow specimens were obtained; in five, the blast count increased to greater than 20 percent. Of the other three with less than 20 percent blasts, one had Auer rods and one had chromosomal abnormalities. The symptoms prior to diagnosis consisted of fever, weakness, fatigue, bone pain, hemorrhage and infection and were present for less than one week to more than 39 months prior to diagnosis. Physical findings were sparse and consisted of gum hyperplasia in one patient, central nervous system involvement in one patient, hepatomegaly in four patients, splenomegaly in two patients and lymphadenopathy in five patients. No patient had evidence of skin infiltration with leukemic cells. There was a 3: 1 male to female predominance of this disease; although the youngest patient was 15 years old and the oldest 79, all but four patients were 50 years of age or older at the time of diagnosis. Although anemia was present in all but one patient (hemoglobin range 3.5 to 15.7 g/dl), most patients were not severely anemic, having hemoglobin levels over 10 g/d1 (average 10.0 g/dl). Platelet counts ranged from 14,000 to 310,000/mm3. The most prominent laboratory finding was leukopenia; all patients but one having low total white blood cell counts (range less than 1,000 to 7,600/mm3). Blast forms were absent or too few in number in the peripheral blood to appear in the lOO-cell differential. The three treatment groups are compared in Table I. Median ages of the three treatment groups were comparable except for the inclusion of the 15 year old patient in the aggressively treated group. The median ages of the conservatively treated group and the aggressively treated group were not statistically different (p >0.05). Hematologic parameters were also comparable, except that the moderately aggressive treatment group was more thrombocytopenic on the average. The distribution of bone marrow cellularity among the treatment groups is shown in Table I. TREATMENT AND SURVIVAL The eight patients who received no specific anti-leukemic chemotherapy had a median survival of five months: one is still alive; the longest survivor lived 29 months. Untreated patients showed progression of disease with rising percentages of blasts in the bone marrow. Of the 10 patients who received moderately aggressive therapy, median survival was 17.5 months, the longest living 48 months, with none still alive. This is not significantly different from the untreated group.
TABLE I
ACUTE LEUKEMIA-HOWE
Comparisonof Treatment Groups* Supportive
Age (yr) Hemoglobin (g/df) White blood cell count (X103/mm3) Platelet count (X 103/mm3) Bone marrow cellularity (number of patients) Slightly Moderately Markedly Percent blasts
l
ET AL,
Moderate
Aggressive
57-79
33-79
15-69
(70) 3.5-14.0
(58) 5.2-15.7
(9.9) 1.0-2.6
(63) 7.2-11.6 (10.6) 1.0-7.6
(1.8) 18-310
(2.0) 14-70
(1.4) 29-304
(96)
(36)
(128)
2 4 2 5.4-70.0 (29.9)
6 4 0 10.2-63.8 (21.1)
(9.9) 1.0-4.3
1 7 3 7.4-67.4 (32.8)
Median values are given in parentheses.
One achieved complete remission. The 11 patients treated aggressively experienced a complete remission rate of 73 percent. Median survival is 40 months: four are still alive and the longest survivor lived 62 months. This is significant at the p CO.05 level (Figure 2). COMMENTS We describe a subset of patients with acute myelogenous leukemia presenting as pancytopenia with a predominance of granulocytopenia, vague systemic symptoms associated with the anemia and thrombocytopenia. Bone marrow specimens are distinctly hypocellular, although the increased numbers of blast forms and other morphologic abnormalities such as Auer rods make the diagnosis of leukemia evident. There is a 3:l male to female predominance of this condition, which generally presents beyond the 50th year of age. The clinical course tends to be a progressive one requiring aggressive chemotherapy rather than supportive care or less than intensive chemotherapy. Patients who received transfusion and antibiotics only, or who received vincristine, prednisone, 6-mercaptopurine, and other antimetabolites as single agents have shorter survivals than those who received more aggressive anti-leukemic therapy regimens containing an anthracycline drug and cytosine arabinoside. Complete remissions secondary to more aggressive chemotherapy are common; the life expectancy of patients managed in this manner is improved over those managed less aggressively. A strict comparison of the patient groups is not possible, since they were neither chronologically simultaneous nor randomized. Improved supportive therapy for bleeding and infectious complications may have contributed significantly to the improved outcome of patients treated at a later date. However, nearly all
March 1982
The American Journal oi Medicine
Volume 72
393
HYPOCELLULAR
ACUTE LEUKEMIA-HOWE
ET AL
0 NO TREATMENT 0
MODERATELY
a
AGGRESSIVE
AGQRESSIVE
*ALIVE
0047---d10
20
30
Figure 2. Survival curves of the three patient groups. The survival of the untreated (II) and moderately aggressive (0) treatment groups is similar; that of the aggressively treated group (A) significantly prolonged (see text).
40
Survival (months)
of the patients in the group receiving supportive therapy were concurrent with those in the group treated aggressively and had access to the same treatment for bleeding and infectious complications. Since these supportive measures make possible more effective remission-induction regimens [l-3], the poor outcome of less aggressively managed patients has encouraged a more aggressive approach. The high remission rate and longer survival of patients so managed favors the approach. Previous recommendations that therapy should be modified or withheld because patients with hypoplastic bone marrow would not tolerate further suppression are not borne out by these results. This condition is distinct from so called preleukemia, although the clinical presentation and peripheral blood picture may be confused with that condition [6]. In contrast to the picture in preleukemia, the bone marrow in these patients is hypocellular and there is distinct evidence of leukemia in the form of increased numbers of blasts and morphologic changes in individual cells diagnostic of leukemia. This form of leukemia also differs from refractory anemia with excess blasts [8], in that in the latter condition, anemia predominates the
clinical picture, whereas leukopenia dominated the peripheral blood picture in the present group. Although some investigators may consider those patients with less than 20 percent myeloblasts to have refractory anemia with excess myeloblasts, nearly all patients with the latter have hypercellularity of the bone marrow. The distinct hypocellularity in our patients is unusual for that condition. The dysplastic changes in the red cell, megakaryocyte and granulocyte lines in the bone marrow qualify this as a myelodysplastic disease. However, most patients so classified also have hyperceilular marrows. Our patients probably should not be classified as having “smoldering” acute leukemia [5], since the course is not benign. Indeed, all of these patients treated with supportive therapy only had progressive disease and a shortened life expectancy compared with those who were managed as if they had acute leukemia. The present group, with hypocellularity and a distinct increase in myeloblasts, should probably be classified as having acute leukemia. The clinical course and response to therapy would support this conclusion. The syndrome of hypocellular acute leukemia is a clinical entity requiring aggressive management.
REFERENCES 1.
2.
394
Yates JW, Wallace HJ, Ellison RR, Holland JF: Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep 1973; 57: 485-488. Gale RP, Cline MJ: High remission-induction rate in acute
March 1982
The American Journal of Medicine
Volume 72
3.
4.
myeloid leukemia. Lancet 1977; I: 497-499. Peterson BA, Bloomfield CD: Prolonged maintained remissions of adult acute non-lymphocytic leukemia. Lancet 1977; II: 158-160. Bloomfield CD: Treatment of adult acute nonlymphocytic
HYPOCELLULAR ACUTE LEUKEMIA-HOWE ET AL.
5. 6.
7.
8.
9.
10.
leukemia. Ann Intern Med 1980; 93: 133-135. Knospe WH, Gregory SA: Smoldering acute leukemia. Arch Intern Med 1971; 127: 910-918. Fisher WB, Armentrout SA, Weisman R Jr, Graham RC: Preleukemia: a myelodysplastic syndrome often terminating in acute leukemia. Arch Intern Med 1973; 132: 226232. Beard MEJ, Bateman CJT, Crowther DC, et al.: Hypoplastic acute myelogenous leukemia. Br J Haemat 1975; 31: 167-176. Rochant H, Dreyfus B. Bouguerr M, Tont-hat H: Refractory anemias, pre-leukemic conditions, and fetal erythropoiesis. Blood 1972; 39: 721-726. Foucar K, McKenna RW, Bloomfield CD, Bowers TK, Brunning RD: Therapy-related leukemia: a panmyelosis. Cancer 1979; 43: 1285-1296. Brynes RK, McKenna RW, Sundberg RD: Bone marrow aspi-
11. 12.
13.
14.
15.
March 1982
ration and trephine biopsy: An approach to a thorough study. Am J Clin Pathol 1978: 70: 753-759. Kaplow LS: Simplified myeloperoxidase stain using benzidine dihydrochloride. Blood 1965; 26: 215-219. Hartsock RJ, Smith EB, Petty CS: Normal variations with aging of the amount of hematopoietic tissue in bone marrow from the anterior iliac crest. Am J Clin Pathol 1965; 43: 326331. Fong TP, Okafor LA, Schmitz TH, Thomas W, Westerman MP: An evaluation of cellularity in various types of bone marrow specimens. Am J Clin Pathol 1979; 72: 812-816. Morley A, Blake J: Observer error in histological assessment of marrow cellularity. J Clin Pathol 1975; 28: 104-108. Acute leukemia group B criteria for evaluating acute leukemia. June 1974 modification of the 1969 criteria. Cancer and Leukemia Group B. Scarsdale, New York.
The American Journal of Medlclne
Volume 72
395
ROBERT CLARA ROBERT
B. HOWE,
M.D.
D. BLOOMFIELD, W.
McKENNA,
M.D. M.D.
Minneapolis, Minnesota
From the Sections of Hematology and Medical Oncology, Department of Medicine and the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota. This work was supported in part by the Ernest Johnson Memorial Leukemia Research Fund, NHLB Training Grant #5T32 HL07062, the Masonic Hospital Foundation and the Minnesota Medical Foundation. Reprint requests should be addressed to Dr. Robert Howe, University of Minnesota Hospitals, Box 480 Mayo Memo&l Building, Minneapolis, Minnesota 55455. Manuscript accepted October 6, 196 1.
We examined the clinical features and therapeutic response of a group of patients with acute leukemia and hypoceiiuiar bone marrow. Therapists have generally avoided, delayed or modified therapy because of hypoceituiarity. We demonstrated not only that aggressive therapy is possible, but also that the remission rate is high (complete remission = 73 percent) and survival prolonged (Z > 40 months). Advances in the management of acute leukemia during the past decade have made the achievement of complete remission almost routine [l-3]. The increasing incidence of long-term remissions has, in fact, raised the hope of cure for many of these patients [4]. However, there remain subsets of patients with acute leukemia in whom the disease proves refractory to therapy or for whom therapy is not generally recommended [5-71. One such group consists of patients who clearly have bone marrow failure and increased numbers of blast forms in the bone marrow but whose bone marrow biopsy specimens are hypocellular. They are sometimes considered to have “smoldering” acute leukemia [5], a myelodysplastic syndrome or preleukemia [6]. However, the term hypoplastic or hypocellular acute leukemia most accurately reflects this condition, which behaves clinically like more typically hypercellular acute leukemia. We describe a group of 29 patients who presented with bone marrow failure involving all cell lines, most dramatically involving the granulocyte series, and who had morphologic findings diagnostic of acute leukemia even though the bone marrow biopsy specimens were hypocelluiar. They are generally over the age of 50, are predominantly male and have nonspecific symptoms and a paucity of physical findings. It has generally been recommended that chemotherapy be withheld from such patients because of a poor response [5-81. However, the patients in the present series who were not treated had a poor prognosis: nearly all have benefited from aggressive chemotherapy in terms of improved bone marrow function and survival. PATIENTS AND METHODS The records of all patients presenting to the University of Minnesota Hospitals in whom the diagnosis of acute leukemia was made between June 1967 and February 1980 were reviewed. We identified 270 patients in whom the diagnosis of acute leukemia could clearly be made. All bone marrow biopsy specimens classified as normocellular or hypocellular were reviewed. No patient with treatment-related leukemia [S] was included. Twenty-nine patients qualified as having hypocellular bone marrow based on criteria to be discussed.
March 1982
The American Journal of Medicine
Volume 72
391
HYPOCELLULAR
ACUTE
LEUKEMIA-HOWE
ET AL.
Figure 1. Representative trephine biopsy specimens of (let?) slightly, (middle) moderately, and (right) markedly hypocellular bone marrow specimens from patients with acute leukemia (original magnification X 100, reduced by 30 percent).
alone; or aggressive therapy, treatment
Bone marrow specimens were obtained and processed as previously described [lo]. In addition to routine stains, bone marrow smears from all patients were studied for myeloperoxidase activity by Kaplow’s method [ 1l] and with the periodic acid-Schiff reaction. Bone marrow cellularity was evaluated in bone marrow sections in all patients; 25 patients had one or more posterior iliac crest trephine biopsy speci-
regimens always including an anthracycline drug and cytosine arabinoside [l-3]. Since this was a retrospective study, there was no randomization of patients to treatment groups. It has been our policy to provide aggressive management of bleeding and febrile complications to all patients. Decisions to attempt remission-induction chemotherapy were made by the patient and family after discussion of risks and benefits with the attending physician. Complete remission criteria were those of Cancer and Leukemia Group B [ 151.
mens of at least 2 cm length and aspirated bone marrow particle sections available for examination: four patients had only bone marrow particle sections. In addition, cellularity was evaluated in direct bone marrow smears and marrow particle smears and quantitative data were obtained from centrifuged marrow aspirates as previously described [lo]. The bone marrow was considered hypocellular only when information derived from all these types of specimens indicated hypocellularity [ 121. Although the possibility of sampling error exists, the reliability of these estimations has been established by others [ 13,141. Specimens were considered markedly hypocellular when the marrow space was predominantly occupied by adipose tissue and less than 15 percent of the marrow consisted of hematopoietic elements; moderately hypocellular when 15 to 30 percent of the marrow space consisted of hematopoietic cells; and slightly hypocellular when 30 to 40 percent of the marrow was occupied by hematopoietic tissue (Figure 1). Charts of all patients were reviewed for duration and type of symptoms prior to diagnosis, physical findings at the time of diagnosis, laboratory findings, treatment and survival from time of diagnosis. Treatment was classified as supportive only, that is, blood transfusions and antibiotics as required; moderately aggressive therapy, treatment consisting of drugs such as prednisone, hydroxyurea, vincristine, and 6-mercaptopurine, daunorubicin alone or cytosine arabinoside
392
March 1992
RESULTS Twenty-nine patients were identified in whom the diagnosis of acute leukemia could be made and who had bone marrow biopsy specimens with less than normal cellularity for the patient’s age. Twenty of the 29 patients had markedly [5] or moderately [ 151 hypocellular bone marrow; nine patients had slightly’ hypocellular bone marrow. The myeloblast percentage ranged from 5 to 70 percent with a median of 28 percent when first examined. The highest pretreatment blast percentage ranged from 14 to 70. In addition to the elevated blast counts, morphologic abnormalities in the maturing hematopoietic cell lines could be identified in 20 patients. There was definite evidence of involvement of more than one cell line in the leukemic process in 14 patients, and seven showed evidence of panmyelosis. There was variability in the predominant abnormal cell line from patient to patient. In 24 patients, the granu-
The American Journal of Medicine Volume 72
HYPOCELLULAR
locyte series was predominantly involved; in three, the erythroid line; in two, the monocytic. In eight of the patients, the initial bone marrow blast percentage was less than 20 percent at diagnosis. Three of these patients had myeloblasts with Auer rods. In six of the eight, follow-up bone marrow specimens were obtained; in five, the blast count increased to greater than 20 percent. Of the other three with less than 20 percent blasts, one had Auer rods and one had chromosomal abnormalities. The symptoms prior to diagnosis consisted of fever, weakness, fatigue, bone pain, hemorrhage and infection and were present for less than one week to more than 39 months prior to diagnosis. Physical findings were sparse and consisted of gum hyperplasia in one patient, central nervous system involvement in one patient, hepatomegaly in four patients, splenomegaly in two patients and lymphadenopathy in five patients. No patient had evidence of skin infiltration with leukemic cells. There was a 3: 1 male to female predominance of this disease; although the youngest patient was 15 years old and the oldest 79, all but four patients were 50 years of age or older at the time of diagnosis. Although anemia was present in all but one patient (hemoglobin range 3.5 to 15.7 g/dl), most patients were not severely anemic, having hemoglobin levels over 10 g/d1 (average 10.0 g/dl). Platelet counts ranged from 14,000 to 310,000/mm3. The most prominent laboratory finding was leukopenia; all patients but one having low total white blood cell counts (range less than 1,000 to 7,600/mm3). Blast forms were absent or too few in number in the peripheral blood to appear in the lOO-cell differential. The three treatment groups are compared in Table I. Median ages of the three treatment groups were comparable except for the inclusion of the 15 year old patient in the aggressively treated group. The median ages of the conservatively treated group and the aggressively treated group were not statistically different (p >0.05). Hematologic parameters were also comparable, except that the moderately aggressive treatment group was more thrombocytopenic on the average. The distribution of bone marrow cellularity among the treatment groups is shown in Table I. TREATMENT AND SURVIVAL The eight patients who received no specific anti-leukemic chemotherapy had a median survival of five months: one is still alive; the longest survivor lived 29 months. Untreated patients showed progression of disease with rising percentages of blasts in the bone marrow. Of the 10 patients who received moderately aggressive therapy, median survival was 17.5 months, the longest living 48 months, with none still alive. This is not significantly different from the untreated group.
TABLE I
ACUTE LEUKEMIA-HOWE
Comparisonof Treatment Groups* Supportive
Age (yr) Hemoglobin (g/df) White blood cell count (X103/mm3) Platelet count (X 103/mm3) Bone marrow cellularity (number of patients) Slightly Moderately Markedly Percent blasts
l
ET AL,
Moderate
Aggressive
57-79
33-79
15-69
(70) 3.5-14.0
(58) 5.2-15.7
(9.9) 1.0-2.6
(63) 7.2-11.6 (10.6) 1.0-7.6
(1.8) 18-310
(2.0) 14-70
(1.4) 29-304
(96)
(36)
(128)
2 4 2 5.4-70.0 (29.9)
6 4 0 10.2-63.8 (21.1)
(9.9) 1.0-4.3
1 7 3 7.4-67.4 (32.8)
Median values are given in parentheses.
One achieved complete remission. The 11 patients treated aggressively experienced a complete remission rate of 73 percent. Median survival is 40 months: four are still alive and the longest survivor lived 62 months. This is significant at the p CO.05 level (Figure 2). COMMENTS We describe a subset of patients with acute myelogenous leukemia presenting as pancytopenia with a predominance of granulocytopenia, vague systemic symptoms associated with the anemia and thrombocytopenia. Bone marrow specimens are distinctly hypocellular, although the increased numbers of blast forms and other morphologic abnormalities such as Auer rods make the diagnosis of leukemia evident. There is a 3:l male to female predominance of this condition, which generally presents beyond the 50th year of age. The clinical course tends to be a progressive one requiring aggressive chemotherapy rather than supportive care or less than intensive chemotherapy. Patients who received transfusion and antibiotics only, or who received vincristine, prednisone, 6-mercaptopurine, and other antimetabolites as single agents have shorter survivals than those who received more aggressive anti-leukemic therapy regimens containing an anthracycline drug and cytosine arabinoside. Complete remissions secondary to more aggressive chemotherapy are common; the life expectancy of patients managed in this manner is improved over those managed less aggressively. A strict comparison of the patient groups is not possible, since they were neither chronologically simultaneous nor randomized. Improved supportive therapy for bleeding and infectious complications may have contributed significantly to the improved outcome of patients treated at a later date. However, nearly all
March 1982
The American Journal oi Medicine
Volume 72
393
HYPOCELLULAR
ACUTE LEUKEMIA-HOWE
ET AL
0 NO TREATMENT 0
MODERATELY
a
AGGRESSIVE
AGQRESSIVE
*ALIVE
0047---d10
20
30
Figure 2. Survival curves of the three patient groups. The survival of the untreated (II) and moderately aggressive (0) treatment groups is similar; that of the aggressively treated group (A) significantly prolonged (see text).
40
Survival (months)
of the patients in the group receiving supportive therapy were concurrent with those in the group treated aggressively and had access to the same treatment for bleeding and infectious complications. Since these supportive measures make possible more effective remission-induction regimens [l-3], the poor outcome of less aggressively managed patients has encouraged a more aggressive approach. The high remission rate and longer survival of patients so managed favors the approach. Previous recommendations that therapy should be modified or withheld because patients with hypoplastic bone marrow would not tolerate further suppression are not borne out by these results. This condition is distinct from so called preleukemia, although the clinical presentation and peripheral blood picture may be confused with that condition [6]. In contrast to the picture in preleukemia, the bone marrow in these patients is hypocellular and there is distinct evidence of leukemia in the form of increased numbers of blasts and morphologic changes in individual cells diagnostic of leukemia. This form of leukemia also differs from refractory anemia with excess blasts [8], in that in the latter condition, anemia predominates the
clinical picture, whereas leukopenia dominated the peripheral blood picture in the present group. Although some investigators may consider those patients with less than 20 percent myeloblasts to have refractory anemia with excess myeloblasts, nearly all patients with the latter have hypercellularity of the bone marrow. The distinct hypocellularity in our patients is unusual for that condition. The dysplastic changes in the red cell, megakaryocyte and granulocyte lines in the bone marrow qualify this as a myelodysplastic disease. However, most patients so classified also have hyperceilular marrows. Our patients probably should not be classified as having “smoldering” acute leukemia [5], since the course is not benign. Indeed, all of these patients treated with supportive therapy only had progressive disease and a shortened life expectancy compared with those who were managed as if they had acute leukemia. The present group, with hypocellularity and a distinct increase in myeloblasts, should probably be classified as having acute leukemia. The clinical course and response to therapy would support this conclusion. The syndrome of hypocellular acute leukemia is a clinical entity requiring aggressive management.
REFERENCES 1.
2.
394
Yates JW, Wallace HJ, Ellison RR, Holland JF: Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep 1973; 57: 485-488. Gale RP, Cline MJ: High remission-induction rate in acute
March 1982
The American Journal of Medicine
Volume 72
3.
4.
myeloid leukemia. Lancet 1977; I: 497-499. Peterson BA, Bloomfield CD: Prolonged maintained remissions of adult acute non-lymphocytic leukemia. Lancet 1977; II: 158-160. Bloomfield CD: Treatment of adult acute nonlymphocytic
HYPOCELLULAR ACUTE LEUKEMIA-HOWE ET AL.
5. 6.
7.
8.
9.
10.
leukemia. Ann Intern Med 1980; 93: 133-135. Knospe WH, Gregory SA: Smoldering acute leukemia. Arch Intern Med 1971; 127: 910-918. Fisher WB, Armentrout SA, Weisman R Jr, Graham RC: Preleukemia: a myelodysplastic syndrome often terminating in acute leukemia. Arch Intern Med 1973; 132: 226232. Beard MEJ, Bateman CJT, Crowther DC, et al.: Hypoplastic acute myelogenous leukemia. Br J Haemat 1975; 31: 167-176. Rochant H, Dreyfus B. Bouguerr M, Tont-hat H: Refractory anemias, pre-leukemic conditions, and fetal erythropoiesis. Blood 1972; 39: 721-726. Foucar K, McKenna RW, Bloomfield CD, Bowers TK, Brunning RD: Therapy-related leukemia: a panmyelosis. Cancer 1979; 43: 1285-1296. Brynes RK, McKenna RW, Sundberg RD: Bone marrow aspi-
11. 12.
13.
14.
15.
March 1982
ration and trephine biopsy: An approach to a thorough study. Am J Clin Pathol 1978: 70: 753-759. Kaplow LS: Simplified myeloperoxidase stain using benzidine dihydrochloride. Blood 1965; 26: 215-219. Hartsock RJ, Smith EB, Petty CS: Normal variations with aging of the amount of hematopoietic tissue in bone marrow from the anterior iliac crest. Am J Clin Pathol 1965; 43: 326331. Fong TP, Okafor LA, Schmitz TH, Thomas W, Westerman MP: An evaluation of cellularity in various types of bone marrow specimens. Am J Clin Pathol 1979; 72: 812-816. Morley A, Blake J: Observer error in histological assessment of marrow cellularity. J Clin Pathol 1975; 28: 104-108. Acute leukemia group B criteria for evaluating acute leukemia. June 1974 modification of the 1969 criteria. Cancer and Leukemia Group B. Scarsdale, New York.
The American Journal of Medlclne
Volume 72
395