Preleukemic State Preceding Adult Acute Lymphoblastic Leukemia MARKA. DAYTON,M.D., Ph.D., KOENVAN BESIEN, M.D., GUIDOTRICOT,M.D., Ph.D., RONALDHOFFMAN,M.D., Indianapolis, Indiana
cute lymphoblastic leukemia (ALL) in adults
A typically presents fulminantly. However, there
are numerous examples in the literature where ALL developed from an antecedent hematologic disorder. These preceding disorders include chronic granulocytic leukemia [1,2], polycythemia vera [3], the myelodysplastic syndromes [4-15], chronic lymphocytic leukemia [16-18], paroxysmal nocturnal hemoglobinuria [19], apparent aplastic anemia in children [20-27] or young adults [28-30], and isolated neutropenia [31,32] or erythroid hypoplasia [33]. These cases are characterized by a lack of morphologically distinguishable lymphoblasts during the "preleukemic phase." There is one case report of a 12-year-old patient with ALL who presented with a syndrome that resembled aplastic anemia and who demonstrated an increased number of CALLA (common acute lymphocytic leukemia antigen)-positive cells in the initial bone marrow. However, the authors were unable to clearly identify lymphoblasts in the bone marrow specimen [20]. Myelodysplasia (MDS) classically encompasses a group of disorders with a relatively high propensity to progress to acute myelogenous leukemia. However, occasional case reports clearly demonstrate that MDS also has the potential to progress to ALL [4-11] or biphenotypic leukemia [12-15]. All these cases showed obvious multilineage maturation abnormalities and no evidence of increased numbers of lymphoblasts prior to acute transformation. In this article, we report data on two patients with adult ALL who presented with an extended preleukemic phase ultimately terminating in overt ALL after several months. These patients differed somewhat in their presentation, yet both were characterized by leukopenia. No morphologic abnormalities were found in any lineage other than the lymphocytic lineage. From the outset, there was ev-
From the Division of Hematology/Oncology Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Requests for reprints should be addressed to Mark Dayton, M.D., Ph.D., Ohio State University Hospitals, Division of Hematology/Oncology, 1ON Doan Hall, 410 West lOth Street, Columbus, Ohio 43210-1228. Manuscript submitted March 30, 1990, and accepted May 31, 1990.
idence of increased numbers of bone marrow lymphoblasts, which persisted for a long period in each patient before they presented with overt ALL.
CASE REPORTS Patient 1 The patient was a young woman who initially developed temperatures up to 40 ° C (104° F) in July 1987 at the age of 18. The fevers recurred on a cycle of approximately 4 weeks' duration with high-grade fevers for 2 weeks and low-grade fevers for 2 weeks. The high-grade fevers seemed to commence at approximately the time of her menses and were associated with migratory myalgias, headaches, and fatigue. There was no weight loss or night sweats. She denied having other symptoms. Physical examination on presentation and on multiple follow-up examinations was unremarkable. She was mildly anemic with a hemoglobin of 127 g/L and leukopenic with a white blood cell count of 3.1 X 109/L with a differential of 2% bands, 58% segmented neutrophils, 36% lymphocytes, 3% monocytes, and 1% eosinophils (Table I). She had a positive antinuclear antibody of 1:160 on one occasion, but this was negative on three subsequent occasions. Her neutrophil count dropped as low as 0.798 X 109/I,. Her bone marrow aspirate and biopsy revealed a marrow cellularity of approximately 30%. The myeloid-to-erythroid ratio was 3:1. There was normal maturation of the myeloid, erythroid, and megakaryocytic lineages; however, there were multiple small aggregates of immature lymphoid cells scattered throughout the marrow with high nucleus/cytoplasm ratios and single nucleoli (Figure 1, top left and top center). Special histochemical stains, including Sudan black, myeloperoxidase, periodic acid-Schiff, and a-naphthyl butyrate esterase, were negative. No ringed sideroblasts were noted in Prussian blue-stained specimens. Immunologic phenotyping studies with monoclonal antibodies to myeloid and lymphoid differentiation antigens revealed no diagnostic evidence of malignancy, although 14% of the cells were positive for CALLA. At this time, these marrow cells were terminal deoxynucleotidyl transferase (TdT) negative (Table II).
November 1990
The American Journal of Medicine
Volume 89
657
PRELEUKEMIA PRECEDING ADULT ALL / DAYTON ET AL
TABLE I Peripheral Blood and Bone Marrow Counts at Presentation (PRES), Initiation of Therapy (INIT), and After Achieving Complete Remission (CR)
PRES
Patient 1 INIT
CR
PRES
Patient2 INIT
CR
Blood Hemoglobin(g/L) Hematocrit (%) Platelets(X I09/L) WBC (X I09/L) Blasts (°h) Myelocytes (%) Metamyelocytes(%) Bands(%) Segmentedneutrophils(%) Lymphocytes(%) Atypical lymphocytes(%) Monocytes (%) Eosinophils(%) Basophils(%)
127 38.3 367 3.1 0 0 0 2 58 36 0 3 1 0
111 32.6 390 2.7 0 0 0 2 56 31 7 4 0 0
111 32.1 910 4.8 1 0 0 3 41 31 0 24 0 0
150 43.9 305 ] .6 0 0 0 2 51 43 0 4 0 0
136 40.4 199 1.9 1 0 0 0 50 46 0 3 0 0
105 30.9 815 7.4 0 1 3 5 49 14 0 27 0 1
Bone marrow (% non-erythroid cells) Blasts Promyelocytes Myelocytes Metamyelocytes Bands Segmentedneutrophils Lymphocytes Monocytes Eosinophils Basophils Normoblasts(/1,000 WBC) Megakaryocytes Biopsy cellularity (%)
4 0 13 13 30 19 23 0 0 0 29 Adeq 30
50 0 12 12 12 0 14 0 0 0 22 Adeq 40
1 ] 7 25 9 13 44 0 0 0 178 SI incr ND
25 0 3 6 9 12 45 0 0 0 57 Adeq 15
35 3 6 2 3 12 34 1 4 0 73 Adeq 10
2 ] 17 12 27 28 5 7 0 1 53 SI incr ND
Adeq= adequate;Sl incr= slightincrease;ND= not determined.
Figure 1. Bone marrow findings for Patient 1 (top left, top center, and top right) and Patient 2 (bottom left, bottom center, and bottom right). Lymphoblasts with a high nucleus-to-cytoplasm ratio and zero to one nucleoli can be seen in the bone marrow aspirate (top left) and touch preparation (bottom left) (Wright stain; original magnification X4,725, reduced by 67%). Progressively larger clusters of lymphoblasts can be seen in the bone marrow biopsy specimens from the time of initial presentation (top center and bottom center) to that of diagnosis (top right and bottom right) (hematoxylin-eosin stain; original magnification x3,000 reduced by 67%).
658
November 1990 The American Journal of Medicine Volume 89
PRELEUKEMIA PRECEDING ADULT ALL / DAYTON ET AL
The results of bone marrow cytogenetic analysis were normal. An extensive work-up including multiple viral and protozoal serologies, cultures, liver biopsy, lumbar puncture, echocardiogram, chest radiogram, and abdominal-pelvic computed tomographic (CT) scan failed to reveal the source of fevers. Additionally, three empiric courses of antibiotics (including penicillin, amoxicillin, and tetracycline) failed to impact upon her fevers. An extensive rheumatologic work-up was also unrevealing. Unfortunately, during a repeat empiric course of tetracycline in December 1987, the patient developed a generalized clonic seizure. Evaluation with a lumbar puncture, electroencephalogram, head CT scan, and head magnetic resonance imaging failed to identify a cause for her seizure. Seizure activity never recurred after discontinuation of the tetracycline. Eventually, 7 months after the onset of her fevers, a bone marrow aspirate repeated at another institution revealed 22% lymphoblasts appearing in a normocellular marrow with normal maturation of the myeloid, erythroid, and megakaryocytic lineages. There were 50% lymphoblasts in the bone marrow biopsy. The morphology of the blasts was similar to that initially seen on presentation (Figure 1, top right). Again, histochemical stains were negative. Immunologic phenotyping of the mononuclear marrow cells revealed approximately 40% TdT-positive and CALLA-positive cells. The diagnosis of common ALL was made. At that time, the patient had a hemoglobin level of 111 g/L, a platelet count of 390 × 109/L, and a white blood cell count of 2.7 × 109/L, including 7% "atypical" lymphocytes (Table I). Antileukemic induction therapy consisting of vincristine 1.4 mg/m 2 weekly for 3 weeks, methylprednisolone 32 mg/m 2 for 21 days, and daunorubicin 50 mg/m2/day for 3 days was started. Intrathecal chemotherapy with methotrexate (15 mg), cytosine arabinoside (Ara-C, 30 rag), and hydrocortisone (15 mg) was instituted early and continued intermittently throughout consolidation therapy. Consolidation therapy consisted of six courses of intermediate-dose methotrexate (500 mg/m 2) with leucovorin rescue, alternating with three courses of Ara-C (1 gm/m 2 every 12 hours for 4 days) plus etoposide (VP-16, 400 mg/m 2 every other day for 2 days). The patient rapidly became afebrile once chemotherapy had been administered. Her bone marrow remained hypocellular on Day 22 with no evidence of residual leukemia, and she had clearly attained a complete remission by Day 30. The initial consolidation therapy with methotrexate was complicated by epigastric and chest pain associated
TABLE II Bone Marrow Immunophenotyping at Presentation (PRES), Initiation of Therapy (INIT), and After AchievingComplete Remission (CR) CD
PRES
1 2 3 4 5 7 8 9 10 11b 13 19 33 34 38 45 W54 K X CylgM
ND 8 ND ND ND 18 ND 14 14 ND ND 7 38 ND ND 56 19 6 0 ND
Patient I INIT ND 38 ND ND ND 39 ND 36 43 16 3 37 14 28 ND 55 25 2
cute lymphoblastic leukemia (ALL) in adults
A typically presents fulminantly. However, there
are numerous examples in the literature where ALL developed from an antecedent hematologic disorder. These preceding disorders include chronic granulocytic leukemia [1,2], polycythemia vera [3], the myelodysplastic syndromes [4-15], chronic lymphocytic leukemia [16-18], paroxysmal nocturnal hemoglobinuria [19], apparent aplastic anemia in children [20-27] or young adults [28-30], and isolated neutropenia [31,32] or erythroid hypoplasia [33]. These cases are characterized by a lack of morphologically distinguishable lymphoblasts during the "preleukemic phase." There is one case report of a 12-year-old patient with ALL who presented with a syndrome that resembled aplastic anemia and who demonstrated an increased number of CALLA (common acute lymphocytic leukemia antigen)-positive cells in the initial bone marrow. However, the authors were unable to clearly identify lymphoblasts in the bone marrow specimen [20]. Myelodysplasia (MDS) classically encompasses a group of disorders with a relatively high propensity to progress to acute myelogenous leukemia. However, occasional case reports clearly demonstrate that MDS also has the potential to progress to ALL [4-11] or biphenotypic leukemia [12-15]. All these cases showed obvious multilineage maturation abnormalities and no evidence of increased numbers of lymphoblasts prior to acute transformation. In this article, we report data on two patients with adult ALL who presented with an extended preleukemic phase ultimately terminating in overt ALL after several months. These patients differed somewhat in their presentation, yet both were characterized by leukopenia. No morphologic abnormalities were found in any lineage other than the lymphocytic lineage. From the outset, there was ev-
From the Division of Hematology/Oncology Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Requests for reprints should be addressed to Mark Dayton, M.D., Ph.D., Ohio State University Hospitals, Division of Hematology/Oncology, 1ON Doan Hall, 410 West lOth Street, Columbus, Ohio 43210-1228. Manuscript submitted March 30, 1990, and accepted May 31, 1990.
idence of increased numbers of bone marrow lymphoblasts, which persisted for a long period in each patient before they presented with overt ALL.
CASE REPORTS Patient 1 The patient was a young woman who initially developed temperatures up to 40 ° C (104° F) in July 1987 at the age of 18. The fevers recurred on a cycle of approximately 4 weeks' duration with high-grade fevers for 2 weeks and low-grade fevers for 2 weeks. The high-grade fevers seemed to commence at approximately the time of her menses and were associated with migratory myalgias, headaches, and fatigue. There was no weight loss or night sweats. She denied having other symptoms. Physical examination on presentation and on multiple follow-up examinations was unremarkable. She was mildly anemic with a hemoglobin of 127 g/L and leukopenic with a white blood cell count of 3.1 X 109/L with a differential of 2% bands, 58% segmented neutrophils, 36% lymphocytes, 3% monocytes, and 1% eosinophils (Table I). She had a positive antinuclear antibody of 1:160 on one occasion, but this was negative on three subsequent occasions. Her neutrophil count dropped as low as 0.798 X 109/I,. Her bone marrow aspirate and biopsy revealed a marrow cellularity of approximately 30%. The myeloid-to-erythroid ratio was 3:1. There was normal maturation of the myeloid, erythroid, and megakaryocytic lineages; however, there were multiple small aggregates of immature lymphoid cells scattered throughout the marrow with high nucleus/cytoplasm ratios and single nucleoli (Figure 1, top left and top center). Special histochemical stains, including Sudan black, myeloperoxidase, periodic acid-Schiff, and a-naphthyl butyrate esterase, were negative. No ringed sideroblasts were noted in Prussian blue-stained specimens. Immunologic phenotyping studies with monoclonal antibodies to myeloid and lymphoid differentiation antigens revealed no diagnostic evidence of malignancy, although 14% of the cells were positive for CALLA. At this time, these marrow cells were terminal deoxynucleotidyl transferase (TdT) negative (Table II).
November 1990
The American Journal of Medicine
Volume 89
657
PRELEUKEMIA PRECEDING ADULT ALL / DAYTON ET AL
TABLE I Peripheral Blood and Bone Marrow Counts at Presentation (PRES), Initiation of Therapy (INIT), and After Achieving Complete Remission (CR)
PRES
Patient 1 INIT
CR
PRES
Patient2 INIT
CR
Blood Hemoglobin(g/L) Hematocrit (%) Platelets(X I09/L) WBC (X I09/L) Blasts (°h) Myelocytes (%) Metamyelocytes(%) Bands(%) Segmentedneutrophils(%) Lymphocytes(%) Atypical lymphocytes(%) Monocytes (%) Eosinophils(%) Basophils(%)
127 38.3 367 3.1 0 0 0 2 58 36 0 3 1 0
111 32.6 390 2.7 0 0 0 2 56 31 7 4 0 0
111 32.1 910 4.8 1 0 0 3 41 31 0 24 0 0
150 43.9 305 ] .6 0 0 0 2 51 43 0 4 0 0
136 40.4 199 1.9 1 0 0 0 50 46 0 3 0 0
105 30.9 815 7.4 0 1 3 5 49 14 0 27 0 1
Bone marrow (% non-erythroid cells) Blasts Promyelocytes Myelocytes Metamyelocytes Bands Segmentedneutrophils Lymphocytes Monocytes Eosinophils Basophils Normoblasts(/1,000 WBC) Megakaryocytes Biopsy cellularity (%)
4 0 13 13 30 19 23 0 0 0 29 Adeq 30
50 0 12 12 12 0 14 0 0 0 22 Adeq 40
1 ] 7 25 9 13 44 0 0 0 178 SI incr ND
25 0 3 6 9 12 45 0 0 0 57 Adeq 15
35 3 6 2 3 12 34 1 4 0 73 Adeq 10
2 ] 17 12 27 28 5 7 0 1 53 SI incr ND
Adeq= adequate;Sl incr= slightincrease;ND= not determined.
Figure 1. Bone marrow findings for Patient 1 (top left, top center, and top right) and Patient 2 (bottom left, bottom center, and bottom right). Lymphoblasts with a high nucleus-to-cytoplasm ratio and zero to one nucleoli can be seen in the bone marrow aspirate (top left) and touch preparation (bottom left) (Wright stain; original magnification X4,725, reduced by 67%). Progressively larger clusters of lymphoblasts can be seen in the bone marrow biopsy specimens from the time of initial presentation (top center and bottom center) to that of diagnosis (top right and bottom right) (hematoxylin-eosin stain; original magnification x3,000 reduced by 67%).
658
November 1990 The American Journal of Medicine Volume 89
PRELEUKEMIA PRECEDING ADULT ALL / DAYTON ET AL
The results of bone marrow cytogenetic analysis were normal. An extensive work-up including multiple viral and protozoal serologies, cultures, liver biopsy, lumbar puncture, echocardiogram, chest radiogram, and abdominal-pelvic computed tomographic (CT) scan failed to reveal the source of fevers. Additionally, three empiric courses of antibiotics (including penicillin, amoxicillin, and tetracycline) failed to impact upon her fevers. An extensive rheumatologic work-up was also unrevealing. Unfortunately, during a repeat empiric course of tetracycline in December 1987, the patient developed a generalized clonic seizure. Evaluation with a lumbar puncture, electroencephalogram, head CT scan, and head magnetic resonance imaging failed to identify a cause for her seizure. Seizure activity never recurred after discontinuation of the tetracycline. Eventually, 7 months after the onset of her fevers, a bone marrow aspirate repeated at another institution revealed 22% lymphoblasts appearing in a normocellular marrow with normal maturation of the myeloid, erythroid, and megakaryocytic lineages. There were 50% lymphoblasts in the bone marrow biopsy. The morphology of the blasts was similar to that initially seen on presentation (Figure 1, top right). Again, histochemical stains were negative. Immunologic phenotyping of the mononuclear marrow cells revealed approximately 40% TdT-positive and CALLA-positive cells. The diagnosis of common ALL was made. At that time, the patient had a hemoglobin level of 111 g/L, a platelet count of 390 × 109/L, and a white blood cell count of 2.7 × 109/L, including 7% "atypical" lymphocytes (Table I). Antileukemic induction therapy consisting of vincristine 1.4 mg/m 2 weekly for 3 weeks, methylprednisolone 32 mg/m 2 for 21 days, and daunorubicin 50 mg/m2/day for 3 days was started. Intrathecal chemotherapy with methotrexate (15 mg), cytosine arabinoside (Ara-C, 30 rag), and hydrocortisone (15 mg) was instituted early and continued intermittently throughout consolidation therapy. Consolidation therapy consisted of six courses of intermediate-dose methotrexate (500 mg/m 2) with leucovorin rescue, alternating with three courses of Ara-C (1 gm/m 2 every 12 hours for 4 days) plus etoposide (VP-16, 400 mg/m 2 every other day for 2 days). The patient rapidly became afebrile once chemotherapy had been administered. Her bone marrow remained hypocellular on Day 22 with no evidence of residual leukemia, and she had clearly attained a complete remission by Day 30. The initial consolidation therapy with methotrexate was complicated by epigastric and chest pain associated
TABLE II Bone Marrow Immunophenotyping at Presentation (PRES), Initiation of Therapy (INIT), and After AchievingComplete Remission (CR) CD
PRES
1 2 3 4 5 7 8 9 10 11b 13 19 33 34 38 45 W54 K X CylgM
ND 8 ND ND ND 18 ND 14 14 ND ND 7 38 ND ND 56 19 6 0 ND
Patient I INIT ND 38 ND ND ND 39 ND 36 43 16 3 37 14 28 ND 55 25 2
