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Biomedical subjects

R A Larson

Publications and source records attributed to R A Larson.

At least 19 recordsLinked to original sources
PubMed1998

CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy.

CBFA2(AML1) has emerged as a gene critical in hematopoiesis; its protein product forms the DNA-binding subunit of the heterodimeric core-binding factor (CBF) that binds to the transcriptional regulatory regions of genes, some of which are active specifically in hematopoiesis. CBFA2 forms a fusion gene with ETO and MDS1/EVI1 in translocations in myeloid leukemia and with ETV6(TEL) in the t(12;21) common in childhood pre-B acute lymphoblastic leukemia. We have analyzed samples from 30 leukemia patients who had chromosome rearrangements involving 21q22 by using fluorescence in situ hybridization (FISH). Our analysis showed that 7 of them involved CBFA2 and new translocation partners. Two patients had a t(17;21)(q11.2;q22), whereas the other 5 had translocations involving 1p36, 5q13, 12q24, 14q22, or 15q22. Five of these novel breakpoints in CBFA2 occurred in intron 6; this same intron is involved in the t(3;21). One breakpoint mapped to the t(8;21) breakpoint region in intron 5, and 1 mapped 5' to that region. All 7 CBFA2 rearrangements resulted from balanced translocations. All 7 patients had myeloid disorders (acute myeloid leukemia or myelodysplastic syndrome); 2 were de novo and 5 had treatment histories that included topoisomerase II targeting agents. The association of therapy-related disorders with translocations involving CBFA2 was significant by Fisher's exact test (P < .003). These results provide further evidence that this region of CBFA2 is susceptible to breakage in cells exposed to topoisomerase II inhibitors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111.

Recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) shortens the time to neutrophil recovery after intensive chemotherapy, but its role in the treatment of adults with acute lymphoblastic leukemia (ALL) is uncertain. We randomly assigned 198 adults with untreated ALL (median age, 35 years; range, 16 to 83) to receive either placebo or G-CSF (5 microgram/kg/d) subcutaneously, beginning 4 days after starting intensive remission induction chemotherapy and continuing until the neutrophil count was >/=1, 000/microL for 2 days. The study assignment was unblinded as individual patients achieved a complete remission (CR). Patients initially assigned to G-CSF then continued to receive G-CSF through 2 monthly courses of consolidation therapy. Patients assigned to placebo received no further study drug. The median time to recover neutrophils >/=1,000/microL during the remission induction course was 16 days (interquartile range [IQR], 15 to 18 days) for the patients assigned to receive G-CSF and 22 days (IQR, 19 to 29 days) for the patients assigned to placebo (P < .001). Patients in the G-CSF group had significantly shorter durations of neutropenia (<1, 000/microL) and thrombocytopenia (<50,000/microL) and fewer days in the hospital (median, 22 days v 28 days; P = .02) compared with patients receiving placebo. The patients assigned to receive G-CSF had a higher CR rate and fewer deaths during remission induction than did those receiving placebo (P = .04 by the chi-square test for trend). During Courses IIA and IIB of consolidation treatment, patients in the G-CSF group had significantly more rapid recovery of neutrophils >/=1,000/microL than did the control group by approximately 6 to 9 days. However, the patients in the G-CSF group did not complete the planned first 3 months of chemotherapy any more rapidly than did the patients in the placebo group. Overall toxicity was not lessened by the use of G-CSF. After a median follow-up of 4. 7 years, there were no significant differences in either the disease-free survival (P = .53) or the overall survival (P = .25) for the patients assigned to G-CSF (medians, 2.3 years and 2.4 years, respectively) compared with those assigned to placebo (medians, 1.7 and 1.8 years, respectively). Adults who received intensive chemotherapy for ALL benefited from G-CSF treatment, but its use did not markedly affect the ultimate outcome.

Adolescent↗
PubMed1998

Pseudo-Gaucher histiocytes identified up to 1 year after transplantation for CML are BCR/ABL-positive.

The results of polymerase chain reaction (PCR) analysis after transplantation for chronic myelogenous leukemia (CML) are difficult to interpret clinically. Positive findings for BCR/ABL can be seen not only in patients who go on to relapse but also in patients who, after years of follow-up, remain in complete remission. The cause for the lack of concordance between PCR findings and relapse is not clear. We identified two patients with CML who had rare pseudo-Gaucher cells in their bone marrow aspirate specimens prior to, and at 1, and 6 or 12 months following syngeneic or allogeneic hematopoietic transplantation. After the transplant, the patients obtained clinical remission and were shown to be cytogenetically normal and to have germline MBCR in blood or bone marrow by Southern analysis. One patient was PCR-positive for BCR/ABL in the marrow at 12 months. In order to determine whether the pseudo-Gaucher histiocytes were BCR/ABL-positive, we used fluorescence in situ hybridization and probes for MBCR and ABL and analyzed Wright-stained smears to correlate molecular cytogenetic findings with cell type. On three aspirate smears from each patient (at 6 or 12 months post-transplant), all of the pseudo-Gaucher cells studied (10/10 in one patient and 12/12 in the other) showed the fusion for BCR/ABL. Other cells analyzed randomly (erythroid precursors, granulocytes and rare monocytes, lymphocytes and plasma cells) did not. Our cases provide the first proof that pseudo-Gaucher cells carry the BCR/ABL fusion. Furthermore, they illustrate that these cells can be found in the marrow for up to 12 months following transplantation. Our results permit speculation that pseudo-Gaucher cells or other long-lived histocytes may be one cause of persistent PCR positivity after transplantation that is not predictive of disease relapse.

Adult↗
PubMed1998

Establishment and characterization of a megakaryoblast cell line with amplification of MLL.

A new cell line with megakaryoblastic features, designated UoC-M1, was established from the malignant cells of a 68-year-old patient with acute myeloid leukemia. The patient's leukemic cells reacted with alpha-naphthyl acetate esterase and acid phosphatase and expressed CD7, CD24, CD34, CD38, CD45, HLA-DR and CD61. Cytogenetic analysis of the patient's malignant cells (and of the UoC-M1 cells) showed a human, male hypodiploid karyotype with many chromosome rearrangements and marker chromosomes. Spectral karyotyping (SKY) analysis complemented the G-banded karyotyping and clarified several chromosomal translocations and identified the marker chromosomes. Fluorescence in situ hybridization (FISH) and SKY analysis demonstrated that one marker chromosome contained three segments of chromosome 9 interspersed with three segments of chromosome 11, as well as a portion of chromosome 19. FISH analysis with a probe for MLL revealed that the UoC-M1 cells contained four copies of the MLL gene. Southern blot analysis determined that the MLL gene had a germline profile while Northern and Western analyses showed that the MLL mRNAs and protein were of the appropriate sizes. This is the first report of amplification of the MLL gene which may be an additional mechanism of leukemogenesis or disease progression.

Aged↗
PubMed1998

Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia.

Among its multiple toxic effects, L-asparaginase induces allergic reactions that may reduce its biological effect. The impact of hypersensitivity reactions on the duration of leukemia-free survival (LFS) was assessed in adults with newly diagnosed acute lymphoblastic leukemia (ALL) receiving intensive multi-agent chemotherapy. In CALGB study 8811 (Blood 1995; 85: 2025-2037), 197 adults were scheduled to receive 14 doses of Escherichia coil L-asparaginase (6000 U/m2 SC) during 7 of the first 12 weeks of chemotherapy. No further L-asparaginase was given. Chemotherapy was given for 24 months. The median follow-up time has been 5.7 years. Of the 141 patients who remained on study after 12 weeks, 82 (58%) had received all 14 planned doses; 38 (27%) had 12-13 L-asparaginase doses documented in their treatment record; 21 (15%) patients had received < or =11 doses due to a variety of toxic effects. The mean number of doses received prior to experiencing any hypersensitivity reaction was seven (range 1-11). Seven patients had mild hypersensitivity reactions, but all seven eventually received 12-14 doses of E. coil L-asparaginase. Twenty-one other patients had severe hypersensitivity reactions that required discontinuation of E. coil L-asparaginase; 20 of these patients were switched to Erwinia L-asparaginase to complete their treatment. Ultimately, 12 of these 20 patients received 14 doses of L-asparaginase in total, and six received 12-13 doses. Thus, only three of the 21 patients who had severe hypersensitivity reactions received < or =11 total L-asparaginase doses. Other L-asparaginase-related complications included pancreatitis (15 patients), hypofibrinogenemia <100mg/dl (29 patients), and deep venous thrombosis or pulmonary embolism (eight patients); some of these patients had L-asparaginase discontinued after these complications. The estimates for LFS at 3 years were 55% (95% confidence interval, 44-65%) for the patients who received all 14 L-asparaginase doses (median LFS, 5.1 years), 47% (95% CI, 33-62%) for those who received 12-13 doses, and 48% (95% CI, 29-67%) for those who received < or =11 doses. There were no significant differences between these three groups in the length of LFS (P=0.68). LFS did not correlate with a history of severe hypersensitivity reaction (P=0.67). In general, E. coil L-asparaginase was well tolerated in these adult patients, and most patients received all of the planned therapy. Patients who had mild L-asparaginase hypersensitivity reactions and patients who switched to Erwinia L-asparaginase because of more severe allergic reactions did not have significantly shorter LFS than the remaining adults treated on this ALL protocol. The possibility that E. coli L-asparaginase is inactivated or destroyed in those individuals who have become hypersensitive to it becomes less important when allergic patients are secondarily treated with Erwinia L-asparaginase.

Adolescent↗
PubMed1998

Metastatic adenocarcinoma arising in a congenital foregut cyst of the esophagus: a case report with review of the literature.

Benign tumors and cysts of the esophagus are rare, and malignant transformation of esophageal cysts is even more rare. In this article, we report on the first case to our knowledge of a patient presenting with metastatic adenocarcinoma arising in a congenital foregut cyst of the esophagus. A 37-year-old woman had multiple cysts along the aerodigestive tract and diffuse soft tissue metastases. Endoscopic biopsies of a mediastinal mass revealed an enteric cyst with a spectrum of columnar epithelium ranging from benign through adenomatous to frankly malignant. There was only transient response to radiotherapy and chemotherapy. Only three other cases of carcinoma arising from esophageal duplication foregut cysts have been reported, and none of these were metastatic. Given the rarity of malignant transformation within an esophageal cyst, prophylactic excision of known esophageal cysts is not warranted. However, biopsy of the cyst may be useful to exclude the possibility of malignancy, particularly if the onset of symptoms has been recent.

Adenocarcinoma↗
PubMed1998

High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase.

PURPOSE: A phase II clinical trial was performed to evaluate the effectiveness of high-dose cladribine (2CDA) for treatment of chronic myelogenous leukemia (CML) in the accelerated or blast phase. PATIENTS AND METHODS: Nineteen patients were treated. The median age was 55 years (range, 30 to 73). Six were older than 60 years. Eight had progressed after intensive combination chemotherapy and three after allogeneic or autologous transplantation. For the first course, 16 patients received 2CDA at 15 mg/m2/d intravenously (i.v.) over 1 hour for 5 days. Two received 18 mg/m2 and one received 21.5 mg/m2 daily. The second course was escalated to 20 mg/m2/d in five patients. RESULTS: Rapid cytoreduction of leukemia occurred in the blood, with the nadir at 10 to 12 days. The median WBC count decreased from 36,900/microL before treatment to 500/microL at the nadir and recovered to 5,200/microL at day 30. The median platelet count changed from 113,000/microL to 24,000/microL at the nadir and 71,000/microL at day 30. The complete remission (CR) plus partial remission (PR) rate was 47% (95% confidence interval [CI], 23% to 72%). One 64-year-old man with lymphoid blast phase of CML had a morphologic and cytogenetic CR that lasted 9 months. The median survival for all patients was 34 weeks, and the median survival for the eight responders was 56 weeks (range, 11 to 167). The median number of days spent in hospital over the entire treatment period was 19 (range, 4 to 60). CONCLUSION: High-dose 2CDA therapy provides effective palliation for CML in accelerated or blast phases, even for heavily pretreated patients.

Adult↗
PubMed1997

Long-term follow-up of Cancer and Leukemia Group B studies in acute myeloid leukemia.

BACKGROUND: During the past 3 decades, the Cancer and Leukemia Group B (CALGB) has conducted numerous large clinical trials in adult patients with acute myeloid leukemia. METHODS: Updated data were obtained for 9 trials initiated by the CALGB between 1974 and 1992. The updated data were compared with the original published results. RESULTS: It was apparent from all the studies that hazard rates for death and relapse are greatest in the first year, decrease substantially between Years 1 and 2, then decrease further between Years 2 and 3. Rates of death and relapse are quite low after 3-4 years. Large numbers of patients are long-term disease free survivors. Overall, these patients have excellent function and a normal quality of life. CONCLUSIONS: Patients with AML who are in complete remission for 3-4 years can be assured that late relapse and death are relatively uncommon events. It is inadvisable to publish results of large studies until this minimal level of follow-up has been reached.

Acute Disease↗
PubMed1997

Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1-1.5 Mb and preparation of a PAC-based physical map.

Loss of a whole chromosome 5 or a deletion of the long arm, del(5q), is a recurring abnormality in malignant myeloid diseases. In previous studies, we delineated a commonly deleted segment of approximately 4 Mb within band 5q31 that was flanked by IL9 on the proximal side and D5S166 on the distal side. We have generated a physical map of P1 (PAC), bacterial (BAC), and yeast artificial chromosome (YAC) clones of this interval. The contig consists of 108 clones (78 PACs, 2 BACs, and 28 YACs) to which 125 markers (5 genes, 11 expressed sequence tags, 12 polymorphisms, and 97 sequence-tagged sites) have been mapped. Using PAC clones for fluorescence in situ hybridization analysis of leukemia cells with a del(5q), we have narrowed the commonly deleted segment to 1-1.5 Mb between D5S479 and D5S500. To search for allele loss, we used 7 microsatellite markers within and flanking the commonly deleted segment to examine leukemia cells from 28 patients with loss of 5q, and 14 patients without cytogenetically detectable loss of 5q. In the first group of patients, we detected hemizygous deletions, consistent with the cytogenetically visible loss; no homozygous deletions were detected. No allele loss was detected in patients without abnormalities of chromosome 5, suggesting that allele loss on 5q is the result of visible chromosomal abnormalities. The development of a stable PAC contig and the identification of the smallest commonly deleted segment will facilitate the molecular cloning of a myeloid leukemia suppressor gene on 5q.

Chromosome Banding↗
PubMed1997

dic(5;17): a recurring abnormality in malignant myeloid disorders associated with mutations of TP53.

We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy-related MDS and/or AML (t-MDS/t-AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t-MDS/t-AML were breast carcinoma and Hodgkin's disease in two patients each, and non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere-specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients.

Acute Disease↗
PubMed1997

Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin's disease and non-Hodgkin's lymphoma.

The relative benefit of allogeneic bone marrow transplantation (alloBMT) vs autologous BMT (autoBMT) for patients with relapsed or refractory Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) remains uncertain. Toxicity from graft-versus-host disease (GVHD) may diminish the potential benefits both of graft-versus-tumor activity and of receiving uncontaminated donor marrow stem cells. From 1987 to 1995, 27 adults (ages 18-60 years; median 36) underwent alloBMT for lymphoma after failure of standard chemotherapy. Twenty-one had NHL and six had HD (nodular sclerosis). Thirteen patients had primary refractory disease or chemotherapy-resistant relapses; two of these had relapsed after autoBMT. Three patients had untested relapses (one of them had relapsed after autoBMT), and 11 had chemotherapy-sensitive relapses. Twenty-four received HLA-matched bone marrow from a sibling (one twin); three received haploidentical marrow cells. Nine (33%) died from lymphoma. Eleven (41%) died of treatment-related causes. Opportunistic infections were a substantial problem leading to eight of these deaths (30%). Six patients (22%) survive free of lymphoma 17-70 months post-BMT (median, 56 months); four had had sensitive relapses, one had had a resistant relapse, and one had had nontested relapse. Three have chronic GVHD (limited in one; extensive in two). One HD patient who had relapsed after autoBMT remains in remission 19 months after alloBMT. No therapy-related myelodysplasia has been observed. We conclude that alloBMT has substantial morbidity in heavily pretreated lymphoma patients due to acute toxicity, infections and GVHD. However, 22% of our HD/NHL patients have had long-term disease-free survival.

Adolescent↗
PubMed1997

Treatment of adult acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) has served as a model for the cure of neoplasia by chemotherapy. Current treatment results in complete remissions in 80% to 90% of cases with long-term survival of 30% to 40%. Mature B cell and T cell ALL cases that previously had a poor prognosis are now viewed as favorable subgroups. Treatment regimens have evolved empirically into complex schemes, although few of the individual components have been rigorously tested in randomized trials. Maintenance therapy is a standard component of pediatric ALL, but its benefit has not been completely established in adults, although two trials which omitted maintenance are notable for short disease-free survival. Optimal consolidation and intensification therapy remains controversial with numerous trials suggesting benefit, but several randomized trials fail to confirm improved disease-free survival. Central nervous system prophylaxis is an integral step in treatment. Identification of subtypes of ALL with different prognosis and treatment requirements offers the potential to improve management and survival in ALL.

Adult↗
PubMed1996

Polymerase chain reaction-based diagnosis of del (5q) in acute myeloid leukemia and myelodysplastic syndrome identifies a minimal deletion interval.

Loss of all or part of the long arm of human chromosome 5 is a recurrent abnormality in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), especially after chemotherapy for a prior malignancy. It is one of the worst prognostic indicators in AML, associated with chemotherapy resistance and short survival. These deletions center at band 5q31, which has thus been proposed as the location of a tumor suppressor gene; this site is to be distinguished from that observed in 5q- syndrome, centering at 5q32. To define the molecular extent and the clinical prevalence of 5q31 deletions, we collected a series of AML and MDS cases of mixed karyotype, taking care to exclude MDS cases with 5q- syndrome. The samples were analyzed for loss of heterozygosity (LOH) using a panel polymerase chain reaction (PCR)-based microsatellite markers from 5q, comparing malignant cells with normal tissue derived from lymphoblastoid cell lines or buccal mucosa scrapings. Losses were detected in seven of 29 matched samples, including four of 17 with MDS, and three of 12 with AML; six of these seven also had a cytogenetically-visible del(5q) or -5. The one case without a cytogenetic deletion showed molecular loss of three contiguous markers, with retention of flanking markers interleukin-9 (IL-9) and D5S414, and thus contained a small deletion that is below cytogenetic resolution. PCR failed to detect 5q loss in two cases with large cytogenetic deletions, but both had been treated and contained low percentages of malignant cells in the samples. This study thus led to the identification of a case with a minimal deletion for the 5q31 tumor suppressor gene, specified by IL-9-D5S414, that is approximately 1 Mb (2 cM) in extent. Additionally, we demonstrate that PCR-based allelotyping is a reliable method for the detection of chromosomal deletion in myeloid malignancy, providing the specimens contain a high proportion of malignant cells. These studies will help to identify the tumor-suppressor gene at 5q31, and will help to develop molecular methods for diagnosis and monitoring of these disorders.

Acute Disease↗
PubMed1996

Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases.

Loss of a whole chromosome 7 or a deletion of the long arm, del(7q), are recurring abnormalities in malignant myeloid diseases. To determine the location of genes on 7q that are likely to play a role in leukemogenesis, we examined the deleted chromosome 7 homologs in a series of 81 patients with therapy-related or de novo myelodysplastic syndrome or acute myeloid leukemia. Our analysis showed that the deletions were interstitial and that there were two distinct deleted segments of 7q. The majority of patients (65 of 81 [80%]) had proximal breakpoints in bands q11-22 and distal breakpoints in q31-36; the smallest overlapping deleted segment was within q22. The remaining 16 patients had deletions involving the distal q arm with a commonly deleted segment of q32-33. To define the proximal deleted segment at 7q22 at a molecular level, we used fluorescence in situ hybridization with a panel of mapped yeast artificial chromosome (YAC) clones from 7q to examine 15 patients with deletion breakpoints in 7q22. We determined that the smallest overlapping deleted segment is contained in a well-defined YAC contig that spans 2 to 3 Mb. These studies delineate the region of 7q that must be searched to isolate a putative myeloid leukemia suppressor gene, and provide the necessary cloned DNA for more detailed physical mapping and gene isolation.

Acute Disease↗
PubMed1996

Therapy-related myeloid leukemia.

One of the most serious possible consequences of cancer therapy is the development of a second cancer, especially leukemia. Several distinct subsets of therapy-related leukemia can be distinguished currently. These include classic therapy-related myeloid leukemia, leukemia that follows treatment with agents that inhibit topoisomerase II, acute lymphoblastic leukemia, and leukemias with 21q22 rearrangements or inv(16) or t(15;17). These types of leukemia are discussed in detail in this article.

Acute Disease↗
PubMed1996

Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies.

PURPOSE: The optimal dose and schedule for cladribine (2CdA) therapy of malignant hematologic diseases have not been determined. This dose-escalation study was designed to assess toxicity when 2CdA is given using five daily 1-hour intravenous infusions. PATIENTS AND METHODS: Forty-two adults with advanced hematologic malignancies were treated in one of nine cohorts, starting at 2.5 mg/m2/d for 5 days. Plasma drug concentrations were measured by high-performance liquid chromatography. Responses were assessed by bone marrow biopsy on day 15 of the first course and by clinical measurements after each course. Patients received one to four courses each. RESULTS: Nonhematologic toxicity was mild, and dose-limiting nonhematologic toxicity was not observed, even at the highest dose level of 21.5 mg/m2/d. In particular, neurotoxicity was not observed. The maximum-tolerated dose (MTD) was not identified. However, prolonged cytopenias and severe infections were more common in the higher 2CdA dose cohorts. Logistic regression analysis suggested that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were identified as having a PS of 0 and platelet count > or = 80,000/microL, PS of 1 and platelet count > or = 120,000/microL, or PS of 2 and platelet count > or = 160,000/microL. Sustained complete responses (CRs) and partial responses (PRs) were observed in eight patients. CONCLUSION: 2CdA can be administered using five daily 1-hour infusions at 21.5 mg/m2/d without dose-limiting nonhematologic toxicity. Unlike continuous intravenous infusions, neurotoxicity was not observed using this schedule. Further dose escalation may be possible in good PS patients with adequate platelet counts.

Adult↗
PubMed1996

Myeloid leukemia after hematotoxins.

One of the most serious consequences of cancer therapy is the development of a second cancer, especially leukemia. Several distinct subsets of therapy-related leukemia can now be distinguished. Classic therapy-related myeloid leukemia typically occurs 5 to 7 years after exposure to alkylating agents and/or irradiation, has a myelodysplastic phase with trilineage involvement, and is characterized by abnormalities of the long arms of chromosomes 5 and/or 7. Response to treatment is poor, and allogenic bone marrow transplantation is recommended. Leukemia following treatment with agents that inhibit topoisomerase II, however, has a shorter latency, no preleukemic phase, a monoblastic, myelomonocytic, or myeloblastic phenotype, and balanced translocations, most commonly involving chromosome bands 11q23 or 21q22. The MLL gene at 11q23 or the AML1 gene at 21q22 are almost uniformly rearranged. MLL is involved with many fusion gene partners. Therapy-related acute lymphoblastic leukemia also occurs with 11q23 rearrangements. Therapy-related leukemias with 11q23 or 21q22 rearrangements, inv(16) or t(15;17), have a more favorable response to treatment and a clinical course similar to their de novo counterparts.

Antineoplastic Agents, Alkylating↗