Risk Of Leukemia In Patients Research Articles

Immune system changes in the pathogenesis of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome occurring with a frequency of 1: 3000 of the population. NF1 is caused by germline heterozygous mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. The disease has a specific progressive course with multiple neurofibromas, in the initiation and growth of which NF1+/ – mast cells, macrophages and lymphocytes play an important role. Accordingly, the deficiency of neurofibromin impairs the differentiation and correct functioning of immune system cells. This is evidenced by the increased risk of leukemia in patients with NF1 and the role of NF1 mutations in the development of sporadic hematological malignancies. The development of neurofibromas is associated with the fact that NF1–/ – Schwann cells stimulate the migration of mast cells into the tumor microenvironment, which actively degranulate. The released cytokines promote neoangiogenesis, inflammation, fibroblast proliferation and the production of excess collagen. Therefore, in the treatment of NF1, the use of ketotifen and a kit/ fms kinase inhibitor is recommended. Macrophages and T-lymphocytes in neurofibromas do not provide an antitumor response, but promote inflammation and tumor growth. They produce STAT3 (signal transducer and activator of transcription 3), TGF-β, EGFR, IL-6, IL-4, and PD-1. Therefore, a promising direction is NF1 therapy with STAT3 inhibitors and immune checkpoint inhibitors that block programmed cell death ligand 1 (PD-L1). Activation of MEK signaling pathways in NF1 leads to PD-L1 stimulation; therefore, MEK inhibitors, which also suppress the RAS/RAF/MEK/ERK system, turned out to be effective in the treatment of NF1. For the treatment of sporadic malignant neoplasms, in the development of which NF1 mutations play a role, the developed methods of NF1 therapy can be used.

Single-cell chromatin accessibility landscape of human umbilical cord blood in trisomy 18 syndrome

BackgroundTrisomy 18 syndrome (Edwards syndrome, ES) is a type of aneuploidy caused by the presence of an extra chromosome 18. Aneuploidy is the leading cause of early pregnancy loss, intellectual disability, and multiple congenital anomalies. The research of trisomy 18 is progressing slowly, and the molecular characteristics of the disease mechanism and phenotype are still largely unclear.ResultsIn this study, we used the commercial Chromium platform (10× Genomics) to perform sc-ATAC-seq to measure chromatin accessibility in 11,611 single umbilical cord blood cells derived from one trisomy 18 syndrome patient and one healthy donor. We obtained 13 distinct major clusters of cells and identified them as 6 human umbilical cord blood mononuclear cell types using analysis tool. Compared with the NC group, the ES group had a lower ratio of T cells to NK cells, the ratio of monocytes/DC cell population did not change significantly, and the ratio of B cell nuclear progenitor and megakaryocyte erythroid cells was higher. The differential genes of ME-0 are enriched in Human T cell leukemia virus 1 infection pathway, and the differential peak genes of ME-1 are enriched in apopotosis pathway. We found that CCNB2 and MCM3 may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin.ConclusionsWe have identified 6 cell populations in cord blood. Disorder in megakaryocyte erythroid cells implicates trisomy 18 in perturbing fetal hematopoiesis. We identified a pathway in which the master differential regulatory pathway in the ME-0 cell population involves human T cell leukemia virus 1 infection, a pathway that is dysregulated in patients with trisomy 18 and which may increase the risk of leukemia in patients with trisomy 18. CCNB2 and MCM3 in progenitor may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin, may be related to chromosomal abnormalities in trisomy 18.

XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

Recent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). The genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyze a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observe a specific mutational pattern and an average of 25-fold increase of mutation rates in XP-C versus sporadic leukemia which we presume leads to its elevated incidence and early appearance. We describe a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients.

The risk of leukemia in patients with rheumatoid arthritis: a systematic review and meta-analysis

The relationship between rheumatoid arthritis (RA) and the risk of leukemia was still controversial. This study aimed to assess the risk of leukemia in patients with rheumatoid arthritis by systematic review and meta-analysis. Relevant studies were identified by searching PubMed, Embase, Cochrane Library, and SinoMed up to December 2019. Random effects model analysis was used to pool standardized incidence ratios (SIRs) and 95% confidence interval. A total of 15 relevant studies that met the criteria were included. Compared with the general population, patients with RA showed an increased risk of leukemia (SIR = 1.51, 95% CI: 1.34-1.70). The statistical heterogeneity was moderate with an I2 of 55.5%. In subgroup analysis, the source of heterogeneity may be due to differences in sample size. Publication bias was not found in the Begg funnel plot and the Egger test. Our findings suggested that the risk of leukemia in RA was increased compared with the general population. Key points • This is the first systematic review and meta-analysis to assess the risk of leukemia in RA. • Our study suggested that the risk of leukemia in RA was increased compared with the general population. • This study indicated that the risk of leukemia in RA was higher in non-Asian populations.

Ontogenic growth as the root of fundamental differences between childhood and adult cancer.

Cancer, the unregulated proliferation of cells, can occur at any age and may arise from almost all cell types. However, the incidence and types of cancer differ with age. Some cancers are predominantly observed in children, others are mostly restricted to older ages. Treatment strategies of some cancers are very successful and cure is common in childhood, while treatment of the same cancer type is much more challenging in adults. Here, we develop a stochastic model of stem cell proliferation that considers both tissue development and homeostasis and discuss the disturbance of such a system by mutations. Due to changes in population size, mutant fitness becomes context dependent and consequently the effects of mutations on the stem cell population can vary with age. We discuss different mutant phenotypes and show the age dependency of their expected abundances. Most importantly, fitness of particular mutations can change with age and advantageous mutations can become deleterious or vice versa. This perspective can explain unique properties of childhood disorders, for example, the frequently observed phenomenon of a self-limiting leukemia in newborns with trisomy 21, but also explains other puzzling observations such as the increased risk of leukemia in patients with bone marrow failure or chemotherapy induced myelodysplasia.

Transmission of clonal chromosomal abnormalities in human hematopoietic stem and progenitor cells surviving radiation exposure

In radiation-induced acute myeloid leukemia (rAML), clonal chromosomal abnormalities are often observed in bone marrow cells of patients, suggesting that their formation is crucial in the development of the disease. Since rAML is considered to originate from hematopoietic stem and progenitor cells (HSPC), we investigated the frequency and spectrum of radiation-induced chromosomal abnormalities in human CD34+ cells. We then measured stable chromosomal abnormalities, a possible biomarker of leukemia risk, in clonally expanded cell populations which were grown for 14 days in a 3D-matrix (CFU-assay). We compared two radiation qualities used in radiotherapy, sparsely ionizing X-rays and densely ionizing carbon ions (29 and 60–85keV/μm, doses between 0.5 and 4Gy). Only a negligible number of de novo arising, unstable aberrations (≤0.05 aberrations/cell, 97% breaks) were measured in the descendants of irradiated HSPC. However, stable aberrations were detected in colonies formed by irradiated HSPC. All cells of the affected colonies exhibited one or more identical aberrations, indicating their clonal origin. The majority of the clonal rearrangements (92%) were simple exchanges such as translocations (77%) and pericentric inversions (15%), which are known to contribute to the development of rAML. Carbon ions were more efficient in inducing cell killing (maximum of ∼30–35% apoptotic cells for 2Gy carbon ions compared to ∼25% for X-rays) and chromosomal aberrations in the first cell-cycle after exposure (∼70% and ∼40% for 1Gy of carbon ions and X-rays, respectively), with a higher fraction of non-transmissible aberrations. In contrast, for both radiation qualities the percentage of clones with chromosomal abnormalities was similar (40%). Using the frequency of colonies with clonal aberrations as a surrogate marker for the leukemia risk following radiotherapy of solid tumors, charged particle therapy is not expected to lead to an increased risk of leukemia in patients.

Congenital neutropenia: diagnosis, molecular bases and patient management

The term congenital neutropenia encompasses a family of neutropenic disorders, both permanent and intermittent, severe (<0.5 G/l) or mild (between 0.5-1.5 G/l), which may also affect other organ systems such as the pancreas, central nervous system, heart, muscle and skin. Neutropenia can lead to life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease, and each successive infection may leave permanent sequelae. The risk of infection is roughly inversely proportional to the circulating polymorphonuclear neutrophil count and is particularly high at counts below 0.2 G/l.When neutropenia is detected, an attempt should be made to establish the etiology, distinguishing between acquired forms (the most frequent, including post viral neutropenia and auto immune neutropenia) and congenital forms that may either be isolated or part of a complex genetic disease.Except for ethnic neutropenia, which is a frequent but mild congenital form, probably with polygenic inheritance, all other forms of congenital neutropenia are extremely rare and have monogenic inheritance, which may be X-linked or autosomal, recessive or dominant.About half the forms of congenital neutropenia with no extra-hematopoetic manifestations and normal adaptive immunity are due to neutrophil elastase (ELANE) mutations. Some patients have severe permanent neutropenia and frequent infections early in life, while others have mild intermittent neutropenia.Congenital neutropenia may also be associated with a wide range of organ dysfunctions, as for example in Shwachman-Diamond syndrome (associated with pancreatic insufficiency) and glycogen storage disease type Ib (associated with a glycogen storage syndrome). So far, the molecular bases of 12 neutropenic disorders have been identified.Treatment of severe chronic neutropenia should focus on prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte-colony-stimulating factor (G-CSF). G-CSF has considerably improved these patients' outlook. It is usually well tolerated, but potential adverse effects include thrombocytopenia, glomerulonephritis, vasculitis and osteoporosis. Long-term treatment with G-CSF, especially at high doses, augments the spontaneous risk of leukemia in patients with congenital neutropenia.

Neutrophil Elastase Mutations and the Risk of Leukemia In Patients with Cyclic and Congenital Neutropenia.

AbstractAbstract 3786Mutations in the gene for neutrophil elastase (ELANE) are the cause for the majority of cases of cyclic and congenital neutropenia. More than 50 different mutations of ELANE have been identified in patients with these disorders. It is not known whether specific ELANE mutations predispose patients to the risk of myelodysplasia (MDS) and acute myeloid leukemia (AML).We have investigated the relationships of ELANE mutations to the risk of MDS/AML in a population of 208 patients with cyclic (N=92) and congenital neutropenia (N=116) having ELANE mutations and receiving granulocyte colony-stimulating factor (G-CSF) therapy for up to 22 years. In the congenital group there were 52 different mutations occurring with increasing frequency from exon 1 (2 mutations) to exon 5 (17 different mutations). In the cyclic group there was a narrower spectrum of mutations; these mutations clustered in exon 4, intron 4 and exon 5. There were 13 different mutations in this group. Mutations P110L, S97L, R191Q, and splice site mutations in intron 4: +5 SD G>A, and +1 SD G>T were observed both in patients with the cyclic and congenital neutropenia.Sixteen congenital neutropenic patients developed MDS/AML. There were 15 different mutations associated with these transformations. There are also 15 congenital patients who have not evolved to develop leukemia who have the same mutations as in the MDS/AML group. In three families with autosomal dominant congenital neutropenia attributed to ELANE mutations, one affected member has developed AML the other has not. The pairs are: father no, daughter yes; father yes, daughter no; and one identical twin yes, other twin no. One patient with a clinical diagnosis of cyclic neutropenia who had received long term immunosuppressive therapy also developed MDS and had a stem cell transplant. There were no MDS/AML transformations in the other 91 cyclic patients. For the overall population of cyclic and congenital patients, missense mutations in ELANE were most commonly found. In the 16 congenital neutropenia patients evolving to MDS/AML by category the mutations were: missense (8), deletion (2) termination (4) intronic (2), a pattern similar to those of the congenital patients who have not evolved to develop MDS/AML: missense (79) deletion (7) termination (8) intronic (6).The 16 patients with congenital neutropenia who developed MDS/AML were treated with G-CSF for a median of 8.6 years (range 3.3 – 15.2). The mean of the median G-CSF dose for patients with MDS/AML transformation was 14.6 mcg/kg/day (range 2–43 mcg/kg/day) and the mean of the median dose of G-CSF for the population not developing MDS/AML was 13.7 mcg/kg/day (range 0–183 mcg/kg/day) (p=0.89). However, a higher proportion of the AML group (69%) were receiving G-CSF at > 8mcg/kg than the non MDS/AML group (40%). The median duration of G-CSF treatment was significantly less (p=0.009) in the MDS/AML group than the group not developing MDS/AML. The mean cumulative G-CSF exposure was not significantly different (p=0.54) for the two groups.These data indicate that there are no specific ELANE mutations or specific types of ELANE mutations predisposing patients with congenital neutropenia to development of MDS or AML. The data confirm previous reports that patients requiring higher daily doses of G-CSF may be at somewhat greater risk of MDS/AML, but there is no distinct dose predicting risk and no association with total G-CSF exposure and the risk of MDS/AML. The specific cause for the high risk of MDS and AML in congenital neutropenia remains unknown. Disclosures:Dale:Amgen: Consultancy, Research Funding.

Stable long‐term risk of leukaemia in patients with severe congenital neutropenia maintained on G‐CSF therapy

In severe congenital neutropenia (SCN), long-term therapy with granulocyte colony-stimulating factor (G-CSF) has reduced mortality from sepsis, revealing an underlying predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We have reported the early pattern of evolution to MDS/AML, but the long-term risk remains uncertain. We updated a prospective study of 374 SCN patients on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. Long-term, the annual risk of MDS/AML attained a plateau (2.3%/year after 10 years). This risk now appears similar to, rather than higher than, the risk of AML in Fanconi anaemia and dyskeratosis congenita.

Stable Long-Term Risk of Leukemia in Patients with Severe Congenital Neutropenia Maintained On G-CSF Therapy.

Abstract 3206Poster Board III-143 BACKGROUNDG-CSF therapy reduces sepsis mortality in patients with severe congenital neutropenia (SCN), but effective therapy has revealed a high syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), particularly in patients who require higher doses of G-CSF. Although the long-term risk of MDS/AML after 10 or more years on therapy remains uncertain, prior data on the limited number of patients with long-term follow-up suggested the hazard rate might be as high as 8%/year after 12 years on G-CSF. METHODSWe updated prospective follow-up of 374 well-characterized patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry (Blood. 2006 Jun 15; 107(12):4628-35). We ascertained event-free time, deaths from sepsis, and MDS/AML events that accrued since our previous report. Follow-up was censored for patients who received a bone marrow transplant. RESULTSThe update yielded 3590 person-years of follow-up versus 2043 in the prior report; among patients treated for 10 or more years, there were 849 person-years versus just 67 previously. In all, there were 61 MDS/AML events and 29 deaths from sepsis, versus prior totals of 44 and 19, respectively. After including up-to-date follow-up, the estimated annual hazard of death from sepsis remained qualitatively stable, at 0.81%/year (95% Confidence Interval, CI: 0.56 – 1.16%/year). Similarly, during the first five years after the start of G-CSF therapy, the updated estimate of the hazard curve for MDS/AML showed the same increasing trend as the previous estimate. However, in contrast to the prior estimate that showed a subsequent increasing trend over time (with a large margin of error), the updated hazard curve attained a plateau: after 10 years on G-CSF, the estimated hazard of MDS/AML was 2.3%/year (95% CI: 1.7 – 2.9%/year). Although this aspect of the natural history appears less dire than first suggested, after 15 years on G-CSF, the cumulative incidence was 10% (95% CI: 6 – 14%) for death from sepsis and 22% (95% CI: 17 – 28%) for MDS/AML. Furthermore, for the subset of patients who failed to achieve at 6 months an absolute neutrophil count at or above the median value for the cohort (2188 cells/μL) despite doses of G-CSF at or above the median (8 μg/kg/day), the cumulative incidence after 15 years on G-CSF was 18% (95% CI: 7 – 28%) for death from sepsis and 34% (95% CI: 21 – 47%) for MDS/AML. With additional follow-up, the association of G-CSF dose at 6 months with the relative hazard of MDS/AML became more strongly statistically significant (P = 0.003 versus P = 0.024; the hazard of MDS/AML increased by 1.24-fold (95% CI: 1.08-1.43-fold) per doubling of the dose of G-CSF). CONCLUSIONSFor SCN patients maintained on G-CSF therapy, the hazard of MDS/AML over the long-term falls significantly below the range suggested by preliminary data. The updated hazard estimate of 2.3%/year after 10 years on G-CSF (which includes both MDS and AML events) is similar to that for other inherited bone marrow failure syndromes with a high intrinsic risk of AML, notably Fanconi anemia and dyskeratosis congenita. Nonetheless, the cumulative incidence of both MDS/AML and sepsis death rises to very high levels, and the data continue to support the hypothesis that SCN patients with higher G-CSF requirements are also at higher risk of leukemia. DisclosuresBoxer:Amgen Inc.: Equity Ownership. Dale:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speaker.

Neutropénies constitutionnelles et acquises

Evaluating a neutropenia induces first documenting its aetiology. Beside the specific aspects of the newborn, neutropenia in a child may be 1) acquired - the most frequent type -, 2) constitutional, part of a complex genetic disease, 3) constitutional, isolated. Primary acquired neutropenia, also called benign chronic neutropenia, is the most frequent cause of chronic neutropenia in children. It is usually well tolerated and has a frequent favourable outcome in 12-36 months. Many complex genetic diseases include a neutropenia, among which several immunologic disorders that must be ruled out before considering the diagnosis of isolated constitutional neutropenia. Severe congenital neutropenia is the main primary constitutional neutropenia. It is profound, usually < 500 polymorphonuclear leukocytes/mm 3 and exposes to severe pyogenic and fungal infections. Mutations in the gene encoding neutrophil elastase (ELA2) are the most common genetic abnormalities in this group of patients, as well as for patients with cyclic neutropenia. In the neonatal period, neutropenia must primarily suggest a bacterial infection, although other aetiologies have to be known, particularly neonatal neutropenia caused by passive transfer of maternal antibodies and neutropenia related to gravidic hypertension. In adulthood, most neutropenias are related to an infection, to the side effect of a drug, to a malignant haemopathy or to an autoimmune disease. A clinical entity, the idiopathic neutropenia, is described, however, apparently completely primitive and acquired. The treatment of severe chronic neutropenia is directed towards the prevention of infections. It includes prophylactic antibiotherapy such as the trimetroprim-sulfamethoxazole association, the most commonly used, and granulocyte colony stimulating factor (G-CSF). G-CSF has considerably improved patients' conditions. It is usually well tolerated, but side effects have been reported (bone pain, thrombocytopenia, glomerulonephritis, vasculitis). Long-term treatment by high-dose G-CSF has been shown to increase the spontaneous natural risk of leukaemia in patients with congenital severe neutropenia.

High cumulative rate of secondary leukemia after continuous etoposide treatment for solid tumors in children and young adults

In a national pediatric case-control study, we observed a very high relative risk of leukemia in patients who had received continuous etoposide (CE) over 6 months or more, but we could not estimate the absolute risk. The purpose of the present study was to estimate this absolute risk after CE. We report a study of 18 patients with refractory or recurrent tumors who received CE over 6 months or more between 1995 and 1997. It was administered either 3 days a week for 3/4 weeks ("3 x 3", 14 patients) or 7 days a week for 3/4 weeks ("7 x 3", four patients). Five patients developed secondary leukemia 10-25 months after the initiation of CE. All the others died of their first tumor. The cumulative incidence of leukemia at 30 months was 28% (95% CI, 10%-53%). A chromosome 11q23 rearrangement was found in 3/5 cases. All four patients who received the "7 x 3" CE schedule developed leukemia compared to 1/14 treated with the "3 x 3" CE schedule (P = 0.002). Given its efficacy, CE may still have a place as a palliative treatment. However, the risk of leukemia must be borne in mind when considering its use in patients with a better prognosis.

Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d'Oncologie Pédiatrique.

To estimate the risk of secondary leukemia as a function of the dose of epipodophyllotoxins and anthracyclines. We conducted a case-control study of the risk of secondary leukemia or myelodysplasia after a solid tumor in childhood within the Société Française d'Oncologie Pédiatrique, including 61 patients with leukemia matched with 196 controls. The characteristics of the first cancer, the patient's family history of cancer, and the treatment (type, cumulative dose of chemotherapy, schedule of etoposide administration, and radiation dose delivered to active bone marrow) were compared in the two groups. Only two factors were found to increase the risk of leukemia in multivariate analysis, namely, the type of the first tumor, with an excess risk in patients with Hodgkin's disease (relative risk 6.4; 95% confidence interval [CI], 1.6 to 24) or osteosarcoma (relative risk 5; 95% CI, 1.3 to 19), and exposure to epipodophyllotoxins and anthracyclines. The risk of leukemia increased regularly with the cumulative dose of etoposide. In summary, patients who received between 1.2 and 6 g/m(2) of epipodophyllotoxins or more than 170 mg/m(2) of anthracyclines had a seven-fold higher risk (95% CI, 2.6 to 19) compared with patients who received lower doses or none of these drugs. The risk of leukemia in patients who received more than 6 g/m(2) of epipodophyllotoxins was multiplied by 197 (95% CI, 19 to 2,058). The risk of leukemia was not increased by exposure to alkylating agents or radiotherapy. Both epipodophyllotoxins and anthracyclines increase the risk of secondary leukemia. The current challenge is to minimize the mutagenic effects of these drugs by diminishing cumulative doses without losing the therapeutic benefits.

Assessing the Risk of Secondary Leukemia in Patients Treated for Hodgkin's Disease — A Report from the International Database on Hodgkin's Disease

Parametric models are used to investigate the time of leukemia latency in patients treated for Hodgkin's disease. A model of induced carcinogenesis provides a stable projection of the leukemia risk for times beyond the follow-up period. The model is applied to data collected in the International Data Base on Hodgkin's Disease. It permits to estimate the contributions of primary and of relapse treatment to the overall risk of induced leukemia. Latency periods appear to be identical after both treatments supporting the concept of induced leukemogenesis.

Secondary tumours following etoposide containing therapy for germ cell cancer

Reports have implied etoposide as the cause of secondary leukaemia in patients treated for germ cell cancer. Between 1979 and 1992, 679 male patients with germ cell cancer received etoposide containing chemotherapy. Six of 679 patients developed acute myeloid leukaemia (relative risk 150; CI: 55-326). None of these patients had a primary mediastinal germ cell tumour and only 1 patient received previous radiotherapy. The median interval between the onset of cytotoxic treatment and the development of leukaemia was 27 months. The FAB M4 morphology was seen in 4 of 6 cases. The benefit of etoposide containing protocols outweigh the risk of leukaemia in patients with intermediate or high risk disease, however in patients with good risk disease non-etoposide containing protocols should be explored.

Leukemia Following Hodgkin's Disease

To investigate the effect of different treatments for Hodgkin's disease on the risk of leukemia, we used an international collaborative group of cancer registries and hospitals to perform a case-control study of 163 cases of leukemia following treatment for Hodgkin's disease. For each case patient with leukemia, three matched controls were chosen who had been treated for Hodgkin's disease but in whom leukemia did not develop. The use of chemotherapy alone to treat Hodgkin's disease was associated with a relative risk of leukemia of 9.0 (95 percent confidence interval, 4.1 to 20) as compared with the use of radiotherapy alone. Patients treated with both had a relative risk of 7.7 (95 percent confidence interval, 3.9 to 15). After treatment with more than six cycles of combinations including procarbazine and mechlorethamine, the risk of leukemia was 14-fold higher than after radiotherapy alone. The use of radiotherapy in combination with chemotherapy did not increase the risk of leukemia above that produced by the use of chemotherapy alone, but there was a dose-related increase in the risk of leukemia in patients who received radiotherapy alone. The peak in the risk of leukemia came about five years after chemotherapy began, and a large excess persisted for at least eight years after it ended. After adjusting for drug regimen, we found that patients who had undergone splenectomy had at least double the risk of leukemia of patients who had not, and an advanced stage of Hodgkin's disease carried a somewhat higher risk of leukemia than Stage I disease. We conclude that chemotherapy for Hodgkin's disease greatly increases the risk of leukemia and that this increased risk appears to be dose-related and unaffected by concomitant radiotherapy. In addition, the risk is greater for patients with more advanced stages of Hodgkin's disease and for those who undergo splenectomy.

Inflammatory bowel disease and leukemia

In a review of a large number of patients with inflammatory bowel disease, leukemia was observed in five patients with chronic ulcerative colitis and in two patients with Crohn's disease. In ulcerative colitis patients, there were three cases of acute myelocytic leukemia and one case each of acute lymphoblastic leukemia and chronic granulocytic leukemia. In Crohn's disease patients, there was one case each of chronic granulocytic leukemia and chronic lymphocytic leukemia associated with thrombocythemia. Sixteen other cases of leukemia have been reported to date in inflammatory bowel disease. All types of leukemia, but particularly acute myelocytic leukemia, have been described. There has been no single common feature as to type (whether ulcerative colitis or Crohn's disease), extent and course, or medical and surgical treatment of the bowel disease. The relative risk of leukemia in patients with ulcerative colitis was 5.3 [95% confidence interval 1.7 to 12.3 (P less than 0.01)] and of acute myelocytic leukemia 11.4 [95% confidence interval 2.3 to 24.9 (P less than 0.01)]. Our data on patients with Crohn's disease were not sufficient to assess the statistical significance of leukemia in this disease. This study suggests that there may be an increased risk of leukemia, particularly acute myelocytic leukemia, in ulcerative colitis. The causal relationship, if any, remains undetermined.

Risk of leukemia in patients treated for Hodgkin's disease

We reviewed 251 consecutive adult patients with Hodgkin's disease treated at the Division of Hematology, Policlinico S. Matteo, Pavia, from January 1970 to December 1979, to assess the risk of development of acute leukemia. The median time of follow-up was 48 months (range 6–135). No leukemia occurred in 88 patients treated with radiotherapy or chemotherapy alone. Six acute non-lymphoid leukemias occurred in the group of 163 patients treated with MOPP and radiotherapy (crude rate of leukemia of 7.5 per 1000 person-years at risk). All cases were in clinical remission and off-therapy; the latent period from initiation of therapy to onset of leukemia ranged between 30 and 90 months. The actuarial probability of leukemia at five and seven years was 2.9 and 4.7% for the entire group of patients, and 3.8 and 5.8% for the combination therapy group. All leukemias, except one, had a preleukemic phase lasting 1–12 months, with cytopenia and dysplastic marrow. The median survival after leukemia was 4.7 months.