Therapy-related Acute Leukemia Research Articles

Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis

Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans. Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.

Predisposition to therapy-related acute leukemia with balanced chromosomal translocations does not result from a major constitutive defect in DNA double-strand break end joining

The frequency of acute myeloid leukemia (AML) with balanced chromosomal translocations arising after anticancer therapy with DNA-damaging agents such as DNA topoisomerase II inhibitors has increased over the last two decades. However, factors that predispose to these therapy-related disorders are still poorly defined. It has been reported that DNA double-strand break (DSB) repair by the non-homologous end-joining (NHEJ) pathway is impaired in myeloid leukemia cells. This led us to hypothesize that therapy-related AML (t-AML) may result from individual differences in the repair of DSBs generated by the treatment. We show here that DSB repair is accurate, in vivo, in non-tumoral cells derived from patients who developed t-AML with t(9;11) or t(15;17) translocation after treatment for a first cancer with DNA topoisomerase II inhibitors. These results indicate that a major constitutive defect in the NHEJ pathway is unlikely to predispose to t-AML with balanced chromosomal translocations.

Chronic myelomonocytic leukaemia after platinum-based therapy for non-small cell lung cancer: case report and review of the literature

Chronic myelomonocytic leukaemia (CMML) is a preleukaemic condition with myeloproliferative features, and classified as a part of myelodysplastic syndrome (MDS). Other than alkylating agents and topoisomerase II inhibitors, there is less evidence that chemotherapeutic drugs are associated with therapy-related CMML, acute leukaemia or MDS. We present a patient who developed CMML within 2 years of platinum-based chemotherapy for a metastatic non-small cell lung cancer. He received a cumulative dose of 240 mg/m(2) of cisplatin, and 1123 mg/m(2) of carboplatin before developing CMML. The cytogenetic study revealed trisomy 8. This is the first reported case that links platinum-based therapy with development of CMML with trisomy 8. Although the relationship between platinum therapy and the development of CMML is difficult to assess due to combinational nature of therapy in most cases, physicians should consider the possibility of CMML in patients with symptoms or signs suggestive of haematologic malignancy after platinum therapy.

SNPs associated with the genetic predisposition to develop therapy-related acute myelogenous leukemia after chemotherapy for breast cancer

8536 Background: t-AML is a syndrome occurring after exposure to chemo or radiotherapy. Since for similar treatments only some patients ends developing a secondary leukemia, it has been proposed a genetic predisposition associated to this syndrome. Methods: To analyse single nucleotide polymorphisms (SNPs) on genes that could be involved on risk of developing t-AML by means of RFLP and SNP genome screening using high density microarrays .Two groups of individuals were genotyped: Group A, composed by patients that develop t-AML after chemotherapy for breast cancer (BC) and Group B (control), formed by chemotherapy treated BC patients that after a period of more than 10 years have not developed t-AML. We have studied 12 polymorphisms on genes from drug detoxification pathways (NOQ1, GSTP1), DNA repair (XPC[3 ], XRCC1[2 ], NBS1, ERCC5 and XRCC3) and DNA synthesis (MTHFR[2 ]), in which the nucleotide change implies a change in the protein sequence (nA=16, nB=18) . Alternatively, for each patient, more than 10.000 SNPs were genotyped by means of of high density microarrays (Affymetrix) (nA=12, nB=18). The alele frequencies for each SNP between two groups were compared. Results: In RFLP study, we observe two SNPs on MTHFR gene displaying remarkably different allele frequencies between BC patients (Table). In microarray study, we found 12 SNPs with differences of allele frequency higher that 45% between A and B groups, located 6 on chromosome 8. Conclusions: The results suggest that the MHFTR gene is a candidate for being studied by its possible relation with the genetic predisposition to develop t-AML after BC treatment although its functional implication with the disease must still be elucidated. Moreover, data from SNP arrays suggest that the genome regions marked by those 12 SNPs, specially those on chromosome 8, are candidate for being studied by its possible relation with the genetic predisposition to develop t-AML after BC treatment. Financed by FIS G03/008. [Table: see text] No significant financial relationships to disclose.

Oxaliplatin-Related Acute Myelogenous Leukemia

A 56-year-old woman diagnosed with a poorly differentiated cecal adenocarcinoma with metastases to ovaries, omentum, and sigmoid colon went into remission after 12 cycles of infusional 5-fluorouracil, luecovorin, and oxaliplatin (FOLFOX-4 regimen). Thirteen months later, a pelvic recurrence was diagnosed, and the patient received nine cycles of FOLFOX-6 plus bevacizumab, resulting in a clinical complete response but the development of pancytopenia. Bone marrow biopsy was consistent with therapy-related acute myelogenous leukemia. Chromosome analysis showed structural rearrangements with partial deletions of the long arms of chromosomes 5, 7, 20, and 21, as well as trisomy of chromosome 8 and losses of chromosomes 3 and 11. Induction chemotherapy led to remission, but the patient died two months later from complications of colon cancer progression. It is likely that the leukemia was related to the oxaliplatin administration.

Graft-versus-brain tumor effect in a child with anaplastic astrocytoma after cord blood transplantation for therapy-related leukemia

The graft-versus-tumor effect has been described for several solid tumors, but little is known regarding the susceptibility of brain tumors to allogeneic immune responses. We report a case of cord blood transplantation for therapy-related acute myelogenous leukemia in a 7-year old boy with active high-grade astrocytoma lesions. This represents the first reported case of a pediatric patient undergoing transplantation for therapy-related leukemia with a coexisting brain tumor. The patient received a preparative regimen consisting of busulfan, cyclophosphamide, and anti-thymocyte globulin for a 5 out of 6 HLA-antigen-matched unrelated donor cord blood transplant.

Searching Polymorphic Markers Associated with the Genetic Predisposition To Develop Therapy-Related Myelodysplastic Syndromes and Acute Myelogenous Leukemia T-(MDS/AML) after Myeloablative Chemotherapy.

INTRODUCTION: Therapy-related MDS/AML constitutes the most frequent secondary neoplasia and his incidence is increasing in the last years. This incidence is especially high when myeloablative chemotherapy is used before autologous stem cell transplantation (ASCT). Since for similar treatments only a percentage of the patients ends up by developing a secondary leukemia, it has been proposed the existence of some type of genetic predisposition associated to this syndrome.OBJETIVE: To search single nucleotide polymorphisms (SNPs) associated with the genetic predisposition to develop a t-MDS/AML by means of SNP genome screening using high density microarrays.MATERIAL AND METHODS: Two groups of individuals were genotyped: Group A, composed by 16 patients with t-MDS/AML post-ASCT (10 NHL, 4 HD, 2 multiple myeloma) and Group B (control), formed by 16 patients submitted to ASCT and that after a period of more than 10 years have not developed t-MDS/AML(14 NHL, 2 HD). For each individual more than 10.000 SNPs were genotyped by means of the use of microarrays of high density (Mapping 10K, Affymetrix®). Those SNPs are distributed along the whole genome and have a high average heterocigosity (0,37). The alele frequencies for each SNP between two groups were compared.RESULTS: We found a group of 4 SNPs located in the q23.3 band of the chromosome 5 in which the differences of alele frequency between the groups A and B were superior to 50 %. These SNPs are located in a region that comprises the only gene, CSS3 (chondroitin sulphate synthetase 3), being the difference of alele frequency of 57 % in the intronic SNP of this gene.CONCLUSIONS: The results suggest that the CSS3 gene is a candidate for being studied by its possible relation with the genetic predisposition to develop LMAt/SMDt, although its putative functional implication with the disease must still be elucidated. There is known that a counterpart of CSS3, CSS1, plays a key role in the proliferation and apoptosis of myeloma cells. Thus, it is possible that CSS3 could be somehow related with the hematopoyesis pathways and implied in the development of t-MDS/AML. Financed by FIS G03/008.

Therapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia After Autologous Bone Marrow Transplantation: Dosis Facit Venenum?

Therapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia After Autologous Bone Marrow Transplantation: <i>Dosis Facit Venenum</i>?

Molecular Pathogenesis of MLL-Associated Leukemias

Chromosome translocations disrupting the MLL gene are associated with various hematologic malignancies but are particularly common in infant and secondary therapy-related acute leukemias. The normal MLL-encoded protein is an essential component of a supercomplex with chromatin-modulating activity conferred by histone acetylase and methyltransferase activities, and the protein plays a key role in the developmental regulation of gene expression, including Hox gene expression. In leukemia, this function is subverted by breakage, recombination, and the formation of chimeric fusion with one of many alternative partners. Such MLL translocations result in the replacement of the C-terminal functional domains of MLL with those of a fusion partner, yielding a newly formed MLL chimeric protein with an altered function that endows hematopoietic progenitors with self-renewing and leukemogenic activity. This potent impact of the MLL chimera can be attributed to one of 2 kinds of activity of the fusion partner: direct transcriptional transactivation or dimerization/oligomerization. Key unresolved issues currently being addressed include the set of target genes for MLL fusions, the stem cell of origin for the leukemias, the role of additional secondary mutations, and the origins or etiology of the MLL gene fusions themselves. Further elaboration of the biology of MLL gene-associated leukemia should lead to novel and specific therapeutic strategies.

Comparison of de novo vs. therapy-related acute leukemia (AL) and myelodysplastic syndromes (MDS) in adults with balanced chromosome aberrations of 11q23

6549 Background: Recurring balanced chromosome aberrations involving band 11q23 have been detected in both de novo AL/MDS and therapy-related AL/MDS (t-AL/MDS), but de novo 11q23 AL/MDS has seldom ...

Acute promyelocytic leukemia with PML-RARA fusion on i(17q) and therapy-related acute myeloid leukemia

We describe a patient with acute promyelocytic leukemia (APL) and the karyotype 46,XX,i(17)(q10) with PML-RARA fusion gene detected by fluorescence in situ hybridization (FISH) and nested reverse transcriptase-polymerase chain reaction (RT-PCR). FISH using dual-color translocation probes for PML (promyelocytic leukemia) and RARA (retinoic acid receptor-alpha) showed fusion signal for PML-RARA on both arms of i(17q). The patient attained complete remission (CR) with all-trans retinoic acid treatment and became PML-RARA negative. One year later, while PML-RARA negative on FISH and RT-PCR, the patient presented with thrombocytopenia. Bone marrow examination suggested an acute monoblastic leukemia (AML-M5a) including the karyotype 46,XX,t(8;16) (p11.2;p13.3),inv(11)(p15q22∼q23)[11]/47,idem,+i(8)(q10)[9]. She is currently in CR. The occurrence of therapy related acute leukemia after successful therapy for APL is an emerging problem.

Successful non‐T‐cell‐depleted HLA‐haploidentical 3‐loci mismatched bone marrow transplantation

A 17-year-old boy with therapy-related acute myelocytic leukemia (FAB classification-M0) successfully received allogeneic non-T-cell depleted (non-TCD) bone marrow transplantation (BMT) from his 3-loci HLA-mismatch mother, although pre-BMT detection of feto-maternal microchimerism was negative. The BMT was performed with reduced intensity conditioning (total body irradiation; 4 Gy, fludarabine; 20 mg/m(2) x 6, and melphalan; 70 mg/m(2) x 2) and short-course methotrexate and tacrolimus for GVHD prophylaxis. Complete donor chimera was obtained on day 19, associated with Grade 3 acute GVHD (skin: Stage 1, liver: Stage 0, gut: Stage 3) that was well controlled with immunosuppressive therapies. At day 200 of transplantation, he was in complete remission with no signs of chronic GVHD. Our case suggests that non-TCD HLA-haploidentical 3-loci mismatched BMT can be safely performed from mother to offspring even when feto-maternal microchimerism is barely detectable with the current detection procedure.

Clonal evolution with inv(11)(p15q22) and NUP98/DDX10 fusion gene in imatinib-resistant chronic myelogenous leukemia

The BCR/ABL tyrosine kinase inhibitor imatinib has shown remarkable efficacy in treating patients with chronic myelogenous leukemia (CML). In a small portion of patients treated with imatinib, however, the disease may progress to advanced stages, frequently accompanied by cytogenetic clonal evolution with the appearance of additional chromosomal aberrations besides the Philadelphia chromosome. Here we report the appearance of an inv(11)(p15q22) as a clonal evolution in a CML patient undergoing treatment with imatinib. Leukemic cells from the patient were found to express the fusion transcript of NUP98 and DDX10, which is in accordance with previously reported cases of de novo or therapy-related acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(p15q22). Although the patient showed resistance to imatinib with the disease rapidly progressing to blast crisis, sequence analysis failed to reveal any mutation in the kinase domain of BCR/ABL that would explain the imatinib resistance. Furthermore, ex vivo treatment of leukemic cells with imatinib significantly reduced tyrosine phosphorylation of CrkL, a target of the BCR/ABL kinase. These observations raise a possibility that the NUP98/DDX10 fusion might be involved in imatinib resistance as well as in acute transformation of CML.

Hematologic aspects of myeloablative therapy and bone marrow transplantation

The transplantation of bone marrow cells or isolated hematopoietic stem cells from the bone marrow or peripheral blood is a widely utilized form of therapy for patients with incurable diseases of the hematopoietic and immune systems. Successful engraftment of the transplanted stem cells in an adequately prepared recipient normally leads to bone marrow reconstitution over a period of several weeks, accompanied by more gradual reconstitution of the immune system. Since the recipient is profoundly ill during the initial treatment period, laboratory data is critical for monitoring engraftment, detecting residual/recurrent disease, and identifying problems that may delay bone marrow reconstitution or lead to other medical complications. Accurate blood cell counts are imperative, and most bone marrow transplantation patients undergo periodic monitoring with bone marrow aspirates and biopsies with cytogenetic, molecular, and multiparametric flow cytometric studies. The potential complications of bone marrow transplantation include engraftment failure and delayed engraftment, infection, residual bone marrow disease, acute and chronic graft versus host disease, myelofibrosis, therapy-related acute leukemia, post-transplant lympho-proliferative disorders, and toxic myelopathy.

NUP98 Is Fused to PRRX2, a New Homeobox Partner Gene in t(9;11)(q34;p15), in a Therapy-Related Acute Myeloid Leukemia.

The nucleoporin gene NUP98 is known to be rearranged in several recurrent translocations occurring in de novo and therapy-related myelodysplastic syndrome and acute leukemia, in children or adults. All these abnormalities seem to have bad prognosis, thus, it is important to identify NUP98 rearrangements. As other genes (MLL, ETV6, RUNX1, ...), NUP98 may fuse to different partners, often homeobox genes such as HOXA, HOXC, HOXD, PMX1, but also non homeobox genes such as RAP1GSD1, NSD1, NSD3, LEDGF, ADD3, DDX10, and TOP1. The fusion transcript always juxtapose the N-terminal FG repeats of NUP98, required for its docking function, to the C-terminus of the partner gene, which contains the homeodomain in the case of a homeobox partner gene. We identified a t(9;11)(q34.1;p15.5) by conventional cytogenetic analysis, in a 65 years old Caucasian female who developed a t-AML four years after lymphoma treatment. The involvement of NUP98 gene was confirmed by FISH analysis using BAC RP11-120E20 and PAC RP11-1173K1. 3′RACE analysis allowed to identified a novel partner gene, the class II homeobox gene PRRX2 (Paired Related homeobox 2), located on 9q34. The breakpoint occurred in an infrequent breaking region in exon 11 of NUP98, and in exon 2 of PRRX2. The NUP98-PRRX2 fusion transcript was cloned and sequenced, and confirmed by RT-PCR. As its homologue PRRX1 (PMX1), PRRX2 is a DNA-binding transcription factor that is essential for fetal development. PRRX1 has been described to be fused with NUP98 in t(1;11)(q23;p15), but it is the first time PRRX2 is implicated in leukemia, and even in malignancy. Further studies are necessary to confirm the recurrence of this translocation and its prognosis. Furthermore, transformation assays in cells lines and transgenic mice studies would be interesting to understand the leukemogenicity induced by the NUP98-PRRX2 fusion transcript.

Arsenic Trioxide (ATO) Downregulates the Expression of the AML1/MDS1/EVI-1 (AME) Oncoprotein and Induces Differentiation and Apoptosis in AME-Leukemic Cells.

Arsenic is an ancient drug, used for many centuries to treat a broad range of ailments including cancer but was largely abandoned in the early 20th century. In the 1990s arsenic trioxide (ATO) was rediscovered as an effective treatment for patients suffering from acute promyelocytic leukemia (APL). ATO has been shown to specifically target the fusion protein resulting from the t(15;17) translocation, PML/RARα, and subsequently stimulate differentiation and apoptosis of APL cells both in vitro and in vivo. The success in using ATO as a targeted therapy for APL underscores the importance of matching the right drug to patients with appropriate molecular targets. We previously reported that expression of the AML1/MDS1/EVI1 (AME) transcription factor fusion protein [a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of chronic myelogenous leukemia during the blast phase and in some patients with de novo and therapy-related myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML)] in mouse bone marrow cells by retroviral transduction impaired hematopoiesis and eventually induced an AML in mice. Our results established a causal role of AME in t(3;21)-positive myeloid malignancies. We went on to examine whether ATO could target AME. We found that ATO treatment downregulated forced-expressed AME protein in Bosc23 (a cell line derived from human 293 kidney cell line) and BM6-4 cells, a primary myeloid blast cell line derived from bone marrow of a mouse with AME-induced AML, in a dose dependent manner (within therapeutic relevant dosage range). We also found that ATO inhibited proliferation of BM6-4 cells, induced these cells to differentiate into macrophages and induced apoptosis in a dose dependent manner. Our results suggest that ATO could be used as a targeted therapy for t(3;21)-positive MDS and AML. The in vivo effect of ATO in the AME mouse model and mechanism of ATO-induced AME downregulation is under investigation. Such research may extend ATO therapy to other hematological malignancies and help to identify new therapeutic targets for human cancer.

The role of the MLL gene in infant leukemia.

The MLL gene is a major player in leukemia, particularly in infant leukemia and in secondary, therapy-related acute leukemia. The normal MLL gene plays a key role in developmental regulation of gene expression (including HOX genes), and in leukemia this function is subverted by breakage, recombination, and chimeric fusion with one of 40 or more alternative partner genes. In infant leukemias, the chromosome translocations involving MLL arise during fetal hematopoiesis, possibly in a primitive lymphomyeloid stem cell. In general, these leukemias have a very poor prognosis. The malignancy of these leukemias is all the more dramatic considering their very short preclinical natural history or latency. These data raise fundamental issues of how such divergent MLL chimeric genes transform cells, why they so rapidly evolve to a malignant status, and what alternative or novel therapeutic strategies might be considered. We review here progress in tackling these questions.

The genotype distribution of the XRCC1gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia

Polymorphisms in several DNA repair genes have been described. These polymorphisms may affect DNA repair capacity and modulate cancer susceptibility by means of gene-environment interactions. We investigated DNA repair capacity and its association with acute myeloblastic leukemia (AML). We studied polymorphisms in 3 DNA repair genes: XRCC1, XRCC3, and XPD. We also assessed the incidence of a functional polymorphism in the NQO1 gene, which is involved in protection of cells from oxidative damage. We genotyped the polymorphisms by using polymerase chain reaction-restriction fragment-length polymorphism analysis in 134 patients with de novo AML, 34 with therapy-related AML (t-AML), and 178 controls. The distributions of the XRCC3 Thr241Met and NQO1 Pro187Ser genotypes were not significantly different in patients and controls. However, the distribution of the XRCC1 Arg399Gln genotypes was significantly different when comparing the t-AML and control groups (chi(2), P =.03). The presence of at least one XRCC1 399Gln allele indicated a protective effect for the allele in controls compared with patients with t-AML (odds ratio 0.44; 95% confidence interval, 0.20-0.93). We found no interactions between the XRCC1 or XRCC3 and NQO1 genotypes. We also found no differences in the distribution of the XPD Lys751Gln or XRCC1 Arg194Trp genotypes. Our data provide evidence of a protective effect against AML in individuals with at least one copy of the variant XRCC1 399Gln allele compared with those homozygous for the common allele.

A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis.

To evaluate the incidence of therapy-related acute leukaemia (t-AL) after single-agent mitoxantrone (MITO) treatment, we reviewed medical records of patients in three studies of single-agent MITO therapy for multiple sclerosis (MS) and existing literature on MITO therapy in MS, leukaemia, and solid tumors. Of 1378 MITO recipients in the three MS studies (mean cumulative dose of 60 mg/m2 and mean follow-up of 36 months), one patient had t-AL, an observed incidence proportion of 0.07% [95% confidence interval (CI) = 0.00-0.40%]. There were no cases of t-AL in published reports of nine additional studies of single-agent MITO therapy for MS. There was one published case report of acute promyelocytic leukoemia detected five years after initiating MITO therapy for MS. The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS. Although these observations provide preliminary reassurance, extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk of t-AL after MITO therapy for MS.

Therapy-related myelodysplastic syndrome after autologous stem cell transplantation for breast cancer.

Therapy-related myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML) are serious complications of chemotherapy and radiotherapy for cancer. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) may be associated with an increased incidence of these complications. The frequency of t-MDS/AML after ASCT for breast cancer is uncertain. We reviewed our database of 379 consecutive breast cancer ASCT patients treated with alkylator-based chemotherapy, followed for a median of 1.52 years (range 0-8.97), with a median survival of 6.16 years. Three patients have developed tMDS/AML. The probability of developing this complication at 5 years is 0.032 in our series. We have used pathologic, cytogenetic and molecular methods to evaluate which portions of therapy may have predisposed to the development of this complication. Cytogenetic abnormalities were not found in the stem cell harvests of these patients by metaphase analysis or by fluorescence in situ hybridization (FISH). One patient demonstrated a clonal X chromosome inactivation pattern in her stem cell harvest, indicating pre-transplant chemotherapy may have been responsible for the development of her leukemia. As two of our patients developed this complication at greater than 4 years post-transplant, the number of cases may increase with longer follow-up. While the incidence appears to be low, further prospective and retrospective analysis will be necessary to determine which portions of therapy predispose to the development of t-MDS/AML in patients undergoing ASCT for treatment of breast cancer.