Therapy-related myeloid neoplasms in lymphoma survivors: Reducing risks

Treatment for Hodgkin (HL) and non-Hodgkin's lymphoma (NHL) has changed dramatically in the last fifty years. While there are increasing numbers of long-term survivors, there has been increasing recognition of the long-term toxicities of treatments, particularly therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). The survival for t-MDS/AML is extremely poor. Multiple heterogeneous retrospective studies have reported risk factors for the development of t-MDS/AML. Chemotherapy and radiation therapy have been most closely examined as possible t-MDS/AML risk factors. In this paper, we will review the risks of t-MDS/AML for HL and NHL patients as reported in the literature and assess for any changes over time. In HL patients, the incidence of t-MDS/AML has decreased with a reduction in alkylating agents. In indolent NHL patients, we anticipate decreased incidence of t-MDS/AML as targeted therapies begin to replace cytotoxic chemotherapy.     

Sequential mutational evaluation of CALR -mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression

In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR-mutated cases. Additional mutations found by next-generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR-mutated patients. We performed a molecular evaluation combining next-generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow-up in a cohort of 45 patients with CALR-mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1-like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow-up, independently of additional mutations and WHO2016-reviewed diagnosis. Patients with disease progression at the time of follow-up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.     

Therapy-related myeloid neoplasms following treatment with radioiodine

Background

Few data are available on therapy-related myelodysplastic syndromes and acute myeloid leukemia developing after radioiodine treatment.

Design and Methods

We retrospectively analyzed 39 patients with myeloid neoplasms following radioiodine treatment, whose data were reported to the Duesseldorf Myelodysplastic Syndromes Register (8 of 3814 patients) and five other German Myelodysplastic Syndromes centers (n=31) between 1982 and 2011. These data were compared with those from 165 patients from our Myelodysplastic Syndromes Register with therapy-related myeloid neoplasms following chemotherapy (n=90), radiation (n=30), or radiochemotherapy (n=45).

Results

With a median latency of 79 months, 18 patients developed therapy-related acute myeloid leukemia and 21 presented with therapy-related myelodysplastic syndromes (8 refractory anemia with excess blasts I/II, 6 refractory anemia with multilineage dysplasia, 3 myelodysplastic syndromes with del(5q), 1 refractory anemia, 1 refractory anemia with ring sideroblasts, 1 chronic myelomonocytic leukemia II, 1 myelodysplastic/myeloproliferative neoplasm unclassifiable). Risk assessment according to the International Prognostic Scoring System was low-risk in 23%, intermediate-1 in 29%, intermediate-2 in 35%, and high-risk in 13%. Karyotype was abnormal in 68%, with chromosomes 7 (30%), 5 (26%), 8 (26%) and 3 (17%) being most frequently affected. No differences in the distribution of gender, World Health Organization subtype, acute myeloid leukemia progression, International Prognostic Scoring System score, and cytogenetic risk were observed between patients with therapy-related myeloid neoplasms following radioiodine or other treatment modalities. Of 17 patients who received induction chemotherapy, 71% were refractory to this treatment or died from treatment-related toxicity. The median overall survival in the entire group was 21.7 months (95%-CI 10.5–33 months) and did not differ significantly in comparison to the survival of patients with therapy-related myeloid neoplasms following other cytotoxic treatments. Patients with therapy-related acute myeloid leukemia had significantly inferior overall survival (12.4 versus 28.7 months, P=0.002).

Conclusions

Patients developing a therapy-related myeloid neoplasm after radioiodine treatment usually present with biological characteristics similar to those seen in patients with therapy-related myeloid neoplasms following other cytotoxic treatment modalities, associated with a low response rate to induction chemotherapy and poor prognosis.     

Molecular pathways in myelodysplastic syndromes and acute myeloid leukemia: relationships and distinctions-a review

The myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are both hematopoietic stem cell disorders. However, while leukemic stem cells have been revealed by clonal tracking experiments, dysplastic stem cells have never been demonstrated by xeno-transplantation assays because of poor engraftment problems. These engraftment difficulties may be due to the unique nature of MDS genetic lesions that are truly able to recapitulate the disease phenotype. MDS and AML of younger patients harbour clonal yet different chromosomal markers, whereas MDS and AML of the elderly present similar defects. Potential involvement of tumor suppressor genes in MDS has been hypothesized but never confirmed, while cooperation between class I and class II mutations has been identified in AML. The reciprocal interactions between stromal cells and neoplastic clones are disrupted in both MDS and AML. In early MDS, stromal and neoplastic cells produce high levels of inhibitory cytokines, whereas in advanced MDS and AML they produce high levels of anti-apoptotic molecules.     

Comparison of genetic and clinical aspects in patients with acute myeloid leukemia and myelodysplastic syndromes all with more than 50% of bone marrow erythropoietic cells

Background

The World Health Organization separates acute erythroid leukemia (erythropoiesis in ≥50% of nucleated bone marrow cells; ≥20% myeloblasts of non-erythroid cells) from other entities with increased erythropoiesis – acute myeloid leukemia with myelodysplasia-related changes (≥20% myeloblasts of all nucleated cells) or myelodysplastic syndromes – and subdivides acute erythroid leukemia into erythroleukemia and pure erythroid leukemia subtypes. We aimed to investigate the biological/genetic justification for the different categories of myeloid malignancies with increased erythropoiesis (≥50% of bone marrow cells).

Design and Methods

We investigated 212 patients (aged 18.5–88.4 years) with acute myeloid leukemia or myelodysplastic syndromes characterized by 50% or more erythropoiesis: 108 had acute myeloid leukemia (77 with acute erythroid leukemia, corresponding to erythroid/myeloid erythroleukemia, 7 with pure erythroid leukemia, 24 with acute myeloid leukemia with myelodysplasia-related changes) and 104 had myelodysplastic syndromes. Morphological and chromosome banding analyses were performed in all cases; subsets of cases were analyzed by polymerase chain reaction and immunophenotyping.

Results

Unfavorable karyotypes were more frequent in patients with acute myeloid leukemia than in those with myelodysplastic syndromes (42.6% versus 13.5%; P<0.0001), but their frequency did not differ significantly between patients with acute erythroid leukemia (39.0%), pure erythroid leukemia (57.1%), and acute myeloid leukemia with myelodysplasia-related changes (50.0%). The incidence of molecular mutations did not differ significantly between the different categories. The 2-year overall survival rate was better for patients with myelodysplastic syndromes than for those with acute myeloid leukemia (P<0.0001), without significant differences across the different acute leukemia subtypes. The 2-year overall survival rate was worse in patients with unfavorable karyotypes than in those with intermediate risk karyotypes (P<0.0001). In multivariate analysis, only myelodysplastic syndromes versus acute myeloid leukemia (P=0.021) and cytogenetic risk category (P=0.002) had statistically significant effects on overall survival.

Conclusions

The separation of acute myeloid leukemia and myelodysplastic syndromes with 50% or more erythropoietic cells has clinical relevance, but it might be worth discussing whether to replace the subclassifications of different subtypes of acute erythroid leukemia and acute myeloid leukemia with myelodysplasia-related changes by the single entity, acute myeloid leukemia with increased erythropoiesis ≥50%.     

REVIEW: Recent advances in the diagnosis and classification of myeloid neoplasms – comments on the 2008 WHO classification

The fourth edition of the World Health Organization (WHO) classification of myeloid neoplasms refined the criteria for some previously described myeloid neoplasms and recognized several new entities based on recent elucidation of molecular pathogenesis, identification of new diagnostic and prognostic markers, and progress in clinical management. Protein tyrosine kinase abnormalities, including translocations or mutations involving ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB, and FGFR1, have been used as the basis for classifying myeloproliferative neoplasms (MPN). Two new entities - refractory cytopenia with unilineage dysplasia and refractory cytopenia of childhood have been added to the group of myelodysplastic syndromes (MDS), and ‘refractory anemia with excess blasts-1’ has been redefined to emphasize the prognostic significance of increased blasts in the peripheral blood. A list of cytogenetic abnormalities has been introduced as presumptive evidence of MDS in cases with refractory cytopenia but without morphologic evidence of dysplasia. The subgroup ‘acute myeloid leukemia (AML) with recurrent genetic abnormalities’ has been expanded to include more molecular genetic aberrations. The entity ‘AML with multilineage dysplasia’ specified in the 2001 WHO classification has been renamed ‘AML with myelodysplasia-related changes’ to include not only cases with significant multilineage dysplasia but also patients with a history of MDS or myelodysplasia-related cytogenetic abnormalities. The term ‘therapy-related myeloid neoplasms’ is used to cover the spectrum of disorders previously known as t-AML, t-MDS, or t-MDS/MPN occurring as complications of cytotoxic chemotherapy and/or radiation therapy. In this review, we summarize many of these important changes and discuss some of the diagnostic challenges that remain.     

Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype

Background

Acute myeloid leukemia is a clonal hematopoietic malignant disease; about 45–50% of cases do not have detectable chromosomal abnormalities. Here, we identified hidden genomic alterations and novel disease-related regions in normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples.

Design and Methods

Thirty-eight normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples were analyzed with high-density single-nucleotide polymorphism microarray using a new algorithm: allele-specific copy-number analysis using anonymous references (AsCNAR). Expression of mRNA in these samples was determined by mRNA microarray analysis.

Results

Eighteen samples (49%) showed either one or more genomic abnormalities including duplication, deletion and copy-number neutral loss of heterozygosity. Importantly, 12 patients (32%) had copy-number neutral loss of heterozygosity, causing duplication of either mutant FLT3 (2 cases), JAK2 (1 case) or AML1/RUNX1 (1 case); and each had loss of the normal allele. Nine patients (24%) had small copy-number changes (< 10 Mb) including deletions of NF1, ETV6/TEL, CDKN2A and CDKN2B. Interestingly, mRNA microarray analysis showed a relationship between chromosomal changes and mRNA expression levels: loss or gain of chromosomes led, respectively, to either a decrease or increase of mRNA expression of genes in the region.

Conclusions

This study suggests that at least one half of cases of normal karyotype acute myeloid leukemia/myelodysplastic syndrome have readily identifiable genomic abnormalities, as found by our analysis; the high frequency of copy-number neutral loss of heterozygosity is especially notable.     

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Background

Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31).

Design and Methods

Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only.

Results

Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations.

Conclusions

Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00761449","term_id":"NCT00761449"}}NCT00761449).     

Redefining monosomy 5 by molecular cytogenetics in 23 patients with MDS/AML

Deletion of the long arm of chromosome 5 [del(5q)] or loss of a whole chromosome 5 (-5) is a common finding, arising de novo in 10% of patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and in 40% of patients with therapy-related MDS or AML. We investigated by molecular cytogenetics 23 MDS/AML patients for whom conventional cytogenetics detected a monosomy 5. Monosomy 5 was redefined as unbalanced or balanced translocation and ring of chromosome 5. Loss of 5q material was identified in all 23 patients, but one. One copy of EGR1(5q31) or CSF1R(5q33-34) genes was lost in 22 of the 23 patients. Chromosome 5p material was a constant chromosomal component of derivative chromosomes or rings in all patients, but one. Sequential fluorescent in situ hybridization studies with whole chromosome paints and region-specific probes, used as a complement to conventional cytogenetic analysis, allow a better interpretation of karyotypes in MDS/AML patients.     

Hypocellular bone marrow with increased blasts

Twenty patients with hypocellular bone marrow and increased blasts (HBMIB) were reviewed. The median age was 60 years with a male:female ratio of 17:3. History of alcohol abuse was noted in 30%, potential exposure to toxic chemicals in 20%, second malignancies in 20%, and aplastic anemia in 25%. Pancytopenia with marrow hypocellularity and increased marrow blast cells were characteristic hematopathologic features. Marrow hypocellularity was moderate to severe (less than or equal to 25%) in over half of the cases and mild to moderate (greater than 25, less than or equal to 35%) in the remainder. Blast cells were the predominant cellular elements in the marrow displaying scanty to moderate amounts of cytoplasm, round to oval nuclei, and one or more nucleoli. Special stains were performed in 19 cases. Blast cells morphologically displayed myeloid features, but Sudan black B and/or peroxidase positivity was noted in only ten patients. The overall mortality was high, especially in patients undergoing chemotherapy. At 1 year follow-up, 11 patients had received chemotherapy and eight of these eleven were dead compared to three of nine patients dead in those not receiving chemotherapy. Only two patients developed "overt" leukemia evidenced by hypercellular marrow and over 30% blast cells in the peripheral blood. HBMIB is a distinct clinicopathologic entity characterized by severe marrow failure and a low response rate to chemotherapy.