MDS-associated Cytogenetic Abnormalities Research Articles

Incidence, Clinical Associations, and Co-Mutation Patterns of UBA1 Mutations in MDS

Background Mutations in UBA1 are associated with VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, an adult-onset inflammatory disorder (Beck DB et al. NEJM 2020). Approximately 40% of VEXAS patients are also diagnosed with myelodysplastic syndromes (MDS). However, the prevalence and characteristics of UBA1 mutations in MDS are unknown. We hypothesize that UBA1 mutations underlie a proportion of MDS cases with systemic inflammation. Methods Molecular data were reviewed from a representative diagnostic and treatment-naive MDS cohort (n= 3,328) ascertained through the International Working Group for MDS (Bernard E et al NEJM Evid 2022). We prioritized 375 cases for UBA1 genotyping based on: 1) male gender; and 2) no identified driver mutations or few mutations, enriched in DTA (DNMT3A, TET2, ASXL1) genes; or 3) unclassifiable (MDS-U or MDS/MPN-U) per 2016 WHO Classification. We identified UBA1 hotspot mutations (M41T/V/L) with digital droplet PCR. Resulting UBA1 status was integrated with cytogenetic and sequencing data from 121 genes involved in myeloid pathogenesis to identify patterns of co-mutation. Clinical associations of UBA1 mutations were evaluated and where available, clinical history was reviewed for inflammatory conditions. Results We identified 30 UBA1 M41T/V/L mutations (median number mutant droplets: 1301; range: 4-12166) in 8% of the cohort (n=28 of 375 patients). This included 15 patients with M41T (c.122T>C), 7 with M41V (c.121A>G), 4 with M41L (c.121A>C), and 2 patients with more than one mutation (1 with M41V/T, and 1 with M41L/V). In 79% of UBA1-mutant cases (22/28), the karyotype was normal. Loss of the Y chromosome was observed in 6 cases. Three cases had MDS-associated cytogenetic abnormalities: del(11q), del(13q) and focal del(20q). In 43% of UBA1-mutant cases (12/28), UBA1 mutations were the sole genetic abnormalities. For a further 43% we observed co-mutation with DTA genes (DNMT3A, TET2, ASXL1) with median variant allele fraction (VAF) of 0.21 (0.02-0.56). SF3B1 co-mutations with VAF >30% were observed in 3 cases. Most UBA1-mutant cases were classified per 2016 WHO as MDS-SLD/MLD (n=18), but two cases were MDS with excess blasts 1, and one case was CMML-1 with 9% blasts. The median age at diagnosis was 72 years (44-89). No significant difference was found when comparing clinical parameters (blast counts, complete blood counts, age) between UBA1 mutant and wildtype MDS MDS. Clinical history was readily available for 4 UBA1-mutant patients. Inflammatory symptoms were reported in 3 patients, localized in the lungs (n=2), skin (n=2) and cartilage (n=1). Two patients also had a diagnosis of inflammatory/rheumatological disease (vasculitis and relapsing polychondritis), two patients had thrombosis, one had a history of monoclonal gammopathy of undetermined significance. The 4th patient, without inflammatory symptoms, had a prior diagnosis of T-cell large granular lymphocytic leukemia. Follow-up for transformation to acute myeloid leukemia (AML) and overall survival was available for 310 and 339 patients, respectively. No UBA1-mutant patients transformed to AML (n=24; median follow-up 2.6 years). There was no difference in overall survival between UBA1-mutant (n=27) and wildtype (n=312) patients (log-rank test p = 0.7), however, when subsetting for patients with no mutations detected by targeted DNA sequencing (UBA1-mutant n=7; wildtype n=45), UBA1-mutant patients had worse overall survival (median 5.2 vs 7.3 years; log-rank test p = 0.03). ConclusionUBA1 mutation in isolation or in combination with other mutations implicated in myeloid pathogenesis account for a significant proportion (8%) of patients diagnosed and treated as MDS but without established disease classification. Ongoing work includes 1) clinical review of inflammatory symptoms for the remaining UBA1-mutant cases and 2) profiling a larger cross-section of MDS by a UBA1 targeted panel to characterize mutations beyond the M41 locus.

The emerging importance and evolving understanding of clonal hematopoiesis in multiple myeloma

Multiple myeloma (MM) is the second most common hematologic malignancy diagnosed in the United States. With a growing arsenal of novel therapies, patients are living longer and hence are at increased risk of secondary cancers such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). While MDS-associated cytogenetic abnormalities have been described in patients with a diagnosis of for decades, clonal hematopoiesis (CH) has been described only recently. CH has been shown to correlate with inferior survival in MM due to increased risk of disease progression in patients who are treated with high-dose melphalan without lenalidomide maintenance. When involving specific high-risk genes, multiple genes, or when present at high variant allelic frequencies, CH could also potentially elevate the risk of secondary MDS and/or AML, cardiovascular events, and venous thromboembolic events. Despite growing knowledge about CH in patients with MM, many questions remain unanswered. Further studies are needed to better understand the prognostic and therapeutic significance of CH in MM and its precursor conditions, as well as the effect of specific treatments on long-term outcome.

Rapid fluorescence in situ hybridisation optimises induction therapy for acute myeloid leukaemia.

Rapid fluorescence in situ hybridisation optimises induction therapy for acute myeloid leukaemia.

Comparative assessment of conventional chromosomal analysis and fluorescence in situ hybridization in the evaluation of suspected myelodysplastic syndromes: a single institution experience.

Background:Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic neoplasms, roughly half of which harbor cytogenetic abnormalities with diagnostic, prognostic, and therapeutic significance. Fluorescence in situ hybridization (FISH) for the most commonly seen abnormalities (5/5q, –7/7q, +8, and –20/20q–) is routinely performed alongside conventional cytogenetics (CC) in the evaluation of suspected MDS despite conflicting reports of its relative contribution compared to CC alone.Objectives:To assess the additional diagnostic and prognostic value of performing concurrent FISH versus CC alone in cases of suspected MDS.Materials and Methods:A total of 127 bone marrow samples submitted to our cytogenetic laboratory with a presumptive diagnosis of MDS were evaluated by concurrent CC and an MDS FISH panel.Results:CC was used as the gold standard method with 100% sensitivity in detecting suspected MDS-associated cytogenetic abnormalities. FISH alone had a sensitivity of 76%, whereas CC alone achieved a sensitivity of 97%. The addition of FISH did not change the diagnosis nor change the Revised International Prognostic Scoring System score in any patient. Moreover, in 12 cases identified as positive by both CC and FISH, CC identified multiple chromosomal aberrations of clinical significance not interrogated by the FISH probe panel.Conclusion:CC alone is sufficiently sensitive in detecting suspected MDS-associated cytogenetic abnormalities that influence clinical decision-making. Routine FISH testing does not provide a significant increase in test sensitivity when an adequate karyotype is obtained. Therefore, FISH testing is best reserved for suspected MDS cases lacking sufficient metaphases.

Myeloid Cell Maturation Is Disrupted By Monosomy 7 or By Gain of Additional Genetic Aberrations during Clonal Evolution in Myelodysplastic Syndromes.

Background: Myelodysplastic syndromes (MDS) are associated with cytogenetic clones. To follow the maturation sequence of original clones and evolved subclones with additional cytogenetic abnormalities, progenitor cells, immature and mature myeloid cells were sorted by flow cytometry and analyzed separately by fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH).Methods: Flow cytometry sorted cell fractions from bone marrows for sixteen patients with MDS-associated cytogenetic abnormalities were evaluated by FISH. Flow cytometric cell sorting was based on CD34+/low side scatter (SS) for progenitors, CD13+/CD16-/high SS for immature myeloid cells, and CD13+/CD16+/high SS for mature myeloid cells. Customized color labeling (spectrum orange, green and aqua) of FISH probe combinations were designed to detect and to analyze clonal evolution for each patient based on their known cytogenetic abnormalities and clonal evolution patterns. Three marrow aspirates were sorted for analysis by SNP/CGH microarray.Results: The 16 bone marrow specimens evaluated by FISH were categorized into three groups: (1) eight patients with a single, good-to-intermediate cytogenetic abnormality; (2) four patients with monosomy 7; and (3) four patients with more than one chromosome abnormality with evidence of clonal evolution by conventional cytogenetic analysis, excluding monosomy 7.The Group-1 abnormalities included deletion 20q (n=4), trisomy 8 (n=2), deletion 5q (n=1), and trisomy 11 (n=1). All specimens from this group showed FISH abnormalities in equal proportions in myeloid progenitors, immature and mature myeloid cells.Group-2 had four patients with monosomy 7. All four had monosomy 7 concentrated in the progenitor cells (45-79%) compared to immature and mature myeloid compartments (less than 9-36%).For Group-3, known original clones with single cytogenetic abnormalities (deletion 20q, monosomy 3, deletion 7q or 5q) were monitored by FISH analysis. Using customized FISH panels, the presence of subclones with additional cytogenetic aberrations (trisomy 8 in three patients and gain of a marker chromosome characterized by the centromere of chromosome 4 in a fourth patient) was assessed using single-cell resolution. The progenitor and immature myeloid compartments had the original founding clones containing a single cytogenetic abnormality at 15-34% and the subclones with the additional aberrations at 23-76%. In contrast, the mature myeloid cells were comprised of the original clone at 20-40%, but the subclones with additional aberrations were absent in the mature myeloid compartment in three patients and reduced by more than half in a fourth.For three patients sorted bone-marrow fractions were analyzed by SNP/CGH microarray. In one patient with trisomy 8 as the sole abnormality, the same aberration was observed in both the immature and mature myeloid compartments. In two other patients, additional abnormalities not seen in the mature myeloid cells were detected in the progenitor and immature myeloid compartments.Conclusions: These data show two main patterns for the distribution of clonal cytogenetic abnormalities among myeloid cells in MDS: 1) A continuous distribution at all stages of maturation was found for single aberrations with good-to-intermediate prognostic associations (Group 1) and 2) A disrupted distribution pattern with accumulation of the cytogenetic aberrations in the progenitor compartment as compared to the immature and mature myeloid compartments for specimens characterized by monosomy 7 (Group 2). Similarly, subclones characterized by additional cytogenetic abnormalities (Group 3) were sequestered in the progenitor and immature myeloid compartments while the original founding clone was evenly distributed throughout maturation.These data demonstrate that specific cytogenetic abnormalities associated with poor prognosis (e.g. monosomy 7) as well as acquired cytogenetic abnormalities as a result of clonal evolution can cause disruption of myeloid cell maturation in MDS. DisclosuresZehentner:HematoLogics Inc.: Employment, Equity Ownership. Hartmann:Hematologics Inc.: Employment. Johnson:Hematologics Inc.: Employment. Bennington:HematoLogics Inc.: Employment. Fritschle:HematoLogics Inc.: Employment. Ghirardelli:HematoLogics Inc.: Employment. Broderson:HematoLogics Inc.: Employment. Chapman:Hematologics Inc.: Employment. Stephenson:Hematologics Inc.: Employment. de Baca:Hematologics Inc.: Employment. Singleton:Hematologics Inc.: Employment. Wells:HematoLogics Inc.: Employment, Equity Ownership. Loken:Hematologics: Employment, Equity Ownership.

Fulminant Onset of Acute Leukemia (FOAL) After Total Therapies (TT) for Multiple Myeloma (MM): Absence of MDS Pathological Criteria within 3 Months of Prior MM Follow-up

AbstractAbstract 1458 Background:Cytogenetic abnormalities (CA) in therapy-related myeloid neoplasms (t-MN) usually correlate with nature of previous therapy and clinical presentation. t-MN following prior therapy with alkylating agents and/or radiotherapy are associated with a long latency period (> 3 years) an antecedent myelodysplastic syndrome (MDS) phase, and unbalanced translocations or a complex karyotype. Majority of t-MNs that initially present as acute leukemia (AL) are associated with prior topoisomerase II therapy, a shorter latency period (1–3 years), lack of MDS phase and balanced translocations, commonly involving 11q23/MLL gene. In our experience the usual course of t-MN in MM patients is a prolonged MDS phase with progressive cytopenia, progressing to acute myeloid leukemia (AML) in a subset of patients. Here we report on 7 patients in complete remission (CR) for MM without cytopenia or morphologic evidence of dysplasia on bone marrow evaluation within 3 months prior to presenting with FOAL. One patient developed FOAL within 2.5 months of first documentation of MDS-associated CA (MDS-CA). Methods:Of 3890 patients at the University of Arkansas who had received melphalan-based autograft supported high dose therapy, 69 patients developed t-MN— 63 initially presented with MDS and 13 progressed to AML. Six of the seven patients had no prior MDS-CA or morphological dysplasia, and one with MDS-CA seen <2.5 months earlier, had fulminant onset of AL. All BM specimens at time of FOAL and within one-year period prior to FOAL were evaluated. Metaphase cytogenetic analysis was performed on unstimulated BM specimens using standard techniques. Interphase FISH was performed on BM samples using probes to detect CA commonly observed in MDS and AML. Results:All FOAL patients were treated on Total Therapy (TT) protocols for newly diagnosed MM including 3 on TT2 with thalidomide arm, 3 on TT3A with VTD maintenance, and 1 on TT4 with VRD maintenance. At the time of FOAL all patients were in CR for MM and on maintenance therapy with dexamethasone, thalidomide, lenalidomide, and bortezomib in combination or as single agents. The clinical and laboratory features prior to and at onset of AL are shown in the table.Patient No. Parameters1234567Karyotype at diagnosis62,XXX,-1,-2, +3,-4, -5, -6,-7, +9,+9,-13, -13, der(14)t(11;14) (q12∼13.1;q32) x2, -16, -17, +18, +19,-21, -22[7]/ 46,XX[cp11]42∼44,X,-X, add(6)(q?22), der(12)t(1;12) (q11∼12; q24.3),-13[cp9]/46, XX[cp11]46,XY[20]38∼40,X, -Y,+1, add(1)(p11), der(1;16)(q10; p10),-4,-6, t(8;14) (q24.1;q32),-8,-12, -13,-16 [cp4]/70∼75, idemx2, inc[cp3]/46, XY[cp13]46,XY[20]46,XY[20]46,XY[20]Interval from start of MM therapy126 months63.5 months9.5 months74.5 months114 months123 months66 monthsMM status at FOALStringent CRStringent CRStringent CRStringent CRStringent CRCRStringent CRKaryotype prior to FOAL53,XX,+X,+4,+4, +7,+8, inc[cp3]/ 46,XX[cp38]46,XX[20]46,XY[20]46,XY[20]46,XY[20]46,XY[20]46,XY[20]FISH+7, +8NDNormalNDNDNormalNDLeukemia subtypeALLALLAMLAMLAMLAMLAMLMDS-CA at time of FOAL55,XX,+X,+4,+4, +der(7;9)(q10;q10), +8, del(12)(q24.2), +14,+18,+21 [cp15]/ 46,XX[5]del(20q)46,XY[20]Complex with -5 and -7Complex with -5,-17, and del(11q23)Complex -5 and -746,XY[20]FISH+8, +21del(20q)Normal-5, del(5q),-7del(5q)del(5q), -7, del(7q)NDND= not done Conclusion:In this cohort, MDS-CA (+8, del20q, −7, del7q, −5, del5q and complex karyotype) were detected in leukemic blasts in 5 of 7 patients with abnormalities of chromosomes 5 and 7 most commonly seen. In contrast to clinical and cytogenetic associations described for t-MN initially presenting as AL, none of our patients showed balanced chromosomal translocations involving 11q23, and all but one (patient 3, 9.5m) had a long latency period of 5 to 10yr. Importantly, the absence of MDS-CA on prior bone marrow evaluations in 6 of 7 of our cases indicates that FOAL cannot be predicted based on surveillance BM metaphase cytogenetics or FISH. Studies using gene expression profile analysis of CD34 stem cells are underway to identify molecular alterations leading to FOAL. Results of these studies may improve t-MN surveillance. Disclosures:No relevant conflicts of interest to declare.

Secondary Myelodysplasia-Associated Metaphase Cytogenetic Abnormalities in Newly Diagnosed Multiple Myeloma Treated On Total Therapies 2 & 3– Influence of Cumulative Dosing of Maintenance Drugs

AbstractAbstract 324▪▪This icon denotes a clinically relevant abstract Background:There has been recent evidence that lenalidomide, while used in the treatment of myelodysplastic syndromes (MDS), also has been associated with an enhanced risk of secondary malignancies including MDS. Here we are examining the impact of maintenance on the development of metaphase-based MDS-associated cytogenetic abnormalities (MDS-CA), and subsequent development of therapy related MDS (t-MDS) and acute leukemia (t-AL) in the two arms of Total Therapy 2 (TT2) and two successive Total Therapy 3 trials (TT3A, TT3B). Methods:The details of TT2/TT3A/TT3B trials and patient outcomes have been reported previously. TT2 (median follow-up 118 months) patients were then randomized to receive thalidomide maintenance (TT2+Thal) for 3 years versus no thalidomide (TT2-Thal). Maintenance in TT3A (median follow-up 78 moths) consisted of VTD in the first year and TD for years 2 and 3 in TT3A, while TT3B (median follow-up 48 months) employed VRD for all 3 years. The patient populations were as follows: TT2-Thal arm (n=283), TT2+Thal arm (n=270), TT3A (n=279) and TT3B (n=162). Bone marrow examination with conventional cytogenetics was performed at baseline, post-induction, post-transplant and then at least semi-annually from maintenance in all patients prospectively. Chi-square and Fisher's exact tests were used to compare baseline characteristics between protocols. Univariate and multivariate Cox proportional hazard regression were used to model associations between baseline covariates and onset of MDS-CA and t-MDS/t-AL. Kaplan and Meier method was used to model cumulative incidence of MDS-CA and t-MDS/t-AL. Results:Baseline characteristics were fairly comparable between the two arms of TT2 and the two TT3 studies, except a higher proportion of GEP70 high risk patients in TT3B. Cumulative incidence of MDS-CA was significantly higher in TT3B protocol from time of first transplant (Figure 1), with the most common cytogenetic abnormality being deletion of chromosome 20 (del20, 35%), followed by monosomy/deletion 7 (27%) and monosomy/deletion 5 (17%) across all protocols. Of the 71 patients with an MDS-CA, 29 were also diagnosed with clinical MDS or AML; for these 29 patients, the median time to this diagnosis from first transplant was 58 months. The cumulative incidence of MDS-CA was higher and achieved more statistical significance (Figure 2) in TT3B compared to TT3A when landmarked from the start of maintenance. In univariate analysis for all patients, TT3B emerged as a significant variable in the univariate Cox regression model for MDS-CA, and in both the univariate and multivariate models for del20. Univariate and multivariate modeling within TT3B patient population did not reveal significance with cumulative dosing of different maintenance drugs. Discussion:Three randomized phase III trials (IFM-2005-02, CALGB 101104 and MM-015) have demonstrated an increase incidence of second malignancies in patients receiving lenalidomide maintenance after having been exposed to alkylating agent melphalan. In our present study, we are reporting an increased incidence of MDS-CA in the TT3B trial that employed VRD maintenance when compared with predecessor TT3A and TT2 trials. The data suggests that the risk is associated with lenalidomide exposure rather than its cumulative dosing in patients with prior exposure to therapy with alkylating agents. [Display omitted] Pairwise log-rank comparisons:TT3B vs. TT3A:p-value = 0.0206TT3B vs. TT2-Thal:p-value = 0.0134TT3B vs. TT2+Thal:p-value = 0.0178TT3A vs. TT2-Thal:p-value = 0.1502TT3A vs. TT2+Thal:p-value = 0.3134TT2-Thal vs. TT2+Thal:p-value = 0.8863 [Display omitted] Disclosures:Sawyer:University of Arkansas for Medical Sciences: Employment, under panding process, under panding process Patents & Royalties.

Second Malignancies in Total Therapy 3 Trials for Newly Diagnosed Multiple Myeloma: Influence of Lenalidomide Versus Thalidomide in Maintenance Phases

Abstract 823 Background:Recent data from IFM, CALGB and GEMIMA trials suggest that utilizing lenalidomide as maintenance therapy is associated with a higher incidence of second cancers, including both hematologic and solid malignancies. Two successive Total Therapy 3 (TT3) trials, one employing as maintenance thalidomide (TT3A, n=303) and the other lenalidomide (TT3B, n=177), after tandem transplants offered the opportunity of investigating whether lenalidomide therapy was associated with greater probability of inducing second malignancies. Patients & Methods: The details of TT3A and TT3B trials and patient outcomes have been reported previously. Briefly, both employed identical induction therapy with 2 cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone plus 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide), followed by melphalan 200mg/m2-based tandem autologous transplantation and 2 cycles of dose-reduced VTD-PACE consolidation. Maintenance consisted of VTD in the first year and TD for years 2 and 3 in TT3A, while TT3B employed VRD for all 3 years. All patients had signed an informed consent in keeping with institutional and federal guidelines. For the purpose of this analysis, the MM data base was interrogated for the development of CA-2 arising after protocol initiation and after start of maintenance therapy in TT3 trials. This was based on frequently scheduled positron emission tomography (PET) scanning, performed at baseline and on average every 3 months in the first year and semi-annually thereafter. For the early detection of potential MDS or AML, all bone marrow examinations included metaphase karyotyping and, when indicated because of pathological or clinical suspicion, inter-phase fluorescence in situ hybridization (FISH) for the detection of MDS- and AML- associated abnormalities. Chi-square and Fisher’s exact tests were used to compare baseline characteristics between protocols. Univariate and multivariate Cox proportional hazard regression were used to model associations between baseline covariates and onset of second malignancy. Furthermore, the Kaplan and Meier method was used to model cumulative incidence of second malignancy from the initiation of maintenance therapy. Results: TT3B patients had notably higher proportions of patients with ISS III disease and GEP70-high risk as compared to TT3A patients. There was an incidence of 16 new second primary cancers on TT3A over the entire period of observation with 7 solid tumors and 9 hematologic malignancies. We only observed 2 new second primaries on protocol TT3B (1 solid, 1 hematologic malignancy). There were no differences in cumulative incidence of hematologic CA2 or solid CA2 between the protocols from the initiation of maintenance therapy on the two TT3 trials (Figure 1). Cox regression analysis identified old age (> 66yrs) and high Kappa FLC levels (>168 mg/dl) as the only factors negatively associated with timing of onset of a second malignancy, when modeled from initiation of maintenance therapy. MDS associated cytogenetic abnormalities (MDS-CA) can occur as either transient or persistent anomalies on serial bone marrow analyses in post-transplant MM patients in absence of cytopenias or morphologic evidence of MDS, as previously reported. The 4-year incidence of MDS-CA in TT3B was significantly higher than TT3A. It remains to be seen whether such MDS-CAs progress to overt clinical MDS and therefore need to be followed prospectively. Conclusion: Our study has the great advantage containing large cohorts of patients who underwent treatment that only differed in the maintenance regimen. Furthermore we did not have to rely on multiple different methods of detecting incidental CA2 but rather obtained PET scans in regular intervals thus avoiding underreporting of CA2s. In terms of treatment our aproach can be best compared to the IFM 2005-02 and CALGB 100104 who both included HDT and HSCT. Overall we had a significant lower incidence of CA2 in the treatment arms than these comparable trials. Taken together, the data suggest that there are no discernable differences in CA-2 when combining different IMiDs with BZ/D as maintenance strategy. There is, however, a higher incidence of MDS karyotypic abnormalities, both transient and persistent, in patients who remain on the Bz/D/Len maintenance after having undergone autologous stem cell transplantation on TT3B. Disclosures:Barlogie:Celgene, Genzyme, Novartis, Millennium: Consultancy, Honoraria, Patents & Royalties.

MDS-associated cytogenetic abnormalities (MDS-CA) after total therapy (TT) regimens for newly diagnosed multiple myeloma (MM): Apparent surge after introduction of post-transplant consolidation chemotherapy (CONS) in TT2 and TT3

8595 Background: We have previously reported on the variables associated with the development of MDS-CA in the context of autologous transplant-supported high-dose therapy regimens for MM (Barlogie et al, Blood 2008). Methods: Due to a perceived increase in MDS-CA frequency, our MM data base was reviewed again to determine the potential effect of CONS introduced in TT2 and retained in TT3 trials. The frequency of MDS-CA post-transplant was determined, using Kaplan-Meier estimate plots, for 183 patients who received TT1, 554 enrolled in TT2 and 305 receiving TT3. Persistence of MDS-CA implied their documentation on 3 successive occasions. Results: 3-year MDS-CA estimates were 2% for both TT1 and TT2 and 4% for TT3 (TT3 v TT2, p=0.04; TT3 v TT1, p=0.11); persistent MDS-CA were also more frequently observed in TT3 in comparison with TT2 and TT1 (2% v 0% v 0%, both p=0.01). Multivariate analysis of features associated with transient and persistent MDS-CA revealed TT3 as an adverse feature (HR=2.84, p=0.043), along with incomplete platelet recovery of &lt;165,000/uL 3mo after 1st transplant. Conclusions: Despite reduced induction chemotherapy prior to and CONS after tandem melphalan (200mg/m2)-based autotransplants from 4 in TT2 to 2 in TT3, overall and persistent MDS-CA increased significantly in TT3. Clinical MDS and AML were rarely observed and a full account of hematopathologic findings will be presented. [Table: see text]

Cytogenetically defined myelodysplasia after melphalan-based autotransplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: the Arkansas experience in more than 3000 patients treated since 1989

Myelodysplastic syndrome (MDS) is a well-recognized complication of chemotherapy for multiple myeloma (MM). Serial bone marrow metaphase examinations were performed for MM restaging in 3,077 patients undergoing high-dose therapy (HDT). MDS-associated cytogenetic abnormalities (MDS-CAs) were observed in 105 of 2,418 patients in whom cytogenetic data were available after HDT. MDS-CAs occurred transiently in 72 patients and on 3 successive occasions (persistent MDS-CAs) in 33 patients, for 10-year estimates of 4% and 2%, respectively; only 21 patients developed overt clinical MDS and 5, acute myeloblastic leukemia (AML). MDS-CA development was linked to lower CD34 yield at collection, longer time interval from MM diagnosis to HDT, older age, and lower platelet recovery after HDT; persistent MDS-CAs were predicted by CD34 yield of less than 3 x 10(6)/kg and need for more than 2 apheresis procedures. Applying a tertile frequency distribution over time to all 105 patients with MDS-CAs, its detection early after HDT was associated with longer time interval from diagnosis and low pre-HDT platelet count (likely resulting from pre-HDT damage), whereas late-onset MDS-CAs were noted among patients treated with Total Therapy 2 and Total Therapy 3 that applied post-HDT consolidation chemotherapy (suggesting possible post-HDT damage). While the risk of MDS-CAs was low and clinical MDS occurred infrequently, monitoring after post-HDT consolidation chemotherapy appears warranted.

Genetic Testing in the Myelodysplastic Syndromes: Molecular Insights Into Hematologic Diversity

The myelodysplastic syndromes (MDS) are associated with a diverse set of acquired somatic genetic abnormalities. Bone marrow karyotyping provides important diagnostic and prognostic information and should be attempted in all patients who are suspected of having MDS. Fluorescent in situ hybridization (FISH) studies on blood or marrow may also be valuable in selected cases, such as patients who may have 5q- syndrome or those who have undergone hematopoletic stem cell transplantation. The MDS-associated cytogenetic abnormalities that have been defined by karyotyping and FISH studies have already contributed substantially to our current understanding of the biology of malignant myeloid disorders, but the pathobiological meaning of common, recurrent chromosomal lesions such as del(5q), del(20q), and monosomy 7 is still unknown. The great diversity of the cytogenetic findings described in MDS highlights the molecular heterogeneity of this cluster of diseases. We review the common and pathophysiologically interesting genetic abnormalities associated with MDS, focusing on the clinical utility of conventional cytogenetic assays and selected FISH studies. In addition, we discuss a series of well-defined MDS-associated point mutations and outline the potential for further insights from newer techniques such as global gene expression profiling and array-based comparative genomic hybridization.