Treatment-related Myelodysplastic Syndrome Research Articles

BK virus nephropathy after allogeneic stem cell transplantation: A case report and literature review

Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus-associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non-renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment-related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy-proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis-dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post-HCT PVAN are provided.

Evaluation of treatment-related acute myeloid leukemia or myelodysplastic syndrome risk following standard chemotherapy versus dose-intensified chemotherapy plus granulocyte colony-stimulating factor.

Abstract Abstract #6135 Background Retrospective studies of the risk of acute myeloid leukemia or myelodysplastic syndrome (t-ML) in cancer patients receiving granulocyte colony-stimulating factor (G-CSF) have reported conflicting findings. To evaluate the impact of chemotherapy with G-CSF support on both overall survival (OS) and the risk of t-ML in patients with breast cancer, an exhaustive literature review and meta-analyses were conducted of prospective, randomized, controlled clinical trials.
 Methods Electronic databases including Medline, EMBASE, BIOSIS were searched through January 2008 identifying 5410 articles for initial screening. Eligibility criteria included: patients with non-myeloid malignancies receiving chemotherapy (CT) with or without G-CSF (filgrastim or pegfilgrastim) with adequate follow-up (≥2 years). Of the 65 publications identified, 6 were from unique, prospective, randomized, controlled trials in patients with breast cancer. Excluded reports consisted of retrospective studies, duplicate reports and studies with either no control group or with stem cell transplantation. Meta-analyses were performed based on the method of Mantel and Haenszel with summary estimates [±95% CLs] provided for both relative risk (RR) and risk difference (RD). Any asymmetry in the associated funnel plots was assessed utilizing the Egger regression intercept.
 Results A total of 2848 and 2839 patients were randomized to receive CT with G-CSF support versus standard CT, respectively. In the only trial to randomize breast cancer patients receiving the same CT to prophylactic G-CSF versus no primary or secondary prophylactic G-CSF, t-ML was reported in 1/254 (0.4%) receiving CT plus G-CSF compared to 0/243 in those not receiving G-CSF. The remaining 5 studies compared treatment with different CT intensities permitting dose intensification with G-CSF support. Meta-analyses for both OS and t-ML were performed comparing dose intensified CT with G-CSF support to standard CT without G-CSF. No significant heterogeneity was observed across trials for both outcomes. A significant increase in OS was found among patients receiving CT with G-CSF support (RR=0.88; 0.80-0.98; P=.020). A non-significant increase in the incidence of t-ML was observed among patients receiving dose intensified CT with G-CSF support (RR=1.94; 0.89-4.22; P=.097 and RD=.003; P=.090). Funnel plot analysis revealed evidence for a publication bias for t-ML reporting studies (t=3.69; 2 sided P=.034).
 Conclusions Of over 5000 studies reviewed, 1 prospective study with the same CT in both study arms found no significant increase in the risk of t-ML with G-CSF support. Meta-analyses demonstrated that chemotherapy with G-CSF support results in a significant improvement in OS with a non-significant increase in t-ML. There is insufficient data to definitively examine the role of G-CSF on t-ML risk independent of the concomitant use of dose intensified chemotherapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6135.

Fludarabine, but Not Mitoxantrone, Increases the Risk of a Poor Stem Cell Harvest and Treatment-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia (tMDS/AML) after Autologous Stem Cell Transplantation (ASCT) in Patients with Follicular Lymphoma (FL).

Both fludarabine (FLU) and mitoxantrone (MIT) are effective agents used to treat FL, but each are suspected as risk factors for poor stem cell harvesting (SCH) and the subsequent development of tMDS/AML in patients undergoing ASCT. We hypothesized that in FL patients treated with ASCT, the association of FLU and MIT with poor SCH and the development of tMDS/AML is either a function of dose, timing, or the concomitant use of these agents pre-transplant.Methods: A total of 171 evaluable patients with FL who received ASCT from 1991–2007 using a uniform preparative regimen of busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP) were identified from the Cleveland Clinic Transplant Center's Unified Transplant Database (UTD). All patients had taken part in IRB approved clinical trials and gave permission for access to their medical records for the purposes of this research. Demographic, clinical, and outcomes data were extracted from the UTD, and a retrospective chart review was then performed on all patients looking at pre-ASCT chemotherapy regimens including exact dates and doses for FLU and MIT.Results: A total of 59 patients were treated with FLU or MIT (FLU alone = 31, MIT alone = 7, FLU + MIT = 21), and 112 patients treated with neither agent. Logistic regression analysis tested the association of FLU dose (total dose > or ≤ 500mg) and timing (last dose of FLU ≤ or > 3 months prior to ASCT) with the number of days of leukopheresis required to harvest an adequate number of CD34+ cells after mobilization; with and without adjustment for MIT dose (total dose > or ≤ 50mg). A poor SCH was defined as one that required > 5 days of leukopheresis. Patients treated with FLU at any dose >3 months prior to ASCT, showed an increased risk of poor SCH, which was not significantly impacted when adjusted for MIT exposure (FLU ≤ 500mg, OR = 10.14, 95% confidence interval (CI) = 1.54–66.61, P = 0.016; FLU >500mg, OR = 4.00, CI = 1.18–13.68, P = 0.027). The 6 patients receiving >500mg of FLU ≤ 3 months prior to ASCT also showed a trend towards a poor SCH, but this association did not reach statistical significance (P=0.08). In order to quantify risk of a poor SCH, logistic regression models were used to calculate model-based probabilities. Adjusting for mitoxantrone dose, these probabilities ranged from 11–19% for patients with no prior FLU exposure, 13–24% for those receiving ≤ 500 mg FLU ≤ 3 months before ASCT, 32–49% for those receiving >500 mg >3 months before ASCT, 35–52% for those receiving >500 mg ≤ 3 months before ASCT, and 55–71% for those receiving ≤ 500 mg >3 months before ASCT. Six patients were identified with tMDS/AML. Cox proportional hazards analysis identified univariable prognostic factors for tMDS/AML, and the only factors to show statistically increased risk are: the number of prior chemotherapy regimens (HR = 1.70, 95% CI = 1.18–2.45, P = 0.004), prior exposure to any FLU (HR = 13.2, CI = 1.54–113, P = 0.019), prior exposure to >500mg FLU (HR = 17.9, CI = 1.85–173, P = 0.013), timing of FLU with the last dose being >3 months prior to ASCT (HR = 17.7, CI = 1.93–162, P = 0.011), and a poor SCH (HR = 18.1, CI = 2.10–156).Conclusions: FL patients who undergo ASCT with pre-transplant FLU exposure >3 months prior to transplant have increased risk of poor SCH and development of tMDS/AML irrespective of FLU dose and MIT exposure. Patients who receive >500mg of FLU ≤ 3 months prior to ASCT have an increased risk of tMDS/AML, and there is a trend towards an increase in the number of poor SCHs for these patients. However, those patients who receive ≤ 500mg of FLU ≤ 3 months prior to ASCT show no significant increase in poor SCH or tMDS/AML. For all patients, poor SCH predicted a higher risk of developing t-MDS/t-AML. Our data should inform treatment decisions in pts with FL who are potential candidates for ASCT.

Rituximab Added to CODOX-M/IVAC Is Highly Effective in HIV-Negative and hiv-Positive Burkitt Lymphoma

Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for nearly 3% of all newly diagnosed NHLs. Treatment of adult non-HIV-related BL with the intensive CODOX-M/IVAC regimen (modified Magrath regimen) produces complete responses (CR) in 75 to 86% of patients, with lower CR rates reported in HIV-related BL. The CD20-directed monoclonal antibody rituximab has never been reported in combination with CODOX-M/IVAC, and here we report the first series in BL patients, with or without HIV infection. A total of 24 patients were identified at our institutions who received rituximab plus CODOX-M/IVAC with curative intent. Rituximab was administered at 375mg/m2 on day 3 of cycle 1, and then on day 1 of subsequent cycles. Twenty-three patients received 4 alternating cycles of R-CODOX-M/R-IVAC for high risk disease, while 1 patient received 3 cycles of R-CODOX-M alone for low risk disease, defined as a single focus less than 10cm with a normal LDH. All patients received white cell growth factor support, and pneumocystis prophylaxis was included for all HIV+ patients. The median age was 45 years (17–67), advanced Ann Arbor stage 80%, LDH > upper limit of normal 80%, extra nodal involvement 80% and ECOG PS <2 in 96% of patients. Eight patients (33%) were HIV positive, all of whom received concurrent HAART therapy. Mean CD4 count in HIV positive patients was 266. Five patients (21%) had CNS involvement at diagnosis. Twenty-three of 24 patients achieved a complete response (CR rate 96%), and one patient developed progressive disease prior to completion of therapy. At a median follow up of 19 months (range 1–32), the event-free (EFS) and overall survival (OS) were 67% and 75%, respectively. All events occurred in high risk patients. Patients older than the age of 45 had both inferior OS (p=0.03, log rank test) and EFS (p=0.041, log rank test), compared to younger patients. Neither HIV status nor CNS involvement had prognostic value in this series. There were two relapses. One patient relapsed at 3 months post therapy and died of infectious complication during salvage treatment with rituximab, gemcitabine, and cisplatin. The other relapse occurred 11 months post therapy and was alive 22 months after salvage with autologous stem cell transplantation. One patient developed progressive disease in the testes during treatment and is currently undergoing salvage treatment with high dose cytarabine followed by gemcitabine, cisplatin and dexamethasone. Neutropenic fever occurred in 71% of patients, and in 33% of treatment cycles overall. Twenty-three of 24 (96%) patients experienced grade 4 neutropenia and 80% experienced grade 4 thrombocytopenia, with one patient developing grade IV bleeding (subdural hematoma while on therapeutic anticoagulation). The average interval between treatment cycles was 22 days, which is similar to results previously reported for this regimen without the addition of rituximab. There were 6 deaths, 2 of which occurred during treatment. The 2 deaths during treatment were both infection-related and occurred in the 2 patients greater than 60 in this series; both were HIV negative. Of the 4 deaths following the end of therapy, 3 occurred within 3 months of completing treatment, 1 from recurrent BL and 2 from infectious complications (1 of whom was HIV-positive). One patient died in CR of treatment-related myelodysplastic syndrome 22 months after diagnosis. Of the 6 deaths in this series, 2 were in HIV-infected patients.CODOX-M/IVAC with rituximab results in high efficacy with a CR rate of 96% and favorable progression-free and overall survivals, but should be used with caution in older patients due largely to infection-related toxicity.

Treatment-related Myelodysplastic Syndrome After Temozolomide Use in a Child

Temozolomide is an effective alkylating agent that is increasingly used for the treatment of pediatric brain tumors. Secondary, or treatment-related, myelodysplasia is a life-threatening complication of alkylating chemotherapy and has been reported in children with brain tumors after treatments other than temozolomide. We describe for the first time a case of temozolomide-related myelodysplasia in a child.

Myelodysplastic syndromes associated with interstitial deletion of chromosome 5q: Clinicopathologic correlations and new insights from the prelenalidomide era

To better estimate prognosis for patients with myelodysplastic syndromes (MDS) associated with clonal interstitial deletions of the long arm of chromosome 5 (del(5q)), we reviewed the medical records of 130 adults with del(5q) MDS seen at our institution over a 15-year period. Overall median survival of this cohort was 9.5 months, shorter than reported in earlier series. The least favorable outcomes are associated with complex cytogenetics, lack of any normal metaphases, normocytic rather than macrocytic erythrocyte indices, and low baseline lymphocyte counts. Lymphopenia but not neutropenia at the time of diagnosis appears to be a new adverse prognostic indicator. Cytogenetic breakpoints defined by G-banded karyotyping correlate poorly with particular disease features. Surprisingly, survival of patients with treatment-related MDS was equivalent to that of de novo MDS with del(5q) in this series. Morphologic features associated with del(5q) are diverse. Most patients with del(5q) MDS do not meet criteria for WHO-defined 5q-syndrome, and the presence of del(5q) does not appear to modify the clinical phenotype otherwise risk-stratified by the International Prognostic Scoring System (IPSS). Additional important prognostic factors not taken into account by the IPSS include the baseline erythrocyte indices, lymphocyte count, and clonal burden.

BRAF mutations are very rare in B- and T-cell pediatric acute lymphoblastic leukemias

We read with interest the study by Gustafsson et al.1 regarding BRAF mutations in childhood acute lymphoblastic leukemia (ALL). They investigated exons 11 and 15 of BRAF and exons 1 and 2 of NRAS in 29 cases (25 pre-B ALL, 3 T-cell ALL and 1 undifferentiated ALL), and identified six (21%) BRAF mutations and seven (24%) NRAS mutations. The frequencies of BRAF mutations seemed to be particularly common in T-cell ALL (two out of three; 67%); only four (16%) of the pre-B ALL harbored a BRAF mutation. All mutations were located in exon 15—three L597Q and one V590I among the pre-B ALL and one V600E and one G596S in the T-cell ALL. Hou et al.2 recently demonstrated that the L597Q mutation is a functional oncogene, at least in an in vitro experimental system. In the study by Gustafsson et al.,1 and as expected based on previous studies,3, 4 the BRAF and NRAS mutations were generally mutually exclusive. The high frequency of BRAF mutations was unexpected since such mutations otherwise have been demonstrated to be very rare in hematologic malignancies. In fact, previous analyses revealed no BRAF mutations in 53 cell lines from leukemias and lymphomas,3 65 multiple myelomas/plasma cell leukemias,5 21 multiple myelomas6 or in 149 acute myeloid leukemias (AML).7, 8 We know of only three additional studies reporting acquired BRAF mutations in malignant hematologic disorders. In a series of 164 B- and T-cell lymphomas, Lee et al.9 detected BRAF mutations in 2.5%. The same group10 also reported such mutations in 20% of B-lineage ALL, 9% of acute biphenotypic leukemia and 4% of AML; all the investigated patients were adults. Finally, Christiansen et al.,11 who analyzed 140 treatment-related myelodysplastic syndromes and AML, found three t-AML with a BRAF mutation; all these were adult acute monoblastic leukemias with t(9;11)(p21;q23). Interestingly, germ line mutations in the closely related RAF1 (previously CRAF) were recently reported in two patients who developed t-AML.8 Hence, there may be an association between mutations in RAF genes and t-AML. It may also be noteworthy that among the 17 BRAF-positive hematologic malignancies reported to date,1, 9, 10, 11 only four (24%)—one T-cell ALL1 and three t-AML11—have carried the highly activating V600E amino-acid substitution, which results in a 500-fold activation of the BRAF protein, inducing a pronounced RAS-RAF-MEK-ERK signaling.3

Reduced-Intensity Conditioning followed by Allogeneic Hematopoietic Cell Transplantation for Adult Patients with Myelodysplastic Syndrome and Myeloproliferative Disorders

Allogeneic hematopoietic cell transplantation (HCT) is the only curative strategy for patients with myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPD). We report the results of 148 patients (median age = 59 years old) with de novo MDS (n = 40), acute myelogenous leukemia (AML) after antecedent MDS/MPD (n = 49), treatment-related MDS (t-MDS) (n = 25), MPD (n = 27), and chronic myelomonocytic leukemia (CMML) (n = 7) who underwent allogeneic HCT using a conditioning regimen of low-dose total body irradiation (TBI) alone (200 cGy) on day 0 (n = 5) or with the addition of fludarabine (Flu) 30 mg/m 2/day on days −4 to −2 (n = 143). Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil (MMF). Seventy-five patients (51%) received an allograft from a matched related donor (MRD), and 73 patients (49%) were recipients of unrelated donor (URD) grafts. There was no significant difference in the incidence of acute (gr II-IV) and chronic extensive graft-versus-host disease (aGVHD, cGVHD) between the recipients of related and unrelated donor grafts. By day +28, 75% of patients demonstrated mixed T cell chimerism. Graft rejection was seen in 15% of patients. With a median follow-up of 47 (range: 6-89) months, the 3-year relapse-free survival (RFS) and overall survival (OS) are both 27% for all patients, with a relapse incidence of 41%. The 3-year RFS for the patients with de novo MDS, AML after antecedent MDS/MPD, t-MDS, MPD, and CMML were 22%, 20%, 29%, 37%, and 43%, respectively, and the 3-year OS was 20%, 23%, 27%, 43%, and 43%, respectively. The 3-year nonrelapse mortality (NRM) was 32%. Factors associated with a lower risk of relapse were the development of extensive cGVHD and having a low risk or intermediate-1 risk International Prognostic Score for the de novo MDS patients. Nonmyeloablative HCT confers remissions in patients who otherwise were not eligible for conventional HCT but for whom relapse is the leading cause of treatment failure.

Amplification of BCR–ABL and t(3;21) in a patient with blast crisis of chronic myelogenous leukemia

The Philadelphia (Ph) chromosome, or t(9;22), is the hallmark of chronic myelogenous leukemia (CML). It results in juxtaposition of the 5′ part of the BCR gene on chromosome 22 to the 3′ part of the ABL1 gene (previously ABL) on chromosome 9. CML is clinically characterized by three distinct phases: chronic, accelerated, and blast phase. Blast crisis is characterized by the rapid expansion of a population of differentiation arrested blast cells (myeloid or lymphoid cells population), with secondary chromosomal abnormalities present. We report a case of myeloid blast crisis of CML resistant to imatinib mesylate and chemotherapy. By use of cytogenetic, fluorescence in situ hybridization, and comparative genomic hybridization methods, we identified a cluster of BCR–ABL amplification on inverted duplication of the Ph chromosome with t(3;21)(q26;q22) and increased genomic levels of the RUNX1 gene (previously AML1). The t(3;21)(q26;q22) is a recurrent chromosomal abnormality in some cases of CML blast phase and in treatment-related myelodysplastic syndrome and acute myeloid leukemia. Amplification or copy number increase of RUNX1 has been reported in childhood acute lymphoblastic leukemia. Our study indicated that the progenitor of CML was BCR–ABL dependent through the amplification of Ph chromosome as a mechanism of resistance to imatinib therapy. The coexistence of BCR–ABL and t(3;21)(q26;q22) with RUNX1 rearrangement might play a pivotal role in the CML blast transformation.

Toxicity and outcome of children with treatment related acute myeloid leukemia

The aim of this study was to evaluate the clinical course and outcome of children with treatment related acute myeloid leukemia (tAML) and compare them to children with primary AML (pAML). We retrospectively reviewed the demographic, treatment, toxicity, and outcome data of children with tAML and treatment related myelodysplastic syndrome (tMDS), treated at our institution between 1975 and 2005. We compared these parameters with matched controlled children with pAML. Finally we compared overall survival (OS) for tAML with all pAML children treated at the study era in our institution. Twenty-one patients with tAML (n = 19) and tMDS (n = 2) were identified. Three years event-free survival (EFS) and OS were both 14 +/- 8%. Compared to pAML patients, tAML had a higher rate of adverse cytogenetics (P < 0.008) and inferior OS (P = 0.027) but no significant difference in treatment toxicity or death. All survivors were treated with allogeneic hematopoietic stem cell transplantation (HSCT). In this population based report of pediatric tAML, outcome was poor and was related to a higher probability of poor cytogenetic features rather than excessive toxicities or inability to deliver therapy. HSCT should be considered for patients with tAML. These preliminary findings should set the stage for prospective cooperative studies.

Immunosuppression for Patients with Low and Intermediate Risk Myelodysplastic Syndrome: A Prospective Randomized Multicenter Trial Comparing Antithymocyte Globulin + Cyclosporine with Best Supportive Care: SAKK 33/99.

Immunosuppressive treatment has been reported to improve cytopenia in some patients with myelodysplastic syndrome (MDS). The combined use of anti-thymocyte globulin (ATG) and cyclosporine (CSA) has been shown to be most effective in patients with immune mediated marrow failure. This trial was designed to assess the impact of immunosuppression on hematopoiesis, transfusion requirements, transformation and survival in MDS. 88 transfusion dependent patients were randomized to receive ATG+CSA (15mg/kg of horse ATG (Lymphoglobuline, Genzyme) for 5 days and oral CSA for 180 days) or best supportive care (BSC), stratified by treatment center and IPSS risk score between 2001 and 2006. The primary endpoint was best response at 6 months. Patients in the BSC arm crossed-over to ATG+CSA after 6 months or earlier in the event of progression: Eligible patients had an ECOG performance status ≤ 2 along with a transfusion dependency of < 2 years duration. Patients with MDS types CMMoL and RAEBt or treatment related MDS were not included in the trial. Statistical analyses consisted of comparisons of response rates and durations between treatment arms and time-to-event analyses including overall-survival (read as time from randomization to all-cause mortality) and transformation-free survival (event defined as death, transformation to higher grade MDS or leukaemia). Also evaluated was medical resource utilization and hematological and non-hematological toxicities.table 1ATG+CSABSCPatients: n4543Age: median years (range)62 (23–75)65 (24–76)Sex: n male (%)25 (56)35 (81)IPSS score: n (low/int-1/int-2/high/na)(8/24/7/1/4)(8/25/5/0/5)MDS type: n (RA/RAS/RAEB-I/RAEB-II/hypoplastic)(21/6/9/0/9)(18/8/11/2/4)Five patients in the ATG+CSA arm did not receive treatment for various reasons whilst 13 patients in the BSC arm crossed-over on to ATG+CSA treatment. At 6 months there were 13 patients with a hematologic response (CR + PR) vs. 29 without in the ATG+CSA arm, compared to 5 with vs. 35 without in the BSC arm (p = 0.04, adjusted for the interim analysis): For various reasons no information was available for the remaining 6 patients. Transformation-free survival probability estimates at 2 years were 42% (23–60%) for patients receiving ATG+CSA and 44% (25–62%) for patients receiving BSC (p-value: 0.50). In total 29 deaths occurred; 15/45 patients randomized to receiving ATG+CSA and 14/43 patients receiving BSC. Overall survival probability estimates at 2 years were 49% (28–66%) for patients receiving ATG+CSA and 61% (40–76%) for patients receiving BSC (p-value: 0.90). The vast majority of adverse events occurred early after randomization, with particularly high WHO hematological toxicity gradings in both treatment arms. There were 24 SAEs; 17 in the ATG+CSA arm and 7 in the BSC arm. Reported SAEs were heterogeneous and included the most common types of infectious and inflammatory complications.Conclusions: In this open label randomized phase III trial of patients with transfusion dependent low and intermediate risk MDS, treatment with ATG + CSA appears to be associated with hematologic response in a subset of patients without apparent impact on transformation-free- and overall- survival.

Prognostic Factors in Treatment-Related Myelodysplastic Syndromes (t-MDS) and Acute Myeloid Leukemia (t-AML).

In the current WHO classification patients (pts) with therapy-associated MDS are merged into a subgroup of AML, termed “AML with MDS, therapy-related”, regardless of dysplastic features, medullary blast count or cytogenetics. To validate the appropriateness of this approach, we combined the MDS/AML data sets of the Duesseldorf as well as the Goettingen data base. We identified 305 pts with t-MDS or t-AML. There were 138 males and 167 females, median age was 64 (22–90). When classified according to the WHO proposals for primary MDS (pMDS), 38% of the pts had AML (28% blast count >30%, 10% blast count 20–30% (RAEB-T)), 10% had RAEB II, 8% RAEB I, 2% CMML II, 3% CMML I, 6% RA, 1.5% RARS, 20% RCMD, 11% RCMD-RS and 0.5% had 5q- Syndrome. 60% of pts had received chemotherapy only, 12% radiotherapy, and 28% underwent combined radiochemotherapy prior to t-MDS/AML diagnosis. The median latency between treatment and diagnosis was 116 months in pts who received radiotherapy as compared to 81 months in pts treated with chemotherapy alone or in combination with radiation (p= 0.0005). Cytogenetics were available in 192 pts (63%). 58% had an abnormal karyotype, the median number of aberrant chromosomes was 2 (0–12). The most frequent aberrant chromosome was chromosome 5 (18%), followed by 7 (14%), 20 (7%) and 17 (7%). 48% of the pts had a low-risk, 18% an intermediate-risk, and 33% a high-risk karyotype according to IPSS. Median survival of the entire group was 10 months compared to 26 months in pMDS in our registry (p=0.00005). Important prognostic parameters for pMDS, like age, hemoglobin level, platelet count, neutrophile count, as well as classification and scoring systems (FAB, WHO, IPSS) could not show an impact on outcome in t-MDS/AML. Pts with <5% medullary blasts had a median survival of 16 months, with 5–9% of 8 months, with 10–19% of 8 months, with 20–29% of 6 months and pts with a blast count >30% had a median survival of 12months (p=n.s.). When we compared pts with a medullary blast count <5 vs ≥5 months the survival difference (15 vs 7 months) became significant (p=0,013). Pts with an elevated LDH level had a median survival of 7 as compared to 17 months in pts with normal LDH (p=0.0006). The karyotype subgroups (IPSS) showed significant survival differences between each of the groups: low-risk -34 months, intermediate-risk -25 months, high-risk -8 months. In a multivariate analysis only karyotype (p=0,011) and LDH level (p=0,014) remained independent prognostic parameters (blast count: p=0,961). These two variables can be combined in a score: LDH elevated= 1 point, high-risk karyotype= 1 point. This score leads to 3 subgroups (0, 1, or 2 points) with a significantly different prognosis of 42, 15, and 7 months (p=0,01). Our analysis shows that there is no substantial difference in survival between t-MDS and t-AML, justifying the combination of both entities in one AML subgroup. Current morphology based classification systems offer no prognostic information. On the other hand the established karyotype classification according to IPSS remains relevant for prognosis and combining this information with the LDH level leads to a simple score that is able to separate prognostically different risk-groups and thus should be validated further. 0%

Pediatric Myelodysplastic Syndrome and Juvenile Myelomonocytic Leukemia in Korea: A Nation-Wide, Multicenter, Retrospective Study.

Recent advances in the diagnosis, molecular pathogenesis, classification and therapy have been made in the field of myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) in childhood. We report a retrospective analysis of children with MDS and JMML diagnosed between 2001 and 2006 in Korea. In total, 135 patients were enrolled from 19 major hospitals with pediatric hematology oncology clinics: MDS, 96 (primary MDS, 77; constitutional anomalies with MDS, 13; treatment-related MDS, 6) and JMML, 39. The incidence of MDS/JMML was around 22.5/year, which is about 6% of childhood leukemia. Various classification systems including FAB, WHO, IPSS, CCC system, and pediatric adjustment of the WHO classification were applied. The median ages at diagnosis were 68 and 10 months in MDS, and JMML, respectively. Males dominated in JMML. Cytogenetic abnormalities were observed in 43% of MDS (monosomy 7, 5; trisomy 8, 3) and in 10% of JMML. Treatment was chosen by each institute's preference: 34 patients with MDS received AML-type intensive chemotherapy, with complete remission rate of 82.0%. The 5-year Kaplan-Meier overall survival rate was 54% each for MDS and JMML. Survival of MDS patients was influenced by the marrow blast % (P = 0.007) and disease category (P= 0.006). Stem cell transplantations (SCT) were undertaken in 56 patients (MDS, 29; JMML, 27). The sources of stem cells were: bone marrow, 36; umbilical cord, 18; peripheral blood, 2). Matched related transplants were 9 cases. Conditioning was various, but BuCy based regimen was used in 68.4%. Acute GvHD ≥ Grade II was found in 43.8% and chronic GvHD in 35.1%. The 5-year Kaplan-Meier overall survival rate was 55% for MDS, and 57% for JMML. Survival after unrelated transplant was comparable with that of matched related transplants. This analysis inspired the necessity of nation-wide prospective studies in Korea, including morphologic study by a central pathology review board, epidemiologic study, molecular pathophysiologic study, and therapeutic trials incorporating SCTs, or new drugs.

Treatment-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Patients Treated With Ibritumomab Tiuxetan Radioimmunotherapy

To investigate the incidence of treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) after treatment with ibritumomab tiuxetan radioimmunotherapy. Analysis of the incidence of t-MDS and t-AML in 746 patients with non-Hodgkin's lymphoma (NHL) treated with the ibritumomab tiuxetan regimen in registration and compassionate-use trials between 1996 and 2002. Nineteen patients (2.5%) developed t-MDS or t-AML at a median follow-up of 4.4 years (range, 0 to 9.3). These malignancies were diagnosed at a median of 5.6 years (range, 1.4 to 13.9) after the diagnosis of NHL and 1.9 years (range, 0.4 to 6.3) after radioimmunotherapy. The annualized rates were 0.3% per year after the diagnosis of NHL and 0.7% per year after treatment. Most patients with t-MDS or t-AML had multiple cytogenetic aberrations, commonly on chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. Analysis of data from patients in registration and compassionate-use trials suggests that the annualized incidences of t-MDS and t-AML are consistent with that expected in patients with NHL who have had extensive previous chemotherapy treatment and do not appear to be increased after treatment with the ibritumomab tiuxetan regimen. Cytogenetic testing before treatment with radioimmunotherapy may identify existing chromosomal abnormalities in previously treated patients, particularly those who have been treated with alkylating agents and purine nucleoside analogs and would be at higher risk for t-MDS or t-AML.

Autologous stem cell transplantation for therapy-related acute myeloid leukemia and myelodysplastic syndrome

We report the results of 65 patients with treatment-related myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) who were transplanted from an autograft and reported to the EBMT. The median age was 39 years (range, 3-69), and stem cell source was bone marrow (n = 31), or peripheral blood progenitor cells (n = 30), or the combination of both (n = 4). The primary disease was solid tumors (n = 37), Hodgkin's disease (n = 13), non-Hodgkin's lymphoma (n = 10), acute lymphoblastic leukemia (n = 2) or myeloproliferative syndromes (n = 3). The types of MDS were as follows: RAEB (n = 1; 2%), RAEB-t (n = 3; 5%), or AML (n = 56; 87%). The median time between diagnosis and transplantation was 5 months (range, 3-86). The Kaplan-Meier estimates of the probability of 3-year overall and disease-free survival were 35% (95% CI: 21-49%) and 32% (95% CI: 18-45%), respectively. The median leukocyte engraftment was faster after transplantation with peripheral blood stem cells than with bone marrow: 12 (range, 9-26) vs 29 (range, 11-67) days (P<0.001). The cumulative incidence of relapse was 58% (95% CI: 44-72%) and of treatment-related mortality 12% (95% CI: 6-38%). Lower relapse rate was seen in patients transplanted in first complete remission (CR1 vs non-CR1: 3 years: 48 vs 89%; P = 0.05). Furthermore, age beyond 40 years resulted in a higher treatment-related mortality (47 vs 7%; P = 0.01). In a multivariate analysis, transplantation in CR1 age as well as their interaction influenced overall survival significantly. Autologous transplantation may cure a substantial number of patients with treatment-related MDS/AML, especially if they are in CR1 and of younger age.

Myelodysplastic syndromes: the complexity of stem-cell diseases

The prevalence of patients with myelodysplastic syndromes (MDS) is increasing owing to an ageing population and increased awareness of these diseases. MDS represent many different conditions, not just a single disease, that are grouped together by several clinical characteristics. A striking feature of MDS is genetic instability, and a large proportion of cases result in acute myeloid leukaemia (AML). We Review three emerging principles of MDS biology: stem-cell dysfunction and the overlap with AML, genetic instability and the deregulation of apoptosis, in the context of inherited bone marrow-failure syndromes, and treatment-related MDS and AML.

Reduced Intensity Conditioning (RIC) with FLU-BU-ATG and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Pediatric Malignancies.

RIC regimens are increasingly used for the treatment of adults with malignancies, relying predominantly on graft-vs-tumor cellular therapy. RIC reduces the risk for regimen related morbidity (RRM) and mortality in adults. Pediatric experience with RIC protocols has been limited despite the potential benefit for reduced long-term morbidity. We report the experience of 35 RIC HSCT for malignancies in pediatric patients (pts), 31 were at very high-risk for complications of full-intensity conditioning due to disease state, prior HSCT (7 allo, 8 auto) and/or co-morbid medical conditions. The RIC regimen was comprised of fludarabine, 30 mg/m2 for 6 consecutive days (days -10 through -5), followed by intravenous busulfan (days -5 and -4), 0.8 - 1 mg/kg for 8 doses (n=15) or targeted AUC 4000 microMol*min for 2 doses (n=20) and ATG days -4 through -1, (equine 40 mg/kg/d or rabbit, 2 mg/kg/d). RIC was followed by allogeneic HSCT. Diagnoses included: recurrent ALL (15, ≥CR3 in 8), AML (5, refractory in 4), refractory neuroblastoma (5), recurrent Non-Hodgkin’s Lymphoma (4), CML (3) or treatment-related myelodysplastic syndrome (3). There were 21 males, 14 females, ages 2 to 17 yrs, median 9.14. Stem cell sources included 22 unrelated donors (URD), 11 matched sibs and 2 mis-matched relatives. 31 of 35 stem cell donations were G-CSF mobilized peripheral blood. The median cell doses infused were 5.05 × 108 MNC/kg and 4.6 × 106 CD34+ cells/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CsA) alone in the first 12 pts, CsA and mycophenolate mofetil (MMF) in the subsequent 23 pts. Significant (&gt;80%) donor chimerism was achieved in 32 pts with a median time to reach an ANC &gt;500/μl of 18 days (range 9–62). Three pts with URD failed to engraft and another 3 had graft loss. An unsupported platelet count &gt; 20,000/μl was achieved in 29 of 35 pts at a median of 15 days (7–228). Six pts developed Gr III–IV acute GVHD, 7 of the 25 pts surviving more than 100 days developed chronic GVHD (4 limited, 3 extensive). Since addition of MMF, only one pt developed chronic GVHD (limited). While there was no immediate RRM, 10 pts (8 URD, 4 prior HSCT) died of infection (4), infection + GVHD (3), GVHD (2) or veno-occlusive disease after a subsequent HSCT (day + 146 post RIC HSCT). Infections included 4 probable fungal, 2 viral and one bacterial infection. Sixteen pts have relapsed from 25 to 427 days post HSCT for an event-free-survival of 22%. Because RIC HSCT creates a platform for cellular immuno-therapy, early post-HSCT relapse or persistent disease was treated by withdrawal of GVHD prophylaxis (n= 11) and/or donor leukocyte infusions (n=3). 4 pts responded to immune modulation and 3 remain in remission. Thus, the projected three-year overall survival in this very high-risk group of pts is 44%. Our results indicate RIC allogeneic HSCT has a role for pediatric pts at high-risk for complications after conventional HSCT.

Analysis of the Incidence of Treatment-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Registration and Compassionate-Use Trials of Ibritumomab Tiuxetan Radioimmunotherapy (RIT).

Radioimmunotherapy (RIT) is a therapeutic modality indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed non-Hodgkin's lymphoma (NHL), where the mechanism of action involves the intrinsic activity of the monoclonal antibody and the cytotoxic effects of radiation. The primary toxicity is a late-occurring, transient, and reversible myelosuppression. Because of concerns regarding the long-term effects of radiation on the bone marrow, we investigated the incidence of treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) after ibritumomab tiuxetan RIT. A total of 746 patients with NHL were treated with the ibritumomab tiuxetan regimen in registration and compassionate-use trials between 1996 and 2002. Patients had a median age of 61 years (range, 24–87) and had received a median of 3 prior therapies (range, 0–9+). The crude incidence of t-MDS or t-AML was 2.3% (17/746), with an incidence of 4.7% (10/211) in patients enrolled in registration trials and of only 1.3% (7/535) in patients included in the compassionate-use trial, with a median follow-up of 5.7 and 3.5 years, respectively. These malignancies were documented at a median of 5.6 years (range, 1.2–13.9) after the diagnosis of NHL and 1.5 years (range, 0.1–5.8) after RIT. The annualized rates were 0.3% (95% CI, 0.2%–0.4%) a year after the diagnosis of NHL and 0.7% (95% CI, 0.4%–1.0%) a year after RIT. Cox multivariate regression analysis found that previous treatment with a purine nucleoside analog was a significant risk factor for t-MDS or t-AML (hazard ratio, 3.9 [95% CI, 1.5–10.4]; P = .006). All patients in whom t-MDS or t-AML developed and in whom cytogenetic data were available (n = 15) had multiple cytogenetic aberrations, commonly of chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. There were documented bone marrow cytogenetic abnormalities before treatment in 2 patients who developed t-MDS or t-AML. These data suggest that the annualized incidence of t-MDS or t-AML following ibritumomab tiuxetan RIT is consistent with that expected on the basis of the patients' history of treatment for NHL. Cytogenetic testing before administration of RIT may identify existing chromosomal abnormalities in previously treated patients, particularly in those who have been treated with alkylating agents and/or purine nucleoside analogs and who are thereby at a higher risk for t-MDS or t-AML.

Treatment-related Myelodysplastic Syndrome After Chemotherapy for Childhood Low-grade Astrocytoma

Treatment-related Myelodysplastic Syndrome After Chemotherapy for Childhood Low-grade Astrocytoma

Risk Factors Before Autologous Stem-Cell Transplantation for Lymphoma Predict for Secondary Myelodysplasia and Acute Myelogenous Leukemia

The risk factors for treatment-related myelodysplastic syndrome (t-MDS) and acute myelogenous leukemia (AML) after autologous stem-cell transplantation (ASCT) are similar to those that increase the risk of difficult stem-cell harvests. We reviewed our experience in 526 patients with lymphoma treated by ASCT to determine whether difficult stem-cell harvests predict for an increased risk of t-MDS/AML. Autologous peripheral stem cells were initially mobilized with granulocyte colony-stimulating factor (G-CSF; or granulocyte-macrophage colony-stimulating factor) alone (n = 334), etoposide and G-CSF (n = 166), or cyclophosphamide and G-CSF with or without etoposide (n = 26). Difficult harvests were those that required more than 5 days to collect enough stem cells and those that required additional attempts with etoposide and/or cyclophosphamide plus G-CSF (n = 52). All patients were then treated with high-dose chemotherapy alone and observed for outcome. With a median follow-up time for surviving patients of 69 months, 20 patients developed t-MDS/AML, for an actuarial incidence of 6.8% at 10 years. Pretransplantation characteristics, including age, diagnosis of non-Hodgkin's lymphoma or Hodgkin's disease, bone marrow involvement, prior radiation therapy, prior exposure to chemotherapy, lactate dehydrogenase at the time of ASCT, disease status, and method of stem-cell mobilization, were then analyzed with respect to the subsequent development of t-MDS/AML. By multivariable analysis, prior exposure to radiation therapy, four or more chemotherapy regimens, and more than 5 days of apheresis needed to harvest enough stem cells were identified as independent risk factors for t-MDS/AML. Bootstrap analysis confirmed these results. These results suggest that identifiable pretransplantation factors predict for t-MDS/AML after ASCT.