Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group.

PURPOSE: An increased risk of therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) after high-dose therapy and autologous stem-cell transplantation (ASCT) for malignant lymphoma has been described by several studies, reporting a highly variable incidence ranging from 1% to 12%. To assess this risk more precisely, the German Low Grade Lymphoma Study Group investigated the incidence of t-MDS/t-AML after ASCT on the basis of a randomized comparison of ASCT versus interferon alfa (IFN-alpha) maintenance in indolent lymphoma. PATIENTS AND METHODS: Between 1996 and 2002, 440 patients with indolent lymphoma were randomly assigned after a cyclophosphamide, doxorubicin, vincristine, and prednisone-like induction therapy regimen to myeloablative radiochemotherapy followed by ASCT or IFN-alpha. The incidence of secondary hematologic malignancies was determined by standardized follow-up of all study patients. Bone marrow samples from patients with proven or suspected t-MDS/t-AML were centrally reviewed. RESULTS: After a median follow-up of 44 months, 431 patients were assessable. Five of 195 patients developed a secondary hematologic malignancy after ASCT. Two of these patients developed a secondary AML. Accordingly, the estimated 5-year risk for secondary hematologic neoplasias after ASCT was 3.8%. In contrast, in the IFN-alpha arm, the 5-year risk of hematologic neoplasias was 0.0% (P = .0248). CONCLUSION: The data of this randomized trial demonstrate an increased risk of secondary hematologic malignancies after myeloablative radiochemotherapy and ASCT compared with conventional chemotherapy. However, as ASCT significantly improves progression-free survival, it is currently not evident to what extent the higher rate of t-MDS/t-AML will diminish the benefit of ASCT in indolent lymphoma.     

ASH 2012: allogeneic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is a developing treatment modality, continuously being adapted to disease-specific requirements, and, even more successfully, to the tolerability in a growing target population. Allogeneic HSCT, in particular, is now accessible as a curative treatment for patients that would have been allocated to palliative concepts 1 or 2 decades ago. However, modern pharmacotherapy of neoplastic diseases is advancing, taking advantage of the increasing insight into cancer biology. Therefore, the role of HSCT in the treatment of hematologic malignancies has to be defined and reconsidered in a continuous fashion. At the ASH Meeting 2012, nearly 900 abstracts covered the field of allogeneic HSCT. The short list of abstracts reviewed here was selected according to the authors’ perception of a particular clinical impact. It is aimed to cover the most relevant issues an HSCT-physician is faced with in clinical practice in 2013, namely the management of the elderly patient (typically with acute myeloid leukemia or myelodysplastic syndromes), the limitations regarding access to a suitable donor, and the management of relapse and the most important cause of nonrelapse mortality, graft versus host disease, after allogeneic HSCT.     

Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011.

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin's lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication. PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML. RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P =.007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months). CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.     

Therapy-related myelodysplastic syndrome with der(17)t(12;17)(q13;p13) as a new recurrent cytogenetic abnormality after treatment for chronic lymphocytic leukemia

A 54-year-old male presented to our hospital for evaluation of peripheral lymphocytosis. He was initially diagnosed with chronic lymphocytic leukemia (CLL) and treated with six cycles of fludarabine, cyclophosphamide, and rituximab chemotherapy. Therapy-related myelodysplastic syndrome (t-MDS) was suspected approximately 2 years later; in addition, complex karyotypic abnormalities including 5q deletion, monosomy 7, and der(17)t(12;17)(q13;p13) were found repeatedly in the patient's chromosome studies. The chromosomal abnormality der(17)t(12;17)(q13;p13) is very rare in hematologic malignancies, and has been reported in only two patients with therapy-related acute myeloid leukemia (t-AML). To our knowledge, this is the first report of t-MDS with der(17)t(12;17)(q13;p13) after treatment for CLL. In addition, we suggest that der(17)t(12;17)(q13;p13) should be considered a new recurrent, nonrandom chromosomal abnormality in patients with t-MDS/AML.     

Hematopoietic stem cell transplantation for myelodysplastic syndrome: a review

Allogeneic hematopoietic stem cell transplantation (HSCT) continues to be the only curative option for myelodysplastic syndrome (MDS). Since the majority of the patients with this disease are often older and frail, treatment-related mortality and morbidity remain major obstacles to be overcome. Reduced-intensity conditioning and continued lines of investigation in the field of allogeneic transplantation are expected to ultimately improve the overall therapeutic approach to MDS. In this review we summarize current recommendations and controversies surrounding HSCT for MDS, as well as the use of novel therapeutics in the peri-transplant period.     

Therapy-related Myelodysplastic Syndrome (t-MDS) in a Patient with Anaplastic Astrocytoma: Successful Treatment with Allogeneic Bone Marrow Transplant

Objective and importance Therapy-related myelodysplastic syndrome (t-MDS) is a rare and typically fatal complication of therapy for cancer, including brain tumors. We report successful therapy of t-MDS that developed after treatment for an anaplastic astrocytoma. Clinical presentation t-MDS developed four and one-half years after successful therapy (resection, radiation and chemotherapy) administered for a cerebral anaplastic astrocytoma in a 34-year-old patient. Intervention The patient was treated with allogeneic bone marrow transplant (BMT) for t-MDS. Conclusion She is alive three years after BMT with no evidence of brain tumor and in complete remission from t-MDS. To our knowledge, this is the first report of allogeneic BMT administered for t-MDS in an adult brain tumor patient. Clinicians must be alert to the development of t-MDS following chemotherapy for brain tumors and initiate appropriate treatment promptly.     

Therapy-related myelodysplastic syndrome in childhood: a retrospective study of 36 patients in Japan

We report here a retrospective analysis of 36 children with therapy-related myelodysplastic syndrome (t-MDS) diagnosed between 1990 and 1999 in Japan. Their median age was 7.7 years and the median latency period for the development of t-MDS was 38.5 months. The primary tumors were hematologic in 15 of the cases and nonhematologic in 21. Chromosomal abnormalities were detected in 32/34(94%) patients: abnormalities of chromosomes 5and/or 7 in 41% and notably, 11q23 abnormalities in 31%. The prognosis of children with t-MDS was very poor as compared to children with primary MDS (5 year survival: 16% versus 54%, p<0.0001).     

A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome

BackgroundThe prognosis for patients with most forms of T-cell lymphoma is poor. Allogeneic hematopoietic stem-cell transplantation (HSCT) may improve the outcome.Patients and methodsThis study examines the outcome of 52 patients who underwent ablative or nonablative allogeneic HSCT for peripheral T-cell lymphoma (PTCL) or advanced mycosis fungoides/Sezary syndrome over a 12-year period at a single institution. We divided the patients into those with predominantly nodal histologies: peripheral T-cell not otherwise specified (PTCL NOS), angioimmunoblastic (AITL), or anaplastic large cell lymphoma, T/null type (systemic) (ALCL), and predominantly extranodal histologies: natural killer (NK)/T cell, enteropathy type, hepatosplenic, subcutaneous panniculitic, mycosis fungoides, or T cell or NK cell other.ResultsMedian follow-up of survivors is 49 months. Non-relapse mortality and relapse at 3 years was 27% and 43%, respectively. The incidence of grade II–IV acute graft-versus-host disease (GVHD) was 21%. The incidence of extensive chronic GVHD at 2 years was 27%. The 3-year progression-free survival was 30%: 45% in patients with predominantly nodal histologies (PTCL NOS, AITL, and ALCL) and 6% in patients with predominantly extranodal histologies (P = 0.016). Overall survival at 3 years was 41% for all patients.ConclusionAllogeneic HSCT can produce long-term remissions in relapsed/refractory T-cell lymphoma, especially those with nodal histologies.     

Feasibility of allogeneic stem-cell transplantation after azacitidine bridge in higher-risk myelodysplastic syndromes and low blast count acute myeloid leukemia: results of the BMT-AZA prospective study

BackgroundAllogeneic stem-cell transplantation (HSCT) is the only curative treatment in myelodysplastic syndromes (MDS). Azacitidine (AZA) is increasingly used prior to HSCT, however in Europe it is only approved for patients who are not eligible for HSCT.Patients and methodsWe conducted a phase II multicenter study to prospectively evaluate the feasibility of HSCT after treatment with AZA in 70 patients with a myelodysplastic syndrome (MDS), 19 with acute myeloid leukemia (AML), and 8 with chronic myelomonocytic leukemia (CMML). After a median of four cycles (range 1–11): 24% of patients achieved complete remission, 14% partial remission, 8% hematologic improvement, 32% had stable and 22% progressive disease. Ten patients discontinued treatment before the planned four cycles, due to an adverse event in nine cases.ResultsA HSC donor was identified in 73 patients, and HSCT was performed in 54 patients (74% of patients with a donor). Main reasons for turning down HSCT were lack of a donor, an adverse event, or progressive disease (9, 12, and 16 patients, respectively). At a median follow-up of 20.5 months from enrolment, response to AZA was the only independent prognostic factor for survival. Compared to baseline assessment, AZA treatment did not affect patients’ comorbidities at HSCT: the HCT-CI remained stable in 62% patients, and worsened or improved in 23% and 15% of patients, respectively.ConclusionsOur study shows that HSCT is feasible in the majority of patients with HR-MDS/AML/CMML-2 after AZA treatment. As matched unrelated donor was the most frequent source of donor cells, the time between diagnosis and HSCT needed for donor search could be ‘bridged’ using azacitidine. These data show that AZA prior to HSCT could be a better option than intensive chemotherapy in higher-risk MDS.The trial has been registered with the EudraCT number 2010-019673-1.     

Monoclonal antibodies for lymphomas and leukemias in 2005

Advances in the development of monoclonal antibody (MAb) have proven major benefice in the treatment of hematologic malignancies. Phase II studies showed similar results than classical chemotherapy in refractory or relapsed patients, with less toxicity in heavily pre-treated population. Moreover, MAb enhanced sensitivity to chemotherapy. Combined treatments resulted in an increase of global response and complete remission in non previously pre-treated patients with follicular lymphoma, diffuse large cell lymphoma and chronic lymphocytic leukemia. Recently, the association of anti-CD20 and 131Iode was shown to be efficient in follicular lymphomas. The benefits of MAb is less clear in myeloid malignancies. The role of MAb in the treatment of myelodysplastic syndrome remains uncertain although the use of anti-CD33 in acute myeloid leukemias is promising. The aim of this review is to present an updated overview of the most used MAb in the treatment of leukemias and lymphomas not involving bone marrow transplantation.     

Treatment-related myelodysplastic syndrome/acute myeloid leukemia in survivors of childhood cancer--an update

Treatment-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/t-AML) is a devastating complication of treatment for childhood cancer. However, the major cause of premature death of children treated for cancer remains their primary cancer. The understanding of the presentation, incidence, predisposing risk factors and pathobiology of t-MDS/t-AML is increasing. This increased understanding has not yet been translated into improved outcomes of therapy for t-MDS/t-AML. However, newer approaches are under study.     

Allogeneic hematopoietic stem cell transplantation following reduced‐intensity conditioning for mycosis fungoides and Sezary syndrome

Advanced‐stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced‐intensity conditioning (RIC) regimen, is a promising treatment for advanced‐stage MF/SS. We performed RIC‐HSCT in nine patients with advanced MF/SS. With a median follow‐up period of 954 days after HSCT, the estimated 3‐year overall survival was 85.7% (95% confidence interval, 33.4–97.9%) with no non‐relapse mortality. Five patients relapsed after RIC‐HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft‐versus‐lymphoma effect and ‘down‐staging’ effect from advanced stage to early stage by HSCT improve the prognosis of advanced‐stage MF/SS. These results suggest that RIC‐HSCT is an effective treatment for advanced MF/SS. Copyright © 2014 John Wiley & Sons, Ltd.     

Allogeneic stem cell transplantation for myelodysplastic syndromes: critical for cure?

Allogeneic stem cell transplantation (SCT) is the treatment of choice for young patients (age ≤ 55 years) with myelodysplastic syndromes (MDS) characterized by poor-risk or intermediate-risk cytogenetics, who have a histocompatible related or unrelated donor. For patients who lack an human leukocyte antigen-compatible donor, autologous SCT, or chemotherapy may be good alternatives for those with MDS and with good-risk cytogenetic characteristics. Iron toxicity is an underestimated cause of hematopoietic stem cell transplantation (HSCT) treatment-related mortality. The pathogenesis, diagnosis, and monitoring of iron-induced organ damage are currently topics of investigation. Prospective studies on the prevention or treatment of iron toxicity before HSCT and/or after HSCT are necessary.     

供体来源嵌合抗原受体T细胞治疗血液系统恶性肿瘤移植后复发的研究进展

异基因造血干细胞移植(allo-HSCT)是治疗血液系统恶性肿瘤的重要手段,而移植后复发是allo-HSCT主要的并发症,也是目前患者移植后总生存(OS)率降低的主要原因.嵌合抗原受体T细胞(CAR-T)免疫疗法是一种疗效显著的针对恶性血液系统肿瘤的新兴治疗方法,而且随着研究的进展,CAR-T的安全性和有效性也在不断提高.研究发现移植后复发患者通过供体来源的CAR-T能够显著提高OS率,控制疾病的复发和进展.现综述近年来将供体来源CAR-T用于allo-HSCT后患者治疗的相关研究,并总结该治疗方法存在的问题及解决措施.     

Treatment-related myelodysplasia in patients with primary brain tumors

Treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) represent rare secondary events in patients with primary tumors of the nervous system and predominantly affect those treated with alkylating agents or topoisomerase II inhibitors. Temozolomide has become the standard chemotherapeutic agent for malignant gliomas. The emergence of this alkylating agent with little acute toxicity or cumulative myelosuppression has led to off-label protracted chemotherapy for many patients with malignant and even low-grade infiltrative gliomas, raising concern for increased risk of t-MDS/t-AML in the few long-term survivors. On the basis of an extensive literature search, we provide a discussion of epidemiology, pathogenesis, clinical presentation, diagnosis, and therapy of these disorders. t-MDS/t-AML remain rare complications of chemotherapy in patients with primary brain tumors, and the vast majority of patients die of their primary neoplasm. Prospective randomized studies with long-term follow-up are required to accurately assess the risk of t-MDS/t-AML; however, unless survival in the most common gliomas substantially increases, t-MDS/t-AML incidence will likely remain low in this patient population.     

Therapy-related myelodysplastic syndrome and acute myeloid leukemia following treatment of acute myeloid leukemia: possible role of cytarabine

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) have been reported only rarely following treatment of AML. We report five patients treated for de novo AML who developed t-MDS/t-AML, all with chromosome 7 abnormalities, including -7, del(7)(q22q36) and del(7)(p11.22p22). All had been treated with cytarabine, topoisomerase 2 inhibitors and granulocyte or granulocyte-monocyte colony-stimulating factor and three with alkylating agents as part of autologous transplant regimens. These cases further document t-MDS/t-AML as a complication of therapy for AML. Presence of chromosome 7 abnormalities in patients with and without prior alkylating agent therapy suggests possible association with the antimetabolite cytarabine.     

Therapy-related acute myeloid leukemia in a primary pulmonary leiomyosarcoma patient with skin metastasis

Primary pulmonary leiomyosarcoma (LMS) is a very unusual tumor.Although LMS has well-known metastatic potential,cutaneous metastasis is a remarkably uncommon.Exposure to cytotoxic agents could lead to "therapy-related myeloid neoplasm" (t-MN).Starting from 2008,the World Health Organization (WHO) has adopted the term to cover the spectrum of malignant diseases previously known as therapy-related acute myeloid leukemia (t-AML),therapy-related myelodysplastic syndrome (t-MDS) and therapy-related myelodysplastic/myelo-proliferative neoplasm (t-MDS/MPN).We described the onset of t-MDS and progression to t-AML in one case diagnosed as primary pulmonary LMS with cutaneous metastasis.This patient achieved complete remission (CR) after three courses of IA regimen chemotherapy (idarubicin 5 mg/d,d 1-3;cytarabine 100 mg/d,d 1-5) and 1 course of HA chemotherapy regimen (homoharringtonine 3 mg/d,d 1-3;cytarabine 100 mg/d,d 1-7).This case presents the natural course of therapy-related neoplasm and provides therapeutic experience for t-AML.     

Secondary hematological malignancies after breast cancer chemotherapy

According to several reports, the 10 year incidence of secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after systemic chemotherapy is approximately 1.5%. The cumulative risk increases by 0.25 - 1% for the first 8 years after treatment. We have reported only 6 cases of hematological malignancies (0.3%) after breast cancer chemotherapy in our institute. We detected 2 cases of secondary AML and 1 case of MDS, 19, 52 and 12 months, respectively, after systemic chemotherapy for breast cancer. Published data on the occurrence of secondary hematological malignancies other than AML or MDS in this setting are scarce. We encountered diffuse large B-cell lymphoma, angioimmunoblastic lymphoma and mantle cell lymphoma as secondary hematological malignancies after systemic chemotherapy for breast cancer.