A historical series suggested that the median survival of a patient who relapses after HD-ASCT is only 3 months, and although a few patients can enjoy durable remissions, the majority succumb to lymphoma very quickly after relapse.
Historically, the results of alloSCT have been disappointing, with high treatment-related mortality and limited disease control. The outcome of this large group of patients is very poor, with essentially no chance at prolonged control of disease. Attempts at conventional salvage regimens in this population of generally older patients do not result in disease control and have substantial morbidity. For this reason, in this population of patients, single-agent therapies, often in combination with rituximab, should be used.
Single-agent rituximab has modest, generally transient activity in this setting. Other well-tolerated agents include gemcitabine or components of salvage regimens such as high-dose cytarabine. Lenalidomide, an approved immunomodulatory agent for multiple myeloma and myelodysplastic syndromes, has significant single-agent activity in this setting.
Given these limited options, this group of patients should be referred for clinical trials. Numerous small molecule inhibitors detailed below , antibodies, and other approaches with minimal toxicity are under study.
The only way to definitively improve outcome and change the natural history for this large majority of patients with relapsed DLBCL is with the incorporation of novel agents and approaches. Several datasets based upon gene-expression analysis of both DLBCL and the corresponding microenvironment have increased our understanding of resistance and our ability to predict which patients may be refractory to standard treatment.
Even more exciting than enhanced prognosis, these analyses have revealed rational therapeutic targets. Several of these novel targeted agents are currently under study; a few examples are listed below. Inhibition of syk has demonstrated activity against a subset of DLBCL in vitro, 51 and this has been confirmed in a clinical trial. To exploit this concept, Dunleavy et al treated patients with relapsed DLBCL with bortezomib alone, followed by a combination of bortezomib and doxorubicin-containing chemotherapy.
Combinations of bortezomib, and other proteasome inhibitors with histone deacetylase inhibitors appear to have particular promise in the laboratory, and currently are in phase I trials. As mentioned, this subgroup appears to have the worst outcome.
Frequently, concomitant bcl-2 translocations are present in this elderly patient population. Although still in preclinical evaluation, there is great promise to specific bcl-6 inhibitors that can kill cell lines and primary DLBCLs from human patients in vitro. For the subset of patients eligible, ASCT should be pursued with the recognition that results in the rituximab-treated population are inferior to historical results.
Patients not eligible for ASCT should be referred for clinical trials. Ultimately, these novel agents may be incorporated as part of first-line therapy, where the impact on preventing relapse will hopefully lead to significantly improved OS for patients with DLBCL.
Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract. Diagnosis and evaluation of the patient with relapsed or refractory disease. Clinical approach to patients eligible for ASCT in the rituximab era. Selected novel approaches under study for relapsed DLBCL: targeted agents from gene-expression analysis.
Article Navigation. Friedberg Jonathan W. This Site. Google Scholar. Cite Icon Cite. Figure 1. View large Download PPT. Figure 2. Figure 3. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia.
Search ADS. Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.
Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Gene expression predicts overall survival in paraffin-embedded tissues of diffuse large B-cell lymphoma treated with R-CHOP. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E study.
Age-adjusted International Prognostic Index predicts autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma.
Conflict-of-interest disclosure: The author has consulted for Novartis. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract. Diagnosis of MF. Treatment is guided by risk stratification and the patient's clinical needs. Allogeneic SCT: cure for whom, when, and at what cost? Management of clinical needs for non-SCT candidates with conventional therapies.
Promises and pitfalls of novel therapies. Article Navigation. Current Issues in Myeloproliferative Neoplasms December 10, Management of Myelofibrosis Alessandro M. Vannucchi Alessandro M. This Site. Google Scholar. Cite Icon Cite. Table 1. Prognostic score systems for patients with PMF. View large. View Large. Table 2. Table 3.
Table 4. JAK2 inhibitors under clinical development in patients with MF. Table 5. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Search ADS. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the international working group for myelofibrosis research and treatment.
Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes. Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy. Survival and risk of leukemic transformation in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study of 1, patients. Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification.
New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. DIPSS Plus: A refined dynamic international prognostic scoring system for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.
Transfusion-dependency at presentation and its acquisition in the first year of diagnosis are both equally detrimental for survival in primary myelofibrosis—prognostic relevance is independent of IPSS or karyotype. Age and platelet count are IPSS-independent prognostic factors in young patients with primary myelofibrosis and complement IPSS in predicting very long or very short survival. Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of patients.
Low JAK2VF allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2VF mutated allele. Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival.
Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. Impact of JAK2VF-mutation status, allele burden and clearance after allogeneic stem cell transplantation for myelofibrosis. Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type.
Effects of extensive splenomegaly in patients with myelofibrosis undergoing a reduced intensity allogeneic stem cell transplantation. Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. International working group for myelofibrosis research and treatment response assessment and long-term follow-up of 50 myelofibrosis patients treated with thalidomide-prednisone based regimens.
Lenalidomide therapy in del 5 q31 -associated myelofibrosis: cytogenetic and JAK2VF molecular remissions. Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis.
Long-term analysis of the palliative benefit of 2-chlorodeoxyadenosine for myelofibrosis with myeloid metaplasia. Another novel formulation, CPX Celator Pharmaceuticals , fixes a ratio of cytarabine to daunorubicin within a liposomal carrier. The concept of targeting leukemic cells and sparing normal ones from the broad attack of chemotherapy is appealing but problematic, because there are many potential targets in AML cells and they may require simultaneous targeting.
These mutations are associated with a poor prognosis, especially when there is a high mutant to wild-type allelic ratio. It has also been used successfully as monotherapy before and after allogeneic stem cell transplantation in selected patients with FLT3 -mutated AML. Efforts to target leukemia stem cells and the BM microenvironment are discussed below. Allogeneic stem cell transplantation is probably still the most effective anti-AML therapy.
As the donor pool expands to include more unrelated donors and umbilical cords, and as treatment-associated morbidity and mortality rates decline with improvements in HLA matching, antimicrobial therapy, and management of GVHD, it is becoming increasingly feasible for more patients with AML to undergo the procedure.
It is critical that the transplantation workup be initiated at the time of initial diagnosis to allow adequate time for donor identification and other preparations. All AML patients with complex cytogenetics or monosomal karyotype who have a good performance status should be considered for allogeneic transplantation.
Pilot data suggest that proceeding with transplantation early in these patients, regardless of the outcome of induction, may be of benefit. For example, should positive assessments be repeated over a period of time before recommending intervention?
Should all patients with positive MRD be referred for allogeneic stem cell transplantation or chemotherapy salvage or a clinical trial? Clinical trials using MRD as a guide for therapy have shown improved outcomes in childhood AML, and similar trials are under development for adults.
Although technologic advances are making real-time identification of MRD more feasible and readily available, the subject of MRD and its clinical and scientific significance has been in the literature for decades.
A more difficult question, however, is whether these cells are, or arise from, so-called leukemia stem cells LSCs. Whereas the exact characteristics of LSCs remain controversial, most agree that they are defined by their ability to recapitulate disease when transplanted into immunodeficient mice.
A high frequency of LSCs at diagnosis is associated with a poor outcome in AML 61 and, similarly, high expression of an LSC gene signature has also been independently associated with inferior survival. LSCs have distinct characteristics, including aberrant surface immunophenotype; dysregulated programs for survival, apoptosis, and differentiation; and complex interactions with their surrounding BM microenvironment, the LSC niche.
Ara-C, which is arguably still the most active antileukemic drug, is notably ineffective against LSCs. A recurrent theme in most of oncology is the observation that it seems to take forever, or at least decades, for new drugs or treatment regimens to arrive in the clinic.
Several current strategies may facilitate this process in AML. In pediatric acute lymphoblastic leukemia, major improvements in outcomes have been achieved without the addition of novel agents, but rather via optimizing the combination, schedule, and duration of treatment using existing and decades-old drugs.
One intriguing proposal is to use the gene-expression signature generated from drugs that effectively ablate LSCs eg, parthenolide to search publicly available databases for other similar signatures. Increasing participation in clinical trials is urgent in AML because there is a growing realization that the traditional phase drug-development paradigm is ineffective in this disease.
Noncytotoxic, molecularly targeted agents do not have much chance for success in this setting, and signals of their true biologic efficacy may be missed. Many scientifically interesting and potentially useful agents seem to die early in development because they fail to demonstrate a signal of efficacy in the phase 1 setting. At least some of these agents should be considered instead in trials to prolong response duration and survival in AML patients who have already achieved remission.
Phase 2 trials in AML are often small and may give misleading efficacy signals. Given the heterogeneity of the disease, subgroup analyses based at least on age, performance status, cytogenetics, and molecular features are essential, yet these are meaningless when the total cohort includes only patients. Finally, phase 3 trials in AML are often unbearably slow and expensive to complete and, unfortunately, for the most part have resulted in only small improvements in outcome.
In addition, as the number of molecularly and clinically defined subgroups increases, it has become more and more difficult to determine a reasonable control arm for new phase 3 trials. This is especially true for older patients, for whom anything from hospice to stem cell transplantation might be a reasonable option. It is hoped that further refinements in the molecular characterization of AML will allow the identification of more homogeneous treatment groups and tailored therapeutics.
Off-label drug use: None disclosed. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract. Making old drugs new again. Older AML patients: when to lower the intensity. Novel and targeted agents. Extending the borders of allogeneic stem cell transplantation.
Eradicating MRD. Accelerating drug development: making clinical trials faster and better. Article Navigation. Roboz Gail J. This Site. Google Scholar. Cite Icon Cite.
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