Clinical Lymphoma and Myeloma最新文献

The successful introduction of the tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with chronic myeloid leukemia (CML). Imatinib therapy induces high rates of complete cytogenetic and major molecular responses, and improves survival in CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and over 80% achieve a complete cytogenetic response. With 7 years of follow-up, the results are still very favorable, resulting in a major change in the natural history of the disease. Resistance to imatinib represents a clinical challenge. Although some clinical and biologic features have been found to be associated with a lower probability of response to imatinib, at present no precise markers allowing for the prediction of outcome for individual patients exist. The most common mechanisms of resistance to imatinib include BCR-ABL kinase domain mutations, amplification, and overexpression of the BCR-ABL oncogene, and clonal evolution with activation of additional transformation pathways. These mechanisms are eventually caused by the genomic instability, which characterizes the Philadelphia chromosome–positive clone. Several approaches to overcome resistance have been proposed. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new therapeutic agents that might overcome this resistance. Novel targeted agents designed to overcome imatinib resistance include second-generation TKIs such as dasatinib, nilotinib, bosutinib, bafetinib, and others. Other approaches are exploring combination therapy, with agents affecting different oncogenic pathways, and immune modulation. Herein, we review some of these targeted therapies, particularly those for which clinical data are already available.

Coexistence of JAK2 mutation and BCR-ABL has been rarely described. We report 3 cases with the presence of 2 different clones, 1 Philadelphia chromosome positive and the other JAK2 mutated, becoming prevalent after treatment with tyrosine kinase inhibitors (TKIs). The presence of a JAK2-positive clone may cause hematologic resistance to TKIs.

Full Abstract

Introduction

In myeloproliferative neoplasms, coexistence of the JAK2 mutation and BCR-ABL rearrangement has been rarely described in patients. We report 3 such cases.

Case 1

Patient 1 was diagnosed as chronic myeloid leukemia (CML) following the discovery of thrombocytosis. She took imatinib with no platelet control, and hydroxyurea (HU) was added. She started nilotinib for leukocytosis, thrombocytosis, and 100% Philadelphia chromosome (Ph) positivity. In 6 months she obtained a complete cytogenetic response (CCyR), but the hematologic improvement was transient. We thus researched the JAK2 mutation that was positive. Interestingly, the JAK2^V617F was present since nilotinib start, but its expression achieved the maximum with CCyR.

Case 2

Patient 2 was diagnosed as primary myelofibrosis with leukocytosis, thrombocytopenia, splenomegaly, and fibrosis in the bone marrow (BM). Karyotype was normal. After 2 years with no treatment, BM showed 15% myeloblasts with 100% Ph positivity. The patient started imatinib. After an initial improvement, a new increase of leukocytes and platelets followed, with normal karyotype. HU was added, but hematologic control remained unsatisfactory and imatinib was stopped. The patient stayed on CCyR with insufficient hematologic response for more than one year, until he developed a Ph-negative myeloblast crisis with homozygosis for JAK2^V617F. We found that before imatinib the patient had a 50% JAK2-mutated phenotype, and after 3 months of therapy, more than 70%.

Case 3

Patient 3 was diagnosed as having essential thrombocytopenia with a normal karyotype. Good control of the thrombocytosis was obtained with HU, which continued for 10 years, and then the patient refused therapy for the next 3 years of stable disease, until he developed bone pain, leukocytosis, and enlarged spleen. Conventional cytogenetics was normal, but fluorescence in situ hybridization disclosed a 47% Ph positivity. The patient started imatinib with a rapid decrease of leukocytes; however, the platelets increased, and HU was added. After 3 months, the BM showed 7.4% Ph-positive cells. JAK2 was found mutated from imatinib start. This report suggests the presence of 2 different clones, one Ph-positive and the other JAK2 mutated and the prevalence of the latter when the former was inhibited by a tyrosine kinase inhibitor (TKI). The presence of a JAK2-positive clone may be a rare cause of hematologic resistance to TKIs.

To our knowledge, radioembolization with 90Y-labeled microspheres has never been reported for lymphomatous diseases. A 77-year-old man with marginal zone lymphoma with symptomatic splenomegaly (SM) was treated with 3700 MBb. This procedure is safe and effective and deserves further investigation in lymphomatous or other malignant SM.

Full Abstract

Introduction

90Y-labeled microsphere (90YRE) is used for the locoregional treatment of hepatic neoplasia. To the best of our knowledge, it has never been reported as a therapeutic approach for lymphomatous diseases.

Patients and Methods

A 77-year-old man with marginal zone lymphoma CD20⁺ and CD5, CD10, CD23⁻ developed a lymphomatous leukemia with symptomatic splenomegaly (SM). After several lines of chemotherapies, he progressed into an aggressive clinical disease with a major enlargement of his spleen responsible for hyperleukocytosis above 200000/μL, anemia requiring regular transfusions, abdominal pain, and anorexia. Palliative irradiation of the spleen with 16 Gy allowed an ephemeral hematologic stabilization. In order to reduce the splenic volume, we performed 90YRE. 3700 MBb of 90Y-labelled microspheres (SIRTEX®) was selectively administered via the splenic artery, which corresponds to a total dose of 36 Gy (calculated from treatment simulation/dosimetry with Technetium-99m—labeled macro-aggregates of albumin). This unusual procedure was safe and led to complete normalization of the blood cell counts.

Discussion

Radioembolization is a well-known safe procedure for hepatic neoplasia. A similar procedure has been previously reported years ago with a successful outcome for congestive hypersplenism due to idiopathic cirrhosis. Radioembolization by classical approach and splenectomy is usually complicated by severe morbidity. Irradiation could injure adjacent organs. In our patient, 90YRE was well tolerated with reduction of splenic volume. Despite major medullar infiltration with circulating leukemic cells, the complete normalization of the BCC suggests a major role of the irradiation of lymphomatous cells stored or circulating through the spleen. The response duration was 3 months, and the treatment has recently been repeated.

Conclusion

This case report suggests that 90YRE is a safe and effective procedure that deserves further investigation in lymphomatous or other malignant SM. Indeed, this procedure was better tolerated than classical embolization, with impressive results in this highly refractory patient.

Chronic myeloid leukemia (CML) is a clonal stem cell disorder that is characterized by the acquired chromosomal translocation BCR-ABL. This gives rise to a constitutively active tyrosine kinase deregulation of the normal mechanisms of cell cycle control. In the normal hematopoietic system, hematopoietic stem cells (HSC) self-renew to form identical daughter cells but also differentiate to mature blood cells. Leukemic stem cells (LSC) share these properties of self-renewal and also differentiate to mature leukemic cells. LSC have been isolated from patients with CML: these cells give rise to leukemia following transplantation into NOD-SCID mice models. Further characterization of CML stem cells has demonstrated that a small percentage of these cells are quiescent despite culture with growth factors. The CML stem cell arises from a normal HSC that has acquired the Philadelphia chromosome. In advanced phase, more mature cells such as granulocyte/monocyte progenitors might also acquire the ability to self-renew and function as LSC. This might be one of the mechanisms underlying the progression to blast crisis. Quiescent stem cells are resistant to treatment with imatinib in vitro and are thought also to show resistance in vivo. The properties of the stem cells that lead to this drug resistance are still being characterized. However, this drug insensitivity leads to disease persistence that may lead to disease relapse even despite an initial response to imatinib. Newer molecular therapies are in development that act to specifically target and eradicate the stem cell pool.

Introduction

Vorinostat, an orally active histone deacetylase inhibitor, was approved in October 2006 by the US Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease during or after treatment with 2 systemic therapies.

Patients and Methods

A multicenter, open-label phase IIb trial evaluated the activity and safety of vorinostat 400 mg orally daily in patients with ≥ stage IB, persistent, progressive, or treatment-refractory mycosis fungoides or Sézary syndrome CTCL subtypes. We report the safety and tolerability of long-term vorinostat therapy in patients who experienced clinical benefit in the previous phase IIb study.

Results

As of December 11, 2008, 6 of 74 patients enrolled in the original study had received vorinostat for ≥ 2 years: median age, 65 years; median number of previous therapies, 2.5; median time from diagnosis to enrollment, 1.8 years. At enrollment into the continuation phase, 5 of the 6 patients had achieved an objective response, and 1 patient had prolonged stable disease. During the follow-up study, the most common drug-related grade 1–4 adverse events (AEs) were diarrhea, nausea, fatigue, and alopecia (6, 5, 4, and 3 patients, respectively). Incidence of grade 3/4 AEs was low: anorexia (n = 1), increased creatinine phosphokinase (n = 1), pulmonary embolism (n = 1), rash (n = 1), and thrombocytopenia (n = 1). Five patients have discontinued the study drug, and 1 patient is continuing therapy.

Conclusion

This post hoc subset analysis provides evidence for the long-term safety and clinical benefit of vorinostat in heavily pretreated patients with CTCL, regardless of previous treatment failures.

In this study, we present data about the feasibility and safety of a prolonged monthly myelosuppressive maintenance therapy as a postremission therapy for acute myeloid leukemia after induction and induction-type consolidation. Maintenance therapy could be started in 57% of CR patients assigned to maintenance and completed in 14%.

Full Abstract

Introduction

We have previously shown that a prolonged monthly myelosuppressive chemotherapy proved superior to high-dose cytarabine consolidation therapy (J Clin Oncol 2003; 21:4496) after induction therapy and induction-type consolidation therapy. In this study, feasibility and safety of this approach was evaluated in the AMLCG 1999 trial.

Patients and Methods

827 patients with a CR before May 2005 were either randomized up front to receive maintenance therapy (< 60 years of age) or assigned to maintenance therapy (≥ 60 years of age) for 3 years after the achievement of a CR.

Results

Out of the 827 patients, 326 patients (39%) did not receive maintenance therapy due to allogeneic (63; 7.6%) or autologous (6; 0.7%) stem cell transplantation (SCT); early relapse (126; 15.3%); withdrawal of consent (19; 2.3%); medical reasons other than relapse (60; 7.3%); other reasons not classified (9; 1.1%); or death in remission (43; 5.2%). In 30 patients (3.6%), the application of maintenance therapy cannot be followed due to loss of follow-up or incomplete documentation. For the remaining 471 patients (57.0%) with a documented start of the maintenance therapy, the median number of maintenance courses applied was 6 (first to third quartile: 2–16) over a median duration from achievement of CR of 10 months (first to third quartile: 5–24). A dose reduction was necessary in all patients. Out of the 471 patients who started maintenance, therapy was terminated early in 348 patients (73.9%) due to an allogeneic SCT in first CR (7 patients; 1.5%); relapse (205; 43.5%); withdrawal of consent (21; 4.5%); medical reasons other than relapse (89; 18.9%); other reasons not classified (17; 3.6%), loss of follow-up or incomplete documentation (55; 11.7%); and death in CR (8; 1.7%). 69 patients (14.4%) completed maintenance for 3 years.

Conclusion

These results show that a prolonged monthly myelosuppressive maintenance therapy as part of a postremission therapy in AML is feasible and safe.

Patients receiving salvage therapy for relapsed CLL following first-line FCR have overall response rates of 60% and median survival of 38 months. We describe pre-treatment characteristics predicting for outcome after salvage therapies. Patients receiving chemoimmunotherapy had better response rates and duration compared to antibody therapy alone.

Brief Abstract

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is an effective initial therapy with an estimated 40% relapse rate at 6 years. There is no consensus salvage therapy for relapsed patients. All patients with chronic lymphocytic leukemia (CLL) who relapsed or were refractory following first-line FCR administered between July 1999 and December 2003 were included for analysis. Patients with Richter's transformation were excluded. We analyzed the impact of pre-treatment characteristics (Table 1) and response duration following FCR on responses and survival after salvage therapy. Response outcomes were analyzed using 1996 National Cancer Institute response criteria. Overall survival (OS) and time to treatment failure (TTF) were calculated using the method of Kaplan and Meier. Of 300 patients treated with first-line FCR, 111 patients (37%) have required salvage therapy. Median age at relapse was 61 years, and 36% of patients had Rai stage III or IV disease (Table 1). The salvage regimen included antibody alone, chemoimmunotherapy, or novel therapeutic approaches including lenalidomide. Responses included 17% CR, 12% nodular PR, and 32% PR with an overall response (OR) of 60%. Median OS was 38 months, and median TTF was 9 months. Rai stage III/IV disease, β2M > 4 mg/L, deletion of 17p by fluorescence in situ hybridization and TTF < 12 months following FCR were associated with significantly shorter TTF and OS following first salvage. Patients treated with single-antibody therapy had low response rates (CR/nPR, 9%; OR, 44%) and short TTF (6 months). Combination of alemtuzumab and rituximab improved responses (CR/nPR, 50%; OR, 75%) but did not improve TTF (8 months). Patients treated with FCR or CFAR (cyclophosphamide/fludarabine/alemtuzumab/rituximab) demonstrated good responses (CR/nPR, 50%; OR, 83%) with improved TTF (20 months) but no significant improvement in OS (44 months) compared to patients receiving antibody only (OS, 41 months). Patients who relapse after FCR can be successfully retreated with a similar chemoimmunotherapy regimen (FCR, CFAR) with reasonable response rates and remission duration; however, chemoimmunotherapy does not appear to improve OS over antibody therapy alone in first salvage.