How I treat refractory CLL

Abstract

Therapy for patients with chronic lymphocytic leukemia (CLL) has greatly changed over the past few years. After years of stagnation, with treatment revolving around the use of rather ineffective drugs such as alkylators, many patients are now being treated with more effective agents such as purine analogs either alone or combined with other drugs and/or monoclonal antibodies. Treatment of patients refractory to these treatments is particularly challenging and should be decided only upon a careful evaluation of the disease, patient characteristics, and prognostic factors. Refractory disease should be clearly separated from relapsing disease. The only curative therapy for patients with CLL, including those with refractory disease, is allogeneic stem cell transplantation. However, the use of allogeneic transplantation is limited because of the advanced age of most patients and the high transplant-related mortality (TRM). Transplants with nonmyeloablative regimens may reduce TRM and allow more patients to receive transplants more safely. For patients in whom an allogeneic transplantation is not feasible or in whom it is deemed inappropriate, participation in phase 2 trials should be encouraged. Finally, to investigate mechanisms to overcome resistance to therapy in CLL and to identify patients that might gain benefit from early, intensive therapies (eg, based on biologic markers) constitute a challenge that needs active investigation. IntroductionChronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of monoclonal peripheral (mature) CD5 ϩ B cells in lymphoid tissues, bone marrow, and peripheral blood. [1][2][3] The basic physiopathologic defect in CLL is the resistance of neoplastic cells to programmed cell death or apoptosis. CLL is the most frequent form of leukemia in Western countries and predominates in older people, the median age of patients at diagnosis being around 65 years. 4 Median survival is about 10 years but it largely varies from one patient to another, from less than 3 years to a normal life expectancy. Treatment should therefore be individualized on the basis of the risk to each patient. 5,6 For many decades, treatment of patients with CLL was based on the use of chlorambucil and other alkylating agents, which resulted in a complete response (CR) rate of less than 10% along with palliation of symptoms and only a modest, if any, impact on survival. Over the last few years, the management of CLL has greatly improved. The introduction of purine analogs and monoclonal antibodies has made possible combined treatments that result in CR rates of up to 60% to 70%; this translates into a longer progression-free interval. [5][6][7] It is important to emphasize that no matter how exciting the results with new, experimental combination chemotherapy and other innovative treatment approaches are, the advantages of these strategies in terms of survival have not yet been demonstrated. In this regard, it is important to keep in mind that the ultimate goal of therapy is to prolong surv...

Genetically identical twin transplantation for chronic lymphocytic leukemia

“…The 5-year leukemia-relapse rate of 50% seems higher than observed in similar patients receiving allotransplants but not necessarily different than in similar patients receiving autotransplants. 11,14,15,19 These findings support GVL effect of allotransplants in CLL. Leukemia cells in the graft may contribute to A, adriamycin; B, bleomycin; BM, bone marrow; C, cyclophosphamide; Cb, chlorambucil; CLL, chronic lymphocytic leukemia; CR, complete remission achieved at any time prior to transplant; D, dexamethasone; F, fludarabine; HCT, hematopoietic cell transplant; If, interferon-a; M, methylprednisolone; mo, number of months; MRD, minimal residual disease; NA, not assessable; Number of prior treatments, number of chemotherapy sequences delivered to control the disease; each sequence was separated with periods of observation, P, prednisone; PD, persistent disease; Rai stage, Rai stage at the time of transplantation; TBI, total-body-irradiation; V, vincristine; VP, etoposide; F ¼ data not available.…”

CMC-544 (inotuzumab ozogamicin), an anti-CD22 immuno-conjugate of calicheamicin, alters the levels of target molecules of malignant B-cells

“…[1][2][3][4] Nevertheless, a considerable percentage of patients are refractory to treatment with rituximab and relapse after an initial response. Several resistant mechanisms have been proposed including escape into CD20-negative cells by limited surface antigen renewal, cell membrane drug efflux pumps, escape into the resting phase of the cell cycle, enhancement of complement inhibitory factors, alterations in intracellular signaling or cell death pathways, FcgRIIIA polymorphism and reduction of effector cells.…”

Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment

“…The prognosis of these patients is very poor with a median survival of less than a year. [7][8][9] The most important molecular mechanism for treatment refractoriness in CLL is p53 dysfunction, a genetic abnormality that appears in 10% of cases. 7 The great majority of cytotoxic drugs like purine analogs and alkylators, act by inducing DNA double-strand breaks.…”