Sherif S. Farag

Outcome of Induction and Postremission Therapy in Younger Adults With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study

PURPOSEnEvaluate the outcome of induction and postremission therapy in adults younger than 60 years with normal cytogenetics acute myeloid leukemia (AML).nnnPATIENTS AND METHODSnIn 490 patients, induction included cytarabine and daunorubicin (AD) or cytarabine and escalated doses of daunorubicin and etoposide +/- PSC-833 (ADE/ADEP). Intensification included one cycle of high-dose cytarabine (HDAC) followed by etoposide/cyclophosphamide and mitoxantrone/diaziquone (group I), three HDAC cycles (group II), four intermediate-dose cytarabine (IDAC) or HDAC cycles (group III), or one HDAC/etoposide cycle and autologous stem-cell transplantation (ASCT; group IV).nnnRESULTSnOf 350 patients receiving AD, 73% achieved complete remission (CR), compared with 82% of 140 receiving ADE/ADEP (P = .04). Splenomegaly was associated with a lower CR rate (P < .001), and ADE/ADEP, with a higher CR rate in younger patients (P = .005). The 5-year disease-free survival (DFS) rate was 28% each for intensification groups I and II, compared with 41% and 45% for groups III and IV, respectively (P = .02). The 5-year cumulative incidence of relapse (CIR) was 62% and 67% for groups I and II, respectively, compared with 54% and 44% for groups III and IV, respectively (P = .049). The type of postremission intensification remained significant for DFS and CIR in multivariable analysis.nnnCONCLUSIONnIn younger adults with normal cytogenetics AML, splenomegaly predicts a lower CR rate, and the postremission strategies of either four cycles of I/HDAC or one cycle of HDAC/etoposide followed by ASCT are associated with improved DFS and reduced relapse compared with therapies that include fewer cycles of cytarabine or no transplantation.

Biology and clinical impact of human natural killer cells.

Natural killer (NK) cells, through elaboration of cytokines and cytolytic activity, are critical to host defense against invading organisms and malignant transformation.Two subsets of human NK cells are identified according to surface CD56 expression. CD56dim cells compose the majority of NK cells and function as effectors of natural cytotoxicity and antibody-dependent cellular cytotoxicity, whereas CD56bright cells have immunomodulatory function through secretion of cytokines. For a long time, NK cells have held promise for cancer immunotherapy because, unlike T-lymphocytes, NK cells can lyse tumor cells without tumor-specific antigen recognition.To date, NK cell therapy, largely focused on in vivo expansion and activation with cytokines, has met with only modest success. However, recent understanding of the importance of NK receptors (NKR) for recognition and lysis of tumor cells while normal cells are spared suggests novel therapeutic strategies.The balance of inhibitory and activating signals through surface receptors that recognize major histocompatibility complex class I and class I-like molecules on target cells determines whether NK cells activate killing. Identification of NKR ligands and their level of expression on normal and neoplastic cells has important implications for the rational design of immunotherapy strategies for cancer.We review recent development in the biology and clinical relevance of NK cells in cancer immunotherapy.

Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901.

Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade Bxa0cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day × 3) and fludarabine phosphate (25 mg/m(2)/day × 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non-Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study.

Monoclonal antibodies for the prevention and treatment of graft-versus-host disease

Acute and chronic graft-versus-host disease (GvHD) remain major obstacles to successful allogeneic hematopoietic stem cell transplantation, contributing substantially to morbidity and non-relapse mortality. Better understanding of the immunopathophysiology of GvHD has identified a number of targets for intervention. Among newly developed agents suitable for the prevention and treatment of GvHD, monoclonal antibodies hold much promise. Monoclonal antibodies currently available, such as infliximab and anti-interferon-gamma (anti-IFN-gamma), are capable of blocking of the action of initiating and effector cytokines. Antibodies directed against activated T cells, including daclizumab, visilizumab and ABX-CBL, may offer more specificity than the more broadly acting pan-T-cell-depleting agents. Finally, the clinical investigation of antibodies to adhesion molecules (such as LFA-1), or distal effector mechanisms (such as FasL) may offer another level of specificity. Many of these monoclonal antibodies have already undergone clinical testing. Campath-1H has been used for the prevention of acute GvHD with success. Daclizumab, infliximab, visilizumab, and ABX-CBL have shown promising activity in steroid-resistant acute GvHD in early clinical testing. This review summarizes current experience with monoclonal antibodies in the management of acute and chronic GvHD. Over the next decade, however, the challenge will be to define the relative place of these antibodies in the therapeutic armamentarium for GvHD and their impact on long-term survival.

High-dose busulfan, cyclophosphamide, and etoposide does not improve outcome of allogeneic stem cell transplantation compared to BuCy2 in patients with acute myeloid leukemia

Summary:To reduce relapse following allogeneic transplantation for AML, intensification of high-dose busulfan/cyclophosphamide using additional agents has been investigated but with few reported comparisons. We compared an intensified regimen of etoposide (60u2009mg/kg), busulphan (14u2009mg/kg), and cyclophosphamide (120u2009mg/kg) (BuCyVP) with BuCy2 in 237 AML patients. No significant difference in overall outcome was observed following BuCyVP (n=127) or BuCy2 (n=110). The 5-year survival was 27.3 and 30.1% following BuCyVP and BuCy2, respectively (P=0.48). Similarly, the 5-year cumulative incidence of relapse (CIR) was 28.3 and 34.8% with BuCyVP and BuCy2 (P=0.45), respectively. On multivariable analysis, patients transplanted in CR1 (P=0.002) and from related donors (P=0.013) had longer survival, while disease status at transplant was the only factor predicting CIR (P=0.002). In a separate analysis of CR1 patients (n=56), there was no significant difference in survival (P=0.37) or CIR (P=0.87) between the two regimens. However, for more advanced disease, there was a trend towards less relapse with BuCyVP (P=0.08), which was balanced by a higher cumulative incidence of transplant-related deaths (P=0.03) compared to BuCy2, resulting in similar survival. Overall, our results do not support the use of the more intensive BuCyVP regimen over BuCy2 in either early or more advanced disease AML patients.

Therapy-related myelodysplasia and leukemia occur infrequently following VP-16 priming and autotransplantation without total body irradiation

Summary:The use of VP-16 for stem cell mobilization has been cited as a significant risk factor for the development of therapy-related myelodysplasia/leukemia (tMDS/tAML) following autologous transplantation. The present study analyzed a large cohort of patients who underwent autotransplantation following stem cell mobilization with VP-16 and radiation-free preparation in order to determine the risk of tMDS/tAML. The estimated incidence of 9.9% at 7 years suggests that in the absence of TBI, VP-16 priming is not associated with an increased incidence of tMDS/tAML.

Diffuse alveolar hemorrhage following gemtuzumab ozogamicin

Diffuse alveolar hemorrhage (DAH) or hemorrhagic alveolitis is a severe, often fatal, pulmonary complication of myeloablative stem cell transplantation (SCT).1 The efficacy of current therapies for DAH remains unproven, although common practice is to treat patients with high-dose, pulsed methylprednisolone.2 The mortality of patients who require intubation and mechanical ventilation for DAH exceeds 80%.3, 4, 5 While primarily a complication of myeloablative SCT in patients with hematologic malignancies, DAH has been described as a rare toxicity of nontransplant therapies. DAH has been observed after use of the antiglycoprotein IIb/IIIa receptor monoclonal antibody abciximab (ReoPro),6, 7 but has not been associated with the humanized anti-CD33 monoclonal antibody gemtuzumab ozogamicin (Mylotarg).

The Therapeutic Use of Natural-Killer Cells in Hematological Malignancies

The role of natural-killer (NK) cells in the treatment of hematological malignancies has been investigated intensively during the past three decades. Until recently, the majority of research has focused on the use of in vitro or in vivo cytokine-expanded and -activated NK cells against autologous cancer cells, with generally disappointing results. The lack of observed efficacy of past attempts to harness the antitumor effect of NK cells can now be explained largely by inhibitory interactions between major histocompatibility complex class I molecules expressed on tumor cells and inhibitory receptors on NK cells. Better appreciation of how NK cells selectively recognize and kill target cells while sparing normal cells is evolving. Major families of cell surface receptors that inhibit and activate NK cells to lyse target cells have been characterized, including killer cell immunoglobulin-like receptors, C-type lectins, and natural cytotoxicity receptors. In addition, identification of NK cell receptor ligands and their expression on normal and transformed cells is becoming better elucidated. The improved understanding of NK cell receptor biology has paved the way for development of novel and rational clinical approaches to manipulating receptor-ligand interactions for immunotherapy.

Post-remission therapy with 4 cycles of intermediate (I) or high-dose (HD) cytarabine (AC) or autologous hematopoietic stem cell transplantation (ASCT) for acute myeloid leukemia (AML) patients <60 years with normal cytogenetics: A Cancer and Leukemia Group B (CALGB) Study

6542 Background: The optimal post-remission treatment (Rx) of AML patients with normal cytogenetics has not been extensively studied.nnnMETHODSnWe compared the outcome of 4 intensive post-remission treatment in 280 AML patients with normal cytogenetics, median age 44 (range, 18-59) years, who achieved complete remission (CR) on 5 successive front-line CALGB protocols. Patients were in CR after induction treatmen with AC + daunorubicin (D), ACD + etoposide (E) or ACDE + PSC-833. Post-remission intensification included 1 cycle HDAC (3 g/m2) followed by 1 cycle E+cyclophosphamide and 1 cycle mitoxantrone +diaziquone (Rx-I); HDAC for 3 cycles (Rx-II); IDAC (400 mg/m2) for 4 cycles or HDAC for 4 cycles (Rx-III), or HDAC+E followed by HD busulfan/E and ASCT (Rx-IV). IDAC and HDAC x 4 gave similar DFS (P=0.99) and OS (0.81) and were combined (I/HDAC) in further analysis. Median follow-up is 7.4 (range, 2.2-16.6) years.nnnRESULTSnThe outcome of an intent-to-treat analysis of post-remission treatment is shown in the table. [Figure: see text] Multivariable analysis (MVA) controlling for number of induction cycles, age, white cell count and other pre-treatment variables showed that I/HDAC x 4 improved DFS over HDAC x 3 (P=0.01) and Rx-I (P=0.0005), but was similar to ASCT (P=0.20). ASCT also improved DFS over Rx-I (P=0.04). On MVA I/HDAC improved OS only over Rx-I (P=0.02), whereas ASCT did not significantly improve OS relative to Rx-I (P=0.28).nnnCONCLUSIONSnIn AML patients <60 years with normal karyotype, either 4 cycles of I/HDAC or ASCT improved DFS relative to less intensive post-remission therapy. No significant financial relationships to disclose.