The following represent additions to UpToDate, since the last version, that were considered by the authors and editors to be of particular interest. The new material described below represents a small subset of the updating that has been performed, since approximately 40 percent of the topic reviews are updated during each four-month cycle.

ACUTE LYMPHOBLASTIC LEUKEMIA

Defining minimal residual disease — A panel of representatives of the major European study groups on childhood and adult acute lymphoblastic leukemia has proposed the following definitions for minimal residual disease (MRD) [1]:

• Complete MRD response — No MRD is detected with assessment that complies with a set of minimal technical requirements for the method used.
• MRD persistence — Presence of a continuously quantifiable MRD positivity measurable at two or more time points with at least one relevant treatment element in between.
• MRD reappearance — Conversion from MRD negativity to quantifiable MRD positivity, ideally with confirmation from a second sample prior to a change in treatment.

These definitions provide a common terminology to report individual patient results and allow for the comparison of trial outcomes. (See "Detection of minimal residual disease in acute lymphoblastic leukemia", section on 'Response defined'.)

Using MRD to escalate therapy in childhood ALL — A large prospective study found that minimal residual disease (MRD) measurements at days 33 and 78 could be used to risk stratify patients with childhood precursor B acute lymphoblastic leukemia [2]. At a median follow-up of four years, the estimated overall survival rates at five years were 98, 93, and 61 percent for patients with standard, intermediate, and high risk MRD, respectively. (See "Clinical use of minimal residual disease detection in acute lymphoblastic leukemia", section on 'Using MRD to escalate therapy'.)

PHF6 deletions in T-cell ALL — A minority of children and adults with primary T-cell acute lymphoblastic leukemia (ALL) display inactivating mutations or deletions in the plant homeodomain finger 6 (PHF6) locus located on the X chromosome [3]. Loss of PHF6 is associated with aberrant expression of the oncogene HOX11. These deletions of an X-linked locus provide a possible explanation for the increased incidence of this disease in males. (See "Cytogenetics in acute lymphoblastic leukemia", section on 'Non-TCR loci'.)

ACUTE MYELOID LEUKEMIA

Allogeneic transplantation in older adults — A large international study of highly selected older adults who underwent reduced intensity or nonmyeloablative allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission reported that rates of non-relapse mortality, acute and chronic graft-versus-host disease, and overall survival appeared to be independent of patient age at the time of transplant [4]. Factors that predicted a decreased overall survival rate included worse performance status, greater HLA disparity, and unfavorable risk cytogenetics. (See "Treatment of acute myeloid leukemia in older adults", section on 'Nonmyeloablative transplantation'.)

Consolidation with gemtuzumab ozogamicin — A randomized phase III trial demonstrated that post-remission therapy with single agent gemtuzumab ozogamicin did not improve clinical outcomes (probability of relapse, overall survival, or disease free survival), but added toxicities [5]. (See "Treatment of acute myeloid leukemia in older adults", section on Post-remission therapy.)

APLASTIC ANEMIA

Transplantation in older subjects — In a series of 23 consecutive patients with severe aplastic anemia over the age of 40 who received allogeneic hematopoietic cell transplantation from an HLA-identical sibling, overall survival was 65 percent [6]. The authors concluded that allogeneic HCT from an HLA-identical sibling could be offered to those with severe aplastic anemia who are >40 years of age and are without significant medical comorbidities. (See "Hematopoietic cell transplantation in aplastic anemia", section on 'Subjects over 40 years of age'.)

CHRONIC LYMPHOCYTIC LEUKEMIA

Superior survival when rituximab is added to fludarabine plus cyclophosphamide — A phase III randomized trial in previously untreated patients with chronic lymphocytic leukemia reported significantly higher response rates and overall survival with six courses of FCR (fludarabine, cyclophosphamide, and rituximab) when compared with six courses of FC (fludarabine, cyclophosphamide) [7]. The combination of FCR is now approved by the US Food and Drug Administration for the treatment of previously untreated and previously treated patients with CLL. (See "Initial treatment of chronic lymphocytic leukemia", section on 'Fludarabine-based therapy'.)

Superior survival with fludarabine over chlorambucil — Long-term follow-up of a randomized phase III trial comparing fludarabine, chlorambucil, or a combination of the two in previously untreated patients with chronic lymphocytic leukemia demonstrated that, when compared with chlorambucil alone, single agent fludarabine results in significantly higher overall survival rates at six years [8]. (See "Randomized clinical trials of chemotherapy in chronic lymphocytic leukemia", section on 'Fludarabine versus chlorambucil'.)

CHRONIC MYELOID LEUKEMIA

Second generation tyrosine kinase inhibitors — Two phase III trials comparing dasatinib or nilotinib to imatinib as initial therapy for chronic myeloid leukemia (CML) in chronic phase have demonstrated faster and deeper responses with these second generation tyrosine kinase inhibitors [9,10]. Further follow-up is needed to confirm whether the substantial short term improvements will result in longer term benefits, such as improved survival. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Second generation TKIs'.)

Nilotinib granted accelerated approval for the initial treatment of chronic phase CML — Nilotinib was granted accelerated approval on June 17, 2010 by the US Food and Drug Administration for the treatment of newly diagnosed CML [11]. The approved dose for the initial treatment of chronic phase CML is 300 mg orally twice daily. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Nilotinib'.)

Compliance with imatinib — A prospective study of patients with chronic myeloid leukemia in stable complete cytogenetic response on imatinib reported that compliance was an independent predictor of major molecular response (MMR) [12]. No patients with compliance ≤80 percent attained a MMR.

Transplant in chronic phase — A prospective trial of allogeneic hematopoietic cell transplantation in a highly selected group of patients with chronic myeloid leukemia (CML) in chronic phase reported a transplant-related mortality rate of 8 percent with an overall survival rate at three years of 91 percent for those treated in chronic phase [13]. HCT may be considered for the treatment of CML in chronic phase in select younger patients with an HLA matched sibling donor. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Hematopoietic cell transplantation'.)

HEMATOPOIETIC CELL TRANSPLANTATION

Source of stem cells — In a nine-year follow-up study of a randomized trial, overall and leukemia-free survival were similar in 329 leukemia patients who underwent hematopoietic cell transplantation using either peripheral blood precursor cells or bone marrow [14]. While significant differences in the incidence of chronic graft-versus-host disease and the duration of immunosuppression were noted, survival, general health, and the incidence of late events were not adversely affected by the stem cell choice. (See "Sources of hematopoietic stem cells", section on 'Allogeneic transplantation'.)

HODGKIN LYMPHOMA

Tissue-associated macrophages — Patients with Hodgkin lymphoma demonstrating increased numbers of tumor-associated macrophages (CD68 positive cells) have decreased overall survival rates [15]. (See "Clinical features of and prognostic factors for relapse of Hodgkin lymphoma after initial chemotherapy", section on 'Tissue macrophages'.)

MULTIPLE MYELOMA

Once weekly dosing of bortezomib — Once weekly dosing of bortezomib has demonstrated lower rates of peripheral neuropathy without compromising efficacy [16]. (See "Initial chemotherapy for patients with high risk multiple myeloma", section on 'Patients who are not candidates for HCT'.)

Lenalidomide maintenance after autologous transplant — Preliminary results of two randomized trials suggest that maintenance lenalidomide prolongs progression-free survival (PFS) in patients with multiple myeloma who have undergone autologous hematopoietic cell transplantation (HCT), but is also associated with substantial rates of severe neutropenia [17,18]. Longer follow-up is needed to evaluate overall survival and long-term toxicities. (See "Autologous hematopoietic cell transplantation in multiple myeloma", section on 'Lenalidomide'.)

Bortezomib thalidomide dexamethasone — Preliminary results from a randomized trial comparing the combination of low dose bortezomib, low dose thalidomide, and dexamethasone (vtD) with standard dose bortezomib plus dexamethasone (VD) as induction therapy prior to autologous HCT in younger adults with newly diagnosed myeloma reported superior response rates with vtD [19]. Longer follow-up is required to evaluate whether the improved response rate translates into improved overall survival. (See "Initial chemotherapy for symptomatic multiple myeloma in patients who are candidates for transplantation", section on 'Bortezomib regimens'.)

Improved understanding of pathobiology — It has become clear over the past few years that virtually all multiple myeloma (MM) cases are preceded by a premalignant plasma cell proliferative disorder known as monoclonal gammopathy of undetermined significance (MGUS) [20]. This understanding has helped us better conceptualize the pathobiology of myeloma as a two-step process. First there is the establishment of a limited stage of clonal proliferation, clinically recognized as MGUS. Then there is progression of MGUS to MM (figure 1). (See "Pathobiology of multiple myeloma".)

NON-HODGKIN LYMPHOMA

Maintenance rituximab in follicular lymphoma — The Primary Rituximab and Maintenance (PRIMA) randomized trial of maintenance rituximab after rituximab containing chemoimmunotherapy for patients with follicular lymphoma reported that patients who received maintenance rituximab demonstrated improved progression-free survival [21]. Further follow-up is needed to measure long-term toxicities and determine if the improvement in progression-free survival translates into an overall survival benefit. For patients with newly diagnosed FL who have had at least a partial response to initial therapy, we suggest maintenance rituximab rather than observation. (See "Initial treatment of follicular lymphoma", section on 'After chemoimmunotherapy'.)

International prognostic index — The international prognostic index (IPI) was designed based upon data from patients treated before the incorporation of rituximab into standard therapy. This index has now been validated in patients with aggressive B cell lymphoma (such as diffuse large B cell lymphoma) treated with rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab plus CHOP-like chemotherapy (table 1) [22]. (See "Evaluation, staging, and prognosis of non-Hodgkin lymphoma", section on 'Use of IPI for patients receiving rituximab'.)

NK/T cell lymphoma prognostic index — The previously defined NK/T cell lymphoma prognostic index (NKPI) stratifies patients by four features: presence of B symptoms, stage III or IV disease, elevated lactate dehydrogenase, and lymph node involvement. A recent study reported that, without central nervous system (CNS) prophylaxis, CNS recurrence will develop in 10 percent of patients with three or four features compared with less than 2 percent of those with one or two features [23]. Prospective studies have not evaluated whether CNS prophylaxis can reduce the CNS recurrence rate, but CNS prophylaxis should be considered for patients with NKPI scores of 3 or 4. (See "Initial treatment of peripheral T cell lymphoma", section on 'Extranodal NK/T cell lymphoma, nasal type' and "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type", section on 'Prognosis'.)

Transplant for enteropathy-associated T cell lymphoma — A retrospective study of patients with enteropathy-associated T cell lymphoma (EATL) treated with an intensive chemotherapy regimen (ifosfamide, vincristine, etoposide, and methotrexate) followed by autologous hematopoietic cell transplantation rescue reported a five-year overall survival rate of 60 percent [24]. In comparison, patients treated with chemotherapy alone demonstrate five-year overall survival rates of 10 to 20 percent. For patients with EATL who have a good performance status and chemotherapy sensitive disease, we now suggest treatment with intensive chemotherapy followed by autologous HCT rather than chemotherapy alone. (See "Management of gastrointestinal lymphomas", section on Enteropathy-associated T-cell lymphoma.)

Denileukin diftitox superior to placebo for relapsed mycosis fungoides — A phase III randomized trial in patients with previously treated mycosis fungoides demonstrated superior response rates and longer median times to progression with the recombinant interleukin-2-diphtheria toxin fusion protein denileukin diftitox when compared with placebo [25]. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides and Sezary syndrome".)

Denileukin diftitox).

Pathobiology of DLBCL — Recent discoveries on the role of EZH2 and the nuclear factor kappa B (NF-KB) signaling pathway have improved our understanding of the pathobiology of diffuse large B cell lymphoma variants. Specifically, some cases of the activated B cell like DLBCL appear to be associated mutations in the oncogene EZH2 or the expression of another BCR signaling component known as Bruton's tyrosine kinase (BTK) [26,27]. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Gene expression heterogeneity of DLBCL'.)

PLATELET TRANSFUSION

Platelet dosing — In a study of hospitalized patients undergoing hematopoietic cell transplantation or chemotherapy, subjects were randomly assigned to receive prophylactic platelet transfusion at a low-, medium-, or high-dose when morning platelet counts were ≤10,000/microL [28]. At doses between 1.1 (low-dose) and 4.4 (high-dose) x 10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (See "Clinical and laboratory aspects of platelet transfusion therapy", section on Platelet dose.)

POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE

Use of rituximab — In a multicenter study of 80 solid organ transplant recipients with post-transplant lymphoproliferative disease, patients who received initial treatment with rituximab plus reduction of immunosuppression had a 73 percent three-year overall survival rate, compared with 33 percent overall survival for those who did not receive rituximab [29]. (See "Lymphoproliferative disorders following solid organ transplantation", section on 'Prognosis'.)

SICKLE CELL DISEASE

Survival — According to a report from the Dallas Newborn Cohort, the estimated overall survival at 18 years is now 94 percent for those with HbSS or HbS/beta(0) thalassemia and 98 percent for those with HbSC or HbS/beta(+) thalassemia [30]. All of the seven deaths in this cohort since 2002 have been in subjects ≥18 years of age. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Survival and prognosis'.)

WARFARIN ANTICOAGULATION

Antibiotics and GI bleeding — In a case-control study of adults ≥66 years of age who had been taking warfarin for at least 180 days, concomitant use of trimethoprim-sulfamethoxazole or ciprofloaxacin was associated with a significant increase in hospital admission for upper gastrointestinal bleeding [31]. Approximately 10 percent of those hospitalized for this complication died before hospital discharge. (See "Therapeutic use of warfarin", section on 'Antibiotics'.)

Genotype testing — In a non-randomized study, the subjects who had undergone warfarin genotyping for CYP2C9 and VKORC1 variants prior to starting warfarin had a significantly lower six-month risk of hospitalization for bleeding or thromboembolism than a matched historical group of controls not receiving such testing [32]. Despite these observations, we and others recommend against routine genotyping in these patients. (See "Therapeutic use of warfarin", section on 'Pharmacogenetic dosing'.)

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