Official reprint from UpToDate® www.uptodate.com
©2012 UpToDate®
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use (click here) ©2012 UpToDate, Inc.
What's new in hematology
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: May 9, 2012.

The following represent additions to UpToDate since the last version of What’s New that were considered by the authors and editors to be of particular interest.

ACUTE LEUKEMIA

Induction failure in children with acute lymphoblastic leukemia — Induction failure occurs in fewer than 5 percent of children with acute lymphoblastic leukemia (ALL) and has historically been considered an ominous sign. An international retrospective analysis of over 44,000 children diagnosed with ALL from 1985 to 2000 identified 1041 children who had induction failure [1]. In this cohort, patients could be stratified by karyotype with estimated overall survival at 10 years ranging from 11 percent among those with t(9;22)/BCR-ABL1 to 72 percent among those with high hyperdiploid cytogenetics. These data highlight the heterogeneity of the induction-failure population. It is not known how these estimated survival rates may be affected by changes in standard therapy that have evolved since the time these patients were treated. In particular, the addition of BCR-ABL tyrosine kinase inhibitors to the standard treatment of BCR-ABL1 positive ALL has improved median survival times in this subset of patients, an effect that may not be reflected in this patient population. (See "Overview of the treatment of acute lymphoblastic leukemia in children", section on 'Induction failure'.)

Gemtuzumab in acute myeloid leukemia — Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to the cytotoxic agent calicheamicin that was initially approved by the US Food and Drug Administration for use in patients age 60 or older with CD33+ acute myeloid leukemia (AML) in first relapse not considered candidates for additional cytotoxic chemotherapy. GO was subsequently removed from the market in the US because a clinical benefit could not be confirmed. A subsequent phase III trial that evaluated a different dosing schedule of GO in older adults with newly diagnosed AML suggests an event-free and overall survival benefit when GO is added to induction chemotherapy in patients with favorable- or intermediate-risk cytogenetics [2]. Further study is needed to clarify this potential benefit in this subgroup of patients. (See "Treatment of acute myeloid leukemia in older adults", section on 'Gemtuzumab'.)

Erwinia asparaginase approved in the United States — For patients who develop an anaphylactic reaction to pegylated asparaginase (pegaspargase), which is derived from escherichia coli (E coli), continued therapy is possible in over 80 percent by switching to the Erwinia formulation. Cross reactivity is uncommon with the E coli and Erwinia derivatives of asparaginase, because the two are antigenically distinct. Erwinia asparaginase was approved in the United States in November 2011. (See "Infusion reactions to systemic chemotherapy", section on 'L-asparaginase'.)

Single dose rasburicase for prevention of tumor lysis syndrome — Rasburicase, recombinant urate oxidase, is an effective agent for lowering serum uric acid levels in patients receiving chemotherapy for leukemia, lymphoma, and some high-risk solid tumors who are at high risk for tumor lysis; the FDA-approved dosing schedule is once daily for up to five days. A randomized trial of single dose versus five daily doses in patients at high to intermediate risk of tumor lysis syndrome demonstrated that single dose therapy was effective in most patients with only a small subset requiring a second dose [3]. Single dose rasburicase therapy with close monitoring of serum uric acid levels and additional doses if needed is a reasonable option for high-risk patients. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Dosing and administration'.)

Maintenance for acute promyelocytic leukemia — Maintenance therapy with all-trans retinoic acid (ATRA), 6-mercaptopurine (6-MP), and methotrexate has been considered a standard component of the treatment of acute promyelocytic leukemia after induction with ATRA plus chemotherapy followed by consolidation therapy. However, induction therapy has evolved to include arsenic trioxide (ATO) in addition to ATRA and chemotherapy. Preliminary results from a large randomized cooperative group trial demonstrated very few relapses among patients who had received ATO for consolidation therapy followed by one year of maintenance with either ATRA alone or a combination of ATRA, 6-MP, and methotrexate [4]. When compared with those who received the three-drug combination maintenance therapy, patients treated with single agent ATRA as maintenance demonstrated similar rates of disease-free and overall survival and lower rates of hematologic and non-hematologic adverse events. For maintenance, we suggest the use of intermittent single agent ATRA rather than the combination of intermittent ATRA, 6-mercaptopurine, and methotrexate. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'Is maintenance necessary?'.)

ANTICOAGULATION

Safety of dabigatran — Increasing concerns have been raised about the safety of the orally active direct thrombin inhibitor dabigatran:

  • The US Food and Drug Administration (FDA drug safety communication) and the European Medicines Agency (European Medicines Agency Update) are evaluating post-marketing reports of approximately 256 serious bleeding events leading to death in patients taking dabigatran. The median age of those with reported bleeding events in 2011 was 80 years, raising a question of safe dosing in older patients, who may also have reduced renal function and other comorbidities.
  • A meta-analysis of seven randomized trials indicated that use of dabigatran for a variety of indications (eg, atrial fibrillation, acute coronary syndrome, venous thromboembolism treatment or prophylaxis), when compared with warfarin, enoxaparin, or placebo controls, was associated with a significantly higher risk of myocardial infarction or acute coronary syndrome [5].

These observations, as well as reports of deaths among trauma victims receiving dabigatran [6], have called into question the safety of this agent in trauma patients, older patients, and those with renal disease. (See "Anticoagulants other than heparin and warfarin", section on 'Bleeding and thrombotic events'.)

CHRONIC LYMPHOCYTIC LEUKEMIA

Alemtuzumab plus fludarabine — Alemtuzumab (Campath-1H), an antibody directed against CD52, is used for the treatment of chronic lymphocytic leukemia (CLL). In general, we favor the use of alemtuzumab in patients with chromosome 17p deletion and discourage its use in patients with bulky lymphadenopathy. A phase III randomized trial compared the combination of alemtuzumab plus fludarabine versus single agent fludarabine in patients with relapsed or refractory CLL [7]. Combination therapy resulted in a significantly longer median progression-free survival, but was associated with higher rates of severe toxicities including cytopenias and infectious complications. Follow-up data on this regimen are awaited to see if this translates into an overall survival advantage. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Alemtuzumab'.)

SF3B1 gene mutations — The SF3B1 gene encodes for part of a nuclear ribonucleoprotein that complexes with other nuclear ribonucleoproteins to create the spliceosome that is responsible for splicing messenger RNA. Numerous studies published this year reported that SF3B1 mutations can be identified in a subset of patients with chronic lymphocytic leukemia (CLL) [8-11]. This finding may help us better understand the pathobiology of CLL and suggests that the spliceosome may be a potential drug target. (See "Pathophysiology and genetic features of chronic lymphocytic leukemia", section on 'SF3B1 gene mutations'.)

BLOOD TRANSFUSION

Optimal transfusion level — The "optimal" transfusion level for postoperative patients with cardiovascular disease or risk factors was examined in the FOCUS trial [12]. Patients ≥50 years of age with a hemoglobin (Hb) concentration <10 g/dL within three days after hip surgery were randomly assigned to liberal (transfuse to raise Hb to >10 g/dL) or restrictive (transfuse only for symptoms or Hb <8 g/dL) treatment groups. The primary outcome (death or inability to walk a distance unassisted at 60 days) was similar for both groups, suggesting that it is reasonable to withhold transfusion in asymptomatic postoperative patients whose Hb is >8 g/dL, even if they are older and have cardiovascular disease or risk factors. (See "Indications for red cell transfusion in the adult", section on 'Optimal transfusion level'.)

CHRONIC MYELOID LEUKEMIA

Third generation tyrosine kinase inhibitors — Imatinib, dasatinib, and nilotinib are BCR-ABL tyrosine kinase inhibitors (TKIs) used for the treatment of chronic myeloid leukemia (CML). Phase II trials have demonstrated promising response rates with two new BCR-ABL inhibitors, ponatinib [13] and bosutinib [14]. Of importance, ponatinib demonstrated responses in patients with CML that contained the T315I BCR-ABL mutation, a mutation known to be resistant to all available TKIs. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Ponatinib' and "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Bosutinib'.)

COAGULOPATHY OF LIVER DISEASE

Prevention of portal vein thrombosis — Preliminary results are available from a prospective, randomized trial of enoxaparin for the prevention of portal vein thrombosis (PVT) in patients with cirrhosis [15]. During the one-year study period, PVT occurred significantly more often in those taking placebo (6 of 36, 17 percent) than in those taking enoxaparin (0 of 34). No hemorrhagic events were attributed to enoxaparin. Enoxaparin use was also associated with a significantly lower incidence of hepatic decompensation (53 versus 12 percent). (See "Coagulation abnormalities in patients with liver disease", section on 'Prevention'.)

HAIRY CELL LEUKEMIA

BRAF mutations in hairy cell leukemia — Two independent studies have implicated an activating point mutation of the BRAF isoform of RAF (BRAF V600E) in the pathogenesis of hairy cell leukemia (HCL). BRAF is a member of the serine-threonine kinase family, which plays a part in the RAS/RAF/MEK/MAPK signaling pathway leading to enhanced cell proliferation and survival. Two independent studies identified a BRAF V600E mutation in all tested patients with HCL; the mutation was indentified in no patients with other lymphoproliferative disorders [16,17]. These findings suggest that this mutation is a disease-defining event. (See "Clinical features and diagnosis of hairy cell leukemia", section on 'Pathogenesis'.)

HEMATOPOIETIC CELL TRANSPLANTATION

HLA-DP haplotype in unrelated transplant — Initial studies of unrelated donor hematopoietic cell transplantation did not consider the class II HLA-DPB1 haplotype in the selection of donors because earlier studies suggested no impact of HLA-DP matching on outcomes. In a large international retrospective analysis of donor and recipient pairs matched for 9 or 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 alleles, HLA-DPB1 status was identified as matched, non-permissive mismatched, or permissive mismatched according to the HLA-DPB1 haplotypes and direction of mismatch [18]. Non-permissive mismatches were associated with higher overall mortality, non-relapse mortality, and acute graft-versus-host disease, but not relapse. These results suggest that delineation of HLA-DPB1 mismatches as permissive and non-permissive allows for more informed donor selection. When all other factors are equal, selection of a 12 of 12 matched donor should be preferred. (See "Donor selection for hematopoietic cell transplantation", section on 'HLA-DP haplotype'.)

Defibrotide prophylaxis in children — Nonrandomized studies in both adults and children have reported reductions in the incidence of post-hematopoietic cell transplantation (HCT) hepatic sinusoidal obstruction syndrome (SOS, previously called hepatic veno-occlusive disease) following the prophylactic use of the oral fibrinolytic agent defibrotide. In a multicenter, open-label trial, 356 children undergoing myeloablative HCT who had one or more risk factor for SOS were randomly assigned to receive prophylactic intravenous defibrotide or not [19]. Patients assigned to defibrotide prophylaxis had a significantly lower cumulative incidence of SOS at 30 days post-HCT (12 versus 20 percent) and a lower incidence of renal failure (1 versus 6 percent). There was no difference in mortality. These results suggest that defibrotide prophylaxis decreases the incidence of SOS in children at high risk for SOS. It is not known whether these results may be extrapolated to the adult population. (See "Treatment and prevention of hepatic sinusoidal obstruction syndrome following hematopoietic cell transplantation", section on 'Defibrotide prophylaxis'.)

Peripheral blood progenitor cell versus bone marrow transplant — Peripheral blood progenitor cells (PBPCs) have replaced bone marrow as the source of hematopoietic stem cells for many patients undergoing allogeneic hematopoietic cell transplantation (HCT). A phase III randomized trial in adults compared PBPCs with bone marrow, both obtained from HLA-matched unrelated donors [20]. When compared with bone marrow, PBPCs resulted in similar survival rates, significantly quicker engraftment, fewer cases of graft failure, similar rates of acute graft versus host disease (GVHD), but increased rates of chronic extensive GVHD. These results suggest that both PBPCs and bone marrow are acceptable stem cell sources. PBPC may be preferred for those at high risk of graft failure or infections in the early post-transplantation period where more rapid hematopoietic recovery could be a particular advantage. (See "Sources of hematopoietic stem cells", section on 'Allogeneic transplantation'.)

HLA-C haplotype in umbilical cord transplant — Initial studies of umbilical cord blood (UCB) transplantation did not consider the HLA-C haplotype in the selection of UCB because earlier studies suggested no impact of HLA-C matching on outcomes. A subsequent large database study reported that, among patients matched for HLA-A,-B, and -DRB1, patients mismatched for HLA-C had greater transplant-related mortality than those matched for HLA-C [21]. These results suggest that efforts should be made to select the UCB unit with the greatest HLA compatibility at HLA-A, HLA-B, HLA-C, and HLA-DRB1, although it is recognized that information on HLA-C status for UCB is often not readily available. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'HLA type'.)

Direction of HLA allele mismatch in umbilical cord transplant — The success of HLA-mismatched umbilical cord blood (UCB) transplantations is purportedly related to the relative immaturity of the immune system in UCB samples that allows for the crossing of immunologic barriers that would otherwise be prohibitive. Two retrospective analyses of patients receiving UCB transplantation evaluated the effect of a unidirectional HLA mismatch [22,23]. Patients with unidirectional mismatches in the graft-versus-host direction had significantly faster rates of engraftment. In contrast, patients with unidirectional mismatches in the host-versus-graft direction had slower engraftment, higher rates of graft failure, and higher relapse rates. Based upon this information, priority should be given to unidirectional mismatches in the graft-versus-host direction and mismatches in the host-versus-graft direction are avoided, if possible. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'HLA type'.)

Guidelines for long-term transplant survivors — There are a growing number of long-term survivors of hematopoietic cell transplantation (HCT), and the transplant community has recognized the importance of providing specialized care to these individuals. Guidelines addressing screening and preventive practices for long-term survivors after HCT have been updated by a group representing the consensus of multiple international transplantation societies and groups [24]. These guidelines included a discussion of ischemic microvascular retinopathy, which is an increasingly recognized potential complication of allogeneic HCT. (See "The approach to hematopoietic cell transplantation survivorship", section on 'Ocular complications'.)

Interleukin-2 for graft-versus-host disease — Interleukin-2 (IL-2) is a T cell derived cytokine that plays a central role in immune responses. A small phase I dose escalation study of IL-2 in patients with glucocorticoid refractory chronic graft-verus-host disease (GVHD) reported a partial response in approximately half of patients and stable disease in the remainder [25]. Prolonged responses were seen in a subset of patients who chose to continue IL-2 for an extended period, many of whom were able to taper glucocorticoid dose. Further study of this agent is needed prior to incorporating it into routine care. (See "Treatment of chronic graft-versus-host disease", section on 'Interleukin-2'.)

HEMOPHILIA

Prophylactic treatment in patients with inhibitors — The efficacy and safety of FEIBA, an activated prothrombin complex concentrate product, was evaluated in a randomized crossover trial that compared prophylactic versus “on demand” use in patients with hemophilia A and high titer inhibitors (>5 Bethesda units) [26]. Prophylaxis was associated with significant reductions in all bleeding episodes (62 percent reduction), hemarthroses (61 percent reduction), and target joint bleeding (72 percent reduction). (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Activated prothrombin complex concentrates'.)

Gene therapy for hemophilia B — A single dose of an adenovirus-associated virus (AAV) expressing a human factor IX (FIX) transgene was given intravenously to six patients with severe hemophilia B (FIX deficiency with <1 percent of normal activity) [27]. AAV-mediated expression of FIX at 2 to 11 percent of normal was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous bleeding. A transient asymptomatic elevation of serum aminotransferase activity was noted in two of the participants receiving the highest dose; both responded rapidly to a short course of glucocorticoid therapy. (See "Treatment of hemophilia", section on 'Gene therapy'.)

HODGKIN LYMPHOMA

Escalated BEACOPP in advanced stage disease — Combination chemotherapy with six to eight cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is the preferred therapy for most patients with advanced stage Hodgkin lymphoma (HL). Eight cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) is an acceptable alternative and is associated with lower relapse rates, but higher initial toxicity and no difference in overall survival. In the German Hodgkin Study Group (GHSG) HD15 trial, 2182 adults with newly diagnosed advanced stage HL were randomly assigned therapy with either eight cycles of escalated BEACOPP, six cycles of escalated BEACOPP, or eight cycles of baseline BEACOPP delivered every 14 days [28]. When compared with eight cycles, six cycles of escalated BEACOPP resulted in higher rates of freedom from treatment failure and overall survival at five years and less treatment-related toxicity. There was no advantage of baseline BEACOPP delivered every 14 days. Reducing the number of escalated BEACOPP treatment cycles from eight to six appears to result in superior efficacy and less toxicity. It is unknown how six cycles of escalated BEACOPP compares with six to eight cycles of ABVD. (See "Initial treatment of advanced (stage III-IV) classical Hodgkin lymphoma", section on 'BEACOPP efficacy'.)

Chemotherapy alone for early stage disease — The administration of chemotherapy alone for the treatment of early stage Hodgkin lymphoma (HL) is controversial. The NCIC/ECOG HD6 randomized trial compared four to six cycles of chemotherapy alone versus treatment that included radiation therapy (RT) in patients with previously untreated stage IA or IIA non-bulky HL [29]. Chemotherapy alone was associated with a lower rate of freedom from disease progression but a higher rate of overall survival at 12 years. This trial confirms that high doses of large field RT are associated with a higher rate of secondary malignancy and cardiovascular deaths. However, it does not accurately compare chemotherapy alone with chemotherapy plus modern RT techniques that utilize lower doses of radiation (eg, 20 to 30 Gy) administered to smaller areas (eg, involved-field or involved-node). For most patients with early stage HL, we continue to suggest treatment with chemotherapy plus radiation therapy. (See "Treatment of favorable prognosis early (stage I-II) classical Hodgkin lymphoma", section on 'Is there a role for chemotherapy alone?'.)

Brentuximab and progressive multifocal leukoencephalopathy — Brentuximab vedotin was granted accelerated approval by the US Food and Drug Administration (FDA) earlier this year for the treatment of patients with relapsed refractory Hodgkin lymphoma or relapsed systemic anaplastic large cell lymphoma. Rare reports of progressive multifocal leukoencephalopathy (PML) prompted the FDA to add a black box warning to the drug label regarding this complication in January 2012 [30]. PML typically presents with subacute neurologic deficits which may include altered mental status, visual symptoms, weakness, ataxia, and seizures [31]. (See "Neurologic complications of cancer treatment with biologic agents", section on 'Brentuximab'.)

MULTIPLE MYELOMA/MGUS

Defining high risk myeloma — Multiple myeloma (MM) is a heterogenous disease and treatment is generally determined using a risk stratification system that incorporates several prognostic factors, such as cytogenetic abnormalities. Hyperdiploidy (commonly due to trisomies) is a well recognized predictor of favorable outcomes while IgH translocations predict worse outcome. Previous studies have suggested that these two findings were mutually exclusive. A retrospective study of 484 patients with newly diagnosed symptomatic MM identified a subset of patients who have both IgH translocations and trisomies detected by fluorescent in situ hybridization (FISH) [32]. Importantly, the presence of a trisomy appeared to ameliorate the poor outcomes usually seen in patients with IgH translocations. Based upon this data, we suggest including FISH for trisomies of odd numbered chromosomes in a standard FISH panel for risk stratification in MM. (See "Staging and prognostic studies in multiple myeloma", section on 'Trisomies and prognosis' and "Staging and prognostic studies in multiple myeloma", section on 'Cytogenetic abnormalities'.)

Prophylactic anticoagulation — Routine venous thromboembolism (VTE) prophylaxis is recommended for patients with multiple myeloma (MM) treated with lenalidomide in combination with other agents (eg, glucocorticoids). The choice of thromboprophylaxis regimen needs to consider the lenalidomide regimen used and the patient population. In a large phase III trial, previously untreated MM patients (median age 58 years) with no other excess risk for VTE received lenalidomide plus low-dose dexamethasone (Rd) for four cycles followed by cyclophosphamide for stem cell mobilization and collection before consolidation with either melphalan, prednisone, and lenalidomide (MPR) or melphalan 200 mg/m2 [33]. Patients were randomly assigned to receive either low-dose aspirin (100 mg/day) or low molecular weight heparin (LMWH, enoxaparin 40 mg daily) during treatment with Rd and MPR. The incidence of symptomatic thromboembolism, as well as other components of a composite cardiovascular outcome, was similar for LMWH and low dose aspirin groups. There were no major bleeding episodes in either group. This provides further support for our suggested use of aspirin rather than LMWH for VTE prophylaxis in this population. (See "Thrombotic complications following treatment of multiple myeloma with thalidomide and its analogues", section on 'Standard risk setting'.)

Maintenance lenalidomide — One non-randomized trial and the preliminary results of two randomized trials have suggested that maintenance lenalidomide prolongs progression-free survival in patients with multiple myeloma who have undergone autologous hematopoietic cell transplantation (HCT), but is also associated with substantial rates of severe neutropenia. Updated results from one of these randomized trials suggested that lenalidomide maintenance is associated with improved overall survival [34]. However, both of the randomized trials have demonstrated an increased number of second cancers in the lenalidomide treated arm [35]. Until further results are available, post-transplant lenalidomide maintenance should be reserved primarily for patients on clinical trials or those with high-risk disease or those who fail to obtain a very good partial response with HCT. (See "Autologous hematopoietic cell transplantation in multiple myeloma", section on 'Lenalidomide'.)

Maintenance thalidomide — Multiple randomized trials have demonstrated that thalidomide maintenance prolongs progression-free survival (PFS) and may improve overall survival in patients with multiple myeloma, but thalidomide is also associated with a significant increase in long-term toxicities, including peripheral neuropathy and thromboembolism. Two recently published large randomized trials evaluating maintenance thalidomide confirmed this improvement in PFS but showed no survival benefit [36,37]. Routine thalidomide maintenance does not appear to offer adequate clinical benefit to overcome the harm of associated toxicities. (See "Autologous hematopoietic cell transplantation in multiple myeloma", section on 'Thalidomide'.)

Nonmyeloablative hematopoietic cell transplantation — Autologous hematopoietic cell transplantation (HCT) is a key component of treatment in patients with newly diagnosed multiple myeloma, but is not curative. In contrast, myeloablative allogeneic HCT is potentially curative, but associated with an extremely high early mortality in this population. A large prospective study evaluated the use of autologous HCT followed by either a second autologous HCT (auto-auto) or nonmyeloablative allogeneic HCT (auto-allo), depending upon the availability of a sibling donor [36]. Auto-allo resulted in similar rates of progression-free and overall survival at three years when compared with auto-auto. As expected, auto-allo was associated with increased toxicity, including graft-versus-host disease. Given the results of this and other studies, the role of nonmyeloablative allogeneic transplantation in patients with multiple myeloma remains investigational. (See "Allogeneic hematopoietic cell transplantation in multiple myeloma", section on 'Autologous followed by nonmyeloablative allogeneic HCT in newly diagnosed myeloma'.)

NON-HODGKIN LYMPHOMA

Radiation for primary mediastinal large B cell lymphoma — When compared with other forms of diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma (PMLBCL) has historically had a higher rate of primary refractoriness and early relapse following CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy without rituximab and poor response rates with second line therapies. A randomized trial evaluating the use of adjuvant involved-field radiation therapy (RT) following achievement of complete remission with CHOP plus rituximab was stopped early when worse outcomes were noted for patients not receiving RT [38]. Administration of 30 Gy involved-field RT resulted in limited toxicity and a significantly higher estimated progression-free (72 versus 20 percent) and overall (72 versus 31 percent) survival at 10 years. For patients with limited stage disease PMLBCL, we recommend treatment with chemotherapy (eg, R-CHOP) plus involved-field RT rather than chemotherapy alone. (See "Initial treatment of limited stage diffuse large B cell lymphoma", section on 'Mediastinum'.)

Influenza vaccination in patients receiving rituximab — The anti-CD20 monoclonal antibody, rituximab, has become a standard part of the treatment of CD20-positive B cell lymphomas. Since this agent depletes normal B cells, there is concern that it will attenuate the response to vaccines. In a study of lymphoma patients who had received a rituximab-containing treatment regimen within the previous six months, none of 67 patients developed seroprotective titers following administration of an adjuvanted inactivated pandemic H1N1 influenza A vaccine [39]. In contrast, 82 percent of healthy controls developed seroprotective titers following vaccination. This study suggests that, when feasible, the influenza vaccine (and other indicated vaccines) should be given to lymphoma patients before initiation of rituximab. (See "Immunizations in patients with cancer", section on 'Influenza vaccine' and "Immunizations in patients with cancer", section on 'General approach'.)

Autologous transplantation in follicular lymphoma — Randomized trials of autologous hematopoietic cell transplantation (HCT) in follicular lymphoma (FL) have had mixed results. Two 2012 systematic reviews and meta-analyses of these trials found that high dose chemotherapy followed by autologous HCT resulted in significantly improved progression-free survival but similar overall survival when compared with combination chemotherapy or immunochemotherapy [40,41]. For patients with previously untreated advanced stage FL who require therapy, we continue to recommend treatment with an immunotherapy-based regimen rather than chemotherapy alone or autologous HCT. (See "Initial treatment of follicular lymphoma", section on 'Transplantation'.)

SMILE for extranodal NK/T-cell lymphoma — Patients with disseminated extranodal NK/T cell lymphoma, nasal type have historically had a poor prognosis in initial therapy and a median survival with conventional chemotherapy of approximately four months. A phase II study from Japan investigating dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) in patients with disseminated extranodal NK/T-cell lymphoma reported an overall response rate of 79 percent with 45 percent complete responses [42]. Approximately half of patients were alive at one year. For patients with disseminated extranodal NK/T cell lymphoma, nasal type not enrolled in a clinical trial, we suggest the use of a combination chemotherapy regimen incorporating L-asparaginase (eg, SMILE) rather than other chemotherapy regimens. (See "Treatment of extranodal NK/T cell lymphoma, nasal type", section on 'Disseminated disease'.)

Maintenance rituximab for follicular lymphoma — For patients with previously untreated follicular lymphoma (FL), the use of a prolonged rituximab schedule (eight doses) has been shown to produce superior event-free survival when compared with a shorter schedule (four doses), but it was unknown whether longer single agent rituximab would improve outcomes further. A randomized trial that compared initial rituximab therapy followed by either maintenance rituximab or rituximab at the time of progression demonstrated that maintenance rituximab was well tolerated [43]. While patients assigned to maintenance rituximab received approximately three times as much rituximab, there was no difference in median time to treatment failure. For patients initially treated with rituximab therapy alone, we continue to suggest a prolonged (extended) rituximab schedule rather than a shorter (four-week) or longer (maintenance) schedule. (See "Initial treatment of follicular lymphoma", section on 'After immunotherapy'.)

Maintenance rituximab for mantle cell lymphoma — Maintenance therapy is commonly employed in the management of some types of lymphoma, but the role of maintenance in mantle cell lymphoma (MCL) is less well understood. This was evaluated in a large randomized trial of older adults (>60 years) with previously untreated MCL who achieved a complete or partial remission (PR) after initial rituximab-based combination chemotherapy and who were not candidates for autologous hematopoietic cell transplantation (HCT) [44]. In preliminary results, maintenance rituximab therapy demonstrated a significant survival benefit in the subset of patients who had initial treatment with R-CHOP. For patients with newly diagnosed MCL who have had at least a PR to initial therapy and do not plan to undergo autologous HCT, we now suggest the use of maintenance rituximab until progression rather than observation with treatment at the time of progression. We do not routinely administer maintenance rituximab after autologous HCT. (See "Initial treatment of mantle cell lymphoma", section on 'Maintenance therapy'.)

Radioimmunoconjugates in follicular lymphoma — Anti-CD20 radioimmunoconjugates (eg, ibritumomab tiuxetan, tositumomab) have demonstrated efficacy in relapsed or refractory follicular lymphoma (FL) and as consolidation therapy in patients with FL whose initial therapy did not include rituximab. In a phase III trial, patients with newly diagnosed FL were randomly assigned to chemoimmunotherapy alone (RCHOP for six cycles) or to chemotherapy plus a radioimmunoconjugate (CHOP for six cycles followed by tositumomab) [45]. Preliminary results demonstrated similar rates of response, progression-free survival, and overall survival. Toxicity was greater among those who received a radioimmunoconjugate. There is no clear benefit from the use of chemotherapy followed by an anti-CD20 radioimmunoconjugate rather than initial chemoimmunotherapy alone. Until more definitive data are available, we do not use of radioimmunoconjugates as part of first-line therapy, but would use them in relapsed or refractory disease. (See "Initial treatment of follicular lymphoma", section on 'Radioimmunoconjugates'.)

Glucarpidase approved in the United States — High-dose methotrexate is used for central nervous system (CNS) prophylaxis in patients with leukemia and high-risk lymphoma, and for the treatment of leptomeningeal metastases, primary CNS lymphoma, and osteosarcoma. These otherwise lethal doses of methotrexate are followed by a two- to three-day period of leucovorin administration to terminate the toxic effects. Successful “rescue” by leucovorin depends on rapid elimination of methotrexate by the kidneys. Glucarpidase (recombinant carboxypeptidase G) is an enzyme that metabolizes antifolates such as methotrexate to inactive metabolites. In January 2012, the US Food and Drug Administration approved glucarpidase injection (Voraxaze®) for the treatment of toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function. Continuation of leucovorin after glucarpidase administration is essential. (See "Therapeutic use of high-dose methotrexate", section on 'Glucarpidase (carboxypeptidase G2)'.)

Proton pump inhibitors in patients receiving high-dose methotrexate — The US Food and Drug Administration has issued a warning about use of proton pump inhibitors (PPIs) in patients receiving methotrexate, particularly high-dose methotrexate [46]. Case reports and published population pharmacokinetic studies suggest that concomitant use of PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. (See "Therapeutic use of high-dose methotrexate", section on 'Use of proton pump inhibitors'.)

PRIMARY MYELOFIBROSIS

Treatment with the JAK1/JAK2 inhibitor ruxolitinib — Results from two phase III trials of the selective JAK1/JAK2 inhibitor ruxolitinib in patients with primary myelofibrosis have indicated a ≥35 percent reduction in splenic volume in 30 to 40 percent of patients, and effective alleviation of constitutional symptoms in the majority [47,48]. Severe anemia or thrombocytopenia occurred in the majority of patients. Drug discontinuation was associated with full relapse of disease symptoms, which sometimes resulted in emergency care for a septic shock-like syndrome (“ruxolitinib withdrawal syndrome”) [49,50]. This agent, which has been approved for use in myelofibrosis, is best reserved for patients with debilitating constitutional symptoms or severely symptomatic splenomegaly. Patients should be fully informed about the ruxolitinib withdrawal syndrome and other side effects (eg, anemia and thrombocytopenia) before being started on therapy. (See "Prognosis and treatment of primary myelofibrosis", section on 'JAK2 inhibitors'.)

SICKLE CELL DISEASE

Increasing expression of fetal hemoglobin — Higher levels of fetal hemoglobin (HbF) are associated with reduced disease severity in patients with sickle cell disease (SCD). Two pioneering studies in mouse models of SCD have shown the beneficial clinical effect of increasing HbF levels by manipulating gene expression in vivo:

  • Forced expression of the nuclear receptors TR2 and TR4, which enhance fetal gamma-globin gene expression in murine adult erythroid cells, increased HbF from 7.6 to 18.6 percent in a humanized sickle cell mouse model, along with improvement in hemolytic anemia and other pathologic defects [51].
  • Inactivation of BCL11A, a gene associated with repression of HbF production in the adult, corrected the hematologic and pathologic defects associated with SCD in a transgenic mouse model through high-level pancellular induction of HbF [52].

These approaches, if duplicated in man, have the ability to drastically alter the clinical course of sickle cell disease. (See "Specific therapies for sickle cell disease", section on 'Increasing expression of HbF'.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

  1. Schrappe M, Hunger SP, Pui CH, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med 2012; 366:1371.
  2. Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012; 379:1508.
  3. Vadhan-Raj S, Fayad LE, Fanale MA, et al. A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome. Ann Oncol 2011.
  4. Powell BL, Moser BK, Stock W, et al. Adding Mercaptopurine and Methotrexate to Alternate Week ATRA Maintenance Therapy Does Not Improve the Outcome for Adults with Acute Promyelocytic Leukemia (APL) in First Remission: Results From North American Leukemia Intergroup Trial C9710 (abstract 258). Blood 2011; 118:118.
  5. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172:397.
  6. Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J Med 2011; 365:2039.
  7. Elter T, Gercheva-Kyuchukova L, Pylylpenko H, et al. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol 2011; 12:1204.
  8. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365:2497.
  9. Rossi D, Bruscaggin A, Spina V, et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 2011; 118:6904.
  10. Hahn CN, Scott HS. Spliceosome mutations in hematopoietic malignancies. Nat Genet 2012; 44:9.
  11. Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 2012; 44:47.
  12. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011; 365:2453.
  13. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Initial findings from the PACE trial: A pivotal phase 2 study of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation (abstract 109). Blood 2011; 118:52.
  14. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 2011; 118:4567.
  15. Villa E, Zecchini R, Marietta M, et al. Enoxaparin prevents portal vein thrombosis (PVT) and decompensation in advanced cirrhotic patients: Final report of a prospective randomized controlled trial (abstract 120). Hepatology 2011; 54:418a.
  16. Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011; 364:2305.
  17. Boyd EM, Bench AJ, van 't Veer MB, et al. High resolution melting analysis for detection of BRAF exon 15 mutations in hairy cell leukaemia and other lymphoid malignancies. Br J Haematol 2011; 155:609.
  18. Fleischhauer K, Shaw BE, Gooley T, et al. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol 2012; 13:366.
  19. Corbacioglu S, Cesaro S, Faraci M, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet 2012; 379:1301.
  20. Anasetti C, Logan BR, Lee SJ, et al. Increased incidence of chronic graft-versus-host disease and no survival advantage with filgrastim-mobilized peripheral blood stem cells compared to bone marrow transplants from unrelated donors: Results of Blood and Marrow Transplant Clinical Trials Network Protocol 0201, a phase III, prospective, randomized trial (abstract 1). Blood 2011; 118:3.
  21. Eapen M, Klein JP, Sanz GF, et al. Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet Oncol 2011; 12:1214.
  22. Stevens CE, Carrier C, Carpenter C, et al. HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection. Blood 2011; 118:3969.
  23. Cutler C, Kim HT, Sun L, et al. Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation. Blood 2011; 118:6691.
  24. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18:348.
  25. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011; 365:2055.
  26. Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med 2011; 365:1684.
  27. Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011; 365:2357.
  28. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 2012.
  29. Meyer RM, Gospodarowicz MK, Connors JM, et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med 2012; 366:399.
  30. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm287710.htm?source=govdelivery (Accessed on January 13, 2012).
  31. http://dailymed.nlm.nih.gov/dailymed/about.cfm (Accessed on January 23, 2012).
  32. Kumar S, Fonseca R, Ketterling RP, et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood 2012; 119:2100.
  33. Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012; 119:933.
  34. McCarthy P, Owzar K, Anderson K, et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma: CALGB ECOG BMT-CTN 100104. Haematologica 2011; 96:S23.
  35. Kyle RA. Role of maintenance therapy after autologous stem cell transplant for multiple myeloma: lessons for cancer therapy. Mayo Clin Proc 2011; 86:419.
  36. Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011; 12:1195.
  37. Morgan GJ, Gregory WM, Davies FE, et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 2012; 119:7.
  38. Avilés A, Neri N, Fernández R, et al. Randomized Clinical Trial to Assess the Efficacy of Radiotherapy in Primary Mediastinal Large B-Lymphoma. Int J Radiat Oncol Biol Phys 2011.
  39. Yri OE, Torfoss D, Hungnes O, et al. Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. Blood 2011; 118:6769.
  40. Al Khabori M, de Almeida JR, Guyatt GH, et al. Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst 2012; 104:18.
  41. Schaaf M, Reiser M, Borchmann P, et al. High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev 2012; 1:CD007678.
  42. Yamaguchi M, Kwong YL, Kim WS, et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. J Clin Oncol 2011; 29:4410.
  43. Kahl BS, Hong F, Williams ME, et al. Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma (abstract LBA 6). Blood 2011; 118.
  44. Kluin-Nelemans JC, Hoster E, Walewski J, et al. R-CHOP Versus R-FC Followed by Maintenance with Rituximab Versus Interferon-Alfa: Outcome of the First Randomized Trial for Elderly Patients with Mantle Cell Lymphoma (abstract 439). Blood 2011; 118:202.
  45. Press OW, Unger JM, Rimsza LM, et al. A phase III randomized intergroup trial (SWOG S0016) of CHOP chemotherapy plus rituximab vs. CHOP chemotherapy plus iodine-131-tositumomab for the treatment of newly diagnosed follicular non-Hodgkin's lymphoma (abstract 98). Blood 2011; 118:48.
  46. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm283114.htm (Accessed on January 16, 2012).
  47. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366:787.
  48. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366:799.
  49. Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med 2011; 365:1455.
  50. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86:1188.
  51. Campbell AD, Cui S, Shi L, et al. Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes. Proc Natl Acad Sci U S A 2011; 108:18808.
  52. Xu J, Peng C, Sankaran VG, et al. Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science 2011; 334:993.
Topic 8359 Version 24.0

TOPIC OUTLINE

RELATED TOPICS

All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.