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What's new in hematology

Authors
Rebecca F Connor, MD
Stephen A Landaw, MD, PhD
Disclosures
Last literature review version 19.3: septiembre 2011 | This topic last
updated: octubre 18, 2011 (More)
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 MYELOID LEUKEMIA/MYELODYSPLASTIC SYNDROME
Cytarabine dose for post-remission chemotherapy - Cytarabine is one of the
most effective agents available for the treatment of acute myeloid leukemia (AML)
and is a key component of consolidation chemotherapy. While it is clear that higher
doses of cytarabine (eg, 3 g/m2) are preferable to lower doses (eg, 100 to 400
mg/m2), the ideal dose for consolidation, optimizing effectiveness while minimizing
toxicity, remains unknown. Two trials have looked at other dosing of cytarabine (2
g/m2 twice daily for five days [1] and cytarabine 1 g/m2 twice daily for six days
combined with mitoxantrone for a first consolidation course followed in some cases
by an autologous or allogeneic transplant [2]). Though neither trial compared these
regimens directly with cytarabine 3 g/m2 used alone, results suggest that
somewhat lower doses of cytarabine may be equally effective to the 3 gm/m2 dose.
Until further studies clarify whether the dose of cytarabine administered for
consolidation can be lowered, we continue to prefer three courses of cytarabine 3
g/m2 administered twice per day on days 1, 3, and 5 for a total of six doses per
course. (See"Post-remission therapy for acute myeloid leukemia in younger adults",
section on 'Dose of cytarabine' and "Post-remission therapy for acute myeloid
leukemia in younger adults", section on 'Administration of consolidation HDAC'.)
Lenalidomide for MDS with del(5q) - Lenalidomide has been used for the
treatment of myelodysplastic syndrome (MDS) with del(5q) based upon
uncontrolled phase II trials that demonstrated high response rates in patients with
the related 5q minus syndrome. In a randomized phase III trial comparing two
doses of lenalidomide (5 or 10 mg) and placebo in patients with transfusion-
dependent MDS and del(5q), patients treated with lenalidomide achieved higher
rates of independence from blood cell transfusion, and response rates were greater
for 10 mg dosing compared with 5 mg with no increased toxicity [3]. This further
supports our recommendation to use lenalidomide 10 mg for patients with
transfusion-dependent anemia due to low or intermediate-1 risk MDS with del(5q)
with or without other cytogenetic abnormalities. (See "Treatment of intermediate-1
or low risk myelodysplastic syndromes", section on 'Patients with 5q deletion'.)
APLASTIC ANEMIA
Horse versus rabbit antithymocyte globulin - Commercially available
antithymocyte globulins (ATG), used for the treatment of aplastic anemia in
subjects without an HLA-matched hematopoietic cell transplant donor, are made
from either horse or rabbit sources. A prospective randomized trial compared the
relative effectiveness of these two preparations when used with cyclosporine as
immunosuppressive therapy in 120 consecutive patients with severe aplastic
anemia [4]. The primary study endpoint, hematologic response at six months, was
reached significantly more often in those treated with horse ATG than in those
treated with rabbit ATG (68 versus 37 percent, respectively). Three-year overall
survival was also significantly better with horse ATG (96 versus 76 percent).
(See "Aplastic anemia: Prognosis and treatment", section on 'Horse versus rabbit
ATG'.)
Preferred stem cell source - The two major sources of hematopoietic stem cells
used for allogeneic hematopoietic cell transplantation in patients with aplastic
anemia are bone marrow (BM) and progenitor cells collected from the peripheral
blood (PBPCs). A retrospective review of data from the Center for International
Blood and Marrow Transplant Research compared outcomes in patients with severe
aplastic anemia who received either BM (225 transplants) or PBPCs (71 transplants)
from HLA-matched donors [5]. Three-year probabilities of overall survival were
significantly better when BM was used compared with PBPC. The risks for grade II
to IV acute graft-versus-host disease also were significantly lower when BM was
used. (See "Hematopoietic cell transplantation in aplastic anemia", section on
'Preferred stem cell source'.)
Atypical hemolytic uremic syndrome and eculizumab - In September 2011,
the United States Food and Drug Administration (FDA) granted accelerated
approval for the use of eculizumab to treat patients with atypical hemolytic uremic
syndrome (HUS) [6,7]. Eculizumab is a monoclonal antibody that inhibits the
activation of complement by binding to complement protein C5, thus preventing the
production of the terminal complement components C5a and the membrane attack
complex C5b-9. FDA approval was based on a review of several case series that
demonstrated that eculizumab therapy was associated with improved renal
function, normalization of hematological parameters (ie, platelet counts and lactate
dehydrogenase [LDH] levels), and discontinuation of plasma therapy. (See "Atypical
hemolytic uremic syndrome in children", section on 'Eculizumab'.)
CHRONIC LYMPHOCYTIC LEUKEMIA
Fludarabine, cyclophosphamide, rituximab, plus alemtuzumab -
Combination chemotherapy with fludarabine, cyclophosphamide,
andrituximab (FCR) is a preferred initial therapy for patients with chronic
lymphocytic leukemia (CLL) and results in overall and complete response rates of
95 and 70 percent, respectively. The anti-CD52 antibody alemtuzumab is also
active in CLL. A phase II trial of fludarabine, cyclophosphamide, rituximab, plus
alemtuzumab (CFAR) in younger patients (<70 years) with previously untreated
CLL reported an overall response rate of 92 percent (70 percent complete) [8].
Severe toxicities included neutropenia, thrombocytopenia, anemia, and infection.
Randomized trials are necessary to determine whether CFAR is superior to FCR in
this population. (See "Initial treatment of chronic lymphocytic leukemia", section on
'Alemtuzumab'.)
Chimeric antigen receptor-modified T cells - The only known curative therapy
for CLL is allogeneic hematopoietic cell transplantation. However, most patients are
not candidates for this approach. A new approach was described in a report of three
patients with relapsed or refractory CLL who received autologous T cells modified
with a lentiviral vector expressing chimeric antigen receptor with specificity for
CD19, coupled with CD137 and CD3-zeta signalling domains after a preparatory
regimen [9]. All three patients demonstrated a tumor response, which persisted in
one for at least 10 months. Toxicity included severe tumor lysis syndrome. Further
follow-up of these patients and larger trials are needed to determine the efficacy of
this approach. (See "Treatment of relapsed or refractory chronic lymphocytic
leukemia", section on 'Investigational therapies'.)
CHRONIC MYELOID LEUKEMIA
EUTOS scoring system for prognosis - By far the strongest single predictor of
outcome in patients with chronic myeloid leukemia (CML) is the stage of disease at
the time of diagnosis. Various scoring systems have been devised in an attempt to
predict disease outcome (table 1). The Sokal and Euro (Hasford) scores were
developed prior to the discovery of tyrosine kinase inhibitors (TKIs) and use
complicated equations. The substantially simpler EUTOS score is intended to be a
better predictor of clinical responses to imatinib and is based only on the
percentage of basophils in the peripheral blood and spleen size as measured on
physical examination (EUTOS score calculator) [10]. The EUTOS score has not yet
been widely utilized to stratify patients in clinical trials, and it remains to be seen
whether EUTOS will be applicable to patients on more potent second generation
TKIs (eg, dasatinib and nilotinib). (See "Clinical manifestations and diagnosis of
chronic myeloid leukemia", section on 'Scoring systems'.)
Transplantation for patients with T315I mutation - BCR-ABL tyrosine kinase
inhibitors (eg, imatinib, dasatinib, nilotinib) provide long-term disease control for
the majority of patients with chronic myeloid leukemia (CML). However, the T315I
BCR-ABL mutation is associated with extremely high rates of resistance to all
available tyrosine kinase inhibitors and patients with this mutation are considered
for allogeneic hematopoietic cell transplantation (HCT). Outcomes after transplant
appear to be primarily dependent upon the disease phase at the time of HCT and
comorbidities. An international retrospective analysis of patients with T315I
mutation who underwent allogeneic HCT reported that patients in chronic phase at
the time of HCT had a relatively low treatment-related mortality rate (9 and 18
percent at 3 and 12 months post HCT, respectively) and a median overall survival
that had not been reached by 26 months, indicating that patients with this TKI
resistant mutation can be transplanted successfully [11]. (See "Treatment of
chronic myeloid leukemia in chronic phase after failure of initial therapy", section on
'Patients eligible for HCT'.)
HEMATOPOIETIC CELL TRANSPLANTATION
Cord colitis syndrome - Cord colitis syndrome is a culture-negative, antibiotic-
responsive diarrhea that has been described solely among recipients of umbilical
cord blood (UCB) transplantation. An initial retrospective case series of UCB
transplantation at a single institution described the occurrence of cord colitis
syndrome in approximately 10 percent of UCB recipients [12]. Patients with cord
colitis most commonly presented with a persistent (>7 days) watery, nonbloody
diarrhea starting four to five months after transplant. The diarrhea was associated
with weight loss and fever, and the majority of patients required hospitalization.
Cord colitis was distinguished from other causes of diarrhea by negative viral and
bacterial cultures and a colon biopsy that demonstrated chronic active colitis,
frequently with associated granulomas. All cases demonstrated a response to
antibacterial treatment (usually metronidazole with or without a fluoroquinolone).
(See "Supportive care after hematopoietic cell transplantation", section on 'Cord
colitis syndrome'.)
raft-versus-host disease grading - Historically, chronic graft-versus-host
disease (GVHD) has been graded as either limited or extensive based upon the
clinical severity and target organs affected. Several other grading systems have
been developed, but none has been compared with the others. One of these, the
National Institutes of Health (NIH) GVHD scoring system, incorporates information
on the number of organs or sites involved and the severity within each affected
organ (eg, skin, mouth, eyes, gastrointestinal tract, liver, lungs, joints/fascia, and
genital tract) (figure 1). In an initial report of adult patients enrolled in a
prospective study, higher NIH chronic GVHD severity was associated with a
significantly higher rate of non-relapse mortality and shorter survival [13].
(See "Clinical manifestations and diagnosis of chronic graft-versus-host disease",
section on 'NIH consensus criteria for GVHD severity'.)
HODKIN LYMPHOMA
Brentuximab vedotin for relapsed or refractory disease - Brentuximab
vedotin (SGN-35) is an immunotoxin with a CD-30 directed antibody linked to the
antitubulin agent monomethyl auristatin E (MMAE). Brentuximab vedotin was
granted accelerated approval by the US Food and Drug Administration for the
treatment of patients with Hodgkin lymphoma after failure of autologous
hematopoietic cell transplantation (HCT) or after failure of at least two prior multi-
agent chemotherapy regimens in patients who are not candidates for HCT [14].
This approval was based upon a phase II multicenter trial, available in abstract
form only, of brentuximab vedotin in patients with relapsed or refractory Hodgkin
lymphoma after prior autologous HCT that demonstrated an overall response rate
of 73 percent (32 percent complete) with median durations of response of 20 and
3.5 months for those with complete and partial responses, respectively [15]. The
most common severe side effects were neutropenia, anemia, thrombocytopenia,
and peripheral sensory and motor neuropathy. (See "Treatment of relapse of
classical Hodgkin lymphoma after initial chemotherapy", section on
'Immunotoxins'.)
Initial treatment for advanced disease - The ideal combination chemotherapy
regimen for patients with advanced stage Hodgkin lymphoma (HL) is controversial.
Clinicians from the United States generally advocate the combination
of doxorubicin, bleomycin, vinblastine, anddacarbazine (ABVD), while clinicians
from Germany advocate the combination of bleomycin, etoposide,
doxorubicin, cyclophosphamide, vincristine,procarbazine,
and prednisone (BEACOPP) (table 2). A multicenter randomized trial compared
initial treatment with BEACOPP or ABVD, each followed by local radiation therapy to
areas of initial bulky lymphoma or residual disease [16]. Patients with residual or
progressive disease following initial treatment proceeded with high dose
chemotherapy plus autologous hematopoietic stem cell rescue. BEACOPP was
associated with a higher rate of complete response after initial therapy and a lower
rate of disease progression, but greater toxicity and similar rates of overall survival
at seven years. This study and others demonstrate that, when compared with
ABVD, BEACOPP provides better initial tumor control, but no difference in overall
survival when relapsed or refractory disease is managed with high dose
chemotherapy followed by autologous stem cell support [17]. (See "Initial
treatment of advanced (stage III-IV) classical Hodgkin lymphoma", section on
'BEACOPP efficacy'.)
IRON CHELATION FOR IRON OVERLOAD STATES
Deferiprone approved for use in the United States - The orally active iron
chelating agent deferiprone has been in regular use in much of the world for many
years, but had not been approved for use in the United States. This agent was
recently approved by the United States FDA for use in the treatment of patients
with transfusional iron overload due to thalassemia syndromes when current
chelation therapy is inadequate. The recommended initial total daily dose is 75
mg/kg per day. Absolute neutrophil counts must be performed weekly to monitor
for evolving neutropenia/agranulocytosis. (See "Chelation therapy for iron overload
states", section on 'Deferiprone'.)
Use of multiple chelating agents - One parenterally active (deferoxamine) and
two orally active (deferiprone and deferasirox) iron chelating agents are available
for the treatment of iron overload states. Parenteral and oral formulations have
often been used in combination when the use of a single iron chelating agent has
been ineffective. A case report describes a 34-year-old patient with beta
thalassemia major and severe iron overload who had a suboptimal response to
treatment with deferiprone alone and was treated with a combination of the two
oral agents (deferiprone and deferasirox) [18]. After 12 months of combined
therapy, her cardiac iron level, as estimated by MRI, decreased dramatically into
the normal range and her serum ferritin was reduced markedly from >2800 to 397
ng/mL. No toxicities were noted from the combined therapy regimen.
(See "Chelation therapy for iron overload states", section on 'Deferiprone plus
deferasirox'.)
MULTIPLE MYELOMA/MUS
Management of smoldering myeloma - Smoldering multiple myeloma (SMM),
is defined as an M-protein l3 g/dL and/or l10 percent bone marrow plasma cells
but no end organ damage that can be attributed to the underlying plasma cell
disorder (table 3). While initial definitions of SMM did not include an upper limit of
bone marrow involvement, subsequent studies have demonstrated that patients
with >60 percent plasma cells in the bone marrow have a clinical course
characterized by progression to symptomatic myeloma within two years [19]. As
such, asymptomatic patients with bone marrow involvement >60 percent may be
managed in a similar fashion to patients with symptomatic myeloma rather than as
SMM. (See "Determination of initial therapy in patients with multiple myeloma",
section on 'Smoldering (asymptomatic) multiple myeloma (SMM)'.)
Secondary MUS - Secondary monoclonal gammopathy of undetermined
significance (MGUS) refers to the development of a new monoclonal protein during
the course of multiple myeloma that has an isotype (heavy and/or light chain)
distinct from the original clone (eg, IgM MGUS in a patient with IgG multiple
myeloma). In a large series of patients with multiple myeloma, secondary MGUS
developed in 6.6 percent at a median of 12 months from the diagnosis of myeloma
[20]. More than one isotype occurred in approximately 30 percent of patients.
Secondary MGUS was more common among patients who had undergone
hematopoietic cell transplantation and was associated with superior survival. The
MGUS commonly resolved without treatment with a median duration of
approximately six months. (See "Diagnosis of monoclonal gammopathy of
undetermined significance", section on 'Secondary MGUS'.)
TEMPI syndrome - Rare cases of telangiectasias, erythrocytosis with elevated
erythropoietin, monoclonal gammopathy of undetermined significance (MGUS),
perinephric fluid collections, and intrapulmonary shunting (TEMPI syndrome) have
been reported in the literature, although little is known about the physiological
basis of this constellation of symptoms [21]. (See "Diagnosis of monoclonal
gammopathy of undetermined significance", section on 'Associated conditions'.)
NON-HODKIN LYMPHOMA
Bortezomib plus rituximab for follicular lymphoma - The anti-CD20
monoclonal antibody rituximab is an essential part of the treatment of previously
untreated and relapsed follicular lymphoma (FL). Rituximab is typically
administered in combination with chemotherapy agents, but the ideal drugs to
combine with rituximab in the relapsed setting remain unknown. A phase III
randomized trial compared bortezomib plus rituximab with rituximab alone in
patients with relapsed or refractory FL [22]. Bortezomib plus rituximab resulted in
higher rates of overall and complete response, but increased toxicity. While there
was a statistically significant increase in median progression-free survival of
approximately two months (11 versus 13 months) with bortezomib plus rituximab,
the clinical benefit of such an improvement was unclear [23]. Given the lack of
meaningful benefit, we do not advocate the use of this combination.
(See "Treatment of relapsed or refractory follicular lymphoma", section on
'Chemoimmunotherapy'.)
Bendamustine, bortezomib, and rituximab for follicular lymphoma - The
ideal treatment of relapsed or refractory follicular lymphoma (FL) is unknown, but
typically includes the anti-CD20 monoclonal antibody rituximab plus chemotherapy
agents. Two multicenter phase II trials investigated the use
of bendamustine, bortezomib, and rituximab in patients with relapsed or refractory
clinically indolent non-Hodgkin lymphoma (including FL) [24,25]. While an at least
partial response was seen in approximately 90 percent, toxicity was common and
often severe, including one death from sepsis. Given the relatively indolent clinical
nature of FL and the high rate of neuropathy with this regimen, we do not advocate
the use of this combination. (See "Treatment of relapsed or refractory follicular
lymphoma", section on 'Chemoimmunotherapy'.)
Brentuximab for anaplastic large cell lymphoma - Brentuximab
vedotin (SGN-35) is an immunotoxin with a CD-30 directed antibody linked to the
antitubulin agent monomethyl auristatin E (MMAE). Brentuximab vedotin was
granted accelerated approval by the US Food and Drug Administration for the
treatment of patients with systemic anaplastic large cell lymphoma (ALCL) after
failure of at least one prior multi-agent chemotherapy regimen [14]. This approval
was based upon a phase II multicenter trial, available in abstract form only, that
found that patients with relapsed or refractory ALCL treated with brentuximab
vedotin demonstrated an overall response rate of 86 percent (57 percent complete)
with median durations of response of 13 and 2 months for those with complete and
partial responses, respectively [26]. The most common severe side effects were
neutropenia, thrombocytopenia, and peripheral sensory neuropathy.
(See "Treatment of relapsed or refractory peripheral T cell lymphoma", section on
'Brentuximab'.)
Romidepsin for peripheral T cell lymphoma - Romidepsin is a histone
deacetylase inhibitor used for the treatment of relapsed or refractory cutaneous T
cell lymphomas, including mycosis fungoides. Romidepsin was granted accelerated
approval by the US Food and Drug Administration for the treatment of patients with
peripheral T cell lymphoma who have received at least one prior therapy. This
approval was based upon two phase II trials that demonstrated an overall response
rate of 25 to 38 percent [27,28]. The most common severe toxicities included
myelosuppression and infections. Of importance, several treatment-emergent
morphological ECG changes (including T-wave and ST-segment changes) have been
reported in trials of this drug in patients with cutaneous T cell lymphomas, but have
not been shown to be clinically significant. (See "Treatment of relapsed or
refractory peripheral T cell lymphoma", section on 'Romidepsin'.)
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