Bloodline
Good heme podcasts here.
EHA's online learning center.
U of Minnesota Hematography
tirsdag den 19. januar 2010
torsdag den 14. januar 2010
Benign Hematology
ITP
Is there a difference between treating with prednisone and dexamethasone? This Italian study examines the question by comparing two prospective series of patients treated with HD-DEX with historical controls. The response rate in the two studies were very good. This figure (1A) shows the fate of the 33 responders out of the 37 in the study. 58% of the responders maintained their reponse at 50 months.
EDTA-dependent pseudo-thrombocytopenia
Large Spanish population study, showing that 0.15% of 20000 individuals have pseudo-thrombocytopenia.
Then this Italian study showed that, at their center, 15% of patients referred for asymptomatic thrombocytopenia has pseudo.
The causative antibodies can be of IgG, IgM or, most commonly, IgG. Some 20% have no detectable antibodies. There is no correlation with lymphoproliferative disease. Study here.
Soluble transferrin receptor. This test is rarely used. The reference interval is a little shifty, but this Finnish study in Blood from 1998 pinned it 1.3-3.3.
Staging
Prognosis
Treatment
Links
Is there a difference between treating with prednisone and dexamethasone? This Italian study examines the question by comparing two prospective series of patients treated with HD-DEX with historical controls. The response rate in the two studies were very good. This figure (1A) shows the fate of the 33 responders out of the 37 in the study. 58% of the responders maintained their reponse at 50 months.
EDTA-dependent pseudo-thrombocytopenia
Large Spanish population study, showing that 0.15% of 20000 individuals have pseudo-thrombocytopenia.
Then this Italian study showed that, at their center, 15% of patients referred for asymptomatic thrombocytopenia has pseudo.
The causative antibodies can be of IgG, IgM or, most commonly, IgG. Some 20% have no detectable antibodies. There is no correlation with lymphoproliferative disease. Study here.
Soluble transferrin receptor. This test is rarely used. The reference interval is a little shifty, but this Finnish study in Blood from 1998 pinned it 1.3-3.3.
Staging
Prognosis
Treatment
Links
Chronic Lymphocytic Leukemia
Staging
Prognosis
CD38 positivity:
In an Italian study from 2001, it was shown in multivariate analysis that higher CD38 levels (cutoff here >30%) was correlated with shorter time to progression.
Dürig et al stidied the same in Nature in 2002 here. There was longer survival correlated with CD38 positivity (>20% positive) in univariate analysis but this did NOT hold up in multivariate analysis. Hgb and IgA levels did hold up, however.
It seems like a lot of the risk factors (CD38, IgA, hypermutations, sCD23, ZAP70 are closely correlated).
17p-
A nice study in Blood from 2009 looked at de novo 17p- CLL. In my opinion, the study showed that 17p- lends a poor prognosis but that it shouldn't be considered a stand-alone entity. Some reports have claimed that only Campath works for 17p- but this may be exaggerated, as shown in this study. Responses to rituximab, alkylators and fludarabine were acceptable to warrant these regimens in 17p-.
IGvH Hypermutations:
This study by Oscier et al (Blood, 2002) showed the risk associated with various risk factors, focusing on the IGvH mutations. The Hazard Ratios came to this. Unmutated patients had a 55% death rate at 10 years, compared to 6% for mutated patients.
This study by Oscier et al (Blood, 2002) showed the risk associated with various risk factors, focusing on the IGvH mutations. The Hazard Ratios came to this. Unmutated patients had a 55% death rate at 10 years, compared to 6% for mutated patients.
Staging
This study shows by Stilgenbauer in NEJM 2000 shows survival based on cytogenetics.
Treatment
Indications (NCCN)
fcg
Links
Myelodysplastic Syndrome
Staging/Prognosis
IPSS Calculaor (qxMD)
Treatment
Links
Questions:
MDS with thrombocytosis but not 5q-.
RARS-T syndrome (easily confused with pre-fibrotic myelofibrosis). Should prompt chromosome analysis (looking for 7- og tri(8), for example) and MPL/JAK-2 analysis.
MDS with Auer Rods: MDS or AML?
If less than 10% blasts in BM and less than 5% in blood, this is RAEB-2.
Oral Demethylating agent?
Sapacitabine, which is given orally 3 or 7 days. A phase 2 study presented at ASH 2010 showed that 29-30% of patients, who had failed azacytidine or decitabine, responded. This may be big.
Links:
How I treat (Blood).
IPSS Calculaor (qxMD)
Treatment
Links
Questions:
MDS with thrombocytosis but not 5q-.
RARS-T syndrome (easily confused with pre-fibrotic myelofibrosis). Should prompt chromosome analysis (looking for 7- og tri(8), for example) and MPL/JAK-2 analysis.
MDS with Auer Rods: MDS or AML?
If less than 10% blasts in BM and less than 5% in blood, this is RAEB-2.
Oral Demethylating agent?
Sapacitabine, which is given orally 3 or 7 days. A phase 2 study presented at ASH 2010 showed that 29-30% of patients, who had failed azacytidine or decitabine, responded. This may be big.
Links:
How I treat (Blood).
Chronic Myelogenous Leukemia
The staging of CML is a little more difficult than most other hematologic cancers. There isn't universal agreement about how to stage.
Accelerated phase has:
11-20% blasts in blood or BM
>20% basophils in blood or bone marrow
Platelets < 100 unrelated to therapy
Platelets > 1000 despite therapy
Development of ACA (additional chromosomal abnormalities)
Increasing metabolic symptoms or splenomegali despite treatment
Blast crisis has:
>20% blasts in blood or BM
Chloromas
Large clusters of blasts in the BM
Prognosis based on the SOKAL score, which is a weighted calculation based on age, blasts in peripheral blood, spleen size and platelet count. The formula reads like this:
e (0.0116({age in years}-43.4)+0.0345({spleen size in cm below coastal margin}-7.51)+0.188(({platelet/ 700x10 9 /l }) 2 -0.563)+0.0877({blast %}-2.1)
but can be calculated here
The Sokal score dates back to 1984 (PROGNOSTIC DISCRIMINATION IN “GOOD RISK”. CHRONIC GRANULOCYTIC LEUKEMIA. J.E. SOKAL, E.B. COX, M. BACCARANI, S. TURA,. G.A. GOMEZ et al, BLOOD 1984). The Hasford score from 1998 is somtimes used and includes number of platelets and eosinophils. A nice review of these scoring systems can be found here.
The scoring systems were devised before TKIs (and the Sokal score before interferon therapy) but continue to hold prognostic validity. There is no newer scoring system.
When discussing prognosis with patients, physicians often quote the IRIS study, as this is the largest and oldest cohort of CML patients treated with any TKI. 553 patients were randomized to what would later be called Gleevec or interferon. Most of the interferon group later got Gleevec, so there are no survival data. There is an 8-year update, which was presented at ASH in 2009. Overall, 92-93% of patients have stayed clear of their disease and the survival curve has flattened out. Only one person succumbed to CML in the 8th year of the study.
This does not mean that it was "smooth sailing" on Gleevec for the whole cohort. In fact, little less than half the patients had to go off study for AEs or disease progression. Some were able to regain their response on a higher dose of Gleevec, and - later - some got second generation TKIs, which induced responses.
Treatment
The big question now is whether someone should get a seond generation TKI up front, and this is already being done in some places. Both Nilotinib (Tasigna) and Dasatinib (Sprycel) have data showing decreased time to cytogenetic and molecular responses. The ENESTnd trail comparing Gleevec to two different doses of Tasigna also showed a trend toward improved survival. The DASISION study is similar for Sprycel.
Links
Accelerated phase has:
11-20% blasts in blood or BM
>20% basophils in blood or bone marrow
Platelets < 100 unrelated to therapy
Platelets > 1000 despite therapy
Development of ACA (additional chromosomal abnormalities)
Increasing metabolic symptoms or splenomegali despite treatment
Blast crisis has:
>20% blasts in blood or BM
Chloromas
Large clusters of blasts in the BM
Prognosis based on the SOKAL score, which is a weighted calculation based on age, blasts in peripheral blood, spleen size and platelet count. The formula reads like this:
e (0.0116({age in years}-43.4)+0.0345({spleen size in cm below coastal margin}-7.51)+0.188(({platelet/ 700x10 9 /l }) 2 -0.563)+0.0877({blast %}-2.1)
but can be calculated here
The Sokal score dates back to 1984 (PROGNOSTIC DISCRIMINATION IN “GOOD RISK”. CHRONIC GRANULOCYTIC LEUKEMIA. J.E. SOKAL, E.B. COX, M. BACCARANI, S. TURA,. G.A. GOMEZ et al, BLOOD 1984). The Hasford score from 1998 is somtimes used and includes number of platelets and eosinophils. A nice review of these scoring systems can be found here.
The scoring systems were devised before TKIs (and the Sokal score before interferon therapy) but continue to hold prognostic validity. There is no newer scoring system.
When discussing prognosis with patients, physicians often quote the IRIS study, as this is the largest and oldest cohort of CML patients treated with any TKI. 553 patients were randomized to what would later be called Gleevec or interferon. Most of the interferon group later got Gleevec, so there are no survival data. There is an 8-year update, which was presented at ASH in 2009. Overall, 92-93% of patients have stayed clear of their disease and the survival curve has flattened out. Only one person succumbed to CML in the 8th year of the study.
This does not mean that it was "smooth sailing" on Gleevec for the whole cohort. In fact, little less than half the patients had to go off study for AEs or disease progression. Some were able to regain their response on a higher dose of Gleevec, and - later - some got second generation TKIs, which induced responses.
Treatment
The big question now is whether someone should get a seond generation TKI up front, and this is already being done in some places. Both Nilotinib (Tasigna) and Dasatinib (Sprycel) have data showing decreased time to cytogenetic and molecular responses. The ENESTnd trail comparing Gleevec to two different doses of Tasigna also showed a trend toward improved survival. The DASISION study is similar for Sprycel.
Links
Follicular Lymphoma
Staging
Prognosis
Treatment
GELF Criteria a guide for need of treatment of indolent lymphomas
One or more of the following:
Involvement of 3 nodal sites, each with a diameter of 3 cm
Any nodal or extranodal tumor mass with a diameter of 7 cm
B symptoms
Splenomegaly (enlarged spleen)
Pleural effusions or peritoneal ascites
Cytopenias (leukocytes < 1.0 x 10 /L andor platelets < 100 x 10 /L)
Leukemia (> 5.0 x 10 /L malignant cells)
Links
Diffuse Large Cell B-Cell Lymphoma
Staging
Ann Arbor Staging:
E Extranodal
S Spleen involvement
A/B B Symptoms
Prognosis
R-IPI (Revised International Prognostic Index) calculator.
R-IPI is determined by
Age (>60)
LDH (above normal)
ECOG PS (>3)
Ann-Arbor Stage (>3)
Extranodal sites (>1)
Extranodal DLBCL is commonly GI (40% of extranodals are GI). The stomach is the most common site. Many have H. Pylori in the tumor. This Italian study shows that CR is achieved in 60% of cases in gastric DLBCL with H. Pylori eradication alone.
Treatment
Interesting review of R-CHOP versus various alternatives.
Pfreundschuh's NHL-B2 study, comparing CHOP14, CHOP21, CHOEP14 and CHOEP21 in older (>60 years) patients.
The corresponding NHL-B1 study, comparing the same four treatments in younger, good-prognosis patients.
A study called by Hotta T, Shimakura Y, Ishizuka H, et al. called "Randomized phase III study of standard CHOP (S-CHOP) versus biweekly CHOP (bi-CHOP) in aggressive non-Hodgkin's lymphoma (NHL): Japan Clinical Oncology Group study, JCOG 9809" was apparently never published. Some of the results seem to be described here. This study was stopped prematurely at the first interim analysis, because of slight inferiority of CHOP14 compared to CHOP21. It sounds like the groups did pretty similarly, though.
Only two studies have compared R-CHOP14 to R-CHOP21. The Delarue study presented at ASH 2009 was critized for not giving G-CSF to everyone. It showed that the groups did equally well, although the follow-up is short and the final paper isn't out yet. Here is a review of the interim analysis.
Another study by Cunningham came out at ASCO 2009. Like the Delarue study, it showed the groups doing equally well.
Age
Treatment
Links
Ann Arbor Staging:
E Extranodal
S Spleen involvement
A/B B Symptoms
Prognosis
R-IPI (Revised International Prognostic Index) calculator.
R-IPI is determined by
Age (>60)
LDH (above normal)
ECOG PS (>3)
Ann-Arbor Stage (>3)
Extranodal sites (>1)
Extranodal DLBCL is commonly GI (40% of extranodals are GI). The stomach is the most common site. Many have H. Pylori in the tumor. This Italian study shows that CR is achieved in 60% of cases in gastric DLBCL with H. Pylori eradication alone.
Treatment
Interesting review of R-CHOP versus various alternatives.
Pfreundschuh's NHL-B2 study, comparing CHOP14, CHOP21, CHOEP14 and CHOEP21 in older (>60 years) patients.
The corresponding NHL-B1 study, comparing the same four treatments in younger, good-prognosis patients.
A study called by Hotta T, Shimakura Y, Ishizuka H, et al. called "Randomized phase III study of standard CHOP (S-CHOP) versus biweekly CHOP (bi-CHOP) in aggressive non-Hodgkin's lymphoma (NHL): Japan Clinical Oncology Group study, JCOG 9809" was apparently never published. Some of the results seem to be described here. This study was stopped prematurely at the first interim analysis, because of slight inferiority of CHOP14 compared to CHOP21. It sounds like the groups did pretty similarly, though.
Only two studies have compared R-CHOP14 to R-CHOP21. The Delarue study presented at ASH 2009 was critized for not giving G-CSF to everyone. It showed that the groups did equally well, although the follow-up is short and the final paper isn't out yet. Here is a review of the interim analysis.
Another study by Cunningham came out at ASCO 2009. Like the Delarue study, it showed the groups doing equally well.
Age
Treatment
Links
Multiple Myeloma
Recommendations from the Danish Myeloma Group
Staging ISS Calculator (qsmd.com)
Prognosis MGUS - The Olmsted County study (NEJM 2002). MGUS - Nice review of risk of progression (Blood reviews). These are progression curves, based on the presence of the following risk factors:
- High M protein >1.5g/dL
- Abnormal FLC ratio
- Non-IgG monoclonal protein (ie. IgM og IgA)
This risk stratification model does not take into account the amount of BM plasma cells. 0-5% is low risk, 5-0% is higher risk and >10% is, by definition, smoldering myeloma.
A similar risk stratification model was published by a Swedish group. They identified high M protein and abnormal FLC ratio (like the Olmsted County study). Interestingly, they did not find a difference in IgG and non-IgG MGUS. Instead, immunoparesis was associated with a worse outcome.
Treatment
Initial Treatment (Danish Myeloma Group)
Relapse Treatment (Danish Myeloma Group)
Elderly Patient:
This Spanish study by Dr. Mateos compared VTP to VMP (ie. thalidomide versus melphalan). Both groups did well with 80% PR or better. They used an interesting Velcade dosing, where they gave it once weekly from cycle 3 onwards (instead of twice weekly).
The Palumbo lenalidomide maintenance study was updated at ASH 2011. It seems like lenalidomide after MPR affords one year of PFS. There is no benefit in OS, but this could be from lack of maturity, use of lenalidomide in the nonmaintenance arm etc. As MM relapses tend to be severe, one year is a good increase in PFS. There was in increase in secondary malignancies, but I think this is more of a problem in MDS. MM patients have such impaired survival that an occasional secondary MDS or AML is acceptable.
The UPFRONT trial is a great trial comparing three commonly used regimens: VMP, VD and VPT. These, along with cyclophosphamide, tend to be the 4 drugs we use and the combination seems to be a little random. Perhaps not surprisingly, the three had comparable outcomes. VPT had slightly higher OR, not statistically significant, and VMP had slightly longer TTP. I worry about the neuropathy with V and T, but perhaps with subq Velcade that is less of a concern. I think it's a shame they did not include the old school arm of straight MP, excluding any novel agent from the initial treatment.
Thankfully, a fiveyear followup of the San Miguel study comparing VMP to MP was updated at ASH 2011, in a sense answering that question. V did way better than no V. The V group lived for 4.6 years, about a year longer than the no V group. Apparently, this was not true in patients with adverse cytogenetics.
Everolimus for treatment of relapsed Waldenström's. The study showed an ORR of 70%. About half of patients had problems with toxicity, so it's not free, although it works through a new mechanism (MTOR-inhibition). The ORR is similar to Velcade'd, which was 78% in a study looking at relapsed patients.
Links
Staging ISS Calculator (qsmd.com)
Prognosis MGUS - The Olmsted County study (NEJM 2002). MGUS - Nice review of risk of progression (Blood reviews). These are progression curves, based on the presence of the following risk factors:
- High M protein >1.5g/dL
- Abnormal FLC ratio
- Non-IgG monoclonal protein (ie. IgM og IgA)
This risk stratification model does not take into account the amount of BM plasma cells. 0-5% is low risk, 5-0% is higher risk and >10% is, by definition, smoldering myeloma.
A similar risk stratification model was published by a Swedish group. They identified high M protein and abnormal FLC ratio (like the Olmsted County study). Interestingly, they did not find a difference in IgG and non-IgG MGUS. Instead, immunoparesis was associated with a worse outcome.
Treatment
Initial Treatment (Danish Myeloma Group)
Relapse Treatment (Danish Myeloma Group)
Elderly Patient:
This Spanish study by Dr. Mateos compared VTP to VMP (ie. thalidomide versus melphalan). Both groups did well with 80% PR or better. They used an interesting Velcade dosing, where they gave it once weekly from cycle 3 onwards (instead of twice weekly).
The Palumbo lenalidomide maintenance study was updated at ASH 2011. It seems like lenalidomide after MPR affords one year of PFS. There is no benefit in OS, but this could be from lack of maturity, use of lenalidomide in the nonmaintenance arm etc. As MM relapses tend to be severe, one year is a good increase in PFS. There was in increase in secondary malignancies, but I think this is more of a problem in MDS. MM patients have such impaired survival that an occasional secondary MDS or AML is acceptable.
The UPFRONT trial is a great trial comparing three commonly used regimens: VMP, VD and VPT. These, along with cyclophosphamide, tend to be the 4 drugs we use and the combination seems to be a little random. Perhaps not surprisingly, the three had comparable outcomes. VPT had slightly higher OR, not statistically significant, and VMP had slightly longer TTP. I worry about the neuropathy with V and T, but perhaps with subq Velcade that is less of a concern. I think it's a shame they did not include the old school arm of straight MP, excluding any novel agent from the initial treatment.
Thankfully, a fiveyear followup of the San Miguel study comparing VMP to MP was updated at ASH 2011, in a sense answering that question. V did way better than no V. The V group lived for 4.6 years, about a year longer than the no V group. Apparently, this was not true in patients with adverse cytogenetics.
Everolimus for treatment of relapsed Waldenström's. The study showed an ORR of 70%. About half of patients had problems with toxicity, so it's not free, although it works through a new mechanism (MTOR-inhibition). The ORR is similar to Velcade'd, which was 78% in a study looking at relapsed patients.
Links
Hodgkin's Lymphoma
Staging
Prognosis
Treatment
Bleomycin pulmonary toxicity in HL. On PFT, toxicity is seen with decreased TLC and VC. Monitoring is done with monthly DLco and treatment is discontinued if the DLco falls below 30-35% of pretreatment values.
Prognosis
Treatment
Bleomycin pulmonary toxicity in HL. On PFT, toxicity is seen with decreased TLC and VC. Monitoring is done with monthly DLco and treatment is discontinued if the DLco falls below 30-35% of pretreatment values.
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