Revisiones, conceptos, análisis de casos, staffs médicos y otros documentos relacionados con hematología benigna, hematología maligna y oncología clínica.


Criterios de respuesta tumoral

Se presentan aquí los criterios de respuesta de valoración respuesta tumoral en oncología basados en los criterios RECIST. También se mencionan los criterios de Lugano (para linfomas) y los criterios de Choi (para tumores estromales gastrointestinales - GISTs). Presentación por la estudiante de medicina de la Universidad CES, Verónica Posada, 28/12/2014.


Lecciones de Oncología - Día 8


Lecciones de Oncología - Día 7


SABCS 2014 - Adjuvant chemotherapy

NSABP-B36: Adjuvant FEC100 x6 vs AC x4 in Node Negative BC
After 82 months, there is no difference in DFS in both arms. Slightly more toxicity with FEC100. Conclusion: No need for 6 cycles of anthracyclines in node-negative disease.

ECOG 1199: How to give adjuvant taxanes in the adjuvant setting (the four arm trial)
Node-positive or high-risk node-negative BC patients received adjuvant AC and were randomized to one of four arms: paclitaxel every three weeks (control), paclitaxel every week, docetaxel every three weeks and docetaxel every week. Several years ago, it was reported that weekly paclitaxel and docetaxel every three weeks had superior DFS compared to the control arm. After 12 years, the results hold. There appear to be some refinements: 1. Obesity and black ethnicity are associated with decreased OS, 2. Weekly paclitaxel is associated with increased DFS and OS in TNBC with a HR of 0.69 (p<0 .05="" a="" i="" in="">post-hoc
analysis (the 10-year DFS went from 59% to 69% and the OS from 66% to 75%). 3. Docetaxel every three weeks appears slightly superior in DFS (but no OS) with a HR of 0.76 in ER+/HER2-/Unknown patients.

ICE: Adjuvant Ibandronate and Capecitabine in 65+ years High-Risk BC and with High Charlson Co-morbidity score
Negative trial.

SABCS 2014 - Hormone Receptor Positive (HR+) BC

Predicting response to hormone therapy in neoadjuvant BC
JM Dixon et al. developed a binary assay that includes: a baseline assessment of mRNA expression of IL-6 related gene and the apoptotic neutral nerve growth factor receptor asociated protein; and also includes two proliferation markers on day 14 on Letrozole. This assay predicts with 96% accuracy the likelihood of response to hormone therapy. The investigators undertook sequential biopsies and subjected them to in-depth genomic analysis. They found that responding patients were losing mutations over time, and the contrary was true in non-responding patients. In Dr. Dixon's view, lack of early biologic effect has ominous implications to the natural history for the BC patient.

OPPORTUNE trial: Pictilisib + Anastrozole vs Anastrozole alone prior to surgery in HR+ BC
The addition of Pictilisib (formerly known as GDC-0941), a pan-PI3k inhibitor, to Anastrozole showed a marked decrease in the Ki67 proliferative index, restricted to the Luminal B cohort or patients. No apparent benefit was seen in the Luminal A patients. The FERGI trial was performed in with the same agent in the metastatic setting, and no clear benefit - so far.

Clinical benefit with 1st-Line hormonal therapy for metastastic breast cancer no different in visceral metastasis to non-visceral metastasis
Disease control of patients with visceral metastasis was carefully assessed in three large randomized trials in the 1st-line metastatic setting in hormone-sensitive breast cancer (Tamoxifen vs Exemestane; Tamoxifen vs Anastrozol; and Tamoxifen vs Fulvestrant). The investigators found that the clinical benefit in this visceral metastasis group was 58% (not unlike the 66% in the soft-tissue/bone metastasis group). Dr. John Robertson concludes that it is unlikely that any 1st-line chemotherapy will afford superior disease control. But he CONTRADICTS himself by stating that if the patient has life-threatening disease she should undergo chemotherapy. If hormone is as good as chemo, why not give it to the sickest?

FIRST trial: Fulvestrant 500 mg vs Anastrozole in 1st-line HR+ mBC
Again, Dr. Robertson, presents the results of this small (205 patient) phase-2 trial with the newer 500 mg formulation of Fulvestrant (a estrogen receptor (ER) inactivator) vs Anastrozole (as the control arm). Fulvestrant has three mechanisms of actions: 1. Blocks the dimerization of ER, 2. Begrades ER and 3. Impairs ER-related pathway cross-talk. The original primary endpoint was clinical benefit rate and it was previously reported. The investigators found a slightly superior, albeit non-statistically significant, clinical benefit rate in favor of the Fulvestrant arm (76% vs 67%). Overall survival was included in a protocol amendment in 2011, the results of which are presented for the first time at this meeting. And the results are impressive: 30% improvement in OS to 54 months median overall survival. We are waiting the results of the phase-3 FALCON trial in 2-3 years. Just a couple of decades ago, the median survival of this group of patients was 24 months.

Lecciones de Oncología - Día 6

SABCS 2014 - Triple negative breast cancer (TNBC)

Myriad-genetics has sponsored two trials on biomarkers in TNBC. The first one in metastatic TNBC comparing Carboplatin to Docetaxel in TNBC (TNT trial). The study showed no difference between Carboplatin and Docetaxel. But, in when the germ-line BRCA+ mTNBC patients were analyzed, the results became quite interesting. The response rate in BRCA+ mTNBC was 68% vs 33% in favor of Carboplatin. The non-basal TNBC (by PAM50) had a remarkable response to Docetaxel (but, it was a small subgroup of patients). The company has also created a genetic test called HRD (Homologous Recombination Deficiency) test to assess the integrity of the DNA repair mechanism in TNBC patients. In a companion trial, patients with early breast cancer had a 52% response rate to platinum if they tested positive to HRD, and only 10% if the results were negative.

Geparsepto: Nab-Paclitaxel in neoadjuvant BC
The germans presented they large Geparsepto trial with about 1200 patients comparing neoadjuvant Paclitaxel followed by EC to nab-Paclitaxel (150 mg/wk) followed by EC. The endpoint was pathologic complete response (pCR). Nab-paclitaxel arm exhibited higher neuropathy and diarrhea. The study met its primary endpoint with an increase in the pCR from 28% to 39% (p=0.001). The results were impressive in the TNBC group with pCR of 48% (25% with the conventional paclitaxel).

Pembrolizumab in TNBC
A phase 1b trial reported by Rita Nanda with Pembrolizumab 10 mg/kg IV q2wk in 32 heavily pretreated PD-L1+ (by IHC) TNBC patients. There were 5 responses in the 27 evaluable patients (ORR: 18.5%), with 1 CR. The median duration of response was >40 weeks (in responding patients), and 1.9 mo (in the others). Treatment was well tolerated, one patient with rapidly progressive metastatic disease died of disseminated intravascular coagulation.


Lecciones de Oncología - Día 5


Lecciones de Oncología - Día 4


ASH 2014 - Lymphoma & Multiple Myeloma

Hodgkin's Lymphoma
Upfront therapy
1. Brentuximab Vedotin instead of Bleomycin in ABVD (both share pulmonary toxicity): 96% 3-yr failure-free survival in advanced-stage Hodgkin's Lymphoma. Phase III studies are under way.

Relapsed / Refractory disease
1. Brentuximab + Bendamustine in preparation to autologous stem-cell transplantation: Small study, outpatient, ORR in the 90% range, and CR in the 80% range.

2. AETHERA trial shows higher 2-yr PFS in patients receiving consolidation with Brentuximab after Stem-Cell Transplantation for Hodgkin's Lymphoma (65% vs 45%), poised to become a new standard-of-care.

3. Nivolumab (anti PD-1 monoclonal antibody) in post-transplant relapse: Hodgkin's lymphoma is an ideal model for immune checkpoint modulation due to high immunocyte infiltration around the tumor cells. There is a Phase 1 study with up to 80% response rate in heavily pretreated patients (including patients previously treated with Brentuximab Vedotin). This is the most exciting result in lymphoma in this ASH 2014 (NEJM On-line first).

Low-grade lymphomas
1. Ibrutinib in follicular lymphoma: Ibrutinib showed only 30% response rate in relapse follicular lymphoma patients (somewhat disappointing). Whereas Idelalisib (PI3k inhibitor) shows 50% response rate with a median PFS of up to a year in chemo & rituximab refractory follicular lymphoma patients (and is FDA approved in that indication).

2. EFS12 as a prognostic marker in follicular lymphoma: A Mayo clinic dataset has shown that patients who have not had an event at 12 months after either initial treatment or observation have a life expectancy similar to age-matched controls. The converse is true, patients that have events within a year will not do well, and require a more aggressive approach.

Diffuse Large B-cell lymphoma (DLBCL)
1. Double-hit DLBCL: Abnormalities in both c-Myc and bcl-2 genes should be looked in high Ki67/proliferative DLCL. Some studies show that DA-EPOCH is effective with PFS in the 60% at 1-year.

2. Selenexor (a nuclear trafficking inhibitor): some 40% response rate in relapsed DLBCL, with some CRs, in phase-I trials.

Mantle-Cell lymphoma (MCL)
1. Intensive therapy is still disappointing in MCL: The current theme in MCL is highly aggressive upfront chemotherapy (R-CHOP alternating with DHAP, followed by transplant; R-CHOP followed by Bortezomib; Bortezomib + Rituximab + Bendamustine). All these trials are showing some relapses at the 3-year mark.

2. Chemo-free for MCL with Lenalidomide + Rituximab in 1-st line: Small study (38 patients) with median age of 65: 88% went into remission and 2-yr EFS in 80%.

Multiple Myeloma
Upfront therapy
1. Carfilzomib in 1st-line multiple myeloma patients: An italian trial showed very high response rate in the order of  >75% in patients receiving high-dose weekly Carfilzomib + Cyclophosphamide + Dexamethasone.

2. Ixazomib, an oral proteasome inhibitor, + Lenalidomide + Dexamethasone: The all oral combination chemotherapy was well tolerated and exhibited high response rate.

Relapsed  / Refractory disease
1. ASPIRE trial (Carfilzomib + Lenalidomide + Dexamethasone): Possibly the most outstanding result of the ASH 2014 (NEJM On-line first). Carfilzomib + Lenalidomide + Dexamethasone increases the PFS by 9 months over Lenalidomide + Dexamethasona in relapsed multiple myeloma patiens (26 months vs 17 months). The benefit was also seen in patients with high-risk cytogenetics. Quality-of-life was also superior in the Carfilzomib-based arm.

2. Oral proteasome inhibitors: Several presentations showed that both Ixazomib and Oprozomib are active in heavily-treated myeloma patients. Specifically, Oprozomib showed a single-agent activity with 30% response-rate in Carfilzomib-refractory patients. A change in formulation to tablet, and the use of antiemetic agents decreased its chemotherapy-induced nausea and vomiting. Still, not ready for prime time.

3. Anti CD38 monoclonal antibodies (MoAbs): CD38 is a surface marker in plasmocytes (and other blood cells). Daratumumab and SAR650984 are MoAbs that have shown activity in myeloma patients. In this ASH it was presented a combination of Daratumumab + Lenalidomide + Dexamethasone in relapsed myeloma patients. No added toxicity was found beyond a few infusion reactions.

4. Histone Deacetylase (HDAC) inhibitors (Panobinostat): Some interesting results with Panobinostat in relapsed/refractory myeloma. Further studies are required, especially to deal with its gastrointestinal toxicity.

5. Ibrutinib: The Bruton Tyrosine Kinase inhibitor, Ibrutinib has exhibited high clinical benefit rate of 50% with a median PFS of 6 months in heavily pre-treated myeloma patients. Another interesting agent that merits further investigation in this condition.

The longer exposure to anti-myeloma agents, the better. Post transplant lenalidomide maintenance is highly effective with responses that occur over several months. Some other trials have shown that Bortezomib maintenance is also highly effective.

1. Single-agent pomalidomide in heavily pre-treated myeloma: The newer imid Pomalidomide has shown to be effective as a single-agent, with a response rate of about 35%.

2. Pomalidomide in combination with other agents: In this ASH there are reports that show that Pomalidomide can be safely combined with Bortezomib + Dexamethasone, with Cyclophosphamide + Dexamethasone, also with Liposomal Doxorubicine + Dexamethasone with very good safety profile, and response rate in the range of 60-70%.

3. Safety of Pomalidomide in renal insufficiency: Some data were presented that show that Pomalidomide can be safely administered in pretty much any patient with any degree of renal dysfunction, provided they are not in dialysis.

ASH 2014 - Myeloproliferative neoplasms, Myelodysplasia, Acute lymphocytic leukemia and Acute Myeloid Leukemia

1. From the mutational perspective there are three driver mutations in myelofibrosis: JAK2, MPL and CALR. Nevertheless, there are about 10% of patients that are triple-negative, with worse prognosis. All three mutations activate the JAK2 pathway and respond to JAK2 inhibitors. But, some patients deemed Low-Risk by clinical criteria can move up to High-Risk based on the mutational pattern, therefore transplantations should be offered sooner to them. Several additional passenger mutations have been discovered that reflect clonal evolution and deal mainly with epigenetic phenomena. 

2. Currently, there are three new research avenues in myelofibrosis: 1. Addition of another agent to the JAK2 inhibitor: JAK2 inhibitors are good at decreasing inflammation and spleen, but they are not good at improving blood counts. There are studies combining JAK2 inhibitors with PI3k inhibitors, Hedgehog inhibitors, HiDAC inhibitors, Antifibrotic agents. 2. Exploring selective JAK1 inhibitor: it appears that JAK1 inhibitor may provide anti-inflammatory effects, but it is less effective on the splenomegaly. 3. A promising anti-Telomerase agent is under study with some patients achieving complete remission. Will have to see the actual results in this meeting.

Polycythemia vera (PV)

Just 3 days ago, Ruxolitinib was approved by the FDA for 2nd-line therapy in PV in patients resistant or intolerant to Hydrea. (The presenter summarizes what the standard of care of PV is: you treat with phlebotomy, aspirin and probably Hydrea the majority of PV patiens. The goal is to keep the hematocrit below 45% in order to decrease the risk of thrombosis. The actual indication for Hydrea is patient older than 60 or a history of thrombosis). About 25% of patients do not tolerate Hydrea, and they don't do well. Ruxolitinib becomes an option for these patients (it is estimated that about 25.000 patients are going to need it in the US alone). In this ASH there will be a presentation on QoL with Ruxoilitinib, showing a marked improvement in several aspects with Ruxolitinib.

Essential thrombocythemia (ET)

1. ET is the most benign of the myeloproliferative neoplasms, with nearly normal life-expectancy. It can be treated with aspirin, Hydrea or Anagrelide. Ruxolitinib is not as good in ET compared to its results in Myelofibrosis and PV. It affords adequate response in 70-80% High-Risk ET patients; but may cause significant anemia. 

2. Pegylated-Interferon (Pegassys) has shown activity in both PV and ET, and appears quite effective in both. In this ASH there is going to be a presentation on the impact of the mutation status and response to pegylated interferon in MPN.

Myelodysplasia (MDS)

1. MDS - Negative results of S117 (Azacytidine vs Azacytidine + Vorinostat vs Azacytidine + Lenalidomide)
Enrolled about 280 patients, no difference in response in the three arms, combination therapy more toxic, more patients came out of the study due to toxicity, some evidence of longer PFS with combination, not powered to detect OS benefit. Does not change practice.

2. Rigosertib not effective in 2nd-Line MDS after hypomethylating agents in a Phase 3 trial

OS increased from 5 to about 8 months, not reaching statistical significance. An oral formulation is still being developed with some encouraging results, but it is not ready for prime-time.

3. New treatment options for Low-Risk (LR) MDS

LR-MDS patients are treated with EPO or Lenalidomide (indicated in del-5q MDS, buy often used "off-label" in other settings). But some patients are refractory to these agents (or have high EPO blood levels predicting a poor response to a pharmacologic EPO formulation).
There are two promising agents in this particular setting, and both share the same mechanism of action as ligand traps to the TGF-Beta receptor superfamily (Sotatercept: an activin type IIA receptor-fusion protein, and ACE-536: a modified activin type IIB receptor-fusion protein). It is known that TGF-Beta mediates anemia and chronic inflammation. Some preliminary results show up to 40% response rate (including transfusion-independence) to Sotatercept, and further results are going to be presented at this ASH with both agents. It is interesting to know that these agents are bone-morphogenetic factors that show promise in osteoporosis, multiple myeloma, thalassemia, and Castleman disease.

Newer agents in Acute Lymphoblastic Leukemia (ALL)

The FDA approved Blinatumumab (CD19-CD3 bi-specific antibody) for refractory and relapsed B-Cell ALL. There are other agents under investigation: a CD-19 conjugated to a toxin, Inotuzumab (CD22 conjugated to ozogamycin), CAR-T-Cells. Inotuzumab also appears very promising and it is now on a Phase III trial.

Acute Myeloid Leukemia (AML)

1. Sorafenib + Anthracycline + Cytarabine in AML: Not quite there.
In the SORAML trial Sorafenib was added to standard induction chemotherapy in AML and was found  to increase event-free survival (3-yr EFS 56% vs 38%, with PFS of 21 vs 9 months, in favor of the Sorafenib arm) and relapse-free survival was also superior in the Sorafenib. But no OS advantage was detected (but the study was underpowered to detect it, with only 276 patients). The speaker points out that Sorafenib is used off-label in relapsed FLT3 mutated patients (sometimes in combination with hypomethylating agents) with very good results. Interestingly, the response to sorafenib in the german trial was not restricted to FLT3 mutation+ AML.

2. DH2 inhibitors are promising in IDH2 mutated AML

Isocytrate dehydrogenase-2 (IDH2) is mutated in about 20% of AML. Anti IDH2 agents are clearly EFFECTIVE in this group of patients achieving significant cytoreduction allowing some highly refractory patients to bridge to allo-transplantation. 


Lecciones de Oncología - Día 3


Lecciones de Oncología - Día 2

Avances en Oncología y Hematología oncológica

Podcasts sobre los estudios, avances, descubrimientos y otros aspectos interesantes de la actualidad en hematología oncológica, oncología clínica y biología molecular del cáncer.


Lecciones de oncología - Día 1

Esta serie de Podcasts son las lecciones impartidas durante la rotación de la Dra. Verónica Posada en el servicio de oncología de la clínica SOMA, en Medellín. Buscan ilustrar la forma como se enfocan los pacientes ya en un entorno asistencial.

Día 1.

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