Linfomas ASH 2008 (3 trabalhos)

Agora, para puxar brasa para a minha sardinha, destaco dois trabalhos feitos aqui no Memorial Sloan-Ketering. Ambos mostram dados de pacientes submetidos a um transplante autólogo de células progenitoras hematopoéticas para tratamento de linfoma de Hodgkin.

No primeiro trabalho, o conceito de quimio-sensibilidade é analisado. Nós sabemos que os pacientes que atingem uma remissão completa antes do transplante têm um melhor prognóstico. Teoricamente, a tomografia por emissão de pósitron (PET) é um ótimo meio de verificar se existe linfoma residual. Neste trabalho, o achado surpreendente é que pacientes em remissão completa anatômica (por tomografia computadorizada) têm uma sobrevida melhor do que aqueles com imagem residual mas PET negativo, o que, em tese, poderia representar apenas tecido fibroso. Aparentemente, não é este o caso.

776 Pre-Transplant Evaluation with Both CT and PET Following Second-Line Therapy Is Essential for Predicting Outcome in Patients with Transplant-Eligible Relapsed and Primary Refractory Hodgkin Lymphoma
Tuesday, December 9, 2008: 8:30 AM
Yerba Buena Ballroom Salon 7 (San Francisco Marriott)
Alison J. Moskowitz, MD1, Stephen D. Nimer2, Andrew D. Zelenetz, MD, PhD3*, Tarun Kewalramani, MD4*, Jill M Vanak, ACNP5*, Jocelyn c Maragulia5*, Joachim Yahalom, MD6 and Craig Moskowitz, MD7

1Education and Training, Medical Oncology, New York, NY
2Laboratory of Molecular Aspects of Hematopoiesis, Memorial Sloan Kettering Cancer Center, New York, NY
3Memorial Sloan-Kettering Cancer Center, New York, NY
4Lahey Clinic, MA
5Medicine, MSKCC, NY, NY
6Memorial Sloan-Kettering Cancer Ctr., New York, NY
7Memorial Sloan Kettering Cancer Ctr., New York, NY

The standard treatment for relapsed and primary refractory (rel/ref) Hodgkin lymphoma (HL) for patients (pts) who demonstrate chemosensitivity to second-line chemotherapy (ST) is high dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT). Since 1994, four studies at our institution evaluated ICE (ifosfamide, carboplatin, and etoposide) based salvage therapy followed by HDT-ASCT in rel/ref HL. Chemosensitivity is a requirement for pts to proceed to HDT-ASCT, however the definition of chemosensitivity is broad. We use both functional imaging (gallium or PET) and CT to assess response to ICE; pts with chemosensitive disease fall into three groups: normalization of CT and FI (NRM), residual mass on CT but with negative FI (RM, FI-), and FI positivity regardless of CT finding (FI+). Here we report the outcome for pts who responded to ICE ST and proceeded to HDT-ASCT.

Between October 1994 and February 2008, 198 pts received ICE on 1 of 4 consecutive protocols (169 pts) or as per protocol (29 pts) and were deemed transplant-eligible. The median follow-up for surviving patients is 7.4 years. There were 99 male pts and 99 female pts; the median age was 31. With respect to the 3 pre-salvage chemotherapy risk factors (RF) (relapse within 1 year of primary treatment, presence of extranodal disease, and B symptoms): 44 pts had 0 RF, 64 had 1 RF, 75 had 2 RF, and 8 had 3 RF. Bulky disease defined as greater than 5cm or 10cm was present in 60 (30%) and 15 (7.5%) pts respectively.

The five year event free survival (EFS) and overall survival (OS) were 69% and 78% respectively. Seventy six (38%) had a NRM response to ST, 73 (37%) had a RM, FI- response, and 49 (25%) were FI+. The 5 year EFS and OS for the three groups were 86% and 93%, 71% and 79%, and 41% and 51% respectively. There was a statistically significant improvement in OS and EFS for the NRM and RM, FI- groups compared to the FI+ group (p<0.0001). Surprisingly, a comparison between the NRM and RM, FI- groups also revealed a statistically significant improvement in EFS and OS for the NRM group (p=0.05 and 0.04 respectively).

Response to ICE ST followed by HDT-ASCT is associated with a prolonged EFS and OS. The quality of response to ICE ST had a significant impact on outcome. Both a residual mass with normalized FI and abnormal FI after ST predicts for an inferior outcome following HDT-ASCT. However, residual radiotracer on FI was associated with the poorest outcome in both EFS and OS.

CONCLUSION: Outcome cannot be predicted by FI alone since both RM, FI- and FI+ groups had an inferior outcome compared to NRM. The most accurate post treatment evaluation includes both CT and PET.

Disclosures: No relevant conflicts of interest to declare.

No segundo trabalho, o novo protocolo para tratamento de linfoma de Hodgkin recaído ou refratário foi analisado. Neste estudo, os pacientes faziam a quimioterapia habitual pré-transplante, ou seja, ICE (ou Mega-ICE, mas isto já é uma outra história). Em seguida, um PET-TC era analisado e se houvesse alguma positividade, o paciente era medicado com mais 4 ciclos de quimioterapia GVD (gencitabina, vinorelbine e doxo-liposomal) antes do transplante. A boa notícia é que os pacientes que entraram em remissão apenas após o GVD tiveram a mesma sobrevida daqueles em que o GVD não foi necessário, muito melhores que os demais. Confiram:

775 Normalization of FDG-PET Pre-ASCT with Additional Non-Cross Resistant Chemotherapy Improves EFS in Patients with Relapsed and Primary Refractory Hodgkin Lymphoma-Memorial Sloan Kettering Protocol 04-047
Tuesday, December 9, 2008: 8:45 AM
Yerba Buena Ballroom Salon 7 (San Francisco Marriott)
Craig H. Moskowitz, MD1, Stephen D. Nimer2, Andrew D. Zelenetz, MD, PhD3*, Paul A. Hamlin Jr., MD3, Steven M. Horwitz, MD3, Ariela Noy, MD4, Carol S. Portlock, MD4, David J. Straus, MD5, John Gerecitano, MD, PhD6, Tarun Kewalramani, MD7*, Jill M. Vanak, ACNP8*, Jocelyn C. Maragulia8* and Joachim Yahalom, MD4

1Memorial Sloan Kettering Cancer Ctr., New York, NY
2Laboratory of Molecular Aspects of Hematopoiesis, Memorial Sloan Kettering Cancer Center, New York, NY
3Memorial Sloan-Kettering Cancer Center, New York, NY
4Memorial Sloan-Kettering Cancer Ctr., New York, NY
5Medicine, MSKCC, New York, NY
6Memorial Sloan-Kettering Cancer Ctr., Lymphoma Service, New York, NY
7Lahey Clinic, MA
8Medicine, MSKCC, NY, NY

We have reported that outcome of transplant-eligible patients (pts) with relapsed and primary refractory HL is determined by three pre-second-line chemotherapy (ST) risk factors (RF): remission duration of <1 yr., extranodal disease and B symptoms. In addition, normalization of FDG-PET prior to ASCT is the most important factor predicting favorable EFS. We now report the preliminary results of an ongoing phase II risk-adapted study where HL pts receive the following: Favorable risk (0-1 RF) - one cycle of standard dose ifosfamide, carboplatin and etoposide (ICE) ST followed by one cycle of augmented ICE; unfavorable risk (2-RF)- 2 cycles of augmented ICE. All pts then underwent a restaging FDG-PET and the results determined the next treatment. Pts with a negative FDG-PET went directly to HDT/ASCT; however if the FDG-PET was still positive, pts received an additional four biweekly cycles of gemcitabine (1000 mg/m2), vinorelbine (20 mg/m2) and liposomal doxorubicin (15 mg/m2) (GVD) followed by repeat FDG-PET scan; pts without evidence of progression then received HDT/ASCT. Preceding high-dose chemotherapy and ASCT, patients that were radiation therapy-naive received involved field radiotherapy (IFRT) followed by total lymphoid irradiation. Selected previously irradiated patients received only IFRT.


Sixty-two pts are evaluable; median follow-up of surviving pts is 30 months; median age was 35. Forty-eight pts had a remission duration of < 1 yr. of those, 28 had primary refractory disease; 28 had extranodal disease and 11 had B symptoms. All patients had previously failed doxorubicin-based chemotherapy; 18 had received prior radiation; of those, 13 failed in the radiation field.


Following first ST chemotherapy with ICE, 3 pts progressed, while 37 pts normalized their FDG-PET scan and currently 31 of these pts are event-free. Twenty-five pts with an improving CT scan after ICE still had a persistently positive FDG-PET; they received the second ST with GVD. Of these, 13 pts normalized their FDG-PET scan and 11 are event-free; the remaining 12 pts had persistently abnormal FDG-PET scan or progressed; only 4 of them are event-free. There was no difference in outcome between the pts who had normal FDG-PET after ICE (pre-ASCT) and those who achieved a negative FDG-PET scan because of the additional ST with GVD. Both of these cohorts had a statistically significant improvement in EFS compared to pts with a persistently positive FDG-PET. In total 46/62 (65%) pts on this program are currently event-free. One pt died from sepsis.


Conclusion: For pts with relapsed and primary refractory HL our evolving strategy is to administer ST until normalization of FDG-PET is achieved prior to HDT/ASCT.

Disclosures: No relevant conflicts of interest to declare.

Finalmente, a atualização do estudo GOELAMS 072 que com um seguimento de quase 10 anos é evidente que o transplante autólogo como parte do tratamento inicial é melhor do que o CHOP para pacientes com fatores de risco adversos. Como o rituximabe entra nisto, é uma outra questão para os próximos 10 anos.

770 High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation (auto-SCT) Versus CHOP Regimen in Patients with Untreated Aggressive Non-Hodgkin’s Lymphoma: An Update of the GOELAMS 072 Trial with a Median Follow-up of 9.8 Years
Tuesday, December 9, 2008: 7:15 AM
Yerba Buena Ballroom Salon 7 (San Francisco Marriott)
Thomas Gastinne1*, Gandhi Damaj2*, Thierry Lamy, PhD3*, Norbert Ifrah4*, Eric Deconinck5, Remy Gressin, MD6, Philippe Colombat, MD, PhD7, Vincent Delwail8*, Christian Berthou9*, Jean François Rossi10*, Jean Luc Harousseau11* and Noel-Jean Milpied, PhD12

1CHU de Nantes, Nantes, France
2Groupe Francophone des Myelodysplasies (GFM), Bobigny, France
3Haematology, CHU Rennes, Rennes, France
4service Hématologie, CHU Angers,, Angers, France
5Hematology, INSERM UMR645 - CHU Jean Minjoz, Besançon
6Dept. of Onc.-Haem., CHU Michallon, Grenoble, France
7Service d'Hématologie et Thérapie Cellulaire, CHU de Tours, Tours, France
8Hématologie et Oncologie médicale, CHU Poitiers, Poitiers, France
9CHU Brest, Brest, France
10INSERM U847, Montpellier, France
11Service d'Hématologie, CHU Hotel Dieu, Nantes, France, NAntes, France
12Hopital Haut Leveque - Pessac, Pessac, France

The interest of autologous stem cell transplantation upfront in aggressive non-Hodgkin's lymphomas (NHL) remains controversial. The GOELAMS 072 was a multicenter randomized prospective trial that enrolled untreated aggressive NHL patients. It was designed to compare the interest of high-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) to the standard CHOP regimen (8 courses every 21 days). From november 1994 to december 1999, 197 patients were enrolled and randomly assigned to receive either auto-SCT (n= 98) or CHOP regimen (n=99). Because the trial has been initiated in 1994, Rituximab was not included in the therapeutic strategy. According to the aa-IPI index, 80 patients presented at diagnosis with a low intermediate and 105 with a high intermediate risk of death. The final results demonstrated that high-dose chemotherapy followed by auto-SCT was superior to CHOP: the 5-year event-free survival estimates (EFS) were 55% versus 37% and the 5-year overall survival (OS) estimates for high intermediate IPI patients were 74% versus 44%, respectively.

The results of the GOELAMS 072 trial was published in the NEJM in 2004 (Milpied et al., NEJM). Second line treatment was left at the discretion of the investigators.This study reports an update of the GOELAMS 072 trial with an extended follow-up (FU) period.

All of the GOELAMS 072 pts were considered elligible for the purpose of this analysis. The primary endpoints were EFS (defined as progression, relapse or death) and OS). To date, 151 among the 197 patients have been evaluated: 77 patients were initially randomized in CHOP Arm and 74 in auto-SCT Arm. Patients characteristics at diagnosis were similar in both arms. The median FU (calculated from time of diagnosis) was 9.8 years. Fifty six events (72.2 % of the patients) have been reported in CHOP arm compared to 41 (55.4%) in the auto-SCT arm. Three patients experienced a secondary malignancy after auto-SCT compared to 4 patients after CHOP. The 9.8 year EFS and OS estimates for patients assigned to receive CHOP versus those assigned to receive auto-SCT were 45.7% vs 27% (p=0.1) and 55% vs 33% (p=0.068); respectively. Among patients with a high intermediate risk of death, the 9.8 year EFS and OS estimates were 47% vs 22% (p=0.049) and 57 vs 28% (p=0.015), respectively (see figure 1).

In conclusion, this long-term analysis (with a median FU of 9.8 years) of the GOELAMS 072 trial confirms that auto-SCT remains superior to CHOP in term of EFS and OS. In note, the advantage of an intensive strategy including auto-SCT is particulary observed for untreated aggressive NHL patients presenting with a high intermediate IPI score. Interstingly, the occurrence of a EFS plateau suggests that a subgroup of patients might be cure by auto-SCT. Because Rituximab has been shown to prolonge OS in aggressive NHL, the interest of high-dose chemotherapy plus Rituximab followed by auto-SCT compared to R-CHOP is still pending. The ongoing GOELAMS 075 prospective trial is addressing this issue.

Disclosures: No relevant conflicts of interest to declare.


Um grande abraço.

transplante autólogo de células-tronco hematopoéticas

Aí vão as indicações mais atuais para o transplante autólogo de células-tronco hematopoéticas (antigo, medula óssea):

1-Linfoma B de grande célula recaído ou com má resposta ao tratamento inicial
2-Linfoma de Hodgkin recaído ou com má resposta ao tratamento inicial
3-Mieloma múltiplo como parte do tratamento inicial
4-Linfomas T agressivos como parte do tratamento inicial (linfoma T periférico NOS, Linfoma anaplásico ALK neg, linfom angio-imunoblástico, linfoma NK-nasal type, linfoma associado a enteropatia, linfoma gama-delta hepato-esplênico)
5-Linfoma folicular em situações especiais (tipicamente recaída precoce após uso de rituximabe)
6-Situações especiais: leucemia mielóide aguda, tumores germinativos

Medicamentos que existem aqui mas não existem no Brasil

Triste lista esta, que nos afasta de várias opções de tratamento para nossos pacientes (lembro que esta lista inclui apenas medicamentos aprovados pelo FDA):

Radioimunoterapia (Bexxar ou Zevalin)
Bendamustina
Bexaroteno
Vorinostat
Pralatrexate
Procarbazina
Nilotinibe

Mais novidades do Congresso americano (Hodgkin)

Outra apresentação de impacto no próximo ASH será a do grupo alemão sobre tratamento de pacientes com linfoma de hodgkin disseminado (protocolo HD12).

No estudo anterior, HD9, publicado há dois anos no New England Journal of Medicine, foi demonstrado em estudo randomizado que o esquema BEACOPP intensificado era superior a dois outros esquemas (BEACOPP padrão e COPP-ABVD). Apesar disto, houve um número importante de leucemias no grupo que recebeu o tratamento superior.

Neste novo estudo, eles demonstram que 4 ciclos de BEACOPP intensificado e mais 4 ciclos de BEACOPP padrão têm o mesmo sucesso e com menos efeitos colaterais.

Está mais que na hora de termos de volta a procarbazina no nosso país!

1558 Eight Cycles of BEACOPP Escalated Compared with 4 Cycles of BEACOPP Escalated Followed by 4 Cycles of BEACOPP Baseline with Our without Radiotherapy in Patients in Advanced Stage Hodgkin Lymphoma (HL): Final Analysis of the Randomised HD12 Trial of the German Hodgkin Study Group (GHSG)
Saturday, December 6, 2008
Hall A (Moscone Center)
Poster Board I-663

Volker Diehl1, Heinz Haverkamp2*, Rolf Peter Mueller3*, Hans Theodor Eich4*, Hans Konrad Mueller-Hermelink5*, Thomas Cerny6*, Jana Markova7*, Anthony Ho8, Lothar Kanz9, Richard Greil10*, Wolfgang Hiddemann11* and Andreas Engert2

1University of Cologne, Cologne/Germany, Germany
2First department of Internal Medicine / German Hodgkin Study Group (GHSG), University of Cologne, Cologne, Germany
3Department of Radiotherapy, University of Cologne, Cologne, Germany
4Department of Radiotherapy, University of Cologne, Cologne/Germany, Germany
5Department of Pathology, University of Wuerzburg, Wuerzburg, Germany
6Department of Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland
7Clinic Hematologia, Fakultne Nemocnice Kralovska Vinohrady, Prague, Czech Republic
8Department of Hematology and Oncology, University of Heidelberg, Heidelberg, Germany
9Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany
10Third Department of Internal Medicine, University of Salzburg, Salzburg, Austria
11Third Department of Internal Medicine, University of Munic, Munic, Germany
Purpose: The GHSG HD9 trial had established BEACOPP escalated (BE) as new standard of care for advanced-stage HL patients by showing significant superiority in terms of failure-free survival (FFTF) and overall survival (OS) over COPP/ABVD and BEACOPP baseline (BB) (each 8 cycles). The successor study, HD12, evaluated a possible reduction in toxicity by comparing 8 cycles of BE with 4 cycles BE followed by 4 cycles BB. The second question in this trial related to the need of additional radiotherapy (RT) to initial bulk and residual disease.
Patients and methods: HL patients in stage IIB with large mediastinal mass and/or E-lesions or stage III/IV were randomised according to a 2x2-factorial design between: 8BE + RT, 8BE no RT, 4BE+4BB + RT, 4BE+4BB no RT. Reviewing CT-images before and after chemotherapy treatment, fields for RT were centrally planned by a multidisciplinary diagnostic panel blinded for the randomisation arm. Primary endpoint of the trial was FFTF. Between 9/1999 and 1/2003, a total of 1,670 patients aged 16-65 were randomized. For this final analysis at a median follow up of 78 months, 99 patients were excluded (42 HL not confirmed, 20 revision of stage, 20 no study treatment or documentation, 17 others) resulting in 1,571 eligible patients.
Results: Patient characteristics in the 4 groups were comparable with 49% of patients in stage III, 35% in stage IV, 68% reporting B-symptoms and 28% having a large mediastinal tumor. An IPS of 3 or greater was reported for 38% of patients, predominant histology was nodular sclerosis with 57% of cases. Treatment-related toxicity of WHO grade III/IV was observed in 97% of patients. Most prominent differences between pooled chemotherapy arms were anemia (65% 8BE vs 51% 4BE+4BB) and thrombopenia (65% vs 51%). Treatment outcome: complete remission 92.4%; early progression 2.2%; progression/relapse 7.8% (6.6% and 8.5%). A total of 156 (9.9%) deaths (72 vs 84) have been observed (22 vs 32 acute or salvage treatment toxicity; 15 vs 24 HL; 22 vs 13 secondary neoplasia). Most treatment related deaths occurred in the >60 years age group, the first 4 cycles and the IPS> 3 RF groups. Secondary neoplasias were observed in 77 patients (4.9%): AML/MDS 1.5% vs 1.4%, NHL 1.4% vs 0.6% and solid tumors/others 2.5% vs 2.3%. At 5 years, OS was 91%, FFTF 85.5% and progression free survival (PFS) 86.2% (Kaplan-Meier estimates). Estimates for the difference at 5 years are 1.8% for OS, 2.3% for FFTF and 2.7% for PFS favoring BE. However, there was no statistical difference between 8x BE and 4BE+4BB in all outcome parameters (p>0.19, log rank test). There is also no significant difference between the RT or no-RT arms in this study with the caveat that a number of high-risk patients receiving RT based on the blinded panel decision.
Conclusion: The adoption of 4BE+4BB as a new standard in the future GHSG studies will depend on a refined analysis of the total data set and will be presented.

Disclosures: No relevant conflicts of interest to declare.

linfomas mesmos subtipos e diferentes respostas

Hoje, assisti a uma conferência do Pesquisador Anthony Letai, do Dana-Farber Camcer Institute em Boston que trabalha em estreita colaboração com gente muito famosa na área dos linfomas, como a Dra Margaret Shipp.
Embora o conteúdo da conferência fosse pesquisa básica, muito do que ele falou merece ser aqui relatado. Basicamente, o foco do estudo dele é um fenômeno que, infelizmente, é conhecido de todos nós que tratamos pacientes com linfoma.

Por que apenas metade dos pacientes com linfoma difuso de grandes células são curados?

Ele estudou 18 tipos de células de linfoma e demonstrou que um tipo específico de proteínas (BH3) se correlaciona com o tipo de reação que a célula terá quando entra em contato com um medicamento.
O objetivo do tratamento é induzir a morte das células malignas. Isto ocorre por um processo denominado APOPTOSE. Para que este processo ocorra, é necessário a presença das proteínas BAX e BAK. Muitas células malignas anulam estas proteínas através da produção de outra proteína, o BCL-2 (ou um do seus 4 irmãos).
É prática comum hoje em dia se demonstrar a presença deste BCL-2 através de imuno-histoquímica, uma técnica disponível em todos os laboratórios de patologia por aí.

O fato interessante que eles demonstraram é que se não houver BAX e BAK na célula, não adianta nada mexer com o BCL-2. Assim, toda uma linha de novos medicamentos voltados para a inibição desta proteína, poderão perder efeito nesta situação, apesar da célula estar cheia do BCL-2.

Mais detalhes em Cancer Cell 12, 171-185 de agosto de 2007