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Cancer is one of the most widespread diseases , Around 12.7 million new cancer cases were diagnosed worldwide in 2008 and around 7.6 million deaths from cancer occurred in 2008 (this data is taken from the GLOBOCAN 2008 database ). About 1,638,910 new cancer cases are expected to be diagnosed in 2012.
Lymphomas are divided into Hodgkin's and non-Hodgkin's categories. According to the new Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 1997, the age-adjusted incidence rates rose by about 80%, with an annual percentage increase of nearly 3%, which is faster than the majority of other types of cancer.
The most recent therapeutic methods is the use of stem cells . Stem cells have indefinite ability to proliferate and differentiate into different organs unlike mature cells which have smaller replicative lifespan , so stem cells opened the door to a large number of researches and scientists do their best to benefit as much as possible from those indefinitely replicating cells.
Hodgkin's lymphoma is diagnosed in about 635.000 every year,so it's one of the widespread diseases in the world.After development of radiotherapy and chemotherapy this disease changed from being fatal to curable one with 70 to 90 % cure rate at initial therapy in chemosensitive Hodgkin's lymphoma. About 10% of those don't reach complete remission and up to 30 % experience relapse .Now we are testing these therapies for chemoresistant Hodgkin's lymphoma (show relapse or primary refractory disease)which have poorer prognosis 11.
As years passed the results improved and this doesn't likely depend on the source of stem cells (whether PBSC or bone marrow).The improvements are likely to be multifactorial depending on the supportive care and refined patient selection,However retrospective study of this nature couldn't confirm this hypothesis 6.
If we want to Â determine the best therapy whether it's ASCT or other therapies we have to do further studies in the future .We can Â do surgical removal of the tumor and better diagnosis to help better to identify the appropriate therapy.we can also use anti CD30 monoclonal antibodies or radiotherapy by means of radioimmunotherapy-based transplant-conditioning regimens, as Â what had been done in non Hodgkin's lymphoma
Leukemia may be a second complication to Hodgkin's so treatment should be associated with alkylating agents or further radiotherapy 8. Long term follow up is essential to measure the efficacy or maybe toxicity issues.
ASCT showed adverse features of early toxicity in some patients as hepatic veno-occlusive disease and cardiac toxicity that we will talk about 6.
Chemotherapy is recommended in relapse if remission is more than 12 months.But if remission
duration was less we suggest the newer techniques for better results 8.
If we want to Â determine the best therapy whether it's ASCT or other therapies we have to do further studies in the future .We can Â do surgical removal of the tumor and better diagnosis to help better to identify the appropriate therapy.we can also use anti CD30 monoclonal antibodies antibodies or radiotherapy by means of radioimmunotherapy-based transplant-conditioning regimens, as Â what have been done in non Hodgkin's lymphoma 8.
Now we are comparing (PBSCT & ABMT) to see which improves engraftment,quality of life and cost effectiveness in patients with relapsed Â Hodgkin's lymphoma after pretherapy with DHAP . PBSCT results in faster engraftment of PNL, it also requires shorter hospital stay and fewer costs & supportive care 17. Â Future studies using monoclonal antibodies ,radiolabeled CD20 or immunotherapy in combination with chemotherapy will make the treatment more effective.
We are going to discuss the use of stem cell transplantation and the associated chemotherapy in treatment of hodgkin's lymphoma.Also the role of stem cell transplantation in chemosensitive and how it differs in case of chemoresistant cases. In case of relapse after initial treatment what is the role of stem cell transplantation for those patients and does this choice differs if the patients were children or adolescents ?
Response assessment before transplantation:
reports about using gallium or FDG PET scanning to predict the outcome post Â ASCT can provide some prognostic informations but they are not enough to determine who should proceed to transplantation 11.
Preparative regimen before ASCT:
the standard preparative regimen before ASCT are high intensity regimens such as Â CBV (cyclophosphamide, BCNU, and etoposide) which are the standard therapy for young patients with lymphoma while in elderly busulfan and cyclophosphamide are used as alternative therapy and they are comparable in toxicity to other Hodgkin's lymphoma Â ASCT regimens.
Inadequate response to salvage chemotherapy is not an uncommon problem ,those who don't respond to salvage chemotherapy undergo non curative treatment 11.The best induction therapy used to achieve remission before transplantation is still not stated. The problem is in the development of secondary malignancies especially breast cancer, lung cancer as late malignancies and leukemia which occurs at early stage, late toxicity and cardiac events..The responsiveness to induction therapy is the most important prognostic factor to determine the outcome 3. Patients with PBSCT have shorter time to engraftment than those received bone marrow 2.
Timing of peripheral stem cell transplantation (PSCT):
the timing of peripheral blood stem cell mobilization differs according to the regimen used , the patient and the basis of disease .PBSC mobilization is delayed with regimens containing melphalan, such as dexa-BEAM or mini-BEAM.
HDT - ASCT:
Clinical Trials state that there is no difference between 2 cycles of dexa-BEAM chemotherapy and high dose therapy with ASCT in OS but there was improvement in freedom of failure of treatment at 3 years in HDT with ASCT, these trials were done on chemosensitive patients but chemoresistant patients achieve a lower response. There isn't enough data for chemoresistant patients 11.
A randomized controlled trial was done and showed that there is no difference between high dose sequential therapy ( HDS therapy) followed by ASCT and standard DHAP followed by ASCT in OS ,PFS 11 . For chemosensitive patients who have HL , HDT followed by ASCT is the treatment of choice Â for advanced Hl according to phase 2,3 trials , however this therapy is denied for chemoresistant cases 6.
Another RCT was done , the patients were randomized into group receiving HDT/ASCT and other group receiving standard chemotherapy (four courses ), it stated that there is no difference between both groups in 10 year OS ,RES and FFS also there was no difference in the associated toxicity . So HDT/ASCT is not better than conventional chemotherapy as consolidation after initial treatment 5.
The safety of using HDT/ASCT is good as an initial therapy but this was stated before the era of FDG-PET as only patients were diagnosed by adverse poor prognostic factors, after the use of FDG-PET ,there is early diagnosis of the patients and HDT/ASCT is not recommended 5.
Role of HDT-auto SCT in chemoresistant patients:
HDT and ASCT is the standard treatment for chemosensitive relapsed and refractory HL but in chemoresistant patients the use of HDT and ASCT is still under study 10 .A study was done to know the overall efficacy of HDT and ASCT in treatment of those patients(Seattle experience) 6. The OS of those patients has recently been improved due to many factors such as improvement of post-relapse therapy, refining patients, more effective supportive care for the patients and more effective control of the disease using gemcitabine based chemotherapy.It's not only due to use of PBSC as a source of stem cell transplantation 6. Although chemoresistant patients in this study showed high PFS, these patients may undergo relapse at a later time. Those who don't respond to traditional chemotherapy showed higher response when treated by gemcitabine based chemotherapy as it causes both debulking of the tumor also better identification of the patients who will need HDT.
Future studies should spot the light on using radioimmunotherapy based transplantation in radiosensitive patients 6. chemorefractory patients with HL have low survival rate with very severe clinical course that overcome the graft versus hodgkin effect (GVHE) 13. those patients who relapse after ASCT together with elderly , chemoresistant and those with significant associated diseases may become incurable ,only minority are eligible for RIC-allo with also many obstacles as the availability of the donors, combination of standard therapy can be used in these cases. Gemcitabine and Vinblastine are frequently used. Whether to choose conventional chemotherapy, HDT, imaging or radiotherapy pre ASCT is still unclear 11
ASCT as a consolidation therapy Â for hodgkin lymphoma :
As consolidation to response after primary chemotherapy ,ASCT ,HDT and radiotherapy can be used . RCT was done by The Scotland and Newcastle Lymphoma Group HD3 and showed that there was no significant difference between ASCT and HDT in OS and another trial was done by the large european intergroup and concluded that there is no benefit of early ASCT for those with advanced non favourable HL (Advanced hodgkin lymphoma is known when the bulk is more than 10cm,stage III or IV and presence of B symptoms) who responded to primary chemotherapy 10.Also as stated before HDT/ASCT is not better than conventional chemotherapy as a consolidation therapy 5.Neither stem cell transplantation nor radiotherapy achieved higher OS. Radiation therapy is better as a consolidation therapy than ASCT as it has less toxicity and easier to be applied and appears to be of benefit in patients who achieved a partial response(PR) after primary chemotherapy but that wasn't confirmed by trials10.
:ASCT related toxicity
Clinical trials show occurrence of mucositis during hospitalization, documented bacterial infections (Coagulase- negative Staphylococcal bacteremia , acute appendicitis , fungal infection (Candida parapsilosis fungemia), localized varicella zoster reactivation, hepatic veno- occlusive disease (VOD) requiring intensive care unit for multiorgan system dysfunction, but improved after treatment with defibrotide and ultimately survived to hospital discharge ,acute cardiac toxicity with transient congestive heart failure , also neurotoxicity can occur. Â
pulmonary complications as shortness of breath with pneumonitis,asymptomatic interstitial lung disease are possibly related to prior chemotherapy and radiation, diffuse alveolar damage ,pulmonary fibrosis and right sided heart failure also may occur ,secondary myeloblastic syndrome was also recorded after ASCT in those who received busulfan orally in their conditioning regimen Â 6
Relapsed or Refractory Hodgkin Lymphoma (RR-HL):
Refractory patients are defined as those who fail to reach complete remission within 3 months of first line therapy. Relapsed patients are those who relapse after at least 3 months after complete remission after first line therapy 3 .Most of the patients relapsing after auto-SCT had bad pretransplantation disease control thus if patients achieved good disease control prior to transplantation this will decrease the rate of relapse 1. Â Â Â Â Â Â
How to diagnose relapsed or refractory HL:
Serial imaging can be used to detect progression of the disease after primary therapy where it appears as asymptomatic radiological abnormalities.11
The standard method used in tumor surveillance is the National Comprehensive Cancer Network (NCCN) Guidelines , these guidelines suggest the routine chest x-ray or CT scan (level of evidence grade A2 ) and routine abdominal x-ray or CT scan for diagnosis of relapse in hodgkin disease , but many reports say that imaging techniques are of limited value to detect the recurrence of the disease11.
Â Â Repeated CT scan can also used for detection of refractory or relapsed hodgkin disease , it's also used in case of late relapse which occur beyond 3 -5 years , or when the doctor suspects another disease , however radiological examination of previously affected sites is better to avoid invasive test with risk of complications.11
Diagnosis can be done by (FDG-PET) , which is used after primary chemotherapy , to detect remission and after the end of treatment (6-8) weeks after chemotherapy , (8-12) weeks after radiation 11 . it's believed that positive predictive value of PET is not the only test to detect recurrent HL, it suggests treatment failure and need to ASCT but not all studies support that.
PET can be false positive in the following cases ;rebound thymic hyperplasia in young patients, local inflammation after chemotherapy or radiotherapy, sarcoidosis, or deposition of brown fat 11.CT-defined chemoresistant patients with negative PET were shown to be like those CT-defined responsive patients , so PET before transplantation is needed, in this study not all patients underwent PET so this data can't be confirmed 6.
patients with negative FDG and transplanted showed better PFS 3.So FDG-PET is important factor affecting the outcome either used in diagnosis or assessing disease progression.it causes better OS and PFS, but in another study there was no significant difference regarding OS and PFS between those who had undergone FDG-PET and those who hadn't before transplantation 3. The use of PET is of benefit in determining the patients who respond to ASCT and who will not respond and should be directed to other strategies 6,3. Â
To summarize ,serial imaging is not recommended to detect recurrent HL so as not to expose the patient to other diagnostic radiation and high cost , rebiopsy is recommended to detect recurrent HL ,biopsy is also done to FDG-PET positive patients before salvage chemotherapy and ASCT 11.
Prognostic factors of RR HL:
Poor performance(Eastern Cooperative Oncology Group score >0),older than 50, failure to obtain temporary remission to initial therapy.
According to GHSG the significant adverse prognostic factors were anemia , advanced clinical stage (III, IV), treatment failure <12 months.Advanced stage at relapse and poor performance are predictors of poor outcome 11.
Stem cell transplantation in treatment of Relapsed or refractory Hl (RR-HL) compared to other regimens:
As HDT caused cure of about 50% of patients with relapsed HL , it was stated as a standard therapy for them 3,10.There are only few reports on using radiotherapy alone for RR-HL although radiotherapy together with conventional chemotherapy are known to be the standard treatment for primary limited hodgkin's lymphoma ,as after that ASCT showed superiority over conventional chemotherapy .GHSG reported a study that was done between 1988 to 1999 and showed that freedom from treatment failure and OS in case of salvage radiotherapy alone was 20%, in chemotherapy regimens was 29 %, and 51% in who had received escalated chemotherapy regimen.Other studies showed that salvage radiotherapy cause long term control in about 23-44% of patients. Radiotherapy can be used in relapsed cases if the patient was not irradiated before in the area of relapse especially in elderly without B symptoms and those who were at early stage at relapse. In patients with late relapse (after 5 years ) ,standard chemotherapy with involved field radiation is used 11.In patients of HL relapsed after allo SCT ,salvage radio-chemotherapy show very low OS raging between 8 and 38 months15.Patients with late relapse may benefit from standard dose chemotherapy and achieve long term disease control . also patients relapsing after use of radiotherapy as initial treatment at limited stage disease benefit from conventional chemotherapy regarding freedom from second treatment failure 10 .
The standard treatment for those who relapse is auto-SCT however this is the standard for chemosensitive patients while those with refractory disease or those relapsing after auto SCT have many options and so far the standard option is under debate 4,10 . To achieve long lasting cure for relapsed patients stem cell transplantation appeared better than other single therapeutic agents .Inspite of this there are many problems facing SCT as toxicity , early transplant related mortality (TRM) thus the use of RIC-SCT showed better results than complete myeloablative allo-SCT 4 .
Allogeneic SCT has been increasingly used in relapsed HL as many patients are young , in addition to the antitumor effect and absence of significant graft versus HL effect, also there is safety especially with reduced intensity SCT 11. The time from auto SCT till relapse affects the prognosis of the disease, when this time is long (about 12 months ) this means that these group are poor risk patients and those with early relapse have bad prognosis. In allo grafted patients no difference was shown. This may be due to the effect of GVHR which overcome the adverse of early relapse 13.
The adverse effects of HSCT is non relapse related mortality (NRM) which is caused mainly by graft versus host disease, infectious complications and organ toxicity. the benefit of allo-SCT in RR-HL is still under discussion, allo-SCT should be done either from the initial procedure or collected , many trials should be done in that field 11,10. second ASCT is recommended in chemosensitive patients with remission for 5 years after the first one 11.
Chemoresistant patients don't usually benefit from allo-SCT but need more aggressive chemotherapy or changing the GVHD prophylaxis. The best outcome was of those having complete remission prior to transplantation 15. Complete response (CR) patients differs from those with partial response (PR) in OS and PFS 13
The use of RIC-allo SCT in relapsed HL:
As we stated allogeneic SCT has been used in advanced stages of HL but its use is still limited as the mortality rate exceeded 50% and relapse isn't uncommon ,in addition to the risk of GVHL .The use of reduced intensity SCT (RIC-SCT ) reduced treatment related mortality but the long term control of the disease is still under depate10. The use of RIC-SCT instead of myeloablative conditioning was associated with lower NRM and better OS. Also many reports suggest the use of RIC-SCT for patients relapsing after ASCT but many trials are still done 15,13,11. GVHD is still present with RIC-SCT 2. NRM is usually higher in those with bad performance ,older age and resistant cases.It's Â calculated from the time of transplantation to death due to any cause other than relapse whenever occurred and was caused by interstitial pneumonitis , pulmonary hemorrhage,infectious episodes , multiorgan failure and other causes related to transplantation ;bacterial infection ,invasive aspergillosis,chronic GVHD and Epstein barr virus positive lymphoproliferative disorder 15 .The previous studies had recruited low number of patients with short term follow up and they were retrospective and thus there was selection bias , this study is prospective with larger number of patients to avoid the faults of the previous studies 15,13. PFS in both myeloablative SCT and RIC-SCT wasn't high 13. In a retrospective study, the patients were divided into 2 groups ; donor and nondonor . It was found that OS and PFS are better in case of donor availability which was shown to have great effect on the outcome Â and as patients in both groups have the same characteristics and salvage therapy was the same, the increase in both OS and PFS is due to RIC-SCT 13. A study was done by Sureda et al comparing between complete myeloablative allo-SCT and RIC-SCT.The group who received RIC-SCT showed lower NRM but relapse did not differ in both groups . NRM was high in both groups in patients who have refractory disease, those received auto-SCT before and who received conventional chemotherapy. The patients receiving previous auto-SCT had higher toxicity with no additional benefit 4 .
Rem at al did a study on patients relapsing after allo RIC-SCT and showed that the rate of relapse was higher in those received previous auto-SCT.The rate of relapse was shown to occur later in HL than NHL.Despite long time to relapse after initial therapy in Hl, the PD was shown to be higher even after response to initial therapy post allo RIC-SCT relapse 4. The use of debulking tumor agents as other drugs or intensifying agents in order to potentiate the antitumor effect is also recommended ,using tandem ASCT after allo-SCT appeared to be beneficial as debulking therapy. PE tomography scanning help in patients selection 15. Â The use of brentuximab vedotin can allow successful RIC-SCT for relapsed or refractory Hl patients . Brentuximab vedotin is monoclonal antibody conjugate which consists of Anti CD30 which is expressed in malignant Hl in Reed Sternberg type conjugated with monomethyl auristatin E which cause disturbance in the microtubules. brentuximab vedotin has no adverse effects on engraftment with no difference from other intervening agents regarding effect on engraftment. Also, there is no effect on both acute and chronic GVHD neither with early <6 months nor distant >6 months use of brentuximab prior to allo SCT with limited toxicity 1.Bentuximab-vedito is considered as an option as shown by Gopal et al study to achieve long lasting remission after RIC-SCT4.The optimal time for allo-SCT after brentuximab is still an unanswered question. it depends on time to best response as donor availability ,relapse and patient choice 1 .
Graft versus host disease (GVHD) associated with stem cell transplantation:
Â Regarding acute GVHD ;data was collected from study on 85 patients showed that (47.1%) of transplanted patients did not develop acute GVHD. Grade I GVHD was present in 16 patients (18.8%) and grade II to IV GVHD developed in 21 patients (24.7%; grade II: 11 patients, grade III: 6 patients, grade IV: 4 patients). No significant impact of acute GVHD on NRM, relapse rate, PFS, or OS was found 2. In another phase II study done on patients with relapsed HL and received RIC-SCT, acute GVHD developed after about 36 days of transplantation ,it was not associated with decrease in rate of relapse and also didn't affect NRM 15.
Regarding chronic GVHD ;data was collected from 53 cases who were at risk for developing spontaneous chronic GVHD. Nineteen patients (35.8%) developed chronic GVHD. Eight of them developed limited and 9 patients experienced extensive chronic GVHD (unknown in 2 cases). Eight (42.1%) of 19 patients with chronic GVHD are alive compared with 21 (61.8%) of 34 patients without chronic GVHD. So chronic GVHD was associated with increased NRM, but RR and PFS were not affected 2. In another phase II study chronic GVHD developed after about 187 days .it was associated with better OS and lower rate of relapse.This was also shown by EBMT and Spanish series 15 . To evaluate the effect of graft versus HL effect in another study , the allo-grafted patients were analyzed. Those with chronic GVHD had a better OS and PFS than those without GVHD or even those having acute GVHD after RIC-SCT.Despite the toxicity caused by GVHD ,the better survival rate in those patients who already have a low outcome covered this problem. Peggs et al study was the first one to state this correlation . EBMT showed that there was decrease in rate of relapse with better PFS and no effect on NRM after GVHD 13. Sureda et al showed that chronic GVHD lead to less RR and better PFS . Also that was stated by Robinson et al study but with no effect on PFS or OS 2. the effect of GVL effect can't be stated in children as the risk for its development is age dependent, few number of patients under study also the methods used in GVHD prophylaxis were too diverse to state this coorrelation 2.An indirect evidence of the GVHE is the platue seen in PFS curve after 3 years15.
Donor lymphocyte infusion (DLI) after stem cell transplantation :
As graft versus lymphoma effect was seen to develop due to cytokine activation , donor lymphocyte infusion appears to be of better efficacy after SCT2. patients relapsing after RIC allo-SCT and don't have grade 2 or more GVHD are eligible to have donor lymphocyte infusion but the results showed that non of patients showing partial remission after DLI showed complete remission and none of those who showed complete remission were long lasting . Relapse occurred in all cases 1,5.
the use of donor lymphocyte infusion still has many conflicts with no adequate data about graft versus lymphoma effect GVLE 13.
Effect of type of the donor used in stem cell transplantation :
A phase II trial was done on patients with relapsed HL and sibling matched or single antigen mismatched donor who received Â salvage chemotherapy followed by allo-SCT .Chemosensitivity is the most important factor affecting the PFS of the patients after RIC-allo SCT which was 70% after one year and 50% after 4 years in this study with no influence of the type of the donor on PFS or OS .OS was bad in those with bad performance and refractory disease15.
A study stated the possibility of use of RIC-SCT for HL patients relapsing after allo-SCT. This study along with other previous trials on RIC-SCT showed that the type of the donor doesn't affect the outcome neither toxicity nor survival . there was no difference between related or unrelated donor as shown by The Center for International Blood and Marrow Transplant Research 13.
donor type was not considered as factor affecting OS in th study done by EMBT.In another study done by The Seattle group ;the haploidentical donors showed the best outcome compared with identical and non identical donors13. Regarding the effect of donor type, Anderlini was not able to detect difference, a retrospective study done by Burroughs Â et al to compare between matched unrelated donors (MUD), matched related donors (MRD) and HLA haploidentical donors. This study showed that NRM was lower in haploidentical donors compared with MRD ,also haploidentical donors have lower rate of relapse when compared with the other two groups. This study also showed that RIC-NMT had lower NRM and the ability to use alternative donors for those who were heavily pretreated .There was no difference between related and unrelated donors in OS,PFS,PD and TRM as stated by a prospective study.4
Allo-SCT for children and adolescents in RR-HL:
Although children and adolescents have very good prognosis in localized and advanced HL with high survival rate , two previous randomized control trials showed superiority of adults over young age in EFS and PFS2.
A study showed that progression or relapse occurred in 36% of patients in year 2 and 44 % of patients in year 5 which is affected by the disease and performance status at HSCT.
The PFS is affected by the conditioning regimen but it's time dependent , after 9 months post-transplantation. PFS was the same in both myeloablative conditioning (MAC) and RIC but after another 9 months PFS was lower in RIC with more rate of relapse and no effect on OS 2 .The results of this study one by EBMT showed that OS and PFS was higher in children than in adults which is considered to be encouraging results especially when knowing that the patients with good risk factors (treatment sensitive and good performance status at SCT ) from whom about half of them failed before in SCT achieved 60% PFS
There is no significant difference in NRM between both children and adults after transplantation after either MAC or RIC , and as it's not affected after MAC regimen ,it's suggested that using intermediate conditioning for both adults and pediatric cases who have good performance but relapsed or refractory disease but also there are attempts to use HDT before transplantation 2
Children and adolescents show no increase in NRM with decrease in relapse rate after myeloablative protocol compared with RIC-SCT 15.
Â Â Stem cell transplantation is one of the treatment stratigies used in patients with hodgkin lymphoma.As a consolidation Â therapy after response to initial treatment SCT has no benefit even the use of HDT/SCT is not better than conventional chemotherapy . HDT/SCT was better than 2 cycles of dexa BEAM regarding FFTF but it was the same regarding OS.
For patients with relapsed or refractory Hl , allo-SCT is considered the standard treatment but that was stated only in chemosensitive persons.Still the best therapy for chemoresistant patients is under depate . the NRM occurring after allo-SCT is higher than that after RIC-SCT which was also better in OS . the use of bentuximab vedotin allowed long term remission after RIC-SCT .
Regarding GVHD ,the data is still inadequate with variability in the effect on OS and PFS but generally acute GVHD had no effect on NRM while chronic GVHD showed increase in it.
The type of the donor didn't affect the results of transplantation but a study showed that haploidentical donor resulted in better OS and PFS than MRD or MUD .
A study done by EBMT showed that OS and PFS were higher in children and adolescents than in adults while the NRM didn't differ neither after use of MAC or RIC.