Current and Future Strategies for Relapsed Neuroblastoma

July 19th, 2013   |   Posted in Relapse,Treatment   |   By: Antonia Palmer   |   1 comment

When a neuroblastoma patient relapses or is classified as having refractory disease, there are a large number of factors to take into consideration when trying to select the most appropriate treatment.  Navigating the options available for relapsed treatment is incredibly difficult and is done without a set of established and well-entrenched guidelines.  This post is a summary of a recent article written by Dr. Morgenstern, Dr. Baruchel and Dr. Irwin from the Hospital for Sick Children (SickKids)[1] in Toronto, Canada.  Their paper focuses on a variety of treatment options for relapsed and refractory neuroblastoma patients which may help to provide a roadmap when making decisions about what therapies to pursue.

 

Considerations at the Time of Relapse:

Overall, neuroblastoma is described as a “heterogeneous” disease where there is little commonality between groups of patients.  When the disease is refractory or has relapsed, the degree of heterogeneity increases, and there are even fewer commonalities between patients.  Even though there are no universally developed or accepted definitions on how different patient populations are identified, relapsed and refractory patients can be loosely classified into three general categories:

  1. Progressive Disease (PD): Disease does not respond and progresses during frontline therapy (in about 10-15% of high-risk patients).
  2. Refractory Disease: Can also be referred to as “first response” patients.  Disease does not respond or minimally responds to frontline therapies and does not progress right away.  Disease is essentially stable, often with the only reduction in disease happening at the time of surgery for tumor resection.
  3. Relapsed Disease: Disease returns after some time while the patient is in remission.  It can occur in days, months, and even years post treatment completion.  The disease can return in the same location or in different parts of the body.

 

When trying to select a treatment pathway at the time of relapse, there are a number of considerations that are taken into account.  The following are some that may be considered:

  • Measuring Disease: Patients with a larger disease burden at the time of relapse typically have lower objective response rates (ORR) than those patients whose disease can be evaluated by MIBG alone or bone marrow histology (aspirates and biopsies).  Many trials stratify patients into two categories of disease:
  1. Measurable: Patients with a larger and measurable disease burden may have soft-tissue masses that meet RECIST criteria.  Tumors can be measured using CT, PET, or MRI scans.
  2. Evaluable: Patients have disease that can only be evaluated by MIBG scan and/or bone marrow biopsies and aspirate.  Bone marrow positivity may also be studied examining the percentage of tumor cells in the sample from the patient.  Some studies require 1%, 5% or possibly a different value of disease to be present.
  • Biopsy: Often for refractory patients, it is becoming more common for clinical trials to require a biopsy of the tumor to determine if the patient has active disease (versus more differentiated ganglioneuroblastoma or ganglioneuroma).
  • Number of Relapses: Some studies only enroll patients that are in their first or second relapse.
  • Type of Relapse: Patients with CNS relapse are often excluded from traditional phase I and phase II studies.  However, it is important to note that they do have other options through trials like those offered from Memorial Sloan Kettering Cancer Centre (MSKCC).
  • Prior Therapy: It is possible that therapies received in frontline treatment may not work or their efficacy may be reduced with relapsed disease.
  • Organ and Hematological Performance: Many clinical trials require patients to have certain baseline measurements for organ function, organ performance, and various hematological measurements (e.g. platelet production).
  • Patient Age: Adolescent and adult patients with high risk neuroblastoma are less likely to be MYCN amplified, often have disease that is slow in its rate of progression, but typically their disease that is very difficult to cure.  Mutations of the ATRX gene have been identified in about 3-5% of neuroblastoma patients, with a trend towards a higher rate of this mutation being detected in older patients.  ATRX is involved in chromatin remodeling and telomere maintenance, meaning that certain therapies could be better targeted to this patient group[2],[3].  Within COG, a large study is currently underway to confirm the association between the ATRX mutation and advanced age.
  • Genetic Status: It is anticipated that as more “targeted” therapies are developed that knowledge of mutation status of specific genes (targeted by these novel therapies) will be required for entry onto certain clinical trials. For example, currently some trials for ALK inhibitors require confirmation of an ALK mutation in tumor tissue from a certified (CLIA) lab.
  • MIBG Avidity: Knowing whether the patient has MIBG avid disease is important if they are interested in pursuing MIBG Therapy.
  • Amount of Banked Stem Cells: Some trials require or strongly recommend that the patient has banked stem cells that can be used for a stem cell rescue post treatment.
  • Access: Treatment decisions may be based the patient’s geographical location and if they are physically close to the hospital of their choice.  For example, there is currently only one MIBG centre in Canada (St. Justine in Montreal) that can deliver MIBG therapy to some patients; however, construction is underway for a new MIBG centre at the Hospital for Sick Children in Toronto.  It may also be based on access to certain drugs due to availability and insurance coverage restrictions.  For example, immunotherapy is still not universally available and is rarely accessible outside of clinical trials.
  • Patient and Family Viewpoints: Deciding what therapy the patient will follow may be based on understanding what the patient and family want and need at various points through their treatment journey.  Treatment may be selected based on an underlying desire to completely eradicate the disease,  treating the neuroblastoma as a chronic illness with an eye to keeping the cancer stable, finding more time in the event of multiple relapses, or relieving symptoms such as pain and other discomforts in the palliative care setting.
  • Quality of Patient Life: Trying to maintain a ‘normal’ quality of life for the patient and their family may also play a role when deciding on treatment options.  It may be important for the patient to be treated at their home hospital, without having to travel long distances and be away from family and friends; or, a higher priority may be to travel to a particular hospital that is able to cater to the patient’s needs in a wide variety of ways.  For some patients, decisions may also be based on whether the patient must be admitted for treatment, or if they are able to receive therapy on an out-patient basis so that they may continue to attend school and other important activities.
  • Trial Status: Relapsed and refractory patients are often in the position of selecting between Phase I and Phase II trials.  Phase I trials may appear to offer a great deal of hope; however, they are often focused on studying the dosing of drugs and the observation of their associated side-effects to determine the safest dosing of medications within the limits of acceptable toxicities.  The early days of Phase I trials may result in patients not getting therapeutic levels of a drug or it may result in them receiving too much of the therapy with concerning side-effects.

 

Chemotherapy Approaches:

 

Topotecan Combinations:

Topotecan is a cytotoxic chemotherapy that is a camptothecin derivative and has the ability to cross the blood-brain barrier.  Topotecan has been studied in combination with a number of other chemotherapies with relative success; however, topotecan and irinotecan together showed unacceptable side-effects and toxicities and has not been studied any further at this time.  The following are topotecan combinations used for relapsed and refractory neuroblastoma patients:

Topotecan and Cyclophosphamide (TopoCy):

Study published in 2010[4]:

  • A study published in 2010 examined the use of topotecan alone versus topotecan and cyclophosphamide; 5 days of infusions of both drugs, repeated every 21 days; G-CSF started on day 6.
  • The objective response rate (ORR) that includes both complete and partial responses was 32% (18/57) for TopoCy versus 19% (11/59) for topotecan alone.
  • No difference in overall survival when using topotecan or topotecan and cyclophosphamide.  Taking all of the factors into consideration, there was a small benefit found with the TopoCy arm of the study.
  • Median overall survival was 1.1 years.
  • Very similar in terms of toxicities from the treatment.  Side-effects included infections, neutropenia, and thrombocytopenia (low platelet count).

 

Study published in 2013[5]:

  • A retrospective study was done by the Hospital for Sick Children (Toronto, Canada) in 2013, examining their use of topotecan and cyclophosphamide for children with first relapse or refractory neuroblastoma.
  • Administered for up to 2 years; delivered over 5 days, every 3 weeks in an outpatient setting.
  • For the 27 patients analyzed, the median number of cycles per patient was 10.  12 patients received 12 or more cycles.
  • 22% (6/27) complete response, 26% (7/27) partial response, 15% (4/27) mixed response, 4% (1/27) stable disease, and 33% (9/27) progressed.  CR + PR + MR = 63% (17/27).  The median number of cycles for the patient to achieve their best response was 4 (with a range from 2 to 11).
  • Median progression-free survival was 1.2 years.
  • Side-effects included febrile neutropenia, transfusions, and bacterial infections. These side effects were not more common in patients who received longer durations of therapy.

TopoCy is now in frontline chemotherapy in the COG protocol and is currently being used as a backbone to test other agents[6],[7].
 

Topotecan, Cyclophosphamide and Vincristine in High-Dose (HD-CTV)[8]

  • Using higher doses.  Results particularly in patients with first relapse.
  • Cyclophosphamide on days 1 and 2; topotecan days 1-4; and vincristine on day 1.

 

Objective Response Rates (complete and partial responses) Major and Mixed Responses
Primary Refractory Patients 19% (11/58) 45% (26/58)
Secondary Refractory Patients 29% (4/14) 71% (10/14)
New First Disease Recurrence 52% (13/25) 80% (20/25)
Progressive Disease 0% (0/13) 8% (1/13)
    • Primary Refractory Patients are patients who did not completely respond in induction but had no evidence of progressive disease.
    • Secondary Refractory Patients have recurrent NB not responding to salvage therapy.
    • New First Disease Recurrence are patients who relapsed when off treatment.
    • Progressive Disease refers to a patient having growing disease while on therapy.
  • All 10 adolescent (over 10 years old) and adult patients treated with this regimen had no response.
  • Main side effects included infections and myelosuppression (overall bone marrow suppression).  90% of patients had been previously treated with cyclophosphamide, doxorubicin or vincristine and 25% of patients had topotecan as prior therapy.

 
Topotecan, Cyclophosphamide and Etoposide (TCE):[9]

  • Cyclophosphamide (1-hour infusion days 1-7), topotecan (168-hour continuous infusion from days 1-7), and etoposide (1-hour infusion days 8-10).  This combination was repeated every 28 days with a maximum of 6 cycles for relapsed patients (unless disease progression occurred).
  • Complete or partial response was achieved in 61% (19/31) of the relapsed patients.  Patients who had not been treated prior achieved a 72% response (8/11).
  • No patient had received cyclophosphamide or topotecan previously.  Patients received a median number of 4 cycles of TCE before the disease progressed or other treatment decisions had to be made.  The mean time from the start of TCE to disease progression was 225 days.
  • Main side-effects were leucopenia (low white blood cell count), thrombocytopenia (low platelet count), neutropenic fever, and mucositis.

 
Topotecan and Etoposide:[10]

  • Topotecan and etoposide (no cyclophosphamide) showed a 47% response rate.  In 36 patients, 11% (4/36) achieved complete remission and 36% (13/36) achieved partial remission.
  • The main side effects of this combination included leucopenia, thrombocytopenia, and neutropenic fever.
  • All patients had received etoposide previously, but no patients had topotecan before this trial.  This trial helped to determine appropriate dosing levels of the two chemotherapy drugs.  At the time of publication, 31/36 patients had died from disease progression.

 
Topotecan, Vincristine, and Doxorubicin (TVD):[11]

  • Topotecan (30-minute infusion days 1-5), followed by continuous infusions of doxorubicin and vincristine (48 hours on days 5 and 6) which was repeated every 21 days (as long as there wasn’t disease progression).  G-CSF was given starting on day 8.
  • 16% (4/25) had a complete response, 48% (12/25) had a partial response, 16% (4/25) had minor response or stable disease, 20% (5/25) had tumor progression.  The overall response rate (complete and partial responses) was 64% in 25 patients.
  • The majority of the patients were refractory rather than relapse (19 refractory and 6 relapse).  Better responses were achieved with the relapsed patients (3 relapsed patients achieved complete response and 1 refractory patient had a complete response).  None of the patients had received topotecan previously.
  • Side-effects included neutropenia, thrombocytopenia (low platelet count), leucopenia (low white blood cell count), and anemia (low number of red blood cells).
  • This is now part of the European protocol for high-risk NB as a salvage therapy for patients who do not achieve metastatic CR/CR after induction with rapid COJEC (8 cycles of chemotherapy delivered in 10 day intervals).

 
Topotecan and Temozolomide:[12]

  • Temozolomide was given orally, followed by topotecan by IV, over 5 days and repeated every 28 days.
  • For the neuroblastoma patients, 3% (1/38) complete response, 18% (7/38) partial responses with an overall response rate of 21% (8/38).  58% (22/38) had stable disease and a 12 month progression free survival rate of 47%.
  • Side effects included neutropenia and febrile neutropenia.

 
 

Irinotecan Combinations:

Like topotecan, irinotecan is another camptothecin derivative; however, it is not typically utilized in frontline therapy.  The following are examples of irinotecan combinations for relapsed and refractory neuroblastoma disease.

Irinotecan and Temozolomide:

A major side-effect of irinotecan is diarrhea, and myelosuppression can also occur.  To combat this, loperamide (Imodium, etc.) and a cephalosporin antibiotic are typically given in conjunction with this chemotherapy.

The following are the results of a study conducted by MSKCC[13]:

  • Irinotecan (IV) and temozolomide (oral) are given over 5 days every 3-4 weeks.  G-CSF used if necessary.
  • Refractory Patients (either during induction or at relapse): 11% (2/19) complete responses, 37% (7/19) mixed responses, and 53% (10/19) stable disease.  All patients with refractory disease showed some benefit.
  • Progressive Disease Patients: 6% (1/17) partial response, 12% (2/17) objective responses, and 29% (5/17) stable, and 53% (9/17) with progressive disease.
  • The ORR was only 8.3% but it worked to keep the disease stable.  Median of 5 courses of irinotecan and temozolomide (1 to 15 courses).

 
The following are the results from a Children’s Oncology Group (COG) Study[14]:

  • Lower doses of the chemotherapies were used in comparison to the MSKCC study.
  • This study was limited to patients at first relapse.  Looking at efficacy of oral temozolomide (days 1-5 and given 1 hour prior to irinotecan) and then IV irinotecan 5 days a week for 2 weeks:

 

Complete Response (CR) Partial Response (PR) Stable Disease Progressive Disease
Stratum 1 (Measurable by MRI and/or CT)

4% (1/28)

7% (2/28)

50% (14/28)

39% (11/28)

Stratum 2 (Evaluable by MIBG or bone marrow aspirate/biopsy)

12% (3/26)

8% (2/26)

58% (15/26)

23% (6/26)

  • 14 patients were classified as having refractory disease, 2/14 had a complete and/or partial response, and 10 with stable disease.
  • Some patients had 11-13 cycles of treatment before going on to other therapies (i.e., transplant) or disease progression.
  • 14/21 patients who had irinotecan before had an objective response or stable disease.
  • Toxicities included neutropenia, thrombocytopenia, anemia, fever, infection, pain, nausea, and diarrhea.

 

The following are the results from a New Approaches to Neuroblastoma Therapy (NANT) Study[15]:

  • Established dosing levels for oral administration of both irinotecan and temozolomide.  Cefixime was also given to combat the side effect of diarrhea from the irinotecan.
  • 7% (1/14) patients had a complete response, 43% (6/14) showed stable disease through 6 courses, 36% (5/14) showed stable disease through an average of 7 courses.
  • Side effects included neutropenia, thrombocytopenia (low platelet count), and diarrhea.  Nausea was not a significant side-effect.
  • Median progression free survival for 15 patients was 4.2 months.

The combination of irinotecan and temozolomide may be a useful therapy even if the patient has had topotecan in frontline therapy.  It is also being used as a chemotherapeutic backbone upon which other treatments are being tested (for example, the addition of bevacizumab – http://clinicaltrials.gov/show/NCT01114555)

 

Ifosfamide, Carboplatin, and Etoposide (ICE):

MSKCC study of high-dose administration of ICE[16]:

  • Ifosfamide (2-hour infusion on days 1-5, with mesna), carboplatin (1-hour infusion on days 1 and 2), and etoposide (1-hour infusion on days 1-5).  Patients with weak bone marrow function (poor hematological reserve) received a stem-cell rescue 72 hours after the completion of the chemotherapy.  G-CSF started 24 hours after stem-cell rescue or completion of the HD-ICE (for patients who did not have a stem-cell rescue).
  • Newly Relapsed Disease: 53% (9/17) had an objective response (soft tissue as well as 131I-MIBG/bone marrow disease), 29% (5/17) had a mixed response, 12% (2/17) had stable disease, and 1 progressed.
  • Primary and Secondary Refractory Disease: 15% (4/26) had an objective response, 35% (9/26) had a mixed response, 46% (12/26) had stable disease and 1 progressed.
  • Progressive Disease: 3% (1/34) had a partial response, 35% (12/34) had mixed response, 26% (9/34) had stable disease and 35% (12/34) progressed.  32 of these patients had been treated for multiple relapses.
  • Most patients received 1 cycle of HD-ICE, 5 patients received 2 cycles and 2 patients received 3 consecutive cycles.
  • Side-effects included grade 4 myelotoxicity, bacterial infections (26%).
  • Better response by patients who are treated for a new relapse after the completion of therapy versus those patients who have persistent (refractory) or progressing disease while on therapy.  However, HD-ICE still showed anti-tumor benefits toward refractory patients, with 65% (22/34) achieving stable disease or better

 

131I-MIBG Therapy:

Approximately 90% of neuroblastoma tumors are MIBG avid, meaning that the neuroblastoma cells “uptake” the MIBG and they can be seen on an MIBG scan.  MIBG therapy allows for “the targeted delivery of short-range beta radiation to the sites of disease”1 (p. 4).  The use of stem-cell rescue after MIBG therapy has allowed for the use of higher doses of 131I-MIBG (and repeat courses) with the hope of better treating the disease and eradicating neuroblastoma cells.

Phase 2 study of 164 patients at 2 dosing levels of MIBG therapy[17]:

  • 36% had evidence of objective response (complete and partial responses).
  • 34% had stable disease (median time to progression for this group was 6 months).
  • 3% of patients had a mixed response.
  • Time to progression for all patients was a median of 4.4 months.  Patients had a median of 3 prior treatment regimens before receiving MIBG therapy.
  • Overall survival was 49% at 1 year, 29% at 2 years.
  • MIBG therapy appears to have additional benefits for adolescents and adults in terms of response rates.
  • Event free survival (EFS) was longer for patients with a complete or partial response, having 3 or fewer prior treatment regimens, and having soft tissue or bone marrow disease only.
  • Myelosuppression, infections and febrile neutropenia are the main short-term side-effects with long-term side-effects that include hypothyroidism and a possible increase in secondary cancers.

MIBG therapy can be used in frontline treatment (this is already done in the Netherlands), for relapse, and for palliative care to help provide relief from pain caused by the disease. There are challenges associated with MIBG therapy, mainly involving limited access to the isotope and hospitals with lead-lined rooms required for treatment, the logistics of delivering higher doses of 131I-MIBG to patients, and the need for stem-cell rescue to help with treatment recovery.  The following are some ways that MIBG therapy is currently being studied:

  1. A COG trial is currently planned to incorporate MIBG therapy into the induction phase of high-risk neuroblastoma treatment, with busulphan and melphalan (BuMel) being used during the consolidation phase for stem-cell transplant (http://clinicaltrials.gov/ct2/show/NCT01175356).
  2. Hopes to increase response rates through repeat administrations of the therapy or combining it with chemotherapy (possibly using topotecan which is a radiosensitizer).  NANT is exploring the use of vorinostat as a potential radiosensitizer (http://clinicaltrials.gov/show/NCT01019850).  Vorinostat is an HDAC inhibitor and is thought to increase the uptake of MIBG in neuroblastoma cells.
  3. “Standard preparations of 131I-MIBG contain a vast excess of nonradioactive (carrier) MIBG molecules that have the potential to inhibit tumor uptake of the radiolabeled 131I-MIBG and exacerbate toxicity.  A phase I study of “no-carrier-added” 131I-MIBG has recently been completed, showing acceptable toxicity and an ORR of 27%”[1] (p. 5).
  4. 177Lutetium-DOTATATE is being developed for patients with 131I-MIBG non-avid disease or who do not respond to 131I-MIBG therapy.  There is currently a study open in the UK with 177Lutetium-DOTATATE for patients with relapsed or refractory neuroblastoma (https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-000510-10/GB).

 

Radiation:

Radiation can be part of frontline therapy and is often used as a relapse treatment to “help control soft-tissue lesions, especially those in proximity to the spinal cord, and provide relief from painful bone metastases”[1] (p. 5).  In a recent study, the use of radiation was examined in the palliative setting for patients with metastatic neuroblastoma.  This retrospective study showed responses of 84% in soft-tissue lesions and 63% in bone metastases[18].

 

Immunotherapy:

Anti-GD2 Antibodies:

Anti-GD2 antibodies (murine – 3F8, chimeric – ch14.18, and humanized – hu14.18 and hu3F8) have benefit for patients with minimal residual disease.  Antibodies are used (or have been used) in frontline therapy and for relapsed neuroblastoma. In 2010, results were reported on the COG trial (ANBL0032) that utilized ch14.18 with the cytokines GM-CSF and IL-2 (and alternating cycles of Accutane)[19].  It was found that patients who received this immunotherapy had about a 20% increase in survival in comparison to those patients who did not receive ch14.18 (but did have cycles of Accutane).
 

ch14.18 has evolved with the development of a humanized version of the antibody called hu14.18 (ch14.18 is a chimeric antibody that is 75% human and 25% mouse derived where hu14.18 is almost entirely human derived).  hu14.18-IL2 is a further evolution of this immunotherapy where the IL-2 cytokine is fused to the antibody instead of being administered separately to the patient.  A study published in 2010 provided the results from a trial using hu14.18-IL2[20].

  • 5/23 (22%) of patients with evaluable disease (evaluable by 131I-MIBG or bone marrow biopsy) had a complete response.  3/5 who had a complete response only had disease in their bone marrow, 1/5 had only one MIBG-avid lesion, and 1/5 had bone marrow disease as well as MIBG-avid sites.  4/5 patients were in first relapse after being in remission after autologous stem-cell transplant.  4/5 had 6 cycles of hu14.18-IL2 and achieved CR after two cycles of hu14.18-IL2 and all 5 patients had prolonged response.
  • Of the remaining patients with evaluable disease, 4/23 had stable disease and 14/23 had progressive disease.
  • Patients with bulky/measurable disease did not respond to the treatment – 3/13 had stable disease and 10/13 had progressive disease.
  • Side-effects included capillary leak, hypoxia, pain, rash and allergic reactions, elevated transaminases and hyperbilirubinemia.  Most side-effects were reversible within a few days after the completion of the treatment course.
  • “Further analysis revealed that all patients who demonstrated response were mismatched for natural killer (NK) cell KIR/KIR-ligand genotypes, there being no responses amongst KIR-matched patients”[1] (p. 5).  It may be possible to use this information to predict a patient’s response to the therapy in the future.

 

The following are other trials that are currently available for anti-GD2 antibodies:

  1. Irinotecan and Temozolomide with ch14.18 or temsirolimus is a COG phase 2 study (ANBL1221) to compare response rates and progression free survival rates between ch14.18 or temsirolimus for patients with first relapse, refractory or progressive neuroblastoma (http://clinicaltrials.gov/ct2/show/NCT01767194).  Temsirolimus is a rapamycin analog (mTOR inhibitor).
  2. Lenalidomide and ch14.18 with or without Accutane for patients with refractory or recurrent neuroblastoma (http://clinicaltrials.gov/ct2/show/NCT01711554).  In this Phase 1 NCI/NANT study, patients receive lenalidomide orally on days 1-21, ch14.18 is given over 10 hours on days 8-11, and then Accutane is taken orally on days 15-28.  Treatments repeat every 28 days for up to 6 courses as long as there is no disease progression or unacceptable toxicity.  The goal is to establish dosing levels and interactions of lenalidomide with ch14.18 and Accutane.  Lenalidomide stimulates the immune system, much GM-CSF and IL-2 which are classified as cytokines.  It is hoped that lenalidomide will not have the same toxicity profile as GM-CSF and IL-2, without reducing effectiveness.
  3. Long-term continuous infusion of ch14.18 with subcutaneous IL-2 is a phase 1/2 study currently offered in Europe where patients receive a lower dose continuous infusion of ch14.18 to determine if this results in reduced levels of pain with the same increase in survival rates (http://clinicaltrials.gov/ct2/show/NCT01701479?term=NCT01701479). Subcutaneous IL-2 is given on days 1-5 and days 8-12, continuous ch14.18/CHO is started on day 8 and duration will range from 10-21 days looking at 3 different dose levels.  Accutane is given for 14 days after the completion of ch14.18 between each course.  It is hoped that if reduced levels of pain are experienced, that patients will not need medications such as morphine.
  4. Hu14.18K322A, a version of hu14.18 that is predicted to cause less neuropathic pain, is being examined at St. Jude Children’s Research Hospital.

 

Other Immunotherapy Approaches:

Anti GD2 immunotherapies are showing efficacy with minimal residual disease; however, new approaches for dealing with bulky disease need to be realized, especially for relapsed and refractory patients.

  1. Ipilimumab is an antibody that stimulates the immune system by blocking CTLA4 which can act as an immune system inhibitor (http://clinicaltrials.gov/show/NCT01445379).  In a recently published study, 24% (5/21) of pediatric cancer patients (of various types of cancers) had stable disease as the best response when treated with ipilimumab.  This phase 1 study determined the dosing levels for ipilimumab with side-effects that ranged from colitis, transaminitis, pancreatitis, autoimmune thyroditis and hypophysitis[21].  At this time, it is not understood if ipilimumab is effective for neuroblastoma.
  2. Dendritic cell vaccine with decitabine chemotherapy.  A single case study presented showed that after three cycles of the vaccine and chemotherapy combination, the patient had no evidence of neuroblastoma in his bone marrow aspirates and biopsies and remained that way for over one year after the patient’s last vaccination[22],[23].
  3. Natural Killer (NK) cell infusions.  Single case study presented of a 6 year old boy with refractory disease.  Reduced intensity conditioning was first performed using fludarabine and busulfan, and total body irradiation.  Immunosuppression was accomplished using OKT3, mycophenolate mofetil, cyclosporine, and methotrexate.  NK cells were transplanted from a donor (father), with the patient experiencing graft versus host disease (GvHD) which resolved with steroids.  Three NK infusions continued after the haplo-HSCT with the patient achieving a complete response 100 days after transplant.  22 months after transplant, new spots appeared on the MIBG.  The patient was given subcutaneous IL-2 with two more donor NK cell infusions.  Topotecan and temozolomide was also given, continuing with the IL-2.  Two months later, the patient achieved complete remission again)[24].
    1. Therapy for Children with Advanced Stage Neuroblastoma, infusion with NK cells, http://clinicaltrials.gov/ct2/show/NCT01857934.
    2. Phase I Study of NK Cell Infusion Following Allogenic Peripheral Blood Stem Cell Transplantation from Related or Matched Unrelated Donors in Pediatric Patients with Solid Tumors and Leukemias, http://clinicaltrials.gov/ct2/show/NCT01287104.
    3. Anti-GD2 3F8 Antibody and Allogenic Natural Killer Cells for High-Risk Neuroblastoma, http://clinicaltrials.gov/ct2/show/NCT00877110.

 

T Cells:

T cells are part of the immune system and carry out a number of different functions but most importantly they are able to recognize and kill cells that are compromised in some way (i.e., infected with a virus).  Each T cell has a receptor that lets it recognize a protein fragment on the surface of other cells.  T cells can identify and target the compromised or ‘foreign’ proteins.

 

T cells only bind to foreign molecules (antigens) that have been modified by other cells and then displayed on the surface of these cells (or on their plasma membranes in a process called antigen presentation).  Many cancer cells, and solid tumors in particular, have defects in their antigen presentation.  To deal with this, T cells can be genetically engineered to express chimeric antigen receptors (CARs)[25] which can then target neuroblastoma tumor cells by identifying markers such as GD2.  Put another way, a patient’s own T cells can be genetically engineered and ‘redirected’ so that they can target neuroblastoma cells1.  CAR-modified T cells are able find the cancer cells that were once able to hide from the patient’s immune system[26].

 

A recent study was completed giving 19 patients GD2-specific CAR-modified T cells[25].  The study showed that these CAR-expressing T cells persisted at low levels for a long period of time, resulting in patient benefits, including 3 complete responses.  The infusion also appears to have long-term safety with side-effects that included fever and pain.

 

The Baylor College of Medicine and Texas Children’s Cancer Center recently announced that a phase 1 trial using enhanced T cells to treat relapsed and refractory neuroblastoma that will open in the summer of 2013 (funded by Solving Kids’ Cancer).

 

Allogeneic Hematopoietic Stem Cell Transplant (HSCT):

Autologous hematopoietic cell transplant (auto-HCT) is a part of the COG frontline therapy protocol for high-risk neuroblastoma.  In auto-HCT, the patient’s stem cells are collected in an apheresis process early on in the treatment protocol and are then reinfused after high-dose chemotherapy.  Allogeneic hematopoietic cell transplant (allo-HCT) also uses high-dose chemotherapy to condition the patient by suppressing their immune system; however, it involves the infusion of stem cells from a donor, and not from the patient.  Once the donor stem cells engraft in the host, it is possible these new cells will recognize any cancer cells as being foreign and then the donor’s T and NK cells would kill these malignant cells.  In the past, allo-HCT has been considered to be a more risky option in comparison to auto-HCT; however, changes to the protocols and chemotherapy conditioning regimens have begun to reduce the risks associated with allo-HCT.
 

A possible result of allo-HCT is graft-versus-host disease (GvHD) where the donor cells recognize the host’s healthy and normal cells as foreign and attacks them.  However, there is an assumption made that if a patient experiences GvHD and the donor cells recognize the host tissue as foreign, then it must also recognize the cancer cells as foreign, killing them too.  This is known as graft-versus-tumor effect.  There is much work to still be done in studying allo-HCT and neuroblastoma, especially in understanding what patients would benefit the most from allo-HCT versus auto-HCT and determining what factors may increase the occurrence of a graft-versus-neuroblastoma effect[27].

 

Novel Targets:

 

Precision/Personalized Medicine:

Precision medicine, also known as personalized medicine, is becoming an increasingly important approach to determining the therapeutic pathway for pediatric cancer patients.  It is helping to identify the most effective treatments for the different sub-types of patients within a particular type of cancer (Trial NCT01802567 with Dr. Sholler at the Van Andel Research Institute).  This method of treatment selection is still very novel; however, essential pathways and procedures are currently being forged, creating a foundation upon which future learnings will be built.  There is a great amount of hope for precision medicine and what it might hold for pediatric cancer in the future.  However, great challenges still lie ahead with personalized medicine for neuroblastoma as there are few recurrent mutations for this particular cancer, as found by the TARGET project lead by Dr. J. Maris[28]. Furthermore, trials that incorporate precision medicine will require novel clinical trial designs since potentially each patient will be treated with different regimens.

 

MYCN Target:

A number of new promising therapies are currently in development using MYCN amplification as the target for neuroblastoma treatment.  Approximately 20% of neuroblastoma patients have tumors that are MYCN amplified, meaning that they have extra copies of the MYCN gene resulting in high levels of MYCN protein.  MYCN amplification has long been associated with high risk disease, therapy resistance, and poor prognosis.  Targeting MYCN for neuroblastoma treatment was once thought to be too risky; however, progress is being made in a number of areas:

  1. PI3K (phosphatidylinositol 3-kinase) is a signalling molecule that plays a role in regulating MYCN.  The P13K inhibitor, NVP-BEZ235, works to destabilize MYCN and was the first to be tested in clinical trial with solid-tumors and a subset of breast cancer patients (http://clinicaltrials.gov/ct2/show/NCT00620594).
  2. A new BET Bromodomain Inhibitor called JQ1 has been developed to compete with MYCN during the transcription process and interfere with its ability to allow the cancer cells to proliferate and escape cellular death.  Laboratory studies showed positive results that resulted in reducing disease and increasing overall survival (when using mouse models).  Preparations are being made for a clinical trial with this therapy.
  3. A review of other MYCN targeted therapies can found in Palmer (2013)[29].

 

ALK Target:

Approximately 2% of neuroblastoma cases are classified as being “familial”, and the majority of these are  reported to have mutations of the ALK.  ALK gene mutations have also been found in about 10% of the sporadic cases of the disease and can also be amplified, a trait found in about 4% of neuroblastoma cases[30],[28].  New therapies are being used to target the ALK gene mutation and one such drug is an ALK inhibitor called crizotinib.  Crizotinib was originally used in lung cancer patients and has a minimal toxicity profile, with some evidence of antitumor response in neuroblastoma patients with particular variations of the ALK mutation[31].

 

COG is planning on opening a trial that combines cyclophosphamide and topotecan or doxorubicin (dexrazoxane is also given to protect the heart if doxorubicin is received) and vincristine with crizotinib (http://clinicaltrials.gov/show/NCT01606878).  Other ALK inhibitors such as LDK378 are also in development and are planned to open in a clinical trial in the future.

 

Others in Development:

The following are other therapies that are currently in development for the treatment of neuroblastoma:

  1. Aurora Kinase A Inhibitors: MLN8237 and AT9283. MLN8237 with irinotecan and temozolomide.
  2. Tyrosine Kinase Inhibitor: Imatinib. COG trial ADVL0122
  3. Akt Inhibitor: Perifosine. MSKCC, single agent trial
  4. mTOR Inhibitor: Temsirolimus (described above). COG trial ANBL1221
  5. Angiogenesis Inhibitors: Bevacizumab
    1. NANT, with cyclophosphamide and zolendronic acid
    2. MSKCC, with irinotecan and temozolomide
    3. MSKCC, with cyclophosphamide and topotecan
  6. Retinoid: Fenretinide is a synthetic renitnoid that has shown activity against neuroblastoma cell lines which are resistant to 13-cisRA (Accutane)
  7. Others possible drugs being studied include DFMO, TPI-287, nifurtimox, bortezomib, thalidomide, sorafenib, and BSO with melphalan.

 

CNS Relapse:

Disease presentation in the central nervous system (CNS) is rare at diagnosis; however, this occurs in about 6-8% of relapsed neuroblastoma patients.  The CNS relapse protocol at Memorial Sloan Kettering Cancer Centre (MSKCC) is showing great promise[32],[33].  Their protocol involves a multi-modal treatment approach that includes surgical resection of the tumor, cranial-spinal radiation with chemotherapy, higher dose chemotherapy with stem cell rescue, 8H9 (or 3F8) intrathecal immunotherapy given through an ommaya port directly into the CNS, and 3F8 immunotherapy for systemic disease control.
 

Future Strategies:

Many current protocols are using a combination approach to testing new drugs using a “pick the winner” or “drop the loser” methodology to determining if a new therapy is effective.  Drugs such as irinotecan and temozolomide are used as a “chemotherapeutic backbone” upon which other therapies are tested.  The hope is that the backbone drugs will keep the patient’s disease stable while being able to evaluate how the disease responds to the new agent that is given in addition to these chemotherapies.  Another strategy to determine effective treatments will be the identification of biomarkers that will help clinicians and researchers predict how well a patient will respond to particular types of treatments.  This may also involve the integration of genetic testing into patient care and making it a standard part of patient treatment.

 

Conclusions:

There is no question that the greatest hope for the future of relapsed neuroblastoma is to find a cure for the disease itself.  Until that lofty goal is realized, there are many positive steps that can be made to improve treatments for relapsed and refractory neuroblastoma.  Continuing to identify patterns of disease in groups and subsets of patients will help to further define treatment pathways and illuminate ways to better predict a patient’s response to a certain therapy.  For example, it may be possible to determine a way to identify patients that will do well in managing neuroblastoma as a chronic disease, and the treatments that will keep the cancer stable for a long period of time with minimal long term toxicities.  In addition, more work needs to be done to identify better ways to treat neuroblastoma for adolescent and adult patients.

 

Neuroblastoma Canada would like to thank Dr. Meredith Irwin and Dr. Daniel Morgenstern for reviewing and editing this post. Their professionalism, dedication, and expertise are greatly appreciated in all that they do for patients with neuroblastoma.
 
 

References:

[1] Morgenstern, D.A., Baruchel, S., and Irwin, M.S. (2013). Current and Future Strategies for Relapsed Neuroblastoma: Challenges on the Road to Precision Therapy.  Journal of Pediatric Hematology Oncology, Vol 35, No. 5, pps. 337-347.  http://www.ncbi.nlm.nih.gov/pubmed/23703550
 

[2] Castelo-Branco, P., Zhang, C., Lipman, T., Fujitani, M., et al. (2011). Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition.  Clinical Cancer Research, 17, pps. 111-121.  http://clincancerres.aacrjournals.org/content/17/1/111.full
 

[3] Palmer, A. (2011). Telomerase Inhibition.  Neuroblastoma Canada.  http://neuroblastoma.ca/blog/treatment/telomerase-inhibition/
 

[4] London, W.B., Frantz, C.N., Campbell, L.A., Seeger, R.C., Brumback, B.A., Cohn, S.L., Matthay, K.K., Castleberry, R.P., and Diller, L. (2010).  Phase II Randomized Comparison of Topotecan Plus Cyclophosphamide Versus Topotecan Alone in Children with Recurrent or Refractory Neuroblastoma: A Children’s Oncology Group Study.  Journal of Clinical Oncology, Vol. 28, No. 24, pps. 3808-3815.
 

[5] Ashraf, K., Shaikh, F., Gibson, P., Baruchel, S., and Irwin, M.S. (2013). Treatment with Topotecan Plus Cyclophosphamide in Children with First Relapse of Neuroblastoma.  Pediatric Blood and Cancer, epub ahead of print, pps. 1-6.
 

[6] Park, J.R., Bagatell, R., and Hogarty, M. (2012). Children’s Oncology Group’s 2013 Blueprint for Research: Neuroblastoma. Pediatric Blood and Cancer, 2012 December 19 (epub ahead of print). http://www.ncbi.nlm.nih.gov/pubmed/23255319
 

[7] Palmer, A. (2013). COG 2013 Blueprint for Neuroblastoma Research.  Neuroblastoma Canada. http://neuroblastoma.ca/blog/treatment/cog-2013-blueprint-for-neuroblastoma-research/
 

[8] Kushner, B.H., Kramer, K., Modak, S., Qin, L-X., Cheung, N-K.V. (2010). Differential Impact of High-Dose Cyclophosphamide, Topotecan, and Vincristine in Clinical Subsets of Patients with Chemoresistant Neuroblastoma. Cancer, June 15, 2010, pps. 3054-3060.
 

[9] Simon, T., Langler, A., Harnischmacher, Fruhwald, M.C., Jorch, N., Claviez, A., Berthold, F., and Hero, B. (2007).  Topotecan, Cyclophosphamide, and Etoposide (TCE) in the Treatment of High-Risk Neuroblastoma.  Results of a phase-II trial.  Journal of Cancer Research Clinical Oncology, 133, pps. 653-661.
 

[10] Simon, T., Langler, A., Berthold, F., Klingebiel, T., and Hero, B. (2007). Topotecan and Etoposide in Treatment of Relapsed High-Risk Neuroblastoma.  Journal of Pediatric Hematology/Oncology, Vol 29, No 2, pps. 101-106.
 

[11] Garaventa, A., Luksch, R., Biasotti, S., Severi, G., Pizzitola, M.R., Viscardi, E., Prete, A., Mastragelo, S., Podda, M., Haupt, R., and Bernardi, B. (2003). A Phase II Study of Topotecan with Vincristing and Doxorubicin in Children with Recurrent/Refractory Neuroblastoma.  Cancer, Vol 98, No 11, pps. 2488-2494.
 

[12] Di Giannatale, A., McHugh, K., Dias, N., Devos, A., Geoerger, B., Jaspan, T., et al. (2012). Phase II Study of Temozolomide in Combination with Topotecan (TOTEM) in Relapsed or Refractory Neuroblastomas and Other Pediatric Solid Malignancies: A European ITCC Study.  Journal of Clinical Oncology, 2012 ASCO Annual Meeting, abstract number 9517. http://meetinglibrary.asco.org/content/97672-114
 

[13] Kushner, B.H., Kramer, K., Modak, S., Cheung, N-K.V. (2006). Irinotecan Plus Temozolomide for Relapsed or Refractory Neuroblastoma.  Journal of Clinical Oncology, Vol. 24, No. 33, pps. 5271-5276.
 

[14] Bagatell, R., London, W.B., Wagner, L.M., Voss, S.D., Stewart, C.F., Maris, J.M., Kretschmar, C. and Cohn, S.L. (2011).  Phase II Study of Irinotecan and Temozolomide in Children with Relapsed or Refractory Neuroblastoma: A Children’s Oncology Group Study.  Journal of Clinical Oncology, Vol. 29, No. 2, pps. 208-213.
 

[15] Wagner, L.M., Villablanca, J.G., Stewart, C.F., Crews, K.R., Groshen, S., Reynolds, C.P., Park, J.R., Maris, J.M., et al. (2009).  Phase I Trial of Oral Irinotecan and Temozolomide for Children with Relapsed High-Risk Neuroblastoma: A New Approach to Neuroblastoma Therapy Consortium Study.  Journal of Clinical Oncology, Vol. 27, No. 8, pps. 1290-1296.
 

[16] Kushner, B.H., Modak, S., Kramer, K., Basu, E.M., Roberts, S.S., and Cheung, N-K.V. (2013). Ifosfamide, Carboplatin, and Etoposide for Neuroblastoma.  Cancer, 119, pps. 665-671.
 

[17] Matthay, K.K., Yanik, G., Messina, J., Quach, Al., Huberty, J., Cheung, S-C., Veatch, J., Goldsby, R., Brophy, P., Kersun, L.S., Hawkins, R.A., and Maris, J.M. (2007). Phase II Study on the Effect of Disease Sites, Age, and Prior Therapy on Response to Iodine-131-Metaiodobenzylguanidine Therapy in Refractory Neuroblastoma. Journal of Clinical Oncology, Vol. 25, No. 9, pps. 1054-1060.
 

[18] Caussa, L., Hijal, T., Michon, J. et al. (2011). Role of Palliative Radiotherapy in the Management of Metastatic Pediatric Neuroblastoma: A Retrospective Single-Institution Study. International Journal of Radiation Oncology, Biology, Physics, 79, pps. 214-219.
 

[19] Yu, A.L., Gilman, A.L., Ozkaynak, M.F., London, W.B., Kreissman, S.G. et al. (2010). Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma.  The New England Journal of Medicine, 363, pps. 1324-1334. http://www.nejm.org/doi/pdf/10.1056/NEJMoa0911123
 

[20] Shusterman, S., London, W.B., Gilles, S.D., Hank, J.A., Voss, S.D., Seeger, R.C. et al. (2010). Antitumor Activity of Hu14.18-IL2 in Patients with Relapsed/Refractory Neuroblastoma: A Children’s Oncology Group (COG) Phase II Study.  Journal of Clinical Oncology, Vol. 28, No. 33, pps. 4969-4975.
 

[21] Merchant, M.S., Baird, K., Wexler, L.H., et al. (2012). Ipilimumab: First Results of a Phase I Trial in Pediatric Patients with Advanced Solid Tumors.  Journal of Clinical Oncology, 2012; 30, suppl abstract 9545.  http://meetinglibrary.asco.org/content/98952-114
 

[22] Krishnadas, D.K., Shapiro, T. And Lucas, K. (2013). Complete Remission Following Decitabine/Dendritic Cell Vaccine for Relapsed Neuroblastoma. Pediatrics, Vol 131, No 1.
 

[23] Palmer, A. (2013). Dendritic Cell Vaccine for Relapsed Neuroblastoma.  NB Globe Neuroblastoma Newshttp://nbglobe.org/dendritic-cell-vaccine-for-relapsed-neuroblastoma/
 

[24] Kanold, J., Paillar, C., Tchirkov, A., Lang, P., Kelly, A., et al. (2012). NK Cell Immunotherapy for High-Risk Neuroblastoma Relapse After Haploidentical HSCT.  Pediatric Blood and Cancer, 59, pps. 739-742.
 

[25] Louis, C.U., Savoldo, B., Dotti, G., Pule, M., Yvon, E., et al. (2013).  Antitumor Activity and Long-Term Fate of Chimeric Antigen Receptor-Positive T Cells in Patients with Neuroblastoma.  Gene Therapy, Vol. 118, No. 23, pps. 6050-6056.
 

[26] Curran, K.J., Pegram, H.J., and Brentjens, R.J. (2012). Chimeric Antigen Receptors for T Cell Immunotherapy: Current Understanding and Future Directions.  The Journal of Gene Medicine, Vol 14, pps. 405-415.
 

[27] Hale, G.A., Arora, M., Ahn, K.W., He, W., Camitta, B., et al. (2013). Allogeneic Hematopoeitic Cell Transplantation for Neuroblastoma: The CIBMTR Experience.  Bone Marrow Transplantation, epub Feb 18, 2013, pps. 1-9.
 

[28] Pugh, T.J., Morozova, O., Attiyeh, E.F., Asgharzadeh, S., Wei, J.S., et al. (2013). The Genetic Landscape of High-Risk Neuroblastoma.  Nature Genetics, Vol. 45, pps. 562-566.
 

[29] Palmer, A. (2013). MYCN Amplification in Neuroblastoma.  NB Globe Neuroblastoma Newshttp://nbglobe.org/mycn-amplification-in-neuroblastoma/
 

[30] Cheung, N-K., Dyer, M.A. (2013). Neuroblastoma: Developmental Biology, Cancer Genomics and Immunotherapy. Nature Reviews Cancer, 13, pps. 397-411.
 

[31] Mosse, Y.P., Lim, M.S., Voss, S.D., Wilner, K., Ruffner, K., et al. (2013). Safety and Activity of Crizotinib for Paediatric Patients with Refractory Solid Tumours or Anaplastic Large-Cell Lymphoma: A Children’s Oncology Group Phase 1 Consortium Study. Lancet Oncology, 14 (6), pps. 472-480.
 

[32] Kramer, K., Kushner, B.H., Modak,S., Tandit-Taskar, N., Smith-Jones, P., et al. (2010). Compartmental Intrathecal Radioimmunotherapy: Results for Treatment for Metastatic CNS Neuroblastoma.  Journal of Neurooncology, 97 (3), pps. 409-418. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533371/pdf/nihms250577.pdf
 

[33] Croog, V.J., Kramer, K., Cheung, N-K., Kushner, B.H., Modak, S., Souweidane, M.M., and Wolden, S.L. (2010). Whole neuraxis irradiation to address central nervous system relapse in high-risk neuroblastoma.  International Journal of Radiation Oncology, Biology, Physics, 78 (3), pps. 849-854.

 

Other References:

For an excellent review of relapsed treatments in the UK, please see the NB Globe article from Nicholas Bird, February 15, 2013.

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