Subtype Review. Lymphoma einformation Project (LeIP) Mantle Cell Lymphoma

Transcription

1 Subtype Review Mantle Cell Lymphoma Worldwide Network of Lymphoma Patient Groups Lymphoma einformation Project (LeIP) Working together, we can change the lymphoma landscape and achieve more for patients.

2 KEY FINDINGS & DISCUSSION: MANTLE CELL LYMPHOMA This section provides a snapshot of the clinical trials and therapies patients with MCL can access in their respective countries. Incidence and mortality by LC member country and an overview of the quality-of-life issues confronting patients with MCL, both those in remission and who have relapsed, are also reviewed. Clinical Trial Availability: Mantle Cell Lymphoma In MCL, there was a large increase in the number of phase II/III clinical trials in 2015 with 188 available compared with 154 in Among the 188 clinical trials available in MCL, 77 were examining the use of novel agents. While it s encouraging to see more MCL clinical trials examining novel therapies, the hope is that they will provide longer and more enduring remissions compared with therapies currently in use. Within the different regions, there were no significant changes in the number of MCL clinical trials available with the exception of the USA with a 17% increase. A number of member countries (n = 9) had fewer MCL clinical trials available compared with 2014 and 11 member countries had none. While the overall number of clinical trials in MCL increased in 2015, LC would like to see them made more widely available in all regions. There are regions, such as Eastern Europe, that are woefully underserved. In addition more effort needs to be made to inform patients about clinical trial options at the time of making a decision about treatment. Results from the 2014 LC Global Patient Survey showed that among respondents with MCL, only 24% were asked to participate. For the full list of clinical trial availability by region, visit lymphomacoalition.org. Therapy Access: Mantle Cell Lymphoma LC examined two treatment guidelines to determine treatment recommendations for the first-line as well as relapsed/refractory settings for MCL and then examined if patients had access. The guidelines LC examined were from ESMO 18 and NCCN. 19 Table 7 outlines ESMO s treatment recommendations and Table 8 outlines NCCN s recommendations. Table 9 shows the therapies with regulatory approval and those with funding/reimbursement approval. Globally, there are 33 therapies with regulatory approval for use in the front-line setting for the treatment of MCL; 46 therapies have approval for use in the relapsed setting. 13 When looking at access to the targeted therapies recommended by ESMO; namely, bortezomib, ibrutinib, lenalidomide and temsirolimus, not many countries have access. Only seven countries have given regulatory approval to bortezomib and it is funded/reimbursed in six countries. Ibrutinib has regulatory approval in 23 countries but is only funded/reimbursed in two countries. Lenalidomide has regulatory approval in five countries and funded/reimbursed in three countries. Temsirolimus has regulatory approval in 23 countries but is funded in one. R-CHOP, one of the therapy regimens mentioned in both the ESMO and NCCN treatment guidelines for the treatment of MCL, has regulatory approval in 29 countries but is only funded/reimbursed in seven countries. Bendamustine, another recommended therapy option, is not readily available with it being funded/reimbursed only in France, Canada, Italy, Sweden, the UK and the USA. In Africa and the Middle East, only Israel has regulatory as well as funding/reimbursement approval for bortezomib and lenalidomide although ibrutinib and temsirolimus have regulatory approval. In South Africa many of the therapies recommended in the guidelines have regulatory approval. Government funding/reimbursement is provided for some but not all components of recommended therapy regimens. For example, with R-CHOP, funding is not provided for cyclophosphamide and prednisone. Private health insurance is available for some of the recommended regimens (see Table 9). Australia is the only country in the Asia/Pacific region that has a number of the recommended MCL therapies with both regulatory and funding/reimbursement approval. In Eastern Europe, in those countries that are members of the EU, many of the ESMO/NCCN recommended therapies have regulatory approval but very few appear to be funded/reimbursed. In non-eu member countries, very few of the recommended therapies have either regulatory approval or are funded/reimbursed. While many of the recommended therapies have regulatory approval in the EU Western European countries, very few appear to be funded/reimbursed. France and the UK appear to have the most funded/reimbursed therapies. In Latin America, Uruguay has the most recommended therapies with both regulatory as well funding/reimbursement approval but does not have any of the newer therapies available. While Argentina has a few of the recommended therapies approved, LC was unable to determine which ones are funded/reimbursed. Canada has a number of the recommended therapies with both regulatory and funding/reimbursement approval. However, bortezomib is the only targeted therapy that is funded/reimbursed. Many of the recommended therapies are available in the USA but patient access will depend on the type of insurance coverage the patient has. Obtaining optimal treatment for MCL, based on the treatment guidelines outlined by ESMO and NCCN, is likely challenging for most patients as very few countries appear to provide funding/reimbursement. As well, few of the recommended targeted therapies are easily accessible.

3 TABLE 7. ESMO TREATMENT GUIDELINES FOR MCL, Stage I Conventional chemotherapy RT Front-Line Treatment Relapsed Disease Higher Relapse Stage I-II (large tumour burden/adverse prognostic features) Young patient ( 65 y) R-CHOP + R-high dose Ara-C autosct Elderly patient (>65 y) R-CHOP or BR rituximab maintenance Compromised patient Watch and wait? R-chlorambucil BR Young patient BR R-DHAP Elderly patient BR targeted approaches * allosct rituximab maintenance FCR targeted approaches * allosct rituximab maintenance Compromised patient BR Targeted approaches * Targeted approaches * * Targeted approaches: bortezomib, ibrutinib, lenalidomide, temsirolimus TABLE 8. NCCN TREATMENT GUIDELINES FOR MCL, Front line Stage I, II Stage II, III, IV Induction therapy: aggressive options: CALGB±RT HyperCVAD±RT NORDIC±RT Alternating CHOP-R/DHAP-R±RT Sequential CHOP-R/RICE±RT CT Induction therapy: aggressive options: CALGB HyperCVAD+R NORDIC Alternating CHOP-R/DHAP-R Sequential CHOP-R/RICE Induction therapy: less aggressive options: BR±maintenance R±RT VR-CAP±RT Cladribine+R±RT CHOP+R±RT HyperCVAD+R±RT Induction therapy: less aggressive options: BR±maintenance R VR-CAP Cladribine+R CHOP+R HyperCVAD-R Candidate for HDT/autoSCT CT, HDT + autosct RT Not a candidate for HDT/autoSCT CHOP-R or BR R maintenance Relapsed Disease Stage I, II Stage II bulky, III, IV If prior treatment RT alone: Induction therapy: aggressive options: CALGB HyperCVAD NORDIC Alternating CHOP-R/DHAP-R Sequential CHOP-R/RICE Induction therapy: less aggressive options: BR±maintenance R VR-CAP CT Second-line treatment; options: RT B±R Cladribine+R CHOP+R HyperCVAD-R If prior treatment with chemotherapy ± RT: CT Second-line treatment; options: RT B±R Bortezomib±R Cladribine±R FC±R FCMR FMR Bortezomib±R Cladribine±R FC±R FCMR FMR Ibrutinib Lenalidomide±R PCR PEPC+R Ibrutinib Lenalidomide±R PCR PEPC+R

4 Africa/Middle East Asia/Pacific Eastern Europe Western Europe Latin America North America TABLE 9. THERAPY ACCESS: MCL 13 MCL Therapies with Regulatory Approval MCL Therapies with Funding/Reimbursement Approval Algeria * HyperCVAD Information not available South Africa CHOP±R, cyclophosphamide, DHAP±R, FCM, fludarabine, GDP, hypercvad±r, RT, Private health insurance available for: rituximab, SCT Bortezomib, chlorambucil, CHOP±R, CNOP±R, COP, CVM, cytarabine, DHAC, DHAP, ESHAP, FCM, GDP, GEM-P, GVD, hypercvad+r, ICE, IGEV, MINE, rituximab, RT, SCT Government funds/reimburses: Carboplatin, cisplatin, cytarabine, doxorubicin, etoposide, gemcitabine, fludarabine, methotrexate, rituximab, vinblastine, vincristine, vinorelbine Israel Bortezomib, hypercvad, ibrutinib, lenalidomide, temsirolimus Bortezomib, hypercvad, lenalidomide Australia B±R, CHOP±R, COPP, cyclophosphamide, DHAP±R, ESHAP±R, GDP, hypercvad±r, CHOP±R, COPP, cyclophosphamide, DHAP±R, ESHAP±R, hypercvad±r, ICE±R, ibrutinib, ICE±R, RT, rituximab, rituximab maintenance, SCT, temsirolimus rituximab, rituximab maintenance China * HyperCVAD HyperCVAD India Bortezomib, hypercvad No funding/reimbursement Japan * Bendamustine, cladribine, fludarabine, hypercvad, rituximab HyperCVAD New Zealand CHOP±R, cyclophosphamide, hypercvad, NORDIC, rituximab, SCT CHOP±R, cyclophosphamide, hypercvad, rituximab, SCT Singapore * CHOP±R, hypercvad, rituximab Information not available Bulgaria Bendamustine, CHOP±R, COPP, CVP±R, cyclophosphamide, DHAP±R, FMR, Information not available hypercvad±r, ibrutinib, IVAC Croatia Czech Republic Bendamustine, CHOP±R, COPP, CVP±R, cyclophosphamide, DHAP±R, FMR, Cyclophosphamide, hypercvad hypercvad±r, ibrutinib, IVAC Hungary * Latvia * Lithuania, rituximab Macedonia * HyperCVAD Information not available Poland Russian Federation * HyperCVAD Information not available Serbia Cyclophosphamide, fludarabine, hypercvad, rituximab, temsirolimus Cyclophosphamide, fludarabine, hypercvad, rituximab Slovakia * Slovenia, rituximab Turkey * Bortezomib, hypercvad Information not available Ukraine * CHOP±R, hypercvad Information not available Belgium Denmark * France Bendamustine, CHOP±R, COPP, CVP±R, cyclophosphamide, DHAP±R, fludarabine, FMR, Bendamustine, cyclophosphamide, fludarabine, hyeprcvad, ibrutinib, rituximab, hypercvad±r, ibrutinib, IVAC temsirolimus Germany, rituximab Ireland Bendamustine, CHOP±R, COPP, CVP±R, cyclophosphamide, DHAP±R, ESHAP, FMR, CHOP±R, cyclophosphamide, ESHAP, hypercvad, rituximab hypercvad±r, ibrutinib, IVAC Italy * Bendamustine±R, bortezomib, CHOP±R, COPP, CVP±R, DHAP±R, FMR, hypercvad±r, Bendamustine, bortezomib, bortezomib±r, hypercvad, lenalidomide, rituximab ibrutinib, IVAC (ara-c)±r, lenalidomide, MCP±R, NORDIC, rituximab, temsirolimus, VR-CAP Netherlands, ibrutinib Portugal * Spain Sweden Bendamustine, CHOP±R, COPP, CVP±R, cyclophosphamide, DHAP±R, FMR, Bendamustine, cyclophosphamide, hypercvad, rituximab hypercvad±r, ibrutinib, IVAC Switzerland CHOP±R, COPP, CVP±R, DHAP±R, FMR, hypercvad±r, IVAC (ara-c)±r, lenalidomide, HyperCVAD MCP±R, mini-beam, NORDIC, rituximab, SCT UK Bendamustine, bendamustine±r, bortezomib, bortezomib±r, CEPP±R, CHOP±R, COPP, CVP±R, cyclophosphamide, DHAP±R, FCM, FCMR, FMR, hypercvad±r, ibrutinib, IVAC (ara-c)±r, MCP±R, mini-beam, NORDIC, rituximab, SCT, temsirolimus, VR-CAP Bendamustine, bendamustine±r, bortezomib, bortezomib±r, FCM, FCMR, fludarabine, hypercvad±r, IVAC (ara-c)±r, MCP, mini-beam, rituximab, SCT, VR-CAP Argentina * Bendamustine, bortezomib, CHOP±R, hypercvad, rituximab Information not available Barbados * CVP, hypercvad Information not available Brazil * HyperCVAD Information not available Colombia * Bortezomib, hypercvad Information not available Mexico * HyperCVAD HyperCVAD Uruguay * CHOP±R, cyclophosphamide, FCM, FCMR, fludarabine, FMR, hypercvad±r, rituximab CHOP±R, cyclophosphamide, FCM, FCMR, fludarabine, FMR, hypercvad±r, rituximab Venezuela * HyperCVAD Information not available Canada Bendamustine, bendamustine±r, bortezomib, CHOP±R, COPP, cyclophosphamide, Bendamustine, bortezomib, CHOP±R, cyclophosphamide, DHAP±R, ESHAP±R, DHAP±R, ESHAP±R, hypercvad, IVAC (ara-c)±r, lenalidomide, mini-beam, RT, hypercvad, IVAC (ara-c)±r, mini-beam, RT, rituximab, SCT rituximab, SCT USA Bendamustine, bendamustine±r, bortezomib, bortezomib±r, CHOP±R, cladribine±r, Medicare, Medicaid, private insurance cyclophosphamide, DHAP±R, EPOCH±R, FCM, FCMR, fludarabine, FMR, hypercvad, ibrutinib, lenalidomide, lenalidomide±r, NORDIC, PCR, RT, rituximab, rituximab maintenance, SCT * LC assumes therapies have regulatory as well as funding/reimbursement approval. LC will continue efforts to confirm status of therapy availability in these member countries.

5 Incidence and Mortality: Mantle Cell Lymphoma The average incidence of MCL per 100,000 people remained unchanged between 2010 and 2011 at 0.7 cases, as shown in Table Among member countries, in 2010 and 2011, 10 had a similar or lower average incidence. The average mortality rate remained relatively unchanged in 2011 compared with Incidence and mortality data could not be obtained for 27 out of 44 member countries. Table 10 shows the changes in incidence and mortality, by region, that occurred between 2010 and 2011 in MCL. The information in Table 10 is gathered from the 362 national and regional registries that are part of the IACR, eight statistical agencies and LC member organisations. However, it is a work in progress and should be interpreted with caution. Not having incidence and mortality data for 2015, to compare with clinical trial and therapy information available for 2015, has an impact on a comparative analysis. Africa/ Middle East Asia/Pacific Eastern Europe Western Europe Latin America North America TABLE 10. INCIDENCE AND MORTALITY DATA, BY REGION, 2010 vs. 2011: MCL 3-11, Population Incidence per 100,000 Mortality, % Population Incidence per 100,000 Mortality, % Algeria 37,062,820 Information not available 37,762,962 Information not available South Africa 50,791,808 Information not available 51,553,479 Information not available Israel 7,623, ,765, Australia 22,031, ,340, China 1,337,705,000 Information not available 1,344,130,000 Information not available India 1,205,624,648 Information not available 1,221,156,319 Information not available Japan 128,070,000 Information not available 127,817,277 Information not available New Zealand 4,350,700 Information not available 4,384, Singapore 5,076, Information not available 5,183, Information not available Bulgaria 7,395, Information not available 7,348, Information not available Croatia 4,417, ,280, Czech Republic 10,474,410 Information not available 10,496,088 Information not available Hungary 10,000,023 Information not available 9,971,727 Information not available Latvia 2,097, ,059, Lithuania 3,097, ,028, Macedonia 2,102,216 Information not available 2,103,890 Information not available Poland 38,042,794 Information not available 38,063,255 Information not available Russian Federation 142,849,449 Information not available 142,960,868 Information not available Serbia 7,291,436 Information not available 7,234,099 Information not available Slovakia 5,391,428 Information not available 5,398,384 Information not available Slovenia 2,048,583 Information not available 2,052,843 Information not available Turkey 72,137,546 Information not available 73,058,638 Information not available Ukraine 45,870, ,706, Belgium 10,920,272 Information not available 11,047,744 Information not available Denmark 5,547,683 Information not available 5,570,572 Information not available France 65,023, Information not available 65,338,149 Information not available Germany 81,776, ,797, Ireland 4,560, ,576, Italy 59,277,417 Information not available 59,379,449 Information not available Netherlands 16,615, * 16,693, * Portugal 10,573,100 Information not available 10,557,560 Information not available Spain 46,576,897 Information not available 46,742,697 Information not available Sweden 9,378, ,449, Switzerland 7,824, ,912, UK -England 52,642, ,700.0 * 53,107, ,150.0 * -Scotland 5,262, ,299, Wales 3,050, * 3,060, ,300.0 * Argentina 40,374,224 Information not available 40,728,738 Information not available Barbados 280,396 Information not available 281,804 Information not available Brazil 195,210,154 Information not available 196,935,134 Information not available Colombia 46,444,798 Information not available 47,078,792 Information not available Mexico 117,886,404 Information not available 119,361,233 Information not available Uruguay 3,371,982 Information not available 3,383,486 Information not available Venezuela 29,043,283 Information not available 29,500,625 Information not available Canada 34,005, ,342,780 Information not available USA 309,326, ,582,

6 Patient Experience: Mantle Cell Lymphoma Respondents in the 2014 LC Global Patient Survey with MCL indicated they faced some form of financial barrier to receiving adequate lymphoma treatment. Access to the treatment centre and prohibitive travel costs were also barriers for respondents in remission and those who had relapsed. Availability of a specialist clinician locally was a greater barrier for respondents in remission while access to the most up-to-date treatments was a bigger barrier to respondents with relapsed MCL. Unfortunately in MCL, no front-line treatments are currently available that result in a durable response. All these barriers will likely have a negative impact on patients sense of well-being resulting in a high degree of uncertainty and fear. Consequently, more attention is needed in ensuring therapies under investigation for MCL result in improved outcomes. Figure 6 shows the main barriers encountered by respondents in remission and those with relapsed MCL as well as the percentage of respondents not encountering any barriers Financial Access to treatment centre/ prohibitive travel Access to most up-to-date treatment Availability of specialty doctor locally None Remission, % Relapsed, % Source: 2014 LC Global Patient Survey FIGURE 6. BARRIERS TO RECEIVING ADEQUATE TREATMENT: MCL Fatigue as well as muscle weakness were issues for the 2014 LC Global Patient Survey respondents who were either in remission or had relapsed MCL. Fatigue may mean that patients cannot continue with their normal daily activities, they may even have to stop work or only work part-time resulting in reduced income, which in turn, can lead to financial anxiety. Not being able to lead normal lives because of fatigue may well make patients feel despondent and they may begin to lose their sense of self. Suffering from muscle weakness may require a patient to make greater efforts than normal to complete a task; yet another challenge to leading a normal life Fatigue Fighting infections Muscle weakness Changes in taste/smell Remission, % Relapsed, % Source: 2014 LC Global Patient Survey FIGURE 7. PHYSICAL ISSUES WITH GREATEST NEGATIVE IMPACT ON SENSE OF WELL-BEING: MCL The physical issues experienced by patients with MCL highlight the need for support that goes beyond clinical treatment so patients know how to manage the physical effects associated with treatment. HCPs need to determine if patients are experiencing any physical side effects and ensure they get support. Figure 7 shows the main physical effects affecting patients sense of well-being.

7 Following diagnosis, respondents with MCL (in remission and relapsed) noted changes in relationships, stress about financial issues and loss of or reduced employment as being issues having the greatest negative impact on their lives. Unfortunately, patients with MCL will relapse after a period of time which likely means most are never free of financial anxiety. Respondents with relapsed MCL also expressed concerns about body image, depression, difficulty on the job or in school, and problems getting health or life insurance. These are challenging issues and patients need someone to talk to who can assist them in getting the help they need. It s incumbent upon HCPs to refer patients to organisations that can help and thus ensure they receive the best care possible both inside and outside the clinic. While 50% or more of respondents told their doctor about their quality-of-life issues, their doctor was only able to help some of them while those with relapsed MCL received the least amount of help from their doctor (see Figure 8). FIGURE 8. COMMUNICATING QOL ISSUES Respondents who communicated QOL issues to their doctor Respondents whose doctor was able to help with their QOL issues Remission, % Relapsed, % Source: 2014 LC Global Patient Survey Figure 8 indicates that most patients are not getting the support they need from their doctors. The survey indicated that education and support groups, patient organisations and counsellors/psychologists had helped patients a great deal. It is likely, however, if there was greater awareness of all available support services, patients could have benefited from a more complete range of support to assist them with their quality-of-life issues. To resolve this issue, the healthcare community needs to educate itself on the patient resources available and, at every point of interaction, let patients know where they can get support throughout their journey. As indicated earlier, having patients complete a quality-of-life questionnaire prior to each appointment with their doctor and to then review it together is a possible solution. Such a form will help facilitate communication and will ensure the doctor is aware of what the patient is experiencing. It would also be an opportunity for the doctor to refer patients to support organisations for ongoing support. So where are MCL patients getting their information from? Nurses, doctors and online research were the main sources of information for both respondents in remission and those with relapsed MCL. While nurses and doctors are reliable sources of information, they do not necessarily have the time to spend with all patients to address all their concerns. Additionally, there is some indication that patients often feel rushed when seeing their doctor. However, what is of greater concern is the use of online research as patients may not be consulting credible sources and thus not obtaining the most reliable information. In summary, patients with MCL (in remission and relapsed) face a number of quality-of-life issues that affect both their physical and psychosocial well-being. Unfortunately, at the present time, no front-line therapies result in durable responses. Encountering these barriers likely result in uncertainty and fear. What all these findings demonstrate is that greater efforts are needed to provide patients with the help they need to cope with not only their treatment but all the other effects that result from undergoing treatment.