Curing Ph⁺ ALL: assessing the relative contributions of chemotherapy, TKIs, and allogeneic stem cell transplant

A 63-year-old woman presented with intolerable bony pain after a few weeks of feeling generally tired and unwell. Bone marrow aspiration confirmed the presence of B-cell acute lymphoblastic leukemia (ALL). The patient was started on a steroid “pre-phase,” pending cytogenetic and BCR-ABL1 testing, which 3 days later showed t(9;22) by fluorescence in situ hybridization and positivity for BCR-ABL1 p210 transcripts. Cytogenetics also shows del(9p). The patient consented to be enrolled in the Philadelphia chromosome-positive (Ph⁺) pathway of a UK national trial (UKALL60+) and began imatinib combined with modest-intensity chemotherapy, consisting of vincristine (VCR), steroid, and intrathecal prophylaxis. She was unable to tolerate a 600-mg dose of imatinib, owing to intractable nausea and facial edema. By the end of 1 month of treatment, the patient’s blood count normalized, and her bone marrow aspirate showed hematological complete remission (CR). Having struggled throughout to tolerate continuous daily imatinib 400 mg, she refused to continue the agent any longer and was switched to dasatinib. The BCR-ABL1 minimal residual disease (MRD) result was 0.1% with an adequate control gene amplification. Tissue typing demonstrated that none of her siblings are HLA matches, and an unrelated donor search was initiated. A sample was sent for BCR-ABL1 mutational analysis. At her next bone marrow evaluation 1 month later, she had no detectable BCR-ABL1, and by that time, a 10/10, cytomegalovirus-matched, unrelated donor was identified. During donor workup, the patient underwent her next round of therapy with high-dose methotrexate, after which she received a fludarabine/melphalan/alemtuzumab reduced intensity conditioning (RIC) allo-HCT. Throughout this article, elements of why this patient was treated as described are reported, with reference to the evidence.

The outcome for the 25% to 30% of adult patients with Ph⁺ ALL is now equivalent to or better than that for those with Ph⁻ disease. Imatinib truly revolutionized outcomes for patients with Ph⁺ ALL, as confirmed by numerous studies. Despite the lack of a large, randomized study, it was very clear from studies with comparable pre–imatinib era data^1,2  and from large single-arm studies that the magnitude of the potential benefit was so great that regulatory and reimbursement authorities were readily convinced of the value of imatinib. A table summarizing the results of imatinib studies in Ph⁺ ALL was published previously.³  Subsequent second- and third-generation tyrosine kinase inhibitors (TKIs) have likewise been tested only in single-arm studies to date, and no direct comparison between TKIs has yet been done, although trials of imatinib compared with ponatinib are ongoing with commercial sponsorship (NCT03589326) and planned as an academic trial (EWALL03). However, it is clear that the benefit of second-/third-generation TKIs over and above imatinib is not the same step change as occurred with the first introduction of TKIs. Attempted analyses using existing data based on comparing trials or propensity scores do suggest an advantage for second-/third-generation^4,5  TKIs, but by contrast, a small, nonrandomized, retrospective comparison of 77 patients treated at the Southern Medical University, Guangzhou, China, showed no significant benefit for first- vs second-generation TKIs.⁶  As a consequence, some health economies do not yet recommend or reimburse second-generation or subsequent generations of TKIs for therapy of de novo Ph⁺ ALL. As examples, Canadian evidence-based guidelines currently do not recommend subsequent generations of TKIs.⁷ 

It is also important to note that the trials conducted to date are unlikely to reflect what is possible in the general population, because patients at highest risk of toxicities from TKIs are typically excluded from phase 2 studies. Furthermore, follow-up of third-generation TKI trials is currently very short, meaning comparisons of long-term survival are impossible. The long-term toxicity and dropout rates are likely to be much higher in daily practice than in reported in trials. For this reason, this article does not offer a definitive, evidence-based response to the question of which specific TKI should be used, in favor of simply reviewing the current evidence. It would not be wrong, in 2019, to treat patients with de novo ALL with imatinib.

The patient in the present clinical case was started on imatinib because this is the only TKI that is routinely reimbursed for de novo Ph⁺ ALL in the United Kingdom, and this was part of the trial protocol she received.

As reviewed by Brattås et al,⁸  dasatinib inhibits not only the BCR-ABL1 tyrosine kinase but also, at a relatively low 50% inhibitory concentration, SRC, LCK, and c-KIT. At higher concentrations, even more kinases are inhibited, including FGFR1, VEGFR2, MEK, CDK2, Akt, and FAK, suggesting that the antileukemic effect does not depend only on BCR-ABL1 inhibition. Dasatinib has now been evaluated in de novo Ph⁺ ALL both with and without chemotherapy. The GIMEMA LAL1205 trial investigated dasatinib combined with just prednisolone in 53 patients over a wide age range of 24 to 77 years.⁹  After a 100% CR rate was achieved, 20-month overall survival (OS) was 69% with disease-free survival (DFS) of 51%. During the course of the study, 23 patients experienced relapse, with 70% of tested relapses expressing the T315I mutation. Because postremission therapy and longer-term follow-up were not part of the trial, it is not possible to draw further conclusions. Dasatinib has been combined with more intensive therapy in the EWALL-PH-01 “elderly” trial, in which 71 patients aged 55 years and older were assigned to receive dasatinib with VCR and dexamethasone induction (CR rate was 96%), followed by 6 months of consolidation wherein cytarabine, asparaginase and methotrexate were added, followed by maintenance with dasatinib dexamethasone/VCR pulses. 5-year OS was 36%. Of those tested for T315I mutation at relapse, 24/36 (75%) had a positive result.¹⁰ 

Dasatinib has also been combined with the more intensive myelosuppressive chemotherapy regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD). Long-term (67 months) follow-up of this study, in which 96% of patients had achieved CR and 12 (17%) of 72 patients had undergone allo-HCT, showed that 43% were alive in CR at 5 years. Yoon et al¹¹  also alternated cycles of dasatinib with cycles of a medium-intensity chemotherapy schedule in a trial that enrolled 51 patients with a median age of 46 years, 39 of whom received allo-HCT in their first complete remission (CR1). Four-year DFS was 52%. The US intergroup study NCT00792948, evaluating dasatinib, chemotherapy, and allogeneic stem cell transplant, is discussed in more detail below. All studies reporting mutational analysis have reported T315I mutation as a primary association with relapse during first-line dasatinib treatment. Although generally well tolerated, dasatinib puts patients at specific risk for pleural effusion. In a very large assessment across the dasatinib clinical trial program (N = 2712) by Hughes et al,¹²  pleural effusion developed in 6% to 9% of patients at risk annually, and drug-related pleural effusion occurred in 28% of patients in the study (NCT00481247) and in 33% of patients in the CA180-034 dose optimization study (NCT00123474). It is entirely possible that this problem is underappreciated in Ph⁺ ALL, because many patients receive allo-HCT and are not given (or do not need) long-term TKIs.

The patient in the present clinical case was switched to dasatinib after clear evidence of intolerance of imatinib. This was fortuitous because her BCR-ABL1 result showed evidence of slow response to her original regimen.

Although efficacy against relapsed Ph⁺ ALL has been reported to be comparable with that of dasatinib in patients with imatinib-resistant or imatinib-intolerant Ph⁺ ALL,¹³  nilotinib has been less studied in de novo ALL. A single-arm phase 2 study of nilotinib combined with dose-intensive cytotoxic chemotherapy was carried out by the Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology in 91 patients with de novo Ph⁺ ALL. The CR rate was 91%, with lack of CR being due to treatment-related mortality (TRM). Fifty-seven patients received allo-HCT. Two-year OS was 72%.¹⁴  In the EWALL-PH-02 study, as yet reported only in abstract form,¹⁵  nilotinib was administered throughout therapy at 400 mg twice daily to 72 patients over 55 years old (median age, 66 years). Five-year OS was 47%. There was a much higher allo-HCT rate than in EWALL-PH-01, and there was a 61% long-term OS after allo-HCT, despite the older age of the study participants.

Ponatinib, a potent third-generation TKI, is active against both unmutated and mutated BCR-ABL, including T315I mutation that is commonly observed when patients relapse after therapy with dasatinib. It was first demonstrated as having efficacy in 32 patients with relapsed Ph⁺ ALL enrolled in the PACE trial,¹⁶  41% of whom had a hematologic response, and 47% of whom had a major cytogenetic response. Serious arterial thrombotic events were observed in 9% of patients. Interestingly, no single mutation was associated with resistance to ponatinib, although compound mutations (≥2 mutations in the same BCR-ABL allele) were associated with less deep or very abbreviated responses. Ponatinib has also been administered in association with hyper-CVAD in de novo Ph⁺ ALL. Long-term follow-up of 76 patients (median age, 47 years) in this study was published in December 2018,¹⁷  albeit the final patient had been enrolled in April 2018. Two patients in that study died of ponatinib-related myocardial infarction before an amendment to reduce the dose from 45 mg to 30 mg after the first cycle. This was not a trivial treatment approach to offer patients; increased bilirubin (n = 13; 17%), pancreatitis (n = 13; 17%), hypertension (n = 12; 16%), and bleeding (n = 10; 13%) stood out among other more typical grade 3/4 events, such as infection. As a result, 48 (63%) of 76 of the participants discontinued trial treatment (albeit 15 of these were for allo-HCT), despite an initial 100% CR. The modest numbers preclude seeing any statistically valid difference between those who did (n = 15) and did not receive allo-HCT. The reported 3-year OS at a median follow-up of 36 months was 76%, but only 43 of the 76 participants had reached the 3-year mark at the time of the report. Even if the combination of ponatinib with intensive myelosuppressive chemotherapy is toxic, the rate of molecular CR is very high, and the logical extension would be to reduce the toxicity by eliminating the myelosuppressive chemotherapy. The LAL1811 study is so far reported only in abstract form.¹⁸  Patients (N = 44) over 60 years old received ponatinib 45 mg plus steroid. The CR rate was 90% at 8 weeks, with a 45% complete molecular response. At week 24, only 15 of 42 patients still in the study could receive 45 mg of ponatinib daily. For physicians who are able and choose to treat patients with de novo Ph⁺ using ponatinib, dose reductions from the initial 45-mg dose are necessary after cycle 1 to avoid excess toxicity.

With enhanced potency of TKIs and with knowledge of the toxicity of intensive myelosuppressive chemotherapy in older persons, the reduction in intensity of chemotherapy schedules reported above has been a natural corollary of wider use of these targeted therapies. Although the chemotherapy-free approach has been pioneered by Italian investigators and will continue in this vein with research into the combination second- or third-generation TKIs with blinatumomab (dasatinib and blinatumomab; D-ALBA, NCT02744768), the GRAAPH-2005 randomized trial (NCT00327678) validated the outcome equivalence of an induction regimen combining reduced-intensity chemotherapy and imatinib compared with combining it with hyper-CVAD. The early CR rate for the “chemotherapy-light” approach was 98.5% compared with 91% in the other arm, owing to TRM. The current study of the French/Belgian/Swiss cooperative uses nilotinib as a TKI and is randomizing patients to a further reduction in intensity during later parts of the protocol (NCT 02611492). Data from the UKALL14 study (NCT01085617) have clearly shown that the combination of pegylated asparaginase and imatinib in older adults is particularly toxic, so where “pediatric-inspired” regimens are used in adults, it would not be appropriate to extend them to adults with Ph⁺ ALL.¹⁹  The balance of evidence suggests that, at least during induction, which is the highest-risk period for TRM, TKIs combined with steroid and VCR can result in all patients achieving CR with minimal toxicity. This is a major advance for patients.

The patient in the present clinical case was enrolled in a trial for older individuals with ALL (UKALL60+; NCT01616238), in which a less intensive dose of chemotherapy is used for Ph⁺ ALL on the basis of existing data from other groups.

The existence of a straightforward real-time quantitative polymerase chain reaction assay that can precisely quantify BCR-ABL transcripts belies the considerable complexity of interpretation of MRD in Ph⁺ ALL. The subject bears an in-depth discussion, because as treatments for the disease evolve and trend toward stratification to reduced therapy by perceived risk, clear guidance on how to carry out and interpret molecular monitoring is needed. The lack of guidance and the plethora of approaches used by both individual physicians and national study groups is underpinned by a genuine knowledge gap in the field. MRD in Ph⁺ ALL can be assessed by quantifying BCR-ABL transcripts for p190 or p210, by identifying and quantifying patient-specific immunoglobulin heavy chain/T-cell receptor (Ig/TCR) gene rearrangements by polymerase chain reaction, by flow cytometry, or by using next-generation sequencing to quantify Ig/TCR.

BCR-ABL transcript quantification (using RNA) is a relatively straightforward assay technically and, for p210 transcript quantification, can be carried out and reported to international standards because of the work done in chronic myeloid leukemia (CML). However, the reports produced for CML characterize the molecular response on a scale that is well validated for CML and is not validated and not suitable for Ph⁺ ALL. p190 quantification is less commonly available and is much less standardized. A highly significant effort to develop international standardization of p190 quantification has been led by Heike Pfeifer on behalf of the EuroMRD Consortium, with 35 laboratories participating.²⁰  In that work, successive quality control rounds demonstrated that standardized use of both “Europe Against Cancer” program primer/probe sets and centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. Nonetheless, at the lowest levels of MRD, there was still variation between laboratories and an appreciable false-negative rate. The extremely detailed laboratory recommendations are a considerable move forward in p190 quantification.

Given that it is accepted that BCR-ABL assays on RNA can be carried out to a reasonable technical standard, what is the evidence that they are predictive of outcome and at what time points should they be measured? Although there is broad agreement among studies that patients in whom BCR-ABL1 does not significantly diminish during initial therapy after second-generation TKI therapy are at higher risk for a poor outcome,^10,11,14,21  the relationship between BCR-ABL1 levels and outcome is not nearly so clear-cut as that between Ig/TCR monitoring and outcome for Ph⁻ disease. Of particular interest in this regard are data connecting BCR-ABL1 and Ig/TCR monitoring. A recent study in childhood Ph⁺ ALL showed that the overall concordance between the 2 methods was only 69%, and Ig/TCR appeared more reliable at predicting outcome. An early MRD response was highly predictive of a favorable outcome.²²  The discrepancies between the 2 methods in a significant subset of patients has led to a highly important biological observation, the full clinical relevance of which is being investigated. Hovorkova et al²³  flow-sorted different subsets of cells and demonstrated a BCR-ABL1–positive clonal hematopoiesis emanating from early progenitors, closely resembling a CML-like disease. These data suggest that at least some of the biological heterogeneity of BCR-ABL1–positive ALL may result from this. In practical terms, these data suggest that, whenever possible, BCR-ABL1 should be monitored early and often, and, if possible, both patient-specific Ig/TCR rearrangements and BCR-ABL1 should be monitored.

Additional genetic lesions have clear prognostic relevance in Ph⁺ ALL. Gross structural lesions such as del(9p) are clearly associated with a higher relapse rate, whereas high hyperploidy is associated with a better outcome.^24,25  Several additional recent papers have also demonstrated that deletions within CDKN2A/B (located at 9p21) are adverse, even in the TKI era,^26,27  and there is evidence that this may not be overcome by allo-HCT.²⁸  Fedullo et al²⁷  noted that, among 116 patients with de novo Ph⁺ ALL, those carrying simultaneous deletions of IKZF1 plus CDKN2A/B and/or PAX5 had a significantly lower DFS rate (24.9% vs 43.3%; P = .026), giving weight to the poor prognostic relevance of the “Ikaros⁺” phenotype.

Although there is no additional targeted therapy directed at such lesions, they can be of great importance in counseling the patient about the possible outcome of various treatment strategies and are highly relevant to understanding more about the science of this disease. There is also evidence that the p190 and p210 transcripts may carry a different prognosis; Chiaretti et al²⁹  showed a significantly faster molecular response in p190 disease than in p210 disease in the GIMEMA LAL0904 study.

The patient in the present clinical case had del(9p). Although Pfeifer et al²⁸  demonstrated an inferior outcome for patients with CDKN2A/B deletions compared with those without the deletion, the Kaplan-Meier curves for OS, DFS, and remission duration all reached an apparent plateau at a level that exceeded expectations from the pre-TKI era; certainly, the data do not suggest that allo-HCT is futile.

Numerous mutations in BCR-ABL1 are associated with resistance to TKI. Most occur within the adenosine triphosphate–binding loop (also known as the P-loop) of the ABL kinase domain, of which E255K/V is an example. The T315I mutation is at the contact site. By now, it is clear that such mutations can be detected at low levels at diagnosis using deep-sequencing approaches,^30,31  but the clinical relevance of these—when, how, and under what pressure, if any, they may develop into resistant clones—is completely unclear. Perhaps for this reason, there are no consensus clinical recommendations on when and how to perform mutational testing. Currently, mutational analysis is done by Sanger sequencing, but this technique does not identify low-level clones. Soverini et al³²  used a next-generation sequencing approach to look for low-level mutated clones in patients who had switched from imatinib to a second-generation TKI without mutational analysis, and, reviewing those who had resistant disease, mutations with 1% to 20% abundance had clearly expanded, suggesting that sensitive mutational analysis is a sine qua non to inform therapeutic decisions. However, it is important to note that mutational analysis of this type requires a minimum disease threshold of about 0.1% MRD. Schmitt et al³³  integrated single-molecule duplex sequencing of the ABL1 gene in computational simulations. Their work predicted that the multiple preexisting resistant cells with single mutants may subtend the emergence of compound mutations after initial use of a TKI that is susceptible to resistance from single point mutations, but there is no clinical trial proof of this interesting work to date. In a clinical scenario, the best advice that can currently be offered is to carry out mutational analysis in case of lack of response, rising MRD, or overt relapse.

Allo-HCT is a very active immunotherapy in ALL. There is strong evidence for a graft-versus-leukemia effect.³⁴  RIC can be applied with good effect in CR1.^35,36  Autologous transplant using the same total body irradiation–based conditioning as for allo-HCT is not better than chemotherapy.³⁷  In addition, there is preliminary evidence for the activity of donor lymphocyte infusion in minimal residual disease states after allo-HCT.³⁸  The vast majority of the older literature, as summarized elsewhere,³⁹  is firmly in favor of allo-HCT in this disease, even in the imatinib era. However, allo-HCT as currently performed is undeniably a very toxic procedure with long-term health impacts and an appreciable TRM of 15% to 20%. For allo-HCT to become dispensable in adult Ph⁺ ALL, the relapse risk would have to reliably exceed the TRM, and it would have to be clear that the reduction in relapse risk was not contingent on long-term application of therapies with unproven long-term safety. For example, if the only way to avoid allo-HCT were to be dependent on on lifelong ponatinib, this would raise new questions that the community is not yet able to answer. Extreme reluctance to use allo-HCT in children and young persons is completely understandable. However, in that setting, traditional intensive chemotherapy combined with TKI is still applied. The AALL0622 study of dasatinib plus intensive chemotherapy recruited 60 patients. Allo-HCT was recommended for patients at high risk on the basis of slow response as well as for those with a matched family donor regardless of response after at least 11 weeks of therapy. With very small numbers of patients in the comparison (n = 9 for high-risk patients and n = 10 for sibling donors), there was no difference between those who did or did not receive allo-HCT. Interestingly, the 5-year OS did not differ from that of the AALL0031 study with imatinib as the TKI.⁴⁰  By contrast, in an older group of patients aged 18 to 60 years, a US intergroup study of patients administered dasatinib plus hyper-CVAD and applied allo-HCT for all patients with a sibling or unrelated donor. Landmark analysis at 175 days from the time of CR/CRi (longest time to HCT) showed statistically superior advantages for recurrence-free survival and OS (P = .038 and 0.037, respectively) for the patients who underwent transplant.⁴¹  There were no MRD data from this study, so it is not known whether MRD could further inform the allogeneic stem cell transplant selection process.

Of course, allo-HCT is not one specific approach, and intensity of conditioning is a highly relevant decision. Large registry data are helpful in showing that RIC can be completely appropriate for patients with Ph⁺ ALL.^9,35,42  The UKALL14 study prospectively assessed RIC for all allografts in patients over the age of 40. In a preliminary analysis in abstract form, in the population as a whole, preallograft MRD was highly relevant for outcome. Yoon et al⁴³  compared myeloablative treatment (n = 116) with RIC (n = 79) for patients in CR1 after imatinib- or dasatinib-based therapy. In a multivariate analysis, the conditioning intensity had no significant impact on transplantation outcomes. Wang et al⁴⁴  were able to conclude that although there was a benefit for allo-HCT, this was no longer evident for patients with low presenting white blood cell counts and a rapid, deep MRD response. A concern is that the very valid increasing reluctance to use allo-HCT in adults is contemporaneously accompanied by a trend toward reduction or cessation of cytotoxic chemotherapy without elucidation of clear evidence of what exactly constitutes low-risk Ph⁺ ALL. There is a risk that if a patient who has received ponatinib and immunotherapy without allo-HCT relapses, there will be no effective salvage therapy, because second complete remission may be a very difficult goal. Hence, omitting allo-HCT in favor of a reduced chemotherapy or nonchemotherapy approach is a risk that is hard to calculate. The author recommends omitting allo-HCT only in the context of informed consent within a clinical trial. If a patient strongly wishes to avoid allo-HCT by personal choice, that is probably safe to recommend only if there is a complete and early disappearance of MRD based on BCR-ABL1 and Ig/TCR and extremely close monitoring of MRD.

The patient in the present clinical case had several risk factors for poor outcome from Ph⁺ ALL, including a poor early MRD response, del(9p), and intolerance of imatinib. On balance, she had achieved molecular remission before allograft; she was fit, well supported, and motivated; and she had a low HCT comorbidity index score and a very good donor. After discussion, the balance of risk fell in favor of allo-HCT.

TKIs are not well tolerated after allo-HCT,^45,46  and a randomized study of prophylactic administration of imatinib vs adding it only on the basis of BCR-ABL1 detection did not show any clear evidence of benefit of prophylactic administration. Nonetheless, many physicians choose to add a TKI. A consensus position statement of the European Society for Blood and Marrow Transplantation is an excellent reference for a clear-headed summary of all the available evidence and clarifies the lack of any grade 1 evidence for the use of posttransplant TKIs.⁴⁷  It is notable for recommending either extremely careful monitoring with restart of TKI or possible prophylactic administration. Intensive MRD monitoring after allo-HCT monitoring is critically important, perhaps more so when RIC has been used. Although peripheral blood measurement is less sensitive, it can be performed more often, so a combination of initial monthly testing of blood interspersed with 2- to 3-monthly testing of bone marrow can be of value. In the United Kingdom, clinicians also choose to add 3-monthly intrathecal chemotherapy to 3-monthly bone marrow testing after non–total body irradiation–based RIC allo-HCT, stemming from a concern that the abbreviated initial therapies lack adequate central nervous system–directed prophylaxis. However, the evidence base for this approach compared with any other is lacking. A genuine real-life problem to which there is no adequate, evidence-based response is when to stop TKI once started, especially if the patient has always had BCR-ABL1–negative disease in monitoring. Every clinic will contain patients who have been taking TKIs in these circumstances for decades, and no one dares stop.

For the patient in the present clinical case, whose disease was BCR-ABL1–negative before and remained so after RIC allo-HCT, the author preferred not to start TKI, especially because of the patient’s prominent nausea during initial therapy. She developed grade 2 skin and gut graft-versus-host disease after cyclosporin A was stopped, and she required an extension of immunosuppression until 1 year posttransplant. After 2 years of 3-monthly intrathecal chemotherapy and bone marrow measurement visits, she was off all medication except prophylactic penicillin, and she had returned to work.

Immunotherapies and chemoimmunotherapy directed at CD19 (blinatumomab,⁴⁸  chimeric antigen receptor T cells⁴⁹ ) and CD22 (inotuzumab ozogamicin⁵⁰ ) have all shown efficacy in relapsed Ph⁺ ALL, and there is no reason to suspect that Ph status specifically impacts response to immunotherapy; hence, these agents are likely to gain increasing prominence in the treatment of de novo Ph⁺ ALL as new data become available. Blinatumomab is currently being evaluated in de novo Ph⁺ ALL in chemotherapy-free combinations with dasatinib (D-ALBA, NCT02744768) and ponatinib (NCT03263572).

This is a very exciting time for the field of Ph⁺ ALL. Patients can now expect to have at least an equivalent outcome to that for Ph⁻ ALL, and, arguably, the outcome will soon surpass that of Ph⁻ ALL, given the combinations of TKIs and immunotherapies. In addition, such combinations may reduce the need for more toxic therapies such as allo-HCT and may allow optimal treatments to be expanded to older persons. Appropriate attention is also being paid to the best methods for sensitive and specific disease monitoring, which will be absolutely key to getting the best from the new agents. Given the modest numbers of patients with this disease, progress is commendable and relies, as always, on the close communication and cooperation of patients, physicians, scientists, and the pharmaceutical sector.

Adele K. Fielding, UCL Cancer Institute, Paul O’Gorman Bldg, 72 Huntley St, London WC1E 6DD, United Kingdom; e-mail: a.fielding@ucl.ac.uk.