Letters to the Editor
818 References 1 Hammond E, Shaw K, Herrmann R. The JAK2V617F mutation is detectable in granulocyte populations at greater than 2 copies per cell among individuals with myeloproliferative disorders. Leukemia, published online. 2 Maas F, Schaap N, Kolen S, Zoetbrood A, Bun I, Dolstra H, de Witte T et al. Quantification of donor and recipient hemopoietic cells by real-time PCR of single nucleotide polymorphisms. Leukemia 2003; 17: 630–633.
3 Hammond E, Shaw K, Carnley B, P’ng S, James I, Herrmann R. Quantitative determination of JAK2 V617F by TaqMan: an absolute measure of averaged copies per cell that may be associated with the different types of myeloproliferative disorders. J of Mol Diagnostics, (in press). 4 Sidon P, El Housni H, Dessars B, Heimann P. The JAK2V617F mutation is detectable at very low level in peripheral blood of healthy donors. Leukemia, 15 June 2006, published online.
The JAK2V617F mutation is detectable in granulocyte populations at greater than 2 copies per cell among individuals with myeloproliferative disorders
Leukemia (2007) 21, 818. doi:10.1038/sj.leu.2404570; published online 1 February 2007
We thank Hammond et al. for having provided technical arguments explaining why they consider the finding of mutant JAK2 copies in normal granulocytes as polymerase chain reaction (PCR) artefacts.1 According to the technical details given, we can understand why the discrimination between the wild-type and mutant JAK2 allele is not absolute as it is only based on the specificity of the 30 -end base of a primer. Our methodology is clearly different.2 Furthermore, the positive results that we obtained were highly reproducible: in patients who showed to be initially positive, the mutation was recurrently found in repeated PCR performed on both genomic DNA and cDNA preparations. Moreover, some of the positive PCR results were confirmed by sequencing. Therefore, we have good reasons to consider that the
JAK2V617F mutation found in some of our normal patients is not a PCR artefact.
HEL Housni, P Sidon, B Dessars and P Heimann Department of Medical Genetics, Faculty of Medicine, Free University of Brussels, Brussels, Belgium E-mail:
[email protected]
References 1 Hammond E, Shaw K, Herrmann R. Reply in reply to &# 00AB: The JAK2 V617F mutation is detectable in granulocyte populations at greater than 2 copies per cell among individuals with myeloproliferative disorders. Leukemia (published online). 2 Sidon P, Heimann P, Lambert F, Dessars B, Robin V, El Housni H. Combined locked nucleic acid and molecular beacon technologies for sensitive detection of the JAK2V617F somatic single-base sequence variant. Clin Chem 2006; 52: 1436–1438.
Assessing response rates in clinical trials of treatment for relapsed or refractory multiple myeloma: a study of bortezomib and thalidomide
Leukemia (2007) 21, 818–820. doi:10.1038/sj.leu.2404573; published online 15 February 2007
We read with interest the International Uniform Response Criteria for multiple myeloma (MM) by Durie et al.,1 and congratulate the authors on this important step toward a more standardized approach to assessing response in MM. We believe that such an approach will help gauge the relative value of the newer biological therapies for MM. Indeed, response rates are often the first demonstration of clinical activity of new anticancer therapies, which are then further assessed by progression and survival outcomes. Although the concept of unifying response criteria appears intuitive, we were unable to find any literature that actually compares response rates using different criteria in the same cohorts of patients. In this report, we explore and illustrate the impact and influence of methods of response Leukemia
assessment using published studies of thalidomide and bortezomib for the treatment of MM. These data emphasize the need to introduce the standardized criteria proposed by Durie et al. as soon as possible. As discussed by Durie et al., there are three primary sets of criteria that are used for determining response in MM (Table 1): (1) M-protein reduction alone, based on criteria developed by the Chronic Leukemia and Myeloma Task Force of the National Cancer Institute;2 of note, although these guidelines did not define the degree of response in terms of complete response (CR) or partial response (PR), the extent of M-protein reduction has since been incorporated into clinical trial designs to develop protocol-specific definitions of CR, PR and minimal response (MR). (2) Southwest Oncology Group (SWOG) criteria,3 identifying only a single category of response: CR, sometimes referred to as ‘objective response’. (3) Blade´ criteria,4 also known as European Group for Blood and Marrow Transplanta-
Letters to the Editor
819 Table 1
Response criteria utilized in multiple myeloma clinical trials
Response to treatment
Description
M-protein reduction alone response criteria CR PR MR
99–100% reduction in serum or urinary M-protein X50% reduction in, but less than complete absence of, serum or urinary M-protein X25%, but less than 50%, reduction in serum or urinary M-protein
SWOG response criteria CR: also referred to as ‘objective response’ Blade´ (or EBMT) response criteria CRa
PRa
MRa
SDa (plateau)
PDb (definite increase in disease activity in patients in partial remission or disease stabilization)
X75% reduction in serum M-protein level or X90% reduction in urinary M-protein level sustained for at least 2 months Absence of M-protein in both serum and urine upon immunofixation and electrophoresis, which must be maintained for a minimum of 6 weeks Absence of plasmacytomas Bone marrow aspirate containing o5% plasma cells Stable bone diseasec X50% decrease in serum M-protein, maintained for 46 weeks 490% (or 4200 mg) decrease in urinary M-protein, maintained for 46 weeks 450% reduction in size of plasmacytomas Stable bone diseasec 25–50% decrease in serum M-protein, maintained for 46 weeks 50–90% (or 4200 mg) decrease in urinary M-protein, maintained for 6 weeks 25–50% reduction in size of plasmacytomas Stable bone diseasec M-protein levels that remain stable (within 25%) of the value that was recorded before therapy, which must be maintained for 43 months Failure to achieve minimal response; no disease progression or relapse 425% increase and a minimum absolute increase of 5 g/L in serum M-protein, confirmed by at least one repeated investigation 425% increase and a minimum absolute increase of 200 mg in urinary M-protein, confirmed by at least one repeated investigation 425% increase in plasma cells Increase in size of existing bone lesions, or development of new lesions Increase in size of plasmacytomas, or development of new plasmacytomas Development of cancer-attributable hypocalcemia
Abbreviations: CR, complete response; EBMT, European Group for Blood and Marrow Transplant; MR, minimal response; PD, progressive disease; PR, partial response; SD, stable disease; SWOG, Southwest Oncology Group. a Achievement of a CR, PR or MR requires that all criteria within each respective response category be met. b A designation of PD only requires that at least one of the criteria within this category be met. c Stable bone disease was defined as no increase in size or number of lytic bone lesions.
tion criteria, which are more rigorous and stringent than the aforementioned criteria sets. Using the Blade´ criteria, complete responders must have 100% reduction in both serum and urine M-protein and all responses must be maintained for X6 weeks. The M-protein reduction alone criteria comprise the same number of response categories as the Blade´ criteria (i.e., CR, PR and MR), but do not require the same number of diagnostic indicators (i.e., plasmacytoma level, percentage of plasma cells in the bone marrow and extent of bone disease) or a minimum response duration. We examined nine studies of single-agent thalidomide in relapsed or refractory MM, which were recently included in a pooled analysis5 (Table 2). The median number of prior therapies, when reported, ranged from 2 to 4. The studies typically used a starting thalidomide dose of 100–200 mg/day, which was escalated to a maximum of 400–800 mg/day. These studies were also similar in that most defined response based on M-protein reduction alone criteria, with the exception of two studies by Neben et al. and Huang et al., which used the Blade´ criteria (Table 2). Those using M-protein alone criteria were not always consistent, however, in their definitions of response categories and the source of M-protein measurement (serum vs urine), and the method of detecting
serum M-protein (electrophoresis or immunofixation) was not always clarified. The pooled CR and PR rates were 1.6 and 26.0%, respectively, yielding an overall response rate of 28% in patients with relapsed or refractory MM.5 In seven of the nine trials, the overall response rate (CR þ PR) ranged from 20 to 30%, whereas the CR rate ranged from 0 to 2% (Table 2). Higher overall response rates were reported by Hus et al. and Yakoub-Agha et al. (35.8 and 48%, respectively), yet it is important to note that these studies used the M-protein alone criteria to evaluate response. In contrast, the studies conducted by Neben et al. and Huang et al. were the only two that used the more rigorous Blade´ criteria. The overall response rate reported by Neben et al. was 20.5%, including one (1.2%) CR, and Huang et al. reported a 20.0% overall response rate with no patients achieving CR. These results provide a useful demonstration of the important impact that response rate criteria have on the value of the response rate achieved. In the phase II SUMMIT trial of bortezomib for relapsed or refractory MM,6 responses were assessed according to the Blade´ criteria. The population was very heavily pretreated with a median of six prior therapies (range, 2–15). Of 193 evaluable patients, seven patients (3.6%) achieved a CR with an additional Leukemia
Letters to the Editor
820 Table 2 patients)
Response rates to single-agent thalidomide therapy in patients with relapsed or refractory multiple myeloma5 (studies with 450
Study
Response criteriaa
Barlogie et al. Blood 2001; 98: 492–494. Hus et al. Haematologica 2001; 86: 404–408. Neben et al. Clin Cancer Res 2002; 8: 3377–3382. Tosi et al. Haematologica 2002; 87: 408–414. Yakoub-Agha et al. Hematol J 2002; 3: 185–192. Mileshkin et al. Blood 2003; 102: 69–77. Schey et al. Leuk Res 2003; 27: 909–914. Huang et al. Ann Hematol 2003; 82: 558–564. Waage et al. Br J Hematol 2004; 125: 149–155.
M-protein M-protein Blade´ M-protein M-protein M-protein M-protein Blade´ M-protein
alone alone alone alone alone alone alone
CR (%)
PR (%)
CR+PR (%)
2.0 7.5 1.2 0.0 0.0 1.3 1.4 0.0 6.0
28.0 28.3 19.3 26.1 48.0 26.7 26.1 20.0 14.0
30.0 35.8 20.5 26.1 48.0 28.0 27.5 20.0 20.0
Abbreviations: CR, complete response; PR, partial response. a Studies using M-protein reduction alone criteria were not always consistent in their definitions of response categories (CR, PR or minimal response) and the source of M-protein measurement (serum vs urine).
12 patients (6.2%) achieving a near-CR (satisfying all CR criteria with the exception that M-protein was detectable by immunofixation, although undetectable by electrophoresis). The overall response rate (CR þ PR) was 27% according to the Blade´ criteria, rising to 37% when measured according to the M-protein alone criteria – the difference between these two response rates illustrates how large an impact that response criteria can have on reported response rates. Moreover, stricter criteria for assessing response may be better at predicting outcome. According to a landmark analysis, the subset of patients achieving a CR or PR after two bortezomib cycles had significantly longer survival relative to all other patients (P ¼ 0.007). On the basis of an extended follow-up report,7 median overall survival was 17.0 months for all patients in the SUMMIT trial and had not yet been reached for responding patients after a 23-month follow-up. In the subsequent phase III APEX trial,8 involving 669 patients who had received a median of two prior therapies, patients were randomized to receive either bortezomib or high-dose dexamethasone. Originally published overall response rates (CR þ PR), using the Blade´ criteria, were 38% for bortezomib versus 18% with dexamethasone (Po0.001);8 an updated analysis that included 22 months of follow-up demonstrated a higher overall response rate of 43% for bortezomib (34% PR þ 9% CR) (Richardson P et al. Blood 2005; 106: 715a–716a. abstract 2547 and poster presentation). When evaluated according to M-protein reduction alone criteria, the overall response rate further improved to 56%, including a 19% CR rate. Another important aspect of the Durie et al. publication is the definitions of disease progression and relapse. We would have liked to explore how response assessment translates into differences in time to progression (TTP), but such analyses would be difficult to interpret given that the definition of progression would inherently vary according to the response criteria used. For example, TTP after a Blade´-defined CR would be defined differently than TTP by the SWOG criteria. Moreover, we would also recommend that consideration be made to introduce standard monitoring criteria, such as the frequency of disease assessment, to standardize further the measurement of progression outcomes. In conclusion, we believe that until the new criteria proposed by Durie et al. become routine in all MM clinical trials, it is important that clinicians pay careful consideration to the criteria
Leukemia
used to measure response when they are making comparisons of data across MM clinical trials.
HM Prince1, B Schenkel2 and L Mileshkin1 Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Victoria, Australia and 2 Global Health Economics, Janssen Pharmaceutica NV, Beerse, Belgium E-mail:
[email protected] 1
References 1 Durie BG, Harousseau J-L, Miguel JS, Blade´ J, Barlogie B, Anderson K, et al., for the International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473. 2 Chronic Leukemia and Myeloma Task Force of the National Cancer Institute. Proposed guidelines for protocol studies. II. Plasma cell myeloma. Cancer Chemother Rep 1973; 4: 145–158. 3 Alexanian R, Bonnet J, Gehan E, Haut A, Hewlett J, Lane M et al. Combination chemotherapy for multiple myeloma. Cancer 1972; 30: 382–389. 4 Blade´ J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, for the Myeloma Subcommittee of the EBMT (European Group for Blood and Marrow Transplant). Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Br J Haematol 1998; 102: 1115–1123. 5 Prince HM, Schenkel B, Mileshkin L. An analysis of clinical trials assessing the efficacy and safety of single-agent thalidomide in patients with relapsed or refractory multiple myeloma. Leuk Lymphoma 2007; 48: 46–55. 6 Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–2617. 7 Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin DH et al. Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial. Cancer 2006; 106: 1316–1319. 8 Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al., for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–2498.
